CN104774236A - Fatty acid-bile acid conjugates having fat lowering activity, and medical uses thereof - Google Patents

Fatty acid-bile acid conjugates having fat lowering activity, and medical uses thereof Download PDF

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CN104774236A
CN104774236A CN201410012629.8A CN201410012629A CN104774236A CN 104774236 A CN104774236 A CN 104774236A CN 201410012629 A CN201410012629 A CN 201410012629A CN 104774236 A CN104774236 A CN 104774236A
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acceptable salt
pharmacy acceptable
compound described
acid
toxic
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仲伯华
祝传宝
姚宜山
史卫国
樊士勇
贾红新
付仁芳
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

The invention relates to new fatty acid-bile acid conjugates having fat lowering activity and represented by a formula I, non-toxic pharmaceutically-acceptable salts, drug compositions containing the compounds as active components, and uses of the fatty acid-bile acid conjugate, the non-toxic pharmaceutically-acceptable salts, and the drug compositions in fat lowering drug preparation. According to the present invention, in the structure formula I, the bile acid 3-OH is conjugated with the alpha amino of lysine, and then the carboxyl of the fatty acid and the epsilon amino of the lysine form the amide bond, such that the bile acid 24-COOH adopted as the specific bile acid recognition group is retained; and in the structure formula I, R1 represents the following formula, R2 represents the following formula, and n is an integer of 8-22.

Description

There is fatty acid bile acid couplet and the medicinal use thereof of Lipid-lowering activities
Technical field
The present invention relates to the new fatty acid bile acid couplet with Lipid-lowering activities and atoxic pharmacy acceptable salt thereof and containing these compounds as the pharmaceutical composition of activeconstituents and preparing the purposes in fat-reducing medicament.
Background technology
Hyperlipidemia is the Major Risk Factors causing cardiovascular disorder, also with obesity, and metabolic syndrome and diabetes B height correlation. use fat-reducing medicament effectively can reduce cardiovascular risk.Fibrate such as fenofibrate and statins such as Simvastatin and Zarator are the most frequently used fat-reducing medicaments.Fibrate and statins are respectively by activation PPAR α acceptor and suppress HMG CoA reductase enzyme to play effect for reducing fat.In general, this two classes drug safety is higher, but has increasing data to show, fibrate and statins can cause liver enzyme and creatinine to raise, and cause myalgia.The life-time service of statins may cause the rising of New-Onset Diabetes Mellitus sickness rate, also may cause cognitive impairment.Therefore, the fat-reducing medicament that clinical needs are safer and more effective.
Lipid acid-bile acid couplet (Fatty Aacid Bile Acid Conjugates, FABACs) be the conjugates (US Patent No. 6384024, US6589946 and US6395722) of the lipid metabolism regulating effect had formed by saturated fatty acid and bile acid derivative coupling, to the hyperlipidaemia caused by disorders of lipid metabolism, atherosclerosis, fatty liver and gallbladdergallstonecholetithiasis, all there is good preventive and therapeutic effect.
In the research work in our early stage, our design and synthesis bile acide 24-COOH is by the new bile acide lipid acid conjugates (BA-L-FA) (Chinese patent CN101367859A) of Methionin and lipid acid coupling.
But, in FABACs molecule, change 3 of bile acide hydroxyls into amino, then form amido linkage with saturated fatty acid.The derivatize of bile acide 3 hydroxyls, causes irreversible change to bile acide structure, may cause unpredictable toxicity or side effect thus; And in BA-L-FA molecule, bile acide 24 carboxyls are connection site; Because 24 carboxyls are the required structures of bile acide specificity, take 24-COOH as crosslinked group, its liver target can be affected.
Summary of the invention
The invention provides by the new fatty acid bile acid couplet shown in structural formula I and non-toxic pharmacy acceptable salt thereof:
In structural formula I, we utilize bile acide 3-OH by the α amino coupled of carbamate and Methionin, and then by amino to the carboxyl of lipid acid and the ε of Methionin become amido linkage; Remain bile acide 24-COOH like this as bile acide specific recognition group.R in structural formula I 1representative or r 2representative or n is the integer of 8-22.
