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WO2007037010A1 - Dérivés d'acide phénoxyacétique et médicaments utilisant lesdits dérivés - Google Patents

Dérivés d'acide phénoxyacétique et médicaments utilisant lesdits dérivés Download PDF

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Publication number
WO2007037010A1
WO2007037010A1 PCT/JP2005/017981 JP2005017981W WO2007037010A1 WO 2007037010 A1 WO2007037010 A1 WO 2007037010A1 JP 2005017981 W JP2005017981 W JP 2005017981W WO 2007037010 A1 WO2007037010 A1 WO 2007037010A1
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group
methyl
compound
substituted
reference example
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PCT/JP2005/017981
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English (en)
Japanese (ja)
Inventor
Katsuji Kagechika
Yoshihiro Shibata
Hiroyuki Usui
Hideo Kubo
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Daiichi Pharmaceutical Co., Ltd.
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Priority to PCT/JP2005/017981 priority Critical patent/WO2007037010A1/fr
Publication of WO2007037010A1 publication Critical patent/WO2007037010A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
    • C07D263/36—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a phenoxyacetic acid derivative, a salt thereof, and a solvate thereof effective as an agent for preventing or treating diabetes. More specifically, the present invention relates to a peroxisome proliferator-activated receptor / y agonist (PPAR / y agonist).
  • PPAR / y agonist peroxisome proliferator-activated receptor / y agonist
  • Diabetes mellitus is a disease that develops and develops various acute and chronic complications such as ischemic heart disease and cerebrovascular disorder, and causes a significant impairment in daily life. Therefore, it is necessary to prevent the onset and progression of these complications through early detection and strict glycemic control.
  • Type 1 diabetes and the production of insulin 'secretion is at a high level from the normal range, but it is very sensitive to the target organ and tissue of insulin. It is classified as type 2 diabetes that is reduced (ie, increased insulin resistance).
  • the main target organs and tissues of insulin are muscle, adipose tissue, and liver, which promotes glucose uptake and glycogen synthesis in muscle, and promotes uptake and utilization of dulose in adipose tissue. In the liver, it suppresses gluconeogenesis and promotes glycogen synthesis. Insulin is also involved in fat metabolism (facilitation of fat synthesis and inhibition of degradation) in adipose tissue that is not just for controlling sugar metabolism as described above.
  • Non-patent document 1 thiazolidinedione derivatives such as pioglitazone (non-patent document 1) having the following structure have been developed as drugs for improving insulin resistance, and patients with type 2 diabetes, particularly those with type 2 diabetes Widely used in the treatment of
  • Non-patent Document 2 The mechanism by which PPAR yagonists improve insulin resistance has not been fully elucidated, but it promotes apoptosis of hypertrophic adipocytes that produce and secrete free fatty acids that cause insulin resistance, and from preadipocytes to adipocytes Incorporation of free fatty acids by promoting differentiation into plants ⁇ Promoting storage is cited as a promising theory.
  • PPAR Gamma-agonist pioglitazone is particularly high when administered to type 2 diabetic patients with obesity and has a therapeutic effect, while weight gain and fluid retention are in Watched! / Speak (Non-Patent Document 3).
  • diabetes causes and develops complications such as ischemic heart disease and cerebrovascular disorder, so such weight gain and fluid retention are not desirable.
  • PPAR a / y agonists in which PPAR ⁇ agonists have been subjected to PPAR ⁇ agonist action. It has also been suggested that it exhibits properties as an excellent anti-diabetic drug.
  • Non-patent Document 4 For example, in a test using db / db mice, it has been shown that PPAR a / ⁇ agost KRP-297 significantly suppresses body weight gain compared to pioglitazone. . PPAR a / yagost LY465608 has been shown to increase high-density lipoprotein (HDL) in a dose-dependent manner and lower plasma triglycerides, reducing the risk of ischemic heart disease. (Non-Patent Document 5).
  • HDL high-density lipoprotein
  • Typical PPAR a / y agonists include the following compounds (Non-patent Documents 6 to 7 and Patent Documents 1 and 2).
  • Non-Patent Document 2 J. Biol. Chem., 270, 12953-12956 (1995)
  • Non-Patent Document 3 Am. J. Med., 115 (8A), 111S- 115S (2003)
  • Non-Patent Document 4 Am. J. Physiol, 284, E966-E971 (2003)
  • Non-Patent Document 5 Diabetes, 51, 1083-1087 (2002)
  • Non-Patent Document 6 Bioorg. Med. Chem. Lett., 9, 533-538 (1999)
  • Non-Patent Document 7 Chem. Pharm. Bull, 51, 138-151 (2003)
  • Patent Literature l WO2001-021602
  • Patent Document 2 WO2004—000785
  • the object of the present invention is that the chemical structure is different from the above-mentioned known PPAR a / y agonist, has an excellent PPAR a / y agonist action, and is desirable and has properties as a pharmaceutical product. Is to provide a compound.
