WO2019076190A1 - 取代的丙-2-烯-1-酮化合物及其药物组合物 - Google Patents

取代的丙-2-烯-1-酮化合物及其药物组合物 Download PDF

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Publication number
WO2019076190A1
WO2019076190A1 PCT/CN2018/108707 CN2018108707W WO2019076190A1 WO 2019076190 A1 WO2019076190 A1 WO 2019076190A1 CN 2018108707 W CN2018108707 W CN 2018108707W WO 2019076190 A1 WO2019076190 A1 WO 2019076190A1
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compound
disease
fibrosis
cancer
liver
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PCT/CN2018/108707
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English (en)
French (fr)
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王义汉
李焕银
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深圳市塔吉瑞生物医药有限公司
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Publication of WO2019076190A1 publication Critical patent/WO2019076190A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • C07B59/001—Acyclic or carbocyclic compounds
    • 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 technical field of medicine, and in particular relates to a substituted prop-2-en-1-one compound and a composition comprising the same and use thereof.
  • Peroxisome Proliferator-Activated Receptor is a type of nuclear receptor that is a nuclear transcription factor activated by a ligand. To date, three subtypes have been discovered: alpha, gamma and delta. These receptors belong to the nuclear receptor and superfamily of transcription factors that are activated upon contact with certain fatty acids and/or their fat metabolites. Activated PPAR forms a heterodimer with a 9-cis retinoic acid receptor (RXR or retinoid X receptor) and is a specific response element of the target gene promoter (PPRE or peroxisome bulk value response element) ), thereby providing transcriptional control.
  • RXR or retinoid X receptor 9-cis retinoic acid receptor
  • PPRE peroxisome bulk value response element
  • PPAR ⁇ controls (liver and muscle) lipid metabolism and glucose homeostasis, affecting the metabolism of intracellular lipids and carbohydrates by directly controlling the transcription of genes encoding proteins involved in liposome homeostasis, with anti-inflammatory and It has anti-proliferative effects and prevents the atherogenic effect of cholesterol accumulation in macrophages by stimulating the flow of cholesterol.
  • PPRA ⁇ is a key regulator of fat formation. Moreover, it is involved in lipid metabolism of mature adipocytes, glucose homeostasis, in particular insulin resistance, inflammation, macrophage cholesterol accumulation and cell proliferation. Therefore, PPRA ⁇ plays a role in the pathogenesis of obesity, insulin resistance and diabetes.
  • PPRA ⁇ is involved in lipid and carbohydrate metabolism control, energy balance, neurodeformation, obesity, macrophage foam cell formation and inflammation.
  • PPAR PPAR ligands
  • these molecules have a pleiotropic spectrum of action due to the extreme diversity of PPAR target genes.
  • These multiplicities make PPAR an interesting therapeutic target for treating the following diseases and reducing overall risk: atherosclerosis, cerebral ischemia, hypertension, cardiovascular disease-related diseases (retinopathy, diabetes, etc.) , inflammation and autoimmune diseases (Crohn's disease, psoriasis, multiple sclerosis, asthma, etc.), oncological diseases (cancer, etc.), neurodegenerative diseases, complications associated with metabolic syndrome, insulin resistance, diabetes, Dyslipidemia, cardiovascular disease, obesity, etc.
  • Elafibranor also known as GFT-505 and chemically known as 1-(4-methylthiophenyl)-3-(3,5-dimethyl-4-carboxydimethylmethoxyphenyl)propan-2- En-1-one (having the structure below) is a PPAR alpha/delta agonist developed by Genfit.
  • NASH non-alcoholic steatohepatitis
  • the present invention discloses a novel substituted prop-2-en-1-one compound and a composition comprising the same and use thereof for treating, preventing and alleviating treatment and/or prevention with PPAR ⁇ and/or PPAR ⁇ Guided disease.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are hydrogen
  • X 2 , X 3 , X 4 and X 5 are CH 3 ;
  • R 5 is selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 or CD 3 ;
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form a pharmaceutical composition.
  • the invention provides a method of treating and/or a disease-related disorder caused by PPAR alpha and/or PPAR delta in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention.
  • the disease caused by PPAR ⁇ and/or PPAR ⁇ is selected from: any acute or chronic liver disease (including fatty liver disease, liver fibrosis, non-hepatic disease involving pathological destruction, inflammation, degeneration, and/or proliferation of liver cells) Alcoholic steatohepatitis, primary biliary cirrhosis or alcoholic liver disease), complications associated with metabolic syndrome, insulin resistance, diabetes, dyslipidemia, atherosclerosis, cardiovascular disease, obesity, hypertension , inflammatory diseases, fibrotic diseases (including pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitone
  • deuterated as used herein means that one or more hydrogens in a compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated are used interchangeably with “one or more deuterated”.
  • Non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • 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 that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and reasonable The benefits/hazard ratios are proportional to those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • non-toxic acid addition salts examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using conventional methods in the art, for example, ion exchange methods.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • prodrug includes a compound of the formula (I) which is biologically active or inactive, which, when taken by a suitable method, is metabolized or chemically reacted in the human body, or converted into a compound of the formula (I), or a formula a salt or solution of a compound of (I).
  • the prodrugs include, but are not limited to, carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphorus of the compound. In the form of an amide, a glucoside, an ether, an acetal or the like.
