Lymph directing prodrugs

Abstract

To develop novel lipid-pharmaceutical agent conjugates that facilitate stable transport of the pharmaceutical agent to the intestinal lymph.SOLUTION: The present invention relates to compounds and uses thereof and particularly to compounds in the form of prodrugs that promote transport of a pharmaceutical agent to the lymphatic system and subsequently enhance release of the parent drug.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to compounds in the form of prodrugs, and in particular to compounds that promote the transport of drugs to the lymphatic system and subsequently improve the release of the parent drug.

Background Art

[0002] The lymphatic system consists of a specialized network of vessels, nodules, and lymphoid tissues that are closely associated with the vascular system and distributed throughout the body. The lymphatic system plays a number of important roles in immune responses, fluid balance, nutrient absorption, lipid homeostasis, and tumor metastasis. Due to the unique anatomical and physiological characteristics of the lymphatic system, targeted drug delivery to and through the lymphatic system has been proposed as a means of improving both pharmacokinetic and pharmacodynamic profiles. Lymphatic drug transport has the potential to improve oral bioavailability through avoidance of first-pass metabolism, alter systemic pharmacokinetics, and improve efficacy against lymph- or lymphocyte-mediated pathologies such as lymphoma, leukemia, lymphatic tumor metastasis, autoimmune diseases, lymphotropic infections, and transplant rejection.

[0003] For drugs to access the intestinal lymph, they must first associate with the lipoproteins of intestinal lymph that are collected in intestinal absorptive cells (enterocytes) in response to lipid absorption. Due to their size, rapid diffusion across the entire vascular endothelium reinforcing the capillaries through which the contents of the small intestine flow out becomes impossible, and this association with these lipoproteins promotes the subsequent transport of the drug into the lymph. Instead, lymphatic endothelium is considerably more permeable than vascular endothelium, so these large colloidal structures enter lymphatic capillaries. Historically, drugs with high lymph transport to promote physical association with lipoproteins are highly lipophilic (usually, but not limited to, logD > 5 and solubility exceeding 50 mg / g in long-chain triglycerides). Thus, highly lipophilic analogs of drugs are envisioned as one way to promote lymph transport of drugs. However, chemical modification of the parent drug can result in a decrease in efficacy, and in many cases, a significant increase in lipophilicity correlates with an increase in toxicity.

[0004] Compounds in the form of lipophilic prodrugs provide a means to temporarily increase the lipophilicity and lipoprotein affinity of pharmaceuticals, thereby increasing lymphatic targeting. Transported via the lymphatic system, the prodrug ultimately reverts to the parent drug to be active at its target site.

[0005] There have been several attempts to exploit the potential of simple aliphatic esters of drugs used as lymphotrophic prodrugs. Testosterone undecanoate provides an example of a commercially available compound where this approach has been utilized. After oral administration, testosterone is almost completely metabolized during its first pass through the liver, resulting in minimal bioavailability. The undecanoate ester of testosterone redirects a small percentage of the absorbed dose towards the lymphatic system, thereby avoiding first-pass metabolism in the liver and increasing the oral bioavailability of testosterone. However, this process remains highly inefficient, and the bioavailability of testosterone after oral administration of the undecanoate ester is thought to be < 5%.

[0006] Another mechanism for promoting the lymphatic transport of drugs is to employ prodrugs incorporated into the endogenous pathways related to the absorption, transport, and pharmacokinetics of dietary lipids. An example of a dietary lipid used as a prodrug is triglyceride. Examples of drug / lipid conjugates in which the parent drug contains an available carboxylic acid group and is directly linked to the glyceride backbone have been disclosed in a number of previous publications (Non-Patent Documents 1 to 6).

[0007] In other examples, short linkers are used to facilitate the binding of drugs that do not contain an available carboxylic acid to drug-triglycerides (Non-Patent Documents 7, 8). These drug-lipid conjugates employ succinic acid to facilitate binding to available hydroxyl functional groups. However, the literature teaches that this structure is not at all useful. For example, Scriba examined the in vitro hydrolysis of a testosterone-succinic acid-glyceride lipid conjugate and concluded that "testosterone is only very slowly released from the prodrug by chemical hydrolysis catalyzed by plasma esterase and mediated by lipase in this test, and thus the conjugate of testosterone appears to be an insufficient prodrug for steroid delivery."

[0008] Others employ ether bonds to glycerides and ester bonds to drugs (Non-Patent Documents 9, 10). The authors of these papers clearly state that the ether bond between glycerol and the n-alkyl chain and the ester bond between the n-alkyl chain and the drug are thought to be necessary for the chemical modification of the drug. However, the inventors have found that the ether bond actually produces undesirable effects and does not enable meaningful lymphatic transport.

Prior Art Documents

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Summary of the Invention

Problems to be Solved by the Invention

[0010] Therefore, there is a need to develop a novel lipid-drug conjugate that facilitates the stable transport of a drug to intestinal lymph and easily reverts to the prodrug to be active.

Means for Solving the Problems

[0011] (Summary of the Invention) It has been found here that the use of a specific "linker" for linking a drug to a triglyceride unit provides an optimal pharmacokinetic profile for a lipid-drug conjugate.

[0012] Accordingly, in one aspect, the present invention provides a compound of formula (I):

[0013] [Chemical formula]

[0014] wherein: R 1 and R 2 each independently represents H or a residue of a C2-C 28 fatty acid; -X- is selected from -O-, -NH- and -S-; -Y- represents an optionally substituted -C3-C 20 alkyl-, -C3-C 20 alkenyl- or -C3-C 20 alkynyl-group, wherein one or more of the carbon atoms in the alkyl, alkenyl or alkynyl group may be substituted by NH, S, O, a C5-C8 aromatic or aliphatic cyclic group, or a C5-C8 aromatic or aliphatic heterocyclic group, provided that the alkyl, alkenyl or alkynyl group does not exceed the length equivalent to a straight-chain C 20 alkyl group;

[0015] [Chemical formula]

[0016] represents a residue of a drug; -L- is -X'- or X'C(O)-; X' is O, S, N, N(R 4 ) or S(O)2NH;

[0017] [Chemical formula]

[0018] represents a single bond when X’ is O, S, N(R 4 ), or S(O)2NH; or

[0019]

Chemical formula

[0020] represents two separate bonds when X’ is N; -Z represents -C(O)- or C(O)R when -L- is -X’- 3 -; or -Z- is absent when -L- is -X’C(O)-; R 3 is a self-immolative group; and R 4 is H or C1-C4 alkyl), or a pharmaceutically acceptable salt thereof.

[0021] In another aspect, the present invention provides a compound of formula (II):

[0022]

Chemical formula

[0023] wherein, R 1 and R 2 each independently represents H, or a residue of a C2-C 28 fatty acid; -X- is selected from -O-, -NH-, and -S-; -Y- represents an optionally substituted -C3-C 20 alkyl-, -C3-C 20 alkenyl-, or -C3-C 20 alkynyl-group, wherein the alkyl, alkenyl, or alkynyl group is a straight-chain C 20On the condition that the length does not exceed that equivalent to an alkyl group, one or more of the carbon atoms in an alkyl group, alkenyl group or alkynyl group may be substituted by NH, S, O, a C5-C8 aromatic or aliphatic cyclic group, or a C5-C8 aromatic or aliphatic heterocyclic group;

[0024]

Chemical formula

[0025] represents the residue of a drug; -L- is -X'- or X'C(O)-; X' is O, S or N(R 4 ); R 4 is H or C1-C4 alkyl; and -Z- is -C(O)- when -L- is -X'-; or -Z- is absent when -L- is X'C(O)-), and provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0026] In another aspect, the present invention relates to formula (III):

[0027]

Chemical formula

[0028] 〔wherein, R 1 、R 2 、-X-、

[0029]

Chemical formula

[0030] and -Z- are as defined for formula (I) or formula (II); R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl; and Provided is a compound of formula (I) represented by [n is from 1 to 18] or a pharmaceutically acceptable salt thereof.

[0031] In a further aspect, the present invention provides a compound of formula (IV):

[0032]

Chemical formula

[0033] 〔wherein, R 1 、R 2 and X are as defined for formula (I); R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl; -Z- is -C(O)- or C(O)R 3 -; R 3 is a self-destructing group; and n is from 1 to 18〕, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0034] Moreover, in a further aspect, the present invention provides a compound of formula (V):

[0035]

Chemical formula

[0036] 〔wherein, R 1 、R 2 、X、R 5 、R 6 and n are as defined for formula (IV); and -Z- is -C(O)-〕, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0037] In another aspect, the present invention provides a method for treating or preventing a disease or disorder in which an increase in testosterone levels is beneficial, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (IV).

[0038] In a further aspect, the present invention provides the use of a compound of formula (IV) in the manufacture of a medicament for treating or preventing a disease or disorder in which an increase in testosterone levels is beneficial.

[0039] In another aspect, the present invention provides a compound of formula (IV) for use in treating or preventing a disease or disorder in which an increase in testosterone levels is beneficial.

[0040] In another aspect, the present invention relates to formula (VI):

[0041]

Chemical formula

[0042] wherein R 1 and R 2 each independently represents H or a residue of a C2-C 28 fatty acid; -X- is selected from -O-, -NH- and -S-; -Y- is an optionally substituted -C3-C 20 alkyl-, -C3-C 20 alkenyl- or -C3-C 20 alkynyl- group, wherein one or more of the carbon atoms of the alkyl, alkenyl or alkynyl group may be substituted by NH, S, O, a C5-C8 aromatic or aliphatic cyclic group, or a C5-C8 aromatic or aliphatic heterocyclic group, provided that the alkyl, alkenyl or alkynyl group does not exceed the length equivalent to a straight-chain C 20 alkyl group; -Z- is -C(O)-, -C(O)R 3 - or -CH2-; R 3 is a self-destructing group; and

[0043]

Chem.

[0044] represents the point at which a linker is attached to an active agent), a prodrug residue or a pharmaceutically acceptable salt thereof, and comprises attaching the prodrug residue or the salt thereof to the agent, thereby providing a method for promoting lymphatic transport and systemic release of the agent.

[0045] These and other aspects of the invention will become more apparent to those skilled in the art upon reading the following detailed description in conjunction with the accompanying examples and claims.

Brief Description of the Drawings

[0046]

Figure 1

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Figure 3

Figure 4

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Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

Figure 24

Mode for Carrying Out the Invention

[0047] When a prodrug strategy is adopted in the field of drug development to improve the pharmacokinetic profile, Prodrugs are generally expected to revert to the parent compound via non-specific degradation or enzyme-mediated in vivo changes prior to exhibiting biological activity. The present invention discloses modified glyceride-based compounds that can promote the lymphatic transport of drugs and improve the reversion of compounds to the active drug.

[0048] Dietary lipids such as triglycerides use a unique metabolic pathway to gain access to the lymph (and ultimately the systemic circulation), which is quite different from other nutrients such as proteins and carbohydrates. After ingestion, dietary triglycerides are hydrolyzed by intestinal lipase, releasing one monoglyceride and two fatty acids for each molecule of triglyceride. The monoglyceride and two fatty acids are absorbed by enterocytes, where they are re-esterified to triglycerides.

[0049] The resynthesized triglycerides are assembled into intestinal lipoproteins (primarily chylomicrons), and the chylomicrons thus formed are exocytosed from enterocytes and then gain preferential access to the intestinal lymphatics. In the lymphatics, the lipids in the form of chylomicrons drain out of a series of capillaries, nodes, and ducts and pour into the systemic circulation at the junction of the left subclavian vein and the internal jugular vein. Following entry into the bloodstream, the triglycerides in chylomicrons are preferentially and efficiently taken up by tissues with high expression of lipoprotein lipase, such as adipose tissue, the liver, and potentially certain types of tumor tissue.

[0050] Lipid-mimicking compounds are expected to behave similarly to natural triglycerides and be transported via the lymphatic system before reaching the systemic circulation. In this way, the pharmacokinetic and pharmacodynamic profiles of the parent drug can be manipulated to improve access to lymphatic and lymphoid tissues, thereby promoting oral bioavailability via avoidance of first-pass metabolism (and potentially intestinal efflux). Lipid-mimicking compounds may also promote drug targeting to sites within the lymph, lymph nodes, and lymphoid tissues, as well as to sites with high lipid utilization and lipoprotein lipase expression, such as adipose tissue and some tumors.

[0051] After transport via the systemic circulation, lipidated prodrugs that are readily convertible to the parent drug reduce the free drug concentration in the digestive (GI) tract, which can provide benefits in reducing gastrointestinal irritation, taste masking, promoting solubilization of the drug in bile salt micelles in the intestinal tract (due to similarity with endogenous monoglycerides), and improving passive membrane permeability (by increasing lipophilicity). Lipidated prodrugs enhance solubility in lipid vesicles that contain lipids alone or in mixtures with lipid surfactants and / or co-solvents, thus enabling higher doses of the drug to be administered in solution than would be possible for the parent drug.

[0052] The inventors have surprisingly found that modifying the moiety of the drug-glyceride conjugate that links the drug to the glyceride unit improves the stability of the drug-glyceride conjugate in the digestive tract, promotes transport into intestinal lymph, and ultimately promotes release of the drug from the drug / glyceride prodrug. Thus, by varying the "linker" that connects the drug to the glyceride unit, an optimal pharmacokinetic profile can be achieved for the resulting compound.

[0053] Numerous terms well known to those skilled in the art are used herein. Nevertheless, for purposes of clarity, a number of terms will be defined.

[0054] As used herein, unless otherwise defined, the term "optionally substituted" means that the group is hydroxyl, alkyl, alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, a It is to be interpreted as meaning that it may or may not be further substituted by one or more groups selected from alkoxy, aryl, aryloxy, acylamino, carboxy, cyano, halogen, nitro, sulfo, phosphono, phosphorylamino, phosphinyl, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, trihalomethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl, amino, and asymmetric di-substituted amines having different substituents selected from alkyl, arylheteroaryl, and heterocyclyl.

[0055] As used herein, the term "alkyl," used alone or in a compound word, refers to a straight-chain alkyl or a branched-chain alkyl. Prefixes such as "C2-C 20 " are used to indicate the number of carbon atoms in the alkyl group (in this case, 2 to 20). Examples of straight-chain alkyls and branched-chain alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, hexyl, heptyl, 5-methylheptyl, 5-methylhexyl, octyl, nonyl, decyl, undecyl, dodecyl, and docosyl (C 22 ).

[0056] As used herein, the term "alkenyl," used alone or in a compound word, refers to a straight-chain or branched-chain hydrocarbon residue containing at least one carbon-carbon double bond for at least one carbon, which is ethylenically mono-, di-, or poly-unsaturated and contains alkyl as defined above. Preferably, the alkenyl group is a straight-chain alkenyl group. "C2-C 20Prefixes such as “ ” are used to indicate the number of carbon atoms in the alkenyl group (in this case, 2 to 20). Examples of alkenyls include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, and 5-docosenyl (C 22 ) and the like.

[0057] As used herein, the term “alkynyl,” used alone or in a compound word, refers to a straight-chain or branched-chain hydrocarbon residue containing at least one carbon-carbon triple bond. Preferably, the alkynyl group is a straight-chain alkynyl group. Prefixes such as “C2-C 20 ” are used to indicate the number of carbon atoms in the alkynyl group (in this case, 2 to 20).

[0058] As used herein, terms such as “heterocycle” or “heterocyclic group,” used alone or in a compound word, refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or fused polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur, and oxygen. Prefixes such as “C5-C8” are used to indicate the number of carbon atoms in the cyclic portion of the group (in this case, 5 to 8). Examples of suitable heterocyclic substituents include pyrrole, furan, benzofuran, benzothiazole, imidazole, benzimidazole, imidazoline, pyrazole, pyrazoline, triazole, oxazole, oxazoline, isoxazole, isoxazoline, furazan, oxadiazole, piperidine, pyridine, pyrimidine, pyridazine, and pyrazine, each of which may be further substituted with 1 to 3 substituents, but are not limited thereto.

[0059] As used herein, terms such as "aryl" or "aromatic cyclic group" refer to single or polynuclear fused or condensed residues of aromatic hydrocarbon ring systems. "C5-C8" Prefixes such as " are used to indicate the number of carbon atoms (in this case, 5-8) in the cyclic portion of the aryl. Examples of aryl include phenyl (mononuclear), naphthyl (fused polynuclear), biphenyl (linked polynuclear), and tetrahydronaphthyl (fused polynuclear).

[0060] As used herein, the term "linker" refers to the portion that bridges from "X" to "L" for a compound of formula (I) as described herein and links the agent to the glyceride unit.

[0061] As used herein, the term "self-immolative group" refers to a chemical moiety that forms a cleavable bond with the linker and a stable bond with the agent, where the bond with the agent becomes unstable upon cleavage of the linker. Examples of self-immolative groups include, but are not limited to, acetal self-immolative groups, para-hydroxybenzylcarbonyl self-immolative groups, flipped ester self-immolative groups, and trimethyl lock self-immolative groups. A number of other suitable self-immolative groups are known in the art as described, for example, in Blencowe et al., Polym. Chem. 2011, 2, 773-790 and Kratz et al., Chem. Med. Chem. 2008, 3, 20-53.

[0062] As used herein, the term "agent" refers to an active pharmaceutical agent or imaging agent (contrast agent) that will benefit from transport via the intestinal lymphatic system to avoid first-pass metabolism or for targeted delivery in the lymphatic system.

[0063] Examples of suitable active agents include testosterone, mycophenolic acid, estrogen (estrogen), morphine, metoprolol, raloxifene, alphaxolone, statins such as atorvastatin, pentazocine, propranolol, L-DOPA, buprenorphine, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, pentazocine, isosorbide dinitrate, glyceryl trinitrate, oxprenolol, labetalol, verapamil, salbutamol, epitioestanol, melphalan, lovastatin, non-steroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin, ibuprofen, naproxen), COX-2 inhibitors (e.g., celecoxib, rofecoxib), corticosteroid anti-inflammatory drugs (e.g., prednisolone, prednisone, dexamethasone), anti-malarial drugs (e.g., hydroxychloroquine), cyclophosphamide, nitrosourea, platinum, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracyclines (e.g., daunorubicin), mitomycin C, bleomycin, mitramycin, drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus), sulfasalazine, leflunomide, mycophenolate, opioids, fingolimod, milcamycin, chlorambucil, doxorubicin, nelarabine, cortisone, dexamethasone, prednisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinib mesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxine mepesuccinate, anastrozole, capecitabine, letrozole, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, albendazole, doxycycline, closantel, maraviroc, enfuvirtide, deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, nevirapine, delavirdine,Examples include, but are not limited to, efavirenz, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, acyclovir, and pharmaceutically active peptides.

[0064] Examples of suitable contrast agents include fluorescent dyes for fluorescence microscopy or fluorescent dye molecules such as the Alexa Fluor series of optical imaging probes having an emission spectrum in the infrared range for in vivo imaging; gamma emitters that can be used for positron emission tomography (PET), such as fluorodeoxyglucose, or chelating agents for chelating magnetic resonance imaging probes such as, for example, gadolinium or iron, but are not limited thereto.

[0065] For compounds of formula (I) where X’ is -O- or -S-, the group

[0066]

Chemical formula

[0067] is

[0068]

Chemical formula

[0069] i.e.,

[0070]

Chemical formula

[0071] represents a single bond. However, when X’ is N,

[0072]

Chemical formula

[0073] represents two separate bonds connecting a nitrogen atom to two separate atoms that form part of the agent, i.e., it does not represent a double bond. For Exemplary Compounds 1, 6, and 7, where the agent has the following chemical structure:

[0074]

Chemical formula

[0075] is sertraline having, the two separate bonds are interpreted as the bond from the nitrogen atom to the 1,2,3,4-tetrahydro naphthalene moiety and the bond from the nitrogen atom to the methyl group when the linker is attached to the secondary nitrogen atom of sertraline. When the agent has, for example, the structure:

[0076]

Chemical formula

[0077] is tenofovir having, the two separate bonds are interpreted as the bond from the nitrogen atom to the purine moiety and the bond from the nitrogen atom to the hydrogen atom when the linker is attached to the available primary amine. Similarly, when the agent has the structure:

[0078]

Chemical formula

[0079] is labetalol having, and if the linker is attached to the available amide group, the two separate bonds are interpreted as the bond from the nitrogen atom to the carboxyl carbon atom and the bond from the nitrogen atom to the hydrogen atom. For the compounds of formula (I)

[0080]

Chemical formula

[0081] Reference to "N" is not intended to mean that the nitrogen atom is attached to the agent via a double bond.

[0082] To avoid any ambiguity, reference to "a length equivalent to a straight-chain C" 20 refers to the length theoretically spanned by 20 singly-bonded carbon atoms.

[0083] In some preferred embodiments of the present invention, and with reference to general formula (I), one or more of the following definitions apply: (a) R 1 and R 2 are independently H, or represent a residue of a C2-C 28 fatty acid. (b) R 1 represents H, and R 2 represents a residue of a C2-C 28 fatty acid. (c) R 2 represents H, and R 1 represents a residue of a C2-C 28 fatty acid. (d) R 1 and R 2 each represent palmitic acid. (e) -X- is -O-. (f) -X- is -NH-. (g) -X- is -S-. (h) -Y- is an optionally substituted -C3-C 20 alkyl group, -C3-C 20 alkenyl group or -C3-C 20 alkynyl group, where one or more of the carbon atoms in the alkyl group, alkenyl group or alkynyl group may be substituted by NH, S, O, a C5-C8 aromatic or aliphatic cyclic group, or a C5-C8 aromatic or aliphatic heterocyclic group, provided that the alkyl group, alkenyl group or alkynyl group does not exceed a length equivalent to a straight-chain C 20 alkyl group. (i) -Y- is an optionally alkyl-substituted -C3-C 20 alkyl group, -C3-C 20 alkenyl group or -C3-C20 Represents an alkynyl group. (j)-Y- may be substituted with methyl and is a -C3-C 20 alkyl group, -C3-C 20 alkenyl group or -C3-C 20 represents an alkynyl group. (k)-Z- is C(O)R when -L- is -X’- and R 3 is a self-destructing group. 3 - (l)R 3 is a self-destructing group selected from an acetal, trimethyloxonium, p-hydroxybenzylcarbonyl or an inverted ester self-destructing group. (m)-Z- is -C(O)- when -L- is -X’-. (n)X’ is O. (o)X’ is S. (p)X’ is N. (q)X’ is N(R 4 ). (r)R 4 is H. (s)R 4 is C1-C4 alkyl. (t)R 4 is methyl.

