CN100513415C - Bile acid derivative and pharmaceutical use thereof - Google Patents
Bile acid derivative and pharmaceutical use thereof Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- acid
- pharmaceutically acceptable
- bile acid
- nitrate
- nitro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Landscapes
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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 invention relates to bile acid nitrate derivatives, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds as active ingredients, and application of the compounds in preparing medicaments for treating diseases such as hepatitis and the like. The invention also relates to a preparation method of the bile acid nitrate derivative and the pharmaceutically acceptable salt thereof.
Background
The incidence rate of liver diseases such as viral hepatitis, hepatic fibrosis, liver cirrhosis and the like is high, and the treatment difficulty is large. 25% of the worldwide patients with hepatitis b and c will develop cirrhosis; the development of fatty liver caused by various causes (alcoholic, obesity, diabetes, etc.) also leads to cirrhosis of the liver. Portal hypertension is one of the main complications of cirrhosis, and patients have symptoms of esophageal and gastric variceal bleeding, ascites and the like, and are important causes of death of cirrhosis patients.
The progression of liver disease is a process from quantitative to qualitative changes. Firstly, liver is damaged by the action of various pathogenic factors such as virus or inflammation medium, so that the synthesis of each component of extracellular matrix mainly containing collagen is increased, the degradation is reduced, and the collagen is deposited in the liver to cause liver fibrosis; with the further development of liver injury and the aggravation of collagen tissue proliferation, the number of apoptotic and necrotic hepatocytes is increased, the liver structure is changed, so that hepatocytes are regenerated, pseudo lobules are formed, and finally cirrhosis is formed; after liver cirrhosis is formed, various functional disorders such as intrahepatic metabolism and immunity appear, complications such as portal hypertension and hepatic ascites often appear, and liver cancer may be caused.
Hepatic fibrosis is the common pathological basis of all chronic liver diseases and is the indispensable stage of cirrhosis. Through rational treatment, the hepatic fibrosis has the possibility of reversion before entering the cirrhosis stage; therefore, treatment of hepatic fibrosis is very important. At present, anti-fibrosis drugs for inhibiting collagen synthesis, such as gamma-interferon (IFN-gamma), colchicine, penicillamine and the like, are mainly used for treating hepatic fibrosis, but the treatment effect is not ideal.
After hepatic fibrosis enters a liver cirrhosis stage, liver tissue lesion is continuously developed, necrotic lesion is increased, and liver tissue structure is changed, so that various liver dysfunctions are caused, and complications such as portal hypertension, hepatic ascites and the like often occur. At present, the main treatment method for the cirrhosis is to correct the complications, maintain the functions of the liver by increasing the supplement of the liver to glucose, vitamins, amino acids and other nutrient substances, prevent the further deterioration of the disease condition and carry out liver transplantation on patients with serious disease conditions. The existing medicine has no definite curative effect on liver cirrhosis and complications such as portal hypertension, ascites and the like.
Research shows that a proper amount of nitric oxide can protect liver cells, prevent liver cell apoptosis, inhibit formation and development of intrahepatic inflammation, repair liver injury, improve intrahepatic blood circulation, reduce intrahepatic pressure, improve hepatic fibrosis and the like, and has a treatment effect on various stages of development of liver diseases.
Nitric oxide can inhibit the release of various pro-inflammatory factors such as interleukin (IL-1, IL-6, IL-18, IL-1 beta) tumor necrosis factor-alpha (TNF-alpha) and the like in liver, and has the function of inhibiting caspase activity related to inflammation and apoptosis. Research proves that nitric oxide can improve liver injury caused by various factors, reduce necrosis of liver cells, inhibit formation and development of intrahepatic inflammation and reduce concentration of intrahepatic transaminase, thereby preventing liver diseases from developing towards fibrosis.
Nitric oxide can also inhibit the aggregation of leukocytes, platelets and neutrophils and the adhesion thereof to the vascular wall, and has the effects of inhibiting the formation of intrahepatic thrombosis, improving microcirculation and the like. Meanwhile, nitric oxide can relax stellate cells in the liver and increase blood flow at the hepatic venous antrum; and can expand the walls of various blood vessels including arterioles and venules, reduce the resistance of blood flow, thereby ensuring or increasing the perfusion of blood to the liver and further generating the function of resisting portal hypertension.
Research shows that the nitric oxide release medicine can inhibit the development of liver inflammation and the formation of hepatic fibrosis and reduce portal hypertension by releasing nitric oxide molecules, thereby generating the curative effect of treating liver cirrhosis and portal hypertension. However, the nitric oxide releasing drugs of organic nitrates currently used clinically for treating liver cirrhosis produce a wide range of systemic side effects due to the non-specificity of in vivo distribution. The side effects of conventional nitrate-based drugs can be reduced or avoided by a liver-targeted administration route.
