CN112142814A - Tauroursodeoxycholic acid derivative, and pharmaceutical composition and preparation comprising same - Google Patents

Tauroursodeoxycholic acid derivative, and pharmaceutical composition and preparation comprising same Download PDF

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CN112142814A
CN112142814A CN201910563425.6A CN201910563425A CN112142814A CN 112142814 A CN112142814 A CN 112142814A CN 201910563425 A CN201910563425 A CN 201910563425A CN 112142814 A CN112142814 A CN 112142814A
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耿仲毅
陈兴海
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Zhenjiang Shengan Pharmaceutical Co ltd
Jiangsu Jibeier Pharmaceutical Co ltd
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Abstract

The invention provides tauroursodeoxycholic acid derivatives, and a pharmaceutical composition, a preparation and a pharmaceutical application comprising the same. The tauroursodeoxycholic acid derivative has a structure shown in a formula (I). Compared with TUDCA, the compound or derivative with the structure shown in the formula (I) has better effect of promoting bile secretion, has the effect of promoting total bile acid secretion, and has higher FXR activation activity.

Description

Tauroursodeoxycholic acid derivative, and pharmaceutical composition and preparation comprising same
Technical Field
The invention belongs to the field of medicines, and provides a 2- [ (3, 7-dihydroxy-24-oxocholestan-24-yl) amino ] -ethanesulfonic acid derivative, a pharmaceutical composition or preparation containing the compound, and application of the compound in medicines.
Background
Tauroursodeoxycholic acid (TUDCA), chemical name 2- [ [ (3 α,5 β,7 β) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] ethanesulfonic acid dihydrate. TUDCA is effective component of bear bile. TUDCA is a hydrophilic bile acid that reduces the secretion of cholesterol by the liver, lowers the saturation of cholesterol in the bile, stimulates the secretion of bile acids, increases the solubility of cholesterol in the bile, promotes the dissolution of cholesterol gallstones or prevents the formation of cholesterol gallstones. In addition, the bile secretion amount can be increased, and the oral sphincter of the bile duct can be loosened to generate the function of benefiting bile.
Tauroursodeoxycholic acid (TUDCA), the major bile acid among the first to be found in bear's gall. At present, for example, the compound can be obtained by the shrinkage between the carboxyl group of ursodeoxycholic acid (UDCA) and the amino group of taurine. Tauroursodeoxycholic acid capsules were successfully developed in 1991 by Besidi pharmaceutical factory, Italy, and were first marketed in Italy under the trade name taurolite. Entered china in 2007, and was sold in china under the trade name taurolite. The traditional Chinese medicine composition is mainly used for treating cholecystolithiasis, primary sclerosing cholangitis and the like in clinic. TUDCA has a faster rate of dissolution of calculus, an improved total dissolution rate, and can be used as a prophylactic agent for gallstone formation compared to ursodeoxycholic acid (Hofmann AF., The stabilizing immunity of bile acids in liver and intestinal disease, Arch Intern Med 1999 Dec 13; 159(22): 2647-58.).
Natural bile acids are the most active physiological ligands of farnesoid X receptors and are involved in many physiological and pathological processes.
Bile Acid Receptor (BAR), also known as Farnesoid X Receptor (FXR), is a member of the Nuclear Receptor (Nuclear Receptor) family. It is mainly expressed in the intestinal system and participates in important links such as bile acid metabolism and cholesterol metabolism. One of the major functions of FXR activation is the inhibition of cholesterol 7 alpha hydroxylase (cyp7a1), a rate-limiting enzyme for the synthesis of bile acids by cholesterol. Receptors for bile acids (e.g., tauroursodeoxycholic acid) can maintain the balance of bile acids in the body by regulating the expression of genes involved in bile acid metabolism.
FXR-dependent processes in the liver and intestine are considered as Targets for the treatment of human diseases (Rizzo G, Renga B, Mencaralli A, Pellicciari R, Fiorucci S (September 2005). "Role of FXR in regulating double acid homeostases and strategies for human diseases". Curr. drug Targets Immune Endocr. Metal. disorder.5 (3):289 "). The bile acid receptor agonist can be developed into a medicament for treating nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, liver cirrhosis, hepatic fibrosis, diabetes, gallstone, primary biliary cirrhosis, hypercholesterolemia, atherosclerosis, hypertriglyceridemia and the like.
TUDCA has also been reported in the prior art to have cytoprotective and anti-apoptotic effects (Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM. Bile acids | regulation of apoptosis by ursodeoxycholic acid. J Lipid Res 2009 Sep; 50 fortuitous): 1721-34). TUDCA is a potent neuroprotective drug (Duan WM, Rodrigues CM, ZHao LR, Steer CJ, Low WC. tauroursodeoxycholic acid improva the subvalvula and function of nigroplants in a rate model of Parkinson' S disease. cell transfer 2002: 11: 3: 195. beta.205.).
Compared with TUDCA, the improved tauroursodeoxycholic acid derivative provided by the invention can better promote bile secretion, has the effect of promoting total bile acid secretion and has higher FXR (X receptor) activation activity.
Disclosure of Invention
Problems to be solved by the invention
The invention provides a compound or a derivative thereof with a structure shown in a formula (I), which has better bile secretion promoting effect, total bile acid secretion promoting effect and higher FXR activating activity compared with TUDCA.