  • Q is a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, a pyrrolidinyl group, a piperidyl group, a piperazyl group, a morpholinyl group, a substituted group Or an unsubstituted phenol group and a substituted or unsubstituted pyridyl group, selected from one or two of the same or different groups, a benzene ring or a pyridine ring,
  • R 1 is a halogen atom, a lower alkenyl group, a lower alkoxy group, a phenoxy group, a substituted or unsubstituted lower alkyl group and a substituted or unsubstituted amino group, one selected from the same or two of the same or different A phenyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyradyl group, a chael group, a furyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, Represents isothiazolyl, isoxazolyl, oxaziazolyl or triazolyl,
  • R 2 represents a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted pyridyl.
  • X, Y and Z each independently represent C, 0, S or N (provided that at least one of X, Y and Z is 0, S or N);
  • R 3 to R 6 each independently represent a hydrogen atom or a lower alkyl group, or R 3 and R 5 and R 6 together with the carbon atom they are substituted with 3 to 6 Indicates that a saturated ring of members may be formed,
  • R 8 and R 9 each independently represent a hydrogen atom or a lower alkyl group, and n represents an integer of 0 to 3.
  • the present invention also provides a compound, salt or solvate thereof, which is a 5-membered oxazole ring, thiazole ring or oxaziazole ring containing X, Y and Z in the general formula (I). .
  • Q in the general formula (I) is one or more of the same or different selected from the group consisting of a halogen atom, a lower alkenyl group, a lower alkoxy group, and a substituted or unsubstituted lower alkyl group.
  • a compound which is substituted with two groups and which is a benzene ring, a salt thereof or a solvate thereof is provided.
  • R 1 in the above general formula (I) may be substituted with one of the halogen atoms and one of the same or different groups of the same or different groups selected from the substituted or unsubstituted lower alkyl groups.
  • R 2 in the above general formula (I) is selected from the group consisting of a halogen atom, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted phenyl group.
  • the present invention provides a compound having a benzoxazolyl group, a salt thereof, or a solvate thereof.
  • R 2 in the above general formula (I) is one or two lower groups of the same or different types.
  • the present invention provides a compound, a salt thereof or a solvate thereof which is a carbamoyl group substituted with an alkyl group.
  • the present invention also provides a pharmaceutical comprising the compound represented by the above general formula (I), a salt thereof or a solvate thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition comprising a compound represented by the above general formula (I), a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier. Furthermore, the present invention provides use of a compound represented by the above general formula (I), a salt thereof or a solvate thereof for the production of a medicament.
  • the present invention provides a method for treating a disease caused by insulin resistance, which comprises administering an effective amount of a compound represented by the above general formula (I), a salt thereof, or a solvate thereof. It is to provide.
  • R 7 represents a hydrogen atom or an unsubstituted lower alkyl group
  • R 1QQ represents a methyl group or a methoxy group
  • R 2 ° represents a hydrogen atom or a methyl group.
  • the present invention provides a medicament containing the compound represented by the above general formula ( ⁇ ), a salt thereof, or a solvate thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the above general formula ( ⁇ ), a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides an insulin resistance improving agent containing the compound represented by the above general formula ( ⁇ ), a salt thereof, or a solvate thereof.
  • the present invention also provides a therapeutic agent for diabetes containing the compound represented by the above general formula ( ⁇ ), a salt thereof or a solvate thereof.
  • the present invention also provides a method for treating a disease caused by insulin resistance, which comprises administering an effective amount of a compound represented by the above general formula ( ⁇ ), a salt thereof, or a solvate thereof.
  • the compound represented by the general formula (I) of the present invention exhibits an excellent PPAR a Z agonist action, and is useful as a preventive / therapeutic agent for diabetes.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • halogen atom a fluorine atom and a chlorine atom are preferable.
  • the unsubstituted lower alkyl group means a linear, branched and cyclic alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, and pentyl.
  • the substituted lower alkyl group is a hydroxyl group, a halogen atom, an amino group, an alkylamino group, dia Kilamino group, lower alkoxy group, carboxy group, lower alkoxy carbo group, carbamoyl group, alkyl strength rubamoyl group, dialkyl strength rubamoyl group, strength rubamoylamino group, alkyl strength rubamoylamino group, dialkyl strength rubamoylamino group, alkylsulfo-lumino Means a lower alkyl group substituted with 1 to 3 groups of the same or different types selected from a group, a lower alkoxycarbolumino group and a lower alkanoylamino group, such as a trifluoromethyl group, hydroxy Methyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2-fluoroethyl group, 2-chloroethyl group, 3-fluoropropy
  • Trifluoromethyl group hydroxymethyl group, 2-hydroxyethyl group, 2-fluoroethyl group, 2-chloroethyl group, aminomethyl group, 2-aminoethyl group, methylaminomethyl group, 2-methylaminoethyl group, Dimethylaminomethyl group, 2-dimethylaminoethyl group, methoxymethyl group, 2-methoxyethyl group, carboxymethyl group, 2-carboxetyl group, methoxycarboromethyl group, 2-methoxycarboruethyl group, rubamoylmethyl Group, 2-force rubamoylethyl, methylcarbamoylmethyl, 2-methylcarbamoylethyl, ethylcarbamoylmethyl, 2-ethylcarbamoylethyl, dimethylcarbamoylmethyl, 2-dimethylcarbamoylethyl, Tylcarbamoylmethyl group, 2-jetylcarb
  • the lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include a bur group, a allyl group, and a butenyl group. it can.
