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WO2008110062A1 - Composés présentant une activité agoniste partielle de ppar et leur application - Google Patents

Composés présentant une activité agoniste partielle de ppar et leur application Download PDF

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Publication number
WO2008110062A1
WO2008110062A1 PCT/CN2008/000441 CN2008000441W WO2008110062A1 WO 2008110062 A1 WO2008110062 A1 WO 2008110062A1 CN 2008000441 W CN2008000441 W CN 2008000441W WO 2008110062 A1 WO2008110062 A1 WO 2008110062A1
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Prior art keywords
compound
methyl
butyl
chloro
imidazole
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PCT/CN2008/000441
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English (en)
Chinese (zh)
Inventor
Jianhui Guo
Yong Jiang
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Shanghai Allist Pharmaceuticals Inc
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Shanghai Allist Pharmaceuticals Inc
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Priority to CN200880007518A priority Critical patent/CN101627030A/zh
Publication of WO2008110062A1 publication Critical patent/WO2008110062A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/68—Halogen atoms

Definitions

  • the present invention relates to a compound having PPAR gamma partial agonist activity, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition comprising the same or a pharmaceutically acceptable salt thereof, and the preparation thereof for use in therapy and/or Use in drugs that prevent PPAR gamma receptor-related diseases, such as diabetes, elevated blood sugar abnormalities, metabolic syndrome, or obesity.
  • Background technique a compound having PPAR gamma partial agonist activity, or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition comprising the same or a pharmaceutically acceptable salt thereof, and the preparation thereof for use in therapy and/or Use in drugs that prevent PPAR gamma receptor-related diseases, such as diabetes, elevated blood sugar abnormalities, metabolic syndrome, or obesity.
  • Diabetes is a disease caused by a variety of genetic disorders that affect human health on a global scale. Diabetes can be divided into two types: (1) Type I diabetes or insulin-dependent diabetes mellitus (IDDM), in which patients have little or no insulin secretion, patients must be injected with insulin daily; (2) Type II diabetes or non-insulin dependence Type 2 diabetes mellitus (MDDM), the level of plasma insulin in patients with type II diabetes is basically the same as that of normal people, mainly due to the decreased sensitivity of insulin and the abnormal function of insulin, which leads to the relative deficiency of insulin, which further affects the sugar and fat in insulin-sensitive tissues. Metabolism in muscle, liver and adipose tissue. The incidence of sputum diabetes is high, accounting for about 90% of diabetic patients.
  • IDDM insulin-dependent diabetes mellitus
  • MDDM non-insulin dependence
  • PPAR peroxisome proliferators-activated receptor
  • PPAR belongs to a member of the ligand-activated transcription factor-nuclear hormone receptor superfamily, which forms a heterodimer with the retinoic acid X receptor (RXR) and is activated by binding to a hormone response element on the target gene. gene expression.
  • RXR retinoic acid X receptor
  • PPAR/RXR heterodimers play an important role in controlling cellular lipid homeostasis and adipocyte differentiation.
  • Mammalian PPAR can be divided into three subtypes, namely PPARa, PPAR ⁇ and PPAR ⁇ .
  • PPAR ⁇ plays an important role in the regulation and expression of adipose tissue-related genes, and is also an important regulator of glucose and lipid metabolism target genes.
  • PPARa stimulates the proliferation of peroxidase, accelerates the oxidation of fatty acids, and thus reduces the fatty acid content in the blood.
  • PPARa agonists such as fibrate derivatives (Fibrates) can be used to treat dyslipidemia.
  • Oral hypoglycemic drugs currently on the market mainly include five major categories, namely sulfonylureas, biguanides, alpha-glucose formulations, Thiazolidinediones (TZD) and potassium channel blockers.
  • TZD Thiazolidinediones
  • Recently developed TZD compounds are novel insulin sensitizers that target PPAR ⁇ , which can improve the body's sensitivity to insulin, thereby correcting abnormal glucose metabolism and reducing high glucose toxicity.
  • rosiglitazone Rosiglitazone, Avandia
  • pioglitazone pioglitazone, Attenin, Actos
  • patient weight gain edema
  • adipose tissue ablation edema
  • bone marrow fatty acid changes during clinical application
  • TZD drugs modulate the differentiation of fat cells by activating PPARy to increase the sensitivity of insulin, which can also aggravate the body's fat storage and cause side effects such as weight gain.