Means for solving the problems
The first aspect of the present invention provides a compound having a structure represented by formula (I) or a derivative thereof, wherein the derivative is a pharmaceutically acceptable salt, prodrug, N oxide, isomer, solvate or hydrate thereof,
Figure BDA0002108892320000031
r in the formula (I)1、R2、R3、R4Each independently hydrogen or deuterium, provided that at least one of them is deuterium, R5Is hydrogen, C1-5 alkyl, C1-5 alkoxy, halogen, nitro or hydroxyl.
In some embodiments of the invention, R1、R2、R3、R4At least two of which are deuterium.
In some embodiments of the invention, at least R1And R2Is deuterium, or, at least R3And R4Is deuterium.
In some embodiments of the invention, R5Is hydrogen or C1-5 alkyl, preferably, R5Is hydrogen or ethyl.
In some embodiments of the invention, the compound comprises:
Figure BDA0002108892320000032
Figure BDA0002108892320000041
Figure BDA0002108892320000051
in some embodiments of the invention, the pharmaceutically acceptable salt is a salt of a compound of formula (I) with a non-toxic base, which is suitable for use as a pharmaceutical.
In some embodiments of the invention, the derivative is a hydrate; preferably, it is a dihydrate.
In some embodiments of the invention, the compound or derivative thereof is a single crystal or a polymorph.
In a second aspect, the present invention provides the use of a compound of formula (I) or a derivative thereof as described above in the manufacture of a medicament for the treatment or prophylaxis of a liver disease selected from Primary Biliary Cirrhosis (PBC), autoimmune hepatitis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft versus host disease, transplanted liver regeneration, congenital liver fibrosis, granulomatous liver disease, an intrahepatic or extrahepatic malignancy.
A third aspect of the present invention provides the use of a compound of formula (I) or a derivative thereof as described above in the manufacture of a medicament for the treatment or prevention of a biliary disorder selected from Primary Sclerosing Cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis in pregnancy, parenteral nutrition-related cholestasis (PNAC), bacterial overgrowth or sepsis-related cholestasis, gallstones.
In a fourth aspect, the present invention provides the use of a compound of formula (I) or a derivative thereof as defined above in the manufacture of a medicament for the treatment of a neurodegenerative disease selected from ALS, alzheimer's disease, parkinson's disease, huntington's disease, retinitis pigmentosa.
A fifth aspect of the present invention provides the use of a compound of formula (I) or a derivative thereof as described above for the manufacture of a medicament for the treatment of diabetes, obesity, arteriosclerosis, gastrointestinal disorders, nephropathy, cardiovascular disorders, metabolic disorders, preferably, the nephropathy is diabetic nephropathy, the cardiovascular disorders are selected from the group consisting of arteriosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemic chronic hepatitis disorder, wherein the arteriosclerosis is atherosclerosis.
In a sixth aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a derivative thereof as described above, and one or more of a pharmaceutically acceptable carrier, excipient, diluent, thickener, adjuvant, and preservative.
In a seventh aspect of the present invention, there is provided a pharmaceutical preparation comprising a compound of formula (I) or a derivative thereof as described above, and one or more of a pharmaceutically acceptable carrier, excipient, diluent, thickener, adjuvant, and preservative, preferably, the pharmaceutical preparation is in the form of a solid, gel, or liquid.
ADVANTAGEOUS EFFECTS OF INVENTION
Compared with TUDCA, the compound or derivative with the structure shown in the formula (I) has better effect of promoting bile secretion, has the effect of promoting total bile acid secretion, and has higher FXR activation activity.
Drawings
FIG. 1 preparation of N, N-dibenzylchloroacetamide (Compound 9)1H NMR spectrum.
FIG. 2 preparation of N, N-dibenzylcarbamoyl methanesulfonic acid sodium salt (Compound 10)1H NMR spectrum.
FIG. 3 sodium N, N-dibenzylcarbamoylmethanesulfonateOf salts (Compound 10)13C NMR spectrum.
FIG. 4 preparation of N, N-dibenzylcarbamoyl-methanesulfonic acid (Compound No. 11)1H NMR spectrum.
FIG. 5 preparation of N, N-dibenzylcarbamoyl methanesulfonic acid (Compound No. 11)13C NMR spectrum.
FIG. 62 preparation of 2-dideuterotaurine (Compound 13)1H NMR spectrum.
FIG. 7 is a mass spectrum of the compound 2- [ [ (3 α,5 β,7 β) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -1, 1,2, 2-tetradeuteroethanesulfonic acid (formula II).
Detailed Description
The invention provides a compound with a structure shown in a formula (I) or a derivative thereof, wherein the derivative is a pharmaceutically acceptable salt, a prodrug, an N oxide, an isomer, a solvate or a hydrate thereof,
Figure BDA0002108892320000071
r in the formula (I)1、R2、R3、R4Each independently hydrogen or deuterium, provided that at least one of them is deuterium, R5Is hydrogen, C1-5 alkyl, C1-5 alkoxy, halogen, nitro or hydroxyl.
The compound represented by the formula (I) provided by the present invention may also be referred to as deuterium-substituted tauroursodeoxycholic acid or deuterated tauroursodeoxycholic acid.
