CONJUGATE COMPOUNDS OF URSODEOXYCHOLIC, BERBERINE OR L-CARNITINE, AND COMPOSITIONS AND METHODS THEREOF

Abstract

The invention provides novel conjugate compounds having at least one of a moiety derived from ursodeoxycholic acid, or eicosapentaenoic acid, or docosahexaenoic acid, or rhein, or -(+)--lipoic acid, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof, and a moiety derived from berberine or L-carnitine or metformin or unsaturated fatty acid, or a derivative or analog thereof. The invention also relates to pharmaceutical compositions, methods of preparation and use of these conjugates in treating and/or preventing, for example, liver diseases or disorders, various diabetes, diabetic complications, dyslipidemia, obesity, metabolic syndromes, pre-diabetes, muscle atrophy, inflammation, and cancers. The compounds of this invention are also useful in improving liver functions in chronic viral associated liver diseases and alcohol-related liver diseases.

Claims

1. A compound having the formula of:
XYZ(I) wherein (a) X is a moiety derived from a pharmacologically active organic base or acid; (b) Z is a moiety derived from a pharmacologically active organic acid; and (c) Y a covalent bond or a linker, wherein at least X is a moiety derived from berberine, or a derivative or analog thereof, or L-carnitine, or a derivative or analog thereof; or metformin, or a derivative or analog thereof; or unsaturated fatty acid, or a derivative or analog thereof; and Z is a moiety derived from ursodeoxycholic acid, or eicosapentaenoic acid, or docosahexaenoic acid, or rhein, or R-(+)--lipoic acid, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof.

2. The compound of claim 1, wherein the linker comprises an amide bond or an ester bond.

3. The compound of claim 1, wherein Z is moiety derived from ursodeoxycholic acid, or a derivative or analog thereof selected from Table 1.

4. The compound of claim 1, wherein X is a moiety derived from berberine, or a derivative or analog thereof selected from Table 3.

5-7. (canceled)

8. The compound of claim 1, wherein X is a moiety derived from berberine, or a derivative or analog thereof, and Z is selected from a bile acid, or a derivative or analog thereof, a fatty acid, or a derivative or analog thereof, rhein or a derivative or analog thereof, R-(+)--lipoic acid, or a derivative or analog thereof.

9-11. (canceled)

12. The compound of claim 1, wherein X is a moiety derived from berberine, or a derivative or analog thereof, and Z is ursolic acid or corosolic acid or a derivative or analog thereof, or hydroxycitric acid or a derivative or analog thereof.

13. (canceled)

14. The compound of claim 1, wherein X is a moiety derived from berberine, or a derivative or analog thereof, and Z is a moiety selected from a pharmacologically active organic acid from Table 2.

15. The compound of claim 1, wherein X is a moiety derived from L-carnitine, or a derivative or analog thereof, and Z is a bile acid, or a derivative or analog thereof, a fatty acid, or a derivative or analog thereof, or rhein or a derivative or analog thereof, or R-(+)--lipoic acid, or a derivative or analog thereof.

16-21. (canceled)

22. The compound of claim 1, wherein Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from berberine.

23. (canceled)

24. The compound of claim 1, wherein Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from one of L-carnitine, metformin, coptisine, palmatine and jatrorrhizine.

25. The compound of claim 1, wherein Z is a moiety derived from ursodeoxycholic acid, or a derivative or analog thereof, and X is a moiety derived from an unsaturated fatty acid.

26-29. (canceled)

30. A pharmaceutical composition comprising an amount of a compound having the formula of:
XYZ(I) wherein (a) X is a moiety derived from a pharmacologically active organic base or acid; (b) Z is a moiety derived from a pharmacologically active organic acid; and (c) Y a covalent bond or a linker, wherein at least X is a moiety derived from berberine, or a derivative or analog thereof, or L-carnitine, or a derivative or analog thereof; or metformin, or a derivative or analog thereof; or unsaturated fatty acid, or a derivative or analog thereof; and Z is a moiety derived from ursodeoxycholic acid, or eicosapentaenoic acid, or docosahexaenoic acid, or rhein, or R-(+)--lipoic acid, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof, effective to treat, prevent, or reduce one or more diseases or disorders selected from liver diseases or disorders, diabetes, diabetic complications, pre-diabetes, dyslipidemia, obesity, metabolic syndromes, muscle atrophy, inflammation, and cancers or a related disease or disorder thereof in a mammal including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

31. The pharmaceutical composition of claim 30, wherein the disease or disorder is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cholestatic liver diseases or graft-versus-host disease of the liver.

32. The pharmaceutical composition of claim 30, wherein the disease or disorder is selected from diabetes, diabetic complications and pre-diabetes.

33. The pharmaceutical composition of claim 30, wherein the disease or disorder is dyslipidemia.

34. The pharmaceutical composition of claim 30, wherein the disease or disorder is obesity.

35. The pharmaceutical composition of claim 30, wherein the disease or disorder is metabolic syndromes.

36. The pharmaceutical composition of claim 30, wherein the disease or disorder is muscle atrophy.

37. The pharmaceutical composition of claim 30, wherein the disease or disorder is inflammation.

38-66. (canceled)

67. A method for treating, reducing, or preventing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising an amount of a compound having the formula of:
XYZ(I) wherein (a) X is a moiety derived from a pharmacologically active organic base or acid; (b) Z is a moiety derived from a pharmacologically active organic acid; and (c) Y a covalent bond or a linker, wherein at least X is a moiety derived from berberine, or a derivative or analog thereof, or L-carnitine, or a derivative or analog thereof; or metformin, or a derivative or analog thereof, or unsaturated fatty acid, or a derivative or analog thereof, and Z is a moiety derived from ursodeoxycholic acid, or eicosapentaenoic acid, or docosahexaenoic acid, or rhein, or R-(+)--lipoic acid, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof, effective to treat, prevent, or reduce one or more diseases or disorders selected from liver diseases or disorders, diabetes, diabetic complications, pre-diabetes, dyslipidemia, obesity, metabolic syndromes, muscle atrophy, inflammation, and cancers, or a related disease or disorder thereof in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