  • the term "subject” includes, but is not limited to, a human (ie, a male or female of any age group, eg, a pediatric subject (eg, an infant, a child, adolescent) or an adult subject (eg, Young adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses , sheep, goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or disease (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a “therapeutically effective amount” of a compound, as used herein, is a quantity sufficient to provide a therapeutic benefit, or one or more associated with a disease, disorder, or condition, in the course of treating a disease, disorder, or condition, unless otherwise stated. Symptoms are delayed or minimized.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, hydrate, solvate or isotope variant thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen or deuterium;
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently CH 3 , CH 2 D, CHD 2 or CD 3 ;
  • the compound of formula (I) contains at least one ruthenium atom, more preferably one ruthenium atom, more preferably two ruthenium atoms, more preferably three ruthenium atoms, more preferably four ruthenium atoms, More preferably, six helium atoms, more preferably seven helium atoms, more preferably nine helium atoms.
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • the strontium isotope content in the location is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, more preferably greater than 30%, and even more preferably greater than 35.
  • the compound of the formula (I) contains at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, ten Three, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three atomic atoms.
  • R 1 , R 2 , R 3 or R 4 are each independently hydrogen or deuterium.
  • R 1 is deuterium
  • R 2 is deuterium
  • R 3 is deuterium
  • R 4 is deuterium
  • R 1 and R 2 are deuterium.
  • R 3 and R 4 are deuterium.
  • R 1 , R 2 , R 3 and R 4 are deuterium.
  • R 5 or R 6 are each independently hydrogen or deuterium.
  • R 5 is deuterium
  • R 6 is deuterium
  • R 5 and R 6 are deuterium.
  • R 7 or R 8 are each independently hydrogen or deuterium.
  • R 7 is deuterium
  • R 8 is deuterium
  • R 7 and R 8 are deuterium.
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently CH 3 , CH 2 D, CHD 2 or CD 3 .
  • X 1 is CD 3 .
  • X 2 and X 3 are CD 3 .
  • X 4 and X 5 are CD 3 .
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, hydrate, solvate or isotope variant thereof:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are hydrogen
  • X 2 , X 3 , X 4 and X 5 are CH 3 ;
  • R 5 is selected from hydrogen or hydrazine
  • X 1 is selected from CH 3 or CD 3 ;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are hydrogen, X 2 , X 3 , X 4 and X 5 are CH 3 and R 5 is deuterium, X 1 is selected from CH 3 or CD 3 .
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are hydrogen, X 2 , X 3 , X 4 and X 5 are CH 3 and X 1 is CD 3 R 5 is selected from hydrogen or hydrazine.
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof:
  • the compound is selected from the group consisting of
  • the compound does not include a non-deuterated compound.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • 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 excipient” means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embedded Seg
  • 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 administration. medicine.
  • Solid dosage forms for oral administration include capsules, tablets, pills, 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 solubilizer, for example, starch , lactose, sucrose, glucose, dry diol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, for example, paraffin; An absorption accelerator, for example, a quaternary amine compound; (g) a wetting agent such as cetyl alcohol and
  • Solid dosage forms such as tablets, troches, 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.
  • Liquid dosage forms can contain, in addition to the active compound, inert release agents 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 release agents 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
  • 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, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan, 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 and compositions of the invention may be administered alone or may be advantageously administered in combination with other therapeutic agents currently available or under development for the treatment of metabolic and/or liver disorders, such as dimethyl Shuanggu, insulin, thiazolidinediones, glitazones, statins, cholesterol inhibitors and/or other lipid lowering drugs.
  • other therapeutic agents currently available or under development for the treatment of metabolic and/or liver disorders, such as dimethyl Shuanggu, insulin, thiazolidinediones, glitazones, statins, cholesterol inhibitors and/or other lipid lowering drugs.
  • 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.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the present invention provides a method of treating and/or a disease-related disorder caused by PPAR ⁇ and/or PPAR ⁇ in a subject in need thereof, comprising the steps of administering a compound of the present invention to a subject in need of treatment, or a pharmaceutical thereof Acceptable salts, stereoisomers, solvates, hydrates, crystal forms, prodrugs or isotopic derivatives, or administration of the pharmaceutical compositions described herein.
  • the compounds of the invention useful for the treatment of PPAR alpha and/or PPAR delta are selected from the group consisting of: any acute or chronic liver disease involving pathological destruction, inflammation, degeneration and/or proliferation of liver cells, complications associated with metabolic syndrome, insulin resistance, Diabetes, dyslipidemia, atherosclerosis, cardiovascular disease, obesity, hypertension, inflammatory disease, fibrotic disease, neurodegenerative disease or cancer.
  • any acute or chronic liver disease involving the pathological destruction, inflammation, degeneration and/or proliferation of liver cells that can be used in the treatment of the compounds of the invention is a marker of hepatic fibrosis, cirrhosis or where hepatocyte damage, alteration or necrosis Any other liver disease in which the plasma level of the substance is elevated compared to normal plasma levels.
  • biochemical markers associated with liver activity and status may be selected from those disclosed in the literature, particularly alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (AP), gamma - glutamyl transpeptidase (GGT), cytokeratin-18 (CK-18) or resistin.
  • the liver disease is fatty liver disease, wherein elevation of one or more of these markers is associated with more or less significant steatosis in the liver, as evidenced by liver tissue biopsy.
  • fatty liver disease include nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and with, for example, hepatitis or metabolic syndrome (obesity, insulin resistance, high triglyceride blood) Disease, etc.) related to fatty liver disease.
  • the liver disease is primary biliary cirrhosis.
  • Fibrotic diseases treatable by the compounds of the invention include, but are not limited to, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis Progressive bulk fibrosis, renal systemic fibrosis, Crohn's disease, old myocardial infarction, scleroderma/systemic sclerosis, joint fibrosis or adhesive bursitis.