  • the lower alkoxy group means an alkoxy group having a linear, branched and cyclic alkyl group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group.
  • Typical examples include butoxy group, isobutoxy group, pentoxy group, and cyclopentyloxy group. Of these, methoxy groups and methoxy groups are preferred, and methoxy groups are more preferred.
  • the substituted amino group is an alkylamino group, a dialkylamino group, a lower alkoxycarboamino group, a strong ruberamoylamino group, an alkyl strength ruberamoylamino group, a dialkyl power ruberamoylamino group, an alkylsulfo-amino group, or a lower alkanoyl group.
  • Mino group for example, methylamino group, ethylamino group, propylamino group, butylamino group, pentylamino group, hexylamino group, 1-methylethylamino group, 1,1-dimethylethylamino group, 1 —Methylpropylamino group, dimethylamino group, jetylamino group, dipropylamino group, dibutylamino group, dipentylamino group, dihexylamino group, di (1 methylethyl) amino group, methylethylamino group, methoxycarbolumino group , Ethoxycarbo-lamino group, methyl
  • Representative examples include carbamoylamino, ethylcarbamoylamino, dimethylcarbamoylamino, jetylcarbamoylamino, methylsulfo-lamino, ethylsulf
  • the substituted phenol group is an alkyl group, a hydroxyl group, a halogen atom, an amino group, or an alkylamino group. It means a phenyl group substituted with one or two groups of the same or different types, wherein the intermediate force of a group, a dialkylamino group, a lower alkoxy group, a phenoxy group and a substituted or unsubstituted amino group is also selected.
  • Specific examples of the mono-substituted phenyl group include methyl, trifluoromethyl, ethyl, hydroxy, fluoro, fluoro, chloro, bromo and aminophenyl groups.
  • the thiol group include a fluoromethylphenol group, a black methylphenyl group, a fluorohydroxyphenyl group, a chloromethyl group, and a chloromethyl group. Mouth hydroxyphenol group, difluorophenol group, dichlorophenol group, black mouth fluorophenol group, aminofluorophenol group, aminochlorophenol group, fluoromethylaminophenol Group, chloromethylaminophenol group, dimethylamino-fluorophenol group, dimethylamino-chlorophenol group, jetylamino-fluorophenol group, chloromethylaminophenol group, fluorine Low methoxyphenyl group, chloromethoxyphenyl group, fluoromethoxycarboaminophenol group, chloromethoxycarbonylaminophenol group, strong rubamoylaminofluorophenol group, strong rubamoyl group Aminochrome mouth group, Fluoromethylcarbamoylaminophenol group, Chloromethyl
  • the mono-substituted phenyl group includes methyl, trifluoromethyl, methoxy, phenoxy, fluoro and chlorophenols, and bromophenol.
  • a methylphenol group, a trifluoromethylphenol group, a methoxyphenyl group, a phenoxyphenol group, a fluorophenol group, and a black mouthphenol group are preferred.
  • Examples of the disubstituted phenol group include a fluoromethylphenol group, a chloromethylphenol group, and a difluorophenol group. Preferred are difluorophenol, dichlorophenol, and chlorophenol, chlorophenol, fluoromethoxy, fluoromethoxy, and methoxyphenol. Mouth Fluorophenol group is more preferred.
  • the substituted pyridyl group is selected from the group consisting of an alkyl group, a hydroxyl group, a halogen atom, an amino group, an alkylamino group, a dialkylamino group, a lower alkoxy group, a phenoxy group, and a substituted or unsubstituted amino group. Or it means that two different groups are substituted.
  • methylpyridyl group trifluoromethylpyridyl group, ethylpyridyl group, hydroxypyridyl group, fluoropyridyl group, cyclopyridyl group, bromopyridyl group, aminoviridyl group, methylaminoviridyl group, and ethylamino.
  • Biridyl group dimethylaminopyridyl group, jetylaminopyridyl group, methoxypyridyl group, phenoxypyridyl group, methoxycarbolaminopyridyl group, rubamoylaminopyridyl group, methylcarbamoylaminopyridyl group, dimethylcarbamoylamino group Pyridyl, methylsulfonylamino, and acetylaminopyridyl groups can be listed as typical examples of mono-substituted pyridyl groups, such as fluoro-methylpyridyl, black-mouthed methylpyridyl, and fluoro-hydroxypyridyl.
