WO2002044129A1 - Substituted carboxylic acid derivatives - Google Patents

Substituted carboxylic acid derivatives

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Publication number
WO2002044129A1
WO2002044129A1 PCT/JP2001/010352 JP0110352W WO0244129A1 WO 2002044129 A1 WO2002044129 A1 WO 2002044129A1 JP 0110352 W JP0110352 W JP 0110352W WO 0244129 A1 WO0244129 A1 WO 0244129A1
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WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
alkyl group
carboxylic acid
pharmaceutically acceptable
Prior art date
Application number
PCT/JP2001/010352
Other languages
French (fr)
Japanese (ja)
Inventor
Hiroyuki Miyachi
Kouji Murakami
Original Assignee
Kyorin Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyorin Pharmaceutical Co., Ltd. filed Critical Kyorin Pharmaceutical Co., Ltd.
Priority to AU2002222549A priority Critical patent/AU2002222549A1/en
Priority to JP2002546499A priority patent/JPWO2002044129A1/en
Publication of WO2002044129A1 publication Critical patent/WO2002044129A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a hypoperoxisomal proliferator-activated receptor (PPAR) agonist, particularly a hypolipidemic agent, particularly a hepatic lipid-lowering agent, and an arteriosclerosis agonizing agent against human PPAR isoform.
  • PPAR hypoperoxisomal proliferator-activated receptor
  • the present invention relates to a substituted carboxylic acid derivative and an addition salt thereof, which are effective as a therapeutic agent for metabolic diseases such as an inhibitor for progress, an antiobesity agent, and a therapeutic agent for diabetes, a method for producing the same, and a pharmaceutical composition containing these compounds.
  • PPAR hypoperoxisomal proliferator-activated receptor
  • Peroxisome proliferator-activated receptor is a ligand-dependent transcription factor that belongs to the nuclear superfamily, like the steroid receptor, retinoid receptor, and thyroid receptor. Three isoforms ( ⁇ -type, ( ⁇ (or ⁇ )-type, and ⁇ -type)) with different tissue distributions have been identified in various animal species including humans (Proc. Natl.
  • PPARs are distributed in the liver and kidney, etc., which have high fatty acid catabolism, and high expression is observed especially in the liver ( ⁇ 2 ⁇ ci / 2oc ⁇ 1995, JJil, 354). Correct the expression of genes related to intratransport (eg, acyl-CoA synthase, fatty acid binding protein lipoprotein lipase) and genes for apolipoprotein 1, 11, (] 111) related to cholesterol and neutral lipid metabolism. ⁇ Negative control. Is ubiquitously expressed in various tissues in the body, mainly in nerve cells. At this time, the physiological significance of PPAR5 is unknown. PPARa is highly expressed in adipocytes and is involved in adipocyte differentiation (. 1996, SI, 907). Thus, each isoform of PPAR performs a specific function in a specific organ or tissue.
  • PPARQ knockout mice exhibit hypertriglyceridemia and hypoglycemia with aging, and become obese mainly due to an increase in white fat cells ( ⁇ 1998, Natl. Acad. Sci., 1999, 747 3), PPARa is a major source of blood lipids (cholesterol and neutral lipids) and darcosyl chloride. It is strongly suggested that it plays an important role in regulating homeostasis and energy balance.
  • fibrate drugs have been widely used for the treatment of hyperlipidemia, especially for hypertriglyceridemia, but the activation of PPAR is considered as a mechanism of action of these fibrates. (Lipid. Res., 19%, SI, 907).
  • a fibrate-based drug suppresses the increase in body weight and adipose tissue weight in insulin-resistant animal models and normalizes decreased glucose tolerance in J. Biol. Chem., 2000, ⁇ , 16638, Biochem. Biophys. Res. Co, 2000, ⁇ , 445), has been shown to be involved in the improvement of insulin resistance.
  • fibrate drugs have a weak ⁇ activating effect, and their efficacy is far from satisfactory.
  • various side effects such as gastrointestinal disorders, rash, headache, hepatic dysfunction, renal dysfunction and gallstones have been reported for fibrate drugs. Non-specific effects are thought to be the cause, and the development of therapeutic drugs for metabolic diseases using specific mechanisms is desired.
  • W represents a (substituted) lactam ring
  • A represents an alkylene group or an alkylenoxy group
  • X represents 0, S, NH, CH 2
  • Y 1 represents an amino, hydroxyl, or alkoxy group.
  • R 1 represents ⁇ or an alkyl group, etc.
  • R 2 represents an alkyl group or a phenyl group
  • R 3 represents ⁇ , an alkyl group or an alkoxy group, etc.
  • these compounds have a carbonyl group under the linking moiety. It differs from the compound of the present invention in that it does not contain a mid group and that it contains a lactam ring in the terminal substituent W, and these compounds have human PPAR binding activity and transcription activation activity. The thing is not described.
  • a 1 represents an aryl group or a heterocyclic group which may have a substituent
  • Y 2 represents an alkylene chain having 1 to 5 carbon atoms
  • X 4 represents a bond, an oxygen atom or a sulfur atom.
  • W 1 represents a naphthylene ring, a quinoline ring, an indole ring, a benzisoxazole ring or a benzo [b] thiophene ring which may have a substituent; 4 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms; X 5 represents an oxygen atom or a sulfur atom; and is an alkyl group having 1 to 8 carbon atoms which may have a substituent, an aralkyl group. Or represents an aryl group).
  • these compounds differ from the compounds of the present invention in that they do not contain a carbonyl group or an amide group in Y 2 and X 4 of the linking moiety and that W 1 bonded to the 3-position of propionic acid is a heterocyclic ring. It is not described that these compounds have different structures and that these compounds have human PPAR binding activity and transcriptional activation activity.
  • R represents a substituent represented by and D 2
  • ⁇ 1 represents an aromatic ring, a cycloalkyl group and a heteroaromatic ring
  • R 5 represents an alkyl group
  • R 4 represents a hydrogen atom or Represents an alkyl group, may be linked to a hydrogen atom or to form a double bond
  • ⁇ 7 is a carboxyl group, an acyl group, an alkoxycarbonyl group which may have a substituent, an alkyl group
  • R 8 represents an aryloxycarbonyl group, an aralkyloxycarbonyl group, a sorbamoyl group, the title R 8 or an OR 8 group
  • H 8 represents an optionally substituted alkyl group or an alkoxycarbonyl group.
  • R 9 represents a hydrogen atom, alkyl group, alkoxy carbonylation group
  • R 1 Q represents a hydrogen atom, an amino group, an alkoxy group, an alkyl group, Ariruokishi group and Ararukiruokishi group) Compounds have been reported.
  • these compounds also differ in structure from the compounds of the present invention in that the substituents on the benzene ring are di-substituted at the 1- and 4-positions, and these compounds also have human PPAR binding activity and transcriptional activation. No effect is stated.
  • A represents a hydrogen atom or a fluorine group
  • m represents an integer of 3 to 10
  • n represents an integer of 1 to 6
  • X represents a C0NH group or an NHC0 group
  • R represents a carboxy group.
  • these compounds do not have a substituent at the 2-position of propionic acid, and all of the R groups have a carbonyl group, so the structure is different from that of the compound of the present invention. No mention is made that it has a PPAR binding activity and a transcriptional activating effect.
  • R 1 represents a hydrogen atom, - 6 alkyl group, Ariru C 4 - 1Q alkyl, ⁇ aryl group, a carboxyl group, an alkoxy group, a carboxy C Q - fi alkyl Group, carboxy C Q - 6 alkoxy group, human Dorokishi _ 6 alkyl group, d_ 4 alkylsulfonyl C Q - 6 alkyl group, C Q - 4 Arukiruamino C.
  • Ra represents a 2-benzoxazolyl group or 2-pyridyl group
  • R b represents a methoxymethyl group or a trifluoromethyl group.
  • these compounds differ in structure from the compounds of the present invention in that the substituent on the benzene ring is a disubstituted derivative at the 1-position and 4-position, and further has a human PPAR binding activity and a transcription activating activity. The thing is not described.
  • X represents a hydrogen atom or a fluorine atom). Have been.
  • these compounds are different from the compound of the present invention in that they are phenoxyacetic acid derivatives, and the positional relationship of the substituents on the benzene ring is di-substituted at the 1-position and 4-position. Also, the transcriptional activation of PPAR is not satisfactory.
  • Atherosclerotic diseases such as ischemic heart disease
  • hyperlipidemia, diabetes mellitus and hypertension are considered as the main risk factors for this arteriosclerotic disease, and the presence of insulin resistance is considered to be important in the pathology. It is clear that obesity due to the accumulation of visceral fat is deeply involved. Therefore, there is a clinical need for the development of a therapeutic agent for metabolic diseases that is totally effective and highly safe for these diseases. Disclosure of the invention
  • the present inventors focused on the specific role of such a human PPAR for the purpose of creating a structurally novel drug having high efficacy and safety as a therapeutic drug for metabolic diseases, and conducted intensive research. As a result, the present inventors have found that the novel substituted carboxylic acid derivative represented by the following general formula (1) has excellent human PPARa binding activity and transcription activating effect, and completed the present invention.
  • the present invention relates to the general formula (1)
  • n 0, 1 or 2
  • IU 0 or 2
  • hydrogen Atom or a lower alkyl group having 1 to 10 carbon atoms and when n is 1, represents a lower alkyl group having 1 to 10 carbon atoms.
  • It relates to salts and hydrates thereof.
  • the salts of the compound represented by the general formula (1) in the present invention are conventional ones, and include metal salts such as alkali metal salts (eg, sodium salt, calcium salt, lithium salt, etc.), Pharmaceutically acceptable salts such as alkaline earth metal salts (for example, calcium salt, magnesium salt, etc.) and aluminum salts.
  • metal salts such as alkali metal salts (eg, sodium salt, calcium salt, lithium salt, etc.)
  • Pharmaceutically acceptable salts such as alkaline earth metal salts (for example, calcium salt, magnesium salt, etc.) and aluminum salts.
  • the compound represented by the general formula (1) in the present invention may include an optical isomer based on a substituted carboxylic acid moiety.
  • compounds obtained in the course of synthesis of the compound represented by the general formula (1) include a mixture of geometric isomers. All such isomers and mixtures thereof are included within the scope of the present invention.
  • Each optical isomer can be produced by a stereoselective synthesis method. They are also obtained by separating the diastereomeric ester derivative oxazolidinone derivative obtained by reacting with an optically active alcohol derivative or an optically active oxazolidinone derivative by fractional crystallization or a method of chromatography and then hydrolyzing it. It can also be manufactured. Further, they can be produced by a technique of mouth chromatography using a chiral support.
  • the “lower alkyl group having 1 to 10 carbon atoms” refers to a linear or branched one having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and the like. No.
  • the compound represented by the above general formula (1) can be produced, for example, by the following method (Scheme 1). 4th process
  • ⁇ represents 0, 1 or 2
  • R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when ⁇ is 0 or 2
  • the substituted carboxylic acid derivative represented by the following formula] or its ester, its pharmaceutically acceptable salt and its hydrate are benzyl 2-methoxy-5-formylbenzoate (2)
  • the compound can be produced by hydrolyzing 1 part of C00H (fourth step).
  • the Wittig reaction or Horner-Eimons reaction in the first step is carried out in a solvent such as tetrahydrofuran, toluene, dioxane or ⁇ -dimethylformamide, and as a base, an alkali metal such as sodium hydride. It is possible to use hydrides, organometallic compounds such as butyllithium, metal amides such as lithium diisopropylamide, and metal alkoxides such as sodium methoxide cadmium-butoxide.
