CN100467480C - Nitrate derivative of bile acid and its medical use - Google Patents
Nitrate derivative of bile acid and its medical use Download PDFInfo
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- CN100467480C CN100467480C CNB2005101083619A CN200510108361A CN100467480C CN 100467480 C CN100467480 C CN 100467480C CN B2005101083619 A CNB2005101083619 A CN B2005101083619A CN 200510108361 A CN200510108361 A CN 200510108361A CN 100467480 C CN100467480 C CN 100467480C
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- nitrooxy
- acid
- nitro
- ursodesoxycholic acid
- ursodesoxycholic
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Abstract
The present invention relates to two nitrate derivatives of bile acid, their pharmaceutically acceptable salts, medicine compositions containing the above-mentioned compounds and application of said described compounds in preparation of medicines for curing hepatic diseases. Said invention also provides the chemical structure formulae of said two nitrate derivatives of bile acid.
Description
Technical field
The present invention relates to bile acide nitrate derivatives and pharmacy acceptable salt thereof, contain these compounds as the pharmaceutical composition of activeconstituents and described compound in the application aspect the medicine of preparation treatment hepatopathy.The invention still further relates to the preparation method of the nitrate derivatives and the pharmacy acceptable salt thereof of bile acide.
Background technology
Nitric oxide molecule is an important regulatory molecule in the body, participates in numerous physiological and pathological processes, has the various biological function.Studies show that an amount of nitrogen protoxide can protect liver cell, prevent hepatocellular apoptosis, suppress the formation and the development of inflammation in the liver, repair liver injury, and have the circulation of the liver of improvement inner blood, reduce and press in the liver and improve multiple effect such as hepatic fibrosis.
Studies show that nitrogen protoxide discharges medicine can suppress formation, the reduction portal hypertension of liver development of inflammation and hepatic fibrosis by the release nitric oxide molecule, and then produce the curative effect of treatment liver cirrhosis and portal hypertension.But the at present clinical nitrogen protoxide that is used for the treatment of the organic nitrates class of liver cirrhosis discharges medicine, because interior distribute non-specific of its body, thereby produce systemic side effects more widely.Can reduce or avoid the side effect of conventional nitrate esters medicine by the approach of liver targeted drug delivery.
Bile acide in liver cell by the cholesterol biosynthesizing, combine with glycine or taurine then, enter digestive tube with the food gruel, the bile acide above 95% is heavily absorbed at the terminal ileum, return liver by postcava then, so constantly carry out the liver sausage circulation; Become the interior liver sausage of human body to circulate and repeat 6 to 15 times every day, participate in round-robin bile acide total amount and reach 17-40g, so bile acide has higher turn-over capacity; Bile acide is that the approach by active transport is absorbed, and is that targeting vector can improve bioavailability of medicament with the bile acide; As endogenic natural aglucon, bile acide has good bio-compatibility. thereby, bile acide and can be used as the carrier of liver targeted drug delivery with glycine or taurine binding substances.
The design of ideal target conjugates medicine must keep the specificity of targeting vector, keeps stable in blood, fully dissociates behind the arrival target cell, discharges active medicine.
International monopoly WO 03095471 discloses the derivative of the ursodesoxycholic acid that contains nitric ether of following structure:
In the structure of said derivative, the nitric ether that discharges component as nitrogen protoxide is by the carboxyl link coupled in connexon and the bile acide molecule.The structure activity study result of bile acide shows that 24 free carboxies of bile acide for keeping the crucial group of its liver specificity, therefore discharge the component coupling by 24 carboxyls and NO, will influence its target.
Summary of the invention
The present invention relates to nitrate derivatives and pharmacy acceptable salt thereof by the bile acide shown in structural formula Ia or the Ib, their preparation method contains the pharmaceutical composition of these compounds, and the application of described compound aspect the medicine of preparation treatment hepatopathy.The invention still further relates to the method for the nitrate derivatives and the pharmacy acceptable salt treatment hepatic diseases thereof of the bile acide by treating significant quantity.
Therefore, first aspect of the present invention provides the nitrate derivatives and the pharmacologically acceptable salt thereof of the bile acide shown in formula Ia or the Ib:
Wherein,
R
1And R
2Representative-OH or-O-NO
2
R
3Represent hydrogen ,-OH or-O-NO
2
R
4Representative-OH ,-NHCH
2COOH or-NHCH
2CH
2SO
3H;
R
5Represent hydrogen or-OH;
L represents C
2-6-alkyl, C
2-6-alkenyl, C
2-6-alkynyl, C
1-3-substituted alkyl, C
3-6Cycloalkyl, two-C
2-6-alkylaryl, described aromatic base is selected from benzene, pyridine etc., and described substituting group is selected from halogen, hydroxyl, C
1-6Alkyl;
Condition is,
R
1, R
2And R
3Can be identical or different, but wherein have at least one to be-OH, and have at least one to be-O-NO
2
Second aspect of the present invention relates to pharmaceutical composition, and it comprises nitrate derivatives or its pharmacologically acceptable salt and one or more the pharmaceutically acceptable carrier or the vehicle of the bile acide of at least a formula Ia or Ib representative.