68-95. (canceled)

Description

DETAILED DESCRIPTION OF THE INVENTION

[0050] The invention provides novel conjugate compounds, each of which has at least one of a moiety derived from ursodeoxycholic acid, or eicosapentaenoic acid, or docosahexaenoic acid, or rhein, or -(+)--lipoic acid, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof and a moiety derived from berberine or L-carnitine or metformin or unsaturated fatty acid, or a derivative or analog thereof. The invention also relates to pharmaceutical compositions, methods of preparation and use of these conjugates in treating and/or preventing liver diseases or disorders, various diabetes, diabetic complications, dyslipidemia, obesity, metabolic syndromes, pre-diabetes, muscle atrophy, inflammation, and cancers, for example. The conjugate compounds and pharmaceutical compositions of the invention are also useful in improving liver functions in chronic viral associated liver diseases and alcohol-related liver diseases.

[0051] A central feature of the invention is the unique and synergistic effect given rise by each of the two parts of the novel conjugate compound and the pharmaceutical composition thereof, i.e., a first pharmaceutically active portion and a second pharmaceutically active portion, that target a disease or disorder with complementary mechanisms of action thereby improving efficacy of treatment.

[0052] In one aspect, the invention generally relates to a compound having the formula of:

XYZ(I)

wherein

[0053] (a) X is a moiety derived from a pharmacologically active organic base or acid;

[0054] (b) Z is a moiety derived from a pharmacologically active organic acid; and

[0055] (c) Y a covalent bond or a linker,

wherein at least

[0056] X is a moiety derived from berberine or a derivative or analog thereof, or L-carnitine or a derivative or analog thereof, or metformin or a derivative or analog thereof, or unsaturated fatty acid or a derivative or analog thereof,

[0057] Z is moiety derived from ursodeoxycholic acid, or eicosapentaenoic acid, or docosahexaenoic acid, or rhein, or -(+)--lipoic acid, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof.

[0058] In certain embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid.

##STR00001##

[0059] Ursodeoxycholic acid (UDCA or ursodiol, with the chemical names of 3,7-dihydroxy-5-cholan-24-oic acid or (R)-4-((3R,5S,7S,8R,9S,10S, 13R, 14S, 17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid) is a secondary bile acid, a substance naturally produced by the body that is stored in the gallbladder. Ursodiol is used to dissolve gallstones in patients as an alternative to surgery. Ursodiol is also used to prevent the formation of gallstones in overweight patients who are losing weight very quickly. Ursodiol works by decreasing the production of cholesterol and by dissolving the cholesterol in bile so that it cannot form stones. Ursodiol is also the first-line therapy for the treatment of PBC, PSC and cholestatic liver diseases. There have been limited studies of ursodiol on NASH, but the results were contradictory and inconclusive. Thus, the effect of ursodiol on NASH remains unclear.

[0060] In certain embodiments of the compound, Z is a moiety derived from a derivative or analog of ursodeoxycholic acid. Exemplary derivatives or analogs of ursodeoxycholic acid are listed in Table 1.

TABLE-US-00001 TABLE 1 Ursodeoxycholic acid Derivatives or Analogs [00002] [00003] [00004] R3 U1 CH.sub.3 U2 CH.sub.3CH.sub.2 U3 n-Bu [00005] [00006] R.sub.1 R.sub.2 R.sub.3 U4 H CH.sub.3 CH.sub.3 U11 CH.sub.3CO H CH.sub.3 U12 H CH.sub.3CO CH.sub.3 U13 CH.sub.3CO CH.sub.3CO CH.sub.3 U15 PhCO H CH.sub.3 U16 PhCO PhCO CH.sub.3 U17 CH.sub.3SO.sub.3 H CH.sub.3 U18 CH.sub.3SO.sub.3 CH.sub.3SO.sub.3 CH.sub.3 U20 CH.sub.3SO.sub.3 CH.sub.3CO CH.sub.3 [00007] R.sub.2 R.sub.3 U5 H H U9 H n-Bu [00008] R.sub.1 R.sub.3 U14 CH.sub.3CO CH.sub.3 U19 CH.sub.3SO.sub.3 CH.sub.3 [00009] R.sub.3 U6 H U7 CH.sub.3 U8 CH.sub.3CH.sub.2 U10 n-Bu [00010] [00011] R1 = OH, R2 = OH R1 = OH, R2 = H R1 = OH, R2 = H R1 = H, R2 = OH R1 = H, R2 = H [00012] [00013] [00014] [00015] [00016] [00017] wherein R represents H, CH3 or COOH and R represents CONHCH.sub.2COOH, CH.sub.2COOH or [00018] [00019] R is a radical selected from CH2SO.sub.3H and COOH and R is a radical selected from H and (CH.sub.2).sub.2CONH, CH.sub.2CONH.sub.1, (CH.sub.2).sub.2SCH.sub.3, CH.sub.2SCH.sub.2COOH, respectively [00020] [00021] R.sub.1 is selected from the group consisting of C.sub.1-C.sub.4 alkyl or a halogen; or an ester

[0061] In certain embodiments of the compound, Z is a moiety derived from eicosapentaenoic acid or docosahexaenoic acid.

##STR00022##

[0062] Eicosapentaenoic acid (EPA or (5Z,8Z,11Z,14Z, 17Z)-5,8,11,14,17-icosapentaenoic acid), and docosahexaenoic acid (DHA, 4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid), are two best-investigated omega-3 polyunsaturated fatty acids. EPA is the active molecule in two FDA-approved anti-hypertriglyceridemic agents. It has been demonstrated that EPA and DHA can reduce free fatty acid and triglyceride synthesis and increase their disposal. Effects of EPA and DHA have also been demonstrated in reducing chronic inflammation, improving insulin resistance, maintaining heart and vascular health and reducing the risk of coronary heart disease.

