HK1142611B - 23-substituted bile acids as tgr5 modulators and methods of use thereof - Google Patents
23-substituted bile acids as tgr5 modulators and methods of use thereof Download PDFInfo
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Description
Technical Field
The present invention relates to compounds capable of modulating TGR5 and compositions that can be used effectively in methods of treatment and/or prevention of various diseases.
Background
The TGR5 receptor is a class of G-protein coupled receptors that have been identified as cell surface receptors that respond to bile acids. In TGR5 of humans, cows, rabbits, rats, and mice, the primary structure of TGR5 and its response to bile acids has been found to be highly conserved, and thus TGR5 is proposed to have an important immunological function. It has been found that TGR5 is not only widely distributed in lymphoid tissues, but also widely distributed in other tissues. High levels of TGR5 mRNA have been detected in placenta, spleen, monocytes/macrophages. Bile acids have been shown to induce internalization of the TGR5 fusion protein from the cell membrane to the cytoplasm. TGR5 has been found to be equivalent to hGPCR19 reported by Takeda et al in FEBS Lett.520, 97-101 in 2002.
Bile acids are metabolites of cholesterol, which are formed in the liver and secreted in the duodenal segment of the intestine. Bile acids are a class of compounds that play a substantial role in the absorption of dietary lipids and in the regulation of bile acid synthesis. For example, Farnesoid X Receptor (FXR) and Pregnane X Receptor (PXR) have recently been identified as specific nuclear receptors for bile acids. Bile acids inhibit the expression of the rate-limiting enzyme in bile acid synthesis through the activation of farnesoid X receptors, wherein the rate-limiting enzyme is cholesterol 7 a-hydroxylase (Cyp7 a). The activation of pregnane X receptors by bile acids triggers both the expression of the cholesterol 7 a-hydroxylase and the transcriptional induction of the bile acid metabolizing enzyme cytochrome P4503a (transcriptional induction). Bile acids at high concentrations are also known to exhibit immunosuppressive effects on cell-mediated immunity and macrophage function. Bile acids include deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), which have been shown to have inhibitory activity against Lipopolysaccharide (LPS) -induced elevation of cytokines present in macrophages, including Interleukin (IL) -1, interleukin-6, and tumor necrosis factor alpha (TNF α).
Bile acid compounds capable of modulating TGR5 have been used in the treatment of various diseases, including central nervous diseases and inflammatory diseases (see WO 01/77325 and WO 02/84286). In particular, bile acid compounds which are alkylation products at position 6 of cholanic acid as farnesoid X receptor agonists have been disclosed in WO 02/072598, WO2004/0007521, and EP 1568706. The bile acid compound 23-methyl-ursodeoxycholic acid (3-alpha, 7-beta-dihydroxy-5-beta-cholestane-24-oic acid) has also been disclosed (see Hepatology 1998, 8(6), 1571-1576) as being useful in the treatment of cholestatic liver diseases.
Cholesterol acid
TGR5 modulators provide methods for modulating the homeostasis of bile acids and cholesterol, fatty acid absorption, and protein and carbohydrate digestion. There is a need to study the use of TGR5 modulators in methods of treatment and/or prevention of various diseases. The present invention has identified compounds that modulate TGR5 and methods of using these compounds in the treatment of diseases such as central nervous system diseases, inflammatory diseases, and metabolic diseases such as obesity and insulin sensitivity. Methods of using the compounds of the invention also include methods of preventing diseases such as central nervous system disorders, inflammatory diseases, and metabolic disorders, e.g., metabolic syndrome, type 2 diabetes, obesity, and the like.
Disclosure of Invention
The present invention relates to TGR5 modulators and the use of said modulators for the treatment and/or prevention of various diseases.
In one aspect, the invention relates to a compound represented by formula a:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: r1Is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen; r2Is hydrogen or is alpha-hydroxy; r3Is hydrogen, hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, substituted or unsubstituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen, unsubstituted or substituted alkyl, or R5And R6Together form a ring of 3 atoms, 4 atoms, 5 atoms, or 6 atoms through the carbon atoms that link them together; r7Is hydrogen, substituted or unsubstituted alkyl, or hydroxy; r8Is hydrogen, substituted or unsubstituted alkyl; r9Is hydrogen, substituted or unsubstituted alkyl or R8And R9Together form a carbonyl group; r10Is R3，SO3H; m is an integer of 0, 1, 2, 3, 4, or 5, and n is an integer of 0, 1, 2, 3, 4, or 5. In one aspect, when R5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
In one aspect of the invention, R1Is hydrogen or hydroxyl. R1Is a hydroxyl group. R1Is hydrogen. R2Is an alpha-hydroxy group. R1Is hydroxy and R2Is an alpha-hydroxy group. R1Is hydroxy and R2Is hydrogen. R1Is hydroxy and R2Is hydrogen. R1Or R2At least one of which is a hydroxyl group. R1Or R2Is hydrogen. R1And R2Are the same. R1And R2Respectively alpha-hydroxy. R1And R2Respectively hydrogen.
In another aspect of the invention, R10Is R3。R3Is hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H。R3Is a hydroxyl group. R3Is not a hydroxyl group. R3Is NH (CH)2)mSO3H。R3Is NH (CH)2)mSO3H and m is 2. R3Is NH (CH)2)nCO2H。R3Is NH (CH)2)nCO2H and n is 1.
In another aspect of the invention, R4Is hydrogen or unsubstituted alkyl. R4Is hydrogen. R4Is unsubstituted alkyl. R4Is unsubstituted alkyl. R4Is methyl or ethyl. R4Is methyl. R4Is ethyl. R3And R4Are the same. R3And R4Is different. R3And R4Respectively hydrogen. R3Is hydroxy and R4Is hydrogen. R3Is NH (CH)2)mSO3H and R4Is hydrogen. R3Is NH (CH)2)mSO3H，R4Is hydrogen and m is 2. R3Is NH (CH)2)nCO2H and R4Is hydrogen. R3Is NH (CH)2)nCO2H，R4Is hydrogen and n is 1. R3Is hydrogen and R4Is unsubstituted alkyl. R3Is hydroxy and R4Is methyl. R3Is hydroxy and R4Is ethyl. R3Is hydroxy and R4Is methyl.
In another aspect, R5Is unsubstituted or substituted alkyl. R5Is of S-configuration. R5Is of the R configuration. R5Is methyl or ethyl. R5Is S-methyl. R5Is R-methyl. R5Is an S-ethyl group. R5Is R-ethyl. R5Is a substituted alkyl group substituted with a phenyl group. R5Is benzyl. R5Is S-benzyl. R5Is R-benzyl. R5Is an aryl group. R5Is phenyl. R4And R5Each unsubstituted alkyl group. R4And R5Are each unsubstituted alkyl, wherein R is5Is of S-configuration and R4Is of the alpha-configuration. R4And R5Are each unsubstitutedAlkyl and R1Is a hydroxyl group. R4And R5Are each unsubstituted alkyl and R2Is hydrogen. R4And R5Are each unsubstituted alkyl, R1Is hydroxy, and R2Is hydrogen.
In one aspect of the invention, R1、R2、R3And R4Is hydrogen. R2、R3And R4Is hydrogen. R2And R3Is hydrogen. R1、R2、R3Or R4Is hydrogen. R1、R2、R3Or R4At least two of which are hydrogen. R1、R2、R3Or R4At least three of which are hydrogen. R1、R2、R3Or R4At least four of which are hydrogen.
In one aspect of the invention, R1、R2And R4Is hydrogen and R3Is a hydroxyl group. R2And R4Is hydrogen and R3Is a hydroxyl group. R2Is hydrogen and R3Is a hydroxyl group. R1、R2Or R4Is hydrogen and R3Is a hydroxyl group. R1、R2Or R4Is hydrogen and R3Is a hydroxyl group. R1、R2And R4All are hydrogen and R3Is a hydroxyl group. R1、R2And R4Is hydrogen and R3Is a hydroxyl group.
In another aspect of the invention, R1Or R7At least one of which is an unsubstituted alkyl group. R1Or R7At least one of which is methyl. R1Or R7At least one of which is ethyl. R1Or R7At least one of which is propyl. R1Is methyl. R1Is ethyl, R1Is propyl. R7Is methyl. R7Is ethyl. R7Is propyl. R1And R7Are both unsubstituted alkyl groups. R1And R7Are both methyl groups. R1And R7Are all ethyl groups. R7Is hydrogen. R7Is a hydroxyl group. R1Is hydrogen. R1Is a hydroxyl group. R1Or R7Is unsubstituted alkyl and R1Or R7The other of (a) is hydrogen. R1Or R7Is unsubstituted alkyl and R1Or R7The other of (a) is a hydroxyl group. R1Or R7At least one of which is unsubstituted alkyl and R5Is unsubstituted or substituted alkyl. R1Or R7At least one of which is methyl and R5Is methyl. R7Is hydroxy and R1And R5Are both unsubstituted alkyl groups. R1Is hydroxy and R7And R5Are both unsubstituted alkyl groups. R1Or R7At least one of which is unsubstituted alkyl and R5Is unsubstituted or substituted alkyl, further wherein R5Is of S-configuration. R1Or R7At least one of which is unsubstituted alkyl and R5Is unsubstituted or substituted alkyl, further wherein R5Is of the R-configuration.
In another aspect, R1Is hydroxy and R7Is methyl. R1Is methyl and R7Is a hydroxyl group. R6Is unsubstituted alkyl. R6Is methyl. R6Is ethyl. R6Is propyl.
In another aspect, R8Is hydrogen. R8Is unsubstituted alkyl. R8Is methyl. R8Is ethyl. R8Is propyl. R2Is alpha-hydroxy and R8Is unsubstituted alkyl. In another aspect, R8And R9A carbonyl group is formed.
In one aspect, R10Is R3。R3Is a hydroxyl group. R8Or R9Is hydrogen. R8And R9Are all hydrogen. R8Or R9At least one of which is an unsubstituted alkyl group. R8Or R9At least one of which is methyl. R8Or R9At least one of which is ethyl. In another aspect, R10Is SO3H。
In another aspect of the invention, when R2、R4And R6Are each hydrogen, R3Is hydroxy, and R1And R7When one of them is hydrogen or hydroxy, then R1Or R7The other of which is not methyl. In another aspect, when R2Is an alpha-hydroxy group; r3Is a hydroxyl group; r4And R6Are each hydrogen; and R is1And R7When one of them is hydrogen or hydroxy, then R1Or R7The other of which is not methyl. In another aspect, the invention does not include the following compounds: 3 α, 7 α -dihydroxy-7 α 0-methyl-5 α 2-cholanic acid, 3 α 1, 7 α 5-dihydroxy-7 α 3-methyl-5 α 9-cholanic acid, 3 α 4-hydroxy-7 β 3-methyl-5 β -cholanic acid, 3 α 6, 7 β 0, 12 α 7-trihydroxy-7 α 8-methyl-5 β 4-cholan-24-oic acid; 3 β 1, 7 β 2, 12 α -trihydroxy-7 β -methyl-5 β -cholestane-24-oic acid; and 3 alpha, 12 alpha-dihydroxy-7 epsilon-methyl-5 beta-cholestane-24-oic acid.
In another aspect of the invention, when R3Is hydroxy and R1And R7One of which is methyl and R1And R7When the other of (A) is hydrogen or hydroxy, then R is2、R4And R6Not all are hydrogen. In another aspect, when R2Is alpha-hydroxy, R3Is hydroxy, and R1And R7One of which is methyl and R1And R7When the other of (A) is hydrogen or hydroxy, then R is4And R6Not all are hydrogen.
The present invention includes a method of treating a disease in a host comprising administering to a host in need thereof a compound of formula a. The present invention includes the use of a compound of formula a, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for the manufacture of a pharmaceutical formulation for the treatment and/or prevention of a disease involving modulation of the TGR5 receptor, said use comprising administering said compound to a host in need thereof. The present invention includes a composition comprising a compound of formula a, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient.
In one aspect of the invention, there is provided a compound of formula I:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R is1Is hydrogen, hydroxy, or halogen; r2Is hydrogen or is alpha-hydroxy; r3Is hydrogen, hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, unsubstituted or substituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen or R5And R6The carbon atoms that join them together form a ring having 3 atoms, 4 atoms, 5 atoms, or 6 atoms; m is an integer of 0, 1, 2, 3, 4, or 5; and n is an integer of 0, 1, 2, 3, 4, or 5. In one aspect, when R5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
In bookIn one aspect of the invention, R1Is hydrogen or hydroxy. R1Is an alpha-hydroxy group. R1Is a beta-hydroxy group. R2Is an alpha-hydroxy group. R1Is beta-hydroxy and R2Is an alpha-hydroxy group. R1Is beta-hydroxy and R2Is hydrogen. R1Is alpha-hydroxy and R2Is hydrogen. R1And R2Respectively alpha-hydroxy. R1And R2Respectively hydrogen.
