WO2016131414A1 - 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 - Google Patents

氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 Download PDF

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WO2016131414A1
WO2016131414A1 PCT/CN2016/073891 CN2016073891W WO2016131414A1 WO 2016131414 A1 WO2016131414 A1 WO 2016131414A1 CN 2016073891 W CN2016073891 W CN 2016073891W WO 2016131414 A1 WO2016131414 A1 WO 2016131414A1
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Prior art keywords
compound
acid
pharmaceutical composition
ethyl
pharmaceutically acceptable
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PCT/CN2016/073891
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English (en)
French (fr)
Inventor
吕彬华
盛泽林
李成伟
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Suzhou Zelgen Biopharmaceutical Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
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Priority to RU2017130849A priority Critical patent/RU2712033C2/ru
Priority to AU2016222174A priority patent/AU2016222174B2/en
Priority to JP2017560864A priority patent/JP6947644B2/ja
Priority to HK18108236.7A priority patent/HK1248712B/zh
Priority to EP16751945.3A priority patent/EP3260463B1/en
Priority to US15/551,224 priority patent/US10544185B2/en
Priority to BR112017017529-0A priority patent/BR112017017529A2/zh
Priority to CN201680010388.0A priority patent/CN107250149B/zh
Priority to CA2977109A priority patent/CA2977109C/en
Priority to KR1020177025774A priority patent/KR102042112B1/ko
Publication of WO2016131414A1 publication Critical patent/WO2016131414A1/zh
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/007—Steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the field of medicine.
  • the present invention relates to novel deuterated chenodeoxycholic acid derivatives and pharmaceutical compositions containing the same.
  • Farnesoid X Receptor is a member of the Nuclear Receptor family. It is mainly expressed in the intestinal system such as the liver and small intestine, and participates in bile acid metabolism and cholesterol metabolism. Bile acids have a variety of physiological functions and play an important role in the process of fat absorption, transport, distribution and cholesterol homeostasis.
  • the farnesoid X receptor acts as a receptor for bile acids such as chenodeoxycholic acid, and maintains the balance of bile acids in the body by regulating gene expression involved in bile acid metabolism. In addition, the farnesoid X receptor also plays an important role in the dynamic balance of glucose and insulin resistance in the body.
  • farnesol X receptor agonists are expected to be developed to treat nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, gallstones, primary biliary cirrhosis, cirrhosis, liver fibrosis, diabetes, hypercholesterolemia , atherosclerosis, obesity, hypertriglyceridemia and other drugs.
  • Chenodeoxycholic acid and derivatives are agonists of a class of farnesoid X receptors.
  • a series of chenodeoxycholic acid derivatives are disclosed in the patents WO2010059859 and WO2005082925, wherein the compound Obeticholic acid is a selective farnesoid X receptor agonist, chemical name 3,7.-two 3,7-dihydroxy-6-ethyl-5-cholan-24-oic acid for the treatment of nonalcoholic steatohepatitis and nonalcoholic fatty liver disease Use in.
  • oleic acid is in a phase III clinical study.
  • abecholic acid has a good clinical effect in improving liver inflammation and fibrosis, and has certain effects of reducing body weight and increasing insulin sensitivity, it also finds side effects such as itching and elevated low-density lipoprotein. Therefore, finding a farnesoid X receptor agonist with selectivity, high activity and safety is also very challenging.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen or deuterium;
  • An additional condition is that at least one of R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is deuterium.
  • the cerium isotope content of the cerium at the cerium substitution site is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%.
  • the ground is greater than 95%, more preferably greater than 99%.
  • the compound of formula (I) contains at least one deuterium atom, more preferably two deuterium atoms, more preferably three deuterium atoms, more preferably five deuterium atoms, more preferably six deuterium atoms. .
  • R 1 is hydrogen or deuterium.
  • R 2 is hydrogen or deuterium.
  • R 3 is hydrogen or deuterium.
  • R 4 and R 5 are independently selected from hydrogen or hydrazine.
  • R 6 is hydrogen or deuterium.
  • R 1 is ⁇ .
  • R 2 is deuterium
  • R 3 is deuterium
  • R 4 is deuterium and/or R 5 is deuterium.
  • R 2 is deuterium and/or R 1 is deuterium.
  • the compound is a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:
  • the compound is a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof: -dihydroxy-6-ethyl-7-indol-5-chol-24-acid;
  • the compound is It has the following characteristics: MS calculated value: 421; MS measured value: 422 (M+H) + , 444 (M+Na) + .
  • the compound is It has the following characteristics: MS calculated value: 423; MS measured value: 424 (M+H) + , 446 (M+Na) + .
  • the compound is It has the following characteristics: MS calculated: 426; MS measured: 427 (M+H) + , 449 (M+Na) + .
  • the compound is It has the following characteristics: MS calculated: 425; MS measured: 426 (M+H) + , 448 (M+Na) + .
  • the compound is It has the following characteristics: MS calculated value: 428; MS measured value: 429 (M+H) + , 451 (M+Na) + .
  • the compound is It has the following characteristics: MS calculated value: 429; MS measured value: 430 (M+H) + , 452 (M+Na) + .
  • the compound is It has the following characteristics: MS calculated value: 422; MS measured value: 423 (M+H) + , 445 (M+Na) + .
  • the compound is It has the following characteristics: MS calculated: 427; MS measured: 428 (M+H) + , 450 (M+Na) + .
  • the compound does not include a non-deuterated compound.
  • the non-deuterated compound is oleic acid, i.e., 3,7.-dihydroxy-6-ethyl-5-chol-24-acid.
  • the compound is prepared by the method described in Examples 1-4.
  • a method of preparing a pharmaceutical composition comprising the steps of: pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, pharmaceutically acceptable
  • the accepted salt, hydrate or solvate is mixed to form a pharmaceutical composition.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, hydrated Or a solvate.
  • the pharmaceutical composition is an injection, a sachet, a tablet, a pill, a powder or a granule.
  • the pharmaceutical composition further comprises an additional therapeutic agent for treating cancer, cardiovascular disease, inflammation, infection, immune disease, metabolic disease, or organ transplantation. drug.
  • the cancer includes, but is not limited to, lung cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, blood cancer (or hematological malignancy), bone cancer, kidney cancer, Gastric cancer, liver cancer or colorectal cancer.
  • the cancer is liver cancer.
  • the additional therapeutic agents include, but are not limited to,: sorafenib, regorafenib, nerofenib, cisplatin, doxorubicin, gemcitabine, FOLFOX, decitabine, Capecitabine, statins (lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, cerivastatin, lovastatin, etc.), rosiglitazone , pioglitazone, metformin, acarbose, voglibose, sulfonylureas (glipizide, gliclazide, glimepiride, etc.), dipeptidyl peptidase-4 (DPP- 4) Inhibitors of hypoglycemic drugs (such as sitagliptin, vildagliptin, saxagliptin, alogliptin, linaglipt
  • the compound of the first aspect of the invention or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, is provided in the pharmaceutical composition according to the third aspect of the invention
  • FXR farnesoid X receptor
  • G-protein coupled cholic acid receptor GBAR or TGR5
  • the pharmaceutical composition is used for the preparation of a medicament for the treatment and prevention of non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, gallstones, primary biliary cirrhosis, cirrhosis, Liver fibrosis, diabetes, atherosclerosis, obesity.
