WO2002046146A1

WO2002046146A1 - Substituted carboxylic acid derivatives

Info

Publication number: WO2002046146A1
Application number: PCT/JP2001/010563
Authority: WO
Inventors: Hiroyuki Miyachi; Yukie Takahashi; Kouji Murakami
Original assignee: Kyorin Pharmaceutical Co., Ltd.
Priority date: 2000-12-05
Filing date: 2001-12-04
Publication date: 2002-06-13
Also published as: AU2002222573A1; JPWO2002046146A1

Abstract

Novel substituted carboxylic acid derivatives which bind to human peroxisome proliferator-activated receptor a (PPARa) 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) and pharmaceutically acceptable salts and hydrates of the same; and a process for producing these compounds: (1) wherein R?1, R3 and R5¿ represent each hydrogen or lower alkyl; R2 represents hydrogen or lower alkoxy; R4 represents hydrogen, trifluoromethyl, lower alkoxy, halogeno, optionally substituted phenoxy or benzyloxy; n is an integer of from 0 to 3; and the carboxylate substituent is located at the p-position concerning R2 or at the p-position concerning (CH¿2?)n.

Description

Satsuki Itoda β-substituted carboxylic acid derivatives '' Technical field

The present invention provides an agonist for human peroxisome proliferator-activated receptor (PPAR) agonist, particularly for human PPAR isoform, for metabolic diseases such as hyperlipidemia, obesity, and diabetes. The present invention relates to a therapeutically effective substituted carboxylic acid derivative, an addition salt thereof, a production method thereof, and a pharmaceutical composition containing these compounds. Background art

Peroxisome proliferator-activated receptor (ΡΡΑΙ is a ligand-dependent transcription factor that belongs to the nuclear family superfamily like steroid receptor, retinoid receptor, thyroid receptor, etc. Three isoforms (α type, (5 (or ^) type, α type)) with different distributions have been identified in various animal species including humans (roc. Natl. Acad. Sci., 1992). Among them, PPAR is distributed in the liver and kidney, etc., which have high catabolism of fatty acids, and high expression is observed especially in the liver.

1995, 1, 1, 354), genes involved in fatty acid metabolism and intracellular transport (eg, acyl-CoA synthetase, fatty acid binding protein lipoprotein lipase), and apolipoproteins involved in cholesterol and neutral lipid metabolism. Controls gene expression (AI, AII, CIII, etc.). PPAR (5 is ubiquitously expressed in various tissues in vivo, especially in neurons. At this time, the physiological significance of PPAR3 has not been fully elucidated. PPARa is highly expressed in adipocytes. are involved in the minute of the fat cells Te (. es., 1996, ai , 907) o of PPAR in this manner Each isoform performs a specific function in a particular organ or tissue.

In addition, it has been reported that PPAR chick knockout mice exhibit hypertriglyceridemia and hypoglycemia with aging, and become obese mainly due to an increase in white adipocytes (Io 1998,, 29577, J. Clin. Invest., Ι ^, Ι ^ ϊ, 1083, Proc. Natl. Acad. Sci., 1999,, 747 3), PPARs have blood lipids (cholesterol and neutral lipids) and blood It is strongly suggested that it plays an important role in regulating the homeostasis and energy balance of Darcos.

By the way, conventionally, fibrates have been widely used as drugs for treating hyperlipidemia, particularly for treating hypertriglyceridemia. Activation of PPAR has been reported as a mechanism of action of this fibrinoid. Lipid. Res. A9, SI, 907). In addition, it has been reported that fibrate drugs suppress the increase in body weight and adipose tissue weight in insulin resistant animal models and normalize the decreased glucose tolerance (J. Biol. Chem. ,?) 00, Ii, 16638 , Biochem .Biophys. Res. Com., 2000, m, 445) s P PAR has been shown to be involved in the improvement of Insurin resistance.

However, the activity of 示す βα exhibited by fibrates is weak, 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 fibrates, and the various causes of fibrates indicate the cause. Non-specific effects are thought to be the cause, and the development of therapeutic drugs for metabolic diseases by specific mechanisms is desired.

Considering the role of the nuclear transcription factor PPARa in regulating lipid metabolism and its involvement in pathologies such as hyperlipidemia, obesity, and diabetes, PPARs specifically bind to human ΡΡΑβ-ligand. If a compound capable of activating human PPARo: can be created, It is expected to be used as a medicament for the treatment of metabolic diseases caused by nism.

