- Facial synthesis of key intermediate of obeticholic acid via Pd-catalyzed Kumada-Tamao-Corriu cross-coupling reaction
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Obeticholic acid (OCA) is used to treatment for Primary Biliary Cholangitis and other Famesoid X Receptor related diseases. Through the palladium catalyzed Kumada-Tamao-Corriu cross-coupling reaction, a novel and efficient method for synthesis of OCA with satisfied yield was successfully developed. The absolute configuration of the key intermediate was confirmed by Single-crystal X-ray Diffraction. It affords good strategy for large-scale synthesis of OCA.
- Di, Xiangjie,Han, Jie,Huang, Qingfei,Wang, Qiwei,Wang, Yuanhua,Wei, Xia,Zhong, Liu,Zhu, Jin,Zou, Sheng
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Read Online
- 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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Read Online
- BILE ACIDS LXIX. SELECTIVE K-SELECTRIDE REDUCTION OF 3,7-DIKETO STEROIDS
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The K-Selectride reduction at low temperature (-45 C) of 7-oxo-5α-cholestan-3β-yl acetate and methyl 7-oxo-3α-hydroxy-5β-cholanoate resulted in almost quantitative yield of the 7α-alcohol in the 5α-compound but only moderate yield of the 5β-analog.The simultaneous reduction of two carbonyl in the 3 and 7 positions afforded good to excellent yields of the diaxial diol in planar steroids (methyl 3,7-dioxo-5α-cholanoate, 3,7-dioxo-5α-cholestane and methyl 3,7-dioxo-5α-cholestan-27-oate) and only 14percent of 3α,7α-(OH)2 from methyl 3,7-dioxo-5β-cholanoate.
- Tal, Daniel M.,Frisch, G. Douglas,Elliott, William H.
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Read Online
- Method for preparing obeticholic acid
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The invention discloses a method for preparing obeticholic acid or pharmaceutically acceptable salt thereof, the method comprises the following steps: (c) carrying out hydrolysis reaction on a compound 5 to remove a carboxyl protecting group Q so as to generate a compound 6; (d) subjecting the compound 6 to a hydrogenation reaction to produce a compound 7; (e) carrying out carbonyl reduction reaction and hydrolysis reaction for removing a hydroxyl protecting group P on the compound 7 by a one-step method to generate obeticholic acid, wherein P is a hydroxyl protecting group, and Q is a carboxyl protecting group. The key intermediate product in a solid form at normal temperature is obtained through design of a synthesis route, separation and purification of the intermediate product and subsequent synthesis operation are facilitated, and the yield of each step and the purity of the intermediate product and the final product are improved.
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Paragraph 0112-0114
(2021/08/19)
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- (E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells
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Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15?μM/EC50 = 26?nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.
- Dracinsky, Martin,Drastik, Martin,Kaspar, Miroslav,Klepetarova, Blanka,Kronenberger, Thales,Kudova, Eva,Micuda, Stanislav,Pavek, Petr,Stefela, Alzbeta
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- SYNTHETIC DERIVATIVES OF CHOLIC ACID 7-SULFATE AND USES THEREOF
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The compositions and methods provided herein are related, in part, to the discovery of cholic acid 7-sulfate as a treatment for diabetes. Provided herein is a method for treating a metabolic disorder (e.g., diabetes, obesity), or an inflammatory disease (e.g., Crohn's disease, inflammatory bowel disease, ulcerative colitis, pancreatitis, hepatitis, appendicitis, gastritis, diverticulitis, celiac disease, food intolerance, enteritis, ulcer, gastroesophageal reflux disease (GERD), psoriatic arthritis, psoriasis, and rheumatoid arthritis) in a subject in need thereof comprising administering to a subject a compound of Formulae (I)-(XVII).
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Paragraph 00348-00349
(2020/07/05)
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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 24; 33
(2019/08/12)
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- 7-ketolithocholic acid intermediate and preparation process and application thereof
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The invention discloses a 7-ketolithocholic acid intermediate and a preparation process and an application thereof. Hyocholic acid is utilized as a starting material, an esterification reaction is carried out first, then a silane protection group protects a 3-hydroxyl group with high selectivity, then a specific spatial structure of 6,7-hydroxyl group of the hyocholic acid is utilized, a conventional protection method can be selectively connected to a strong leaving group at 6-position to obtain the 7-ketolithocholic acid intermediate, and the 7-ketolithocholic acid intermediate is subjected to oxidation, removal, reduction, and hydrolysis to remove a protection group to obtain a target product 7-ketolithocholic acid. The 7-ketolithocholic acid prepared by the process is high in degree ofpurity, is also simple in process step, enables a synthetize route to be greatly simplified, and enables the industrialization cost to be saved.