[0084] In a preferred embodiment, -Z- is -C(O)- when -L- is -X’-.

[0085] Accordingly, in a further embodiment, the present invention provides formula (II):

[0086]

Chemical formula

[0087] wherein, R 1 and R 2 independently represent H, or a residue of a C2-C 28 fatty acid; -X- is selected from -O-, -NH- and -S-; -Y- represents an optionally substituted -C3-C 20 alkyl-, -C3-C 20 alkenyl- or -C3-C 20 alkynyl-group, where the alkyl group, alkenyl group or alkynyl group has one or more of the carbon atoms in the alkyl group, alkenyl group or alkynyl group optionally substituted by NH, S, O, a C5-C8 aromatic or aliphatic cyclic group, or a C5-C8 aromatic or aliphatic heterocyclic group, provided that the alkyl group, alkenyl group or alkynyl group does not exceed the length equivalent to a straight-chain C 20 alkyl group;

[0088]

Chemical formula

[0089] represents the residue of the agent; -L- is -X'- or -X'C(O)-; -Z- is -C(O)- when -L- is -X'-; or -Z- is absent when -L- is X'C(O)-; X' is selected from O, S or N(R 4 ); R 4 is H or C1-C4 alkyl), a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0090] In a further embodiment, the present invention relates to formula (III):

[0091]

Chemical formula

[0092] 〔wherein, R 1 , R 2 , -X-,

[0093]

Chemical formula

[0094] and -Z- is as defined for formula (I); R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl; and n is from 1 to 18), or a pharmaceutically acceptable salt thereof, of a compound of formula (I).

[0095] In another embodiment, the compound of formula (III) is selected from those compounds listed in Table 1.

[0096]

Table 1

[0097] In one embodiment, the agent is testosterone or a derivative or analog thereof. Testosterone replacement therapy (TRT) is commonly used in patients with hypogonadism (a disease characterized by abnormally low serum testosterone levels) to restore serum testosterone levels to the normal range, and thus alleviates a number of symptoms of hypogonadism, such as mood disorders, sexual dysfunction, etc.

[0098] Accordingly, in one embodiment, the present invention provides a compound of formula (IV):

[0099]

Chemical formula

[0100] 〔wherein, R 1 , R 2 and X are as defined for formula (I); R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl; -Z- is -C(O)- or -C(O)R 3 -; R 3 is a self-destructing group; and Provided is a compound of formula (I) represented by n is from 1 to 18 or a pharmaceutically acceptable salt thereof.

[0101] In another embodiment, the compound of formula (IV) is selected from those compounds listed in Table 2.

[0102] [Table 2]

[0103] In another embodiment, the present invention provides a method for treating or preventing a disease or disorder in which an elevated testosterone level is beneficial, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to formula (IV).

[0104] In a further embodiment, the present invention provides the use of a compound according to formula (IV) in the manufacture of a medicament for treating or preventing a disease or disorder in which an elevated testosterone level is beneficial.

[0105] In yet another embodiment, the present invention provides a compound of formula (IV) for use in treating or preventing a disease or disorder in which an elevated testosterone level is beneficial.

[0106] Diseases or disorders in which an elevated testosterone level may be beneficial include, but are not limited to, hypogonadism, anemia due to bone marrow failure, anemia due to renal failure, chronic respiratory failure, chronic heart failure, steroid-dependent autoimmune diseases, AIDS wasting, hereditary angioedema or urticaria, advanced breast cancer, or menopause.

[0107] In another embodiment, the agent is mycophenolic acid (MPA). MPA acts on the purine synthesis pathway in lymphocytes and is an immunosuppressant widely used in the treatment of autoimmune diseases and organ transplant rejection.

[0108] Accordingly, in a further embodiment, the present invention is formula (VII):

[0109]

Chem.

[0110] 〔In the formula, R 1 and R 2 , X and X' are as defined for formula (I); R 5 and R 6 are each independently selected from hydrogen and C1-C4 alkyl; and n is from 1 to 18〕, to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0111] In another embodiment, the compound of formula (VII) is selected from those compounds listed in Table 3.

[0112]

Table 3

[0113] In another embodiment, the present invention provides a method for treating or preventing an autoimmune disease and organ transplant rejection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to formula (VII).

[0114] In a further embodiment, the present invention provides the use of a compound according to formula (VII) in the manufacture of a medicament for treating or preventing an autoimmune disease and organ transplant rejection.

[0115] In yet another embodiment, the present invention provides a compound of formula (VII) for use in treating or preventing an autoimmune disease and organ transplant rejection.

[0116] In another embodiment, the present invention relates to formula (VI):

[0117]

Chem.

[0118] [In the formula, R 1 and R 2 each independently represents H or a residue of a C2-C 28 fatty acid; -X- is selected from -O-, -NH-, and -S-; -Y- is an optionally substituted -C3-C 20 alkyl-, -C3-C 20 alkenyl-, or -C3-C 20 alkynyl-group, where one or more of the carbon atoms of the alkyl group, alkenyl group, or alkynyl group may be substituted by NH, S, O, a C5-C8 aromatic or aliphatic cyclic group, or a C5-C8 aromatic or aliphatic heterocyclic group, provided that the alkyl group, alkenyl group, or alkynyl group does not exceed the same length as a straight-chain C 20 alkyl group; -Z- is -C(O)-, -C(O)R 3 -, or -CH2-; R 3 is a self-destructing group; and

[0119] [Chemical formula]

[0120] represents the point to which a linker is attached to an active agent), a method for promoting lymphatic transport and systemic release of a drug, which comprises attaching a prodrug residue of formula

[0121] In one embodiment, Y and Z for a compound as defined above will be selected to facilitate stable transport of the agent into the intestinal lymphatics. In another embodiment, Y and Z will be selected to facilitate release of the agent in lymph, lymphocytes, lymphoid tissues, such as tissues with high lipase activity like adipose tissue, certain cancers, the liver or the systemic circulation. In yet another embodiment, Y and Z are selected to facilitate stable transport of the agent into the intestinal lymphatics and to facilitate release of the agent in lymph, lymphocytes, lymphoid tissues, such as tissues with high lipase activity like adipose tissue, certain cancers, the liver or the systemic circulation.

[0122] The compounds of the present invention are useful for the stable transport of an agent into the intestinal lymphatics and for the release of the agent in lymph, lymphocytes, lymphoid tissues, such as tissues with high lipase activity like adipose tissue, certain cancers, the liver or the systemic circulation. The compounds of the present invention are particularly useful for the transport and release of agents that benefit from avoidance of first-pass metabolism, such as compounds that exhibit greater than 50% first-pass metabolism. In one embodiment, it is contemplated that the agent will exhibit greater than 60% first-pass metabolism. In another embodiment, the agent will exhibit greater than 70% first-pass metabolism. In a further embodiment, the agent will exhibit greater than 80% first-pass metabolism. In yet another embodiment, the agent will exhibit greater than 90% first-pass metabolism.

[0123] Agents that may benefit from stable transport to intestinal lymph and release in lymph, lymphocytes, lymphoid tissues, such as tissues with high lipase activity like adipose tissue, certain cancers, the liver, or the systemic circulation include, but are not limited to, testosterone, mycophenolic acid, estrogen, morphine, metoprolol, raloxifene, alphaxolone, statins such as atorvastatin, pentazocine, propranolol, L-DOPA, buprenorphine, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, pentazocine, isosorbide dinitrate, glyceryl trinitrate, oxprenolol, labetalol, verapamil, salbutamol, epitioestanol, melphalan, lovastatin, and pharmaceutically active peptides.

[0124] The compounds of the present invention are also useful for targeted release of agents in the lymphatic system, such as lymph, lymphocytes, and lymphoid tissues, and tissues with high lipase activity like adipose tissue, certain cancers, or the liver.

[0125] Agents that may benefit from targeted release within the lymphatic system or adipose tissue include non-steroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin, ibuprofen, naproxen), COX-2 inhibitors (e.g., celecoxib), corticosteroid anti-inflammatory drugs (e.g., prednisolone, dexamethasone), anti-malarial drugs (e.g., hydroxychloroquine), cyclophosphamide, PPAR agonists (e.g., fibrates), nitrosoureas, platinum, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracyclines, mitomycin C, bleomycin, mitramycin, drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus), sulfasalazine, leflunomide, mycophenolate, opioids, fingolimod, milrinone, chlorambucil, doxorubicin, nelarabine, cortisone, dexamethasone, prednisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinib mesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxine mepesuccinate, anastrozole, capecitabine, letrozole, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, doxycycline, croxanthine, maraviroc, enfuvirtide, deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, nevirapine, delavirdine, efavirenz, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, acyclovir, and immunosuppressive agents such as mycophenolic acid, cyclosporine, tacrolimus, and sirolimus, but are not limited thereto.

[0126] As a general strategy, the compounds of the present invention may be synthesized via one of the following routes.

[0127]

Chem.

[0128] For the compounds of the present invention in which -Y- is an unsubstituted alkyl group, they can be prepared by reaction of an acid / triglyceride (IV) with an alcohol-containing agent (A-OH) under the conditions of standard ester bond formation as shown in Scheme 1. In most cases, the acid / triglyceride (IV) can be accessed from an acid anhydride (I) (for n = 1) or a diacid chloride (II) (for n>1), and 1,3-diacylglycerol (I II) can be obtained from the corresponding dicarboxylic acid by treatment with pyridine.

[0129] For the synthesis of compounds in which -Y- is an α-substituted or β-substituted alkyl group, the conversion of an anhydride (I) or a diacid chloride (II) to an acid / triglyceride (IV) via the route described in Scheme 1 is usually not feasible because the starting materials are asymmetric. Therefore, the synthesis via Scheme 1 will also result in the formation of a mixed acid / triglyceride product. In these cases, the linker unit can be constructed from simpler starting materials and then coupled to diacylglycerol (III) at an appropriate point in the sequence to ultimately provide the acid / triglyceride (IV).

[0130]

Chem.

[0131] For the synthesis of compounds containing an α-alkyl-substituted alkyl linker, the carbon framework required for the spacer can be assembled by a Wittig reaction between an aldehyde derived from an alcohol (VI) and a stabilized ylide (VII), and an α-alkyl-α,β-unsaturated ester (VIII) is obtained. The free acid (IX) is freed After hydrolysis of the ester formed, coupling with diacylglycerol (III) under standard conditions provides triglyceride (X). One-step hydrogenation / hydrocracking provides saturated alcohol (XI), which can first be oxidized to aldehyde (XII) using PCC, and then further oxidized under pinic conditions to give the desired α-substituted acid / triglyceride (IV).

[0132]

Chemical formula

[0133] For the synthesis of compounds containing β-alkyl-substituted alkyl linkers, in the specific case where n = 1, the method outlined in Scheme 1 above can be used since the β-substituent maintains symmetry with the diacid chloride (II). Scheme 3 above provides a method for the synthesis of compounds containing β-alkyl substituents when n > 1. First, for example, deprotonation of TMS acetylene using a strong base such as n-BuLi followed by addition of alkyl bromide (XIII) as an electrophile results in the formation of silyl alkyne (XIV). Following desilylation, Sonogashira cross-coupling of the alkyne (XV) with enol triflate (XVI) mediated by Pd II and Cu I gives enyne (XVII) containing the required β-alkyl substituent. Catalytic hydrogenation of enyne (XVII) then gives β-methyl-ω-hydroxy ester (XVIII), which can be converted to TBDPS ether (XIX) in preparation for the introduction of the glyceride functionality. This is then achieved by hydrolysis of ester (XIX) under forced basic conditions (2 M KOH in EtOH at 60 °C) followed by standard coupling of the resulting acid (XX) with diacylglycerol (III) to give triglyceride (XXI). Desilylation using TBAF then gives hydroxytriglyceride (XI), which is converted to the target acid / triglyceride (IV) by a similar method as outlined in Scheme 2.

[0134] [Chem.]

[0135] When the active agent has a carboxylic acid group that can be coupled to form the compounds of the present invention, the compounds can generally be prepared according to Scheme 4. To form an ester bond between the glyceride and the desired linker, ω-halocarboxylic acid (XXII) is coupled with 1,3-diacylglycerol (III) in the presence of standard coupling conditions to provide ω-halotriglyceride (XXIII). Then, the bond of the carboxylic acid-containing agent can be achieved by substituting the halogen leaving group with a suitable carboxylate nucleophile to provide the compounds (XXIV) of the present invention. If the halocarboxylic acid (XXII) is not commercially available, further synthesis from simple precursors is required. For short-chain (n = 2, 3) α- or β-alkyl-substituted examples, or long-chain (e.g., n = 12) unsubstituted examples, the required acid (XXII) can be accessed by ring-opening of the corresponding lactone (see Examples 6, Compounds aj - am). For long-chain α- or β-alkyl examples (n > 3), the required halotriglyceride (XXIII) can be prepared from the hydroxytriacylglycerol (XI) described in Schemes 2 and 3 above. When the compounds of the present invention require purification, techniques such as recrystallization and chromatographic methods including high performance liquid chromatography (HPLC) and normal or reverse phase silica gel chromatography may be used. The compounds may be characterized by nuclear magnetic resonance (NMR), mass spectrometry and / or other suitable methods.

[0136]

[0137] ​It will be understood that the compounds of the present invention may exist in the form of one or more stereoisomers (e.g., diastereomers). The present invention encompasses all such forms of stereoisomers, whether isolated (e.g., enantiomerically pure) or in combination (including racemic mixtures and mixtures of diastereomers).

[0138] Accordingly, the present invention also relates to compounds in substantially pure stereoisomeric form, for example, greater than about 90%, for example, about 95% - 97%, or greater than 99%, with respect to the asymmetric centers of the amino acid residues, as well as mixtures thereof including their racemic mixtures. Such diastereomers may be prepared, for example, by asymmetric synthesis using chiral intermediates, or the mixtures may be separated by conventional methods, for example, chromatography, or by the use of resolving agents.

[0139] When the compound contains one or more functional groups that may be protonated or deprotonated (e.g., at physiological pH), the compound may be prepared as and / or isolated as a pharmaceutically acceptable salt. It will be well understood that the compound may be an zwitterion at a given pH. As used herein, the expression "pharmaceutically acceptable salt" refers to a salt of a given compound, where the salt is suitable for administration as a pharmaceutical. Such salts may be formed, respectively, by reaction of the amine or carboxylic acid group with an acid or a base.

[0140] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0141] Pharmaceutically acceptable base addition salts may be prepared from inorganic bases and organic bases. Corresponding counterions derived from inorganic bases include salts of sodium, potassium, lithium, ammonium, calcium and magnesium. Organic bases include primary, secondary and tertiary amines, substituted amines, dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucosamine, theobromine, purine, piperazine, piperidine, and N-ethylpiperidine, including naturally occurring amines and cyclic amines including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine.

[0142] Acid / base addition salts tend to be more soluble in aqueous solvents than the corresponding free acid / base forms.

[0143] The compounds of the present invention may be in crystalline form or as solvates (e.g., hydrates), and both forms are intended to be within the scope of the present invention. The term "solvate" is a variable stoichiometric complex formed by a solute and a solvent. Such a solvent should not interfere with the biological activity of the solute. The solvent may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the scope of the art.

[0144] The route of administration of the compounds of the present invention is intended to include oral administration and enteral administration. Accordingly, the active compounds may be formulated with an inert diluent or with an edible carrier that can be absorbed, or it may be encapsulated in a gelatin capsule of a hard or soft shell, or it may be compressed into tablets, or it may be taken directly with food in the diet. For oral therapeutic administration, the active compounds are incorporated with excipients and may be used in the form of ingestible tablets, oral or sublingual tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. The amount of the active compounds in such therapeutically useful compositions is such that a suitable dosage is obtained.

[0145] Tablets, troches, pills, capsules, etc. may also contain ingredients such as those listed below: binders such as gum, gum acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweetening agents such as sucrose, lactose or saccharin may be added, or flavoring agents such as peppermint, wintergreen or cherry flavor may be added. When the unit dosage form is a capsule, it may contain a liquid carrier in addition to the substances of the above types. Various other substances may be present as coatings or otherwise to modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with shellac, sugar or both. Syrups or elixirs may contain the active compound, sucrose as a sweetening agent, methylparaben and propylparaben as preservatives, dyes and flavoring agents such as cherry flavor or orange flavor. Of course, the substances used to prepare the unit dosage forms should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the compounds of the present invention may be incorporated into sustained release preparations and formulations, including those that enable specific delivery of active peptides to specific regions of the gastrointestinal tract.

[0146] The liquid preparation may also be administered into the intestine via the stomach or the esophagus. In one embodiment, the compounds of the present invention will be administered orally with food to facilitate transport to the intestinal lymph.

[0147] In another embodiment, the compounds of the present invention will be co-administered with a lipid-based formulation to facilitate transport to the intestinal lymph, with or without concomitant food.

[0148] Lipid-based formulations for oral delivery are known in the art and may include, for example, a substantially non-aqueous vehicle that typically contains one or more lipid components. The lipid vehicle and the resulting lipid formulations may be usefully classified according to common features they share according to the Lipid Formulation Classification System (LFCS) (Pouton, C.W., Eur. J. Pharm. Sci. 11(Supp. 2), S93-S98, 2000; Pouton, C.W., Eur. J. Pharm. Sci. 29, 278-287, 2006).

[0149] Accordingly, the lipid vehicle and the resulting lipid formulations may optionally contain an oil / lipid and / or surfactant together with a co-solvent. Type I formulations include, for example, oils or lipids that require digestion, such as mono-, di- and tri-glycerides and combinations thereof. Type II formulations are water-insoluble SEDDS that contain the lipids and oils used in Type I formulations, with additional water-insoluble surfactants. Type III formulations are SEDDS or self-microemulsifying drug delivery systems (SMEDDS) that contain the lipids and oils used in Type I formulations, with additional water-soluble surfactants and / or co-solvents (Type IIIa) or a large proportion of water-soluble components (Type IIIb). Type IV formulations predominantly contain hydrophilic surfactants and co-solvents (e.g., PEG, propylene glycol and diethylene glycol monoethyl ether) and are useful for drugs that are poorly water-soluble but not lipophilic. Such lipid formulations (Types I-IV) are contemplated herein.

[0150] In some embodiments, the lipid vehicle contains one or more oils or lipids without the accompaniment of additional surfactants, co-surfactants or co-emulsifiers or co-solvents, in other words, consists essentially of one or more oils or lipids. In some further embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-insoluble surfactants and optionally together with one or more co-solvents. In some further embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-soluble surfactants and optionally together with one or more co-solvents. In some embodiments, the lipid vehicle contains a mixture of an oil / lipid, a surfactant and a co-solvent. In some embodiments, the lipid vehicle consists essentially of one or more surfactants / co-surfactants / co-emulsifiers and / or solvents / co-solvents.

[0151] Examples of oils or lipids that may be used in the present invention include almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard seed oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, walnut oil, wheat germ oil, avocado oil, rice bran oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, caprylic / capric glyceride, fractionated triglyceride, glyceryl tricaprate, glyceryl tricaprylate, glyceryl tricaprylate, glyceryl caprylate / caprate, glyceryl caprylate / caprate, glyceryl caprylate / caprate / laurate, glyceryl caprylate / caprate / linoleate, glyceryl caprylate / caprate / stearate, glyceryl trilaurate, glyceryl monolaurate, glyceryl behenate, glyceryl monolinoleate, glyceryl trilinolenate, glyceryl trioleate, glyceryl tridecanoate, glyceryl tristearate linoleate, saturated polyglycolated glyceride, C8-C 12 Synthetic medium-chain triglycerides mainly containing fatty acid chains, C8-C 12Medium-chain triglycerides mainly containing fatty acid chains, >C 12 Long-chain triglycerides mainly containing fatty acid chains of 12 , modified triglycerides, fractionated triglycerides, and mixtures thereof.

[0152] Examples of monoglycerides and diglycerides that may be used in the present invention include glycerol monoesters and glycerol diesters having fatty acid chains of 8 to 40 carbon atoms, including hydrolyzed coconut oil (e.g., Capmul® MCM) and hydrolyzed corn oil (e.g., Maisine™ 35-1). In some embodiments, the monoglycerides and diglycerides are mono- or di-saturated fatty acid esters of glycerol having fatty acid chains with a carbon chain length of 8 to 18 (e.g., glyceryl monostearate, glyceryl distearate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate, and glyceryl dicaprate).

[0153] Surfactants suitable for use in lipid formulations include those sold under trade names such as Capryol® 90, Labrafac® PG, Lauroglycol® FCC, for example, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate, but not limited to these, C8 - C 22Fatty acid propylene glycol mono- and di-esters, sucroses such as sucrose palmitate, sucrose laurate, sucrose stearate, but not limited to these; sorbitan fatty acid esters such as sorbitan laurate, sorbitan palmitate, sorbitan oleate, but not limited to these; polyoxyethylene sorbitan fatty acid esters such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, polysorbate 85, but not limited to these; polyoxyethylene mono- and di-fatty acid esters including but not limited to polyoxyl 40 stearate and polyoxyl 40 oleate; C8-C 22 Polyoxyethylene mono- and di-esters of fatty acids and C8-C 22 Mixtures with glyceryl mono-, di-, and tri-esters of fatty acids; polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, and polyoxyl 60 hydrogenated castor oil, but not limited to these, such as those sold under trade names like Cremophor® / Kolliphor EL, Cremophor® / Kolliphor® RH40, Cremophor® / Kollipohor® RH60; polyoxyethylene alkyl ethers including but not limited to polyoxyl 20 cetostearyl ether and polyoxyl 10 oleyl ether; DL-α-tocopheryl polyethylene glycol succinate which may be sold under a trade name; glyceryl mono-, di-, and tri-esters; C8-C 22 Glyceryl mono-, di-, and tri-esters of fatty acids; sucrose mono-, di-, and tri-esters; sodium dioctyl sulfosuccinate; poloxamer 124, poloxamer 188, p Polyoxyethylene-polyoxypropylene copolymers such as, but not limited to, Loxamer 407; polyoxyethylene lauryl alcohol, polyoxyethylene cetyl alcohol, polyoxyethylene stearyl alcohol, polyoxyethylene oleyl alcohol, sold under trade names such as Brij® 35, Brij® 58, Brij® 78, Brij® 98, including, but not limited to, C8-C 22 Polyoxyethylene ethers of fatty alcohols, or mixtures of two or more thereof.