The present invention also provides lipid acid conjugates and the non-toxic pharmacy acceptable salt thereof of the cholic acid shown in formula I or ursodesoxycholic acid, and these salt can be formed by the carboxyl in I molecule and various positively charged ion such as sodium ion, potassium ion, ammonium ion, calcium ion, zine ion, magnesium ion or ammonium ion etc.
The pharmaceutical composition that the present invention also provides on the other hand the lipid acid conjugates containing the cholic acid representated by formula I or ursodesoxycholic acid and atoxic pharmacy acceptable salt thereof to be formed as activeconstituents and suitable excipient.These pharmaceutical compositions can be solution, tablet, capsule or injection; These pharmaceutical compositions can pass through injection administration or oral administration.
The present invention also provides the lipid acid conjugates of the cholic acid representated by the formula I by awarding effective therapeutic dose or ursodesoxycholic acid and atoxic pharmacy acceptable salt and pharmaceutical composition thereof thereof to treat the purposes of the disease medicaments such as hyperlipidemia, gallbladdergallstonecholetithiasis, fatty liver and atherosclerosis in preparation on the other hand.
Compound I can be prepared by following synthetic route:
Embodiment
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.
Embodiment 1N α-acyl-oxygen cholic acid-N ε-mnyristoyl-Methionin (I 1) synthesis
1.1 Methyl cholate (II 1) synthesis
The bath of 200ml anhydrous methanol cryosel is cooled to-10 DEG C, and after homo(io)thermism, slowly drip 20ml Acetyl Chloride 98Min., reacting liquid temperature is no more than-5 DEG C.Maintain cryosel and bathe 1 hour, after clear-cutting forestland room temperature, add 20g (48.95mM) cholic acid, react 2 hours, TLC monitors reaction.After completion of the reaction, by reaction solution impouring 400ml water, ether (100ml × 3) extraction 3 times, merges diethyl ether solution, uses saturated NaHCO respectively 3solution, saturated NaCl solution are washed, anhydrous Na 2sO 4dry.Filtering siccative, removal of solvent under reduced pressure, obtains crude white solid 19.14g, yield 92.53%.(TLC: sherwood oil: ethyl acetate=1: 2, R f=0.2-0.3)
1.2O-(p-nitrophenyl oxygen acyl group)-Methyl cholate (III 1) synthesis
By 19.86g (47mM) Methyl cholate (II at 0 DEG C 1) be dissolved in 60ml pyridine, add 14.30g (71mM) 4-chloroformate nitrophenyl ester while stirring.Reaction solution stirs 30 minutes at 0 DEG C, then stirred at ambient temperature 1 hour.Reaction solution is poured in 500ml1N hydrochloric acid, and be extracted with ethyl acetate 3 times.Combined ethyl acetate, washs 3 times by saturated NaCl solution, anhydrous Na 2sO 4dry.Filtering siccative, removal of solvent under reduced pressure, (sherwood oil: ethyl acetate=3: 1), obtains white solid 5.5g to column chromatography for separation, yield 19.91%. 1H-NMR，δ(ppm，DMSO-d 6)：8.322-8.299(2H，m)；7.563-7.541(2H，m)；4.504-4.482(1H，m)；4.200-4.192(2H)；3.799-3.792(1H)；3.593-3.576(4H)；0.596(3H，s)。
1.3N εthe synthesis of-carbobenzoxy-(Cbz)-lysine methyl ester tosilate
2.8g (10mM) N ε-carbobenzoxy-(Cbz) Methionin (H-Lys (Z)-OH) is suspended in 45ml methyl alcohol, adds 2.10g (11mM) hydration tosic acid (TsOHH 2o), reflux, solution clarification soon, refluxes 24 hours.React complete, concentrating under reduced pressure obtains light yellow viscous liquid, adds 100ml anhydrous diethyl ether, and grinding makes it solidification, filters to obtain white solid 4.45g, yield 95.7%.