In another aspect of the invention, R3Is hydrogen, hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H。R3Is a hydroxyl group. R3Is not a hydroxyl group. R3Is NH (CH)2)mSO3H。R3Is NH (CH)2)mSO3H and m is 2. R3Is NH (CH)2)nCO2H。R3Is NH (CH)2)nCO2H and n is 1.
In another aspect of the invention, R4Is hydrogen or unsubstituted alkyl. R4Is hydrogen. R4Is unsubstituted alkyl. R4Is methyl or ethyl. R3And R4Are the same. R3And R4Is different. R3And R4Respectively hydrogen. R3Is hydroxy and R4Is hydrogen.
In another aspect of the invention, R3Is NH (CH)2)mSO3H and R4Is hydrogen. R3Is NH (CH)2)mSO3H，R4Is hydrogen and m is 2. R3Is NH (CH)2)nCO2H and R4Is hydrogen. R3Is NH (CH)2)nCO2H，R4Is hydrogen and n is 1. R3Is hydroxy and R4Is an alkyl group. R3Is hydroxy and R4Is unsubstituted alkyl. R3Is hydroxy and R4Is methyl.
In another aspect of the invention, R5Is unsubstituted or substituted alkyl. R5Is of S-configuration. R5Is of the R configuration. R5Is methyl or ethyl. R5Is S-methyl. R5Is R-methyl. R5Is an S-ethyl group. R5Is R-ethyl. R5Is an alkyl group substituted with an aryl group. R5Is an alkyl group substituted with a phenyl group. R5Is benzyl. R5Is S-benzyl. R5Is R-benzyl. R5Is an aryl group. R5Is phenyl.
In another aspect of the invention, R4And R5Each unsubstituted alkyl group. R4And R5Are each unsubstituted alkyl and R5Is in the S-configuration. R4Is unsubstituted alkyl and R5Is a substituted alkyl group. R4And R5Are each unsubstituted alkyl and R1Is an alpha-hydroxy group. R4And R5Are each unsubstituted alkyl and R2Is hydrogen. R4And R5Are each unsubstituted alkyl, R1Is alpha-hydroxy, and R2Is hydrogen.
In another aspect of the invention, R1、R2、R3And R4Is hydrogen. R2、R3And R4Is hydrogen. R2And R3Is hydrogen. R1、R2And R4Is hydrogen and R3Is a hydroxyl group.
In another aspect of the invention, R1、R2、R3Or R4Is hydrogen. R1、R2、R3Or R4At least two of which are hydrogen. R1、R2、R3Or R4At least three of which are hydrogen. R1、R2、R3Or R4Is hydrogen.
In another aspect of the invention, R1、R2Or R4Is hydrogen and R3Is a hydroxyl group. R1、R2Or R4Is hydrogen and R3Is a hydroxyl group. R1、R2Or R4All are hydrogen and R3Is a hydroxyl group.
Another aspect of the invention includes a composition or pharmaceutical formulation comprising a compound of formula I.
Or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient, wherein R is1Is hydrogen, hydroxy, or halogen; r2Is hydrogen or is alpha-hydroxy; r3Is hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, unsubstituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen or R5And R6The carbon atoms that join them together form a ring having 3 atoms, 4 atoms, 5 atoms, or 6 atoms; m is an integer of 0, 1, 2, 3, 4, or 5; and n is an integer of 0, 1, 2, 3, 4, or 5. In one aspect the invention comprises a composition or pharmaceutical formulation comprising a compound of formula I having the following provisos when R is5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
Another aspect of the present invention includes a method of treating a disease in a host, comprising administering to a host in need thereof a therapeutically effective amount of a compound of formula I, formula IA, formula II, and formula a. Another aspect of the present invention includes a method of preventing a disease in a host, comprising administering to a host in need thereof a prophylactically effective dose of a compound of formula I, formula IA, formula II, and formula a. The present invention includes treatment and/or prevention of diseases involving modulation of the TGR5 receptor. The invention includes the use of compounds of formula a, formula I, formula IA, and formula II for the preparation of pharmaceutical formulations for the treatment and/or prevention of diseases in which modulation of the TGR5 receptor is implicated. In one aspect, the disease is a metabolic disorder, including obesity and insulin sensitivity. In another aspect, the disease is an inflammatory disease, including rheumatoid arthritis and allergy. In another aspect, the disease is cholestasis or bile desaturation. The present invention includes the case where the host is a human.
The invention also relates to compounds of formula IA and formula II:
and
r in the above formula IA1，R2，R3，R4，R5，R6，R7And R8And R in the above formula II1，R2，R4，R5，R6，R7And R8As described hereinafter. The invention relates to a composition or a pharmaceutical preparation of a compound shown as a formula IA or a formula II. The invention includes the use of compounds of formula I, formula IA, formula a, and formula II for the preparation of pharmaceutical compositions for the treatment and/or prevention of disease states in which modulation of TGR5 is implicated.
The foregoing has outlined rather broadly the more important features of the present invention in order that the detailed description that follows may be better understood, and in order that the present contribution to the art may be better appreciated. Other objects and features of the present invention will become apparent from the following detailed description considered in conjunction with the described embodiments.
Detailed Description
The details of one or more embodiments of the invention are set forth in the description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description that follows. In the specification, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification will control.
Definition of
For convenience, certain terms used in the specification, examples, and appended claims are summarized here.
The term "treating," as used herein, refers to alleviating, reducing, eliminating, modulating, or ameliorating the disease state or condition, i.e., causing a decrease in the disease state or condition.
The term "preventing", as used herein, means completely terminating or substantially completely terminating a disease state or condition occurring in a patient or host, particularly when the patient or host has been previously exposed to the disease state or condition, or the patient or host is at risk of contracting the disease state or condition. Prevention may also include inhibiting, i.e., terminating the development of, a disease state or condition, and alleviating or ameliorating the disease state or condition, i.e., causing a decline in the disease state or condition, e.g., when the disease state or condition already exists.
"alkyl" includes saturated aliphatic groups, including straight chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched chain alkyl groups (e.g., isopropyl, t-butyl, isobutyl), cycloalkyl (e.g., alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight or branched chain alkyl group has six or fewer carbon atoms in its backbone (e.g., C for straight chain)1-C6For a branched chain is C3-C6). In some embodiments, a straight or branched alkyl group has four or fewer carbon atoms in its backbone. Further, cycloalkyl groups have three to eight carbon atoms in their ring structure.
The term "substituted alkyl" refers to an alkyl moiety having a substituent on one or more hydrogen atoms on at least one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate (phosphonato), phosphinate (phosphonato), cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureide), amidino, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azide, heterocycle, alkylaryl, or an aromatic or heteroaromatic moiety.
"aryl" includes groups with aromatic character, including five or six membered "nonconjugated", or monocyclic aromatic groups, which may include zero to four heteroatoms, and also includes "conjugated", or polycyclic systems having at least one aromatic ring. Examples of aryl groups include benzene, phenyl, pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyridazinyl, and pyrimidinyl, and the like. Furthermore, the term "aryl" includes polycyclic aryl groups, e.g., tricyclic groups, bicyclic groups, e.g., naphthyl, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinolinyl, isoquinolinyl, naphthyridinyl, indolyl, benzofuran, purine, benzofuran, azapurine, or indolizine (indolizine). Those aryl groups having heteroatoms in their ring structure may also be referred to as "aryl heterocycles," isoaryls, "or" isoaromatics. The aromatic ring may be substituted at least one ring position with a substituent as described above, for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and acylurea), amidino, imino, mercapto, alkylthio, arylthio, a thiocarboxylate salt, a sulfate salt, an alkylsulfinyl group, a sulfonic group, a sulfamoyl group, a sulfonamide group, a nitro group, a trifluoromethyl group, a cyano group, an azide group, a heterocycle, an alkylaryl group, or an aromatic or heteroaromatic moiety. The aryl group may also be fused or bridged to an aliphatic or heterocyclic ring which is not aromatic, thereby forming a polycyclic ring system (e.g., tetralin, methylenedioxyphenyl).
Unless the number of carbon atoms is specifically stated otherwise, "lower alkyl" includes alkyl groups as described above, but which have from one to ten carbon atoms, e.g., from one to six carbon atoms, in the backbone structure.
The term "alkoxy" includes alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups (or alkoxy radicals) include methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy groups.
The term "ether" includes such compounds or moieties: which contains an oxygen atom in combination with two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" groups, which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom, which is also covalently bonded to another alkyl group.
The term "ester" includes such compounds or moieties: which contains a carbon or heteroatom bound to an oxygen atom that is bound to a carbon atom in a carbonyl group. The term "ester" includes alkoxycarboxyl groups such as methoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and the like. The alkyl, alkenyl, or alkynyl groups are as defined above.
The term "Hydroxy "includes having-OH or-O-A group of (1).
The term "halogen" includes fluorine, bromine, chlorine, iodine, and the like. The term "perhalogenated" generally refers to moieties in which all hydrogen atoms are replaced with halogen atoms.
As used herein, "anionic group" refers to a group that is negatively charged at physiological pH. Anionic groups include carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate, or thiophosphate or functional equivalents of the foregoing groups. "functional equivalents" of anionic groups are intended to include bioisosteres, e.g., bioisosteres of carboxylate groups. Bioisosteres include classical bioisosteres equivalents as well as non-classical bioisosteres equivalents. Classical bioisosteres as well as non-classical bioisosteres are known in The art (see, e.g., The literature published in Silverman, R.B. 1992 in The Organic Chemistry of Drug Design and Drug action, Academic Press, Inc.: San Diego, Calif. (California), pp.19-23). Another anionic group is carboxylate.
The term "labile functionality" refers to a type of substitution that contains a labile linkage, e.g., a functionality or bond that is susceptible to hydrolysis or cleavage under physiological conditions (e.g., aqueous solutions in a neutral pH range). Examples of labile functionalities include acetals as well as ketals.
The term "crystalline polymorph" or "polymorph" refers to a compound, or a salt or solvate thereof, in which more than one crystalline form is present. Crystalline polymorphs of the bile acid analog compounds can be prepared by crystallization under various conditions.
In addition, the compound described in the present invention, for example, a salt of the compound, may exist in a hydrated form or a non-hydrated (anhydrous) form, or may exist in a solvated form together with other solvent molecules. Non-limiting examples of hydrates include monohydrate, dihydrate, and the like. Non-limiting examples of solvates include solvates of ethanol, solvates of acetone, and the like.
"solvate" refers to a form of addition of a solvent containing either stoichiometric or non-stoichiometric amounts of the solvent. Certain compounds have a tendency to trap a fixed molar ratio of solvent molecules in their crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate, and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed as a result of the binding of one or more water molecules to a substrate in which the water remains in its molecular state H2O, such combination being capable of forming one or more hydrates.
It is worth noting that some of the compounds described herein include symmetrical carbon atoms in their structure. It is therefore to be understood that, unless otherwise indicated, such isomers (e.g., all enantiomers as well as diastereomers) resulting from such symmetry are included within the scope of the invention. Such isomers can be obtained in essentially pure form by classical separation techniques as well as by stereochemically controlled synthesis. Enantiomers (R-configuration as well as S-configuration) are named according to the system established by r.s.cahn, c.ingold and v.prelog.
Further, the structures and other compounds discussed in this application include all atropisomers thereof. Atropisomers are a type of stereoisomer in which the atoms of the two isomers have different spatial arrangements. The existence of atropisomers is attributed to the inhibition of rotation which is caused by the inhibition of rotation of the bulky group along the central bond. Such atropisomers are usually present as mixtures, however due to recent developments in chromatographic techniques it has become possible to separate mixtures of two atropisomers in selected situations.
"stable compound" and "stable structure" are intended to indicate that a compound is sufficiently robust to survive isolation from the reaction mixture in an effective degree of purity and formulation as an effective therapeutic agent.
The term "analog" as used herein refers to a chemical compound that: it is structurally similar to another chemical compound, but differs somewhat in composition (either by the substitution of one atom with a different elemental atom, the presence of a particular functional group, or the substitution of one functional group with another). Thus, an analog refers to a compound that is similar or equivalent in function and appearance to a control compound.