[0154] Co-emulsifiers or co-surfactants may be used in the formulation. Suitable co-emulsifiers or co-surfactants are phosphoglycerides; phospholipids such as lecithin, or free fatty acids that are liquid at room temperature such as isostearic acid, oleic acid, linoleic acid, linolenic acid, palmitic acid, stearic acid, lauric acid, capric acid, caprylic acid and caproic acid.

[0155] Suitable solvents / co-solvents include ethanol, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether and glycerol.

[0156] Polymers may be used in the formulation to inhibit precipitation of the drug. A range of polymers have been shown to confer these properties and are well known to those skilled in the art. Suitable polymers include hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, other cellulose-derived polymers such as, for example, methylcellulose; poly(meth)acrylates such as the Eudragit series of polymers including Eudragit E100, polyvinylpyrrolidone or others such as described, for example, in Warren et al. Mol. Pharmaceutics, 2013, 10, 2823-2848.

[0157] The formulation may also contain substances generally known to those skilled in the art that are included in liquid formulations, such as antioxidants, for example, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT), and solidifying agents such as fine porous silica, for example, magnesium aluminometasilicate (Neusilin).

[0158] In another embodiment, the compound may be co-administered orally with an enzyme inhibitor that enhances the stability of the prodrug in the gastrointestinal tract or intestinal cells. In certain embodiments, the enzyme inhibitor is envisioned to inhibit pancreatic lipase, examples of which include, but are not limited to, Alli and Orlistat. In other embodiments, the enzyme inhibitor is envisioned to inhibit cellular lipase enzymes such as, for example, monoacylglycerol lipase, examples of which include, but are not limited to, JZL184 (4-nitrophenyl-4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate).

[0159] While the compound as described above or a pharmaceutically acceptable salt thereof may be the sole active ingredient administered to a subject, administering other active ingredients together with the compound is within the scope of the present invention. In one or more embodiments, it is envisioned that two or more combinations of the compounds of the present invention will be administered to a subject.

[0160] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as defined above, together with at least one pharmaceutically acceptable carrier or diluent.

[0161] The term "composition" is intended to include formulations of the active ingredient with an enclosing substance such as a carrier so as to obtain a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier. The term "composition" is intended to include formulations of the active ingredient with an enclosing substance such as a carrier so as to obtain a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier.

[0162] As will be readily and fully appreciated by those skilled in the art, the nature of the pharmaceutically acceptable carrier will depend on the condition being treated and the nature of the mammal. The selection of a particular carrier or delivery system can be readily determined by those skilled in the art. In the preparation of a formulation containing the active compound, care should be taken to ensure that the activity of the compound is not destroyed during the process and that the compound can reach the site of action without being destroyed. In some situations, it may be necessary to protect the compound by means known in the art, such as microencapsulation.

[0163] Those skilled in the art may readily determine an appropriate formulation for the compounds of the present invention using conventional approaches. The determination of the preferred pH range and suitable excipients, such as antioxidants, is conventional in the art. Buffer systems are commonly used to provide the desired range of pH and include carboxylic acid buffers such as acetates, citrates, lactates, and succinates. A variety of antioxidants, including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulfites, and metal chelating agents such as EDTA, are available for such formulations.

[0164] Pharmaceutically acceptable vehicles and / or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is contemplated, except insofar as any conventional media or agent is incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the compositions.

[0165] The compounds may also be administered in combination with one or more additional therapeutic agents. The combination may allow for separate, sequential, or simultaneous administration of the compounds with other active ingredients as described above. The combination may be provided in the form of a pharmaceutical composition.

[0166] As used herein, the term "co-administration" refers to the use of a different fixed combination with a co-administered partner in an amount that can be administered dependently or independently, or distinguished, as defined above, i.e., a composition or a portion of a kit that can be administered simultaneously or at different times. The co-administered partner is then administered, for example, simultaneously or at adjusted times, at the same or different time intervals for portions of a kit. For example, the ratio of the total amount of the co-administered partner administered in combination may vary to address the needs of a subpopulation of patients being treated or the different needs, which may be due to, for example, the age, sex, weight, etc. of a single patient, of a single patient.

[0167] It is particularly advantageous to formulate the composition in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as a single dosage for a mammalian subject to be treated, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in association with a pharmaceutically acceptable vehicle as required. The specifications for the novel unit dosage forms of the present invention are dictated by, and directly responsive to, (a) the unique characteristics of the active substance and the particular therapeutic effect to be achieved, and (b) the constraints inherent in the art of compounding the active substance for treating a disease in a living subject having a disease state in which the physical well-being is impaired as disclosed in detail herein.

[0168] As noted above, the main active ingredient may be formulated in a therapeutically effective amount, conveniently and effectively, with a pharmaceutically acceptable vehicle suitable for unit dosage form. The unit dosage form can contain the main active compound, for example, in an amount ranging from 0.25 μg to about 2000 mg. Expressed as a ratio, the active compound may be present in an amount of about 0.25 μg to about 2000 mg per 1 mL of the carrier. In the case of a composition containing supplementary active ingredients, the dosage is determined with reference to the usual dosage and the method of administration of the said ingredients.

[0169] As used herein, the term "effective amount" refers to the amount of a compound that, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Administration may be carried out once, at intervals of several minutes or hours, or continuously over any one of these times. Suitable dosages may be in the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. Typical dosages are in the range of 1 μg to 1 g per kg of body weight per dosage, for example, in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, for example, up to 50 mg per kg of body weight per dosage.

[0170] As used herein, the terms "treatment" and "treating" encompass the treatment of a condition or disease in an animal, preferably a mammal, more preferably a human, and include the treatment of diseases or disorders in which elevated levels of testosterone are beneficial. The terms "prevention" and "preventing" encompass the defense or prevention of a condition or disease in an animal, preferably a mammal, more preferably a human, and include the prevention of diseases or disorders in which elevated levels of testosterone are beneficial.

[0171] The present invention will now be described with reference to the following non-limiting examples. The following examples are representative of general formula (I) and provide detailed methods for preparing the exemplary compounds of the present invention.

Example

[0172] Example 1. A method for preparing a compound of formula (I) in which Y represents an unsubstituted alkyl group and L represents X' (where X' is O) (a) 5-((1,3-Bis(palmitoyloxy)propan-2-yl)oxy)-5-oxopentanoic acid (IV)

[0173]

Chem.

[0174] 4-(Dimethylamino)pyridine (64.4 mg, 0.527 mmol) was added to a solution of diglyceride (III) (300 mg, 0.527 mmol) and glutaric anhydride (I) (120 mg, 1.05 mmol) in pyridine / THF / CH2Cl2 (1.5 mL each), and the mixture was stirred at room temperature for 2 days. The reaction was diluted with ethyl acetate (20 mL), washed with 1 M HCl and brine (20 mL each), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Acid triglyceride IV (140 mg, 39%) was obtained as a colorless solid by silica gel chromatography (10% - 15% ethyl acetate / hexane). 1 1H-NMR (400 MHz, CDCl3) δ 5.26 (m, 1H), 4.31 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.44 (t, J = 7.4 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.31 (t, J = 7.6 Hz, 4H), 1.96 (pent, J = 7.3 Hz, 2H), 1.67 - 1.54 (m, 4H), 1.49 - 1.18 (m, 48H), 0.88 (t, J = 6.8 Hz, 6H) (b) Octanedioyl dichloride (II)

[0175]

Chem.

[0176] A mixture of suberic acid (84.2 mg, 0.483 mmol) and a drop of DMF in thionyl chloride (351 μL, 4.83 mmol) was heated at reflux for 1.5 h. The reaction was cooled to room temperature, diluted with toluene (5 mL), and concentrated under reduced pressure to give diacid chloride (II) (102 mg, quantitative) as a yellow oil, which was used without purification. 1H-NMR (400 MHz, CDCl3) δ 2.90 (t, J = 7.2 Hz, 4H), 1.78 - 1.68 (m, 4H), 1.42 - 1.35 (m, 4H) (c) 8 - ((1,3 - bis(palmitoyloxy)propan - 2 - yl)oxy) - 8 - oxooctanoic acid (IV)

[0177]

Chem.

[0178] A solution of diglyceride (III) (50.0 mg, 0.0879 mmol) and pyridine (71.1 μL, 0.879 mmol) in CH2Cl2 (2 mL) was added to dioctanedioyl dichloride (II) (102 mg, 0.483 mmol) in CH2Cl2 (1.5 mL), and the mixture was stirred at room temperature for 3.5 h. The reaction was cooled to room temperature, diluted with water (10 mL) and 1 M HCl (3 mL), and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with 1 M HCl (30 mL) and brine (30 mL, twice), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% - 50% ethyl acetate / hexane) gave acid triglyceride (IV) (29.5 mg, 46%) as a pale yellow solid. 1 H-NMR (400 MHz, CDCl3) δ 5.25 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.37 - 2.28 (m, 8H), 1.68 - 1.56 (m, 8H), 1.39 - 1.21 (m, 52H), 0.87 (t, J = 6.8 Hz, 6H) (d) 1 - ((3R,5S,8S,9S,10S,13S,14S,17S) - 17 - acetyl - 10,13 - dimethyl - 11 - oxohexadecahydro - 1H - cyclopenta a]phenanthren - 3 - yl) 10 - (1,3 - bis(palmitoyloxy)propan - 2 - yl) decanedioate (2)

[0179]

Chem.

[0180] 4-(Dimethylamino)pyridine (DMAP, 5.2 mg, 42.5 μmol), EDC·HCl (20.4 mg, 106 μmol), and alfaxolone (22.6 mg, 68.0 μmol) were added to a CH2Cl2 (1.5 mL) solution of acid-TG(IV) (32.0 mg, 42.5 μmol), and the mixture was stirred at room temperature for 22 h. The reaction mixture was diluted with CH2Cl2, silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (15% - 20% ethyl acetate / hexane) gave compound 2 (20.5 mg, 45%) as a colorless solid. 1 H-NMR (400 MHz, CDCl3) δ 5.25 (m, 1H), 5.00 (m, 1H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.71 (t, J = 9.0 Hz, 1H), 2.56 (d, J = 11.9 Hz, 1H), 2.48 (d, J = 12.0 Hz, 1H), 2.34 - 2.18 (m, 10H), 2.09 (s, 3H), 1.86 - 1.37 (m, 18H), 1.36 - 1.07 (m, 62H), 1.00 (s, 3H), 0.87 (t, J = 6.8 Hz, 6H), 0.57 (s, 3H) (e) 1-(1,3-Bis(palmitoyloxy)propan-2-yl) 10-(1-((tert-butoxycarbonyl)(isopropyl)amino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-yl) decanedioate (XXV)

[0181]

Chemical Structure

[0182] 4-(Dimethylamino)pyridine (DMAP, 5.6 mg, 45.4 μmol) and EDC·HCl (17.4 mg, 90.0 μmol) were added to a CH₂Cl₂ (2 mL) solution of pre-prepared N-Boc-metoprolol (16.7 mg, 45.4 μmol) and acid-TG (IV) (34.2 mg, 45.4 μmol), and the mixture was stirred at room temperature for 19 hours. Subsequently, the reaction mixture was concentrated under reduced pressure to obtain a crude product. Purification by silica gel chromatography (10% - 20% ethyl acetate / hexane) gave the protected prodrug (XXV) (23.3 mg, 47%) as a colorless solid. 1 H-NMR (400 MHz, CDCl₃) δ 7.12 (d, J = 8.5 Hz, 2H), 6.83 - 6.78 (m, 2H), 5.33 (m, 1H), 5.25 (m, 1H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 4.22 - 3.98 (m, 3H), 3.55 (t, J = 7.1 Hz, 2H), 3.47 (m, 1H), 3.34 (s, 3H), 3.31 (m, 1H), 2.81 (t, J = 7.1 Hz, 2H), 2.33 - 2.27 (m, 8H), 1.64 - 1.56 (m, 8H), 1.46 (s, 9H), 1.37 - 1.20 (m, 56H), 1.18 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H), 0.87 (t, J = 6.9 Hz, 6H) (f) 1-(1,3-Bis(palmitoyloxy)propan-2-yl) 10-(1-(isopropylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-yl) decanedioate (3)

[0183]

Chemical Structure

[0184] Trifluoroacetic acid (TFA) (7.7 μL, 0.104 mmol) was added to a solution of Boc carbamate (XXV) (23.0 mg, 0.0209 mmol) in CH2Cl2 (1 mL), and the reaction mixture was stirred at room temperature for 6 h. TLC analysis at this point showed slow progress of the reaction, so additional TFA (15.4 μL, 0.208 mmol) was added and the mixture was stirred at room temperature for an additional 18 h. Triethylamine (Et3N, 50 μL) was added, and the reaction mixture was concentrated under a stream of N2 to give the crude product. Purification by silica gel chromatography (ethyl acetate / hexane with 1% Et3N, 20% - 40% - 60%) gave compound 3 (19.0 mg, 91%) as a colorless oil. 1 1H-NMR (400 MHz, CDCl3) δ 7.16 - 7.09 (m, 2H), 6.87 - 6.81 (m, 2H), 5.29 - 5.18 (m, 2H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 4.11 - 4.08 (m, 2H), 3.55 (t, J = 7.1 Hz, 2H), 3.34 (s, 3H), 2.99 - 2.88 (m, 2H), 2.86 - 2.77 (m, 3H), 2.35 - 2.28 (m, 8H), 1.69 - 1.49 (m, 8H), 1.37 - 1.16 (m, 56H), 1.05 (d, J = 6.2 Hz, 6H), 0.88 (t, J = 6.8 Hz, 6H) (g) Synthesis of 1-(1,3-bis(palmitoyloxy)propan-2-yl) 10-(4-(6-hydroxy-3-(4-(2-(piperidin-1-yl)ethoxy)benzoyl)benzo[b]thiophen-2-yl)phenyl) decanedioate (4)

[0185]

Chemical Structure

[0186] In the case of raloxifene (RAL) containing two phenolic hydroxyl groups, mono - protection of the parent molecule is necessary to prevent the formation of mixed mono - acyl and bis - acyl products in the subsequent coupling step. Treatment of raloxifene with 1 equivalent of TBSCI in the presence of a base yields a mixture of positional isomer monosilyl ethers that can be partially separated by chromatography. Coupling of the less polar phenolic isomer (XXVI) with acid - TG(IV) under standard conditions yields the protected prodrug (XXVII). Removal of the silyl protecting group using TBAF provided compound 4. It should be noted that this procedure can also convert the positional isomers of phenol (XXVI) into the corresponding isomeric prodrugs. (g)(i)(6 - ((tert - butyldimethylsilyl)oxy)-2-(4 - hydroxyphenyl)benzo[b]thiophen - 3 - yl)(4-(2-(piperidin - 1 - yl)ethoxy)phenyl)methanone (XXVI)

[0187]

Chemical Structure

[0188] 4 - (Dimethylamino)pyridine (DMAP, 108 mg, 0.882 mmol) was added to raloxifene hydrochloride (180 mg, 0.353 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 1 h. The reaction was cooled to 0 °C, tert - butyl(chloro)dimethylsilane (TBSCl, 53.2 mg, 0.353 mmol) was added, and the resulting mixture was stirred at room temperature for a further 2.5 h. The reaction was diluted with ethyl acetate (60 mL), and the organic phase was washed with water (2 × 50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (MeOH / CH2Cl2 with 1% Et3N at 0 - 12.5%) gave the protected monosilyl ether (XXVI) as a yellow oil (25.0 mg, 12%) along with the mixed positional isomer monosilyl ethers and unreacted raloxifene. 1 H-NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.87 (dd, J = 8.7, 2.0 Hz, 1H), 6.65 (d, J = 7.9 Hz, 4H), 4.06 (t, J = 5.9 Hz, 2H), 2 .75 (t, J = 5.9 Hz, 2H), 2.55 - 2.47 (m, 4H), 1.65 - 1.58 (m, 4H), 1.48 - 1.41 (m, 2H), 0.92 (s, 9H), 0.11 (s, 6H) (g)(ii) 1-(1,3-bis(palmitoyloxy)propan-2-yl) 10-(4-(6-((tert-butyldimethylsilyl)oxy)-3-(4-(2-(piperidin-1-yl)ethoxy)benzoyl)benzo[b]thiophen-2-yl)phenyl) decanedioate (XXVII)

[0189]

Chem.

[0190] 4-(Dimethylamino)pyridine (DMAP, 2.4 mg, 19.9 micromol) and EDC·HCl (9.5 mg, 49.8 micromol) were added to a CH2Cl2 (0.6 mL) solution of acid-TG(IV) (15.0 mg, 19.9 micromol) and XXVI (11.7 mg, 19.9 micromol), and the mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (MeOH / CH2Cl2 with 1% Et3N at 0 - 1.5%) gave the protected prodrug (XXVII) (16.0 mg, 61%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.74 - 7.67 (m, 3H), 7.59 (d, J = 2.1 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.06 (dd, J = 8.8, 2.1 Hz, 1H), 6.73 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 5.26 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 4.07 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 5.9 Hz, 2H), 2.58 (t, J = 7.5 Hz, 2H), 2.53 - 2.44 (m, 4H), 2.35 - 2.27 (m, 6H), 1.82 - 1.73 (m, 2H), 1.68 - 1.53 (m, 10H), 1.49 - 1.39 (m, 4H), 1.38 - 1.19 (m, 54H), 0.93 (s, 9H), 0.87 (t, J = 6.8 Hz, 6H), 0.12 (s, 6H) (g)(iii) 1-(1,3-bis(palmitoyloxy)propan-2-yl) 10-(4-(6-hydroxy-3-(4-(2-(piperidin-1-yl)ethoxy)benzoyl)benzo[b]thiophen-2-yl)phenyl) decanedioate (4) Tetra-n-butylammonium fluoride (TBAF, 0.1 M in THF, 70.0 μL, 7.0 micromoles) and acetic acid (1.0 M in THF, 10.0 μL, 10.0 micromoles) were added to a solution of TBS ether (XXVII) (7.1 mg, 5.4 micromoles) in THF (0.4 mL) at 0 °C, and the mixture was stirred at 0 °C for 50 minutes. The reaction was diluted with ethyl acetate (20 mL), washed with water and brine (15 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (MeOH / CH2Cl2 with 1% Et3N at 0 - 2%) gave compound 4 (4.9 mg, 75%) as a pale yellow oil. 1 H-NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 2.1 Hz, 1H), 7. 19 (d, J = 8.6 Hz, 2H), 7.08 (dd, J = 8.8, 2.2 Hz, 1H), 6.67 (d, J = 7.3 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 5.26 (m, 1H), 4.30 (dd, J = 11.9, 4.3 Hz, 2H), 4.15 (dd, J = 11.9, 5.9 Hz, 2H), 4.09 (t, J = 5.7 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 2.62 - 2.50 (m, 6H), 2.37 - 2.27 (m, 6H), 1.82 - 1.73 (m, 2H), 1.69 - 1.55 (m, 10H), 1.50 - 1.19 (m, 58H), 0.87 (t, J = 6.8 Hz, 6H) Example 2. A method for preparing a compound of formula (I) wherein Y represents an α-methyl substituted alkyl group and L represents X' (X' is O) (h) (E)-Methyl 10-(benzyloxy)-2-methyldec-2-enoate (VIII)

[0191] [Chemical formula]

[0192] Pyridinium chlorochromate (PCC, 39.7 mg, 0.184 mmol) and celite (30 mg) were added to a solution of alcohol (VI) (29.0 mg, 0.123 mmol) in CH2Cl2 (1.5 mL), and the reaction mixture was stirred at room temperature for 1.5 h. The resulting dark suspension was filtered through a short pad of silica gel and eluted with 50% ethyl acetate / hexane. The eluate was concentrated under reduced pressure to give a crudely purified aldehyde, which was immediately redissolved in toluene (1.5 mL). Ylide (VII) (85.5 mg, 0.245 mmol) was added, and the mixture was heated at reflux for 20 h. The reaction was cooled to room temperature and concentrated under reduced pressure to give a crude product. Purification by silica gel chromatography (5% - 8% ethyl acetate / hexane) gave the α,β-unsaturated methyl ester (VIII) (26.2 g, 70%) as a yellow oil was obtained. 1H-NMR (400 MHz, CDCl3) δ 7.38 - 7.26 (m, 5H), 6.76 (m, 1H), 4.50 (s, 2H), 3.73 (s, 3H), 3.46 (t, J = 6.6 Hz, 2H), 2.10 - 2.02 (m, 2H), 1.83 (d, J = 1.3 Hz, 3H), 1.65 - 1.58 (m, 2H), 1.47 - 1.28 (m, 8H) (i) (E)-10-(Benzyloxy)-2-methyldec-2-enoic acid (IX)

[0193]

Chem.

[0194] A solution of sodium hydroxide (2.0 M, 256 μL, 0.512 mmol) was added to ester (VIII) (26.0 mg, 0.0854 mmol) in methanol (0.9 mL) and water (0.65 mL), and the mixture was stirred at room temperature for 30 minutes and then at 0 °C for 20 hours. The reaction was acidified to pH 1 by the addition of 1 M HCl, diluted with water (5 mL), and the aqueous phase was extracted with ethyl acetate (4 × 15 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO4), and concentrated under reduced pressure to give crude acid (IX) (24.8 mg, quantitative) as a colorless oil, which was used without purification. 1 H-NMR (400 MHz, CDCl3) δ 7.39 - 7.26 (m, 5H), 6.9 1 (td, J = 7.5, 1.3 Hz, 1H), 4.51 (s, 2H), 3.47 (t, J = 6.6 Hz, 2H), 2.23 - 2.15 (m, 2H), 1.83 (d, J = 0.7 Hz, 3H), 1.67 - 1.56 (m, 2H), 1.49 - 1.25 (m, 8H) (j) (E)-2-((10-(Benzyloxy)-2-methyldec-2-enoyl)oxy)propane-1,3-diyl dipalmitate (X)

[0195]

Chem.

