WO1999015520A1 - Composes de benzene fusionnes ou non fusionnes - Google Patents

Composes de benzene fusionnes ou non fusionnes Download PDF

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Publication number
WO1999015520A1
WO1999015520A1 PCT/JP1998/004116 JP9804116W WO9915520A1 WO 1999015520 A1 WO1999015520 A1 WO 1999015520A1 JP 9804116 W JP9804116 W JP 9804116W WO 9915520 A1 WO9915520 A1 WO 9915520A1
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WIPO (PCT)
Prior art keywords
group
methyl
benzodioxane
compound
tetrazole
Prior art date
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PCT/JP1998/004116
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English (en)
Japanese (ja)
Inventor
Hisao Tajima
Yoshisuke Nakayama
Daikichi Fukushima
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Ono Pharmaceutical Co., Ltd.
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Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Priority to AU90027/98A priority Critical patent/AU9002798A/en
Publication of WO1999015520A1 publication Critical patent/WO1999015520A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring

Definitions

  • the present invention relates to a condensed or non-condensed benzene compound represented by the general formula (I), a non-toxic salt thereof, an acid addition salt thereof and a hydrate thereof, a method for producing the same, and a method for producing the compound.
  • the present invention relates to a peroxisome proliferator-activated receptor regulator contained as a component.
  • PPAR receptor nuclear receptor, peroxisome proliferator activated receptor
  • cDNA is cloned from various animal species, and multiple isoform genes have been found.
  • mammals three types of "," and "" are known (J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Gene Expression, 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431 (1996); Mol. Endocrinology, 6, 1634 (1992)).
  • type A is mainly expressed in adipose tissue, immune cells, adrenal gland, spleen and small intestine
  • type ⁇ is mainly expressed in adipose tissue, liver and retina
  • type S is ubiquitously expressed without tissue specificity.
  • the thiazolidine derivatives shown below are known as therapeutic agents for non-insulin-dependent diabetes mellitus (NIDDM), and are hypoglycemic agents used to correct hyperglycemia in diabetic patients.
  • NIDDM non-insulin-dependent diabetes mellitus
  • it is a compound that has been shown to be extremely promising as an insulin sensitizer because it is effective in correcting or improving hyperinsulinemia, improving glucose tolerance, and lowering serum lipids.
  • PPAR 7 activator agonist
  • PPAR Gonists are known to enhance the expression of PPARa protein itself (Genes &
  • Drugs that increase the expression of the PPARa protein itself are also considered clinically useful.
  • the nuclear receptor PPARa is involved in adipocyte sorting (see J. Biol. Chem., 272, 5637-5670 (1997) and Cell, 83, 803-812 (1995)).
  • thiazolidine derivatives which can be converted promote adipocyte differentiation.
  • an antagonist (antagonist) that suppresses PPAR7 activity and an agent that can reduce the expression of PPAR7 protein itself are considered to be clinically useful.
  • PPARa receptor activator agonist
  • PPARa protein expression regulator that can increase the expression of protein itself are hypoglycemic agents, hypolipidemic agents, diabetes, obesity, syndrome X, is useful as a prophylactic and therapeutic agent for metabolic disorders such as hypercholesterolemia and hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, hypertension, cardiovascular disease, bulimia, etc. It is expected to be.
  • antagonists that suppress the transcriptional activity of the PPARa receptor or PPAR7 protein expression regulators that can suppress the expression of the protein itself include hypoglycemic drugs, diabetes, obesity, metabolic disorders such as syndrome X, and hyperlipidemia. Is expected to be useful as a prophylactic and / or therapeutic agent for diseases, arteriosclerosis, hypertension, bulimia and the like.
  • fibrous compounds for example, clofibrate
  • fibrous compounds for example, clofibrate
  • agonists that activate PPAR "receptors” and PPAR-regulators that increase the expression of PPAR "protein itself are useful not only as lipid-lowering agents and drugs for treating hyperlipidemia, but also as HDL cholesterol-elevating agents, It is expected to reduce cholesterol and Z or VLD L cholesterol, and to suppress and treat the progression of arteriosclerosis, and to suppress obesity. Onset of ischemic heart disease It seems promising for prevention.
  • PPAR S is sometimes referred to as PPAR?, Or NUC 1 in humans.
  • hNUC IB P PAR subtype that is one amino acid different from human NUC 1
  • hNUC IB P PAR subtype that is one amino acid different from human NUC 1
  • compounds (agonists) having a high affinity for PPARS protein and significantly activating PPARS have been found, and those compounds have been further identified. It has been reported that HDL (high density lipoprotein) has a cholesterol increasing effect.
  • agonists capable of activating PPAR ⁇ are expected to have an effect of increasing HDL cholesterol, thereby suppressing the progression of arteriosclerosis and its application, as lipid-lowering agents and hypoglycemic agents, and for treating hyperlipidemia. It is also considered to be useful for hypoglycemic drugs, treatment of diabetes, reduction of the risk factor of syndrome X, and prevention of the development of ischemic heart disease.