The term "derivative" as used herein, for example, in the term "bile acid derivative", refers to compounds having a common core four-membered ring structure and which are substituted with the various groups described herein.
The term "bioisostere" refers to compounds that: which results from the exchange of one atom or group of atoms with another, broadly similar atom or group of atoms. The bioisosteric replacements may be physicochemical based or topologically based. Examples of bioisosteres of carboxylic acids include acylsulfimides, tetrazolyls, sulfonates, and phosphates. See, for example, the literature published by Patani and La Voie (1996) in chem. rev., chemical review, 96, 3147-3176.
"combination therapy" (or "co-therapy") includes the administration of a compound of the invention and at least one second agent as a specific treatment regimen intended to provide a beneficial effect through the combined action of these therapeutic agents (i.e., the compound of the invention and the at least one second agent). The beneficial effects of the combinations include, but are not limited to, the combined pharmacokinetic and pharmacodynamic effects of the combinations of the therapeutic agents. The combined administration of these therapeutic agents is typically completed over a specified period of time (typically minutes, hours, days or weeks depending on the combination selected). "combination therapy" may, but is not generally intended to, encompass the administration of two or more such therapeutic agents as part of separate monotherapy regimens, thereby allowing for the concomitant and arbitrary formation of the combinations described herein. "combination therapy" is intended to include the administration of the therapeutic agents in a sequential manner, i.e., each of the therapeutic agents is administered at a different time, as well as the administration of the therapeutic agents in a substantially simultaneous manner, or the administration of at least two of the therapeutic agents. Substantially simultaneous administration may be accomplished, for example, by: administering to said host a single capsule containing a fixed ratio of each therapeutic agent, or administering to said host a plurality of capsules each containing one of said therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent may be effected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination may be administered by intravenous injection, while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. The order of administration of these therapeutic agents is not strictly limited.
"combination therapy" also includes the administration of the therapeutic agents described above in further combination with other bioactive ingredients and non-drug therapies (e.g., surgical or mechanical therapies). When the combination therapy further includes a non-drug treatment, the non-drug treatment can be carried out at any suitable time as long as the beneficial effects of the combination of the therapeutic agent and the non-drug treatment are achieved. For example, the beneficial effect can still be achieved when the non-drug treatment is temporarily stopped from the administration of the therapeutic agent, where the stop may be several days or even weeks, as appropriate.
The terms "parenteral administration" and "parenteral administration" as used herein refer to forms of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intracameral, intracardiac, intradermal, intraperitoneal, ventilation, subcutaneous, sub-cuticular, intraarticular, subcapsular, subarachnoid, intraspinal injection and forms of fusion.
The term "pulmonary" as used herein refers to any part, tissue or organ of a patient's body that primarily functions to exchange gas with the external environment, such as oxygen/carbon dioxide. "pulmonary" generally refers to the tissues in the respiratory tract in question. Thus, the term "pulmonary administration" refers to the administration of the formulation described in this invention into any part, tissue or organ whose primary function is gas exchange with the external environment (e.g., mouth, nose, pharyngeal cavity, oropharynx, pharyngeal door, laryngeal opening, trachea, carina, bronchi, bronchioles, alveoli). For the purposes of the present invention, "pulmonary" also includes tissues or cavities that are incidentally connected to the respiratory tract (continent to), specifically, a sinus.
The term "effective amount" refers to a "therapeutically effective amount" and/or a "prophylactically effective amount".
A "therapeutically effective dose" of a compound or composition of compounds of the invention refers to the dose (mass or concentration) of the compound. In one embodiment, the symptoms caused by the disease are ameliorated immediately upon administration of the compound to a host in need of treatment at a therapeutically effective dose or after one or more administrations of the compound. The dose of the compound to be administered to a host will depend on the particular disease, the mode of administration, the co-administered compound, if any, and the characteristics of the host, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. It will be within the ability of one skilled in the art to determine the appropriate dosage based on these and other factors.
The term "prophylactically effective amount" refers to an amount (by mass or concentration) of a compound of the invention or a composition of compounds that prevents or reduces the risk of disease when administered-in other words, a "prophylactically effective amount" refers to an amount that is required to provide a prophylactic or preventative effect. The dosage of the compounds of the invention to be administered to a host will depend on the particular disease, the mode of administration, the co-administered compound, if any, and the characteristics of the host, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. It will be within the ability of one skilled in the art to determine the appropriate dosage based on these and other factors.
The term "reduced risk" as used herein refers to a reduction in the likelihood or probability that a central nervous system disease, inflammatory disease and/or metabolic disease will occur in a patient, particularly when the patient or host has been previously exposed to such an environment.
"pharmaceutically acceptable salts" or "salts" of the compounds of the present invention refer to the products of the compounds which contain an ionic bond, and which are generally prepared by reacting the compounds with an acid or base which is suitable for administration to a host.
"composition" refers to a formulation containing a compound of the invention in a form suitable for administration to a host. In another embodiment, the pharmaceutical composition is in bulk (in bulk) or is in unit dosage form. The unit dosage form is any of a variety of different forms, including, for example, a capsule, an Intravenous (IV) bag, a tablet, a single-flow pump on an aerosol spray, or a vial. The amount of active ingredient (e.g., a formulation of a compound of the invention or a salt thereof) in a unit dose of the composition is an effective dose and will vary according to the particular treatment involved. Those skilled in the art will recognize that routine variations in the dosage described are sometimes necessary depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like. Dosage forms of the compounds of the present invention for topical or transdermal administration include powders, sprays, ointments, patches, creams, lotions, gels, solutions, tablets and inhalants. In another embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
The term "flash dose" refers to a preparation of a compound in a rapidly dispersing dosage form.
The term "immediate release" is defined as the ability of a compound to be released from a dosage form over a relatively brief period of time, typically amounting to about 60 minutes. The term "modified release" is defined to include delayed release, extended release, and pulsed release. The term "pulsatile release" defines a cascade of drug release from a dosage form. The term "sustained release" or "extended release" defines a continuous release of a compound from a dosage form over an extended period of time.
"host" includes mammals, e.g., humans, companion animals (e.g., dogs, cats, birds, and the like), farm animals (e.g., cattle, sheep, pigs, horses, poultry, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, birds, and the like). Typically, the host is a human.
The compounds of the present invention also include prodrugs or physiologically equivalent derivatives. "prodrug" or "physiologically equivalent derivative" includes precursor forms of the drug that are metabolically converted in vivo to produce the active drug. The invention further contemplates The use of such prodrugs which are capable of being converted in vivo to TGR5 modulatory compounds for use in The methods of The invention (see, e.g., r.b. silverman, 1992, in "The organic chemistry of Drug Design and Drug Action", Academic Press, chapter 8 (chp.8)). Such prodrugs can be used to alter the biodistribution (e.g., may allow compounds that are not normally able to cross the blood-brain barrier) or pharmacokinetic properties of the TGR 5-modulating compound. For example, an anionic group, such as carboxylate, sulfate, or sulfonate, can be esterified with, for example, an alkyl group (e.g., methyl group) or phenyl group, thereby forming an ester. When the ester is administered to a host, the ester is cleaved enzymatically or non-enzymatically, reductively or hydrolytically, thereby exposing the anionic group. Such esters may be cyclic, e.g., cyclic sulfates or sulfonates, or two or more anionic moieties may be esterified via a linking group. The anionic group can undergo an esterification reaction with a moiety (e.g., acetoxymethyl ester) which cleaves to expose the intermediate TGR5 modulatory compound which is subsequently decomposed to yield the active TGR5 modulatory compound. In one embodiment, the prodrug is a carboxylate, sulfate or sulfonate in the form of a reducing species, e.g., an alcohol or thiol, which is oxidized in vivo to form the TGR5 modulatory compound. Furthermore, the anionic moiety may be esterified to such groups: the group can be actively transported in vivo, or the group can be selectively absorbed by a target organ.
The term "amino acid conjugate" as used herein refers to the conjugate product of a compound of formula I, formula IA, and formula a with any suitable amino acid. Taurine (NH (CH)2)SO3H) And glycine (NHCH)2CO2H) Are examples of amino acid conjugates. Suitable amino acid conjugates of the compounds of formula I, formula IA, and formula a above have the additional advantage of enhancing the integrity of bile or intestinal fluids. Suitable amino acids are not limited to taurine and glycine. The invention includes amino acid conjugates of the compounds of formula I, formula IA, and formula A described above.
The term "TGR 5 modulator" refers to any compound that is capable of reacting with the TGR5 receptor. The response is not limited to the compound acting as an antagonist, agonist, local agonist, or inverse agonist of the TGR5 receptor. In one aspect, the compounds of the invention act as antagonists of the TGR5 receptor. In another aspect, the compounds of the invention act as agonists at the TGR5 receptor. In another aspect, the compounds of the invention act as local agonists at the TGR5 receptor. In another aspect, the compounds of the invention act as inverse agonists at the TGR5 receptor. Traditionally, the profile (profile) of an endogenous ligand or synthetic ligand was defined by its intrinsic efficacy 'e', originally described by Furchgott in 1966. It is used to express the extent of different biological responses that different ligands produce when they possess the same number of receptors. In general, the term "agonist" refers to a compound that enhances the activity of another molecule or receptor site. In the classical definition, an agonist, whether an orthosteric agonist, an allosteric agonist, an inverse agonist, or a synergistic agonist, has the property of binding to the receptor, changing its receptor state, and eliciting a biological response. Thus, agonism is defined as a property of an agonist or ligand to produce a biological response. In contrast, an "antagonist" is an agonist that has essentially a high affinity for the same receptor macromolecule, but has weak or negligible intrinsic potency, and is therefore capable of sterically hindering the biological effects of the agonist. As a property, antagonism can be functional or physiological, in which an agonist first has a direct competitive effect on the receptor site, after which the opposite effect occurs via different receptor-messenger systems. More specifically, a TGR5 agonist is a receptor ligand or compound that binds to TGR5 and increases cyclic adenosine monophosphate (cAMP) concentration in cells expressing the receptor by at least 20%. Conversely, a TGR5 antagonist may be a compound that antagonizes or blocks the activity of the agonist, resulting in a decrease in cyclic adenosine monophosphate concentration.
The term "metabolic disorders" includes, but is not limited to, dyslipidemia, atherosclerosis, obesity, coronary heart disease, stroke, insulin resistance/sensitivity, and diabetes.
The term "inflammatory disease" refers to an inflammatory response that can trigger damage to autologous tissues. Inflammatory diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, cervical spondylosis, cumulative trauma disease, allergy, endometriosis, pelvic inflammatory disease, adhesive peritonitis, appendicitis, pericarditis, and costal meningitis.
The present invention relates to compounds having TGR5 receptor modulating activity and the use of these compounds for the treatment and/or prevention of various diseases including central nervous system diseases, inflammatory diseases, and metabolic diseases such as obesity and insulin sensitivity. Further, the present invention relates to compounds of formula a, formula I, formula IA, and formula II. According to one aspect, the present invention provides a compound of formula I:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: r1Is hydrogen, hydroxy, or halogen; r2Is hydrogen or is alpha-hydroxy; r3Is hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, unsubstituted or substituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen or R5And R6Together form a ring of 3 atoms, 4 atoms, 5 atoms, or 6 atoms through the carbon atoms that link them together; m is an integer of 0, 1, 2, 3, 4, or 5; and n is an integer of 0, 1, 2, 3, 4, or 5. In one aspect, when R5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
In one aspect, the invention provides R in a compound1Is hydrogen or hydroxy. R1Is a hydroxyl group. R1Is hydrogen. R1Is an alpha-hydroxy group. R1Is a beta-hydroxy group.
In another aspect, the invention provides a compound wherein R is1Is a halogen. R1Is fluorine. R1Is alpha-fluoro. R1Is beta-fluoro. The alpha-configuration and the beta-configuration of R1The stereochemical conformation of (a) is as follows:
R1alpha (alpha-) configuration R1beta (beta-) configuration
In another aspect, the invention provides a compound wherein R is2Is an alpha-hydroxy group. R2Is hydrogen. R1Is beta-hydroxy and R2Is an alpha-hydroxy group. R1Is beta-hydroxy and R2Is hydrogen. R1Is alpha-hydroxy and R2Is hydrogen.
In another aspect, the invention provides a compound wherein R is1Or R2At least one of which is a hydroxyl group. In another aspect, R1Or R2Is hydrogen. R1And R2Are the same. R1And R2Respectively alpha-hydroxy. R1And R2Respectively hydrogen.