[0063] In certain embodiments of the compound, Z is a moiety derived from rhein.

##STR00023##

[0064] Rhein (4,5-dihydroxy-9,10-dioxoanthracene-2-carboxylic acid), is one of the most important active components of rhubara (Rheum officinale), a traditional Chinese herb showing broad pharmacological effects. Rhein was reported to affect oxidative phosphorylation by inhibiting both electron transfer and ADP-driven H+ uptake in mitochondria, which is responsible for the formation of lipid peroxides. It has also demonstrated protective effects in diabetic nephropathy animal models in various studies. The pharmacokinetics of rhein have not been intensively studied in humans, an oral dose of 50 mg twice per day was shown to be safe when administered for five days to elderly patients with chronic congestive heart failure.

[0065] In certain embodiments of the compound, Z is a moiety derived from -(+)--Lipoic acid.

##STR00024##

[0066] -(+)--Lipoic acid ((R)-6,8-Dithiooctanoic acid, (R)-6,8-Thioctic acid, (R)-(+)-1,2-Dithiolane-3-pentanoic acid) was identified as a catalytic agent for oxidative decarboxylation of pyruvate and -ketoglutarate. In human, R-(+)--lipoic acid exists in the body as a portion of several multi-enzyme complexes involved in energy formation and is an essential component of mitochondrial respiratory enzymes. R-(+)--Lipoic acid is best known for its potent anti-oxidant effects and has been used for the treatment of diabetic neuropathy, degenerative neuronal disease, atherosclerosis and other oxidative stress related abnormalities.

[0067] In certain embodiments of the compound, Z is a moiety derived from ursolic acid or corosolic acid.

##STR00025##

[0068] Ursolic acid ((1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a, 10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid) and corosolic acid ((1 S,2R,4aS,6aR,6aS,6bR,8aR,10R, 11R, 12aR, 14bS)-10,11-Dihydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid) are members of the pentacyclic triterpene acid class of compounds widely distributed in the plant kingdom. They have been shown to exhibit favorable pharmacological effects both in vivo and in vitro, including glucose reduction, anti-obesity, anti-inflammatory, reduce muscle atrophy, anti-cancer, liver protection, anti-oxidative stress.

[0069] In certain embodiments of the compound, Z is a moiety derived from hydroxycitric acid.

##STR00026##

[0070] Hydroxycitric acid (1,2-dihydroxypropane-1,2,3-tricarboxylic acid) is a derivative of citric acid found in a variety of tropical plants including Garcinia cambogia and Hibiscus subdariffa. Hydroxycitric acid is the active component of Garcinia cambogia extract, which has been widely utilized as dietary supplement for weight loss. There have been reports on hydroxycitric acid's effects in improving glucose tolerance, providing liver protection against toxicity associated with ethanol and dexamethasone, and controlling blood pressure. In addition, the compound has been found to reduce markers of inflammation in brain, intestines, kidney and serum.

[0071] In certain embodiments of the compound, Z is a moiety derived from a pharmacologically active organic acid, such as Cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid or biotin (Table 2).

TABLE-US-00002 TABLE 2 Exemplary Pharmacologically Active Organic Acids Name IUPAC Name Structure Cinnamic acid (E)-3-phenylprop-2-enoic acid [00027] Cholic acid (R)-4- ((3R,5S,7R,8R,9S,10S,12S, 13R,14S,17R)- 3,7,12-trihydroxy-10,13- dimethylhexadecahydro- 1H- cyclopenta[a]phenanthren- 17-yl)pentanoic acid [00028] Oleanolic acid (4aS,6aR,6aS,6bR,8aR,10S, 12aR,14bS)-10-hydroxy- 2,2,6a,6b,9,9,12a- heptamethyl- 1,3,4,5,6,6a,7,8,8a,10,11, 12,13,14b- tetradecahydropicene-4a- carboxylic acid [00029] Salicylic acid 2-Hydroxybenzoic acid [00030] Betulinic acid (3)-3-Hydroxy-lup- 20(29)-en-28-oic acid [00031] Chlorogenic acid (1S,3R,4R,5R)-3-{[(2Z)-3- (3,4- dihydroxyphenyl)prop-2- enoyl]oxy}-1,4,5- trihydroxycyclohexane- carboxylic acid [00032] Caffeic acid 3-(3,4-Dihydroxyphenyl)-2- propenoic acid 3,4-Dihydroxy- cinnamic acid trans-Caffeate 3,4-Dihydroxy-trans-cinnamate) (E)-3-(3,4-dihydroxyphenyl)-2- propenoic acid 3,4-Dihydroxy- benzeneacrylicacid 3-(3,4- Dihydroxyphenyl)-2-propenoic acid [00033] Bassic acid (4aR,6bS,9R,10R,11S,12aR, 14bS)-10,11-dihydroxy-9- (hydroxymethyl)- 2,2,6b,9,12a-pentamethyl- 1,2,3,4,4a,5,6,6a,6b,7,9,10, 11,12,12a,12b,13,14b- octadecahydropicene-4a- carboxylic acid [00034] Acetyl L- carnitine (R)-3-Acetyloxy-4- trimethylammonio- butanoate [00035] S-allyl-L- cysteine sulphoxide (2R)-2-amino-3-[(S)-prop- 2-enylsulfinyl]propanoic acid [00036] S-methyl-L- cysteine sulfoxide 3-(methylsulfinyl)-L- alanine [00037] Pantothenic acid 3-[(2,4-Dihydroxy-3,3- dimethylbutanoyl)amino] propanoic acid [00038] Ascorbic acid (5R)-[(1S)-1,2- dihydroxyethyl]-3,4- dihydroxyfuran-2(5H)-one [00039] Retinoic acid (2E,4E,6E,8E)-3,7- dimethyl-9-(2,6,6- trimethylcyclohexen-1- yl)nona-2,4,6,8-tetraenoic acid [00040] Nicotinic acid pyridine-3-carboxylic acid [00041] Biotin 5-[(3aS,4S,6aR)-2- oxohexahydro-1H- thieno[3,4-d]imidazol-4- yl]pentanoic acid [00042]

[0072] In certain embodiments of the compound, X is a moiety derived from berberine.

