- Preparation method of obeticholic acid impurities
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The invention discloses a preparation method of obeticholic acid impurities, relates to a synthesis method of five impurities of obeticholic acid, and has important significance for synthesizing high-quality obeticholic acid. (E)-3 [beta]-hydroxy-6-ethylene-7-keto-5[ beta]-cholestane-24-acid (D), 3 [alpha], 7 [alpha]-dihydroxy-6 [beta]-ethyl-5 [beta]-cholestane-24-acid (F), 3 [alpha], 7 [beta]-dihydroxy-6 [beta]-ethyl-5 [beta]-cholestane-24-acid (G), 3 [alpha]-(3 [alpha], 7 [alpha]-dihydroxy-6 [alpha]-ethyl-5 [beta]-cholestane-24-acyloxy)-7 [alpha]-hydroxy-6 [alpha]-ethyl-5 [beta]-cholestane-24-acid (I) and 3-keto-7 [alpha]-hydroxy-6 [alpha]-ethyl-5 [beta]-cholestane-24-acid (L) are mainly researched.
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Paragraph 0059; 0070-0071
(2020/08/02)
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- PROCESS FOR THE PREPARATION OF 3α,7α-DIHYDROXY6α-ETHYL-5β-CHOLAN-24-OIC ACID
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The present invention relates to an improved process for the preparation of 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid compound of formula-1, represented by the following structural formula: Formula-1 The present invention also relates to process for the preparation of ethylene diamine and tertiary butyl amine salts of 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid which are useful in the preparation of pure 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid.
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Page/Page column 26
(2019/08/12)
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- Compound for treating metabolic diseases as well as preparation method and application thereof
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The invention provides a compound for treating metabolic diseases, the compound has a structure represented by formula (I) or formula (II), or a racemate, a stereoisomer, a geometric isomer, a tautomer, a solvate, a hydrate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. The compounds provided by the invention are FXR and/or TGR5 receptor activators, and the compounds havethe activity of activating FXR and/or TGR5 receptors, and can be used for preparing medicines for treating chronic liver diseases, metabolic diseases or portal hypertension.
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Paragraph 0170; 0180-0182
(2019/07/04)
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- Process Research and Impurity Control Strategy for Obeticholic Acid, a Farnesoid X Receptor Agonist
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The process to obtain ICH-grade quality obeticholic acid (OCA) was improved, and the overall yield was 25.9%. The critical process parameters were established to reduce or avoid process-related impurities. The formation mechanisms, purge pathways, and control strategies for these impurities were also discussed for the first time. An high-performance liquid chromatography instrument utilizing the charged aerosol detection technique was applied for an impurity content assay in OCA for the first time. The developed process was robust and suitable for manufacturing scale-up.
- Feng, Wei-Dong,Zhuo, Song-Ming,Zhang, Fu-Li
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p. 1979 - 1989
(2019/10/11)
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- Synthesis method of obeticholic acid and intermediate
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The invention discloses a synthesis method of obeticholic acid and an intermediate. The method specifically comprises seven steps: an oxidation reaction, an esterification reaction, a protection reaction, an Aldol reaction, hydrogenation reduction, hydrolysis and a carbonyl reduction reaction with raw materials including chenodeoxycholic acid, NBS, concentrated sulfuric acid, methanol, sodium iodide, trimethyl silicon chloride, trimethylamine, acetaldehyde, boron trifluoride diethyl etherate, palladium on carbon, hydrogen, NaOH and NaBH4. The synthesis method of obeticholic acid and the intermediate is high in yield, low in cost, environmentally friendly, easy to operate and suitable for industrialization.
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Paragraph 0022
(2018/05/16)
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- New obeticholic acid preparation method
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The invention relates to an obeticholic acid (represented by a structure formula 7) preparation method, which has characteristics of less purification steps, simple and convenient operation, high yield and low environmental pollution, and is suitable for industrial production. The formula 7 is defined in the specification.
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Paragraph 0032-0034
(2019/09/02)
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- STEROID DERIVATIVE FXR AGONIST
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The present invention relates to a compound represented by formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof, and relates to applications thereof in the preparation of drugs for treating FXR related diseases.
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Paragraph 0098; 0106
(2018/12/13)
-
- 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester
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The invention belongs to the technical field of medicines, relates to a method of preparing obeticholic acid through adopting 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester as an intermediate, and particularly relates to the 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester that is a chemical compound, a method of preparing the compound, and a use of the compound for preparation of the obeticholic acid. The invention also relates to a method of preparing the obeticholic acid. The method of preparing the obeticholic acid includes (1) preparing the 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester and (2) preparing the obeticholic acid through adopting the 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester as the intermediate.