  • a method of treatment or a disease of a farnesoid X receptor (FXR) agonist and/or a G-protein coupled cholic acid receptor (GPBAR or TGR5) agonist eg cancer, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, gallstones, primary biliary cirrhosis, cirrhosis, liver fibrosis, diabetes, atherosclerosis, obesity
  • FXR farnesoid X receptor
  • G-protein coupled cholic acid receptor G-protein coupled cholic acid receptor
  • the present inventors have unexpectedly discovered that the deuterated chenodeoxycholic acid derivatives of the present invention and pharmaceutically acceptable salts thereof have significantly superior pharmacokinetics and/or compared to undeuterated compounds.
  • Pharmacodynamic properties therefore more suitable as a compound of a farnesyl alcohol X receptor (FXR) agonist and / or G-protein coupled bile acid receptor (GPBAR or TGR5) agonist, and thus more suitable for the preparation of therapeutic farnesol Drugs that are associated with X receptor (FXR) and/or G-protein coupled to bile acid receptor (GPBAR or TGR5).
  • FXR farnesyl alcohol X receptor
  • halogen refers to F, Cl, Br, and I. More preferably, the halogen atom is selected from the group consisting of F, Cl and Br.
  • excellent pharmacokinetic and/or pharmacodynamic properties refers to a longer drug half-life (t 1/2 ), or a higher drug exposure (AUC), or a higher maximum drug. Concentration (Cmax), or lower drug clearance.
  • deuterated means that one or more hydrogens in a compound or group are replaced by deuterium.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural rhenium isotope content (0.015%).
  • the cerium isotope content of cerium at the cerium substitution site is greater than the natural strontium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95%, more preferably The ground is greater than 97%, more preferably greater than 99%, and even more preferably greater than 99.5%.
  • the compound of formula (I) contains at least one deuterium atom, more preferably two deuterium atoms, three deuterium atoms, more preferably four deuterium atoms, more preferably six deuterium atoms.
  • O is 16 O.
  • the isotope content of 16 O at the position of the oxygen atom is ⁇ 95%, more preferably ⁇ 99%.
  • compound of the invention refers to a compound of formula (I).
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
  • the term "pharmaceutically acceptable salt” means a salt suitable for use as a medicament formed by the compound of the present invention and an acid or a base.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to, amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and the like.
  • Another preferred class of salts are the salts of the compounds of the invention with bases, such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • Salts and other pharmaceutically acceptable amine salts such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butyl
  • a base amine salt an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trihydroxyethylamine salt, and an amine salt formed of morpholine, piperazine, and lysine, respectively.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate It refers to a complex formed by the coordination of the compound of the present invention with water.
  • the compound of the present invention further includes a chiral enantiomer or a racemate of the chenodeoxycholic acid derivative represented by the formula (I).
  • the compound of the present invention further includes a glucuronides and a taurine conjugate of a chenodeoxycholic acid derivative represented by the formula (I).
  • the compound of the present invention further comprises a prodrug of a chenodeoxycholic acid derivative represented by the formula (I).
  • prodrug includes a compound of the formula (I) which may be biologically active or inactive, which, when taken by a suitable method, is metabolized or chemically reacted in the human body, or a salt or solution of a compound of formula (I).
  • the prodrug includes, but is not limited to, a carboxylic acid ester, a carbonate, a phosphate, a nitrate, a sulfate, a sulfone ester, a sulfoxide, an amino compound, a carbamate, an azo compound of the compound. , phosphoramide, glucoside, ether, acetal and the like.
  • the preparation of the non-deuterated chenodeoxycholic acid derivatives and physiologically compatible salts thereof for use in the present invention is known.
  • the preparation of the chenodeoxycholic acid derivative corresponding to the deuterated can be carried out by the same route using the corresponding deuterated starting compound as a raw material.
  • the compound of the formula (I) of the present invention can be produced according to the preparation method described in WO02072598, except that the non-deuterated raw material is replaced with a deuterated raw material in the reaction.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 200 ° C, preferably 0 ° C to 100 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 48 hours.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 have the same meanings as defined above, and X is a halogen.
  • compound II is protected by THP to obtain compound III; III is substituted with compound V under the action of a base to obtain compound IV; compound IV is deprotected and esterified in acid and methanol to obtain compound VI; Compound VI is reduced to give compound VII, and finally, by hydrolysis, compound I of the present invention can be obtained.
  • the above reaction is carried out in an inert solvent such as dichloromethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetic acid, butanol
  • an inert solvent such as dichloromethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetic acid, butanol
  • the temperature is carried out at 0 to 200 °C.
  • the methyl ester compound XII is protected by TMS to obtain the compound VIII; the VIII and the aldehyde compound XI are eliminated by aldol condensation to obtain the compound IX; the compound IX is reduced to obtain the compound VI; and the compound VI is hydrolyzed to obtain the compound X.
  • the compound I of the present invention is obtained by reduction.
  • the above reaction is carried out in an inert solvent such as dichloromethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetic acid, butanol , propanol, etc., temperature -100 ° C ⁇ It was carried out at 200 °C.
  • an inert solvent such as dichloromethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetic acid, butanol , propanol, etc., temperature -100 ° C ⁇ It was carried out at 200 °C.
  • the compound of the present invention Since the compound of the present invention has excellent activity for activation of farnesyl alcohol X receptor (FXR) and/or G-protein coupled cholic acid receptor (GPBAR or TGR5), the compound of the present invention and various crystal forms thereof are pharmaceutically Acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the invention as the main active ingredient are useful for the treatment, prevention, and alleviation of the farnesol X receptor (FXR) and/or G - Protein-conjugated cholic acid receptor (GPBAR or TGR5) mediated disease.
  • FXR farnesyl alcohol X receptor
  • G-protein coupled cholic acid receptor G-protein coupled cholic acid receptor
  • the compounds of the present invention can be used for the treatment of cancer, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, gallstones, primary biliary cirrhosis, cirrhosis, liver fibrosis, diabetes, atherosclerosis Hardening, obesity, etc.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 0.5 to 2000 mg of the compound of the invention per agent, more preferably from 1 to 500 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, duodenal, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical Dosing.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant, for example, Agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) an absorption accelerator, for example, a quaternary amine compound; (g) Wetting agents, such as cetyl
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually 0.5 to 2000 mg, preferably 1 to 500 mg.
  • the specific dose should also be tested Factors such as the route of administration, the health of the patient, etc., are all within the skill of the skilled physician.
  • the compounds of the present invention have a number of advantages over non-deuterated compounds known in the art.
  • the main advantages of the invention include:
  • the compound of the present invention has excellent activation activity against farnesyl alcohol X receptor (FXR) and/or G-protein coupled bile acid receptor (GPBAR or TGR5).
  • FXR farnesyl alcohol X receptor
  • G-protein coupled bile acid receptor G-protein coupled bile acid receptor
  • the compound By changing the metabolism of the compound in the organism by the technique of deuteration, the compound has better pharmacokinetic parameter characteristics.
  • the dosage can be changed and a long-acting preparation can be formed to improve the applicability.