Bile acid is currently the only orally available small molecule liver targeting vehicle. Bile acid is biosynthesized from cholesterol in hepatocytes, then is combined with glycine or taurine, enters the digestive tract along with chyme, more than 95% of the bile acid is reabsorbed in the terminal ileum, then returns to the liver through the inferior vena cava, and thus is continuously circulated in the liver and intestines; the liver and intestine circulation in an adult body is repeated 6 to 15 times every day, and the total amount of bile acid participating in the circulation reaches 17 to 40g, so that the bile acid has higher transport capacity; the bile acid is absorbed through an active transport way, and the bioavailability of the medicine can be improved by taking the bile acid as a targeting carrier; as endogenous natural ligands, bile acids have good biocompatibility and are therefore suitable as carriers for targeted drugs. The bile acid in vivo consists of Cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid and lithocholic acid, wherein Cholic Acid (CA) and ursodeoxycholic acid (UDCA) have no membrane dissolving effect of other types of bile acid, and are good in vivo safety and strong in transport capacity, so that the bile acid is often selected as a liver targeting drug carrier. Ursodeoxycholic acid also has the wide pharmacological actions of protecting liver, benefiting gallbladder, reducing glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase and gamma-glutamyl transpeptidase (gamma-GT), reducing blood fat, obviously relieving fatty liver symptoms, and has certain therapeutic action on chronic hepatitis. Therefore, the ursodeoxycholic acid not only can be used as a drug carrier, but also can generate a synergistic effect with the drug.
International patent WO 03095471 discloses conjugates of ursodeoxycholic acid containing nitrate esters; in the structure of these conjugates, the nitrate as the nitric oxide releasing component is linked to the carrier bile acid via an ester linkage. The structure of its representative compound NCX1000 is as follows:
research shows that NCX1000 can effectively inhibit various inflammatory factors such as interleukin, tumor necrosis factor and the like, and has better treatment effect on liver injury and inflammation, portal hypertension, liver cirrhosis and liver fibrosis caused by various reasons.
However, in the NCX1000 molecule, the targeting vector is coupled to the nitrate component via two ester linkages; since the ester bond is easily hydrolyzed, the carrier part and the active part are dissociated and the targeting effect is lost. The results of pharmacokinetic studies show that the drug is released by ester bond coupled nitrates and that no intact original drug is detectable in blood after oral administration.
Disclosure of Invention
The invention solves the defect of the prior art that the medicament loses the targeting effect because ester bonds between carrier bile acid and the medicament are easy to hydrolyze by providing nitrate derivatives of cholic acid or ursodeoxycholic acid shown in the following formulas Ia and Ib
Accordingly, one aspect of the present invention relates to nitrate derivatives of cholic acid or ursodeoxycholic acid represented by structural formulae Ia and/or Ib, respectively, and pharmaceutically acceptable salts thereof:
cholic acid derivatives:
R2＝OH
ursodeoxycholic acid derivatives:
R2＝H
wherein,
a represents a serine, threonine or cysteine residue of L-or D-type, a 3-hydroxyproline or 4-hydroxyproline residue of cis-or trans-form;
x is oxygen or sulfur.
Another aspect of the present invention relates to a method for preparing nitrate derivatives of cholic acid or ursodeoxycholic acid represented by formula Ia or Ib, and pharmaceutically acceptable salts thereof.
Another aspect of the present invention relates to pharmaceutical compositions containing nitric acid ester derivatives of cholic acid or ursodeoxycholic acid represented by formula Ia and/or Ib and pharmaceutically acceptable salts thereof as an active ingredient together with one or more pharmaceutically acceptable carriers or excipients.
The invention also relates to application of the nitric acid ester derivative of cholic acid or ursodeoxycholic acid shown in formula Ia and/or Ib and pharmaceutically acceptable salts thereof in preparing medicines for treating liver diseases such as hepatitis, hepatic fibrosis and liver cirrhosis.
Yet another aspect of the present invention relates to a method for treating liver diseases such as hepatitis, hepatic fibrosis and liver cirrhosis, said method comprising administering to a patient in need thereof a therapeutically effective amount of a nitrate derivative of cholic acid or ursodeoxycholic acid represented by formula Ia and/or Ib, and pharmaceutically acceptable salts thereof.
Specifically, the invention relates to bile acid nitrate derivatives shown as formulas Ia and Ib and pharmaceutically acceptable salts thereof:
wherein,
r1 represents trans or cis OH;
r2 represents H or OH;
a represents a serine, threonine or cysteine residue of L-or D-type, a 3-hydroxyproline or 4-hydroxyproline residue of cis-or trans-form;
x is oxygen or sulfur.
According to the invention, the formula Ia is a coupling compound formed by connecting the carboxyl at the 24-position of cholic acid or ursodeoxycholic acid with the alpha amino of 0-nitrated or S-nitrated amino acid through an amido bond; the Ib is a coupling compound formed by connecting the 24-carboxyl of cholic acid or ursodeoxycholic acid with nitrated amino acid through lysine, and the release rate of the medicament can be better controlled by introducing the lysine.
