CN100513415C - Bile acid derivative and pharmaceutical use thereof - Google Patents
Bile acid derivative and pharmaceutical use thereof Download PDFInfo
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- CN100513415C CN100513415C CNB2005100890199A CN200510089019A CN100513415C CN 100513415 C CN100513415 C CN 100513415C CN B2005100890199 A CNB2005100890199 A CN B2005100890199A CN 200510089019 A CN200510089019 A CN 200510089019A CN 100513415 C CN100513415 C CN 100513415C
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Abstract
The invention discloses bile nitrate derivant in the Ia and Ib as drug composition of activated ingredient, which treats hepatitis virus, wherein R1 is trans- or cis-OH; R2 is H or OH; A is L- or D-serine, threonine or cysteine residue, cis- or trans-3-hydroxyproline or 4-hydroxyproline residue; X is oxygen or sulphur.
Description
Technical field
The present invention relates to the bile acide nitrate derivatives, its pharmacy acceptable salt contains the pharmaceutical composition of these compounds as activeconstituents, and described compound is used to prepare the purposes of the medicine for the treatment of diseases such as hepatitis.The invention still further relates to the preparation method of bile acide nitrate derivatives and pharmaceutically-acceptable salts thereof.
Background technology
Hepatic diseases sickness rate height such as viral hepatitis, hepatic fibrosis, liver cirrhosis, the treatment difficulty is big.Among the whole world hepatitis B more than 500,000,000 and third hepatopath, 25% will develop into liver cirrhosis; The development of the fatty liver that a variety of causes (alcohol, obesity, diabetes etc.) causes also can cause liver cirrhosis.Portal hypertension is one of major complications of liver cirrhosis, and oesophagus and the varices of fundus of stomach symptoms such as hemorrhage, ascites of breaking can appear in the patient, are the major reasons that causes patient with liver cirrhosis death.
The development of hepatic diseases is a process by quantitative change to qualitative change.At first, the effect that liver is subjected to multiple paathogenic factors such as virus or inflammatory mediator causes liver injury, causes based on the synthetic of each composition of extracellular matrix of collagen and increases, and degraded reduces, and is deposited on to cause hepatic fibrosis in the liver; Along with further development and the outgrowth aggravation of collagenous tissue of liver injury, apoptosis and downright bad liver cell quantity increase, and liver structure changes, and causes liver cell regeneration, and pseudolobuli forms, and finally forms liver cirrhosis; After liver cirrhosis forms, multiple malfunctions such as intrahepatic metabolism and immunity occur, often follow complication such as portal hypertension and liver ascites occur, and may cause the generation of liver cancer.
Hepatic fibrosis is the common pathological basis of all chronic hepatopathys, is the only stage which must be passed by of liver cirrhosis.By proper treatment, hepatic fibrosis enter liver cirrhosis still had before the stage reverse may; Therefore, extremely important to the treatment of hepatic fibrosis.Mainly use gamma-interferon (IFN-γ), colchicine, Trolovol etc. to suppress collagen synthetic anti-fibrosis medicine to the treatment of hepatic fibrosis at present, but its result of treatment is unsatisfactory.
Enter liver cirrhosis after the stage by hepatic fibrosis, liver tissue lesions constantly develops, and the gangrenosum acne pathology increases, and the hepatic tissue structure changes, and cause the multiple malfunction of liver, and complication such as portal hypertension, liver ascites appears in regular meeting.Main methods of treatment to liver cirrhosis is to correct its complication at present, and by increasing liver replenishing to nutritive substances such as glucose, VITAMIN and amino acid, keep the function of liver, prevent that the state of an illness from further worsening, carry out liver transplantation for the needs of patients that is in a bad way.Existing medicine is to no definite curative effects such as liver cirrhosis and complication portal hypertension, ascites.
Studies show that an amount of nitrogen protoxide can protect liver cell; prevent hepatocellular apoptosis; the formation that suppresses inflammation in the liver and development, 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, all there is therapeutic action in each stage that hepatic diseases is developed.
Nitrogen protoxide can suppress the release of multiple preceding inflammatory factors such as interleukin-(IL-1, IL-6, IL-18, IL-1 β) tumor necrosis factor-alpha (TNF-α) in liver, have the inhibition caspase active effect relevant with inflammation and apoptosis.Studies have shown that nitrogen protoxide can improve the liver injury due to the multiple factor, reduce hepatocellular necrosis, suppress the formation and the development of inflammation in the liver, reduce the concentration of transaminase in the liver, thereby can prevent that hepatopathy from developing to the fibrosis direction.
Nitrogen protoxide can also suppress white corpuscle, thrombocyte, bites the gathering of neutrophil leucocyte and to the vessel wall adhesion, have effect such as thrombosis and microcirculation improvement in the liver of inhibition.The stellate cell of nitrogen protoxide in can the diastole liver simultaneously increases the blood flow of hepatic vein Dou Chu; And can expand the tube wall of the multiple blood vessel that comprises arteriole, Venule, reduce resistance of blood flow, thereby guarantee or increase the perfusion of blood liver, and then the effect that produces anti-portal hypertension.