  • a partial agonist generally has a certain affinity, but its intrinsic activity is low, and it can only produce a weak effect when combined with a receptor. Even if the concentration is increased, it cannot reach the maximum of a full agonist. effect. However, the presence of a high concentration of a partial agonist will occupy the receptor and antagonize the action of a full agonist.
  • Metabolda's oral hypoglycemic agent Metaglidasen has a different chemical structure than the rosiglitazone. Studies have shown that MeUglidasen is a PPARy partial agonist that selectively modulates genes that improve insulin sensitivity without activating genes that increase weight and fluid retention.
  • W09402467 discloses a series of imidazole ether compounds having an activity of an angiotensin II (AT II ) receptor antagonist. Summary of invention
  • the technical problem to be solved by the present invention is to provide a novel compound having a PPAR gamma partial agonist activity (structure I as follows) or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, or a pharmaceutically acceptable compound thereof
  • a composition of a salt and its use in the preparation of a disease associated with the treatment and/or prevention of a PPAR gamma receptor such as diabetes, a disease associated with elevated blood glucose abnormalities, metabolic syndrome or obesity.
  • halogen selected from halogen, dC 4 alkyl, halogen-substituted d-C 4 alkyl, dC 4 alkoxy, C 3 -C 7 cycloalkyl, hydroxy, cyano, C,-C 4 alkoxycarbonyl,
  • n 1 ⁇ 5, and is an integer.
  • the compound according to claim 1 which is selected from the group consisting of halogen, C, -C 4 alkyl, halogen-substituted d-C 4 alkyl and cyano.
  • R is selected from the group consisting of halogen, a group and a halogen-substituted ⁇ ,-C 4 alkyl group.
  • a pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • composition of claim 10 further comprising one or more other hypoglycemic agents.
  • the other hypoglycemic agent is selected from the group consisting of a sulfonylurea, a biguanide, an alpha-glucosidase inhibitor, and a diketone, preferably the other hypoglycemic
  • the drug is selected from the group consisting of metobutyramide, glibenclamide, glipizide, phenformin, diterpene, diammonium, acarbose, miglitol, voglibose, rosiglitazone, and Pioglitazone.
  • composition according to claim 10 wherein the pharmaceutical composition is a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in an amount of from 0.6 mg to 12 g, preferably It is a unit dose of the drug of 0.6 mg to 6 g, more preferably 0.6 mg to 3 g.
  • the compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 10 to 13 for use in the preparation and/or prevention of PPAR The use of drugs for gamma receptor-related diseases.
  • the disease is selected from the group consisting of diabetes, a disease associated with abnormally elevated blood glucose, a lipid disorder, a metabolic syndrome, a cardiovascular disease, a coronary artery disease, hypercholesterolemia, and obesity.
  • a method of treating and/or preventing a PPAR gamma receptor-associated disease in a mammal comprising administering a therapeutically and/or prophylactically effective amount of a compound of any one of claims 1-8, or a pharmaceutically acceptable thereof
  • the salt or the pharmaceutical composition according to any one of claims 10 to 13 is administered to a mammal in need thereof.
  • the disease is selected from the group consisting of diabetes, a disease associated with abnormally elevated blood glucose, a lipid disorder, a metabolic syndrome, a cardiovascular disease, a coronary artery disease, hypercholesterolemia, and obesity.
  • halogen selected from halogen, C, -C 4 alkyl, halogen-substituted d-C 4 alkyl, C,-C 4 alkoxy C 3 - ( 7 -cycloalkyl, hydroxy, cyano, _( 4 alkoxy) a carbonyl group, an aromatic ring, and at least one a heteroaryl ring selected from the group consisting of N, S and 0 heteroatoms, preferably halogen, C, -alkyl, halogen substituted ( 4 alkyl or cyano;
  • n 1 ⁇ 5 and is an integer, preferably 1 or 2.
  • n 1, ⁇ is a 3- or 4-position substituent selected from the group consisting of halogen, C, -C 4 alkyl, halogen-substituted C, -C 4 alkyl and cyanide base.
  • halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine
  • C, -C 4 alkyl means a straight or branched alkyl group having 1 to 4 carbon atoms, such as a Base, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, propyl, isopropyl, most preferably methyl, ethyl;
  • - (: 4 alkoxy means an alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butyl Oxyl or tert-butoxy;
  • C 3 -C 7 cycloalkyl means cycloalkyl having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl,
  • pharmaceutically acceptable salts include acid addition salts and base addition salts.
  • Representative acid addition salts include hydrobromide, hydrochloride, sulfate, sulfite, phosphate, acetate, oxalate, valerate, oleate, palmitate, stearic acid Salt, laurate, borate, benzoate, lactate, citrate, maleate, fumarate, succinate, tartrate, benzoate, methanesulfonate, Gluconate, lactobionate, lauryl sulfonate, and the like.
  • Representative base addition salts include alkali metal cation salts, alkaline earth metal cation salts, and quaternary ammonium cations.
  • the compounds of the present invention may be selected from 2-butyl-4-chloro-1_ ⁇ [2'-tetrazole-5-yl)--biphenyl-4-yl]nonyl ⁇ - 5-[(4-fluorobenzyloxy)indolyl] 1#-imidazole;
  • R, n are as defined above; suitable solvents in step A include DMF, DMS 0, acetone or a mixed solvent thereof, and suitable bases include Na H, KOH, NaOH, Na NH 2 or a mixed base thereof; a suitable solvent in the step B includes methanol, ethanol, isopropanol, tetrahydrofuran, DMF, acetone or a mixed solvent thereof, and a suitable base includes NaOH, K0H, NaOE t purification, for example, by column chromatography. method.
  • the reaction shown in the step A may be at -10.
  • C is carried out at a reflux temperature, preferably a reaction temperature of 5 to 100 ° C, more preferably 20 to 80 ° C;
  • the reaction shown in step B is usually carried out under heating, preferably a reaction
  • the temperature is 4 (TC to reflux temperature, more preferably 50 °C to reflux temperature;
  • the reaction time of each reaction is usually not particularly limited, and those skilled in the art can easily determine the reaction time by means of techniques conventional in the art.
  • the reaction endpoint is monitored, for example, by TLC.
  • a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be administered to a mammal (e.g., a human) and can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, etc., with oral administration being most preferred.
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a mammal (e.g., a human) in need of treatment and/or prevention.
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a mammal (e.g., a human) in need of treatment and/or prevention.
  • therapeutic and/or prophylactically effective amount means sufficient to feed The amount of active compound in a mammal, such as a human, that causes a biological or medical response as sought by a veterinarian or clinician.
  • An exemplary physician, veterinarian, and clinician can readily determine the effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, required to treat and/or prevent a given condition.
  • it is 0. 01 ⁇ 200 mg / kg patient body weight per day, preferably 0. 01 ⁇ 1 00 mg / kg patient body weight, preferably 0. 01 ⁇ 50 mg / kg patient weight per day.
  • 6mg ⁇ 3 ⁇ The specific dose of 0. 6mg ⁇ 1 2 g, preferably 0. 6mg ⁇ 6g, preferably 0. 6mg ⁇ 3g.
  • the specific dose should also take into account the route of administration, the age, sex, weight and health of the patient, as well as the specific condition being treated, which are within the skill of the skilled physician.
  • the term "mammal" as used herein includes, but is not limited to, cats, dogs, rabbits, goats, sheep, rats, mice, humans, and the like, with humans being particularly preferred.
  • the pharmaceutical composition may be formulated as a solid dosage form for oral administration, including capsules, tablets, pills, powders, granules and the like.
  • the solid dosage form usually contains 0. 5 ⁇ 50 ° /.
  • the active ingredient preferably contains from 1 to 25% of the active ingredient.
  • the compounds provided herein, or a pharmaceutically acceptable salt thereof may be admixed with at least one conventional inert excipient (or carrier) including, but not limited to: (a) Fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose And gum arabic; (c) humectants, for example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch, tapioca, alginic acid, certain complex silicates, polyvinylpolypyrrolidone and Sodium carbonate; (e) a slow solvent such as paraffin; (f) an absorption accelerator, for example, a quaternary amine compound; (g) a wetting agent such as cetyl alcohol and glyce
  • Solid dosage forms such as tablets, 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 in such compositions may be released in a portion of the digestive tract in a delayed manner. If necessary, the active compound may also form a microcapsule form with one or more of the above excipients.
