Cannabinoid prodrug compounds

Abstract

To provide cannabinoid prodrug compounds that enable site-specific delivery to an area of interest.SOLUTION: A prodrug compound of cannabidiol (CBD), pharmaceutical compositions thereof and methods of use thereof in patients in need are provided. In at least some embodiments, the prodrug compounds of the present invention target a member of the soluble carrier 15 (SLC15) peptide transport family, including the PEPT1 (Peptide transporter 1) transporter system and enhances the uptake of the cannabinoid by at least 2 folds, 3 folds, 4 folds or preferably at least 5 folds higher than the degree if the cannabinoid was being delivered in its natural form.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 906,228, filed on 26 September 2019, which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to cannabinoid prodrug compounds and methods for using such compounds in patients who require them. [Background technology]

[0003] Current scientific evidence suggests that cannabinoids play a role in maintaining homeostasis in the immune system as well as the central and peripheral nervous systems. The positive and negative feedback loops triggered by the action of cannabinoids alter various physiological processes. When normal equilibrium is not achieved, including those involved in neurological, endocrine, and oncolytic functions, a variety of diseases can arise.

[0004] Cannabinoids are compounds derived from hemp (Cannabis sativa), an annual plant belonging to the Cannabaceae family. This plant contains approximately 60 cannabinoids. The majority of the active and naturally occurring cannabinoids is tetrahydrocannabinol (THC), which is used to treat a wide range of conditions, including glaucoma, AIDS wasting syndrome, neuropathic pain, spasticity associated with multiple sclerosis, fibromyalgia, and chemotherapy-induced nausea. Furthermore, THC is particularly effective as an antiemetic and is administered to suppress vomiting, a common side effect associated with the use of opioid analgesics and anesthetics, remarkably effective antiretroviral therapies, and cancer chemotherapy.

[0005] Other cannabinoids or intermediate components that may be present in herbaceous cannabis include, but are not limited to, cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabinol (CBN), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabinolic acid (CBNA), and cannabidiol (CBD). Cannabidiol was previously considered an inactive component, but evidence is emerging that it has pharmacological activity that differs in some respects from that of THC. Furthermore, the medical use of cannabinoids has historically been hampered not only by the lack of standardized methods for verifying methodologies for manufacture, identification, and reproducibility, but also by the inability to precisely and specifically target the biochemistry and physiology of the body, as well as by the stability and other difficult physicochemical properties that limit the bioavailability and efficiency of these compounds with respect to delivery to specific sites. This invention addresses this drawback in the art. [Overview of the Initiative]

[0006] This patent document discloses cannabinoid prodrug compounds that provide site-specific delivery to a region of interest. At least one embodiment relates to a prodrug of cannabidiol (CBD). The prodrug compounds of the present invention overcome the physicochemical property deficiencies of CBD that limit formulation options while enhancing the delivery of CBD to a target site of interest. Furthermore, key pharmaceutically acceptable properties, including solubility, permeability or distribution, chemical or enzymatic stability, and transporter affinity, can be improved.

[0007] One aspect of this disclosure provides a prodrug compound represented by formula I: [ka] (In the formula, X is a) [ka] (In the formula, R1 is H, C 1-10 alkyl, C 1-4 alkyl-aryl, C 1-4 selected from the group consisting of alkyl and heteroaryl; R 2 is H, or optionally OH, SH, SC 1-4 alkyl, heteroaryl (e.g., indolyl), CONH2, COOH, NH2, NHC(NH)NH2, imidazolyl, or aryl (e.g., phenyl) (optionally substituted with C 1-4 alkyl or OH) and is optionally substituted, C 1-10 alkyl, R 3 is C 1-10 alkyl, C 1-4 alkyl-aryl, C 1-4 alkyl-heteroaryl, and

Chemical formula

[0008] Another embodiment discloses a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I for use in the treatment of cancer.

[0009] In some embodiments, the present invention provides a kit comprising a compound of formula I or a pharmaceutical composition of said compound. In some embodiments, the kit further comprises one or more additional therapeutic agents used in combination with the composition comprising formula I.

[0010] In at least some embodiments, the prodrug compounds of the present invention target members of the soluble carrier 15 (SLC15) peptide transport family, including, but not limited to, the PEPT1 (peptide transporter 1) transporter system, and enhance cannabinoid uptake by at least 2, 3, 4, or preferably at least 5 times higher than when cannabinoids are delivered in their natural form. In one embodiment, the cannabinoid is CBD. In at least one embodiment, the peptide transport system is PEPT1.

[0011] Another aspect of this patent document discloses a method for modulating the GPR55 receptor at a target tissue site. In some embodiments, preferred modulation involves inhibiting GPR55 by administering an effective amount of a compound of formula I to a patient requiring such a compound, thereby inhibiting or reducing GPR55 activation at a target tissue site. Another embodiment discloses a method for treating a target cancer. This method includes the step of administering a compound of formula I or a pharmaceutical composition of said compound to a subject in need. [Brief explanation of the drawing]

[0012] [Figure 1]Figure 1 shows that compound A inhibits the proliferation of the human pancreatic tumor cell line HPAF-11. [Figure 2] Figure 2 shows that compound A, when combined with gemcitabine, inhibits HPAF-11 proliferation more effectively than compound A or gemcitabine alone. [Figure 3] Figure 3 shows that compound A can reduce phospho-ERK levels in HPAF-11 pancreatic tumor cells. [Figure 4] Figures 4(a) and 4(b) show that compound A inhibits the proliferation of human mkn1 gastric tumor cells. [Figure 5] Figures 5(a) and 5(b) show that compound A enhances gemcitabine's inhibition of human mkn1 gastric tumor cell proliferation. [Figure 6] Figures 6(a) and 6(b) show that compound A inhibits the proliferation of human hct116 colorectal tumor cells. [Figure 7] Figures 7(a) and 7(b) show that compound a inhibits the proliferation of human h727 lung tumor cells. [Figure 8] Figures 8(a) and 8(b) show that compound a enhances gemcitabine's inhibition of growth in human H727 lung tumor cells. [Figure 9] Figure 9 shows the synthesis of compound A. [Figure 10] Figure 10 shows the properties of compound A determined by NMR. [Modes for carrying out the invention]

[0013] Various embodiments of this patent document disclose methods of administering a prodrug of cannabidiol (CBD) and a cannabinoid prodrug targeting PEPT1 to a patient who needs the treatment. In at least one aspect, the present invention is directed to a method of inhibiting GPR55 and treating cancer in a patient who needs it. Advantages of the prodrug include high permeability, stability, and / or excellent bioavailability after oral administration. The prodrug can be activated by an endogenous or exogenous enzyme, protein, or appropriate biological conditions.

[0014] Here, some examples of the present disclosure will be more fully described below with respect to the illustrated embodiments. In fact, various aspects of the present disclosure can be embodied in many different forms and should not be construed as limited to the examples described herein. Rather, these examples are provided so that this disclosure will be thorough and complete and will fully convey the scope of the disclosure to those skilled in the art.

[0015] The articles "a" and "an", as used in this specification, represent "one or more" or "at least one" unless otherwise specified. That is, a reference to any element or component of an embodiment by the indefinite article "a" or "an" does not exclude the possibility that more than one element or component exists.

[0016] The term "about", as used in this specification, represents the recited numerical value ± 10% of the recited numerical value.

[0017] The term "C 1-5 alkyl", as used in this specification, represents a linear or branched alkyl group having 1, 2, 3, 4, or 5 carbons. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, etc. Similarly, the term "C 1-10 alkyl", as used in this specification, represents a linear or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons.

