CN106854229A - One class soap, it is prepared and its in application pharmaceutically - Google Patents
One class soap, it is prepared and its in application pharmaceutically Download PDFInfo
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- CN106854229A CN106854229A CN201510890931.8A CN201510890931A CN106854229A CN 106854229 A CN106854229 A CN 106854229A CN 201510890931 A CN201510890931 A CN 201510890931A CN 106854229 A CN106854229 A CN 106854229A
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- cholic acid
- shellfish cholic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Steroid Compounds (AREA)
Abstract
The invention discloses a class soap, it is prepared and its in application pharmaceutically.Specifically, the present invention relates to the new derivative shown in a kind of logical formula (I) and the pharmaceutical composition containing it, and preparation method thereof.Pharmaceutical composition the invention also discloses the derivative and containing it is in farnesoid X receptor activator, and the application in treatment and/or prevention PBC and non-alcohol fatty liver, hepatic injury, the medicine of dyslipidemic disease is prepared.Each substitution base of its formula of (I) is identical with the definition in specification.
Description
Technical field
The invention discloses a class soap, it is prepared and its in application pharmaceutically.
Pharmaceutical composition the invention also discloses the derivative and containing it is in farnesoid X receptor activator, and the application in treatment and/or prevention PBC and non-alcohol fatty liver, hepatic injury, the medicine of dyslipidemic disease is prepared.
Background technology
Nonalcoholic fatty liver disease is a kind of chronic liver disease, and the cause of disease not yet clearly, causes chronic inflammation to cause cirrhosis at present.In the U.S., about 12% adult suffers from the disease, and 2.7% final develops into cirrhosis (patient's number up to 6,000,000).Nonalcoholic fatty liver disease is the principal indication of liver transfer operation, more than chronic hepatitis C, AML.
The liver-protecting medicines such as the drug therapy disease that there is no FDA to ratify at present, clinic conventional Polyene Phosphatidylcholine, silymarin, urso, glycyrrhizic acid.
Farnesoid X receptor activator Austria shellfish cholic acid (Obeticholic acid, OCA) of Intercapt Pharmaceuticals exploitations, by activating farnesoid X receptor, suppresses the gene expression of cytochromes 7A1 (CYP7A1) indirectly.Because CYP7A1 is the rate-limiting enzyme of cholic acid biosynthesis, therefore shellfish cholic acid difficult to understand can suppress cholic acid synthesis, for treating PBC (Primary biliary cirrhosis,) and non-alcohol fatty liver (Nonalcoholic steatohepatis, NASH) PBC.On January 9th, 2014, Intercept Pharmaceuticals announce that the clinical test of shellfish cholic acid treatment PBC difficult to understand reaches Major Clinical terminal, therefore determine to shift to an earlier date termination test, and application for quotation is have submitted to FDA and EMA.III clinical trial phases for non-alcohol fatty liver are in progress.2015, FDA authorized breakthrough sex therapy status of the shellfish cholic acid difficult to understand to the NASH with hepatic fibrosis-renal tubular ectasia syndrome.
But reported according to document (US2013345188), the solubility of shellfish cholic acid difficult to understand is excessively poor, equilbrium solubility in hydrochloric acid is about 3.8ug/ml, specification solubility is 20ug/ml for 5mg/250ml, belongs to the IV medicines of low-solubility hypotonicity in Biopharmaceutics Classification (BCS).
Therefore, we perform the derivatization the shellfish cholic acid difficult to understand of slightly solubility, are made carboxylate, significantly improve the dissolubility of proto-drug.In addition, choline is the fat metabolism regulating drug being currently known, can be cooperateed with shellfish cholic acid difficult to understand, the lipid metaboli to metabolic disorder patient plays coordinated regulation effect.
The content of the invention
A class soap as described in leading to formula (I),
Wherein：B is selected from organic amine, inorganic metal ion.
Compound of the present invention, wherein B are selected from fatty amine, basic amino acid.
Compound of the present invention, wherein B are selected from alkali metal ion.
Compound of the present invention, preferably with the compound of following structure：
The present invention also provides a kind of pharmaceutical composition, it is characterised in that comprising compound and one or more pharmaceutical carrier and/or diluent described in 0.001-10g claim any one of 1-4, be made suitable for clinical pharmaceutical preparation.
The present invention also provides a kind of pharmaceutical composition, preferably is selected from tablet, capsule.
The present invention also provides the application of the compound and pharmaceutical composition in the medicine for preparing treatment and/or prevention PBC and non-alcohol fatty liver.