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 is present unique orally active small molecules liver targeting vector.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 is suitable for the carrier as targeted drug.Intravital bile acide is made up of cholic acid, ursodesoxycholic acid, gallodesoxycholic acid, Septochol and lithocholic acid, cholic acid (Cholic acid wherein, CA) with ursodesoxycholic acid (Ursodeoxycholicacid, UDCA) there is not the molten membrane interaction of other type bile acide, security is good in the body, turn-over capacity is strong, thereby normal selected as the hepatic targeting drug carrier.Ursodesoxycholic acid itself also has pharmacological actions widely such as hepatic cholagogic, can reduce gpt, glutamic-oxal(o)acetic transaminase, (γ-GT), blood fat reducing is obviously alleviated the fatty liver symptom to gamma glutamyl transpeptidase, and chronic hepatitis is also had certain therapeutic action.Thereby ursodesoxycholic acid not only can be used as pharmaceutical carrier, also can produce synergy with medicine.
International monopoly WO 03095471 discloses the conjugates of the ursodesoxycholic acid that contains nitric ether; In the structure of these conjugates, the nitric ether that discharges component as nitrogen protoxide is connected with the carrier bile acide by ester bond.The structure of its representative compounds NCX1000 is as follows:
Studies show that NCX1000 can effectively suppress multiple inflammatory factors such as interleukin, tumour necrosis factor, liver injury and inflammation, portal hypertension, liver cirrhosis and hepatic fibrosis that a variety of causes is caused all have therapeutic action preferably.
But in the molecule of NCX1000, targeting vector is by two ester bonds and the coupling of nitric ether composition; Because the ester bond facile hydrolysis, carrier part and active part dissociate and lose targeting.Pharmacokinetic is the result show, discharges medicine by ester bond link coupled nitrate esters, detects less than complete originality medicine in the oral administration blood.
Summary of the invention
The present invention has solved the shortcoming that the ester bond facile hydrolysis because of between carrier bile acide and the medicine that exists in the prior art causes medicine forfeiture targeting by the nitrate derivatives that has with cholic acid shown in following formula Ia and the Ib or ursodesoxycholic acid is provided
Therefore, one aspect of the present invention relates to respectively nitrate derivatives and the pharmacy acceptable salt thereof by cholic acid shown in structural formula Ia and/or the Ib or ursodesoxycholic acid:
Chlolic acid derivatives:
R
2=OH
The ursodeoxycholic acid derivative:
R
2=H
Wherein,
A represents Serine, Threonine or the cysteine residues of L-or D-type, cis or trans 3-Hydroxyproline or 4-Hydroxyproline residue;
X is oxygen or sulphur.
Another aspect of the present invention relates to the preparation method of the nitrate derivatives and the pharmaceutically-acceptable salts thereof of cholic acid shown in formula Ia or the Ib or ursodesoxycholic acid.
Another aspect of the present invention relates to the nitrate derivatives that contains cholic acid shown in formula Ia and/or the Ib or ursodesoxycholic acid and pharmaceutically-acceptable salts thereof the pharmaceutical composition as activeconstituents and one or more pharmaceutically acceptable carriers or excipient.
Another aspect of the present invention relates to the purposes that the nitrate derivatives of cholic acid shown in formula Ia and/or the Ib or ursodesoxycholic acid and pharmacy acceptable salt thereof are used to prepare the medicine of hepatic diseases such as treatment hepatitis, hepatic fibrosis and liver cirrhosis.
The method that relates in one aspect to hepatic diseases such as treatment hepatitis, hepatic fibrosis and liver cirrhosis etc. more of the present invention, described method comprise the formula Ia that the patient treatment of these needs significant quantity is arranged and/or the nitrate derivatives and the pharmacy acceptable salt thereof of cholic acid shown in the Ib or ursodesoxycholic acid.
Particularly, the present invention relates to bile acide nitrate derivatives and the pharmacy acceptable salt thereof shown in formula Ia and the Ib:
Wherein,
R1 represents the OH of trans or cis;
R2 represents H or OH;
A represents Serine, Threonine or the cysteine residues of L-or D-type, cis or trans 3-Hydroxyproline or 4-Hydroxyproline residue;
X is oxygen or sulphur.
According to the present invention, the conjugates that the amino acid whose α amino that above-mentioned formula Ia is cholic acid or ursodesoxycholic acid 24-position carboxyl by amido linkage and 0-nitration or S-nitration is connected to form; The conjugates that the amino acid that above-mentioned Ib is cholic acid or ursodesoxycholic acid 24-position carboxyl by Methionin and nitration is connected to form, the introducing of Methionin can be controlled release rate of drugs.
In Ia or Ib, the nitric ether composition is connected on the carrier of cholic acid by amido linkage, has guaranteed its stability in blood plasma; And after entering liver cell, the sulfydryl component in nitric ether and the cell forms unsettled S-nitroso-group sulfide, further decomposes to discharge the NO molecule performance pharmacological action.Simultaneously, with the electronegativity of the carboxyl of 24 of amino acid whose α carboxyl simulation cholic acid or ursodeoxycholic acid molecules, kept the constitutional features of cholic acid or ursodesoxycholic acid to greatest extent, to guarantee its liver target; Connexon is a natural amino acid, has good bio-compatibility.