In Ia or Ib, the nitrate component is connected to a carrier of cholic acid through an amido bond, so that the stability of the cholic acid in plasma is ensured; after entering liver cells, nitrate and sulfhydryl components in the cells form unstable S-nitroso sulfide, which is further decomposed to release NO molecules, thereby playing pharmacological action. Meanwhile, the alpha carboxyl of the amino acid is used for simulating the electronegativity of the 24-site carboxyl of cholic acid or ursodeoxycholic acid molecules, so that the structural characteristics of the cholic acid or the ursodeoxycholic acid are maintained to the maximum extent, and the liver targeting property of the cholic acid or the ursodeoxycholic acid is ensured; the linker is natural amino acid and has good biocompatibility.
The invention also provides pharmaceutically acceptable salts of nitrate derivatives of cholic acid or ursodeoxycholic acid shown in formulas Ia and Ib, and the salts can be formed by carboxyl in Ia or Ib molecules and various cations such as sodium ions, potassium ions, ammonia ions, calcium ions, zinc ions, magnesium ions or ammonia ions and the like.
According to the present invention, the synthesis route of the target compound Ia has three main routes.
The first synthetic route is that in alcoholic solution of hydrogen chloride, carboxyl of amino acid is protected through esterification, and hydroxyl in amino acid molecule protected by carboxyl reacts with phosphorus pentachloride to prepare halogenated amino acid; under the action of condensing agent such as DCC, free amino is condensed with carboxyl in cholic acid or ursodeoxycholic acid molecule, the condensation product is saponified and removed of protective group, and finally the condensation product is reacted with silver nitrate to obtain the target compound.
Taking the coupling compound of ursodeoxycholic acid-O-nitroserine as an example, the specific synthesis reaction is as follows:
the second synthetic route is that hydroxyl in amino acid molecules protected by carboxyl esterification reacts with nitric acid to prepare nitrate; under the action of condensing agent such as DCC, the free amino group is condensed with carboxyl group in cholic acid or ursodeoxycholic acid molecule, and the condensation product is saponified and the protecting group is removed to obtain the target compound.
Taking the coupling compound of ursodeoxycholic acid-O-nitroserine as an example, the specific synthesis reaction is as follows:
the third synthesis route is to nitrify the hydroxyl in the amino acid molecule without protecting carboxyl directly to prepare nitrate, and then condense the free amino with the carboxyl in the cholic acid or ursodeoxycholic acid molecule to obtain the target compound.
Taking the coupling compound of ursodeoxycholic acid-O-nitroserine as an example, the specific synthesis reaction is as follows:
according to the invention, the synthesis route of the target compound Ib is that a carboxyl group in a cholic acid or ursodeoxycholic acid molecule and an alpha-amino group in a lysine molecule with a protected terminal amino group are condensed and deprotected to prepare the cholic acid-lysine coupling compound. Protecting amino group of O-nitrated amino acid with BOC, condensing with terminal amino group of lysine in cholic acid-lysine coupling compound molecule, and removing protecting group BOC to obtain target molecule.
With Nα-ursodeoxycholic acid- [ N [ ]ω- (3-O-nitro-L-seryl) -lysine]For example, the specific synthesis reaction is as follows:
the term "pharmaceutically acceptable salt" in the present invention may be a pharmaceutically acceptable inorganic or organic salt. The compounds having a basic group in formula Ia and Ib of the present invention can form pharmaceutically acceptable salts with inorganic acids, such as sulfate, hydrochloride, hydrobromide, phosphate; pharmaceutically acceptable salts can also be formed with organic acids such as acetates, oxalates, citrates, gluconates, succinates, tartrates, p-toluenesulfonates, methanesulfonates, benzoates, lactates, maleates, and the like. The compounds of the invention having an acidic group in formula Ia and Ib may form pharmaceutically acceptable salts with alkali metals or alkaline earth metals, preferably but not limited to sodium, potassium, magnesium or calcium salts.
The compounds of the present invention may be administered alone or in the form of pharmaceutical compositions. The administration route can be oral, parenteral or topical, preferably oral and injectable. The pharmaceutical composition can be formulated into various suitable dosage forms according to the administration route.
When administered orally, the compounds of the present invention may be formulated in any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or suspensions. Among these, carriers for tablets generally include lactose and corn starch, and additionally, lubricating agents such as magnesium stearate may be added. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are generally prepared by mixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweetener, aromatic or colorant may be added into the above oral preparation.
When applied topically to the skin, the compounds of the present invention may be formulated in a suitable ointment, lotion, or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions or solutions. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
It is further noted that the dosage and method of administration of the compounds of the present invention will depend upon a variety of factors including the age, weight, sex, physical condition, nutritional status, the activity level of the compound, time of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. The preferred dosage is between 0.01-100mg/kg body weight/day.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.
All starting materials for use in the present invention are commercially available.