Present invention also offers the preparation method of the compound, it is characterised in that：Shellfish cholic acid difficult to understand, in a solvent into salt, obtains compound described in logical formula (I) with alkali.
General compound synthesis route is as follows：
In preparation method of the present invention, " alkali compounds " is using known organic base or inorganic base in organic synthesis, include but are not limited to, choline, NaOH, calcium carbonate, calcium bicarbonate, potassium carbonate, sodium carbonate, sodium acid carbonate, cesium carbonate, potassium fluoride, pyridine, triethylamine, diethylamine, N, N- lutidines, monoethanolamine, diethanol amine, lysine, arginine, methyllysine etc.；The solvent is known common solvent in organic synthesis, is included but are not limited to, water, methyl alcohol, ethanol, isopropanol, normal propyl alcohol, n-butanol, isobutanol, ethyl acetate, methyl acetate, isopropyl acetate, toluene, dichloromethane, chloroform etc..
Formula (I) compound is used for mammal shown in of the invention, and such as mankind, preparation used includes but are not limited to oral formulations.
Oral formulations of the present invention include tablet, capsule.In these solid pharmaceutical preparations, formula (I) compound of the present invention is active component, is mixed with one or more inert excipients, such as diluent, includes but are not limited to microcrystalline cellulose, starch, cornstarch, mannitol, lactose etc.；Adhesive, includes but are not limited to hydroxymethyl cellulose, gelatin, polyvinylpyrrolidone etc.；Disintegrant, includes but are not limited to sodium carboxymethylcellulose, sodium carboxymethyl starch, agar, starch etc.；Lubricant, includes but are not limited to talcum, magnesium stearate, calcium stearate etc..
Specific embodiment
Embodiment 1：The preparation of 3 α, 7-6 α of alpha-dihydroxy-β of ethyl-5-cholanic acid choline (OCAS-1)
By in shellfish cholic acid (420mg, 1mmol) difficult to understand addition 10mL isopropanols, 60 DEG C are heated to.It is added thereto to the 2mL aqueous isopropanols of the methanol solution (270mg, 1mmol) of 45%wt choline.Mixture it is molten it is clear after continue at 60 DEG C and stir 30 minutes, be subsequently reduced to room temperature, be stirred at room temperature overnight.Suction filtration, filter cake isopropanol is washed (5mL), collects solid, and 40-45 DEG C of drying under reduced pressure 6 hours obtains OCAS-1,480mg, yield 91.6%, white solid.
1H NMR (400MHz, DMSO-d6) δ 4.32 (m, 1H), 4.20 (m, 1H), 4.05 (d, 1H), 3.90 (m, 2H), 3.55 (m, 2H), 3.48 (m, 1H), 3.28 (s, 9H), 3.13 (m, 1H), 2.23 (m, 1H), 2.13 (m, 1H), 1.90 (m, 1H), 1.82-1.69 (m, 6H), 1.54-0.81 (m, 27H), 0.61 (m, 3H)
LCMS (ESI) m/z, 421.4 (M+1)+, 104.2 (choline)
Embodiment 2：The preparation of 3 α, 7-6 α of alpha-dihydroxy-β of ethyl-5-cholanic acid ethanolamine salt (OCAS-2)
Method replaces choline solution, obtains OCAS-2,451mg, yield 93.9%, white solid with embodiment 1, the aqueous isopropanol (2mL) using monoethanolamine (61mg, 1mmol).
1H NMR (400MHz, DMSO-d6) δ 9.51 (br s, 3H), 4.31 (m, 1H), 4.20 (m, 2H), 4.11 (m, 1H), 4.04 (d, 1H), 3.55 (m, 2H), 3.46 (m, 1H), 3.12 (m, 1H), 2.21 (m, 1H), 2.11 (m, 1H), 1.88 (m, 1H), 1.82-1.65 (m, 6H), 1.51-0.80 (m, 27H), 0.60 (m, 3H)
LCMS (ESI) m/z, 421.4 (M+1)+
Embodiment 3：The preparation of 3 α, 7-6 α of alpha-dihydroxy-β of ethyl-5-cholanic acid diethanolamine salt (OCAS-3)
Method replaces choline solution, obtains OCAS-3,490mg, yield 93.3%, white solid with embodiment 1, the aqueous isopropanol (2mL) using diethanol amine (107mg, 1mmol).