  • RA is selected from a hydrogen atom, C 1-6 alkyl, C 5-10 aryl, and C 5 10 heteroaryl, wherein the alkyl, aryl and heteroaryl are
  • the reel may be substituted with 1 to 3 R a A;
  • R 1 A is selected from a hydrogen atom, C 1 to 15 alkyl, C 2 to 15 alkenyl, C 2 to 15 alkynyl and C 3 to 10 cycloalkyl, and the above alkyl, alkenyl, alkynyl, The cycloalkyl may be substituted by 1 to 3 R a A ;
  • R 3 A is a hydrogen atom, NHR 1 A, NH Ashiru, C. 1 to: I 5 alkyl, C 3 ⁇ : 1 0 cycloalkyl, C. 2 to 1 5 alkenyl, C. 1 to 1 5 alkoxy, C0 2 Aruki Le, OH, C2 ⁇ : 15 alkynyl, C5 ⁇ 10 aryl, C5 ⁇ 10 heteroaryl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl are from 1 May be substituted with three R a A;
  • R8A is CR6AR7A, 0, NR6A and S (0) is selected from p A;
  • R 6 A and R 7 A are each independently selected from hydrogen atom, C 1 to 6 alkyl;
  • BA is below 1) to 3 ) Is selected from;
  • heterocyclic ring containing 0 to 2 double bonds and 1 hetero atom selected from 0, S, N, and a hetero atom is a 5- or 6-membered hetero ring
  • the heterocyclic ring may be substituted at any position of the ring, and the heterocyclic ring may be substituted with 1 to 3 R a A,
  • the heterocyclic ring may be substituted at any position of the ring, and the heterocyclic ring may be substituted with 1 to 3 R a A. May be done;
  • X 1 A and X 2 A are each independently a hydrogen atom, OH, C l-15 alkyl, C
  • said alkyl, alkenyl, alkynyl, aryl and heteroaryl are optionally substituted by 1 to 3 R A A;
  • Ra A is a halogen atom, asyl, aaryl, heteroaryl, CF 3 , ⁇ CF 3 ,
  • R 3 A, OR 3 A, SR 3 A, N (0 R A), S (0) R 3 A, S 0 2 R 3 A, NR 3 AR 3 ⁇ NR 3 ACOR 3 A, NR 3AC 0 2 R 3A, NR 3 AC 0 N (R 3 A) 2 , NR 3 AS 0 2 R 3 A, COR 3 A, C ⁇ 2 R 3 A, C ON (R 3 a) 2, S_ ⁇ 2 N (R 3 a) 2 , is selected from ⁇ CON (R3 a) 2, the Ariru and heteroaryl are optionally substituted with one or et three halogen atoms or C.
  • 1 to 6 alkyl YA is S (0) ⁇ ⁇ , — CH 2- , — C (0)-, -C (0) NH-, — NRA—, 1 0—, 1 S 0 2 NH—, 1 NH S 0 2 — selected from, Y 1 A selected from 0 and C,
  • Z A is selected from C0 2 R 3 A, R 3 A C0 2 R3A, C0NH S 0 2 Me, C0NH 2 and 5 _ (1 H- tetrazol Ichiru)
  • t A and V A each independently represent 0 or 1, 1; 8 + 8 is 1;
  • Q A represents a saturated or unsaturated, straight-chain 2 to 4 carbon atoms at the opening, and p A is 0 to 2.
  • a pharmaceutically acceptable salt thereof is a P PAR receptor modulator and is described as being useful for the treatment of diabetes, obesity, hyperlipidemia and the like.
  • WO 9728137 also describes that compounds similar to the above are P PAR d receptor modulators and are useful for similar diseases.
  • RB is hydrogen, C L ⁇ 6 alkyl, C. 5 to 10 Ariru, and C 5 ⁇ is selected from 1 0 Heteroariru said alkyl, Ariru and to Teroa reel with 1-3 R a B May be substituted;
  • R 1 B is selected from a hydrogen atom, C 1 to: I 5 alkyl, C 2 to 15 alkenyl, C 2 to 15 alkynyl and C 3 to 10 cycloalkyl, and the above alkyl, alkenyl, alkynyl, and Cycloalkyl may be substituted by 1 to 3 R a B;
  • R 2 B is a hydrogen atom, C. 1 to 1 5 alkyl, Ashiru, C. 2 to 1 5 alkenyl, OR3B, C0 2 alkyl, C ( ⁇ ) R 3 B, OH, one OC ( ⁇ ) R3B, C2 ⁇ 15 alkynyl , C. 5 to: 1 0 Ariru, is selected from C. 5 to 10 Heteroariru, the alkyl, alkenyl, alkynyl, Ariru and heteroaryl may be substituted with 1-3 R a B;
  • (ZB—WB—) represents ZB—CR6BR7B—
  • ⁇ represents 0
  • R 4 ⁇ represents R 2 ⁇
  • R2B represents acetyl, hydrogen atom, alkyl, alkoxy, aryl. If not;
  • R8B represents 0.