Example 1.NαPreparation of (E) -ursodeoxycholic acid- (3-O-nitro-L-serine) (Ia-1) Synthesis of 1.13-O-nitro-L-serine nitrate
25 ml of fuming nitric acid is put into a three-mouth bottle, and the salt bath is cooled to-10 ℃; 5g of serine was added to the reaction mixture in portions, and the reaction mixture was stirred for 30 minutes while controlling the temperature of the reaction mixture to be lower than 0 ℃. After the reaction, the reaction solution was dropped into 100ml of ether to precipitate a precipitate, the precipitate was filtered off, washed with ether, and dried to obtain 7.9 g of a white solid, melting point: 85-88 ℃ and the yield is 78 percent. IR (film, cm)-1)：3398，3005，1648，1570，1384，1285，985，845，757，643。1H-NMR(DMSO-d6)：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+HNO3-1)，299.1(2M-1)。
1.2 NαSynthesis of (E) -ursodeoxycholic acid- (3-O-nitro-L-serine) (Ia-1)
1.9 g (8.9 mmol) of 3-O-nitro-L-serine nitrate was dissolved in 17.8 ml of 1N sodium hydroxide solution in ice bath, and the mixture was cooled to 0 ℃. Dissolving ursodeoxycholic acid 3.5 g (8.9 mmol) in tetrahydrofuran 45 ml, and cooling to-15 deg.C under ice salt bath; 1.06 ml of N-methylmorpholine and 1.29 ml of isobutyl chloroformate are added in sequence and reacted for 8 to 10 minutes in an ice salt bath. Nitric acid of serineThe ester mixture was added to the reaction solution and stirred for 1.5 hours under ice bath. After the reaction, the pH was adjusted to 3-4 with 5% citric acid, and the mixture was extracted with ethyl acetate 3 times, and the ethyl acetate layers were combined, washed with 5% citric acid and saturated brine in this order, and dried over anhydrous magnesium sulfate overnight. Filtration, removal of the solvent under reduced pressure, column chromatography (petroleum ether: ethyl acetate: methanol: 4:1) gave 3.8 g of a white solid, m.p.: 130 ℃ and 134 ℃ with the yield of 81 percent. TLC Rf0.4-0.5, petroleum ether, ethyl acetate, methanol and glacial acetic acid are 4:4:1:2.1H-NMR(DMSO-d6): 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, steroid ring CH)2And CH); 0.89(d, 3H, J ═ 8.1 Hz); 0.61(s, 3H). MS (FABm/e): 523.6(M-1)1047.9 (2M-1).
Example 2.NαPreparation of (E) -ursodeoxycholic acid- (3-O-nitro-D-serine) (Ia-2)
3-O-nitro-D-serine nitrate was obtained in the same manner as in example 1.1 except that D-serine was used instead of L-serine, and the yield was: 72%, melting point: 87-91 ℃.1H-NMR(DMSO-d6)：8.49(brs，3H)5.01(brm，2H)4.68(brm，1H)。MS(FABm/e)：151.1(M+1)301.0.1(2M+1)。
The target compound Ia-2 was obtained by the method described in example 1.2, except that 3-O-nitro-D-serine nitrate was used in place of 3-O-nitro-L-serine nitrate. Yield: 74%, melting point: 133 ℃ and 136 ℃.1H-NMR(DMSO-d6): 13.16(br m, 1H); 8.38(d, 1H, J ═ 7.0 Hz); 4.84(m, 1H); 4.68(m, 2H); 2.16(br m, 2H); 1.99(s, 3H); 1.95-0.84(brm, steroid ring CH)2And CH); 0.89(d, 3H, J ═ 8.1 Hz); 0.61(s, 3H).
Example 3.NαPreparation of (E) -cholyl- (3-O-nitro-L-serine) (Ia-3)
The objective compound Ia-3 was obtained by the method of example 1.2 using cholic acid instead of ursodeoxycholic acid. Yield: 71%, melting point: 133 ℃ and 136 ℃.1H-NMR(DMSO-d6)：13.11(br m，1H)；8.38(d，1H, J ═ 7.2 Hz); 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, steroid ring CH)2And CH); 0.93(d, 3H, J ═ 5.9 Hz); 0.81(s, 3H); 0.58(s, 3H).
Example 4.NαPreparation of (E) -cholyl- (3-O-nitro-D-serine) (Ia-4)
The target compound Ia-4 was obtained by the method of example 1 using D-serine in place of L-serine and cholic acid in place of ursodeoxycholic acid. Yield: 79%, melting point: 134 ℃ and 136 ℃. MS (FABm/e): 542.7(M-1).1H-NMR(DMSO-d6): 13.19(br m, 1H); 8.39(d, 1H, J ═ 7.6 Hz); 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, steroid ring CH)2And CH); 0.94(d, 3H, J ═ 6.4 Hz); 0.81(s, 3H); 0.58(s, 3H).