1.4N α-acyl-oxygen Methyl cholate-N ε-carbobenzoxy-(Cbz)-lysine methyl ester (IV 1) synthesis
By 5.24g (11.23mM) N ε-carbobenzoxy-(Cbz)-lysine methyl ester tosilate is dissolved in 50ml and heavily steams in DMF, adds 6g (10.2mM) III 1, drip 3.43ml (24.7mM) triethylamine, in reaction solution, produce white precipitate.React 12 hours at 50 DEG C, TLC monitors reaction, and after completion of the reaction, poured into by reaction solution in 150m11N hydrochloric acid, extraction into ethyl acetate 3 times, combined ethyl acetate layer, washs 3 times by saturated NaCl solution, anhydrous Na 2sO 4dry.After filtering siccative, (sherwood oil: ethyl acetate: methyl alcohol=30: 30: 1), obtains pale yellow oil 4.50g to column chromatography for separation, yield 59.38%.
1.5N α-acyl-oxygen Methyl cholate-lysine methyl ester (V 1) synthesis
By 4.50g (6.06mM) IV 1be dissolved in 20ml anhydrous methanol, under cold salt bath cooling, add 3g Pd-C (moisture 67.8%).Catalytic hydrogenation under normal temperature and pressure, TLC monitors reaction, until raw material total overall reaction is complete.Suction filtration removing Pd-C, 30 DEG C of removal of solvent under reduced pressure, obtain faint yellow solid 2.543g, yield 68.93%.
1.6N α-acyl-oxygen Methyl cholate-N ε-mnyristoyl-lysine methyl ester (VI 1)
0.609g (1mM) V 1be dissolved in 2ml THF, add 0.116ml (1.05mM) N-methylmorpholine, put into refrigerator stand-by.Take 0.24g (1.05mM) 14 carbon fatty acid, be dissolved in 10ml THF, cryosel bath is cooled to-10 DEG C, adds 0.116ml (1.05mM) N-methylmorpholine, 0.138ml (1.05mM) isobutyl chlorocarbonate successively.After 5 minutes, the THF solution of I-5 is poured in reaction flask.Maintain cryosel and bathe 1 hour, clear-cutting forestland room temperature, stir and spend the night (24 hours).TLC monitors reaction, after completion of the reaction, and removal of solvent under reduced pressure.DCM dissolves, and uses 1N H successively 3pO 4solution, saturated NaCl solution, 5%NaHCO 3solution, saturated NaCl solution wash 3 times, anhydrous Na 2sO 4dried overnight.Filtering siccative, removal of solvent under reduced pressure, column chromatography for separation (sherwood oil: ethyl acetate: methyl alcohol=30: 30: 1).Obtain pale yellow oil 0.573g, yield 69.96%.
1.7N α-acyl-oxygen cholic acid-N ε-mnyristoyl-Methionin (I 1) synthesis
0.573g (0.70mM) VI 1be dissolved in 6ml methyl alcohol, drip the 6ml2N LiOH aqueous solution (0.504g LiOHH 2o, 12mM).React 12 hours, TLC monitors reaction.After reaction terminates, removal of solvent under reduced pressure at 30 DEG C.Add 150ml distilled water to dissolve, after elimination insolubles, with vigorous stirring, slowly drip 1N H 3pO 4solution is about 3 to pH value.Filtration obtains white precipitate, with 30ml distilled water wash filter cake, dry, weighs, obtains product 0.402g, yield 72.56%. 1H-NMR，δ(ppm，DMSO-d6)：12.230(2H，br)；7.742-7.728(1H，t)；7.238-7.217(1H，d)；4.150-4.120(3H)；3.792(2H，m)；3.621(1H，m)；2.997-2.982(2H，m)；0.592(3H，s)。
Embodiment 2N α-acyl-oxygen cholic acid-N ε-hexadecanoyl-Methionin (I 2) synthesis