In another aspect, the invention provides a compound wherein R is3Is hydrogen, hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H。R3Is a hydroxyl group. R3Is not a hydroxyl group. R3Is NH (CH)2)mSO3H. In another aspect, R3Is NH (CH)2)mSO3H and m is 2. R3Is NH (CH)2)nCO2H. In another aspect, R3Is NH (CH)2)nCO2H andn is 1.
In another aspect, R4Is hydrogen or alkyl. R4Is hydrogen. R4Is a lower alkyl group. R4Is a lower alkyl group and said lower alkyl group is in the alpha configuration. R4Being of alpha configuration means R4Has a stereochemistry as shown below.
R4alpha (alpha-) configuration
In another aspect, R4Is a halogen. R4Is fluorine. R4Is halogen and said halogen is in the alpha configuration. R4Is alpha-fluoro.
In another aspect, R4Is methyl or ethyl. R4Is methyl. Is ethyl. R4Is an alpha-methyl group. R4Is an alpha-ethyl group. R3And R4Are the same. R3And R4Is different. R3And R4Respectively hydrogen. R3Is NH (CH)2)mSO3H and R4Is hydrogen. R3Is hydroxy and R4Is hydrogen. In another aspect, R3Is NH (CH)2)mSO3H，R4Is hydrogen and m is 2. R3Is NH (CH)2)nCO2H and R4Is hydrogen. In another aspect, R3Is NH (CH)2)nCO2H，R4Is hydrogen and n is 1.
In another aspect, R3Is hydroxy and R4Is an alkyl group. R3Is hydroxy and R4Is a lower alkyl group. Lower alkyl is in the alpha configuration. R3Is hydroxy and R4Is methyl. R3Is hydroxy and R4Is ethyl. R3Is a hydroxyl groupAnd R is4Is an alpha-methyl group. R3Is hydroxy and R4Is an alpha-ethyl group.
In another aspect, R5Is unsubstituted or substituted alkyl. R5Is unsubstituted or substituted lower alkyl. R5Is of S-configuration. R5Is of the R-configuration. R5Is methyl or ethyl. R5Is S-methyl, R-methyl. R5Is S-ethyl, R-ethyl. R5Is an alkyl group substituted with a phenyl group. R5Is lower alkyl substituted by phenyl. R5Is benzyl. R5Is S-benzyl. R5Is R-benzyl.
In another aspect, R5Is an aryl group. R5Is phenyl.
In another aspect, R4And R5Each unsubstituted alkyl group. R4And R5Each lower unsubstituted alkyl. R4And R5Each is a lower unsubstituted alkyl group and R5Is of S-configuration. R4And R5Each is a lower unsubstituted alkyl group and R4Is of the alpha configuration. In another aspect, R4Is not hydrogen.
In another aspect, R4And R5Each is a lower unsubstituted alkyl group and R1Is an alpha-hydroxy group. R4And R5Each is a lower unsubstituted alkyl group and R2Is hydrogen. R4And R5Each being a lower unsubstituted alkyl radical, R1Is alpha-hydroxy, and R2Is hydrogen.
In another aspect, R5And R6The carbon atoms that join them together form a ring having 3 atoms, 4 atoms, 5 atoms, or 6 atoms. R5And R6The carbon atoms that join them together form a ring having 3 atoms. The third mentionedThe membered ring has the following stereochemistry:the three-membered ring has the following stereochemistry:
in another aspect, R1、R2、R3And R4Is hydrogen. R2、R3And R4Is hydrogen. R2And R3Is hydrogen. In another aspect, R1、R2And R4Is hydrogen and R3Is a hydroxyl group. R2And R4Is hydrogen and R3Is a hydroxyl group. R2Is hydrogen and R3Is a hydroxyl group.
In another aspect, R1、R2、R3Or R4Is hydrogen.
In another aspect, R1、R2、R3Or R4At least two of which are hydrogen.
In another aspect, R1、R2、R3Or R4At least three of which are hydrogen.
In another aspect, R1、R2、R3Or R4Is hydrogen.
In another aspect, R1、R2Or R4Is hydrogen and R3Is a hydroxyl group. In another aspect, R1、R2Or R4Is hydrogen and R3Is a hydroxyl group.
In another aspect, R1、R2Or R4All are hydrogen and R3Is a hydroxyl group.
In another aspect, the invention does not include when R5Is methyl, R4Is hydrogen, and R2A compound that is hydrogen or hydroxyl.
In another aspect of the invention, the compound is selected from the group consisting of compounds Ia, Ib, Ic, Ig, Ih, Ii, Io, Ip, Iq, Ia, Ib, Ic, Ig, Ih, Ii, Il, Im, In, Io, Ip, Iq, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Im, In, Ia, Ib, Ic, Id, Ie, If, Ig, Ii, Ih, 1 Ii, Il, Im, In, Ia, Ib, Ic, Id, Ie, If, Ig, Ii, Ih, Ii, Il, Im and In.
In another aspect of the invention, the compound is not selected from the group consisting of compounds Id, Ie, If, Id1, Il, Im, and In. In another aspect, the compound is not selected from Ie1 and If 1.
In another aspect of the invention, said compounds are capable of modulating the activity of said TGR5 receptor. The present invention includes compounds that are agonists of the TGR5 receptor. In one aspect, the invention includes those compounds that are highly selective for the TGR5 receptor as compared to the Farnesoid X Receptor (FXR) receptor.
Another aspect of the invention includes a composition or pharmaceutical formulation comprising a compound of formula I:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient, wherein R is1Is hydrogen, hydroxy, or halogen; r2Is hydrogen or is alpha-hydroxy; r3Is hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, unsubstituted or substituted alkyl, or halogen; r5Is unsubstituted or substituted lower alkyl, or aryl; r6Is hydrogen or R5And R6Together form a ring of 3 atoms, 4 atoms, 5 atoms, or 6 atoms by linking them together at the carbon atoms; m is an integer of 0, 1, 2, 3, 4, or 5; and n is an integer of 0, 1, 2, 3, 4, or 5. In another aspect, the invention includes a composition or pharmaceutical formulation comprising a compound of formula I, provided that when R is5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
Another aspect of the present invention includes a method of treating and/or preventing a disease in a host, comprising administering to a host in need thereof an effective amount of a compound of formula I:or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: r1Is hydrogen, hydroxy, or halogen; r2Is hydrogen or alpha-hydroxy; r3Is hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, unsubstituted or substituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen or R5And R6The carbon atoms that join them together form a ring having 3 atoms, 4 atoms, 5 atoms, or 6 atoms; m is an integer of 0, 1, 2, 3, 4, or 5; and n is an integer of 0, 1, 2, 3, 4, or 5. The present invention includes methods of treating and/or preventing a disease or condition involving modulation of the TGR5 receptor.
The invention includes a method comprising administering a compound of formula I. The invention includes a method comprising administering a therapeutically effective amount of a compound of formula I. The invention includes a method comprising administering a prophylactically effective dose of a compound of formula I.
In one aspect of the invention, the compound is a modulator of physiology, wherein the physiology is related to TGR5, or the compound is an agent for the prevention or treatment of pathology or disease, wherein the pathology or disease is related to TGR 5. In another aspect, the compound is a glucagon-like peptide (GLP-1) secretion promoter or an insulin secretagogue. In another aspect, the compound is an appetite suppressant agent, pancreatic regenerator (pancreatic regenerator), pancreatic beta cell differentiation promoter, pancreatic beta cell growth promoter or insulin sensitizer. In another aspect, the compound is an agent for preventing or treating heart failure, myocardial infarction, acute renal failure, angina, arrhythmia, bronchial asthma, chronic obstructive pulmonary disease, atherosclerosis, rheumatoid arthritis, diabetes, obesity, insulin hyposecretion, pancreatic fatigue (pancreatic fatigue), gastric ulcer, ulcerative colitis, allergy, osteoarthritis, lupus erythematosus, excessive immune response after transplantation, or an infectious disease, or is an immunosuppressant.
The present invention includes a method of treating a host infected with a disease in which the TGR5 receptor is implicated, wherein the method comprises administering to the host a compound of formula I.
In another aspect, the invention includes a method of treating or preventing a metabolic disorder by administering a compound of the invention. In one aspect, the metabolic disorder is obesity. In another aspect, the metabolic disorder is insulin sensitivity. In another aspect, the metabolic disorder is diabetes. In another aspect, the metabolic disorder is insulin hyposecretion. In another aspect, the metabolic disorder is pancreatic fatigue (pancreatic fatigue).
The invention includes a method of treating or preventing an inflammatory disease by administering a compound of the invention. In one aspect, the inflammatory disease is rheumatoid arthritis. In another aspect, the inflammatory disease is an allergy.
The present invention includes the case where the host is a human.
The invention includes the use of the compounds for the conventional use of known bile acids. The traditional uses of bile acids include the treatment of cholelithiasis, bile desaturation, cholesterol metabolism, and as antioxidants, free radical scavengers, anti-cholestatic agents, endogenetics, anti-metabolic disorders (anti-dysstereogenic), and hepatocyte protectants.
In another aspect, the method comprises administering a compound of formula I, wherein if R is5Is methyl; r1Is a hydroxyl group; and R is3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
In another aspect, the method comprises administering a compound, wherein the compound is selected from the group consisting of: ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Im, In, Io, Ip, Iq, Ia, Ib, Ic, Id1, Ie1, If, Ig, Ih, Ii, Il, Im, In, Io, Ip, Iq, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Im, In, Io, Ip, Iq, Ia, Ib, Ic, Id, If, Ig, Ih, Ii, Ia, Ic, Ii, Ib, Ic, Id, Ie, If, Ig, Ii, Il, Ii, Ia, Ii, and In.
In another aspect, the method comprises administering a compound, wherein the compound is selected from the group consisting of: ia, Ib, Ic, Ig, Ih, Ii, Io, Ip, Iq, Ia, Ib, Ic, Ig, Ih, Ii, Il, Im, In, Io, Ip, Iq, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Im, In, Ia, Ib, Ic, Ii, Ih, In, Ia, If, Ig, Ih, Ii, Il, Im, In, Ia, Ib, Ic, Id, Ii, Ih, Ii, Il, Ii, and In.
In one aspect, the methods described herein do not include administering a compound selected from the group consisting of: id, Ie, If, Id1, Il, Im and In. In another aspect, the methods described herein do not include the administration of Ie1 and If 1.
Another aspect of the invention is a compound of formula I:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient for the manufacture of a pharmaceutical formulation for the treatment and/or prevention of a disease in which modulation of TGR5 is desired, wherein: r1Is hydrogen, hydroxy, or halogen; r2Is hydrogen or alpha-hydroxy; r3Is hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, alkyl, or halogen; r5Is unsubstituted or substituted lower alkyl, or aryl; r6Is hydrogen or R5And R6The carbon atoms that join them together form a ring having 3 atoms, 4 atoms, 5 atoms, or 6 atoms; m is an integer of 0, 1, 2, 3, 4, or 5; and n is an integer of 0, 1, 2, 3, 4, or 5. At the other oneIn one aspect, the invention includes the use for the preparation of a pharmaceutical formulation for the treatment and/or prevention of a disease in which modulation of TGR5 is desired, in which use a compound of formula I is used, with the proviso that when R is5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
The invention also provides a radiolabeled compound of formula I. Radiolabelled compounds of formula I may be prepared using conventional techniques. For example, the following method can be used: reacting a compound of formula I with tritium gas in the presence of a suitable catalyst to produce a radiolabeled compound of formula I. In one embodiment, the compound of formula I is tritium-containing.
Another aspect of the present invention includes compounds of formula IA:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: r1Is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen; r2Is hydrogen or is alpha-hydroxy; r3Is hydroxy, hydrogen, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, substituted or unsubstituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen, unsubstituted or substituted alkyl, or R5And R6The carbon atoms that join them together form a ring having 3 atoms, 4 atoms, 5 atoms, or 6 atoms; r7Is hydrogen, substituted or unsubstituted alkyl, or hydroxy; m is an integer of 0, 1, 2, 3, 4, or 5(ii) a And n is an integer of 0, 1, 2, 3, 4, or 5. In one aspect, when R5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
In one aspect, R1Is hydrogen or hydroxyl. R1Is a hydroxyl group. R1Is hydrogen. R1Is hydroxy and R2Is an alpha-hydroxy group. R1Is hydroxy and R2Is hydrogen. R1Is hydroxy and R2Is hydrogen. R1Or R2At least one of which is a hydroxyl group. R1Or R2Is hydrogen. R1And R2Are the same. R1Is hydroxy and R2Is an alpha-hydroxy group. R1And R2Respectively hydrogen.
