Conjugate molecules

Abstract

To provide multifunctional conjugate molecules comprising a target binding component bound to one or more cannabinoids and / or to one or more cannabinoid conjugate components.SOLUTION: In some embodiments, the target binding component is covalently linked to one or more active agent components. The disclosed conjugate molecule is designed to deliver therapeutic benefits of respective components of the conjugate molecule, and can be used to treat cancer and other disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Each reference cited in this disclosure is incorporated herein in its entirety.

[0002] Technical Field The present disclosure relates generally to therapeutic treatments. DETAILED DESCRIPTION OF THE INVENTION

[0003] Detailed Description definition "C1-C3 straight or branched alkyl" means "methyl, ethyl, propyl, and isopropyl."

[0004] "C1-C8 straight or branched alkyl" means "methyl, ethyl, C3, C4, C5, C6, C7, and C8 straight chain alkyl, and C3, C4, C5, C6, C7, and C8 branched alkyl."

[0005] "C1-C3 straight or branched chain heteroalkyl" means "a straight or branched chain heteroalkyl containing 1, 2, or 3 carbon atoms."

[0006] "C1-C8 straight-chain or branched heteroalkyl" means "each of C1, C2, C3, C4, C5, C6, C7, and C8 straight-chain heteroalkyl, and C1, C2, C3, C4, C5, C6, C7, and C8 branched heteroalkyl."

[0007] "C1-C12 straight-chain or branched heteroalkyl" means "C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 straight-chain heteroalkyl, and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12 branched heteroalkyl, respectively."

[0008] "C1-C24 straight chain or branched heteroalkyl" means "C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, and C24 straight chain heteroalkyl, and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, and C24 branched heteroalkyl, respectively."

[0009] "C1-C6 straight or branched chain alkoxyl" means "straight or branched chain alkoxyl containing 1, 2, 3, 4, 5, or 6 carbon atoms."

[0010] "C1-C6 straight-chain or branched alkylamino" means "straight-chain or branched alkylamino containing 1, 2, 3, 4, 5, or 6 carbon atoms."

[0011] "C1-C6 straight-chain or branched dialkylamino" means "each straight-chain or branched dialkylamino in which each alkyl independently contains 1, 2, 3, 4, 5, or 6 carbon atoms."

[0012] The term "6- to 10-membered aromatic" means "each of 6-, 7-, 8-, 9-, and 10-membered aromatics."

[0013] "5- to 10-membered heteroaromatic" means "each of 6-, 7-, 8-, 9-, and 10-membered heteroaromatic."

[0014] The term "3- to 9-membered cycloheteroalkyl" refers to "each of 3-, 4-, 5-, 6-, 7-, 8-, and 9-membered cycloheteroalkyl."

[0015] "C3-C6 cycloalkyl" means "C3, C4, C5, and C6 cycloalkyl."

[0016] "Halide" means "Cl, Br, and I."

[0017] "Group 1 substituents" are (a) -OH, (b) -NH2, (c)=O, (d)=S, (e) = NR7 (wherein R7 is H or C1-C3 straight or branched alkyl or C1-C3 straight or branched heteroalkyl containing O, N, or S atoms); (f) —C(O)OR4, where R4 is H or C1-C3 straight or branched alkyl; (g) -C(O)NR5R6, where R5 and R6 are independently H or C1-C6 straight or branched alkyl; (h) halides, (i) C1-C6 linear or branched alkoxyl, (j) C1-C6 linear or branched alkylamino, (k) C1-C6 linear or branched dialkylamino, (l)(i) phenyl, (ii) halides, (iii) cyano, (iv)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (v) containing 1, 2, or 3 atoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched heteroalkyl optionally substituted with a 6- to 10-membered aromatic optionally substituted with 1, 2, 3, or 4 substituents independently selected from (m)(i) phenyl, (ii) halides, (iii) cyano, (iv)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (v) containing 1, 2, or 3 atoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) C1-C6 linear or branched heteroalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2. a 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from (n) having 1, 2, or 3 heteroatoms independently selected from O, N, and S; (i) phenyl, (ii) halides, (iii) cyano, (iv)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (v) containing 1, 2, or 3 atoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched heteroalkyl optionally substituted with and a 3- to 9-membered cycloheteroalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from (o)(i) phenyl, (ii) halides, (iii) cyano, (iv)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (v) containing 1, 2, or 3 atoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched heteroalkyl optionally substituted with C3-C6 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from is a group of substituents consisting of:

[0018] "Group 2 substituents" are (a) -OH, (b) -NH2, (c)=O, (d)=S, (e) = NR7 (wherein R7 is H or C1-C3 straight or branched alkyl or C1-C3 straight or branched heteroalkyl containing O, N, or S atoms); (f) —C(O)OR4, where R4 is H or C1-C3 straight or branched alkyl; (g) -C(O)NR5R6, where R5 and R6 are independently H or C1-C6 straight or branched alkyl; (h) halides, (i) cyano, (j) trifluoromethyl, (k) C1-C6 linear or branched alkoxyl, (l) C1-C6 linear or branched alkylamino, (m) C1-C6 linear or branched dialkylamino, (n) 6- to 10-membered aromatics, and (o) a 5- to 10-membered heteroaromatic group containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; is a group of substituents consisting of:

[0019] The above definitions apply to the following descriptions: For example, the phrase "R4 is H or a C1-C3 straight chain or branched alkyl" should be read to describe each of the five sets of embodiments: R4 is H, R4 is methyl, R4 is ethyl, R4 is propyl, and R4 is isopropyl, respectively. Conjugate molecules

[0020] The conjugate molecule comprises a target binding component covalently bound to one or more cannabinoids and / or one or more cannabinoid conjugate components. In some embodiments, the target binding component is also covalently bound to one or more active agent components. The disclosed conjugate molecules are designed to deliver the therapeutic benefits of each component of the conjugate molecule and can be used to treat cancer and other disorders.

[0021] For the purposes of this disclosure, the conjugate molecules described below are divided into Types I, II, and III, which are briefly described below, followed by a detailed description of the various components of the conjugate molecules.

[0022] In the Type I, II, and III embodiments described in this disclosure, the values ​​of m and n apply to embodiments in which the binding moiety is an antibody. However, other target binding moieties can also be used, and in these embodiments, the values ​​for m and n will vary depending on the type of binding moiety. For example: 1. In some embodiments where B is an oligonucleotide (e.g., an aptamer), m is 1 to 20, n is 0 to 20, and the sum of m+n is 1 to 20. See, for example, Xuan et al., Biomaterials 182, 216-226, 2018; Zhu et al. PNAS, 110, 7998-8003, 2013. 2. In some embodiments where B is a DARPin, m is 1 and n is 0, e.g., as described in Simon et al. Bioconjug Chem. 24, 1955-1966, 2013; Laviolette et al. See Cancer Research Proceedings: AACR Annual Meeting 2019, Abstract 215, 2019. 3. In some embodiments where B is a peptide, m is 1 to 3 and n is 0. See, e.g., Fureder et al. Neuro-Oncology 18, iv16-iv17, 2016; Vrettos et al. Beilstein J Org Chem. 14, 930-954, 2018.

[0023] Type I conjugate molecules have the formula: [ka] It has.

[0024] wherein CBNC is a cannabinoid conjugate moiety comprising a therapeutic agent moiety covalently bonded to a cannabinoid moiety directly or via a linker, as described below; L cc is a CBNC linker but may be absent, B is a target binding moiety, and L a is an active moiety linker and A is an active moiety. In embodiments where B is an antibody, m is 1 to 30, n is 0 to 29, and the sum of m+n is 1 to 30. Type II conjugate molecules have the formula: [ka] (wherein, as shown below, PCAN is a platinum complex anti-neoplastic agent component, and L pc is a PCAN linker but may be absent, B is a target binding moiety, and L a is an active ingredient linker and A is an active ingredient. In embodiments where B is an antibody, m is 1 to 30, n is 0 to 29, and the sum of m+n is 1 to 30. It has.

[0025] Type III conjugate molecules have the formula: [ka] (In the formula, as shown below, CBN is a cannabinoid component, and L c is a cannabinoid moiety linker but may be absent, B is a target binding moiety, and A is an active moiety. In embodiments where B is an antibody, m is 1 to 30, n is 0 to 29, and the sum of m+n is 1 to 30. It has. Target binding component (B)

[0026] As used in this disclosure, a "target binding moiety" is a moiety that binds to a target molecule (e.g., a cell surface or circulating target molecule). The target binding moiety may itself have a therapeutic effect or may simply function to target the component molecule.

[0027] In some embodiments, the target binding moiety is a peptide. See, e.g., Reverdatto et al. (Curr. Top. Med. Chem. 15, 1082-1101, 2015); Yakimchuk (Mater. Methods 5, 1417, 2015); Squillacioti et al. (Acta Vet Scand. 61, 46, 2019). ;See Ojeda et al. (Drug Discov. Today 2019).

[0028] In some embodiments, the target binding moiety is an oligonucleotide. See, e.g., Yakimchuk (Mater. Methods 5, 1417, 2015); Santosh and Yadava (BioMed Res. Intl. 2014, 540451, 2014).

[0029] In some embodiments, the target binding moiety is a receptor binding domain. See, for example, Xia et al. al. (Curr. Top. Microbiol. Immunol. 199, 39-46, 1995);Zhou et al. (J. Formos. Med. Assoc. 113, 143-147, 2014);Zhang et al. (Virus. Res. 202, 151-159, 2015); Liu et al. (Biomed. Res Int. 2015, 594109, 2015); Zhou et al. (Viruses 11, E60, 2019).

[0030] In some embodiments, the target-binding moiety is a designed ankyrin repeat protein (DARPin), such as those described by Pluckthun (Ann. Rev. Pharmacol. Toxicol. 55, 489-511, 2015); Binz et al. (J. Mol. Biol. 332, 489-503, 2003); Mosavi et al. (Proc. Nat'l. Acad. Sci (USA) 99, 16029-34, 2002); Binz et al. (Nature Biotechnology 22, 575-82, 2004); Steiner et al. (Mol. Biol. 382, 1211-27, 2008);Steiner et al. (Nature Biotechnology 24, 823-31, 2006);Kohl et al. (Proc. Natl. Acad. Sci. USA. 100, 1700-75, 2003);Wetzel et al. (J. Mol. Biol. 376, 241-57, 2008);Simon et al. (Bioconjugate Chem. 24, 1955-66, 2013); Martin-Killias et al. (Clin. Cancer Res. 17, 100-10, 2011); Zahnd et al. (Cancer Res. 70, 1595-1605, 2010).

[0031] In some embodiments, the target binding moiety is an interferon, e.g., interferon alfa-2a (ROFERON-A®), interferon alfa-2b (INTRON-A®), interferon alfa-n3 (ALFERON-N®), pegylated interferon alfa-2b (PEGINTRON®, SYLATRON®), interferon beta-1a (AVONEX®), interferon beta-1a (REBIF®), interferon beta-1b (BETASERON®), interferon beta-1b (EXTAVIA®).

[0032] In some embodiments, the target binding moiety is an antibody. An "antibody" includes, for example, an anti-idiotype (anti-Id) antibody, a camelized antibody, a chimeric antibody, a disulfide-linked Fvs (sdFv), a F(ab') fragment, a Fab fragment, a human antibody, a humanized antibody, a murine antibody, an intrabody, a monoclonal antibody, a bispecific antibody, a multispecific antibody, or a monoclonal antibody. The antibody may be a single chain Fv (scFv), or an epitope-binding fragment thereof. In some embodiments, the antibody is IgG, IgE, IgM, IgD, IgA, or IgY. IgG antibodies include IgG1, IgG2 (e.g., IgG2a, IgG2b), IgG3, and IgG4 antibodies. IgA antibodies include IgA1 and IgA2 antibodies.

[0033] In some embodiments, the antibody may be radiolabeled.

[0034] The types of antigens that the antibodies can bind include, but are not limited to, antigens from the following categories (in some cases listed under attributes in more than one category): i. Cluster of differentiation (CD) antigens, such as CD2, CD3, CD4, CD11a, CD19, CD20, CD25 (ILR2), CD30, CD33, CD38, CD52, CD139, CD152 (cytotoxic T-lymphocyte-associated protein 4, CTLA-4), CD274 (PD-L1), CD319 (signaling lymphocyte activation molecule family 7, SLAMF7), ii. Checkpoint inhibitors, such as programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1, CD274), iii. vascular target antigens, such as prostate-specific membrane antigen (PSMA); iv. stromal antigens, such as bone marrow stromal antigen 2; v. Extracellular matrix antigens, such as type I, III, IV, and V collagen (CI, CIII, CIV, CV), laminin (LM), fibronectin (FN), vi. Circulating antigens, e.g., Factor IXa, Factor X, vii. Interleukins, such as IL-1β, IL-2, IL-5, IL-6, IL-12, IL-17A, IL-23, viii. Interleukin receptors, such as ILR2 (CD25), IL-4RA, IL-5RA, IL-6R, IL-17RA, ix. Growth factors, such as vascular endothelial growth factor A (VEGFA), x. Growth factor receptors, such as epidermal growth factor receptor (EGFR, ErbB1), fibroblast growth factor receptor 1, 2, 3, 4, 23 (FGFR, FGFR2, FGFR3, FGFR4, FGFR23), human epidermal growth factor 2 (HER2 / neu), ErbB2 receptor tyrosine kinase 3 (HER3, ErbB3), ErbB2 receptor tyrosine kinase 4 (HER4), platelet-derived growth factor receptor alpha (PDGFRA), vascular endothelial growth factor receptor 1, 2, 3 ( VEGFR1, VEGFR2, VEGFR3), A-type ephrin receptors 1, 2, 3, 4, 5, 6, 7, 8 (EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8), B-type ephrin receptors 1, 2, 3, 4, 5, 6, 7 (EphB1, EphB2, EphB3, EphB4, EphB5, EphB6, EphB7), hepatocyte growth factor receptor (HGFR, c-Met), insulin-like growth factor 2 receptor (IGF2R), xi. Drugs, such as digoxin, dabigatran, xii. Adhesion molecules, e.g. epithelial cell adhesion molecule (EpCAM), xiii. Tumor necrosis factors, such as TNF-α, TNF-β, xiv. Tumor necrosis factor-related apoptosis-inducing ligand receptors, such as TRAIL-R1, TRAIL-R2, xv. insulin receptor (IR), xvi. Receptor tyrosine kinases (RTKs), such as FMS-like receptor tyrosine kinase-3 (FLT3), macrophage colony-stimulating factor 1 receptor (CSF-1R), obesity / stem cell growth factor receptor (KIT / SCFR), macrophage-stimulating factor 1 receptor (RON, SEA), Axl receptor tyrosine kinase (AXL, UFO), Mer receptor tyrosine kinase (MER), TYRO3, MUSK, RET, TIE1, discoidin domain receptor family member 1, 2 (DDR1, DDR2), receptor tyrosine kinase-like orphan receptor 1, 2 (ROR1, ROR2), ROS, LTL, ALK, KLG, "related tyrosine kinase receptor" (RYK), xvii. Cytokine receptors, e.g., type I, type II, immunoglobulin superfamily, tumor necrosis factor family, chemokines, CC motif chemokine receptor 4 (CCR4), TGF-β receptors (including activin receptors), xviii. Tropomyosin receptor kinase (TRK), for example, TRKA, TRKB, TRKC, xix. Integrins, such as integrin α4, integrin α4β1, integrin α4β7, xx. immunoglobulins, e.g., IgE; xxi. Antigens of infectious organisms, such as respiratory syncytial virus (e.g., protein F), Bacillus anthracis (e.g., B. anthracis protective antigen), Clostridium difficile (e.g., C. difficile toxin B), and xxii. Other antigens, such as proprotein convertase subtilisin / kexin type 9 (PSCK9), calcitonin gene-related peptide receptor (CGRPR) / calcitonin receptor-like receptor (CRLR), receptor activator of nuclear factor kappa-B ligand (RANKL), glycoprotein (GP) IIb / IIIa receptor, ganglioside G2 (GD2), B lymphocyte stimulator (BLyS), complement component 5 (C5), insulin receptor-related receptor (IRR), tumor-associated glycoprotein 72 (TAG72).

[0035] Examples of therapeutic antibodies include, but are not limited to, abciximab (e.g., REOPRO®), adalimumab (e.g., HUMIRA®, TRUDEXA®), adalimumab-adbm (e.g., CYLTEZO®, XARXIO®), adalimumab-atto (e.g., AMJEVITA®), alefacept (e.g., AMEVIVE®), alemtuzumab (e.g., CAMPATH®, MABCAMPATH®), alirocumab (e.g., PRALU®), ENT®), atezolizumab (e.g., TECENTRIQ®), avelumab (e.g., BAVENCIO®), basiliximab (e.g., SIMULECT®), belimumab (e.g., BENLYSTA®), benralizumab (e.g., FASENRA®), bevacizumab (e.g., AVASTIN®), bevacizumab-awwb (e.g., MVASI®), bezlotoxumab (e.g., ZINPLAVA®), blinatumomab (e.g., BLINC®), YTO®), brodalumab (e.g., SILIQ®), burosumab-twza (e.g., CRYSVITA®), canakinumab (e.g., ILARIS®), catumaxomab (e.g., REMOVAB®), cemiplimab (e.g., LIBTAYO®), certolizumab pegol (e.g., CIMZIA®), cetuximab (e.g., ERBITUX®), daclizumab (e.g., ZENAPAX®, ZINBRYTA®), daratumumab (e.g., For example, PROLIA®, XGEVA®, DARZALEX®), denileukin diftitox (e.g., ONTAK®), denosumab (e.g., PROLIA®, XGEVA®), digoxin immune Fab (e.g., DIGIBIND®, DIGIFAB®), dinutuximab (e.g., UNITUXIN®), dupilumab (e.g., DUPIXENT®), durvalumab (e.g., IMFINZI®), eculizumab (e.g.,SOLIRIS®), efalizumab (e.g., RAPTIVA®), elotuzumab (e.g., EMPLICITI®), emicizumab-kxwh (e.g., HEMLIBRA®), erenumab-aooe (e.g., AIMOVIG®), etanercept (e.g., ENBREL®), evolocumab (e.g., REPATHA®), golimumab (e.g., SIMPONI®), guselkumab (e.g., TREMFYA®), ibalizumab-uiyk (e.g., TROGARZO®), ibritumomab tiuxetan (e.g., ZEVALIN®), idarucizumab Mabs (e.g., PRAXBIND®), infliximab (e.g., REMICADE®), infliximab-abda (e.g., ENFLEXIS®), infliximab-dyyb (e.g., INFLECTRA®), infliximab-qbtx (e.g., IXIFI®), ipilimumab (e.g., YERVOY®), ixekizumab (e.g., TALTZ®), mepolizumab (e.g., NUCALA®), mogamulizumab (e.g., POTELIGEO®), muromonab (e.g., ORTHOCLONE®), natalizumab (e.g., TYSABRI®), necitumumab (e.g., PORTRAZZA®), nivolumab (e.g., OPDIVO®), nofetumomab (e.g., VERLUMA®), obiltoxaximab (e.g., ANTI-ALPHA®), HEM®), obinutuzumab (e.g., GAZYVA®), ocrelizumab (e.g., OCREVUS®), ofatumumab (e.g., ARZERRA®), olaratumab (e.g., LARTRUVO®), omalizumab (e.g., XOLAIR®), palivizumab (e.g., SYNAGIS®), panitumumab (e.g., VECTIBIX®), )), pembrolizumab (e.g., KEYTRUDA®), pertuzumab (e.g., PERJETA®), ramucirumab (e.g., CYRAMZA®), ranibizumab (e.g., LUCENTIS®), raxibacumab (e.g., ABTHRAX®), reslizumab (e.g., CINQAIR®), rituximab (e.g., RITUXAN, MABTHERA®), trademark), rituximab (e.g., RITUXAN®) and hyaluronidase (e.g., HYCELA®), sarilumab (e.g., KEVZARA®), satumomab (e.g., ONTOSCINT®), secukinumab (e.g., COSENTYX®), siltuximab (e.g., SYLVANT®), tildrakizumab-asmn (e.g., ILUMYA®), trastuzumab (e.g., HERCEPTIN®), trastuzumab-dkst (e.g., OGIVRI®), ustekinumab (e.g., STELARA®), and vedolizumab (e.g., ENTYVIO®).

[0036] In some embodiments, the antibody is part of an antibody-drug conjugate (ADC), and in these embodiments, the active agent component is the "warhead" portion of the ADC. Examples of ADCs include, but are not limited to, adotrastuzumab emtansine (e.g., KADCYLA®), brentuximab vedotin (e.g., ADCETRIS®), inotuzumab ozogamicin (BESPONSA®), and gemtuzumab ozogamicin (e.g., MYLOTARG®). Activator component (A)

[0037] As used in this disclosure, an "active agent moiety" is a moiety that has therapeutic activity. As noted above, in some embodiments, the active agent moiety is the "warhead" portion of the ADC, either when B is an antibody or when B is another type of target-binding moiety. Active ingredient linker (L a ) and a cannabinoid moiety linker (L cc )

[0038] As used in this disclosure, an "active moiety linker," when present, connects a target-binding moiety to an active agent moiety. As used in this disclosure, a "cannabinoid moiety linker" connects a target-binding moiety to a cannabinoid conjugate moiety (described below). In each case, these linkers include self-cleaving linkers such as acid-labile linkers and protease-labile linkers, non-cleavable linkers, linkers containing negatively charged groups, linkers containing sugar moieties, and other linkers used in the ADC field.

[0039] Examples of acid-labile linkers include acetals, hydrazones (including acylhydrazones and hydrazines), imines, esters, linkers containing disulfide bonds, and linkers containing pH-sensitive chelators. See, e.g., Vlahov & Leamon, Bioconjug. Chem. 23, 1357-69, 2012; Xiao et al., Nanoscale 4, 7185-93, 2012; Abu et al., Eur. J. Cancer 48, 2054-65, 2011; DiJoseph et al., Clin. Cancer Res. 12, 242-49, 2006;Kale & Torchilin, Bioconjugate Chemistry 18, 363-70, 2007; Sawant et al., Bioconjugate Chemistry 17, 943-49, 2006; Reddy et al., Sci. Rep. 8, 8943, 2018.

[0040] Examples of protease-labile linkers include linkers containing a valine-citrulline bond, β-glucuronic acid-based linkers, and imides. See, e.g., Weinstein et al. al., Chem. Commun. (Camb.) 46, 553-55, 2010;Shao et al., Cancer 118, 2986-96, 2010;Liang et al., J. Controlled Release 160, 618-29, 2012;Barthel et al., J. Med. Chem. 55, 6595-607, 2012;Nolting, Methods Mol. Biol. 1045, 71-100, 2013;Erickson, Cancer Res. 66, 4426-33, 2006;Jeffrey et al., Bioconjugate Chem. 17, 831-40, 2006;Dubowchik et al., See Bioconjugate Chem. 13, 855-69, 2002; Mhidia et al., Org. Lett. 12, 3982-85, 2010.

[0041] Examples of non-cleavable linkers include thioether-based linkers and N-succinimidyl-4-(N-maleimidylmethyl)cyclohexane-1-carboxylate (SMCC) linkers (see, e.g., Juarez-Hernandez et al., ACS Med. Chem. Lett. 3, 799-803, 2012).

[0042] Examples of linkers containing negatively charged groups are described, for example, in Leamon et al., J. Pharm. Exp. Ther. 336, 336-43, 2011.

[0043] Examples of linkers containing sugar moieties are described, for example, in Mikuni et al., Biol. Pharm. Bull. 31, 1155-58, 2008.

[0044] Other types of linkers include: i. Linkers containing an acetamide moiety and linkers containing sulfur-containing amides or esters (Davaran et al., J. Pharm. Pharmacol. 55, 513-17, 2003); ii. A linker comprising an enzymatically hydrolyzable unit, such as: 1. a carboxylic acid ester or amide bond (e.g., succinyl, glutaryl), or 2. Peptides recognized by cathepsin B (e.g., Val-Cit (valine-citrulline), GFLG (SEQ ID NO: 1), or peptides recognized by MMP-2 and MMP-9, e.g., GPLGIAGQ (SEQ ID NO: 2), PLGLAG (SEQ ID NO: 3), and GPVGLIGK (SEQ ID NO: 4), iii. Stimuli-responsive or degradable linkers (e.g., linkers containing imine, oxime, hydrazone, orthoester, acetal, vinyl ether, or polyketal bonds), and iv. A linker containing para-aminobenzyl alcohol (PABC). Cannabinoid conjugate ingredients

[0045] As used in this disclosure, a "cannabinoid conjugate component" comprises at least one therapeutic agent component covalently bonded directly or via a linker to at least one cannabinoid component. A "cannabinoid component" is a portion of a cannabinoid molecule present in either a Type III conjugate molecule or a cannabinoid conjugate component of a Type I or Type II conjugate molecule, as described below. As used in this disclosure, a "therapeutic agent component" is a therapeutic agent or portion of a therapeutic agent present in a cannabinoid conjugate component (described below).

[0046] In some embodiments, the therapeutic moiety is covalently bonded directly to a hydroxy or carboxylic acid group of the cannabinoid moiety. In some embodiments, the cannabinoid conjugate moiety comprises a therapeutic moiety and a cannabinoid moiety joined by a linker that is covalently bonded to the therapeutic moiety at one end and to a hydroxy or carboxylic acid group of the cannabinoid moiety at the other end. In some embodiments, the hydroxy group is an "aromatic hydroxy group," i.e., a hydroxy group directly bonded to an aromatic hydrocarbon. In some embodiments, the hydroxy group is an "aliphatic hydroxy group," i.e., a hydroxy group bonded to a carbon that is not part of an aromatic ring.

[0047] In some embodiments, the conjugate molecule contains only one therapeutic agent component. In other embodiments, the conjugate molecule can contain two or more therapeutic agent components, which can be the same or different, for example, when the cannabinoid component has at least two hydroxy groups, or at least one hydroxy group and at least one carboxylic acid group, or at least two carboxylic acid groups.

[0048] In some embodiments where the therapeutic moieties are attached via linkers, the two or more linkers may be the same or different, and independently, the two or more therapeutic moieties may be the same or different. Also, independently, when the cannabinoid moiety contains two or more hydroxy groups, the two or more hydroxy groups may be aliphatic, or the two or more hydroxy groups may be aromatic, or, for example, a first hydroxy group may be aliphatic and a second hydroxy group may be aromatic.

[0049] In some embodiments, using certain types of linkers described below, the conjugate molecule can contain two therapeutic moieties, which can be the same or different, both attached to a single linker.

[0050] In some embodiments, the conjugate molecule may contain an additional cannabinoid component. Cannabinoid components

[0051] The cannabinoid components can be provided by naturally occurring molecules, either isolated or synthetic, or modified naturally occurring molecules. See, for example, Morales et al. See al., Frontiers in Pharmacology June 2017 review, 1-18.

[0052] Examples of cannabinoids include, but are not limited to, cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol.

[0053] Examples of cannabigerols include cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGAM), cannabigerol (CBG), cannabigerol monomethyleither (CBGM), cannabigerovaric acid (CBGVA), and cannabigerovarin (CBGV).

[0054] Examples of cannabichromenes include cannabichromenic acid (CBC), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), and cannabichromevaline (CBCV).

[0055] Examples of cannabidiols include cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethyl ether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivaric acid (CBDVA), cannabidivarin (CBDV), and cannabidiorcol (CBD-C1).