The present invention also provides the nitrate derivatives pharmacy acceptable salt of cholic acid shown in formula Ia and the Ib or ursodesoxycholic acid, and these salt can be formed by the carboxyl in Ia or the Ib molecule and various positively charged ion such as sodium ion, potassium ion, ammonium ion, calcium ion, zine ion, magnesium ion or ammonium ion etc.
According to the present invention, the synthetic route of target compound Ia mainly contains three.
Article one, synthetic route is in the alcoholic solution of hydrogenchloride, earlier amino acid whose carboxyl is protected by esterification, and hydroxyl in the amino acid molecular of carboxy protective and phosphorus pentachloride reaction prepare halogenated amino acid; Under the effect of condensing agents such as DCC, free amino again with cholic acid or ursodeoxycholic acid molecule in the carboxyl condensation, protecting group is sloughed in the condensation product saponification, last react with Silver Nitrate, obtain target compound.
Conjugates with ursodesoxycholic acid-O-nitro Serine is an example, and concrete building-up reactions is as follows:
The second synthetic route is hydroxyl and the nitric acid reaction in the amino acid molecular of carboxyl esterification protection, the preparation nitric ether; Under the effect of condensing agents such as DCC, free amino again with cholic acid or ursodeoxycholic acid molecule in the carboxyl condensation, protecting group is sloughed in the condensation product saponification, obtain target compound.
Conjugates with ursodesoxycholic acid-O-nitro Serine is an example, and concrete building-up reactions is as follows:
Article three, synthetic route for carboxyl without the direct nitrated nitric ether of making of the hydroxyl in the amino acid molecular of protection, free amino again with cholic acid or ursodeoxycholic acid molecule in the carboxyl condensation, obtain target compound.
Still the conjugates with ursodesoxycholic acid-O-nitro Serine is an example, and concrete building-up reactions is as follows:
According to the present invention, the synthetic route of target compound Ib is earlier with the alpha-amino group condensation in the Methionin molecule of carboxyl in cholic acid or the ursodeoxycholic acid molecule and terminal amino group protection, deprotection, preparation cholic acid-Methionin conjugates.With BOC with the amino acid whose amido protecting of O-nitration, again with cholic acid-Methionin conjugates molecule in the terminal amino group condensation of Methionin, at last protecting group BOC is sloughed, obtain target molecule.
With N
α-ursodeoxycholic acyl-[N
ω-(3-O-nitro-L-seryl)-Methionin] be example, concrete building-up reactions is as follows:
Term among the present invention " pharmacy acceptable salt " can be medicinal inorganic or organic salt.The compound that has basic group among formula Ia of the present invention and the formula 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 and the formula Ib can form pharmaceutical salts with basic metal or alkaline-earth metal, and is preferred but be not limited to sodium salt, sylvite, magnesium salts or calcium salt.
The compounds of this invention can be separately or with the form administration of pharmaceutical composition.Route of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration.Pharmaceutical composition can be made into various suitable formulations according to route of administration.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.Randomly, also can add some sweeting agents, perfume compound or tinting material in the above oral preparations form.
When topical application, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, sorbitan monostearate, polysorbate60, n-Hexadecane ester type waxes, cetene are fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
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 the 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.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
All commercially available the getting of all starting raw materials that the present invention is used.
Embodiment 1.N
αSynthesizing of-ursodeoxycholic acyl-(3-O-nitro-L-Serine) preparation 1.13-O-nitro-L-Serine nitrate (Ia-1)
Get 25 milliliters of nitrosonitric acids and drop in the there-necked flask, cryosel is bathed and is cooled to-10 ℃; 5 gram Serines are added in the reaction solution in batches, and the control reacting liquid temperature is lower than 0 ℃, stirs reaction down 30 minutes.Reaction is finished, and reaction solution is splashed in 100 milliliters of ether, separates out precipitation, the leaching precipitation, and the ether thorough washing gets 7.9 gram white solids after the drying, and fusing point: 85-88 ℃, yield 78%.IR(film，cm
-1)：3398，3005，1648，1570，1384，1285，985，845，757，643。
1H-NMR(DMSO-d
6)：8.53(br?s，3H)；4.98(q，1H)；4.85(q，1H)；4.50(br?s，1H)。MS(FAB?m/e)：211.9(M+HNO
3-1)，299.1(2M-1)。
1.2 N
α(Ia-1) synthetic of-ursodeoxycholic acyl-(3-O-nitro-L-Serine)
1.9 gram (8.9 mmole) 3-O-nitro-L-Serine nitrate are dissolved under ice bath in 17.8 milliliters of 1N sodium hydroxide solutions, and mixed solution is cool but to 0 ℃.Get ursodesoxycholic acid 3.5 grams (8.9 mmole) and be dissolved in 45 milliliters of tetrahydrofuran (THF)s, under cryosel is bathed, be cooled to-15 ℃; Add 1.06 milliliters of N-methylmorpholines, 1.29 milliliters of isobutyl chlorocarbonates successively, reaction is 8-10 minute under cryosel is bathed.Serine nitric ether mixed solution is joined in the reaction solution, and ice bath stirred 1.5 hours down.Reaction is finished, and the citric acid with 5% is regulated pH value to 3-4, uses ethyl acetate extraction 3 times, and the combined ethyl acetate layer is used 5% citric acid, saturated common salt water washing successively, and anhydrous magnesium sulfate drying spends the night.Filter removal of solvent under reduced pressure, column chromatography for separation (sherwood oil: ethyl acetate: methyl alcohol=4:4:1), get white solid 3.8 grams, fusing point: 130-134 ℃, yield 81%.TLC:R
f=0.4-0.5, sherwood oil: ethyl acetate: methyl alcohol: Glacial acetic acid=4:4:1:2.