  • Substituting a hydrogen atom in a compound with hydrazine may increase the safety of the compound because certain metabolites are inhibited.
  • lithium diisopropylamide (68 ml, 135.9 mmol, 2M in THF/heptane/ethylbenzene) and anhydrous tetrahydrofuran (50 ml) were sequentially added; and while stirring at -70 ° C, trimethyl chloride was added to the mixture.
  • the baking solution was slowly added dropwise to the baking solution to quench the reaction, and the aqueous phase was extracted with acetic acid. The ethyl acetate was extracted, and the organic layer was combined, evaporated, evaporated, evaporated, evaporated
  • 3,7.-Dihydroxy-6-ethyl-7-indole-5-chol-24-acid (0.2 g) was dissolved in a ruthenium oxide aqueous solution of ruthenium oxide and stirred at room temperature for 24 hours. The solvent was evaporated to dryness under high vacuum, and the residue was dissolved in EtOAc EtOAc EtOAc. The pH was adjusted to 2 to 3 with 3N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed successively with pure water and brine and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude solid which was purified by silica gel column chromatography( ESI-MS (m / z) : 424 (M + H) +, 446 (M + Na) +.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test. The drug is dissolved in physiological saline. Blood was collected from the left femoral vein, and the time of blood collection was 0.5 hours before administration, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, and 3.5 hours after administration. Bile was collected during the administration period and at intervals of 15 minutes within 2.5 hours after administration.
  • Plasma and bile were stored at -70 °C prior to analysis.
  • the concentration of the compound of the invention in plasma and bile was determined by LC-MS/MS.
  • Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points and the drug concentration in bile.
  • the compound of the present invention has higher plasma exposure and drug biliary excretion (Biliary Secretion) in animals relative to the control compound oleic acid, and thus has better pharmacodynamics and treatment effect.
  • Example 10 In vitro pharmacodynamic evaluation of the compound of the present invention on farnesyl alcohol X receptor (FXR)
  • FXR farnesoid X receptor activation of the compounds of the invention is determined by the Recruitment Coactivator Assay, the AlphaScreen technique, and the specific in vitro pharmacodynamic evaluation protocol is described in J Pharmacol Exp Ther 350: 56-68, July 2014.
  • Compound FXR activation activity (EC 50 ) Chenodeoxycholic acid >10000nM, ⁇ 20000nM Obecholic acid ⁇ 300nM
  • Example 1 ⁇ 200nM
  • Example 2 ⁇ 200nM
  • Example 3 ⁇ 200nM
  • Example 4 ⁇ 200nM
  • Example 5 ⁇ 200nM
  • Example 6 ⁇ 200nM
  • Example 7 ⁇ 200nM
  • Example 8 ⁇ 200nM
  • the above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules.

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Abstract

本发明涉及氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物。具体地，本发明公开了式(I)所示的氘代鹅去氧胆酸衍生物以及含有该化合物、或其晶型、药学上可接受的盐、水合物或溶剂合物的药物组合物。本发明的上述化合物可用于治疗和/或预防非酒精性脂肪肝炎、非酒精性脂肪肝病、胆结石、原发性胆汁性肝硬化、肝硬化等。

Description

氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 技术领域
本发明属于医药领域。具体地，本发明涉及新型的氘代鹅去氧胆酸衍生物以及含该化合物的药物组合物。
背景技术
法尼醇X受体(Farnesoid X Receptor，FXR)是核受体(Nuclear Receptor)家族的一员，它主要表达在肝脏、小肠等肠道系统之中，参与胆汁酸代谢与胆固醇代谢等环节。胆汁酸具有多种生理功能，在脂肪的吸收、转运、分配及胆固醇的动态平衡等过程中发挥重要作用。法尼醇X受体作为鹅去氧胆酸等胆汁酸的受体，通过调控参与胆汁酸代谢的基因表达来维持胆汁酸在体内的平衡。另外，法尼醇X受体在体内葡萄糖的动态平衡和胰岛素抵抗等方面也发挥着重要功能。因此，法尼醇X受体激动剂有望开发成治疗非酒精性脂肪肝炎、非酒精性脂肪肝病、胆结石、原发性胆汁性肝硬化、肝硬化、肝纤维化、糖尿病、高胆固醇血症、动脉粥样硬化、肥胖、高甘油三酯血症等的药物。
鹅去氧胆酸及衍生物是一类法尼醇X受体的激动剂。在专利WO2010059859和WO2005082925中公开了系列鹅去氧胆酸衍生物，其中，化合物奥贝胆酸(Obeticholic acid)是选择性的法尼醇X受体激动剂，化学名为3,7.-二羟基-6-乙基-5-胆-24-酸(3,7-dihydroxy-6-ethyl-5-cholan-24-oic acid)，具有治疗非酒精性脂肪肝炎以及非酒精性脂肪肝相关疾病中的用途。目前奥贝胆酸处于三期临床研究中。
虽然奥贝胆酸在改善肝脏炎症和纤维化水平等方面表现出较好的临床效果，并有一定的减轻体重和增加胰岛素敏感等作用，但是，也发现瘙痒以及低密度脂蛋白升高等副作用，因此，寻找具有选择性、高活性和安全性的法尼醇X受体激动剂还具有很大的挑战性。
因此，本领域仍需要开发具有对法尼醇X受体具有很好激活作用或更好药效学/药代动力学性能的化合物。
发明内容