[0018] The term "aryl" refers to the aromatic moiety of monocyclic and fused dicyclic rings. Typically, this ring system contains 5 to 12 ring member atoms. Examples of aryl groups, but not limited to, include phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Heteroaryl" refers to an aromatic monocyclic and fused dicyclic heterocyclic ring that contains one or more heteroatoms selected from N, O, and S in the aromatic ring system, and which may be optionally substituted. Heteroatom inclusion allows for the inclusion of 5-membered and 6-membered rings. Examples of aryl groups, though not limited to them, include indolyl, azaindolyl, imidazolyl, pyrimidopyridyl, quinazolinyl, quinoxalinyl, naphthyridinyl, purinyl, imidizopyridinyl, furopyridinyl, isoindolylinyl, benzodioxynyl, dihydrobenzodioxynyl, benzothiazolyl, pyrrolopyridinyl, dihydropyrrolopyridinyl, benzimidazolyl, imidazopyridinyl, dihydroimidazopyridinyl, tetrahydroisoindolyl, clomenyl, benzothiophene, benzotriazolyl, benzofuranyl, benzoxadiazolyl, indazolyl, quinolinyl, and isoquinolinyl.

[0019] The term "subject" refers to a human or an animal.

[0020] The term “treating” and its derivatives, as used herein, means a therapeutically effective regimen for a patient in need of such treatment. With respect to a particular medical condition, treating means (1) relieving or preventing one or more of the biological findings of that condition; (2) (a) preventing one or more points in the biological cascade that gives rise to or contributes to that condition; or (b) preventing one or more of the biological findings of that condition; (3) reducing one or more of the symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the condition or one or more of its biological findings. Preventive treatment is also intended by this. Those skilled in the art will understand that “prevention” is not an absolute term. In medicine, “prevention” is understood to mean the preventive administration of a drug to substantially reduce the likelihood or severity of a medical condition or its biological findings, or to delay the onset of such condition or its biological findings. Preventive treatment is appropriate, for example, when a subject is considered to be at high risk of developing cancer, such as when the subject has a strong family history of cancer or has been exposed to carcinogens.

[0021] The term “therapeutically effective dose” or “effective dose” refers to the amount of a drug or pharmacological agent that elicits a biological or medical response in a tissue, system, animal, or human, as perceived by, for example, a researcher or clinician. Furthermore, the term “therapeutically effective dose” means any amount that results in an improved treatment, cure, prevention, or remission of a disease, disorder, or side effect, or a reduction in the rate of progression of the disease or disorder, compared to a corresponding subject that did not receive that amount. The term also includes amounts effective for enhancing normal physiological function.

[0022] The term “specific period” and its derivatives, as used herein, refers to the time interval between the administration of one of the drug components of the combination of the present invention and the drug component of the other. Unless otherwise defined, a specific period may include simultaneous administration. In one embodiment of a combination of two drug components, if both compounds of the present invention are administered once daily, the specific period refers to the timing of the administration of one drug and the other drug in the relevant order within a day. If one or both compounds of the present invention are administered more than once daily, the specific period is calculated based on the first administration of each compound on a specific day. All subsequent administrations of the compounds of the present invention within a specific day are not considered when calculating the specific period.

[0023] G protein-coupled receptors are active in many biological and neurological events, including, but not limited to, intoxication, anxiety, appetite, nausea, pain, sleep, and vomiting. GPR55 is a mammalian G protein and is expressed in, but not limited to, the cerebral cortex, appendix, lymph nodes, tonsils, spleen, lungs, gallbladder, and GI duct tissues (e.g., esophagus, salivary glands, small intestine, duodenum, rectum, colon, stomach, testes, mammary glands, and skin).

[0024] Cannabinoid receptor antagonists are used to treat a variety of conditions including inflammatory pain, reflex sympathetic dystrophy / causalgia, cataracts, macular degeneration, peripheral neuropathy, constrictive neuropathy, complex regional pain syndrome, nociceptive pain, neuropathic pain, fibromyalgia, scleroderma, chronic low back pain, visceral pain, acute ischemic pain, chronic pain, psoriasis, eczema, acute pain, postherpetic neuralgia (PHN), neuropathy, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, ocular pain, headaches of various etiologies including migraines, stroke, acute herpes zoster (shingles), pain-related disorders such as contact allodynia and hyperalgesia, and rheumatoid arthritis pain. Pain, osteoarthritis pain, back pain, cancer pain, toothache, muscle pain, breast pain, pain resulting from skin injury, fibromyalgia, neuritis, sciatica, inflammation, neurodegenerative diseases, cough, bronchial stenosis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, cerebral ischemia, vomiting, vomiting induced by cancer chemotherapy, rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, dermatitis, seasonal allergic rhinitis, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disorders, irritable bowel syndrome, cutaneous T-cell lymphoma, multiple sclerosis, osteoarthritis, psoriasis, systemic lupus erythematosus, diabetes, glaucoma, osteoporosis, glomerulonephritis, renal ischemia, nephritis, hepatitis, stroke (cerebral It can be used to treat a variety of diseases, including stroke, vasculitis, myocardial infarction, cerebral ischemia, reversible airway obstruction, adult respiratory disease syndromes, chronic obstructive pulmonary disease (COPD), idiopathic fibrotic alveolitis, and bronchitis.

[0025] Cannabidiol (CBD) is a plant-derived cannabinoid. CBD exhibits its physiological effects through mechanisms different from those of psychoactivity such as THC. For example, CBD exerts an antidepressant effect by binding to the hydroxytryptamine serotonin receptor (HTSR) of the G-coupled protein receptor. HTSR is another member of the GPR family. Cannabidiolic acid (CBDA), another plant cannabinoid, has an even stronger affinity for HTSR. The binding of CBD or CBDA inhibits HTSR signaling, requiring stronger signals of serotonin or related excitatory neurotransmitters. CBD has a profound antagonistic effect on GPR55 regarding the regulation of its bone density and blood pressure. Also, CBD is receptor-active in the cerebellum, jejunum, and ileum. CBD derivatives have significant potential in the treatment of various GPR55-related diseases.

[0026] One aspect of this patent document provides a CBD prodrug compound of formula I:

Chemical formula

Chemical formula

[0027] In some embodiments, the compound is [ka] (In the formula, R 1 and R 2 These are H and R respectively. 3 C 1-10 It is alkyl, and in some embodiments, R 2 and R 3 These are OH, SH, and SC, respectively. 1-4 Alkyl, heteroaryl (e.g., indolyl), CONH2, COOH, NH2, NHC(NH)NH2, imidazolyl, or aryl (e.g., phenyl) (optionally C 1-4 C (which may be optionally substituted with alkyl and / or OH) 1-10 (It is alkyl.) That is the case.

[0028] In some embodiments, the compound is represented by formula Ia, R 3 teeth, [ka] And R 1 H is R c H is and m is 1 to 4. In some embodiments, R 2 This may be optionally substituted with OH, SH, SMe, or NH2, C 1-4 It is alkyl, R a OH is R b This may be optionally replaced with OH, SH, SMe, CONH2, COOH, NH2, or NHC(NH)NH2. 1-4 It is an alkyl group, and m is 1.

[0029] In some embodiments, each [ka] These are independently derived from lysine, leucine, isoleucine, glycine, aspartic acid, glutamic acid, methionine, alanine, valine, proline, histidine, tyrosine, serine, arginine, phenylalanine, or tryptophan. In some embodiments, [ka] It is derived from aspartic acid.