1H-NMR (DMSO-d
6): 12.09 (br m, 1H); 8.08 (br s, 1H); 5.58 (m, 1H); 4.57 (m, 2H); 2.24 (br m, 2H); 1.99 (s, 3H); 1.95-0.84 (brm, cyclopentanoperhydro-phenanthrene CH
2And CH); 0.89 (d, 3H, J=8.1Hz); 0.61 (s, 3H).MS(FABm/e)：523.6(M-1)1047.9(2M-1)。
Embodiment 2.N
α-ursodeoxycholic acyl-(3-O-nitro-D-Serine) preparation (Ia-2)
Replace the L-Serine with the D-Serine,, obtain 3-O-nitro-D-Serine nitrate, yield with reference to the method for embodiment 1.1: 72%, fusing point: 87-91 ℃.
1H-NMR(DMSO-d
6)：8.49(brs，3H)5.01(brm，2H)4.68(brm，1H)。MS(FABm/e)：151.1(M+1)301.0.1(2M+1)。
Replace 3-O-nitro-L-Serine nitrate with 3-O-nitro-D-Serine nitrate, obtain target compound Ia-2 with reference to the method for embodiment 1.2.Yield: 74%, fusing point: 133-136 ℃.
1H-NMR (DMSO-d
6): 13.16 (br m, 1H); 8.38 (d, 1H, J=7.0Hz); 4.84 (m, 1H); 4.68 (m, 2H); 2.16 (br m, 2H); 1.99 (s, 3H); 1.95-0.84 (brm, cyclopentanoperhydro-phenanthrene CH
2And CH); 0.89 (d, 3H, J=8.1Hz); 0.61 (s, 3H).
Embodiment 3.N
α-courage acyl-(3-O-nitro-L-Serine) preparation (Ia-3)
Replace ursodesoxycholic acid with cholic acid,, obtain target compound Ia-3 with reference to the method for embodiment 1.2.Yield: 71%, fusing point: 133-136 ℃.
1H-NMR (DMSO-d
6): 13.11 (br m, 1H); 8.38 (d, 1H, J=7.2Hz); 4.81 (brd, 1H); 4.69 (m, 2H); 3.78 (s, 1H); 3.61 (s, 1H); 3.39 (q, 2H); 3.18 (br m, 1H); 2.23-1.07 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH); 0.93 (d, 3H, J=5.9Hz); 0.81 (s, 3H); 0.58 (s, 3H).
Embodiment 4.N
α-courage acyl-(3-O-nitro-D-Serine) preparation (Ia-4)
Replace the L-Serine with the D-Serine, cholic acid replaces ursodesoxycholic acid, with reference to the method for embodiment 1, obtains target compound Ia-4.Yield: 79%, fusing point: 134-136 ℃.MS (FABm/e): 542.7 (M-1).
1H-NMR (DMSO-d
6): 13.19 (br m, 1H); 8.39 (d, 1H, J=7.6Hz); 4.84 (m, 1H); 4.68 (m, 2H); 3.78 (s, 1H); 3.62 (s, 1H); 3.39 (q, 2H); 3.19 (br m, 1H); 2.23-1.08 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH); 0.94 (d, 3H, J=6.4Hz); 0.81 (s, 3H); 0.58 (s, 3H).
Embodiment 5.N
α-ursodeoxycholic acyl-(3-O-nitro-L-Threonine) preparation (Ia-5)
Replace the L-Serine with the L-Threonine,, obtain 3-O-nitro-L-Threonine nitrate, yield with reference to the method for embodiment 1.1: 81%, fusing point: 125-127 ℃.
1H-NMR(DMSO-d
6)：8.91(br?s，3H)5.59(m，1H，)4.33(br?s，1H，)1.46(d，1H，J＝6.7)。
Replace 3-O-nitro-L-Serine nitrate with 3-O-nitro-L-Threonine nitrate, obtain target compound Ia-5 with reference to the method for embodiment 1.2.Yield: 83%, fusing point: 138-142 ℃.
1H-NMR (DMSO-d
6): 13.16 (br m, 1H); 8.38 (d, 1H, J=9.0Hz); (5.59 br m, 1H, J=3.9 and 6.7Hz); (4.74 dd, 1H, J=9.0 and 3.9Hz); 4.02 (q, 2H); 2.21 (br m, 2H); 1.99 (s, 3H); 1.95-0.82 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH); 1.27 (d, 3H, J=6.7Hz); 0.89 (d, 3H, J=6.7Hz); 0.61 (s, 3H).