  • YB represents S or 0, and R4B represents — ⁇ R5B, ⁇ 0 does not represent 0 or S;
  • R5B is selected from c5-10 aryl and C5-10 heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one to three RaBs;
  • BB is selected from 0, S (0) pB and NR 1 B ;
  • R8B is CR6BR7B, ⁇ is selected from NR6B and S (0) p B;
  • R6B and R7B are each independently selected from a hydrogen atom, C1-6 alkyl;
  • X1B and ⁇ 2B are each independently a hydrogen atom, 0H, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, halogen atom, OR3B, c5-10 aryl, C5-10 aralkyl, C5-: selected from L0 heteroaryl and C1-10 acyl, and the above alkyl, alkenyl, alkynyl, Early And heteroaryl may be substituted with one to three R A B;
  • R a B is a halogen atom, acyl, aryl, heteroaryl, CF 3 , OCF 3 ,
  • CON (R 3 B) 2, S 0 2 N (R 3 B) 2, is selected from OCON (R3 B) 2, the above Ariru Contact Yopi Heteroariru with 1-3 halogen atoms or C. 1 to 6 alkyl May be substituted;
  • YB is from S (0) ⁇ ⁇ , — CH 2 —, — C (0) one, one C (0) NH—, — NRB—, one 0—, one S 0 2 NH—, one NHS 0 2 — Selected,
  • Y 1 B is selected from o, NRB and C;
  • ⁇ 2 ⁇ is ⁇ , N (C l to 1 5) alkyl, N (C_ ⁇ 2) alkyl, N-0 alkyl Le, is selected from N-0 Ashiru and N-0H, however, display the is 0 Y2B and, 1? 38 Gazi 11 3 If the table Wasu, Itabeta is assumed to represent 2,
  • ⁇ is selected from C0 2 R 3 B , R 3 B C0 2 R3B, C0 NHS 0 2 R B > C0 NH 2 and 5 _ (1 H-tetrazole),
  • t B and V B each independently represent 0 or 1, 8 +: 6 is 1;
  • QB represents a 2-4 Haidoroka one carbon linear, saturated or unsaturated, and p B is from 0 to 2.
  • a pharmaceutically acceptable salt thereof is a PPARS receptor modulator and is described to be useful for similar diseases.
  • AC is phenyl or the like, wherein the phenyl is one or more halogen atoms, C1-6 alkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, nitrile or 1NR7CR8C (formula Wherein R7C and R8C independently represent a hydrogen atom or C1-3 alkyl;
  • BC represents C 1-6 alkylene, one M c —C 1-6 alkylene, C 1-6 alkylene —MC—C 1-6 alkylene group (in the group, MC represents 0, S or NR 2 C) and the like. Represent;
  • a 1 k C represents C 1-3 alkylene
  • R 1 C represents a hydrogen atom or C 1-3 alkyl
  • ZC is selected from one (Cl-3 alkylene) phenyl or one NR3 CR4C. ) Or a pharmaceutically acceptable salt thereof is described as having PPAR7 agonist activity. (The explanation of the groups in the formula is that necessary parts are extracted.) .
  • Ar ID represents a nitrogen, sulfur or oxygen heterocyclic or aromatic ring
  • a rD represents a phenyl ring or a nitrogen, oxygen or sulfur heterocycle
  • 80-108 is completely substituted by H, CH 3 , lower alkyl, aryl, arealkyl, noguchi, hydroxy, lower alkoxy, CF 3 , carboxy, alkyl alkoxy, oxo, nitro, etc. Or may be incompletely substituted;
  • XD is 0 (CHR 1D) nD —, -NR2D (CHR 1D) nD —, alkylene
  • ZD is an alkylene chain having up to 10 carbon atoms and up to 12 carbon atoms and 0 to 2 double bonds in the main chain, wherein the alkylene chain is bonded through an oxygen, sulfur or amino nitrogen atom. May be connected to A r D,
  • R 1 D represents H or CH 3 ;
  • R4D represents OR2D or the like
  • nD 0 or 1
  • nE represents an integer from 3 to 10
  • R 1 E represents a hydrogen atom or lower alkoxy
  • R 2 E represents a hydrogen atom, halogen, nitro, hydroxyl group, lower alkoxy, etc.
  • R 3 E represents a hydrogen atom, a hydroxyl group or lower alkoxy.
  • DE represents carboxy, lower alkoxycarbonyl or ⁇ , ⁇ .
