WO2007085135A1 - Dérivés d'acide 1,3-benzodioxolecyclopentène-2,2-dicarboxylique, procédé de préparation et applications médicales - Google Patents

Dérivés d'acide 1,3-benzodioxolecyclopentène-2,2-dicarboxylique, procédé de préparation et applications médicales Download PDF

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WO2007085135A1
WO2007085135A1 PCT/CN2006/000372 CN2006000372W WO2007085135A1 WO 2007085135 A1 WO2007085135 A1 WO 2007085135A1 CN 2006000372 W CN2006000372 W CN 2006000372W WO 2007085135 A1 WO2007085135 A1 WO 2007085135A1
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formula
compound
methyl
methylthio
benzodioxole
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PCT/CN2006/000372
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English (en)
Chinese (zh)
Inventor
Song Li
Jianlei Kang
Zhibing Zheng
Lili Wang
Dan Qin
Junhai Xiao
Wu Zhong
Hao Cui
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Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
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Publication of WO2007085135A1 publication Critical patent/WO2007085135A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P3/06—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

Definitions

  • the present invention relates to novel compounds, and in particular to the 1, 3-benzodioxole-2, 2- which activates the human peroxisome proliferator-activated receptor (hPPAR).
  • hPPAR human peroxisome proliferator-activated receptor
  • the peroxisome proliferator-activated receptor is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily equivalent to the glucocorticoid receptor, retinoic acid receptor, and thyroxine receptor.
  • alpha alpha
  • gamma gamma
  • delta also known as ⁇
  • ⁇ is divided into two isoforms due to different promoters and splicing methods: ⁇ , ⁇ 2 , and only the terminal sequence is not (Vidal-Puig, J. Cl in. Inves t., 97: 2553-2561, 1996).
  • PPARs When activated by a specific small molecule, PPARs interact with the PPARs response element (PPRE) of the target gene promoter region to regulate expression of the gene. PPARs are important transcriptional regulators of glucose, lipids, and cholesterol metabolism in the body.
  • PPRE PPARs response element
  • PPARa is mainly expressed in tissues with very high catabolic activity in lipids such as ochre adipose tissue and liver, followed by kidney, heart and skeletal muscle (Endocnnology, 1995, 137, 354). It can positively or negatively control genes involved in fatty acid metabolism and intracellular delivery (such as acyl-CoA synthetase, fatty acid-binding protein and lipoprotein lipase) and apolipoproteins involved in the metabolism of cholesterol and neutral lipids ( AI, Al l , CI II) gene expression.
  • ⁇ is mainly found in adipose tissue, and is also present in bone in a small amount! Muscle, liver, colon, retina, immune system.
  • Thiazolidinediones such as rosiglitazone, have been clinically shown to enhance insulin action in patients with type 2 diabetes and reduce serum glucose. Thiazolidinediones have been reported to be potent and selective activators of PPARy and bind directly to ⁇ receptors (J. ⁇ . Lehmann et al, J. Biol. Chera. 12953-12956, 270 (1995)).
  • Firbrates have been widely used as therapeutic agents for hyperlipidemia, which can lower serum triglycerides (20-50%), LDLc (10-15%), and increase HDLc (10-15%). ).
  • PPARa PPARa-activated PPARa
  • Activation of PPARa causes transcription of enzymes that increase fatty acid catabolism and reduce the re-synthesis of fatty acids in the liver, causing triglyceride synthesis and reduced VLDL production/secretion.
  • PPARa activation reduces the production of apoC-I II.
  • the reduction in apoC-II I increases clearance of VLDL (J. Auwerx et al, Atherosc leros i s, J59-S37, 124 (Suppl), (1996)).
  • PPAR PPAR involves many biological processes and disease states, including hypercholesterolemia, dyslipidemia and diabetes. However, current drugs are not ideal due to toxic side effects, etc. Therefore, a safe and effective PPAR agonistic drug is needed. Selectively activate one subtype, or activate multiple subtypes simultaneously. Summary of the invention
  • the object of the present invention is to find and develop a small molecule compound having PPAR agonistic activity.