本发明的目的是提供一类新型的具有法尼醇X受体激活活性和更好药效学/药代动力学性能的化合物及其用途。
在本发明的第一方面中，提供了一种式(I)所示的氘代鹅去氧胆酸衍生物、或其晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2016073891-appb-000001
式中：
R1、R2、R3、R4、R5和R6各自独立地为氢或氘；
附加条件是R1、R2、R3、R4、R5或R6中至少一个是氘。
在另一优选例中，氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含量(0.015％)，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
在另一优选例中，式(I)化合物至少含有1个氘原子，更佳地2个氘原子，更佳地3个氘原子，更佳地5个氘原子，更佳地6个氘原子。
在另一优选例中，R1为氢或氘。
在另一优选例中，R2为氢或氘。
在另一优选例中，R3为氢或氘。
在另一优选例中，R4和R5独立地选自氢或氘。
在另一优选例中，R6为氢或氘。
在另一优选例中，R1是氘。
在另一优选例中，R2是氘。
在另一优选例中，R3是氘。
在另一优选例中，R4为氘和/或R5为氘。
在另一优选例中，R2为氘和/或R1为氘。
在另一优选例中，所述化合物是选自下组的化合物或其药学上可接受的盐：
Figure PCTCN2016073891-appb-000002
Figure PCTCN2016073891-appb-000003
Figure PCTCN2016073891-appb-000004
在另一优选例中，所述化合物是选自下组的化合物或其药学上可接受的盐：
Figure PCTCN2016073891-appb-000005
-二羟基-6-乙基-7-氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000006
3,7-二羟基-6-乙基-6,7-二氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000007
3,7-二羟基-6-乙基-7,23,23-三氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000008
Figure PCTCN2016073891-appb-000009
-二羟基-6-(乙基-d5)-7-氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000010
Figure PCTCN2016073891-appb-000011
-二羟基-6-(乙基-d5)-5-胆-24-酸；
Figure PCTCN2016073891-appb-000012
Figure PCTCN2016073891-appb-000013
-二羟基-6-乙基-23,23-二氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000014
Figure PCTCN2016073891-appb-000015
-二羟基-6-(乙基-d5)-23,23-二氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000016
Figure PCTCN2016073891-appb-000017
-二羟基-6-(乙基-d5)-6,23,23-三氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000018
Figure PCTCN2016073891-appb-000019
-二羟基-6-(乙基-d5)-7,23,23-三氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000020
Figure PCTCN2016073891-appb-000021
-二羟基-6-乙基-6,7,23,23-四氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000022
3,7-二羟基-6-(乙基-d5)-6,7,23,23-四氘-5-胆-24-酸；
Figure PCTCN2016073891-appb-000023
在另一优选例中，所述的化合物为
Figure PCTCN2016073891-appb-000024
其具有如下特征：MS计算值:421；MS测量值:422(M+H)+，444(M+Na)+。
在另一优选例中，所述的化合物为
Figure PCTCN2016073891-appb-000025
其具有如下特征：MS计算值:423；MS测量值:424(M+H)+，446(M+Na)+。
在另一优选例中，所述的化合物为
Figure PCTCN2016073891-appb-000026
其具有如下特征：MS计算值:426；MS测量值:427(M+H)+，449(M+Na)+。
在另一优选例中，所述的化合物为
Figure PCTCN2016073891-appb-000027
其具有如下特征：MS计算值:425；MS测量值:426(M+H)+，448(M+Na)+。
在另一优选例中，所述的化合物为
Figure PCTCN2016073891-appb-000028
其具有如下特征：MS计算值:428；MS测量值:429(M+H)+，451(M+Na)+。
在另一优选例中，所述的化合物为
Figure PCTCN2016073891-appb-000029
其具有如下特征：MS计算值:429；MS测量值:430(M+H)+，452(M+Na)+。
在另一优选例中，所述的化合物为
Figure PCTCN2016073891-appb-000030
其具有如下特征：MS计算值:422；MS测量值:423(M+H)+，445(M+Na)+。
在另一优选例中，所述的化合物为
Figure PCTCN2016073891-appb-000031
其具有如下特征：MS计算值:427；MS测量值:428(M+H)+，450(M+Na)+。
在另一优选例中，所述的化合物不包括非氘代的化合物。
在另一优选例中，所述的非氘代的化合物为奥贝胆酸，即3,7.-二羟基-6-乙基-5-胆-24-酸。
在另一优选例中，所述的化合物由实施例1-4所述的方法制备的。
在本发明的第二方面中，提供了一种制备药物组合物的方法，包括步骤：将药学上可接受的载体与本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。
在本发明的第三方面中，提供了一种药物组合物，它含有药学上可接受的载体和本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物。
在另一优选例中，所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
在另一优选例中，所述的药物组合物还含有另外的治疗药物，所述的另外治疗药物为治疗癌症、心血管疾病、炎症、感染、免疫性疾病、代谢性疾病、或器官移植的药物。
在另一优选例中，所述的癌症包括(但并不限于)：肺癌、乳腺癌、前列腺癌、食道癌、直肠癌、结肠癌、血癌(或恶性血液病)、骨癌、肾癌、胃癌、肝癌或大肠癌。
在另一优选例中，所述的癌症为肝癌。
更佳地，所述的另外的治疗药物包括(但并不限于)：索拉非尼、瑞格非尼、多纳非尼、顺铂、阿霉素、吉西他滨、FOLFOX、地西他滨、卡培他滨、他汀类药物(洛伐他丁、辛伐他汀、普伐他汀、美伐他汀、氟伐他汀、阿托伐他汀、西立伐他汀、罗伐他汀等)、罗格列酮、吡格列酮、二甲双胍、阿卡波糖、伏格列波糖、磺脲类降糖药物(格列吡嗪、格列齐特、格列美脲等)、二肽基肽酶-4(DPP-4) 抑制剂降糖药物(如西格列汀、维格列汀、沙格列汀、阿格列汀、利格列汀等)、钠依赖葡糖转运体(SGLT2)抑制剂降糖药物(如达格列净、卡格列净等)、胰高血糖素样肽-1(GLP-1)受体激动剂(如艾塞那肽、利拉鲁肽、利司那肽等)、干扰素、聚乙二醇干扰素、抗丙肝药物(如索非布韦、特拉匹维、Boceprevir、ACH-3102、Daclatasvir、Deleobuvir、Ledipasvir等)、抗乙肝药物(如拉米夫定，阿德福韦酯，替比夫定，恩替卡韦，替诺福韦酯，克拉夫定等)。
在本发明的第四方面中，提供了本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物本发明第三方面所述的药物组合物的用途，它们被用于制备法尼醇X受体(FXR)激动剂和/或G-蛋白偶联胆酸受体(GPBAR或TGR5)激动剂的药物组合物。
在另一优选例中，所述的药物组合物用于制备治疗和预防以下疾病的药物：非酒精性脂肪肝炎、非酒精性脂肪肝病、胆结石、原发性胆汁性肝硬化、肝硬化、肝纤维化、糖尿病、动脉粥样硬化、肥胖。