Example 5.NαPreparation of (3-O-nitro-L-threonine) (Ia-5) ursodeoxycholic acid
3-O-nitro-L-threonine nitrate was obtained in the same manner as in example 1.1 except that L-serine was replaced with L-threonine, and the yield was as follows: 81%, melting point: 125 ℃ and 127 ℃.1H-NMR(DMSO-d6)：8.91(br s，3H)5.59(m，1H，)4.33(br s，1H，)1.46(d，1H，J＝6.7)。
The target compound Ia-5 was obtained by the method described in example 1.2, except that 3-O-nitro-L-serine nitrate was replaced with 3-O-nitro-L-threonine nitrate. Yield: 83%, melting point: 138 ℃ and 142 ℃.1H-NMR(DMSO-d6): 13.16(br m, 1H); 8.38(d, 1H, J ═ 9.0 Hz); 5.59(br m, 1H, J ═ 3.9 and 6.7 Hz); 4.74(dd, 1H, J ═ 9.0 and 3.9 Hz); 4.02(q, 2H); 2.21(br m, 2H); 1.99(s, 3H); 1.95-0.82(br m, steroid ring CH)2And CH); 1.27(d, 3H, J ═ 6.7 Hz); 0.89(d, 3H, J ═ 6.7 Hz); 0.61(s, 3H).
Example 6.NαPreparation of (3-O-nitro-D-threonine) (Ia-6)
3-O-nitro-D-threonine nitrate was obtained in the same manner as in example 1.1 except that D-threonine was used instead of L-serine, and the yield was: 71%, melting point: 126 ℃ and 128 ℃.1H-NMR(DMSO-d6)δ：8.89(br s，3H)5.56(m，1H，)4.31(br s，1H，)1.42(d，1H，J＝6.7)。
The target compound Ia-6 was obtained by the method described in example 1.2, except that 3-O-nitro-D-threonine nitrate was used in place of 3-O-nitro-L-serine nitrate. Yield: 85%, melting point: 135 ℃ and 139 ℃.1H-NMR(DMSO-d6): 13.16(br m, 1H); 8.37(d, 1H, J ═ 9.0 Hz); 5.60(br m, 1H, J ═ 3.9 and 6.4 Hz); 4.78(dd, 1H, J ═ 9.0 and 3.9 Hz); 4.02(q, 1H); 2.21(br s, 2H); 1.99(s, 3H); 1.95-0.84(br m, steroid ring CH)2And CH); 1.28(d, 3H, J ═ 6.4 Hz); 0.89(d, 3H, J ═ 6.4 Hz); 0.60(s, 3H).
Example 7.NαPreparation of (E) -cholyl- (3-O-nitro-L-threonine) (Ia-7)
The objective compound Ia-7 was obtained by the method of example 1.2 using cholic acid instead of ursodeoxycholic acid and 3-O-nitro-L-threonine nitrate instead of 3-O-nitro-L-serine nitrate. Yield: 75%, melting point: 140 ℃ and 142 ℃.1H-NMR(DMSO-d6): 13.17(br m, 1H); 8.41(d, 1H, J ═ 9.0 Hz); 5.60(br m, 1H); 4.76(dd, 1H, J ═ 9.0 and 3.9 Hz); 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, steroid ring CH)2And CH); 0.95(d, 3H, J ═ 6.2 Hz); 0.81(s, 3H)0.58(s, 3H).
Example 8.NαPreparation of (E) -cholyl- (3-O-nitro-D-threonine) (Ia-8)
The objective compound Ia-8 was obtained by the method of example 1.2 using cholic acid instead of ursodeoxycholic acid and 3-O-nitro-D-threonine nitrate instead of 3-O-nitro-L-serine nitrate. Yield: 81%, melting point: 139 ℃ and 143 ℃.1H-NMR(DMSO-d6)：13.09br m，1H)；8.34(d，1H，J＝9.0Hz)；5.56(br m, 1H); 4.74(dd, 1H, J ═ 9.0 and 3.9 Hz); 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, steroid ring CH)2And CH); 0.91(d, 3H, J ═ 6.1 Hz); 0.77(s, 3H); 0.53(s, 3H).
Example 9.NαPreparation of (E) -ursodeoxycholic acid- (trans-4-O-nitro-hydroxy-L-proline) (Ia-9)
trans-4-O-nitro-hydroxy-L-proline nitrate was obtained by the method of example 1.1, except that trans-4-hydroxy-L-proline was used instead of L-serine. Yield: 76%, melting point: 129-131 ℃.
The target compound Ia-9 was obtained by the method of example 1.2 using trans-4-O-nitro-hydroxy-L-proline nitrate instead of 3-O-nitro-L-serine nitrate. Yield: 77%, melting point: 133 ℃ and 136 ℃.1H-NMR(DMSO-d6): 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, steroid ring CH)2And CH); 0.90(d, 3H, J ═ 6.4 Hz); 0.62(s, 3H).