  • JP-T 8-504194 (corresponding to WO 9412 181) describes the general formula (F)
  • aryl F is a monocyclic aromatic 6-membered ring system containing 0, 1, 2, 3, or 4 N atoms and having no substituents or substituted with R 5 F ;
  • X F contains N, 0, 0 is selected from S, 1, 2, 3 or 4 heteroatom, or R 1 F no substituent, R 2 F, is substituted by R3F or R4F Just A cyclic or polycyclic aromatic or non-aromatic 4- to 10-membered ring system or the like, wherein RlF, R2F, 1 ⁇ 3 ?? ⁇ 4 are hydrogen, C1-10 Independently selected from the group consisting of alkyl, C1-4alkoxyC0-6alkyl, and the like;
  • ZF and AF are (CH 2 ) MF , (CH 2 ) MF ⁇ (CH 2 ) NF , (CH 2 ) M F NR 3 F (CH 2 ) n F , (CH 2 ) mF S0 2 (CH 2 ) n F , (CH 2 ) mF S (CH 2 ) n F , (CH 2 ) mF SO (CH 2 ) n F, etc., where mF and nF are independently selected from 0-6 Where AF is (CH 2 ) mF , the "Aryl F" ring attached to ZF and AF must contain at least one heteroatom;
  • R 5 F is hydrogen, C 1-6 alkyl, C 0-6 alkyloxy C 0-6 alkyl, halogen and the like;
  • R 6 F, R 7 F, R 8 F, R 9 F, R 1 OF and R 11 F are independently selected from hydrogen, C 1-8 alkyl, etc.
  • R 12 F is selected from hydroxy, C 1-8 alkyloxy and the like.
  • a pharmaceutically acceptable salt thereof have a platelet aggregation inhibitory activity based on fibrinogen receptor antagonist activity and are effective for thrombosis. In the explanation of, the necessary parts were extracted.
  • JP-A-61-118380 describes the general formula (G)
  • R 1 G is hydroxymethyl or carboxy which may be protected
  • R 2 G is hydrogen, linear or branched lower alkyl or lower alkenyl, C 4-7 cyclic alkyl, Phenyl, phenyl-lower alkyl, hydroxy, thienyl or furyl, and the broken line represents the presence or absence of a double bond.
  • the present inventors have conducted intensive studies to find a compound having a PPAR receptor regulating action, and as a result, have found that the compound represented by the general formula (I) achieves the object, and completed the present invention.
  • the present invention is a.
  • R 1 and R 2 each independently represent a hydrogen atom, a Cl-8 alkyl group, a Cl-4 alkoxy group, a halogen atom, a nitro group, or a trifluoromethyl group;
  • A represents a linear C 1-3 alkylene group, a single C O— group or a —CH (OH) — group;
  • R3 represents a —COOR5 group (wherein, R5 represents a hydrogen atom or a c1-4 alkyl group), or a 1H-tetrazol-15-yl group;
  • Y represents a 10_, 1S- or -NR7- group (wherein, R7 represents a hydrogen atom or a C1-4 alkyl group). ) Represents a group represented by )
  • the alkyl group, the alkylene group, and the alkoxy group include those having a straight chain and those having a branched chain. It also includes isomer groups resulting from the presence of asymmetric carbon atoms, such as when a branched alkyl group is present.
  • the c1-4 alkyl group represented by R5 and R7 is a methyl, ethyl, propyl, butyl group or a heterobiogenic group thereof.
  • the C 1-8 alkyl group represented by R 1 and R 2 is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomer groups thereof. .
  • the halogen atoms represented by R 1 and R 2 are a fluorine, chlorine, bromine and iodine atom.
  • the linear C1-3 alkylene group represented by A is a methylene, ethylene or trimethylene group, preferably a methylene group.
  • A is preferably a methylene group or a C 1 O— group, and more preferably a C 1 O— group.
  • Examples of the 8- to 11-membered saturated or unsaturated bicyclic carbocyclic group represented by are: pentalene, indene, naphthalene, dihydroindene, dihydronaphthalene, tetrahydronaphthalene and the like.
  • Preferred heterocyclic groups include
  • More preferred heterocyclic groups are It is 14-hexane represented by.
  • Specific compounds include the compounds described in Tables 1 to 8 below, their non-toxic salts, their acid addition salts, their hydrates, and the compounds described in Examples.
  • the specific compounds shown below include isomers generated by the presence of asymmetric carbon, that is, R-form, S-form, and RS-form.
  • Me represents a methyl group
  • MeO represents a methoxy group.
  • the above oxidation reaction can be carried out, for example, by generally well-known Jones oxidation or the like.
  • R3 is a —COOR5-1 group (wherein, R5-1 represents c 1-4 alkyl), and A is a —CO— group, that is, a compound represented by the general formula (I—c)
  • the compound of the present invention represented by the general formula (Ib) can be produced by subjecting the compound represented by the general formula (Ib) to an esterification reaction. it can.