  • Mono-substituted pyridyl groups include methylpyridyl group, trifluoromethylpyridyl group, methoxypyridyl group, phenoxypyridyl group, fluoropyridyl group, A methylpyridyl group, a trifluoromethylpyridyl group, a methoxypyridyl group, a phenoxypyridyl group, a fluoropyridyl group, and a chloropyridyl group, which are preferred to a zyl group and a bromopyridyl group, are more preferred.
  • Examples of the di-substituted pyridyl group include a fluoro-methylpyridyl group, a chloromethylpyridyl group, a difluoropyridyl group, a dichloropyridyl group, a black chloropyridyl group, a fluoro-methoxypyridyl group, and a chloro-methoxypyridyl group.
  • a difluoropyridyl group, a dichloropyridyl group, and a chlorofluoropyridyl group are more preferable.
  • R 1 is selected from the group consisting of a halogen atom, a lower alkenyl group, a lower alkoxy group, a phenoxy group, a substituted or unsubstituted lower alkyl group and a substituted or unsubstituted amino group, one or the same or different 2 More specifically, phenyl group, pyridyl group, and chael group, which may be substituted with one group, are preferred, such as phenyl group, fluorophenyl group, chlorophenol group, and bromophenol.
  • R 2 represents a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted phenol group, and a substituted or non-substituted group.
  • Q includes benzene ring, hydroxybenzene ring, fluorobenzene ring, black benzene ring, bromobenzene ring, bullbenzene ring, arylbenzene ring, methoxybenzene ring, ethoxybenzene ring, methylbenzene ring, ethylbenzene ring, methoxymethylbenzene.
  • benzene ring hydroxybenzene ring, fluorobenzene ring, black benzene ring, arylbenzene, methoxybenzene ring, methylbenzene ring, phenylbenzene ring, pyridylbenzen ring, pyridine ring, hydroxypyridine.
  • Preferred examples include a ring, a fluoropyridine ring, a black pyridine ring, an aryl pyridine ring, a methoxy pyridine ring, and a methyl pyridine ring.
  • a benzene ring a fluorobenzene ring, a black benzene ring, a bromobenzene ring, a Benzene ring, methoxybenzene ring, methylbenzene ring, difluorobenzene ring, dimethylbenzene ring, methyl-ethylbenzene ring, methyl-methoxybenzene ring, methyl-chlorobenzene ring, methoxy-fluorobenzene ring, dimethoxybenzene ring, and
  • a more preferred example is a pyridine ring.
  • a benzene ring, an arylbenzene ring, a methoxybenzene ring, a methylbenzene ring, a dimethylbenzene ring, a methylethylbenzene ring, a methyl-methoxybenzene ring, a methylchlorobenzene ring, and a dimethoxybenzene ring are particularly preferable.
  • a hydrogen atom in which a hydrogen atom, a methyl group and an ethyl group are preferable and a hydrogen atom in which a methyl group is more preferable are more preferable.
  • R 5 and R 6 are each preferably a hydrogen atom, a methyl group, or an ethyl group, or a 3- to 6-membered saturated ring formed by combining R 6 with a carbon atom. ,. R 5 and R 6 are each preferably a hydrogen atom and a methyl group, and more preferably a methyl group. R 5 and R 6 are both particularly preferably a methyl group.
  • R 7 is preferably a hydrogen atom, a methyl group, an ethyl group, or a tert-butyl group.
  • R 8 and R 9 are each preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom, a methyl group, or an ethyl group.
  • n is a force that is an integer of 0 to 3 0 to 2 force S, preferably 1 to 2.
  • the ring containing X, Y and Z in the general formula (I) means a 5-membered heterocyclic ring, and is a thiophene ring, a furan ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an oxazole ring.
  • Specific examples include an isothiazole ring, an isoxazole ring, an oxaziazole ring, and a triazole ring.
  • this 5-membered heterocyclic ring is a thiazole ring, an oxazole ring, an isothiazole ring, an isoxazole ring or a triazole ring, it is considered that there is no R 9 substituted for this heterocyclic ring. If is an oxadiazole ring, it is considered that there are no R 8 and R 9 substituted on this heterocycle.
  • the 5-membered heterocyclic ring in which the substituents R 8 and R 9 are substituted on the 5-membered heterocyclic ring includes a thiophene ring, a furan ring, a pyrrole ring, an imidazole substituted with one methyl group or one ethyl group.
  • Preferred examples include rings, pyrazole rings, thiazole rings, oxazole rings, isothiazole rings, isoxazole rings and triazole rings, and thiophene rings, furan rings, pyrrole rings, imidazole rings, and pyrazole rings substituted with two methyl groups. be able to.
  • a methyl group substituted by one methyl group a thiophene ring, a furan ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an oxazole ring, an isothiazole ring, an isoxazole ring and a triazole ring are more preferred.
  • Particularly preferred are a thiazole ring and an oxazole ring substituted by one.
  • an oxadiazole ring can be mentioned as the ring.