The compounds with an affinity for PPAR as a ligand of PPAH occurs through by that oxidation shea Tokuromu P- 450 in addition to LTB ₄ is a metabolite of Arakidon acid HETE (hydroxycarboxylic Eiko satay Toraen acid ) Eicosanoids of the group, especially 8-HETE, 8-HEPE, etc. have been reported (/ »o ίΙ. Αοαά. Βοί. Λ ^ Ί, Μ., 312). However, these endogenous unsaturated fatty acid derivatives are metabolically and chemically unstable and cannot be used as a medicine.

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.

JP-A-11-158144 (SSP) as a -substituted phenylpropionic acid derivative having a hypoglycemic effect and a hypolipidemic effect

General formula (A)

(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 group, a hydroxyl group or Represents an alkoxy group, R ¹ represents a hydrogen atom or an alkyl group, etc., represents an alkyl group or a phenyl group, and represents a hydrogen atom, an alkyl group, an alkoxy group, or the like. It has been reported.

However, these compounds have a laid group at one part of the linking moiety. It differs from the compounds of the present invention in that they do not contain them and that they contain a lactam ring in the terminal substituent W, and it is described that these compounds have human ΡΡΑβα binding activity and transcriptional activation activity. Absent.

International Publication No. W098 / 28254 (Nippon Chemifa Corporation) as a compound with hypoglycemic action

General formula (Β)

(B)

(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, and R ⁴ is hydrogen X represents an atom or an alkyl group having 1 to 8 carbon atoms, X ⁵ represents an oxygen atom or a sulfur atom, and R ⁵ represents an alkyl group having 1 to 8 carbon atoms which may have a substituent; Or represents an aryl group).

However, these compounds have a different structure from the compounds of the present invention in that they do not contain a peridot group in Y ² and X ⁴ of the linking moiety and are heterocyclic rings bonded to the 3-position of propionic acid. It is not described that these compounds have a human PPARa binding activity and a transcription activating effect.

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) R ⁵

(C)

(Wherein, represents a substituent represented by 芳香 and D ₂ , R 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 form a double bond and consolidated hydrogen atom or a beta ^9, beta ⁷ is a carboxyl group, Ashiru group which may have a substituent alkoxycarbonyl group, an alkyl R ⁸ represents an aryl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a group and an OR ⁸ group, and R ⁸ represents an optionally substituted aryl group or an alkoxycarbonyl group. represents a group, R ⁹ represents a hydrogen atom, Al kill group, an alkoxycarbonyl two Le group, R ^{1 Q} is represented by a hydrogen atom, an amino group, an alkoxy group, an alkyl group, Ariruokishi group and Ararukiruokishi group) Compounds have been reported .

However, these compounds differ in structure from the compounds of the present invention in that the linkage between the H-containing side chain moiety and the benzene ring is limited to oxygen atoms, and these compounds have a human PPAR binding activity, It is not described that it has a transcription activating effect.

Published Patent Publication No. 63-91354 (Yamanouchi Pharmaceutical Co., Ltd.) as a carboxylic acid derivative having a leukotriene receptor agonizing action

General formula (E)

(E)

(Where A represents a hydrogen atom or a fluoro 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. Compounds represented by a lower alkyl group or a carboxy lower alkylcarbamoyl group (where A represents a phenyl group and R represents a carboxy lower alkyl carbamoyl lower alkyl group) have been reported.

However, these compounds have a different structure from the compounds of the present invention because all carbonyl groups are present in the R group, and it is unlikely that these compounds have human PPARa binding activity and transcription activation activity. Not described.