  • esterification reaction The reaction of converting an acid into an ester (esterification reaction) is known, and for example,
  • the method of using diazoalkanes is, for example, using the corresponding diazoalkanes in an inert organic solvent (getyl ether, ethyl acetate, methylene chloride, acetate, methanol, ethanol, etc.) at a temperature of 10 to 40 ° C.
  • the method using an alkyl halide may be performed, for example, in an organic solvent (acetone, dimethylformamide (DMF), N, N-dimethylacetamide, dimethylsulfoxide (DMSO), etc.) in a base (potassium carbonate). , Sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.)
  • the reaction is carried out at a temperature of 110 ° C to 40 ° C.
  • the method using DMF-dialkyl acetal is performed, for example, by using the corresponding DMF-dialkyl acetal in an inert organic solvent (benzene, toluene, etc.) at a temperature of 10 t: up to 40 ° C. It is done in.
  • an inert organic solvent benzene, toluene, etc.
  • the method of reacting with a corresponding alkanol is, for example, as follows: in a corresponding alkanol, an acid (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, hydrogen chloride gas, etc.) or a condensing agent (dicyclohexylcarbodiimide) (DCC), Vivaloyl halide, arylsulfonyl halide, alkylsulfonyl halide, etc.).
  • these reactions may be carried out by adding an inert organic solvent which does not participate in the reaction (tetrahydrofuran (THF), methylene chloride, etc.).
  • an inert organic solvent which does not participate in the reaction (tetrahydrofuran (THF), methylene chloride, etc.).
  • R3 is one COOR5-1 group (wherein, R5-1 represents c1-4 alkyl), and A is a —CO— group, that is, a compound represented by the general formula (1-1)
  • X 1 represents a halogen atom, and the other symbols have the same meanings as described above.).
  • the reaction is performed using an inert organic solvent (tetrahydrofuran (THF), getyl ether, methylene chloride, chloroform).
  • THF tetrahydrofuran
  • getyl ether methylene chloride, chloroform
  • Mouth form carbon tetrachloride, pentane, hexane, benzene, toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphamide (HMPA), etc., base (hydrogenation)
  • the reaction is performed at 0 to 80 ° C in the presence of sodium, potassium carbonate, triethylamine, pyridine, sodium iodide, cesium carbonate, and the like.
  • the compound represented by the general formula (Y-1) is —NHR 7 group
  • the compound is in an inert organic solvent as described above or in the absence of a solvent, if necessary, in the presence of a tertiary amine such as triethylamine. At 0-80 ° C.
  • the compound represented by the general formula (1-1) can be produced by subjecting the compound represented by the general formula (1-1) to a saponification reaction.
  • the saponification reaction is a known reaction, for example, an organic solvent miscible with water.
  • an alkali potassium hydroxide, sodium carbonate, sodium carbonate
  • an inert organic solvent miscible with water such as methanol, ethanol, and dioxane
  • the reaction is carried out at 0 to 50 ° C using an aqueous solution of
  • reaction of reacting the above cyano group with an azide and leading to a 1 H-tetrazole-5-yl group is known.
  • an inert organic solvent dimethylformamide, N-methylpyrrolidone, etc.
  • azide sodium azide, lithium azide, potassium azide, etc.
  • a weak acid eg, pyridium chloride, ammonium chloride, dimethylanilin hydrochloride
  • a 3 represents a straight-chain C 1-2 alkylene group, and other symbols have the same meanings as described above.).
  • Compound A 4 is a C 1 to 3 alkylene group, straight chain, a compound having a water group obtained above is obtained by subjecting the further reduction reaction.
  • This reaction For example, using ammonium formate as a hydrogen source, an organic solvent (methanol, ethanol, THF, acetic acid, etc.) and a catalyst (palladium carbon, palladium, platinum black, nickel, etc.) at 40 to 110 ° Performed at a temperature of C.
  • HMPA hexamethylphosphamide
  • acetone etc.
  • a base sodium hydride, potassium carbonate, triethylamine, pyridine, sodium iodide, cesium carbonate, etc.
  • R 3 is one CO 0H group
  • A is a linear C 1-3 alkylene group or a CO— group, that is, a compound represented by the general formula (I— h)
  • the compound of the present invention represented by the general formula (Ig) can be produced by subjecting the compound represented by the general formula (Ig) to a saponification reaction.
  • the saponification reaction can be performed in the same manner as described above.
  • reaction for treating with an alcohol and the reaction for acting on azide can be carried out in the same manner as described above.
  • the reduction reaction can be performed in the same manner as described above.
  • the compounds represented by (IX) and (X) are known compounds per se, or can be produced by known methods or the methods described in Examples.
  • the compound represented by the general formula (Z) is a compound known per se, or can be produced by a known method or a method similar to the production methods (a) to (e) described above.
  • the compounds represented by the general formulas (IV), (Y-1), (V), (VI), (Z), (VII), (IX) and (X) are obtained by the following reaction schemes 1-1 It can be manufactured by the method indicated by 1.