The 3rd aspect of the present invention relates to the nitrate derivatives of bile acide of formula Ia or Ib representative or the preparation method of its pharmacologically acceptable salt.
The 4th aspect of the present invention relates to the nitrate derivatives of bile acide of formula Ia or Ib representative or the purposes that its pharmacologically acceptable salt is used to prepare the medicine for the treatment of hepatic diseases.
The 5th aspect of the present invention relates to the method for the treatment of hepatic diseases, and described method comprises nitrate derivatives or its pharmacologically acceptable salt of the bile acide of at least a formula Ia that the patient treatment of these needs significant quantity is arranged or Ib representative.
According to an embodiment of the invention, the invention provides the nitrate derivatives and the pharmacologically acceptable salt thereof of the bile acide shown in formula Ia or the Ib:
Wherein,
R
1And R
2Representative-OH or-O-NO
2
R
3Represent hydrogen ,-OH or-O-NO
2
R
4Representative-OH ,-NHCH
2COOH or-NHCH
2CH
2SO
3H;
R
5Represent hydrogen or-OH;
L represents C
2-6-alkyl, C
2-6-alkenyl, C
2-6-alkynyl, C
1-3-substituted alkyl, C
3-6Cycloalkyl, two-C
2-6-alkylaryl, described aromatic base is selected from benzene, pyridine etc., and described substituting group is selected from halogen, hydroxyl, C
1-6Alkyl;
Condition is,
R
1, R
2And R
3Can be identical or different, but wherein have at least one to be-OH, and have at least one to be-O-NO
2
With the example that synthesizes of chlolic acid derivatives, Compound I a can prepare according to following synthetic route:
At first, 24 carboxyls are become ester with cholic acid and hydrochloric acid methanol reaction; Then Methyl cholate and acetic anhydride are formed the triacetyl derivative; The triacetyl derivative is optionally sloughed 3 ethanoyl hydroxyl that dissociates in methanol hydrochloride solution, form nitric ether with nitric acid reaction, and last deprotection obtains target compound Ia-1; Methyl cholate and excess acetyl chloride, optionally with 3-position glycoloylization, hydroxyl on 7,12 and nitric acid reaction form nitric ether, and last deprotection obtains target compound Ia-2.
With the example that synthesizes of ursodeoxycholic acid derivative, compounds ib can prepare according to following synthetic route:
7-O-ethanoyl ursodesoxycholic acid methyl esters and methylsulfonyl chloride reaction; 3 hydroxyls are converted into methanesulfonates; be reacted into ehter bond with wherein the defined glycol with general formula HO-L-OH of L cotype Ib again, then with the nitrated nitric ether of making of terminal hydroxyl, last deprotection obtains target compound.
Employed raw material all is obtained commercially in the invention described above synthetic route.
Term among the present invention " pharmacologically acceptable salt " can be medicinal inorganic or organic salt.The compound that has basic group among formula Ia of the present invention or the Ib can form pharmaceutical salts with mineral acid, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Also can form pharmaceutical salts, for example acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc. with organic acid.The compound that has acidic-group among formula Ia of the present invention or the Ib can form pharmaceutical salts with basic metal or alkaline-earth metal such as sodium ion, potassium ion, ammonium ion, calcium ion, zine ion, magnesium ion etc., and is preferred but be not limited to sodium salt, sylvite, magnesium salts or calcium salt.
The compounds of this invention or its pharmacologically acceptable salt can form solvate, for example hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges described activeconstituents in vivo after the metabolism metabolism.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.
As mentioned above, The compounds of this invention can be used for preparing the medicine for the treatment of hepatic diseases, and described hepatic diseases comprises hepatitis, hepatic fibrosis or liver cirrhosis etc.
The compounds of this invention or its pharmacologically acceptable salt can be separately or with the form administration of pharmaceutical composition.Pharmaceutical composition of the present invention can be made into various suitable formulations according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they help active compound is processed into can be at the preparation that pharmaceutically uses.The appropriate formulations form depends on selected route of administration, can make according to general knowledge well known in the art.
Route of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration.Can comprise capsule and tablet etc. by oral pharmaceutical preparation.Patient swallows when having any problem, and also can adopt Sublingual tablet or other non-mode administrations of swallowing.The compounds of this invention also can be prepared and be used for administered parenterally or transdermal administration or mucosal.Perhaps adopt the mode administration of suppository or implants.It will be understood by those skilled in the art that The compounds of this invention can adopt suitable drug delivery system (DDS) to obtain more favourable effect.
It may be noted that in addition, The compounds of this invention using dosage and using method depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01～100mg/kg body weight/day.
Embodiment
Can further describe the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.