在本发明的第五方面中，提供了一种法尼醇X受体(FXR)激动剂和/或G-蛋白偶联胆酸受体(GPBAR或TGR5)激动剂的治疗方法或一种疾病(如癌症、非酒精性脂肪肝炎、非酒精性脂肪肝病、胆结石、原发性胆汁性肝硬化、肝硬化、肝纤维化、糖尿病、动脉粥样硬化、肥胖)的治疗方法，它包括步骤：给需要治疗的对象施用本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物，或施用本发明第三方面中所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过研究，意外地发现，本发明的氘代鹅去氧胆酸衍生物及其药学上可接受的盐与未氘代的化合物相比，具有明显更优异的药物动力学和/或药效学性能，因此更适合作为法尼醇X受体(FXR)激动剂和/或G-蛋白偶联胆酸受体(GPBAR或TGR5)激动剂的化合物，进而更适用制备治疗法尼醇X受体(FXR)和/或G-蛋白偶联胆酸受体(GPBAR或TGR5)相关疾病的药物。在此基础上完 成了本发明。
定义
如本文所用，“卤素”指F、Cl、Br、和I。更佳地，卤原子选自F、Cl和Br。
如本文所用，“更优异的药物动力学和/或药效学性能”是指更长的药物半衰期(t1/2)，或者更高的药物暴露量(AUC)，或者更高的最大药物浓度(Cmax)，或者更低的药物清除率。
如本文所用，“氘代”指化合物或基团中的一个或多个氢被氘所取代。
如本文所用，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。
在另一优选例中，氘在氘取代位置的氘同位素含量是大于天然氘同位素含量(0.015％)，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于97％，更佳地大于99％，更佳地大于99.5％。
在另一优选例中，式(I)化合物至少含有1个氘原子,更佳地2个氘原子、3个氘原子，更佳地4个氘原子，更佳地6个氘原子。
优选地，式(I)化合物中，O为16O。
在另一优选例中，所述化合物中，16O在氧原子所在位置的同位素含量≥95％，更佳地≥99％。
活性成分
如本文所用，术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
其中，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物” 是指本发明化合物与水进行配位形成的配合物。
此外，本发明化合物还包括式(I)所示的鹅去氧胆酸衍生物的手性对映异构体、或消旋体。
此外，本发明化合物还包括式(I)所示的鹅去氧胆酸衍生物的葡萄糖苷酸结合物(glucuronides)、牛磺酸(taurine)结合物。
此外，本发明化合物还包括式(I)所示的鹅去氧胆酸衍生物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)的一类化合物，或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
本发明使用的未氘代的鹅去氧胆酸衍生物及其生理上相容的盐的制备方法是已知的。对应氘代的鹅去氧胆酸衍生物的制备可以用相应的氘代起始化合物为原料，用同样的路线合成。例如，本发明式(I)化合物可按WO02072598中所述的制备方法制备，不同点在于在反应中用氘代的原料代替非氘代的原料。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～200℃，优选0℃～100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
下面的通用制备路线一和二可以用于合成本发明式(I)结构的化合物。
Figure PCTCN2016073891-appb-000032
其中：R1、R2、R3、R4、R5、R6的定义同前，X是卤素。
如合成路线一所示，化合物II经THP保护羟基得到化合物III；III经碱作用下和化合物V发生取代反应得到化合物IV；化合物IV在酸和甲醇中发生脱保护和酯化反应得到化合物VI；化合物VI经还原得到化合物VII，最后经水解反应可得到本发明化合物I。上述反应在惰性溶剂，如二氯甲烷、乙腈、正己烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙酸、丁醇、丙醇等中，温度0～200℃下进行。
Figure PCTCN2016073891-appb-000033
如合成路线二所示，甲酯化合物XII经TMS保护羟基得到化合物VIII；VIII和醛类化合物XI经羟醛缩合再消除得到化合物IX；化合物IX经还原得到化合物VI；化合物VI经水解得到化合物X，最后经还原作用得到本发明化合物I。上述反应在惰性溶剂，如二氯甲烷、乙腈、正己烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙酸、丁醇、丙醇等中，温度-100℃～ 200℃下进行。
药物组合物和施用方法
由于本发明化合物具有优异的对法尼醇X受体(FXR)和/或G-蛋白偶联胆酸受体(GPBAR或TGR5)激活活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由对法尼醇X受体(FXR)和/或G-蛋白偶联胆酸受体(GPBAR或TGR5)介导的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：癌症、非酒精性脂肪肝炎、非酒精性脂肪肝病、胆结石、原发性胆汁性肝硬化、肝硬化、肝纤维化、糖尿病、动脉粥样硬化、肥胖等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有0.5-2000mg本发明化合物/剂，更佳地，含有1-500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2016073891-appb-000034
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、十二指肠、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如， 琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为0.5～2000mg，优选1～500mg。当然，具体剂量还应考 虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的化合物与现有技术中已知的非氘代化合物相比，具有一系列优点。本发明的主要优点包括：
(1)本发明化合物对法尼醇X受体(FXR)和/或G-蛋白偶联胆酸受体(GPBAR或TGR5)具有优异的激活活性。
(2)通过氘化这一技术改变化合物在生物体中的代谢，使化合物具有更好的药代动力学参数特性。在这种情况下，可以改变剂量并形成长效制剂，改善适用性。
(3)用氘取代化合物中的氢原子，由于其氘同位素效应，能够提高化合物在动物体内的药物浓度，以提高药物疗效。
(4)用氘取代化合物中的氢原子,由于某些代谢产物被抑制，可能提高化合物的安全性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
实施例1制备3,7-二羟基-6-乙基-7-氘-5-胆-24-酸(化合物1)
Figure PCTCN2016073891-appb-000035
1、制备3～四氢吡喃氧基-7-酮-5-胆-24-酸(化合物3)
向烧瓶中加入3～羟基-7-酮-5-胆-24-酸(10.0g,25.6mmol)和二氧六环(150mL)，搅拌溶解。向其依次加入对甲苯磺酸一水合物(0.49g,2.56mmol)和3，4- 二氢-2H-吡喃(4.31g,51.2mmol)。室温搅拌1小时后，向其滴加氨气甲醇溶液调节pH值为8～9。浓缩除去挥发性有机物后，乙酸乙酯萃取。依次用饱和的碳酸氢钠水溶液、水和饱和食盐水洗涤。硫酸钠干燥，过滤。滤液经旋转蒸发仪真空下除去溶剂得到粗品。粗品经硅胶柱层析(洗脱液：乙酸乙酯/石油醚＝1/3)分离纯化得到类白色固体目标产物(9.72g，80％)。
2、制备3～四氢吡喃氧基-6-乙基-7-酮-5-胆-24-酸(化合物4)
向烧瓶中二异丙基胺(5.8g，57.6mmol)和无水四氢呋喃(400mL)，冷却到-78℃。保持温度低于-60℃，向其依次滴加正丁基锂(23.1mL，2.5M正己烷溶液)和六甲基磷酰三胺(HMPA，10.3g，57.6mmol)。加完后，保持温度-70℃搅拌1小时。向其滴加已预冷到-78℃的3～四氢吡喃氧基-7-酮-5-胆-24-酸(9.1g，19.2mmol)的无水四氢呋喃(200mL)溶液，搅拌30分钟。向其慢慢滴加碘乙烷(29.9g，192mmol)的无水四氢呋喃(1000mL)溶液，室温搅拌过夜。真空下除去有机挥发物，10％盐酸调节pH值2～3，乙酸乙酯萃取。合并有机相，依次用5％硫代硫酸钠水溶液、水和饱和食盐水洗涤。有机相用无水硫酸钠干燥，浓缩得目标化合物，不经纯化直接用于下一步反应。
3、制备3-羟基-6-乙基-7-酮-5-胆-24-酸甲酯(化合物5)
将上一步制备得到的3～四氢吡喃氧基-6-乙基-7-酮-5-胆-24-酸粗品溶解在氯化氢甲醇溶液(2N，120mL)中，回流搅拌16小时。真空浓缩蒸除有机挥发物，乙酸乙酯萃取，合并有机物，依次用纯水、饱和碳酸氢钠水溶液及食盐水洗涤，无水硫酸钠干燥，浓缩得残余物。残余物经硅胶柱层析(20％～40％乙酸乙酯/正己烷)分离纯化得到固体(1.8g，两步收率21.7％)。.