1H NMR (400MHz, DMSO-d6) δ 9.40 (br s, 2H), 4.29 (m, 1H), 4.25 (m, 4H), 4.16 (m, 2H), 4.06 (d, 1H), 3.56 (m, 4H), 3.41 (m, 1H), 3.13 (m, 1H), 2.25 (m, 1H), 2.14 (m, 1H), 1.90 (m, 1H), 1.84-1.60 (m, 6H), 1.49-0.81 (m, 27H), 0.61 (m, 3H)
LCMS (ESI) m/z, 421.4 (M+1)+, 106.1 (diethanol amine)
Embodiment 4：The preparation of 3 α, 7-6 α of alpha-dihydroxy-β of ethyl-5-cholanic acid triethylamine salt (OCAS-4)
Method replaces choline solution, obtains OCAS-4,475mg, yield 91.2%, white solid with embodiment 1, the aqueous isopropanol (2mL) using triethylamine (101mg, 1mmol).
1H NMR (400MHz, DMSO-d6) δ 8.99 (br s, 1H), 4.27 (m, 1H), 4.08 (d, 1H), 3.41 (m, 1H), 3.22 (m, 6H), 3.15 (m, 1H), 2.25 (m, 1H), 2.13 (m, 1H), 1.92 (m, 1H), 1.80-1.59 (m, 6H), 1.51-0.80 (m, 36H), 0.61 (m, 3H)
LCMS (ESI) m/z, 421.4 (M+1)+, 102.1 (triethylamines)
Embodiment 5：The preparation of 3 α, 7-6 α of alpha-dihydroxy-β of ethyl-5-cholane acid sodium-salt (OCAS-5)
Shellfish cholic acid (420mg, 1mmol) difficult to understand is added in 5mL methyl alcohol, add the 5mL aqueous solution of NaOH (40mg, 1mmol), be stirred overnight at room temperature.Reaction system is freezed, OCAS-5,438mg, quantitative yield, white solid is obtained.
1H NMR (400MHz, DMSO-d6) δ 4.30 (m, 1H), 4.03 (d, 1H), 3.46 (m, 1H), 3.12 (m, 1H), 2.26 (m, 1H), 2.16 (m, 1H), 1.90 (m, 1H), 1.80-1.65 (m, 6H), 1.50-0.80 (m, 27H), 0.62 (m, 3H)
LCMS (ESI) m/z, 421.4 (M+1)+
Embodiment 6：The preparation of 3 α, 7-6 α of alpha-dihydroxy-β of ethyl-5-cholane acid calcium salt (OCAS-6)
Shellfish cholic acid (420mg, 1mmol) difficult to understand is added in 5mL methyl alcohol, add the 5mL aqueous solution of calcium bicarbonate (161mg, 1mmol), be stirred overnight at room temperature.Reaction system is freezed, OCAS-6,440mg, quantitative yield, white solid is obtained.
1H NMR (400MHz, DMSO-d6) δ 4.31 (m, 1H), 4.01 (d, 1H), 3.46 (m, 1H), 3.13 (m, 1H), 2.23 (m, 1H), 2.13 (m, 1H), 1.91-1.70 (m, 7H), 1.53-0.81 (m, 27H), 0.61 (m, 3H)
LCMS (ESI) m/z, 421.4 (M+1)+
Embodiment 7：The preparation of 3 α, 7-6 α of alpha-dihydroxy-β-cholanic acids-1B salt of ethyl-5 (OCAS-7)
Method, using 1B (146mg, 1mmol), obtains OCAS-7,544mg, quantitative yield, white solid with embodiment 5
1H NMR (400MHz, D2O) δ 4.40 (m, 1H), 4.11 (d, 1H), 3.38 (m, 1H), 3.11 (m, 1H), 3.00 (m, 2H), 2.25 (m, 1H), 2.08 (m, 1H), 1.91-0.81 (m, 40H), 0.61 (m, 3H)
LCMS (ESI) m/z, 421.4 (M+1)+, 147.1 (lysines)
Embodiment 8：Compound solubility is determined
Embodiment 9：The preparation of OCAS-1 pieces
OCAS-1 is well mixed with microcrystalline cellulose, sodium carboxymethyl starch, using wet granulation, is dried (moisture 1-2%).It is well mixed with magnesium stearate, compressing tablet, is coated, packaging.
Embodiment 10：The preparation of OCAS-1 capsules
OCAS-1 is well mixed with microcrystalline cellulose, sodium carboxymethyl starch, using wet granulation, is dried (moisture 1-2%).It is well mixed with magnesium stearate, is packed into No. 0 capsule shells, is packed.
Claims (8)
1. lead to formula (I) as described in a class soap,
Wherein：B is selected from organic amine, amino acid, inorganic metal ion.
2. the compound of claim 1, wherein B is selected from fatty amine, basic amino acid.