In one aspect, R3Is hydrogen, hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H。R3Is a hydroxyl group. R3Is not a hydroxyl group. R3Is NH (CH)2)mSO3H。R3Is NH (CH)2)mSO3H and m is 2. R3Is NH (CH)2)nCO2H。R3Is NH (CH)2)nCO2H and n is 1.
In another aspect, R4Is hydrogen or unsubstituted alkyl. R4Is hydrogen. R4Is unsubstituted alkyl. R4Is unsubstituted alkyl. R4Is methyl or ethyl. R4Is methyl. R4Is ethyl. R3And R4Are the same. R3And R4Is different. R3And R4Respectively hydrogen. R3Is hydroxy and R4Is hydrogen.
In another aspect, R3Is NH (CH)2)mSO3H and R4Is hydrogen. R3Is NH (CH)2)mSO3H，R4Is hydrogen and m is 2. R3Is NH (CH)2)nCO2H and R4Is hydrogen. R3Is NH (CH)2)nCO2H，R4Is hydrogen and n is 1. R3Is hydroxy and R4Is unsubstituted alkyl. R3Is hydroxy and R4Is unsubstituted alkyl. R3Is hydroxy and R4Is methyl. R3Is hydroxy and R4Is ethyl. R3Is hydroxy and R4Is methyl.
In one aspect, R5Is unsubstituted or substituted alkyl. R5Is of S-configuration. R5Is of the R configuration. R5Is methyl or ethyl. R5Is S-methyl. R5Is R-methyl. R5Is an S-ethyl group. R5Is R-ethyl. R5Substituted by phenyl. R5Is benzyl. R5Is S-benzyl. R5Is R-benzyl. In another aspect, R5Is an aryl group. For example, R5Is phenyl.
R4And R5Each unsubstituted alkyl group. R4And R5Each being unsubstituted alkyl, further wherein R5Is of S-configuration. R4And R5Each unsubstituted alkyl group. R4And R5Are each unsubstituted alkyl and R1Is a hydroxyl group. R4And R5Are each unsubstituted alkyl and R2Is hydrogen. R4And R5Are each unsubstituted alkyl, R1Is hydroxy, and R2Is hydrogen.
In one aspect, R1、R2、R3And R4Is hydrogen. R2、R3And R4Is hydrogen. R2And R3Is hydrogen. R1、R2、R3Or R4Is hydrogen. R1、R2、R3Or R4At least two of which are hydrogen. R1、R2、R3Or R4At least three of which are hydrogen. R1、R2、R3Or R4Is hydrogen.
In one aspect, R1、R2And R4Is hydrogen and R3Is a hydroxyl group. R2And R4Is hydrogen and R3Is a hydroxyl group. R2Is hydrogen and R3Is a hydroxyl group. R1、R2Or R4Is hydrogen and R3Is a hydroxyl group. R1、R2Or R4Is hydrogen and R3Is a hydroxyl group. R1、R2Or R4Is hydrogen and R3Is a hydroxyl group. R1、R2And R4All are hydrogen and R3Is a hydroxyl group.
In another aspect, R1Or R7At least one of which is an unsubstituted alkyl group. R1Or R7At least one of which is methyl. R1Or R7At least one of which is ethyl. R1Or R7At least one of which is propyl. R1And R7Are both unsubstituted alkyl groups. R1And R7Are both methyl groups. R1And R7Are all ethyl groups. R1And R7Are the same. R1And R7Is different. R7Is hydrogen. R7Is a hydroxyl group. R1Or R7Is unsubstituted alkyl and R1Or R7The other of (a) is hydrogen. R1Or R7Is unsubstituted alkyl and R1Or R7The other of (a) is a hydroxyl group. R1Or R7At least one of which is unsubstituted alkyl and R5Is unsubstituted or substituted alkyl. R1Or R7At least one of which is methyl and R5Is methyl.
R1And R5Are both unsubstituted alkyl and R7Is a hydroxyl group. R7And R5Are both unsubstituted alkyl and R1Is a hydroxyl group. R1Or R7Is unsubstituted alkyl and R5Is unsubstituted or substituted alkyl, further wherein R5Is of S-configuration. R1Or R7Is unsubstituted alkyl and R5Is unsubstituted or substituted alkyl, further wherein R5Is of the R-configuration.
In another aspect, R1Is hydroxy and R7Is methyl. R1Is methyl and R7Is a hydroxyl group. R6Is unsubstituted alkyl. R6Is methyl. R6Is ethyl. R2And R6Respectively hydrogen. R2And R6Is hydrogen and R5Is unsubstituted alkyl. R2And R6Is hydrogen, R5Is unsubstituted alkyl, and R1Or R7At least one of which is an unsubstituted alkyl group.
In one aspect, the compound is selected from the group consisting of: ia, Ib, Ic, Ig, Ih, Ii, Io, Ip, Iq, Ia, Ib, Ic, Ig, Ih, Ii, Il, Im, In, Io, Ip, Iq, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Im, In, 108, Ip, Iq, Ia, Ib, Ic, Id, Ie, If, Ig, Ii, Il, Im, In, Ia, Ib, Ic, Ii, Im, In, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Im, In, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Ii, and Im.
In another aspect of the invention, when R2，R4And R6Are each hydrogen, R3Is hydroxy, and R1And R7When one of them is hydrogen or hydroxy, then R1Or R7The other of which is not methyl. In another aspect, when R2Is an alpha-hydroxy group; r3Is a hydroxyl group; r4And R6Are each hydrogen; and R is1And R7When one of them is hydrogen or hydroxy, then R1Or R7The other of which is not methyl. In another aspect, the invention does not include compounds as described below: 3 α, 7 α -dihydroxy-7 α 0-methyl-5 α 2-cholanic acid, 3 α 1, 7 α 5-dihydroxy-7 α 3-methyl-5 α 9-cholanic acid, 3 α 4-hydroxy-7 β 3-methyl-5 β -cholanic acid, 3 α 6, 7 β 0, 12 α 7-trihydroxy-7 α 8-methyl-5 β 4-cholan-24-oic acid; 3 β 1, 7 β 2, 12 α -trihydroxy-7 β -methyl-5 β -cholestane-24-oic acid; and 3 alpha, 12 alpha-dihydroxy-7 epsilon-methyl-5 beta-cholestane-24-oic acid.
In another aspect of the invention, when R3Is hydroxy and R1And R7One of which is methyl and R1And R7When the other of (A) is hydrogen or hydroxy, then R is2、R4And R6Not all are hydrogen. In another aspect, when R2Is alpha-hydroxy, R3Is hydroxy, and R1And R7One of which is methyl and R1And R7When the other of (A) is hydrogen or hydroxy, then R is4And R6Not all are hydrogen.
Another aspect of the present invention includes a composition or pharmaceutical formulation comprising a compound of formula IA:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient, wherein: r1Is hydrogen, hydroxy, substituted or unsubstituted alkyl or halogen; r2Is hydrogen or alpha-hydroxy; r3Is hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, substituted or unsubstituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen, unsubstituted or substituted alkyl, or R5And R6The carbon atoms that join them together form a ring having 3 atoms, 4 atoms, 5 atoms, or 6 atoms; r7Is hydrogen, substituted or unsubstituted alkyl, or hydroxy; and m is an integer of 0, 1, 2, 3, 4, or 5; and n is an integer of 0, 1, 2, 3, 4, or 5.
In one aspect of the invention, when R5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
Another aspect of the present invention includes a method of treating and/or preventing a disease in a host, said method comprising administering to a host in need thereof a compound of formula IA:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: r1Is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen; r2Is hydrogen or alpha-hydroxy; r3Is hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；R4Is hydrogen, substituted or unsubstituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen, unsubstituted or substituted alkyl, or R5And R6By carbon atoms joining them togetherForm a ring having 3 atoms, 4 atoms, 5 atoms, or 6 atoms; r7Is hydrogen, substituted or unsubstituted alkyl, or hydroxy; and m is an integer of 0, 1, 2, 3, 4, or 5; and n is an integer of 0, 1, 2, 3, 4, or 5. In one aspect, treatment and/or prevention of the disease involves modulation of TGR5 receptors in the host. The disease is obesity. The disease is insulin sensitivity. The disease is inflammation. The host is a human.
In one aspect, when R5Is methyl; r1Is a hydroxyl group; and R is3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen. In another aspect, the method involves administering a compound selected from the group consisting of: ia6, Ib6, Ic6, Id6, Ie6, If6, Ig6, Ih6, Ii6, Il6, Im6, In6, 106, Ip6, Iq6, Ia7, Ib7, Ic7, Id7, Ie7, If7, Ig7, Ih7, Ii7, Il7, Im7, In7, Io7, Ip7, Iq7, Ia7, Ib7, Ic7, Id7, Ic7, If7, Ig7, Ih7, Ii7, Il7, In7, Im7, Ip7, Iq7, i7, i, 7, i7, i, 7, i7, i7, i 36.
In another aspect, the method involves administering a compound selected from the group consisting of: ia, Ib, Ic, Ig, Ih, Ii, 1o, Ip, Iq, Ia, Ib, Ic, Ig, Ih, Ii, Il, Im, In, Io, Ip, Iq, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ig, Il, Im, In, Ia, Ib, Ic, Ii, If, Ig, Il, Ih, Ii, Ia, Ib, Im, In, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Im, Ii, Il, Ii, and In.
In another aspect, the method involves administering a compound of formula IA, wherein the compound is provided: when R is5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
The present invention includes a method of treating and/or preventing a disease in a host comprising administering to a host in need thereof a compound of formula IA. The disease is selected from cholestasis or bile desaturation. The present invention relates to the use of a compound of formula IA for the preparation or manufacture of a pharmaceutical formulation for the treatment and/or prophylaxis of a disease wherein said use relates to modulation of the TGR5 receptor in a host, said use comprising administering said compound to a host in need thereof.
The invention also provides a radiolabeled compound of formula IA. The radiolabeled compounds of formula IA may be prepared using conventional techniques. For example, the following method can be used: reacting a compound of formula IA with tritium gas in the presence of a suitable catalyst to produce a radiolabeled compound of formula IA. In one embodiment, the compound of formula IA is tritium-containing.
Another aspect of the invention includes a compound of formula II:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: r1Is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen; r2Is hydrogen or is alpha-hydroxy; r4Is hydrogen, substituted or unsubstituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen, unsubstituted or substitutedOr R is5And R6Together form a ring of 3 atoms, 4 atoms, 5 atoms, or 6 atoms through the carbon atoms that link them together; r7Is hydrogen, substituted or unsubstituted alkyl, or hydroxy; and R is8Is hydrogen, substituted or unsubstituted alkyl. In one aspect, when R5Is methyl and R1When it is hydroxy, then R4Is not hydrogen.
In one aspect, R1Is hydrogen or hydroxyl. R1Is a hydroxyl group. R1Is hydrogen. R1Is a beta-hydroxy group. R2Is an alpha-hydroxy group. R1Is hydroxy and R2Is an alpha-hydroxy group. R1Is hydroxy and R2Is hydrogen. R1Or R2At least one of which is a hydroxyl group. R1Or R2Is hydrogen. R1And R2Are the same. R1Is hydroxy and R2Is an alpha-hydroxy group. R1And R2Respectively hydrogen.
In another aspect, R4Is hydrogen or unsubstituted alkyl. R4Is hydrogen. R4Is unsubstituted alkyl. R4Is unsubstituted alkyl. R4Is methyl or ethyl. R4Is methyl. R4Is ethyl.
In one aspect, R5Is unsubstituted or substituted alkyl. R5Is of S-configuration. R5Is of the R configuration. R5Is methyl or ethyl. R5Is S-methyl. R5Is R-methyl. R5Is an S-ethyl group. R5Is R-ethyl. R5Substituted by phenyl. R5Is benzyl. R5Is S-benzyl. R5Is R-benzyl. R5Is an aryl group. R5Is phenyl. R4And R5Each unsubstituted alkyl group. R4And R5Each being unsubstituted alkyl, further wherein R5Is of S-configuration. R4And R5Are each unsubstituted alkyl and R1Is a hydroxyl group. R4And R5Are each unsubstituted alkyl and R2Is hydrogen. R4And R5Are each unsubstituted alkyl, R1Is hydroxy, and R2Is hydrogen.
In one aspect, R1、R2And R4Is hydrogen. R2And R4Is hydrogen. R2Is hydrogen. R1、R2Or R4Is hydrogen. R1、R2Or R4At least two of which are hydrogen. R1、R2Or R4Is hydrogen.