US5227490 (Merck Co., Ltd.) as a carboxylic acid derivative with fibrinogen receptor antagonistic activity

General formula (F)

(Wherein, R ¹ is a hydrogen atom, an alkyl group, an aryl C ₄ _ 1 _Q alkyl group, an aryl group, a carboxyl group, a ₆ alkoxy group, a carboxy C _Q _ ₆ alkyl Group, forces Rupokishi C _Q - ₆ alkoxy group, human Dorokishi CH alkyl group, (^ _ ₄ alkylsulfonyl C _Q - ₆ alkyl group, C ₄ Arukiruamino C _Q - ₆ alkyl group, Ariru Co- _{1 ()} Arukiruamino C ₀ _ ₆ alkyl groups, C ₂ - _{1 ()} Ashiruami Bruno C _Q _ ₆ alkyl group, ₍₄ carboalkoxy C _Q _ ₆ alkyl or halogen atoms, the same or different hydrogen atom, androgenic atom, human de port hexyl group, CH alkoxy group, Ariru Co- ₄ alkyl group, Ari Le C _Q - ₆ alkoxy group which may have a substituent - represents an _alkyl group, R ³ is a hydrogen atom, _ ₆ represents an alkyl group or Ariru _{1 Q} alkyl group, X is an oxygen atom, a sulfur atom, SO group, S0 ₂ group, CO group, NR ⁴ C0 group, C0NR ⁴ group, CH ₂ group, CH two CH groups, NR ⁴ CS Y represents an unsubstituted or optionally substituted alkyl , C ₄ _ ₈ consequent opening alkyl group, § Li Ichiru groups, C

0 - 3 alkyl § reel C _Q _ ₃ alkyl group, C _Q - ₃ alkyl § reel C _Q _ ₃ § Le kills carbonyl group, C _Q - ₃ alkyl § reel C _Q - ₃ alkyl carboxy § Mi de group, C. _ ₃ alkylaryloxy C _D _ ₃ alkyl group, C0NH group, NHC0 group or (CH ₂ ) m-Q- (CH ₂ ) n group (where Q is one to three kinds selected from oxygen or sulfur Represents a C ₃ _ _8- membered heterocyclic ring containing a heteroatom, m and n represent 0 to 4, and Z represents an NR ⁴ R ⁵ group (where ^ and R ⁵ are the same or different Te hydrogen atom, ₍₆ alkyl group, an alkyl group Ariru alkyl group unsubstituted or ₍₄ alkoxy, carboxy C _Q _ ₆ alkyl group, human de port hexyl groupヽandrogenic atom or nitrogen, is selected Ri by oxygen and sulfur Which may be substituted with a 4- to 9-membered monocyclic or bicyclo ring containing 1-3 heteroatoms) or a guanidino group which may have a substituent) Have been reported.

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 PPAR binding. No activity or transcriptional activation is described. Regarding patents reporting PPAR agonism, International Publication No. WO 97/25042 (SmithKline Beecham Co., Ltd.) is a compound having PPAR agonism and PPAR agonism.

General formula (G)

(Wherein ^Ra represents a 2-benzoxazolyl group or a 2-pyridyl group, and ^Rb represents a methoxymethyl group or a trifluoromethyl group). However, these compounds differ in structure from the compounds of the present invention in that the substitution mode between the side chain containing Γ and the Zensen ring is limited to an ether bond, and furthermore, human PPARa binding activity and transcription activation No effect is described.

International Publication No. W097 / 36579 (Glaxopercum Co., Ltd.) as a compound having PPA R agonistic action

General formula (H)

(H)

(Wherein X represents a hydrogen atom or a fluorine atom). However, these compounds differ in structure from the compounds of the present invention in that the linkage between the side chain containing a carboxyl group and the benzene ring is limited to an oxygen atom, and the transcriptional activation of PPAR is never satisfactory. Not strong.

The frequency of atherosclerotic diseases, such as ischemic heart disease, is increasing due to rapid changes in diet and lifestyle. Hyperlipidemia, diabetes, and hypertension are considered to be the main risk factors for this arteriosclerotic disease, and the presence of insulin resistance is considered to be important in the pathology. It has been shown that obesity due to fat accumulation 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 have focused on the specific role of such a human PPAR for the purpose of creating a structurally novel drug that is highly effective and safe as a therapeutic drug for metabolic diseases, and conducted extensive research. 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 activity, and completed the present invention. That is, the present invention relates to the general formula (1)

[Wherein, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or a lower alkoxy group having 1 to 4 carbon atoms, Represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and R ⁴ represents a hydrogen atom, a trifluoromethyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halogen atom, or an unsubstituted or substituted R ⁵ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, n represents an integer of 0 to 3, and the substitution position of the carboxylic acid residue is represented by R ² Para to the substituent or para to the (CH ₂ ) _n substituent]], a pharmaceutically acceptable salt thereof, and a hydrate 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.