  • the reaction can be carried out at a reaction temperature of -20 ° C to 150 ° C, preferably at 0 ° C to 50 ° C.
  • the reduction reaction in the second step is carried out in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, and -dimethylformamide in the presence of a metal catalyst such as palladium-supported activated carbon, platinum-supported activated carbon, platinum oxide, and alumina supported on mouth.98. It can be implemented at 1 kPa to 491 kPa.
  • the reaction can be carried out at a reaction temperature of 0 ° C to 100 ° C, preferably at room temperature to 80 ° C.
  • the condensation reaction in the third step can be carried out by leaving the carboxyl group as it is or by converting it into a reactive derivative.
  • Examples of the “reactive group for carboxyl group” include acid chlorides, acid bromides, acid anhydrides, carbonimidazoles, and the like.
  • an alkali metal hydride such as sodium hydride or sodium hydroxide is used as a base.
  • Al-like metal hydroxide such as Pum It can be carried out in the presence or absence of an alkali metal carbonate such as potassium carbonate, or an organic base such as pyridine or triethylamine.
  • reaction When the reaction is carried out in the form of a carboxylic acid, the reaction is carried out in the presence of a condensing agent in a solvent such as methylene chloride, chloroform, dioxane, or ⁇ -dimethylformamide. Can be performed in the presence or absence of a condensing agent in a solvent such as methylene chloride, chloroform, dioxane, or ⁇ -dimethylformamide. Can be performed in the presence or absence of
  • Examples of the condensing agent include dicyclohexylcarbodiimide, tri [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, getyl cyanophosphate, azide diphenylphosphate, carbonyldiimidazole and the like.
  • Can be Examples of the base include alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as potassium carbonate, and organic bases such as pyridine and triethylamine.
  • Examples of the additives include -hydroxybenzotriazole, -hydroxysuccinimide ⁇ 3,4-dihydroxy-3-hydroxy-4-oxo-1,2,3-benzotriazine and the like. No. The reaction can be carried out at a reaction temperature of -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
  • the hydrolysis reaction in the fourth step can be performed under alkaline conditions.
  • the alkaline conditions lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. are used.
  • the reaction can be carried out at a temperature of 0 ° C to 80 ° C, preferably at room temperature to 60 ° C.
  • Examples of the dosage form of the novel compound of the present invention include solid compositions, liquid compositions and other compositions for oral administration, and injections, external preparations and suppositories for parenteral administration.
  • Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, mouthwashes and the like.
  • Other compositions for oral administration include sp Laying agents are included.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • reaction solution was washed with a 10% aqueous solution of citric acid, a 0.5 mol / L aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and then anhydrous sodium sulfate. Dried and concentrated. The residue was purified by silica gel chromatography (eluent ⁇ -hexane: ethyl acetate 2: 3 v / v) to give 770 mg (85%) of the title compound as a colorless oil. I got it.
  • reaction solution is washed successively with a 10% aqueous solution of citric acid, a 0.5 mol / L aqueous solution of sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate and concentrated. 800 mg of the condensate was obtained quantitatively.
  • the obtained condensate (550 mg, 1.30 mmol) was mixed with 2 mol / L sodium hydroxide aqueous solution (5fflL) and methanol (30 mL), and the mixture was stirred at 60 ° C for 4 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was dissolved in water and acidified with diluted hydrochloric acid.
  • the DNA-binding domain of yeast transcription factor and the ligand-binding domain of human PPAR were added to CH0 cells cultured in Dulbecco's modified Eagle's medium (FCS / DMEM) containing 10% defatted bovine serum Biocheittistry, 1993, ⁇ l , 5598), a receptor plasmid expressing the fusion protein and its repo overnight plasmid (STRATAGENE), and an internal standard, such as MYCHIKELCIFFERASE Plasmid (PR0MEGA), were not available in Lipofectamine. Cotransfection was performed in serum. Thereafter, the test compound was added in 10% SFCS / DMEM, and 24 hours later, both luciferase activities were measured, and corrected using an internal standard.
  • FCS / DMEM Dulbecco's modified Eagle's medium
  • STRATAGENE a receptor plasmid expressing the fusion protein and its repo overnight plasmid
  • PR0MEGA MYCHIKELCIFF
  • Table 5 shows the results. From these results, it was shown that the compound of the present invention has a strong transcriptional activating effect on the receptor for activating the hyperperoxisome proliferator. (Table 5) Example Transcriptional activation
  • the substituted carboxylic acid derivatives of the present invention are a group of novel compounds having an excellent PPAR transcription activating effect.
  • these compounds of the present invention have a strong agonistic activity against PPAR, the above-mentioned lipid-lowering drugs, especially drugs for lowering lipids in the liver, drugs for suppressing the progression of arteriosclerosis, anti-obesity drugs, drugs for treating diabetes, etc. It is a compound that is effective as a drug for treating metabolic diseases.

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Abstract

Novel substituted carboxylic acid derivatives which bind to human peroxisome proliferator-activated receptor α (PPARα) as a ligand thereof and activate the same to thereby exert a lipid-lowering effect, an arteriosclerosis-preventing effect, an anti-obesity effect, a hypoglycemic effect, etc.; and a process for producing the same. Namely, substituted carboxylic acid derivatives represented by the following general formula (1), esters thereof and pharmaceutically acceptable salts and hydrates of the same; and a process for producing these compounds: (1) wherein n is 0, 1 or 2; and R represents hydrogen or lower (C1-10) alkyl in case where n is 0 or 2, or lower (C1-10) alkyl in case where n is 1.

Description

m 糸田 β 置換カルボン酸誘導体 技術分野  m Itoda β-substituted carboxylic acid derivatives
本発明はヒ トペルォキシゾーム増殖薬活性化受容体（PPARと略す） ァゴニス ト、 特にヒ ト PPARひアイソフォームに対するァゴニス ト と して脂質低下薬、 特に肝臓における脂質の低下薬、 動脈硬化の進展 に対する抑制薬、 抗肥満薬、 糖尿病治療薬等の代謝性疾患治療薬と して有効な置換カルボン酸誘導体とその付加塩及びこれらの製造方 法並びにこれらの化合物を含有する医薬組成物に関する。 背景技術  The present invention relates to a hypoperoxisomal proliferator-activated receptor (PPAR) agonist, particularly a hypolipidemic agent, particularly a hepatic lipid-lowering agent, and an arteriosclerosis agonizing agent against human PPAR isoform. The present invention relates to a substituted carboxylic acid derivative and an addition salt thereof, which are effective as a therapeutic agent for metabolic diseases such as an inhibitor for progress, an antiobesity agent, and a therapeutic agent for diabetes, a method for producing the same, and a pharmaceutical composition containing these compounds. Background art
ペルォキシゾーム増殖薬活性化受容体（ΡΡΑβ)はステロイ ド受容体、 レチノィ ド受容体やサイ ロイ ド受容体等と同様核内受容体スーパー ファミ リーに属する リガン ド依存性の転写因子であり、 これまでに 組織分布を異にする三つのアイソフォーム（ α型、（^ (又は^ )型、ァ 型）がヒ トをはじめ種々の動物種で同定されている（Proc. Natl. Peroxisome proliferator-activated receptor (ΡΡΑβ) is a ligand-dependent transcription factor that belongs to the nuclear superfamily, like the steroid receptor, retinoid receptor, and thyroid receptor. Three isoforms (α-type, (^ (or ^)-type, and α-type)) with different tissue distributions have been identified in various animal species including humans (Proc. Natl.
Acad. Sci., 1992, l, 4653)。 この内 PPARひは脂肪酸の異化能の 高い肝臓や腎臓等に分布しており、 特に肝臓において高発現が認め られ（^2^c i/2o c^ 1995， JJil, 354)、 脂肪酸の代謝や細胞内輸 送に関連する遺伝子 (例えばァシル CoA合成酵素、 脂肪酸結合タン パク質ゃリポ蛋白 リパーゼ） 及びコレステロールや中性脂質の代謝 に関連するァポリポ蛋白 1、 11、 (]111)遺伝子の発現を正ゃ負に制御 している。 は神経細胞を中心として生体内各組織に普遍的に 発現している。 現時点では PPAR5の生理的意義については不明であ る。 PPARァは脂肪細胞に高発現していて脂肪細胞の分化に関与して いる（ . 1996， SI, 907)。この様に PPARの各アイソフォ一 ムは特定の臓器や組織において特異的な機能を果たしている。 Acad. Sci., 1992, l, 4653). Among them, PPARs are distributed in the liver and kidney, etc., which have high fatty acid catabolism, and high expression is observed especially in the liver (^ 2 ^ ci / 2oc ^ 1995, JJil, 354). Correct the expression of genes related to intratransport (eg, acyl-CoA synthase, fatty acid binding protein lipoprotein lipase) and genes for apolipoprotein 1, 11, (] 111) related to cholesterol and neutral lipid metabolism.ゃ Negative control. Is ubiquitously expressed in various tissues in the body, mainly in nerve cells. At this time, the physiological significance of PPAR5 is unknown. PPARa is highly expressed in adipocytes and is involved in adipocyte differentiation (. 1996, SI, 907). Thus, each isoform of PPAR performs a specific function in a specific organ or tissue.
又、 PPARQ:のノ ックァゥ トマウスは加齢に伴い高中性脂肪血症及 び低血糖症を呈し、 さらに白色脂肪細胞の増加を主と した肥満にな る事が報告されており（ ^ 1998, , 29577, J.clin. Invest., m^,101A^,Proc. Natl. Acad. Sci., 1999， 747 3)、PPARaが血中脂質（コレステロール及び中性脂質）や血中ダルコ一 スの恒常性及びエネルギーバランスの調節において重要な役割を果 たしている事が強く示唆されている。  In addition, it has been reported that PPARQ: knockout mice exhibit hypertriglyceridemia and hypoglycemia with aging, and become obese mainly due to an increase in white fat cells (^ 1998, Natl. Acad. Sci., 1999, 747 3), PPARa is a major source of blood lipids (cholesterol and neutral lipids) and darcosyl chloride. It is strongly suggested that it plays an important role in regulating homeostasis and energy balance.
ところで、 従来より高脂血症治療薬、 特に高ト リグリセライ ド血 症治療薬してフィ ブラー ト系薬剤が汎用されているが、 このフイ ブ ラート系薬剤の作用機作として P P A Rひの活性化が報告されている（ Lipid. Res. ,19%, SI, 907)。 更にフイ ブラート系薬剤がイ ンス リ ン 抵抗性モデル動物において体重や脂肪組織重量の増加抑制、 更には 低下した耐糖能を正常化させる事が報告されており J.Biol.Chem., 2000,Ζϋ, 16638, Biochem .Biophys. Res. Co ,2000,^,445)、 ΡΡΑβひがィ ンスリン抵抗性の改善にも関与している事が示されてい る ο  By the way, fibrate drugs have been widely used for the treatment of hyperlipidemia, especially for hypertriglyceridemia, but the activation of PPAR is considered as a mechanism of action of these fibrates. (Lipid. Res., 19%, SI, 907). In addition, it has been reported that a fibrate-based drug suppresses the increase in body weight and adipose tissue weight in insulin-resistant animal models and normalizes decreased glucose tolerance in J. Biol. Chem., 2000, Ζϋ , 16638, Biochem. Biophys. Res. Co, 2000, ^, 445), has been shown to be involved in the improvement of insulin resistance.