[0196] 4-(Dimethylamino)pyridine (DMAP, 10.4 mg, 0.0854 mmol), EDC·HCl (40.9 mg, 0.214 mmol), and diglyceride (III) (77.7 mg, 0.137 mmol) were added to a CH₂Cl₂ (2 mL) solution of acid (IX) (24.8 mg, 0.0854 mmol), and the mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with CH₂Cl₂ (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (3% - 7.5% ethyl acetate / hexane) gave triglyceride (44.6 mg, 62% over two steps) as a colorless solid. 1 ¹H-NMR (400 MHz, CDCl₃) δ 7.37 - 7.24 (m, 5H), 6.76 (m, 1H), 5.30 (m, 1H), 4.50 (s, 2H), 4.31 (dd, J = 11.8, 4.5 Hz, 2H), 4.22 (dd, J = 11.8, 5.8 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H), 2.31 (t, J = 7.5 Hz, 4H), 2.16 (dt, J = 7.4, 7.4 Hz, 2H), 1.81 (d, J = 1.1 Hz, 3H), 1.66 - 1.55 (m, 6H), 1.47 - 1.19 (m, 56H), 0.88 (t, J = 6.9 Hz, 6H) (k) 2-((10-Hydroxy-2-methyldecanoyl)oxy)propane-1,3-diyl dipalmitate (XI)

[0197]

Chemical Structure

[0198] A solution of benzyl ether (X) (40.0 mg, 47.6 micromoles) in ethyl acetate (5 mL) in a three-necked flask was evacuated twice, N2 gas was passed through, and then palladium on carbon (10% w / w, 12.7 mg, 11.9 micromoles) was added. The resulting suspension was evacuated again and N2 was passed through twice. The flask was fixed with an H2 balloon, evacuated, and H2 was passed through three times. The reaction mixture was stirred at room temperature for 3 hours under 1 atm of H2. The reaction product was filtered through a pad of celite, washed with ethyl acetate, and concentrated under reduced pressure to give the saturated alcohol (XI) (32.1 mg) as a colorless oil, which was used without purification. 1 1H-NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J = 11.7, 3.9 Hz, 2H), 4.14 (dd, J = 11.9, 6.1 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.44 (m, 1H), 2.30 (t, J = 7.6 Hz, 4H), 1.67 - 1.50 (m, 8H), 1.42 - 1.20 (m, 58H), 1.14 (d, J = 7.0 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H) (l) 2-((2-Methyl-10-oxodecanoyl)oxy)propane-1,3-diyl dipalmitate (XII)

[0199]

Chemical Structure

[0200] Pyridinium chlorochromate (PCC, 15.2 mg, 70.4 micromoles) was added to a suspension of alcohol (XI) (26.5 mg, 35.2 micromoles) and celite (20 mg) in CH2Cl2 (1 mL) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction product was filtered through a short pad of silica gel, eluted with 50% ethyl acetate / hexane, and the filtrate was concentrated under reduced pressure to give the crudely purified aldehyde (XII) (26.4 mg) as a yellow oil, which was used without purification. 1H-NMR (400 MHz, CDCl3) δ 9.76 (t, J = 1.8 Hz, 1H), 5.27 (m, 1H), 4.29 (ddd, J = 11.9, 4.3, 3.1 Hz, 2H), 4.14 (dd, J = 11.9, 6.1 Hz, 2H), 2.42 (m, 1H), 2.41 (td, J = 7.3, 1.8 Hz, 2H), 2.30 (t, J = 7.5 Hz, 4H), 1.67 - 1.54 (m, 8H), 1.44 - 1.18 (m, 56H), 1.14 (d, J = 7.0 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H) (m) 10 - ((1,3 - bis(palmitoyloxy)propan - 2 - yl)oxy) - 9 - methyl - 10 - oxodecanoic acid (IV)

[0201] [Chemical formula]

[0202] A solution of sodium chloride (28.6 mg, 0.317 mmol) and sodium monobasic phosphate (NaH2PO4, 29.5 mg, 0.246 mmol) in water (0.5 mL) was added dropwise to aldehyde (XII) (26.4 mg, 0.0352 mmol) in t - BuOH (1 mL) and 2,3 - dimethyl - 2 - butene (0.2 mL), and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (5 mL), and the aqueous layer was extracted with hexane (3 × 5 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give the crude product as a colorless oil The purified acid (IV) (27.0 mg) was obtained and used without further purification 1 H-NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (ddd, J = 11.8, 4.3, 3.2 Hz, 2H), 4.14 (dd, J = 11.9, 6.1 Hz, 2H), 2.43 (m, 1H), 2.36 - 2.28 (m, 6H), 1.65 - 1.55 (m, 8H), 1.38 - 1.19 (m, 56H), 1.14 (d, J = 7.0 Hz, 3H), 0.88 (t, J = 7.0 Hz, 6H) Method for preparing a compound of formula (I) wherein Y represents an alkyl group substituted with β-methyl and L represents X' (X' is O) (n)(7-(Benzyloxy)hept-1-yn-1-yl)trimethylsilane (XIV)

[0203]

Chemical formula

[0204] n-Butyllithium (n-BuLi, 1.6 M in hexane, 765 μL, 1.23 mmol) was slowly added to a solution of TMS-acetylene (198 μL, 1.40 mmol) in THF (1.5 mL) at -78 °C. The mixture was stirred at -78 °C for 5 minutes, then warmed to room temperature and stirred for an additional 15 minutes. The reaction mixture was cooled again to -50 °C, and a solution of bromide (XIII) (90.0 mg, 0.350 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at -50 °C for 15 minutes and then at room temperature for 17 hours. The reaction mixture was diluted with brine (15 mL), and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), and concentrated under reduced pressure to obtain a crude product. Purification by silica gel chromatography (4% - 5% ethyl acetate / hexane) gave the desilylated alkyne (XV) (9.7 mg, 14% by 1H-NMR integration) and the TMS alkyne (XIV) (45.9 mg, 48%) as a colorless oil, also containing a small amount of PPh3. 1 H-NMR (400 MHz, CDCl3) δ 7.37 - 7.26 (m, 5H), 4.50 (s, 2H), 3.48 (t, J = 6.5 Hz, 2H), 2.23 (t, J = 7.0 Hz, 2H), 1.68 - 1.60 (m, 2H), 1.58 - 1.42 (m, 4H), 0.14 (s, 7H) (o)((Hept-6-yn-1-yloxy)methyl)benzene (XV)

[0205]

Chemical formula

[0206] Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 201 μL, 0.201 mmol) was slowly added to a 7:2 mixture of silyl alkyne (XIV) and alkyne (XV) (55.6 mg total, 0.215 mmol) in THF (1 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction was diluted with water (5 mL) and saturated aqueous NH4Cl solution (3 mL), and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% ethyl acetate / hexane) gave alkyne (XV) (37.5 mg, 53% over two steps) as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ 7.39 - 7.27 (m, 5H), 4.51 (s, 2H), 3.49 (t, J = 6.5 Hz, 2H), 2.21 (td, J = 6.9, 2.6 Hz, 2H), 1.95 (t, J = 2.7 Hz, 1H), 1.70 - 1.61 (m, 2H), 1.60 - 1.48 (m, 4H) (p)(Z)-Ethyl 10-(benzyloxy)-3-methyldec-2-en-4-ynoate (XVII)

[0207]

Chemical Structure

[0208] A suspension of PdCl2(PPh3)2 (16.8 mg, 0.0240 mmol) in DMF (1.5 mL) was degassed for 5 minutes using N2 gas, and then CuI (9.1 mg, 0.0480 mmol), Et3N (66.8 μL, 0.480 mmol), alkyne (XV) (48.5 mg, 0.240 mmol), and a degassed DMF (2 mL) solution of enol triflate (XVI) (94.3 mg, 0.360 mmol) were added. The mixture was further degassed for 5 minutes using a N2 stream and then heated at 0 °C for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with 1 M HCl, saturated aqueous NaHCO3, water, and brine (each 20 mL), dried (MgSO4), and concentrated under reduced pressure to obtain the crude product. Enin (XVII) (46.6 mg, 62%) was obtained as a pale yellow oil by silica gel chromatography (4% - 5% ethyl acetate / hexane). 1 1H-NMR (400 MHz, CDCl3) δ 7.37 - 7.24 (m, 5H), 5.92 (m, 1H), 4.50 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.48 (t, J = 6.5 Hz, 2H), 2.45 (t, J = 7.0 Hz, 2H), 2.01 (d, J = 1.4 Hz, 3H), 1.69 - 1.59 (m, 4H), 1.56 - 1.49 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H) (q) Ethyl 10-hydroxy-3-methyldecanoate (XVIII)

[0209]

Chemical Structure

[0210] A solution of benzyl ether (XVII) (31.4 mg, 0.100 mmol) in ethyl acetate (8 mL) in a 2-necked flask was evacuated twice, N2 gas was passed through, and then palladium on carbon (10% w / w, 26.6 mg, 0.0250 mmol) was added. The resulting suspension was evacuated again, and N2 gas was passed through three times. The flask was fixed with an H2 balloon, evacuated, and H2 was passed through three times. The reaction mixture was stirred at room temperature for 1 hour under 1 atm of H2. The reaction product was filtered through a pad of celite, washed with ethyl acetate, and concentrated under reduced pressure to give the saturated alcohol (XVIII) (23.0 mg, quantitative) as a colorless oil, which was used without purification. 1 1H-NMR (400 MHz, CDCl3) δ 4.12 (q, J = 7.1 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.28 (dd, J = 14.6, 6.1 Hz, 1H), 2.09 (dd, J = 14.6, 8.1 Hz, 1H), 1.94 (m, 1H), 1.60 - 1.50 (m, 2H), 1.25 (t, J = 6.6 Hz, 3H), 1.40 - 1.13 (m, 10H), 0.92 (d, J = 6.6 Hz, 3H) (r) Ethyl 10 - ((tert-butyldiphenylsilyl)oxy)-3-methyldecanoate (XIX)

[0211]

Chemical formula

[0212] Imidazole (9.6 mg, 0.141 mmol) and tert-butyl(chloro)diphenylsilane (TBDPSCl, 50.8 μL, 0.195 mmol) were added to a solution of alcohol (XVIII) (18.0 mg, 0.0781 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 16 hours. The reaction product was diluted with ethyl acetate (20 mL), washed with brine (2 × 15 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% ethyl acetate / hexane with 0.5% Et3N) gave the TBDPS ether (XIX) (33.7 mg, 92%) as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ 7.70 - 7.64 (m, 4H), 7.45 - 7.33 (m, 6H), 4.13 (q, J = 7.1 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.28 (dd, J = 14.6, 6.0 Hz, 1H), 2.09 (dd, J = 14.6, 8.2 Hz, 1H), 1.94 (m, 1H), 1.60 - 1.50 (m, 2H), 1.38 - 1.21 (m, 3H), 1.05 (s, J = 2.9 Hz, 2H), 1.05 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H) (s) 10 - ((tert-butyldiphenylsilyl)oxy)-3-methyldecanoic acid (XX)

[0213]

Chem.

[0214] A solution of potassium hydroxide (2.0 M, 427 μL, 0.853 mmol) was added to ester (XIX) (40.0 mg, 0.0853 mmol) in ethanol (2 mL), and the mixture was heated at 80 °C for 2 hours. The reaction was acidified to pH 1 by the addition of 1 M HCl, and the organic solvent was removed under reduced pressure. The residue was diluted with water (5 mL), the aqueous phase was extracted with ethyl acetate (3 × 15 mL), the combined organic extracts were washed with brine (30 mL), dried (MgSO4), and concentrated under reduced pressure to give crude purified acid (XX) (37.6 mg, quantitative) as a colorless oil, which was used without further purification. When run at high concentration, 1 doubling of the signals was observed in both the 13 1H-NMR spectrum and 1H-NMR (400 MHz, CDCl3) δ 7.74 - 7.63 (m, 4H), 7.45 - 7.34 (m, 6H), 3.65 (t, J = 6.5 Hz, 2H), 2.35 (dd, J = 15.0, 5.9 Hz, 1H), 2.14 (dd, J = 15.0, 8.2 Hz, 1H), 1.95 (m, 1H), 1.61 - 1.50 (m, 2H), 1.38 - 1.18 (m , 10H), 1.04 (s, 9H), 0.96 (d, J = 6.6 Hz, 3H) (t) 2 - ((10 - ((tert-butyldiphenylsilyl)oxy)-3-methyldecanoyl)oxy)propane-1,3-diyl dipalmitate (XXI)

[0215]

Chem.

[0216] 4-(Dimethylamino)pyridine (DMAP, 10.1 mg, 0.0831 mmol) and EDC·HCl (39.8 mg, 0.208 mmol) and diglyceride (III) (70.9 mg, 0.125 mmol) were added to a CH2Cl2 (2.5 mL) solution of acid (XX) (36.6 mg, 0.0831 mmol), and the mixture was stirred at room temperature for 21 h. The reaction mixture was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (4% - 5% ethyl acetate / hexane) gave triglyceride (XXI) (39.9 mg, 48% over two steps) as a colorless solid. 1H-NMR (400 MHz, CDCl3) δ 7.69 - 7.64 (m, 4H), 7.44 - 7.34 (m, 6H), 5.28 (m, 1H), 4.29 (ddd, J = 11.8, 4.2, 0.6 Hz, 2H), 4.14 (dd, J = 12.0, 5.9 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 2.37 - 2.27 (m, 5H), 2.11 (dd, J = 14.7, 8.4 Hz, 1H), 1.92 (m, 1H), 1.67 - 1.50 (m, 8H), 1.39 - 1.14 (m, 56H), 1.04 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H) (u) 2-((10-Hydroxy-3-methyldecanoyl)oxy)propane-1,3-diyl dipalmitate (XI)

[0217]

Chem.

[0218] Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 98.3 μL, 98.3 μmol) was added to a solution of TBDPS ether (XXI) (39.0 mg, 39.3 μmol) in THF (2.5 mL) at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The organic extracts were washed with brine (30 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% - 20% ethyl acetate / hexane) gave the alcohol (XI) (21.8 mg, 74%) as a colorless solid. 1 H-NMR (400 MHz, CDCl3) δ 5.28 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 3.64 (t, J = 6.6 Hz, 2H), 2.36 - 2.27 (m, 5H), 2.1 2 (dd, J = 14.7, 8.2 Hz, 1H), 1.93 (m, 1H), 1.65 - 1.52 (m, 6H), 1.39 - 1.16 (m, 58H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H) (v) 2 - ((3 - Methyl - 10 - oxodecanoyl)oxy)propane - 1,3 - diyl dipalmitate (XII)

[0219]

Chem.

[0220] Pyridinium chlorochromate (PCC, 12.0 mg, 55.8 micromol) was added to a suspension of alcohol (XI) (21.0 mg, 27.9 micromol) and celite (15 mg) in CH2Cl2 (1.5 mL) at 0 °C, and the mixture was stirred at room temperature for 1.75 h. The reaction mixture was filtered through a short pad of silica gel, eluted with ethyl acetate, and the filtrate was concentrated under reduced pressure to give the crudely purified aldehyde (XII) (20.9 mg, quantitative) as a yellow oil, which was used without purification. 1 1H - NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 5.28 (m, 1H), 4.29 (dd, J = 11.6, 3.5 Hz, 2H), 4.14 (dd, J = 11.6, 5.7 Hz, 2H), 2.42 (t, J = 7.1 Hz, 2H), 2.36 - 2.25 (m, 5H), 2.12 (dd, J = 14.5, 8.3 Hz, 1H), 1.93 (m, 1H), 1.72 - 1.53 (m, 6H), 1.42 - 1.05 (m, 56H), 0.93 (d, J = 6.5 Hz, 3H), 0.88 (t, J = 6.6 Hz, 6H) (w) 10 - ((1,3 - Bis(palmitoyloxy)propan - 2 - yl)oxy) - 8 - methyl - 10 - oxodecanoic acid (IV)

[0221]

Chem.

[0222] A solution of sodium chloride (22.7 mg, 0.251 mmol) and sodium monobasic phosphate (NaH2PO4, 23.4 mg, 0.195 mmol) in water (1 mL) was added dropwise to aldehyde (XII) (20.9 mg, 0.0279 mmol) in t-BuOH (1.5 mL) and 2,3-dimethyl-2-butene (0.3 mL), and the reaction mixture was stirred at room temperature for 2.25 hours. The reaction mixture was diluted with water (10 mL), and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), and concentrated under reduced pressure to obtain a crude product. Purification by silica gel chromatography (10% - 20% ethyl acetate / hexane with 0.5% AcOH) gave acid (IV) (16.1 mg, 75%) as a colorless solid. 1 H-NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 12.0, 6.0 Hz, 2H ), 2.37 - 2.27 (m, 7H), 2.12 (dd, J = 14.7, 8.2 Hz, 1H), 1.93 (m, 1H), 1.67 - 1.55 (m, 6H), 1.40 - 1.14 (m, 56H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H) (x) 1-(1,3-bis(palmitoyloxy)propan-2-yl) 10-((8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl) 3-methyldecanedioate (19)

[0223]

Chem.

[0224] 4-(Dimethylamino)pyridine (DMAP, 2.5 mg, 20.6 μmol), EDC·HCl (9.9 mg, 51.4 μmol), and testosterone (10.7 mg, 37.1 μmol) were added to a solution of acid-TG(IV) (13.6 mg, 17.7 μmol) in CH2Cl2 (1 mL), and the mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (15% ethyl acetate / hexane) gave compound 19 (10 mg, 55%) as a colorless solid. 1 1H-NMR (400 MHz, CDCl3) δ 5.73 (s, 1H), 5.27 (m, 1H), 4.61 (dd, J = 9.0, 7.9 Hz, 1H), 4.29 (dd, J = 11.9, 3.8 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 2.48 - 2.24 (m, 11H), 2.23 - 1.99 (m, 4H), 1.93 (m, 1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.72 - 1.22 (m, 68H), 1.19 (s, 3H), 1.16 - 0.96 (m, 4H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H), 0.83 (s, 3H) Further exemplary compounds of formula (I) are provided below in Table 4.

[0225]

Table 4-1

[0226]

Table 4-2

[0227] Example 4. A method for preparing a compound of formula (I) wherein Z represents C(O)R 3 and R 3 represents an acetal-cleavable group and L represents X’ (where X’ is O or N(R 4 ))

[0228]

Chemical formula

[0229] For the synthesis of compounds containing an acetal self - destructing linker placed between a drug and an alkyl spacer to facilitate systemic release of the parent molecule (Wittman, M.D.; et al., Bioorg. Med. Chem. Lett. 2001, 11, 811 - 814), drugs with an alcohol must be functionalized and activated prior to their coupling with an acid / triglyceride (IV) as outlined in Scheme 5. Treatment of the alcohol with DMSO in a mixture of acetic anhydride and acetic acid results in the formation of a (methylthio)methyl (MTM) ether (XXVIII). Activation of the MTM ether with sulfuryl chloride forms a putative sulfoxide species that can react with the carboxylate of the acid / triglyceride (IV) to produce a compound (XXIX) with an acetal. (y)(8R,9S,10R,13S,14S,17S)-10,13 - dimethyl - 17 - ((methylthio)methoxy)-1,2,6,7,8,9,10,11 - 12,13,14,15,16,17 - tetradecahydro - 3H - cyclopenta[a]phenanthren - 3 - one (XXVIII)

[0230]

Chemical Structure

[0231] Acetic acid (44 μL, 0.769 mmol) and acetic anhydride (140 μL, 1.48 mmol) were added to testosterone (36.1 mg, 0.125 mmol) in DMSO (216 μL, 3.04 mmol), and the mixture was stirred at room temperature for 2 days and 18 hours. LCMS analysis of the reaction mixture at this point showed that there was no unreacted testosterone, 55% was converted to the desired MTM ether, and a number of other testosterone-containing species accounted for the mass balance. A total of 5 reactions were carried out on the same scale under slightly different conditions (see the table below), and then combined for isolation of the desired product. The combined reaction mixture was diluted with water (15 mL) and neutralized with 10% K2CO3 solution. The aqueous phase was extracted with ethyl acetate (3 × 20 mL), and the combined organic extracts were washed with saturated aqueous NaHCO3 (40 mL) and brine (40 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% - 15% ethyl acetate / hexane with 1% EtN) gave testosterone MTM ether (XXVIII) (113 mg, 52%) as a pale

[0232] [Number]

[0233] 1 H-NMR (400 MHz, CDCl3) δ 5.73 (s, 1H), 4.67 (d, J = 11.2 Hz, 1H), 4.58 (d, J = 11.2 Hz, 1H), 3.68 (t, J = 8.4 Hz, 1H), 2.48 - 2.24 (m, 4H), 2.13 (s, 3H), 2.08 - 1.97 (m, 2H), 1.93 - 1.80 (m, 2H), 1.75 - 1.22 (m, 8H), 1.19 (s, 3H), 1.07 - 0.90 (m, 3H), 0.82 (s, 3H) (z)1,3-bis(palmitoyloxy)propan-2-yl (((8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)oxy)methyl adipate (21)

[0234] [Chemical formula]

[0235] Sulfuryl chloride (0.81 M in CH2Cl2, 100 μL, 80.9 micromoles) was added to a solution of MTM ether (XXVIII) (22.3 mg, 63.9 micromoles) in CH2Cl2 (0.8 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for an additional 1 hour. The reaction mixture was concentrated under a stream of N2 and dried under reduced pressure. The crude residue was then redissolved in CH2Cl2 (0.8 mL) and added to a solution of acid-TG(IV) (29.7 mg, 42.6 micromoles) and DBU (7.6 μL, 51.1 micromoles) in toluene (0.8 mL) that had been stirred for 20 minutes beforehand. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with CH2Cl2 (20 mL), and the organic phase was washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried (MgSO4), and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (10% - 12.5% ethyl acetate / hexane) gave compound 21 (18.8 mg, 44%) as a pale yellow solid. 1 ​H-NMR (400 MHz, CDCl3) δ 5.72 (s, 1H), 5.30 - 5.21 (m, 3H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.13 (dd, J = 11.6, 5.5 Hz, 2H), 3.53 (dd, J = 8.3, 8.3 Hz, 1H), 2.48 - 2.22 (m, 12H), 2.08 - 1.98 (m, 2H), 1.92 - 1.80 (m, 2H), 1.75 - 1.50 (m, 13H), 1.49 - 1.20 (m, 49H), 1.18 (s, 3H), 1.17 - 0.83 (m, 5H), 0.87 (t, J = 6.9 Hz, 6H), 0.79 (s, 3H)

[0236]

Chem.