  • risk factors or conditions such as dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type 1 diabetes, type II diabetes, insulin resistance, Diabetes complications, glucose insufficiency, X syndrome, heart failure, cardiovascular disease, regulation of appetite and food absorption in patients with obesity, anorexia, bulimia and anorexia nervosa.
  • the invention provides a compound of formula I, a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof,
  • 1 ⁇ and 11 2 are independently selected from the linear or branched alkyl group of H, d-C 6 , optionally a benzyl group substituted by one or more on the phenyl ring, said substituent being selected from d - C 6 Linear or branched alkoxy, d-C 6 straight or branched alkyl, C 2 -C 6 straight or branched alkenyl, C 3 -C fi cycloalkyl, halogen, nitrile Base, trifluoromethyl, trifluoromethoxy;
  • X is selected from the group consisting of 0 and S atoms
  • n is selected from 1, 2, 3 and 4;
  • One of Y and Z is N, and the other is S or 0;
  • R 3 is selected from H, halogen, a straight or branched alkyl group of d - C 6 , a C 2 - C 6 linear or branched alkenyl group and a C 3 - C 6 cycloalkyl group;
  • Ar is an aromatic carbocyclic ring or an aromatic heterocyclic ring in which the ring may be monocyclic, bicyclic or tricyclic; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1 to 4 From the heteroatoms of 0, N, S, the above aromatic carbocyclic or aromatic heterocyclic ring is optionally substituted by 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, Fluoromethoxy, d - C 6 straight or branched alkyl, C 2 - C 6 straight or branched alkenyl, d - C 4 alkoxy, C 2 - (alkenyloxy, phenoxy , benzyloxy, carboxy or amino.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) according to the invention, which comprises at least one compound of formula I, its racemate or optical isomer or a pharmaceutically acceptable salt or solvate thereof And one or more pharmaceutically acceptable carriers or excipients.
  • the invention is also directed to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.
  • the invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment and/or prevention of a hPPAR mediated disease or condition.
  • the invention provides a method of treating and/or preventing a hPPAR mediated disease, risk factor or disorder comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of the invention.
  • the hPPAR-mediated diseases, risk factors or conditions described in the present invention include dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type I diabetes, type II diabetes, insulin resistance, Diabetes complications, glucose insufficiency, X syndrome, heart failure, cardiovascular disease, regulation of appetite and food absorption in patients with obesity, anorexia, bulimia and anorexia nervosa.
  • the invention provides a compound of formula I, a racemate or an optical isomer thereof, a pharmaceutically acceptable salt or solvate thereof,
  • 1 ⁇ and 11 2 are independently selected from the linear or branched alkyl group of H, d-C 6 , optionally a benzyl group substituted by one or more on the phenyl ring, said substituent being selected from d-C 6 Linear or branched alkoxy, dC 6 straight or branched alkyl, C 2 -C 6 linear or branched alkenyl, C 3 -C 6 cycloalkyl, halogen, nitrile, Trifluoromethyl, trifluoromethoxy;
  • X is selected from the group consisting of 0 and S atoms
  • n is selected from 1, 2, 3 and 4;
  • One of Y and Z is N, and the other is S or 0;
  • R 3 is selected from H, halogen, a linear or branched alkyl group of dC 6 , a C 2 -C 6 linear or branched alkenyl group and a C 3 -C 6 cycloalkyl group;
  • Ar is an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1-4 selected from 0, N
  • the hetero atom of S, the above aromatic carbocyclic ring or aromatic heterocyclic ring is optionally substituted by 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy , d-C 6 straight or branched alkyl, C 2 -C 6 straight or branched alkenyl, d -C 4 alkoxy, C 2 -C 4 alkenoxy, phenoxy, benzyloxy , carboxyl or amino.
  • aromatic carbocyclic ring examples include, but are not limited to, benzene, naphthalene, anthracene, phenanthrene, 1, 3-benzodioxole, anthracene, anthracene, amaranth.