  • R 7 represents a hydrogen atom or an unsubstituted lower alkyl group
  • R 1QQ represents a methyl group or a methoxy group
  • R 2 ° represents a hydrogen atom or a methyl group. ) The compound represented by these can be mentioned.
  • Compound ( ⁇ ) also showed a high blood glucose lowering effect in dbZdb mice, and decreased blood insulin levels.
  • the decrease in blood insulin level is thought to be the result of improved insulin resistance as follows.
  • insulin-dependent peripheral tissue uptake is impaired due to a decrease in insulin sensitivity (insulin resistance) in peripheral tissues, which is considered to be mainly caused by obesity.
  • insulin sensitivity insulin sensitivity
  • peripheral tissues which is considered to be mainly caused by obesity.
  • insulin secretion from spleen j8 cells is enhanced, and the insulin concentration in the blood is high (hyperinsulinemia).
  • hypoinsulinemia hyperinsulinemia
  • a decrease in blood insulin level due to administration of the above-mentioned compound ( ⁇ ) is considered to result from a decrease (normalization) in insulin concentration as a result of an improvement in insulin resistance and a decrease in blood glucose level (normalization).
  • the compound represented by the general formula (I) of the present invention may have stereoisomers or optical isomers derived from asymmetric carbon atoms. These stereoisomers and optical isomers may exist. And deviations of these mixtures are also included in the present invention.
  • the salt of the compound represented by the general formula (I) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specific examples include hydrochloride, hydrobromide, iodine, and the like.
  • Organic sulfonates such as hydroacids, phosphates, nitrates and sulfates, mineral salts such as benzoates, methanesulfonates, 2-hydroxyethanesulfonates and p-toluenesulfonates
  • organic carboxylic acids such as acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and mandelate Examples thereof include salts.
  • the compound represented by the general formula (I) may be a salt of an alkali metal ion or an alkaline earth metal ion.
  • the solvate is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrates and ethanol solvates.
  • the compound of the present invention suppresses excessive weight gain.
  • the compound of the present invention has a strong agonizing action on both the PPAR a receptor and the PPAR y receptor, and the insulin resistance is improved by the PPAR y receptor agonizing action. It is considered that excessive weight gain is suppressed by the action of PPAR a receptor agonist.
  • the compound of the present invention has excellent qualities as a therapeutic agent for diabetes.
  • the absorption rate of gastrointestinal tract is generally low due to the low solubility.
  • the compound of the present invention exhibits sufficient water solubility under acidic to neutral conditions and has excellent qualities as a pharmaceutical product.
  • la and lb type compounds may be substituted, pyridyl group, pyrimidyl Group, birazinyl group, pyridazinyl group, imidazolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, isothiazolyl group, isoxazolyl group, oxadiazolyl group, triazolyl group, quinolyl group, isoquinolyl group, quinazolyl group, cinnolyl group, quinazolyl group, phthaloxalyl group Nyl group, naphthyridinyl group, indolyl group, benzoimidazolyl group, indazolyl group, benzothiazolyl group, benzoxazolyl group, benzoisothiazolyl group, benzoisoxazolyl group, or benzotriazolyl group) Natsu!
  • R 1 R 2 .R 5 to RS, Q, X, Y, ⁇ and ⁇ are as defined above.
  • Compound 3 can be synthesized by reacting compound 1 and aldehyde 2 in the presence of a reducing agent. Compound 1 and aldehyde 2 are generated in the presence or absence of an acid such as acetic acid, and then a reducing agent is allowed to act to give compound 3. In this case, compound 3 can also be synthesized by dissolving compound 1 and aldehyde 2 in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base. Usually, aldehyde 2 is used in an equimolar amount or an excess molar amount relative to compound 1.
  • Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the compound 1 is usually equimolar or excess molar, preferably 3 Use from 5 to 5 moles of reducing agent.
  • Examples of the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, dichloromethane and chloroform-form alkane, and the like.
  • the reaction temperature is up to the boiling point of the solvent which also uses 20 ° C force, preferably 0 ° C to 50 ° C, and the reaction time is 15 minutes to 24 hours, preferably about 30 minutes to 10 hours.
  • Synthesis of compound la from compound 3 is achieved by reacting compound 3 and aldehyde 4 in the presence of a reducing agent.
  • a reducing agent usually, an equimolar amount or an excess molar amount of aldehyde 4 is used with respect to compound 3.
  • the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, preferably sodium triacetoxyborohydride, and usually equimolar or excess to compound 3. Mol, preferably 2 to 3 moles of reducing agent is used.
  • reaction solvent examples include halogenated alkanes such as dichloromethane and black mouth form
  • the reaction temperature is 0 ° C force up to 40 ° C, preferably 0 ° C to 30 ° C
  • reaction time is 1 hour force. 48 hours, preferably 1 to 30 hours.
  • the solvent examples include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, water, and mixed solvents thereof.
  • the reaction temperature is 0 ° C to 100 ° C, preferably 0 ° C to 60 ° C.