In one aspect, R1Or R7Is unsubstituted alkyl. R1Or R7Is methyl. R1Or R7Is ethyl. R1Or R7Is propyl. R1And R7Are both unsubstituted alkyl groups. R7Is hydrogen. R7Is a hydroxyl group. R1Or R7Is unsubstituted alkyl and R1Or R7The other of (a) is hydrogen. R1Or R7Is unsubstituted alkyl and R1Or R7The other of (a) is a hydroxyl group. R1Or R7At least one of which is unsubstituted alkyl and R5Is unsubstituted or substituted alkyl. R1Or R7At least one of which is methyl and R5Is methyl. R7Is hydroxy and R1And R5Are both unsubstituted alkyl groups. R1Is hydroxy and R7And R5Are both unsubstituted alkyl groups. R1Or R7At least one of which is unsubstituted alkyl and R5Is unsubstituted or substituted alkyl, further wherein R5Is of S-configuration. R1Or R7At least one of which is unsubstituted alkyl and R5Is not takenSubstituted or substituted alkyl, further wherein R5Is of the R-configuration. R7Is hydroxy and R1And R5Are both unsubstituted alkyl, further wherein R5Is of S-configuration. R7Is hydroxy and R1And R5Are both unsubstituted alkyl, further wherein R5Is of the R-configuration. R1Is hydroxy and R7And R5Are both unsubstituted alkyl, further wherein R5Is of S-configuration. R1Is hydroxy and R7And R5Are both unsubstituted alkyl, further wherein R5Is of the R-configuration. R1Is hydroxy and R7Is methyl. R1Is methyl and R7Is a hydroxyl group.
In another aspect, R6Is unsubstituted alkyl. R6Is methyl. R6Is ethyl. R8Is hydrogen.
R8Is unsubstituted alkyl. R8Is methyl. R8Is ethyl. R2Is alpha-hydroxy and R8Is unsubstituted alkyl.
In another aspect of the invention, the compound is selected from the group consisting of: ia12, Ib12, Ic12, Ig12, Ih12, Ii12, Io12, Ip12, Iq12, Ia13, Ib13, Ic13, Ig13, Ih13, Ii13, Il13, Im13, In13, Io13, Ip13, Iq13, Ia14, Ib14, Ic14, Id14, Ie14, If14, Ig14, Ih14, Ii14, Il14, Im14, In14, Io14, Ip14, Iq14, Ia14, Ib14, Id14, Ie14, If14, Ig14, Ih14, Il14, Im 72, Il14, Im 72, Ib14, Ib 72, Ic14, Id14, i.
Another aspect of the present invention includes a composition or pharmaceutical formulation comprising a compound of formula II:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient, wherein: r1Is hydrogen, hydroxy, substituted or unsubstituted alkyl or halogen; r2Is hydrogen or alpha-hydroxy; r4Is hydrogen, substituted or unsubstituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen, unsubstituted or substituted alkyl, or R5And R6Together form a ring of 3 atoms, 4 atoms, 5 atoms, or 6 atoms through the carbon atoms that link them together; r7Is hydrogen, substituted or unsubstituted alkyl, or hydroxy; and R is8Is hydrogen or a substituted or unsubstituted alkyl group. In one aspect, when R5Is methyl, R1Is hydroxy, and R3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
One aspect of the present invention includes a method of treating and/or preventing a disease in a host, said method comprising administering to a host in need thereof a compound of formula II:
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein: r1Is hydrogen, hydroxy, substituted or unsubstituted alkyl, or halogen; r2Is hydrogen or alpha-hydroxy; r4Is hydrogen, substituted or unsubstituted alkyl, or halogen; r5Is unsubstituted or substituted alkyl, or aryl; r6Is hydrogen, unsubstitutedOr substituted alkyl, or R5And R6The carbon atoms that join them together form a ring having 3 atoms, 4 atoms, 5 atoms, or 6 atoms; r7Is hydrogen, substituted or unsubstituted alkyl, or hydroxy; and R is8Is hydrogen, substituted or unsubstituted alkyl.
The present invention includes a method of treating a disease involving modulation of the TGR5 receptor in a host. The present invention includes a method of preventing disease involving modulation of the TGR5 receptor in a host. The disease is obesity. The disease is insulin sensitivity. The disease is inflammation. The host is a human. In one aspect, when R5Is methyl; r1Is a hydroxyl group; r3Is hydroxy or NHCH2CH2SO3H is then R4Is not hydrogen.
One aspect of the present invention relates to a method in which a compound selected from the group consisting of: ia12, Ib12, Ic12, Id12, Ie12, If12, Ig12, Ih12, Ii12, Il12, Im12, In12, Io12, Ip12, Iq12, Ia13, Ib13, Ic13, Id13, Ie13, If13, Ig13, Ih13, Ii13, Il13, Im13, In13, Io13, i13, Iq13, Ia13, Ib13, Ic13, Id13, Ie13, If13, Ig13, Ih13, Ii13, Il13, Im13, In13, i13, Ip13, Iq13, Ib13, Ii13, Il 72.
In another aspect the invention relates to a method in which a compound selected from the group consisting of: ia, Ib, Ic, Ig, Ih, Ii, Io, Ip, Iq, Ia, Ib, Ic, Ig, Ih, Ii, Il, Im, In, Io, Ip, Iq, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Im, In, Ia, Ib, Ic, Ii, Ih, In, Ia, Ib, Ii, Im, In116, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Il, Ii, and In.
Another aspect of the invention includes a method involving administering a compound of formula II, wherein the compound is provided: when R is5Is methyl, and R1When it is hydroxy, then R4Is not hydrogen.
The present invention includes a method of treating a disease in a host comprising administering to a host in need thereof a therapeutically effective amount of a compound of formula II. The present invention includes a method of preventing a disease in a host, comprising administering to a host in need thereof a prophylactically effective dose of a compound of formula II. The disease is selected from cholestasis or bile desaturation. The present invention relates to the use of a compound of formula II for the manufacture of a pharmaceutical formulation for the treatment and/or prophylaxis of a disease state, wherein said use relates to modulation of TGR5 receptor in a host, said use comprising administering to a host in need thereof an effective amount of said compound, wherein said effective amount is a therapeutically effective amount or a prophylactically effective amount.
The invention also provides a radiolabeled compound of formula II. The radiolabelled compound of formula II may be prepared using conventional techniques. For example, the following method can be used: reacting the compound of formula II with tritium gas in the presence of a suitable catalyst to produce a radiolabeled compound of formula II. In one embodiment, the compound of formula II is tritium-containing.
Some representative compounds of the invention are shown below.
The following compounds Ia-In5 belong at least to the structure of formula I:
Ia：R1α -hydroxy, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ib：R1α -hydroxy, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Ic：R1α -hydroxy, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Id：R1β -hydroxy, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ie：R1β -hydroxy, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
If：R1β -hydroxy, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Ig：R1α -hydroxy, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ih：R1α -hydroxy, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Ii：R1α -hydroxy, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Il：R1β -hydroxy, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Im：R1β -hydroxy, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
In：R1β -hydroxy, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Io：R1Hydrogen, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ip：R1Hydrogen, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Iq：R1Hydrogen, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Ia1：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ib1：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Ic1：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Id1：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ie1：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
If1：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Ig1：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ih1：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Ii1：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Il1：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Im1：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
In1：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Io1：R1Hydrogen, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ip1：R1Hydrogen, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Iq1：R1Hydrogen, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Ia2：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ib2：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Ic2：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Id2：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ie2：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
If2：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Ig2：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ih2：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Ii2：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Il2：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Im2：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
In2：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Io2：R1Hydrogen, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ip2：R1Hydrogen, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen ═ hydrogen
Iq2：R1Hydrogen, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(R) methyl, R6Hydrogen ═ hydrogen
Ia3：R1α -hydroxy, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ib3：R1α -hydroxy, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
Ic3：R1α -hydroxy, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Id3：R1β -hydroxy, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ie3：R1β -hydroxy, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
If3：R1β -hydroxy, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Ig3：R1α -hydroxy, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ih3：R1α -hydroxy, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
Ii3：R1α -hydroxy, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Il3：R1β -hydroxy, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Im3：R1β -hydroxy, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
In3：R1β -hydroxy, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Ia4：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ib4：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
Ic4：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Id4：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ie4：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
If4：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Ig4：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ih4：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
Ii4：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Il4：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Im4：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
In4：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Ia5：R1α -hydroxy, R2Hydrogen ═ hydrogen，R3＝NHCH2CO2H，R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ib5：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
Ic5：R1α -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Id5：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ie5：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
If5：R1β -hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
Ig5：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Ih5：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
Ii5：R1α -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5＝(S) methyl, R6Hydrogen ═ hydrogen
Il5：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(S, R) methyl, R6Hydrogen ═ hydrogen
Im5：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(S) methyl, R6Hydrogen ═ hydrogen
In5：R1β -hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(R) methyl, R6Hydrogen ═ hydrogen
The following compounds In6-In11 belong at least to the structure of formula IA:
Ia6：R1hydroxy, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ib6：R1Hydroxy, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl group
Ic6：R1Hydroxy, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl group
Id6：R1Methyl, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Ie6：R1Methyl, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy group
If6：R1Methyl, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Ig6：R1Hydroxy, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ih6：R1Hydroxy, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl group
Ii6：R1Hydroxy, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl group
Il6：R1Methyl, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Im6：R1Methyl, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy group
In6：R1Methyl, R2α -hydroxy, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Io6：R1Hydrogen, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ip6：R1Hydrogen, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl group
Iq6：R1Hydrogen, R2Hydrogen, R3Hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl group
Ia7：R1Hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ib7：R1Hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl group
Ic7：R1Hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl group
Id7：R1Methyl, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Ie7：R1Methyl, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy group
If7：R1Methyl, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Ig7：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ih7：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl group
Ii7：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl group
Il7：R1Methyl, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Im7：R1Methyl, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy group
In7：R1Methyl, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Io7：R1Hydrogen, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ip7：R1Hydrogen, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl group
Iq7：R1Hydrogen, R2Hydrogen, R3＝NHCH2CH2SO3H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl group
Ia8：R1Hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ib8：R1Hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl group
Ic8：R1Hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl group
Id8：R1Methyl, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Ie8：R1Methyl, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy group
If8：R1Methyl, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Ig8：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ih8：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl group
Ii8：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl group
Il8：R1Methyl, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Im8：R1Methyl, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy group
In8：R1Methyl, R2α -hydroxy, R3＝NHCH2CO2H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Io8：R1Hydrogen, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ip8：R1Hydrogen, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl group
Iq8：R1Hydrogen, R2Hydrogen, R3＝NHCH2CO2H，R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl group
Ia9：R1Hydroxy, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ib9：R1Hydroxy, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl group
Ic9：R1Hydroxy, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl group
Id9：R1Methyl, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Ie9：R1Methyl, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy group
If9：R1Methyl, R2Hydrogen, R3Hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Ig9：R1Hydroxy, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ih9：R1Hydroxy, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl group
Ii9：R1Hydroxy, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl group