Example 10.NαPreparation of (E) -cholyl- (trans-4-O-nitro-hydroxy-L-proline) (Ia-10)
The objective compound Ia-10 was obtained by the method of example 1.2 using cholic acid instead of ursodeoxycholic acid and trans-4-O-nitro-hydroxy-L-proline nitrate instead of 3-O-nitro-L-serine nitrate. Yield: 83%, melting point: 131 ℃ and 134 ℃.1H-NMR(DMSO-d6) 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, steroid ring CH2 and CH); 0.95(d, 3H, J ═ 6.2 Hz); 0.81(s, 3H); 0.59(s, 3H).
Example 11.Nα-deoxidation of the bearCholyl- [ N ]ω- (3-O-nitro-L-seryl) -lysine]Preparation of (Ib-1)
11.1 NαSynthesis of (E) -tert-butyloxycarbonyl-3-O-nitro-L-serine
5.8 g (22.6 mmol, 1.2 times the amount) of BOC anhydride was dissolved in 20 ml of dioxane to prepare a BOC solution. A mixed solution of 44 ml of 1N sodium hydroxide and 20 ml of dioxane was cooled to 0 ℃ with ice bath, and 4.7 g (22.1 mmol) of 3-O-nitro-L-serine was added; BOC anhydride solution and 22 ml of 1N sodium hydroxide solution were alternately added under ice bath, and stirred for 1 hour under ice bath. After the reaction, the reaction solution was added to 100ml of ice water, extracted three times with 30 ml of ether, 50 ml of ethyl acetate was added to the water layer, the PH was acidified to 3 with 5% citric acid under stirring, the ethyl acetate layer was separated, and the water layer was extracted two times with 50 ml of ethyl acetate; the ethyl acetate layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4.8 g of a colorless viscous liquid. The yield thereof was found to be 87%. TLC Rf0.7, petroleum ether, ethyl acetate, methanol and glacial acetic acid, 4:4:1: 0.03.
11.2 NαUrsodeoxycholic acid- (N)ω-benzyloxycarbonyl lysine) synthesis
11.8 g (42.1 mmol) of NωBenzyloxycarbonyl lysine was dissolved in 160 ml of 1N sodium hydroxide solution and the mixture was cooled to 0 ℃. Dissolving 15 g (38.2 mmol) of ursodeoxycholic acid in 110 ml of tetrahydrofuran, and cooling to-15 ℃ under an ice salt bath; 4.20 ml of N-methylmorpholine and 5.02 ml of isobutyl chloroformate are added in sequence and reacted for 8 to 10 minutes in an ice salt bath. Will NωThe solution of benzyloxycarbonyl lysine was added to the reaction mixture, stirred for 1.5 hours under ice bath, removed from the ice bath, and stirred at room temperature for 2 hours. After the reaction, the mixture was acidified to pH3 with 5% citric acid, extracted with ethyl acetate 3 times, and the ethyl acetate layers were combined, washed with 5% citric acid and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and column chromatography was performed (developing solvent: petroleum ether: ethyl acetate: methanol: 4:0.3) to give 18.1 g of a white solid, yield 91%。TLC:Rf0.3-0.4, developing agent petroleum ether, ethyl acetate, methanol and glacial acetic acid, 4:4:1:2.
11.32.2.3 NαSynthesis of ursodeoxycholic-lysine
Get NαUrsodeoxycholic acid- (N)ωBenzyloxycarbonyl lysine) 4.1 g (6.26 mmol) was dissolved in 40 ml of methanol, 1 g of 10% Pd-C was added thereto, hydrogen gas was introduced at room temperature, and the reaction was carried out for 36 hours with stirring. After the reaction is finished, filtering the reaction liquid and recovering the catalyst; the filtrate was freed of the solvent under reduced pressure to give 3.3 g of a white solid, melting point: 215 ℃ and 220 ℃ with a yield of 99 percent.
11.4 Nα-ursodeoxycholic acid- [ N [ ]ω- (Nalpha-tert-Butoxycarbonyl-3-O-nitro-L-seryl) -lysine]Synthesis of (2)
2.4 g (4.6 mmol) of NαUrsodeoxycholic-lysine was dissolved in 25 ml of an aqueous solution containing 4.6 mmol of sodium hydroxide, and the mixture was cooled to 5 ℃. 2.1 g (8.4 mmol) of N are takenα-tert-butoxycarbonyl-3-O-nitro-L-serine was dissolved in 40 ml of tetrahydrofuran and cooled to-15 ℃ under ice salt bath; 0.92 ml (8.4 mmol) of N-methylmorpholine and 1.10 ml (8.4 mmol) of isobutyl chloroformate were added in this order and reacted for 8 to 10 minutes in an ice salt bath. Will NαAdding ursodeoxycholic acid-lysine solution into the reaction solution, and stirring for 1.5 hours under ice bath. After completion of the reaction, the mixture was acidified to pH3 with 5% citric acid, extracted 3 times with ethyl acetate, and the ethyl acetate layers were combined, washed with 5% citric acid and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and column chromatography was performed (petroleum ether: ethyl acetate: methanol: 4:1) to give 2.53 g of a white solid, which was decomposed at 151 ℃ to yield 73%. TLC, Rf is 0.7-0.8, developing agent is petroleum ether, ethyl acetate, methanol and glacial acetic acid are 4:4:1:2.