##STR00043##

[0073] Berberine (5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolo[5,6-a]quinolizinium), an isoquinoline alkaloid isolated from Rhizoma Coptidis, has had a long history of medicinal use in China to treat various gastrointestinal diseases. Berberine is found in a variety of plants such as Berberis, Hydrastis canadensis, Xanthorhiza simplicissima, Phellodendron amurense, Coptis chinensis, Tinospora cordifolia, Argemone mexicana, and Eschscholzia californica. In the last two decades, in vitro and in vivo studies have demonstrated the efficacy of berberine when using alone or as a combination for diabetes, dyslipidemia, cancer, neuroprotection and cardiovascular diseases. Currently, berberine can be obtained commercially in the form of chloride, sulfate or tannate salt, with berberine hydrochloride being the form used in almost all previous studies. While some studies appear to show benefits of berberine in treating NAFLD, the low bioavailability and poor absorption of berberine in the current available forms, combining with the gastrointestinal side effects at high doses have made its clinical applications very challenging.

[0074] In certain embodiments of the compound, X is a moiety derived from a derivative or analog of berberine. Exemplary berberine derivatives or analogs are listed in Table 3.

TABLE-US-00003 TABLE 3 Berberine Derivatives or Analogs [00044] R.sub.1 = R.sub.2 = R.sub.3 = R.sub.4 = CH.sub.3 [00045] R = H [00046] R = C.sub.8-C.sub.12 alkyl [00047] R.sub.1 = OH, carbonyl; R.sub.2, R.sub.3 = H, carbonyl; n = 2-6; X = O R.sub.1 = OH, carbonyl; R.sub.2, R.sub.3 = H, OH, carbonyl; n = 2-6; X = NH [00048] R.sub.1, R.sub.3, R.sub.2, R.sub.4 = OH, C.sub.1-C.sub.8 alkoxy, OCH.sub.2O G = ZAr, YAr.sub.2 Z = O(CH.sub.2).sub.m, CONH(CH.sub.2).sub.m, NHCO(CH.sub.2).sub.m Y = O(CH.sub.2).sub.mCH, CONH(CH.sub.2).sub.mCH, NHCO(CH.sub.2).sub.mCH n = 1-5; m = 1-3; Ar = 5-15 membered unsaturated or aromatic ring [00049] R.sub.1, R.sub.3, R.sub.2, R.sub.4 = OH, C.sub.1-C.sub.8 alkoxy, OCH.sub.2O G = ZAr, YAr.sub.2 Z = O(CH.sub.2).sub.m, CONH(CH.sub.2).sub.m, NHCO(CH.sub.2).sub.m Y = O(CH.sub.2).sub.mCH, CONH(CH.sub.2).sub.mCH, NHCO(CH.sub.2).sub.mCH n = 1-5; m = 1-3; Ar = 5-15 membered unsaturated or aromatic ring [00050] R.sub.1, R.sub.3, R.sub.2, R.sub.4 = OH, C.sub.1-C.sub.8 alkoxy, OCH.sub.2O G = ZAr, YAr.sub.2 Z = O(CH.sub.2).sub.m, CONH(CH.sub.2).sub.m, NHCO(CH.sub.2).sub.m Y = O(CH.sub.2).sub.mCH, CONH(CH.sub.2).sub.mCH, NHCO(CH.sub.2).sub.mCH n = 1-5; m = 1-3; Ar = 5-15 membered unsaturated or aromatic ring [00051] R.sub.1, R.sub.3, R.sub.2, R.sub.4 = OH, C.sub.1-C.sub.8 alkoxy, OCH.sub.2O G = ZAr, YAr.sub.2 Z = O(CH.sub.2).sub.m, CONH(CH.sub.2).sub.m, NHCO(CH.sub.2).sub.m Y = O(CH.sub.2).sub.mCH, CONH(CH.sub.2).sub.mCH, NHCO(CH.sub.2).sub.mCH n = 1-5; m = 1-3; Ar = 5-15 membered unsaturated or aromatic ring [00052] R.sub.1, R.sub.3, R.sub.2, R.sub.4 = OH, C.sub.1-C.sub.8 alkoxy, OCH.sub.2O G = ZAr, YAr.sub.2 Z = O(CH.sub.2).sub.m, CONH(CH.sub.2).sub.m, NHCO(CH.sub.2).sub.m Y = O(CH.sub.2).sub.mCH, CONH(CH.sub.2).sub.mCH, NHCO(CH.sub.2).sub.mCH n = 1-5; m = 1-3; Ar = 5-15 membered unsaturated or aromatic ring [00053] R.sub.1, R.sub.2, R.sub.3, R.sub.4 = OCH.sub.3, OH, OCH.sub.2O [00054] [00055] [00056] R.sub.1 = H, Me R.sub.2 = Bn, 3,5-dinitrobenzyl [00057] X = F, Cl, Br, I, SO.sub.4, NO.sub.3, PO.sub.4, citrate, acetate, lactate R.sub.1 and R.sub.2 = independently alkyl; R.sub.3 = H, F, Cl, Br, or I [00058] X = F, Cl, Br, I, SO.sub.4, NO.sub.3, PO.sub.4, citrate, acetate, lactate R.sub.1 and R.sub.2 = independently alkyl; R.sub.3 = H, F, Cl, Br, or I [00059] Y = CH.sub.2, CO, CS; X = C having a linear, branched, saturated/unsaturated linear structure; n = 1-10 [00060] [00061] Y = CH.sub.2, CO, CS; X = C having a linear, branched, saturated/unsaturated linear structure; n = 1-10 [00062] [00063] Y = CH.sub.2, CO, CS; X = C having a linear, branched, saturated/unsaturated linear structure; n = 1-10 [00064] [00065] [00066] R = glucosyl, mannosyl, maltosyl, lactosyl, galactosyl, fructosyl, xylosyl, arabinosyl X = Cl, Br, I [00067] R.sub.1, R.sub.2 = H, C.sub.1-C.sub.4 alkoxy, OCH.sub.2O R.sub.3 = C.sub.1-C.sub.3 alkyl R.sub.4, R.sub.5 = C.sub.1-C.sub.2 alkoxy [00068] R.sub.1, R.sub.2 = H, C.sub.1-C.sub.4 alkoxy, OCH.sub.2O R.sub.3 = CN, COOR.sub.6 (R.sub.6 = C.sub.1-C.sub.2 alkyl) R.sub.4, R.sub.5 = C.sub.1-C.sub.2 alkoxy [00069] R.sub.1, R.sub.2 = H, C.sub.1-C.sub.4 alkoxy, OCH.sub.2O R.sub.3 = C.sub.1-C.sub.3 alkyl, phenyl R.sub.4, R.sub.5 = C.sub.1-C.sub.2 alkoxy [00070] R.sub.1, R.sub.2 = H, (CH.sub.2).sub.0-6CO.sub.2R, C(O)R, OR, NR.sub.10R.sub.11, C(O)NR.sub.10R.sub.11, alkyl R.sub.1R.sub.2 = OCH.sub.2CH.sub.2O; R.sub.3, R.sub.8 = H, OH, Cl, Br, F, I, CN, NH.sub.2, (:O)NH.sub.2, CO.sub.2H, alkyl; R.sub.3 = H; R.sub.3R.sub.3 = O; R.sub.4 = H, halogen, OR, OSO.sub.2R, OC(:O)R, OCO2R OC(O)NRR, O-alkylene-NRR, O-alkylene-OSO.sub.2R, O-alkylene-NRSO.sub.2R, O-alkylene-NRCOR, alkyl; R.sub.5, R.sub.6 = H, halogen, OH, alkoxy R.sub.4R.sub.5 = OCH.sub.2O; R.sub.5R.sub.6 = OCH.sub.2O; R.sub.7 = H, OH, halogen, alkyl or alkoxy R.sub.10, R.sub.11 = H, CO.sub.2R, alkyl [00071] R = SO.sub.2C.sub.6H.sub.4-3-F [00072] [00073] [00074] [00075] [00076] [00077] X = (CH.sub.2).sub.n, (CH.sub.2).sub.mCO; n = 2-10; m = 1-9 Y = NR.sub.1Ar, OAR, Ar = substituted aryl R.sub.1 = H, Me, Et, Pr, i-Pr; Z = F, Cl, Br, I [00078] R = 2-acetic acid Me ester, 3-acetic Me ester, 4-acetic Me ester, 2-acetic me Et ester, 3-acetic Me Et ester, 4-acetic Me Et ester, 2-acetate, 3-acetate, 4-acetate, 2-acetate potassium, 3-acetate potassium, 4-acetate potassium; n = 2-6