[0237] When the agent contains a primary or secondary amine, a modified form of the acetal self - destructing group containing an additional carbamate bond can be used (see Scheme 6). Chloromethyl chloroformate reacts with the amine to give chloromethyl carbamate (XXX). Then, substitution of the halogen - leaving group is achieved by treatment with the carboxylate derived from acid - TG(IV) in refluxing toluene to obtain the modified ASI prodrug (XXXI). (aa) Chloromethyl ((1S,4S)-4-(3,4 - dichlorophenyl)-1,2,3,4 - tetrahydronaphthalen - 1 - yl)(methyl)carbamate (XXX)

[0238]

Chem.

[0239] Chloromethyl chloroformate (8.3 μL, 93.3 μmol) and pyridine (14.1 μL, 175 μmol) were added to sertraline hydrochloride (20.0 mg, 58.3 μmol) in CH2Cl2 (4.5 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 4 hours. The reaction mixture was diluted with CH2Cl2 (20 mL), and the organic phase was saturated It was washed with aqueous NaHCO3 solution (2×20 mL) and brine (20 mL each), dried (MgSO4), and concentrated under reduced pressure to obtain a crude product. Purification by silica gel chromatography (10% - 15% ethyl acetate / hexane) gave chloromethyl carbamate (XXX) (20.5 mg, 88%) as a colorless solid. 1 1H-NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.3 Hz, 1H), 7.29 (m, 1H), 7.23 - 7.19 (m, 2H), 7.08 (s, br, 1H), 6.97 (m, 1H), 6.81 (m, 1H), 5.93 - 5.83 (m, 2H), 5.51 (dd, J = 10.5, 6.4 Hz, 0.6H), 5.33 (m, 0.4H), 4.20 (m, 1H), 2.77 (s, 1.2H), 2.72 (s, 1.8H), 2.29 (m, 1H), 2.02 (m, 1H), 1.79 (m, 2H). Note: The fractional integration reflects the presence of an approximately 3:2 mixture of rotamers due to restricted rotation around the N-methylcarbamate functional group. (ab) 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(((((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamoyl)oxy)methyl) 3-methylpentanedioate (7)

[0240]

Chemical Structure

[0241] 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (8.6 μL, 57.2 μmol) and tetra-n-butylammonium iodide (TBAI, 5.8 mg, 14.3 μmol) were added to a solution of acid-TG(IV) (20.5 mg, 29.4 μmol) and chloromethyl ether (XXX) (11.8 mg, 29.6 μmol) in toluene (1.5 mL), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), and the organic phase was washed with water (3×15 mL) and brine (2×15 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% - 20% ethyl acetate / hexane) gave compound 7 (21.1 mg, 68%) as a colorless oil. 1 1H-NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.3 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.21 - 7.16 (m, 2H), 7.09 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.80 (td, J = 8.0, 2.0 Hz, 1H), 5.89 - 5.82 (m, 2H), 5.49 (dd, J = 10.3, 6.5 Hz, 0.6H), 5.37 - 5.30 (m, 0.4H), 5.27 (m, 1H), 4.33 - 4.25 (m, 2H), 4.19 (m, 1H), 4.15 - 4.10 (m, 2H), 2.74 (s, 1.2H), 2.69 (s, 1.8H), 2.54 - 2.39 (m, 3H), 2.36 - 2.23 (m, 3H), 2.30 (t, J = 7.5 Hz, 4H), 2.01 (m, 1H), 1.84 - 1.70 (m, 2H), 1.66 - 1.57 (m, 4H), 1.33 - 1.20 (m, 48H), 1.05 (d, J = 6.2 Hz, 2H), 1.02 (d, J = 6.0 Hz, 1H), 0.88 (t, J = 6.9 Hz, 6H). Note: The fractional integrations reflect the presence of an approximately 3:2 mixture of rotamers due to restricted rotation around the N-methylcarbamate functional group. Example 5. Z is C(O)R 3 represents, R 3 represents a trimethyl lock self-destructing group, and L is X’( X’ is O, NR 4A method for preparing a compound of formula (I) (which is or S(O)2NH)

[0242]

Chemical formula

[0243] Regarding the synthesis of a prodrug containing a "trimethyl lock" (TML) self - destructing linker (Levine, M.N.; Raines, R.T. Chem. Sci. 2012, 3, 2412 - 2420) that is placed again between the drug and the alkyl spacer to facilitate systemic release of the parent molecule, as outlined in Scheme 7, the acid / triglyceride (IV) must be functionalized at the TML moiety prior to coupling with the drug. The triglyceride (XXXIII) is obtained by coupling of the acid - TG(IV) with the TML phenol (XXXII) under standard conditions and can be converted to the desired acid (XXXVI) in a manner similar to that described in Scheme 4. TBS ether (XXXIII) deprotection is achieved under acidic conditions (10 - camphorsulfonic acid), and the resulting alcohol (XXXIV) is oxidized in a two - step process to afford the acid (XXXVI). Then, under standard conditions, coupling to a drug containing an alcohol, amine, or sulfonamide can be carried out to obtain the target compound (XXXVII). (ac) 1,3 - bis(palmitoyloxy)propan - 2 - yl (2 - (4 - ((tert - butyldimethylsilyl)oxy)-2 - methylbutan - 2 - yl)-3,5 - dimethylphenyl) adipate (XXXIII)

[0244]

Chemical formula

[0245] 4 - (dimethylamino)pyridine (DMAP, 4.0 mg, 33.1 micromoles) and EDC·HCl (12.6 mg, 66.2 micromoles) was added to a CH₂Cl₂ (1 mL) solution of acid-TG(IV) (30.0 mg, 43.0 micromoles) and phenol (XXXII) (10.7 mg, 33.1 micromoles), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH₂Cl₂ (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (4% - 6% ethyl acetate / hexane) gave TML triglyceride (XXXIII) (19.8 mg, 59%) as a colorless oil. 1 ¹H-NMR (400 MHz, CDCl₃) δ 6.80 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 1.9 Hz, 1H), 5.27 (m, 1H), 4.31 (dd, J = 11.9, 4.3 Hz, 2H), 4.15 (dd, J = 11.9, 5.9 Hz, 2H), 3.47 (t, J = 7.5 Hz, 1H), 2.55 (t, J = 7.1 Hz, 2H), 2.51 (s, 3H), 2.39 (t, J = 7.0 Hz, 2H), 2.31 (t, J = 7.6 Hz, 4H), 2.22 (s, 3H), 2.02 (t, J = 7.5 Hz, 1H), 1.82 - 1.72 (m, 4H), 1.65 - 1.56 (m, 4H), 1.45 (s, 6H), 1.36 - 1.20 (m, 48H), 0.88 (t, J = 6.9 Hz, 6H), 0.84 (s, 9H), -0.03 (s, 6H) (ad) 1,3-bis(palmitoyloxy)propan-2-yl (2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethylphenyl) adipate (XXXIV)

[0246]

Chemical Structure

[0247] A solution of 10-camphorsulfonic acid (0.122 M in MeOH, 10 μL, 1.2 micromoles) was added to TBS ether (XXXIII) (6.1 mg, 6.1 micromoles) in CH2Cl2 (0.4 mL) and MeOH (0.4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (5 mL), and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 and brine (20 mL each), dried (MgSO4), and concentrated under reduced pressure to give crudely purified alcohol (XXXIV) (6.1 mg, quantitative) as a colorless oil, which was used without purification. 1 1H-NMR (400 MHz, CDCl3) δ 6.82 (d, J = 1.4 Hz, 1H), 6.53 (d, J = 1.2 Hz, 1H), 5.27 (m, 2H), 4.31 (dd, J = 11.9, 4.3 Hz, 2H), 4.15 (dd, J = 11.9, 5.8 Hz, 2H), 3.53 (t, J = 7.2 Hz, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.52 (s, 3H), 2.40 (t, J = 6.9 Hz, 2H), 2.31 (t, J = 7.6 Hz, 4H), 2.23 (s, 3H), 2.04 (t, J = 7.2 Hz, 2H), 1.82 - 1.72 (m, 4H), 1.65 - 1.53 (m, 4H), 1.48 (s, 6H), 1.36 - 1.13 (m, 48H), 0.88 (t, J = 6.7 Hz, 6H) (ae) 1,3-bis(palmitoyloxy)propan-2-yl (3,5-dimethyl-2-(2-methyl-4-oxobutan-2-yl)phenyl) adipate (XXXV)

[0248]

Chemical formula

[0249] Pyridinium chlorochromate (PCC, 2.6 mg, 12.2 micromol) was added to a suspension of alcohol (XXXIV) (5.4 mg, 6.1 micromol) and Celite (5 mg) in CH2Cl2 (0.5 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a short pad of silica gel, eluted with 50% ethyl acetate / hexane, and the filtrate was concentrated under reduced pressure to give the crudely purified aldehyde (XXXV) (5.4 mg, quantitative) as a yellow oil, which was used without further purification. 1 1H-NMR (400 MHz, CDCl3) δ 9.53 (t, J = 2.6 Hz, 1H), 6.84 (d, J = 1.4 Hz, 1H), 6.57 (d, J = 1.8 Hz, 1H), 5.27 (m, 1H), 4.31 (dd, J = 11.9, 4.3 Hz, 2H), 4.15 (dd, J = 11.9, 5.9 Hz, 2H), 2.80 (d, J = 2.6 Hz, 2H), 2.57 (t, J = 7.1 Hz, 2H), 2.53 (s, 3H), 2.40 (t, J = 7.0 Hz, 2H), 2.31 (t, J = 7.6 Hz, 5H), 2.24 (s, 3H), 1.83 - 1.72 (m, 4H), 1.65 - 1.56 (m, 4H), 1.55 (s, 6H), 1.35 - 1.16 (m, 48H), 0.88 (t, J = 6.7 Hz, 6H) (af) 3-(2-((6-((1,3-Bis(palmitoyloxy)propan-2-yl)oxy)-6-oxohexanoyl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic acid (XXXVI)

[0250]

Chemical Structure

[0251] A solution of potassium permanganate (0.0775 M in 1:1 acetone / water, 200 μL, 15.5 μmol) was added to aldehyde (XXXV) (12.5 mg, 0.0340 μmol) in acetone (0.5 mL) and water (0.1 mL), and the mixture was stirred at room temperature for 18 h. The reaction was diluted with water (10 mL), acidified to pH 2 with 1 M HCl, and the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% - 20% ethyl acetate / hexane) gave acid (XXXVI) (9.5 mg, 75%) as a colorless solid. 1 H-NMR (400 MHz, CDCl3) δ 6.82 (d, J = 1.3 Hz, 1H), 6.56 (d, J = 1.7 Hz, 1H), 5.26 (m, 1H), 4.32 (dd, J = 11.9, 4.4 Hz, 2H), 4.15 (dd, J = 11.9, 5.8 Hz, 2H), 2.82 (s, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.55 (s, 3H), 2.40 (t, J = 6.9 Hz, 2H), 2.31 (t, J = 7.6 Hz, 4H), 2.22 (s, 3H), 1.84 - 1.72 (m, 4H), 1.66 - 1.49 (m, 4H ), 1.58 (s, 6H), 1.36 - 1.19 (m, 48H), 0.88 (t, J = 6.8 Hz, 6H) (ag) 1,3-bis(palmitoyloxy)propan-2-yl (2-(4-(((8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13-14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)oxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl) adipate (22)

[0252]

Chemical Structure

[0253] 4-(Dimethylamino)pyridine (DMAP, 1.8 mg, 14.4 μmol), EDC·HCl (6.9 mg, 36.1 μmol), and testosterone (7.5 mg, 26.0 μmol) were added to a CH2Cl2 (1 mL) solution of acid (XXXVI) (13.0 mg, 14.4 μmol), and the mixture was stirred at room temperature for 26 h. The reaction mixture was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (15% - 20% ethyl acetate / hexane) gave compound 22 (8.6 mg, 51%) as a colorless solid. 1 1H-NMR (400 MHz, CDCl3) δ 6.80 (d, J = 1.8 Hz, 1H), 6.55 (d, J = 1.7 Hz, 1H), 5.72 (s, 1H), 5.27 (m, 1H), 4.45 (dd, J = 9.1, 7.3 Hz, 1H), 4.31 (dd, J = 11.9, 4.4 Hz, 2H), 4.15 (dd, J = 11.9, 5.8 Hz, 2H), 2.80 (ABq, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.54 (s, 3H), 2.48 - 2.23 (m, 10H), 2.21 (s, 3H), 2.11 - 1.97 (m, 2H), 1.86 - 1.47 (m, 16H), 1.55 (s, 6H), 1.43 - 1.19 (m, 49H), 1.17 (s, 3H), 1.12 - 0.82 (m, 4H), 0.88 (t, J = 6.9 Hz, 6H), 0.65 (s, 3H) (ah) 1,3-Bis(palmitoyloxy)propan-2-yl (2-(4-(((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)amino)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl) adipate (1)

[0254]

Chemical formula

[0255] 4-(Dimethylamino)pyridine (DMAP, 0.9 mg, 7.8 μmol), EDC·HCl (4.4 mg, 23.3 μmol), Et3N (5.0 μL, 66.6 μmol), and sertraline hydrochloride (5.3 mg, 15.5 μmol) were added to a solution of acid (XXXVI) (7.0 mg, 7.8 μmol) in CH2Cl2 (0.5 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (3 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (10% - 20% ethyl acetate / hexane) gave compound 1 (5.6 mg, 61%) as a colorless solid. 1 1H-NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.3 Hz, 0.7H), 7.31 (d, J = 8.3 Hz, 0.3H), 7.25 - 7.11 (m, 2H), 7.09 - 7.02 (m, 1.3H), 6.97 - 6.90 (m, 1H), 6.87 - 6.78 (m, 2.4H), 6.72 (dd, J = 8.3, 2.0 Hz, 0.3H), 6.58 (d, J = 1.5 Hz, 0.7H), 6.55 (d, J = 1.5 Hz, 0.3H), 5.88 (dd, J = 10.7, 6.3 Hz, 0.7H), 5.25 (m, 1H), 4.94 (dd, J = 10.8, 5.7 Hz, 0.3H), 4.30 (dd, J = 11.9, 4.4 Hz, 2H), 4.20 - 4.14 (m, 1H), 4.14 (dd, J = 11.9, 4.4 Hz, 2H), 3.07 (d, J = 15.4 Hz, 0.7H), 3.00 (d, J = 4.9 Hz, 0.6H), 2.82 (d, J = 15.4 Hz, 0.7H), 2.64 (s, 2.1H), 2.62 - 2.53 (m, 5.3H), 2.48 (t, J = 7.1 Hz, 0.6H), 2.39 (t, J = 7.1 Hz, 1.4H), 2.31 (t, J = 7.6 Hz, 4.6H), 2.23 (s, 2.1H), 2.21 (s, 0.9H), 1.99 - 1.91 (m, 1H), 1.85 - 1.72 (m, 4H), 1.71 - 1.53 (m, 13H), 1.36 - 1.19 (m, 48H), 0.88 (t, J = 6.9 Hz, 6H). Note: The fractional integrations reflect the presence of an approximately 7:3 mixture of rotamers due to restricted rotation around the N-methylamide functional group.

[0256] Characteristic data for further examples of trimethyl lock-containing compounds of formula (I) are provided below in Table 5.

[0257] [Table 5]

[0258] Example 6. A method for preparing a compound of formula (I) wherein Y represents an unsubstituted alkyl group or a short-chain (n = 2, 3) α- or β-methyl-substituted alkyl group, and L represents X'C(O) (X' is O). (ai) 2-((4-Bromobutanoyl)oxy)propane-1,3-diyl dipalmitate (XXIII)

[0259] [Chemical formula]

[0260] 4-(Dimethylamino)pyridine (DMAP, 64.4 mg, 0.527 mmol) and N,N'-dicyclohexylcarbodiimide (DCC, 218 mg, 1.05 mmol) were sequentially added to a solution of 4-bromobutyric acid (XXII) (141 mg, 0.844 mmol) and III (300 mg, 0.527 mmol) in CH2Cl2 (12 mL). The mixture was stirred at room temperature for 19 hours. The resulting suspension was diluted with CH2Cl2 (15 mL), cooled to 0 °C, filtered through celite, and washed with additional CH2Cl2 (20 mL). The organic phase was washed with 1 M HCl, water, saturated aqueous NaHCO3, and brine (30 mL each), dried (MgSO4), and concentrated under reduced pressure to obtain a crude product. Bromotriglyceride (XXIII )(352 mg, 93%) was obtained as a colorless solid by silica gel chromatography (5% ethyl acetate / hexane). 1H-NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.32 (dd, J = 12.0, 4.2 Hz, 2H), 4.14 (dd, J = 12.0, 6.0 Hz, 2H), 3.46 (t, J = 6.5 Hz, 2H), 2.53 (t, J = 7.1 Hz, 2H), 2.32 (t, J = 7.6 Hz, 4H), 2.20 - 2.15 (m, 2H), 1.65 - 1.58 (m, 4H), 1.36 - 1.21 (m, 48H), 0.88 (t, J = 6.9 Hz, 3H) In some examples where ω-halocarboxylic acid (XXII) is not commercially available, the synthesis can be achieved by accessing the corresponding lactone and then ring-opening it as described below. (aj) Oxacyclohexadecan-2-one (XXXVIII)

[0261] [Chemical formula]

[0262] m-Chloroperoxybenzoic acid (m-CPBA, 70% pure, 687 mg, 2.79 mmol) was added to a solution of cyclopentadecanone (500 mg, 2.23 mmol) in CH2Cl2 (6 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 4 days and 22 hours. An aliquot of the reaction taken after 3 days 1 H-NMR analysis showed consumption of 74% of the ketone, and at this point an additional portion of m-CPBA (150 mg) was added. After 4 days and 22 hours, the reaction mixture was diluted with CH2Cl2 (6 mL), washed with saturated aqueous NaHCO3 (3 × 20 mL), water (20 mL), and brine (20 mL), and concentrated under reduced pressure to obtain the crude product. The lactone (XXXVIII) (463 mg, 86%) was obtained as a colorless oil by silica gel chromatography (5% - 10% ethyl acetate / hexane). 1 H-NMR (400 MHz, CDCl3) δ 4.15 - 4.11 (m, 2H), 2.35 - 2.29 (m, 2H), 1.71 - 1.58 (m, 4H), 1.45 - 1.27 (m, 20H) (ak) 15-Iodopentadecanoic acid (XXII)

[0263] [Chem.]

[0264] Chlorotrimethylsilane (TMSCl, 242 μL, 1.91 mmol) was added to a suspension of XXXVIII (153 mg, 0.636 mmol) and sodium iodide (286 mg, 1.91 mmol) in acetonitrile (1.5 mL), and the mixture was heated at reflux for 21 h. The reaction was cooled to room temperature, diluted with water (10 mL) and 10% aqueous Na2S2O3 solution (10 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Iodic acid (XXII) (87.4 mg, 37%, 70% pure) was obtained as a yellow oil by silica gel chromatography (50% ethyl acetate / hexane). 1 It was observed that some impurity signals in the 1H-NMR spectrum increased in intensity after chromatography and one of the two minor components was suspected to be a hydroxy acid formed by hydrolysis of the iodine functional group (δ 3.53 for hydroxy and δ 3.18 for iodine). 1 1H-NMR (400 MHz, CDCl3) δ 3.18 (t, J = 7.1 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 1.86 - 1.78 (m, 2H), 1.68 - 1.57 (m, 2H), 1.42 - 1.22 (m, 20H) (al) 3-Methyltetrahydro-2H-pyran-2-one (XXXIX)

[0265] [Chem.]

[0266] A solution of n-butyllithium (1.0 M in hexane, 5.49 mL, 5.49 mmol) was added dropwise to diisopropylamine (910 μL, 6.49 mmol) in THF (4 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min to obtain a pale yellow solution of LDA, which was then cooled to -40 °C. A cooled (-40 °C) solution of δ-valerolactone (500 mg, 4.99 mmol) in THF (4 mL) was added dropwise via cannula. The resulting mixture was stirred at -40 °C for 10 min and then cooled to -78 °C. Iodomethane (466 μL, 7.49 mmol) was then added dropwise, and the mixture was slowly warmed to 0 °C over 4 h. The reaction was quenched by the slow addition of acetic acid (320 μL). The reaction was diluted with ethyl acetate (10 mL) and water (15 mL), and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 and brine (each 30 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. α-Methyl-δ-valerolactone (XXXIX) (144 mg, 25%) was obtained as a colorless oil by silica gel chromatography (15% - 17.5% ethyl acetate / hexane with 1% Et3N). 1 1H-NMR (400 MHz, CDCl3) δ 4.37 - 4.26 (m, 2H), 2.58 (ddt, J = 11.1, 7.0, 7.0 Hz, 1H), 2.09 (tt, J = 12.4, 6.2 Hz, 1H), 1.98 - 1.83 (m, 2H), 1.54 (ddt, J = 13.4, 11.1, 7.4 Hz, 1H), 1.26 (d, J = 6.9 Hz, 3H) (am) 4-Methyltetrahydro-2H-pyran-2-one (XL)

[0267]

Chem.