  • Cancers treatable by the compounds of the invention include, but are not limited to, renal cell carcinoma, gastrointestinal stromal tumors (GIST), gastric cancer, liver cancer, meningiomas associated with neurofibroma, pancreatic neuroendocrine tumors, pancreatic exocrine tumors, leukemia, Myeloproliferative/myelodysplastic disease, mastocytosis, cutaneous fibrosarcoma, solid cancer including breast cancer, lung cancer, thyroid cancer or colorectal cancer, or prostate cancer.
  • GIST gastrointestinal stromal tumors
  • the compounds of the present invention have a number of advantages over non-deuterated compounds known in the art.
  • Advantages of the present invention include: First, the compounds and compositions employing the technical solutions of the present invention provide a more advantageous therapeutic tool for the treatment of liver diseases, particularly fatty liver diseases including NAFLD and NASH. Second, the metabolism of the compound in the organism is improved, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, the drug concentration of the compound in the animal is increased, and the drug efficacy is improved. Fourth, certain metabolites are inhibited and the safety of the compounds is increased.
  • TsOMe methyl p-toluenesulfonate
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • the activation assay of PPAR was carried out in vitro and in the RK13 fibroblast cell line, and the transcriptional activity of the chimera consisting of the DNA binding domain of the yeast ga14 transcription factor and the ligand binding domain of different PPARs was determined. These latter results were then confirmed in the cell line according to the following method:
  • RK13 cells were derived from BCACC (porton Down, UK) and supplemented with 10% (v/v) fetal bovine serum, 100 U/ml penicillin (Gibco, Paisley, UK) and 2 mM L-glutamate (Gibco, Paisley). , UK) grow in DMEM medium, and the culture medium is changed every other day. The cells were stored at 37 ° C and stored in a humidified atmosphere of 95% air / 5% CO 2 .
  • Raspe, Madsen et al. have described plastids pG5TkpGL3, pRL-CMV, pGa14-hPPPAR ⁇ , pGa14-hPPPAR ⁇ and pGa14- ⁇ (1999).
  • the construction of pGa14-hPPPAR ⁇ and pGa14-hPPPAR ⁇ was obtained by cloning into the pGa14- ⁇ vector of the PCR-amplified DNA fragment, which corresponds to the DEF functional region of the human PPPAR ⁇ and PPPAR ⁇ nuclear receptors.
  • RK13 cells were seeded in 24-well culture dishes at 5 ⁇ 10 4 cells per well, using the plastid pG5TkpGL3 (50 ng/well), expression vectors pGa14- ⁇ , pGa14-mPPPAR ⁇ , pGa14-hPPPAR ⁇ , pGa14-hPPPAR ⁇ (100 ng/ The wells were transfected for 2 hours with the transfection rate control vector pRL-CMV (1 ng/well) and then incubated with the test compound for 36 hours.
  • the compound of the present invention and the undeuterated compound Elafibranor were tested in the above experiments, and it was found that luciferase activity was increased in cells treated with the compound of the present invention and transfected with pGa14-hPPPAR ⁇ and pGa14-hPPPAR ⁇ plastids.
  • the induction of the luciferase activity indicates that the compound of the present invention is a PPAR ⁇ and PPPAR ⁇ agonist, and even has a stronger activity than the undeuterated compound Elafibranor.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of human and rat liver microsomes was evaluated by simultaneous testing of the compound of the present invention and its compound Elafibranor without deuteration.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 1.