[0056] Examples of tetrahydrocannabinols include Δ-9-tetrahydrocannabinolic acid A (THCA-A), Δ-9-tetrahydrocannabinolic acid B (THCA-B), Δ-9-tetrahydrocannabinol (THC), Δ-9-tetrahydrocannabinolic acid-C4 (THCA-C4), Δ-9-tetrahydrocannabinol-C4 (THC-C4), Δ-9-tetrahydrocannabivarinic acid (THCVA), Δ-9-tetrahydrocannabivarin (THCV), Δ-9-tetrahydrocannabiorcholic acid (THCA-C1), Δ-9-tetrahydrocannabiorcholic acid (THC-C1), Δ-7-cis-tetrahydrocannabivarin, Δ-8-tetrahydrocannabinolic acid (Δ 8 -THCA), and Δ-8-tetrahydrocannabinol (Δ 8 -THC).

[0057] Examples of cannabicyclols include cannabicyclolic acid (CBLA), cannabicyclol (CBL), and cannabicyclovalin (CBLV).

[0058] Examples of cannabielsoins include cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), and cannabielsoin (CBE).

[0059] Examples of cannabinols and cannabinodivarins include cannabinolic acid (CBNA), cannabinol (CBN), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabinol-C2 (CBN-C2), cannabiolcol (CBN-C1), cannabinodivarin (CBND), and cannabinodivarin (CBVD).

[0060] Examples of cannabidiols include cannabidiol (CBT), 10-ethoxy-9-hydroxy-Δ-6α-tetrahydrocannabinol, cannabidiol valine (CBTV), and ethoxy-cannabidiol valine (CBTVE).

[0061] Cannabifurans include dehydrocannabifuran (DCBF) and cannabifuran (CBF).

[0062] Examples of other cannabinoids include cannabichromanone (CBCN), 10-oxo-Δ-6a-tetrahydrocannabinol (OTHC), cannabilipsol (CBR), and trihydroxy-Δ-9-tetrahydrocannabinol (triOH-THC).

[0063] The cannabinoid conjugate component can have one or more asymmetric centers and can therefore be prepared either as a mixture of isomers (e.g., racemic or diastereomeric mixtures) or in enantiomerically or diastereomerically pure form. Such forms include, but are not limited to, diastereomers, enantiomers, and atropisomers. The conjugate molecule can also contain an alkene and can therefore be prepared either as a mixture of double bond isomers or independently as either E or Z isomers. Isotopic variants of the cannabinoid conjugate component can also be prepared. Type I conjugate molecules

[0064] As noted above, Type I conjugate molecules have the formula: [ka] wherein CBNC is a cannabinoid conjugate moiety comprising a therapeutic agent moiety covalently bonded to a cannabinoid moiety directly or via a linker; and L cc is a CBNC linker, B is a target binding moiety, and L a is an active ingredient linker and A is an active ingredient. In embodiments where B is an antibody, m is 1 to 30, n is 0 to 29, and the sum of m+n is 1 to 30. It has.

[0065] In type I conjugate molecules, B, L a , L cc , and A is as defined above.

[0066] In some embodiments, the cannabinoid component is provided by cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabidiol, dehydrocannabifuran, cannabifuran, cannabichromanone, or cannabilipsol. In some embodiments, the cannabinoid component is provided by cannabidiol. In some embodiments, the cannabinoid component is provided by cannabigerol.

[0067] In embodiments where m is at least 2, each of the cannabinoid components may be the same or different and may independently be linked by a linker, L c Each of may be the same or different.

[0068] In embodiments where n is at least 2, each of the active agent components, which may be the same or different, is independently a linker, L a Each of may be the same or different.

[0069] In some embodiments, n is 0 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0070] In some embodiments, n is 1 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29.

[0071] In some embodiments, n is 2 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28.

[0072] In some embodiments, n is 3 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27.

[0073] In some embodiments, n is 4 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

[0074] In some embodiments, n is 5 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

[0075] In some embodiments, n is 6 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24.

[0076] In some embodiments, n is 7 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0077] In some embodiments, n is 8 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.

[0078] In some embodiments, n is 9 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21.

[0079] In some embodiments, n is 10 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0080] In some embodiments, n is 11 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19.

[0081] In some embodiments, n is 12 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.

[0082] In some embodiments, n is 13 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17.

[0083] In some embodiments, n is 14 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0084] In some embodiments, n is 15 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0085] In some embodiments, n is 16 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.

[0086] In some embodiments, n is 17 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13.

[0087] In some embodiments, n is 18 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0088] In some embodiments, n is 19 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0089] In some embodiments, n is 20 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0090] In some embodiments, n is 21 and m is 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0091] In some embodiments, n is 22 and m is 1, 2, 3, 4, 5, 6, 7, or 8.

[0092] In some embodiments, n is 23 and m is 1, 2, 3, 4, 5, 6, or 7.

[0093] In some embodiments, n is 24 and m is 1, 2, 3, 4, 5, or 6.

[0094] In some embodiments, n is 25 and m is 1, 2, 3, 4, or 5.

[0095] In some embodiments, n is 26 and m is 1, 2, 3, or 4.

[0096] In some embodiments, n is 27 and m is 1, 2, or 3.

[0097] In some embodiments, n is 28 and m is 1 or 2.

[0098] In some embodiments, n is 29. In these embodiments, m is 1.

[0099] In embodiments in which B is an antibody, the antibody is an anti-idiotype (anti-Id) antibody, a camelized antibody, a chimeric antibody, a disulfide-linked Fvs (sdFv), an F(ab') fragment, a Fab fragment, a human antibody, a humanized antibody, a murine antibody, an intrabody, a monoclonal antibody, a bispecific antibody, a multispecific antibody, or a single-chain Fv (scFv), or an epitope-binding fragment thereof.

[0100] In some embodiments where B is an antibody, the antibody is IgG, IgE, IgM, IgD, IgA, or IgY.

[0101] In some embodiments where B is an antibody, the antibody is IgG1, IgG2 (eg, IgG2a, IgG2), IgG3, IgG4, IgA1, or IgA2.

[0102] In some embodiments, where B is an antibody, the antibody binds to: i.Cluster of differentiation (CD) antigens, ii. checkpoint inhibitors, iii. Vascular target antigen, iv. stromal antigens, v. extracellular matrix antigen, vi. circulating antigens, vii. Interleukins, viii. Interleukin receptor, ix. growth factors, x. growth factor receptors, xi. Drugs, xii.Adhesion molecules, xiii. tumor necrosis factor, xiv. Tumor necrosis factor-related apoptosis-inducing ligand receptor, xv. insulin receptor, xvi. receptor tyrosine kinase, xvii. Cytokine receptors, xviii. Tropomyosin receptor kinase, xix. Integrin xx. immunoglobulin, or xxi.Antigens of infectious organisms.

[0103] In some embodiments, where B is an antibody, a -A)" is an ADC.

[0104] In some embodiments, where B is an antibody, the antibody binds to: i. an antigen selected from the group consisting of CD2, CD3, CD4, CD11a, CD19, CD20, CD25 (ILR2), CD30, CD33, CD38, CD52, CD139, CD152 (CTLA-4), CD274 (PD-L1), or CD319 (SLAMF); ii. an antigen selected from the group consisting of PD-1 and PD-L1 (CD274); iii.PSMA, iv. bone marrow stromal antigen 2, v. An antigen selected from the group consisting of CI, CIII, CIV, CV, LM, and FN; vi. Factor IXa or Factor X, vii. An antigen selected from the group consisting of IL-1β, IL-2, IL-5, IL-6, IL-12, IL-17A, and IL-23; viii. An antigen selected from the group consisting of ILR2 (CD25), IL-4RA, IL-5RA, IL-6R, and IL-17RA; ix.VEGFA, x. An antigen selected from the group consisting of EGFR (ErbB1), FGFR, FGFR2, FGFR3, FGFR4, FGFR23, HER2 / neu, HER3, (ErbB3), HER4, PDGFRA, VEGFR1, VEGFR2, VEGFR3, EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB5, EphB6, EphB7, HGFR (c-Met), and IGF2R; xi. digoxin or dabigatran, xii.EpCAM, xiii. TNF-α or TNF-β, xiv.TRAIL-R1 or TRAIL-R2, xv.IR, xvi. An antigen selected from the group consisting of FLT3, CSF-1R, KIT / SCFR, RON (SEA), AXL (UFO), MER, TYRO3, MUSK, RET, TIE1, DDR1, DDR2, ROR1, ROR2, ROS, LTL, ALK, KLG, and RYK; xvii. An antigen selected from the group consisting of type I cytokine receptors, type II cytokine receptors, TNF receptors, CCR4, TGF-β receptors, and activin receptors; xviii. An antigen selected from the group consisting of TRKA, TRKB, and TRKC; xix. An antigen selected from the group consisting of integrin α4, integrin α4β1, and integrin α4β7; xx.IgE, xxi. An antigen selected from the group of infectious organisms consisting of respiratory syncytial virus, Bacillus anthracis, and Clostridium difficile, or xxii. An antigen selected from the group consisting of PSCK9, CGRPR, CRLR, RANKL, GP IIb / IIIa receptor, GD2, BLyS, C5, IRR, and TAG72.

[0105] The present disclosure describes three types of Type I conjugate molecules: Type iI-A conjugate molecules comprise a cannabinoid conjugate moiety, with one or more therapeutic moieties directly attached to one or more cannabinoid moieties. ii. Type IB conjugate molecules comprise a cannabinoid conjugate moiety, wherein one or more therapeutic moieties are covalently attached to the one or more cannabinoid moieties via a linker. iii. Type IC conjugate molecules comprise a cannabinoid conjugate component, wherein one or more β-lactam antibiotic components are covalently attached to one or more cannabinoid components via a linker. Type IA cannabinoid conjugate molecules

[0106] Type IA conjugate molecules comprise a cannabinoid conjugate moiety, with one or more therapeutic moieties directly attached to one or more cannabinoid moieties.

[0107] In some embodiments, the therapeutic component is: [ka] wherein # indicates a site of covalent attachment to the cannabinoid moiety; R is (a) H, (b)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) one, two, or three substituents independently selected from the substituents of Group 1; C1-C8 straight or branched alkyl optionally substituted with (c) containing 1, 2, or 3 heteroatoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) one, two, or three substituents independently selected from the substituents of Group 1; C1-C8 straight chain or branched heteroalkyl optionally substituted with (d)(1)(i) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (ii) one or two substituents independently selected from the substituents of Group 2; C1-C6 straight or branched alkyl optionally substituted with (2) contains 1 or 2 heteroatoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (ii) one or two substituents independently selected from the substituents of Group 1 C1-C6 straight or branched heteroalkyl optionally substituted with phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (e)(1) phenyl, (2) halides, (3) Cyano, (4)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) C1-C6 straight or branched alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2; and (5) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched heteroalkyl optionally substituted with a 6- to 10-membered aromatic optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (f) containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; (1) phenyl, (2) halides, (3) Cyano, (4) trifluoromethyl, (5)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (6) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched heteroalkyl optionally substituted with a 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from (g)(1)(i) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: [ka] (h) having 1, 2, or 3 heteroatoms independently selected from O, N, and S; (1)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (2)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched heteroalkyl optionally substituted with (3) phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2, and (4) A 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2. a 3- to 9-membered cycloheteroalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (i)(1)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (2)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched heteroalkyl optionally substituted with (3) phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2, and (4) A 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2. C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from is selected from the group consisting of R1 and R2 are independently (a)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents of Group 1 C1-C12 straight or branched alkyl optionally substituted with (b)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents of Group 1; C2-C12 straight or branched alkenyl optionally substituted with (c) containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents of Group 1 C1-C12 straight chain or branched heteroalkyl, optionally substituted with (d)R or selected from the group consisting of or R1 and R2, together with the atoms to which they are bonded, form a 3- to 9-membered cycloheteroalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, said cycloheteroalkyl being (a)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (b)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched heteroalkyl optionally substituted with (c) phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2, and (d) a 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2; and R3, R 3a , and R 3b is, independently, (a)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 1 C1-C8 straight or branched alkyl optionally substituted with (b) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-C6 straight or branched alkyl; (1) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (2) one or two substituents independently selected from the substituents of Group 2 phenyl optionally substituted with is selected from.

[0108] In some embodiments, the therapeutic moiety has the structure [ka] and Q is CO, CS, or CR. 6a R 6b and R 6a and R 6b are independently R.

[0109] In some embodiments, the therapeutic moiety has the structure [ka] and R8 and R9 are independently selected from H, CH3, and CH2CH3.

[0110] Examples of therapeutic agents that can be used to provide a Michael acceptor moiety include, but are not limited to: [ka] Type IB conjugate molecules

[0111] Type IB conjugate molecules comprise a cannabinoid conjugate moiety, wherein one or more therapeutic moieties are covalently attached to one or more cannabinoid moieties via a linker.

[0112] In some embodiments, the therapeutic moiety is attached to the cannabinoid moiety via a "type IB linker," as shown below. [ka] [In the formula, [ka] indicates the bond connecting the Type (Ib) linker to the therapeutic moiety, # indicates the site of covalent attachment to the cannabinoid moiety, Y, Y1, and Y2 are independently absent, or Y, Y1, and Y2 are independently (a)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents of Group 1 C1-C12 straight or branched alkyl optionally substituted with (b)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents of Group 1; C2-C12 straight or branched alkenyl optionally substituted with (c) containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents of Group 1; C1-C12 straight or branched heteroalkyl optionally substituted with (d)(1) phenyl, (2) halides, (3)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (4) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) C1-C6 straight-chain or branched heteroalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2 a 6- to 10-membered aromatic optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (e) containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; (1) phenyl, (2) halides, (3) trifluoromethyl, (4)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (5) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) C1-C6 straight-chain or branched heteroalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2. and a 6- to 10-membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from (f) containing 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, 3, 4, 5, or 6 substituents selected from the substituents of Group 1; C1-C24 straight or branched heteroalkyl optionally substituted with is selected from the group consisting of Ar is (a)(1) phenyl, (2) halides, (3)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with a 6- to 10-membered aromatic optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (b) contains 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; (1) phenyl, (2) halides, (3) trifluoromethyl, (4)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched alkyl optionally substituted with (5) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 C1-C6 straight or branched heteroalkyl optionally substituted with a 6- to 10-membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from Either R e , R f , and R g are independently R as defined above]

[0113] In some embodiments, the therapeutic component is: [ka] and R ais absent or is a C1-C3 straight or branched chain alkyl or a C1-C3 straight or branched chain heteroalkyl containing an O, N, or S atom.

[0114] In some embodiments, the therapeutic component is: [ka] and R a is as defined above, and R b is R or -PS(NR c1 R c2 ) and R c1 and R c2 is independently a C1-C6 straight or branched alkyl or a C1-C6 cycloalkyl, and R is as defined above.

[0115] In some embodiments, the therapeutic component is: [ka] and R d teeth, (a)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 1 C1-C8 straight or branched alkyl optionally substituted with (b) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-C6 straight or branched alkyl; (i) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (ii) one or two substituents independently selected from the substituents of Group 2 phenyl optionally substituted with is.

[0116] In some embodiments, the therapeutic component is: [ka] and X is Cl, Br, or I.

[0117] In some embodiments, the therapeutic component is temozolomide or a temozolomide analog, [ka] and R x and R y are independently H or C1-C3 straight chain or branched alkyl.

[0118] In some embodiments, the therapeutic moiety is 5-fluorouracil or a 5-fluorouracil analog: [ka] and G1 and G2 are independently selected from the group consisting of O, S, and NR.

[0119] In some embodiments, the therapeutic agent component is diclofenac or a diclofenac analog: [ka] is.

[0120] In some embodiments, the diclofenac component has the structure [ka] In some embodiments, the diclofenac component has the structure [ka] In some embodiments, the diclofenac component has the structure [ka] It has.

[0121] Conjugates containing a diclofenac component may be used alone or in combination with diclofenac-containing products, such as, for example, MOBIZOX® (diclofenac, paracetamol, and clozoxazone), SOLARAZE® (diclofenac sodium), VOLTAREN® (diclofenac sodium), VOLITRA® (benzyl alcohol, capsaicin, diclofenac diethylamine, linseed oil, menthol, methyl salicylate), VOLITRA® MR (diclofenac, thiocolchicoside), VOLITRA® PLUS (diclofenac diethylamine, linseed oil, methyl salicylate, menthol, eucalyptus globulus), and the like. It may be administered as part of the following: IV diclofenac oil, VOLITRA® S (diclofenac sodium ip, serratiopeptidase), FLEXURA® D (diclofenac potassium bp, metaxalone), MOBISWIFT® D (diclofenac, methoxolone), THIOACT® D (thiocochicoside, diclofenac sodium ip).

[0122] In some embodiments, the therapeutic agent component is celecoxib (e.g., CELEBREX®) or a celecoxib analog: [ka] is.

[0123] In some embodiments, the celecoxib component has the structure [ka] It has.

[0124] In some embodiments, the therapeutic moiety is gemcitabine (e.g., GEMZAR®) or an analog of gemcitabine: [ka] is.

[0125] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] In some embodiments, the gemcitabine moiety has the structure [ka] It has.

[0126] In some embodiments, the therapeutic agent moiety is emtricitabine (e.g., DESCOVY®, BIKTARVY®, EMTRIVA®) or an analog of emtricitabine: [ka] is.

[0127] In some embodiments, the emtricitabine moiety has the structure [ka] In some embodiments, the emtricitabine moiety has the structure [ka] In some embodiments, the emtricitabine moiety has the structure [ka] It has.

[0128] In some embodiments, the therapeutic agent component is entecavir (e.g., BARACLUDE®) or an analog of entecavir: [ka] is.

[0129] In some embodiments, the entecavir moiety has the structure: [ka] It has.

[0130] In some embodiments, the therapeutic agent moiety is axitinib (e.g., INLYTA®) or an analog of axitinib: [ka] is.

[0131] In some embodiments, the axitinib component has the structure [ka] It has.

[0132] In some embodiments, the therapeutic component is batimastat or an analog of batimastat: [ka] is.

[0133] In some embodiments, the batimastat component has the structure [ka] It has.

[0134] In some embodiments, the therapeutic moiety is bosutinib (e.g., BOSULIF®) or an analog of bosutinib: [ka] is.

[0135] In some embodiments, the bosutinib moiety has the structure [ka] It has.

[0136] In some embodiments, the therapeutic moiety is crizotinib (e.g., XALKORI®) or an analog of crizotinib: [ka] is.

[0137] In some embodiments, the crizotinib component has the structure [ka] In some embodiments, the crizotinib component has the structure [ka] In some embodiments, the crizotinib component has the structure [ka] It has.

[0138] In some embodiments, the therapeutic moiety is erlotinib (e.g., TARCEVA®) or an analog of erlotinib: [ka] is.

[0139] In some embodiments, the erlotinib component has the structure [ka] It has.

[0140] In some embodiments, the therapeutic moiety is gefitinib (e.g., IRESSA®) or an analog of gefitinib: [ka] is.

[0141] In some embodiments, the gefitinib component has the structure [ka] It has.

[0142] In some embodiments, the therapeutic component is everolimus (e.g., ZORTRESS®, AFINITOR DISPERZ®, AFINITOR®) or an analog of everolimus: [ka] is.

[0143] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] In some embodiments, the everolimus component has the structure [ka] It has.

[0144] In some embodiments, the therapeutic component is temsirolimus (e.g., TORISEL®) or an analog of temsirolimus: [ka] is.

[0145] In some embodiments, the temsirolimus moiety has one of the following structures, with each arrow indicating a point where a linker, as described below, can be attached. [ka] [ka] [ka]

[0146] In some embodiments, the therapeutic moiety is ganetespib or an analog of ganetespib: [ka] is.

[0147] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] In some embodiments, the ganetespib moiety has the structure [ka] It has.

[0148] In some embodiments, the therapeutic agent component is glasdegib (e.g., GLASDEGIB®) or an analog of glasdegib: [ka] is.

[0149] In some embodiments, the glasdegib component has the structure [ka] It has.

[0150] In some embodiments, the therapeutic moiety is imatinib (e.g., GLEEVEC®) or an analog of imatinib: [ka] is.

[0151] In some embodiments, the imatinib component has the structure [ka] In some embodiments, the imatinib component has the structure [ka] In some embodiments, the imatinib component has the structure [ka] It has.

[0152] In some embodiments, the therapeutic moiety is lapatinib (e.g., TYKERB®) or an analog of lapatinib: [ka] is.

[0153] In some embodiments, the lapatinib moiety has the structure [ka] In some embodiments, the lapatinib moiety has the structure [ka] In some embodiments, the lapatinib moiety has the structure [ka] It has.

[0154] In some embodiments, the therapeutic component is navitoclax or an analog of navitoclax: [ka] is.

[0155] In some embodiments, the navitoclax component has the structure [ka] In some embodiments, the navitoclax ingredient has the structure [ka] In some embodiments, the navitoclax ingredient has the structure [ka] It has.

[0156] In some embodiments, the therapeutic moiety is nilotinib (e.g., TASIGNA®) or an analog of nilotinib: [ka] is.

[0157] In some embodiments, the nilotinib component has the structure [ka] In some embodiments, the nilotinib component has the structure [ka] In some embodiments, the nilotinib component has the structure [ka] It has.

[0158] In some embodiments, the therapeutic moiety is pazopanib (e.g., OPDIVO®, VOTRIENT®) or an analog of pazopanib: [ka] is.

[0159] In some embodiments, the pazopanib component has the structure [ka] In some embodiments, the pazopanib component has the structure [ka] In some embodiments, the pazopanib component has the structure [ka] It has.

[0160] In some embodiments, the therapeutic moiety is luminespib or an analog of luminespib: [ka] is.

[0161] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] In some embodiments, the luminespib component has the structure [ka] It has.

[0162] In some embodiments, the therapeutic component is obatoclax or an analog of obatoclax: [ka] is.

[0163] In some embodiments, the obatoclax component has the structure [ka] In some embodiments, the obatoclax component has the structure [ka] In some embodiments, the obatoclax component has the structure [ka] It has.

[0164] In some embodiments, the therapeutic moiety is ruxolitinib (e.g., JAKAFI®) or an analog of ruxolitinib: [ka] is.

[0165] In some embodiments, the ruxolitinib moiety has the structure [ka] It has.

[0166] In some embodiments, the therapeutic agent moiety is saridegib (e.g., ODOMZO®) or an analog of saridegib: [ka] is.

[0167] In some embodiments, the saridegib component has the structure [ka] In some embodiments, the saridegib component has the structure [ka] In some embodiments, the saridegib component has the structure [ka] It has.

[0168] In some embodiments, the therapeutic moiety is sunitinib (e.g., SUTENT®) or an analog of sunitinib: [ka] is.

[0169] In some embodiments, the sunitinib component has the structure: [ka] In some embodiments, the sunitinib component has the structure [ka] In some embodiments, the sunitinib component has the structure [ka] In some embodiments, the sunitinib component has the structure [ka] In some embodiments, the sunitinib component has the structure [ka] In some embodiments, the sunitinib component has the structure [ka] In some embodiments, the sunitinib component has the structure [ka] It has.

[0170] In some embodiments, the therapeutic agent moiety is trametinib (e.g., MEKINIST®) or an analog of trametinib: [ka] is.

[0171] In some embodiments, the trametinib moiety has the structure [ka] In some embodiments, the trametinib moiety has the structure [ka] In some embodiments, the trametinib moiety has the structure [ka] It has.

[0172] In some embodiments, the therapeutic agent component is warfarin (e.g., COUMADIN®, JANTOVEN®) or a warfarin analog: [ka] is.

[0173] In some embodiments, the warfarin component has the structure [ka] It has.

[0174] In some embodiments, the therapeutic agent moiety is daclatasvir (e.g., DAKLINZA®) or an analog of daclatasvir: [ka] is.

[0175] Because daclatasvir is a symmetric drug, many multiple conjugate structures are envisioned, with up to at least four cannabinoid moieties attached to the parent drug. In some embodiments, the daclatasvir moiety has a cannabinoid moiety attached at one or more of positions (a), (b), (c), (d), (e), and (f) depicted below, in any combination. [ka]

[0176] In some embodiments, the cannabinoid component is attached at site (a).

[0177] In some embodiments, the cannabinoid component is attached at site (a) and site (b). In some embodiments, the cannabinoid component is attached at site (a) and site (c). In some embodiments, the cannabinoid component is attached at site (a) and site (d). In some embodiments, the cannabinoid component is attached at site (a) and site (e). In some embodiments, the cannabinoid component is attached at site (a) and site (f).

[0178] In some embodiments, the cannabinoid components are bound at site (a), site (b), and site (c). In some embodiments, the cannabinoid components are bound at site (a), site (b), and site (d). In some embodiments, the cannabinoid components are bound at site (a), site (b), and site (e). In some embodiments, the cannabinoid components are bound at site (a), site (b), and site (f).

[0179] In some embodiments, the cannabinoid components are attached at site (a), site (c), and site (d). In some embodiments, the cannabinoid components are attached at site (a), site (c), and site (e). In some embodiments, the cannabinoid components are attached at site (a), site (c), and site (f).

[0180] In some embodiments, the cannabinoid components are attached at sites (a), (d), and (e). In some embodiments, the cannabinoid components are attached at sites (a), (d), and (f).

[0181] In some embodiments, the cannabinoid components are attached at positions (a), (e), and (f).

[0182] In some embodiments, the cannabinoid components are attached at site (a), site (b), site (c), and site (d). In some embodiments, the cannabinoid components are attached at site (a), site (b), site (c), and site (e). In some embodiments, the cannabinoid components are attached at site (a), site (b), site (c), and site (f).

[0183] In some embodiments, the cannabinoid components are attached at site (a), site (d), site (d), and site (e). In some embodiments, the cannabinoid components are attached at site (a), site (d), site (d), and site (f).

[0184] In some embodiments, the cannabinoid components are attached at positions (a), (d), (e), and (f).

[0185] In some embodiments, the cannabinoid components are attached at site (a), site (b), site (c), site (d), and site (e). In some embodiments, the cannabinoid components are attached at site (a), site (b), site (c), site (d), and site (f).

[0186] In some embodiments, the cannabinoid components are attached at site (a), site (b), site (c), site (d), site (e), and site (f).

[0187] In some embodiments, the cannabinoid component is attached at site (b).

[0188] In some embodiments, the cannabinoid component is attached at site (b) and site (c). In some embodiments, the cannabinoid component is attached at site (b) and site (d). In some embodiments, the cannabinoid component is attached at site (b) and site (e). In some embodiments, the cannabinoid component is attached at site (b) and site (f).

[0189] In some embodiments, the cannabinoid components are attached at sites (b), (c), and (d). In some embodiments, the cannabinoid components are attached at sites (b), (c), and (e). In some embodiments, the cannabinoid components are attached at sites (b), (c), and (f).

[0190] In some embodiments, the cannabinoid components are attached at sites (b), (d), and (e). In some embodiments, the cannabinoid components are attached at sites (b), (d), and (f).

[0191] In some embodiments, the cannabinoid components are attached at positions (b), (e), and (f).

[0192] In some embodiments, the cannabinoid components are attached at sites (b), (c), (d), and (e). In some embodiments, the cannabinoid components are attached at sites (b), (c), (d), and (f).

[0193] In some embodiments, the cannabinoid components are attached at positions (b), (d), (e), and (f).

[0194] In some embodiments, the cannabinoid components are attached at positions (b), (c), (d), (e), and (f).

[0195] In some embodiments, the cannabinoid component is attached at site (c).

[0196] In some embodiments, the cannabinoid component is attached at site (c) and site (d). In some embodiments, the cannabinoid component is attached at site (c) and site (e). In some embodiments, the cannabinoid component is attached at site (c) and site (f).