The preparation of embodiment 1 3-O-nitro-cholic acid (Ia-1)
1.1 Methyl cholate is synthetic
Get 11 gram cholic acid and be dissolved in 110 milliliters the methanol hydrochloride solution, stirred liquid under the room temperature; Reaction is finished, in the water with 200 milliliters of reaction solution impourings, extract with ether (35 milliliters * 4), merge ether solution, wash successively with saturated sodium bicarbonate, saturated aqueous common salt, anhydrous magnesium sulfate drying, the filtering siccative, removal of solvent under reduced pressure gets white solid 10.9 grams, fusing point 69-73 ℃, yield 96%.
1H NMR (CDCl
3): 3.96 (s, 1H); 3.84 (s, 1H); 3.66 (s, 3H); 3.44 (br, s, 1H); 3.11-2.90 (br, m, 3H); 2.38 (m, 2H); 2.21br m, 2H); 1.90-1.04 (br m, steroidal CH
2And CH); 0.99 (d, 3H, J=5.9); 0.89 (s, 3H); 0.67 (s, 3H).
1.2 3,7,12-three-O-ethanoyl Methyl cholate synthetic
10 gram Methyl cholates (0.0245 mole) are dissolved in 20 ml acetic anhydride, add 30 milliliters of pyridines and 1.80 gram 4-Dimethylamino pyridines then, stirred 6 hours under the room temperature, reaction is finished, and in 300 milliliters of ether of reaction mixture impouring, washs successively with 0.15M hydrochloric acid, saturated sodium bicarbonate, saturated aqueous common salt, anhydrous magnesium sulfate drying, filter, decompression removes down and desolvates, and gets colourless liquid.Separate (eluent sherwood oil: ethyl acetate=9:1), get white solid 11.9 grams with silica gel column chromatography.Fusing point 103-105 ℃, yield 92%.
1H NMR (CDCl
3): 5.08 (s, 1H); 4.92 (s, 1H); 4.59 (br, s, 1H); 3.66 (s, 3H); 2.39 (br, m, 1H); 2.23 (s, 3H); 2.14 (s, 3H); 2.08 (s, 3H); 2.05 (s, 3H); 2.25-1.04 (brm, steroidal CH
2And CH); 0.92 (s, 3H); 0.82 (d, 3H, J=6.2); 0.73 (s, 3H).
1.3 7,12-two-O-ethanoyl Methyl cholate synthetic
With 1 gram 3,7,12-three-O-ethanoyl Methyl cholate is dissolved in 10.5 milliliters of methanol hydrochloride solutions.Reaction is 1-3 hour under the room temperature, and the thin layer monitoring reaction finishes.In the frozen water with 100 milliliters of reaction solution impourings, extract with ether (50 milliliters * 4), combined ether layer washs successively with saturated sodium bicarbonate, saturated aqueous common salt, uses anhydrous magnesium sulfate drying, filter, reduce pressure to remove down and desolvate, get colourless liquid. separate (eluent sherwood oil: ethyl acetate=7:3), get white solid 0.72 gram with silica gel column chromatography, fusing point: 59-63 ℃, yield 78%.
1HNMR (CDCl
3): 5.08 (s, 1H); 4.90 (s, 1H); 3.66 (s, 3H, 3.50 (br, s, 1H); 2.38 (br, m, 1H); 2.25 (br, m, 1H); 2.13 (s, 3H); 2.09 (s, 3H); 2.06-0.97 (brm, steroidal CH
2And CH); 0.91 (s, 3H); 0.82 (d, 3H, J=6.5); 0.73 (s, 3H).
1.4 3-O-nitro-7,12-two-O-ethanoyl Methyl cholate synthetic
150 milliliters aceticanhydrides and 42 milliliters of nitrosonitric acid mixing solutionss are cooled to-5 ℃.Splash into 15 grams 7 under stirring, 12-two-O-ethanoyl Methyl cholate is dissolved in the solution of 75 milliliters of methylene dichloride.Drip and finish ,-5 ℃ were reacted 1 hour down.Reaction is finished, in the water coolant with reaction drop to 200 milliliter, separate organic layer, water layer extracts with methylene dichloride (70 milliliters * 4), merge organic layer, wash successively with saturated sodium bicarbonate, saturated aqueous common salt, anhydrous magnesium sulfate drying filters, removal of solvent under reduced pressure, get white solid 15.7 grams, fusing point 93-94 ℃, yield 96%.
1H NMR (CDCl
3): 5.08 (s, 1H); 4.92 (s, 1H); 4.79 (br, s, 1H); 3.66 (s, 3H); 2.39 (br, m, 1H); 2.14 (s, 3H); 2.08 (s, 3H); 2.25-1.04 (brm, steroidal CH
2And CH); 0.94 (s, 3H); 0.82 (d, 3H, J=6.4); 0.73 (s, 3H).