[0268] Methyllithium (1.0 M in Et2O, 2.00 mL, 2.00 mmol) was added to a suspension of CuI (190 mg, 1.00 mmol) in Et2O (2 mL) at 0 °C, and the pale yellow reaction mixture was immediately cooled to -40 °C. A solution of 5,6-dihydro-2H-pyran-2-one (43.1 μL, 0.50 mmol) in Et2O (2 mL) was added dropwise via a cannula, and the reaction was stirred at -40 °C for 10 minutes, then at 0 °C for 10 minutes, and at room temperature for 30 minutes. The resulting yellow suspension was transferred by syringe to a mixture of saturated aqueous NH4Cl (5 mL) and ethyl acetate (5 mL) vigorously stirred at -40 °C to quench the reaction, and it was slowly warmed to room temperature over 30 minutes. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (3 × 15 mL), and the combined organic extracts were washed with 1 M Na2S2O3 and brine (30 mL each). It was dried (MgSO4) and concentrated under reduced pressure to give crudely purified β-methyl-δ-valerolactone (XL) (22.7 mg, 40%) as a yellow oil, which was used without purification. 1 1H-NMR (400 MHz, CDCl3) δ 4.42 (ddd, J = 11.4, 4.9, 4.0 Hz, 1H), 4.27 (ddd, J = 11.4, 10.6, 3.8 Hz, 1H), 2.68 (m, 1H), 2.17 - 2.06 (m, 2H), 1.92 (dqd, J = 13.8, 3.9, 1.5 Hz, 1H), 1.52 (m, 1H), 1 (E)-Allyl 6-(4-(allyloxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-hex-4-enoate (XLI)

[0269]

Chemical Structure

[0270] 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (602 μL, 4.03 mmol) and allyl bromide (238 μL, 2.82 mmol) were added to a solution of mycophenolic acid (250 mg, 0.809 mmol) in DMF (15 mL), and the mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (20 mL) and water (20 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with water and brine (40 mL each), dried (MgSO4), and concentrated under reduced pressure to give the crude product. The allyl ester (XLI) (292 mg, 93%) was obtained as a colorless oil by silica gel chromatography (30% ethyl acetate / hexane). 1 1H-NMR (400 MHz, CDCl3) δ 6.09 (ddt, J = 17.1, 10.4, 5.9 Hz, 1H), 5.86 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H), 5.37 (dq, J = 17.2, 1.5 Hz, 1H), 5.30 - 5.15 (m, 4H), 5.13 (s, 2H), 4.78 (dt, J = 5.9, 1.3 Hz, 2H), 4.52 (dt, J = 5.7, 1.4 Hz, 2H), 3.76 (s, 3H), 3.41 (d, J = 6.5 Hz, 2H), 2.44 - 2.39 (m, 2H), 2.35 - 2.27 (m, 2H), 2.17 (s, 3H), 1.79 (s, 3H) (ao)(E)-6-(4-(allyloxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid (XLII)

[0271]

Chemical formula

[0272] A mixture of the ester (XLI) (44.0 mg, 0.110 mmol) in 2 M NaOH (330 μL, 0.660 mmol), water (1 mL), and MeOH (1.3 mL) was stirred at room temperature for 1.5 h. The reaction was acidified to pH 1 with 1 M HCl, diluted with water (5 mL), and then extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine It was washed with (30 mL) and dried (MgSO4), and concentrated under reduced pressure to obtain a crude product. Acid (XLII) (32.7 mg, 83%) was obtained as a colorless oil by silica gel chromatography (40% - 60% ethyl acetate / hexane). 1 H-NMR (400 MHz, CDCl3) δ 6.09 (m, 1H), 5.36 (ddd, J = 17.2, 3.1, 1.5 Hz, 1H), 5.25 - 5.16 (m, 2H), 5.13 (s, 2H), 4.77 (dt, J = 5.9, 1.3 Hz, 2H), 3.76 (s, 3H), 3.42 (d, J = 6.7 Hz, 2H), 2.45 - 2.39 (m, 2H), 2.35 - 2.25 (m, 2H), 2.17 (s, 3H), 1.79 (s, 3H) (ap)E)-2-((4-((6-(4-(allyloxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)butanoyl)oxy)propane-1,3-diyl dipalmitate (XLIII)

[0273]

Chem.

[0274] 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (18.5 μL, 124 micromoles) was added to a toluene (2 mL) suspension of XLII (30.6 mg, 85.0 micromoles) and bromide (XXIII) (55.5 mg, 77.3 micromoles), and the mixture was heated at reflux for 3.5 hours. The reaction was cooled to room temperature, acidified by the addition of 1 M HCl (3 - 4 drops), and diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 15 mL), and the combined organic extracts were washed with water and brine (each 30 mL), dried (MgSO4), and concentrated under reduced pressure to obtain a crude product. MPA triglyceride (XLIII) (56.2 mg, 73%) was obtained as a colorless oil by silica gel chromatography (15% - 20% ethyl acetate / hexane). 1H-NMR (400 MHz, CDCl3) δ 6.10 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.37 (dq, J = 17.2, 1.5 Hz, 1H), 5.29 - 5.15 (m, 3H), 5.13 (s, 2H), 4.78 (dt, J = 5.9, 1.3 Hz, 2H), 4.30 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.8 Hz, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.77 (s, 3H), 3.42 (d, J = 6.8 Hz, 2H), 2.41 - 2.35 (m, 4H), 2.34 - 2.25 (m, 6H), 2.18 (s, 3H), 1.97 - 1.88 (m, 2H), 1.79 (s, 3H), 1.65 - 1.52 (m, 4H), 1.35 - 1.19 (m, 48H), 0.88 (t, J = 6.9 Hz, 6H) (aq)(E)-2-((4-((6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)butanoyl)oxy)propane-1,3-diyl dipalmitate (30)

[0275]

Chemical Structure

[0276] 1,3-Dimethylbarbituric acid (12.4 mg, 79.2 micromol) and Pd(PPh3)4 (9.2 mg, 7.92 micromol) were added to allyl ether (XLIII) (39.5 mg, 39.6 micromol) in CH2Cl2 (3 mL), and the mixture was stirred at 30 °C for 2 h. The reaction mixture was applied directly to a short pad of silica gel and eluted with ethyl acetate (40 mL), and the filtrate was concentrated under reduced pressure to give the crude product. Compound 30 (36.2 mg, 96%) was obtained as a colorless solid by silica gel chromatography (15% - 20% ethyl acetate / hexane). 1H-NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 5.30 - 5.21 (m, 2H), 5.20 (s, 2H), 4.30 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.8 Hz, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.76 (s, 3H), 3.38 (d, J = 7.0 Hz, 2H), 2.43 - 2.35 (m, 4H), 2.34 - 2.27 (m, 6H), 2.15 (s, 3H), 1.97 - 1.89 (m, 2H), 1.80 (s, 3H), 1.65 - 1.52 (m, 4H), 1.34 - 1.21 (m, 48H), 0.87 (t, J = 6.9 Hz, 3H) (ar)2-((5-((2-Acetoxybenzoyl)oxy)penta-noyl)oxy)propane-1,3-diyl dipalmitate (8)

[0277] [Chemical Structure]

[0278] 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (14.7 mL, 98.4 mmol) was added to a suspension of acetylsalicylic acid (aspirin, 14.8 mg, 81.9 mmol) and bromide (XXIII) (40.0 mg, 54.7 mmol) in toluene (2 mL), and the mixture was heated at reflux for 3.5 h. The reaction was cooled to room temperature and diluted with ethyl acetate (5 mL) and water (15 mL). The aqueous layer was separated, acidified to pH 2 with 1 M HCl, and then extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with water and brine (40 mL each), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Compound 8 (23.9 mg, 53%) was obtained as a colorless solid by silica gel chromatography (10% ethyl acetate / hexane). 1H-NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 7.9, 1.6 Hz, 1H), 7.56 (ddd, J = 8.1, 7.5, 1.7 Hz, 1H), 7.31 (td, J = 7.7, 1.2 Hz, 1H), 7.10 (dd, J = 8.1, 1.0 Hz, 1H), 5.26 (m, 1H), 4.31 (dd, J = 11.9, 4.3 Hz, 2H), 4.28 (t, J = 6.9 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H ), 2.40 (t, J = 6.9 Hz, 2H), 2.35 (s, 3H), 2.30 (t, J = 7.6 Hz, 4H), 1.83 - 1.74 (m, 4H), 1.64 - 1.54 (m, 4H), 1.35 - 1.19 (m, 48H), 0.88 (t, J = 6.9 Hz, 6H) (as) Synthesis of 2 - ((6 - (((3R,5R) - 7 - (2 - (4 - fluorophenyl) - 5 - isopropyl - 3 - phenyl - 4 - (phenylcarbamoyl) - 1H - pyrrol - 1 - yl) - 3,5 - dihydroxyheptanoyl)oxy)hexanoyl)oxy)propane - 1,3 - diyl dipalmitate (9)

[0279]

Chemical formula

[0280] In the case of atorvastatin (ATV), the diol functional group needs to be masked as an acetonide (isopropylidene acetal) to prevent its interference in subsequent reactions. Treatment of ATV acetonide (XLIV) with DBU and ω - bromo - TG (XXXIII) in refluxing toluene as described above gives the protected prodrug (XLV). Deprotection of the diol under acidic conditions then provides compound 9. as (i) 2 - ((4R,6R) - 6 - (2 - (2 - (4 - fluorophenyl) - 5 - isopropyl - 3 - phenyl - 4 - (phenylcarbamoyl) - 1H - pyrrol - 1 - yl)ethyl) - 2,2 - dimethyl - 1,3 - dioxane - 4 - yl)acetic acid (XLIV)

[0281]

Chemical formula

[0282] p-Toluenesulfonic acid (p-TsOH, 10.1 mg, 0.053 mmol) was added to atorvastatin (160 mg, 0.265 mmol) in 2,2-dimethoxypropane (1.5 mL) and acetone (1.5 mL), and the mixture was stirred at room temperature for 15 hours. The reaction was diluted with ethyl acetate (30 mL), and the organic phase was washed with water (25 mL) and brine (2 × 25 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% - 30% - 50% ethyl acetate / hexane) gave acetonide / acid (XLIV) (72.2 mg, 46%) as a colorless foam. 1 H-NMR (400 MHz, CDCl3) δ 7.22 - 7.13 (m, 9H), 7.07 (d, J = 7.7 Hz, 2H), 7.03 - 6.97 (m, 3H), 6.86 (brs, 1H), 4.20 (m, 1H), 4.09 (m, 1H), 3.85 (m, 1H), 3. 71 (m, 1H), 3.57 (m, 1H), 2.54 (dd, J = 15.8, 6.8 Hz, 1H), 2.43 (dd, J = 15.8, 5.6 Hz, 1H), 1.71 - 1.61 (m, 2H), 1.53 (d, J = 7.1 Hz, 6H), 1.38 (s, 3H), 1,36 (m, 1H), 1.34 (s, 3H), 1.09 (m, 1H) as (ii) 2 - ((6 - (2 - ((4R,6R) - 6 - (2 - (2 - (4 - fluorophenyl) - 5 - isopropyl - 3 - phenyl - 4 - (phenylcarbamoyl) - 1H - pyrrol - 1 - yl) ethyl) - 2,2 - dimethyl - 1,3 - dioxan - 4 - yl) acetoxy) hexanoyl) oxy) - propane - 1,3 - diyl dipalmitate (XLV)

[0283]

Chemical Structure

[0284] 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (4.3 μL, 29.0 micromoles) was added to a solution of acetonide - acid (XLIV) (11.6 mg, 19.3 micromoles) and ω-bromo-TG (XXIII) (12.0 mg, 16.1 micromoles) in toluene (1.5 mL), and the mixture was heated at reflux for 2.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), and the organic phase was washed with water (25 mL), saturated aqueous NaHCO3 (25 mL), and brine (25 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Silica gel chromatography (20% ethyl acetate / hexane) gave ATV - triglyceride (XLV) (13.0 mg, 64%) as a colorless oil. 1 1H-NMR (400 MHz, CDCl3) δ 7.23 - 7.12 (m, 9H), 7.06 (d, J = 7.8 Hz, 2H), 7.03 - 6.94 (m, 3H), 6.86 (brs, 1H), 5.25 (m, 1H), 4.30 (dd, J = 11.9, 4.4 Hz, 2H), 4.19 (m, 1H), 4.14 (dd, J = 11.9, 5.8 Hz, 2H), 4.07 (m, 1H), 4.07 (t, J = 6.6 Hz, 2H), 3.82 (m, 1H), 3.70 (m, 1H), 3.57 (m, 1H), 2.48 (dd, J = 15.7, 7.0 Hz, 1H), 2.36 - 2.27 (m, 7H), 1.70 - 1.58 (m, 10H), 1.53 (d, J = 7.1 Hz, 6H), 1.36 (s, 3H), 1.29 (s, 3H), 1.44 - 1.20 (m, 51H), 1.05 (m, 1H), 0.88 (t, J = 6.9 Hz, 6H) as (iii) 2 - ((6 - (((3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoyl)oxy)hexanoyl)oxy)propane-1,3-diyl dipalmitate (9) p-Toluenesulfonic acid (1.6 mg, 8.4 mmol) was added to a solution of acetonide (XLV) (35.2 mg, 27.9 mmol) in CH2Cl2 (0.5 mL) and MeOH (1 mL), and the reaction mixture was stirred at room temperature for 5.5 h. The reaction mixture was diluted with CH2Cl2 (20 mL), and the organic layer was washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% - 35% ethyl acetate / hexane) gave compound 9 (14.6 mg, 43%) as a colorless oil. The 1 1H-NMR (400 MHz, CDCl3) δ 7.22 - 7.13 (m, 9H), 7.06 (d, J = 7.6 Hz, 2H), 7.02 - 6.96 (m, 3H), 6.85 (brs, 1H), 5.25 (m, 1H), 4.30 (dd, J = 11.9, 4.4 Hz, 2H), 4.16 (m, 1H), 4.14 (dd, J = 11.9, 5.6 Hz, 2H), 4.10 (t, J = 7.5 Hz, 2H), 4.10 (m, 1H), 3.94 (m, 1H), 3.74 (m, 1H), 3.58 (m, 1H), 2.40 (d, J = 6.1 Hz, 2H), 2.33 (t, J = 7.4 Hz, 2H), 2.31 (t, J = 7.6 Hz, 4H), 1.73 - 1.51 (m, 10H), 1.54 (d, J = 7.4 Hz, 6H), 1.50 - 1.34 (m, 3H), 1.33 - 1.20 (m, 49H), 0.88 (t, J = 6.9 Hz, 1H) Further exemplary compounds of formula (I) in which L represents X'C(O) are provided below in Table 6.

[0285] [Table 6-1]

[0286] [Table 6-2]

[0287] Example 7. Z represents C(O)R 3 and R 3represents a p-hydroxybenzylcarbonyl (PHB) self-destructive group, and L represents X’ (where X’ is O, S, or NR 4 ), a method for preparing a compound of formula (I)

[0288]

Chemical formula

[0289] Regarding the synthesis of prodrugs containing p-hydroxybenzylcarbonyl (PHB) self-destructive groups, the primary hydroxyl group of p-hydroxybenzyl alcohol (XLVI) is first protected as a silyl ether, and the free hydroxyl group is combined with acid-TG (IV) to obtain PHB triglyceride (XLVIII). After removing the silicon protecting group, the primary alcohol (XLIX) is activated by treatment with p-nitrophenyl chloroformate (PNP) to obtain PNP carbonate (L). Subsequently, substitution of the PNP group is achieved by reaction with a drug (AX’H) under basic conditions to obtain the desired PHB prodrug (LI). (at) 4-(((tert-butyldimethylsilyl)oxy)methyl)phenol (XLVII)

[0290]

Chemical formula

[0291] Imidazole (85.1 mg, 1.25 mmol) and tert-butyl (chloro)dimethylsilane (TBSCl, 90.4 mg, 0.600 mmol) were added to a solution of 4-hydroxybenzyl alcohol (XLVI) (62.1 mg, 0.500 mmol) in DMF (4 mL), and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with ethyl acetate (30 mL), and the organic phase was washed with water (30 mL), saturated aqueous NaHCO3 solution (30 mL), and brine (30 mL), dried (MgSO4), and concentrated under reduced pressure to obtain TBS ether (XLVII) (119 mg, quantitative) as a colorless oil, which was used without purification. 1H-NMR (400 MHz, CDCl3) δ 7.21 - 7.15 (m, 2H), 6.83 - 6.78 (m, 2H), 4.66 (s, 2H), 0.93 (s, 9H), 0.08 (s, 6H) (au) 1-(1,3-bis(palmitoyloxy)propan-2-yl) 10-(4-(((tert-butyldimethylsilyl)oxy)methyl)-phenyl) decanedioate (XLVIII)

[0292] [Chemical formula]

[0293] 4-(Dimethylamino)pyridine (DMAP, 11.8 mg, 0.0966 mmol) and EDC·HCl (46.3 mg, 0.241 mmol) were added to a CH2Cl2 (2.5 mL) solution of acid-TG(IV) (80.0 mg, 0.106 mmol) and phenol (XLVII) (23.0 mg, 0.0966 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with CH2Cl2 (10 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (5% - 7.5% - 10% ethyl acetate / hexane) gave PHB triglyceride (XLVIII) (60.7 mg, 65% over two steps) as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ 7.35 - 7.28 (m, 2H), 7.05 - 6.99 (m, 2H), 5.26 (m, 1H), 4.72 (s, 2H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 2.30 (t, J = 7.5 Hz, 4H), 1.78 - 1.70 (m, 2H), 1.67 - 1.55 (m, 6H), 1.43 - 1.20 (m, 56H), 0.93 (s, 9H), 0.87 (t, J = 6.8 Hz, 6H), 0.09 (s, 6H) (av) 1-(1,3-bis(palmitoyloxy)propan-2-yl) 10-(4-(hydroxymethyl)phenyl) decanedioate (XLIX)

[0294]

Chem.

[0295] 10-Camphorsulfonic acid (2.1 mg, 8.91 μmol) was added to TBS ether (XLVIII) (57.8 mg, 59.4 μmol) in CH2Cl2 (0.8 mL) and MeOH (0.8 mL), and the mixture was stirred at room temperature for 2 hours. The reaction was diluted with CH2Cl2 (20 mL), and the organic phase was washed with saturated aqueous NaHCO3 and brine (20 mL each), dried (MgSO4), and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (25% - 35% ethyl acetate / hexane) gave alcohol (XLIX) (46.9 mg, 92%) as a colorless solid. 1 H-NMR (400 MHz, CDCl3) δ 7.41 - 7.32 (m, 2H), 7.10 - 7.01 (m, 2H), 5.25 (m, 1H), 4.67 (s, 2H), 4.28 ( dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 2.30 (t, J = 7.5 Hz, 4H), 1.89 (brs, 1H), 1.78 - 1.70 (m, 2H), 1.65 - 1.55 (m, 6H), 1.46 - 1.20 (m, 56H), 0.87 (t, J = 6.9 Hz, 6H) (aw) 1-(1,3-Bis(palmitoyloxy)propan-2-yl) 10-(4-((((4-nitrophenoxy)carbonyl)oxy)meth-yl)phenyl) decanedioate (L)

[0296]

Chem.

[0297] 4-Nitrophenyl chloroformate (13.9 mg, 69.1 μmol) and pyridine (7.8 μL, 96.0 μL) were added to alcohol (XLIX) (33.0 mg, 38.4 μmol) in CH2Cl2 (2 mL) at 0 °C, and the mixture was stirred at 0 °C for 20 minutes and then at room temperature for 2.5 hours. The reaction was diluted with CH2Cl2 (20 mL), and the organic phase was washed with saturated aqueous NaHCO3 and brine (20 mL each), dried (MgSO4), and concentrated under reduced pressure to obtain the crude product. Purification by silica gel chromatography (10% - 20% ethyl acetate / hexane) gave PNP (L) carbonate as a colorless solid (38.7 mg, 98%). 1 1H-NMR (400 MHz, CDCl3) δ 8.30 - 8.23 (m, 2H), 7.49 - 7.43 (m, 2H), 7.41 - 7.35 (m, 2H), 7.15 - 7.09 (m, 2H), 5.28 (s, 2H), 5.26 (m, 1H), 4.30 (dd, J = 11.9, 4.3 Hz, 2H), 4.15 (dd, J = 11.9, 5.9 Hz, 2H), 2.56 (t, J = 7.5 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 2.31 (t, J = 7.5 Hz, 4H), 1.79 - 1.71 (m, 2H), 1.66 - 1.55 (m, 6H), 1.45 - 1.20 (m, 56H), 0.87 (t, J = 6.9 Hz, 6H) (ax) 1-(1,3-Bis(palmitoyloxy)propan-2-yl) 10-(4-((((((8R,9S,10R,13S,14S,17S)-10,13-Dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]-phenanthren-17-yl)oxy)carbonyl)oxy)methyl)phenyl) decanedioate (28)

[0298]

Chemical Structure

[0299] 4-(Dimethylamino)pyridine (DMAP, 6.2 mg, 50.8 μmol) and DIPEA (0.16 M in CH2Cl2, 80.0 μL, 12.7 μmol) were added to a solution of testosterone (11.7 mg, 40.6 μmol) and PNP(L) carbonate (26.0 mg, 25.4 μmol) in CH2Cl2 (0.8 mL), and the mixture was stirred at room temperature for 4 days and 20 hours. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 and brine (2 × 15 mL each), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% - 20% ethyl acetate / hexane) afforded compound 28 (9.8 mg, 33%) as a colorless solid. 1 1H-NMR (400 MHz, CDCl3) δ 7.43 - 7.38 (m, 2H), 7.10 - 7.05 (m, 2H), 5.73 (s, 1H), 5.26 (m, 1H), 5.12 (s, 2H), 4.52 (dd, J = 8.9, 7.8 Hz, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 2.47 - 2.17 (m, 11H), 2.02 (m, 1H), 1.89 - 1.81 (m, 2H), 1.78 - 1.54 (m, 12H), 1.47 - 1.19 (m, 59H), 1.18 (s, 3H), 1.10 - 0.93 (m, 4H), 0.87 (t, J = 6.8 Hz, 6H), 0.85 (s, 3H) (ay) 1-(1,3-Bis(palmitoyloxy)propan-2-yl) 10-(4-(((((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamoyl)oxy)methyl)phenyl) Decanedioate (6)

[0300]

Chemical formula

[0301] 4-(Dimethylamino)pyridine (DMAP, 6.3 mg, 51.2 μmol) and DIPEA (0.59 M in CH2Cl2, 10.0 μL, 5.9 μmol) were added to a solution of sertraline hydrochloride (10.0 mg, 29.3 μmol) and PNP(L) carbonate (15.0 mg, 14.6 μmol) in CH2Cl2 (0.6 mL), and the mixture was stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 (25 mL) and washed with saturated NaHCO3( 3 × 20 mL) aqueous solution and brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (3% - 6% ethyl acetate / hexane) gave compound 6 (11.3 mg, 65%) as a colorless solid. 1 1H-NMR (400 MHz, CDCl3) δ 7.46 - 7.28 (m, 3.5H), 7.25 - 7.16 (m, 2.5H), 7.12 - 7.02 (m, 3H), 6.95 (d, J = 7.2 Hz, 1H), 6.81 (m, 1H), 5.51 (m, 0.6H), 5.36 (m, 0.4H), 5.27 (m, 1H), 5.20 (s, 2H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.19 (m, 1H), 4.15 (dd, J = 11.9, 5.6 Hz, 2H), 4.15 (dd, J = 11.6, 5.6 Hz, 1H), 2.73 (s, 1.2H), 2.69 (s, 1.8H), 2.59 - 2.52 (m, 2H), 2.36 - 2.24 (m, 7H), 2.00 (m, 1H), 1.83 - 1.69 (m, 4H), 1.66 - 1.55 (m, 6H), 1.45 - 1.19 (m, 56H), 0.88 (t, J = 6.9 Hz, 6H). Note: The fractional integrals reflect the presence of an approximately 3:2 mixture of rotamers due to restricted rotation around the N-methylcarbamate functional group. Example 8. A method for preparing a compound of formula (I) wherein Z represents C(O)R 3 and R 3 represents an invert ester self-destructing group and L represents X’ (where X’ is O, S or N(R 4 ))

[0302]

Chemical formula

[0303] The reverse ester self-immolative (FSI) group is designed to release the free drug by a cyclization mechanism. The FSI prodrug can be synthesized by coupling the drug (A-X’H) with 4-bromobutyric acid (XXII) to obtain the bromide (LII). Substitution of the bromide (LII) with the carboxylate derived from acid-TG (IV) generates the desired ester bond in the target FSI prodrug (LIII). (az)(8R,9S,10R,13S,14S,17S)-10,13-Dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl 4-bromobutanoate (LII)

[0304]

Chem.