[0197] In some embodiments, the cannabinoid components are attached at sites (c), (d), and (e). In some embodiments, the cannabinoid components are attached at sites (c), (d), and (f).

[0198] In some embodiments, the cannabinoid components are attached at positions (c), (e), and (f).

[0199] In some embodiments, the cannabinoid components are attached at positions (c), (d), (e), and (f).

[0200] In some embodiments, the cannabinoid component is attached at position (d).

[0201] In some embodiments, the cannabinoid component is attached at positions (d) and (e). In some embodiments, the cannabinoid component is attached at positions (d) and (f).

[0202] In some embodiments, the cannabinoid components are attached at positions (d), (e), and (f).

[0203] In some embodiments, the cannabinoid component is attached at position (e).

[0204] In some embodiments, the cannabinoid components are attached at positions (e) and (f).

[0205] In some embodiments, the cannabinoid component is attached at site (f).

[0206] In some embodiments, the therapeutic agent component is etoposide (e.g., ETOPOPHOS®, TOPOSAR®) or an analog of etoposide: [ka] is.

[0207] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] In some embodiments, the etoposide moiety has the structure [ka] It has.

[0208] In some embodiments, the therapeutic agent moiety is atazanavir (e.g., REYATAZ®) or an analog of atazanavir: [ka] is.

[0209] Either or both carbamates of atazanavir can be attached to the cannabinoid moiety in addition to the OH group, or potentially the NH hydrazinyl group. In some embodiments, the atazanavir moiety has the structure [ka] In some embodiments, the atazanavir moiety has the structure [ka] It has. [ka] In some embodiments, the atazanavir moiety has the structure [ka] In some embodiments, the atazanavir moiety has the structure [ka] In some embodiments, the atazanavir moiety has the structure [ka] It has.

[0210] In some embodiments, the therapeutic agent moiety is pravastatin (e.g., PRAVACHOL®) or an analog of pravastatin: [ka] is.

[0211] Any or all of the three hydroxyl groups and the carboxylic acid group can be attached to the cannabinoid moiety. In some embodiments, the pravastatin moiety has one of the following structures: [ka] [ka]

[0212] In some embodiments, the therapeutic moiety is dasatinib (e.g., SPRYCEL®) or an analog of dasatinib: [ka] is.

[0213] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] In some embodiments, the dasatinib moiety has the structure [ka] It has.

[0214] In some embodiments, the therapeutic moiety is didanosine (e.g., VIDEX®) or an analog of didanosine: [ka] is.

[0215] In some embodiments, the didanosine moiety has the structure [ka] In some embodiments, the didanosine moiety has the structure [ka] In some embodiments, the didanosine moiety has the structure [ka] It has.

[0216] In some embodiments, the therapeutic agent component is stavudine (e.g., ZERIT®) or an analog of stavudine: [ka] is.

[0217] In some embodiments, the stavudine moiety has the structure [ka] In some embodiments, the stavudine moiety has the structure [ka] In some embodiments, the stavudine moiety has the structure [ka] It has.

[0218] Additional therapeutic agents can be conjugated as described above. Examples are shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] IC-type conjugate molecules

[0219] The cannabinoid-conjugate moiety in the type IC conjugate molecule is a "β-lactam antibiotic cannabinoid-conjugate moiety," wherein the β-lactam antibiotic moiety is covalently attached to a hydroxy or carboxylic acid group of the cannabinoid moiety via a type IC linker.

[0220] As used in this disclosure, a "β-lactam antibiotic" is a molecule that contains a four-membered lactam ring (β-lactam) and has antibacterial activity. As used in this disclosure, a "β-lactam antibiotic moiety" is the portion of the β-lactam antibiotic present in a β-lactam antibiotic cannabinoid conjugate component that is covalently attached to a linker.

[0221] In some embodiments, the β-lactam antibiotic moiety is covalently attached at its 3-position to the IC-type linker of the cannabinoid conjugate moiety. In some of these embodiments, the β-lactam antibiotic moiety is a cephem moiety. In some of these embodiments, the β-lactam antibiotic moiety is a carbacephem moiety. In some of these embodiments, the β-lactam antibiotic moiety is a penem moiety. In some of these embodiments, the β-lactam antibiotic moiety is a carbapenem moiety.

[0222] In some embodiments, the β-lactam antibiotic moiety is a monobactam moiety covalently attached at its 2-position to a type IC linker of a first cannabinoid moiety.

[0223] Several β-lactam antibiotics can be used to provide the β-lactam antibiotic moiety. Cephalosporins and carbacephalosporins

[0224] In some embodiments, the β-lactam antibiotic moiety is a cephem moiety. As used in this disclosure, a "cephem moiety" is a cephem lacking the substituent normally present at the 3-position of the molecule, as illustrated below: [ka] [ka]

[0225] Cephem components include, but are not limited to, cefazolin, cephalexin, cefadroxil, cephapirin, cefazedone, cefazaflur, cephradine, cefroxadine, ceftezole, cephaloglycin, cephacetrile, cephalonium, cephaloridine, cephalothin, cefatrizine, cefaclor, cefotetan, cephamycin, cefoxitin, cefprozil, cefuroxime, cefuroxime axetil, cefaman Dole, cefminox, cefonicid, ceforanide, cefotiam, cefbuperazone, cefzonam, cefmetazole, cefixime, ceftriaxone, ceftazidime, cefoperazone, cefdinir, cefcapene, cefdaloxime, ceftizoxime, cefmenoxime, cefotaxime, cefpiramide, cefpodoxime, ceftibuten, cefditoren, cefetamet, cefodizime, cefpimizole, cefsulodin, cefteram It can be provided by any of a variety of cephems, including ceftiolene, flomoxef, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftaroline fosamil, ceftolozane, ceftobiprole, ceftiofur, cefquinome, and cefovecin. See also, e.g., U.S. Patent Nos. 9,751,894; 7,696,354; and 6,150,351.

[0226] In some embodiments, the β-lactam antibiotic moiety is a carbacephem moiety. As used in this disclosure, a "carbacephem moiety" is a carbacephem without the substituent normally present at the 3-position of the molecule, as illustrated below: [ka]

[0227] Carbacephems include, but are not limited to, loracarbef. See also, for example, U.S. Patent No. 8,445,476 and U.S. Patent No. 4,980,348.

[0228] In some embodiments, the β-lactam antibiotic moiety has structural formula (A): [ka] wherein X is S, C, or O; 2a is the side chain of the first cephem or the side chain of the first carbacephem, and R 2b is H or -OCH3) Cephem side chains include, for example: [ka] Carbacephem side chains include, for example: [ka] Penems and carbapenems

[0229] In some embodiments, the β-lactam antibiotic moiety is a penem moiety. As used in this disclosure, a "penem moiety" is a penem without the substituent normally present at the 3-position of the molecule, as illustrated below: [ka]

[0230] Penems include, but are not limited to, faropenem and ritipenem. See also U.S. Patent No. 6,271,222; U.S. Patent No. 5,757,583.

[0231] In other embodiments, the β-lactam antibiotic moiety is a carbapenem moiety. As used in this disclosure, a "carbapenem moiety" is a carbapenem lacking the substituent normally present at the 3-position of the molecule, as illustrated below: [ka]

[0232] Carbapenems include, but are not limited to, ertapenem, doripenem, imipenem, meropenem, biapenem, and panipenem. See also U.S. Patent No. 9,937,151; U.S. Patent No. 8,318,716.

[0233] In some embodiments, the β-lactam antibiotic moiety has structural formula (B): [ka] (Wherein W is S or C, R2c is the side chain of the first penem or the side chain of the first carbapenem, and when W is C, R 2d is H, -CH3, or phenyl, wherein phenyl is optionally substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of halide, trifluoromethyl, C1-C6 straight chain or branched alkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and C1-C6 straight chain or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S and optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms. It's inside.

[0234] In some embodiments, the side chain of the penem or carbapenem is: [ka] is.

[0235] In some embodiments, R d is β-methyl. Monobactam

[0236] In some embodiments, the β-lactam antibiotic component is a monobactam component. As used in this disclosure, a "monobactam component" is a monobactam that lacks the substituent normally present at the 2-position of the molecule, as illustrated in the examples below. [ka]

[0237] Monobactams include, but are not limited to, aztreonam, tigemonam, carumonam, and nocardicin A. See also, for example, U.S. Patent No. 9,174,978.

[0238] In some embodiments, the β-lactam antibiotic moiety has structural formula (C): [ka] (In the formula, R M3 is a monobactam substituent at the 3-position, and R M1 is the monobactam substituent at position 1) It's inside.

[0239] R M3 Examples include: [ka] Examples include:

[0240] R M1 Examples include: [ka] Examples include: IC-type linker

[0241] The type IC linkers used to connect the β-lactam antibiotic moiety and the cannabinoid moiety are typically 2-10 atoms in length and are functionalized to facilitate release of the cannabinoid when the β-lactam antibiotic engages its biological target. When the β-lactam antibiotic moiety is provided by a cephem, carbacephem, penem, or carbapenem, the linker is covalently attached to position 3 of the β-lactam antibiotic moiety, for example: [ka] is.

[0242] When the β-lactam antibiotic moiety is provided by a monobactam, the linker is covalently attached to position 2 of the monobactam moiety, for example: [ka] is.

[0243] A variety of linkers can be used in Type IC cannabinoid conjugate components, including ethers, acetals, alkenes, propenylamines, carbamates, carbonates, xanthates, aminals, propenylcarbamates, propenylthiocarbamates, propenylcarbonates, propenylthiocarbonates, S-alkylthiocarbonates, thiocarbamates, thiocarbonates, and thiohemiacetal ethers.

[0244] When the β-lactam antibiotic moiety is provided by a cephem, carbacephem, penem, or carbapenem, the type IC linker may be selected from the group of linkers shown below (“Group AB linkers”). [ka] where # indicates the site of covalent attachment from the OH of the cannabinoid component to the oxygen atom, and ## indicates the site of covalent attachment to the carbon atom of the carbonyl component of the carboxylic acid-bearing cannabinoid component, such as in the case of esters, amides, and thioesters; [ka] represents the bond covalently attaching the linker to the β-lactam antibiotic moiety, T is absent or is —CH, —CHCH, or —CH-phenyl; Z is CR 1A R 2A and R 1A and R 2A are independently R)

[0245] When the β-lactam antibiotic moiety is provided by a monobactam, the Type IC linker that covalently attaches the β-lactam antibiotic moiety to the cannabinoid moiety may be selected from the group of linkers shown below (“Group C linkers”). [ka] wherein #, ##, Z, and R are as defined for the linkers of group AB.

[0246] In some embodiments where the cannabinoid component has at least two hydroxy groups, at least one hydroxy group and at least one carboxylic acid group, or at least two carboxylic acid groups, the second β-lactam antibiotic component can be covalently linked to the second hydroxy group by a second linker such that the conjugate molecule contains a first β-lactam antibiotic component and a second β-lactam antibiotic component covalently linked to the cannabinoid component by a first linker and a second linker, respectively.

[0247] In some embodiments, the first β-lactam antibiotic component is a cephem component. In some embodiments, the first β-lactam antibiotic component is a carbacephem component. In some embodiments, the first β-lactam component is a penem component. In some embodiments, the first β-lactam component is a carbapenem component. In some embodiments, the first β-lactam component is a monobactam component. In any of these embodiments, the second β-lactam antibiotic component can be a carbapenem component, a cephem component, a carbacephem component, or a monobactam component. That is, the two β-lactam antibiotic components can be the same or different, in any combination.

[0248] In addition, the first and second linkers may be the same or different. In some embodiments, the first and second linkers are independently selected from linkers in group AB. In some embodiments, the first and second linkers are independently selected from linkers in group C. In some embodiments, the first linker is selected from linkers in group AB, and the second linker is selected from linkers in group C. Examples of IC-type cannabinoid conjugates

[0249] Examples of Type IC cannabinoid conjugate moieties containing cephem, carbacephem, penem, carbapenem, and beta-methylcarbapenem moieties are shown below. For simplicity, the cannabinoid moiety shown is a cannabidiol moiety covalently bound to a single beta-lactam antibiotic. In each case, "R 3A " is the side chain of a cephem or carbacephem, and "R 3B " is the side chain of a penem or carbapenem, * is the linker L cc indicates the attachment point to Type IC cannabinoid conjugates with ether bonds: [ka] Type IC cannabinoid conjugates with acetal bonds: [ka] Type IC cannabinoid conjugate components with alkene bonds: [ka] Type IC cannabinoid conjugates with propenylamine bonds: [ka] Type IC cannabinoid conjugate components with carbamate bonds: [ka] Type IC cannabinoid conjugate components with carbonate bonds: [ka] Type IC cannabinoid conjugates with xanthate linkages: [ka] Type IC cannabinoid conjugates with aminal bonds: [ka] Type IC cannabinoid conjugates with propenyl carbamate bonds: [ka] Type IC cannabinoid conjugates with propenylthiocarbamate bonds: [ka] Type IC cannabinoid conjugates with propenyl carbonate bonds: [ka] Type IC cannabinoid conjugate components with propenylthiocarbonate linkage: [ka] Type IC cannabinoid conjugates with thiocarbamate bonds: [ka] Type IC cannabinoid conjugate components with S-alkylthiocarbonate linkages: [ka] Type IC cannabinoid conjugate components with thiohemiacetal bonds: [ka]

[0250] An example of a Type IC cannabinoid conjugate moiety containing a monobactam moiety is shown below: For simplicity, the cannabinoid moiety is a cannabidiol moiety covalently bound to a single aztreonam moiety: * is the linker L cc indicates the attachment point to [ka] [ka] [ka] [ka] [ka] Type II conjugate molecules

[0251] In some embodiments, the conjugate molecule has the formula: [ka] (wherein PCAN is a platinum complex anti-neoplastic agent component, L pc is a PCAN linker as described below, but may be absent; B is a target binding moiety; and L a is an active ingredient linker and A is an active ingredient In embodiments where B is an antibody, m is 1-30, n is 0-29, and the sum of m+n is 1-30.

[0252] In type II conjugate molecules, B, L a , and A is as defined above.

[0253] In some embodiments, the cannabinoid component is provided by cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabidiol, dehydrocannabifuran, cannabifuran, cannabichromanone, or cannabilipsol. In some embodiments, the cannabinoid component is provided by cannabidiol. In some embodiments, the cannabinoid component is provided by cannabigerol.

[0254] In embodiments where m is at least 2, each of the cannabinoid conjugate components may independently be the same or different and may independently be a linker, L cc Each of may be the same or different.

[0255] In embodiments where n is at least 2, each of the active agent components, which may be the same or different, is independently a linker, L a Each of may be the same or different.

[0256] In embodiments where m is at least 2, each of the platinum-conjugated anti-neoplastic agent moieties may independently be the same or different and independently comprise a linker, L pc Each of may be the same or different.

[0257] In some embodiments, n is 0 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0258] In some embodiments, n is 1 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29.

[0259] In some embodiments, n is 2 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28.

[0260] In some embodiments, n is 3 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27.

[0261] In some embodiments, n is 4 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

[0262] In some embodiments, n is 5 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

[0263] In some embodiments, n is 6 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24.

[0264] In some embodiments, n is 7 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0265] In some embodiments, n is 8 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.

[0266] In some embodiments, n is 9 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21.

[0267] In some embodiments, n is 10 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0268] In some embodiments, n is 11 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19.

[0269] In some embodiments, n is 12 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.

[0270] In some embodiments, n is 13 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17.

[0271] In some embodiments, n is 14 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0272] In some embodiments, n is 15 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0273] In some embodiments, n is 16 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.

[0274] In some embodiments, n is 17 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13.

[0275] In some embodiments, n is 18 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0276] In some embodiments, n is 19 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0277] In some embodiments, n is 20 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0278] In some embodiments, n is 21 and m is 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0279] In some embodiments, n is 22 and m is 1, 2, 3, 4, 5, 6, 7, or 8.

[0280] In some embodiments, n is 23 and m is 1, 2, 3, 4, 5, 6, or 7.

[0281] In some embodiments, n is 24 and m is 1, 2, 3, 4, 5, or 6.

[0282] In some embodiments, n is 25 and m is 1, 2, 3, 4, or 5.

[0283] In some embodiments, n is 26 and m is 1, 2, 3, or 4.

[0284] In some embodiments, n is 27 and m is 1, 2, or 3.

[0285] In some embodiments, n is 28 and m is 1 or 2.

[0286] In some embodiments, n is 29. In these embodiments, m is 1.

[0287] In embodiments in which B is an antibody, the antibody is an anti-idiotype (anti-Id) antibody, a camelized antibody, a chimeric antibody, a disulfide-linked Fvs (sdFv), an F(ab') fragment, a Fab fragment, a human antibody, a humanized antibody, a murine antibody, an intrabody, a monoclonal antibody, a bispecific antibody, a multispecific antibody, or a single-chain Fv (scFv), or an epitope-binding fragment thereof.

[0288] In some embodiments where B is an antibody, the antibody is IgG, IgE, IgM, IgD, IgA, or IgY.

[0289] In some embodiments where B is an antibody, the antibody is IgG1, IgG2 (eg, IgG2a, IgG2), IgG3, IgG4, IgA1, or IgA2.

[0290] In some embodiments, where B is an antibody, the antibody binds to: i.Cluster of differentiation (CD) antigens, ii. checkpoint inhibitors, iii. Vascular target antigen, iv. stromal antigens, v. extracellular matrix antigen, vi. circulating antigens, vii. Interleukins, viii. Interleukin receptor, ix. growth factors, x. growth factor receptors, xi. Drugs, xii.Adhesion molecules, xiii. tumor necrosis factor, xiv. Tumor necrosis factor-related apoptosis-inducing ligand receptor, xv. insulin receptor, xvi. receptor tyrosine kinase, xvii. Cytokine receptors, xviii. Tropomyosin receptor kinase, xix. Integrin xx. immunoglobulin, or xxi.Antigens of infectious organisms.

[0291] In some embodiments, where B is an antibody, a -A)" is an ADC.

[0292] In some embodiments, where B is an antibody, the antibody binds to: i. an antigen selected from the group consisting of CD2, CD3, CD4, CD11a, CD19, CD20, CD25 (ILR2), CD30, CD33, CD38, CD52, CD139, CD152 (CTLA-4), CD274 (PD-L1), or CD319 (SLAMF); ii. an antigen selected from the group consisting of PD-1 and PD-L1 (CD274); iii.PSMA, iv. bone marrow stromal antigen 2, v. An antigen selected from the group consisting of CI, CIII, CIV, CV, LM, and FN; vi. Factor IXa or Factor X, vii. An antigen selected from the group consisting of IL-1β, IL-2, IL-5, IL-6, IL-12, IL-17A, and IL-23; viii. An antigen selected from the group consisting of ILR2 (CD25), IL-4RA, IL-5RA, IL-6R, and IL-17RA; ix.VEGFA, x. An antigen selected from the group consisting of EGFR (ErbB1), FGFR, FGFR2, FGFR3, FGFR4, FGFR23, HER2 / neu, HER3, (ErbB3), HER4, PDGFRA, VEGFR1, VEGFR2, VEGFR3, EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB5, EphB6, EphB7, HGFR (c-Met), and IGF2R; xi. digoxin or dabigatran, xii.EpCAM, xiii. TNF-α or TNF-β, xiv.TRAIL-R1 or TRAIL-R2, xv.IR, xvi. An antigen selected from the group consisting of FLT3, CSF-1R, KIT / SCFR, RON (SEA), AXL (UFO), MER, TYRO3, MUSK, RET, TIE1, DDR1, DDR2, ROR1, ROR2, ROS, LTL, ALK, KLG, and RYK; xvii. An antigen selected from the group consisting of type I cytokine receptors, type II cytokine receptors, TNF receptors, CCR4, TGF-β receptors, and activin receptors; xviii. An antigen selected from the group consisting of TRKA, TRKB, and TRKC; xix. An antigen selected from the group consisting of integrin α4, integrin α4β1, and integrin α4β7; xx.IgE, xxi. An antigen selected from the group of infectious organisms consisting of respiratory syncytial virus, Bacillus anthracis, and Clostridium difficile, or xxii. An antigen selected from the group consisting of PSCK9, CGRPR, CRLR, RANKL, GP IIb / IIIa receptor, GD2, BLyS, C5, IRR, and TAG72. Platinum Complex Antineoplastic Agent (PCAN) Components

[0293] A platinum complex comprises a central platinum atom complexed to leaving and non-leaving ligands. A "non-leaving ligand component" can be a single (bidentate or tridentate) non-leaving ligand, or it can be two or three individual non-leaving ligands. A "leaving ligand component" can be one or two individual ligands, or it can be a bidentate leaving ligand.

[0294] Both Pt(II) and Pt(IV) complex anti-neoplastic agents are well known in the art. Agents in commercial use include cisplatin, carboplatin, oxaliplatin, eptaplatin, lobaplatin, nedaplatin, and satraplatin. As illustrated below, these agents act by alkylating DNA at the expense of bonds between one or two leaving ligands (circles) and the central platinum atom. [ka] [ka]

[0295] The platinum-conjugated antineoplastic agent component ("PCAN component") present in the type (II) conjugate molecule contains at least one cannabinoid ligand as either a leaving ligand or an axial ligand. After the agent enters the cell, the cannabinoid ligand is released as a cannabinoid, which can then provide additional therapeutic benefits. These benefits include, but are not limited to, antitumor activity (Massi et al., J. Pharmacol. Exp. Ther. 308, 838-45, e-pub 2003;Guindon & Hohmann, Br. J. Pharmacol. 163, 1447-63, 2011;Borrelli et al., Carcinogenesis 35, 2787-97, 2014; McAllister et al., J. Neuroimmune Pharmacol. 10, 255-67, 2015) and inhibition of tumor progression (Velasco et al., Nat. Rev. Cancer 12, 436-44, 2012).

[0296] As described in more detail below, cannabinoids can be bound to the central platinum atom as a leaving ligand or to the Pt(IV) complex as an axial ligand. In various embodiments, a Pt(II)PCAN component can incorporate a cannabinoid in place of one leaving ligand or in place of each of two leaving ligands. In various embodiments, a Pt(IV)PCAN component can incorporate a cannabinoid in place of one axial ligand or in place of each of two axial ligands. In addition, a Pt(IV)PCAN component can incorporate a cannabinoid in place of one leaving ligand or in place of each of two leaving ligands. Thus, a Pt(II)PCAN component can incorporate and release one or two cannabinoids, and a Pt(IV)PCAN component can incorporate and release one, two, three, or four cannabinoids. In any particular PCAN component incorporating two or more cannabinoids, the cannabinoids can be the same or different.

[0297] In the following description, whenever a leaving ligand, a non-leaving ligand component, or an axial ligand is not specified in an embodiment of a PCAN component, such a ligand may be a ligand of any platinum-complexed anti-neoplastic agent. For example, see Kozubik et al., Metal-Based Drugs, Volume 2008, Article ID 417897, 2008; Johnstone et al., Chem. Rev. 116, 3436-86, 2016;Intini et al., Inorg. Chem. 56, 1483-97, 2017;Neumann et al., ChemMedChem. 2014 Jun;9(6):1150-3, 2014;Tolan et al., Appl. Organometal Chem. 33:e4763, 2019;Jia et al., Molecules 24, 581, 2019;Zhou et al., Chem. Commun. 54, 2788-91, 2018;Li et al., Bioinorganic Chemistry and Applications Volume 2018, Article ID 8276139;Ndagi et al., Drug Design, Development and Therapy 11, 599-616, 2017;Monroe See U.S. Patent No. 7,268,244; U.S. Patent No. 7,759,488; U.S. Patent No. 9,227,991; U.S. Patent No. 9,593,139; U.S. Patent No. 9,771,387; U.S. Patent No. 10,053,478.

[0298] For the sake of simplicity, PCAN component is shown in this disclosure without showing any stereochemistry.However, it is well known that both cannabinoid and platinum complex exhibit various stereochemistry.In this disclosure, unless otherwise indicated, any specific PCAN component structure includes all possible isomers, including the isomers of the cannabinoid ligand that is incorporated into PCAN component.

[0299] Additionally, the use of any particular leaving ligand, non-leaving ligand, or cannabinoid ligand in the following structural examples is for simplicity and is not intended to limit any of the ligands of the disclosed PCAN components. cannabinoid ligands

[0300] As used in this disclosure, a "cannabinoid ligand" is a moiety of a cannabinoid that is present on a PCAN component in place of a leaving or axial ligand. An illustration is provided in the examples below. [ka] [ka]

[0301] The cannabinoid ligand, either a cannabinoid leaving ligand or a cannabinoid axial ligand, can be provided by any cannabinoid containing a hydroxyl group (aromatic or aliphatic) or a carboxyl group that allows the cannabinoid to be attached to the central platinum atom either directly or via a linker. The cannabinoid can be a naturally occurring molecule, either isolated or synthetic, or a modified naturally occurring molecule. See, e.g., Morales et al., Frontiers in See Pharmacology June 2017 review, 1-18.

[0302] Examples of cannabinoids include, but are not limited to, those cannabinoids mentioned above in connection with the cannabinoid component. PCAN components containing cannabinoid leaving ligands

[0303] In some embodiments, the PCAN component comprises (a) a central platinum atom, (b) a non-leaving ligand component, and (c) a leaving ligand component comprising a first cannabinoid leaving ligand attached to the central platinum atom via an oxygen atom of either (i) a first hydroxy group of the first cannabinoid ligand or (ii) a first carboxy group of the first cannabinoid ligand. Non-limiting examples are shown below: * is the linker L pc indicates the attachment point to [ka]

[0304] In some embodiments, the leaving ligand component comprises a second cannabinoid ligand ("second cannabinoid leaving ligand"). The first and second cannabinoid leaving ligands may be the same or different. Non-limiting examples are provided below: * is the linker L pc indicates the attachment point to [ka] [ka]

[0305] In some embodiments, the cannabinoid ligand component is a bidentate cannabinoid ligand (a "bidentate cannabinoid leaving ligand"). Non-limiting examples are shown below: * is the linker L pc indicates the attachment point to [ka]

[0306] In some embodiments, the PCAN component further comprises (d) a first axial ligand and a second axial ligand. Non-limiting examples of these embodiments are shown below, where ● represents an axial ligand: * is the linker L pc indicates the attachment point to [ka] [ka]

[0307] In some embodiments, the cannabinoid leaving ligand is attached to the central platinum atom by a linker, such as: ** is the attachment point for the cannabinoid leaving ligand, ***is the point of attachment to the central platinum atom. In some embodiments, the first cannabinoid leaving ligand is connected to the central platinum atom by a linker. In some embodiments, the first and second cannabinoid leaving ligands are connected to the central platinum atom by linkers. The linkers may be the same or different and are described below.

[0308] In some embodiments, the linker is [ka] and (a)R q , R r , R s , and R t is independently selected from the group consisting of: (i) H, (ii) C1-C6 straight chain or branched alkyl, (iii) C1-C6 straight chain or branched heteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, S, and N, (iv) C3-C6 cycloalkyl, (v) 3-9 membered cycloheteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, N, and S, (vi) phenyl, and (vii) 5-10 membered heteroaromatic having 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; or (b)R q , R r , R s , and R t are independently (i) a C1-C6 straight-chain or branched alkyl or (ii) a C1-C6 straight-chain or branched heteroalkyl having 1, 2, or 3 heteroatoms independently selected from O, S, and N, then R q , R r , R s , and R t Two of these, together with the carbons to which they are bonded, form a 3- to 6-membered ring.

[0309] In some embodiments, the linker is [ka] and ** , *** , R q , R r , R s , and R t is as defined above.