[0075] In certain embodiments of the compound, X is a moiety derived from berberine or a derivative or analog thereof and Z is a bile acid or a derivative or analog thereof.

[0076] In certain embodiments of the compound, X is a moiety derived from berberine or a derivative or analog thereof and Z is a fatty acid or a derivative or analog thereof.

[0077] In certain embodiments of the compound, X is a moiety derived from berberine or a derivative or analog thereof and Z is a rhein, or -(+)--lipoic, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof.

[0078] In certain embodiments of the compound, X is a moiety derived from L-carnitine or a derivative or analog thereof selected from Table 4.

##STR00079##

[0079] L-Carnitine is a naturally occurring amino acid. It is biosynthesized in the liver and kidneys from lysine and methionine. L-Carnitine plays an important role in the metabolism of fat, functioning as a transporter of fatty acids into the mitochondria. Exemplary L-carnitine derivatives or analogs are listed in Table 4.

TABLE-US-00004 TABLE 4 L-carnitine Derivatives or Analogs [00080] [00081] [00082] [00083] [00084] Formula 1 [00085] Wherein A is selected from the group consisting of a single bond, Of, or iCH2i; m and n vary independently and are an integer from 1 to 15; p and q vary independently from 0 to 1; B is iCR3R4; D is selected from the group consisting of iCOzRs, ADR6, ADCOR7, iSO3R8, iSO2NH2, iOPO(OR9)(OR1O), A)PO(OR9)(NH2), iOPO(OR9)i OiPO(OR1O)(OR11), wherein R1 to R4 are independently selected from C1-C6 alkyl; and R5 to R11 are independently selected from the group consisting of hydrogen; C1-C6 alkyl; C3-C6 cycloalkyl;C2-C6 alkenyl; C6 alkynyl; C5-C10 aryl unsubstituted or substituted With C1-C6 alkyl, hydroxyl, C1-C6 alkoxyl, 1,3-dioxolanyl, cyano, halo, nitro, trihaloalkyl, carboxyl, C1-C6 acyl, C1-C6 hydroxyalkyl, amino, C1-C6 alkylamino, C1-C6 dialky lamino, C1-C6 acylamino, C1-C6 alkoxylcarbonyl; C5-C6 ary lalkyl unsubstituted or substituted With C1-C6 alkyl, hydroxyl, C1-C6 alkoxyl, 1,3-dioxolanyl, cyano, halo, triha loalkyl, carboxyl, C1-C6 acyl, C1-C6 hydroxyalkyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxylcarbonyl; C1-C6 carboxyalkyl; C1-C6 acylamino; C1-C6 sulfonatoalkyl; C1-C6 sulfamylalkyl; and C1-C6 phosphonatoalkyl. [00086] Wherein X is an integer betWeen about 0 and 5 [00087] [00088] [00089] [00090]

[0080] In certain embodiments of the compound, X is a moiety derived from L-carnitine or a derivative or analog thereof and Z is a bile acid or a derivative or analog thereof.