[0030] In some embodiments, each [ka] It is independently derived from glycine, aspartic acid, glutamic acid, methionine, alanine, valine, proline, histidine, tyrosine, serine, arginine, phenylalanine, or tryptophan, R 1 and R 2 These are H and C, respectively, independently. 1-10 Alkyl, C1-4 Alkyl-aryl, C 1-4 Selected from the group consisting of alkyl-heteroaryl compounds.

[0031] R 3 An exemplary embodiment relating to this is as follows, when X is equation Xa:

[0032] Table 1 [Table 1]

[0033] In some embodiments, the compound is [ka] (In the formula, R 4 (is H) That is the case.

[0034] In some embodiments, the compound is [ka] And, [ka] It can also be represented as follows. In some embodiments, n is 2 or 3. The amino acid residue represents a structure resulting from the formation of an amide bond between adjacent amino acids. The amino acid may be a synthetic or naturally occurring amino acid. In some embodiments, the amino acid is an α-amino acid. In some embodiments, the amino acid is in an L-configuration (L-stereoconfiguration). In some embodiments, the amino acid has polar terminal ends.

[0035] In some embodiments, the amino acid residues of formula Ic are independently lysine (Lys), leucine (Leu), isoleucine (Ile), glycine (Gly), aspartic acid (Asp), glutamic acid (Glu), methionine (Met), alanine (Ala), valine (Val), proline (Pro), histidine (H) (is), tyrosine (Tyr), serine (Ser), Nord-leucine (Norleucine) (Nor), arginine (Arg), phenylalanine (Phe), tryptophan (Trp), hydroxyproline (Hyp), homoserine (Hsr), carnitine (Car), ornithine (Ort), canavanine (Kana) Derived from canavanine (Cav), asparagine (Asn), glutamine (Gln), carnosine (Can), taurine (Tau), deujenkolic acid (Djk), gamma-aminobutyric acid (GABA), cysteine ​​(Cys), cystine (dcy), sarcosine (Sar), methionine (Thr), and their derivatives and / or analogs.

[0036] In some embodiments, the amino acid residues of formula Ic are independently selected from the group consisting of Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys, and Ser, and any combination thereof. In some embodiments, the amino acid terminus may be presented in a polar state that carries a charge. In some embodiments, the amino acid terminus may be a positively charged amino acid residue. In some embodiments, -NH3 +The terminal ends of the amino acid residues supporting the amino acid may be exposed. In some embodiments, the terminal ends of the amino acid residues may be negatively charged. In some embodiments, the amino acid is proline, lysine, or aspartic acid, or residues thereof, forming a prolyl, lysyl, or aspartyl bond. In some embodiments, the compound of formula Ic contains two amino acid residues. In some embodiments, the compound of formula Ic contains three amino acid residues.

[0037] An exemplary embodiment of formula Xc (wherein A represents an amino acid residue and n is an integer from 1 to 10) is as follows:

[0038] Table 2 [Table 2]

[0039] In some embodiments, the compound of formula I is formula Id. [ka]

[0040] In some embodiments, the compound of formula I is formula Ie. [ka] In some embodiments, carbonate groups generally improve the solubility of the compound. For example, R 10 R may be an alkyl group in which one or more carbon atoms are replaced with O, S, NH, or NH2. 10 Examples include CH2CH2SS, CH2CH2NH2, and CH2CH2O(CH2CH2). x OC 1-2 Examples include alkyl groups (where X is an integer that includes any number greater than or equal to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 10).

[0041] In some embodiments, the compound of formula I is formula If: [ka] (In the formula, R 11 This is an optionally substituted arylalkyl, sugar moiety, or C 1-10 It is alkyl, C 1-10 (One or more carbon atoms in the alkyl group are replaced with O, S, NH, or NH2). Examples of sugar moieties are: [ka] Examples of substituted arylalkyls are: [ka] (In the formula, the hydroxyl group may be glycosylated.) After the sugar portion is removed by enzyme, the elimination process 1-6 reveals the active ingredient.

[0042] The compounds of formula I may contain one or more chiral atoms, or may otherwise exist as two enantiomers and their suitable pharmaceutically acceptable salts. Thus, the compounds of the present invention include mixtures of enantiomers and purified enantiomers or mixtures containing a large amount of enantiomers. This principle of encompassing scope also applies to secondary agents such as “cytotoxic drugs” and “molecularly targeted drugs.” For example, the term “cisplatin” as used herein, when used in combination with the compounds of formula I, encompasses all of its tautomers and mixtures of tautomers, as well as its pharmaceutically acceptable solvates and / or salts, in exactly the same way as the term “cytotoxic drug.”

[0043] In exemplary embodiments relating to any of the compounds disclosed herein, the stereochemistry may be one of the following: [ka]

[0044] In further exemplary embodiments relating to any of the compounds of formula Xa disclosed herein, the stereochemistry may be one of the following: [ka]

[0045] In further exemplary embodiments relating to A of any of the compounds of formula Xc disclosed herein, the stereochemistry may be one of the following: [ka]

[0046] Any of the amino acid residues (for example, R in formula Xa) 3 In formula Xc(A), the stereochemistry can be R or S. In some embodiments, the amino acid residue portion is derived from a native amino acid. In some embodiments, the amino acid residue portion is derived from an essential amino acid.

[0047] The compounds of the present invention may form solvates, which are understood to be complexes of variable stoichiometry formed by a solute (in the present invention, the solute may be a compound of formula I or a salt thereof, accompanied by a cytotoxic drug or a salt thereof) and a solvent. Such solvents for the present invention should not interfere with the bioactivity of the solute. Examples of suitable solvents, but not limited to, include water, methanol, dimethyl sulfoxide, ethanol, and acetic acid. A suitably used solvent is a pharmaceutically acceptable solvent. A suitably used solvent is water.

[0048] In some embodiments, the process for synthesizing such prodrugs may follow well-known chemical steps, including the steps of protecting the amino acid moiety with a protective agent such as tert-butyloxycarbonyl (boc), using a suitable solvent system such as N,N.dicyclohexylcarbodiimide, or N,N-dimethylaminopyridine, trifluoroacetic acid (TFA), or DMF, and isolating the amino acid cannabinoid prodrug using a suitable separation step (see, for example, Vig et al. Pharm Res 2003; 20; 1381-8). In preferred embodiments, the purity of the prodrug compound may be in the range of 90% to 99%.

[0049] Various synthetic methods can be applied to the compounds disclosed herein. For example, in compounds having a carbamate moiety of formula Xa, the carbamate moiety can be constructed by alcoholization of chloroformamide, a reaction between chloroformate and an amine, or a reaction between isocyanate and an alcohol. In compounds having an acyloxymethyl ether moiety of formula Xb, this synthesis can be achieved by reacting a halomethyl ether with an acid in the presence of a base. Similarly, in compounds having an N-amidemethyl ether moiety of formula Xd, a reaction between a halomethyl ether and a primary or secondary amide in the presence of a base provides the desired compound. In compounds having a multipeptide moiety of formula Xc, the formation of the amide bond can be facilitated with coupling agents such as dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide (DIC). Compounds of formula Ie having a carbonate bond can be prepared, for example, by reacting an ester having an activated carbonyl with an alcohol. Ethers can be prepared by reacting a phenol with an alkyl halide in the presence of a base. Furthermore, various other methods may be used for any of the compounds disclosed herein. Exemplary synthetic methods are provided in references such as Modern Organic Synthesis: An Introduction, 2nd Edition, Wiley, 2017 and Organic Synthesis: The Disconnection Approach 2nd Edition, Wiley, 2008.