  • aromatic heterocycle of the present invention include, but are not limited to pyridine, pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, oxazole P, iso-breathing of fish oxazole, indole, benzofuran, benzo-imidazol- , oxazole, noisy, pyrimidine, dipyridamole, pyridyl, qin, quinoline, isoquinoline, hydrazine, phenothiazine, phenazine.
  • the invention provides a compound represented by the formula ,, including the racemate or optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof:
  • R 2 is selected from a straight or branched alkyl group of H, d-C 6 , optionally a benzyl group substituted by one or more on the phenyl ring, said substituent being selected from the group consisting of d- ( 6 straight chain or Branched alkoxy, d-C 6 straight or branched alkyl, C 2 -C 6 straight or branched alkenyl, C 3 -C 6 cycloalkyl, halogen, nitrile, trifluoro Methyl, trifluoromethoxy;
  • X is selected from the group consisting of 0 and S atoms
  • n is selected from 1, 2, 3 and 4;
  • One of Y and Z is N, and the other is S or 0;
  • Ar is an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1-4 selected from 0, N
  • the hetero atom of S, the above aromatic carbocyclic ring or aromatic heterocyclic ring is optionally substituted by 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxydecyl, trifluoromethyl, trifluoromethoxy , dC 6 straight or branched alkyl, C 2 -C 6 straight or branched alkenyl, d -oxy, C 2 - ( 4 alkenyloxy, phenoxy, benzyloxy, decyl or amino .
  • Preferred compounds of the invention include:
  • the above compound of the formula I and / or formula 11 or a pharmaceutically acceptable salt or solvate thereof can be prepared by the following method, which comprises the steps of: 1) Reacting catechol with sodium thiocyanate in the presence of bromine and sodium bromide
  • the compound of formula V and the compound of formula VI (W is a halogen or a hydroxyl group) in a base such as sodium hydroxide, cesium carbonate, potassium carbonate, or DEAD (diethyl azodicarboxylate, available from ACROS) and PPh 3 Reaction in the presence of (triphenylphosphine),
  • a base such as sodium hydroxide, cesium carbonate, potassium carbonate, or DEAD (diethyl azodicarboxylate, available from ACROS) and PPh 3 Reaction in the presence of (triphenylphosphine),
  • R l 5 R 2 is as defined in the formula I, but not H;
  • the compound of the above formula I is reacted with an alkali metal hydroxide or with an acid such as dilute hydrochloric acid or trifluoroacetic acid, and hydrolyzed to obtain a compound of the formula I in which H or both are H:
  • X, Y, Z, n, Ar, R 19 R 2 , R 3 are as defined for Formula I, and ⁇ and R 2 are either H or both.
  • R 3 is a methyl group, it is a compound of the formula II.
  • Ar ⁇ (CH 2 )n.
  • R 2 is as defined for Formula II.
  • the synthesis scheme of the compounds of the formula I and the formula II is detailed in the following reaction scheme: Reaction step one:
  • the compound of the formula III, triethyl orthoformate, acidic ion exchange resin, 4A molecular sieve is refluxed in anhydrous benzene for 72-96 hours, filtered, concentrated, and separated by column (eluent: n-hexane/ethyl acetate system).
  • the compound of formula IV is obtained as a pale yellow oil.
  • the silica gel used herein is a silica gel for conventional column chromatography, having a particle size of 10 - 40 ⁇ ;
  • Ar, Y, Z, R 3 , n are as defined in the formula I, and W is a halogen, preferably Br, Cl.
  • the compound of the formula VI 11 is reacted with a compound of the formula IX (purchased from ACR0S, Aldrich) in anhydrous acetonitrile or acetone at room temperature for 3-5 hours in the presence of a base of cesium carbonate or potassium carbonate, filtered, concentrated and separated by a column (eluent) : n-hexane/ethyl acetate system), a yellow oily compound of formula I, Ar, Y, ⁇ , ⁇ , X, R l9 R 2 , R 3 are as defined for formula I, but ⁇ and R 2 are not H.
  • X, Y, Z, n, Ar, R 2 are as defined for Formula II.