しかしフィ ブラート系薬剤の示す ΡΡΑβα活性化作用は弱く、 効力 の面で決して満足のいく ものではない。 またフィ ブラー ト系薬剤に 閧しては胃腸障害、発疹、頭痛、肝機能障害、腎機能障害や胆石等の 種々の副作用が報告されていて、 その原因としてフイ ブラート系薬 物の示す種々の非特異的な作用が原因と考えられており、特異的なメ 力ニズムによる代謝性疾患治療薬の開発が望まれている。  However, fibrate drugs have a weak ββα activating effect, and their efficacy is far from satisfactory. In addition, various side effects such as gastrointestinal disorders, rash, headache, hepatic dysfunction, renal dysfunction and gallstones have been reported for fibrate drugs. Non-specific effects are thought to be the cause, and the development of therapeutic drugs for metabolic diseases using specific mechanisms is desired.
そこで ΡΡΑβαという核内転写因子の脂質代謝調節機構に関する役 割及び高脂血症や肥満症、 糖尿病との病態との関わり を考えると、 PPARひ特にヒ ト型 PPAR リガン ドとして直接結合してヒ ト型 PPAR αを活性化しう る化合物を創製する事ができれば極めて特異的なメ 力ニズムによる代謝性疾患治療薬と しての医薬用途が期待される。 Considering the role of the nuclear transcription factor ΡΡΑβα in regulating lipid metabolism and its relationship to hyperlipidemia, obesity, and diabetes, direct binding to PPARs, especially human PPAR ligands, has been considered. G type PPAR If a compound capable of activating α can be created, it is expected to be used as a therapeutic drug for metabolic diseases by extremely specific mechanism.
PPARひのリガン ドとして PPAR に対する親和性を有する化合物に はァラキ ドン酸の代謝物である LTB4の他にシ トクローム P- 450によ る酸化を介して生じる HETE (ヒ ドロキシエイコサテ トラェン酸）群の エイコサノィ ド、 特に 8-HETE、 8-HEPE等が報告されている（ ro Na tl . Acad. Sci. } mi,M., 312 )。 しかしこれらの内因性の不飽和脂 肪酸誘導体は代謝的にも化学的にも不安定であり、 医薬として供す る事はできない。 PPAR Hino addition to shea Tokuromu P- 450 that by the results through the oxide HETE (hydroxycarboxylic Eiko satay Toraen acid is a compound having an affinity for PPAR as ligand is a metabolite of Araki Don acid LTB 4 A group of eicosanoids, especially 8-HETE, 8-HEPE, etc. has been reported (ro Natl. Acad. Sci. } Mi, M., 312). However, these endogenous unsaturated fatty acid derivatives are metabolically and chemically unstable and cannot be used as pharmaceuticals.
一方、 本発明の置換カルボン酸誘導体の類似構造化合物としては 以下に示す化合物群等が報告されている。  On the other hand, the following compounds and the like have been reported as compounds having a similar structure to the substituted carboxylic acid derivative of the present invention.
公開特許公報 特開平 1 1 - 158144 号 （エスエス製薬株式会社） に 血糖低下作用及び脂質低下作用を有するひ-置換フヱニルプロピオン 酸誘導体と して  Published Japanese Patent Application Laid-Open No. 11-158144 (SS Pharmaceutical Co., Ltd.) as a di-substituted phenylpropionic acid derivative having a hypoglycemic effect and a hypolipidemic effect
一般式（A ) General formula (A)
Figure imgf000005_0001
Figure imgf000005_0001
(式中、 Wは（置換）ラクタム環を表し、 Aはアルキレン基又はアルキレ ンォキシ基を表し、 X は 0、 S、 NH、 CH2 を表し、 Y1はァミノ基、 水酸 基又はアルコキシ基を表し、 R1は Η又はアルキル基等を表し、 R2はァ ルキル基又はフヱニル基等を表し、 R3は Η、 アルキル基又はアルコ キシ基等を表す）で表される化合物が報告されている。 (Wherein, W represents a (substituted) lactam ring, A represents an alkylene group or an alkylenoxy group, X represents 0, S, NH, CH 2 , and Y 1 represents an amino, hydroxyl, or alkoxy group. R 1 represents Η or an alkyl group, etc., R 2 represents an alkyl group or a phenyl group, and R 3 represents Η, an alkyl group or an alkoxy group, etc.). ing.
しかしながらこれらの化合物は連結部分の Αにカルボニル基ゃァ ミ ド基を含まない点及び末端置換基である Wにラクタム環を含む点 で本発明の化合物とは構造が異なり、またこれらの化合物がヒ ト PPA Rひ結合活性、転写活性化作用を有する事は記述されていない。 However, these compounds have a carbonyl group under the linking moiety. It differs from the compound of the present invention in that it does not contain a mid group and that it contains a lactam ring in the terminal substituent W, and these compounds have human PPAR binding activity and transcription activation activity. The thing is not described.
国際公開番号 W098/28254号（日本ケミ ファ株式会社） に血糖降下 作用を有する化合物として  International Publication No. W098 / 28254 (Nippon Chemifa Corporation) as a compound with hypoglycemic action
一般式（B ) General formula (B)
Figure imgf000006_0001
Figure imgf000006_0001
(B)  (B)
(式中、 A1 は置換基を有していても良いァリール基又は複素環基を 表し、 Y2は炭素数 1 から 5のアルキレン鎖を表し、 X4は結合手、 酸素 原子又は硫黄原子を表し、 W1 は置換基を有していても良いナフ夕 レ ン環、キノ リ ン環、イ ン ドール環、ベンズィソキサゾール環又はべンゾ [b ]チオフヱン環を表し、 R4は水素原子又は炭素数 1 から 8のアルキ ル基を表し、 X5は酸素原子又は硫黄原子を表し、そして は置換基を 有していても良い炭素数 1から 8のアルキル基、ァラルキル基又はァ リ一ル基を表す）で表される化合物が報告されている。 (In the formula, A 1 represents an aryl group or a heterocyclic group which may have a substituent, Y 2 represents an alkylene chain having 1 to 5 carbon atoms, X 4 represents a bond, an oxygen atom or a sulfur atom. W 1 represents a naphthylene ring, a quinoline ring, an indole ring, a benzisoxazole ring or a benzo [b] thiophene ring which may have a substituent; 4 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms; X 5 represents an oxygen atom or a sulfur atom; and is an alkyl group having 1 to 8 carbon atoms which may have a substituent, an aralkyl group. Or represents an aryl group).
しかしながらこれらの化合物は連結部分の Y2及び X4にカルボ二 ル基ゃアミ ド基を含まない点及びプロピオン酸の 3位に結合する W1 は複素環である点で本発明の化合物とは構造が異なり、またこれらの 化合物がヒ ト PPAR «結合活性、転写活性化作用を有する事は記述さ れていない。 However, these compounds differ from the compounds of the present invention in that they do not contain a carbonyl group or an amide group in Y 2 and X 4 of the linking moiety and that W 1 bonded to the 3-position of propionic acid is a heterocyclic ring. It is not described that these compounds have different structures and that these compounds have human PPAR binding activity and transcriptional activation activity.
国際公開番号 W098/07699号（日本たばこ産業株式会社） に血糖降 下作用及び脂質低下作用を有するプロピオン酸誘導体として 一般式（C )
Figure imgf000007_0001
International Publication No. W098 / 07699 (Nippon Tobacco Inc.) as a propionic acid derivative having hypoglycemic action and lipid-lowering action, represented by the general formula (C)
Figure imgf000007_0001
(C)  (C)
(式中、 Rは 及び D2で示される置換基を表し、 β 1は芳香族環、 シク 口アルキル基及び複素芳香族環を表し、R5 はアルキル基を表し、 R4 は水素原子又はアルキル基を表し、 は水素原子又は と連結し て二重結合を形成していても良く、 β7 はカルボキシル基、ァシル基、 置換基を有していても良いアルコキシカルボニル基、アルキル基、ァ リールォキシカルボニル基、ァラルキルォキシカルボニル基、力ルバ モイル基、題 R8基及び OR8基を表し、 H8は置換基を有していても良い ァシル基及びアルコキシカルボ二ル基を表し、 R9は水素原子、アルキ ル基、アルコキシカルボ二ル基を表し、 R1 Qは水素原子、アミノ基、アル コキシ基、アルキル基、ァリールォキシ基及びァラルキルォキシ基を 表す）で表される化合物が報告されている。 (Wherein, R represents a substituent represented by and D 2 , β 1 represents an aromatic ring, a cycloalkyl group and a heteroaromatic ring, R 5 represents an alkyl group, R 4 represents a hydrogen atom or Represents an alkyl group, may be linked to a hydrogen atom or to form a double bond, and β 7 is a carboxyl group, an acyl group, an alkoxycarbonyl group which may have a substituent, an alkyl group, R 8 represents an aryloxycarbonyl group, an aralkyloxycarbonyl group, a sorbamoyl group, the title R 8 or an OR 8 group, and H 8 represents an optionally substituted alkyl group or an alkoxycarbonyl group. the stands, R 9 represents a hydrogen atom, alkyl group, alkoxy carbonylation group, represented by R 1 Q represents a hydrogen atom, an amino group, an alkoxy group, an alkyl group, Ariruokishi group and Ararukiruokishi group) Compounds have been reported.
しかしながらこれらの化合物もベンゼン環上の置換基が 1位と 4位 の二置換体である点で本発明の化合物とは構造が異なり、 またこれ らの化合物がヒ ト PPAR 結合活性、転写活性化作用を有する事は記 述されていない。 However, these compounds also differ in structure from the compounds of the present invention in that the substituents on the benzene ring are di-substituted at the 1- and 4-positions, and these compounds also have human PPAR binding activity and transcriptional activation. No effect is stated.
公開特許公報 昭 63- 91354号 （山之内製薬株式会社） にロイコ ト リエン受容体作動作用を有するカルボン酸誘導体として  Published Patent Publication No. 63-91354 (Yamanouchi Pharmaceutical Co., Ltd.) as a carboxylic acid derivative with leukotriene receptor agonizing action
一般式（E ) A-(CH2)m-0 (CH2)n-COOH General formula (E) A- (CH 2 ) m-0 (CH 2 ) n-COOH
(式中、 Aは水素原子またはフヱ二ル基を表し、 mは 3から 10の整数を 表し、 nは 1 から 6の整数を表し、 Xは C0NH基或いは NHC0基を表し、 R はカルボキシ低級アルキル基又はカルボキシ低級アルキル力ルバ モイル基（但し、 Aがフヱニル基の時は Rはカルボキシ低級アルキル 力ルバモイル低級アルキル基である）を表す）で表される化合物が報 告されている。 (In the formula, A represents a hydrogen atom or a fluorine group, m represents an integer of 3 to 10, n represents an integer of 1 to 6, X represents a C0NH group or an NHC0 group, and R represents a carboxy group. A compound represented by a lower alkyl group or a carboxy-lower-alkyl rubamoyl group (however, when A is a phenyl group, R represents a carboxy-lower-alkyl rubamoyl-lower alkyl group) has been reported.
しかしながらこれらの化合物はプロピオン酸の 2位に置換基を有 さず、又 R基部分には全てにカルボニル基が存在するので本発明の化 合物とは構造が異なり、またこれらの化合物がヒ ト PPARひ結合活性、 転写活性化作用を有する事は記述されていない。  However, these compounds do not have a substituent at the 2-position of propionic acid, and all of the R groups have a carbonyl group, so the structure is different from that of the compound of the present invention. No mention is made that it has a PPAR binding activity and a transcriptional activating effect.