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 process of synthesizing 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 can also be produced by reacting an optically active alcohol derivative or an optically active oxazolidinone derivative with a diastereomeric ester derivative ゃ oxazolidinone derivative obtained by fractional crystallization or chromatography. . Further, they can be produced by a technique of mouth chromatography using a chiral support.

In the general formula (1) of the present invention, “a lower alkyl group having 1 to 4 carbon atoms” means a straight chain such as methyl, ethyl, propyl, isopropyl and butyl Or branched ones having 1 to 4 carbon atoms.

The term "lower alkoxy group having 1 to 4 carbon atoms" includes straight or branched ones having 1 to 4 carbon atoms such as methoxy group, ethoxy group, propoxy group, isopropoxy group and butoxy group. Can be

The “alkyl group having 1 to 10 carbon atoms” includes those having 1 to 10 carbon atoms that are linear or branched such as methyl, ethyl, propyl, isopropyl, heptyl, and decyl.

Substituents allowed in the “unsubstituted or optionally substituted phenoxy group” represent a lower alkoxy group having 1 to 4 carbon atoms or a halogen atom.

“Halogen atom” includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the compounds represented by the above general formula (1), R ³ is a hydrogen atom, n is 0, and the carboxylic acid moiety is in the para position of R ^{2 in} the general formulas (la ′ and la). Certain compounds can be produced, for example, by the following method (Scheme 1).

Scheme 1

That is, the general formula (la)

[In the formula, β ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a lower alkoxy group having 1 to 4 carbon atoms, R ⁴ represents a hydrogen atom, trifluoromethyl Represents a lower alkoxy group having 1 to 4 carbon atoms, a nitrogen atom, an unsubstituted or optionally substituted phenoxy group or a benzyloxy group] is represented by the general formula (2)

[Wherein, and R ² are as described above, and represents a lower alkyl group having 1 to 4 carbon atoms] (Japanese Patent Application No. 2000-158424) and the general formula (3)

[Wherein R ⁴ is as described above]. A general formula (la ′) which can be synthesized by reacting a compound represented by the formula (first step).

(1a,)

[Wherein, RR ² , R ⁴ and are as described above]. The compound can be produced by hydrolyzing the C00R ⁶ site of the compound (second step). The reaction in the first step can be carried out in a solvent such as methylene chloride, chloroform, tetrahydrofuran, ethyl acetate, and ^ -dimethylformamide. The reaction can be carried out at a reaction temperature of -50 ° C to 150 ° C, preferably at room temperature to the reflux temperature of the solvent.

The reaction in the second step can be performed under alkaline conditions. As the alkaline conditions, lithium hydroxide, sodium hydroxide, lithium hydroxide or a mixture of these alkali metal hydroxides with methanol, ethanol, tetrahydrofuran and the like are used. The reaction can be carried out at a reaction temperature of −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.

Further, among the compounds represented by the above general formula (1), β ³ is an alkyl group having 1 to 10 carbon atoms, η is 1, and the carboxylic acid moiety is in the para position of H ² (lb. And lb) can be produced, for example, by the following method (Scheme 2).

(1b ') (1b) Scheme 2 That is, the general formula (lb)

[Wherein, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom, a lower alkoxy group having 1 to 4 carbon atoms, and R ³ represents a 1 to 10 carbon atoms. Represents an alkyl group, and R ⁴ represents a hydrogen atom, a trifluoromethyl group, a lower alkoxy group having 1 to 4 carbon atoms, a nitrogen atom, an unsubstituted or optionally substituted benzyloxy group or a benzyloxy group. Represents] the general formula (4)

[Wherein, and R ² are as described above, and represents a lower alkyl group having 1 to 4 carbon atoms] (Japanese Patent Application No. 2000-158424) and a general formula (6)

[Wherein, R ³ is as described above]. A general formula (5) which can be synthesized by reacting a compound represented by the following formula (Step ³ ).

[Wherein, R \ R ³ and β ⁶ are as described above] and a compound represented by the general formula (3)

[Wherein, R ⁴ is as described above]. A general formula (1) which can be synthesized by reacting a compound represented by the following formula (Step ⁴ ).

Wherein,, \ \ fi ⁴ and are as described above] can be prepared by the C 00R ⁶ sites of the compound represented by hydrolyzing (second step).