Embodiment 6.N
α-ursodeoxycholic acyl-(3-O-nitro-D-Threonine) preparation (Ia-6)
Replace the L-Serine with the D-Threonine,, obtain 3-O-nitro-D-Threonine nitrate, yield with reference to the method for embodiment 1.1: 71%, fusing point: 126-128 ℃.
1H-NMR(DMSO-d
6)δ：8.89(br?s，3H)5.56(m，1H，)4.31(br?s，1H，)1.42(d，1H，J＝6.7)。
Replace 3-O-nitro-L-Serine nitrate with 3-O-nitro-D-Threonine nitrate, obtain target compound Ia-6 with reference to the method for embodiment 1.2.Yield: 85%, fusing point: 135-139 ℃.
1H-NMR (DMSO-d
6): 13.16 (br m, 1H); 8.37 (d, 1H, J=9.0Hz); (5.60 br m, 1H, J=3.9 and 6.4Hz); (4.78 dd, 1H, J=9.0 and 3.9Hz); 4.02 (q, 1H); 2.21 (br s, 2H); 1.99 (s, 3H); 1.95-0.84 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH); 1.28 (d, 3H, J=6.4Hz); 0.89 (d, 3H, J=6.4Hz); 0.60 (s, 3H).
Embodiment 7.N
α-courage acyl-(3-O-nitro-L-Threonine) preparation (Ia-7)
Replace ursodesoxycholic acid with cholic acid, 3-O-nitro-L-Threonine nitrate replaces 3-O-nitro-L-Serine nitrate, obtains target compound Ia-7 with reference to the method for embodiment 1.2.Yield: 75%, fusing point: 140-142 ℃.
1H-NMR (DMSO-d
6): 13.17 (br m, 1H); 8.41 (d, 1H, J=9.0Hz); 5.60 (br m, 1H); (4.76 dd, 1H, J=9.0 and 3.9Hz); 4.34 (brs, 1H); 4.12 (brs, 1H); 4.04 (brs, 1H); 3.79 (brs, 1H); 3.61 (br s, 1H); 3.39 (q, 2H); 3.18 (br m, 1H); 2.26-1.11 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH); 0.95 (d, 3H, J=6.2Hz); 0.81 (s, and 3H) 0.58 (s, 3H).
Embodiment 8.N
α-courage acyl-(3-O-nitro-D-Threonine) preparation (Ia-8)
Replace ursodesoxycholic acid with cholic acid, 3-O-nitro-D-Threonine nitrate replaces 3-O-nitro-L-Serine nitrate, with reference to the method for embodiment 1.2, obtains target compound Ia-8.Yield: 81%, fusing point: 139-143 ℃.
1H-NMR (DMSO-d
6): 13.09br m, 1H); 8.34 (d, 1H, J=9.0Hz); 5.56 (br m, 1H); (4.74 dd, 1H, J=9.0 and 3.9Hz); 4.26 (brs, 1H); 4.04 (brs, 1H); 3.94 (brs, 1H); 3.75 (brs, 1H); 3.57 (br s, 1H); 3.35 (q, 2H); 3.14 (br m, 1H); 2.16-1.05 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH); 0.91 (d, 3H, J=6.1Hz); 0.77 (s, 3H); 0.53 (s, 3H).
Embodiment 9.N
α-ursodeoxycholic acyl-(trans-4-O-nitro-hydroxyl-the L-proline(Pro)) preparation (Ia-9)
Replace the L-Serine with trans-4-hydroxy-l-proline,, obtain trans-4-O-nitro-hydroxyl-L-proline(Pro) nitrate with reference to the method for embodiment 1.1.Yield: 76%, fusing point: 129-131 ℃.
Replace 3-O-nitro-L-Serine nitrate with trans-4-O-nitro-hydroxyl-L-proline(Pro) nitrate, obtain target compound Ia-9 with reference to the method for embodiment 1.2.Yield: 77%, fusing point: 133-136 ℃.
1H-NMR (DMSO-d
6): 12.69 (br m, 1H); 5.65 (s, 1H); 5.57 (br s, 0.5H); 4.65 (t, 0.5H); 4.46 (t, 1H); 4.04 (q, 1H); 3.93 (brm, 4H); 2.36 (br m, 1H); 2.26 (br m, 1H); 2.15 (br m, 1H); 1.99 (s, 3H); 1.95-0.84 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH); 0.90 (d, 3H, J=6.4Hz); 0.62 (s, 3H).
Embodiment 10.N
α-courage acyl-(trans-4-O-nitro-hydroxyl-the L-proline(Pro)) preparation (Ia-10)
Replace ursodesoxycholic acid with cholic acid, trans-4-O-nitro-hydroxyl-L-proline(Pro) nitrate replaces 3-O-nitro-L-Serine nitrate, obtains target compound Ia-10 with reference to the method for embodiment 1.2.Yield: 83%, fusing point: 131-134 ℃.
1H-NMR (DMSO-d
6) δ: 12.83 (brm, 1H); 5.65 (s, 1H); 5.57 (br s, 0.5H); 4.64 (t, 0.5H); 4.24 (t, 1H); 4.11 (brs, 1H); 4.03 (q, 1H); 3.93 (brm, 2H); 3.79 (brs, 1H); 3.39 (q, 1H); 3.21 (br m, 1H); (2.65-0.81 br m, cyclopentanoperhydro-phenanthrene CH2 and CH); 0.95 (d, 3H, J=6.2Hz); 0.81 (s, 3H); 0.59 (s, 3H).