1.5 3-O-nitro-cholic acid (Ia-1) is synthetic
With 12 gram 3-O-nitros-7,12-two-O-ethanoyl Methyl cholate is dissolved in the methanol solution of 100 milliliter of 5% potassium hydroxide reflux 2-4 hour; the thin layer monitoring, reaction is finished, and will react in drop to the 400 milliliter hydrochloric acid frozen water liquid (containing 40 milliliters of concentrated hydrochloric acids); separate out white precipitate; filter is done, and distilled water wash is after the vacuum-drying; separate (eluent sherwood oil: ethyl acetate=9:1) with silica gel column chromatography; get white solid 6.65 grams, fusing point 217-220 ℃, yield 67%.MS(FAB?m/e):452.5(M-1)。
1H NMR (DMSO-d
6): 11.93 (s, 1H); 4.85 (br, s, 1H); 3.79 (s, 1H); 3.63 (s, 1H); 2.22 (br, m, 1H); 2.13 (s, br, m, 1H); 2.02-0.97 (brm, steroidal CH
2And CH); 0.93 (d, 3H, J=6.5); 0.85 (s, 3H); 0.59 (s, 3H).
Embodiment 27, the preparation of 12-two-O-nitro cholic acid (Ia-2)
2.1 3-O-ethanoyl Methyl cholate is synthetic
10 gram (23.7 mmole) Methyl cholates are dissolved in 75 milliliters of pyridines, under the ice bath mixed solution are reduced to 0 ℃.Acetyl Chloride 98Min. with 2.03 milliliters (1 equivalents) under stirring slowly splashes into to reaction solution, and reaction is 1 hour under ice bath, removes ice bath, stirs 2 hours under the room temperature.Reaction is complete, and reaction mixture is inclined in 300 milliliters of ethyl acetate, uses 0.5M hydrochloric acid, saturated aqueous common salt, saturated sodium bicarbonate, saturated common salt water washing successively, and anhydrous magnesium sulfate drying filters, and decompression removes down and desolvates, and gets colourless liquid.Separate (eluent sherwood oil: ethyl acetate=4:1), get white solid 9.2 grams, yield 84% with silica gel column chromatography.
1H NMR (CDCl
3): 4.58 (br m, 1H); 3.99 (s, 1H); 3.86 (br, s, 1H); 3.66 (s, 3H); 2.39 (br, m, 2H); 2.00 (s, 3H); 2.05 (s, 3H); 2.25-1.04 (br m, steroidal CH
2And CH); 0.97 (d, 3H, J=6.2); 0.91 (s, 3H); 0.70 (s, 3H).
2.2 3-O-ethanoyl-7,12-two-O-nitro Methyl cholate synthetic
80 milliliters aceticanhydrides and 22 milliliters of nitrosonitric acid mixing solutionss are cooled to-5 ℃.Splash into 8 under stirring and restrain the solution that 3-O-ethanoyl Methyl cholates are dissolved in 75 milliliters of methylene dichloride. drip and finish ,-5 ℃ were reacted 1 hour down.Reaction is finished, and in the water coolant with reaction drop to 200 milliliter, separates organic layer, water layer extracts with methylene dichloride (50 milliliters * 4), merge organic layer, wash anhydrous magnesium sulfate drying with saturated sodium bicarbonate, saturated aqueous common salt successively, filter, removal of solvent under reduced pressure is separated (eluent sherwood oil: ethyl acetate=9:1), get white solid 8.9 grams with silica gel column chromatography, fusing point 83-87 ℃, yield 93%.
1H NMR (CDCl
3): 5.3 (s, 1H); 5.01 (s, 1H); 4.58 (br m, 1H); 3.68 (s, 3H); 2.39 (br, m, 2H); 2.04 (s, 3H); 2.25-1.04 (br m, steroidal CH
2And CH); 0.95 (s, 3H); 0.86 (d, 3H, J=6.4); 0.82 (s, 3H).
2.3 7,12-two-O-nitro cholic acid synthetic
With 5 gram 3-O-ethanoyl-7,12-two-O-nitre oxygen base Methyl cholate is dissolved in 120 milliliter of 5% potassium hydroxide methanol solution reflux 1 hour; the thin layer monitoring reaction finishes; to react in drop to the 400 milliliter hydrochloric acid frozen water liquid (containing 40 milliliters of concentrated hydrochloric acids), and separate out white precipitate, filter is done; distilled water wash; after the vacuum-drying, separate (eluent sherwood oil: ethyl acetate=9:1), get white solid 3.4 grams with silica gel column chromatography; fusing point 191-195 ℃, yield 76%.MS(FAB?m/e):497.7(M-1)。
1H NMR (DMSO-d
6): 11.98 (s, 1H); 5.39 (br, s, 1H); 5.09 (s, 1H); 4.56 (d, 1H); 3.24 (br s, 1H); 2.23-0.97 (br m, steroidal CH
2And CH); 0.93 (d, 3H, J=6.5); 0.85 (s, 3H); 0.78 (s, 3H).
The preparation of embodiment 3 3-O-nitro-ursodesoxycholic acids (Ia-3)
3.1 the ursodesoxycholic acid methyl esters is synthetic
With ursodeoxycholic acid substitution cholic acid, method according to 1.1, preparation ursodesoxycholic acid methyl esters, fusing point: 65-68 ℃.