[0310] Non-limiting examples are given below: * is the linker L pc It is the connection point to [ka] [ka] Platinum complex antineoplastic agents containing cannabinoid axial ligands.

[0311] In some embodiments, the PCAN component comprises (a) a central platinum atom, (b) a non-leaving ligand component, (c) a leaving ligand component, and (d) a first axial ligand and a second axial ligand. In these embodiments, at least the first axial ligand is a first cannabinoid ligand ("first cannabinoid axial ligand") bonded to the central platinum atom via an oxygen atom of either (i) a first hydroxy group of the first cannabinoid ligand or (ii) a first carboxy group of the first cannabinoid ligand. In some embodiments, the first and second axial ligands are independently selected cannabinoid ligands bonded to the central platinum atom via an oxygen atom of either (i) a hydroxy group of the first or second cannabinoid ligand or (ii) a carboxy group of the first or second cannabinoid ligand. In some embodiments, one or both of the leaving ligands are cannabinoid leaving ligands as described above. In some embodiments, the leaving ligand component is a bidentate leaving ligand.

[0312] In the following non-limiting examples, for simplicity, each cannabinoid axial ligand is a cannabidiol axial ligand. [ka] each represent a cannabinoid leaving ligand, which may be the same or different; * is the linker L pc It is the connection point to [ka]

[0313] In some embodiments, the axial cannabinoid ligand is attached to the central platinum atom by a linker, such as the linker described below: ** is the attachment point for the cannabinoid axial ligand, *** is the point of attachment to the central platinum atom. In some embodiments, the first cannabinoid axial ligand is connected to the central platinum atom by a linker. In some embodiments, the first and second cannabinoid axial ligands are connected to the central platinum atom by linkers. The linkers may be the same or different and are described below.

[0314] In some embodiments, the linker is [ka] and R q , R r , R s , and R t is as defined above.

[0315] In some embodiments, the linker is [ka] is.

[0316] In some embodiments, the linker is [ka] and R q , R r , Rs , and R t is as defined above.

[0317] In some embodiments, the linker is [ka] is.

[0318] In some embodiments, the linker is [ka] and R q and R r is as defined above.

[0319] In the following non-limiting examples, for simplicity, each cannabinoid axial ligand is a cannabidiol axial ligand. [ka] each represent a cannabinoid leaving ligand, which may be the same or different; * is the linker L pc indicates the attachment point to [ka] [ka] [ka] [ka] [ka] Non-leaving ligand component

[0320] In some embodiments, the non-leaving ligand components are (i) a first non-leaving ligand and a second non-leaving ligand, as illustrated, for example, by cisplatin, carboplatin, and nedaplatin. [ka]

[0321] In some embodiments, the non-leaving ligand components of the PCAN component are a first non-leaving ligand, a second non-leaving ligand, and a third non-leaving ligand, as illustrated, for example, by pyriplatin and phenanthriplatin. [ka]

[0322] In some embodiments, the non-leaving ligand moiety is a bidentate non-leaving ligand, as illustrated by, for example, oxaliplatin, lobaplatin, heptaplatin, and eptaplatin. [ka]

[0323] In some embodiments, the non-leaving ligand component of the PCAN component is, for example, [Pt(diene)Cl] + and [Pt(Et2diene)Cl] + A tridentate ligand is illustrated by: [ka] Modified Ligands

[0324] In some embodiments, non-leaving ligand or axial ligand is modified to include a biologically active moiety, for example, to modify the pharmacokinetic properties of PCAN component, provide targeting function, or provide additional therapeutic effect.Bioactive moieties include, but are not limited to, targeting ligands such as steroid units, carbohydrates, bile acids, peptides (e.g., netropsin, distamycin), and folate units, histone deacetylase inhibitors, p53 agonists, alkylating agents, nonsteroidal anti-inflammatory complexes, and adamantylamines.For example, see Johnstone et al., Chem. Rev. 116, 3436-86, 2016; Li et al., Bioinorganic Chemistry and Applications Volume 2018, Article ID 8276139; Kozubik et al., Metal-Based Drugs, Volume 2008, Article ID 417897. Isomers

[0325] As mentioned above, platinum complexes exhibit various stereoisomers. In some embodiments, the PCAN component is a cis isomer. In some embodiments, the PCAN component is a trans isomer. In some embodiments, the PCAN component is a λ stereoisomer. In some embodiments, the PCAN component is a δ stereoisomer. Type III conjugate molecules

[0326] Type III conjugate molecules have the formula: [ka] (wherein CBN is a cannabinoid component, L c is a cannabinoid moiety linker, B is a target binding moiety, and L a is an active ingredient linker and A is an active ingredient In embodiments where B is an antibody, m is 1-30, n is 0-29, and the sum of m+n is 1-30.

[0327] In some embodiments, the cannabinoid component is provided by cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabidiol, dehydrocannabifuran, cannabifuran, cannabichromanone, or cannabilipsol. In some embodiments, the cannabinoid component is provided by cannabidiol. In some embodiments, the cannabinoid component is provided by cannabigerol.

[0328] In embodiments where m is at least 2, each of the cannabinoid components, which may be the same or different, is independently selected from the group consisting of a linker, L c Each of may be the same or different.

[0329] In embodiments where n is at least 2, each of the active agent components, which may be the same or different, is independently selected from the group consisting of a linker, L a Each of may be the same or different.

[0330] In some embodiments, n is 0 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0331] In some embodiments, n is 1 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29.

[0332] In some embodiments, n is 2 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28.

[0333] In some embodiments, n is 3 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27.

[0334] In some embodiments, n is 4 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

[0335] In some embodiments, n is 5 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

[0336] In some embodiments, n is 6 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24.

[0337] In some embodiments, n is 7 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0338] In some embodiments, n is 8 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.

[0339] In some embodiments, n is 9 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21.

[0340] In some embodiments, n is 10 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0341] In some embodiments, n is 11 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19.

[0342] In some embodiments, n is 12 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.

[0343] In some embodiments, n is 13 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17.

[0344] In some embodiments, n is 14 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0345] In some embodiments, n is 15 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0346] In some embodiments, n is 16 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14.

[0347] In some embodiments, n is 17 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13.

[0348] In some embodiments, n is 18 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0349] In some embodiments, n is 19 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0350] In some embodiments, n is 20 and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0351] In some embodiments, n is 21 and m is 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0352] In some embodiments, n is 22 and m is 1, 2, 3, 4, 5, 6, 7, or 8.

[0353] In some embodiments, n is 23 and m is 1, 2, 3, 4, 5, 6, or 7.

[0354] In some embodiments, n is 24 and m is 1, 2, 3, 4, 5, or 6.

[0355] In some embodiments, n is 25 and m is 1, 2, 3, 4, or 5.

[0356] In some embodiments, n is 26 and m is 1, 2, 3, or 4.

[0357] In some embodiments, n is 27 and m is 1, 2, or 3.

[0358] In some embodiments, n is 28 and m is 1 or 2.

[0359] In some embodiments, n is 29. In these embodiments, m is 1.

[0360] In embodiments in which B is an antibody, the antibody is an anti-idiotype (anti-Id) antibody, a camelized antibody, a chimeric antibody, a disulfide-linked Fvs (sdFv), an F(ab') fragment, a Fab fragment, a human antibody, a humanized antibody, a murine antibody, an intrabody, a monoclonal antibody, a bispecific antibody, a multispecific antibody, or a single-chain Fv (scFv), or an epitope-binding fragment thereof.

[0361] In some embodiments where B is an antibody, the antibody is IgG, IgE, IgM, IgD, IgA, or IgY.

[0362] In some embodiments where B is an antibody, the antibody is IgG1, IgG2 (eg, IgG2a, IgG2), IgG3, IgG4, IgA1, or IgA2.

[0363] In some embodiments, where B is an antibody, the antibody binds to: i.Cluster of differentiation (CD) antigens, ii. checkpoint inhibitors, iii. Vascular target antigen, iv. stromal antigens, v. extracellular matrix antigen, vi. circulating antigens, vii. Interleukins, viii. Interleukin receptor, ix. growth factors, x. growth factor receptors, xi. Drugs, xii.Adhesion molecules, xiii. tumor necrosis factor, xiv. Tumor necrosis factor-related apoptosis-inducing ligand receptor, xv. insulin receptor, xvi. receptor tyrosine kinase, xvii. Cytokine receptors, xviii. Tropomyosin receptor kinase, xix. Integrin xx. immunoglobulin, or xxi.Antigens of infectious organisms.

[0364] In some embodiments, where B is an antibody, a -A)" is an ADC.

[0365] In some embodiments, where B is an antibody, the antibody binds to: i. an antigen selected from the group consisting of CD2, CD3, CD4, CD11a, CD19, CD20, CD25 (ILR2), CD30, CD33, CD38, CD52, CD139, CD152 (CTLA-4), CD274 (PD-L1), or CD319 (SLAMF); ii. an antigen selected from the group consisting of PD-1 and PD-L1 (CD274); iii.PSMA, iv. bone marrow stromal antigen 2, v. An antigen selected from the group consisting of CI, CIII, CIV, CV, LM, and FN; vi. Factor IXa or Factor X, vii. An antigen selected from the group consisting of IL-1β, IL-2, IL-5, IL-6, IL-12, IL-17A, and IL-23; viii. An antigen selected from the group consisting of ILR2 (CD25), IL-4RA, IL-5RA, IL-6R, and IL-17RA; ix.VEGFA, x. An antigen selected from the group consisting of EGFR (ErbB1), FGFR, FGFR2, FGFR3, FGFR4, FGFR23, HER2 / neu, HER3, (ErbB3), HER4, PDGFRA, VEGFR1, VEGFR2, VEGFR3, EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB5, EphB6, EphB7, HGFR (c-Met), and IGF2R; xi. digoxin or dabigatran, xii.EpCAM, xiii. TNF-α or TNF-β, xiv.TRAIL-R1 or TRAIL-R2, xv.IR, xvi. An antigen selected from the group consisting of FLT3, CSF-1R, KIT / SCFR, RON (SEA), AXL (UFO), MER, TYRO3, MUSK, RET, TIE1, DDR1, DDR2, ROR1, ROR2, ROS, LTL, ALK, KLG, and RYK; xvii. An antigen selected from the group consisting of type I cytokine receptors, type II cytokine receptors, TNF receptors, CCR4, TGF-β receptors, and activin receptors; xviii. An antigen selected from the group consisting of TRKA, TRKB, and TRKC; xix. An antigen selected from the group consisting of integrin α4, integrin α4β1, and integrin α4β7; xx.IgE, xxi. An antigen selected from the group of infectious organisms consisting of respiratory syncytial virus, Bacillus anthracis, and Clostridium difficile, or xxii. An antigen selected from the group consisting of PSCK9, CGRPR, CRLR, RANKL, GP IIb / IIIa receptor, GD2, BLyS, C5, IRR, and TAG72. Type III-A conjugate molecules

[0366] Type III-A conjugate molecules have the formula: [ka] (In the formula, CBN, L c , and B are as defined above, and m is at least 1. In embodiments where B is an antibody, m is 1-30.

[0367] In some embodiments, the cannabinoid component is provided by cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabidiol, dehydrocannabifuran, cannabifuran, cannabichromanone, or cannabilipsol. In some embodiments, the cannabinoid component is provided by cannabidiol. In some embodiments, the cannabinoid component is provided by cannabigerol.

[0368] In embodiments where m is at least 2, each of the cannabinoid components may be the same or different and may independently be linked by a linker, L c Each of may be the same or different.

[0369] In embodiments in which B is an antibody, the antibody is an anti-idiotype (anti-Id) antibody, a camelized antibody, a chimeric antibody, a disulfide-linked Fvs (sdFv), an F(ab') fragment, a Fab fragment, a human antibody, a humanized antibody, a murine antibody, an intrabody, a monoclonal antibody, a bispecific antibody, a multispecific antibody, or a single-chain Fv (scFv), or an epitope-binding fragment thereof.

[0370] In some embodiments where B is an antibody, the antibody is IgG, IgE, IgM, IgD, IgA, or IgY.

[0371] In some embodiments where B is an antibody, the antibody is IgG1, IgG2 (eg, IgG2a, IgG2), IgG3, IgG4, IgA1, or IgA2.

[0372] In some embodiments, where B is an antibody, the antibody binds to: i.Cluster of differentiation (CD) antigens, ii. checkpoint inhibitors, iii. Vascular target antigen, iv. stromal antigens, v. extracellular matrix antigen, vi. circulating antigens, vii. Interleukins, viii. Interleukin receptor, ix. growth factors, x. growth factor receptors, xi. Drugs, xii.Adhesion molecules, xiii. tumor necrosis factor, xiv. Tumor necrosis factor-related apoptosis-inducing ligand receptor, xv. insulin receptor, xvi. receptor tyrosine kinase, xvii. Cytokine receptors, xviii. Tropomyosin receptor kinase, xix. Integrin xx. immunoglobulin, or xxi.Antigens of infectious organisms.

[0373] In some embodiments, where B is an antibody, the antibody binds to: i. an antigen selected from the group consisting of CD2, CD3, CD4, CD11a, CD19, CD20, CD25 (ILR2), CD30, CD33, CD38, CD52, CD139, CD152 (CTLA-4), CD274 (PD-L1), or CD319 (SLAMF); ii. an antigen selected from the group consisting of PD-1 and PD-L1 (CD274); iii.PSMA, iv. bone marrow stromal antigen 2, v. An antigen selected from the group consisting of CI, CIII, CIV, CV, LM, and FN; vi. Factor IXa or Factor X, vii. An antigen selected from the group consisting of IL-1β, IL-2, IL-5, IL-6, IL-12, IL-17A, and IL-23; viii. An antigen selected from the group consisting of ILR2 (CD25), IL-4RA, IL-5RA, IL-6R, and IL-17RA; ix.VEGFA, x. An antigen selected from the group consisting of EGFR (ErbB1), FGFR, FGFR2, FGFR3, FGFR4, FGFR23, HER2 / neu, HER3, (ErbB3), HER4, PDGFRA, VEGFR1, VEGFR2, VEGFR3, EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB5, EphB6, EphB7, HGFR (c-Met), and IGF2R; xi. digoxin or dabigatran, xii.EpCAM, xiii. TNF-α or TNF-β, xiv.TRAIL-R1 or TRAIL-R2, xv.IR, xvi. An antigen selected from the group consisting of FLT3, CSF-1R, KIT / SCFR, RON (SEA), AXL (UFO), MER, TYRO3, MUSK, RET, TIE1, DDR1, DDR2, ROR1, ROR2, ROS, LTL, ALK, KLG, and RYK; xvii. An antigen selected from the group consisting of type I cytokine receptors, type II cytokine receptors, TNF receptors, CCR4, TGF-β receptors, and activin receptors; xviii. An antigen selected from the group consisting of TRKA, TRKB, and TRKC; xix. An antigen selected from the group consisting of integrin α4, integrin α4β1, and integrin α4β7; xx.IgE, xxi. An antigen selected from the group of infectious organisms consisting of respiratory syncytial virus, Bacillus anthracis, and Clostridium difficile, or xxii. An antigen selected from the group consisting of PSCK9, CGRPR, CRLR, RANKL, GP IIb / IIIa receptor, GD2, BLyS, C5, IRR, and TAG72. Type III-B conjugate molecules

[0374] Type III-B conjugate molecules have the formula: [ka] (In the formula, CBN, L c , L a , and A are as defined above, and "B-(L a -A)" is an ADC) It has.

[0375] In some embodiments, the cannabinoid component is provided by cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabidiol, dehydrocannabifuran, cannabifuran, cannabichromanone, or cannabilipsol. In some embodiments, the cannabinoid component is provided by cannabidiol. In some embodiments, the cannabinoid component is provided by cannabigerol.

[0376] In some embodiments, the antibody is an anti-idiotype (anti-Id) antibody, a camelized antibody, a chimeric antibody, a disulfide-linked Fvs (sdFv), an F(ab') fragment, a Fab fragment, a human antibody, a humanized antibody, a murine antibody, an intrabody, a monoclonal antibody, a bispecific antibody, a multispecific antibody, or a single-chain Fv (scFv), or an epitope-binding fragment thereof.

[0377] In some embodiments where B is an antibody, the antibody is IgG, IgE, IgM, IgD, IgA, or IgY.

[0378] In some embodiments where B is an antibody, the antibody is IgG1, IgG2 (eg, IgG2a, IgG2), IgG3, IgG4, IgA1, or IgA2.

[0379] In some embodiments, the antibody binds to: i.Cluster of differentiation (CD) antigens, ii. checkpoint inhibitors, iii. Vascular target antigen, iv. stromal antigens, v. extracellular matrix antigen, vi. circulating antigens, vii. Interleukins, viii. Interleukin receptor, ix. growth factors, x. growth factor receptors, xi. Drugs, xii.Adhesion molecules, xiii. tumor necrosis factor, xiv. Tumor necrosis factor-related apoptosis-inducing ligand receptor, xv. insulin receptor, xvi. receptor tyrosine kinase, xvii. Cytokine receptors, xviii. Tropomyosin receptor kinase, xix. Integrin xx. immunoglobulin, or xxi.Antigens of infectious organisms.

[0380] In some embodiments, the antibody binds to: i. an antigen selected from the group consisting of CD2, CD3, CD4, CD11a, CD19, CD20, CD25 (ILR2), CD30, CD33, CD38, CD52, CD139, CD152 (CTLA-4), CD274 (PD-L1), or CD319 (SLAMF); ii. an antigen selected from the group consisting of PD-1 and PD-L1 (CD274); iii.PSMA, iv. bone marrow stromal antigen 2, v. An antigen selected from the group consisting of CI, CIII, CIV, CV, LM, and FN; vi. Factor IXa or Factor X, vii. An antigen selected from the group consisting of IL-1β, IL-2, IL-5, IL-6, IL-12, IL-17A, and IL-23; viii. An antigen selected from the group consisting of ILR2 (CD25), IL-4RA, IL-5RA, IL-6R, and IL-17RA; ix.VEGFA, x. An antigen selected from the group consisting of EGFR (ErbB1), FGFR, FGFR2, FGFR3, FGFR4, FGFR23, HER2 / neu, HER3, (ErbB3), HER4, PDGFRA, VEGFR1, VEGFR2, VEGFR3, EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB5, EphB6, EphB7, HGFR (c-Met), and IGF2R; xi. digoxin or dabigatran, xii.EpCAM, xiii. TNF-α or TNF-β, xiv.TRAIL-R1 or TRAIL-R2, xv.IR, xvi. An antigen selected from the group consisting of FLT3, CSF-1R, KIT / SCFR, RON (SEA), AXL (UFO), MER, TYRO3, MUSK, RET, TIE1, DDR1, DDR2, ROR1, ROR2, ROS, LTL, ALK, KLG, and RYK; xvii. An antigen selected from the group consisting of type I cytokine receptors, type II cytokine receptors, TNF receptors, CCR4, TGF-β receptors, and activin receptors; xviii. An antigen selected from the group consisting of TRKA, TRKB, and TRKC; xix. An antigen selected from the group consisting of integrin α4, integrin α4β1, and integrin α4β7; xx.IgE, xxi. An antigen selected from the group of infectious organisms consisting of respiratory syncytial virus, Bacillus anthracis, and Clostridium difficile, or

[0381] An antigen selected from the group consisting of PSCK9, CGRPR, CRLR, RANKL, GP IIb / IIIa receptor, GD2, BLyS, C5, IRR, and TAG72. Type III-C conjugate molecules

[0382] Type III-C conjugate molecules have the formula: [ka] (In the formula, CBN, L c , B, L a , and A is as defined above) In embodiments where B is an antibody, n is 2-29.

[0383] In some embodiments, the cannabinoid component is provided by cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabidiol, dehydrocannabifuran, cannabifuran, cannabichromanone, or cannabilipsol. In some embodiments, the cannabinoid component is provided by cannabidiol. In some embodiments, the cannabinoid component is provided by cannabigerol.

[0384] In some embodiments in which B is an antibody, the antibody is an anti-idiotype (anti-Id) antibody, a camelized antibody, a chimeric antibody, a disulfide-linked Fvs (sdFv), an F(ab') fragment, a Fab fragment, a human antibody, a humanized antibody, a murine antibody, an intrabody, a monoclonal antibody, a bispecific antibody, a multispecific antibody, or a single-chain Fv (scFv), or an epitope-binding fragment thereof.

[0385] In some embodiments where B is an antibody, the antibody is IgG, IgE, IgM, IgD, IgA, or IgY.

[0386] In some embodiments where B is an antibody, the antibody is IgG1, IgG2 (eg, IgG2a, IgG2), IgG3, IgG4, IgA1, or IgA2.

[0387] In some embodiments, the antibody binds to: i.Cluster of differentiation (CD) antigens, ii. checkpoint inhibitors, iii. Vascular target antigen, iv. stromal antigens, v. extracellular matrix antigen, vi. circulating antigens, vii. Interleukins, viii. Interleukin receptor, ix. growth factors, x. growth factor receptors, xi. Drugs, xii.Adhesion molecules, xiii. tumor necrosis factor, xiv. Tumor necrosis factor-related apoptosis-inducing ligand receptor, xv. insulin receptor, xvi. receptor tyrosine kinase, xvii. Cytokine receptors, xviii. Tropomyosin receptor kinase, xix. Integrin xx. immunoglobulin, or xxi.Antigens of infectious organisms.

[0388] In some embodiments, where B is an antibody, the antibody binds to: i. an antigen selected from the group consisting of CD2, CD3, CD4, CD11a, CD19, CD20, CD25 (ILR2), CD30, CD33, CD38, CD52, CD139, CD152 (CTLA-4), CD274 (PD-L1), or CD319 (SLAMF); ii. an antigen selected from the group consisting of PD-1 and PD-L1 (CD274); iii.PSMA, iv. bone marrow stromal antigen 2, v. An antigen selected from the group consisting of CI, CIII, CIV, CV, LM, and FN; vi. Factor IXa or Factor X, vii. An antigen selected from the group consisting of IL-1β, IL-2, IL-5, IL-6, IL-12, IL-17A, and IL-23; viii. An antigen selected from the group consisting of ILR2 (CD25), IL-4RA, IL-5RA, IL-6R, and IL-17RA; ix.VEGFA, x. An antigen selected from the group consisting of EGFR (ErbB1), FGFR, FGFR2, FGFR3, FGFR4, FGFR23, HER2 / neu, HER3, (ErbB3), HER4, PDGFRA, VEGFR1, VEGFR2, VEGFR3, EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB5, EphB6, EphB7, HGFR (c-Met), and IGF2R; xi. digoxin or dabigatran, xii.EpCAM, xiii. TNF-α or TNF-β, xiv.TRAIL-R1 or TRAIL-R2, xv.IR, xvi. An antigen selected from the group consisting of FLT3, CSF-1R, KIT / SCFR, RON (SEA), AXL (UFO), MER, TYRO3, MUSK, RET, TIE1, DDR1, DDR2, ROR1, ROR2, ROS, LTL, ALK, KLG, and RYK; xvii. An antigen selected from the group consisting of type I cytokine receptors, type II cytokine receptors, TNF receptors, CCR4, TGF-β receptors, and activin receptors; xviii. An antigen selected from the group consisting of TRKA, TRKB, and TRKC; xix. An antigen selected from the group consisting of integrin α4, integrin α4β1, and integrin α4β7; xx.IgE, xxi. An antigen selected from the group of infectious organisms consisting of respiratory syncytial virus, Bacillus anthracis, and Clostridium difficile, or xxii. An antigen selected from the group consisting of PSCK9, CGRPR, CRLR, RANKL, GP IIb / IIIa receptor, GD2, BLyS, C5, IRR, and TAG72. III-D type conjugate molecules

[0389] Type III-D conjugate molecules have the formula: [ka] where CBN1 is the first cannabinoid component and L c1 is a first cannabinoid moiety linker, CBN2 is a second cannabinoid moiety, and L c2 is a second cannabinoid moiety linker, B is a target binding moiety, and L a is an active ingredient linker, A is an active ingredient, and m1 and m2 are each at least 1. In embodiments in which B is an antibody, m1 and m2 are independently 1 to 30, n is 0 to 29, and the sum of m1, m2, and n is 2 to 30.

[0390] In some embodiments where m1 and m2 are each 1, the first and second cannabinoid components are the same. In some embodiments where m1 and m2 are each 1, at least the first and second cannabinoid components are different.

[0391] In some embodiments, the first and second cannabinoid components are independently provided by cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, or cannabilipsol. In some embodiments, the first and second cannabinoid components are independently provided by cannabidiol. In some embodiments, the first and second cannabinoid components are independently provided by cannabigerol.

[0392] In some embodiments, at least the first and second cannabinoid components are the same. In some embodiments, at least the first and second cannabinoid components are different.

[0393] In some embodiments in which B is an antibody, the antibody is an anti-idiotype (anti-Id) antibody, a camelized antibody, a chimeric antibody, a disulfide-linked Fvs (sdFv), an F(ab') fragment, a Fab fragment, a human antibody, a humanized antibody, a murine antibody, an intrabody, a monoclonal antibody, a bispecific antibody, a multispecific antibody, or a single-chain Fv (scFv), or an epitope-binding fragment thereof.

[0394] In some embodiments where B is an antibody, the antibody is IgG, IgE, IgM, IgD, IgA, or IgY.

[0395] In some embodiments where B is an antibody, the antibody is IgG1, IgG2 (eg, IgG2a, IgG2), IgG3, IgG4, IgA1, or IgA2.

[0396] In some embodiments, the antibody binds to: i.Cluster of differentiation (CD) antigens, ii. checkpoint inhibitors, iii. Vascular target antigen, iv. stromal antigens, v. extracellular matrix antigen, vi. circulating antigens, vii. Interleukins, viii. Interleukin receptor, ix. growth factors, x. growth factor receptors, xi. Drugs, xii.Adhesion molecules, xiii. tumor necrosis factor, xiv. Tumor necrosis factor-related apoptosis-inducing ligand receptor, xv. insulin receptor, xvi. receptor tyrosine kinase, xvii. Cytokine receptors, xviii. Tropomyosin receptor kinase, xix. Integrin xx. immunoglobulin, or xxi.Antigens of infectious organisms.

[0397] In some embodiments, where B is an antibody, the antibody binds to: i. an antigen selected from the group consisting of CD2, CD3, CD4, CD11a, CD19, CD20, CD25 (ILR2), CD30, CD33, CD38, CD52, CD139, CD152 (CTLA-4), CD274 (PD-L1), or CD319 (SLAMF); ii. an antigen selected from the group consisting of PD-1 and PD-L1 (CD274); iii.PSMA, iv. bone marrow stromal antigen 2, v. An antigen selected from the group consisting of CI, CIII, CIV, CV, LM, and FN; vi. Factor IXa or Factor X, vii. An antigen selected from the group consisting of IL-1β, IL-2, IL-5, IL-6, IL-12, IL-17A, and IL-23; viii. An antigen selected from the group consisting of ILR2 (CD25), IL-4RA, IL-5RA, IL-6R, and IL-17RA; ix.VEGFA, x. An antigen selected from the group consisting of EGFR (ErbB1), FGFR, FGFR2, FGFR3, FGFR4, FGFR23, HER2 / neu, HER3, (ErbB3), HER4, PDGFRA, VEGFR1, VEGFR2, VEGFR3, EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB5, EphB6, EphB7, HGFR (c-Met), and IGF2R; xi. digoxin or dabigatran, xii.EpCAM, xiii. TNF-α or TNF-β, xiv.TRAIL-R1 or TRAIL-R2, xv.IR, xvi. An antigen selected from the group consisting of FLT3, CSF-1R, KIT / SCFR, RON (SEA), AXL (UFO), MER, TYRO3, MUSK, RET, TIE1, DDR1, DDR2, ROR1, ROR2, ROS, LTL, ALK, KLG, and RYK; xvii. An antigen selected from the group consisting of type I cytokine receptors, type II cytokine receptors, TNF receptors, CCR4, TGF-β receptors, and activin receptors; xviii. An antigen selected from the group consisting of TRKA, TRKB, and TRKC; xix. An antigen selected from the group consisting of integrin α4, integrin α4β1, and integrin α4β7; xx.IgE, xxi. An antigen selected from the group of infectious organisms consisting of respiratory syncytial virus, Bacillus anthracis, and Clostridium difficile, or xxii. An antigen selected from the group consisting of PSCK9, CGRPR, CRLR, RANKL, GP IIb / IIIa receptor, GD2, BLyS, C5, IRR, and TAG72.