US5227490 号 （メルク株式会社） にフイ ブリノ一ゲン受容体拮抗 作用を有するカルボン酸誘導体として  US5227490 (Merck Co., Ltd.) as a carboxylic acid derivative with fibrinogen receptor antagonistic activity
一般式（F ) General formula (F)
Figure imgf000008_0001
Figure imgf000008_0001
(式中、 R1は水素原子、 -6アルキル基、ァリール C4-1Qアルキル基、 ァ リール基、カルボキシル基、 アルコキシ基、カルボキシ CQ— fiアルキ ル基、カルボキシ CQ— 6アルコキシ基、ヒ ドロキシ _6アルキル基、 d_4 アルキルスルホニル CQ-6アルキル基、 CQ-4アルキルァミノ C。_6アルキ ル基、ァリール C0—10アルキルァミノ C0-6アルキル基、 C2—10ァシルァミ ノ CQ-6アルキル基、 CHカルボアルコキシ CQ_6アルキル基又はハ口ゲ ン原子を表し、 R2 は同一又は相異なって水素原子、ハロゲン原子、ヒ ド口キシル基、 CHアルコキシ基、ァリール CQ—4アルキル基、ァリール C0_6アルコキシ基、 置換基を有していても良い -6 アルキル基を表 し、β3は水素原子、 ( 6アルキル基又はァリール CWQアルキル基を表 し、 Xは酸素原子、硫黄原子、 SO基、 S02基、 CO基、 NR4C0基、 C0NR4基、 CH2 基、 CH=CH基、 NR4CS 基を表し、 Y は無置換又は置換基を有していても 良い アルキル基、 C4_8シク口アルキル基、ァリール基、 CQ_3アルキ ルァリール Co-3アルキル基、 Co-3アルキルァリール Co-3アルキルカル ボニル基、 CQ-3アルキルァリ一ル C0_3アルキルカルボキシァミ ド基、 C 0-3アルキルァリールォキシ CQ—3アルキル基、 C0NH基、 NHC0基又は（CH 2)m- Q-(CH2)n基（但し、 Qは酸素又は硫黄から選ばれる 1 から 3種類 のへテロ原子を含む C3—8員環複素環を表し、mと nは 0から 4である） を表し、 Zは NR4R5基 （但し、 R4と R5は同一又は相異なって水素原子、 アルキル基、ァリール Ci-1Qアルキル基でアルキル基は無置換又は ( 4アルコキシ基、カルボキシ C 6アルキル基、ヒ ドロキシル基、ハ口 ゲン原子又は窒素、酸素及び硫黄より選択される 1-3のへテロ原子を 含む 4-9員環の単環又はビシク口環で置換されていても良い） 又は 置換基を有していても良いグァニジノ基を表す）で表される化合物が 報告されている。 (Wherein, R 1 represents a hydrogen atom, - 6 alkyl group, Ariru C 4 - 1Q alkyl, § aryl group, a carboxyl group, an alkoxy group, a carboxy C Q - fi alkyl Group, carboxy C Q - 6 alkoxy group, human Dorokishi _ 6 alkyl group, d_ 4 alkylsulfonyl C Q - 6 alkyl group, C Q - 4 Arukiruamino C. _ 6 alkyl group, Ariru C 0 - 10 Arukiruamino C 0 - 6 alkyl group, C 2 - 10 Ashiruami Bruno C Q - 6 alkyl group, a CH carboalkoxy C Q _ 6 alkyl or C port gain down atoms, R 2 denote identically or differently hydrogen atoms, halogen atoms, human de port hexyl group, CH alkoxy group, Ariru C Q - 4 alkyl group, Ariru C 0 _ 6 alkoxy group which may have a substituent - 6 represents an alkyl group, β 3 represents a hydrogen atom, ( 6 represents an alkyl group or an aryl C WQ alkyl group, X represents an oxygen atom, a sulfur atom, an SO group, an SO 2 group, a CO group, an NR 4 C0 group, C0NR 4 group, CH 2 group, CH = CH group, an NR 4 CS group, Y represents an unsubstituted or which may have a substituent alkyl groups, C 4 _ 8 consequent opening alkyl group, Ariru groups, C Q _ 3 alkylene Ruariru Co-3 alkyl group, Co-3-alkyl § reel Co-3 alkyl Cal Boniru group, CQ- 3 Al Kiruari Ichiru C 0 _ 3 alkyl carboxy § Mi de group, C 0-3 alkyl § reel O carboxymethyl C Q - 3 alkyl group, C0Nh group, NHC0 group or (CH 2) m- Q- (CH 2) n group (where, Q is C 3 containing heteroatoms from 1 selected from oxygen or sulfur to three of - represents the 8-membered heterocyclic ring, m and n are 0 to 4.) represents, Z is NR 4 R 5 groups (provided that R 4 and R 5 are the same or different and are each a hydrogen atom, an alkyl group, an aryl Ci- 1Q alkyl group and the alkyl group is unsubstituted or ( 4 alkoxy group, carboxy C 6 alkyl group, hydroxyl group, May be substituted with a 4- to 9-membered monocyclic or bicyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur) or a substituent Which represents a guanidino group).
しかしながらこれらの化合物は Z基部分に全て置換基を有してい ても良いアミ ノ基を必ず含むアミノ酸誘導体である事から本発明の 化合物とは構造が異なり、またこれらの化合物がヒ ト ΡΡΑβ 結合活 性、転写活性化作用を有する事は記述されていない。 PPAR a作動作用を報告している特許に関しては、 国際公開番号 W0 97/25042号 （ス ミスクラインビーチヤム株式会社） に PPAR o:及び P PARァ作動作用を有する化合物として However, these compounds are structurally different from the compounds of the present invention because they are amino acid derivatives that always contain an amino group which may have a substituent in the Z group, and these compounds have a human ΡΡΑβ bond. No activity or transcriptional activation is described. Regarding patents reporting PPARa agonism, International Publication No. WO 97/25042 (SmithKlein Beach Yam Co., Ltd.) is a compound having PPARa: and PPARa agonism.
一般式 （G) ' General formula (G) ''
Figure imgf000010_0001
Figure imgf000010_0001
(式中、 Ra は 2-ベンズォキサゾリル基又は 2-ピリジル基を表し、 Rb はメ トキシメチル基又はトリフルォロメチル基を表す）で表される化 合物が報告されている。 しかしながらこれらの化合物はベンゼン環 上の置換基は 1位及び 4位の二置換誘導体である点で本発明の化合 物とは構造が異なり、更にヒ ト PPARひ結合活性、 転写活性化作用を 有する事は記述されていない。 (Wherein Ra represents a 2-benzoxazolyl group or 2-pyridyl group, and R b represents a methoxymethyl group or a trifluoromethyl group). . However, these compounds differ in structure from the compounds of the present invention in that the substituent on the benzene ring is a disubstituted derivative at the 1-position and 4-position, and further has a human PPAR binding activity and a transcription activating activity. The thing is not described.
国際公開番号 W097/36579 (グラクソウエルカム株式会社） に PPA Rひ作動作用を有する化合物と して  International publication number W097 / 36579 (GlaxoWelcome Co., Ltd.)
一般式 （H) General formula (H)
Figure imgf000010_0002
Figure imgf000010_0002
(H)  (H)
式中、 Xは水素原子又はフッ素原子を表す）で表される化合物が報告 されている。 In the formula, X represents a hydrogen atom or a fluorine atom). Have been.
しかしながらこれらの化合物はフヱノキシ酢酸誘導体であり、また ベンゼン環上の置換基の位置関係は 1位及び 4位の二置換体である 点で本発明の化合物とは構造が異なる。又 PPARひの転写活性化作用 も決して満足のいく強さではない。  However, these compounds are different from the compound of the present invention in that they are phenoxyacetic acid derivatives, and the positional relationship of the substituents on the benzene ring is di-substituted at the 1-position and 4-position. Also, the transcriptional activation of PPAR is not satisfactory.
食生活やライフスタイルの急激な変化に伴い虚血性心疾患などの 動脈硬化性疾患の頻度が増加し問題となっている。 この動脈硬化性 疾患の主たる危険因子と して高脂血症、 糖尿病、 高血圧が考えられ ており、 その病態にはイ ンス リン抵抗性の存在が重要であるとされ ているが、 その成因基盤と して内臓脂肪の蓄積による肥満が深く関 与している事が明らかとなっている。 そこでこれらの疾患に対し総 合的に有効でかつ安全性の高い代謝性疾患治療薬の開発が臨床上望 まれている。 発明の開示  The frequency of atherosclerotic diseases, such as ischemic heart disease, is increasing due to rapid changes in diet and lifestyle. Hyperlipidemia, diabetes mellitus and hypertension are considered as the main risk factors for this arteriosclerotic disease, and the presence of insulin resistance is considered to be important in the pathology. It is clear that obesity due to the accumulation of visceral fat is deeply involved. Therefore, there is a clinical need for the development of a therapeutic agent for metabolic diseases that is totally effective and highly safe for these diseases. Disclosure of the invention
本発明者らは、代謝性疾患治療薬として有効性及び安全性の高い構 造上新規な薬物の創製を目的としてかかるヒ ト PPARひの特異的な役 割に着目し、鋭意研究を重ねた結果下記一般式（1 )で表される新規置 換カルボン酸誘導体が優れたヒ ト PPAR a結合活性並びに転写活性化 作用を有する事を見出し本発明を完成した。  The present inventors focused on the specific role of such a human PPAR for the purpose of creating a structurally novel drug having high efficacy and safety as a therapeutic drug for metabolic diseases, and conducted intensive research. As a result, the present inventors have found that the novel substituted carboxylic acid derivative represented by the following general formula (1) has excellent human PPARa binding activity and transcription activating effect, and completed the present invention.
即ち本発明は一般式（1 )  That is, the present invention relates to the general formula (1)
Figure imgf000011_0001
Figure imgf000011_0001
[式中、 nは 0、 1又は 2を表し、 IUま nが 0あるいは 2の場合は水素 原子又は炭素数 1 から 10の低級アルキル基を表し、 nが 1の場合は 炭素数 1 から 10の低級アルキル基を表す]で表される置換カルボン 酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその 水和物に関する。 [Wherein, n represents 0, 1 or 2, and if IU is 0 or 2, hydrogen Atom or a lower alkyl group having 1 to 10 carbon atoms, and when n is 1, represents a lower alkyl group having 1 to 10 carbon atoms.] It relates to salts and hydrates thereof.
本発明における一般式（1 )で表される化合物の塩類は慣用のもので あって、 金属塩例えばアル力 リ金属塩 （例えばナ ト リ ウム塩、 カ リ ゥム塩、 リチウム塩など） 、 アルカ リ土類金属塩 (例えばカルシゥ ム塩、 マグネシウム塩など） 、 アルミニウム塩等薬理学的に許容し うる塩が挙げられる。  The salts of the compound represented by the general formula (1) in the present invention are conventional ones, and include metal salts such as alkali metal salts (eg, sodium salt, calcium salt, lithium salt, etc.), Pharmaceutically acceptable salts such as alkaline earth metal salts (for example, calcium salt, magnesium salt, etc.) and aluminum salts.