  • the reaction time varies depending on the type of ester, and is usually 1 to 72 hours, preferably 1 to 24 hours.
  • R 7 of compound la is a tert butyl group
  • the reaction can be carried out by a method of reacting an acid such as trifluoroacetic acid or hydrochloric acid. Trifluoroacetic acid, hydrochloric acid Uses molar excess.
  • the solvent include solvents such as dichloromethane and dioxane.
  • the reaction temperature is 0 ° C up to the boiling point of the solvent to be used, preferably 0 ° C to 30 ° C, and the reaction time is 1 hour at 48 hours, preferably 1 to 24 hours.
  • the compound la is synthesized from the compound 3 by the following synthesis method 1.
  • Synthesis of compound la from compound 3 is carried out by allowing compound 5 to act on compound 3 in an equimolar to excess mole, preferably equimolar to 2 moles in the presence of a base.
  • Reaction accelerators such as -um and yodo potassium can be used.
  • the base tertiary amines such as triethylamine, carbonates such as potassium carbonate and cesium carbonate are used in equimolar or excess moles.
  • the solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, solvents such as N, N dimethylformamide, and acetonitrile.
  • the reaction temperature is from 20 ° C to the boiling point of the solvent used, preferably from room temperature to 80 ° C, and the reaction time is from 1 hour to 7 days, preferably from 1 hour to 48 hours.
  • synthesis method 1-1 is preferred.
  • R 1 R 2 , R 5 to R 9 , X, ⁇ , ⁇ and ⁇ represent the above, and R 10 and R 11 represent a hydrogen atom or a lower alkyl group. .
  • Synthesis of compound 7 from compound 3 is carried out by synthesizing compound 3 and darioxylic acid 6 with a metal hydride complex such as sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, preferably sodium triacetoxyborohydride. It is done by acting. Usually, equimolar or excess molar amount of dalioxylic acid 6 is used with respect to compound 3.
  • the metal hydride complex is usually used in an equimolar amount or an excess molar amount, preferably 2 to 3 moles, relative to Compound 3.
  • the reaction solvent include inert solvents such as tetrahydrofuran, dichloromethane, and chloroform.
  • the reaction temperature is 0 ° C force up to 40 ° C, preferably about 0 ° C to 30 ° C, and the reaction time is 1 The time is 48 hours, preferably 1 hour to 10 hours.
  • the compound Ic can be synthesized from the compound 7 by allowing the amine 7 to act on the compound 7 in the presence of a condensing agent.
  • a condensing agent for example, equimolar to excess molar amount of amine 8 with respect to compound 7 is ⁇ 50 ° C. in an inert solvent! This is done by acting in the presence.
  • the reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 12 hours.
  • Condensation agents include N, N'-dicyclo Xylcarbodiimide, 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide, cetyl cyanophosphate, benzotriazolyloxy-tris [pyrrolidino] -phospho-um hexafluorophosphate, 2- (1H benzotriazole 1 — 1, 1, 3, 3-Tetramethinore mouth-um Tetrafluoroborate, etc.
  • the compound 7 is used in an equimolar to excess molar amount, preferably 1 to 5 molar relative to compound 7.
  • the inert solvent include solvents such as dichloromethane, N, N-dimethylformamide, tetrahydrofuran, and ethyl acetate, or a mixture thereof. If necessary, it can be carried out in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine or 4-dimethylaminopyridine.
  • N-hydroxy compounds such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc., or 4-nitrophenol, 2,4 dinitrophenol, 2,4,5 triclonal phenol, pentachromic Phenolic compounds such as phenol can be added as a reaction accelerator.
  • Compound Ic Force Compound Id can be synthesized by the same method as in the synthesis of Compound la force Compound lb in Synthesis Method 11.
  • the synthesis method of the compound 2 used in the synthesis method 11 can be synthesized according to the following synthesis method 3.
  • Compound 2 can be synthesized by reacting compound 10 with compound 10 in the presence of a base.
  • Compound 10 with an excess molar amount of cesium carbonate and potassium carbonate with respect to compound 9
  • a tertiary amine such as carbonate or triethylamine.
  • an inert solvent such as N, N dimethylformamide or dichloromethane is used.
  • the reaction temperature is up to the boiling point of the solvent used at room temperature, and the reaction time is from 1 hour to 3 days, preferably from about 1 hour to 1 day.
  • the compound of the present invention can be administered as a prophylactic / therapeutic agent for diabetes by various methods such as oral administration.
  • oral administration it may be a free form or a salt form.
  • an appropriate preparation can be selected according to the administration method, and it can be prepared by various preparation methods commonly used.
  • examples of the form of the preparation include tablets, fine granules, powders, granules, turnips.
  • Cell agents and the like can be exemplified as oral preparations, among which tablets are preferable.
  • Solid preparations include active pharmaceutical ingredients and pharmaceutically acceptable additives, such as fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants. It is possible to select and mix types as necessary to prepare a formulation.