  • the undeuterated compound Elafibranor was used as a control in Table 1.
  • the compounds of the invention significantly improved metabolic stability by comparison to the undeuterated compound Elafibranor.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

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Abstract

本发明涉及式(I)所示的取代的丙-2烯-1-酮类化合物，及其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体。所述化合物是PPARα和PPARδ激动剂，因此可用于治疗和/或预防与PPARα和/或PPARδ导致的疾病的方法，例如非酒精性脂肪性肝炎的治疗方法中。本发明还提供了包含本发明化合物的药物组合物。

Description

取代的丙-2-烯-1-酮化合物及其药物组合物 技术领域
本发明属于医药技术领域，尤其涉及一种取代的丙-2-烯-1-酮化合物及包含该化合物的组合物及其用途。
背景技术
过氧化物酶体增殖因子活化受体(Peroxisome Proliferator-Activated Receptor，PPAR)是一类细胞核受体，是由配体激活的核转录因子。迄今为止，已发现三种亚型：α、γ和δ。这些受体属于细胞核受体和转录因子超家族，它们在与某些脂肪酸和/或它们的脂肪代谢产物接触时被激活。激活的PPAR与9-顺式维甲酸受体(RXR或者类视黄质X受体)形成异二聚体并于靶基因启动子的特定应答元件(PPRE或者过氧化物酶体增值物应答元件)结合，由此提供转录控制。
PPARα控制(肝脏和肌肉的)脂质代谢和葡萄糖的体内稳态，通过直接控制编码涉及脂质体内稳态的蛋白质的基因的转录来影响细胞内脂质和糖类的代谢，具有抗炎和抗增殖效力，并且通过刺激胆固醇流出来防止胆固醇在巨噬细胞中蓄积的致动脉粥样硬化效应。
PPRAγ是脂肪形成的关键调节剂。而且，它参与成熟脂肪细胞的脂质代谢、葡萄糖体内稳态，特别是胰岛素抵抗、炎症、巨噬细胞胆固醇蓄积和细胞增殖。因此，PPRAγ在肥胖症、胰岛素抵抗和糖尿病的发病机理中起作用。
PPRAδ参与脂质和碳水化合物代谢的控制、能量平衡、神经变形、肥胖症、巨噬泡沫细胞的形成和炎症。
除了PPAR配体直接作用于脂质和糖类代谢的调节，这些分子因为PPAR的靶基因的极其多样性而具有多效性的作用谱。这些多重性使PPAR成为对治疗以下疾病和降低总体风险的令人感兴趣的治疗靶点：动脉粥样硬化、脑缺血、高血压、与心血管形成有关的疾病(视网膜病变、糖尿病等)、炎症和自身免疫疾病(克罗恩病、银屑病、多发性硬化、哮喘等)、肿瘤病(癌发生等)、神经变形疾病、与代谢综合征相关的并发症、胰岛素抵抗、糖尿病、血脂异常、心血管疾病、肥胖症等。
Elafibranor，又名GFT-505并且化学名为1-(4-甲基硫苯基)-3-(3,5-二甲基-4-羧基二甲基甲氧基苯基)丙-2-烯-1-酮(具有如下结构)，是Genfit公司研发PPARα/δ激动剂。
Figure PCTCN2018108707-appb-000001
目前，Elafibranor用于治疗非酒精性脂肪性肝炎(non-alcoholic steatohepatitis，NASH)的研究处于临床三期，用于治疗原发性胆汁性肝硬化(PBC)、2型糖尿病、血脂异常、动脉粥样硬化和胰岛素抵抗处于临床二期。
尽管已获得了Elafibranor的有益活性，但对于治疗前述疾病和病症的新化合物的需要一直存在。尽管已存在Elafibranor，仍存在对在PPARα/δ介导相关疾病的治疗中具有提高的药代动力学和/或药效动力学表现的有效化合物的需要。
发明内容
本发明公开了一种新的取代的丙-2-烯-1-酮化合物及包含该化合物的组合物及其用途，可用于治疗、预防以及缓解治疗和/或预防与PPARα和/或PPARδ介导的疾病。
对此，本发明采用以下技术方案：
本发明的第一方面中，提供了式(I)化合物：
Figure PCTCN2018108707-appb-000002
其中，
R 1、R 2、R 3、R 4、R 6、R 7和R 8是氢；
X 2、X 3、X 4和X 5是CH 3；
R 5选自氢或氘；
X 1选自CH 3或CD 3；
条件是如果X 1是CH 3，那么R 5是氘；
或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体 实施方案中，本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。
在另一方面，本发明提供了一种如上所述的药物组合物的制备方法，包括以下步骤：将药学上可接受的赋形剂与本发明化合物进行混合，从而形成药物组合物。
在另一方面，本发明提供了在需要其的受试者中治疗和/或PPARα和/或PPARδ导致的疾病相关病症的方法，所述方法包括给予受试者有效量的本发明化合物。在具体实施方案中，所述PPARα和/或PPARδ导致的疾病选自：涉及肝脏细胞的病理破坏、炎症、退化和/或增殖的任何急性或慢性肝病(包括脂肪性肝病、肝纤维变形、非酒精性脂肪性肝炎、原发性胆汁性肝硬化或酒精性肝病)、与代谢综合症相关的并发症、胰岛素抵抗、糖尿病、血脂异常、动脉粥样硬化、心血管疾病、肥胖症、高血压、炎性疾病、纤维化疾病(包括肺纤维化、特发性肺纤维化、囊性纤维化、心内膜心肌纤维化、纵膈纤维化、骨髓纤维化、腹膜后纤维化、进行性大块纤维化、肾源性系统化纤维化、克罗恩病、陈旧性心肌梗塞、硬皮病/系统性硬化症、关节纤维化或粘连性囊炎)、神经变形疾病或者癌症(包括肾细胞癌、胃肠道间质瘤(GIST)、胃癌、肝癌、与神经纤维瘤相关的脑膜瘤、胰腺神经内分泌肿瘤、胰腺外分泌肿瘤、白血病、骨髓增殖性/骨髓增生异常疾病、肥大细胞增多症、皮肤纤维肉瘤、包括乳腺癌、肺癌、甲状腺癌或结直肠癌的实体癌、或前列腺癌)等。在具体实施方案中，口服、皮下、静脉内或肌肉类给药所述化合物。在具体实施方案中，长期给药所述化合物。
具体实施方式
定义
如本文中所用的术语“氘代”指化合物或基团中的一个或多个氢被氘所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
“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。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H， 3H， 13C， 14C， 15N， 17O， 18O， 31P， 32P， 35S， 18F以及 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易，是同位素中的首选。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的 试剂，用示例中的方案可以制备。
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。
如本文所用，术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和无机和有机碱的盐。药学上可接受的无毒的酸加成盐的实例是与无机酸形成的盐，例如盐酸、氢溴酸、磷酸、硫酸和高氯酸，或与有机酸形成的盐，例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸。也包括使用本领域常规方法形成的盐，例如，离子交换方法。其它药学上可接受的盐包括：已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐，等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N +(C 1-4烷基) 4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐，等等。如果合适的话，其它的药学上可接受的盐包括与反离子形成的无毒的铵盐、季铵盐和胺阳离子，反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