また、 本発明における一般式（1 )で表される化合物には、 置換カル ボン酸部分に基づく光学異性体が含まれる事がある。また一般式（1 ) で表される化合物の合成の過程で得られる化合物の中には幾何異性 体の混合物が含まれる場合がある。 そのような異性体及びそれらの 混合物はすべてこの発明の範囲内に含まれるものである。  The compound represented by the general formula (1) in the present invention may include an optical isomer based on a substituted carboxylic acid moiety. In some cases, compounds obtained in the course of synthesis of the compound represented by the general formula (1) include a mixture of geometric isomers. All such isomers and mixtures thereof are included within the scope of the present invention.
各光学異性体は立体選択的な合成法によ り製造する事ができる。 またそれらは光学活性なアルコール誘導体や光学活性なォキサゾリ ジノ ン誘導体と反応させて得られるジァステレオマリ ヅクなエステ ル誘導体ゃォキサゾリジノン誘導体を分別結晶又はクロマトグラフィ 一の手法により分離した後加水分解する事によ り製造する事もでき る。 さらにそれらはキラル支持体を使用するク口マ トグラフィ 一の 手法により製造する事もできる。  Each optical isomer can be produced by a stereoselective synthesis method. They are also obtained by separating the diastereomeric ester derivative oxazolidinone derivative obtained by reacting with an optically active alcohol derivative or an optically active oxazolidinone derivative by fractional crystallization or a method of chromatography and then hydrolyzing it. It can also be manufactured. Further, they can be produced by a technique of mouth chromatography using a chiral support.
本発明の一般式（1 )において、 「炭素数 1から 10の低級アルキル 基」 とは、 メチル、 ェチル、 プロピル、 イソプロピル、 ブチル等の 直鎖も しくは分岐した炭素数 1から 10のものが挙げられる。  In the general formula (1) of the present invention, the “lower alkyl group having 1 to 10 carbon atoms” refers to a linear or branched one having 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and the like. No.
上記一般式（1 )である化合物は例えば以下の方法により製造すること ができる（スキーム 1 )。 第四工程The compound represented by the above general formula (1) can be produced, for example, by the following method (Scheme 1). 4th process
Figure imgf000013_0001
すなわち、 一般式（1 )
Figure imgf000013_0001
That is, the general formula (1)
Figure imgf000013_0002
Figure imgf000013_0002
[式中、 ηは 0、 1又は 2を表し、 Rは ηが 0あるいは 2の場合は水素 原子又は炭素数 1 から 10の低級アルキル基を表し、 ηが 1の場合は 炭素数 1 から 10の低級アルキル基を表す]で表される置換カルボン 酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその 水和物は 2-メ トキシ- 5-ホルミル安息香酸ベンジルエステル（2 )  [In the formula, η represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when η is 0 or 2, and a carbon atom having 1 to 10 carbon atoms when η is 1. The substituted carboxylic acid derivative represented by the following formula] or its ester, its pharmaceutically acceptable salt and its hydrate are benzyl 2-methoxy-5-formylbenzoate (2)
Figure imgf000013_0003
と一般式（6)
Figure imgf000014_0001
Figure imgf000013_0003
And general formula (6)
Figure imgf000014_0001
[式中、 IT は炭素数 1 から 4の低級アルキル基であ り、 Xは PPh3 基または P0(0C2H5)2基を表す] で表される化合物を塩基存在下作用 させる （Wittig反応又は Horner- Emmons反応；第一工程） 事によ り 合成される一般式（3)
Figure imgf000014_0002
[Wherein IT is a lower alkyl group having 1 to 4 carbon atoms and X represents a PPh 3 group or a P0 (0C 2 H 5 ) 2 group]. Reaction or Horner-Emmons reaction; first step) General formula (3)
Figure imgf000014_0002
[式中、 R1 は前述の通り ] で表される化合物を還元及び水素化分解 する （第二工程） 事により得られる一般式（4)
Figure imgf000014_0003
[Wherein, R 1 is as described above]. The general formula (4) obtained by subjecting the compound represented by the formula: to reduction and hydrogenolysis (second step)
Figure imgf000014_0003
[式中、 R1 は前述の通り ] で表される化合物に一般式 （7)
Figure imgf000014_0004
[Wherein R 1 is as described above] to a compound represented by the general formula (7)
Figure imgf000014_0004
[式中、 n及び βは前述の通り ] で表される化合物を反応させ （第 三工程） 、 得られた一般式（5)
Figure imgf000015_0001
[Wherein n and β are as described above], and the resulting compound is reacted with a compound represented by the following general formula (5).
Figure imgf000015_0001
[式中、 RJ1 及び nは前述の通り ] で表される化合物の C00H1 部 位を加水分解する （第四工程） 事により製造する事ができる。 [Wherein RJ 1 and n are the same as those described above]. The compound can be produced by hydrolyzing 1 part of C00H (fourth step).
第一工程の Wittig反応又は Horner-Eimons反応はテ トラヒ ドロフ ラン、 トルエン、 ジォキサン、 ^ -ジメチルホルムアミ ド等の溶媒 中、 塩基と しては例えば水素化ナ ト リゥムのようなアル力 リ金属水 素化物、 ブチルリチウムのような有機金属化合物、 リチウムジイ ソ プロピルアミ ドのような金属アミ ド、 ナ ト リ ウムメ トキシ ドゃカ リ ゥム έ-ブトキシ ドのような金属アルコキシドを用いる事ができる。 反応温度と しては- 20°Cから 150°Cにて、 好適には 0°Cから 50°Cにて 実施する事ができる。  The Wittig reaction or Horner-Eimons reaction in the first step is carried out in a solvent such as tetrahydrofuran, toluene, dioxane or ^ -dimethylformamide, and as a base, an alkali metal such as sodium hydride. It is possible to use hydrides, organometallic compounds such as butyllithium, metal amides such as lithium diisopropylamide, and metal alkoxides such as sodium methoxide cadmium-butoxide. The reaction can be carried out at a reaction temperature of -20 ° C to 150 ° C, preferably at 0 ° C to 50 ° C.
第二工程の還元反応はパラジウム担持活性炭、 白金担持活性炭、 酸化白金、口ジゥム担持アルミナ等の金属触媒存在下、エタノール、 メタノール、 テ トラヒ ドロフラン、 酢酸ェチル、 -ジメチルホル ムアミ ド等の溶媒中 98. 1kPa から 491 kPa で実施する事ができる。 反応温度と しては 0°Cから 100°Cにて、 好適には室温から 80°Cにて 実施する事ができる。  The reduction reaction in the second step is carried out in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, and -dimethylformamide in the presence of a metal catalyst such as palladium-supported activated carbon, platinum-supported activated carbon, platinum oxide, and alumina supported on mouth.98. It can be implemented at 1 kPa to 491 kPa. The reaction can be carried out at a reaction temperature of 0 ° C to 100 ° C, preferably at room temperature to 80 ° C.
第三工程の縮合反応はカルボキシル基をそのままで、 または反応 性の誘導体に変換して実施する事ができる。  The condensation reaction in the third step can be carried out by leaving the carboxyl group as it is or by converting it into a reactive derivative.
「カルボキシル基の反応性誘導基」としては酸塩化物、酸臭化物、 酸無水物、 カルボ二ルイ ミダゾール等が挙げられる。 反応性誘導体 を用いた反応の場合には、 ジォキサン、 ^ -ジメチルホルムアミ ド 等の溶媒中、 塩基として例えば水素化ナ ト リ ゥムのようなアル力 リ 金属水素化物、 水酸化ナ ト リ ゥムのようなアル力リ金属水酸化物、 炭酸カ リ ウム等のアルカ リ金属炭酸塩、 又はピリジン、 ト リェチル ァミ ンのような有機塩基の存在下または非存在下に実施する事がで きる。 Examples of the “reactive group for carboxyl group” include acid chlorides, acid bromides, acid anhydrides, carbonimidazoles, and the like. In the case of a reaction using a reactive derivative, in a solvent such as dioxane or ^ -dimethylformamide, an alkali metal hydride such as sodium hydride or sodium hydroxide is used as a base. Al-like metal hydroxide, such as Pum It can be carried out in the presence or absence of an alkali metal carbonate such as potassium carbonate, or an organic base such as pyridine or triethylamine.
カルボン酸体のままで反応を行う場合には塩化メチレン、 クロ口 ホルム、 ジォキサン、 ^ ^-ジメチルホルムアミ ド等の溶媒中縮合剤 の存在下塩基の存在下又は非存在下で更には添加剤の存在下又は非 存在下実施する事ができる。  When the reaction is carried out in the form of a carboxylic acid, the reaction is carried out in the presence of a condensing agent in a solvent such as methylene chloride, chloroform, dioxane, or ^^-dimethylformamide. Can be performed in the presence or absence of
縮合剤としては例えばジシクロへキシルカルボジィ ミ ド、卜 [ 3- (ジ メチルァミ ノ）プロピル] -3-ェチルカルボジィ ミ ド塩酸塩、シァノ リ ン酸ジェチル、 ジフエニルリ ン酸アジ ド、 カルボニルジイ ミダゾー ル等が挙げられる。 塩基としては例えば水酸化ナ ト リ ゥムのような アルカ リ金属水酸化物、 炭酸カ リ ウム等のアルカ リ金属炭酸塩、 又 はピリ ジン、 ト リェチルァミ ンのような有機塩基が挙げられる。 添 加剤と しては -ヒ ドロキシベンゾ ト リァゾ一ル、 -ヒ ドロキシス クシンイ ミ ドゃ 3 , 4-ジヒ ドロ- 3-ヒ ドロキシ- 4-ォキソ - 1 , 2， 3-ベン ゾト リァジン等が挙げられる。 反応温度としては- 20°Cから 100°Cに て、 好適には 0 °Cから 50°Cにて実施する事ができる。  Examples of the condensing agent include dicyclohexylcarbodiimide, tri [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, getyl cyanophosphate, azide diphenylphosphate, carbonyldiimidazole and the like. Can be Examples of the base include alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as potassium carbonate, and organic bases such as pyridine and triethylamine. Examples of the additives include -hydroxybenzotriazole, -hydroxysuccinimide ゃ 3,4-dihydroxy-3-hydroxy-4-oxo-1,2,3-benzotriazine and the like. No. The reaction can be carried out at a reaction temperature of -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
第四工程の加水分解反応はアル力 リ性条件下で行う事ができる。 アル力 リ性条件と しては水酸化リチウム、 水酸化ナ ト リ ゥム、 水酸 化カ リ ウム等が用いられる。 反応温度と しては 0°Cから 80 °Cにて、 好適には室温から 60°Cにて実施する事ができる。  The hydrolysis reaction in the fourth step can be performed under alkaline conditions. As the alkaline conditions, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. are used. The reaction can be carried out at a temperature of 0 ° C to 80 ° C, preferably at room temperature to 60 ° C.