1H NMR (CDCl
3): 3.66 (s, 3H); 3.60 (br m, 2H); 2.35 (br, s, 1H); 2.24 (br, s, 1H); 2.02-0.99 (brm, steroidal CH
2And CH); 0.94 (s, 3H); 0.93 (d, 3H, J=6.4); 0.68 (s, 3H).
3.2 3,7-two-O-ethanoyl ursodesoxycholic acid methyl esters synthetic
Replace Methyl cholate with the ursodesoxycholic acid methyl esters, the method according to 1.2, preparation 3,7-two-O-ethanoyl ursodesoxycholic acid methyl esters, fusing point: 97-99 ℃.
3.3 7-O-ethanoyl ursodesoxycholic acid methyl esters is synthetic
With 3,7-two-O-ethanoyl ursodesoxycholic acid methyl esters replaces 3,7,12-three-O-ethanoyl Methyl cholate, the method according to 1.3, preparation 7-O-ethanoyl ursodesoxycholic acid methyl esters, fusing point: 129-132 ℃.
1H NMR (CDCl
3): 4.78 (br m, 1H); 3.66 (s, 3H); 3.59 (br, m, 1H); 2.35 (br, s, 1H); 2.24 (br, s, 1H); 1.98 (s, 3H); 1.85-0.98 (brm, steroidal CH
2And CH); 0.96 (s, 3H); 0.92 (d, 3H, J=6.4); 0.67 (s, 3H).
3.4 3-O-nitro-7-O-ethanoyl ursodesoxycholic acid methyl esters is synthetic
Replace 7 with 7-O-ethanoyl ursodesoxycholic acid methyl esters, 12-two-O-ethanoyl Methyl cholate, method, preparation 3-O-nitro-7-O-ethanoyl ursodesoxycholic acid methyl esters, fusing point: 138-139 ℃ according to 1.4.
3.5 3-O-nitro ursodesoxycholic acid (Ia-3) is synthetic
Replace 3-O-nitro-7 with 3-O-nitro-7-O-ethanoyl ursodesoxycholic acid methyl esters, 12-two-O-ethanoyl Methyl cholate, method, preparation 3-O-nitro ursodesoxycholic acid methyl esters, fusing point: 186-188 ℃ according to 1.5.
1H NMR (DMSO-d
6): 11.84 (s, 1H); 4.85 (br, s, 1H); 3.60 (br, m, 1H); 2.24 (br, s, 1H); 2.02-0.97 (br m, steroidal CH
2And CH); 0.94 (s, 3H); 0.85 (d, 3H, J=6.4); 0.63 (s, 3H).
The preparation of embodiment 4 N-(3-O-nitro-courage acyl)-glycine (Ia-4)
3-O-nitro-cholic acid 1 gram of getting embodiment 1 preparation is dissolved in 10 milliliters of dimethyl formamides; Add dicyclohexylcarbodiimide 0.4 gram then, N-hydroxy-succinamide 0.3 gram, stirring reaction spends the night; In reaction solution, add glycine 0.2 gram, continue reaction 8 hours.Filter,, in residue, add 20 milliliters of ethyl acetate and 10 milliliters of 1N hydrochloric acid, extraction the filtrate decompression evaporate to dryness; Tell organic layer, water layer extracts 2 times for 20 milliliters with ethyl acetate again, and the combined ethyl acetate extracting solution is washed with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, evaporated under reduced pressure.(the eluent sherwood oil: ethyl acetate=8:2), get white solid 0.34 gram, fusing point is greater than 200 ℃ with the silica gel column chromatography separation with residue.
1HNMR (DMSO-d
6): 11.47 (s, 1H); 4.38 (br, s, 1H); 3.96 (d, 2H); 3.66 (s, 1H); 3.52 (s, 1H); 3.34 (m, 2H); 2.20 (br, m, 1H); 2.08 (s, br, m, 1H); 2.01-0.97 (br m, steroidal CH
2And CH); 0.90 (d, 3H, J=6.5); 0.81 (s, 3H); 0.62 (s, 3H).
The preparation of embodiment 5 N-(3-O-nitro-courage acyl)-taurine (Ia-5)
Replace glycine with taurine, prepare N-(3-O-nitro-courage acyl)-taurine with reference to the method for embodiment 4, fusing point is greater than 200 ℃.
1HNMR (DMSO-d
6): 12.64 (s, 1H); 4.51 (br, s, 1H); 4.02 (d, 2H); 3.66 (s, 1H); 3.52 (s, 1H); 3.34 (m, 2H); 2.20 (br, m, 1H); 2.08 (s, br, m, 1H); 2.01-0.97 (br m, steroidal CH
2And CH); 0.90 (d, 3H, J=6.5); 0.81 (s, 3H); 0.62 (s, 3H).