[0398] In some embodiments, L c1 and L c2 are the same linker. c1 and L c2 are different linkers. Synthesis method

[0399] The disclosed conjugate molecules can be synthesized using methods well known in the art. Exemplary methods for synthesizing cannabinoid conjugate components are provided in the Examples below. pharmaceutically acceptable salts

[0400] The disclosed conjugate molecules can form salts. A "pharmaceutically acceptable salt" is a salt that retains at least some of the biological activity of the free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. These salts include, for example, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc., and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion, or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 Jan; 66(1):1-19. Pharmaceutical Composition

[0401] The pharmaceutical composition comprises one or more of the above-mentioned conjugate molecules, or a pharmaceutically acceptable salt of the conjugate molecule, together with a pharmaceutically acceptable vehicle, such as water or an aqueous buffer solution. The pharmaceutical composition can be provided as a lyophilized powder containing, for example, sodium chloride and mannitol, to be reconstituted using water for injection.

[0402] In some embodiments, the pharmaceutical composition comprises both cis and trans isomers. In some embodiments, the pharmaceutical composition comprises substantially only the cis isomer or substantially only the trans isomer. A pharmaceutical composition comprises "substantially only" the cis isomer or substantially only the trans isomer if the relevant isomer is below detectable levels as measured by conventional analytical methods such as spectroscopy or chromatography.

[0403] In some embodiments, the pharmaceutical composition comprises both the λ and δ stereoisomers. In some embodiments, the pharmaceutical composition comprises substantially only the λ stereoisomer, or substantially only the δ stereoisomer. A pharmaceutical composition comprises "substantially only" the λ stereoisomer, or substantially only the δ stereoisomer, if the relevant stereoisomer is below detectable levels as measured by conventional analytical methods such as spectroscopy or chromatography. Delivery Vehicle

[0404] In some embodiments, the pharmaceutical composition comprises a delivery vehicle for the conjugate molecule.Delivery vehicles include, but are not limited to, carbon nanotubes, carbon nanoparticles, PEGylated nanosized graphene oxide, gold nanoparticles, nanosized metal-organic frameworks, nanoparticles containing polysiloxane, polymeric micelle nanoparticles, block copolymer micelle nanoparticles, and liposomes.See, for example, Johnstone et al., Chem. Rev. 116, 3436-86, 2016. Treatment method

[0405] The disclosed conjugate molecules have a variety of therapeutic uses depending on which therapeutic moiety(s) are included in the conjugate molecule. As used in this disclosure, "treating" means reducing or inhibiting the progression of one or more symptoms, e.g., inflammation or pain, of the disorder or disease for which the conjugate molecule is administered.

[0406] Suitable administration routes include, but are not limited to, intravenous, intraperitoneal, intratumoral, intraarterial, intraarterial with blood-brain barrier disruption, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, urethral, ​​intranasal, subcutaneous, and intrapleural.The dosage of conjugate molecule can be based on the dosage typically used for various components of conjugate molecule (e.g., platinum-conjugated anti-neoplastic agent component, β-lactam antibiotic).These dosages are well known in the art. 1. Hyperproliferative disorders

[0407] The conjugated molecules can be used to treat hyperproliferative disorders, including cancer. For example, treating cancer can include inhibiting cancer progression, for example, by reducing the proliferation of neoplastic or pre-neoplastic cells, destroying neoplastic or pre-neoplastic cells, or inhibiting metastasis, or reducing tumor size. Cancers that can be treated include, but are not limited to, multiple myeloma (systemic light chain amyloidosis and Waldenstrom's macroglobulinemia / lymphoplasmocytic leukemia), leukemia, and leukemia-associated lymphoma. myelodysplastic syndromes, myeloproliferative neoplasms, gastrointestinal malignancies (e.g., esophageal, gastroesophageal junction, gallbladder, stomach, colon, pancreas, hepatobiliary, anal, and rectal cancer), leukemias (e.g., acute myeloid, acute myelogenous, chronic myeloid, chronic myeloid, myelogenous), acute lymphocytic, acute lymphoblastic, chronic lymphocytic, and hairy cell leukemia), Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., B-cell lymphoma, hairy cell leukemia, primary cutaneous B-cell lymphoma, and T-cell lymphoma), lung cancer (e.g., small cell and non-small cell lung cancer), basal cell carcinoma, plasmacytoma, breast cancer, bladder cancer, kidney cancer, neuroendocrine tumors, adrenal tumors, bone cancer, soft tissue sarcoma, head and neck cancer, thymoma, thymic carcinoma, cervical cancer, uterine cancer, ovarian cancer (e.g., fallopian tube and primary peritoneal carcinoma) ), vaginal cancer, vulvar cancer, penile cancer, testicular cancer, prostate cancer, melanoma (e.g., cutaneous and uveal melanoma), non-melanoma skin cancer (e.g., basal cell skin cancer, dermatofibrosarcoma protuberans, Merkel cell carcinoma, and squamous cell skin cancer), malignant pleural mesothelioma, central nervous system (CNS) cancer (e.g., astrocytoma, oligodendroglioma, anaplastic glioma, glioblastoma, intracranial ependymoma, spinal ependymoma, medulloblastoma, CNS lymphoma, spinal cord tumor, meningioma, brain metastasis, leptomeningeal metastasis, metastatic spinal tumor), and occult primary cancer (i.e., cancer of unknown cause).

[0408] The conjugated molecules described in this disclosure can be administered in combination with one or more other cancer therapies, such as chemotherapy, immunotherapy, tumor treating fields (TTFs, e.g., the OPTUNE® System), radiation therapy (XRT), and other therapies (e.g., hormones, autologous bone marrow transplants, autologous stem cell transfusions). "In combination with" includes administration with, before, or after one or more other cancer therapies.

[0409] Chemotherapy includes, but is not limited to, FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, irinotecan), FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan, oxaliplatin), irinotecan (e.g., CAMPTOSAR®), capecitabine (e.g., XELODA®), gemcitabine (e.g., GEMZAR®), paclitaxel ( For example, ABRAXANE®), dexamethasone, lenalidomide (for example, REVLIMID®), pomalidomide (for example, POMALYST®), cyclophosphamide, regorafenib (for example, STIVARGA®), erlotinib (for example, TARCEVA®), ixazomib (for example, NINLARO®), bevacizumab (for example, AVASTIN®), bortezomib (for example, VELCADE®, NEOM®), IB®), cetuximab (e.g., ERBITUX®), daratumumab (e.g., DARZALEX®), elotuzumab (e.g., EMPLICITI™), carfilzomib (e.g., KYPROLIS®), palbociclib (e.g., IBRANCE®), fulvestrant (e.g., FASLODEX®), carboplatin, cisplatin, taxol, nab-paclitaxel (e.g., ABRAX®), ANE®), 5-fluorouracil, RVD (lenalidomide, bortezomib, dexamethasone), pomalidomide (e.g., POMALYST®), temozolomide (e.g., TEMODAR®), pCV (procarbazine, lomustine, vincristine), methotrexate (e.g., TREXALL®, RASUVO®, XATMEP®), carmustine (e.g., BICNU®, GLIADEL®),WAFER®), etoposide (e.g., ETOPOPHOS®, TOPOSAR®), sunitinib (e.g., SUTENT®), everolimus (e.g., ZORTRESS®, AFINITOR®), rituximab (e.g., RITUXAN®, MABTHERA®), r-MPV (vincristine, procarbazine, rituximab), cytarabine (e.g., DEPOCYT®, CYTOSAR-U®), thiotepa (e.g., TEPADINA®), busulfan (e.g., BUSULFEX®, MYLERAN®), TBC (thiotepa, busulfan, cyclophosphamide), ibrutinib (e.g., IMBRUVICA®), topotecan (e.g., HYCAMTIN®), pemetrexed (e.g., A LIMTA®), vemurafenib (e.g., ZELBORAF®), cobimetinib (e.g., COTELLIC®), dabrafenib (e.g., TAFINLAR®), trametinib (e.g., MEKINIST®), alectinib (e.g., ALECENSA®), lapatinib (e.g., TYKERB®), neratinib (e.g., NERLYNX®), ceritinib (e.g., ZYKADIA®), brigatinib (e.g., ALUNBRIG®), afatinib (e.g., GILOTRIF®, GIOTRIF®), gefitinib (e.g., IRESSA®), osimertinib (e.g., TAGRISSO®, TAGRIX®), and crizotinib (e.g., XALKORI®).

[0410] Immunotherapies include, but are not limited to, checkpoint inhibitors, including monoclonal antibodies such as ipilimumab (e.g., YERVOY®), nivolumab (e.g., OPDIVO®), pembrolizumab (e.g., KEYTRUDA®), cytokines, cancer vaccines, and adoptive cell transfer.

[0411] In some embodiments, one or more of the conjugated molecules described above are administered to a patient with cancer, including any of the cancers listed above. In some embodiments, the patient has colon cancer, rectal cancer, pancreatic cancer, multiple myeloma, or glioblastoma multiforme, as described below, and the conjugated molecule(s) are administered in combination with an additional therapy appropriate for the particular cancer.

[0412] Conjugated molecules with a hydroxyurea moiety can be used to treat chronic myeloid leukemia, ovarian cancer, and squamous cell carcinoma of the head and neck, as well as to reduce the incidence of pain and the need for blood transfusions in patients with sickle cell anemia.

[0413] Conjugated molecules having a temozolomide moiety can be used to treat brain cancers (eg, astrocytoma, glioblastoma multiforme).

[0414] Conjugated molecules with physostigmine-based carbamate moieties can be used to treat glaucoma and reverse central or peripheral anticholinergic disorders. Conjugate molecules having a rivastigmine-based carbamate moiety can be used to treat confusion or dementia, for example, in patients with Alzheimer's disease or Parkinson's disease.

[0415] The disclosed conjugate molecules can be used to treat these and other disorders in the same way as the therapeutic component of the molecule, and these methods are well known.For example, conjugate molecules containing entecavir, emtricitabine, daclatasvir, atazanavir, didanosine, and / or stavudine can be used to treat viral infections, conjugate molecules containing diclofenac or celecoxib components can be used as anti-inflammatory agents, conjugate molecules containing warfarin components can be used as anticoagulants, and conjugate molecules containing pravastatin components can be used to treat cardiovascular disorders.However, the advantage of conjugate molecules is that cannabinoids can be delivered directly to the therapeutic agent's site of action, where the released cannabinoids can provide additional therapeutic benefits.The therapeutic and potential benefits of cannabinoids are well known. For example, see Dzierzanowski, Cancers 11, 129-41, 2019 (Oncology and Palliative Care); Urits et al., Pain Ther. 8, 41-51, 2019 (Pain); Hillen et al., Ther. Adv. Drug Safety 10, 1-23 2019 (Neuropsychiatric symptoms of dementia). 2. Additional Therapeutic Uses of Type IC Conjugate Molecules

[0416] Type IC conjugate molecules have a variety of therapeutic uses depending on which β-lactam antibiotic moiety(s) are included in the conjugate molecule.

[0417] For example, bacterial infections (including chronic lung infections in cystic fibrosis; see e.g., Kirkby et al., Core Evidence 6, 59-66, In addition to treating various conditions (e.g., US2011), β-lactam antibiotics have been proposed for the treatment of type 1 diabetes (e.g., US2014 / 0234282, US2007 / 0060561), the treatment of cancer (e.g., US2006 / 0160787), neuroprotective compounds (e.g., US2007 / 0238717), as proteasome inhibitors for the treatment of, for example, Alzheimer's disease, cachexia and muscle-wasting diseases, allergies, and inflammation (in connection with rheumatoid arthritis, scleroderma, rheumatic fever, inflammatory bowel disease, myasthenia gravis, multiple sclerosis, Guillain-Barré syndrome, ocular conjunctiva, systemic lupus erythematosus, encephalitis, adult respiratory distress syndrome, psoriasis, emphysema, and muscular dystrophy (e.g., US2007 / 0060561).

[0418] The disclosed conjugate molecules can be used to treat these and other disorders in the same way as using the β-lactam antibiotic component of the molecule, and these methods are well known. However, the advantage of the conjugate molecules is that the cannabinoid can be delivered directly to the site of action, which can provide additional therapeutic benefits. The therapeutic benefits and potential benefits of cannabinoids are well known. For example, Dzierzanowski, Cancers 11, 129-41, 2019 (Oncology and Palliative Care); Urits et al., Pain Ther. 8, 41-51, 2019 (Pain );See Hillen et al., Ther. Adv. Drug Safety 10, 1-23 2019 (Neuropsychiatric symptoms of dementia).

[0419] Additionally, C. sativa extracts have in vitro microbicidal activity against Gram-positive bacteria (e.g., Bacillus subtilis, Bacillus pumilus, Staphylococcus aureus, Micrococcus flavus, Clostridium sporogenes, Enterococcus faecium, and Streptococcus salivarius), Gram-negative bacteria (e.g., Proteus vulgaris, Bordetella bronchiseptica, Pectobacterium carotovorum, and Pseudomonas savastanoi), and fungi (e.g., Aspergillus niger). See Elphick, Gene 399, 65-71, 2007; Wasim et al., J. Pharm. Sci. 8, 29-38, 1995; Nissen et al., Fitoterapia 81, 413-19, 2010; and Hernandez-Cervantes et al., Neuroimmunomodulation 24, 183-99, 2017. See also Appendino et al., J. Nat. Prod. 71, 1427-30, 2008. [Example]

[0420] Example β-lactam antibiotic cannabinoid conjugate component The following synthetic methods are general. They can be used to generate these examples or related β-lactam antibiotic cannabinoid conjugate components using alternative building blocks, intermediates, or reagents. Alternative reagent systems and conditions can be used to achieve the desired transformations. Alternative protecting group strategies can be used. Standard purification techniques can be used at any stage of the synthesis. For simplicity, cannabidiol (CBD) is used as a representative cannabinoid. Example 1 Ether-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0421] Cephem ether-linked β-lactam antibiotic cannabinoid conjugate components are synthesized according to the following scheme. CAS numbers for the two key building blocks are shown. Reaction conditions follow standard conditions for amine acylation in the first step to attach to the cephem side chain, alkylation of the phenolic group of the cannabinoid in the second step with the optional use of a catalyst or enhancer such as NaI, followed by standard removal of the p-methoxybenzyl protecting group in the third step to yield the product. Di-alkylated products can also be obtained. [ka] Carbacephem conjugates

[0422] The carbacephem ether linked β-lactam antibiotic cannabinoid conjugate components are synthesized according to the following scheme: The common starting material [177472-75-2] is reported in racemic form as [54296-34-3] (Journal of The iodide intermediate is synthesized after the introduction of the selected side chain using a previously reported process (WO 96 / 04247). Alkylation of CBD with iodide, followed by deprotection, both steps carried out under standard conditions, yields the desired product. [ka] Penem conjugates

[0423] The penem ether-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [145354-22-9] is prepared as reported (Journal of Organic Chemistry, 58(1), 272-4; 1993), but is reacted with CBD under standard alkylation conditions. The silyl ether TBS protecting group is then removed, followed by deallylation under known conditions to give the desired product. [ka] Carbapenem conjugates

[0424] The carbapenem ether-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [136324-03-3] is reacted with CBD under standard alkylation conditions. The silyl ether TES protecting group is then removed, followed by removal of the p-methoxybenzyl ester protecting group under known conditions, to yield the desired product. [ka] Example 2 Carbonate-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0425] Cephem carbonate-linked β-lactam antibiotic cannabinoid conjugate components are synthesized according to the following scheme: The starting material is acylated with the selected side chain, and the acid is then protected as previously described (WO 96 / 04247). The resulting alcohol is then treated with phosgene, and the adduct reacts with CBD in the presence of base to form a carbonate-linked intermediate, which is then deprotected with acid to yield the desired product. [ka] Carbacephem conjugates

[0426] Carbacephem carbonate-linked β-lactam antibiotic cannabinoid conjugate components are synthesized according to the following scheme: The starting material is acylated with the selected side chain, and the acid is then protected as previously described (WO 96 / 04247). The resulting alcohol is then treated with phosgene, and the adduct reacts with CBD in the presence of base to form a carbonate-linked intermediate, which is then deprotected with acid to yield the desired product. [ka] Penem conjugates

[0427] The penem carbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [88585-78-8] is prepared as reported (U.S. Pat. No. 4,631,150), but is reacted with phosgene, and the intermediate is reacted with CBD under standard basic conditions. The silyl ether TBS protecting group is then removed, followed by deallylation under known conditions to give the desired product. [ka] Carbapenem conjugates

[0428] The carbapenem carbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [118990-99-1] is prepared as reported (Journal of Antibiotics (1988), 41(6), 780-7), but is reacted with phosgene, and the intermediate is reacted with CBD under standard basic conditions. Deallylation under known conditions gives the desired product. [ka] Example 3 Thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0429] Cephem thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate components are synthesized according to the following scheme: The starting material is acylated with the selected side chain, and the acid is then protected as previously described (WO 96 / 04247). The resulting alcohol is then treated with thiophosgene, and the adduct reacts with CBD in the presence of base to form the thiocarbonate product, which is then deprotected with acid to yield the desired product. [ka] Carbacephem conjugates

[0430] Carbacephem thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate components are synthesized according to the following scheme: The starting material is acylated with the selected side chain, and the acid is then protected as previously described (WO 96 / 04247). The resulting alcohol is then treated with thiophosgene, and the adduct reacts with CBD in the presence of base to form the thiocarbonate product, which is then deprotected with acid to yield the desired product. [ka] Penem conjugates

[0431] The penem thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [88585-78-8] is prepared as reported (U.S. Pat. No. 4,631,150), but is reacted with thiophosgene, and the intermediate is reacted with CBD under standard basic conditions. The silyl ether TBS protecting group is then removed, followed by deallylation under known conditions to give the desired product. [ka] Carbapenem conjugates

[0432] The carbapenem thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [118990-99-1] is prepared as reported (Journal of Antibiotics (1988), 41(6), 780-7), but is reacted with thiophosgene, and the intermediate is reacted with CBD under standard basic conditions. Deallylation under known conditions gives the desired product. [ka] Example 4 Carbamate-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0433] Cephem carbamate-linked β-lactam antibiotic cannabinoid conjugate components are synthesized according to the following scheme: The starting material [6187-87-7] is acylated at the selected side chain. The acetate group is then converted to the iodide with TMS-I as reported for similar molecules (WO 96 / 04247). The iodide is then converted to the azide, which is then reduced to the amine. Both steps are carried out under standard conditions. Reaction of the amine with phosgene, followed by addition of CBD, forms the carbamate bond. Deprotection of the t-butyl ester under standard conditions affords the desired product. [ka] Carbacephem conjugates

[0434] The carbacephem carbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [177472-75-2] has been previously described (WO96 / 04247; Journal of the American Chemical Society (1974), 96(24), 7584). It is then reacted with 177472-75-2 under established isobutylene conditions. The amine is converted to the t-butyl ester with HCl and then acylated with the side chain of choice. The acetate group is then converted to the iodide with TMS-I as reported for similar molecules (WO 96 / 04247). The iodide is then converted to the azide, which is then reduced to the amine. Both steps are carried out under standard conditions. Reaction of the amine with phosgene followed by addition of CBD forms the carbamate bond. Deprotection of the t-butyl ester under standard conditions gives the desired product. [ka] Penem conjugates

[0435] The penem carbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [83572-65-0] has been previously described (Journal of Antibiotics (1982), 35(9), 1248-51). It is converted to a t-butyl ester under established isobutylene conditions, and the hydroxy group is then protected as a TBDMS ether. The acetate group is then converted to an iodide with TMS-I, as reported for similar molecules (WO 96 / 04247). The iodide is then converted to an azide, which is then reduced to an amine. Both steps are carried out under standard conditions. Reaction of the amine with phosgene, followed by addition of CBD, forms the carbamate bond. Removal of the TBDMS ether and t-butyl ester protecting groups under standard conditions affords the desired product. [ka] Carbapenem conjugates

[0436] The carbapenem carbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [112064-40-1] has been previously described (Journal of Antibiotics (1988), 41(6), 780-7). It is converted to a t-butyl ester under established isobutylene conditions, and the hydroxy group is then protected as a TBDMS ether. The acetate group is then converted to an iodide with TMS-I, as reported for similar molecules (WO 96 / 04247). The iodide is then converted to an azide, which is then reduced to an amine. Both steps are carried out under standard conditions. Reaction of the amine with phosgene, followed by addition of CBD, forms the carbamate bond. Removal of the TBDMS ether and t-butyl ester protecting groups under standard conditions affords the desired product. [ka] Example 5 Thiocarbamate-linked β-lactam antibiotics as components of cannabinoid conjugates Cephem conjugates

[0437] The cephem thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [6187-87-7] is acylated at the selected side chain. The acetate group is then converted to the iodide with TMS-I as reported for similar molecules (WO 96 / 04247). The iodide is then converted to the azide, which is then reduced to the amine. Both steps are carried out under standard conditions. Reaction of the amine with thiophosgene, followed by addition of CBD, forms the thiocarbamate linkage. Deprotection of the t-butyl ester under standard conditions affords the desired product. [ka] Carbacephem conjugates

[0438] The carbacephem thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [177472-75-2] has been previously described (WO 96 / 04247; Journal of the American Chemical Society (1974), 96(24), 7584). The thiocarbamate bond is formed by reaction of the amine with thiophosgene followed by addition of CBD. Deprotection of the t-butyl ester under standard conditions affords the desired product. [ka] Penem conjugates

[0439] The penem thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [83572-65-0] has been previously described (Journal of Antibiotics (1982), 35(9), 1248-51). It is converted to a t-butyl ester under established isobutylene conditions, and the hydroxy group is then protected as a TBDMS ether. The acetate group is then converted to an iodide with TMS-I, as reported for similar molecules (WO 96 / 04247). The iodide is then converted to an azide, which is then reduced to an amine. Both steps are carried out under standard conditions. Reaction of the amine with thiophosgene, followed by addition of CBD, forms the thiocarbamate bond. Removal of the TBDMS ether and t-butyl ester protecting groups under standard conditions affords the desired product. [ka] Carbapenem conjugates

[0440] The carbapenem thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [112064-40-1] has been previously described (Journal of Antibiotics (1988), 41(6), 780-7). It is converted to a t-butyl ester under established isobutylene conditions, and the hydroxy group is then protected as a TBDMS ether. The acetate group is then converted to an iodide with TMS-I, as reported for similar molecules (WO 96 / 04247). The iodide is then converted to an azide, which is then reduced to an amine. Both steps are carried out under standard conditions. Reaction of the amine with thiophosgene, followed by addition of CBD, forms the thiocarbamate bond. Removal of the TBDMS ether and t-butyl ester protecting groups under standard conditions affords the desired product. [ka] Example 6 Propenylamine-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0441] The cephempropenylamine-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [6187-87-7] is acylated at the selected side chain. The acetate group is then converted to the iodide with TMS-I, as reported for similar molecules (WO 96 / 04247). The iodide is then converted to the azide, which is then reduced to the amine. Both steps are carried out under standard conditions. Condensation of the amine with 3-halopropanal (3-bromo, 65032-54-4) generates a bromopropenyl intermediate, which is then used to alkylate the cannabinoid (in this case, CBD) under standard basic conditions. Removal of the t-butyl ester protecting group under acidic conditions yields the desired product. [ka] Carbacephem conjugates

[0442] The carbacephempropenylamine-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [177472-75-2] is protected as the t-butyl ester under standard isobutylene conditions and then acylated with the selected side chain. The acetate group is then converted to the iodide with TMS-I, as reported for similar molecules (WO 96 / 04247). The iodide is then converted to the azide, which is then reduced to the amine. Both steps are carried out under standard conditions. Condensation of the amine with 3-halopropanal (3-bromo, 65032-54-4) generates a bromopropenyl intermediate, which is then used to alkylate the cannabinoid (CBD) under standard basic conditions. Removal of the t-butyl ester protecting group under acidic conditions yields the desired product. [ka] Penem conjugates

[0443] The penempropenylamine-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [83572-65-0] is protected as the t-butyl ester under standard isobutylene conditions, and the secondary alcohol is then protected as the TBDMS ether. The acetate group is then converted to the iodide with TMS-I, as reported for similar molecules (WO 96 / 04247). The iodide is then converted to the azide, which is then reduced to the amine. Both steps are carried out under standard conditions. Condensation of the amine with 3-halopropanal (3-bromo, 65032-54-4) generates a bromopropenyl intermediate, which is then used to alkylate the cannabinoid (CBD) under standard basic conditions. Removal of the TBDMS ether and t-butyl ester protecting groups under standard conditions affords the desired product. [ka] Carbapenem conjugates

[0444] The carbapenem propenylamine-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [112064-40-1] is protected as the t-butyl ester under standard isobutylene conditions, and the secondary alcohol is then protected as the TBDMS ether. The acetate group is then converted to the iodide with TMS-I, as reported for similar molecules (WO 96 / 04247). The iodide is then converted to the azide, which is then reduced to the amine. Both steps are carried out under standard conditions. Condensation of the amine with 3-halopropanal (3-bromo, 65032-54-4) generates a bromopropenyl intermediate, which is then used to alkylate the cannabinoid (CBD) under standard basic conditions. Removal of the TBDMS ether and t-butyl ester protecting groups under standard conditions affords the desired product. [ka] Example 7 Alkene-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0445] The cephem alkene-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [130516-07-3] has been previously reported (Journal of Organic Chemistry (1993), 58(8), 2296-2301). This is reacted with an organostannane under conditions described for related molecules (WO 99 / 62906) to give the allylic alcohol intermediate. The alcohol is then activated as the mesylate and reacted with a cannabinoid (CBD) under basic conditions to produce the alkene-linked intermediate. Removal of the DPM protecting group under standard conditions gives the desired product. [ka] Carbacephem conjugates

[0446] The carbacephem alkene-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [123078-32-0] has been previously reported (Journal of Organic Chemistry, 54(24), 5828-30; 1989). It is then subjected to organic cleavage under conditions described for related molecules (WO99 / 62906). Reaction with a stannane affords the allylic alcohol intermediate. The alcohol is then activated as the mesylate and reacted with a cannabinoid (CBD) under basic conditions to produce the alkene-linked intermediate. Removal of the DPM protecting group under standard conditions affords the desired product. [ka] Penem conjugates

[0447] The penem alkene-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [127941-62-2] has been previously reported (U.S. Pat. No. 4,895,940). It is converted to an allylic alcohol intermediate as previously described for similar molecules (WO 99 / 62906). The alcohol is then activated as the mesylate and reacted with a cannabinoid (CBD) under basic conditions to produce the alkene-linked intermediate. Removal of the TBDMS ether and trimethylsilylethyl ester protecting groups is achieved under standard conditions with an excess of TBAF to give the desired product. [ka] Carbapenem conjugates