  • compositions may also be formulated in liquid dosage forms for oral administration, including pharmaceutically acceptable emulsions, solutions, suspensions or elixirs, and the like.
  • liquid dosage form may comprise a conventional hydrazine in the art.
  • An inert diluent such as water or other solvent, solubilizer and emulsifier, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimercaptoamide or vegetable oil , especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil or sesame oil, or a mixture of these substances.
  • the compositions may contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavorings or flavors, or suitable mixtures thereof.
  • the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, poly Oxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar, or a mixture of these, and the like.
  • a suspending agent for example, ethoxylated isostearyl alcohol, poly Oxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar, or a mixture of these, and the like.
  • the pharmaceutical composition may be formulated for parenteral injection, including physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and for reconstitution into sterile injectable solutions or A sterile powder of the dispersion.
  • Aqueous or non-aqueous vehicles, diluents, solvents or excipients can be employed in the preparation of such sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions.
  • Suitable aqueous or nonaqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols, or suitable mixtures thereof and the like.
  • compositions may be formulated in a dosage form for topical administration, including ointments, powders, patches, propellants, and inhalants.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof, can be combined under sterile conditions with physiologically acceptable carriers and any preservatives, buffers, or propellants which may be required if necessary.
  • the pharmaceutical composition may also include other pharmaceutically acceptable therapeutic agents, especially other hypoglycemic agents.
  • the other hypoglycemic agents include, but are not limited to, sulfonylureas such as metobutyramide, glibenclamide, glipizide, etc.; biguanide drugs such as phenformin, diterpene, diterpene, etc., alpha- Glucosidase inhibitors such as acarbose, miglitol, voglibose, etc.; thiazolidine diones (TZD) drugs such as rosiglitazone, pioglitazone and the like.
  • sulfonylureas such as metobutyramide, glibenclamide, glipizide, etc.
  • biguanide drugs such as phenformin, diterpene, diterpene, etc., alpha- Glucosidase inhibitors such as acarbos
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, can be used for the preparation of a PPAR ⁇ -related therapeutic and/or prophylactic Diseased drugs, especially those associated with RXR and PPAR nuclear receptor regulation.
  • the disease is selected from the group consisting of diabetes, diseases associated with abnormal blood glucose elevation, lipid disorders, metabolic syndrome, cardiovascular disease, coronary artery disease, hypercholesterolemia, and obesity, particularly diseases associated with elevated diabetes and abnormal blood glucose.
  • Degree of agonistic activity a preferred method of evaluation is described as follows:
  • a reporter model was used to activate the transcription of downstream genes after activation of nuclear receptors.
  • a screening model for screening nuclear receptor activators in living cells was designed to verify the activity of compounds to activate PPARy. .
  • the experimental method is as follows: The RT-PCR method (reverse transcription (RT) and cDNA polymerase chain amplification (PCR) combined technique) was cloned from adipose tissue into PPARy full-length cDNA, and the amplified PCR product was obtained. The expression vector pcDNA3.1 was inserted and sequenced.
  • the reporter gene was constructed using Promega's luciferase assay vector pGL3 - Promoter. The transfection experiments were carried out in 96-well plates using U20S cells.
  • the RXR and PPARy genes were co-transfected at the same time as the transfection of the reporter gene, and the compound to be detected was added 24 hours after the transfection, and the final concentration of the solvent DMS0 was maintained at 0.1%. After 24 hours of compound action, the cells were lysed and tested for luciferase activity. The intensity of activation of the nuclear receptor by the compound can be known by observing the intensity of the luminescence. In order to correct the experimental error caused by factors such as transfection efficiency, cell inoculation amount and compound toxicity, GFP plasmid was also co-transfected as an internal reference. The luminescence values of all the test wells were corrected by GFP value in the analysis of the experimental results.
  • test results are expressed as relative activation multiples, and the solvent control has a value of 1, and a larger value indicates a higher activation ability.
  • the activation of the receptor at six different concentrations was observed, and the pharmacological properties of the compound were more comprehensively analyzed, and the concentration effect curve of the compound action was fitted by the iterative calculation according to the following formula. calculate the respective half-effective concentration (EC 50).