  • the dosage when administered as a prophylactic or therapeutic agent for diabetes, is preferably 0.1 mg to 1500 mg, more preferably 1 mg to 500 mg per person per person. This dose may be administered once a day or divided into 2 to 3 times.
  • Reference Example 1 Dissolving the compound (5.3 g) in (1) in tetrahydrofuran (150 ml) and adding triphenylphosphine (6. Og) and water (1. Oml) at 0 ° C. And stirred at room temperature all day and night. After evaporating the solvent under reduced pressure, the residue was dissolved in dichloromethane (100 ml), ditert-butyl dicarbonate (8. Oml) and saturated aqueous sodium hydrogen carbonate (50 ml) were added, and the mixture was stirred at room temperature for 1 hr.
  • Reference Example 1 The compound (2. Og) of 1 (3) and the compound of Reference Example 2 (2.4 g) were dissolved in black mouth form (30 ml) and heated to reflux for 5 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in methanol (40 ml), sodium borohydride (0.85 g) was added at 0 ° C, and the mixture was stirred for 1 hour while gradually returning to room temperature. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous layer and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form methanol) to give the title compound (4.21 g) as a yellow oil.
  • Oxazole (3. Og) was dissolved in tetrahydrofuran (120 ml), and n-butyllithium (1.6 M hexane solution, 41 ml) was added dropwise with stirring at 78 ° C. The reaction solution was stirred at ⁇ 10 ° C. for 10 minutes, then cooled again to ⁇ 78 ° C. and stirred for 6 hours. 4 formylmol in the reaction solution Ruphorin (22 ml) was added dropwise and stirred at room temperature for 15 hours.
  • the compound of Reference Example 12 (15.8 g) was dissolved in tetrahydrofuran (300 ml), glycine tert-butyl ester (9 ml) and magnesium sulfate (50 g) were added, and the mixture was heated to reflux for 4 hours.
  • the reaction solution was returned to room temperature, filtered using Celite, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in methanol (100 ml), sodium borohydride (2.3 g) was added while cooling with ice water, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • the residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Reference Example 14 Compound (1. Og) of (3) was dissolved in N, N dimethylformamide (3 ml), and hydrazinecarboxylic acid tert-butyl ester (400 mg), 1- (3-dimethylaminopropyl pill) ) -3-Ethylcarbodiimide hydrochloride (776 mg) and 1-hydroxybenzotriazole (622 mg) were added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed successively with water, 10% aqueous citrate solution, saturated multilayered water, and saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as a yellow oil, which was directly used in the next reaction.
  • Reference Example 16 In the same manner as in (1), the compound of Reference Example 14- (3) (400 mg) and acetic hydrazide (77 mg) title compound (503 mg) were obtained as a pale yellow oil. Got as.
  • Reference Example 14 The compound (0.200 g) obtained in 1 (3) and 2 amino-1 propanol (0.063 ml) were dissolved in methanol (3 ml), and 4- (4, 6 dimethoxy-1, 3, 5 Triazine 2-yl) -4 methylmorpholine n hydrate (0.224 g) was added and stirred at room temperature for 24 hours. Again 2-amino-1-propanol (0.063 ml) and salt 4- (4, 6 dimethoxy-1, 3, 5 triazine-2-yl) -4-methylmorpholine n hydrate (0.224 g) And stirred for another 16 hours.
  • Reference Example 24 In the same manner as (2), the compound (0.15 g) obtained in Reference Example 24 (1) and 2-thiophenecarboxylic acid hydrazide (0.053 g) were also used in the title compound. (0.12 g) was obtained as a yellow oil.
  • Reference Example 24 In the same manner as (2), the compound (0.15 g) obtained in Reference Example 24- (1) and Reference Example 2 7- (1) (0.053 g) The title compound was obtained as a brown oil and used directly in the next reaction.
  • Example 18 In the same manner as (1), the title compound (1. Og) was obtained as a colorless solid from the compound (1. lg) obtained in Reference Example 30- (3). It was.
  • Reference Example 30 The compound (1. Og) obtained in (4) was dissolved in tetrahydrofuran (50 ml), and 1,8 diazabicyclo [5.4.0] undane 7 sen (2%) was cooled with ice water. Tetrahydrofuran solution (42.2 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine.
  • Reference Example 30 The compound (1.70 g) obtained in (2) was dissolved in methanol (30 ml).
  • Reference Example 34 The compound (0.258 g) obtained in (1) was dissolved in dichloromethane (5.2 ml), 4N hydrochloric acid-dioxane solution (5.2 ml) was added, and the mixture was stirred at room temperature for 2 days. Stir. After drying under reduced pressure, the title compound (0.232 g) was obtained as a colorless oil.
  • Reference Example 34 In the same manner as (1), 4-chloromethyl-2- (3-chlorophenol) 5-methyloxazole (0.134 g) and Reference Example 14- (1) compound (0.190 g) Gave the title compound (0.236 g) as a colorless oil.