  • the compounds represented by the general formula (Z) are represented by the general formulas (Z_l), (Z-2),
  • R 6 General protecting group for hydroxyl group, for example, methoxymethyl group, THP group, acetyl group, etc.
  • Y a a hydroxyl group protected with a protecting group for a hydroxyl group (eg, a methoxymethyl group, a THP group, an acetyl group, etc.) or a mercapto group protected with a protecting group for a mercapto group (eg, a methoxymethyl group, a THP group, etc.)
  • a protecting group for a hydroxyl group eg, a methoxymethyl group, a THP group, an acetyl group, etc.
  • a mercapto group protected with a protecting group for a mercapto group eg, a methoxymethyl group, a THP group, etc.
  • An NHR group protected with an amino protecting group for example, a Boc group
  • HOB t 1—hydroxybenzotriazole
  • TMSNQ trimethylsilyl azide
  • the starting materials in each reaction scheme are known per se or can be prepared by known methods.
  • the compounds described herein are converted to salts by known methods.
  • the salt is preferably non-toxic and water-soluble. Suitable salts include salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium). , Triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine methane, lysine, arginine, N-methyl-D-glucamine Etc.).
  • Non-toxic acid addition salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate, or acetate, lactate, tartrate, oxalate, and fumarate Such as acid, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethonate, glucuronate, gluconate Organic acid salts and the like.
  • the compound of the present invention, a non-toxic salt thereof, or an acid addition salt thereof described herein may be converted into a hydrate by a known method. [Pharmacological activity]
  • TK thymidine kinase
  • a response element of Ga14 protein a yeast basic transcription factor, is inserted upstream of the TK promoter, and an enhancer sequence that repeats UAS four times is inserted into 4 XUAS-TK-Luc.
  • the enhancer sequence SEQ ID NO: 1 used is shown below. Sequence number 1: Enhancer sequence which repeated Ga14 protein response element
  • a vector expressing the quinula receptor protein fused with the ligand-binding region of the PPAR7 receptor was constructed as follows. That is, PicaGene Basic Vector 2 (trade name, Toyo Ink Co., Catalog No. 309-04821) was used as a basic expression vector, while the promoter-enhancer region was kept as it was, and the structural gene was replaced with that of the chimeric receptor protein.
  • the DNA encoding the ligand-binding region of the human PPAR7 receptor is fused downstream of the DNA encoding the amino acid sequence from the 1st to the 147th amino acid sequence of the DNA binding region of the Ga14 protein so that the frame matches. It was inserted downstream of the promoter region of PicaGene Basic Vector 2 (trade name). At this time, the expressed chimera The protein is localized in the nucleus, and the amino terminus of the ligand binding region of the human PPARa receptor has a nuclear translocation signal derived from SV40 T-antigen, A la Pro Lys Lys LysA rg LysVa.
  • CV-1 cells used as host cells were cultured according to a conventional method. That is, fetal bovine serum (GIBCOBRL, catalog No. 26140-061) was added to Dulbecco's modified Eagle's medium (DMEM) to a final concentration of 10%, and further, a 50 U / m1 final concentration of benicillin was added. The cells were cultured at 37 ° C. in 5% carbon dioxide gas in a medium containing G and 50 gZm1 of streptomycin sulfate.
  • DMEM Dulbecco's modified Eagle's medium
  • reporter gene and Ga14-PPAR expression vector into host cells.
  • transfection seed cells 2 x 106 cells in a 10 cm dish in advance, and use serum After washing once with a medium containing no, 10 ml of the same medium was added.
  • Reporter gene 1 Q ⁇ g , G a 14—P PAR expression 0.5 g of Vector-1 and 50 ⁇ 1 of LipofectA NE (trade name, GIBCO BRL, catalog No. 18324-012) were mixed well and added to the culture dish. The culture was continued at 37 ° C for 5 to 6 hours, and a medium containing 20 ⁇ 3 ⁇ 4 of dialyzed fetal bovine serum (GIBCO BRL, Kataguchi No.
  • the compounds of the present invention represented by the general formula (I), their non-toxic salts, their acid addition salts, and their hydrates have an effect of controlling PPAR receptors (particularly, PFAR receptor).
  • PPAR receptors particularly, PFAR receptor.
  • hypoglycemic agents, hypolipidemic agents, diabetes, obesity, syndrome X, hypercholesterolemia, metabolic disorders such as hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, hypertension, circulation It is useful as a prophylactic or therapeutic agent for nervous system diseases, bulimia, ischemic heart disease, etc., an HDL cholesterol-elevating agent, an agent for reducing LDL cholesterol and / or VLDL cholesterol, a risk factor reducing agent for diabetes and syndrome X It is expected to be.
  • the toxicity of the compound of the present invention was sufficiently low, and it was confirmed that the compound was sufficiently safe for use as a pharmaceutical.