With reference to the method for embodiment 1, replace tetradecacarbon fatty acid, with V with 16 carbon fatty acids 1reaction, obtains N α-acyl-oxygen Methyl cholate-N ε-hexadecanoyl-lysine methyl ester (VI 2); By VI 2deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：12.214(2H，br)；7.739-7.725(1H，t)；7.240-7.220(1H，d)；4.155(1H，m)；4.148-4.126(2H，d)；3.794(2H，m)；3.621(1H，m)；2.997-2.982(2H，m)；0.591(3H，s)。
Embodiment 3N α-acyl-oxygen cholic acid-N ε-stearoyl-Methionin (I 3) synthesis
With reference to the method for embodiment 1, replace tetradecacarbon fatty acid, with V with 18 carbon fatty acids 1reaction, obtains N α-acyl-oxygen Methyl cholate-N ε-stearoyl-lysine methyl ester (VI 3); By VI 3deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：12.179(2H，br)；7.733-7.719(1H，t)；7.218-7.199(1H，d)；4.278(1H，m)；4.143-4.120(2H，d)；3.793(2H，m)；3.623(1H，m)；2.999-2.984(2H，m)；0.591(3H，s)。
Embodiment 4N α-acyl-oxygen cholic acid-N ε-two ten acyls-Methionin (I 4) synthesis
With reference to the method for embodiment 1, replace tetradecacarbon fatty acid, with V with 20 carbon fatty acids 1reaction, obtains N α-acyl-oxygen Methyl cholate-N ε-two ten acyls-lysine methyl ester (VI 4); By VI 4deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：12.202(2H，br)；7.741-7.727(1H，t)；7.217-7.197(1H，d)；4.144-4.120(3H)；3.794(2H，m)；3.625(1H，m)；3.001-2.986(2H，m)；0.592(3H，s)。
Embodiment 5N α-acyl-oxygen cholic acid-N ε-two dodecanoyl-Methionin (I 5) synthesis
With reference to the method for embodiment 1, replace tetradecacarbon fatty acid, with V with 22 carbon fatty acids 1reaction, obtains N α-acyl-oxygen Methyl cholate-N ε-two dodecanoyl-lysine methyl ester (VI 5); By VI 5deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：12.17(2H，br)；7.717-7.703(1H，t)；7.189-7.169(1H，d)；4.177-4.087(3H)；3.791(2H)；3.623(1H，m)；2.998-2.983(2H，m)；0.591(3H，s)。Embodiment 6N α-acyl-oxygen ursodesoxycholic acid-N ε-mnyristoyl-Methionin (I 6) synthesis
With reference to the method for embodiment 1, replace cholic acid with ursodesoxycholic acid, with excess acetyl chloride, prepare ursodesoxycholic acid methyl esters (II 2); Use II 2replace II 1react with 4-chloroformate nitrophenyl ester, preparation O-(p-nitrophenyl oxygen acyl group)-ursodesoxycholic acid methyl esters (III 2); Use III 2replace III 1with N ε-carbobenzoxy-(Cbz)-lysine methyl ester tosic acid reactant salt, preparation N α-acyl-oxygen ursodesoxycholic acid methyl esters-N ε-carbobenzoxy-(Cbz)-lysine methyl ester (IV 2); By IV 2catalytic hydrogenation, preparation N α-acyl-oxygen ursodesoxycholic acid methyl esters-lysine methyl ester (V 2); Use V 2replace V 1react with 14 carbon fatty acids, obtain N α-acyl-oxygen ursodesoxycholic acid methyl esters-N ε-mnyristoyl-lysine methyl ester (VI 6); By VI 2deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：12.240(2H，br)；7.753-7.740(1H，t)；7.219-7.199(1H，d)；4.378-4.367(1H，m)；3.929(1H，d)；3.846(1H，m)；3.001-2.986(2H，m)；0.618(3H，s)。
Embodiment 7N α-acyl-oxygen ursodesoxycholic acid-N ε-hexadecanoyl-Methionin (I 7) synthesis
With reference to the method for embodiment 1, use V 2replace V 1react with 16 carbon fatty acids, obtain N α-acyl-oxygen ursodesoxycholic acid methyl esters-N ε-hexadecanoyl-lysine methyl ester (VI 7); By VI 7deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：7.722-7.695(1H，t)；6.867-6.849(1H，d)；4.379-4.360(1H，m)；3.787-3.757(1H，m)；3.282-3.254(1H，m)；2.994-2.979(2H，m)；0.618(3H，s)。