本発明の新規化合物の投与形態としては、 経口投与のための固体 組成物、 液体組成物及びその他の組成物及び非経口投与のための注 射剤、 外用剤、 坐剤等を挙げる事ができる。 経口投与のための固体 組成物には、 錠剤、 丸剤、 カプセル剤、 散剤、 顆粒剤等が含まれる。 経口投与のための液体組成物は薬剤的に許容される乳濁剤、 シ口ッ プ剤等が含まれる。 経口投与のためのその他の組成物としてはスプ レー剤が含まれる。 また非経口投与のための注射剤としては、 無菌 の水性または非水性の溶液剤、 懸濁剤、 乳濁剤等が含まれる。 発明を実施するための最良の形態 Examples of the dosage form of the novel compound of the present invention include solid compositions, liquid compositions and other compositions for oral administration, and injections, external preparations and suppositories for parenteral administration. . Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, mouthwashes and the like. Other compositions for oral administration include sp Laying agents are included. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. BEST MODE FOR CARRYING OUT THE INVENTION
次に本発明を具体例によって説明するが れらの例によって本発 明が限定されるものではない。  Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
(実施例 1) (Example 1)
2 -「「3 - -「2 -「4- ( ト リ フルォロ メチル）フエ二 ェ  2-"" 3--"2-" 4- (trifluoromethyl) phene
ルト 4 -メ トキシフエニル 1メチル 1酪酸ェチル 4-Methoxyphenyl 1-methyl 1-ethyl butyrate
Figure imgf000017_0001
Figure imgf000017_0001
3 -（3-カルボキシ- 4-メ トキシフェニル）-2-ェチルプロピオン酸ェチ ル（特願 2000-157600; 560rag3 2.00mmol)、 ト リェチルァミ ン（977 Ml, 7·00ΙΜΙΟ1)と脱水ジクロロメタン 80mL を混合し、 氷冷攪拌下 クロ口炭酸ェチル（228mg， 2.10mmol)を脱水ジクロロメタン 5mL に 溶かし滴下した。 氷冷下 10分攪拌後 4- ( ト リ フルォロメチル）フェ ネチルァミ ン 塩酸塩（566mg， 2,51mmol)を脱水ジクロロメタン 15m Lに懸濁させ滴下した。 次に氷冷下 30分、 室温にて 6時間攪拌後反 応液を 10%クェン酸水溶液、 0.5mol/L炭酸水素ナ ト リ ゥム水溶液、 飽和食塩水で順次洗浄後無水硫酸ナ ト リ ゥムで乾燥し濃縮した。 残 留物をシリカゲルクロマ トグラフィー（溶出液 Λ-へキサン：酢酸ェ チルニ 2:3v/v)にて精製し、 770mg(85%)の表題化合物を無色油状物と して得た。 3- (3-carboxy-4-methoxyphenyl) -2-ethylpropionate (Japanese Patent Application 2000-157600; 560 rag 3 2.00 mmol), triethylamine (977 Ml, 7000-1) and dehydrated dichloromethane 80 mL of the mixture was mixed, and ethyl ethyl carbonate (228 mg, 2.10 mmol) was dissolved in 5 mL of dehydrated dichloromethane under ice cooling and stirring, and added dropwise. After stirring for 10 minutes under ice cooling, 4- (trifluoromethyl) phenethylamine hydrochloride (566 mg, 2,51 mmol) was suspended in 15 mL of dehydrated dichloromethane and added dropwise. After stirring for 30 minutes at room temperature under ice-cooling for 6 hours, the reaction solution was washed with a 10% aqueous solution of citric acid, a 0.5 mol / L aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and then anhydrous sodium sulfate. Dried and concentrated. The residue was purified by silica gel chromatography (eluent Λ-hexane: ethyl acetate 2: 3 v / v) to give 770 mg (85%) of the title compound as a colorless oil. I got it.
質量分析値 m/z 451(M+) (実施例 2-5) Mass spectrometry value m / z 451 (M + ) (Example 2-5)
実施例 1 と同様にして表 1に示す化合物を合成した Compounds shown in Table 1 were synthesized in the same manner as in Example 1.
(表 1) (table 1)
Figure imgf000018_0001
実施例 R R n 質量分析値 （m/z)
Figure imgf000018_0001
Example RR n mass spectrometry value (m / z)
2 CH3 C2H5 451 on 2 CH 3 C 2 H 5 451 on
3 ^5"11 C2H5 507 or) 4 C7H15 C2H5 535 3 ^ 5 "11 C 2 H 5 507 or) 4 C 7 H 15 C 2 H 5 535
5 C10H2i C2H5 577 (M+) 5 C 10 H 2 i C2H5 577 (M +)
(実施例 6) (Example 6)
2 - [「3-「N-「2-「4- ( ト リ フルォロメチル）フェニル 1ェチル，力ルバモイ — - 4- ト ^ジフエニル 1 チル 1酩酴  2-[[3- "N-" 2- "4- (trifluoromethyl) phenyl 1-ethyl, l-rubamoi —-4-tri-diphenyl 1-tyl
Figure imgf000018_0002
2-[[3- [N- [2- [4- ( ト リフルォロメチル）フヱニル]ェチル]力ルバモイ ル]- 4-メ トキシフエ二ル]メチル]酪酸ェチル （770mg, 1.71iMiol;実 施例 1) とメ夕ノ一ル 30mL、 2mol/L 水酸化ナ ト リ ウム水溶液 5mL を混合し、 60°Cで 4時間撹拌後反応液を減圧下濃縮した。 残留物を 水冷下 2mol/L塩酸で酸性とした。 生じた沈殿を濾過、 乾燥した後 n
Figure imgf000018_0002
2-[[3- [N- [2- [4- (Trifluoromethyl) phenyl] ethyl] ethyl rubamoyl] -4-methoxyphenyl] methyl] ethyl ester (770 mg, 1.71 iMiol; Example 1) And 30 mL of methanol and 5 mL of a 2 mol / L sodium hydroxide aqueous solution were mixed, and the mixture was stirred at 60 ° C. for 4 hours and concentrated under reduced pressure. The residue was acidified with 2 mol / L hydrochloric acid under water cooling. The precipitate formed is filtered and dried, then n
-へキサンと酢酸ェチルの混合溶媒にて再結晶し、無色粉末の表題化 合物を 580mg (80%) 得た。 Recrystallization from a mixed solvent of -hexane and ethyl acetate gave 580 mg (80%) of the title compound as a colorless powder.
融点 146— 147°C; 質量分析値 m/z 423(M+); 146-147 ° C; mass spec m / z 423 (M +);
元素分析値 C22H24F3N04 (423.43): Elemental analysis C 22 H 24 F 3 N0 4 (423.43):
計算値 C, 62.40; H, 5.71; , 3.31. Calculated C, 62.40; H, 5.71;, 3.31.
実測値 C, 62.20; H， 5.62; N, 3.32. ; Found C, 62.20; H, 5.62; N, 3.32 .;
-匪 R (400MHz, CDC13) (50.95 (3H， t, J = 7.8 Hz), 1.54-1.7 0 (2H, m), 2.58-2.65 (1H, m), 2.76 (1H} dd,J = 13.7, 8.3 H z), 2.94 (1H, dd,J = 13.7, 8.3 Hz), 2.99 (2H, t, J = 6.8 H z), 3.72 (3H, s)， 3.73 (2H, ), 6.83 (1H, d, J = 8.3 Hz), 7. 24 (1H, d, J = 2.4 Hz), 7.37 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 7.8 Hz), 7.89 (1H, t, J : 4.9 Hz) , 8.04 (1H, d， J = 2.4Hz). - negation R (400MHz, CDC1 3) ( 50.95 (3H, t, J = 7.8 Hz), 1.54-1.7 0 (2H, m), 2.58-2.65 (1H, m), 2.76 (1H} dd, J = 13.7 , 8.3 Hz), 2.94 (1H, dd, J = 13.7, 8.3 Hz), 2.99 (2H, t, J = 6.8 Hz), 3.72 (3H, s), 3.73 (2H,), 6.83 (1H, d, J = 8.3 Hz), 7.24 (1H, d, J = 2.4 Hz), 7.37 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 7.8 Hz), 7.89 (1H, t, J: 4.9 Hz), 8.04 (1H, d, J = 2.4Hz).
(実施例 7— 10) (Examples 7-10)
実施例 6 と同様にして表 2の化合物を得た。 表 2) In the same manner as in Example 6, the compounds in Table 2 were obtained. (Table 2)
Figure imgf000020_0001
Figure imgf000020_0001
質量分析値 — → Mass spectrometry value → →
実施例 R 元素分析（％) Example R Elemental analysis (%)
(M/Z) 不性式  (M / Z)
f†ffffl;C62.40,H5.71,N3.31 f † ffffl; C62.40, H5.71, N3.31
CH3 1 423(M+) C2oH24F3NO CH 3 1 423 (M + ) C 2 oH 24 F 3 NO
¾;lii;C62.16,H5.72,N3.33 計算値；065.12,16.73 2.92 ¾; lii; C62.16, H5.72, N3.33 Calculated; 065.12, 16.73 2.92
8 GsH 1 479(M+) C26H3,F3NO, H;fJii;C64.97,H6.82,N3.00 f†S:fil;C66.25,H7.15(N2.76 8 GsH 1 479 (M + ) C 26 H 3 , F 3 NO, H; fJii; C64.97, H6.82, N3.00 f † S: fil; C66.25, H7.15 ( N2.76
9 C7H- 507(M+) C28H5 実測値 ;C65.96,H7.17,N2.77 f† :fll;C67.74,H7.70,N2.559 C 7 H-507 (M + ) C 28 H 5 actual value; C65.96, H7.17, N2.77 f †: fll; C67.74, H7.70, N2.55
10 C10H. 549(M+) C31H42F3NO, 実測値 ;C67.47,H7.70,N2.64 10 C 10 H. 549 (M + ) C 31 H 42 F 3 NO, found; C67.47, H7.70, N2.64
(実施例 11) (Example 11)
2-「「3-「N - μ- (ト リ フルォロヌチル〗フェニル 1カルバ千ィル 1-4 - ト キシフエ  2-"" 3- "N-μ- (trifluoronyldiphenyl 1-carbacarbyl 1-4-toxifue
Figure imgf000020_0002
Figure imgf000020_0002
3 -（3-カルボキシ -4-メ トキシフェニル）-2-ェチルプロピオン酸ェチ ル（特願 2000- 157600; 530mg, 1.89mmol )、 4-ト リフルォロメチルァ 二リ ン（382mg, 2·37ΙΜΙΟ1)ヽ ト リェチルァミ ン（657 iL, 4.71mmol) と脱水ジクロロメタン 30mLを混合し、 氷冷攪拌下 2-クロロ- 1,3 -ジ メチルイ ミダゾリ ゥムクロライ ド（467mg, 2.76mmol)を脱水ジク口 ロメタン 20mLに溶かし滴下した。次に室温にて 6時間攪拌後反応液 を 10%クェン酸水溶液、 0.5mol/L炭酸水素ナ ト リ ウム水溶液、 飽和 食塩水で順次洗浄後無水硫酸ナ ト リ ゥムで乾燥し濃縮して 800mgの 縮合体を定量的に得た。 3- (3-carboxy-4-methoxyphenyl) -2-ethylpropionate (Japanese Patent Application 2000-157600; 530 mg, 1.89 mmol), 4-trifluoromethylaline (382 mg, 237ΙΜΙΟ1) ヽ Triethylamine (657 iL, 4.71 mmol) and 30 mL of dehydrated dichloromethane were mixed. Under ice-cooling and stirring, 2-chloro-1,3-dimethylimidazo dimethyl chloride (467 mg, 2.76 mmol) was dissolved in 20 mL of dehydrated dichloromethane and added dropwise. Next, after stirring at room temperature for 6 hours, the reaction solution is washed successively with a 10% aqueous solution of citric acid, a 0.5 mol / L aqueous solution of sodium hydrogen carbonate, and saturated saline, dried over anhydrous sodium sulfate and concentrated. 800 mg of the condensate was obtained quantitatively.