In some embodiments of the invention, R1、R2、R3、R4At least two of which are deuterium.
In some embodiments of the invention, at least R1And R2Is deuterium, or, at least R3And R4Is deuterium.
In some embodiments of the invention, R1、R2、R3、R4Are all deuterium.
In some embodiments of the invention, R5Is hydrogen, C1-5 alkyl, C1-5 alkoxyA group; in some embodiments of the invention, R5Is hydrogen or ethyl.
The deuterium substituted 2- [ (3, 7-dihydroxy-24-oxocholestan-24-yl) amino ] -ethane sulfonic acid compound or its derivative is a preferred compound or its derivative selected from the group consisting of:
compound 1: 2- [ [ (3 alpha, 5 beta, 7 beta) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -1, 1,2, 2-tetradeuteroethanesulfonic acid
Figure BDA0002108892320000072
Compound 2: 2- [ [ (3 alpha, 5 beta, 7 beta) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -2, 2-dideuteroethane sulfonic acid
Figure BDA0002108892320000081
Compound 3: 2- [ [ (3 alpha, 5 beta, 7 beta) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -1, 1-dideuteroethane sulfonic acid
Figure BDA0002108892320000082
Compound 4: 2- [ [ (3 alpha, 5 beta, 7 beta) -3, 7-dihydroxy-6 alpha-ethyl-24-oxocholestan-24-yl ] amino ] -1, 1,2, 2-tetradeuteroethanesulfonic acid
Figure BDA0002108892320000083
Compound 5: 2- [ [ (3 alpha, 5 beta, 7 beta) -3, 7-dihydroxy-6 alpha-ethyl-24-oxocholestan-24-yl ] amino ] -2, 2-dideuteroethanesulfonic acid
Figure BDA0002108892320000091
Compound 6: 2- [ [ (3 alpha, 5 beta, 7 beta) -3, 7-dihydroxy-6 alpha-ethyl-24-oxocholestan-24-yl ] amino ] -1, 1-dideuteroethanesulfonic acid
Figure BDA0002108892320000092
The term "substituted" means that one or more hydrogen atoms in a given structure may be replaced with a particular substituent. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. The term "hydrogen" denotes a single hydrogen atom. The term "deuterium" denotes a single deuterium atom.
Deuterium substitution means that one or more hydrogens of a compound or group are replaced with deuterium, which may be mono-, di-or poly-substituted, e.g. by deuterium substitution of a methyl group, to give a mono-deuterated methyl group (-CDH)2) Dideuteromethyl (-CD)2H) Or trideuteromethyl (-CD)3). The deuterium isotope content of deuterium at the deuterium substitution position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%. The terms "deuterated one or more" and "deuterated one or more" are used interchangeably.
The term "solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. The physical association includes various degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvates" includes both solution phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is where the solvent molecule is H2A solvate of O. The preparation of solvates is generally known. A typical, non-limiting method involves dissolving the compound in the desired amount of solvent (organic or water or mixtures thereof) at a temperature above ambient temperature, cooling the solution at a rate sufficient to form crystals, and then cooling the solutionThe crystals were then isolated by standard methods. Analytical techniques such as infrared spectroscopy can confirm the presence of solvent (or water) in the crystals as solvates (or hydrates).
The term "prodrug" refers to a substance that is converted in vivo to produce a compound having the structure shown in formula I or a derivative thereof. The conversion may occur by various mechanisms (e.g., by metabolic or chemical treatment), such as by hydrolysis in blood.
Examples of prodrug derivatives in various forms can be found in the following prior art documents: "design and application of prodrugs", edited h. bundgaard, page 113 and 191 (1991); "Pro-drugs as Novel Delivery Systems," eds T.Higuchi and W.Stella, Vol.14 of A.C.S.Sympossium Series, "eds Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987.
The isomers of the present invention include stereoisomers, geometric isomers or tautomers, and the like. Where "stereoisomers" includes all enantiomerically/stereoisomerically pure and enantiomerically/stereoisomerically enriched compounds of the invention. Isomers may be prepared using conventional methods by reacting optically pure or optically enriched starting materials or by isolating isomers of the compounds of formula (I).
The pharmaceutically acceptable salt is a salt which is formed by the compound shown as the formula (I) and nontoxic alkali and is suitable for being used as a medicament, and comprises an inorganic salt and an organic salt. For example, basic salts such as alkali or alkali-aliphatic metal salts prepared from lithium, magnesium, potassium, sodium, and zinc, or organic salts prepared from N, N' -dibenzylethylenediamine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and the like may be included. Pharmaceutically acceptable salts with amines such as lysine, arginine, tromethamine, triethylamine and the like may also be used. Salts of these compounds of formula (I) may be prepared using conventional techniques, for example by reacting a compound of formula (I) with a suitable base.
All pharmaceutically acceptable salts, hydrates, solvates, prodrugs, isomers, N-oxides, single crystals or polymorphs of the compounds of formula (I) provided by the present invention are within the scope of the present invention.
The invention provides a pharmaceutical composition, which comprises the compound shown in the formula (I) or a derivative thereof and one or more of pharmaceutically acceptable carriers, excipients, diluents, thickening agents, auxiliary materials and preservatives.
The invention also provides a drug delivery preparation containing the pharmaceutical composition, and the dosage form of the drug delivery preparation can be solid, gel or liquid.