  • the intermediate compound of the formula VI used in the above reaction scheme of the present invention can be produced by the following method:
  • the compound of formula X is aromatic formamide (V is 0, purchased from ACR0S and Aldrich, Or prepared from the corresponding aromatic formic acid) or thioaromatic formamide (V is S, derived from the corresponding aromatic formamide) and 2-?3 ⁇ 4-3-oxo-carboxylic acid ethyl ester or XI compound (R 3 is as defined in formula 1, valence is halogen, (1 is selected from 1, 2, 3; available from ACR0S and Aldr ich, or from the corresponding compound! 3 ⁇ 4 generation).
  • the compound (Y, Z, Ar, R 3 has the same meaning as the formula I, m is selected from 0, 1, 2, 3 ).
  • the compound of the formula XI I is reduced by lithium tetrahydrogenate (LiAlH 4 , purchased from ACR0S) Further, a compound of the formula VI is obtained, wherein Y, Z, Ar, R 3 , n have the same meaning as in claim 1, and W is a halogen.
  • LiAlH 4 lithium tetrahydrogenate
  • a compound of formula I or formula I I has a chiral center.
  • a compound of formula I or formula II can be prepared using reactants in the form of a single enantiomer in all possible steps, or in the form of a single enantiomer. It is prepared by carrying out the reaction in the presence of a catalyst or by dissolving a mixture of stereoisomers by a conventional method. Some preferred methods include resolution using a microorganism, resolution of a diastereomeric salt formed with any usable acid such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, or the like, or splitting with a hand.
  • Salts of diastereomers formed by alkaloids such as brac ine, cinchona alkaloids and derivatives thereof.
  • alkaloids such as brac ine, cinchona alkaloids and derivatives thereof.
  • Jaques et al. “Enant iomers, Racemates and Resolution” (Wiley Interscience, 1981).
  • Physiologically acceptable salts of the compounds of formula I or formula II include the conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and the acid addition salts of quaternary ammonium salts. More specific examples of suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid.
  • citric acid citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene Sulfur Salts of acid, hydroxycarotic acid, hydroiodic acid, malic acid, s teroic, citric acid, and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts.
  • Suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N, N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-methylglucamine and procaine salts.
  • the present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs.
  • prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula (I).
  • conventional methods for selecting and preparing suitable prodrug derivatives are described in "Des ign Of Prodrugs", H Bund Saard, El Sevier, ed., 1985.
  • the invention also includes active metabolites of the compounds of the invention.
  • compositions comprising a racemate or an optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible.
  • the pharmaceutical compositions can be prepared in a variety of forms depending on the route of administration.
  • the compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.
  • the agonistic effects of the compounds of the invention on PPAR can be determined by screening the functional effects of transient transfection of compounds in 293-T cells to determine their ability to activate PPAR isoforms.
  • the effect of the receptor subtype on the transcriptional activity of the same target gene was compared using a pre-established chimeric receptor system, and R luc was used as an internal standard to reduce endogenous effects.
  • the human PPARou PPARy and ⁇ ligand binding domains are each fused to the yeast transcription factor GAL4 DNA binding domain.
  • the mammalian expression vector p ⁇ was ligated, and three plasmids pM-hPPARa/GAL4, pM-PPARy/GAL4 and pM-PPAR3/GAL4 were constructed. Linking the GAL4 DNA binding region to pB4-tk-luc pB4-RES-tk-luc (a reporter gene for firefly luciferase containing a GAL4 DNA binding site). Transfection efficiency and endogenous effects were corrected using pRL-CMV-Rluc as an internal standard.
  • the 293-T cells were seeded in 48-well plates at a cell density of 2-4xl 0 4 / well, culture was 10% defatted fetal calf serum (FCS) in phenol red-free 1640 medium without antibiotics. After 48 hours, the culture medium was changed to 5% defatted FCS phenol red-free antibiotic-free 1640 medium, and then three subtypes of pM-hPPAR/GAL4, pB4-RES-tk-luc and pRL-CMV-, respectively. Three plasmids of Rluc were co-transfected into 293-T cells, administered 24 hours later, and the intensity of luciferase was measured 24 hours after administration. 0.2% 0 DMS0 was used as a blank control. The results indicate that the compounds of the present invention have some agonistic effects on various subtypes of PPAR.