Embodiment 11.N
α-ursodeoxycholic acyl-[N
ω-(3-O-nitro-L-seryl)-Methionin] (Ib-1) preparation
11.1 N
αSynthesizing of-tertbutyloxycarbonyl-3-O-nitro-L-Serine
Get 5.8 gram (22.6 mmoles, 1.2 times of amounts) BOC acid anhydrides and be dissolved in 20 milliliters the dioxane, make BOC solution.The sodium hydroxide of 44 milliliters of 1N and the mixing solutions of 20 milliliters of dioxane are cooled to 0 ℃ with ice bath, add 4.7 gram (22.1 mmole) 3-O-nitro-L-Serines; Alternately add BOC acid anhydrides solution and 22 milliliters of 1N sodium hydroxide solutions under the ice bath, ice bath stirred 1 hour down.Reaction is finished, and reaction solution is added in 100 milliliters of frozen water, with 30 milliliters of ether extraction three times, adds 50 milliliters of ethyl acetate in the water layer, with 5% citric acid acidifying pH value to 3, tells ethyl acetate layer under stirring, and water layer is with 50 milliliters of ethyl acetate extraction secondaries; The combined ethyl acetate layer, the saturated common salt water washing, anhydrous magnesium sulfate drying, removal of solvent under reduced pressure gets colourless viscous liquid 4.8 grams.Yield 87%.TLC:R
f=0.7, developping agent=sherwood oil: ethyl acetate: methyl alcohol: Glacial acetic acid=4:4:1:0.03.
11.2 N
α-ursodeoxycholic acyl-(N
ωSynthesizing-carbobenzoxy-(Cbz) Methionin)
With 11.8 gram (42.1 mmole) N
ω-carbobenzoxy-(Cbz) Methionin is dissolved in 160 milliliters of 1N sodium hydroxide solutions, and mixed solution is cool but to 0 ℃.Get ursodesoxycholic acid 15 grams (38.2 mmole) and be dissolved in 110 milliliters of tetrahydrofuran (THF)s, under cryosel is bathed, be cooled to-15 ℃; Add 4.20 milliliters of N-methylmorpholines, 5.02 milliliters of isobutyl chlorocarbonates successively, reaction is 8-10 minute under cryosel is bathed.With N
ωThe solution of-carbobenzoxy-(Cbz) Methionin joins in the reaction solution, and ice bath stirred 1.5 hours down, removed ice bath, at room temperature stirred 2 hours.Reaction is finished, and the citric acid acidifying pH value to 3 with 5% is used ethyl acetate extraction 3 times, and the combined ethyl acetate layer is used 5% citric acid, saturated common salt water washing, anhydrous magnesium sulfate drying successively.Removal of solvent under reduced pressure, column chromatography for separation (developping agent=sherwood oil: ethyl acetate: methyl alcohol=4:4:0.3), get white solid 18.1 grams, yield 91%.TLC:R
f=0.3-0.4, developping agent=sherwood oil: ethyl acetate: methyl alcohol: Glacial acetic acid=4:4:1:2.
11.32.2.3 N
αSynthesizing of-ursodeoxycholic acyl-Methionin
Get N
α-ursodeoxycholic acyl-(N
ω-carbobenzoxy-(Cbz) Methionin) 4.1 grams (6.26 mmole) are dissolved in 40 ml methanol, add 1 gram 10%Pd-C, feed hydrogen under the room temperature, stir reaction down 36 hours.Reaction is finished, and with reacting liquid filtering, reclaims catalyzer; Filtrate decompression is removed and is desolvated, and gets white solid 3.3 grams, and fusing point: 215-220 ℃, yield 99%.
11.4 N
α-ursodeoxycholic acyl-[N
ω-(N α-tertbutyloxycarbonyl-3-O-nitro-L-seryl)-Methionin] synthetic
With 2.4 gram (4.6 mmole) N
α-ursodeoxycholic acyl-Methionin is dissolved in the 25 ml water solution that contain 4.6 mmole sodium hydroxide, and mixed solution is cool but to 5 ℃.Get 2.1 gram (8.4 mmole) N
α-tertbutyloxycarbonyl-3-O-nitro-L-Serine is dissolved in 40 milliliters of tetrahydrofuran (THF)s, is cooled to-15 ℃ under cryosel is bathed; Add 0.92 milliliter of (8.4 mmole) N-methylmorpholine, 1.10 milliliters of (8.4 mmole) isobutyl chlorocarbonates successively, reaction is 8-10 minute under cryosel is bathed.With N
α-ursodeoxycholic acyl-lysine solution joins in the reaction solution, and ice bath stirred 1.5 hours down.Reaction is finished, and the citric acid acidifying with 5% is used ethyl acetate extraction 3 times to PH3, and the combined ethyl acetate layer is used 5% citric acid, saturated common salt water washing, anhydrous magnesium sulfate drying successively.Removal of solvent under reduced pressure, column chromatography for separation (sherwood oil: ethyl acetate: methyl alcohol=4:4:1), get white solid 2.53 grams, product 144-151 ℃ decomposition, yield 73%.TLC:Rf=0.7-0.8, developping agent=sherwood oil: ethyl acetate: methyl alcohol: Glacial acetic acid=4:4:1:2.