  • Reference Example 37 In the same manner as (1), 3, 5 dimethyl-4-hydroxybenzaldehyde (1 5. Og) and 2 bromo-2-methylpropanoic acid tert butyl ester (56 ml) were added to potassium carbonate (55.3 g). The title compound (4.47 g) was obtained as a pale yellow oil by treatment at 80 ° C for 2 days in the presence of.
  • Reference Example 16 In the same manner as (1), the compound (0.350 g) obtained in Reference Example 41 (3) and hydrazine carboxylic acid 9H fluorene-9-ylmethyl ester (0.24 g) The compound (0.48 g) was obtained as a yellow oil.
  • Example 19 In the same manner as (2), the title compound (0.73 g) was obtained as a pale yellow oil from the compound (1.10 g) obtained in Reference Example 45- (2). .
  • Reference Example 45 The compound (0.73 g) obtained in (3) was dissolved in dichloromethane (5 ml), and hydrogen bromide (30% acetic acid solution, 5 ml) was added while cooling with ice water. Stir for hours. Vacuum concentration After drying, the title compound hydrobromide (0.345 g) was obtained as a brown oil and used as such in the next reaction.
  • Reference Example 14- In the same manner as (3), the compound (0.173 g) strength obtained in Reference Example 47- (1) was also used to obtain the hydrochloride of the title compound as a colorless oil, Used for.
  • Reference Example 14 In the same manner as (2), 4-chloromethyl mono 5-methyl 2-m-tolylazole (0.175 g) and Reference compound 14- (1) compound (0.23 lg The title compound (0.335 g) was also obtained as a pale yellow oil.
  • Reference Example 14 Similar to (3), Reference Example 49—The compound (0.173 g) obtained in (1) was also used to obtain the hydrochloride of the title compound as a colorless oil, and the reaction Used for.
  • Reference Example 14 In the same manner as in (2), Reference Example 55—The compound obtained in (1) (0.242 g) and Reference Example 14—in the compound obtained in (1) (0.333). g) The title compound (0.435 g) was also obtained as a pale yellow oil.
  • Reference Example 14 In the same manner as (2), Reference Example 57—The compound (0.251 g) obtained in (1) and Reference Example 14— g) The title compound (0.466 g) was also obtained as a pale yellow oil.
  • Reference Example 14 Obtained in the same manner as (2) using 4-chloromethyl-1- (3,5 dichlorophenol) -5-methyloxazole (0.258 g) and Reference Example 14- (1). The title compound (0.406 g) was obtained as a pale yellow oil from the obtained compound (0.322 g).
  • Reference Example 14 In the same manner as in (2), Reference Example 61—The compound (0.334 g) obtained in (1) and Reference Example 14— g) The title compound (0.471 g) was also obtained as a pale yellow oil.
  • Reference Example 14 Obtained in the same manner as (2) in 5-chloromethyl-1-p-tolyl [1,2,4] oxadiazole (0.66 g) and Reference Example 14- (1) Compound (1. Og) force The title compound (1.29 g) was obtained as a pale yellow oil.

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Abstract

La présente invention porte sur un nouveau composé présentant d'excellentes propriétés agonistes des PPAR α/Ϝ et des propriétés intéressantes en tant que médicament. Un agoniste des récepteurs activés par les proliférateurs des peroxysomes α/Ϝ de formule générale (I) (où Q représente un cycle benzénique ou pyridinique éventuellement substitué ; R1 et R2 représentent chacun un groupement phényle éventuellement substitué ou un groupement hétérocyclique aromatique à 5 ou 6 chaînons ; X, Y et Z représentent chacun indépendamment C, O, S ou N ; R3 à R9 représentent chacun un atome d'hydrogène, un groupement alkyle court, etc. ; et n représente un entier compris entre 0 et 3 inclus.
PCT/JP2005/017981 2005-09-29 2005-09-29 Dérivés d'acide phénoxyacétique et médicaments utilisant lesdits dérivés WO2007037010A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532049A (zh) * 2011-12-22 2012-07-04 凯莱英医药集团（天津）股份有限公司 一种制备2-醛基恶唑的方法
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074495A1 (fr) * 2002-03-01 2003-09-12 Smithkline Beecham Corporation Activateurs de hppars
WO2004000785A2 (fr) * 2002-06-19 2003-12-31 Smithkline Beecham Corporation Composes chimiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074495A1 (fr) * 2002-03-01 2003-09-12 Smithkline Beecham Corporation Activateurs de hppars
WO2004000785A2 (fr) * 2002-06-19 2003-12-31 Smithkline Beecham Corporation Composes chimiques

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US10076519B2 (en) 2010-04-23 2018-09-18 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US10272030B2 (en) 2010-04-23 2019-04-30 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10765624B2 (en) 2010-04-23 2020-09-08 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US11369565B2 (en) 2010-04-23 2022-06-28 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
CN102532049A (zh) * 2011-12-22 2012-07-04 凯莱英医药集团（天津）股份有限公司 一种制备2-醛基恶唑的方法

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