[0448] The carbapenem alkene-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [165817-82-3] has been previously described (WO 99 / 62906) along with its conversion to an allylic alcohol intermediate. The alcohol is then activated as a mesylate and reacted with a cannabinoid (CBD) under basic conditions to produce the alkene-linked intermediate. Removal of the TES ether and PNB ester groups under standard conditions produces the desired product. [ka] Example 8 Propenyl carbonate-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0449] The cephempropenyl carbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [130516-07-3] has been previously reported (Journal of Organic Chemistry (1993), 58(8), 2296-2301), which has been previously described for similar molecules (WO99 / 629 The resulting intermediate is then reacted with cannabinoid (CBD) under basic conditions to form the carbonate group. Removal of the DPM ester protecting group under standard acidic conditions yields the desired product. [ka] Carbacephem conjugates

[0450] The carbacephem propenyl carbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [123078-32-0] has been previously reported (Journal of Organic Chemistry (1993), 58(8), 2296-2301). This is similar to the method previously described for similar molecules (WO99 / The resulting intermediate is converted to an allylic alcohol intermediate via standard procedures (see 62906). This alcohol is reacted with phosgene, and the resulting intermediate is reacted with cannabinoid (CBD) under basic conditions to form a carbonate group. Removal of the DPM ester protecting group under standard acidic conditions yields the desired product. [ka] Penem conjugates

[0451] The penempropenyl carbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [127941-62-2] has been previously reported (U.S. Pat. No. 4,895,940). It is converted to an allylic alcohol intermediate as previously described for similar molecules (WO 99 / 62906). The alcohol is then reacted with phosgene, and the resulting intermediate is reacted with a cannabinoid (CBD) under basic conditions to form the carbonate group. Removal of the TBDMS ether and trimethylsilylethyl ester protecting groups is achieved under standard conditions with an excess of TBAF to give the desired product. [ka] Carbapenem conjugates

[0452] The carbapenem propenyl carbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [165817-82-3] has been previously described (WO 99 / 62906) along with its conversion to an allylic alcohol intermediate. The alcohol is then reacted with phosgene, and the resulting intermediate is reacted with a cannabinoid (CBD) under basic conditions to form the carbonate group. Removal of the TES ether and PNB ester groups under standard conditions produces the desired product. [ka] Example 9 Propenylthiocarbonate-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0453] The cephempropenyl thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [130516-07-3] has been previously reported (Journal of Organic Chemistry (1993), 58(8), 2296-2301). This is similar to the method previously described for similar molecules (WO99 / 6 The allylic alcohol intermediate is converted to aryl alcohol via the procedure described in (2906). This alcohol is reacted with thiophosgene, and the resulting intermediate is reacted with cannabinoid (CBD) under basic conditions to form the thiocarbonate group. Removal of the DPM ester protecting group under standard acidic conditions yields the desired product. [ka] Carbacephem conjugates

[0454] The carbacephempropenyl thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [12078-32-0] has been previously reported (Journal of Organic Chemistry (1993), 58(8), 2296-2301), which has been previously described for similar molecules (WO99 The resulting intermediate is then reacted with cannabinoid (CBD) under basic conditions to form the thiocarbonate group. Removal of the DPM ester protecting group under standard acidic conditions yields the desired product. [ka] Penem conjugates

[0455] The penempropenyl thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [127941-62-2] has been previously reported (U.S. Pat. No. 4,895,940). It is converted to an allylic alcohol intermediate as previously described for similar molecules (WO 99 / 62906). The alcohol is then reacted with thiophosgene, and the resulting intermediate is reacted with a cannabinoid (CBD) under basic conditions to form the thiocarbonate group. Removal of the TBDMS ether and trimethylsilylethyl ester protecting groups is achieved under standard conditions with an excess of TBAF to give the desired product. [ka] Carbapenem conjugates

[0456] The carbapenem propenyl thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [165817-82-3] has been previously described (WO 99 / 62906) along with its conversion to an allylic alcohol intermediate. The alcohol is then reacted with thiophosgene, and the resulting intermediate is reacted with a cannabinoid (CBD) under basic conditions to form the thiocarbonate group. Removal of the TES ether and PNB ester groups under standard conditions yields the desired product. [ka] Example 10 Propenylcarbamate-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0457] The cephempropenyl carbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [57562-43-3] has been reported (CN103588788A 20140219). This was converted to the enol triflate under standard conditions, which was then catalyzed with a BOC-protected aminoorganostannane [139111-44-7] (for use in the analogous cephem triflate: Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4635-4638), and then The BOC is removed under standard conditions to give a propenylamine intermediate. This amine is reacted with phosgene, and the resulting intermediate is reacted with a cannabinoid (CBD) under basic conditions to form a carbamate group. Removal of the PNB ester group under standard conditions yields the desired product. [ka] Carbacephem conjugates

[0458] The carbacephem propenyl carbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [119892-46-5] (WO2010 / 030810 and references cited therein) is converted under standard conditions to the enol triflate, which is reacted with a BOC-protected aminoorganostannane [139111-44-7] (used in the analogous cephem triflate: Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4635-4638). Subsequent removal of the BOC under standard conditions gives the propenylamine intermediate. This amine is reacted with phosgene, and the resulting intermediate is reacted with cannabinoid (CBD) under basic conditions to form the carbamate group. Removal of the PNB ester group under standard conditions yields the desired product. [ka] Penem conjugates

[0459] The penempropenyl carbamate-linked β-lactam antibiotic cannabinoid conjugate component was synthesized according to the following scheme: The starting material [127941-62-2] was previously reported (U.S. Pat. No. 4,895,940). The BOC-protected aminoorganostannane [139111-44-7] (used in the analogous cephem triflate: Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4635-4638) and Reaction of the amine with phosgene followed by removal of the BOC group under standard conditions yields the propenylamine intermediate. This amine is reacted with phosgene, and the resulting intermediate is reacted with cannabinoid (CBD) under basic conditions to form the carbamate group. Removal of the TES ether and trimethylsilylethyl ester groups under standard conditions yields the desired product. [ka] Carbapenem conjugates

[0460] The carbapenem propenyl carbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [165817-82-3] has been previously described (WO99 / 62906). Reaction with a BOC-protected aminoorganostannane [139111-44-7] (used in the analogous cephem triflate: Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4635-4638) Reaction of the amine with phosgene followed by removal of the BOC group under standard conditions yields the propenylamine intermediate. This amine is reacted with phosgene, and the resulting intermediate is reacted with cannabinoid (CBD) under basic conditions to form the carbamate group. Removal of the TES ether and PNB ester groups under standard conditions yields the desired product. [ka] Example 11 Propenylthiocarbamate-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0461] The cephempropenyl thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate component was synthesized according to the following scheme. The starting material [57562-43-3] was reported (CN103588788A 20140219). This was converted to the enol triflate under standard conditions, which was then reacted with a BOC-protected aminoorganostannane [139111-44-7] (used in the analogous cephem triflate: Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4635-4638). Subsequent removal of the BOC under standard conditions gives the propenylamine intermediate. This amine is reacted with thiophosgene, and the resulting intermediate is reacted with cannabinoid (CBD) under basic conditions to form the thiocarbamate group. Removal of the PNB ester group under standard conditions yields the desired product. [ka] Carbacephem conjugates

[0462] The carbacephem propenyl thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [119892-46-5] (WO2010 / 030810 and references cited therein) is converted under standard conditions to the enol triflate, which is reacted with a BOC-protected aminoorganostannane [139111-44-7] (for use in the analogous cephem triflate: Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4635-4638). This is followed by removal of the BOC under standard conditions to give a propenylamine intermediate. This amine is reacted with thiophosgene, and the resulting intermediate is reacted with a cannabinoid (CBD) under basic conditions to form a thiocarbamate group. Removal of the PNB ester group under standard conditions yields the desired product. [ka] Penem conjugates

[0463] The penempropenyl thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme. The starting material [127941-62-2] has been previously reported (U.S. Pat. No. 4,895,940). The BOC-protected aminoorganostannane [139111-44-7] (used in the analogous cephem triflate: Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4635-4638) Reaction of the amine with thiophosgene followed by removal of the BOC group under standard conditions provides the propenylamine intermediate. This amine is reacted with thiophosgene, and the resulting intermediate is reacted with cannabinoid (CBD) under basic conditions to form the thiocarbamate group. Removal of the TES ether and trimethylsilylethyl ester groups under standard conditions yields the desired product. [ka] Carbapenem conjugates

[0464] The carbapenem propenyl thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate component was synthesized according to the following scheme: The starting material [165817-82-3] was previously described (WO99 / 62906). BOC-protected aminoorganostannane [139111-44-7] (used in the analogous cephem triflate: Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4635-4638) and Reaction of the amine with thiophosgene followed by removal of the BOC group under standard conditions yields the propenylamine intermediate. This amine is reacted with thiophosgene, and the resulting intermediate is reacted with cannabinoid (CBD) under basic conditions to form the thiocarbamate group. Removal of the TES ether and PNB ester groups under standard conditions yields the desired product. [ka] Example 12 S-Alkylthiocarbonate-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0465] The cephem S-alkylthiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [61781-78-0] has been previously described (US (1976), US3979384A 19760907). Reaction with phosgene and cannabinoid (CBD) under standard basic conditions to form the S-alkylthiocarbonate-linked intermediate. Removal of the diphenylmethyl ester protecting group affords the desired product. [ka] Carbacephem conjugates

[0466] The carbacephem S-alkylthiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [177325-29-0] is converted to a thiol intermediate using conditions previously described for related systems (Faming Zhuanli Shenqing, 108623617, 09 Oct 2018). The diphenylmethyl ester intermediate is reacted with phosgene and cannabinoid (CBD) under standard basic conditions to form the S-alkylthiocarbonate-linked intermediate. Removal of the diphenylmethyl ester protecting group affords the desired product. [ka] Penem conjugates

[0467] The penem S-alkylthiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [88585-78-8] is converted to a thiol intermediate using conditions previously described for related systems (Faming Zhuanli Shenqing, 108623617, 09 Oct 2018). The resulting product is reacted with phosgene and cannabinoid (CBD) under standard basic conditions to form an S-alkylthiocarbonate-linked intermediate. Removal of the silyl ether and allyl ester protecting groups affords the desired product. [ka] Carbapenem conjugates

[0468] The carbapenem S-alkylthiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [118990-99-1] is converted to a thiol intermediate using conditions previously described for related systems (Faming Zhuanli Shenqing, 108623617, 09 Oct 2018). The intermediate is reacted with phosgene and cannabinoid (CBD) under standard basic conditions to form the S-alkylthiocarbonate linked intermediate. Removal of the allyl protecting group affords the desired product. [ka] Example 13 Xanthate-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0469] The cefem xanthate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [61781-78-0] has been previously described (US (1976), US3979384A 19760907). Reaction with thiophosgene and cannabinoid (CBD) under standard basic conditions to form the xanthate-linked intermediate. Removal of the diphenylmethyl ester protecting group affords the desired product. [ka] Carbacephem conjugates

[0470] The carbacefem xanthate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [177325-29-0] was prepared as previously described for related systems (Faming Zhuanli Shenqing, 108623617, 09 Oct 2018) conditions to convert the thiol intermediate to the standard Reaction of the xanthate-linked intermediate with thiophosgene and cannabinoid (CBD) under moderately basic conditions affords the desired product upon removal of the diphenylmethyl ester protecting group. [ka] Penem conjugates

[0471] The penem xanthate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [88585-78-8] was prepared as previously described for related systems (Faming Zhuanli Shenqing, 108623617, 09 Oct). The thiol intermediate is converted to a xanthate-linked intermediate using conditions from (2018). The thiol intermediate is reacted with thiophosgene and cannabinoid (CBD) under standard basic conditions to form a xanthate-linked intermediate. Removal of the silyl ether and allyl ester protecting groups affords the desired product. [ka] Carbapenem conjugates

[0472] The carbapenem xanthate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [118990-99-1] is converted to a thiol intermediate using conditions previously described for related systems (Faming Zhuanli Shenqing, 108623617, 09 Oct 2018). The thiol intermediate is then reacted with the standard Reaction with thiophosgene and cannabinoid (CBD) under mildly basic conditions forms a xanthate-linked intermediate. Removal of the allyl protecting group affords the desired product. [ka] Example 14 Acetal-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0473] The cephem acetal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [15690-38-7] is converted to a hydroxymethyl intermediate containing the selected side chain and a protective ester as described in the literature (WO96 / 04247). The cannabinoid (CBD) is converted to an O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). The hydroxymethyl and O-chloromethyl intermediates were reacted under previously reported conditions (Tetrahedron, 60(12), 2771-2784; 2004). Removal of the diphenylmethyl ester protecting group affords the product. [ka] Carbacephem conjugates

[0474] The carbacephem acetal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [177472-75-2] is converted to a hydroxymethyl intermediate containing the selected side chain and a protective ester as described in the literature (WO96 / 04247). The cannabinoid (CBD) is converted to an O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). The hydroxymethyl and O-chloromethyl intermediates were prepared under previously reported conditions (Tetrahedron, 60(12), 2771-2784; 2004). Reaction under HCl affords the formation of an acetal bond. Removal of the diphenylmethyl ester protecting group affords the product. [ka] Penem conjugates

[0475] The penem acetal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: Cannabinoid (CBD) is converted to its O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). This intermediate is converted to hydroxymethylpenem [88585-7] under reported conditions (Tetrahedron, 60(12), 2771-2784; 2004). 8-8] to form an acetal bond. Removal of the silyl ether and allyl ester protecting groups under standard conditions affords the product. [ka] Carbapenem conjugates

[0476] The carbapenem acetal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: Cannabinoid (CBD) is converted to its O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). This intermediate is converted to hydroxymethyl carbapenem [1] under reported conditions (Tetrahedron, 60(12), 2771-2784; 2004). 18990-99-1] to form an acetal bond. Removal of the allyl protecting group under standard conditions affords the product. [ka] Example 15 Aminal-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0477] The cephem aminal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The aminomethyl cephem intermediate is synthesized according to the scheme shown above for the cephem carbamate-linked β-lactam antibiotic cannabinoid conjugate component. The cannabinoid (CBD) is converted to its O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). This intermediate is reacted with aminomethylcephem (see Journal of Chemical and Pharmaceutical Sciences, 6(3), 175-180; 2013 for conditions and related examples) to give the aminal-linked intermediate. Removal of the t-butyl ester protecting group gives the product. [ka] Carbacephem conjugates

[0478] The carbacephem aminal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: An aminomethyl carbacephem intermediate is synthesized according to the scheme shown above for the carbacephem carbamate-linked β-lactam antibiotic cannabinoid conjugate component. The cannabinoid (CBD) is converted to its O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). This intermediate is reacted with an aminomethyl carbacephem (see Journal of Chemical and Pharmaceutical Sciences, 6(3), 175-180; 2013) , to give the aminal-linked intermediate. Removal of the t-butyl ester protecting group gives the product. [ka] Penem conjugates

[0479] The penem aminal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The aminomethylpenem intermediate is synthesized in five steps according to the scheme shown above for the penem carbamate-linked β-lactam antibiotic cannabinoid conjugate component. The cannabinoid (CBD) is converted to its O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). This intermediate is reacted with aminomethylpenem (see Journal of Chemical and Pharmaceutical Sciences, 6(3), 175-180; 2013 for conditions and relevant examples) to give the aminal-linked intermediate. Removal of the t-butyl ester protecting group gives the product. [ka] Carbapenem conjugates

[0480] The carbapenem aminal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The aminomethyl carbapenem intermediate is synthesized in five steps according to the scheme shown above for the carbapenem carbamate-linked β-lactam antibiotic cannabinoid conjugate component: The cannabinoid (CBD) is converted to its O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). The intermediate is reacted with an aminomethylcarbapenem (see Journal of Chemical and Pharmaceutical Sciences, 6(3), 175-180; 2013 for conditions and relevant examples) to give the aminal-linked intermediate. Removal of the silyl ether and t-butyl ester protecting groups gives the product. [ka] Example 16 Thioacetal-linked β-lactam antibiotic cannabinoid conjugate components Cephem conjugates

[0481] The cephem thioacetal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: cannabinoid (CBD) is converted to its O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). This intermediate is reacted with thiomethylcephem [61781-78-0] (see Bioorganic Chemistry for conditions and related examples). & Medicinal Chemistry, 18(4), 1441-1448; 2010) to give a thioacetal-linked intermediate. Removal of the diphenylmethyl ester protecting group gives the product. [ka] Carbacephem conjugates

[0482] The carbacephem thioacetal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [177325-29-0] is converted to a thiol intermediate using conditions previously described for related systems (Faming Zhuanli Shenqing, 108623617, 09 Oct 2018). D) is converted to its O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). This intermediate is reacted with a thiolcarbacephem intermediate (see Bioorganic & Medicinal Chemistry, 18(4), 1441-1448; 2010 for conditions and related examples) to give a thioacetal-linked intermediate. Removal of the diphenylmethyl ester protecting group gives the product. [ka] Penem conjugates

[0483] The penem thioacetal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [88585-78-8] is converted to the thiol intermediate [1027391-97-4] using conditions previously described for related systems (Faming Zhuanli Shenqing, 108623617, 09 Oct 2018). Cannabinoids (CBD) are converted to their O-chloromethyl intermediates via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014;Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). This intermediate was reacted with a thiol penem intermediate (see for conditions and related examples). (See Bioorganic & Medicinal Chemistry, 18(4), 1441-1448; 2010) to give a thioacetal-linked intermediate. Removal of the silyl ether and allyl ester protecting groups gives the product. [ka] Carbapenem conjugates

[0484] The carbapenem thioacetal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [118990-99-1] was prepared as previously described for related systems (Faming Zhuanli Shenqing, 108623617, (09 Oct 2018) conditions to convert cannabinoids (CBD) to thiol intermediates. ) is converted to its O-chloromethyl intermediate via reported conditions (Bioorg. & Med. Chem., 26(2), 386-393; 2018; J. Amer. Chem. Soc., 136(26), 9260-9263; 2014; Faming Zhuanli Shenqing, 105037382, 11 Nov 2015). This intermediate is reacted with a thiol carbapenem intermediate (see Bioorganic & Medicinal Chemistry, 18(4), 1441-1448; 2010 for conditions and relevant examples) to give a thioacetal-linked intermediate. Removal of the allyl protecting group affords the product. [ka] Example 17 Monobactam ether-linked β-lactam antibiotics as components of cannabinoid conjugates

[0485] The monobactam ether-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [76855-69-1] is reacted under conditions for phenolic compounds (Journal of Organic Chemistry, 55(2), 434-7; 1990) to form an ether bond. Removal of the silyl ether protecting group under standard conditions, followed by sulfonation using established conditions, affords the product. [ka] Example 18 Monobactam acetal-linked β-lactam antibiotics as components of cannabinoid conjugates

[0486] The monobactam acetal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [76855-69-1] is deprotected under reported conditions (Journal of Fluorine Chemistry, 72(2), 255-9; 1995). Acetylation affords the 2-hydroxy intermediate. This hydroxy group is then alkylated with an O-chloromethylcannabinoid, prepared as described in the cephem acetal example herein, to form the acetal bond. Removal of the silyl ether protecting group, followed by sulfonation using established conditions, affords the product. [ka] Example 19 Monobactam carbonate-linked β-lactam antibiotic cannabinoid conjugate components

[0487] The monobactam carbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: Starting material [76855-69-1] was reacted under reported conditions (Journal of Fluorine Chemistry, 72(2), 255-9; 1995). Deacetylation affords the 2-hydroxy intermediate. This hydroxy group is then reacted with phosgene and cannabinoid (CBD) under standard basic conditions to form a carbonate bond. Removal of the silyl ether protecting group followed by sulfonation using established conditions affords the product. [ka] Example 20 Monobactam thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate components

[0488] The monobactam thiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [76855-69-1] was reacted with 76855-69-1 under reported conditions (Journal of Fluorine Chemistry, 72(2), 255-9; 1995). Deacetylation under HCl affords the 2-hydroxy intermediate. This hydroxy group is then reacted with thiophosgene and cannabinoid (CBD) under standard basic conditions to form a carbonate bond. Removal of the silyl ether protecting group followed by sulfonation using established conditions affords the product. [ka] Example 21 Monobactam imidate-linked β-lactam antibiotic cannabinoid conjugate components

[0489] The monobactam imidate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [76855-69-1] is deprotected under reported conditions (Journal of Fluorine Chemistry, 72(2), 255-9; 1995). Acetylation affords the 2-hydroxy intermediate. This hydroxy group is then reacted with methylimidocarbonyl chloride [5652-90-4] and cannabinoid (CBD) under reported conditions (Tetrahedron Letters, 23(35), 3539-42; 1982) to form an imidate bond. Removal of the silyl ether protecting group followed by sulfonation using established conditions affords the product. [ka] Example 22 Monobactam aminal-linked β-lactam antibiotics as components of cannabinoid conjugates

[0490] The monobactam aminal-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [76855-69-1] is converted to the corresponding amine under reported conditions (Organic Chemistry: An Indian Journal, 9(6), 229-235; 2013) to give the 2-amino intermediate. This amino group is then alkylated with an O-chloromethyl cannabinoid, prepared as described in the cephem acetal example herein, to form the acetal linkage. Removal of the silyl ether protecting group followed by sulfonation using established conditions affords the product. [ka] Example 23 Monobactam carbamate-linked β-lactam antibiotic cannabinoid conjugate components

[0491] The monobactam carbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [76855-69-1] is converted to the corresponding amine under reported conditions (Organic Chemistry: An Indian Journal, 9(6), 229-235; 2013) to give the 2-amino intermediate. This amino group is then reacted with phosgene and cannabinoid (CBD) under standard basic conditions to form the carbamate bond. Removal of the silyl ether protecting group and subsequent sulfonation using established conditions affords the product. [ka] Example 24 Monobactam thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate components

[0492] The monobactam thiocarbamate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [76855-69-1] was prepared by the reported conditions (Organic Chemistry: An Indian Journal, 9(6), 229-235; The 2-amino intermediate is then converted to the corresponding amine under standard basic conditions with thiophosgene and cannabinoids (CBD) to form the thiocarbamate bond. Removal of the silyl ether protecting group and subsequent sulfonation using established conditions affords the product. [ka] Example 25 Monobactam isourea-linked β-lactam antibiotics as components of cannabinoid conjugates

[0493] The monobactam isourea-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [76855-69-1] is converted to the corresponding amine under reported conditions (Organic Chemistry: An Indian Journal, 9(6), 229-235; 2013) to give the 4-amino intermediate. This amino group is then reacted with methylimidocarbonyl chloride [5652-90-4] and a cannabinoid (CBD) under reported conditions (Tetrahedron Letters, 23(35), 3539-42; 1982) to form the isourea bond. Removal of the silyl ether protecting group and subsequent sulfonation using established conditions affords the product. [ka] Example 26 Monobactam thioacetal-linked β-lactam antibiotics as components of cannabinoid conjugates

[0494] The monobactam thioacetal-linked β-lactam antibiotic cannabinoid conjugate component was synthesized according to the following scheme: The starting material [76855-69-1] was synthesized using the reported conditions (Shenyang Yaoke Daxue Xuebao, 18(1), 20-22; 2001). The thiol group is then alkylated with an O-chloromethylcannabinoid, prepared as described in the cephem acetal example herein, to form a thioacetal bond. Removal of the silyl ether protecting group and subsequent sulfonation using established conditions affords the product. [ka] Example 27 Monobactam S-Alkylthiocarbonate-Linked β-Lactam Antibiotics as Components of Cannabinoid Conjugates

[0495] The monobactam S-alkylthiocarbonate-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [76855-69-1] is converted to a thiol silver salt using reported conditions (Shenyang Yaoke Daxue Xuebao, 18(1), 20-22; 2001) to give the 2-SH intermediate. The ol group is reacted with phosgene and cannabinoid (CBD) under standard basic conditions to form an S-alkylthiocarbonate bond. Removal of the silyl ether protecting group followed by sulfonation using established conditions affords the product. [ka] Example 28 Monobactam xanthate-linked β-lactam antibiotic cannabinoid conjugate components

[0496] The monobactam xanthate-linked β-lactam antibiotic cannabinoid conjugate component was synthesized according to the following scheme: Starting material [76855-69-1] was synthesized using the reported conditions (Shenyang Yaoke Daxue Xuebao, 18(1), 20-22; 2001). The thiol group is then reacted with thiophosgene and a cannabinoid (CBD) under standard basic conditions to form a xanthate linkage. Removal of the silyl ether protecting group and subsequent sulfonation using established conditions affords the product. [ka] Example 29 Monobactam thioimidate-linked β-lactam antibiotic cannabinoid conjugate components

[0497] The monobactam thioimidate-linked β-lactam antibiotic cannabinoid conjugate component was synthesized according to the following scheme: The starting material [76855-69-1] was synthesized using the reported conditions (Shenyang Yaoke Daxue Xuebao, 18(1), 20-22; 2001). The thiol group is then converted to a silver thiol salt using a thiol-silver ester to give the 2-SH intermediate. This thiol group is then reacted with methylimidocarbonyl chloride [5652-90-4] and cannabinoid (CBD) under reported conditions (Tetrahedron Letters, 23(35), 3539-42; 1982) to form a thioimidate bond. Removal of the silyl ether protecting group and subsequent sulfonation using established conditions gives the product. [ka] Example 30 Monobactam alkenyl ester-linked β-lactam antibiotic cannabinoid conjugate components

[0498] The monobactam alkenyl ester-linked β-lactam antibiotic cannabinoid conjugate component is synthesized according to the following scheme: The starting material [592528-28-4] is esterified with the cannabinoid (CBD) under standard conditions. Removal of the silyl ether protecting group and subsequent sulfonation using established conditions affords the product. [ka] Example 31 Monobactam alkenyl ether, alkenyl acetal, alkenyl carbonate, alkenyl thiocarbonate, and alkenylimidate-linked β-lactam antibiotic cannabinoid conjugate components

[0499] Monobactam alkenyl ether, alkenyl acetal, alkenyl carbonate, alkenyl thiocarbonate, and alkenylimidate-linked β-lactam antibiotic cannabinoid conjugate components are synthesized as shown in the following scheme. The starting material [410524-32-2] is reduced to an alcohol intermediate using previously reported conditions (Organic Letters, 15(16), 4142-4145; 2013). This alcohol is reacted with a cannabinoid and connected to it via one of the aforementioned linkages using the chemistry and conditions previously described for the non-alkenyl variants. [ka] Example 32 Monobactam alkenyl aminal, alkenyl carbamate, alkenyl thiocarbamate, and alkenylisourea-linked β-lactam antibiotic cannabinoid conjugate components

[0500] Monobactam alkenylaminal, alkenylcarbamate, alkenylthiocarbamate, and alkenylisourea-linked β-lactam antibiotic cannabinoid conjugate components are synthesized as shown in the following scheme. The starting material [410524-32-2] is reduced to an alcohol intermediate. This alcohol is then converted to an iodide using known conditions (Tetrahedron, 73(29), 4150-4159; 2017). The iodide intermediate is converted to a primary amine using the two-step azide addition / reduction protocol described above for the synthesis of the propenylamine cephem β-lactam antibiotic cannabinoid conjugate component. This amine is then reacted with a cannabinoid and connected to it via one of the aforementioned linkages using the chemistry and conditions previously described for the non-alkenyl variants. [ka] Example 33 Monobactam alkenyl thioacetal, alkenyl S-alkyl thiocarbonate, alkenyl dithiocarbonate, and alkenyl thioimidate-linked β-lactam antibiotic cannabinoid conjugate components