Il9：R1Methyl, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Im9：R1Methyl, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy group
In9：R1Methyl, R2α -hydroxy, R3Hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Ia10：R1Hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ib10：R1Hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl group
Ic10：R1Hydroxy, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl group
Id10：R1Methyl, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Ie10：R1Methyl, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy group
If10：R1Methyl, R2Hydrogen, R3＝NHCH2CH2SO3H，R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Ig10：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ih10：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl group
Ii10：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl group
Il10：R1Methyl, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Im10：R1Methyl, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy group
In10：R1Methyl, R2α -hydroxy, R3＝NHCH2CH2SO3H，R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Ia11：R1Hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ib11：R1Hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl group
Ic11：R1Hydroxy, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl group
Id11：R1Methyl, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Ie11：R1Methyl, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy group
If11：R1Methyl, R2Hydrogen, R3＝NHCH2CO2H，R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy group
Ig11：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl group
Ih11：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl group
Ii11：R1Hydroxy, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl group
Il11：R1Methyl, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy group
Im11：R1Methyl, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy group
In11：R1Methyl, R2α -hydroxy, R3＝NHCH2CO2H，R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy group
The following compounds Ia12-In17 belong at least to the formula II:
Ia12：R1hydroxy, R2Hydrogen, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ib12：R1Hydroxy, R2Hydrogen, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ic12：R1(ii) a hydroxyl group, or a hydroxyl group,R2hydrogen, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Id12：R1Methyl, R2Hydrogen, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ie12：R1Methyl, R2Hydrogen, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
If12：R1Methyl, R2Hydrogen, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ig12：R1Hydroxy, R2α -hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ih12：R1Hydroxy, R2α -hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ii12：R1Hydroxy, R2α -hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Il12：R1Methyl, R2α -hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Im12：R1Methyl, R2α -hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
In12：R1Methyl, R2α -hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Io12：R1Hydrogen, R2Hydrogen, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ip12：R1Hydrogen, R2Hydrogen, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Iq12：R1Hydrogen, R2Hydrogen, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ia13：R1Hydroxy, R2Hydrogen, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ib13：R1Hydroxy, R2Hydrogen, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ic13：R1Hydroxy, R2Hydrogen, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Id13：R1Methyl, R2Hydrogen, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ie13：R1Methyl, R2Hydrogen, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
If13：R1Methyl, R2Hydrogen, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ig13：R1Hydroxy, R2α -hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ih13：R1Hydroxy, R2α -hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ii13：R1Hydroxy, R2α -hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Il13：R1Methyl, R2α -hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Im13：R1Methyl, R2α -hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
In13：R1Methyl, R2α -hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Io13：R1Hydrogen, R2Hydrogen, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ip13：R1Hydrogen, R2Hydrogen, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Iq13：R1Hydrogen, R2Hydrogen, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ia14：R1Hydroxy, R2Hydrogen, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ib14：R1Hydroxy, R2Hydrogen, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ic14：R1Hydroxy, R2Hydrogen, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Id14：R1Methyl, R2Hydrogen, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ie14：R1Methyl, R2Hydrogen, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
If14：R1Methyl, R2Hydrogen, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ig14：R1Hydroxy, R2α -hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ih14：R1Hydroxy, R2α -hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ii14：R1Hydroxy, R2α -hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Il14：R1Methyl, R2α -hydroxy, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Im14：R1Methyl, R2α -hydroxy, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
In14：R1Methyl, R2α -hydroxy, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Io14：R1Hydrogen, R2Hydrogen, R4Hydrogen, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ip14：R1Hydrogen, R2Hydrogen, R4Hydrogen, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Iq14：R1Hydrogen, R2Hydrogen, R4Hydrogen, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ia15：R1Hydroxy, R2Hydrogen, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ib15：R1Hydroxy, R2Hydrogen, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ic15：R1Hydroxy, R2Hydrogen, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Id15：R1Methyl, R2Hydrogen, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ie15：R1Methyl, R2Hydrogen, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
If15：R1Methyl, R2Hydrogen, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ig15：R1Hydroxy, R2α -hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ih15：R1Hydroxy, R2α -hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ii15：R1Hydroxy, R2α -hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Il15：R1Methyl, R2α -hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Im15：R1Methyl, R2α -hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
In15：R1Methyl, R2α -hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ia16：R1Hydroxy, R2Hydrogen, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ib16：R1Hydroxy, R2Hydrogen, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ic16：R1Hydroxy, R2Hydrogen, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Id16：R1Methyl, R2Hydrogen, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ie16：R1Methyl, R2Hydrogen, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
If16：R1Methyl, R2Hydrogen, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ig16：R1Hydroxy, R2α -hydroxy, R4α -methyl group，R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ih16：R1Hydroxy, R2α -hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ii16：R1Hydroxy, R2α -hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Il16：R1Methyl, R2α -hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Im16：R1Methyl, R2α -hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
In16：R1Methyl, R2α -hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ia17：R1Hydroxy, R2Hydrogen, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ib17：R1Hydroxy, R2Hydrogen, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ic17：R1Hydroxy, R2Hydrogen, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Id17：R1Methyl, R2Hydrogen, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ie17：R1Methyl, R2Hydrogen, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
If17：R1Methyl, R2Hydrogen, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Ig17：R1Hydroxy, R2α -hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ih17：R1Hydroxy, R2α -hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Ii17：R1Hydroxy, R2α -hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Methyl, R8Hydrogen ═ hydrogen
Il17：R1Methyl, R2α -hydroxy, R4α -methyl, R5(S, R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
Im17：R1Methyl, R2α -hydroxy, R4α -methyl, R5(S) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
In17：R1Methyl, R2α -hydroxy, R4α -methyl, R5(R) methyl, R6Hydrogen, R7Hydroxy, R8Hydrogen ═ hydrogen
All publications and patent documents cited in this specification are herein incorporated by reference as if each such publication or document were specifically and individually indicated to be incorporated by reference. Citation of publications and patent documents is not intended as an admission that any of them is pertinent prior art, nor does it constitute any admission as to the contents or date thereof. While the invention has been described by way of written description, those skilled in the art will recognize that the invention can be practiced in a variety of different embodiments, and that the foregoing description, as well as the following examples, are intended to be illustrative, and not to be construed as limiting the claims which follow.
Example 1: synthesis of TGR5 Modulator
The compounds described herein and their related derivatives may be synthesized using methods known to those skilled in the art. Detailed methods for synthesizing these compounds will be described below. See also, WO 02/072598, WO2004/0007521, EP 1568706 and EP 135782. When R in said compound is1Is hydrogen, R2And R3Is hydroxy and R4Is a lower alkyl group, in this case, the compound represented by the formula (I) can be obtained according to the following scheme:
scheme 1
Scheme 1
(i)3, 4-Dihydroxypyran (DHP), p-toluenesulfonic acid (p-TSA), dioxane, room temperature (r.t.);
(ii) a) Lithium Diisopropylamide (LDA), methyl iodide, -78 ℃; b) hydrochloric acid, methanol, room temperature;
(iii) sodium hydroxide and methanol are refluxed.
The 3-and 7-positions of chenodeoxycholic acid methyl ester (1) were protected with 3, 4-dihydro-2H-pyran in dioxane in the presence of a catalytic amount of p-toluenesulfonic acid (p-TSA) to yield the corresponding 3 α, 7 α -tetrahydropyranyloxy analog (2). Reaction of 2 with methyl iodide (or with a suitable alkyl halide) followed by treatment with methanol hydrochloride (methanolic HCl) at-78 ℃ using lithium diisopropylamide as base and Tetrahydrofuran (THF) as solvent gave the corresponding methyl 23-methyl-3 α, 7 α -dihydroxy-5 β -cholestane-24-oate (3). The above methyl ester 3 was hydrolyzed with a base and purified by flash chromatography to give the desired 23(S) -methyl-3 α, 7 α -dihydroxy-5 β -cholestane-24-oic acid (Ib) and 23(R) -methyl-3 α, 7 α -dihydroxy-5 β -cholestane-24-oic acid (Ic).
Preparation of 23(R) -methyl-3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-oic acid and 23(S) -methyl-3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-oic acid (Ib, Ic)
a)3 α, 7 α -Ditetrahydropyranyloxy-5 β -cholestane-24-oic acid methyl ester (2)
To a solution of methyl 3 α, 7 α -dihydroxy-5 β -cholestane-24-oate (1) (2.0 g, 4.9 mmol) in dioxane (6 ml) was added p-toluenesulfonic acid (78 mg, 0.41 mmol), 3, 4-dihydro-2H-pyran (20.1 ml, 0.098 mol). The reaction mixture was stirred at room temperature for 15 minutes. Water (50 ml) was then added to it and the mixture was partially concentrated under vacuum and extracted with ethyl acetate (EtOAc) (3 × 50 ml). The resulting combined organic fractions were washed with brine (1 × 50 ml), dried (sodium sulfate) and evaporated under vacuum. The residue obtained is purified by chromatography on a silica gel column. Elution with 80/20 petroleum ether/ethyl acetate gave 2.5 g of pure compound 2 (90% yield).
1H-NMR (deuterated chloroform) δ: 0.64(s, 3H, CH)3-18)，0.89(s，3H，CH3-19)，0.92(d，3H，CH3-21)，3.31-3.67(m，4H，-CH2OCH-)，3.65(s，3H，CO2CH3)，3.67(m，1H，CH-3)，3.88(brs，1H，CH-7)，4.67(brs，1H，-O-CH-O-)，4.73(brs，1H，-O-CH-O-)。
b)23(R, S) -methyl-3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-oic acid methyl ester (3)
To a solution of diisopropylamine (1.4 ml, 10.1 mmol) in anhydrous Tetrahydrofuran (THF) (50 ml) was added n-butyllithium (4.3 ml, 2.2M in hexane) dropwise at-78 ℃. The above system was kept at-78 ℃ for another 30 minutes and then 3 α, 7 α, 12 α -tetrahydropyranyloxy-5 β -cholestane-24-oic acid methyl ester (2) (1.8 g, 3.2 mmol) dissolved in anhydrous tetrahydrofuran (14 ml) was added dropwise to the above mixture. After 20 minutes, methyl iodide (1.4 ml, 22.0 mmol) dissolved in anhydrous tetrahydrofuran (7 ml) was added slowly and the mixture was warmed up overnight at room temperature. The solvent was removed under vacuum and acidified with 10% hydrochloric acid and extracted with ethyl acetate (5x50 ml), washed with 5% sodium thiosulfate solution (2x50 ml), dried (over anhydrous sodium sulfate), filtered, and evaporated under vacuum. The crude residue was then treated with 2N hydrochloric acid in methanol (50 ml) for 12 hours. The residue was evaporated under vacuum and taken up with ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution (2 × 50 ml), dried (sodium sulfate) and evaporated under vacuum. The residue was purified by flash chromatography on silica gel. Elution was carried out with 70/30 petroleum ether/ethyl acetate to obtain 1.1 g (2.7 mmol) of said pure compound 3 (84% yield).
1H-NMR (deuterated chloroform) δ: 0.62(s, 3H, CH)3-18)，0.87(s，3H，CH3-19)，0.92(d，3H，CH3-21)，2.38(m，1H，CH-23)，3.27-3.40(m，1H，CH-3)，3.55(brs，1H，CH-7)，3.63(s，3H，CO2CH5)。
c)23(R) -methyl-3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-oic acid (Ib) and 23(S) -methyl-3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-oic acid (Ic)
0.97 g (2.3 mmol) of 23-methyl-3 α, 7 α -dihydroxy-5 β -cholestane-24-oic acid methyl ester was dissolved in methanol (25 ml) and 10% sodium hydroxide in methanol (5.7 ml, 14.2 mmol) was added. The mixture was refluxed for 16 hours. The mixture was acidified with 3N hydrochloric acid and extracted with ethyl acetate (3 × 20 ml). The combined organic fractions were washed with brine (1 × 50 ml), dried (sodium sulfate) and evaporated under vacuum. The residue was purified by flash chromatography on silica gel. Elution was carried out with chloroform: methanol (95/5) to give 1.5 g (65%) of 23(S) -methyl-3 α, 7 α -dihydroxy-5 β -cholestane-24-oic acid and 330 mg of 23(R) -methyl-3 α, 7 α -dihydroxy-5 β -cholestane-24-oic acid.
23(S) -methyl-3 α, 7 α -dihydroxy-5 β -cholestane-24-oic acid (Ib): melting point: 125 ℃ and 126 ℃.1H-NMR (deuterated chloroform + deuterated methanol) δ: 0.44(s, 3H, CH)3-18)，0.69(s，3H，CH3-19)，0.73-0.76(d，3H CH3-21)，0.93-0.97(d，3H，-CH3)，2.36(m，1H，CH-23)，3.15-3.38(m，1H，CH-3)，3.62(brs，1H，CH-7).13C-NMR (deuterated chloroform + deuterated methanol) δ: 11.55, 18.43, 18.87, 20.49, 22.69, 28.15, 28.57, 30.14, 32.65, 34.43, 34.61, 34.94, 35.23, 37.06, 39.17, 39.60, 40.81, 41.40, 42.57, 46.54, 50.29, 56.63, 68.24, 71.62, 179.99.
23(R) -methyl-3 α, 7 α -dihydroxy-5 β -cholestane-24-oic acid (Ic): melting point: 163 ℃ and 164 ℃.1H-NMR (deuterated chlorine)Imitation + deuterated methanol) δ: 0.43(s, 3H, CH)3-18)，0.65(s，3H，CH3-19)，0.65-0.69(d，3H CH3-21)，0.83-0.86(d，3H，-CH3)，2.20(m，1H，CH-23)，3.09-3.15(m，1H，CH-3)，3.58(brs，1H，CH-7).13C-NMR (deuterated chloroform + deuterated methanol) δ: 11.94, 16.40, 18.30, 20.93, 23.06, 23.89, 28.85, 30.52, 33.08, 34.16, 34.91, 35.38, 35.68, 37.14, 39.49, 39.64, 40.04, 40.17, 41.92, 43.05, 50.69, 57.10, 68.51, 72.01, 181, 09.