[0081] In certain embodiments of the compound, X is a moiety derived from L-carnitine or a derivative or analog thereof and Z is a fatty acid or a derivative or analog thereof.

[0082] In certain embodiments of the compound, X is a moiety derived from L-carnitine or a derivative or analog thereof and Z is a rhein, or -(+)--lipoic, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof.

[0083] In certain embodiments of the compound, X is a moiety derived from metformin or a derivative or analog thereof selected from Table 5.

[0084] Metformin (N,N-Dimethylimidodicarbonimidic diamide) is a potent anti-hyperglycemic agent now recommended as the first line oral therapy for type 2 diabetes (T2D). The main effect of this drug is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory-chain complex 1. In addition, the resulting decrease in hepatic energy status activates the AMP-activated protein kinase (AMPK), a cellular metabolic sensor, providing a generally accepted mechanism for metformin action on hepatic gluconeogenic program. Beyond its effect on glucose metabolism, metformin was reported to restore ovarian function in polycystic ovary syndrome, reduce fatty liver and to lower microvascular and macrovascular complications associated with T2D. Its use was also recently suggested as an adjuvant treatment for cancer or gestational diabetes, and for the prevention in pre-diabetic populations. Studies of metformin for NAFLD and NASH have multiplied in the past few years, however, its efficacy for NAFLD and NASH remains to be approved.

##STR00091##

TABLE-US-00005 TABLE 5 Metformin Derivatives or Analogs [00092] [00093] L.sup.1 and L.sup.2 are independently a bond or NHC(NH); R.sup.1 is NR.sup.1AR.sup.1B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein R.sup.1A and R.sup.1B are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; R.sup.2 is NR.sup.2AR.sup.2B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R.sup.2A and R.sup.2B are optionally joined together to form a substituted or unsubstituted heterocycloalkyl; R.sup.1A, R.sup.1B, R.sup.2A, and R.sup.2B are independently hydrogen, OR.sup.4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R.sup.3 is hydrogen or unsubstituted C1-C5 alkyl; and R.sup.4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; [00094] [00095] [00096] [00097] R = H, Ph, substituted Ph R = R.sub.1 substituted Ph R.sub.1 = C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkyl, fluorinated alkyl, acyl, ester, aryl, halogen, NO.sub.2, NH.sub.2, H, OR.sub.2, SR.sub.2 R.sub.2 = C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 fluorinated alkyl, acyl

[0085] In certain embodiments of the compound, X is a moiety derived from metformin or a derivative or analog thereof and Z is a bile acid or a derivative or analog thereof.

[0086] In certain embodiments of the compound, X is a moiety derived from metformin or a derivative or analog thereof and Z is a fatty acid or a derivative or analog thereof.

[0087] In certain embodiments of the compound, X is a moiety derived from metformin or a derivative or analog thereof and Z is a rhein, or -(+)--lipoic, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof.

[0088] In certain preferred embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from berberine. [0089] BBR-Y-UDCA

[0090] In certain preferred embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from L-carnitine. [0091] (L-carnitine)-Y-UDCA

[0092] In certain preferred embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from one of metformin, coptisine, palmatine and jatrorrhizine. [0093] Metformin-Y-UDCA [0094] Coptisine-Y-UDCA [0095] Palmatine-Y-UDCA [0096] Jatrorrhizine-Y-UDCA

[0097] Beyond its effect on glucose metabolism, metformin was reported to restore ovarian function in polycystic ovary syndrome, reduce fatty liver and to lower microvascular and macrovascular complications associated with T2D. Its use was also recently suggested as an adjuvant treatment for cancer or gestational diabetes, and for the prevention in pre-diabetic populations. Studies of metformin for NAFLD and NASH have multiplied in the past few years, however, its efficacy for NAFLD and NASH remains to be approved.

[0098] Coptisine [6,7-Dihydro-bis(1,3)benzodioxolo (5,6-a:4,5-g)quinolizinium], palmatine [2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium], and jatrorrhizine [2,9,10-trimethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium-3-ol] are naturally alkaloids that have demonstrated similar pharmacological properties as berberine in previous studies.

##STR00098##

[0099] In certain embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid, or a derivative or analog thereof, and X is a moiety derived from an unsaturated fatty acid. In certain embodiments of the compound, the unsaturated fatty acid is selected from Table 6.

TABLE-US-00006 TABLE 6 Unsaturated Fatty Acids Common Name Chemical Structure Myristoleic acid CH.sub.3(CH.sub.2).sub.3CHCH(CH.sub.2).sub.7COOH Palmitoleic acid CH.sub.3(CH.sub.2).sub.5CHCH(CH.sub.2).sub.7COOH Sapienic acid CH.sub.3(CH.sub.2).sub.8CHCH(CH.sub.2).sub.4COOH Oleic acid CH.sub.3(CH.sub.2).sub.7CHCH(CH.sub.2).sub.7COOH Elaidic acid CH.sub.3(CH.sub.2).sub.7CHCH(CH.sub.2).sub.7COOH Vaccenic acid CH.sub.3(CH.sub.2).sub.5CHCH(CH.sub.2).sub.9COOH Linoleic acid CH.sub.3(CH.sub.2).sub.4CHCHCH.sub.2CHCH(CH.sub.2).sub.7COOH Linoelaidic acid CH.sub.3(CH.sub.2).sub.4CHCHCH.sub.2CHCH(CH.sub.2).sub.7COOH -Linolenic acid CH.sub.3(CH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCH(CH.sub.2).sub.7COOH Arachidonic acid CH.sub.3(CH.sub.2).sub.4CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCH(CH.sub.2).sub.3COOH Eicosapentaenoic acid CH.sub.3CH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCH(CH.sub.2).sub.3COOH Erucic acid CH.sub.3(CH.sub.2).sub.7CHCH(CH.sub.2).sub.11COOH Docosahexaenoic acid CH.sub.3CH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCH(CH.sub.2).sub.2COOH

[0100] In certain embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid, or a derivative or analog thereof, and X is a moiety derived from eicosapentaenoic acid (EPA). [0101] EPA-Y-UDCA

[0102] In certain embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid, or a derivative or analog thereof, and X is a moiety derived from docosahexaenoic (DHA). [0103] DHA-Y-UDCA

[0104] In certain embodiments of the compound, the linker includes an amide bond or an ester bond. In certain preferred embodiments, the linker includes an amide bond. In certain embodiments, the linker includes a moiety derived from a natural or synthetic amino acid, for example, selected from Table 7. In certain preferred embodiments, the linker includes an ester bond.