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”指本发明化合物与水进行配位形成的配合物。
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种“立体异构体”形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
术语“前药”包括其本身可以是具有生物活性的或非活性的，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(但不限于)所属化合物的羧酸酯、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。
如本文所用，术语“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在另一些实施方案中，受试者是非人动物。
“疾病”、“障碍”和“病症”在本文中可以互换地使用。
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括受试者开始患有具体疾病、障碍或疾病之前发生的作用(“预防性治疗”)。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药物动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗和预防性治疗有效量。
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗有益处的数量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化。化合物的治疗有效量是指单独使用或与其他疗法联用的治疗剂的数量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其他治疗剂的治疗效能的数量。
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的数量，或足以预防与疾病、障碍或病症有关的一或多种症状的数量，或防止疾病、障碍或病症复发的数量。化合物的预防有效量是指单独使用或与其它药剂联用的治疗剂的数量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的数量，或增强其它预防药剂的预防效能的数量。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如，本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药，或与另一治疗剂一起呈单一单位剂型同时给药。
化合物
本发明提供式(I)化合物，或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体：
Figure PCTCN2018108707-appb-000003
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8各自独立地是自氢或氘；
X 1、X 2、X 3、X 4和X 5各自独立地是CH 3、CH 2D、CHD 2或CD 3；
条件是如果X 1、X 2、X 3、X 4和X 5每个都是CH 3，那么R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8中的至少一个是氘。作为本发明的优选实施方案，式(I)中化合物至少含有一个氘原子，更加地一个氘原子，更佳地二个氘原子，更佳地三个氘原子，更佳地四个氘原子，更佳地六个氘原子，更佳地七个氘原子，更佳地九个氘原子。
作为本发明的优选实施方案，氘在氘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％。
具体地说，在本发明中R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、X 1、X 2、X 3、X 4和X 5，各氘代位置中氘同位素含量至少是5％，较佳地大于10％，更佳地大于15％，更佳地大于20％，更佳地大于25％，更佳地大于30％，更佳地大于35％，更佳地大于40％，更佳地大于45％，更佳地大于50％，更佳地大于55％，更佳地大于60％，更佳地大于65％，更佳地大于70％，更佳地大于75％，更佳地大于80％，更佳地大于85％，更佳地大于90％，更佳地大于95％，更佳地大于99％。
在另一具体实施方案中，式(I)中化合物的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、X 1、X 2、X 3、X 4和X 5，至少其中一个含氘，更佳地两个含氘，更佳地三个含氘，更佳地四个含氘，更佳地五个含氘，更佳地六个含氘，更佳地七个含氘，更佳地八个含氘，更佳地九个含氘，更佳地十个含氘，更佳地十一个含氘，更佳地十二个含氘，更佳地十三个含氘，更佳地十四个含氘，更佳地十五个含氘，更佳地十六个含氘，更佳地十七个含氘，更佳地十八个含氘，更佳地十九个含氘，更佳地二十个含氘，更佳地二十一个含氘、更加地二十二个含氘，更佳地二十三个含氘。具体而言，式(I)中化 合物至少含有一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个、十五个、十六个、十七个、十八个、十九个、二十个、二十一个、二十二个、二十三个氘原子。
作为本发明的优选实施方案，R 1、R 2、R 3或R 4各自独立地是自氢或氘。
在另一优选实施方案中，R 1是氘。
在另一优选实施方案中，R 2是氘。
在另一优选实施方案中，R 3是氘。
在另一优选实施方案中，R 4是氘。
在另一优选实施方案中，R 1和R 2是氘。
在另一优选实施方案中，R 3和R 4是氘。
在另一优选实施方案中，R 1、R 2、R 3和R 4是氘。
作为本发明的优选实施方案，R 5或R 6各自独立地是自氢或氘。
在另一优选实施方案中，R 5是氘。
在另一优选实施方案中，R 6是氘。
在另一优选实施方案中，R 5和R 6是氘。
作为本发明的优选实施方案，R 7或R 8各自独立地是自氢或氘。
在另一优选实施方案中，R 7是氘。
在另一优选实施方案中，R 8是氘。
在另一优选实施方案中，R 7和R 8是氘。
作为本发明的优选实施方案，X 1、X 2、X 3、X 4和X 5各自独立的是CH 3、CH 2D、CHD 2或CD 3。
在另一优选实施方案中，X 1是CD 3。
在另一优选实施方案中，X 2和X 3是CD 3。
在另一优选实施方案中，X 4和X 5是CD 3。
在优选实施方案中，本发明涉及式(I)化合物，或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体：
Figure PCTCN2018108707-appb-000004
Figure PCTCN2018108707-appb-000005
其中，
R 1、R 2、R 3、R 4、R 6、R 7和R 8是氢；
X 2、X 3、X 4和X 5是CH 3；
R 5选自氢或氘；
X 1选自CH 3或CD 3；
条件是如果X 1是CH 3，那么R 5是氘。
在一个具体实施方案中，R 1、R 2、R 3、R 4、R 6、R 7和R 8是氢，X 2、X 3、X 4和X 5是CH 3，R 5是氘，X 1选自CH 3或CD 3。
在一个具体实施方案中，R 1、R 2、R 3、R 4、R 6、R 7和R 8是氢，X 2、X 3、X 4和X 5是CH 3，X 1是CD 3，R 5选自氢或氘。