Embodiment 8N α-acyl-oxygen ursodesoxycholic acid-N ε-stearoyl-Methionin (I 8) synthesis
With reference to the method for embodiment 1, use V 2replace V 1react with 18 carbon fatty acids, obtain N α-acyl-oxygen ursodesoxycholic acid methyl esters-N ε-stearoyl-lysine methyl ester (VI 8); By VI 8deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：7.720-7.692(1H，t)；6.970-6.952(1H，d)；4.382(1H，m)；3.802-3.782(1H，m)；2.996-2.981(2H，q)；0.618(3H，s)。
Embodiment 9N α-acyl-oxygen ursodesoxycholic acid-N ε-ten nine acyls-Methionin (I 9) synthesis
With reference to the method for embodiment 1, use V 2replace V 1react with 19 carbon fatty acids, obtain N α-acyl-oxygen ursodesoxycholic acid methyl esters-N ε-ten nine acyls-lysine methyl ester (VI 9); By V1 9deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：12.21(2H，br)；7.71-7.69(1H，t)；7.17-7.15(1H，d)；4.34-4.32(1H，m)；3.91-3.89(1H，d)；3.80(1H，m)；2.96-2.94(2H，m)；0.58-0.54(3H，s)。
Embodiment 10N α-acyl-oxygen ursodesoxycholic acid-N ε-two ten acyls-Methionin (I 10) synthesis
With reference to the method for embodiment 1, use V 2replace V 1react with 20 carbon fatty acids, obtain N α-acyl-oxygen ursodesoxycholic acid methyl esters-N ε-two ten acyls-lysine methyl ester (VI 10); By VI 10deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：12.243(2H，br)；7.750-7.722(1H，t)；7.211-7.191(1H，d)；4.388-4.379(1H，m)；3.948-3.932(1H，d)；3.852(1H，m)；3.003-2.989(2H，m)；0.619(3H，s)。
Embodiment 11N α-acyl-oxygen ursodesoxycholic acid-N ε-two dodecanoyl-Methionin (I 11) synthesis
With reference to the method for embodiment 1, use V 2replace V 1react with 22 carbon fatty acids, obtain N α-acyl-oxygen ursodesoxycholic acid methyl esters-N ε-two dodecanoyl-lysine methyl ester (VI 11); By VI 11deprotection under LiOH effect, obtains target compound. 1H-NMR，δ(ppm，DMSO-d 6)：12.135(2H，br)；7.720-7.706(1H，t)；7.176-7.156(1H，d)；4.389-4.369(1H，m)；3.910-3.893(2H，m)；3.004-2.989(2H，m)；0.619(3H，s)。
The screening of Lipid-lowering activities in embodiment 12 body
Adopt single dose, the Lipid-lowering activities of target compound gastric infusion is screened.
Balb/c mouse, 20 ± 5g, , by body weight random packet (often organizing 5): control group, model group, test-compound group (100mg/kg).Except control group, each group every morning gavage lipomul (10ml/kg/ days); After 8 hours, control group and model group give the solvent of equivalent, and all the other treatment groups give relative medicine.After administration 19d, get blood, measure the content of serum total cholesterol (TC) and triglyceride (TG).
Hypolipidemic activity screening in table 1. target compound body
The further evaluation of embodiment 13 activity in vivo
To the good I of activity found in screening 7and I 3carry out further activity rating, investigate its dose-effect relationship.
Balb/c mouse, 20 ± 5g, , by body weight random packet (often organizing 8): the test-compound group of control group, model group, various dose.Except control group, each group every morning sink grease fat emulsion (10ml/kg/ days); Afternoon control group and model group give the solvent of equivalent, all the other treatment groups give relative medicine.After administration 19d, get blood, measure serum total cholesterol (TC), triglyceride (TG), the content of transaminase ALT and AST.