Synthesizing of the preparation 6.13-O-methylsulfonyl of embodiment 6 3-O-(4-nitrooxy-butyl)-ursodesoxycholic acid (Ib-1)-7-O-ethanoyl ursodesoxycholic acid methyl esters
3 gram 7-O-ethanoyl ursodesoxycholic acid methyl esters are dissolved in 20 milliliters of pyridines; under the ice bath mixed solution is reduced to 0 ℃. the Methanesulfonyl chloride with 1 milliliter (2eq) under stirring slowly splashes into to reaction solution; reaction is 30 minutes under ice bath, removes ice bath, stirs 2 hours under the room temperature.Reaction is finished, and reaction mixture is inclined in 150 milliliters of ethyl acetate, uses 0.5M hydrochloric acid, saturated sodium bicarbonate, saturated common salt water washing successively, anhydrous magnesium sulfate drying filters, and decompression removes down and desolvates, get white solid 3.4 grams, fusing point 124-127 ℃, yield 97%.
1H NMR (CDCl
3): 4.75 (br m, 1H); 4.62 (br s, 1H); 3.66 (s.3H); 3.01 (s, 3H); 2.34 (br, m, 2H); 2.05 (s, 3H); 2.25-1.04 (br m, steroidal CH
2And CH); 0.92 (s, 3H); 0.82 (d, 3H, J=6.2); 0.68 (s, 3H).
6.2 3-O-(4-hydroxybutyl)-7-O-ethanoyl ursodesoxycholic acid methyl esters is synthetic
Get 4.3 gram 3-O-methylsulfonyl-7-O-ethanoyl ursodesoxycholic acid methyl esters and be dissolved in 25 milliliter 1, in the mixed solution of 4-butyleneglycol and 5 milliliters of pyridines, reacted 2 hours down in 100 ℃.Reaction is finished, reaction mixture is inclined in 250 milliliters of ethyl acetate, add 150 ml distilled waters, ethyl acetate layer is told in extraction, water layer ethyl acetate extraction three times, the combined ethyl acetate layer washs anhydrous magnesium sulfate drying successively successively with 0.5M hydrochloric acid, saturated aqueous common salt, saturated sodium bicarbonate, saturated aqueous common salt.Filtration, decompression remove down and desolvate, and separate (eluent sherwood oil: ethyl acetate=4:1), get colourless viscous liquid 4.1 grams with silica gel column chromatography.
6.3 3-O-(4-nitrooxy-butyl)-7-O-ethanoyl ursodesoxycholic acid methyl esters is synthetic
40 milliliters aceticanhydrides and 12 milliliters of nitrosonitric acid mixing solutionss are cooled to-5 ℃.Stir to splash into down and be dissolved in the solution of 20 milliliters of methylene dichloride by 4 gram 3-O-(4-hydroxybutyl)-7-O-ethanoyl ursodesoxycholic acid methyl esters.Drip and finish, reacted 1 hour down in-5 ℃.Reaction is finished, in the frozen water with reaction drop to 100 milliliter, tell organic layer, water layer extracts with methylene dichloride (30 milliliters * 4), merges organic layer, wash successively with saturated sodium bicarbonate, saturated aqueous common salt, anhydrous magnesium sulfate drying filters removal of solvent under reduced pressure, separate (eluent sherwood oil: ethyl acetate=9:1), get colourless viscous liquid 4.1 grams with silica gel column chromatography.
6.4 3-O-(4-nitrooxy-butyl)-ursodesoxycholic acid (Ib-1) is synthetic
4.1 gram 3-O-(4-nitrooxy-butyl)-7-O-ethanoyl ursodesoxycholic acid methyl esters are dissolved in 100 milliliter of 5% potassium hydroxide methanol solution; reflux 2-4 hour; the thin layer monitoring; reaction is finished; to react in drop to the 270 milliliter hydrochloric acid frozen water liquid (containing 27 milliliters of concentrated hydrochloric acids), separate out white precipitate, filter; use distilled water wash, vacuum-drying.Separate (eluent sherwood oil: ethyl acetate=4:1), get white solid 2.6 grams, fusing point 185-189 ℃ with silica gel column chromatography.
1H NMR (CDCl
3): 11.96 (s, 1H); 4.56 (t, 2H); 3.84 (d, 1H, J=7.0); 3.48 (br, s, 1H); 3.34 (t, 2H); 3.26 (br, m, 1H); 2.22 (br, m, 1H); 2.11 (br, m, 1H); 2.25-1.04 (br m, steroidal CH
2And CH); 0.94 (s, 3H); 0.88 (d, 3H, J=6.4); 0.62 (s, 3H).
The preparation of embodiment 7 3-O-(2-nitrooxy-ethyl)-ursodesoxycholic acid (Ib-2)
Spent glycol replaces butyleneglycol, with reference to the method for embodiment 6, and preparation 3-O-(2-nitrooxy-ethyl)-ursodesoxycholic acid (Ib-2).Fusing point 172-180 ℃.MS(FAB?m/e):480.5(M-1)。
1H NMR (CDCl
3): 12.05 (s, 1H); 4.56 (t, 2H); 3.90 (d, 1H); 3.47 (br, s, 1H); 3.37 (t, 2H); 3.24 (br, m, 1H); 2.28 (br, m, 1H); 2.13 (br, m, 1H); 2.26-1.04 (br m, steroidal CH
2And CH); 0.97 (s, 3H); 0.89 (d, 3H, J=6.4); 0.61 (s, 3H).