4、制备3，7-二羟基-6-乙基-7-氘-5-胆-24-酸甲酯(化合物6)
向烧瓶中依次加入3-羟基-6-乙基-7-酮-5-胆-24-酸甲酯(1.5g，3.5mmol)和甲醇(6mL)，搅拌，加入氘代硼氢化钠(NaBD4，0.3g，7mmol，Sigma-Aldrich)。室温下搅拌3小时。水淬灭反应，高真空浓缩。乙酸乙酯萃取。合并有机相依次用纯水及食盐水洗涤，无水硫酸钠干燥，浓缩得到白色固体目标产物(1.3g，85％)。
5、制备3,7.-二羟基-6-乙基-7-氘-5-胆-24-酸(化合物1)
向反应瓶中依次加入3，7-二羟基-6-乙基-7-氘-5-胆-24-酸甲酯(1.2g,2.8mmol)、氢氧化钠水溶液(10％，2.24g，5.6mmol)和四氢呋喃/甲醇/水(1/3/2，20mL)。混合物在40℃下搅拌6小时。3N盐酸调节pH值2～3，乙酸乙酯萃取。合并有机相依次用纯水及食盐水洗涤，无水硫酸钠干燥。过滤，浓缩得到固体粗 品，经硅胶柱层析(5％甲醇/二氯甲烷)分离纯化得到目标产物(0.87g，75％)。1H NMR(400MHz,CDCl3+CD3OD)δ3.46(m,1H),2.35-0.74(m,27H),0.95(d,3H),0.89-0.92(m,6H),0.68(s,3H)。ESI-MS(m/z)：422(M+H)+，444(M+Na)+。
化合物1的另一种制备方法：
Figure PCTCN2016073891-appb-000036
向反应瓶中依次加入3α-羟基-6α-乙基-7-酮-5β-胆-24-酸甲酯(2.0g,4.6mmol)、氢氧化钠水溶液(10％，4.0ml)和甲醇/水(3/1，20mL)。混合物在35℃下搅拌16小时。浓缩，加水10ml，加1N盐酸调节pH值2～3，过滤，纯水洗涤干燥得化合物5-1(1.7g，88％)。
向反应瓶中依次加入化合物5-1(1.0g,2.4mmol)、氢氧化钠水溶液(50％，0.5ml)和水(8.0mL)。搅拌下加入硼氘化钠(103mg,2.4mmol)，混合物在100℃下搅拌过夜。冷却至室温，加1N盐酸调节pH值2～3，过滤，纯水洗涤干燥得目标化合物(520mg，51％)。NMR(400MHz,DMSO-d6)δ:11.95(brs,1H),4.23-4.01(m,2H),3.16-3.11(m,1H),2.28-2.20(m,1H),2.15-2.07(m,1H),1.93-0.83(m,34H),0.61(s,3H)。
实施例2制备3,7.-二羟基-6-(乙基-d5)-7-氘-5-胆-24-酸(化合物10)
Figure PCTCN2016073891-appb-000037
1、制备3～四氢吡喃氧基-6-(乙基-d5)-7-酮-5-胆-24-酸(化合物7)
向烧瓶中二异丙基胺(2.3g，23mmol)和无水四氢呋喃(200mL)，冷却到-78℃。保持温度低于-60℃，向其依次滴加正丁基锂(9.2mL，2.5M正己烷溶液)和六甲基磷酰三胺(HMPA，4.2g，23mmol)。加完后，保持温度-70℃搅拌1小时。向其滴加已预冷到-78℃的3～四氢吡喃氧基-7-酮-5-胆-24-酸(3.6g，7.6mmol)的无水四氢呋喃(100mL)溶液，搅拌30分钟。向其慢慢滴加五氘代碘乙烷(6.2g，38mmol)的无水四氢呋喃(200mL)溶液，室温搅拌过夜。真空下除去有机挥发物，10％盐酸调节pH值2～3，乙酸乙酯萃取。合并有机相，依次用5％硫代硫酸钠水溶液、水和饱和食盐水洗涤。有机相用无水硫酸钠干燥，浓缩得目标化合物，不经纯化直接用于下一步反应。
2、制备3-羟基-6-(乙基-d5)-7-酮-5-胆-24-酸甲酯(化合物8)
将上一步制备得到的3～四氢吡喃氧基-6-(乙基-d5)-7-酮-5-胆-24-酸粗品溶解在氯化氢甲醇溶液(2N，30mL)中，回流搅拌16小时。真空浓缩蒸除有机挥发物，乙酸乙酯萃取，合并有机物，依次用纯水、饱和碳酸氢钠水溶液及食盐水洗涤，无水硫酸钠干燥，浓缩得残余物。残余物经硅胶柱层析(20％～40％乙酸乙酯/正己烷)分离纯化得到固体(0.6g，两步收率18％)。.
3、制备3，7-二羟基-6-(乙基-d5)-7-氘-5-胆-24-酸甲酯(化合物9)
向烧瓶中依次加入3-羟基-6-(乙基-d5)-7-酮-5-胆-24-酸甲酯(0.3g，0.68mmol)和甲醇(3mL)，搅拌，加入氘代硼氢化钠(NaBD4，60mg，1.4mmol)。室温下搅拌3小时。水淬灭反应，高真空浓缩。乙酸乙酯萃取。合并有机相依次用纯水及食盐水洗涤，无水硫酸钠干燥，浓缩得到白色固体目标产物(0.25g，82％)。
4、制备3,7.-二羟基-6-(乙基-d5)-7-氘-5-胆-24-酸(化合物10)
向反应瓶中依次加入3，7-二羟基-6-(乙基-d5)-7-氘-5-胆-24-酸甲酯(0.24g,0.54mmol)、氢氧化钠水溶液(10％，0.44g，1.1mmol)和四氢呋喃/甲醇/水(1/3/2，5mL)。混合物在40℃下搅拌6小时。3N盐酸调节pH值2～3，乙酸乙酯萃取。合并有机相依次用纯水及食盐水洗涤，无水硫酸钠干燥。过滤，浓缩得到固体粗品，经硅胶柱层析(5％甲醇/二氯甲烷)分离纯化得到目标产物(0.18g，78％)。1H NMR(400MHz,CDCl3+CD3OD)δ3.47(m,1H),2.36-0.74(m,25H),0.95(d,3H),0.91(s,3H),0.66(s,3H)。ESI-MS(m/z)：427(M+H)+，449(M+Na)+。
实施例3制备3,7.-二羟基-6-(乙基-d5)-5-胆-24-酸(化合物12)
Figure PCTCN2016073891-appb-000038
1、制备3，7-二羟基-6-(乙基-d5)-5-胆-24-酸甲酯(化合物11)
向烧瓶中依次加入3-羟基-6-(乙基-d5)-7-酮-5-胆-24-酸甲酯(0.3g，0.68mmol)和甲醇(3mL)，搅拌，加入硼氢化钠(NaBH4，60mg，1.4mmol)。室温下搅拌3小时。水淬灭反应，高真空浓缩。乙酸乙酯萃取。合并有机相依次用纯水及食盐水洗涤，无水硫酸钠干燥，浓缩得到白色固体目标产物(0.24g，81％)。
2、制备3,7.-二羟基-6-(乙基-d5)-5-胆-24-酸(化合物12)
向反应瓶中依次加入3，7-二羟基-6-(乙基-d5)-5-胆-24-酸甲酯(0.24g,0.54mmol)、氢氧化钠水溶液(10％，0.44g，1.1mmol)和四氢呋喃/甲醇/水(1/3/2，5mL)。混合物在40℃下搅拌6小时。3N盐酸调节pH值2～3，乙酸乙酯萃取。合并有机相依次用纯水及食盐水洗涤，无水硫酸钠干燥。过滤，浓缩得到固体粗品，经硅胶柱层析(5％甲醇/二氯甲烷)分离纯化得到目标产物(0.16g，72％)。1H NMR(400MHz,DMSO-d6)δ:11.97(brs,1H),4.32(d,J＝4.0Hz,1H),4.07(d,J＝4.0Hz,1H),3.50(s,1H),3.14-3.13(m,1H),2.27-2.20(m,1H),2.15-2.07(m,1H),1.93-0.84(m,29H),0.61(s,3H)。ESI-MS(m/z)：426(M+H)+，448(M+Na)+。