11.5 N
α-ursodeoxycholic acyl-[N
ω-(3-O-nitro-L-seryl)-Methionin] (Ib-1) preparation
Get 0.5 gram (0.66 mmole) N
α-ursodeoxycholic acyl-[N
ω-(N
α-tertbutyloxycarbonyl-3-O-nitro-L-seryl)-and Methionin] be dissolved in 25 milliliters of dioxane; add 10 milliliters of dry 4N hydrochloric acid dioxane under the room temperature; stir reaction down 30 minutes; the leaching precipitation; the ether thorough washing, thorough drying gets white solid 0.53 gram; fusing point: 162-167 ℃, yield 77%.TLC:R
f=0.5, developping agent: Virahol: methyl alcohol: ammoniacal liquor=8:2:0.1.
1H-NMR (DMSO-d
6): 7.46 (br s, 1H) 4.12 (br m, 2H) 3.90 (m, 1H) 3.72 (m, 1H) 3.71 (br s, 1H) 3.65 (br m, 2H) 1.83-0.25 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH).
Embodiment 12.N
α-ursodeoxycholic acyl-[N
ω-(3-O-nitro-L-Threonyl)-Methionin] (Ib-2) preparation
Replace 3-O-nitro-L-Serine with 3-O-nitro-L-Threonine, the method with reference to embodiment 11.1 obtains N
α-tertbutyloxycarbonyl-3-O-nitro-L-Threonine.
Use N
α-tertbutyloxycarbonyl-3-O-nitro-L-Threonine replaces N
α-tertbutyloxycarbonyl-3-O-nitro-L-Serine, the method with reference to embodiment 11.4 obtains N
α-ursodeoxycholic acyl-[N
ω-(N
α-tertbutyloxycarbonyl-3-O-nitro-L-Threonyl)-Methionin].
Use N
α-ursodeoxycholic acyl-[N
ω-(N
α-tertbutyloxycarbonyl-3-O-nitro-L-Threonyl)-and Methionin] replacement N
α-ursodeoxycholic acyl-[N
ω-(N
α-tertbutyloxycarbonyl-3-O-nitro-L-seryl)-and Methionin], the method with reference to embodiment 11.5 obtains N
α-ursodeoxycholic acyl-[N
ω-(3-O-nitro-L-Threonyl)-Methionin] (Ib-2), fusing point: 172-178 ℃.MS(FABm/e)：667.6(M+1)；。
1H-NMR (DMSO-d
6): 8.13 (d, 1H, J=5.9Hz); 7.20 (br d, 1H); 5.32 (m, 2H); 4.42 (d, 1H, J=3.9Hz); 3.87 (d, 1H, J=6.7); 3.71 (br s, 1H); 3.03 (br m, 2H); 2.02-0.84 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH); 1.24 (s, 3H); 0.89 (d, 3H, J=7.6Hz); 0.61 (s, 3H).
Embodiment 13.N
α-ursodeoxycholic acyl-[N
ω-(3-O-nitro hydroxyl dried meat acyl group)-Methionin] (Ib-3) synthetic
Replace 3-O-nitro-L-Serine with 3-O-nitro-oxyproline, the method with reference to embodiment 11.1 obtains N
α-tertbutyloxycarbonyl-3-O-nitro-oxyproline.
Use N
α-tertbutyloxycarbonyl-3-O-nitro-oxyproline replaces N
α-tertbutyloxycarbonyl-3-O-nitro-L-Serine, the method with reference to embodiment 11.4 obtains N
α-ursodeoxycholic acyl-[N
ω-(N
α-tertbutyloxycarbonyl-3-O-nitro-L-hydroxyl dried meat acyl group)-Methionin].
Use N
α-ursodeoxycholic acyl-[N
ω-(N
α-tertbutyloxycarbonyl-3-O-nitro-L-hydroxyl dried meat acyl group)-and Methionin] replacement N
α-ursodeoxycholic acyl-[N
ω-(N
α-tertbutyloxycarbonyl-3-O-nitro-L-seryl)-and Methionin], the method with reference to embodiment 11.5 obtains N
α-ursodeoxycholic acyl-[N
ω-(3-O-nitro-hydroxyl dried meat acyl group)-Methionin] (Ib-3), fusing point: 164-168 ℃.MS (FAB m/e): 677.9 (M-1) 713.9 (M+HC1-1);
1H-NMR (DMSO-d
6): 10.16 (br m, 1H); 8.99 (br s, 1H); 8.58 (br s, 1H); 8.07 (m, 1H); 5.71 (t, 1H); 4.15-3.57 (m, 6H); 3.41 (q, 1H); 3.37 (br m, 2H); 3.12 (br m, 2H); 2.25-0.90 (br m, cyclopentanoperhydro-phenanthrene CH
2And CH); 1.09 (s, 3H); 0.88 (d, 3H, J=6.5Hz); 0.61 (s, 3H).