3. the compound of claim 1, wherein B is selected from alkali metal ion.
4. compound described in any one of claim 1-3, wherein preferred compound is；Shellfish cholic acid choline difficult to understand, it is difficult to understand
Shellfish cholic acid ethanolamine salt, shellfish cholic acid diethanolamine salt difficult to understand, shellfish cholic acid triethylamine salt difficult to understand, shellfish sodium taurocholate difficult to understand is difficult to understand
Shellfish cholic acid calcium, shellfish cholic acid -1B salt difficult to understand.
5. a kind of pharmaceutical composition, it is characterised in that comprising the change described in 0.001-10g claim any one of 1-4
Compound and one or more pharmaceutical carrier and/or diluent, are made suitable for clinical pharmaceutical preparation.
6. claim 5 described pharmaceutical composition, preferably is selected from tablet, capsule.
7. compound described in any one of claim 1-6 and pharmaceutical composition are preparing treatment and/or prevention primary courage
Application in juice cirrhosis and non-alcohol fatty liver, hepatic injury, the medicine of dyslipidemic disease.
8. the preparation method of compound described in any one of claim 1-6, it is characterised in that：Shellfish cholic acid difficult to understand and alkalescence
Compound obtains compound described in logical formula (I) in a solvent into salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510890931.8A CN106854229A (en) | 2015-12-08 | 2015-12-08 | One class soap, it is prepared and its in application pharmaceutically |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510890931.8A CN106854229A (en) | 2015-12-08 | 2015-12-08 | One class soap, it is prepared and its in application pharmaceutically |
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| CN106854229A true CN106854229A (en) | 2017-06-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510890931.8A Pending CN106854229A (en) | 2015-12-08 | 2015-12-08 | One class soap, it is prepared and its in application pharmaceutically |
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002072598A1 (en) * | 2001-03-12 | 2002-09-19 | Roberto Pellicciari | Steroids as agonists for fxr |
| WO2010069604A1 (en) * | 2008-12-19 | 2010-06-24 | Royal College Of Surgeons In Ireland | Treatment of diarrhoea |
| CN102282157A (en) * | 2008-11-19 | 2011-12-14 | 英特塞普特医药品公司 | TGR5 Modulators and Methods of Use Thereof |
| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
| WO2015183794A1 (en) * | 2014-05-27 | 2015-12-03 | City Of Hope | Tgr5 agonist complexes for treating diabetes and cancer |
| CN106279328A (en) * | 2015-05-20 | 2017-01-04 | 重庆药友制药有限责任公司 | A kind of method preparing 6 alpha-alkyl chenodeoxycholic acid |
| CN106589038A (en) * | 2015-10-15 | 2017-04-26 | 重庆医药工业研究院有限责任公司 | Method for preparing 3alpha,7alpha-dyhydroxyl-6alpha-ethyl-5beta-cholanic acid |
| CN106632564A (en) * | 2015-10-30 | 2017-05-10 | 苏州泽璟生物制药有限公司 | Obeticholic acid salt and amorphous material thereof, and pharmaceutical composition |
-
2015
- 2015-12-08 CN CN201510890931.8A patent/CN106854229A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002072598A1 (en) * | 2001-03-12 | 2002-09-19 | Roberto Pellicciari | Steroids as agonists for fxr |
| CN102282157A (en) * | 2008-11-19 | 2011-12-14 | 英特塞普特医药品公司 | TGR5 Modulators and Methods of Use Thereof |
| WO2010069604A1 (en) * | 2008-12-19 | 2010-06-24 | Royal College Of Surgeons In Ireland | Treatment of diarrhoea |
| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
| WO2015183794A1 (en) * | 2014-05-27 | 2015-12-03 | City Of Hope | Tgr5 agonist complexes for treating diabetes and cancer |
| CN106279328A (en) * | 2015-05-20 | 2017-01-04 | 重庆药友制药有限责任公司 | A kind of method preparing 6 alpha-alkyl chenodeoxycholic acid |
| CN106589038A (en) * | 2015-10-15 | 2017-04-26 | 重庆医药工业研究院有限责任公司 | Method for preparing 3alpha,7alpha-dyhydroxyl-6alpha-ethyl-5beta-cholanic acid |
| CN106632564A (en) * | 2015-10-30 | 2017-05-10 | 苏州泽璟生物制药有限公司 | Obeticholic acid salt and amorphous material thereof, and pharmaceutical composition |
Non-Patent Citations (1)
| Title |
|---|
| 尤启冬: "《药物化学》", 28 February 2011, 中国医药科技出版社 * |
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Application publication date: 20170616 |