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Paragraph 0062; 0071; 0073; 0082
(2019/11/21)
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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 0019-0022
(2018/05/16)
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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; 0102
(2018/12/13)
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- Crystal form H of 3 alpha,7 alpha-dihydroxyl-6 alpha-ethyl-5 beta-cholanic acid as well as preparation method and application of crystal form H
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The invention provides a novel crystal form, namely a crystal form H, of 3 alpha,7 alpha-dihydroxyl-6 alpha-ethyl-5 beta-cholanic acid and further provides a preparation method of the crystal form H of 3 alpha,7 alpha-dihydroxyl-6 alpha-ethyl-5 beta-cholanic acid. The crystal form H of 3 alpha,7 alpha-dihydroxyl-6 alpha-ethyl-5 beta-cholanic acid, disclosed by the invention contains no crystal solvents or water, has a good crystal form and is good in stability, not easy to absorb moisture, suitable for recrystallization purification and capable of effectively removing impurities.
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Paragraph 0062; 0063
(2018/04/01)
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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; 0037; 0038
(2017/08/28)
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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; 0032; 0033; 0034
(2017/08/28)
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- Synthetic method of medicine intermediate for treating liver disease
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The invention discloses a synthetic method of a medicine intermediate for treating a liver disease. The intermediate is 3 alpha-hydroxy-7-keto-5 beta-cholanic acid methyl ester (II) and prepared by performing esterification reaction on raw materials such as 3 alpha-hydroxy-7-keto-5 beta-cholanic acid (I), methyl alcohol and sulfuric acid with the mass fraction of 98%. Compared with the prior art, the synthetic method has the advantages that the sulfuric acid directly replaces methane sulfonic acid, strong irritation caused by the methane sulfonic acid is decreased, harm to bodies is reduced, a product is precipitated by tap water, industrial production cost is reduced, 2mol/L sodium hydroxide solution is directly used for adjusting the pH (potential of hydrogen) of a reaction system, dosage is less, no gas is discharged, the danger of stamping is avoided, a crystallization mode is finally optimized, yield is improved, the product is purified, a column purification product is omitted, a crystallization purification product is directly used, operation is simplified while the yield and product purity are improved, time is saved, the yield can reach 96%, and the purity can reach 99%.
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Paragraph 0043; 0060-0066
(2017/08/31)
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- Method for preparing obeticholic acid from new derivative of 3alpha-hydroxy-7-oxo-5beta-cholanic acid
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The invention discloses a method for preparing obeticholic acid from a new derivative of 3alpha-hydroxy-7-oxo-5beta-cholanic acid. The synthesis method comprises the following steps: firstly, carrying out hydroxyl and carboxyl protection on the 3alpha-hydroxy-7-oxo-5beta-cholanic acid to prepare the corresponding new derivative; secondly, obtaining the obeticholic acid respectively according to two synthesis routes. According to the method disclosed by the invention, a safer protecting group reagent is utilized, and the problem that ultraviolet absorption of an intermediate is not strong is solved; the intermediate is easier to purify, the yield is improved, and the cost is reduced, so that the method is more suitable for industrialized amplification, and has remarkable creativity and actual application value.
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Paragraph 0009
(2018/03/01)
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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 0057-0059
(2017/07/20)
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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
(2017/04/11)
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- Synthesis and Biological Evaluation of Bile Acid Analogues Inhibitory to Clostridium difficile Spore Germination
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Standard antibiotic-based strategies for the treatment of Clostridium difficile infections disrupt indigenous microbiota and commonly fail to eradicate bacterial spores, two key factors that allow recurrence of infection. As an alternative approach to controlling C. difficile infection, a series of bile acid derivatives have been prepared that inhibit taurocholate-induced spore germination. These analogues have been evaluated in a highly virulent NAP1 strain using optical density and phase-contrast microscopy assays. Heterocycle substitutions at C24 were well-tolerated and several tetrazole-containing derivatives were highly potent inhibitors in both assays, with complete inhibition of spore germination observed at 10-25 μM. To limit intestinal absorption, C7-sulfated analogues designed to avoid active and passive transport pathways were prepared. One of these derivatives, compound 21b, was found to be a potent inhibitor of C. difficile spore germination and poorly permeable in a Caco-2 model of intestinal epithelial absorption, suggesting that it is likely to be gut-restricted.
- Stoltz, Kristen L.,Erickson, Raymond,Staley, Christopher,Weingarden, Alexa R.,Romens, Erin,Steer, Clifford J.,Khoruts, Alexander,Sadowsky, Michael J.,Dosa, Peter I.