[0305] 4-(Dimethylamino)pyridine (DMAP, 15.5 mg, 0.130 mmol) and DCC (43.8 mg, 0.210 mmol) were added to a solution of testosterone (29.9 mg, 0.100 mmol) and 4-bromobutyric acid (XXII) (21.0 mg, 0.130 mmol) in CH2Cl2 (3 mL), and the mixture was stirred at room temperature for 24 h. Another 0.6 equivalent of acid, 1 equivalent of DCC, and 0.6 equivalent of DMAP were added, and the mixture was stirred at room temperature for an additional 2 days. The reaction was diluted with CH2Cl2 (10 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (25% ethyl acetate / hexane) gave the bromide (LII) (26.7 mg, 59%) as a colorless solid. 1H-NMR (400 MHz, CDCl3) δ 5.73 (s, 1H), 4.62 (dd, J = 9.1, 7.9 Hz, 1H), 3.47 (t, J = 6.5 Hz, 2H), 2.50 (td, J = 7.1, 1.0 Hz, 2H), 2.47 - 2.23 (m, 4H), 2.22 - 2.13 (m, 3H), 2.06 - 1.99 (m, 1H), 1.85 (m, 1H), 1.78 (m, 1H), 1.74 - 1.63 (m, 2H), 1.61 - 1.53 (m, 2H), 1.52 - 1.32 (m, 3H), 1.23 - 1.15 (m, 1H), 1.19 (s, 3H) 1.11 - 0.91 (m, 3H), 0.83 (s, 3H). (ba) 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(4-(((8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)oxy)-4-oxobutyl) 3-methylpentanedioate (29)

[0306]

Chemical Structure

[0307] 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (19 μL, 125.7 micromol) was added to a suspension of acid-TG(IV) (43.8 mg, 62.9 micromol), bromide (LII) (27.5 mg, 62.9 micromol), and tetrabutylammonium iodide (TBAI, 11.6 mg, 31.4 micromol) in toluene (3 mL). The mixture was heated at reflux for 6 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL) and concentrated under reduced pressure to obtain a crude product. Compound 29 (18.6 mg, 28%) was obtained as a colorless solid by silica gel chromatography (15% - 35% ethyl acetate / hexane). Concentration under reduced pressure gave a crude product. Compound 29 (18.6 mg, 28%) was obtained as a colorless solid by silica gel chromatography (15% - 35% ethyl acetate / hexane). 1H-NMR (400 MHz, CDCl3) δ 5.72 (s, 1H), 5.26 (m, 1H), 4.61 (dd, J = 9.1, 7.9 Hz, 1H), 4.29 (ddd, J = 11.9, 4.3, 1.6 Hz, 2H), 4.12 (m, 4H), 2.50 - 2.12 (m, 16H), 2.03 - 1.92 (m, 3H), 1.84 (m, 1H), 1.77 (m, 1H), 1.74 - 1.54 (m, 8H), 1.53 - 1.32 (m, 2H), 1.31 - 1.21 (m, 49H), 1.18 (s, 3H), 1.16 (m, 1H), 1.10 - 1.01 (m, 2H), 1.02 (d, J = 6.5 Hz, 3H), 0.95 (m, 1H), 0.87 (t, J = 6.9 Hz, 6H), 0.83 (s, 3H) Example 8. Test of Lymph Transport in Rats In order to confirm that the prodrug described in the present invention was able to promote lymph transport, a test was conducted in rats to insert a cannula into the intestinal lymphatic vessel so as to enable continuous collection of intestinal lymph fluid. Subsequently, a lipid preparation containing the target compound was administered to the animals, and the collected lymph fluid and the drug concentration in the lymph fluid were continuously quantified.

[0308] The lipid formulations of the compounds of the present invention or control compounds were prepared as previously described (Trevaskis, N.L. et al., Pharmaceutical Research, 2005, 22(11), 1863 - 1870). Briefly, approximately 2 mg of the compound (1 mg in the case of compound 35 and compound 1) was mixed with 40 mg of oleic acid and 25 mg of Tween 80 in a glass vial until equilibration (gentle heating (below 50 °C) may be applied for a short time). Subsequently, 5.6 mL of an aqueous phase consisting of phosphate - buffered saline (PBS, pH 7.4) was added to the lipid phase (in the case of control compounds containing mycophenolic acid, metoprolol tartrate, atorvastatin calcium, aspirin and sertraline hydrochloride, each compound was dissolved in PBS instead of the lipid phase to prepare a formulation containing the control compound), and the formulation was emulsified by sonication using a sonicator equipped with a 3.2 mm microprobe tip operating at an amplitude of 240 μm and a frequency of 20 kHz for 2 minutes at room temperature. The concentration of the compound in all formulations was verified using HPLC - MS.

[0309] Male Sprague-Dawley (SD) rats were selected for the lymph transport study where the drug was mycophenolic acid (MPA), metoprolol (MET), atorvastatin (ATV), sertraline (SER) or celecoxib (CEL). Female SD rats were selected for the study where the drug was testosterone. This was to eliminate the possibility of relatively high and variable levels of endogenous testosterone in male rats that would interfere with the quantification of exogenously administered testosterone. The rats (240 - 320 g) were maintained on a standard diet, fasted overnight prior to the experiment, and had free access to water. The anesthetized rats were placed on a pad heated to 37°C, and cannulas were inserted into the duodenum (for administration of the formulation and for rehydration), the intestinal lymphatic vessels (for collection of lymph fluid), and the carotid artery (for blood sampling) as previously described (Edwards et al. Advanced Drug Delivery, Reviews, 2001, 50(1), 45 - 60). After surgery, the rats were rehydrated for 0.5 h via a duodenal drip of normal saline at 2.8 mL / h. The lipid formulation was infused from the duodenum at 2.8 mL / h for 2 h, and then for the remainder of the experiment the infusion was changed to normal saline at 2.8 mL / h. Lymph fluid was collected continuously for 6 - 8 h into pre-weighed Eppendorf tubes containing 10 μL of heparin at 1,000 IU / mL. The collection tubes were changed every hour, and the flow of lymph fluid was measured by gravimetry. Aliquots of the lymph fluid samples at each time point were stored at -80°C prior to assay.

[0310] Drug concentration in the lymph fluid is expressed as the total drug and includes free drug and drug associated with different glycerides. This was assayed by hydrolysis of the lymph fluid (release of the drug from re-esterified glycerides) prior to the evaluation of free drug.

[0311] The transport of the derivatives of MPA, TST, MET, ATV, SER or CEL into lymphatic fluid between the collection times at each time point was calculated from the product of the volume of the collected lymphatic fluid and the concentration measured in the lymphatic fluid. Figure 1 shows the cumulative lymphatic transport (% of the administered dose) of all testosterone-related derivatives over time in female Sprague-Dawley rats anesthetized and cannulated into intestinal lymphatic vessels after injection of the formulation from the duodenum for 0 - 2 hours. Each formulation contained 2 mg of the exemplary compound or control, testosterone undecanoate (TU), dispersed in 40 mg of oleic acid, 25 mg of Tween 80, and 5.6 mL of PBS. The data are presented as mean ± SEM for TU (n = 4), the compound in which testosterone is bound to triglyceride units via succinic acid (Compound 41, n = 4) and Compound 11 (n = 3) previously described by Seriba et al., and for Compound 10 and Compound 14 with n = 1. The inset shows the end point of the data (cumulative % dose transported into lymphatic fluid over 8 hours) in the form of a bar graph. As is evident in Figure 1 and Table 7, each of the exemplary compounds significantly improved the delivery of testosterone into the intestinal lymphatic system by approximately 7 - 9 times compared to the control TU.

[0312]

Table 7

[0313] Figure 2 shows the cumulative lymphatic transport (% of the administered dose) of the entire MPA-containing compounds over time in male Sprague-Dawley rats anesthetized and cannulated into intestinal lymphatic vessels after injection of the formulation from the duodenum for 0 - 2 hours. The formulation contained 2 mg of the exemplary compound or MPA alone dispersed in 40 mg of oleic acid, 25 mg of Tween 80, and 5.6 mL of PBS. The data are presented as mean ± SEM. The data were obtained from animals with n = 5 for MPA, n = 3 for Compound 30 and Compound 34, n = 6 for Compound 31, and n = 4 for Compound 32, Compound 33, and Compound 35. The inset shows the end point of the data (cumulative % dose transported into lymph over 8 hours) in the form of a bar graph.

[0314] Figures 2 and Table 8 show that the compounds of the present invention significantly enhance the lymphatic transport of MPA by 43 to 132 times compared to MPA alone. Increasing the length of the linker improves the transport of MPA. Compound 30 improves the lymphatic transport of MPA up to 7.1% of the administered dose, and compound 34 improves the transport by 22.1%. The correlation between the length of the linker and the increase in transport is likely due to the ease of re-esterification of the monoglyceride intermediate, as the longer alkyl chain more closely mimics the monoglyceride resulting from the digestion of natural triglycerides. Interestingly, further increasing the length of the linker does not seem to be efficient, and the administration of compound 35 where -Y- is a C 20 alkyl group resulted in less lymphatic transport than that achieved by compound 34 where -Y- is a C 14 alkyl group. As can be seen from Figure 3 and Table 8, replacing the ester bond between the drug and the linker with a thioester does not change the lymphatic transport of the resulting compounds (see, for example, compounds 31 and 40).

[0315]

Table 8

[0316] As is clear from Figure 4, Figure 19, and Table 9, protecting the ester bond to the glyceride subunit with either an α-methyl group or a β-methyl group can enhance the stability of the compound in the lumen and promote lymphatic transport. The β-methyl branch in compound 18 or the α-methyl branch in compound 16 significantly stabilized the monoglyceride intermediate in the digestive fluid compared to their linear counterparts, compound 10 or compound 13 (see Figure 19). This allows more monoglyceride-mimicking intermediates to be absorbed and re-esterified in enterocytes, resulting in significantly higher lymphatic drug transport.

[0317]

Table 9

[0318] Similarly, TG-mimicking prodrugs with methyl substitution in the spacer (either α- or β- for the ester bond linking the alkyl spacer to the glyceride backbone) improved the stability of MPA in the GI lumen (Figure 23) and tended to result in better in vivo lymphatic transport of MPA (Figure 5 and Table 10). Figures 5 and Table 10 show that lymphatic transport is improved for Compounds 36 (9.1%) and 38 (12.1%) compared to Compound 31 (8.2%), and that Compounds 37 (12.6%) and 39 (28.4%) result in more lymphatic transport than Compounds 32 (9.6%) and 34 (22.1%), respectively.

[0319]

Table 10

[0320] The compounds of the present invention linked to the 2'-position of the triglyceride via an ester bond are even more effective in promoting lymphatic transport compared to a bond at the 1' (or 3')-position or a bond linked via an ether bond.

[0321] The data of the present inventors indicate that positional specificity and functional group specificity are important for efficient lymphatic targeting of MPA prodrugs. In Figures 6 and Table 11, for example, compounds of the present invention such as Compounds 30 and 32 promoted the lymphatic recovery of MPA 43 - 60-fold more effectively. Conversely, compounds in which MPA is directly linked at the 1' (or 3')-position of the glycerol unit (Compound 42), compounds in which the MPA linker moiety is linked to the glycerol unit via an ether bond and the equivalent of -Y- is a C4 alkyl group (Compound 43) or a C6 alkyl group (Compound 44), or compounds in which MPA is linked to the 1'-position of the glycerol unit via an ether bond and the equivalent of -Y- is a C8 alkyl group (Compound 45) are poor substrates for lymphatic transport and resulted in lymphatic transport similar to that of MPA alone.

[0322]

Table 11

[0323] Figures 7-11 and Table 12 provide additional evidence that the TG mimic prodrug strategy can be extended to compounds beyond MPA and testosterone. The figures present the lymphatic transport (% of dose) of the total compound after ID injection into rats anesthetized and cannulated in the mesenteric lymphatics. The data show that the lymphatic transport of MET (Figure 7), ATV (Figure 8), and ASP (Figure 9) is improved after administration of Compounds 3, 9, and 8, respectively.

[0324] Figure 10 provides further evidence of the present invention. In addition to examples of carboxylic acid-terminated drugs such as MPA and hydroxyl-terminated drugs such as TST, the lymphatic drug transport of amine-terminated drugs such as sertraline (SER), for example, can be improved by the formation of glyceride mimic prodrugs incorporating a self-destructing linker between the drug and the glyceride. Figure 10 presents the lymphatic transport (% of dose) of the total compound after ID injection in rats anesthetized and cannulated in the mesenteric lymphatics (data are presented as the mean ± range (n = 2) of Compound 1 incorporating a trimethyloxonium self-destructing group and the drug sertraline), resulting in a transport of 41.0 ± 7.0% of the total sertraline derivative in the lymph. Similarly, modifications containing a para-hydroxylbenzoic acid self-destructing group (Compound 6) or a combination of an acetal self-destructing group and methyl protection of the ester bond to the glyceride (Compound 7) provide an improvement in lymphatic drug transport compared to the drug alone. As a further example, the lymphatic transport of a prodrug (CEL, Compound 5) of the non-steroidal anti-inflammatory drug celecoxib, as a trimethyloxonium self-destructing prodrug of an amine-containing drug, is shown in Figure 11.

[0325]

Table 12

[0326] Example 9. Pharmacokinetic (PK) Studies in Rats and Dogs To evaluate the oral bioavailability of the compounds of the present invention, pharmacokinetic tests were conducted in rats and dogs. In the rat tests, female (for testosterone-related tests) and male (for alfaxolone-related tests) Sprague-Dawley rats (240 - 320 g) were anesthetized, and a cannula was inserted into the carotid artery the day before drug administration. The rats were then allowed to regain consciousness, fasted overnight prior to the start of the experiment, and given free access to water. The next morning, the compounds (except for alfaxolone (ALP) and compound 2) were administered via oral gavage with a lipid formulation containing 1 - 2 mg of the compound dispersed in 2 mL of PBS, 40 mg of oleic acid, and 25 mg of Tween 80 (as described above for the lymph transport test in rats, the only difference being a small amount of PBS for the unconscious test here). The oral formulation of ALP contained 7.5 mg of ALP suspended in 1 mL of 0.5% (w / v) carboxymethylcellulose and 0.4% (v / v) Tween 80 in physiological saline. The oral formulation of compound 2 contained 3 mg of the compound dispersed in 1 mL of PBS, 20 mg of oleic acid, and 12.5 mg of Tween 80. Blood samples were collected from the carotid artery cannula from 5 minutes before administration until 24 hours after administration, and centrifuged at 5000 rpm for 5 minutes to separate plasma. During the blood sampling period, the rats had free access to water at all times but were kept fasting for an additional 8 hours after drug administration. Plasma samples were stored at -80 °C prior to analysis by HPLC-MS-MS. In this case, the samples were assayed for free drug (i.e., drug not associated with glyceride), and hydrolysis was not performed prior to the assay (as was the case for lymph fluid samples). Thus, this data reflects the drug that is transported to the lymph and then released from the drug-glyceride complex that is re-esterified in the systemic circulation.

[0327] For the dog studies, female greyhound dogs were maintained at a large animal research facility for at least 5 days prior to the start of the study. They were acclimated for at least 4 days prior to the start of the study. The dogs were fasted for 12 hours until 30 minutes before drug administration. For the feeding state studies (n = 4 for TU or Compound 13), the dogs ingested 680 g of a standard commercially available dog food containing 5% fat 30 minutes before drug administration. For the fasting study (n = 1 for Compound 13), the dog remained fasting until 4 hours after administration. Water was freely available to all dogs throughout the study. On the day of the study , A 20-gauge intravenous catheter was inserted into the cephalic vein to enable blood sampling. After cannula insertion, the dogs were allowed to move freely (not restrained). For the feeding state test, Andriol Testocaps (a commercially available TU product) or Compound 13 was administered to the dogs. Andriol Testocaps was supplied by Merck Sharp & Dohme (Australia) Pty Limited and formulated as a soft gelatin capsule containing a 12.0% (w / w) solution of TU in lauroyl glycol FCC / castor oil [40:60% (w / w)]. The composition of each capsule was 40 mg of TU, lauroyl glycerol FCC, castor oil, gelatin, glycerol, and sunset yellow (E110). Compound 13 was prepared in a long-chain lipid-based self-emulsifying drug delivery system (SEDDS) consisting of 30.5% w / w soybean oil, 30.5% w / w Maisine 35-1, 31.6% w / w Cremophor EL, and 7.4% w / w ethanol. The formulation was filled into hard gelatin capsules. The capsules were placed as far back in the pharynx as possible, the mouth was closed, and swallowing was stimulated by stroking the throat. Two capsules of Andriol Testocaps containing 80 mg of TU or two capsules of Compound 13 containing a total dose of 90 mg of Compound 13 dissolved in 2 g of the SEDDS formulation were administered to greyhound dogs that had been fed. Subsequently, 50 mL of water was administered orally via a syringe. Two capsules of the Compound 13 formulation were also administered to dogs that had been fasted for the fasting state test. After oral administration, blood samples (approximately 3 mL each) were collected via the cephalic vein catheter from 5 minutes before administration to 10 hours after administration. The patency of the catheter was maintained by flushing with a small amount of heparinized saline (1 - 2 IU / mL) after each blood sampling. Blood samples at 24 hours were collected by venipuncture. Plasma was separated by centrifugation, and aliquots of each plasma sample were transferred to Eppendorf tubes and stored at -80 °C prior to analysis by LC-MS-MS.

[0328] Figure 12 shows the plasma concentration of testosterone normalized for dose after oral forced administration of the formulation to conscious female Sprague-Dawley rats with a cannula inserted into the carotid artery. The formulation contained 1 mg of TU dispersed in 40 mg of oleic acid, 25 mg of Tween 80 and 2 mL of PBS, or 2 mg of the compound of the present invention containing testosterone. The dose was normalized relative to a dose equivalent to 2 mg / kg of testosterone. Data are shown as mean ± SEM for all groups (n = 4 or 3 for each group). The inset is a plot of the plasma AUC 0-24h (nanomol × time / L) of testosterone normalized for dose.

[0329] Compounds of the present invention having a linker with a length exceeding C5 resulted in a significant increase in the systemic exposure (oral bioavailability) of testosterone after administration. This is demonstrated by Figure 12 and Table 13, where, despite the fact that the lymphatic transport of all four compounds was similar (see Figures 1 and 7), the systemic exposure of the parent testosterone after oral administration of Compound 11, Compound 13 or Compound 14 was 10-fold higher than that obtained after administration of Compound 41 or Compound 10 (plasma AUC of testosterone normalized for dose 0-24h )(about 12 - 27 times higher than that achieved with TU). In this case, a longer linker appears to be important for improving drug release.

[0330]

Table 13

[0331] The usefulness of the compounds of the present invention that promote the systemic exposure of testosterone was also demonstrated in a different animal, dogs. This is demonstrated by Figure 13 and Table 14. Consistent with the rat data, the systemic exposure of the parent testosterone after oral administration of Compound 13 was significantly higher than that obtained after administration of TU (about 8-fold, plasma AUC of testosterone normalized for dose 0-24h)。In particular, the increased exposure to compound 13 did not appear to be affected by co - administration with food.

[0332]

Table 14

[0333] Compounds having an ester bond to a glyceride protected by an α - methyl group or a β - methyl group enhance the oral bioavailability of testosterone for longer - chain analogs.