  • the compound provided by the present invention has a good hypoglycemic effect
  • a preferred experimental evaluation method is as follows: Healthy spontaneous type 2 diabetes animal model, male GK rat (Goto-Kakizaki rat), weighing 200 g The animals were fasted for 12 hours. The blood glucose meter measured the fasting blood glucose level, and then continued intragastric administration (20 mg/kg) or control solution 0.5% CMC-Na (carboxymethylcellulose sodium) (10 mL/kg). The fasting blood glucose level was measured again 10 days after the drug, and the hypoglycemic effect of the test compound was evaluated by comparing the fasting blood glucose values before and after administration.
  • the invention relates to a method of treating and/or preventing a PPARY receptor-associated disease in a mammal comprising administering a therapeutically and/or prophylactically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a a compound of the invention or a pharmaceutically acceptable compound thereof
  • the pharmaceutical composition of the salt is administered to a mammal in need of such treatment and/or prevention, preferably the disease is selected from the group consisting of diabetes, a disease associated with abnormal blood glucose elevation, a lipid disorder, a metabolic syndrome, a cardiovascular disease, a coronary artery disease, and a high Blood cholesterol and obesity, especially those associated with elevated levels of diabetes or abnormal blood sugar.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents. Administration, especially in combination with other diabetes treatment and/or prophylaxis drugs.
  • the therapeutic agents include, but are not limited to, sulfonylureas such as chlorpheniramine, glibenclamide, glipizide, and the like; biguanides such as phenformin, diterpene, diterpene, etc., (X-glucose) Glycosidase inhibitors such as acarbose, miglitol, voglibose, etc.; thiazolidinediones (TZD) drugs such as rosiglitazone, pioglitazone, etc.
  • sulfonylureas such as chlorpheniramine, glibenclamide, glipizide, and the like
  • biguanides such as phenformin, diterpene, diterpene, etc., (X-glucose) Glycosidase inhibitors such as acarbose, miglitol, voglibose, etc.
  • the main advantages of the present invention are:
  • the experiments demonstrate that the compounds provided by the present invention have PPAR Y partial agonist activity, retain the beneficial effects of hypoglycemia, and reduce the weight gain caused by the complete PPARy agonist, compared to the existing full PPARy agonist, Side effects of edema, adipose tissue ablation, changes in bone marrow fatty acids, etc.
  • the invention is further illustrated by the following examples, which are to be construed as illustrative only and not to limit the scope of the invention. Explain the specific conditions of the experimental method, usually in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. It is commercially available or can be readily prepared by those skilled in the art according to known literature methods.
  • DMF N,N-dimethylformamide
  • DMS0 dimercaptosulfoxide
  • PVPP polyvinylpolypyrrolidone
  • PVP polyvinylpyrrolidone
  • Step A 2-butyl-4-chloro-1-( ⁇ [2'-(1-triphenyl)-tetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl ⁇ - 5- [(4-Fluorobenzyloxy)methyl]-imidazole
  • Trityl hydrazine losartan (chemical name: 2-butyl 4-chloro-1- 1-[[2'-(1-triphenylmethyltetrazol-5-yl)-1, 1'- linkage Benz-4-yl]methyl ⁇ _5-hydroxymethylimidazole) (purchased from Zhejiang Tianyu Pharmaceutical Chemical Co., Ltd.) 665mg (lmmol) dissolved in 10mL DMF, added NaH (silver gray solid particles, content >60%, active Amount of hydrogen (purity) >97%) 44 mg, react at room temperature for half an hour, then add 122 ⁇ 4-fluorobenzyl bromide (1 mmol). Continue to react for 12h.