The pharmaceutical compositions of the present invention may be in solid form including, but not limited to, capsules, tablets, pills, granules, dry powders for inhalation, powders, or suppositories. The pharmaceutical compositions of the present invention may also be in liquid form including, but not limited to, solutions, suspensions or emulsions. Preferably: and (4) capsules.
Solid dosage forms such as tablets, dragees, bulk powders, capsules, pills, and granules, including compressed chewable lozenges and tablets, may be film-coated, sugar-coated, or enteric-coated according to methods known in the art. The capsules may be hard or soft gelatin capsules. Granules and powders may be in non-effervescent or effervescent form. The pharmaceutical compositions of the present invention may employ a time delay material including, but not limited to, glyceryl monostearate or glyceryl distearate.
The pharmaceutical composition of the present invention may further comprise, in addition to a sufficient amount of the tauroursodeoxycholic acid derivative of the present invention: diluents, lubricants, emulsifiers, solubilizers, pH buffers, binders, wetting agents, disintegrants, glidants, sweeteners and/or flavoring agents and the like.
The diseases or conditions treated or prevented by the FXR receptor agonists of the invention may include cardiovascular disease, atherosclerosis, arteriosclerosis, hyperbilirubinemia, hyperlipidemic chronic hepatitis disease, gastrointestinal disease, renal disease, cardiovascular disease, metabolic disease, cancer, or neurological signs such as stroke. Preferably, the chronic liver disease is primary cirrhosis (PBC), Primary Sclerosing Cholecystitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, extra-intestinal absorption-related cholestasis (PNAC), autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver transplantation-related graft-versus-host disease, live donor liver transplantation regeneration, congenital liver fibrosis, choledocholithiasis, granulomatous liver disease, intrahepatic-or extrahepatic malignancy.
The nephropathy to be treated or prevented according to the present invention may be diabetic nephropathy, Focal Segmental Glomerulosclerosis (FSGS), hypertensive nephropathy, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, or polycystic kidney disease.
Cardiovascular disease to be treated or prevented according to the present invention may include atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, or hypertriglyceridemia, insulin resistance, type I and type II diabetes, or obesity.
Preferably, the present invention provides a pharmaceutical composition for treating or preventing a disease selected from the group consisting of liver diseases and related diseases thereof, biliary diseases and related diseases thereof, neurodegenerative diseases, and the like, in a mammal, including a human.
Accordingly, the present invention also provides a pharmaceutical composition for treating or preventing a disease selected from liver diseases and related diseases, biliary diseases and related diseases, neurodegenerative diseases, and the like, in a mammal, including a human. In addition, the present invention also provides a method for treating a disease selected from a liver disease and related diseases thereof, a biliary disease and related diseases thereof, a neurodegenerative disease, and the like, using the compound of formula (I) or a derivative thereof or a pharmaceutical composition comprising the compound of formula (I) or a derivative thereof provided by the present invention.
The liver disease is selected from Primary Biliary Cirrhosis (PBC), autoimmune hepatitis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft-versus-host disease, transplanted liver regeneration, congenital liver fibrosis, granulomatous liver disease, and intrahepatic or extrahepatic malignancy.
The biliary disorder is selected from Primary Sclerosing Cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis during pregnancy, parenteral nutrition-related cholestasis (PNAC), bacterial overgrowth or sepsis-related cholestasis, cholesterol-type gallstones.
The neurodegenerative disease is selected from ALS, Alzheimer's disease, Parkinson's disease, Huntington's disease, retinitis pigmentosa.
Pharmaceutical compositions or formulations of the compounds of the invention may be administered by any oral route, intravenous or intra-arterial injection, intralipid or liposomal administration, aerosol inhalation, parenteral or intraperitoneal administration, rectal administration, intraadipose or intra-articular administration, subcutaneous administration, nasal administration, via local delivery (e.g., catheter or stent), buccal administration, vaginal administration or via an implanted kit. Preferred modes of administration of the pharmaceutical composition are oral administration, intraperitoneal administration or intravenous injection.
Suitable routes of administration for the pharmaceutically acceptable salts of the compounds of formula (I) according to the invention include oral or parenteral routes, preferably oral routes.
The pharmaceutical compositions of the present invention may be administered by sterile injection in the form of aqueous or oleaginous suspensions which may be formulated according to the known art using suitable dispersing, wetting and suspending agents.
The compound of the present invention may be administered orally to the ordinary adult in a dose of 5 to 2000 mg, and may be administered in 1 to 4 divided doses per day.
The compounds of formula (I) may be administered alone or in combination with one or more additional agents in a pharmaceutically acceptable dosage form. These drugs are selected from NASH drugs based on regulation of glycolipid metabolism (PPAR agonists, THR β agonists and ACC inhibitors), NASH drugs based on regulation of bile acid metabolism (ileal bile acid transport inhibitors), NASH drugs based on anti-inflammatory principles (CCR2/5 inhibitors), NASH drugs based on cell damage (apoptosis protease inhibition) and other target drugs (SSAO inhibitors, ASK1 inhibitors, FGF19 analogs and cuprammine oxidase 3 inhibitors etc.).