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Paragraph 0117; 0119; 0120; 0121
(2017/08/27)
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- METHODS OF PROMOTING HEPATIC REGENERATION
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The present invention relates to methods of accelerating, promoting or increasing hepatic regeneration, or increasing liver mass in a subject, by using a compound of formula (A): or a pharmaceutically acceptable salt thereof, and wherein R1, R2, R3, R4, R5, R6, m, and n are as described herein.
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Page/Page column 22-23
(2017/04/11)
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- Sulfonylurea derivative and pharmaceutical composition and application thereof
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The invention relates to a preparation method and application of a sulfonylurea compound and a composition containing the same component as FXR and / or TGR5 agonist, the FXR and / or TGR5 agonist is a compound shown as a formula (I), or a pharmaceutically acceptable salt, a solvate, a prodrug, an isomer and a stable isotope derivative thereof. The compounds can be used for treatment of FXR and / or TGR5 mediated diseases including primary biliary cirrhosis, nonalcoholic fatty liver, portal hypertension, bile acid diarrhea and cholestasis, type II diabetes and obesity and other field.
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Paragraph 0138; 0139; 0149; 0150
(2017/04/25)
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- A high-purity aobeiAobei cholic acid preparation method (by machine translation)
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The invention relates to a method for preparing high-purity aobeiAobei cholic acid. As shown in formula II compound chenodeoxycholic acid (CDCA) as the starting material, through oxidation, esterification, hydroxyl protection, ethylidene, catalytic hydrogenation, and carbonyl reduction of an ester of a reaction to obtain high-purity aobeiAobei cholic acid. The present invention provides a method of preparing aobeiAobei cholic acid with low toxicity, low pollution, high purity, stereoselectivity is good, there is little impurity content, mild reaction conditions, high safety, production simple operation and the like, and is suitable for industrial production. (by machine translation)
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Paragraph 0072-0074
(2017/07/20)
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- Process for preparing aobeiAobei cholic acid (by machine translation)
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The invention application discloses a process for preparing aobeiAobei cholic acid, includes the following steps: AB - 1 — AB - 2 — AB - 3 — AB - 4 — AB - 5 — AB - 6 — AB - 7 — AB - 8 — AB - 9 — AB - 10, the preparation process in the process of preparing a simple and highly efficient reaction conditions, so as to ensure that the quality of the final product aobeiAobei cholic acid can be controlled. (by machine translation)
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Paragraph 0091; 0094; 0095
(2017/07/21)
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- Preparation method for 3[alpha],7[alpha]-dihydroxyl-6[alpha]-ethyl cholanic acid
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The invention belongs to the technical field of pharmaceutical synthesis, and discloses a preparation method for 3[alpha],7[alpha]-dihydroxyl-6[alpha]-ethyl cholanic acid. The method comprises the steps: with 3[alpha]-hydroxyl-7-carbonyl cholanic acid as a raw material, carrying out methyl esterification, and under alkaline and low temperature conditions and with estersil as a catalyst, carrying out a reaction with halogenated silane to obtain 3[alpha],7-di(trimethyl siloxy)-6-en-methyl cholanate; then under conditions of low temperature and boron trifluoride acetonitrile, carrying out a reaction with Mukaiyama aldol, to obtain 3[alpha]-hydroxyl-6-ethidene-7-carbonyl methyl cholanate; and then with palladium carbon as a catalyst, carrying out catalytic hydrogenation and deprotection reaction in an alkaline alcohol/aqueous solution, acidifying to obtain 3[alpha]-hydroxyl-6[alpha]-ethyl-7-carbonyl cholanic acid; and finally reducing with sodium borohydride to obtain the target product. The method has the advantages of simple synthesis process, mild conditions and high yield, and is suitable for industrialization.
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Paragraph 0025; 0038; 0039; 0040
(2017/08/28)
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- PROCESS FOR PREPARATION OF OBETICHOLIC ACID
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The invention of the present application relates to the process for the preparation of intermediates of obeticholic acid and their conversion to obeticholic acid. The process involves the conversion of compound of formula (VI) to compound of formula (VII) in presence of an organic base.
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Page/Page column 22
(2018/01/17)
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- Single crystal of OCA-E, and preparation method and application thereof
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The invention relates to a single crystal of OCA-E, and a preparation method and application thereof. In the X-ray powder diffraction pattern of the single crystal of OCA-E, characteristic peaks appear when the diffraction angle 2theta is equal to 6.1 DEG, 11.5 DEG, 12.3 DEG, 14.0 DEG, 15.6 DEG, 16.8 DEG, 17.9 DEG, 18.4 DEG, 23.1 DEG and 24.1 DEG. The single crystal has not been reported. According to determination results, the crystal structure of the single crystal belongs to a prismatic crystal system; the space group of the single crystal is P2(1)2(1)2(1); the number Z of molecules in a unit cell is 8; and the single crystal is a light yellow flaky crystal at normal temperature and has good morphology and purity of as high as 99.0%. The preparation method enables OCA-E to be perfectly separated from other impurities and has good reproducibility.