The reaction in the third step is performed in the presence of a metal catalyst such as activated carbon supported on palladium, activated carbon supported on platinum, platinum oxide, or alumina supported on rhodium, in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, or -dimethylformamide. Hydrogen pressure can be reduced from 98.1kPa to 491kPa. The reaction can be carried out at a temperature of 0 ° C to 100 ° C, preferably at room temperature to 80 ° C.

The reaction of the fourth step was carried out in a solvent such as methylene chloride, chloroform, tetrahydrofuran, ethyl acetate, ^^ dimethylformamide, etc. You can do it. The reaction can be carried out at a reaction temperature of -50 ° C to 150 ° C, preferably at room temperature to the reflux temperature of the solvent.

The reaction in the fifth step can be carried out under alkaline conditions. As the alkaline conditions, lithium hydroxide, sodium hydroxide, lithium hydroxide or a mixture of these alkali metal hydroxides with methanol, ethanol, tetrahydrofuran and the like are used. The reaction can be carried out at a reaction temperature of −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° 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, syrups and the like. Other compositions for oral administration include sprays. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

(Example 1)

2- -3-Γ3- “4- (Trifluoromethyl) phenyl 1 ゥ Rate 4-Methoxyphenyl] tyl 1Ethyl butyrate HH

Ethyl 2-[(3-amino-4-methoxyphenyl) methyl] butyrate (208 mg, 0.828 mmol) was dissolved in 10 mL of dehydrated methylene chloride under an argon atmosphere. Next, 4- (trifluoromethyl) phenylisocyanate (0.133 mL, 0.912 ol) was added thereto, and the mixture was left overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 363 mg (100%) of the title compound as a brown oil.

Mass spec m / z 438 (M ⁺ ).

W-Fiber (400MHz, CDClg) άθ.92 (3Η, t, J = 7.8 Hz), 1.19 (3H, t, J = 7.3 Hz), 1.52-1.72 (2H, m), 2.56-2.63 (1H, m ), 2.

73 (1H, dd, J = 13.7, 6.3 Hz), 2.87 (1H, dd, J = 13.7, 8.8

Hz), 3.82 (3H, s), 4.03-4.14 (2H, m), 6.76 (1H, d, J = 8.3 Hz), 6.83 (1H, dd, J = 8.3, 2.0 Hz), 6.99 (2H, br s), 7.20

(2H, d, J = 8.3 Hz), 7.59 (2H, d, J = 8.3 Hz), 7.85 (1H, d, J-2.0 Hz).

(Example 2-12)

The compounds shown in Table 1 were obtained in the same manner as in Example 1.

(table 1)

a) Ion mode FAB +

(Example 13)

-Γ “3-“ 3- Γ4- (trifluoro-nutyl) file: I-uredo 4-

ぇぇ Paper (Rule 26) 2-[[3- [3- [4- (Trifluoromethyl) phenyl] -reido] -4-ethylmethoxyphenyl] methyl] butyrate (464 mg, 0.815 mmol) is dissolved in ethanol (7 mL), and lmol / L sodium hydroxide is dissolved. 4 mL of thorium was added, and the mixture was heated and stirred at 50 ° C for 17.5 hours. The reaction solution was concentrated, the residue was dissolved in water, and washed with getyl ether. Next, the pH was adjusted to 3 with dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated to give 332 mg (99%) of the title compound as pale brown crystals. Further, the title compound purified by recrystallization from ethyl acetate was obtained as a colorless powder.

193-194 ° C; mass spec m / z 410 (M +);

Elemental analysis _{_{(%) C 20 H 21 F}} 3 N 2 0 4 (410.39):

Calculated C, 58.53; H, 5.16; N, 6.83.

Found C, 58.65; H, 5.21; N, 6.85.

1H-NMR. (400MHz, DMS0 - d 6) δ 0.87 (3Η, t, J = 7.3 Hz), 1.46-1 55 (2H, m), 2.37-2.44 (1H, m), 2.60 (1H, dd, J = 13.2, 6.8 Hz), 2.75 (1H, dd, J2 13.2, 8.3 Hz), 3.85 (3H, s), 6.78 (1H, dd, J = 8.3, 2.0 Hz), 6.92 (1H, d , J = 8.3 Hz), 7.63 (2H, d, J = 9.3 Hz), 7.66 (2H, ά, J = 9.3 Hz), 8.01 (1H, d, J = 2.0 Hz), 8.29 (1H, s), 9.70 (1H, s), 12.07 (1H, br s),