  • Step B 2-Butyl- 4-chloro- 1- ⁇ [2'-(1#-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl ⁇ - 5-[ (4-fluorobenzyloxy)methyl] -imidazole
  • Step A 2-butyl-4-chloro-1 - ⁇ [2'-(1-trityl-tetrazol-5-yl)-1,-biphenyl-4-yl]methyl ⁇ -5 - [(4-bromobenzyloxy)methyl]imidazole
  • Step A 2-butyl-4-chloro-1 - ⁇ [2'-(1-trityltetrazole-5-yl)- 1, V-biphenyl-4-yl]methyl ⁇ -5 -[(4-methylbenzyloxy)methyl] - I imidazole
  • Step B 2-Butyl- 4-chloro-1- ⁇ 2'-tetrazole-5-yl)-1,-biphenyl-4-yl]methyl ⁇ -5-[(4-mercaptobenzyl) Oxy)methyl]-imidazole
  • Step B 2-butyl-4-chloro-1-( ⁇ [2'-tetrazole-5-yl)- 1,1'-biphenyl-4-yl] fluorenyl ⁇ - 5- [(4-3 Fluoromethylbenzyloxy)indolyl] -imidazole
  • Step B 2-Butyl- 4-chloro- 1- ⁇ [2'-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl ⁇ _5_[(4-cyanobenzyl) Oxy)methyl] -imidazole
  • 122 ⁇ 3-fluorobenzyl bromide (1 mmol ) was used instead of 122 L 4-fluorobenzyl bromide to prepare the intermediate 2-butyl-4-chloro- 1- ⁇ [2'-( 1-triphenylsulfonyltetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl ⁇ - 5_[(3-fluorobenzyloxy)indolyl] - 1#-imidazole 620mg ( White powder), yield 80°/. .
  • Step B 2-Butyl-4-chloro- 1- ⁇ [2'-(1#-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl ⁇ - 5- [ (3-fluorobenzyloxy)methyl]imidazole
  • Step A 2-butyl-4-chloro-1_ ⁇ [2'-(1-trityl-tetrazol-5-yl)- 1, V-biphenyl-4-yl]fluorenyl ⁇ - 5 - [(3-Trifluoromethylbenzyloxy)methyl] -imidazole
  • Step B 2-Butyl-4-chloro-1- ⁇ [2'-tetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl ⁇ - 5_[(3-trifluoro Methylbenzyloxy)methyl]imidazole
  • Step B 2-butyl-4-chloro-1- ⁇ 2'-tetrazol-5-yl)-1,-biphenyl-4-yl]methyl ⁇ - 5- [(2, 5-di) Fluorobenzyloxy)indolyl] - 1 -imidazole
  • the intermediate 2-butyl-4 was obtained by the procedure shown in the procedure of Example 1, Step ⁇ , using 307 mg of 2,5-bis(trifluoromethyl)benzyl bromide (1 sec ol) instead of 122 L 4 -fluorobenzyl bromide.
  • Step B 2-butyl-4-chloro-1_ ⁇ [2'-(1#-tetrazole-5- Base)-1,1'-biphenyl-4-yl]methyl ⁇ - 5- ⁇ [2,5-bis(trifluoromethyl)benzyloxy]methyl ⁇ - 1 ⁇ -imidazole
  • the PPAR Y full-length cDNA was cloned from adipose tissue by RT-PCR method (reverse transcription (RT) and cDNA polymerase chain amplification (PCR)), and the amplified PCR product was inserted into the expression vector. Sequencing after pcDNA3.1 was identified.
  • the reporter gene was constructed using Promega's luciferase assay vector pGL3 - Promoter.
  • the transfection experiments were carried out in 96-well plates using U20S cells.
  • the RXR and PPARy genes were co-transfected at the same time as the transfection of the reporter gene.
  • the compound to be detected was added 24 hours after transfection, and the final concentration of the solvent DMS0 was maintained at 0.1%.
  • the cells were lysed and tested for luciferase activity.
  • the intensity of activation of the nuclear receptor by the compound can be known by observing the intensity of the luminescence.
  • GFP plasmid was also co-transfected as an internal reference.
  • the luminescence values of all the test wells were corrected by GFP value in the analysis of the experimental results.
  • the test results are expressed as relative activation multiples, and the solvent control has a value of 1, and a larger value indicates a higher activation ability.
  • the PPAR y full-length cDNA was cloned from adipose tissue by RT-PCR method (reverse transcription (RT) and cDNA polymerase chain amplification (PCR)), and the amplified PCR product was inserted into the expression vector. After pcDNA3.1, sequencing was identified.
  • the reporter gene was constructed using Promega's luciferase assay vector GL3 - Promoter. The transfection experiment was carried out in 96-well plates with U20S cells. The RXR and PPAR ⁇ genes were co-transfected at the same time as the transfection of the reporter gene.
  • the intensity of activation of nuclear receptors by the above groups can be known by observing the intensity of luminescence. Furthermore, the antagonism of the test compound against the PPAR y agonistic activity of the full agonist rosiglitazone was revealed. In order to correct the experimental error caused by factors such as transfection efficiency, cell inoculation amount and compound toxicity, GFP plasmid was also co-transfected as an internal reference, and the luminescence values of all the test wells were used in the analysis of the experimental results. The GFP value was corrected. The results of the test are expressed as relative activation multiples.