  • FCS fetal calf serum
  • compositions of the present invention comprise an effective amount of a compound of formula I according to the invention or a pharmaceutically acceptable salt or hydrate thereof and one or more suitable pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer shields such as phosphate, glycerin, sorbic acid, potassium sorbate, Partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyethylene Pyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Intra, intraventricular, intrasternal, and intracranial injection or input, or by means of an explant reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for tablets generally includes lactose and corn starch, and a lubricant such as a hardener may also be added.
  • Magnesium citrate The diluent used in the capsule formulation generally comprises lactose and dried cornstarch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
  • the compounds of the invention When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the invention may be formulated into different topical preparations according to different affected faces or organs.
  • the form is specifically described as follows:
  • the compound of the present invention can be formulated into a preparation form of a micronized suspension or solution, and the carrier used is an isotonic pH of sterile saline, which may or may not be added.
  • Preservatives such as benzyl chloride alkoxide.
  • the compound can also be formulated into a bone form such as vaseline.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers for cartilage preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams may be used including but not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions.
  • a sterile injectable preparation including sterile aqueous or oily suspension or sterile injection solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor.
  • a preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is from 5 mg/kg to 10 mg/kg body weight per day.
  • the melting point of the compound was determined by a YRT-3 type melting point apparatus, and the temperature was not corrected.
  • - NMR spectra were determined by a Bruker ARX 400 nuclear magnetic instrument.
  • the FAB quality was measured by a Zabspect high resolution magnetic mass spectrometer.
  • the title compound was prepared from phenyl hydrazide as a general procedure to afford a white solid.
  • the title compound was prepared using p-bromobenzamide as a crude material.
  • reaction product of (II) is dissolved in 40 ml of 90% aqueous methanol solution, added with 500 mg of p-toluenesulfonic acid, and reacted at room temperature for 12-24 hours, concentrated, and separated by column (elution system: chloroform / decyl alcohol) to obtain light yellow To yellow 4-[(2-aryl-4-methylthiazol-5-yl)methylthio]-1,2-catechol.
  • Example 1 5-[(4-Methyl-2-phenyl-1,3-thiazol-5-yl)-methylthio]-1,3-benzodioxole-2, 2-dicarboxylic acid monomethyl ester 0.86 g (2.61 ⁇ ol) of intermediate 14 and 2.56 g (7.88 ol) of cesium carbonate were added to 40 dl of dry acetone, and 0.86 g (2.70 mmol) of diethyl 2,2-dibromomalonate was added dropwise in 15 ml of dryness.
  • Elution system methylene chloride / decyl alcohol), 5-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)-methylthio]-l, 3 as a pale yellow solid - inter-benzo dioxole - 2, 2 - dicarboxylic acid monomethyl ester 0.116g (0.26mraol), a yield of 60.5%.
  • Example 2 Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 15 to give 5- ⁇ [4-methyl-2-(4-trifluoromethylphenyl)-1,3 as a pale yellow solid. - Thiazol-5-yl]-methylthio ⁇ -1,3-benzodioxole-2,2-dicarboxylic acid monomethyl ester.
  • Example 8 Using the preparation method of Example 8, the intermediate 15 was changed to the intermediate 16 to give 5- ⁇ [4-mercapto-2-(4-bromophenyl)-1,3-thiazole as a pale yellow solid. 5- yl] - yl ⁇ methylthio inter-1,3-benzo-dioxole - 2,2-dicarboxylic acid monoethyl ester.
  • Example 8 Using the preparation method of Example 8, the intermediate 15 was changed to the intermediate 17 to give 5- ⁇ [4-indol-2-(4-methoxyphenyl)-1,3- as a pale yellow solid. Thiazol-5-yl]-indolyl ⁇ -1,3-benzodioxole-2,2-dicarboxylic acid monoethyl ester.
  • the intermediate 15 was changed to the intermediate 18 to give 5- ⁇ [4-methyl-2-(3,5-dimethoxyphenyl)- 1, 3-thiazol-5-yl]-methylthio ⁇ -1,3-benzodioxol-2,2-dicarboxylic acid monoethyl ester.