(Example 14-24)

The compounds shown in Table 2 were obtained in the same manner as in Example 13.

a) Ion mode FAB +

Replacement form (Rule 26) 20/1

(Example 25)

?-“Γ4-Nutoxy-3- (propylaminobutyl) phenyl 1-methyl-1-butyrate

Replacement form (Rule 26) twenty one

Methyl 2-[(3-formyl-4-methoxyphenyl) methyl] butyrate (1.90 g, 759 1) and propylamine (0.624 mL, 7.59 IMIO1) of well-known (patent application 2000-158424) in 50 mL of ethanol After melting, 10% palladium-loaded activated carbon (4 OO mg) was added, and hydrogenation was performed at an initial pressure of 294 kPa. After completion of the reaction, the catalyst was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluent: ethyl acetate, then ethyl acetate: methanol = l: lv / v) to give 1.63 g (73%) of the title compound as a pale yellow oil.

Mass spec (FAB +) in / z 294 [M + H] ⁺ .

(Examples 26-27)

The compounds shown in Table 3 were obtained in the same manner as in Example 25.

twenty two

(Table 3)

a) Ion mode FAB +

(Example 28)

2- "" 3- "3- (2.4-difluorophenyl) -1-propyl

-4 -Methoxyxenyl 1-yl 1-Nutyl butyrate

2-[[4-Methoxy-3- (propylaminomethyl) phenyl] methyl] methylbutyrate (400 mg, 1.36 mmol) 2,4- (difluorophenyl) isocyanate (211 mg, 1.36fflinol) and methylene chloride 20 mL was mixed and stirred at room temperature overnight. Next, tris (2-aminoethyl) amine polymer bound (500 mg,

2.05 ol) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (eluent: n-hexane: ethyl acetate 2 l: lv / v) to give 480 mg (72%) of the title compound as a yellow oil. Obtained.

Mass spec.m / z 448 (M +)

Negation _{R (400MHz, CDC1 3) d} 0.87-0.93 (6H, m), 1.52-1.66 (6H, m), 2.52-2.56 (1H, m), 2.70 (1H, dd, J = 13.7, replacement sheet (Rule 26) twenty three

6.3 Hz), 2.89 (1H, dd, J = 13.7, 8.3 Hz), 3.34 (2H, dd, J 8.8, 6.3 Hz), 3.58 (3H, s), 3.87 (3H, s), 4.47 (2H, s), 6.84 (2H, d, J = 8.8 Hz), 7.02 (IH, d, J = 2.0 Hz), 7.09

(2H, dd, J = 8.3, 2.4 Hz), 7.98-8.04 (IH, m).

(Examples 29-35)

The compounds shown in Table 4 were obtained in the same manner as in Example 28.

twenty four

(Table 4)

The transcription activating effect on the human PPAR isoform of the present invention is confirmed by the following test methods. Transcriptional activation test for peroxisome proliferator-activated receptor>

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. Biochemistry, 1993, 31, 5598 Receptor plasmid that expresses a protein and its repo overnight plasmid (STRATAGENE), and ゥ Michitake luciferase for internal standard

Replacement form (Rule 26) 25 Plasmid (PR0MEGA) was serum-free with ribofectamine and cotransfected. Thereafter, the test compound was added in 10 SFCS / DMEM, and 24 hours later, both luciferase activities were measured and corrected by the internal standard. Industrial applicability ''

The substituted carboxylic acid derivative represented by the general formula (1) which is a compound of the present invention, a pharmaceutically acceptable salt thereof and a hydrate thereof have a transcription activating effect on human PPAR isoform and have hyperlipidemia. It is useful as a prophylactic / therapeutic agent for metabolic diseases such as arteriosclerosis, glucoseuria and obesity.

Claims

26

Scope of word blue

1. General formula (1)

[Wherein, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or a lower alkoxy group having 1 to 4 carbon atoms,

R ³ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, represents a hydrogen atom, a trifluoromethyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halogen atom, an unsubstituted or substituted Represents a phenoxy group or a benzyloxy group, represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, η represents an integer from 0 to 3, and the substitution position of the carboxylic acid residue is Γ In the para position or in the para position to the (CH ₂ ) _n substituent.] And pharmaceutically acceptable salts thereof and hydrates thereof.