[0501] Monobactam alkenylthioacetal, alkenyl S-alkylthiocarbonate, alkenyl dithiocarbonate, and alkenyl thioimidate-linked β-lactam antibiotic cannabinoid conjugate components are synthesized as shown in the following scheme. The starting material [410524-32-2] is reduced to an alcohol intermediate using previously reported conditions (Organic Letters, 15(16), 4142-4145; 2013). This alcohol is reacted with Lawesson's reagent under reported conditions (Journal of the American Chemical Society, 130(15), 5052-5053; 2008) to give the corresponding thiol intermediate. This thiol is then reacted with a cannabinoid and connected to it via one of the aforementioned linkages using the chemistry and conditions previously described for non-alkenyl variants. [ka] Example: (IA)-Type Cannabinoid Conjugate Components Example 34 Hydroxyurea aminal-linked (IA)-type cannabinoid conjugate components

[0502] The hydroxyurea aminal linked cannabinoid conjugate component is synthesized as follows: The cannabinoid (CBD in this example) is converted to its chloromethyl derivative using previously described conditions (see scheme below). The chloromethyl group is converted to the corresponding aminomethyl intermediate using standard conversion, in this case with an azide. The aminomethyl group is converted to the isocyanate intermediate using the referenced conditions (scheme below). Reaction of the isocyanate with hydroxylamine gives the desired product. [ka]

[0503] The hydroxyurea carbamate-linked cannabinoid conjugate component is synthesized as follows: the cannabinoid (CBD in this example) is reacted with phosgene (or a suitable surrogate) and the adduct is converted to the carbamate intermediate using the referenced conditions (see scheme). Conversion to the isocyanate (referenced conditions) followed by reaction with hydroxylamine gives the desired product. [ka]

[0504] The hydroxyurea thiocarbamate linked cannabinoid conjugate component is synthesized as follows: the cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable surrogate) and the adduct is converted to the thiocarbamate intermediate using the referenced conditions (see scheme). Conversion to the isocyanate (referenced conditions) followed by reaction with hydroxylamine gives the desired product. [ka] Example 35 Cannabinoid conjugate components containing Michael acceptors

[0505] The Michael acceptor amide cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an alkynyl ester, in this case [623-47-2], under reported conditions (see scheme) to give an unsaturated acid intermediate. Reaction with an amine, in this case diethylamine, under standard amide bond forming conditions gives the desired product. [ka]

[0506] The Michael acceptor ester cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an alkynyl ester, in this case [623-47-2], under reported conditions (see scheme) to give the desired product. [ka]

[0507] The Michael acceptor nitrile cannabinoid conjugate component is synthesized using the conditions referenced below. [ka]

[0508] The Michael acceptor amide cannabinoid conjugate component containing the neratinib component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an alkynyl ester, in this case [623-47-2], under reported conditions (see scheme) to give an unsaturated acid intermediate. Reaction with an amine, in this case [848139-78-6], under standard amide bond forming conditions gives the desired product. [ka]

[0509] The Michael acceptor amide cannabinoid conjugate component containing the dacomitinib component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an alkynyl ester, in this case [623-47-2], under reported conditions (see scheme) to give an unsaturated acid intermediate. Reaction with an amine, in this case [179552-75-1], under standard amide bond forming conditions gives the desired product. [ka]

[0510] The Michael acceptor amide cannabinoid conjugate component containing the osimertinib component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an alkynyl ester, in this case [623-47-2], under reported conditions (see scheme) to give an unsaturated acid intermediate. Reaction with an amine, in this case [1421372-66-8], under standard amide bond forming conditions gives the desired product. [ka]

[0511] The Michael acceptor amide cannabinoid conjugate component containing the ibrutinib component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an alkynyl ester, in this case [623-47-2], under reported conditions (see scheme) to give an unsaturated acid intermediate. Reaction with an amine, in this case [1022150-12-4], under standard amide bond forming conditions gives the desired product. [ka]

[0512] The Michael acceptor amide cannabinoid conjugate component containing the afatinib component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an alkynyl ester, in this case [623-47-2], under reported conditions (see scheme) to give an unsaturated acid intermediate. Reaction with an amine, in this case [314771-76-1], under standard amide bond forming conditions gives the desired product. [ka]

[0513] The Michael acceptor vinyl sulfone cannabinoid conjugate component is prepared from CBD and building block [13894-21-8] using conditions similar to those referenced in the following scheme. Double bond isomers can be separated and isolated by chromatography. [ka]

[0514] The Michael acceptor vinyl sulfonamide cannabinoid conjugate component is prepared from a cannabinoid (CBD) and an alkynyl sulfonamide building block, in this case [250583-24-5], using conditions similar to those referenced above for the related vinyl sulfone and Michael acceptor ester cannabinoid conjugate components. [ka]

[0515] Carbamate cannabinoid (I) type conjugate components can be synthesized by reacting a cannabinoid (CBD) with phosgene (or a suitable surrogate) and the appropriate amine building block under standard basic conditions, as shown in the scheme below. [ka] Example: (IB)-type cannabinoid conjugate components

[0516] The following procedures for synthesizing various types and classes of Type (II) cannabinoid conjugate components are general and representative procedures for building on the key functionality of the cannabinoid conjugate component. Reagent systems, reaction conditions, and protecting group strategies can vary for any particular analog. The specific building blocks will vary according to the particular desired product. Bromide cannabinoid conjugate components can be synthesized as the corresponding chloride or iodide cannabinoid conjugate components. The following procedures show cannabidiol (CBD) as the representative cannabinoid, but other cannabinoids containing hydroxyl groups can be substituted to produce alternative analogs. Example 36 Epoxide-containing cannabinoid conjugate components

[0517] The epoxide carbamate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and an aminoepoxide (5689-75-8 in this example) under standard basic conditions to form the desired carbamate-linked product. [ka]

[0518] The epoxide carbonate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and a hydroxy epoxide ([556-52-5] in this example) under standard basic conditions to form the desired carbonate-linked product. [ka]

[0519] The epoxide ester linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is esterified with an epoxy acid building block [86310-98-7] in this example under standard conditions to give the desired product. [ka]

[0520] The epoxide imidate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an imide carbonyl chloride (in this case [5652-90-4]) and a hydroxy epoxide ([556-52-5] in this example) under standard basic conditions to form the desired imidate-linked product. [ka]

[0521] The epoxide isourea-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this case [5652-90-4]) and an aminoepoxide ([5689-75-8] in this example) under standard basic conditions to form the desired isourea-linked product. [ka]

[0522] The epoxide phosphorodiamide-linked cannabinoid conjugate component is synthesized as follows: N,N-dimethylphosphoramidodichloridate ([677-43-0]) is reacted with an aminoepoxide ([5689-75-8] in this example) using conditions similar to those referenced in the scheme. The adduct is then reacted with a cannabinoid (CBD in this example) under standard basic conditions to form the desired product. [ka]

[0523] The epoxide S-alkylthiocarbonate linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and a thiol-epoxide ([45357-98-0] in this example) under standard basic conditions to form the desired S-alkylthiocarbonate linked product. [ka]

[0524] The epoxide thiocarbamate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and an aminoepoxide (5689-75-8 in this example) under standard basic conditions to form the desired thiocarbamate-linked product. [ka]

[0525] The epoxide thiocarbonate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and a hydroxy epoxide ([556-52-5] in this example) under standard basic conditions to form the desired thiocarbonate-linked product. [ka]

[0526] The epoxide thioimidate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an imide carbonyl chloride (in this case [5652-90-4]) and a thiol-epoxide (45357-98-0] in this example) under standard basic conditions to form the desired thioimidate-linked product. [ka]

[0527] The epoxidethiophosphinodiamide-linked cannabinoid conjugate component is synthesized as follows: Dimethyl phosphoramidothioic acid dichloride ([1498-65-3]) is reacted with an aminoepoxide ([5689-75-8] in this example) using conditions similar to those referenced in the scheme. The adduct is then reacted with a cannabinoid (CBD in this example) under standard basic conditions to form the desired product. [ka]

[0528] The epoxide xanthate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and a thiol-epoxide ([45357-98-0] in this example) under standard basic conditions to form the desired xanthate-linked product. [ka] Example 37 Aziridine-containing cannabinoid conjugate component

[0529] The aziridine carbamate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and aminoaziridine (88714-40-3 in this example) under standard basic conditions to form the desired carbamate-linked product. [ka]

[0530] The aziridine carbonate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and hydroxyaziridine (25662-15-1 in this example) under standard basic conditions to form the desired carbonate-linked product. [ka]

[0531] The aziridine ester-linked cannabinoid conjugate component is synthesized as follows: The previously reported hydroxymethyl building block [126587-35-7] is treated with base, in this example sodium hydride, to generate the aziridinyl intermediate. Removal of the BOC protecting group followed by alkylation of the resulting amine affords the alkylaziridine-ester intermediate. Standard hydrolysis of the ester affords the carboxylic acid precursor, which is esterified with a cannabinoid under standard esterification conditions to yield the desired product. [ka]

[0532] The aziridine imidate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with imidocarbonyl chloride (in this case [5652-90-4]) and hydroxyaziridine (25662-15-1] in this example) under standard basic conditions to form the desired imidate-linked product. [ka]

[0533] The aziridine isourea-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with imidocarbonyl chloride (in this case [5652-90-4]) and aminoaziridine (88714-40-3] in this example) under standard basic conditions to form the desired isourea-linked product. [ka]

[0534] The aziridine phosphorodiamide-linked cannabinoid conjugate component is synthesized as follows: Using conditions similar to those referenced in the scheme, N,N-dimethylphosphoramidodichloridate ([677-43-0]) is reacted with an aminoaziridine ([88714-40-3] in this example). The adduct is then reacted with a cannabinoid (CBD in this example) under standard basic conditions to form the desired product. [ka]

[0535] The aziridine thiocarbamate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and an aminoaziridine (88714-40-3 in this example) under standard basic conditions to form the desired thiocarbamate-linked product. [ka]

[0536] The aziridine thiocarbonate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and hydroxyaziridine (25662-15-1 in this example) under standard basic conditions to form the desired thiocarbonate-linked product. [ka]

[0537] The aziridinethiophosphinodiamide-linked cannabinoid conjugate component is synthesized as follows: Using conditions similar to those referenced in the scheme, dimethylphosphoramidothioic acid dichloride ([1498-65-3]) is reacted with an aminoaziridine ([88714-40-3] in this example). The adduct is then reacted with a cannabinoid (CBD in this example) under standard basic conditions to form the desired product. [ka] Example 38 Sulfonate-linked conjugate components

[0538] The sulfonate carbamate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and an amino-alcohol (156-87-6 in this example) under standard basic conditions to form a carbamate-linked intermediate. Reaction with a sulfonyl chloride, in this case mesyl chloride, gives the desired product. [ka]

[0539] The sulfonate carbonate-linked cannabinoid conjugate component is synthesized as follows: A diol compound, in this case 1,3-propanediol [13392-69-3], is reacted with a sulfonyl chloride, in this case tosyl chloride, to give a monosulfonate intermediate. Reaction of the remaining hydroxyl group on this intermediate with phosgene (or a suitable surrogate) and a cannabinoid (CBD in this example) under standard basic conditions forms the desired carbonate-linked product. [ka]

[0540] The sulfonate ester-linked cannabinoid conjugate component is synthesized as follows: The hydroxy acid starting material, in this case [13392-69-3], is esterified under the conditions referenced for the selective esterification of aromatic OH in the presence of aliphatic OH. The ester-linked intermediate is then sulfonylated under the conditions referenced, in this case with mesyl chloride, to give the desired product. [ka]

[0541] The sulfonate imidate-linked cannabinoid conjugate component is synthesized as follows: A diol compound, in this case 1,3-propanediol [13392-69-3], is reacted with a sulfonyl chloride, in this case tosyl chloride, to give a monosulfonate intermediate. Reaction of the remaining hydroxyl group of this intermediate with an imidocarbonyl chloride (in this case [5652-90-4]) under standard basic conditions forms the desired imidate-linked product. [ka]

[0542] The sulfonate-isourea linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this example, [5652-90-4]) and an amino-alcohol (in this example, [156-87-6]) under standard basic conditions to form an isourea linked intermediate. Sulfonylation under referenced conditions (see sulfonate esters above), in this case with mesyl chloride, gives the desired product. [ka]

[0543] The sulfonate phosphorodiamide-linked cannabinoid conjugate component is synthesized as follows: Using conditions similar to those referenced in the epoxide phosphorodiamide scheme, N,N-dimethylphosphoramidodichloridate ([677-43-0]) is reacted with a cannabinoid (CBD in this example) and an amino-alcohol ([156-87-6] in this example). The adduct is then sulfonylated under the referenced conditions (see sulfonate esters above), in this case with mesyl chloride, to give the desired product. [ka]

[0544] The sulfonate S-alkylthiocarbonate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and a thiol-alcohol ([19721-22-3] in this example) under standard basic conditions to form an S-alkylthiocarbonate-linked intermediate. Sulfonylation, in this case with tosyl chloride, gives the desired product. [ka]

[0545] The sulfonate-thiocarbamate-linked cannabinoid conjugate component is synthesized as follows: The cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and an amino-alcohol (156-87-6 in this example) under standard basic conditions to form a thiocarbamate-linked intermediate. Sulfonylation under referenced conditions (see sulfonate esters above), in this case with mesyl chloride, gives the desired product. [ka]

[0546] The sulfonate-thiocarbonate linked cannabinoid conjugate component is synthesized as follows: A diol compound, in this case 1,3-propanediol [13392-69-3], is reacted with a sulfonyl chloride, in this case tosyl chloride, to give a monosulfonate intermediate. Reaction of the remaining hydroxyl group of this intermediate with thiophosgene (or a suitable thiophosgene surrogate) and a cannabinoid (CBD in this example) under standard basic conditions forms the desired thiocarbonate linked product. [ka]

[0547] The sulfonate thioimidate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this example, [5652-90-4]) and a thiol-alcohol (in this example, [19721-22-3]) under standard basic conditions to form a thioimidate-linked intermediate. Sulfonylation under referenced conditions (see sulfonate esters above), in this case with tosyl chloride, gives the desired product. [ka]

[0548] The sulfonate thiophosphinodiamide-linked cannabinoid conjugate component is synthesized as follows: Using conditions similar to those referenced in the epoxide thiophosphinodiamide scheme, dimethyl phosphoramidothioic acid dichloride ([1498-65-3]) is reacted with a cannabinoid (CBD in this example) and an amino-alcohol ([156-87-6] in this example). Sulfonylation of this adduct, in this case with mesyl chloride, under the referenced conditions (see sulfonate esters above), gives the desired product. [ka]

[0549] The sulfonate xanthate-linked cannabinoid conjugate component is synthesized as follows: The cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and a thiol-alcohol ([19721-22-3] in this example) under standard basic conditions to form a xanthate-linked intermediate. Sulfonylation under referenced conditions (see sulfonate esters above), in this case with mesyl chloride, gives the desired product. [ka] Example 39 Halide-containing cannabinoid conjugate components

[0550] The halide carbamate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and an amino halide ([18370-81-5] in this example) under standard basic conditions to form the desired carbamate-linked product. [ka]

[0551] The halide carbonate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and a hydroxyalkyl halide ([627-18-9] in this example) under standard basic conditions to form the desired carbonate-linked product. [ka]

[0552] The halide ester linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is esterified with a haloalkyl acid building block [2067-33-6] in this example under standard conditions to give the desired product. [ka]

[0553] The halide imidate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this case [5652-90-4]) and a hydroxyalkyl halide (627-18-9] in this example) under standard basic conditions to form the desired imidate-linked product. [ka]

[0554] The halide isourea-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this case [5652-90-4]) and an aminoalkyl halide (in this example [18370-81-5]) under standard basic conditions to form the desired isourea-linked product. [ka]

[0555] The halide phosphorodiamide-linked cannabinoid conjugate component is synthesized as follows: Using conditions similar to those referenced in the epoxide phosphorodiamide scheme, N,N-dimethylphosphoramidodichloridate ([677-43-0]) is reacted with a cannabinoid (CBD in this example) and an aminoalkyl halide ([18370-81-5] in this example) to form the desired product. [ka]

[0556] Halide S-alkylthiocarbonate linked cannabinoid conjugate components are synthesized as follows: A cannabinoid (CBD in this example) is reacted with phosgene (or a suitable phosgene surrogate) and a haloalkylthiol ([75694-39-2] in this example) under standard basic conditions to form the desired S-alkylthiocarbonate linked product. [ka]

[0557] The halide thiocarbamate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and an aminoalkyl halide ([18370-81-5] in this example) under standard basic conditions to form the desired thiocarbamate-linked product. [ka]

[0558] The halide thiocarbonate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and a hydroxyalkyl halide ([627-18-9] in this example) under standard basic conditions to form the desired thiocarbonate-linked product. [ka]

[0559] The halide thioimidate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with an imidocarbonyl chloride (in this case [5652-90-4]) and a haloalkylthiol (75694-392] in this example) under standard basic conditions to form the desired thioimidate-linked product. [ka]

[0560] The halidethiophosphinodiamide linked cannabinoid conjugate component is synthesized as follows: Using conditions similar to those referenced in the epoxidethiophosphinodiamide scheme, dimethylphosphoramidothioic acid dichloride ([1498-65-3]) is reacted with a cannabinoid (CBD in this example) and an aminoalkyl halide ([18370-81-5] in this example) to form the desired product. [ka]

[0561] The halide xanthate-linked cannabinoid conjugate component is synthesized as follows: A cannabinoid (CBD in this example) is reacted with thiophosgene (or a suitable thiophosgene surrogate) and a haloalkylthiol ([75694-39-2] in this example) under standard basic conditions to form the desired xanthate-linked product. [ka]

[0562] The building block for the cannabinoid conjugate component shown below, [18709-11-0], is commercially available from Synnovator (SYNN76481) or can be synthesized by reacting 2-chloroethylmethylamine [32315-92-7] with ethyl bromoacetate [105-36-2], followed by hydrolysis under standard conditions. Esterification is then carried out under standard conditions, such as with carbodiimides. Diester products can also be obtained. [ka]

[0563] The cannabinoid conjugate component shown below can be synthesized by reacting reagent [677-43-0] (Alfa Aesar, L07231) with one equivalent of 2-chloroethylmethylamine [32315-92-7] to give the monochloro adduct. See Asian J. Chem. 21, 195-205, 2009. Addition of CBD to this intermediate yields This gives the desired product after purification. See Organic Lett. 20, 8057-60, 2018. and. [ka]

[0564] The cannabinoid conjugate component D1 is synthesized using the chemistry utilized in the synthesis of [98650-18-1] (J. Med. Chem. 32, 1491-96, 1989). The initial reaction of the phenol group with POCl3 is described, for example, in Bioorganic & Medicinal Chemistry 13, 3219-27, 2005. [ka]

[0565] Cannabinoid conjugate component F1 can be synthesized by esterification of chlorambucil [305-03-3] with CBD under standard esterification conditions. Cannabinoid conjugate component F2 can also be synthesized. [ka] Example 40 Cannabinoid conjugate components including temozolomide components

[0566] Compounds conjugated to a temozolomide moiety are synthesized as follows: Iodo acid [7425-27-6] is reacted with a cannabinoid (CBD) under standard esterification conditions to yield an iodoester intermediate. The desired cannabinoid conjugate moiety is generated by N-alkylation of [108030-65-5] following conditions similar to those published for the synthesis of temozolomide from iodomethane (see scheme). Cannabinoid conjugate moieties containing two temozolomide moieties can also be obtained. [ka]

[0567] Alternatively, the heterocycle can be first alkylated with an iodoester, then the ester is removed and the heterocycle is esterified with CBD to form the cannabinoid-temozolomide conjugate moiety.

[0568] The building block [108030-65-5] can be obtained commercially or synthesized using, for example, the published two-step route shown below (Bioorganic & Medicinal Chemistry Letters 6, 185-88, 1996): [ka] Example 41 Cannabinoid conjugate component containing 5-FU component a. Bonding at position 1 of 5-FU

[0569] A cannabinoid conjugate moiety containing an ester linkage to a 5-fluorouracil moiety at the 1-position is synthesized as follows: The known building block [6214-60-4] is reacted with a cannabinoid (CBD) under standard esterification conditions to give the product. [ka]

[0570] Cannabinoid conjugate moieties containing a carbonate linkage to a 5-fluorouracil moiety at the 1-position are synthesized as follows: The building block [106206-99-9] is reacted with phosgene (or a suitable surrogate) and CBD under standard basic conditions to give the product. [ka]

[0571] Cannabinoid conjugate moieties containing a carbamate bond to a 5-fluorouracil moiety at the 1-position are synthesized as follows: Building block [1339797-10-2] is reacted with phosgene (or a suitable surrogate) and CBD under standard basic conditions to give the product. [ka]

[0572] Cannabinoid conjugate components 3A and 3B can be synthesized by alkylation of CBD followed by acylation. [ka]

[0573] One approach to preparing cannabinoid conjugate component 8A involves the reaction of a tosylate with a thiocyanate (RSC Advances, 4(54), 28794-28797; 2014). Thus, acylation of 5-FU with 4-hydroxybutyric acid followed by tosylation yields a tosylate intermediate. Reaction of [71999-74-1] with ammonium thiocyanate yields a thiocyanate intermediate. This intermediate is reacted (cited above) to yield a disulfide intermediate. After removal of the BOC group, the amine is reacted with CBD and phosgene or an equivalent reagent to yield cannabinoid conjugate component 8A. Cannabinoid conjugate component 5B can also be produced. [ka]

[0574] Synthesis of cannabinoid conjugate component 9A can be achieved by acylation of 5-FU at the 1-position with [57294-38-9]. Removal of the BOC group followed by reaction with CBD and phosgene or an equivalent reagent forms cannabinoid conjugate component 9A. Cannabinoid conjugate component 9B can also be produced. [ka] b. Binding at position 3 of 5-FU

[0575] A cannabinoid conjugate moiety containing an ester linkage to a 5-fluorouracil moiety at the 3-position is synthesized as follows: A known building block [905265-53-4] is reacted with a cannabinoid (CBD) under standard esterification conditions to give the product. [ka]

[0576] Cannabinoid conjugate components containing a carbonate linkage to a 5-fluorouracil moiety at the 3-position are synthesized as follows: Building block [948036-30-4] is reacted with phosgene (or a suitable surrogate) and CBD under standard basic conditions to give the product. [ka]

[0577] The synthesis of cannabinoid conjugate components 1A and 1B can be carried out with protection of the NH group, such as BOC, as reported in the synthesis of the corresponding ethyl compound [192625-76-6], or [[(benzyloxy)carbonyl]oxy]methyl, as in the corresponding propyl compound [118004-34-5]. [ka]

[0578] The synthesis of cannabinoid conjugate components 2A and 2B can proceed by alkylation of CBD followed by acylation of 5-FU at position 3, if necessary utilizing protection at position 1. Alternatively, acylation can be performed first and CBD can be added as the final step. [ka]

[0579] Synthesis of cannabinoid conjugate component 5A can proceed by 3-acylation of 5-FU using N-methyl BOC-β-alanine [124072-61-3] as described above, with protecting groups if necessary. After removal of the BOC group, the resulting amine is reacted with CBD and phosgene or an equivalent reagent to form a carbamate. Removal of any remaining protecting groups produces cannabinoid conjugate component 5A. Cannabinoid conjugate component 5B can also be produced. [ka]

[0580] Synthesis of cannabinoid conjugate component 6A can proceed by 3-alkylation of 5-FU as described above using BOC-protected N-methyl-3-chloropropylamine [114326-14-6] with NaI, if necessary, with protecting groups as needed. After removal of the BOC group, the resulting amine is reacted with phosgene or an equivalent reagent and CBD to form a carbamate. Removal of any remaining protecting groups produces cannabinoid conjugate component 6A. Cannabinoid conjugate component 6B can also be produced. [ka] c. Binding at position 6 of 5-FU

[0581] Cannabinoid conjugate component 4A can be produced using cannabinoid conjugate component 4A, which can be prepared by adding CBD to [13593-36-7] using a method similar to that for the synthesis of 6-phenoxyuracil [15422-04-5], which is reportedly carried out by adding phenol to 6-chlorouracil [4270-27-3] (Journal of Heterocyclic Chemistry, 19(2), 301-4; 1982). Cannabinoid conjugate component 4B can also be produced. It is possible. [ka]

[0582] The synthesis of cannabinoid conjugate component 7A begins with the addition of diamine [111-33-1] to [13593-36-7]. See PCT International Application No. 2013013503, January 31, 2013, for a report of the addition of a secondary amine to 6-chlorouracil [4270-27-3]. The remaining unreacted secondary amine is then reacted with CBD and phosgene or an equivalent reagent to form cannabinoid conjugate component 7A. Cannabinoid conjugate component 7B can also be produced. [ka] Example: Synthesis of PCAN Components Example 42 Synthesis of PCAN component 1

[0583] PCAN component 1 can be synthesized as follows.

[0584] Ortho-dihydroxybenzenes are coupled to platinum in the presence of AgNO3 (Faming Zhuanli Shenqing, 101177435, 14 May 2008, Faming Zhuanli Shenqing, 101177434, 14 May 2008). The coupling of one or two phenolic groups (as shown) from cannabinoids (CBD in this example) is done in a similar manner. [ka]

[0585] PCAN component 1a can also be formed: [ka] Example 43 Synthesis of PCAN components 2a, 2b, and 2c

[0586] PCAN component 2a can be synthesized as follows. [ka]

[0587] PCAN component 2b can be synthesized as follows. [ka]

[0588] PCAN component 2c can be synthesized as follows. [ka] Example 44 Synthesis of PCAN components 3a and 3b

[0589] PCAN component 3a can be synthesized as follows. [ka]

[0590] PCAN component 3b can be synthesized as follows. [ka] [ka] Example 45 Synthesis of PCAN component 4

[0591] PCAN component 4 can be synthesized as follows: Related Pt dicarbonates (129551-82-2, 129551-94-6, 160953-30-0, Inorganic Chemistry (1995), 34(5), 1015-2, EP328274A1 19890816) ) is made from [62928-11-4] and pyrocarbonate. 4+ Acylation of the OH group on the cannabinoid is well known. Thus, reaction of CBD and [62928-11-4] with phosgene or a suitable surrogate reagent system results in the formation of a carbonate bond between the cannabinoid and platinum. Alternatively, Pt 4+ The OH group can react with alkyl carbonates to form new alkyl carbonates, and it may therefore be possible to generate a reagent where both X groups are CBD, which can then be reacted with a Pt reagent. [ka] Example 46 Synthesis of PCAN components 5a and 5b

[0592] PCAN component 5a can be synthesized as follows. [ka]

[0593] Alternatively, cannabidiol can be acylated with succinic anhydride to form the cannabidiol propionic acid derivative shown in the synthesis of compound 5b below. Reaction of this intermediate with [62928-11-4] under esterification conditions affords the cannabinoid conjugate component 5a.

[0594] PCAN component 5b can be synthesized as follows. [ka] [ka] Example 47 Synthesis of PCAN component 6

[0595] PCAN component 6 can be synthesized as follows.