作为本发明的优选实施方案中，所述化合物选自下组化合物或其药学上可接受的盐：
Figure PCTCN2018108707-appb-000006
Figure PCTCN2018108707-appb-000007
作为本发明的更优选实施方案中，所述化合物选自：
Figure PCTCN2018108707-appb-000008
在另一优选实施方案中，所述化合物不包括非氘代化合物。
药物组合物和施用方法
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。
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。
“药学上可接受的赋形剂”是指不会破坏一起调配的化合物的药理学活性的无毒载体、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载体、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
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)填料或增溶剂，例如，淀粉、乳糖、蔗糖、葡萄糖、干露醇和硅酸；(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，如肠衣和其他本领域公知的材料。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释放剂，如水或其他溶剂，增溶剂和乳化剂，例如，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扥。
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、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。
本发明化合物和组合物可以单独给药，或可以有利地与目前市场上可获得的或正在开发的用于治疗代谢性和/或肝脏疾患的其他治疗药剂联合给药，所述药剂例如二甲双孤、胰岛素、噻唑烷二酮类、格列酮类、他汀类、胆固醇抑制剂和/或其他降脂药物。
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。
治疗疾病的方法
本发明提供了在需要其的受试者中治疗和/或PPARα和/或PPARδ导致的疾病相关病症的方法，它包括步骤：给需要治疗的受试者给药本发明化合物，或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素衍生物，或给药本发明所述的药物组合物。
本发明化合物可用于治疗PPARα和/或PPARδ导致的疾病选自：涉及肝脏细胞的病理破坏、炎症、退化和/或增殖的任何急性或慢性肝病，与代谢综合症相关的并发症、胰岛素抵抗、糖尿病、血脂异常、动脉粥样硬化、心血管疾病、肥胖症、高血压、炎性疾病、纤维化疾病、神经变形疾病或者癌症。
具体来说，本发明化合物可用于治疗的涉及肝脏细胞的病理破坏、炎症、退化和/或增殖的任 何急性或慢性肝病是肝纤维变形、肝硬化或其中肝细胞损伤、改变或坏死的一些标志物的血浆水平与正常血浆水平相比时升高的任何其他肝脏疾病。这些与肝脏活动和状态相关的生物化学标志物可以选自在文献中所公开的，特别是丙氨酸转氨酶(ALAT)、天冬氨酸转氨酶(ASAT)、碱性磷酸酶(AP)、γ-谷氨酰基转肽酶(GGT)、细胞角蛋白-18(CK-18)或抵抗素。在特定实施方案中，肝脏疾病是脂肪性肝病，其中一种或多种这些标志物的升高与肝脏中或多或少显著的脂肪变性相关，这可以通过肝组织活检证实。脂肪性肝病的非穷举姓名单包括非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)和与诸如肝炎或代谢综合症(肥胖症、胰岛素抗性、高甘油三酯血症等)的疾患相关的脂肪性肝病。在特定实施方案中，肝脏疾病是原发性胆汁性肝硬化。
本发明化合物可治疗的纤维化疾病包括但不限于：肺纤维化、特发性肺纤维化、囊性纤维化、心内膜心肌纤维化、纵膈纤维化、骨髓纤维化、腹膜后纤维化、进行性大块纤维化、肾源性系统化纤维化、克罗恩病、陈旧性心肌梗塞、硬皮病/系统性硬化症、关节纤维化或粘连性囊炎。
本发明化合物可治疗的癌症包括但不限于：肾细胞癌、胃肠道间质瘤(GIST)、胃癌、肝癌、与神经纤维瘤相关的脑膜瘤、胰腺神经内分泌肿瘤、胰腺外分泌肿瘤、白血病、骨髓增殖性/骨髓增生异常疾病、肥大细胞增多症、皮肤纤维肉瘤、包括乳腺癌、肺癌、甲状腺癌或结直肠癌的实体癌、或前列腺癌。
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。本发明的优点包括：第一，采用本发明技术方案的化合物和组合物为肝脏疾患，特别是脂肪性肝病包括NAFLD和NASH的治疗提供了更有利的治疗工具。第二，改进了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。第三，提高了化合物在动物体内的药物浓度，提高了药物疗效。第四，抑制了某些代谢产物，提高化合物的安全性。
实施例
下面结合具体实施例，作进一步阐述本发明。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。
本文所用的缩写具有以下含义：
TsOMe：对甲苯磺酸甲酯
HCl：氯化氢
i-PrOH：异丙醇
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℃～100℃，优选0℃～80℃)下进行。反应时间通常为0.1-60小时，优选地为0.5-24小时。
实施例1  (E)-1-(4-((甲基-d 3)硫基)苯基)-3-(3,5-二甲基-4-羧基二甲基甲氧基苯基)丙-2-烯-1-酮 (化合物T-1)的制备。
Figure PCTCN2018108707-appb-000009
具体合成步骤如下：
Figure PCTCN2018108707-appb-000010
步骤1 化合物3的合成。
依次往配有磁力搅拌的100mL单口烧瓶中加入化合物1(3.0g，20mmol)和乙腈(20mL)，搅拌溶清，加入化合物2(8.96g，40mmol)和碳酸铯(Cs 2CO 3，13g，40mmol)，反应混合物N 2氛下加热回流4小时。冷却到室温，加入乙酸乙酯(30mL)，过滤，滤液浓缩，残留物经硅胶柱分离得白色固体980mg，收率16.8％。LC-MS(APCI):m/z＝291(M-1) -. 1H NMR(300MHz,DMSO-d 6)δ9.87(s,1H),7.59(s,2H),2.24(s,6H),1.45(s,9H),1.39(s,6H).
步骤2 化合物5的合成。
依次往配有磁力搅拌的100mL单口烧瓶中加入化合物4(3.0g，20mmol)和乙腈(20mL)，搅拌溶清，加入TsOMe-d 3(4.5g，24mmol)和碳酸钾(3.3g，24mmol)，N 2氛下室温搅拌反应过夜。加入乙酸乙酯(30mL)，过滤，滤液浓缩，经硅胶柱分离得白色固体2.1g，收率60.2％。 1H NMR(300MHz,CDCl 3)δ7.86(d,J＝6.6Hz,2H),7.26(d,J＝6.6Hz,2H),2.53(s,3H).
步骤3 化合物T-1的合成。
依次往配有磁力搅拌的25mL单口烧瓶中加入化合物5(85mg，0.5mmol)、化合物3(146mg， 0.5mmol)和HCl的i-PrOH溶液(4mL，5M)，反应液N 2氛下室温搅拌反应4小时。减压浓缩，经硅胶柱分离得白色固体86mg，收率44％。LC-MS(APCI):m/z＝386(M-1) -. 1H NMR(300MHz,DMSO-d 6)δ12.91(br s,1H),8.09(d,J＝6.3Hz,2H),7.81(d,J＝12Hz,1H),7.61(d,J＝11.7Hz,1H),7.56(s,2H),7.39(d,J＝6.3Hz,2H),2.22(s,6H),1.39(s,6H).