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Paragraph 0025; 0041; 0042; 0043; 0044
(2017/08/28)
-
- Ursodeoxycholic acid compound for preventing or treating FXR (farnesol X receptor)-mediated disease
-
The invention relates to an ursodeoxycholic acid compound for preventing or treating an FXR (farnesol X receptor)-mediated disease. Specially, the invention discloses the ursodeoxycholic acid compound shown in formula (I) and a drug combination containing the compound or the crystalline pharmaceutically-acceptably salt of the compound, a produg, tautomer, stereisomer, enantiomer, aquo-complex or solvate. The compound can serve as FXR stimulant and then is applicable to preparation of drugs for treating FXR related diseases such as fatty liver.
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Paragraph 0064; 0065; 0071; 0072; 0073
(2017/04/26)
-
- Preparing method of (E)-3alpha-hydroxy-6-ethidene-7-keto-5beta-cholane-24-acid
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The invention discloses a preparing method of (E)-3alpha-hydroxy-6-ethidene-7-keto-5beta-cholane-24-acid. Particularly, the preparing method includes the following steps of synchronously protecting of the 3-alcoholic hydroxyl group and the 7-enolic hydroxyl group; introducing a 6-carbon-carbon double bond and removing a protecting group; hydrolyzing an ester intermediate and recrystallizing the final product. Compared with a method for preparing (E)-3alpha-hydroxy-6-ethidene-7-keto-5beta-cholane-24-acid in the prior art, the preparing method has the advantages of being stable in reaction, high in yield, small in amount of side reaction, high in quality and the like and has broad development and application prospects.
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Paragraph 0023; 0024; 0026; 0027
(2017/11/01)
-
- SULFONYLAMINOCARBONYL DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USES THEREOF
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This disclosure is related to a sulfonylaminocarbonyl derivative of formula (I) and/or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the sulfonylaminocarbonyl derivatives of formula (I) and/or a pharmaceutically acceptable salt thereof, preparation methods thereof, and use thereof in treating FXR and/or TGR5 mediated diseases, including primary biliary cirrhosis, nonalcoholic fatty liver, portal hypertension, bile acid diarrhea and cholestasis, type II diabetes and obesity, etc.
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Page/Page column 23; 24
(2016/11/17)
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- Synthetic method of 6-ethylchenodeoxycholic acid
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The invention discloses a synthetic method of 6-ethylchenodeoxycholic acid. The synthetic method comprises steps as follows: chenodeoxycholic acid and an oxidizing agent are subjected to an oxidizing reaction and an esterification reaction, and a compound with a structure represented as a formula III is prepared; hydroxyl and carbonyl on rings of the compound with the structure represented as the formula III are protected with tert-butyldimethylsilyl chloride, and a compound with a structure represented as a formula IV is obtained; the compound with the structure represented as the formula IV and paraldehydeare are subjected to an electrophilic addition reaction and then are subjected to deprotection, and a compound with a structure represented as a formula V is obtained; the compound with the structure represented as the formula V is subjected to catalytic hydrogenation and is subjected to reduction and hydrolysis finally, and the compound 6-ethylchenodeoxycholic acid with a structure represented as a formula VI is obtained. The method is simple and convenient to operate, adopts mild conditions, has higher yield and is suitable for being popularized to industrial production.
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- Novel application of 7-keto-6[beta]-alkyl cholanic acid derivative in preparation of obeticholic acid and in field of medicine
-
The invention provides a preparation method of a 7-keto-6[alpha]-alkyl cholanic acid derivative. According to the preparation method provided by the invention, a 7-keto-6[beta]-alkyl cholanic acid derivative, as shown by a formula II, is used as a raw material, and the 7-keto-6[alpha]-alkyl cholanic acid derivative is prepared by converting a 6[beta] configuration into a 6[alpha] configuration under an acid or alkali condition. The invention also provides a 7-keto-6[beta]-alkyl cholanic acid derivative and an application thereof in preparation of 3[alpha],7[alpha]-dihydroxy-6[alpha]-alkyl-5[beta]-cholanic acid. The preparation method provided by the invention is simple and convenient, and is high in configuration conversion rate, and the product, the 7-keto-6[alpha]-alkyl cholanic acid derivative, is easy to purify, so that the purification difficulty for preparing the 3[alpha],7[alpha]-dihydroxy-6[alpha]-alkyl-5[beta]-cholanic acid is reduced.