  • the value of the solvent control is 1, and the larger the value indicates the higher the activation ability, the weaker the antagonism of the test compound on the PPAR gamma agonistic activity of the full agonist rosiglitazone.
  • the experimental results showed that the compounds of Examples 1 to 9 were added at a concentration of 1. ⁇ ⁇ rosiglitazone and 0 ⁇ 001 ⁇ , 0.01 ⁇ ⁇ 0.1 ⁇ ⁇ , 1 ⁇ , 5 ⁇ ⁇ or 10 ⁇ ⁇ .
  • the ratio of the relative activation multiples obtained to the relative activation multiples measured with 1.0 ⁇ M rosiglitazone was less than 1, indicating that the compounds of Examples 1 to 9 were 0.001 ⁇ , 0.01 ⁇ 0.1 ⁇ , 1 ⁇ , 5
  • Example 13 Long-term administration of weight gain experiment Animal model of healthy spontaneous type 2 diabetes, male GK rats (Goto-Kakizaki rats) weighing 200 g, randomized, and continuously administered the feed containing the compound of Example 3, 4, 7 or rosiglitazone (20 mg/ Kg/day), the normal feed group was used as a control, and the weight gain was observed after 40 days of continuous administration. Experimental results: The body weight of the blank control group increased by 23.2%; the weight gain of the compound group 3, 4, and 7 of the example compound was 26.
  • Example 14 Pharmaceutical composition
  • a capsule containing the compound of Example 3 was prepared from the following components:
  • the compound 3 was mixed with starch and sieved, and then uniformly mixed with the above other components, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
  • Example 15 Pharmaceutical composition
  • a tablet containing the compound of Example 3 was prepared from the following components:
  • Compound 3 is mixed with starch in a conventional manner and mixed with the other components described above. After homogenization, the tablets were directly compressed to obtain 1,000 tablets.

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Abstract

La présente invention porte sur des composés présentant une activité agoniste partielle de PPAR, représentés par la formule I, sur des sels pharmaceutiquement acceptables de ces composés, sur leur préparation, sur des compositions pharmaceutiques contenant les composés ou leurs sels pharmaceutiques, et sur leur application dans la préparation de médicaments utilisés pour le traitement et/ou la prévention des maladies associées à PPARγ, telles que le diabète, les maladies associées à l'augmentation singulière du sucre dans le sang, au syndrome métabolique ou à l'adiposité.
PCT/CN2008/000441 2007-03-09 2008-03-05 Composés présentant une activité agoniste partielle de ppar et leur application Ceased WO2008110062A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine
EP2821071A1 (fr) 2013-07-04 2015-01-07 Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) Composés pour le traitement du cancer du sein

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WO1994002467A1 (fr) * 1992-07-28 1994-02-03 Instituto Luso Farmaco D'italia S.P.A. Ethers de l'imidazole ayant une activite antagoniste des recepteurs a l'angiotensine ii
CN1829511A (zh) * 2003-07-31 2006-09-06 贝林格尔.英格海姆国际有限公司 血管紧张素ⅱ受体拮抗剂,特别是泰米沙坦用于提高胰岛素敏感性的用途
CN101085772A (zh) * 2006-06-07 2007-12-12 上海艾力斯医药科技有限公司 一类具有PPARγ激动剂活性的化合物及其应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002467A1 (fr) * 1992-07-28 1994-02-03 Instituto Luso Farmaco D'italia S.P.A. Ethers de l'imidazole ayant une activite antagoniste des recepteurs a l'angiotensine ii
CN1829511A (zh) * 2003-07-31 2006-09-06 贝林格尔.英格海姆国际有限公司 血管紧张素ⅱ受体拮抗剂,特别是泰米沙坦用于提高胰岛素敏感性的用途
CN101085772A (zh) * 2006-06-07 2007-12-12 上海艾力斯医药科技有限公司 一类具有PPARγ激动剂活性的化合物及其应用

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine
EP2821071A1 (fr) 2013-07-04 2015-01-07 Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) Composés pour le traitement du cancer du sein

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