实施例2 (E)-1-(4-(甲基硫基)苯基)-3-(3,5-二甲基-4-羧基二甲基甲氧基苯基)丙-2-烯-1-酮-2-d (化合物T-2)的制备。
Figure PCTCN2018108707-appb-000011
具体合成步骤如下：
Figure PCTCN2018108707-appb-000012
步骤1 化合物7的合成。
依次往配有磁力搅拌的100mL单口烧瓶中加入化合物6(2.0g，12.0mmol)、二氧六环(20mL)和重水(20mL)，搅拌溶清，加入四氢吡咯(pyrrolidine，86mg，1.2mmol)，N 2氛下室温搅拌反应过夜。加入乙酸乙酯(20mL)，分层，水相乙酸乙酯萃取(15mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得白色固体1.8g，收率90％。 1H NMR(300MHz,CDCl 3)δ7.86(d,J＝6.6Hz,2H),7.26(d,J＝6.6Hz,2H),2.57(s,3H).
步骤2 化合物8的合成。
依次往配有磁力搅拌的25mL单口烧瓶中加入化合物7(85mg，0.5mmol)、化合物3(146mg，0.5mmol)和EtOD(3mL)，搅拌溶清，滴加入NaOD的重水溶液(50mg，0.5mmol，40％质量分数)，滴毕，N 2氛下室温搅拌反应过夜。浓缩，经硅胶柱分离得白色固体106mg，收率48％。 1H  NMR(300MHz,DMSO-d 6)δ8.09(d,J＝6Hz,2H),7.61(s,1H),7.56(s,2H),7.40(d,J＝6.3Hz,2H),2.56(s,3H),2.21(s,6H),1.45(s,9H),1.38(s,6H).
步骤3 化合物T-2的合成。
依次往配有磁力搅拌的25mL单口烧瓶中加入化合物8(106mg，0.24mmol)和二氯甲烷(5mL)，搅拌溶清，滴加入三氟醋酸(TFA,1mL)，N 2氛下室温搅拌反应1小时。浓缩，经硅胶柱分离得白色固体71mg，收率77％。 1H NMR(300MHz,DMSO-d 6)δ12.92(br s,1H),8.07(d,J＝6.3Hz,2H),7.59(s,1H),7.54(s,2H),7.38(d,J＝6.3Hz,2H),2.54(s,3H),2.20(s,6H),1.37(s,6H).
实施例3 (E)-1-(4-((甲基-d 3)硫基)苯基)-3-(3,5-二甲基-4-羧基二甲基甲氧基苯基)丙-2-烯-1-酮 -2-d(化合物T-3)的制备。
Figure PCTCN2018108707-appb-000013
具体合成步骤如下：
Figure PCTCN2018108707-appb-000014
步骤1 化合物9的合成。
依次往配有磁力搅拌的100mL单口烧瓶中加入化合物5(2.0g，12.0mmol)、二氧六环(20mL)和重水(20mL)，搅拌溶清，加入四氢吡咯(86mg，1.2mmol)，N 2氛下室温搅拌反应过夜。加入乙酸乙酯(20mL)，分层，水相乙酸乙酯萃取(15mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离得白色固体1.8g，收率90％。 1H NMR(300MHz,CDCl 3)δ7.86(d,J＝6.6Hz,2H),7.26(d,J＝6.6Hz,2H).
步骤2 化合物10的合成。
依次往配有磁力搅拌的25mL单口烧瓶中加入化合物9(85mg，0.5mmol)、化合物3(146mg， 0.5mmol)和EtOD(3mL)，搅拌溶清，滴加入NaOD重水溶液(50mg，0.5mmol，40％质量分数)，滴毕，N 2氛下室温搅拌反应过夜。浓缩，经硅胶柱分离得白色固体106mg，收率48％。 1H NMR(300MHz,DMSO-d 6)δ8.09(d,J＝6Hz,2H),7.61(s,1H),7.56(s,2H),7.40(d,J＝6.3Hz,2H),2.21(s,6H),1.45(s,9H),1.38(s,6H).
步骤3 化合物T-3的合成。
依次往配有磁力搅拌的25mL单口烧瓶中加入化合物10(106mg，0.24mmol)和二氯甲烷(5mL)，搅拌溶清，滴加入三氟醋酸(1mL)，N 2氛下室温搅拌反应1小时。浓缩，经硅胶柱分离得白色固体71mg，收率77％。 1H NMR(300MHz,DMSO-d 6)δ12.92(br s,1H),8.07(d,J＝6.3Hz,2H),7.59(s,1H),7.54(s,2H),7.38(d,J＝6.3Hz,2H),2.20(s,6H),1.37(s,6H).