  • a non-toxic salt thereof, an acid addition salt thereof or a hydrate thereof for the above-mentioned purpose, it is usually required to administer orally or non-systemically or locally. It is administered in oral form.
  • the dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but it is usually from 1 mg to 1000 mg per adult, once to several times a day. It is orally administered or parenterally (preferably intravenously) once or several times daily, in the range of 1 mg to 100 mg per adult per day. It is continuously administered intravenously for 1 to 24 hours a day.
  • the doses to be used depend upon various conditions. Therefore, in some cases in an amount less than the above Symbol dose sufficient, also may be necessary beyond the range Oh O 0
  • the compound of the present invention is administered, it is used as a solid composition, a liquid composition and other compositions for oral administration and as an injection, an external preparation, a suppository and the like for parenteral administration.
  • Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Force capsules include hard force capsules soft capsules.
  • the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose. , Starch, polyvinylpyrrolidone, and magnesium aluminate metasilicate.
  • the composition may contain additives other than inert diluents, such as lubricants, such as magnesium stearate, disintegrants, such as calcium cellulose glycolate, and stabilizing agents, such as lactose. Agents, solubilizing agents such as glutamate or aspartic acid.
  • the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary, or with two or more layers. Is also good. Also included are absorbable substances such as gelatin.
  • a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary, or with two or more layers. Is also good.
  • absorbable substances such as gelatin.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like.
  • one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol).
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.
  • the composition may contain a buffering agent, other than an inert diluent, to render it isotonic with stabilizers such as sodium bisulfite, such as sodium chloride, sodium citrate or It may contain isotonic agents such as citric acid.
  • stabilizers such as sodium bisulfite, such as sodium chloride, sodium citrate or It may contain isotonic agents such as citric acid.
  • the method for producing sprays is described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.
  • Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • water-insoluble solution and suspension examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (registered trademark).
  • Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid). Is also good. These are sterilized by filtration through a bacteria retention filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions, for example, sterilized or dissolved in sterile distilled water for injection or other solvents before use of the lyophilized product.
  • compositions for parenteral administration include external solutions, ointments, salves, suppositories for rectal administration and intravaginal administration, which contain one or more active substances and are formulated in a conventional manner. Includes a pouch for administration.
  • the solvent in the kakkou indicated by the chromatographic separation and TLC indicates the elution solvent or developing solvent used, and the ratio indicates the # 1 ratio.
  • Example L A solution of the compound (3.64 g) produced in Reference Example 4, sodium azide (3.4 g) and ammonium chloride (2.8 g) in dimethylformamide (25 ml) was stirred at 110 ° C. for 30 minutes. After cooling the reaction mixture to room temperature,
  • Examples 2 and 2 (1) 1,2-dimethoxybenzene was used instead of 4-methyl-1,2-dimethoxybenzene in Reference Example 1.
  • Example 2 (2) and 2 (3) in Example 1, benzaldehyde was used instead of 4-pentylbenzaldehyde.
  • Example 2 (6) is different from Reference Example 1 in that 4-pentylbenzylaldehyde was used instead of 4-pentylbenzaldehyde, and 1,2-dimethoxy was used instead of 4-methyl-1,2_dimethoxybenzene. Benzene was used.
  • Example 3 Example 3
  • Reference Example 1 Reference Example 2—Reference Example 3—Reference Example 4—The same operation as in Example 1 was performed to obtain a compound having the following physical property values.
  • Example 7 4-methyl-1-methoxybenzene was used in place of 4-methyl-1,2-dimethoxybenzene in Reference Example 1.
  • Example 7 (1) 4-methyl-1,1-methoxybenzene was used instead of 4-methyl-1,2-dimethoxybenzene in Reference Example 1.
  • Example 7 4-t-l-butyl) 1-methoxybenzene was used in place of 4-methyl-1,2-dimethoxybenzene in Reference Example 1. ⁇
  • Example 7 4-t-l-butyl) 1-methoxybenzene was used in place of 4-methyl-1,2-dimethoxybenzene in Reference Example 1. ⁇
  • Example 1 was performed using the compound produced in Reference Example 6, to give the title compound having the following physical data.
  • Example 4 4-Methyl-1- (4-pentylbenzoyl) phenoxyacetic acid Reference Example 1 ⁇ Reference Example 2—Reference Example 3—Example 4—Operations similar to those in Example 5 were performed to obtain the title compound having the following physical property values. However, in Reference Example 1, 4-methyl-11-methoxybenzene was used in place of 4-methyl-1,2-dimethoxybenzene.
  • the solution is sterilized by the conventional method, filled into ampoules in 5 ml portions, freeze-dried by the conventional method, and an ampoule containing 20 mg of the active ingredient in one ampule I got 100.