得られた縮合体（550mg, 1.30mmol)を 2mol/L水酸化ナ ト リ ゥム水 溶液 5fflL及びメタノール 30mL と混合し、 60°Cで 4時間撹拌した。反 応液を減圧下濃縮し、 残留物を水に溶解させ希塩酸で酸性とした。 生じた沈殿を濾過しシリカゲルクロマトグラフィー（溶出液 塩化メ チレン： メ夕ノール =15:lv/v)にて精製し、 200mg(39%)の表題化合物 を無色粉末として得た。  The obtained condensate (550 mg, 1.30 mmol) was mixed with 2 mol / L sodium hydroxide aqueous solution (5fflL) and methanol (30 mL), and the mixture was stirred at 60 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water and acidified with diluted hydrochloric acid. The resulting precipitate was filtered and purified by silica gel chromatography (eluent: methylene chloride: methanol = 15: lv / v) to give 200 mg (39%) of the title compound as a colorless powder.
融点 141一 142°C; 質量分析値 m/z 395(M+); Melting point 141-142 ° C; mass spec m / z 395 (M +);
元素分析値 C20H20F3N04 (395.37): Elemental analysis C 20 H 20 F 3 N0 4 (395.37):
計算値 C， 60.76; H, 5.10; N, 3.54. Calculated C, 60.76; H, 5.10; N, 3.54.
実測値 C， 60.72; H, 5.25; N3 3.53.; Found C, 60.72; H, 5.25; N 3 3.53 .;
^-NMR (400MHz, CDC13) 60.97 (3H, t, J = 7.3 Hz), 1.56-1.7 2 (2H, m), 2.60-2.67 ( 1H， m) , 2.80 (1H, dd,J = 14.2, 8.3 H z), 2.98 (1H, dd3J = 14.2, 8.3 Hz), 4.05 (3H， s),6.96 (1H, d, J = 8.3 Hz), 7.34 (1H, dd, J = 8.3, 2.4 Hz), 7.61 (2H， d, J二 8.3 Hz), 7.79 (2H， d, J = 8.8 Hz) , 8.10 (1H3 d, J = 2. 0 Hz), 10.00 (1H, s). ^ -NMR (400MHz, CDC1 3) 60.97 (3H, t, J = 7.3 Hz), 1.56-1.7 2 (2H, m), 2.60-2.67 (1H, m), 2.80 (1H, dd, J = 14.2, 8.3 Hz, 2.98 (1H, dd 3 J = 14.2, 8.3 Hz), 4.05 (3H, s), 6.96 (1H, d, J = 8.3 Hz), 7.34 (1H, dd, J = 8.3, 2.4 Hz ), 7.61 (2H, d, J 2 8.3 Hz), 7.79 (2H, d, J = 8.8 Hz), 8.10 (1H 3 d, J = 2.0 Hz), 10.00 (1H, s).
(実施例 12) (Example 12)
N- \A-( ト リ フルォロ メチル）フエニル 1ヌチル 1ペンタナミ ド
Figure imgf000022_0001
N- \ A- (Trifluoromethyl) phenyl 1-Nutyl 1-Pentamide
Figure imgf000022_0001
4- (ト リ フルォロメチル）ベンジルァミ ン（1.06g， 6.05mmol)、 ト リ ェチルァミ ン（l.OOmL, 7.17nimol)及びジクロロメタン 30mL を混合 し、 氷冷撹拌下 吉草酸クロライ ド（716〃L， 6.00賴 ol)を加えた。 水冷下 30分撹拌後室温にて 2時間撹拌した。 反応液を lmol/L塩 酸、 飽和炭酸水素ナ ト リ ウム水溶液、 飽和食塩水で順次洗浄後無水 硫酸ナ ト リ ゥムで乾燥し濃縮した。 残留物をシリカゲルクロマ ト グラフィー（溶出液 fl-へキサン ： 酢酸ェチル =2:lv/v)にて精製し、 1.41g(90%)の表題化合物を無色結晶と して得た。 4- (Trifluoromethyl) benzylamine (1.06 g, 6.05 mmol), triethylamine (l.OOmL, 7.17 nmol) and 30 mL of dichloromethane are mixed, and valeric acid chloride (716 L, 6.00 mL) is stirred under ice-cooling and stirring.賴 ol) was added. After stirring under water cooling for 30 minutes, the mixture was stirred at room temperature for 2 hours. The reaction solution was washed sequentially with lmol / L hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluent: fl-hexane: ethyl acetate = 2: lv / v) to give 1.41 g (90%) of the title compound as colorless crystals.
質量分析値 m/z 259(M+). Mass spectrum m / z 259 (M + ).
(実施例 13-14) (Example 13-14)
実施例 12 と同様にして表 3の化合物を得た。 In the same manner as in Example 12, the compounds in Table 3 were obtained.
(表 3) (Table 3)
Figure imgf000023_0001
Figure imgf000023_0001
実施例 R， 質量分析値 （m/z)  Example R, mass spectrometry (m / z)
13 287 (r) 13 287 (r)
Figure imgf000023_0002
Figure imgf000023_0002
(実施例 15)(Example 15)
[4- (ト リフルォロメ エー— —nーぺンチルアミ ン 塩酸塩  [4- (Trifluorome-—n-pentylamine hydrochloride
Figure imgf000023_0003
水素化アルミニゥムリチウム（210mg, 5.53mmol)と脱水テ トラヒ ド 口フラン lOmLの懸濁液中に、アルゴン雰囲気、氷冷攪拌下 [[4- (ト リフルォロメチル）フエニル]メチル]ペン夕ナミ ド（1.41g， 5.44mmo 1)を脱水テ トラヒ ドロフラン 20mLに溶かし滴下した。 8時間還流後 放冷し、 5mol/L水酸化ナ ト リ ゥム水溶液 0.5inLを加えた。 30分還流 後冷却し、 セライ トを通して濾過した。 テ トラヒ ドロフランでセラ ィ トを洗浄し、濾液及び洗浄液を合わせ濃縮した。残留物をエタノー ル 50ml に溶かし水、飽和食塩水で洗浄後無水硫酸ナ ト リ ゥムで乾燥 し濃縮した。 残留物を酢酸ェチル 20mlに溶かし氷冷撹拌下メタノ一 ル性塩酸を加え濃縮した。残留物に酢酸ェチル 10ml を加え不溶性の 結晶を濾取し酢酸ェチルで洗浄後乾燥して 1 .05g( 69° )の表題化合物 を黄色結晶として得た。
Figure imgf000023_0003
[[4- (Trifluoromethyl) phenyl] methyl] penamide in a suspension of lithium aluminum hydride (210 mg, 5.53 mmol) and 10 mL of dehydrated tetrahydrofuran with stirring under ice and ice (1.41 g, 5.44 mmol) was dissolved in 20 mL of dehydrated tetrahydrofuran and added dropwise. After refluxing for 8 hours, the mixture was allowed to cool, and 0.5 mol / L of a 5 mol / L sodium hydroxide aqueous solution was added. After refluxing for 30 minutes, the mixture was cooled and filtered through celite. Serra at Te Trahi drofran The filtrate was washed, and the filtrate and the washing solution were combined and concentrated. The residue was dissolved in 50 ml of ethanol, washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in 20 ml of ethyl acetate, and methanolic hydrochloric acid was added thereto under ice-cooling and stirring, followed by concentration. To the residue was added 10 ml of ethyl acetate, and the insoluble crystals were collected by filtration, washed with ethyl acetate and dried to obtain 1.05 g (69 °) of the title compound as yellow crystals.
質量分析値 m/z 245 (M+ ;遊離塩基として）. Mass spectrum m / z 245 (M + ; as free base).
(実施例 16-17) (Example 16-17)
実施例 15 と同様にして表 4の化合物を得た。 In the same manner as in Example 15, the compounds in Table 4 were obtained.
(表 4) (Table 4)
Figure imgf000024_0001
実施例 R ΙΪ量分析値 （m/z)
Figure imgf000024_0001
Example R Mass analysis value (m / z)
16 273 (M+; 遊離埴基として ） 16 273 (M + ; as free clay)
17 G1 0n2i 315 (IT: 遊離堪基として ） 17 G 1 0 n 2 i 315 (IT: As a free radical)
(実施例 18 ) (Example 18)
^メチル- 4 -（ ト リ フルォロメチル）ベンズアミ ド
Figure imgf000025_0001
^ Methyl-4- (trifluoromethyl) benzamide
Figure imgf000025_0001
4 -（ ト リ フルォロメチル）安息香酸（1.14g, 6.00mmol)の脱水べンゼ ン 15mL懸濁液に塩化チォニル（660 /L, 9.05mmol )及び ^ -ジメチ ルホルムアミ ドー滴を加え 2時間加熱還流した。 放冷後反応液を濃 縮し、残留物に脱水ベンゼン 30mLを加え濃縮した （この操作を再度 繰り返した）。残留物を脱水塩化メチレン 30mLに溶かし氷冷攪拌下 ト リエチルアミ ン（4.20mL, 30.1mmol)、 硫酸メチルアミン（1.15g, 7.18mmol)を加えた。 氷冷下 30分、 室温にて 2時間攪拌後反応液を 塩化メチレン .50mLで希釈し、 lmol/L塩酸、 飽和炭酸水素ナ ト リ ウ ム水溶液、 飽和食塩水で順次洗浄後無水硫酸ナ ト リ ゥムで乾燥し濃 縮した。残留物をシリカゲルクロマ トグラフィー（溶出液 へキサ ン ： 酢酸ェチル =2:lv/v)にて精製し、 683mg(56°/ の表題化合物を無 色結晶と して得た。  To a suspension of 4-(trifluoromethyl) benzoic acid (1.14 g, 6.00 mmol) in 15 mL of dehydrated benzene was added thionyl chloride (660 / L, 9.05 mmol) and a drop of ^ -dimethylformamide, and the mixture was heated under reflux for 2 hours. . After cooling, the reaction solution was concentrated, and 30 mL of dehydrated benzene was added to the residue, followed by concentration (this operation was repeated again). The residue was dissolved in 30 mL of dehydrated methylene chloride, and triethylamine (4.20 mL, 30.1 mmol) and methylamine sulfate (1.15 g, 7.18 mmol) were added under ice-cooling and stirring. After stirring under ice-cooling for 30 minutes and room temperature for 2 hours, the reaction solution was diluted with methylene chloride (.50 mL), washed successively with lmol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, and then dried over anhydrous sodium sulfate. Dried and concentrated in a reamer. The residue was purified by silica gel chromatography (eluent hexane: ethyl acetate = 2: lv / v) to obtain 683 mg (56 ° /) of the title compound as colorless crystals.
質量分析値 m/z 203( +). Mass spec.m / z 203 ( + ).
(実施例 19)(Example 19)
-メチル- 4 -（ ト リ フルォロ チル）フエニル チル]ァミ ン 塩酸
Figure imgf000026_0001
実施例 15 と同様にして、 -メチル- 4-(ト リ フルォロメチル）ベンズ アミ ド（680mg, 3.35mmol)より 483mg(64%)の表題化合物を淡黄色結 晶と して得た。 -Methyl-4- (trifluoroethyl) phenylethyl] amine hydrochloride
Figure imgf000026_0001
In the same manner as in Example 15, 483 mg (64%) of the title compound was obtained as pale yellow crystals from -methyl-4- (trifluoromethyl) benzamide (680 mg, 3.35 mmol).
質量分析値 m/z 188(遊離塩基として；（M- 1)+). Mass spec.m / z 188 (as free base; (M-1) +).