The following describes the preparation of the compounds of formula (I) according to the invention in more detail, but these specific methods are only examples and do not constitute a limitation of the scope of protection. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
The reagents and materials used in the examples and tests provided herein are commercially available.
Example 1
Preparation of compound 2: 2- [ [ (3 α,5 β,7 β) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -2, 2-dideuteroethane sulfonic acid (formula III)
Step 1: preparation of intermediate N, N-dibenzylchloroacetamide (9)
Figure BDA0002108892320000131
To a solution of chloroacetyl chloride 7(3.98mL,50mmol) in tetrahydrofuran (100mL) was added dibenzylamine 8(9.61mL,50mmol) dropwise under ice-bath followed by triethylamine (6.97mL,50mmol) and stirred at room temperature for 8 h. Dilute with ether (100mL), wash with dilute hydrochloric acid (75mL,1M), wash with saturated aqueous sodium bicarbonate (20mL), wash with brine (30mL), dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation to give 9 as a yellow oily liquid in 96% yield.
1H NMR(400MHz,CDCl3)7.41–7.28(m,6H),7.25–7.21(m,2H),7.17(d,J＝7.4Hz,2H),4.62(s,2H),4.52(s,2H),4.15(s,2H).
Step 2: preparation of intermediate N, N-dibenzylcarbamoyl methanesulfonic acid sodium salt (10)
Figure BDA0002108892320000141
Compound 9(10.95g,40mmol) was dissolved in aqueous ethanol (100mL, 50%), sodium sulfite (7.56g,60mmol) was added, refluxed for 5h, the solvent was removed by rotary evaporation, and column chromatography was performed with DCM: MeOH ═ 10:1 to give white solid 10, yield 90%.
1H NMR(400MHz,CDCl3)7.16–7.00(m,7H),6.92(t,J＝6.1Hz,3H),4.34(d,J＝23.5Hz,4H),4.18(s,2H).
13C NMR(101MHz,CDCl3)167.8,136.3,135.9,128.6(2C),128.5(2C),128.0(2C),127.3,127.1,127.0(2C),53.7,50.5,47.9.
And step 3: preparation of intermediate N, N-dibenzylcarbamoyl methanesulfonic acid (11)
Figure BDA0002108892320000142
Dissolving the compound 10(12g) in 60ml of water, adding 12 ml of concentrated hydrochloric acid, stirring for 2 hours, cooling in an ice bath, performing suction filtration, leaching a filter cake with trace ice water, dissolving the filter cake in dichloromethane, drying with anhydrous sodium sulfate, performing suction filtration, and spin-drying the filtrate to obtain a white solid 11 with the yield of 100%.
1H NMR(400MHz,DMSO)7.35(dd,J＝8.1,6.6Hz,2H),7.32–7.22(m,6H),7.20–7.16(m,2H),4.74(s,2H),4.48(s,2H),3.65(s,2H).
13C NMR(101MHz,DMSO)166.6,137.5,137.5,128.7(2C),128.3(2C),127.3(2C),127.2,126.8,126.5(2C),56.3,50.5,47.7.
And 4, step 4: preparation of intermediate N, N-dibenzyl-2, 2-dideuterotaurine (12)
Figure BDA0002108892320000151
Compound 11(3.19g,10mmol) was dissolved in anhydrous THF (75mL) and NaBD was added slowly under ice bath4(4.41g,100mmol, 95%) with Ar, and boron trifluoride etherate (12.34mL,100mmol) was slowly added dropwise under ice-bath, and stirred at room temperature for 4 h. Quenching by saturated ammonium chloride aqueous solution, extracting by ethyl acetate, and drying to obtain a white solid crude product 12.
HRMS(ESI-)Calc.Mass for C16H17D2NO3S-H:306.1133；found:306.1131[M-H]-.
And 5: preparation of intermediate 2, 2-dideuterotaurine (13)
Figure BDA0002108892320000152
Dissolving the crude product 12 in methanol (30mL), adding 10% palladium-carbon (1.06g,1mmol, 10%), introducing hydrogen, reacting overnight at 50 ℃, filtering to remove the palladium-carbon, spin-drying, adding a small amount of water to dissolve, recrystallizing with anhydrous ethanol, performing suction filtration, leaching with ethanol to obtain a white solid 13, and obtaining a yield of 70% in the two steps (step 4 and step 5).
1H NMR(400MHz,D2O)3.22(s,2H).
HRMS(ESI-)Calc.Mass for C2H5D2NO3S-H:126.0194；found:126.0200[M-H]-.
Step 6: preparation of the compound 2- [ [ (3 α,5 β,7 β) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -2, 2-dideuteroethane sulfonic acid (formula III)
Figure BDA0002108892320000153
Dissolving sodium hydroxide (0.30g,7.5mmol) in 8mL of water, adding deuterated taurine 13(0.70g,5.5mmol) in batches under ice bath, and stirring at room temperature for 30min to obtain a deuterated sodium taurate aqueous solution for later use; dissolving ursodeoxycholic acid 14(1.96g and 5.0mmol) in 1, 4-dioxane (75mL), adding triethylamine (0.83mL and 6.0mmol), dropwise adding isobutyl chloroformate (0.71mL and 5.5mmol) in an ice bath, stirring at room temperature for 1h, performing suction filtration, dropwise adding a deuterated sodium taurate aqueous solution in a filtrate in an ice bath, stirring at room temperature for 5h, performing suction filtration, acidifying the filtrate to a pH value of 1-2 by adding concentrated hydrochloric acid, stirring for 30min, extracting for 3 times by using ethyl acetate, taking a water phase, performing spin drying, adding absolute ethyl alcohol, stirring for 30min, filtering out insoluble substances, performing spin drying, adding a small amount of methanol, recrystallizing by using acetone, performing suction filtration, and leaching by using acetone to obtain a white powdery solid formula III, wherein the yield is 80%.