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Paragraph 0141; 0144; 0145
(2016/12/01)
-
- Method for preparing 3,7-bis(trimethylsilyl oxyl)-6-alkene-5 beta-cholane-24-methyl gallate
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The invention belongs to the technical field of medicines, and relates to a method for preparing 3,7-bis(trimethylsilyl oxyl)-6-alkene-5 beta-cholane-24-methyl gallate. Preferentially, 3,7-bis(trimethylsilyl oxyl)-6-alkene-5 beta-cholane-24-methyl gallate is 3 alpha,7-bis(trimethylsilyl oxyl)-6-alkene-5 beta-cholane-24-methyl gallate. According to the method, 3,7-bis(trimethylsilyl oxyl)-6-alkene-5 beta-cholane-24-methyl gallate, especially 3 alpha,7-bis(trimethylsilyl oxyl)-6-alkene-5 beta-cholane-24-methyl gallate, prepared through the method can be used for preparing obeticholic acid.
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Paragraph 0235; 0236; 0237; 0238; 0239
(2017/08/25)
-
- Design, synthesis, and biological evaluation of potent dual agonists of nuclear and membrane bile acid receptors
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Bile acids exert genomic and nongenomic effects by interacting with membrane G-protein-coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions; thus, GP-BAR1/FXR dual agonists, by enhancing the biological response, represent an innovative strategy for the treatment of enteroendocrine disorders. Here, we report the design, total synthesis, and in vitro/in vivo pharmacological evaluation of a new generation of dual bile acid receptor agonists, with the most potent compound, 19, showing promising pharmacological profiles. We show that compound 19 activates GP-BAR1, FXR, and FXR regulated genes in the liver, increases the intracellular concentration of cAMP, and stimulates the release of the potent insulinotropic hormone GLP-1, resulting in a promising drug candidate for the treatment of metabolic disorders. We also elucidate the binding mode of the most potent dual agonists in the two receptors through a series of computations providing the molecular basis for dual GP-BAR1/FXR agonism.
- D'Amore, Claudio,Di Leva, Francesco Saverio,Sepe, Valentina,Renga, Barbara,Del Gaudio, Chiara,D'Auria, Maria Valeria,Zampella, Angela,Fiorucci, Stefano,Limongelli, Vittorio
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p. 937 - 954
(2014/03/21)
-
- Treatment of Pulmonary Disease
-
The present invention relates to methods of treating, reducing the risk of preventing, or alleviating a symptom of a pulmonary disease or condition, reducing or suppressing inflammation in the lung, and promoting lung repair, by using a compound of formula A: or a pharmaceutically acceptable salt thereof.
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Paragraph 0181
(2014/06/11)
-
- PREPARATION, USES AND SOLID FORMS OF OBETICHOLIC ACID
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The present invention relates to obeticholic acid: or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof. Obeticholic acid is useful for the treatment or prevention of a FXR mediated disease or condition, cardiovascular disease or cholestatic liver disease, and for reducing HDL cholesterol, for lowering triglycerides in a mammal, or for inhibition of fibrosis. The present invention also relates to processes for the synthesis of obeticholic acid.
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Page/Page column 59; 60
(2014/01/09)
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- Extending SAR of bile acids as FXR ligands: Discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor- 5β-cholan-23-amine
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Within our efforts in the discovery of novel potent and selective ligands for the FXR receptor, 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy- 6α-ethyl-24-nor-5β-cholan-23-amine was synthesized and evaluated for its ability to activate and modulate the biological response of the receptor. Alphascreen and RT-PCR revealed that the 6α-ethyl-24-norcholanyl-23-amine derivate behaves as full FXR agonist endowed with high binding affinity and efficacy, representing a promising lead candidate for further optimization. In addition, docking studies provide new insights into the molecular basis governing the partial and full agonist activity at FXR.
- Gioiello, Antimo,MacChiarulo, Antonio,Carotti, Andrea,Filipponi, Paolo,Costantino, Gabriele,Rizzo, Giovanni,Adorini, Luciano,Pellicciari, Roberto
-
experimental part
p. 2650 - 2658
(2011/06/11)
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- PROCESS FOR PREPARING 3α(β)-7α(β)-DIHYDROXY-6α(β)-ALKYL-5β-CHOLANIC ACID
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Process for preparing 3α-7α(β)-dihydroxy-6α(β)-alkyl-5β-cholanic acid (I) in which R is a linear or branched C1-C5 alkyl and the relative intermediates 3α-hydroxy-6β- alkyl-7-keto-5β-cholanic (VIII) and 3α-hydroxy-6α-alkyl-7-keto-5β-cholanic (IX).
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Page/Page column 13
(2008/06/13)
-
- Novel steroid agonist for FXR
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The invention relates to a FXR agonist of formula (I): ???and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.
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Page/Page column 8
(2008/06/13)
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