Example 2: preparation of 23(S) -methyl-6 alpha-methyl-3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-oic acid and 23(R) -methyl-6 alpha-methyl-3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-oic acid (Ib3, Ic3)
The following compounds were prepared according to the procedure in example 1 by alkylation of 6 α -methyl-3 α, 7 α -dihydroxy-5 β -cholestan-24-oic acid.
23(S) -methyl-6 α -methyl-3 α, 7 α -dihydroxy-5 β -cholestane-24-oic acid (Ib 3): melting point: 98-100 ℃.1H-NMR (deuterated chloroform) δ: 0.63(s, 3H, CH)3-18)，0.89(s，3H，CH3-19)，0.92-1.00(m，6H，CH3-21 and CH3-6)，1.15-1.19(d，3H，-CH3)，2.45-2.73(m，1H，CH-23)，3.31-3.52(m，1H，CH-3)，3.58(brs，1H，CH-7).13C-NMR (deuterated chloroform) delta: 11.76, 15.72, 18.58, 18.88, 20.63, 23.11, 23.65, 28.19, 30.21, 30.47, 32.64, 33.79, 33.97, 34.61, 35.42, 35.66, 37.03, 39.60, 40.01, 40.71, 42.71, 47.35, 50.44, 56.60, 72.34, 72.87, 182.37.
23(R) -methyl-6 α -methyl-3 α, 7 α -dihydroxy-5 β -cholestan-24-oic acid (Ic 3): melting point: 89-90 ℃.1H-NMR (deuterated chloroform + deuterated methanol) δ: 0.65(s, 3H, CH)3-18)，0.88(s，3H，CH3-19)，0.88-0.92(m，3H，CH3-6)，0.95-0.99(d，3H，CH3-21)，1.08-1.14(d，3H-CH3)，2.35(m，1H，CH-23)，3.29-3.48(m，1H，CH-3)，3.57(brs，1H，CH-7).13C-NMR (deuterated chloroform + deuterated methanol) δ: 11.70, 15.66, 16.02, 18.00, 20.61, 23.09, 23.60, 28.51, 30.39, 32.61, 33.72, 33.92, 35.38, 35.65, 36.33, 39.57, 39.94, 42.77, 47.30, 50.39, 56.53, 72.22, 72.83, 180.50.
Example 3: preparation of 23(R) -methyl-3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestane-24-oic acid and 23(S) -methyl-3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestane-24-oic acid (Ih, Ii)
The following compounds were prepared according to the procedure in example 1 by alkylation of 3 α, 7 α, 12 α -trihydroxy-5 β -cholestan-24-oic acid.
23(S) -methyl-3 α, 7 α, 12 α -trihydroxy-5 β -cholestan-24-oic acid (Ih): melting point: 237 ℃ and 239 ℃.1H-NMR (deuterated chloroform) δ: 0.63(s, 3H, CH)3-18)，0.87(s，3H，CH3-19)，0.96-0.98(m，3H，CH3-21)，1.07-1.11(d，3H，-CH3)，2.44-2.73(m，1H，CH-23)，3.35-3.50(m，1H，CH-3)，3.82(brs，1H，CH-7)3.95(brs，`H，CH-12).13C-NMR (dimethylsulfoxide) delta: 12.72, 17.60, 19.24, 19.24, 23.00, 23.19, 26.59, 27.78, 28.88, 30.72, 34.77, 35.22, 35.66, 37.19, 41.84, 46.19, 47.27, 49.01, 66.69, 70.88, 71.45, 178.25.
23(R) -methyl-3 α, 7 α, 12 α -trihydroxy-5 β -cholestane-24-oic acid (Ii): melting point: 221-223 ℃.1H-NMR (deuterated chloroform) δ: 0.63(s, 3H, CH)3-18)，0.87(s，3H，CH3-19)，0.96-0.98(m，3H，CH3-21)，1.07-1.11(d，3H，-CH3)，2.44-2.73(m，1H，CH-23)，3.35-3.50(m，1H，CH-3)，3.82(brs，1H，CH-7)3.95(brs，1H，CH-12).13C-NMR (dimethylsulfoxide) delta: 12.76, 16.88, 17.31, 23.04, 23.24, 26.62, 28.12, 28.94, 30.81, 33.97, 34.80, 35.28, 35.71, 37.20, 41.85, 46.29, 47.44, 66.67, 70.86, 71.45, 178.77.
Example 4: 23(R) -methyl-6 alpha-methyl-3 alphaPreparation of 7 alpha, 12 alpha-trihydroxy-5 beta-cholestane-24-oic acid and 23(S) -methyl-6 alpha-methyl-3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestane-24-oic acid (Ih3, Ii3)
The following compounds were prepared according to the procedure in example 1 by alkylation of 6 α -methyl-3 α, 7 α, 12 α -trihydroxy-5 β -cholestane-24-oic acid.
23(S) -methyl-6 α -methyl-3 α, 7 α, 12 α -trihydroxy-5 β -cholestane-24-oic acid (Ih 3): melting point: 131 ℃ and 134 ℃.1H-NMR (deuterated chloroform + deuterated methanol) δ: 0.65(s, 3H, CH)3-18)，0.87(s，3H，CH3-19)，0.97-1.00(m，3H，CH3-21)，1.14-1.18(d，3H，-CH3)，1.23(m，1H，CH-6)，2.52(m，1H，CH-23)，3.32-3.50(m，1H，CH-3)，3.55(brs，1H，CH-7)3.94(brs，1H，CH-12).13C-NMR (deuterated chloroform + deuterated methanol) δ: 12.43, 145.66, 17.62, 18.92, 22.70, 23.14, 26.21, 27.45, 28.01, 30.03, 33.44, 34.11, 34.42, 35.30, 36.71, 39.97, 40.45, 41.73, 46.45, 47.25, 72.13, 72.76, 73.01, 180.53.
23(R) -methyl-6 α -methyl-3 α, 7 α, 12 α -trihydroxy-5 β -cholestane-24-acid (Ii 3): melting point: 109 ℃ and 110 ℃.1H-NMR (deuterated methanol) delta: 0.72(s, 3H, CH)3-18)，0.91(s，3H，CH3-19)，1.07-1.11(m，6H，-CH3 andCH3-21)，2.37-2.53(m，1H，CH-23)，3.15-3.42(m，1H，CH-3)，3.53(brs，1H，CH-7)3.97(brs，1H，CH-12).13C-NMR (deuterated methanol) delta: 11.61, 15.04, 15.32, 16.15, 22.04, 22.75, 26.27, 27.62, 28.18, 29.61, 32.91, 33.74, 34.31, 35.06, 35.18, 36.56, 39.70, 40.25, 41.68, 46.19, 46.31, 71.76, 71.77, 72.62, 180.11.
Example 5: preparation of 23(R) -methyl-3 alpha-hydroxy-5 beta-cholestane-24-oic acid and 23(S) -methyl-3 alpha-hydroxy-5 beta-cholestane-24-oic acid (Ip, Iq)
The following compounds were prepared according to the procedure in example 1 by alkylation of 3 α -hydroxy-5 β -cholestan-24-oic acid.
23(S) -methyl-3 α -hydroxy-5 β -cholestane-24-oic acid (Ip): melting point: 161-162 ℃.1H-NMR (deuterated chloroform + deuterated methanol) δ: 0.60(s, 3H, CH)3-I8)，0.88(s，3H，CH3-19)，0.92-1.01(m，3H，CH3-21)，1.13-1.16(d，3H，-CH3)，2.55(m，1H，CH-23)，3.60(m，1H，CH-3).13C-NMR (deuterated chloroform + deuterated methanol) δ: 11.97, 18.52, 18.87, 20.73, 23.30, 24.14, 26.34, 27.10, 28.15, 30.18, 34.48, 34.50, 35.23, 35.74, 36.06, 37.01, 40.13, 40.34, 40.74, 41.99, 42.68, 56.43, 56.75, 71.70, 181.42.
23(R) -methyl-3 α -hydroxy-5 β -cholestane-24-oic acid (Iq): melting point: 152 ℃ and 153 ℃.1H-NMR (deuterated chloroform + deuterated methanol) δ: 0.63(s, 3H, CH)3-18)，0.89(s，3H，CH3-19)，0.94-1.03(m，3H，CH3-21)，2.45(m，1H，CH-23)，3.59(m，1H，CH-3).13C-NMR (deuterated methanol) delta: 11.98, 15.97, 18.00, 20.75, 23.31, 24.14, 26.34, 27.11, 28.48, 30.26, 33.68, 34.50, 35.26, 35.77, 36.15, 36.46, 39.59, 40.13, 40.36, 42.01, 42.79, 56.45, 56.76, 71.71, 181.02.
Example 6: biological activity
The potency and efficacy of the compounds of the invention at the TGR5 receptor was assessed by ex vivo assays. See, Kawamata, published in 2003 in j.biol.chem. "journal of biochemistry. (Vol) 278, No. (phase) 11, p.9435-9440). The activity towards Farnesoid X Receptor (FXR) was detected by Fluorescence Resonance Energy Transfer (FRET) and human farnesoid X receptor was supplemented with the SRC-1 (steroid receptor coactivator-1) peptide by a cell-free enzyme-linked immunosorbent assay (EliSA). See, WO 00/37077 to Blancard et al.
Table 1: example compounds EC50 values (micromolar) for farnesoid X receptor and TGR5 receptor
The compounds of the present invention are potent and selective modulators of TGR 5. The introduction of an alkyl group at the C-23 position of the bile acid gives selectivity of the TGR receptor over the farnesoid X receptor. The above-mentioned view is obvious by observing the biological results shown in table 1, which are obtained by the action of chenodeoxycholic acid (CDCA), 6-methyl chenodeoxycholic acid and 6, 23-dimethyl-chenodeoxycholic acid (23-R, S isomer mixture) on farnesyl ester X receptor (FXR) and TGR 5.6, 23-dimethyl-chenodeoxycholic acid produced 100-fold more potency against TGR5 relative to the farnesoid X receptor.
Other embodiments
While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.
Claims (11)
1. A compound according to formula A:
(A) or a pharmaceutically acceptable salt thereof, wherein:
R1is a hydroxyl group;
R2is an alpha-hydroxy group;
R3is hydroxy, NH (CH)2)mSO3H, or NH (CH)2)nCO2H；
R4Is unsubstituted alkyl;
R5is unsubstituted alkyl;
R6is hydrogen;
R7is hydrogen;
R8and R9Together form a carbonyl group; and is
R10Is R3；
m is an integer of 0, 1, 2, 3, 4, or 5; and is
n is an integer of 0, 1, 2, 3, 4, or 5,
wherein the unsubstituted alkyl group represents a straight-chain alkyl group or a branched-chain alkyl group having six or less carbon atoms in its main chain.
2. The compound of claim 1, wherein R4Is methyl or ethyl.
3. The compound of claim 1, wherein R5Is methyl or ethyl.
4. The compound of claim 1, wherein R3Is a hydroxyl group.
5. A compound according to claim 3, wherein R5Is methyl.
6. The compound of claim 1, wherein R5Is of S-configuration.
7. The compound of claim 2, wherein R4Is methyl.
8. The compound of claim 2, wherein R4Is ethyl.
9. A pharmaceutical composition comprising a compound of claim 1, or a salt of the compound, and at least one pharmaceutically acceptable excipient.
10. Use of a compound or salt thereof according to any one of claims 1-8 in the manufacture of a medicament for the treatment and/or prevention of a disease in a host in need thereof, wherein the disease is selected from obesity, insulin sensitivity, inflammation, cholestasis, and bile desaturation.
11. Use of the composition of claim 9 in the manufacture of a medicament for the treatment and/or prevention of a disease in a host in need thereof, wherein the disease is selected from the group consisting of obesity, insulin sensitivity, inflammation, cholestasis, and bile desaturation.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07001143A EP1947108A1 (en) | 2007-01-19 | 2007-01-19 | TGR5 modulators and methods of use thereof |
| EP07001143.2 | 2007-01-19 | ||
| EP07012079.5 | 2007-06-20 | ||
| EP07012079 | 2007-06-20 | ||
| PCT/US2008/000658 WO2008091540A2 (en) | 2007-01-19 | 2008-01-18 | 23-substituted bile acids as tgr5 modulators and methods of use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1142611A1 HK1142611A1 (en) | 2010-12-10 |
| HK1142611B true HK1142611B (en) | 2015-02-13 |
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