[0050] In at least some embodiments, the present invention relates to a method for synthesizing the molecules in Table 1 by the following general synthesis process steps shown in Figure 9. In at least one embodiment, compound A is produced by the following process steps: [ka]

[0051] Another aspect of this patent document provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described compound or a salt thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable salt may be an inorganic salt or an organic salt. The inorganic salt may be a salt of hydrochloric acid, phosphoric acid, sulfuric acid, or disulfuric acid. Further examples include calcium salts, sodium salts, magnesium salts, strontium salts, or potassium salts. The organic salt may be a salt of malic acid, maleic acid, citric acid, fumaric acid, besylic acid, camsylic acid, or edisylic acid.

[0052] The pharmaceutical composition may also contain one or more physiologically acceptable surfactants, further carriers, diluents, excipients, lubricants, suspending agents, film-forming substances, and coating aids, or combinations thereof. Further carriers or diluents acceptable for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated in whole by reference herein. Preservatives, stabilizers, colorants, sweeteners, fragrances, flavorings, etc., may be provided in the pharmaceutical composition. For example, esters of sodium benzoate, ascorbic acid, and p-hydroxybenzoic acid may be added as preservatives. Furthermore, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, etc., may be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminometasilicate, synthetic aluminum silicate, calcium carbonate, acidic sodium carbonate, calcium hydrogen phosphate, carboxymethylcellulose calcium, etc., may be used as excipients; magnesium stearate, talc, hydrogenated oils, etc., may be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean oil, etc., may be used as suspending agents or lubricants; cellulose phthalate acetate as a derivative of carbohydrates such as cellulose or sugar, or methyl acetate-methacrylate copolymer as a derivative of polyvinyl, may be used as suspending agents; plasticizers such as phthalate esters may be used as suspending agents.

[0053] The pharmaceutical composition may exist in unit dosage forms containing a predetermined amount of the active ingredient per unit dose. As is known to those skilled in the art, the amount of the active ingredient per dose varies depending on the condition being treated, the route of administration, and the patient's age, weight, and condition. Preferred unit dose formulations are those containing a daily dose or lower dose of the active ingredient, or appropriate fractions thereof. Furthermore, such pharmaceutical formulations may be prepared by any method well known in the field of medicine.

[0054] Another aspect of this patent document provides a kit comprising the compound or pharmaceutical composition described above. In some embodiments, the kit may comprise one or more secondary therapeutic compounds / active agents. The components of the kit may be provided in a form suitable for continuous administration, separate administration, and / or simultaneous administration. In some embodiments, the compounds may be administered simultaneously, and at least two of the compounds may be physically separate or in a single pharmaceutical composition such as a tablet. In some embodiments, the compounds are not administered simultaneously, and the kit here comprises the compound of formula I and the other components as drugs or pharmaceutically acceptable salts or solvates thereof in separate pharmaceutical compositions. The kit comprises the compound of formula I and the other components as drugs or pharmaceutically acceptable salts or solvates thereof in separate pharmaceutical compositions in a single package or in separate packages.

[0055] In some embodiments, the secondary active agent of this kit is a cytotoxic drug that has a cytotoxic effect on cells. Cytotoxic effect refers to the depletion, elimination, and / or killing of target cells (i.e., tumor cells). The cytotoxic drug may be at least one selected from the group consisting of antimetabolites, mitotic inhibitors, alkylating agents, platinum-based antineoplastic agents, antibody-based EGFR inhibitors, antibody-based HER2 / 3 inhibitors, angiogenesis inhibitors, mTOR inhibitors, CDK4 and CDK6 inhibitors, or aromatase inhibitors. This combination may include at least two cytotoxic drugs. For example, this combination may include at least two, at least three, at least four, or all of these selected from the group consisting of antimetabolites, mitotic inhibitors, alkylating agents, angiogenesis inhibitors, and platinum-based antineoplastic agents.

[0056] Antimetabolites are drugs that inhibit DNA synthesis in cells by suppressing the formation of purines or pyrimidines, which are bases of nucleotides. In one embodiment, antimetabolites may be selected from the group consisting of capecitabine, 5-fluorouracil, gemcitabine, pemetrexed, methotrexate, 6-mercaptopurine, cladribine, cytarabine, doxifludine, phloxuridine, fludarabine, hydroxycarbamide, decarbazine, hydroxyurea, and asparaginase. In a more specific embodiment, the antimetabolite is a base analogue, and the term base analogue as used herein includes nucleotide and nucleoside analogues in addition to purine base analogues such as 5-fluorouracil.

[0057] Mitotic inhibitors may be microtubule destabilizers, microtubule stabilizers, or combinations thereof. Mitotic inhibitors may be selected from taxanes, vinca alkaloids, epothirone, or combinations thereof. In certain embodiments, the mitotic inhibitor is a taxane, including, but not limited to, paclitaxel, docetaxel, and cabaitaxel. In other specific embodiments, the mitotic inhibitor is a vinca alkaloid or derivative thereof, including, but not limited to, vinblastine, vincristine, vinflunin, vinorelbine, vincaminol, vinbrunin, vineridine, and vindesine.

[0058] Mitotic inhibitors include BT-062, HMN-214, eribulin mesylate, vindesine, EC-1069, EC-1456, EC-531, vintafolide, 2-methoxyestradiol, GTx-230, trastuzumab emtansine (T-DM1), chloribulin, D1302A-mytansinoid conjugate IMGN-529, lorbotuzumab meltansine, SAR-3419, SAR-566658, IMP-03138, and topotecan / vincristine. Combinations, BPH-8, phosphobrintromethamine, estramustine phosphate sodium, vincristine, vinflunin, vinorelbine, RX-21101, cabazitaxel, STA-9584, vinblastine, epotilone A, patopilone, ixabepyrone, epotilone D, paclitaxel, docetaxel, DJ-927, discodermorid, eryuterobin, and their pharmaceutically acceptable salts or combinations may be selected.

[0059] Angiogenesis inhibitors are substances that inhibit the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous, being part of the body's normal control, while others are obtained exogenously through compounded medications or diet. In at least one embodiment, angiogenesis inhibitors include bevacizumab, sunitinib, sorafenib, or pazopatinib.

[0060] Platinum-based anti-cancer drugs may be selected from the group consisting of cisplatin, carboplatin, dicycloplatin, eptaplatin, lovaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, and satraplatin.

[0061] As used herein, “molecularly targeted drug” is a substance that, when administered to a target, interferes with the function of a single molecule or group of molecules, preferably a function involved in tumor growth and progression. Non-limiting examples of molecularly targeted drugs of the present invention include signaling inhibitors, gene expression and other cellular function modifiers, immune system modifiers, antibody-drug conjugates (ADCs), and combinations thereof.

[0062] Molecularly targeted drugs include epidermal growth factor receptor family inhibitors (EGFRi), mTOR (mammalian target of rapamycin) inhibitors, immune checkpoint inhibitors, anaplastic lymphoma kinase (ALK) inhibitors, B-cell lymphoma-2 (BCL-2) inhibitors, B-Raf inhibitors, cyclin-dependent kinase inhibitors (CDKi), such as CDK4 / CDK6 inhibitors, palbociclib, ERK inhibitors, histone deacetylase inhibitors (HDACi), heat shock protein 90 inhibitors (HSP90i), Janus kinase inhibitors, mitogen-activated protein kinase (MAPK) inhibitors, MEK inhibitors, such as MEK1 / MEK2 inhibitors, trametinib, poly-ADP-ribose polymerase (PARP) inhibitors, phosphoinositide 3 kinase inhibitors (PI3Ki), Ras inhibitors, and SGLT (sodium-glucose linked phosphoinositide 3 kinase inhibitors). Transporter inhibitors, PD-1 checkpoint inhibitors, such as nivolumab (Opdivo®), pembrolizumab (Keytruda®), atezolizumab, durvalumab, cempirimab, avelumab, and any combination thereof may be selected.