TABLE-US-00007 TABLE 7 Common Amino Acids Gly [00099] Ala [00100] Val [00101] Leu [00102] Ile [00103] Met [00104] Phe [00105] Pro [00106] Asp [00107] Glu [00108] Ser [00109] Thr [00110] Cys [00111] Tyr [00112] Asn [00113] Gln [00114] Trp [00115] Lys [00116] Arg [00117] His [00118]

[0105] In another aspect, the invention generally relates to a pharmaceutical composition comprising an amount of a compound having the formula of:

XYZ(I)

wherein

[0106] (a) X is a moiety derived from a pharmacologically active organic base or acid;

[0107] (b) Z is a moiety derived from a pharmacologically active organic acid; and

[0108] (c) Y a covalent bond or a linker,

wherein at least

[0109] X is a moiety derived from berberine or a derivative or analog thereof, or L-carnitine or a derivative or analog thereof, or metformin or a derivative or analog thereof, or unsaturated fatty acid or a derivative or analog thereof,

[0110] Z is moiety derived from ursodeoxycholic acid, or eicosapentaenoic acid, or docosahexaenoic acid, or rhein, or -(+)--lipoic acid, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof, wherein the amount is effective to treat, prevent, or reduce one or more diseases or disorders selected from liver diseases or disorders, diabetes, diabetic complications, pre-diabetes, dyslipidemia, obesity, metabolic syndromes, muscle atrophy, inflammation, and cancers or a related disease or disorder thereof in a mammal including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0111] In certain embodiments of the pharmaceutical composition, the disease or disorder is selected from NAFLD, NASH, cholestatic liver diseases or graft-versus-host disease of the liver.

[0112] In certain embodiments of the pharmaceutical composition, the disease or disorder is selected from diabetes, diabetic complications and pre-diabetes.

[0113] In certain embodiments of the pharmaceutical composition, the disease or disorder is dyslipidemia.

[0114] In certain embodiments of the pharmaceutical composition, the disease or disorder is obesity.

[0115] In certain embodiments of the pharmaceutical composition, the disease or disorder is metabolic syndromes.

[0116] In certain embodiments of the pharmaceutical composition, the disease or disorder is muscle atrophy.

[0117] In certain embodiments of the pharmaceutical composition, the disease or disorder is inflammation.

[0118] In certain embodiments of the pharmaceutical composition, the disease or disorder is cancer.

[0119] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from ursodeoxycholic acid, or a derivative or analog thereof selected from Table 1.

[0120] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from eicosapentaenoic acid or docosahexaenoic acid, or a derivative or analog thereof.

[0121] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from rhein or a derivative or analog thereof.

[0122] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from -(+)--lipoic acid or a derivative or analog thereof.

[0123] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from ursolic acid or corosolic acid or a derivative or analog thereof.

[0124] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from hydroxycitric acid or a derivative or analog thereof.

[0125] In certain embodiments of the pharmaceutical composition, Z is a moiety selected from a pharmaceutically active organic acid from Table 2.

[0126] In certain embodiments of the pharmaceutical composition, X is a moiety derived from berberine or a derivative or analog thereof selected from Table 3

[0127] In certain embodiments of the compound, X is a moiety derived from L-carnitine or a derivative or analog thereof selected from Table 4.

[0128] In certain embodiments of the compound, X is a moiety derived from metformin or a derivative or analog thereof selected from Table 5.

[0129] In certain embodiments of the pharmaceutical composition, X is a moiety derived from berberine, or a derivative or analog thereof, and Z is a bile acid, or a derivative or analog thereof.

[0130] In certain embodiments of the pharmaceutical composition, X is a moiety derived from berberine, or a derivative or analog thereof, and Z is a fatty acid, or a derivative or analog thereof.

[0131] In certain embodiments of the pharmaceutical composition, X is a moiety derived from L-carnitine, or a derivative or analog thereof, and Z is a bile acid, or a derivative or analog thereof.

[0132] In certain embodiments of the pharmaceutical composition, X is a moiety derived from L-carnitine, or a derivative or analog thereof, and Z is a fatty acid, or a derivative or analog thereof.

[0133] In certain embodiments of the pharmaceutical composition, X is a moiety derived from metformin, or a derivative or analog thereof, and Z is a bile acid, or a derivative or analog thereof.

[0134] In certain embodiments of the pharmaceutical composition, X is a moiety derived from metformin, or a derivative or analog thereof, and Z is a fatty acid, or a derivative or analog thereof.

[0135] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from berberine. In certain embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from L-carnitine. In certain embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from one of metformin, coptisine, palmatine and jatrorrhizine. In certain embodiments of the compound, Z is moiety derived from ursodeoxycholic acid or a derivative or analog and X is a moiety derived from an unsaturated fatty acid. In certain embodiments of the compound, the unsaturated fatty acid is selected from Table 6.

[0136] In certain embodiments of the pharmaceutical composition, the linker includes an amide bond or an ester bond. In certain preferred embodiments, the linker includes an amide bond. In certain embodiments, the linker includes a moiety derived from an amino acid selected from Table 7. In certain preferred embodiments, the linker comprises an ester bond.