生物活性测试。
(1)化合物对PPARα/γ的激动活性评价
PPAR的活化试验是在体外、在RK13成纤维细胞系中进行，测定的是由酵母ga14转录因子的DNA结合功能区和不同PPAR的配体结合功能区组成的嵌合体的转录活性。然后，根据以下方法在细胞系中证实后面的这些结果：
以RK13细胞为例：
a.培养方法：
RK13细胞来自于BCACC(porton Down，UK)，并在补充有10％(V/V)胎牛血清，100U/ml青霉素(Gibco，Paisley，UK)和2mM L-谷氨酸盐(Gibco，Paisley，UK)的DMEM介质中生长，培养介质每隔一天更换一次。细胞保存在37℃下，保存在湿润的95％空气/5％CO 2的气氛中。
b.用于转染的质体的描述
Raspe，Madsen等人对质体pG5TkpGL3、pRL-CMV、pGa14-hPPPARα、pGa14-hPPPARγ和pGa14-φ已经有过描述(1999)。pGa14-hPPPARα和pGa14-hPPPARγ的构造是通过克隆到PCR-放大的DNA片段的pGa14-φ矢量得到的，其中所述DNA片段相当于人体PPPARα和PPPARγ核受体的DEF功能区。
c.转染
将RK13细胞种在24孔培养皿中，每孔5x10 4个细胞，用所述质体pG5TkpGL3(50ng/孔)、表达载体pGa14-φ、pGa14-mPPPARα、pGa14-hPPPARα、pGa14-hPPPARγ(100ng/孔)以及转染率控制矢量pRL-CMV(1ng/孔)转染2小时，然后用试验化合物孵化36小时。当实验结束时，将 细胞溶解(Gibco，Paisley，UK)，用Dual-Luciferase TM Reporter Assay System试剂盒(Promega，Madison，WLUSA)，根据供应商的说明书，如先前描述的那样测定荧光素酶活性。然后用Bio-Rad Protein Assay(Bio-Rad，Munich，Germany)，根据供应商的指导，测定细胞提取物额蛋白质含量。
在上述实验中测试了本发明化合物和未经氘代的化合物Elafibranor，发现用本发明化合物处理并用pGa14-hPPPARα和pGa14-hPPPARγ质体转染的细胞中，荧光素酶活性增加。所述荧光素酶活性的诱发表明了本发明的化合物是PPARα和PPPARγ激动剂，甚至具有比未氘代化合物Elafibranor更强的活性。
(2)代谢稳定性评价
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；大鼠肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的实施例化合物的粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的150mL的0.5M磷酸二氢钾和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL 0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生系统溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液，启动反应，开始计时。相应化合物的 反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS系统检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t 1/2和CL int，其中V/M即等于1/蛋白浓度。
Figure PCTCN2018108707-appb-000015
对本发明化合物及其没有氘代的化合物Elafibranor同时测验比较，评价其在人和大鼠肝微粒体的代谢稳定性。作为代谢稳定性的指标的半衰期及肝固有清除率如表1所示。表1中采用未经氘代的化合物Elafibranor作为对照品。在人和大鼠肝微粒体实验中，通过与未经氘代的化合物Elafibranor相比，本发明化合物可以明显改善代谢稳定性。
表1：
Figure PCTCN2018108707-appb-000016
(3)大鼠药代动力学实验
6只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组3只，经静脉或口服单个剂量的化合物(口服10mg/kg)，比较其药代动力学差异。
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PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入乙醚后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素盐溶液。使用前，试管于60℃烘干过夜。在最后一个时间点血样采集完成之后，大鼠乙醚麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆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进计算。
实验表明，本发明化合物在动物体内具有更好的药代动力学性质，因此具有更好的药效学和治理效果。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (10)

  1. 式(I)的化合物，或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体：
    Figure PCTCN2018108707-appb-100001
    其中，
    R 1、R 2、R 3、R 4、R 6、R 7和R 8是自氢；
    X 2、X 3、X 4和X 5是CH 3；
    R 5选自氢或氘；
    X 1选自CH 3或CD 3；
    条件是如果X 1是CH 3，那么R 5是氘。
  2. 根据权利要求1所述的化合物，其中R 5是氘。
  3. 根据权利要求1或2所述的化合物，其中X 1是CD 3。
  4. 化合物选自：
    Figure PCTCN2018108707-appb-100002
    Figure PCTCN2018108707-appb-100003
  5. 一种药物组合物，其含有药学上可接受的赋形剂和如权利要求1～4中任一项所述的式(I)的化合物，或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体。
  6. 制备权利要求1～4中任一项所述的式(I)的化合物，或其药学上可接受的盐、多晶型、互变异构体、立体异构体、水合物、溶剂化合物或同位素变体，或权利要求5所述的药物组合物用于治疗和/或预防由PPARα和/或PPARδ导致的疾病的药物的方法。
  7. 根据权利要求6所述的方法，其中所述疾病为涉及肝脏细胞的病理破坏、炎症、退化和/或增殖的任何急性或慢性肝病、与代谢综合症相关的并发症、胰岛素抵抗、糖尿病、血脂异常、动脉粥样硬化、心血管疾病、肥胖症、高血压、炎性疾病、纤维化疾病、神经变形疾病或者癌症。
  8. 根据权利要求7所述的方法，其中所述肝病为脂肪性肝病、肝纤维变形、非酒精性脂肪性肝炎、原发性胆汁性肝硬化或酒精性肝病。
  9. 根据权利要求7所述的方法，其中纤维化疾病为肺纤维化、特发性肺纤维化、囊性纤维化、心内膜心肌纤维化、纵膈纤维化、骨髓纤维化、腹膜后纤维化、进行性大块纤维化、肾源性系统化纤维化、克罗恩病、陈旧性心肌梗塞、硬皮病/系统性硬化症、关节纤维化或粘连性囊炎。
  10. 根据权利要求7所述的方法，其中癌症为肾细胞癌、胃肠道间质瘤(GIST)、胃癌、肝癌、与神经纤维瘤相关的脑膜瘤、胰腺神经内分泌肿瘤、胰腺外分泌肿瘤、白血病、骨髓增殖性/骨髓增生异常疾病、肥大细胞增多症、皮肤纤维肉瘤、包括乳腺癌、肺癌、甲状腺癌或结直肠癌的实体癌、或前列腺癌。
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