The preparation of embodiment 8 3-O-(4-nitrooxy-butyl)-cholic acid (Ib-3)
With 7,12-two-O-ethanoyl Methyl cholate replaces 7-O-ethanoyl ursodesoxycholic acid methyl esters, with reference to the method for embodiment 6, and preparation 3-O-(4-nitrooxy-butyl)-cholic acid.Fusing point: 186-195 ℃.MS(FAB?m/e):524.8(M-1)。
1H NMR (CDCl
3): 11.92 (s, 1H); 4.53 (t, 2H); 3.84 (d, 1H, J=7.0); 3.46 (br, s, 1H); 3.36 (t, 2H); 3.21 (br, m, 1H); 2.25 (br, m, 1H); 2.11 (br, m, 1H); 2.25-1.04 (br m, steroidal CH
2And CH); 0.93 (s, 3H); 0.85 (d, 3H, J=6.4); 0.61 (s, 3H).
Embodiment 9 N-[3-O-(4-nitrooxy-butyl)-ursodeoxycholic acyl]-preparation of glycine (Ib-4)
With 3-O-(4-nitrooxy-butyl)-ursodeoxycholic acid substitution 3-O-nitro-cholic acid, prepare N-[3-O-(4-nitrooxy-butyl)-ursodeoxycholic acyl according to the method for embodiment 4]-glycine.Fusing point 187-195 ℃.
1H NMR (CDCl
3): 11.74 (s, 1H); 4.41 (t, 2H); 3.74 (d, 1H, J=7.0); 3.52 (br, s, 1H); 3.43 (t, 2H); 3.30 (m, 2H); 3.22 (br, m, 1H); 2.16 (br, m, 1H); 2.08 (br, m, 1H); 2.25-1.04 (br m, steroidal CH
2And CH); 0.91 (s, 3H); 0.85 (d, 3H, J=6.4); 0.69 (s, 3H).
The preparation of embodiment 10 3-O-(3-nitrooxy-butyl)-ursodesoxycholic acid (Ib-5)
Replace 1 with 1,3 butylene glycol, the 4-butyleneglycol, with reference to the method for embodiment 6, preparation 3-O-(3-nitrooxy-butyl)-ursodesoxycholic acid (Ib-5).
1H NMR (CDCl
3): 12.04 (s, 1H); 4.13 (m, 1H); 3.90 (d, 1H); 3.47 (br, s, 1H); 3.40 (t, 2H); 3.24 (br, m, 1H); 2.28 (br, m, 1H); 2.13 (br, m, 1H); 2.26-1.04 (br m, steroidal CH
2And CH); 0.97 (s, 3H); 0.89 (d, 3H, J=6.4); 0.61 (s, 3H).
The preparation of embodiment 11 3-O-(4-nitrooxy-crotyl)-ursodesoxycholic acid (Ib-6)
With cis-2-butene-1, the 4-glycol replaces 1, the 4-butyleneglycol, and with reference to the method for embodiment 6, preparation 3-O-(4-nitrooxy-crotyl)-ursodesoxycholic acid (Ib-6).
1H NMR (CDCl
3): 12.05 (s, 1H); 4.65 (d, 2H); 4.32 (d, 2H); 3.94 (d, 1H); 3.45 (br, s, 1H); 3.21 (br, m, 1H); 2.30 (s, 1H); 2.28 (br, m, 1H); 2.18 (m, 1H); 2.15 (br, m, 1H); 2.25-1.06 (br m, steroidal CH
2And CH); 0.96 (s, 3H); 0.92 (d, 3H, J=6.4); 0.63 (s, 3H).
The preparation of embodiment 12 3-O-(4-nitrooxy-cyclohexyl)-ursodesoxycholic acid (Ib-7)
With 1, the 4-cyclohexanediol replaces 1, the 4-butyleneglycol, and with reference to the method for embodiment 6, preparation 3-O-(4-nitrooxy-cyclohexyl)-ursodesoxycholic acid (Ib-7).
1HNMR (DMSO-d
6): 11.87 (s, 1H); 4.83 (br, s, 1H); 4.10 (m, 1H); 3.92 (m, 1H); 3.61 (br, m, 1H); 2.25 (br, s, 1H); 2.00-0.90 (m, steroidal and hexanaphthene CH
2And CH); 0.94 (s, 3H); 0.92 (d, 3H, J=6.4); 0.61 (s, 3H).
Embodiment 13 3-O-[(6-nitrooxy methyl-pyridine-2-yls)-methyl]-preparation of ursodesoxycholic acid (Ib-8)
With 2,6-pyridine dimethanol replaces 1, the 4-butyleneglycol, and with reference to the method for embodiment 6, preparation 3-O-[(6-nitrooxy methyl-pyridine-2-yl)-methyl]-ursodesoxycholic acid (Ib-7).