Embodiment 14. anti-CCl
4The pharmacodynamics evaluation of poisoning induced mice liver injury
Get the Baclb/c mouse of the about 20-25g of quality, random packet, every group of 5 mouse.Testing compound by the orally give various dose; Behind the 1h, according to the dosage of 10mL/kg, the CCl of subcutaneous injection 100mL/L%
4, the 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 anti-CCl of table 1. The compounds of this invention
4The therapeutic action of poisoning induced mice liver injury
The pharmacodynamics evaluation of embodiment 15. anti-paracetamol induced mice liver injuries
Get the Baclb/c mouse of the about 20-25g of quality, random packet, every group of 5 mouse.Testing compound by the orally give various dose; Behind the 1h, prepare liver injury model with the paracetamol subcutaneous injection of 100mL/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, unified with full automatic biochemical apparatus for the ALT in the serum, the AST level detects.Evaluation result sees Table 2.
The therapeutic action of the anti-paracetamol induced mice of table 2. The compounds of this invention liver injury
Pharmacodynamics evaluation result by table 1 and listed tetracol phenixin of table 2 and the damage of paracetamol inductive chmice acute shows that Compound I a1-4, Ib1-3 have tangible reduction effect to Serum ALT, AST level.
Claims (8)
1, the bile acide nitrate derivatives shown in formula Ia and the Ib or its pharmacy acceptable salt:
Wherein,
R1 represents the OH of trans or cis;
R2 represents H or OH;
A represents Serine, Threonine or the cysteine residues of L-or D-type, cis or trans 3-Hydroxyproline or 4-Hydroxyproline residue;
X is oxygen or sulphur.
2, according to bile acide nitrate derivatives or its pharmacy acceptable salt of claim 1, bile acide wherein is a cholic acid.
3, according to bile acide nitrate derivatives or its pharmacy acceptable salt of claim 1, bile acide wherein is a ursodesoxycholic acid.
4, the method for preparing each described bile acide nitrate derivatives of claim 1-3 or its pharmacy acceptable salt, the preparation method of its Chinese style Ia compound comprises:
With carboxyl without the direct nitrated nitric ether of making of the hydroxyl in the amino acid molecular of protection, free amino again with cholic acid or ursodeoxycholic acid molecule in the carboxyl condensation.
5, the method for preparing each described bile acide nitrate derivatives of claim 1-3 or its pharmacy acceptable salt, the preparation method of its Chinese style Ib compound comprises:
With alpha-amino group condensation and the deprotection in the Methionin molecule of carboxyl in cholic acid or the ursodeoxycholic acid molecule and terminal amino group protection; preparation cholic acid-Methionin conjugates; then with BOC with the amino acid whose amido protecting of O-nitration; again with cholic acid-Methionin conjugates molecule in the terminal amino group condensation of Methionin, slough protecting group BOC at last.
6. contain as each the described bile acide nitrate derivatives of claim 1-3 of activeconstituents or the pharmaceutical composition of its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or excipient.
7. the pharmaceutical composition of claim 6, its form with solution, tablet, capsule or injection exists.
8. each described bile acide nitrate derivatives of claim 1-3 or its pharmacy acceptable salt are used to prepare the purposes of the medicine of the hepatic diseases for the treatment of hepatitis, hepatic fibrosis and liver cirrhosis.
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| CN101440113B (en) * | 2007-11-19 | 2012-02-08 | 中国人民解放军军事医学科学院毒物药物研究所 | Colchicine derivative-bile acid coupling compounds and medical use thereof |
| CN101439187B (en) * | 2007-11-19 | 2011-11-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Novel coupling compound of bile acid and anti-hepatitis virus medicament and medical use thereof |
| EP2468762A1 (en) * | 2010-11-30 | 2012-06-27 | Dr. Falk Pharma Gmbh | Optimized synthesis of pure, non-polymorphic, crystalline bile acids with defined particle size |
| CN102153610B (en) * | 2011-02-28 | 2012-12-12 | 中国药科大学 | Nitric oxide donor type bile acid derivatives as well as preparation methods and medicinal application thereof |
| CN107383143A (en) * | 2017-07-31 | 2017-11-24 | 江西中医药大学 | A kind of cucurbitane type triterpenoid saponin and its preparation method and application |
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| CN1420891A (en) * | 1999-04-13 | 2003-05-28 | 尼科克斯公司 | Pharmaceutical compound |
| WO2003095471A2 (en) * | 2002-05-14 | 2003-11-20 | Nicox S.A. | Deoxycholic acid derivatives for the treatment of acute dysfunctions of portal and hepatic venous circulation |
| CN1142939C (en) * | 1996-10-04 | 2004-03-24 | 尼科克斯公司 | Nitrate esters of corticoid compounds and pharmaceutical applications thereof |
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| CN1142939C (en) * | 1996-10-04 | 2004-03-24 | 尼科克斯公司 | Nitrate esters of corticoid compounds and pharmaceutical applications thereof |
| CN1420891A (en) * | 1999-04-13 | 2003-05-28 | 尼科克斯公司 | Pharmaceutical compound |
| WO2003095471A2 (en) * | 2002-05-14 | 2003-11-20 | Nicox S.A. | Deoxycholic acid derivatives for the treatment of acute dysfunctions of portal and hepatic venous circulation |
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