[0596] Phenols can be converted to the corresponding vinyl ethers as shown with reference to the following scheme: Reaction of the vinyl ether with isocyanic acid [75-13-8] (JOC, 28(8), 2082-5; 1963) produces the isocyanate. [62928-11-4](Inorganic Chemistry (1995), 34(5), 1015-2;E P328274A1 19890816) to form Example 6. [ka] [ka] Example 48 Synthesis of PCAN components 7 and 7a

[0597] PCAN component 7 can be synthesized as follows. [ka]

[0598] PCAN component 7a can be synthesized in an analogous manner. [ka] In one embodiment, for example, the following items are provided: (Item 1) formula [ka] [In the formula, CBNC is a cannabinoid conjugate moiety that includes a therapeutic agent moiety covalently attached to a cannabinoid moiety directly or via a linker; L cc is a CBNC linker, but may be absent, B is a target binding moiety, said target binding moiety being an antibody; L a is the active ingredient linker, A is an active ingredient, m is 1 to 30, n is 0 to 29, and the sum of m+n is 1 to 30; CBNC is (I) the therapeutic component is directly bound to the cannabinoid component, and the therapeutic component is (1) [ka] [# indicates the covalent attachment site to the cannabinoid moiety] a Michael acceptor moiety having a structure selected from: (2) [ka] [Wherein Q is CO, CS, or CR 6a R 6b is], and (3) Structure [ka] wherein R8 and R9 are independently selected from H, CH3, and CH2CH3. a carbamate moiety having is selected from R is (a) H, (b)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) one, two, or three substituents independently selected from the substituents of Group 1; C1-C8 straight or branched alkyl optionally substituted with (c) containing 1, 2, or 3 heteroatoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 1 above; C1-C8 straight chain or branched heteroalkyl optionally substituted with (d)(1)(i) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (ii) one or two substituents independently selected from the substituents of Group 2; C1-C6 straight or branched alkyl optionally substituted with (2) contains 1 or 2 heteroatoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (ii) one or two substituents independently selected from the substituents of Group 1 above; C1-C6 straight or branched heteroalkyl optionally substituted with phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (e)(1) phenyl, (2) halides, (3) Cyano, (4)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above; C1-C6 straight or branched alkyl optionally substituted with (5) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with a 6- to 10-membered aromatic optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (f) containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; (1) phenyl, (2) halides, (3) Cyano, (4) trifluoromethyl, (5)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (6) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with a 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from (g)(1)(i) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: [ka] (h) having 1, 2, or 3 heteroatoms independently selected from O, N, and S; (1)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (2)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with (3) phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the substituents in Group 2 above; and (4) A 5- to 10-membered heteroaromatic group optionally substituted with 1, 2, or 3 substituents independently selected from the substituents in Group 2. a 3- to 9-membered cycloheteroalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (i)(1)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (2)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with (3) phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the substituents in Group 2 above; and (4) A 5- to 10-membered heteroaromatic group optionally substituted with 1, 2, or 3 substituents independently selected from the substituents in Group 2. C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from is selected from the group consisting of The substituents of Group 1 are (a) -OH, (b) -NH2, (c)=O, (d)=S, (e) = NR7, where R7 is H or C1-C3 straight or branched alkyl or C1-C3 straight or branched heteroalkyl containing O, N, or S atoms; (f) —C(O)OR4, where R4 is H or C1-C3 straight or branched alkyl; (g) -C(O)NR5R6, wherein R5 and R6 are independently H or C1-C6 straight or branched alkyl; (h) halides, (i) C1-C6 linear or branched alkoxyl, (j) C1-C6 linear or branched alkylamino, (k) C1-C6 linear or branched dialkylamino, (l)(i) phenyl, (ii) halides, (iii) cyano, (iv)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (v) containing 1, 2, or 3 atoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with a 6- to 10-membered aromatic optionally substituted with 1, 2, 3, or 4 substituents independently selected from (m)(i) phenyl, (ii) halides, (iii) cyano, (iv)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (v) containing 1, 2, or 3 atoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above; C1-C6 straight or branched heteroalkyl optionally substituted with a 5- to 10-membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from (n) having 1, 2, or 3 heteroatoms independently selected from O, N, and S; (i) phenyl, (ii) halides, (iii) cyano, (iv)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (v) containing 1, 2, or 3 atoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with and a 3- to 9-membered cycloheteroalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from (o)(i) phenyl, (ii) halides, (iii) cyano, (iv)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (v) containing 1, 2, or 3 atoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with C3-C6 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from is a group of substituents consisting of The substituents of Group 2 are (a) -OH, (b) -NH2, (c)=O, (d)=S, (e) = NR7, where R7 is H or C1-C3 straight or branched alkyl or C1-C3 straight or branched heteroalkyl containing O, N, or S atoms; (f) —C(O)OR4, where R4 is H or C1-C3 straight or branched alkyl; (g) -C(O)NR5R6, wherein R5 and R6 are independently H or C1-C6 straight or branched alkyl; (h) halides, (i) cyano, (j) trifluoromethyl, (k) C1-C6 linear or branched alkoxyl, (l) C1-C6 linear or branched alkylamino, (m) C1-C6 linear or branched dialkylamino, (n) 6- to 10-membered aromatics, and (o) a 5- to 10-membered heteroaromatic group containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; is a group of substituents consisting of R1 and R2 are independently (a)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents in Group 1 above C1-C12 straight or branched alkyl optionally substituted with (b)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents of Group 1 above; C2-C12 straight or branched alkenyl optionally substituted with (c) containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents in Group 1 above C1-C12 straight chain or branched heteroalkyl, optionally substituted with (d)R or selected from the group consisting of or R1 and R2, together with the atoms to which they are bonded, form a 3- to 9-membered cycloheteroalkyl having 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, said cycloheteroalkyl being (a)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) C1-C6 linear or branched alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the substituents in Group 2; (b)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) C1-C6 linear or branched heteroalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2; (c) phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the substituents in Group 2 above; and (d) a 5- to 10-membered heteroaromatic group optionally substituted with 1, 2, or 3 substituents independently selected from the substituents of Group 2 above; and R3, R 3a , and R 3b is, independently, (a)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) a C1-C8 straight-chain or branched alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the substituents in Group 1 above; or (b) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-C6 straight or branched alkyl; (1) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (2) one or two substituents independently selected from the substituents of Group 2 above phenyl optionally substituted with is selected from R 6a and R 6b are independently R Type IA cannabinoid conjugate component, (II) The therapeutic agent component is (i) covalently bonded via an IB-type linker, wherein the IB-type linker is (a) a first hydroxy group of a first cannabinoid component, or (b) a first carboxylic acid group of the first cannabinoid component; covalently bonded to, or (ii) the therapeutic agent moiety is covalently attached to a first hydroxy group or a first carboxylic acid group of the cannabinoid moiety; (A) The therapeutic component is (1) [ka] [In the formula, R a is absent or is a C1-C3 straight-chain or branched alkyl or a C1-C3 straight-chain or branched heteroalkyl containing an O, N, or S atom; (2) [ka] [In the formula, R a is as defined above, and R b is R or -PS(NR c1 R c2 ) and R c1 and R c2are independently C1-C6 straight or branched alkyl or C1-C6 cycloalkyl, and R is as defined above; (3) [ka] [In the formula, R d teeth, (a)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) a C1-C8 straight or branched alkyl optionally substituted with one, two, or three substituents independently selected from the substituents in Group 1 above; or (b) optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-C6 straight or branched alkyl; (i) 1, 2, 3, 4, 5, or 6 fluorine atoms, and / or (ii) one or two substituents independently selected from the substituents of Group 2 above; phenyl optionally substituted with is], (4) [ka] wherein X is Cl, Br, or I; (5) [ka] [In the formula, R x and R y are independently H or C1-C3 straight chain or branched alkyl; (6) [ka] wherein G1 and G2 are independently selected from the group consisting of O, S, and NR. (7) Diclofenac component, celecoxib component, gemcitabine component, entecavir component, emtricitabine component, axitinib component, batimastat component, bosutinib component, crizotinib component, erlotinib component, gefitinib component, erlotinib component, everolimus component, temsirolimus component, ganetespib component, glasdegib component, imatinib component, lapatinib component a therapeutic agent component selected from the group consisting of a navitoclax component, a nilotinib component, a pazopanib component, a component, a luminespib component, an obatoclax component, a ruxolitinib component, a slidegib component, a sunitinib component, a trametinib component, a warfarin component, a daclatasvir component, an etoposide component, an atazanavir component, a pravastatin component, a dasatinib component, a didanosine component, and a stavudine component. is selected from the group consisting of and (B) The IB type linker is [ka] [In the formula, [ka] indicates the bond connecting the Type (Ib) linker to the therapeutic moiety, and # indicates the site of covalent attachment to the cannabinoid moiety; Y, Y1, and Y2 are independently absent, or Y, Y1, and Y2 are independently (a)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents in Group 1 above C1-C12 straight or branched alkyl optionally substituted with (b)(1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents of Group 1 above; C2-C12 straight or branched alkenyl optionally substituted with (c) containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S; (1) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (2) 1, 2, or 3 substituents selected from the substituents of Group 1 above; C1-C12 straight or branched heteroalkyl optionally substituted with (d)(1) phenyl, (2) halides, (3)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (4) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with a 6- to 10-membered aromatic optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (e) containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; (1) phenyl, (2) halides, (3) trifluoromethyl, (4)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (5) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with and a 6- to 10-membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from (f) containing 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, 3, 4, 5, or 6 substituents selected from the substituents of Group 1 above. C1-C24 straight or branched heteroalkyl optionally substituted with is selected from the group consisting of Ar is (a)(1) phenyl, (2) halides, (3)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with a 6- to 10-membered aromatic optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (b) contains 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S; (1) phenyl, (2) halides, (3) trifluoromethyl, (4)(i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched alkyl optionally substituted with (5) containing 1, 2, or 3 atoms independently selected from O, N, and S; (i) 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and / or (ii) 1, 2, or 3 substituents independently selected from the substituents of Group 2 above. C1-C6 straight or branched heteroalkyl optionally substituted with a 6- to 10-membered heteroaromatic ring optionally substituted with 1, 2, 3, or 4 substituents independently selected from Either R e , R f , and R g are independently R as defined above] selected from the group consisting of Type IB cannabinoid conjugate components, and (III) the therapeutic moiety is covalently attached to a hydroxy group of the cannabinoid moiety (IC) via a cannabinoid moiety (IC) linker, and the therapeutic moiety is a β-lactam antibiotic moiety; (a) the β-lactam antibiotic moiety is selected from the group consisting of a cephem moiety, a carbacephem moiety, a penem moiety, and a carbapenem moiety covalently attached at its 3-position to an IC-type linker; or (b) the β-lactam antibiotic moiety is a monobactam moiety covalently attached at its 2-position to the IC-type linker; IC-type cannabinoid conjugate component selected from the group consisting of A conjugate molecule having the formula: (Item 2) The cannabinoid conjugate component is a Type IC cannabinoid conjugate component, and the β-lactam antibiotic component has structural formula (A): [ka] wherein X is S, C, or O; 2a is the side chain of a cephem or a carbacephem, and R 2b is H or -OCH3] 2. The conjugate molecule according to item 1, wherein the conjugate molecule is within (Item 3) The cannabinoid conjugate component is a Type IC component and the β-lactam antibiotic component has structural formula (B): [ka] wherein W is S or C, and R 2c is the side chain of a penem or the side chain of a carbapenem, and when W is C, R 2d is H, —CH3, or phenyl, wherein said phenyl is optionally substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of halide, trifluoromethyl, C1-C6 straight chain or branched alkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, and C1-C6 straight chain or branched heteroalkyl containing 1, 2, or 3 atoms independently selected from O, N, and S and optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms. 2. The conjugate molecule according to item 1, wherein the conjugate molecule is within (Item 4) The IC type linker is a linker of group AB: [ka] wherein # represents a covalent bond site from an OH of a cannabinoid component to an oxygen atom, and ## represents a covalent bond site to a carbon atom of a carbonyl component of a carboxylic acid-bearing cannabinoid component; [ka] represents the bond covalently attaching the linker to the β-lactam antibiotic moiety; T is absent, -CH, -CHCH, or -CH-phenyl; Z is CR 1A R 2A and R 1A and R 2A are independently R] 4. The conjugate molecule according to item 2 or 3, selected from the group consisting of: (Item 5) The cannabinoid conjugate component is the Type IC component and the β-lactam antibiotic component has structural formula (C): [ka] [In the formula, R M3 is a monobactam substituent at the 3-position, and R M1 is the monobactam substituent at position 1] 2. The conjugate molecule according to item 1, wherein the conjugate molecule is within (Item 6) The IC type linker is a linker of group C: [ka] wherein #, ##, Z, and R are as defined for the linkers of group AB. (Item 7) formula [ka] [In the formula, PCAN is a platinum complex anti-neoplastic agent component; L pc is the PCAN linker, but may not be present, B is a target binding moiety, said target binding moiety being an antibody; L a is the active ingredient linker, A is an active ingredient, m is 1 to 30, n is 0 to 29, and the sum of m+n is 1 to 30; PCAN is (a) Central platinum atom, (b)(i) a first non-leaving ligand and a second non-leaving ligand; (ii) a first non-leaving ligand, a second non-leaving ligand, and a third non-leaving ligand; (iii) bidentate non-leaving ligands, and (iv) tridentate non-leaving ligands; a non-leaving ligand component selected from the group consisting of: (c)(i) a first leaving ligand, the first cannabinoid leaving ligand being bonded to the central platinum atom through a first oxygen atom of either (1) a first hydroxy group of a first cannabinoid leaving ligand or (2) a first carboxy group of the first cannabinoid leaving ligand; (ii) a first leaving ligand and a second leaving ligand, wherein the first leaving ligand is the first cannabinoid leaving ligand; and (iii) a bidentate leaving ligand, the first cannabinoid leaving ligand bonded to the central platinum atom via first and second oxygen atoms independently selected from: (1) the oxygen atom of a first hydroxy group of the first cannabinoid leaving ligand; (2) the oxygen atom of a second hydroxy group of the first cannabinoid leaving ligand; (3) the oxygen atom of a first carboxy group of the first cannabinoid leaving ligand; and (4) the oxygen atom of a second carboxy group of the first cannabinoid leaving ligand. a leaving ligand moiety selected from the group consisting of: [including A conjugate molecule having the formula: (Item 8) 9. The conjugate molecule of claim 7, wherein the leaving ligand component comprises the second leaving ligand, the second leaving ligand being the second cannabinoid leaving ligand attached to the central platinum atom via either (1) a second hydroxy group of the second cannabinoid leaving ligand or (2) a second carboxy group of the second cannabinoid leaving ligand. 8. The conjugate molecule of claim 7, wherein the leaving ligand component comprises the second leaving ligand, and the second leaving ligand is a leaving ligand of a platinum-conjugated anti-neoplastic agent selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, eptaplatin, lobaplatin, nedaplatin, and satraplatin. (Item 10) (d) a first axial ligand and a second axial ligand 10. The conjugate molecule according to any of items 7 to 9, further comprising: (Item 11) 11. The conjugate molecule of claim 10, wherein the first axial ligand is a first cannabinoid axial ligand attached to the central platinum atom via a first oxygen atom of either (1) a first hydroxy group of a first cannabinoid axial ligand or (2) a first carboxy group of the first cannabinoid axial ligand. (Item 12) 12. The conjugate molecule of claim 11, wherein the second axial ligand is a second cannabinoid axial ligand attached to the central platinum atom via a first oxygen atom of either (1) a first hydroxy group of the second cannabinoid axial ligand or (2) a first carboxy group of the second cannabinoid axial ligand. (Item 13) the first cannabinoid leaving ligand is (a) [ka] [In the formula, ** is the attachment point for the first cannabinoid leaving ligand;*** is the point of attachment to the central platinum atom, and (1) R 11 , R 12 , R 13 , and R 14 are independently R or (2) R 11 , R 12 , R 13 , and R 14 are connected to form one or more rings], and (b) [ka] [In the formula, ** , *** , R 11 , R 12 , R 13 , and R 14 is as defined above] 14. The conjugate molecule according to any of items 7 to 13, wherein the conjugate molecule is attached to the central platinum atom via a linker selected from the group consisting of: (Item 14) the second cannabinoid leaving ligand is [ka] [In the formula, ** , *** , R 11 , R 12 , R 13 , and R 14 is as defined above] 14. The platinum conjugate anti-neoplastic agent according to any of items 7 to 13, wherein the platinum conjugate is linked to the central platinum atom via a linker selected from the group consisting of: (Item 15) the first cannabinoid axial ligand is [ka] [ka] [In the formula, ** , *** , R11 , R 12 , R 13 , and R 14 is as defined above] 15. The conjugate molecule according to any of items 11 to 14, wherein said central platinum atom is linked via a linker selected from the group consisting of: (Item 16) the second cannabinoid axial ligand is [ka] [ka] [In the formula, ** , *** , R 11 , R 12 , R 13 , and R 14 is as defined above] 16. The conjugate molecule according to any of items 12 to 15, wherein said central platinum atom is linked via a linker selected from the group consisting of: (Item 17) formula [ka] [In the formula, PCAN is a platinum complex anti-neoplastic agent component; L pc is the PCAN linker, B is a target binding moiety, the target moiety being an antibody; L a is the active ingredient linker, A is an active ingredient, m is 1 to 30, n is 0 to 29, and the sum of m+n is 1 to 30; PCAN is (a) Central platinum atom, (b)(i) a first non-leaving ligand and a second non-leaving ligand; (ii) a first non-leaving ligand, a second non-leaving ligand, and a third non-leaving ligand; (iii) bidentate non-leaving ligands, and (iv) tridentate non-leaving ligands; a non-leaving ligand component selected from the group consisting of: (c)(i) a first leaving ligand; (ii) a first leaving ligand and a second leaving ligand, and (iii) bidentate leaving ligand a leaving ligand moiety selected from the group consisting of: (d) a first axial ligand and a second axial ligand, wherein the first axial ligand is a first cannabinoid axial ligand bonded to the central platinum atom through an oxygen atom of either (1) a first hydroxy group of the first cannabinoid axial ligand or (2) a first carboxy group of the first cannabinoid axial ligand. [including A conjugate molecule having the formula: (Item 18) 18. The conjugate molecule of claim 17, wherein the second axial ligand is a second cannabinoid axial ligand attached to the central platinum atom via (1) a first hydroxy group of the second cannabinoid axial ligand or (2) a first carboxy group of the second cannabinoid axial ligand. (Item 19) the first cannabinoid axial ligand is [ka] [In the formula, ** , *** , R 11 , R 12 , R 13 , and R 14 is as defined above] 19. The conjugate molecule according to claim 17 or 18, wherein said central platinum atom is linked via a linker selected from the group consisting of: (Item 20) the second cannabinoid axial ligand is [ka] [In the formula, ** , *** , R 11 , R 12 , R 13 , and R 14 is as defined above] 20. The conjugate molecule of claim 18 or 19, wherein the central platinum atom is linked via a linker selected from the group consisting of: (Item 21) 17. The conjugate molecule according to any one of items 7 to 16, wherein the first cannabinoid leaving ligand is provided by a cannabinoid selected from the group consisting of cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol, or an active metabolite thereof. (Item 22) 21. The conjugate molecule according to any one of items 8 to 16 and 20, wherein the second cannabinoid leaving ligand is provided by a cannabinoid selected from the group consisting of cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol, or an active metabolite thereof. (Item 23) 21. The conjugate molecule according to any one of items 17 to 20, wherein the first cannabinoid axial ligand is provided by a cannabinoid selected from the group consisting of cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol, or an active metabolite thereof. (Item 24) 24. The conjugate molecule according to any one of items 18 to 20 and 23, wherein the second cannabinoid axial ligand is provided by a cannabinoid selected from the group consisting of cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol, or an active metabolite thereof. (Item 25) 25. The conjugate molecule of any of items 7 to 24, wherein the first platinum-conjugated anti-neoplastic agent component is an isomer selected from the group consisting of cis isomers, trans isomers, λ stereoisomers, and δ stereoisomers. (Item 26) formula [ka] [In the formula, CBN is a cannabinoid compound L c is a cannabinoid moiety linker, but may be absent, B is a target binding moiety, said target binding moiety being an antibody; m is 1 to 30] A conjugate molecule having the formula: (Item 27) formula: [ka] [In the formula, CBN is a cannabinoid compound L c is a cannabinoid moiety linker, but may be absent, L a is the active ingredient linker, A is an active ingredient, and B is a.Cluster of differentiation (CD) antigens, b. checkpoint inhibitors, c. Vascular target antigen, d. stromal antigens, e. extracellular matrix antigen, f. circulating antigens, g. Interleukin h. Interleukin receptor, i. growth factors, j. a growth factor receptor selected from the group consisting of EGFR (ErbB1), FGFR, FGFR2, FGFR3, FGFR4, FGFR23, HER2 / neu, HER3, (ErbB3), HER4, PDGFRA, VEGFR1, VEGFR2, VEGFR3, EphA1, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB5, EphB6, EphB7, HGFR (c-Met), and IGF2R; K. Drugs, l. adhesion molecules, m. tumor necrosis factor, n.Tumor necrosis factor-related apoptosis-inducing ligand receptor, o. insulin receptor, p. receptor tyrosine kinase, q. Cytokine receptors, r. tropomyosin receptor kinase, s. integrin, t. immunoglobulin, or Antigens of infectious organisms [An antibody that binds to A conjugate molecule having the formula: (Item 28) formula [ka] [In the formula, CBN is a cannabinoid compound L c is a cannabinoid moiety linker, but may be absent, B is a target binding moiety, said target binding moiety being an antibody; L a is the active ingredient linker, A is an active ingredient, and n is 2 to 29. A conjugate molecule having the formula: (Item 29) 29. The conjugate molecule according to any of items 26 to 28, wherein the cannabinoid component is provided by a cannabinoid selected from the group consisting of cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol, and active metabolites thereof. (Item 30) formula [ka] [In the formula, CBN1 is the first cannabinoid component, L c1 is a first cannabinoid moiety linker, but may be absent; CBN2 is the second cannabinoid component, L c2 is a second cannabinoid moiety linker, but may be absent; B is a target binding moiety, said target binding moiety being an antibody; L a is the active ingredient linker, A is an active ingredient, and m1 and m2 are independently 1 to 30, n is 0 to 29, and the sum of m1, m2, and n is 2 to 30. A conjugate molecule having the formula: (Item 31) 31. The conjugate molecule of claim 30, wherein the first cannabinoid component and the second cannabinoid component are independently provided by a cannabinoid selected from the group consisting of cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol, and active metabolites thereof. (Item 32) 32. The conjugate molecule of item 31, wherein the cannabinoid is cannabidiol or cannabigerol. (Item 33) 33. The conjugated molecule according to any of items 1 to 32, wherein the antibody is selected from the group consisting of anti-idiotypic (anti-Id) antibodies, camelized antibodies, chimeric antibodies, disulfide-linked Fvs (sdFv), F(ab') fragments, Fab fragments, human antibodies, humanized antibodies, murine antibodies, intrabodies, monoclonal antibodies, bispecific antibodies, multispecific antibodies, and single-chain Fvs (scFv), and epitope-binding fragments thereof. (Item 34) The antibody (a) IgG, IgE, IgM, IgD, IgA, or IgY; (b) IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2, or (c) IgG2a or IgG2b 33. The conjugate molecule according to any of items 1 to 32, wherein (Item 35) 35. The conjugate molecule according to any of items 1 to 25 and 27 to 34, further comprising a second active ingredient linker and a second active ingredient. (Item 36) The second active ingredient is (a) a second cannabinoid component, or (b) a second cannabinoid conjugate moiety comprising a second cannabinoid moiety; (Item 37) 38. The conjugate molecule of claim 37, comprising (a) the second cannabinoid component or (b) the second cannabinoid conjugate component, wherein the first cannabinoid component and the second cannabinoid component are independently provided by a cannabinoid selected from the group consisting of cannabigerol, cannabichromene, cannabidiol, tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabiditriol, dehydrocannabifuran, cannabifuran, cannabichromanone, and cannabilipsol, and active metabolites thereof. (Item 38) 36. The conjugate molecule of claim 35, wherein the second active ingredient is an active ingredient that is not a cannabinoid conjugate component or a cannabinoid component. (Item 39) 39. A pharmaceutically acceptable salt of the conjugate molecule according to any of items 1 to 38. (Item 40) 39. A pharmaceutical composition comprising a conjugate molecule according to any of items 1 to 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. (Item 41) 40. The pharmaceutical composition of item 39, comprising a racemic mixture of the conjugate molecule, a single enantiomer of the conjugate molecule, a mixture of diastereomers of the conjugate molecule, a mixture of double bond isomers of the conjugate molecule, a Z-double bond isomer of the conjugate molecule, an E-double bond isomer of the conjugate molecule, and / or an isotopic variant of the conjugate molecule. (Item 42) 42. The pharmaceutical composition of item 41, wherein the conjugate molecule comprises cis and trans isomers of the platinum-conjugated antineoplastic agent, comprises substantially only the cis isomer of the platinum-conjugated antineoplastic agent, comprises substantially only the trans isomer of the platinum-conjugated antineoplastic agent, comprises the λ and δ stereoisomers of the platinum-conjugated antineoplastic agent, comprises substantially only the λ stereoisomer of the platinum-conjugated antineoplastic agent, or comprises substantially only the δ stereoisomer of the platinum-conjugated antineoplastic agent. (Item 43) 43. A pharmaceutical composition according to any of items 40 to 42, comprising a delivery vehicle. (Item 44) 44. The pharmaceutical composition of item 43, wherein the delivery vehicle is selected from the group consisting of carbon nanotubes, carbon nanoparticles, PEGylated nanosized graphene oxide, gold nanoparticles, nanosized metal-organic frameworks, polysiloxane-containing nanoparticles, polymeric micelle nanoparticles, block copolymer micelle nanoparticles, and liposomes. (Item 45) 39. A method for treating a hyperproliferative disorder, comprising administering to a patient in need thereof a conjugate molecule according to any of items 1 to 38, or a pharmaceutically acceptable salt thereof. (Item 46) 46. ​​The method of claim 45, wherein the hyperproliferative disorder is cancer. (Item 47) 47. The method of claim 46, wherein the conjugated molecule is administered in combination with a second cancer therapy. (Item 48) 39. A method for treating glaucoma or reversing central or peripheral anticholinergic disorders, comprising administering to a patient in need thereof a type IA conjugate molecule according to any of items 1, 29 and 32 to 38, or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent moiety is a physostigmine-based carbamate moiety. (Item 49) 39. A method for treating confusion or dementia, comprising administering to a patient in need thereof a Type IA conjugate molecule according to any of items 1, 29 and 32 to 38, or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent moiety is a rivastigmine-based carbamate moiety. (Item 50) 39. A method for treating a bacterial infection, comprising administering to a patient in need thereof a type IC conjugate molecule according to any of items 1 to 6, 29, and 32 to 38, or a pharmaceutically acceptable salt thereof. (Item 51) 51. The method of claim 50, wherein the patient has cystic fibrosis and the at least first beta-lactam antibiotic component is a first monobactam component. (Item 52) 52. The method of claim 50 or 51, further comprising co-administering a beta-lactamase inhibitor to the patient. (Item 53) 39. A method for treating inflammation, comprising administering to a patient in need thereof a conjugated molecule according to any of items 1 to 38, or a pharmaceutically acceptable salt thereof. (Item 54) 54. The method of claim 53, wherein the inflammation is associated with a disorder selected from the group consisting of type 1 diabetes, cancer, Alzheimer's disease, cachexia, muscle wasting disease, allergy, rheumatoid arthritis, scleroderma, rheumatic fever, inflammatory bowel disease, myasthenia gravis, multiple sclerosis, Guillain-Barre syndrome, conjunctiva of the eye, systemic lupus erythematosus, encephalitis, adult respiratory distress syndrome, psoriasis, emphysema, and muscular dystrophy.

Claims

[Claim 1] The invention described in this specification.

Images