实施例4制备3,7-二羟基-6-(乙基-d3)-7-氘-5-胆-24-酸(化合物18)
Figure PCTCN2016073891-appb-000039
1、制备3α,7-二(三甲基甲硅氧基)-5β-胆-6-烯-24-酸甲酯(化合物14)
向四口烧瓶中依次加入二异丙基氨基锂(68ml，135.9mmol，2M in THF/heptane/ethylbenzene)、无水四氢呋喃(50ml)；-70℃搅拌下，向混合液中加入三甲基氯硅烷(12.1g，111.1mmol)，氮气保护下搅拌30分钟；-70℃左右缓慢滴 入2,3α-羟基-7-氧代-胆烷酸-24-甲酯的四氢呋喃溶液(10.0g，化合物13溶于50ml四氢呋喃)，约半小时滴完，-70℃左右搅拌1小时；-70℃左右加入三乙胺(35.2g，348mmol)，搅拌1小时后自然升温至室温，搅拌过夜；冰浴下，向混合液中缓慢滴入小苏打溶液淬灭反应，萃取，水相用乙酸乙酯萃取，合并有机相，用饱和小苏打和食盐水洗涤，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(EA:PE＝2％)得到目标化合物12.9g，收率：95％。
2、制备3α-羟基-6-(亚乙基-d3)-7-酮-5β-胆-24-酸甲酯(化合物15)
向四口烧瓶中依次加入上一步制备的3α,7-二三甲基甲硅氧基-5β-胆-6-烯-24-酸甲酯(11.0g，18.2mmol)、二氯甲烷(60ml)；-40℃搅拌下，向混合液中加入(乙基-d3)醛(2.1ml，36.4mmol)，-60℃左右搅拌10分钟；缓慢滴入三氟化硼乙醚的二氯甲烷混合液(10.0ml BF3.OEt2溶于20ml二氯甲烷)，加完后控温-60℃搅拌3小时，自然升温至室温搅拌过夜；冰浴下，向混合液中缓慢滴入小苏打溶液，搅拌均匀，萃取，二氯甲烷(60ml)洗涤水相，合并有机相中加入3N盐酸，冰浴搅拌1小时，饱和小苏打淬灭，再次萃取并用二氯甲烷洗涤水相，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(EA:PE＝25％～35％)得目标化合物6.1g，收率：70％。
3、制备3-羟基-6-(乙基-d3)-7-酮-5-胆-24-酸甲酯(化合物16)
向烧瓶中依次加入3α-羟基-6-(亚乙基-d3)-7-酮-5β-胆-24-酸甲酯(0.18g，0.42mmol)和醋酸(10mL)，浓盐酸(0.5ml)，二氧化铂(20mg)；室温换气后加氢反应12h，过滤浓缩得到目标化合物(0.17g，94％)。
4、制备3-羟基-6-(乙基-d3)-7-酮-5-胆-24-酸(化合物17)
向反应瓶中依次加入3α-羟基-6α-(乙基-d3)-7-酮-5β-胆-24-酸甲酯(0.17g,0.39mmol)、氢氧化钠水溶液(10％，8.0ml)和甲醇/水(4.5/1，11mL)。混合物在35℃下搅拌16小时。浓缩，加水，加1N盐酸调节pH值2～3，过滤，纯水洗涤干燥得目标化合物(0.14g，79％)。
5、制备3,7-二羟基-6-(乙基-d3)-7-氘-5-胆-24-酸(化合物18)
向反应瓶中依次加入3-羟基-6-(乙基-d3)-7-酮-5-胆-24-酸(65mg,0.15mmol)、氢氧化钠水溶液(50％，200mg)和水(3.0mL)。搅拌下加入硼氘化钠(13mg,0.30mmol)。混合物在100℃下搅拌16小时。冷却至室温，加1N盐酸调节pH值2～3，过滤，纯水洗涤干燥得目标化合物(45mg，69％)。1H NMR(400MHz,DMSO-d6)δ:11.95(brs,1H),4.31(s,J＝4.0Hz,1H),4.04(d,J＝8.0Hz,1H), 3.14-3.13(m,1H),2.27-2.20(m,1H),2.15-2.07(m,1H),1.93-0.84(m,31H),0.61(s,3H)。ESI-MS(m/z):425(M+H)+，447(M+Na)+。
实施例5制备3,7-二羟基-6-(乙基-d3)-5-胆-24-酸(化合物19)
Figure PCTCN2016073891-appb-000040
向反应瓶中依次加入3-羟基-6-(乙基-d3)-7-酮-5-胆-24-酸(65mg,0.15mmol)、氢氧化钠水溶液(50％，200mg)和水(3.0mL)。搅拌下加入硼氢化钠(13mg,0.30mmol)。混合物在100℃下搅拌16小时。冷却至室温，加1N盐酸调节pH值2～3，过滤，纯水洗涤干燥得目标化合物(51mg，78％)。1H NMR(400MHz,DMSO-d6)δ:11.97(brs,1H),4.32(d,J＝4.0Hz,1H),4.07(d,J＝4.0Hz,1H),3.50(s,1H),3.14-3.13(m,1H),2.27-2.20(m,1H),2.15-2.07(m,1H),1.93-0.84(m,31H),0.61(s,3H)。ESI-MS(m/z):424(M+H)+，446(M+Na)+。
实施例6制备3,7-二羟基-6-(乙基-d4)-7-氘-5-胆-24-酸(化合物23)
Figure PCTCN2016073891-appb-000041
1、制备3α-羟基-6-(亚乙基-d4)-7-酮-5β-胆-24-酸甲酯(化合物20)
向四口烧瓶中依次3α,7-二三甲基甲硅氧基-5β-胆-6-烯-24-酸甲酯(11.0g，18.2mmol)、二氯甲烷(60ml)；-40℃搅拌下，向混合液中加入乙醛-d4(2.1ml，36.4mmol)，-60℃左右搅拌10分钟；-60℃左右缓慢滴入三氟化硼乙醚的二氯甲烷混合液(10.0ml BF3.OEt2溶于20ml二氯甲烷)，加完后控温-60℃搅拌3小时，自然升温至室温搅拌过夜；冰浴下，向混合液中缓慢滴入小苏打溶液，搅拌均匀， 萃取，二氯甲烷洗涤水相，合并有机相中加入3N盐酸，冰浴搅拌1小时，饱和小苏打淬灭，再次萃取并用二氯甲烷洗涤水相，合并有机相，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(EA:PE＝25％～35％)得目标化合物5.2g，收率：59％。
2、制备3α-羟基-6α-(乙基-d4)-7-酮-5β-胆-24-酸甲酯(化合物21)
向烧瓶中依次加入3α-羟基-6-(亚乙基-d4)-7-酮-5β-胆烷-24-酸甲酯(0.18g，0.42mmol)和醋酸(10mL)，浓盐酸(0.5ml)，二氧化铂(20mg)，室温换气后加氢反应12h，过滤浓缩得到目标化合物(0.16g，88％)。.