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p. 3451 - 3471
(2017/05/05)
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- COMPOSITIONS AND METHODS FOR TREATING CLOSTRIDIUM ASSOCIATED DISEASES
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The present disclosure provides compounds for preventing, treating, and/or reducing the risk of developing a Clostridium-associated disease in a mammalian subject. Also provided are pharmaceutically acceptable salts of such compounds and compositions that include such compounds and/or pharmaceutically acceptable salts thereof.
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Page/Page column 58
(2017/09/08)
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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; 0143; 0144
(2017/04/25)
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- METHODS FOR PREPARATION OF BILE ACIDS AND DERIVATIVES THEREOF
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The present application relates to a method of preparing compounds of Formula (A) or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof.
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Page/Page column 72; 73
(2017/03/08)
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- DEUTERATED BILE ACID DERIVATIVES AS FXR/TGR5 AGONISTS AND METHODS OF USE THEREOF
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The present invention provides compounds of Formula (I) or Formula (II): pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated by FXR and/or TGR5.
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Paragraph 0211
(2017/09/08)
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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 18
(2018/01/17)
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- Synthesis method for obeticholic acid intermediate 7-ketolithocholic acid
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The invention discloses a chemical synthesis method for an obeticholic acid intermediate 7-ketolithocholic acid (3alpha-hydroxy-7-keto-5beta-cholestane-24-acid), and belongs to the field of organic chemical synthesis. The method adopts cholic acid as a raw material, and through 7alpha-hydroxyl selective oxidation, side chain carboxyl esterification, 3alpha-hydroxyl etherification, 12alpha-hydroxyl methanesulfonic acid esterification, elimination, hydrogenation, hydrolysis and other reactions, the obeticholic acid intermediate 7-ketolithocholic acid is synthesized. The synthesis method for 7-ketolithocholic acid adopts cheap cholic acid as the raw material, and has the advantages of novel synthesis method, low cost, high yield, environmental friendliness and convenience in industrialized production.
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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 0071; 0074; 0075
(2017/07/21)
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- 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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Paragraph 0045; 0047
(2017/01/02)
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- Chenodeoxycholic acid compound and preparation method and application thereof
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The invention discloses a compound with a structural formula (I) and a pharmaceutically-acceptable salt, solvate or amino acid conjugate thereof (shown in the description). Six substituent groups are respectively located at alpha or beta positions, the R1 represents COOH or OSO3H, and the R2 represents a halogen alkyl group, a naphthenic base, a naphthenic-alkyl group, a heterocyclic group, a heterocyclic-alkyl group, a heterocyclic aryl group, a heterocyclic aryl-alkyl group, an acyl group or an alkoxyalkyl group.
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- Method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid through copper-carrying active carbon catalytic oxidation-reduction method
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The invention discloses a method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid through a copper-carrying active carbon catalytic oxidation-reduction method. Adopted copper-carrying active carbon efficiently promotes an oxidation-reduction reaction of chenodeoxycholic acid methyl ester under the adsorption of active carbon and the catalysis of copper. According to the preparing method, under the catalysis of copper-carrying active carbon, reaction conditions are mild, and reaction efficiency is high. The purity of ursodeoxycholic acid prepared through the preparing method is high and can reach 98% or above, and the yield of ursodeoxycholic acid is 53% or so.
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- Method for synthesizing ursodesoxycholic acid with chenodeoxycholic acid by photochemical method
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The invention discloses a method for synthesizing ursodesoxycholic acid with chenodeoxycholic acid by a photochemical method. The method comprises the following steps: preparing chenodeoxycholic acid methyl ester, preparing 3alpha-hydroxyl-7-keto-5beta-methyl cholanate by a photochemical oxidation process, preparing ursodesoxycholic acid methyl ester by a photochemical reduction method, and preparing ursodesoxycholic acid. The method mainly uses the photochemical method for converting chenodeoxycholic acid to ursodesoxycholic acid, the method has the advantages of mild reaction condition, high reaction efficiency and high selectivity; and the prepared ursodesoxycholic acid has the advantages of high yield, high purity and stable quality.
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- CHOLANE DERIVATIVES FOR USE IN THE TREATMENT AND/OR PREVENTION OF FXR AND TGR5/GPBAR1 MEDIATED DISEASES
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13073PTWO 56 ABSTRACT The present invention relates to compounds having cholane scaffolds of formula (I), said compounds for use in the treatment and/or prevention of FXR and TGR5/GPBAR1 mediated diseases. 5
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Page/Page column 23-25
(2015/12/17)
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- DEUTERATED BILE ACIDS
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This disclosure relates to deuterated bile acid compositions. A deuterated compound is selected from the disclosed groups of bile acids and their derivatives, analogs and salts. At least one of the hydrogen atoms in the compound is replaced with deuterium.