Abstract

L'invention porte sur des composés représentés par la formule générale (I), sur des sels non toxiques et des sels d'addition acide de ceux-ci et sur leurs hydrates. L'invention porte également sur des contrôleurs du récepteur activé par le proliférateur de peroxisome (PPAR) contenant ces composés comme ingrédients actifs. (Chaque symbole de la figure (I) est tel que défini dans le descriptif). Les composés de cette invention présentent des effets répressifs contre PPAR, et sont par conséquent utiles, par exemple, comme médicaments antihyperglycémiques, antihyperlipidimiques ou comme agents préventifs et/ou thérapeutiques dans les maladies métaboliques telles que les diabètes, l'obésité, le syndrome X, l'hypercholestérolémie et l'hyperlipoprotéinémie, l'hyperlipémie, l'artériosclérose, les maladies circulatoires, la polyphagie et les maladies cardiaques ischémiques.
PCT/JP1998/004116 1997-09-19 1998-09-11 Composes de benzene fusionnes ou non fusionnes WO1999015520A1 (fr)

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JP25578797 1997-09-19

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WO2000064888A1 (fr) * 1999-04-28 2000-11-02 Aventis Pharma Deutschland Gmbh Derives diaryle acide en tant que ligands se fixant sur le recepteur ppar
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6436993B1 (en) 1999-07-13 2002-08-20 The Salk Institute For Biological Studies Use of RAR antagonists as modulators of hormone mediated processes
US6924295B2 (en) 2001-06-18 2005-08-02 Ono Pharmaceutical Co., Ltd. Tetrahydroquinoline derivative compound and drug containing the compound as active ingredient
EP1911462A2 (fr) 2001-01-26 2008-04-16 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
JP2009502777A (ja) * 2005-07-22 2009-01-29 ジュリアーニ インターナショナル リミテッド Ｐｐａｒ受容体及びｅｇｆ受容体に特異的な化合物及びそれらの塩並びに医療分野におけるそれらの使用
JP2009502775A (ja) * 2005-07-22 2009-01-29 ジュリアーニ インターナショナル リミテッド Ｐｐａｒ受容体及びｅｇｆ受容体に特異的な化合物及びそれらの塩並びに医療分野におけるそれらの使用
US7579479B2 (en) 1999-09-22 2009-08-25 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US7951793B2 (en) 2002-07-09 2011-05-31 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
EP2336113A1 (fr) 2004-05-29 2011-06-22 7TM Pharma A/S Ligands de récepteur CRTH2 à usage médical
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
US9682923B2 (en) 2012-02-09 2017-06-20 Nogra Pharma Limited Methods of treating fibrosis
US9682050B2 (en) 2012-04-18 2017-06-20 Nogra Pharma Limited Methods of treating lactose intolerance
US9901557B2 (en) 2009-02-16 2018-02-27 Nogra Pharma Limited Methods of treating hair related conditions
US9913817B2 (en) 2008-12-05 2018-03-13 Nogra Pharma Limited Methods for preventing or reducing colon carcinogenesis
US11905232B2 (en) 2019-02-08 2024-02-20 Nogra Pharma Limited Process of making 3-(4′-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof

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USRE40558E1 (en) 1999-04-28 2008-10-28 Sanofi-Aventis Deutschland Gmbh Therapeutic uses of di-aryl acid derivatives
WO2000064888A1 (fr) * 1999-04-28 2000-11-02 Aventis Pharma Deutschland Gmbh Derives diaryle acide en tant que ligands se fixant sur le recepteur ppar
US6635655B1 (en) 1999-04-28 2003-10-21 Aventis Pharma Deutschland Gmbh Therapeutic uses of di-aryl acid derivatives
US6436993B1 (en) 1999-07-13 2002-08-20 The Salk Institute For Biological Studies Use of RAR antagonists as modulators of hormone mediated processes
US6919358B2 (en) 1999-09-22 2005-07-19 Bristol-Meyers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6727271B2 (en) 1999-09-22 2004-04-27 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7579479B2 (en) 1999-09-22 2009-08-25 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7053106B2 (en) 1999-09-22 2006-05-30 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7084162B2 (en) 1999-09-22 2006-08-01 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US7241780B2 (en) 1999-09-22 2007-07-10 Bristols-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6653314B2 (en) 1999-09-22 2003-11-25 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
EP1911462A2 (fr) 2001-01-26 2008-04-16 Schering Corporation Combinaisons comprenant un inhibiteur d'absorption de stérol
US6924295B2 (en) 2001-06-18 2005-08-02 Ono Pharmaceutical Co., Ltd. Tetrahydroquinoline derivative compound and drug containing the compound as active ingredient
US7951793B2 (en) 2002-07-09 2011-05-31 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
EP2336113A1 (fr) 2004-05-29 2011-06-22 7TM Pharma A/S Ligands de récepteur CRTH2 à usage médical
JP2009502775A (ja) * 2005-07-22 2009-01-29 ジュリアーニ インターナショナル リミテッド Ｐｐａｒ受容体及びｅｇｆ受容体に特異的な化合物及びそれらの塩並びに医療分野におけるそれらの使用
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