1H NMR(400MHz,D2O)3.59(s,2H),3.07(s,2H),2.32(s,1H),2.17(s,1H),2.02(d,J＝11.9Hz,1H),1.84(d,J＝34.0Hz,5H),1.73–1.53(m,5H),1.47(s,5H),1.38–1.22(m,6H),1.14(s,2H),0.99(s,6H),0.73(s,3H).
13C NMR(101MHz,D2O)176.5,70.9,70.7,55.6,54.7,49.7,43.5,43.1,42.3,40.2,39.3,36.8,36.2,35.3,35.0,35.0,33.8,32.9,31.8,29.7,28.5,26.7,23.4,21.4,18.5,12.1.
LC-MS：500.3[M-H]-.
Example 2
Preparation of compound 1: 2- [ [ (3 α,5 β,7 β) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -1, 1,2, 2-tetradeuteroethanesulfonic acid (formula II)
Figure BDA0002108892320000161
Step 1: preparation of intermediate 16
Figure BDA0002108892320000162
Dissolving deuterated dichloroethane 15(2g,1equiv) in 60mL of ethanol aqueous solution (1:1), adding anhydrous sodium sulfite (3.67g,1.5equiv) and copper powder (19mg,0.015equiv), connecting a condenser tube, reacting at 70 ℃ for 22h, then spin-drying the solvent, adding 100mL of anhydrous ethanol, refluxing at 80 ℃ for 10min, carrying out suction filtration while hot, and spin-drying the filtrate to obtain a white solid 16 with the yield of 32%.
TOF MS：146.9823[M-Na]
Step 2: preparation of intermediate Tetradeuterated sodium taurate (17)
Figure BDA0002108892320000171
Compound 16(0.94g,1.0equiv) was dissolved in 100mL of aqueous ammonia, reacted at 80 ℃ for 16h in a condenser tube, then the solvent was spin-dried, 30mL of absolute ethanol was added, and the filtrate was removed by suction filtration to give 17 as a white solid in 80% yield.
TOF MS：128.0317[M-Na].
And step 3: preparation of the Compound 2- [ [ (3 α,5 β,7 β) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -1, 1,2, 2-tetradeuteroethanesulfonic acid (formula II)
Figure BDA0002108892320000172
Dissolving sodium tetradeuterotaurate 17(0.67g,1.1equiv) in 6mL of water, and stirring for later use; dissolving ursodeoxycholic acid 14(1.57g,1.0equiv) in 1, 4-dioxane (60mL), adding triethylamine (0.67mL,1.2equiv), dropwise adding isobutyl chloroformate (0.57mL,1.1equiv) at 0-20 ℃, stirring for 2h, performing suction filtration, dropwise adding deuterated sodium taurate aqueous solution into the filtrate under ice bath, stirring for 5h, then removing the solvent by spinning, adding 40mL water, acidifying with concentrated hydrochloric acid to pH 1, stirring for 30min, extracting with ethyl acetate for 4 times, taking out the water phase, spin-drying, adding 30mL absolute ethanol, stirring for 30min, filtering out insoluble substances, spin-drying the filtrate, performing column chromatography with DCM: MeOH ═ 4:1 to obtain a white solid 2- [ [ (3 alpha, 5 beta, 7 beta) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -1, 1,2, 2-tetraethane sulfonic acid (deuterium shown in formula II), the yield thereof was found to be 37%.
TOF MS：502.3140[M-H]-.
Example 3
Preparation of compound 3: 2- [ [ (3 α,5 β,7 β) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -1, 1-dideuteroethane sulfonic acid (formula IV)
Figure BDA0002108892320000181
2- [ [ (3 α,5 β,7 β) -3, 7-dihydroxy-24-oxocholestan-24-yl ] amino ] -1, 1-dideuteroethane sulfonic acid (formula IV) was prepared according to the procedure of example 1 by replacing 2, 2-deuterotaurine-d 2 in example 1 with 1, 1-deuterotaurine-d 2
LC-MS：500.3[M-H]-.
Example 4
Preparation of compound 4: 2- [ [ (3 α,5 β,7 α) -3, 7-dihydroxy-6 α -ethyl-24-oxocholestan-24-yl ] amino ] -1, 1,2, 2-tetradeuteroethanesulfonic acid (formula V)
Figure BDA0002108892320000182
2- [ [ (3 α,5 β,7 α) -3, 7-dihydroxy-6 α -ethyl-24-oxocholestan-24-yl ] amino ] -1, 1,2, 2-tetradeuteroethanesulfonic acid (formula V) was prepared according to the procedure of example 1 by replacing 2, 2-deuterotaurine-d 2 in example 1 with 1,1,2, 2-deuterotaurine-d 4 and ursodeoxycholic acid 14 in example 1 with 6 α -ethyl-3 α,7 α -dihydroxy-5 β -chole-24-oic acid
LC-MS：530.8[M-H]-.