1H NMR (DMSO-d
6): 11.84 (s, 1H); 8.12 (m, 1H); 7.61 (d, 1H); 7.45 (d, 1H); 4.85 (br, s, 1H); 3.86 (s, 2H); 3.68 (s, 2H); 3.60 (br, m, 1H); 2.24 (br, s, 1H); 2.02-0.97 (br m, steroidal CH
2And CH); 0.94 (s, 3H); 0.84 (d, 3H, J=6.4); 0.62 (s, 3H).
The pharmacodynamics evaluation of embodiment 14 anti-CC14 poisoning induced mice liver injuries
Get the Baclb/c mouse of the about 20-25g of body weight, random packet, every group of 10 mouse.Testing compound by the orally give various dose; Behind the 1h, according to the dosage of 10mL/kg, the CC14 of subcutaneous injection 100mL/L%, preparation liver injury model; Subcutaneous injection physiological saline is as the normal control group.After the modeling after 12 hours, the testing compound of orally give various dose once more.After the administration 24 hours for the second time, put to death animal, leave and take serum specimen, unified with full automatic biochemical apparatus for the ALT in the serum, the AST level detects.Evaluation result sees Table 1.
The pharmacodynamics evaluation of embodiment 15 anti-paracetamol induced mice liver injuries
Get the Baclb/c mouse of the about 20-25g of body weight, random packet, every group of 10 mouse. by the testing compound of orally give various dose; Behind the 1h, prepare liver injury model with the paracetamol subcutaneous injection of 100mg/kg, subcutaneous injection physiological saline is as the normal control group.Behind the modeling 1h, by the oral testing compound that gives various dose once more.After the administration 24 hours for the second time, put to death animal, leave and take serum specimen, unifiedly detect for ALT in the serum and AST level with full automatic biochemical apparatus.Evaluation result sees Table 2.
Table 1, anti-CCl
4The therapeutic action of poisoning induced mice liver injury
The therapeutic action of table 2, the liver injury of anti-paracetamol induced mice
Claims (5)
1, the nitrate derivatives of the bile acide shown in formula Ia or the Ib or its pharmacy acceptable salt:
Wherein,
R
1And R
2Representative-OH or-O-NO
2
R
3Represent hydrogen ,-OH or-O-NO
2
R
4Representative-OH ,-NHCH
2COOH or-NHCH
2CH
2SO
3H;
R
5Represent hydrogen or-OH;
L represents C
2-6-alkyl, C
2-6-alkenyl, C
2-6-alkynyl, C
3-6Cycloalkyl, two-C
2-6-alkylaryl, described aromatic base is selected from benzene and pyridine;
Condition is,
R
1, R
2And R
3Can be identical or different, but wherein have at least one to be-OH, and have at least one to be-O-NO
2
2. the nitrate derivatives of the formula Ia of claim 1 or Ib bile acide, or its pharmacy acceptable salt is selected from:
3-O-nitro-cholic acid;
7,12-two-O-nitro cholic acid;
3-O-nitro-ursodesoxycholic acid;
N-(3-O-nitro-courage acyl)-glycine;
N-(3-O-nitro-courage acyl)-taurine;
3-O-(4-nitrooxy-butyl)-ursodesoxycholic acid;
3-O-(2-nitrooxy-ethyl)-ursodesoxycholic acid;
3-O-(4-nitrooxy-butyl)-cholic acid;
N-[3-O-(4-nitrooxy-butyl)-ursodeoxycholic acyl]-glycine;
3-O-(3-nitrooxy-butyl)-ursodesoxycholic acid;
3-O-(4-nitrooxy-crotyl)-ursodesoxycholic acid;
3-O-(4-nitrooxy-cyclohexyl)-ursodesoxycholic acid; With
3-O-[(6-nitrooxy methyl-pyridine-2-yl)-methyl]-ursodesoxycholic acid.
3, pharmaceutical composition, it comprises nitrate derivatives or its pharmacologically acceptable salt and one or more the pharmaceutically acceptable carrier or the vehicle of the bile acide of the formula Ia of at least a claim 1 or 2 or Ib representative.
4, the nitrate derivatives of claim 1 or 2 described formula Ia or Ib bile acide or its pharmacologically acceptable salt purposes that is used to prepare the medicine for the treatment of hepatic diseases.
5, the purposes of claim 4, described hepatic diseases are hepatitis, hepatic fibrosis or liver cirrhosis.
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| CN102675404B (en) * | 2012-05-10 | 2014-04-09 | 福建天泉药业股份有限公司 | Preparation method of glycyrrhetinic acid butyl nitrate |
| CN104367556B (en) * | 2014-11-14 | 2016-10-19 | 郑州大学 | A kind of preparation method and applications being provided that nitric oxide production hyaluronic acid nitrate deoxycholic acid polymer micelle |
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