[0137] The pharmaceutical composition may further include one or more of vitamin E, omega-3 fatty acids, S-adenosylmethionine, N-acetyl cysteine, silymarin, polyenylphosphatidylcholine, resveratrol, and vitamin D.

[0138] In yet another aspect, the invention generally relates to a method for treating, reducing, or preventing a disease or disorder. The method includes: administering to a subject in need thereof a pharmaceutical composition comprising an amount of a compound having the formula of:

XYZ(I)

wherein

[0139] (a) X is a moiety derived from a pharmacologically active organic base or acid;

[0140] (b) Z is a moiety derived from a pharmacologically active organic acid; and

[0141] (c) Y a covalent bond or a linker,

wherein at least

[0142] Z is moiety derived from ursodeoxycholic acid, or eicosapentaenoic acid, or docosahexaenoic acid, or rhein, or -(+)--lipoic acid, or ursolic acid, or corosolic acid, or hydroxycitric acid, or cinnamic acid, or cholic acid, or oleanolic acid, or salicylic acid, or betulinic acid, or chlorogenic acid, or caffeic acid, or bassic acid, or acetyl L-carnitine, or S-allyl cysteine sulphoxide, or S-methyl cysteine sulfoxide, or pantothenic acid, or ascorbic acid, or retinoic acid, or nicotinic acid, or biotin, or a derivative or analog thereof,

[0143] X is a moiety derived from berberine or a derivative or analog thereof, or L-carnitine or a derivative or analog thereof, or metformin or a derivative or analog thereof, wherein the amount is effective to treat, prevent, or reduce one or more diseases or disorders selected from liver diseases or disorders, diabetes, diabetic complications, pre-diabetes, dyslipidemia, obesity, metabolic syndromes, muscle atrophy, inflammation, and cancers, or a related disease or disorder thereof in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0144] In certain embodiments of the method, the disease or disorder is selected from NAFLD, NASH, cholestatic liver diseases or graft-versus-host disease of the liver.

[0145] In certain embodiments of the method, the disease or disorder is selected from diabetes, diabetic complications and pre-diabetes.

[0146] In certain embodiments of the method, the disease or disorder is dyslipidemia.

[0147] In certain embodiments of the method, the disease or disorder is obesity.

[0148] In certain embodiments of the method, the disease or disorder is metabolic syndromes.

[0149] In certain embodiments of the method, the disease or disorder is muscle atrophy.

[0150] In certain embodiments of the method, the disease or disorder is inflammation.

[0151] In certain embodiments of the method, the disease or disorder is cancer.

[0152] In certain embodiments of the method, Z is a moiety derived from ursodeoxycholic acid, or a derivative or analog thereof selected from Table 1.

[0153] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from eicosapentaenoic acid or docosahexaenoic acid, or a derivative or analog thereof.

[0154] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from rhein or a derivative or analog thereof.

[0155] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from -(+)--lipoic acid or a derivative or analog thereof.

[0156] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from ursolic acid or corosolic acid or a derivative or analog thereof.

[0157] In certain embodiments of the pharmaceutical composition, Z is a moiety derived from hydroxycitric acid or a derivative or analog thereof.

[0158] In certain embodiments of the pharmaceutical composition, Z is a moiety selected from a pharmacologically active organic acid from Table 2.

[0159] In certain embodiments of the method, X is a moiety derived from berberine, or a derivative or analog thereof selected from Table 3. In certain embodiments of the compound, X is a moiety derived from L-carnitine, or a derivative or analog thereof selected from Table 4. In certain embodiments of the compound, X is a moiety derived from metformin, or a derivative or analog thereof selected from Table 5.

[0160] In certain embodiments of the method, X is a moiety derived from berberine, or a derivative or analog thereof, and Z is a bile acid, or a derivative or analog thereof.

[0161] In certain embodiments of the method, X is a moiety derived from berberine, or a derivative or analog thereof, and Z is a fatty acid, or a derivative or analog thereof.

[0162] In certain embodiments of the pharmaceutical composition, X is a moiety derived from L-carnitine, or a derivative or analog thereof, and Z is a bile acid, or a derivative or analog thereof.

[0163] In certain embodiments of the method, X is a moiety derived from L-carnitine, or a derivative or analog thereof, and Z is a fatty acid, or a derivative or analog thereof.

[0164] In certain embodiments of the method, X is a moiety derived from metformin, or a derivative or analog thereof, and Z is a bile acid, or a derivative or analog thereof.

[0165] In certain embodiments of the method, X is a moiety derived from metformin, or a derivative or analog thereof, and Z is a fatty acid, or a derivative or analog thereof.

[0166] In certain embodiments of the method, Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from berberine. In certain embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from L-carnitine. In certain embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid and X is a moiety derived from one of metformin, coptisine, palmatine and jatrorrhizine.

[0167] In certain embodiments of the compound, Z is a moiety derived from ursodeoxycholic acid, or a derivative or analog thereof, and X is a moiety derived from an unsaturated fatty acid. In certain embodiments of the compound, the unsaturated fatty acid is selected from Table 6.

[0168] In certain embodiments of the method, the linker includes an amide bond or an ester bond. In certain preferred embodiments, the linker includes an amide bond. In certain embodiments, the linker includes a moiety derived from an amino acid selected from Table 6. In certain preferred embodiments, the linker includes an ester bond.

[0169] In certain embodiments of the method, the pharmaceutical composition further includes one or more of vitamin E, omega-3 fatty acids, S-adenosylmethionine, N-acetyl cysteine, silymarin, polyenylphosphatidylcholine, resveratrol, and vitamin D.

[0170] In this specification and the appended claims, the singular forms a, an, and the include plural reference, unless the context clearly dictates otherwise.

[0171] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.

INCORPORATION BY REFERENCE

[0172] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

EQUIVALENTS

[0173] The representative examples disclosed herein are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.