  • Example 8 Using the preparation method of Example 8, the intermediate 15 was changed to the intermediate 21 to give 5- ⁇ [4-methyl-2-(naphthalen-2-yl)-1,3-thiazole as a pale yellow solid. 5-Alkyl]-indolyl ⁇ -1,3-benzodioxole-2,2-dicarboxylic acid monoethyl ester.
  • Example 13 Using the preparation method of Example 13, the intermediate 15 was changed to the intermediate 22 to give 5- ⁇ [4-methyl-2-(1,3-benzodioxole) as a yellow solid. 5 -amino)-1,3-thiazol-5-yl]-methylthio ⁇ -1,3-benzodioxole-2,2-dicarboxylic acid.
  • Example 2 Using the preparation method of Example 1, the intermediate 14 was changed to an intermediate. 23, 5-[2-(5-methyl-2-phenyl-1,3-Poxazol-4-yl)-ethoxy]-1,3-benzodioxane as a pale yellow solid Monoheterocyclopentene-2,2-dicarboxylic acid monomethyl ester.
  • the 293-T cells were seeded into 48-well plates at a cell density of 2-4xl0 4 cells / well, culture was 10% defatted fetal calf serum (FCS) in phenol red-free 1640 medium without antibiotics. After 48 hours, the culture medium was changed to 5% defatted FCS phenol red-free antibiotic-free 1640 medium, and then three subtypes of pM-hPPAR/GAL4, pB4-RES-tk-luc and pRL-CMV-, respectively. Three plasmids of Rluc were co-transfected into 293-T cells, administered 24 hours later, and the intensity of luciferase was measured 24 hours after administration. The results were expressed in terms of photon number and growth factor, as shown in Table 1. At 0.2%. DMS0 was used as a blank control. Table 1. P The agonistic effect of the compounds of the invention on PPAR ( ⁇ )

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Abstract

La présente invention concerne des composés représentés par la formule générale (I), des racémates, ou des isomères optiques, des sels de qualité pharmaceutique ou des solvates de ces composés, ainsi que des compositions pharmaceutiques contenant ces composés. Dans la formule générale (I), chaque substituant désigne un élément défini dans les revendications. L'invention concerne également un procédé de fabrication de ces composés et leur utilisation dans l'élaboration de médicaments destinés au traitement et/ou à la prévention de diverses maladies et facteurs de risques associés au récepteur activé par les proliférateurs des peroxysomes (hPPAR).
PCT/CN2006/000372 2006-01-25 2006-03-13 Dérivés d'acide 1,3-benzodioxolecyclopentène-2,2-dicarboxylique, procédé de préparation et applications médicales WO2007085135A1 (fr)

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CN2006100018763A CN101007804B (zh) 2006-01-25 2006-01-25 1,3-苯并间二氧杂环戊烯-2,2-二羧酸衍生物、其制备方法和医疗用途
CN200610001876.3 2006-01-25

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
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
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0107622A1 (fr) * 1982-10-22 1984-05-02 Ciba-Geigy Ag Dérivés de benzodioxole, leur procédé de préparation et compositions pharmaceutiques les contenant
JPS6239583A (ja) * 1985-08-14 1987-02-20 Yamanouchi Pharmaceut Co Ltd ベンゾジオキソ−ル誘導体及びその製造法
US6924276B2 (en) * 2001-09-10 2005-08-02 Warner-Lambert Company Diacid-substituted heteroaryl derivatives as matrix metalloproteinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0107622A1 (fr) * 1982-10-22 1984-05-02 Ciba-Geigy Ag Dérivés de benzodioxole, leur procédé de préparation et compositions pharmaceutiques les contenant
JPS6239583A (ja) * 1985-08-14 1987-02-20 Yamanouchi Pharmaceut Co Ltd ベンゾジオキソ−ル誘導体及びその製造法
US6924276B2 (en) * 2001-09-10 2005-08-02 Warner-Lambert Company Diacid-substituted heteroaryl derivatives as matrix metalloproteinase inhibitors

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
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
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
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

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