[0063] Suitable SGLT inhibitors, also known as sodium-dependent glucose cotransporter inhibitors, include inhibitors of sodium / glucose-coupled transporter 1 (SGLT1).

[0064] Molecularly targeted drugs include ado-trastuzumab emtansine (T-DM1), alemtuzumab, cetuximab, ipilimumab, ofatumumab, panitumumab, pertuzumab, rituximab, tocitumomab, 131I-tocitumomab, trastuzumab, brentuximab vedotin, denileukin difutitox, ibritumomab tiuxetan, axitinib, bortezomib, bosutinib, cabozantinib, crizotinib, carfilzomib, dasatinib, erlotinib, and gefitinib. The following may be selected: imatinib mesylate, lapatinib, nilotinib, pazopanib, ponatinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tofacitinib, vandetanib, vemurafenib, alitretinoin, bexarotene, everolimus, romidepsin, temsirolimus, tretinoin, vorinostat, nivolumab, pembroluzumab, atezolizumab, and their pharmaceutically acceptable salts or combinations.

[0065] EGFR inhibitors may be selected from erlotinib, gefitinib, lapatinib, canetinib, peritinib, neratinib, (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)buto-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazole-2-yl)-2-methylisonicotinamide, trastuzumab, margetuximab, panitumumab, matsuzumab, necitumumab, pertuzumab, nimotuzumab, zaltumumab, cetuximab, icotinib, afatinib, and their pharmaceutically acceptable salts. In one embodiment, the EGFR inhibitor may be an antibody-based EGFR inhibitor, such as cetuximab; in another embodiment, it may be nesitumumab; and in yet another embodiment, it may be panitumumab. The molecularly targeted drug may be an anti-EGFR family antibody or a conjugate containing an anti-EGFR family antibody. The anti-EGFR family antibody may be an anti-HER1 antibody, an anti-HER2 antibody, or an anti-HER4 antibody.

[0066] The kit may also be provided with instructions, such as dosage and administration instructions. Such dosage and administration instructions may be of the type provided to physicians on the drug label, or they may be of the type provided by physicians, such as instructions for patients.

[0067] Compounds of formula I or one or more additional active ingredients and combinations thereof may be incorporated into convenient dosage forms such as capsules, tablets, or injectable formulations. Solid or liquid pharmaceutical carriers may be used. Examples of solid carriers include starch, lactose, calcium sulfate dihydrate, clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, carriers may contain sustained-release substances, such as glyceryl monostearate or glyceryl distearate, either alone or with wax. The amount of solid carrier varies widely, but can be about 25 mg to about 1 g / dosage unit as appropriate. When liquid carriers are used, formulations may be in the form of syrups, elixirs, emulsions, soft gelatin capsules, sterile injectable liquids such as ampoules, or aqueous or non-aqueous liquid suspensions as appropriate.

[0068] For example, in oral administration in the form of tablets or capsules, the active drug components may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier, such as ethanol, glycerol, or water. Powders are prepared by grinding the compound to a suitable fine size and mixing it with a similarly ground pharmaceutically acceptable carrier, such as edible carbohydrates, such as starch or mannitol. One or more of flavoring agents, preservatives, dispersants, and coloring agents may also be present.

[0069] In addition to the ingredients mentioned above, please understand that this formulation may contain other active ingredients common in the field, depending on the type of formulation in question. For example, formulations suitable for oral administration may contain flavoring agents.

[0070] The SLC15 (Solute Carrier 15) family of peptide transporters, also known as H +The conjugated oligopeptide cotransporter family is a group of membrane transporters known for their important roles in the cellular uptake of dipeptides and tripeptides (di / tripeptides). In at least one embodiment, the present invention relates to a method for enhancing uptake of the compound via transport to a desired tissue. In at least one embodiment, such transport systems include, but are not limited to, PEPT1, PEPT2, PHT1, PHT2, their associated subfamilies, or any combination thereof. In some embodiments, the present invention enhances cannabinoid uptake to at least 2, 3, 4, or preferably at least 5 times higher than when the cannabinoid is delivered in its natural form.

[0071] Another aspect of the present invention relates to a method for enhancing the uptake of the active portion of PEPT1 in tissues expressing PEPT1. PEPT1 has been described as nutritionally important due to its role in the intestinal absorption of small molecule peptides from food and the reabsorption of amino nitrogen bound to peptides derived from glomerular filtrate in the kidney (see Hu et al, Mole. Pharmaceutics 2008, 5, 1122-1130). PEPT1 also plays an important role in the delivery of therapeutic agents to cells. In some embodiments, the prodrugs described herein enhance the uptake of the cannabinoid's activity by at least 2, 3, 4, or preferably at least 5 times higher than when the cannabinoid is delivered in its natural form. In one embodiment, the cannabinoid is CBD. In at least one aspect of the present invention, the inventors propose a modified ALA-ASP-cannabinoid molecule and an ALA-Glu benzyl ester of the cannabinoid molecule as a prodrug having affinity for PEPT1. In one embodiment, the cannabinoid is THC or CBD, or a salt thereof.

[0072] Another aspect of this patent document provides a method for inhibiting GPR55, comprising the step of contacting GPR55 with a therapeutically effective amount of a compound of formula I, a salt thereof, or a pharmaceutical composition containing said compound. GPR55 is a G protein-coupled receptor activated by cannabinoids (CBs) and also activated by non-CBs with LPI (lysophosphatidylinositol), which is considered to be its putative endogenous ligand and potent agonist. It is a phospholipid receptor expressed in bone marrow, spleen, immune cells, endothelial cells, central nervous system, vascular structures, placenta, and throughout the intestines (duodenum, jejunum, ileum, and colon), and is also found in cancer tissues and cancer cell lines. Recent studies have shown that it can coexist with CB1 and CB2, act independently, or form heteromers to modulate downstream signaling based on the activation or inhibition of these receptors. Furthermore, CBD has been shown to affect cancer through four key pathways: the ERK pathway, the PI3K pathway, the ROS pathway, and the MAPK pathway. Therefore, in at least one embodiment, the use of CBD in treating cancer or improving patient outcomes in populations at risk of developing resistance to first-line cancer treatment is also considered. In at least one embodiment, the use of the novel compound of the present invention provides a longer period during which patients can observe drug resistance to first-line treatment compared to patients who received only first-line treatment.

[0073] GPR55 is overexpressed in several cancers, including pancreatic cancer, colorectal cancer, triple-negative breast cancer, and glioblastoma, increasing cell proliferation and tumor growth. Conversely, its inhibition reduces properties such as increased cell adhesion, enhanced migration / invasion (an indicator of metastasis), and increased cell division. Activation of GPR55 leads to increased intracellular Ca2+ and ERK phosphorylation. When GPR55 is activated, activated T cell nuclear factor (NFAT), NFκB (nuclear factor k-light chain-enhancer of activated B cells), and MAP kinases (p38 and ERK 1 / 2 MAK), which are involved in tumor migration, have been shown to be activated. Studies suggest that inhibition of GPR55 has therapeutic effects in many disease areas, including obesity, diabetes mellitus, inflammatory and neuropathic pain, vascular structures, cancer, inflammation, gastrointestinal diseases, and bone diseases. Overall, clinical trials have shown that high GPR55 expression correlates with decreased patient survival.