11.5 Nα-ursodeoxycholic acid- [ N [ ]ω- (3-O-nitro-L-seryl) -lysine]Preparation of (Ib-1)
0.5 g (0.66 mmol) of N are takenα-ursodeoxycholic acid- [ N [ ]ω-(Nα-tert-butyloxycarbonyl-3-O-nitro-L-seryl) -lysine]Dissolving in 25 ml dioxane, adding 10ml dry 4N dioxane hydrochloride at room temperature, reacting for 30 min under stirring, filtering to obtain precipitate, washing with ether, and drying to obtain white solid 0.53 g, melting point: 162 ℃ and 167 ℃, and the yield is 77 percent. TLC Rf0.5, 8:2:0.1 of developing solvent isopropanol, methanol and ammonia water.1H-NMR(DMSO-d6): 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, steroid ring CH)2And CH).
Example 12.Nα-ursodeoxycholic acid- [ N [ ]ω- (3-O-nitro-L-threonyl) -lysine]Preparation of (Ib-2)
By substituting 3-O-nitro-L-threonine for 3-O-nitro-L-serine in accordance with the procedure of example 11.1, N was obtainedα-tert-butoxycarbonyl-3-O-nitro-L-threonine.
With Nα-Boc-3-O-nitro-L-threonine instead of Nα-tert-Butoxycarbonyl-3-O-nitro-L-serine, according to the method of example 11.4, N is obtainedα-ursodeoxycholic acid- [ N [ ]ω-(Nα-tert-butyloxycarbonyl-3-O-nitro-L-threonyl) -lysine]。
With Nα-ursodeoxycholic acid- [ N [ ]ω-(Nα-tert-butyloxycarbonyl-3-O-nitro-L-threonyl) -lysine]In place of Nα-ursodeoxycholic acid- [ N [ ]ω-(Nα-tert-butyloxycarbonyl-3-O-nitro-L-seryl) -lysine]By reference to the procedure of example 11.5, N was obtainedα-ursodeoxycholic acid- [ N [ ]ω- (3-O-nitro-L-threonyl) -lysine](Ib-2), melting Point: 172 ℃ and 178 ℃. MS (FABm/e): 667.6(M + 1); .1H-NMR(DMSO-d6): 8.13(d, 1H, J ═ 5.9 Hz); 7.20(br d, 1H); 5.32(m, 2H); 4.42(d, 1H, J ═ 3.9 Hz); 3.87(d, 1H, J ═ 6.7); 3.71(br s, 1H); 3.03(br m, 2H); 2.02-0.84(br m, steroid ring CH)2And CH); 1.24(s, 3H); 0.89(d, 3H, J ═ 7.6 Hz); 0.61(s, 3H).
Example 13.Nα-ursodeoxycholic acid- [ N [ ]ω- (3-O-Nitro-Hydroxypropionyl) -lysine]Synthesis of (Ib-3)
N was obtained in the same manner as in example 11.1 except that 3-O-nitro-hydroxyproline was used instead of 3-O-nitro-L-serineα-tert-butoxycarbonyl-3-O-nitro-hydroxyproline.
With Nα-Boc-3-O-nitro-hydroxyproline instead of Nα-tert-Butoxycarbonyl-3-O-nitro-L-serine, according to the method of example 11.4, N is obtainedα-ursodeoxycholic acid- [ N [ ]ω-(Nα-Boc-3-O-nitro-L-hydroxyproloyl) -lysine]。
With Nα-ursodeoxycholic acid- [ N [ ]ω-(Nα-Boc-3-O-nitro-L-hydroxyproloyl) -lysine]In place of Nα-ursodeoxycholic acid- [ N [ ]ω-(Nα-tert-butyloxycarbonyl-3-O-nitro-L-seryl) -lysine]By reference to the procedure of example 11.5, N was obtainedα-ursodeoxycholic acid- [ N [ ]ω- (3-O-nitro-hydroxyproloyl) -lysine](Ib-3), melting Point: 164 ℃ and 168 ℃. MS (FAB m/e): 677.9(M-1)713.9(M + HC 1-1);1H-NMR(DMSO-d6): 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, steroid ring CH)2And CH); 1.09(s, 3H); 0.88(d, 3H, J ═ 6.5 Hz); 0.61(s, 3H).