<生物活性 > <Biological activity>
(試験例 1)  (Test Example 1)
ペルォキシ、ゾーム: t曾硝 活 ィ h ィ太 に対する 写活件ィ 験 Peroxy and the somes: Photographing test for the soviet glass
10%脱脂牛血清を含むダルベッコ変法イーグル培地（FCS/DMEM)にて 培養した CH0細胞に、 酵母の転写因子の DNA結合領域とヒ ト型 PPAR ひのリガン ド結合領域 Biocheittistry, 1993, ^l, 5598) との融合 蛋白質を発現する受容体プラスミ ド及びそのレポ一夕一プラスミ ド (STRATAGENE社） 、 及び内部標準用のゥミシィ夕ケルシフェラ一ゼ プラスミ ド （PR0MEGA 社） をリポフエク トァミ ンにて無血清状態に てコ トランスフヱクシヨンした。その後 10%SFCS/DMEM中で被検化合 物を添加して 24時間後に両ルシフエラーゼ活性を測定し、内部標準 により補正した。  The DNA-binding domain of yeast transcription factor and the ligand-binding domain of human PPAR were added to CH0 cells cultured in Dulbecco's modified Eagle's medium (FCS / DMEM) containing 10% defatted bovine serum Biocheittistry, 1993, ^ l , 5598), a receptor plasmid expressing the fusion protein and its repo overnight plasmid (STRATAGENE), and an internal standard, such as MYCHIKELCIFFERASE Plasmid (PR0MEGA), were not available in Lipofectamine. Cotransfection was performed in serum. Thereafter, the test compound was added in 10% SFCS / DMEM, and 24 hours later, both luciferase activities were measured, and corrected using an internal standard.
結果を表 5に示す。 これらの結果より、 本発明化合物はヒ トペルォ キシゾーム増殖薬活性化受容体ひに対して強力な転写活性化作用を 有することが示された。 (表 5 ) 実施例 転写活性化作用 Table 5 shows the results. From these results, it was shown that the compound of the present invention has a strong transcriptional activating effect on the receptor for activating the hyperperoxisome proliferator. (Table 5) Example Transcriptional activation
EC50 ilxlO-fimo l/L) (EC 50 ilxlO- fi mo l / L)
6 0. 74  6 0. 74
1 1 6. 0  1 1 6.0
産業上利用可能性 Industrial applicability
上述の結果から、 本発明の置換カルボン酸誘導体は優れた PPARひ 転写活性化作用を有する新規な化合物群である。  From the above results, the substituted carboxylic acid derivatives of the present invention are a group of novel compounds having an excellent PPAR transcription activating effect.
これら本発明の化合物では、 PPARびに対する強い作動活性を有す る事から前述した脂質低下薬、 特に肝臓における脂質の低下薬、 動 脈硬化の進展に対する抑制薬、 抗肥満薬、 糖尿病治療薬等の代謝性 疾患治療薬として有効な化合物と言える。  Since these compounds of the present invention have a strong agonistic activity against PPAR, the above-mentioned lipid-lowering drugs, especially drugs for lowering lipids in the liver, drugs for suppressing the progression of arteriosclerosis, anti-obesity drugs, drugs for treating diabetes, etc. It is a compound that is effective as a drug for treating metabolic diseases.

Claims

口青求の範囲 一般式（υ Range of mouth blue general formula (υ
Figure imgf000028_0001
Figure imgf000028_0001
[式中、 nは 0、 1又は 2 を表し、 ϋは nが 0あるいは 2の場合は水素 原子又は炭素数 1 から 10の低級アルキル基を表し、 nが 1 の場合は 炭素数 1 から 10の低級アルキル基を表す]で表される置換カルボン 酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその 水和物。  [In the formula, n represents 0, 1 or 2, ϋ represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and 1 to 10 carbon atoms when n is 1. Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
2 . nが 0である請求項 1 記載の置換カルボン酸誘導体又はその エステル及びその薬剤上許容される塩並びにその水和物。 2. The substituted carboxylic acid derivative or its ester, its pharmaceutically acceptable salt and its hydrate according to claim 1, wherein n is 0.
3 . nが 2である請求項 1 記載の置換カルボン酸誘導体又はその エステル及びその薬剤上許容される塩並びにその水和物。 3. The substituted carboxylic acid derivative or ester thereof according to claim 1, wherein n is 2, a pharmaceutically acceptable salt thereof, and a hydrate thereof.
4 . 2-ェチル -3- [ 4-メ トキシ- 3- [ - [4- (ト リフルォロメチル）フェ ニル]力ルバモイル]フエニル]プロピオン酸又はそのエステルである 請求項 1記載の置換カルボン酸誘導体及びその薬剤上許容される塩 並びにその水和物。 4. The substituted carboxylic acid derivative and the substituted carboxylic acid derivative according to claim 1, which is 2-ethyl-3- [4-methoxy-3-[-[4- (trifluoromethyl) phenyl] potassium] phenyl] propionic acid or an ester thereof. Pharmaceutically acceptable salts thereof and hydrates thereof.
5 . 2-ェチル -3- [ 4-メ トキシ- 3- [ #- [ 2- [4- (ト リフルォロメチル） フエニル]ェチル]力ルバモイル]フエニル]プロピオン酸又はそのェ ステルである請求項 1記載の置換カルボン酸誘導体及びその薬剤上 許容される塩並びにその水和物。 5.5. 2-Ethyl-3- [4-methoxy-3-[#-[2- [4- (trifluoromethyl) phenyl] ethyl] ethylrubamoyl] phenyl] propionic acid or an ester thereof. On substituted carboxylic acid derivatives and their drugs Acceptable salts and hydrates thereof.
6 般式（1 ) 6 General formula (1)
(1)
Figure imgf000029_0001
(1)
Figure imgf000029_0001
[式中、 nは 0、 1又は 2を表し、 IUま nが 0あるいは 2の場合は水素 原子又は炭素数 1から 10の低級アルキル基を表し、 nが 1 の場合は 炭素数 1 から 10の低級アルキル基を表す]で表される置換カルボン 酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその 水和物の少なく とも 1種類以上を有効成分とする脂質低下薬。  [In the formula, n represents 0, 1 or 2, when IU or n is 0 or 2, it represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms, and when n is 1, 1 to 10 carbon atoms And a pharmaceutically acceptable salt thereof, and a hydrate thereof, a lipid-lowering drug comprising at least one active ingredient.
7 . '般式（1 ) 7. General formula (1)
く \ (CH2)n、\ (CH 2 ) n,
Figure imgf000029_0002
Figure imgf000029_0002
[式中、 nは 0、 1又は 2を表し、 Rは nが 0あるいは 2の場合は水素 原子又は炭素数 1から 10の低級アルキル基を表し、 nが 1の場合は 炭素数 1 から 10の低級アルキル基を表す]で表される置換カルボン 酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその 水和物の少なく とも 1種類以上を有効成分とするヒ トペルォキシゾー ム増殖薬活性化受容体（PPAR ) aァゴニス ト。 [In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and 1 to 10 carbon atoms when n is 1. A substituted carboxylic acid derivative or an ester thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which contains at least one active ingredient as an active ingredient. Body (PPAR) a gonist.
8 一般式（1 ) 8 General formula (1)
Figure imgf000030_0001
Figure imgf000030_0001
[式中、 nは 0、 1又は 2 を表し、 Rは nが 0あるいは 2の場合は水素 原子又は炭素数 1から 10の低級アルキル基を表し、 nが 1の場合は 炭素数 1 から 10の低級アルキル基を表す]で表される置換カルボン 酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその 水和物の少なく とも 1種類以上を有効成分とする動脈硬化治療薬。  [In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and R represents 1 to 10 carbon atoms when n is 1. And a pharmaceutically acceptable salt thereof, and a hydrate thereof, which comprises at least one active ingredient.
9 . 般式（1 ) 9. General formula (1)
Figure imgf000030_0002
Figure imgf000030_0002
[式中、 nは 0、 1又は 2 を表し、 Rは nが 0あるいは 2の場合は水素 原子又は炭素数 1から 10の低級アルキル基を表し、 nが 1の場合は 炭素数. 1 から 10の低級アルキル基を表す]で表される置換カルボン 酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその 水和物の少なく とも 1種類以上を有効成分とする抗肥満薬。  [In the formula, n represents 0, 1 or 2, R represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms when n is 0 or 2, and a carbon atom when n is 1. Represented by 10 lower alkyl groups], an ester thereof, a pharmaceutically acceptable salt thereof, and an anti-obesity agent comprising at least one or more hydrates thereof as an active ingredient.
1 0 一般式 U ) く \ />~(CH2)n、N (1) 1 0 General formula U) \ \ /> ~ (CH 2 ) n, N (1)
R [式中、 nは 0、 1又は 2 を表し、 ΙΠま nが 0あるいは 2の場合は水素 原子又は炭素数 1から 10の低級アルキル基を表し、 nが 1 の場合は 炭素数 1 から 10の低級アルキル基を表す]で表される置換カルボン 酸誘導体又はそのエステル及びその薬剤上許容される塩並びにその 水和物の少なく とも 1種類以上を有効成分とする糖尿病治療薬。 R [In the formula, n represents 0, 1 or 2, and when n is 0 or 2, it represents a hydrogen atom or a lower alkyl group having 1 to 10 carbon atoms, and when n is 1, it has 1 to 10 carbon atoms. And a pharmaceutically acceptable salt thereof, and a hydrate thereof, comprising at least one active ingredient as the active ingredient.
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Cited By (4)

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Publication number Priority date Publication date Assignee Title
JP2006503916A (en) * 2002-10-21 2006-02-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Substituted tetralin and indane
JP2006503915A (en) * 2002-10-21 2006-02-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Treatment of syndrome X with substituted tetralin and indane
JP2006503917A (en) * 2002-10-21 2006-02-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Substituted tetralin and indane and their use
JP2007001912A (en) * 2005-06-22 2007-01-11 Univ Of Tokyo Substituted phenylpropionic acid derivative

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JP2000256194A (en) * 1999-01-06 2000-09-19 Mitsui Chemicals Inc Intranuclear receptor agonist and agent for enhancing its effect
WO2000075103A1 (en) * 1999-06-09 2000-12-14 Kyorin Pharmaceutical Co., Ltd. SUBSTITUTED PHENYLPROPIONIC ACID DERIVATIVES AS AGONISTS TO HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) $g(a)
WO2001025181A1 (en) * 1999-10-01 2001-04-12 Eisai Co., Ltd. Carboxylic acid derivatives and drugs containing the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000256194A (en) * 1999-01-06 2000-09-19 Mitsui Chemicals Inc Intranuclear receptor agonist and agent for enhancing its effect
WO2000075103A1 (en) * 1999-06-09 2000-12-14 Kyorin Pharmaceutical Co., Ltd. SUBSTITUTED PHENYLPROPIONIC ACID DERIVATIVES AS AGONISTS TO HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) $g(a)
WO2001025181A1 (en) * 1999-10-01 2001-04-12 Eisai Co., Ltd. Carboxylic acid derivatives and drugs containing the same

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006503916A (en) * 2002-10-21 2006-02-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Substituted tetralin and indane
JP2006503915A (en) * 2002-10-21 2006-02-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Treatment of syndrome X with substituted tetralin and indane
JP2006503917A (en) * 2002-10-21 2006-02-02 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Substituted tetralin and indane and their use
JP2007001912A (en) * 2005-06-22 2007-01-11 Univ Of Tokyo Substituted phenylpropionic acid derivative

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