[0334] As is clear from FIG. 4 and Table 9, methyl - branched TG - mimicking prodrugs facilitate the lymphatic transport of testosterone by stabilizing the MG intermediate. However, modification with a methyl group can also reduce the systemic release of the parent testosterone from the prodrug molecule. As shown in FIG. 14 and Table 15, for example, after administration of compound 18, even though the lymphatic transport of compound 18 was approximately 2 - fold higher (see Table 9), the systemic exposure of testosterone in plasma was lower than that of its linear counterpart, compound 10.

[0335] To improve lymphatic transport and enable systemic release of testosterone, the inventors have found that the combination of methyl group substitution and a longer alkyl chain length attenuates the reduced exposure observed in compounds with an α - methyl group or a β - me thyl group. From FIG. 14 and Table 15, it can be understood that as - Y - increases up to a C8 alkyl group, after methyl group modification, the release of free testosterone in plasma is similar for β - methylated analogs compared to the linear (compound 13) and is somewhat delayed, potentially providing an extended release.

[0336]

Table 15

[0337] Compounds incorporating a self - destructing group between the drug agent and the linker facilitate the release of the prodrug in the systemic system and achieve higher oral bioavailability than compounds with ester linkages.

[0338] As can be seen in Figure 15 and Table 16, after oral administration of Compounds 22 and 26 (having a trimethyl lock self - destructing group), the systemic exposure of testosterone in plasma was higher than that achieved after administration of Compounds 11 and 13 (corresponding compounds without a self - destructing group, and note that Compound 13 was one of the prodrugs with the best performance before). When compared to TU, the plasma AUC of testosterone was approximately 40 - fold higher after administration of Compound 22 and approximately 90 - fold higher after administration of Compound 26. Similarly, the addition of a trimethyl lock self - destructing group to the prodrug of β - methyl - protected testosterone (which had high lymphatic transport (Figure 4) but incomplete systemic release (Figure 15)) resulted in a significant increase in systemic exposure for Compounds 25 and 27 (approximately 60 - 100 - fold higher than TU).

[0339]

Table 16

[0340] The trimethyl lock self - destructing group is not the only effective self - destructing group, and it is also clear that other examples are similarly effective. For example, in Figure 16 and Table 17, Compound 21 (having an acetal self - destructing group) produced higher systemic testosterone levels than Compound 11. This effect is even more pronounced when an acetal self - destructing group is added to the β - methyl - protected C5 prodrug (Compound 18 vs Compound 23), where the self - destructing analog produces a 90 - fold increase in systemic exposure of testosterone compared to TU.

[0341]

Table 17

[0342] In a further illustration of the potential benefits of self-destructing groups, the data in FIGS. 17 and 18 provide evidence of the utility of inverse ester self-destruction (FSI). The data for compound 29 show that the insertion of an inverse ester group into a C5β-methyltestosterone prodrug results in a significant increase in the level of systemic testosterone after oral administration compared to both the linear prodrug (compound 10) and the β-methyl protected compound (compound 18). The addition of para-hydroxybenzylcarbonyl (PHB) self-destruction (compound 28) also resulted in an increase in testosterone exposure compared to TU, but was less effective than the other self-destructing groups. It has also been shown that the compounds of the present invention can promote the systemic exposure of drugs other than testosterone, for example, alfaxolone (ALP), another agent with a high first-pass effect (FIGS. 18 and 19). FIG. 18 shows the plasma concentration of ALP after oral forced administration of the formulation to conscious male SD rats cannulated in the carotid artery. The formulation contained 7.5 mg of ALP suspended in 1 mL of 0.5% (w / v) carboxymethylcellulose and 0.4% (v / v) Tween 80 in physiological saline, or 3 mg of compound 2 dispersed in 20 mg of oleic acid, 12.5 mg of Tween 80 and 1 mL of PBS. The data are shown as mean ± SEM for the group of compound 2 (n = 4), and the control compound ALP group had n = 1. After oral administration of ALP in the suspension formulation, the plasma concentration was extremely low (below the limit of quantification (LOD, 10 ng / mL)), most likely due to the strong first-pass metabolism of ALP. The data are shown in FIG. 18 as a qualitative indicator to appreciate that they were below the limit of quantification of the assay. In contrast, although compound 2 did not allow for a quantitative comparison of relative bioavailability due to the very low exposure of ALP after ALP administration, it clearly resulted in a marked increase in the systemic exposure (oral bioavailability) of ALP compared to the control compound ALP.

[0343]

Table 18

[0344] It is further evident that the compounds of the present invention can promote the systemic exposure of drugs other than testosterone, for example, alfaxolone (ALP), another agent with a high first-pass effect (FIGS. 18 and 19). FIG. 18 shows the plasma concentration of ALP after oral forced administration of the formulation to conscious male SD rats cannulated in the carotid artery. The formulation contained 7.5 mg of ALP suspended in 1 mL of 0.5% (w / v) carboxymethylcellulose and 0.4% (v / v) Tween 80 in physiological saline, or 3 mg of compound 2 dispersed in 20 mg of oleic acid, 12.5 mg of Tween 80 and 1 mL of PBS. The data are shown as mean ± SEM for the group of compound 2 (n = 4), and the control compound ALP group had n = 1. After oral administration of ALP in the suspension formulation, the plasma concentration was extremely low (below the limit of quantification (LOD, 10 ng / mL)), most likely due to the strong first-pass metabolism of ALP. The data are shown in FIG. 18 as a qualitative indicator to appreciate that they were below the limit of quantification of the assay. In contrast, although compound 2 did not allow for a quantitative comparison of relative bioavailability due to the very low exposure of ALP after ALP administration, it clearly resulted in a marked increase in the systemic exposure (oral bioavailability) of ALP compared to the control compound ALP.

[0345]

Table 19

[0346] Example 10. In Vitro Hydrolysis of Compounds by Rat Digestive Fluid or Porcine Pancreatic Lipase In vitro hydrolysis of MPA-related compounds was carried out via incubation with rat digestive fluid. The rat digestive fluid was collected from anesthetized rats via cannulation into the common bile duct-pancreatic duct (i.e., below the entry point of pancreatic secretion) immediately before the entrance of the tube into the duodenum. This enabled simultaneous collection of bile and pancreatic juice. The digestive fluid was collected continuously for 2 hours, during which time a blank lipid formulation (prepared as described in the rat lymph transport study but without addition of drug) was infused into the duodenum at a rate of 2.8 mL / hour to mimic the state after drug administration. The bile and pancreatic juice were maintained at 37 °C and used for in vitro prodrug hydrolysis experiments within 0.5 hour of collection. The hydrolysis experiment was carried out by incubating (at 37 °C) 0.375 mL of rat digestive fluid with 0.625 mL of a drug-loaded lipid formulation (such as that described in the rat lymph transport study). The volume ratio of the digestive fluid to the formulation mimicked the bile and pancreatic juice flow rates (about 1.5 mL / hour) and the infusion rate of the formulation into the duodenum (2.8 mL / hour) during the in vivo lymph transport study. 10 μL aliquots (samples taken at 0, 2, 5, 10, 15, 30, 60, 90, 120, 180 minutes) were added to 990 μL of acetonitrile:water (4:1, v / v) to stop lipid breakdown, vortexed for 1 minute, and centrifuged at 4500 g for 5 minutes to precipitate proteins before analysis. The supernatant was analyzed by HPLC-MS for residual compound concentration and for possible products of compound hydrolysis.

[0347] To provide a higher throughput of the experiment, in vitro hydrolysis of TST-related compounds was carried out via incubation with porcine pancreatic lipase, unless otherwise stated. This provides a more reproducible source of pancreatic enzymes, facilitates improved experimental throughput, and is also a greater challenge than the rat enzymes harvested (due to the low enzyme activity in rat intestinal fluid). Briefly, a pancreatic lipase solution was prepared prior to the hydrolysis experiment by dispersion of 1 g of porcine pancreatin in 5 mL of lipolytic buffer and 16.9 μL of 5 M NaOH. The suspension was mixed well and centrifuged at 3500 rpm for 15 minutes at 5 °C to provide the supernatant. A 1000 mL volume of lipolytic buffer was prepared with 0.474 g of tris-maleic acid (2 mM), 0.206 g of CaCl2·H2O (1.4 mM), and 8.775 g of NaCl (150 mM), adjusted to pH 6.5 with NaOH. To evaluate the potential hydrolysis of the prodrug in the intestine, 20 μL of the prodrug solution (1 mg / mL dissolved in acetonitrile), 900 μL of the simulated intestinal micellar solution [prepared with 0.783 g of NaTDC (3 mM) and 0.291 g of phosphatidylcholine (0.75 mM) in 500 mL of lipolytic buffer], and 100 μL of the enzyme solution were incubated at 37 °C. 20 μL samples of the incubation solution were taken at 0, 5, 10, 15, 30, 60, 90, 120, and 180 minutes of incubation, added to 180 μL of ACN to stop the lipolysis. The mixture was vortexed and centrifuged at 5000 rpm for 5 minutes to precipitate the protein before analysis. The supernatant was analyzed by HPLC-MS for the residual compound concentration and the possible products of compound hydrolysis were analyzed.

[0348] When incubating with digestive enzymes, the monoglyceride form of the prodrug is formed very rapidly. Therefore, the stability of the monoglyceride form generated by the initial digestive process better evaluates the stability in the simulated intestinal state. The monoglyceride form must remain intact to be absorbed by intestinal cells and re-esterified before entering the lymphatic vessels. Comparison of the stability characteristics of the monoglyceride forms of compound 10 (n = 3) with compound 18 (n = 1), and compound 13 (n = 3) with compound 16 (n = 3) during in vitro incubation with freshly collected rat bile and pancreatic fluid (BPF), or with porcine pancreatic lipase, shows that the inclusion of a methyl group at the α-carbon or β-carbon significantly enhances the stability of the monoglyceride intermediate (Figure 19). This is consistent with the increased lymphatic transport of compound 18 compared to compound 10, and the high degree of lymphatic transport of compound 16 in Figure 4. This is consistent with the increased lymphatic transport of compound 18 compared to compound 10, and the high degree of lymphatic transport of compound 16 in Figure 4.

[0349] Figures 20 - 22 provide further evidence of the ability of methyl substitution to improve the intraluminal stability of testosterone prodrugs containing self-destructing linkers. Here, the self-destructing group might be expected to decrease intraluminal stability. For example, in Figure 20, the monoglyceride forms of compound 11 or compound 13 were not highly stable in the in vitro lipolysis assay, which was similar to or worse than that for the trimethyloxolane self-destructing analogs (compound 22 and compound 23). In contrast, the methyl-substituted monoglycerides (compound 25 and compound 27) were significantly stable under in vitro hydrolysis challenge, resulting in increased testosterone exposure (Figure 15).

[0350] In Figure 21, a similar comparison is evident for the acetal self-destructing prodrug. The intraluminal stability of compound 21 (with a self-destructing linker) was lower than that of compound 11, and compound 24 had less stability than compound 13. The combination of β-methyl protection in addition to acetal self-destruction in compound 23 resulted in significantly improved intraluminal stability (Figure 21) and in vivo exposure (Figure 16).

[0351] Regarding reverse ester self-destruction, the combination of β-methyl substitution (Compound 29) in addition to the insertion of self-destruction resulted in an increase in cavity stability compared to the linear counterpart (Compound 10) that is not self-destructive (Figure 22), and a significant increase in in vivo testosterone exposure (Figure 17).

[0352] Similarly, the comparison of the stability characteristics of the monoglyceride forms of Compounds 31 (n = 5), 32 (n = 4), 34 (n = 1), 36 (n = 2), 37 (n = 1), 38 (n = 1), and 39 (n = 1) during in vitro incubation with freshly collected bile and pancreatic fluid (BPF) is shown in Figure 23 for MPA derivatives. Data are presented as mean ± SEM when n ≥ 3, or mean ± range when n = 2.

[0353] Compounds with methyl substitution at the linker (α- or β- to the ester bond connecting the alkyl group to the glyceride backbone) effectively reduce the degradation of monoglyceride intermediates in the gastrointestinal (GI) cavity and result in improved in vivo lymphatic transport compared to their linear counterparts.

[0354] The comparison of the degradation characteristics of the monoglyceride digestion products of Compound 36 and Compound 38 with Compound 31, Compound 37 with Compound 32, and Compound 39 with Compound 34 demonstrates significant differences in stability. Optimization of the prodrug stability in the GI cavity also resulted in a tendency for better in vivo lymphatic transport. Figures 5 and Table 10 show that the lymphatic transport of Compound 36 (9.1%) or Compound 38 (12.1%) was slightly better than that of Compound 31 (8.2%), Compound 37 (12.6%) resulted in higher transport than Compound 32 (9.6%), and Compound 39 (28.4%) was higher than Compound 34 (22.1%).

[0355] The data also demonstrate that the monoglyceride (MG) intermediates of prodrugs containing a linear linker (e.g., Compound 31 and Compound 32) are relatively rapidly degraded by BPF. The instability of these MG intermediates is likely the result of degradation via hydrolytic enzymes such as monoacylglycerol lipase and pancreatic lipase. This results in a decrease in the availability of the MG-like intermediates that are bound to the drug and can be utilized for re-esterification. Ultimately, this decreases the lymphatic transport of the drug. Therefore, protection of the MG intermediates from degradation may improve the lymphatic transport of the agent. This can be achieved structurally (e.g., incorporation of α- or β-methyl substitution), or by co-administration of an enzyme inhibitor. For example, the data in Figure 24 and Table 20 show that the lymphatic transport of Compound 32 increased from 9.6% to 18.8% by co-administration with the monoacylglycerol lipase inhibitor (JZL184) and the pancreatic lipase inhibitor (orlistat) (p < 0.05). The co-administration with the monoacylglycerol lipase inhibitor (JZL184) and the pancreatic lipase inhibitor (orlistat) increased it from 9.6% to 18.8% of the dose (p < 0.05).

[0356] [[Table 20]]

[0357] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", are to be interpreted as including the stated integer or integers or group of integers or steps but not as excluding any other integer or group of integers.

[0358] Any reference in this specification to a prior publication (or information derived therefrom) or to any matter which is known is not, and should not be taken as, an admission or acknowledgement or any form of suggestion that the prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. Formula (I): 【Chemistry 1】 [During the ceremony, R １ and R ２ are independently H or C ２ ~C ２８ represents a residue of a fatty acid; -X- is selected from -O-, -NH-, and -S-; -Y- is an optionally substituted -C ３ ~C ２０ Alkyl-, -C ３ ~C ２０ Alkenyl- or -C ３ ~C ２０ alkynyl-, where the alkyl, alkenyl or alkynyl group is a straight-chain C ２０ One or more of the carbon atoms in the alkyl, alkenyl or alkynyl group may be substituted with NH, S, O, C, or OH, provided that the length does not exceed the same length as the alkyl group. ５ ~C ８ Aromatic or aliphatic cyclic groups, or C ５ ~C ８ may be substituted with an aromatic or aliphatic heterocyclic group; 【Chemistry 2】 represents a residue of a drug; -L- is -X'- or -X'C(O)-; X' is O, S, N, N(R ４ ) or S(O) ２ NH; 【Chemistry 3】 X' is O, S, N (R ４ ) or S(O) ２ When it is NH, it represents a single bond; or 【Chemistry 4】 represents two separate bonds when X′ is N; When -L- is -X'-, -Z is -C(O)- or -C(O)R ３ - or -Z- is absent when -L- is -X'C(O)-; R ３ is a self-immolative group; and R ４ is H or C １ ~C ４ or a pharma- ceutically acceptable salt thereof.

2. R ３ but 【Chemistry 5】 2. The compound of claim 1 , selected from:

3. Formula (II): 【Chemistry 6】 [During the ceremony, R １ and R ２ are independently H or C ２ ~C ２８ represents a residue of a fatty acid; -X- is selected from -O-, -NH-, and -S-; -Y- is an optionally substituted -C ３ ~C ２０ Alkyl-, -C ３ ~C ２０ Alkenyl- or -C ３ ~C ２０ alkynyl-, where the alkyl, alkenyl or alkynyl group is a straight-chain C ２０ One or more of the carbon atoms in the alkyl, alkenyl or alkynyl group may be substituted with NH, S, O, C, or OH, provided that the length does not exceed the same length as the alkyl group. ５ ~C ８ Aromatic or aliphatic cyclic groups, or C ５ ~C ８ may be substituted with an aromatic or aliphatic heterocyclic group; 【Chemistry 7】 represents a residue of a drug; -L- is -X'- or -X'C(O)-; X' is O, S or N(R ４ ) and R ４ is H or C １ ~C ４ is alkyl; and -Z- is -C(O)- when -L- is -X'-; or 2. The compound of claim 1, wherein -Z- is absent when -L- is X'C(O)-, or a pharma- ceutical acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein Y and Z are selected to facilitate stable transport of the drug to the intestinal lymph.

5. 5. The compound of claim 4, wherein Y and Z are selected to facilitate release of the drug in lymph, lymphocytes, lymphoid tissue, tissues with high lipase activity such as adipose tissue, tumors, liver or systemic circulation.

6. Formula (III): 【Chemistry 8】 [During the ceremony, R １ 、R ２ 、-X-、 【Chemistry 9】 and -Z- is as defined in claim 1; R ５ and R ６ are individually hydrogen and C １ ~C ４ alkyl; and and n is 1 to 18; or a medicamentously acceptable salt thereof.

7. 7. The compound of any one of claims 1 to 6, wherein the agent exhibits greater than 50% first pass metabolism or has highly variable first pass metabolism following oral administration.

8. 8. The compound of any one of claims 1 to 7, wherein the drug is selected from testosterone, mycophenolic acid, estrogen, morphine, metoprolol, raloxifene, alphaxolone, statins such as atorvastatin, buprenorphine, pentazocine, propranolol, L-DOPA, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, isosorbide dinitrate, oxprenolol, labetalol, verapamil, salbutamol, epithiostanol, melphalan, or lovastatin.

9. The agent is testosterone and the compound has formula (IV): 【Chemistry 10】 [During the ceremony, R １ , R ２ and X is as defined in claim 1; R ５ and R ６ are individually hydrogen and C １ ~C ４ alkyl; -Z- is -C(O)- or C(O)R ３ - and R ３ is a self-immolative group; and and n is 1 to 18; or a pharma- ceutical acceptable salt thereof.

10. R ５ is methyl, R ６ The compound according to any one of claims 6 to 9, wherein is hydrogen.

11. R ５ is hydrogen, R ６ The compound according to any one of claims 6 to 9, wherein is methyl.

12. The compound according to any one of claims 1 to 11, wherein X and X' are oxygen.

13. R １ and R ２ The compound according to any one of claims 1 to 12, wherein is a residue of palmitic acid.

14. A method for treating or preventing a disease or disorder in which elevated levels of testosterone are beneficial, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 9 to 13.

15. 15. The method of claim 14, wherein the disease or disorder is hypogonadism, anemia due to bone marrow failure, anemia due to renal failure, chronic respiratory failure, chronic heart failure, steroid-dependent autoimmune disease, AIDS wasting syndrome, hereditary angioedema or urticaria, end-stage breast cancer, or menopause.

16. 1. A method for enhancing lymphatic transport and systemic release of a drug, comprising: Formula (VI): 【Chemistry 11】 [During the ceremony, R １ and R ２ are independently H or C ２ ~C ２８ represents a residue of a fatty acid; -X is selected from -O-, -NH-, and -S-; -Y- is an optionally substituted -C ３ ~C ２０ Alkyl-, -C ３ ~C ２０ Alkenyl- or -C ３ ~C ２０ alkynyl-, where the alkyl, alkenyl or alkynyl group is a straight-chain C ２０ One or more of the carbon atoms of the alkyl, alkenyl or alkynyl group may be substituted with NH, S, O, C, or OH, provided that the length does not exceed the same as that of the alkyl group. ５ ~C ８ Aromatic or aliphatic cyclic groups, or C ５ ~C ８ may be substituted with an aromatic or aliphatic heterocyclic group; -Z is -C(O)-, -C(O)R ３ - or CH ２ - and R ３ is a self-immolative group; and 【Chemistry 12】 represents the point at which the linker is attached to the active drug, or a pharma- ceutically acceptable salt thereof.

17. R ３ but, 【Chemistry 13】 The method of claim 16, wherein the compound is selected from the group consisting of

18. The method of any one of claims 14 to 17, wherein the compound is administered orally with food to promote transport to the intestinal lymphatics.

19. The method of any one of claims 14 to 18, wherein the compound is orally co-administered with a lipid-based formulation to facilitate transport to the intestinal lymphatics.

20. The method of any one of claims 14 to 17, wherein the compound is orally co-administered with an enzyme inhibitor.

21. The compound of any one of claims 1 to 6, wherein the compound is selected to facilitate targeted delivery of the agent within the lymphatic system.

22. The drug may be a nonsteroidal anti-inflammatory drug (NSAIDS such as aspirin, ibuprofen, naproxen, etc.), a COX-2 inhibitor (e.g., celecoxib, rofecoxib), a corticosteroid anti-inflammatory drug (e.g., prednisolone, dexamethasone), an antimalarial drug (e.g., hydroxychloroquine), cyclophosphamide, nitrosourea, platinum, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracycline (e.g., daunarubicin), mycobacterial agent (e.g., cyclophosphamide ... Tommycin C, bleomycin, mithramycin, drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus), sulfasalazine, leflunomide, mycophenolate, opioids, fingolimod, myriocin, chlorambucil, doxorubicin, nelarabine, cortisone, dexamethasone, prednisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinib Silate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxine mepecosinate, anastrozole, capecitabine, letrozole, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, albendazole, doxycycline, closantel, maraviroc, enfuvirtide, 22. The compound of claim 21, selected from deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, nevirapine, delavirdine, efavirenz, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, acyclovir, immunosuppressants (e.g., mycophenolic acid, cyclosporine, tacrolimus, sirolimus) and pharma- ceutical active peptides.

23. 27. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13, 21 or 22, or a pharma- ceutically acceptable salt thereof, together with at least one pharma- ceutically acceptable carrier or diluent.

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