Example 5
Preparation of compound 5: 2- [ [ (3 α,5 β,7 α) -3, 7-dihydroxy-6 α -ethyl-24-oxocholestan-24-yl ] amino ] -2, 2-dideuteroethanesulfonic acid (formula VI)
Figure BDA0002108892320000191
Preparation of 2- [ [ (3 α,5 β,7 α) -3, 7-dihydroxy-6 α -ethyl-24-oxocholestan-24-yl ] amino ] -2, 2-dideuteroethane sulfonic acid (formula VI) by substituting ursodeoxycholic acid 14 in example 1 with 6 α -ethyl-3 α,7 α -dihydroxy-5 β -chol-24-oic acid
LC-MS：528.6[M-H]-.
Example 6
Preparation of compound 6: 2- [ [ (3 α,5 β,7 α) -3, 7-dihydroxy-6 α -ethyl-24-oxocholestan-24-yl ] amino ] -1, 1-dideuteroethanesulfonic acid (formula VII)
Figure BDA0002108892320000192
2- [ [ (3 α,5 β,7 α) -3, 7-dihydroxy-6 α -ethyl-24-oxocholestan-24-yl ] amino ] -1, 1-dideuteroethanesulfonic acid (formula VII) was prepared according to the procedure of example 1 by replacing 2, 2-deuterated taurine-d 2 in example 1 with 1, 1-deuterated taurine-d 2 and replacing ursodeoxycholic acid 14 in example 1 with commercial 6 α -ethyl-3 α,7 α -dihydroxy-5 β -cholesta-24-oic acid
LC-MS：528.6[M-H]-.
Cholagogic experiment:
the experimental method comprises the following steps:
normal male rats are anesthetized by 20% urethane intraperitoneal injection, bile ducts are separated by operation, bile ducts are intubated and tied for fixation, bile is drained into a graduated centrifuge tube, after the bile is stabilized for 20min, the bile for 30min is collected firstly and serves as a basic value before administration, then administration is carried out through duodenum, and the bile for a certain time after administration is collected.
Control group (normal group), tauroursodeoxycholic acid (TUDCA) and the compound of formula II prepared in example 2 were administered in 2 dose groups, 5 groups, each consisting of 8 to 10 animals.
TABLE 1 bile secretion data (Mean + -SD) for each time period before and after administration
Figure BDA0002108892320000201
P <0.05, p <0.01, compared to control; # p <0.05, # p <0.01, 100mg/kg group of example 2 compared to TUDCA 100mg/kg group; and & p <0.01, the 200mg/kg group of example 2 was compared to the TUDCA 200mg/kg group.
In the time periods of 1.5-2 h and 2-2.5 h after administration, compared with a control group, the TUDCA 200mg/kg dose group can significantly increase the bile secretion of the rat, and the TUDCA 100mg/kg and 200mg/kg dose groups of the embodiment 2 can significantly increase the bile secretion of the rat; and the difference is significant when compared with different drug groups with the same dose. Compared with 100mg/kg and 200mg/kg dose groups of TUDCA, the 100mg/kg and 200mg/kg dose groups of example 2 have significantly increased bile secretion amount within the time periods of 1.5-2 h and 2-2.5 h after administration.
TABLE 2 Change data of bile acid and cholesterol in bile 2-2.5 h after administration (Mean + -SD)
Figure BDA0002108892320000211
P <0.01, compared to control group; # p <0.01, example 2100 mg/kg group compared to TUDCA 100mg/kg group; and & p <0.01, example 2200 mg/kg group compared to TUDCA 200mg/kg group.
Compared with a control group, the TUDCA and the 2 dose groups of example 2 both significantly increase the content of total bile acid and total cholesterol in the rat bile within a time period of 2-2.5 hours after administration; the total bile acid secretion promoting effect is obviously different among different drug groups with the same dosage; the total cholesterol secretion promoting effect is not obviously different from the groups with different dosages.
In vitro pharmacodynamic evaluation:
farnesoid X Receptor (FXR) activation of the disclosed compounds was determined by the recirculatont cooperator Assay, AlphaScreen technology, a specific in vitro pharmacodynamic evaluation protocol for reference to J Pharmacol Exp Ther 350:56-68, July 2014.
Experimental results show that the disclosed compound has excellent activation activity on Farnesoid X Receptor (FXR). Among them, the compound of formula III prepared in example 1 and the compound of formula II prepared in example 2 have higher FXR activation activity than non-deuterated TUDCA, specifically, EC50A 10-50% reduction compared to non-deuterated TUDCA.
The compound of formula VI prepared in example 5 and the compound of formula V prepared in example 4 have an FXR-activating activity ratio of 2- [ [ (3. alpha., 5. beta., 7. alpha. -3, 7-dihydroxy-6. alpha. -ethyl-24-oxocholestan-24-yl)]Amino group]Higher-than-ethanesulfonic acid (undeuterated), in particular EC of Compound VI50At 0.24uM, EC for Compound V50Is 0.26uM, and 2- [ [ (3 alpha, 5 beta, 7 alpha) -3, 7-dihydroxy-6 alpha-ethyl-24-oxocholestan-24-yl]Amino group]EC of ethanesulfonic acid (undeuterated)50It was 0.33 uM.