3、制备3-羟基-6-(乙基-d4)-7-酮-5-胆-24-酸(化合物22)
向反应瓶中依次加入3α-羟基-6α-(乙基-d4)-7-酮-5β-胆-24-酸甲酯(0.16g,0.36mmol)、氢氧化钠水溶液(10％，8.0ml)和甲醇/水(4.5/1，11mL)。混合物在35℃下搅拌16小时。浓缩，加水，加1N盐酸调节pH值2～3，过滤，纯水洗涤干燥得目标化合物(0.12g，73％)。
4、制备3,7-二羟基-6-(乙基-d4)-7-氘-5-胆-24-酸(化合物23)
向反应瓶中依次加入3-羟基-6-(乙基-d4)-7-酮-5-胆-24-酸(60mg,0.14mmol)、氢氧化钠水溶液(50％，200mg)和水(3.0mL)。搅拌下加入硼氘化钠(13mg,0.30mmol)混合物在100℃下搅拌16小时。冷却至室温，加1N盐酸调节pH值2～3，过滤，纯水洗涤干燥得目标化合物(40mg，67％)。1H NMR(400MHz,DMSO-d6)δ:11.97(brs,1H),4.32(s,1H),4.07(d,J＝8.0Hz,1H),3.16-3.11(m,1H),2.28-2.19(m,1H),2.15-2.07(m,1H),1.93-0.84(m,30H),0.61(s,3H)。ESI-MS(m/z):426(M+H)+，448(M+Na)+。
实施例7制备3,7-二羟基-6-(乙基-d4)-5-胆-24-酸(化合物24)
Figure PCTCN2016073891-appb-000042
向反应瓶中依次加入3-羟基-6-(乙基-d4)-7-酮-5-胆-24-酸(30mg,0.07mmol)、氢氧化钠水溶液(50％，50mg)和水(2.0mL)。搅拌下加入硼氢化钠(10mg,0.15mmol)混合物在100℃下搅拌16小时。冷却至室温，加1N盐酸调节pH值2～3，过滤，纯水洗涤干燥得目标化合物(22mg，70％)。1H NMR(400MHz, DMSO-d6)δ:11.97(brs,1H),4.32(d,J＝4.0Hz,1H),4.07(d,J＝4.0Hz,1H),3.50(s,1H),3.14-3.13(m,1H),2.27-2.20(m,1H),2.15-2.07(m,1H),1.93-0.84(m,30H),0.61(s,3H)。ESI-MS(m/z):425(M+H)+，447(M+Na)+。
实施例8制备3,7.-二羟基-6-乙基-7，23，23-三氘-5-胆-24-酸(化合物25)
Figure PCTCN2016073891-appb-000043
将3,7.-二羟基-6-乙基-7-氘-5-胆-24-酸(0.2g)溶解在氘氧化纳的氘水溶液中，室温搅拌24小时。高真空旋干蒸除溶剂，将残留物溶解在氘氧化纳的氘水溶液中，室温下继续搅拌24小时。3N盐酸调节pH值2～3，乙酸乙酯萃取。合并有机相依次用纯水及食盐水洗涤，无水硫酸钠干燥。过滤，浓缩得到固体粗品，经硅胶柱层析(5％甲醇/二氯甲烷)分离纯化得到目标化合物。ESI-MS(m/z):424(M+H)+，446(M+Na)+。
实施例9：大鼠中的药代动力学评价
雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，每组6只，十二指肠给药1μmol/min/kg剂量的(a)对照组：奥贝胆酸或(b)试验组：实施例1～8制备的化合物。给药1小时，给药流速2.5mL/h。比较其血浆药代动力学和胆汁排泄动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用生理盐水溶解。左股静脉采血，采血的时间点为给药前0.5小时、给药后0.5小时、1小时、1.5小时、2小时、2.5小时、3小时和3.5小时。给药期间和给药后2.5小时内间隔15min分别收集胆汁。
血浆和胆汁在进行分析前保存在-70℃。用LC-MS/MS测定血浆和胆汁中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度和胆汁中药物浓度进行计算。
从结果看出，相对于对照化合物奥贝胆酸，本发明化合物在动物体内具有更高的血浆暴露量和药物胆汁排泄量(Biliary Secretion)，因而具有更好的药效学和 治疗效果。
实施例10：本发明化合物对法尼醇X受体(FXR)的体外药效学评价
本发明化合物的法尼醇X受体(FXR)激活是通过Recruitment Coactivator Assay，即AlphaScreen技术测定，具体的体外药效学评价试验方案参照文献J Pharmacol Exp Ther 350:56–68,July 2014。
实验结果如表1所示。可见，本发明所述的化合物对法尼醇X受体(FXR)具有优异的激活活性。
表1
化合物 对FXR激活活性(EC50)
鹅去氧胆酸 >10000nM，<20000nM
奥贝胆酸 ＜300nM
实施例1 ＜200nM
实施例2 ＜200nM
实施例3 ＜200nM
实施例4 ＜200nM
实施例5 ＜200nM
实施例6 ＜200nM
实施例7 ＜200nM
实施例8 ＜200nM
实施例11药物组合物
化合物(实施例1～8)     10g
羧甲基淀粉钠           12g
微晶纤维素             180g
按常规方法，将上述物质混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式(I)所示的氘代鹅去氧胆酸衍生物、或其晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2016073891-appb-100001
    其中：
    R1、R2、R3、R4、R5和R6各自独立地为氢或氘；
    附加条件是R1、R2、R3、R4、R5或R6中至少一个是氘。
  2. 如权利要求1中任一所述的化合物，其特征在于，R2为氘和/或R1为氘。
  3. 如权利要求1所述的化合物，其特征在于，所述化合物是选自下组的化合物或其药学上可接受的盐：
    Figure PCTCN2016073891-appb-100002
    Figure PCTCN2016073891-appb-100003
  4. 如权利要求1所述的化合物，其特征在于，所述的化合物不包括非氘代的 化合物。
  5. 如权利要求4所述的化合物，其特征在于，所述的非氘代的化合物是3α,7α-二羟基-6α-乙基-5β-胆-24-酸。
  6. 一种药物组合物，其特征在于，它含有药学上可接受的载体和权利要求1-5任一项所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物。
  7. 如权利要求6所述的药物组合物，其特征在于，它还含有另外的治疗药物，所述的另外的治疗药物为治疗癌症、心血管疾病、炎症、感染、免疫性疾病、或代谢性疾病的药物。
  8. 如权利要求6所述的药物组合物，其特征在于，所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
  9. 一种权利要求1所述的化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求6所述的药物组合物的用途，其特征在于，用于制备法尼醇X受体(FXR)激动剂和/或G-蛋白偶联胆酸受体(GPBAR或TGR5)激动剂的药物组合物。
  10. 如权利要求9所述的用途，其特征在于，所述的药物组合物用于制备用于治疗和预防以下疾病的药物：非酒精性脂肪肝炎、非酒精性脂肪肝病、胆结石、原发性胆汁性肝硬化、肝硬化、肝纤维化、糖尿病、动脉粥样硬化、肥胖。
PCT/CN2016/073891 2015-02-16 2016-02-16 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 Ceased WO2016131414A1 (zh)

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