[0074] Because CBD exhibits inhibitory activity against GPR55, prodrug compounds of CBD are also expected to be effective against the same target. Furthermore, pharmacological inhibition of GPR55 with CBD has been shown to enhance the effects of gemcitabine in cancer treatment. In other embodiments, CBD may be used in combination with GRP55 inhibitors to delay, prevent, or minimize drug resistance to GRP55 inhibitors at receptor sites. For this reason, at least one embodiment will focus on the use of CBD in prolonging or maximizing the duration of GPR55 therapy compared to administration of the drug alone by reducing or decreasing the risk of drug therapy resistance at the site of interest. While not bound by any particular theory, the antagonistic effect of GPR55 is hypothesized to block the metastatic behavior (adhesion, invasion, and migration) of cancer cells and halt cancer cells in liver tissue. In some embodiments, GPR55 is overexpressed in tumor cells of the subject, whether animal or human.

[0075] In some embodiments, the present invention relates to treating cancer or killing tumor cells, which are selected from the group consisting of hepatocellular carcinoma, lung cancer (including non-small cell lung cancer), pancreatic cancer, gastric cancer, squamous cell carcinoma, ovarian cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, glioblastoma, leukemia (including chronic lymphocytic leukemia), and breast cancer, including triple-negative. In some embodiments, the cancer is pancreatic ductal adenocarcinoma or colorectal cancer. In some embodiments, tumor cells are screened for biomarkers specific to each of those cancers. In some embodiments, tumor cells may be screened for the expression of GPR 55 and PEPT1.

[0076] In at least one embodiment, the method relates to administering the prodrug compound to a patient in need to modulate and / or inhibit GPR55 to increase the patient's survival rate. In at least some embodiments, the treatment method relates to detecting the degree of GPR55 expression in a patient, administering a prodrug compound containing a cannabinoid portion, inhibiting GPR55 and reducing the proliferation of pancreatic cancer cells, and / or enhancing the antitumor effect of the cannabinoid, with respect to prolonging the survival rate of the patient in need of the treatment. In one embodiment, the cannabinoid is THC, CBD, a salt thereof, or any combination thereof. In some embodiments, the present invention relates to a method for treating a cancer-stricken subject in which GPR55 is overexpressed at the cellular level, the method comprising the steps of: obtaining a biological sample from the subject; determining the degree of GPR55 expression at the cellular level from the biological sample; and applying a prodrug to the biological sample to reduce or inhibit GPR55 activity.

[0077] Another aspect of this patent document provides a method for treating a target cancer. The method comprises the step of administering a therapeutically effective amount of a cannabinoid prodrug compound or a pharmaceutical composition described herein to the target. Non-limiting examples of cancer include pancreatic cancer, squamous cell carcinoma, ovarian cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, glioblastoma (GBM), liver cancer, and triple-negative breast cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma or colorectal cancer. In some embodiments, the subject is human.

[0078] In at least one embodiment, subjects may be screened for specific cancer biomarkers. In at least one embodiment, a sample of the subject's tissue, blood, or plasma may be independently analyzed for the degree of tissue expression of GPR 55 and PEPT1 or other cancer-specific biomarkers. In at least one embodiment, a method for treating the cancer of the subject, but not limited to, includes the steps of identifying subjects that show overexpression of cancer-specific biomarkers including GPR55 and / or PEPT1, and administering a compound of formula I to subjects that require it.

[0079] In some embodiments, the method further includes the step of administering a secondary active agent simultaneously with or immediately following the administration of a compound of formula I or a pharmaceutical composition thereof. The secondary active agent is as described above in this kit.

[0080] Appropriate routes of administration may include, for example, oral, rectal, transmucosal, topical, or intra-intestinal administration; intramuscular, subcutaneous, intravenous, intrathecal injection; and parenteral delivery including intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection. The compound may also be administered in sustained-release or extended-release formulations, including depot injections, osmotic pumps, pills, and transdermal (including electrotransport) patches, for long-term and / or time-limited pulsed administration at a predetermined rate.

[0081] For oral administration, drug compounds or compositions can be readily formulated by combining the compound or composition of interest with pharmaceutically acceptable carriers well known in the art, as described above. Such carriers, which may be used in addition to cationic polymer carriers, can be used to formulate compositions for oral intake by patients being treated, such as tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, and the like.

[0082] Injectable substances may be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid before injection, or emulsions. Suitable excipients include, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, monosodium glutamate, and cysteine ​​hydrochloride. Furthermore, if desired, injectable pharmaceutical compositions may include small amounts of non-toxic auxiliary substances, such as wetting agents and pH buffers. Physiologically compatible buffers include, but are not limited to, Hanks' solution, Ringer's solution, or saline buffer. Absorption enhancers may be used if desired.

[0083] For buccal administration, the composition may take the form of tablets or medicinal candies formulated using conventional methods. Administration via the buccal mucosa and sublingual administration are intended.

[0084] For inhalation administration, the composition can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer, using a suitable nebulizer, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dose unit can be determined by providing a valve for delivering a measured amount. Capsules and cartridges, for example, of gelatin for use in inhalers or inhalers, can be formulated containing a mixture of the compound and a suitable powder base, such as lactose or starch powder.

[0085] The therapeutically effective dose of the compound of formula I or a pharmaceutically acceptable salt thereof, as required as a dose, varies depending on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the specific animal under study. The dose may be adjusted to achieve the desired effect, but it may vary depending on factors such as body weight, diet, concomitant medications, and other factors recognized by those skilled in the art. More specifically, the therapeutically effective dose means the amount of compound effective in preventing, reducing, or relieving the symptoms of the disease being treated, or in prolonging survival. Determining the therapeutically effective dose may be achieved by those skilled in the art using established pharmacological methods. Typically, clinical application of a product in humans begins at a low dose level, which is increased until the desired effect is achieved. Alternatively, acceptable in vitro studies may be used to establish useful doses and routes of administration of the composition identified by this method using established pharmacological methods. In non-human animal studies, the application of a promising product begins at a high dose level, which is decreased until adverse side effects disappear and the desired effect is no longer achieved. The dose may range broadly depending on the desired effect and therapeutic indicator. Typically, the dose may be about 10 micrograms / kg to about 100 mg / kg body weight, preferably about 100 micrograms / kg to about 10 mg / kg body weight. Alternatively, the dose may be calculated based on the patient's surface area, as understood by those skilled in the art.

[0086] In at least one embodiment, the cannabinoid of the prodrug described herein is CBD. CBD exhibits low dose-dependent oral and oral mucosal bioavailability of about 35%. CBD administration via the IV route overcomes these limitations and results in the highest plasma CBD levels. In at least one embodiment, the effective dose is a dose that achieves the desired serum concentration of CBD in the range of about 400 ng / ml to about 1500 ng / ml. In at least one embodiment, the systemic drug delivery of the CBD prodrug is sufficient to enhance drug uptake and GPR 55 inhibition by PEPT1-expressing cells.

[0087] In some embodiments, the combination of the compound of the present invention with a second anticancer agent, such as a taxol derivative or gemcitabine derivative, provides a synergistic clinical response corresponding to at least a 10% improvement in targeting and killing tumor cells compared to the second anticancer agent alone. In some embodiments, the synergistic improvement may be due to increased intracellular uptake of the compound in the region of interest.