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Paragraph 0051
(2015/04/28)
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- Treatment of Pulmonary Disease
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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 0178
(2014/06/11)
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- 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)
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- 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 57; 58
(2014/01/09)
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- Chemical synthesis of 3β-sulfooxy-7β-hydroxy-24-nor-5-cholenoic acid: An internal standard for mass spectrometric analysis of the abnormal Δ5-bile acids occurring in Niemann-Pick disease
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In Niemann-Pick disease, type C1, increased amounts of 3β,7β-dihydroxy-5-cholenoic acid are reported to be present in urinary bile acids. The compound occurs as a tri-conjugate, sulfated at C-3, N-acetylglucosamidated at C-7, and N-acylamidated with taurine or glycine at C-24. For sensitive LC-MS/MS analysis of this bile acid, a suitable internal standard is needed. We report here the synthesis of a satisfactory internal standard, 3β-sulfooxy-7β-hydroxy-24-nor-5-cholenoic acid (as the disodium salt). The key reactions involved were (1) the so-called "second order" Beckmann rearrangement (one-carbon degradation at C-24) of hyodeoxycholic acid (HDCA) 3,6-diformate with sodium nitrite in a mixture of trifluoroacetic anhydride and trifluoroacetic acid, (2) simultaneous inversion at C-3 and elimination at C-6 of the ditosylate derivatives of the resulting 3α,6α-dihydroxy-24-nor-5β-cholanoic acid with potassium acetate in aqueous N,N-dimethylformamide, and (3) regioselective sulfation at C-3 of an intermediary 3β,7β-dihydroxy-24-nor-Δ5 derivative using sulfur trioxide-trimethylamine complex. Overall yield of the desired compound was 1.8% in 12 steps from HDCA.
- Kakiyama, Genta,Muto, Akina,Shimada, Miki,Mano, Nariyasu,Goto, Junichi,Hofmann, Alan F.,Iida, Takashi
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p. 766 - 772
(2009/09/05)
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- Selective dimethyldioxirane oxidation of bile acid methyl esters
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DMDO oxidation of the hydroxy groups of bile acid methyl esters establishes the positional order of reactivity as 3-7 > 6 > 12 and supports a mechanism involving C-H oxygen insertion through a planar intramolecularly hydrogen bonded transition state.
- Buxton, P. Christopher,Marples, Brian A.,Toon, Richard C.,Waddington, Victoria L.
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p. 4729 - 4732
(2007/10/03)
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- Microwave-induced organic reactions of bile acids: Esterification, deformylation and deacetylation using mild reagents
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An efficient and convenient procedure for the esterification, deformylation, and deacetylation of bile acids is described.This is achieved by the addition of a catalytic amount of methanesulfonic acid or para-toluene sulfonic acid to a solution of bile acid in methanol in the domestic microwave oven.All these reactions were completed in the microwave oven within 1-3 min at 60percent power (390 W) and the desired bile acids, namely trihydroxy-5β-cholestanoic acid, (23R)-3α,7α,23-trihydroxy-5β-cholan-24-oic acid, ursocholic acid and 7-ketolithocholic acid were isolated in 86-94percent yield. - Keywords: microwave; bile acids; esterification; deformylation; deacetylation; methanesulfonic acid/methanol; para-toluene sulfonic acid/methanol
- Dayal, B.,Rao, Keshava,Salen, G.
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p. 453 - 457
(2007/10/02)
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- An efficient synthesis of 4β and 6α-hydroxylated bile acids
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An efficient method for the preparation of 4β- and 6α-hydroxylated bile acids has been developed.It involved a highly stereoselective acetoxylation at the 4β and 6α positions of 3- and 7-oxo bile acids, respectively, with lead tetraacetate in the presence of boron trifluoride etherate in acetic acid.Reduction of the resulting α-acetoxy ketones with sodium borohydride or tert-butylamine borane complex, and alkaline hydrolysis, provided the desired bile acids in good yields. Keywords: sterols; bile acid; 4β-hydroxylated bile acid;6α-hydroxylated bile acid; acetoxylation; lead tetraacetate oxidation
- Yoshimura, Teruki,Mahara, Reijiro,Kurosawa, Takao,Ikegawa, Shigeo,Tohma, Masahiko
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- REGIOSELECTIVE REDUCTION OF POLYKETONES ON SILICA GEL SURFACE WITH BORANE-TRIMETHYLAMINE COMPLEX
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Steroidal diones and trione, bicyclic diones (7 and 8) and a tricyclic dione were adsorbed on silica gel and reduced with BH3*NMe3.The carbonyl groups at C-3 of the steroids, at C-4 of 7 and at C-3 of 8 were reduced regioselectively.The FT-IR spectra of 5α- and 5β-androstane-3,17-dione adsorbed on silica gel were measured.
- Gohzu, Shun-ichi,Tada, Masahiro
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