Pharmacokinetic experiments:
6 SD rats, each half of male and female, are taken, and are subjected to single oral gavage administration, blood is collected in the orbit after administration, and the blood collection time points are 10 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours and 24 hours after administration.
Immediately after blood collection, the tubes were gently inverted at least 5 times to ensure mixing and then placed on ice. Blood was anticoagulated with heparin and then centrifuged at 8000rpm for 5 minutes to separate serum from erythrocytes. Serum was pipetted off to a 2mL polypropylene tube, indicating the name of the compound and the time point, and stored in a-40 ℃ freezer before LC-MS analysis and tested. High concentration samples were diluted with rat blank plasma.
When the determination is carried out, 50. mu.L of plasma is taken and 2.5. mu.L of Meth-H is added2O, 5. mu.L of internal standard solution (20ng/mL IS), protein was precipitated with 150. mu.L of methanol and centrifuged at 13000 rpm. times.5 min. The upper organic phase was taken, filtered through a 0.22 μ M microporous membrane, and 2 μ L of sample was taken for LC-MS analysis.
The experimental data show that AUC of the compound of formula III prepared in example 1 is used0-tFor 1468 ng. h/L, the AUC of the compound of formula II prepared in example 2 was used0-tAUC of 1554 ng.h/L and TUDCA (undeuterated)0-tOnly 1106ng h/L.
The compound of formula VI prepared in example 5 was used in comparison with 2- [ [ (3 α,5 β,7 α) -3, 7-dihydroxy-6 α -ethyl-24-oxocholestan-24-yl]Amino group]Ethanesulfonic acid (undeuterated), AUC0-tThe improvement is 10 to 50 percent.

Claims (14)

1. A compound or derivative having a structure represented by formula (I), wherein the derivative is a pharmaceutically acceptable salt, prodrug, N oxide, isomer, solvate or hydrate thereof,
Figure FDA0002108892310000011
r in the formula (I)1、R2、R3、R4Each independently hydrogen or deuterium, provided that at least one of them is deuterium, R5Is hydrogen, C1-5 alkyl, C1-5 alkoxy or hydroxy.
2. A compound or derivative thereof according to claim 1, wherein R1、R2、R3、R4At least two of which are deuterium.
3. A compound or derivative thereof according to claim 1 or 2, wherein at least R1And R2Is deuterium, or, at least R3And R4Is deuterium.
4. A compound or derivative thereof according to claim 1 or 2, wherein R5Is hydrogen or C1-5 alkyl, preferably hydrogen or ethyl.
5. A compound according to claim 1 or 2, or a derivative thereof, the compound comprising:
Figure FDA0002108892310000012
Figure FDA0002108892310000021
Figure FDA0002108892310000031
6. a compound or derivative thereof according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of the compound of formula (I) with a non-toxic base.
7. A compound or derivative thereof according to any one of claims 1 to 6, wherein the derivative is a hydrate; preferably, it is a dihydrate.
8. A compound or derivative thereof according to any one of claims 1 to 7, wherein the compound or derivative thereof is a single crystal or polymorph.
9. Use of a compound or derivative thereof according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prevention of a liver disease selected from Primary Biliary Cirrhosis (PBC), autoimmune hepatitis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), graft versus host disease, transplanted liver regeneration, congenital liver fibrosis, granulomatous liver disease, an intrahepatic or extrahepatic malignancy.
10. Use of a compound according to any one of claims 1 to 8 or a derivative thereof in the manufacture of a medicament for the treatment or prevention of a biliary disorder selected from Primary Sclerosing Cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis in pregnancy, parenteral nutrition-related cholestasis (PNAC), bacterial overgrowth or sepsis-related cholestasis, gallstones.
11. Use of a compound according to any one of claims 1 to 8 or a derivative thereof in the manufacture of a medicament for the treatment of a neurodegenerative disease selected from ALS, alzheimer's disease, parkinson's disease, huntington's disease, retinitis pigmentosa.
12. Use of a compound according to any one of claims 1 to 8 or a derivative thereof for the manufacture of a medicament for the treatment of diabetes, obesity, arteriosclerosis, gastrointestinal diseases, nephropathy, cardiovascular diseases, metabolic diseases, preferably, the nephropathy is diabetic nephropathy, the cardiovascular diseases are selected from the group consisting of arteriosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia and chronic hepatitis, wherein the arteriosclerosis is atherosclerosis.
13. A pharmaceutical composition comprising a compound or derivative thereof according to any one of claims 1 to 8 and one or more of a pharmaceutically acceptable carrier, excipient, diluent, thickener, adjuvant, preservative.
14. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 8 or a derivative thereof and one or more of a pharmaceutically acceptable carrier, excipient, diluent, thickener, adjuvant, preservative, preferably in the form of a solid, gel or liquid.
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CN101522703A (en) * 2006-06-27 2009-09-02 英特塞普特医药品公司 Bile acid derivatives as fxr ligands for the prevention or treatment of fxr-mediated deseases or conditions
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CN101522703A (en) * 2006-06-27 2009-09-02 英特塞普特医药品公司 Bile acid derivatives as fxr ligands for the prevention or treatment of fxr-mediated deseases or conditions
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