[0088] The precise formulation, route of administration, and dosage of this pharmaceutical composition may be selected by individual physicians in light of the target condition (see, for example, Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics,” which is incorporated in its entirety by reference herein, particularly with respect to Ch.1, p.1). In some embodiments, the dosage of the composition administered to the subject may range from about 0.5 to about 1000 mg / kg (patient's body weight). This dosage may be a single dose or a series of two or more doses provided over a period of one day or more, as required by the patient. In cases where human doses for the compound have been established for at least some conditions, the same dose, or a dose of about 0.1% to about 500%, more preferably about 25% to about 250%, of the established human dose may be used. In cases where human doses have not been established because it is a newly developed pharmaceutical composition, an appropriate human dose will be determined by ED. 50 Value or ID 50 It can be inferred from the values ​​themselves, or from other appropriate values ​​derived from in vitro or in vivo studies, which are quantified by animal toxicity and efficacy studies.

[0089] It should be noted that the attending physician is aware of how to terminate, interrupt, or adjust administration in the event of toxicity or organ failure, and when to do so. Conversely, the attending physician also knows how to adjust treatment to a higher level (while eliminating toxicity) if the clinical response is inadequate. The size of the dose administered in the management of the desired disorder will vary depending on the severity of the condition being treated and the route of administration. The severity of the condition can be assessed in part, for example, by standard prognostic assessment methods. Furthermore, the dose and possibly the frequency of administration will also vary depending on the age, weight, and response of the individual patient. A program comparable to those described above may be used in veterinary medicine.

[0090] While the exact dose is determined by drug-specific criteria, in most cases several generalities regarding dosage may be provided. A daily dose regimen for adult human patients may be, for example, an oral administration of about 0.1 mg to 2000 mg, preferably about 1 mg to 500 mg, for example, 5 to 200 mg of the active ingredient. In other embodiments, intravenous, subcutaneous, or intramuscular administration of about 0.01 mg to 100 mg, preferably about 0.1 mg to 60 mg, for example, about 1 to 40 mg of the active ingredient is used. In the case of administration of pharmaceutically acceptable salts, the dose may be calculated as free acid. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively, the composition may be administered by continuous intravenous infusion, preferably in doses up to about 1000 mg per day. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts exceeding or even significantly exceeding the preferred dose ranges described above, particularly to efficiently and aggressively treat invasive diseases or infections. In some embodiments, the compound is administered during a period of continuous treatment, for example, for more than one week, or for several months or years.

[0091] In at least some embodiments, the compounds in Tables 1 and 2 can provide effective inhibition of solid tumor cell line proliferation in a dose-dependent manner. Figures 4–6 provide examples of at least one such compound that can selectively target tumors co-expressing GPR55 / SCL15A1. In some embodiments, compound A offers a further advantage over other GPR55 antagonists in that it is co-targeted to SLC15A1 on the cell surface. This co-targeting may also increase the bioavailability of compound A in vivo compared to other GPR55 antagonists.

[0092] The dosage and interval of administration may be individually adjusted to provide sufficient plasma levels of the active portion to maintain antibiotic activity or the minimum effective concentration (MEC). While the MEC varies for each compound, it can be estimated from in vitro data. The dose required to achieve the MEC varies depending on the individual characteristics and route of administration. However, plasma concentrations can be determined using HPLC assays or bioassays.

[0093] The administration interval may also be determined using the MEC value. For example, the composition may be administered using a regimen that maintains plasma levels above the MEC for 10-90%, preferably 30-90%, and most preferably 50-90% of the time.

[0094] The compositions disclosed herein may be evaluated for efficacy and toxicity using known methods. For example, the toxicity of the compound may be established by determining its in vitro toxicity to cell lines, such as mammalian, preferably human cell lines. The results of such tests often predict toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit, or monkey, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for almost all classes of pathological conditions. Similarly, the efficacy of a chemical for treating a particular pathological condition may be evaluated using an acceptable animal model. When selecting a model to determine efficacy, those skilled in the art may refer to the latest technology to select an appropriate model, dose, and route of administration, as well as a regimen. Naturally, human clinical trials may also be used to determine the efficacy of a compound in humans.

[0095] With regard to the administration of a “specific period” in some embodiments during the course of treatment, the compound of Formula I or its combination with further active agents is administered within a specific period of at least 1, 2, 3, 5, 7, 14, or 30 days—in this case, the period is at least 1, 2, 3, 5, 7, 14, or 30 days. If, during the course of treatment, a single compound or individual components of a combination are administered within a specific period of 30 days, the treatment is considered a long-term treatment and continues until a modified event, such as a reassessment of the patient’s cancer status or a reassessment of changes in the disease state, signals a modification to the protocol.

[0096] In some embodiments, the compound of formula I and further active substances are administered within a “specific period” and not simultaneously, and both are administered within approximately 24, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 hour from each other—in this case, the specific period is approximately 24, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 hour. In one embodiment of a two-component drug combination as used herein, administration of the compound of formula I and the other component drug separated by less than approximately 45 minutes is considered simultaneous administration.

[0097] In some embodiments, when a combination of drugs disclosed herein is administered for a “specific period,” the compound is administered for a certain “duration.” The term “duration of time” and its derivatives, as used herein, means that both of the compounds or active substances disclosed herein are administered within a “specific period” for a number of consecutive days indicated, and then optionally for a number of consecutive days (in which case only one of the compound components is administered).

[0098] Examples MTT cell survival assay in HPAF-II (pancreatic) tumor cells method A 10 mM stock solution of compound A was prepared by dissolving 8.2 mg of compound A in powder form in 1.468 mL of DMSO to form the stock solution. The stock solution was aliquoted into 0.6 mL microcentrifuge tubes, and 20 μl of the solution was placed into each microcentrifuge tube.

[0099] MTT assay Pancreatic cancer cell line HPAF-II was seeded at 5000 cells / well in 96-well plates and incubated overnight at 37°C. The following day, the cells were treated by removing the cell medium in a triple cycle and replaced with fresh medium containing compound A alone at increasing concentrations (10 μM, 20 μM, 20 μM, 50 μM, 75 μM, 100 μM, 125 μM, 150 μM, 175 μM, 200 μM) and combinations of compound A at 10 μM and gemcitabine at increasing concentrations (0 μM, 0.01 μM, 0.05 μM, 0.1 μM, 0.5 μM, 1 μM, 5 μM, 10 μM). A drug vehicle (DMSO, Sigma) was used as a control for treatment. The cells were then grown in the presence of the drug for the next 72 hours.

[0100] After 72 hours, the culture medium was discarded, and the cells were incubated in fresh cell growth medium with a working concentration of 0.5 mg / ml MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) solution (5 mg / ml stock) at 37°C for 2 hours. This reaction was stopped when the majority of the cells were stained. The MTT solution was then aspirated, and the plate was dried for several hours. The stained cells were then resuspended in 70 μl of DMSO and thoroughly mixed. Absorbance was read at 570 nm using a plate-reading spectrophotometer. CompuSyn data for the drug combination of compound A and gemcitabine in each cell line were generated and analyzed using CompuSyn software, configured by Dr. Dorothy Chou and published by ComboSyn, Inc.

[0101] Figure 1 shows that compound A is effective in inhibiting the proliferation of the human pancreatic tumor cell line HPAF-11. As shown, at a concentration of 50 μM, compound A provides at least 50% elimination of pancreatic tumor cells, and at a concentration of approximately 175 μM, compound A can reduce elimination of tumor cells by more than 80%.