Example 14 CCl resistance4Pharmacodynamic evaluation of mouse liver injury caused by poisoning
Approximately 20-25g of Baclb/c mice were taken and randomly grouped, 5 mice per group. Administering different doses of the test compound orally; after 1h, 100 mL/L% CCl was injected subcutaneously at a dose of 10mL/kg4Preparing a liver injury model; normal control group was injected with saline subcutaneously. After 12 hours from molding, different doses of test compound were administered orally again. 24 hours after the second administration of the drug,the animals are sacrificed, serum samples are reserved, and the ALT and AST levels in the serum are detected by a full-automatic biochemical analyzer. The evaluation results are shown in Table 1.
TABLE 1 anti-CCl Compounds of the invention4Therapeutic action of mouse liver damage caused by poisoning
Example 15 pharmacodynamic evaluation of anti-Acetaminophen induced liver injury in mice
Approximately 20-25g of Baclb/c mice were taken and randomly grouped, 5 mice per group. Administering different doses of the test compound orally; after 1h, a liver injury model was prepared by subcutaneous injection of 100mL/kg acetaminophen, and normal control group was prepared by subcutaneous injection of physiological saline. After 1h of molding, different doses of test compound were re-administered orally. 24 hours after the second administration, the animals were sacrificed, serum samples were kept, and ALT and AST levels in the serum were measured using a fully automatic biochemical analyzer. The evaluation results are shown in Table 2.
TABLE 2 therapeutic effect of the compounds of the present invention against acetaminophen induced liver injury in mice
The pharmacodynamic evaluation results of mouse acute injury induced by carbon tetrachloride and acetaminophen listed in tables 1 and 2 show that the compounds Ia1-4 and Ib1-3 have obvious effect of reducing the ALT and AST levels in serum.
Claims (8)
1. A bile acid nitrate derivative represented by formulae Ia and Ib:
wherein,
r1 represents trans or cis OH;
r2 represents H or OH;
a represents a serine, threonine or cysteine residue of L-or D-type, a 3-hydroxyproline or 4-hydroxyproline residue of cis-or trans-form;
x is oxygen or sulfur.
2. A bile acid nitrate derivative according to claim 1, wherein the bile acid is cholic acid, or a pharmaceutically acceptable salt thereof.
3. A bile acid nitrate derivative according to claim 1, wherein the bile acid is ursodeoxycholic acid, or a pharmaceutically acceptable salt thereof.
4. A process for preparing a bile acid nitrate derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the process for preparing a compound of formula Ia comprises:
directly nitrifying hydroxyl in amino acid molecules without protection of carboxyl to prepare nitrate, and condensing free amino with carboxyl in cholic acid or ursodeoxycholic acid molecules.
5. A process for the preparation of a bile acid nitrate derivative according to any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein a compound of formula Ib is prepared by a process comprising:
condensing carboxyl in cholic acid or ursodeoxycholic acid molecules and alpha-amino in lysine molecules with terminal amino protected and deprotecting to prepare a cholic acid-lysine conjugate, then protecting amino of O-nitrated amino acid with BOC, condensing with terminal amino of lysine in the cholic acid-lysine conjugate molecules, and finally deprotecting BOC.
6. A pharmaceutical composition comprising as an active ingredient a bile acid nitrate derivative according to any of claims 1 to 3 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or excipients.
7. The pharmaceutical composition according to claim 6, which is in the form of a solution, tablet, capsule or injection.
8. Use of a bile acid nitrate derivative according to any of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of liver diseases of hepatitis, liver fibrosis and cirrhosis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100890199A CN100513415C (en) | 2005-08-03 | 2005-08-03 | Bile acid derivative and pharmaceutical use thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100890199A CN100513415C (en) | 2005-08-03 | 2005-08-03 | Bile acid derivative and pharmaceutical use thereof |
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| Publication Number | Publication Date |
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| CN1908001A CN1908001A (en) | 2007-02-07 |
| CN100513415C true CN100513415C (en) | 2009-07-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2005100890199A Expired - Fee Related CN100513415C (en) | 2005-08-03 | 2005-08-03 | Bile acid derivative and pharmaceutical use thereof |
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| CN (1) | CN100513415C (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101367859B (en) * | 2007-08-17 | 2011-05-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Fatty acid bile acid couplet and medical uses 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 |
| 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 |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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2005
- 2005-08-03 CN CNB2005100890199A patent/CN100513415C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Publication number | Publication date |
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| CN1908001A (en) | 2007-02-07 |
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Inventor after: Zhong Bohua Inventor after: Li Hongwu Inventor after: Liu He Inventor after: Chen Lanfu Inventor after: Wu Bo Inventor after: Shi Weiguo Inventor after: Zhang Zhenqing Inventor after: Xie Jianwei Inventor before: Zhong Bohua Inventor before: Li Hongwu Inventor before: Liu He Inventor before: Chen Lanfu Inventor before: Wu Bo |
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Free format text: CORRECT: INVENTOR; FROM: ZHONG BOHUA LI HONGWU LIU HE CHEN LANFU WU BO TO: ZHONG BOHUA LI HONGWU LIU HE CHEN LANFU WU BO SHI WEIGUO ZHANG ZHENQING XIE JIANWEI |
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