Table 2. target compound activity in vivo evaluation result
From table 2, I 7and I 3not only dose-dependently can reduce the rising of serum total cholesterol (TC) caused by high lipid food and triglyceride, the transaminase caused high lipid food raises also has restraining effect.The serum total cholesterol (TC) of high dosage (200mg/kg) treated animal, triglyceride (TG), content and the normal group of transaminase ALT and AST are suitable.Carbon 16 lipid acid (FA16), carbon 18 lipid acid (FA18) and cholic acid (CA) be effect not; Ursodesoxycholic acid has certain reducing effect to transaminase, but does not affect total cholesterol and triglyceride.
The evaluation of embodiment 14 acute toxicity
Kunming mouse 18-22g, male and female half and half, random packet, intraperitoneal injection, to observe after administration reaction of animals and death toll in 24h, Bliss method calculates LD 50.
The acute toxicity of table 3 target compound intraperitoneal administration

Claims (10)

1. the compound representated by structural formula I and non-toxic pharmacy acceptable salt thereof:
In structural formula I, R 1representative or r 2representative or n is the integer of 8-22.
2. according to claim 1, formula I 1-5representative compound:
Structural formula I 1-5in, n is respectively 12,14,16,18 or 20.
3. according to claim 1, formula I 6-11representative compound:
Structural formula I 6-11in, n is respectively 12,14,16,18,19 or 20.
4. the salt that the carboxyl in the compound molecule described in any one of claim 1-3 and various positively charged ion are formed as sodium ion, potassium ion, ammonium ion, calcium ion, zine ion, magnesium ion or ammonium ion etc.
5. the compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof are as activeconstituents, and the pharmaceutical composition that suitable excipient is formed.These pharmaceutical compositions can be solution, tablet, capsule or injection; These pharmaceutical compositions can pass through injection administration or oral administration.
6. the compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof, and preparing the purposes for the treatment of the disease medicaments such as hyperlipidemia, gallbladdergallstonecholetithiasis, fatty liver and atherosclerosis containing the compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents.
7. the compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof, and preparing the purposes for the treatment of the disease medicaments such as hyperlipidemia, gallbladdergallstonecholetithiasis, fatty liver and atherosclerosis containing the compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents.
8. according to claim 7, compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof, and preparing the purposes in treatment high blood cholesterol drug containing the compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents.
9. according to claim 7, compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof, and preparing the purposes in treatment gallbladdergallstonecholetithiasis medicine containing the compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents.
10. according to claim 7, compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof, and preparing the purposes in treatment fatty liver medicament containing the compound described in any one of claim 1-3 and non-toxic pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents.
CN201410012629.8A 2014-01-13 2014-01-13 Fatty acid-bile acid conjugates having fat lowering activity, and medical uses thereof Pending CN104774236A (en)

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CN108218946A (en) * 2016-12-15 2018-06-29 宁波百纳西药业有限公司 A kind of deoxycholic aicd class compound, preparation method and application
CN109503693A (en) * 2018-12-12 2019-03-22 合肥工业大学 A kind of new process efficiently synthesizing Aramchol for raw material using cholic acid and arachidic acid
CN114524857A (en) * 2022-02-22 2022-05-24 中国科学院微生物研究所 Cholic acid derivative and application thereof
CN116063371A (en) * 2023-03-15 2023-05-05 苏州当量生物医药有限公司 Synthesis method of 3- [3- (cholesteryl amidopropyl) dimethylamino ] propane sulfonate inner salt

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108218946A (en) * 2016-12-15 2018-06-29 宁波百纳西药业有限公司 A kind of deoxycholic aicd class compound, preparation method and application
CN108218946B (en) * 2016-12-15 2021-04-16 宁波百纳西药业有限公司 Deoxycholic acid compound, preparation method and application thereof
CN109503693A (en) * 2018-12-12 2019-03-22 合肥工业大学 A kind of new process efficiently synthesizing Aramchol for raw material using cholic acid and arachidic acid
CN114524857A (en) * 2022-02-22 2022-05-24 中国科学院微生物研究所 Cholic acid derivative and application thereof
CN116063371A (en) * 2023-03-15 2023-05-05 苏州当量生物医药有限公司 Synthesis method of 3- [3- (cholesteryl amidopropyl) dimethylamino ] propane sulfonate inner salt

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