[0102] When combined with gemcitabine, a known anticancer therapeutic agent approved for the treatment of certain cancers, compound A can significantly enhance the growth inhibitory effect of gemcitabine. As provided herein, Figure 2 shows that compound A combined with gemcitabine inhibits HPAF-11 growth by at least 10% more than compound A or gemcitabine alone, resulting in an increased rate of cell killing.

[0103] The combination of compound A and gemcitabine in this example provides at least 5%, 10%, 15%, 20%, or 25% superior clinical utility compared to gemcitabine alone. These results suggest that compound A may provide effective antitumor activity against the condition of pancreatic cancer.

[0104] Cells were treated with compound A at the specified concentration in DMEM containing 10% FBS for 48 hours. ERK phosphorylation was evaluated by Western blotting using antibodies that detect total ERK and phospho-ERK. Actin detection was used as a loading control for total lysate protein.

[0105] As shown in Figure 3, cultures of compound A were able to efficiently reduce phospho-ERK levels in tumor cells compared to the control.

[0106] CellTiter-Glo® Cell Viability Assay material MKN1 (stomach), PC3 (prostate), NCIH727 (lung), and HCT116 (colorectal) tumor cell lines; control = 0.1% DMSO

[0107] To prepare a 10 mM FL41 stock from powder, 4.1 mg of FL41 powder was dissolved in 0.74 ml of DMSO, aliquoted, and stored at -20°C until use. DMSO stock from Sigma or other suitable vendors must be reagent or ACS grade or higher.

[0108] As shown in the 96-well plate diagram below, 5000 cells per well (200 μl) were placed in double rows in their preferred media. After reducing the final FBS (serum) concentration to 5%, the cells were added to the media. The cells were incubated overnight, then the old media was carefully removed, and fresh media containing 5% FBS was added. Then, DMSO alone, compound A alone, or in combination with GEM (gemcitabine) was added to the wells at the final concentrations indicated. The cells were incubated in a CO2 incubator for a further 72 hours at 37°C in the presence of the compounds. At the end of the 72-hour period, Promega Titerglo reagent was added to the wells, and the relative cell count was assessed by measuring the luminescence.

[0109] In at least this embodiment, compound A can bind to both GPR55 and SLC15A1 (PEPT1). This selectively targets cancer cells that co-express these two receptors. RNA seg results of published cell lines have reported that several human tumor cell lines can co-express these two receptors at high levels. Here, these results indicate that a subset of these tested human tumor cell lines co-express the GPR55 and SLC15A1 proteins as determined by Western blotting. When looking at the effect of compound A alone on human tumor cells, these results indicate that compound A was able to inhibit the proliferation of HPAFII (pancreas), MKN1 (stomach), HCT116 (colorectal), H727 (lung), and PC3 (prostate) tumor cell lines compared to controls. Despite concentration-dependent inhibition, compound A can effectively inhibit cell line proliferation in each of the aforementioned cell lines.

[0110] Figures 4(a) and 4(b) show that compound A inhibits the proliferation of human mkn1 gastric tumor cells. Figures 5(a) and 5(b) show that compound A synergistically affects gemcitabine's inhibition of human mkn1 gastric tumor cell proliferation. Figures 6(a) and 6(b) show that compound A inhibits the proliferation of human hct116 colorectal tumor cells. Figures 7(a) and 7(b) show that compound A inhibits the proliferation of human h727 lung tumor cells. Figures 8(a) and 8(b) show that compound A enhances gemcitabine's inhibition of human h727 lung tumor cell proliferation.

[0111] The property of compound A to inhibit the proliferation of solid tumor cell lines suggests potential for the development of anticancer drugs that can selectively target tumors co-expressing GPR55 / SCL15A1. Compound A may offer an advantage over other GPR55 antagonists by being co-targeted to SLC15A1 on the cell surface. This co-targeting may also increase the bioavailability of compound A in vivo compared to other GPR55 antagonists.

[0112] Many modifications and other examples of the disclosure described herein, having the advantages of the teachings presented in the above description and the associated drawings, will be recalled by those skilled in the art who are involved in this disclosure. Therefore, it should be understood that this disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims.

[0113] Furthermore, while the above description and related embodiments describe aspects of this disclosure in the context of specific combinations of structural elements and / or functions, it should be understood that different combinations of elements and / or functions may be provided by other embodiments without departing from the scope of the appended claims. In this regard, for example, it is intended that different combinations of elements and / or functions other than those specified above may also be described as part of the appended claims. Certain terms are used herein, but these are used merely in a general and descriptive sense and not to limit.

Claims

1. Formula Ic: 【Chemistry 1】 A compound represented by the formula, in which, A is an amino acid residue, and each A independently 【Chemistry 2】 This is expressed by, where, R ５ It is either H, or OH, SH, SC １－４ Alkyl, heteroaryl, CONH ２ COOH, NH ２ ,NHC(NH)NH ２ , imidazolyl, or aryl (C １－４ C may be substituted with alkyl or OH. １－１０ It is alkyl, R ６ and R ７ are, in each case, independently H, or OH, SH, SC １－４ alkyl, heteroaryl, CONH ２ , COOH, NH ２ , or C １－１０ alkyl optionally substituted with aryl, provided that R ７ is a covalent bond to a carbonyl group when the amino acid residue is in a non-terminal position n is 2, R ５ and R ６ They may bond to form a 5-7 membered ring. compound.

2. The compound according to claim 1, wherein each A is independently selected from lysine, leucine, isoleucine, glycine, aspartic acid, glutamic acid, methionine, alanine, valine, proline, histidine, tyrosine, serine, arginine, phenylalanine, and tryptophan.

3. The compound according to claim 1, wherein each A is independently selected from lysine, leucine, isoleucine, glycine, aspartic acid, glutamic acid, methionine, and alanine.

4. At least one of A is 【Transformation 3】 The compound according to any one of claims 1 to 3.

5. At least one of A is 【Chemistry 4】 The compound according to any one of claims 1 to 3.

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 5.

7. A kit comprising a compound according to any one of claims 1 to 5, and a secondary active agent selected from the group consisting of antimetabolites, immune checkpoint inhibitors, mitotic inhibitors, alkylating agents, platinum-based anti-cancer agents, antibody-based EGFR inhibitors, antibody-based HER2 / 3 inhibitors, angiogenesis inhibitors, mTOR inhibitors, CDK4 inhibitors, CDK6 inhibitors, and aromatase inhibitors.

8. The kit according to claim 7, wherein the secondary active substance is gemcitabine.

9. A composition for use in inhibiting GPR55, comprising a compound according to any one of claims 1 to 5.

10. The composition according to claim 9, wherein GPR55 is associated with increased ERK phosphorylation.

11. The composition according to claim 9 or 10, wherein GPR55 is overexpressed in the target tumor cells.

12. A composition for use in adjusting PEPT1, comprising a compound according to any one of claims 1 to 5.

13. A composition for use in treating a disease in a subject, comprising the compound described in any one of claims 1 to 5, The aforementioned diseases are selected from the group consisting of cancer, obesity, diabetes mellitus, inflammatory and neuropathic pain, inflammation, gastrointestinal diseases, and bone diseases. composition.

14. The composition according to claim 13, wherein the cancer is selected from the group consisting of lung cancer, stomach cancer, pancreatic cancer, squamous cell carcinoma, ovarian cancer, prostate cancer, colorectal cancer, ovarian cancer, cholangiocarcinoma, glioblastoma, and triple-negative breast cancer.

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