2. The substituted carboxylic acid derivative according to claim ¹ , wherein R ¹ is an ethyl group, and a pharmaceutically acceptable salt thereof.

3. The substituted carboxylic acid derivative according to claim 1, wherein R is a methoxy group, a pharmaceutically acceptable salt thereof, and a hydrate thereof. 27

4. The substituted carboxylic acid derivative according to claim 1, wherein is a heptyl group, a pharmaceutically acceptable salt thereof and a hydrate thereof,

5. The substituted carboxylic acid derivative according to claim 1, wherein is a hydrogen atom, a pharmaceutically acceptable salt thereof, and a hydrate thereof.

6. The substituted carboxylic acid derivative, the pharmaceutically acceptable salt thereof, and the hydrate thereof according to claim 1, wherein the substitution position of the carboxylic acid residue is para to the R-substituent.

[Wherein, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or a lower alkoxy group having 1 to 4 carbon atoms, and represents a hydrogen atom or a 1 to 10 carbon atoms. Represents a hydrogen atom, a trifluoromethyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halogen atom, a phenyloxy group which may be unsubstituted or substituted or a benzyloxy group. , R ⁵ represents a lower alkyl group having 1 to 4 hydrogen or C, n represents an integer of 0 to 3, the substitution position of Chikararu Bonn acid residue moiety R ² para to the substituent or ( A CH ₂ ) _n- substituent in the para-position], a lipid-lowering drug comprising at least one or more of pharmaceutically acceptable salts and hydrates thereof as an active ingredient. 28

8. General formula (1)

R

[Wherein, R represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or a lower alkoxy group having 1 to 4 carbon atoms,

R ³ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and IT has a hydrogen atom, a trifluoromethyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halogen atom, and an unsubstituted or substituted group. R ⁵ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, n represents an integer of 0 to 3, and the substitution position of the carboxylic acid residue portion is At least one of a substituted carboxylic acid derivative represented by the formula ( ₁ ), a para-position to the R ² substituent or a para-position to the (CH ₂ ) _n substituent, or a pharmaceutically acceptable salt thereof and a hydrate thereof. The above is an active ingredient of a human peroxisome proliferator-activated receptor (PPAI agonist.

9. General formula (1)

29

[Wherein, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, β represents a hydrogen atom or a lower alkoxy group having 1 to 4 carbon atoms, and If represents a hydrogen atom or 1 to 10 carbon atoms. R ⁴ represents a hydrogen atom, a trifluoromethyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halogen atom, an unsubstituted or optionally substituted phenoxy group or a benzyloxy group. R ⁵ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, n represents an integer of 0 to 3, and the substitution position of the carboxylic acid residue is para or relative to the R ² substituent. Atherosclerosis treatment comprising at least one of a substituted carboxylic acid derivative represented by〗 which is para to the (CH ₂ ) _n substituent, a pharmaceutically acceptable salt thereof, and a hydrate thereof. medicine.

1 0. General formula (1)

[In the formula, represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or a lower alkoxy group having 1 to 4 carbon atoms,

R ³ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and has a β-hydrogen atom, a trifluoromethyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halogen atom, an unsubstituted or substituted group. Represents a phenoxy group or a benzyloxy group, represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, η represents an integer from 0 to 3, and the substitution position of the carboxylic acid residue portion is an R substituent. Or (CH ₂ ) _η 30 in the para position with respect to the substituent], a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, and an anti-obesity agent comprising at least one hydrate thereof as an active ingredient.

1 1 · General formula (1)

[Wherein β represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or a lower alkoxy group having 1 to 4 carbon atoms, and R ³ represents a hydrogen atom or a lower alkoxy group having 1 to 4 carbon atoms. Represents an alkyl group of 10, R ⁴ represents a hydrogen atom, a trifluoromethyl group, a lower alkoxy group having 1 to 4 carbon atoms, a halogen atom, a phenyloxy group which may be unsubstituted or substituted or a benzyloxy group; represents a group, represents a lower alkyl group having 1 to 4 hydrogen or C, eta represents an integer of 0 to 3, the substitution position of cull Bonn acid residue moiety R ² substituent para or relative ( CH ₂ ) _n is a para-position to the _n- substituent], and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, and a hydrate thereof, which comprises at least one or more hydrates as an active ingredient.