Activator of peroxisome proliferator-activated receptor

Abstract

There is provided an activator of peroxisome proliferator-activated receptor α which contains: a compound represented by the following Formula (I); a tautomer or stereoisomer of the compound; or a pharmaceutically acceptable salt or solvate thereof (where, in a case where R.sup.1, R.sup.2, R.sup.3, and R.sup.8 do not constitute a ring, in the Formula, R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7, and R.sup.8 may be the same as or different from each other and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a hydroxy group, an amino group, a carboxyl group, a mercapto group, an alkylsulfanyl group having 1 to 8 carbon atoms, a nitro group, or a cyano group).

Claims

1. A method for treating fatty liver or chronic kidney disease, comprising administering a therapeutically effective amount of a compound represented by the following Formula (I) or a salt thereof to a patient in need thereof: ##STR00025## where, where R.sup.1, R.sup.2, R.sup.3, and R.sup.8 constitute a ring, a combination of R.sup.1 and R.sup.2, R.sup.2 and R.sup.8, or R.sup.3 and R.sup.8 are bonded to each other to form a benzene ring, a pyridine ring, or a 5-membered heteroaryl ring containing 1 to 3 heteroatoms, as a ring constituent element, selected from a nitrogen atom, an oxygen atom, and a sulfur atom together with two carbon atoms to which the combination is bonded, provided that at least one combination of R.sup.1 and R.sup.2, R.sup.2 and R.sup.8, or R.sup.3 and R.sup.8 constitute the ring, and wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7, and R.sup.8 may be the same as or different from each other and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a hydroxy group, an amino group, a carboxyl group, a mercapto group, an alkylsulfanyl group having 1 to 8 carbon atoms, a nitro group, or a cyano group, where, the benzene ring, the pyridine ring, and the heteroaryl ring may be unsubstituted or may have 1 to 4 same or different substituents selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a hydroxy group, an amino group, a carboxyl group, a mercapto group, an alkylsulfanyl group having 1 to 8 carbon atoms, a nitro group, or a cyano group, R.sup.4 and R.sup.5 are bonded to each other to form a benzene ring together with two carbon atoms to which R.sup.4 and R.sup.5 are bonded, or represent the same as that of R.sup.1, where, the benzene ring may be unsubstituted or may have 1 to 4 same or different substituents selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a hydroxy group, an amino group, a carboxyl group, a mercapto group, an alkylsulfanyl group having 1 to 8 carbon atoms, a nitro group, or a cyano group, W represents CR.sup.9 or N, where, R.sup.9 represents the same as that of R.sup.1, X represents NR.sup.10, an oxygen atom or a sulfur atom, where, R.sup.10 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, Y represents an alkylene chain having 1 to 8 carbon atoms or an alkenylene chain having 2 to 6 carbon atoms, where, the alkylene chain and the alkenylene chain may be unsubstituted or substituted with 1 to 4 groups selected from an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 substituted with 1 to 3 halogen atoms, or an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, the alkylene chain may be a linear or branched alkylene chain and the branched alkylene chain may have a 3- to 7-membered ring formed by side chains bonded to same carbon atom or different carbon atoms, together with the or each carbon atom to which the side chains are bonded and may have a double bond in the chain thereof in a case where the alkylene chain is an alkylene chain having 2 to 8 carbon atoms, Z represents CO.sub.2H, CO.sup.2R.sup.11, a tetrazolyl group, or SO.sub.2NR.sup.12R.sup.13, where, R.sup.11 represents an alkyl group having 1 to 8 carbon atoms, and R.sup.12 and R.sup.13 may be the same as or different from each other and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted wit 1 to 3 halogen atoms, where, in a case where R.sup.3 and R.sup.8 are bonded to each other to form a benzene ring together with two carbon atoms to which R.sup.3 and R.sup.8 are bonded, X represents an oxygen atom, R.sup.4 and R.sup.5 are bonded to each other to form a benzene ring together with two carbon atoms to which R.sup.4 and R.sup.5 are bonded, R.sup.7 represents neither an alkoxy group having 1 to 8 carbon atoms nor a hydroxy group.

2. A method for improving aciduria comprising administering an effective amount of the compound or a salt thereof as defined in claim 1 for improving aciduria associated with the disease mediated by the peroxisome proliferator-activated receptor α.

3. The method according to claim 2, for treating urolithiasis and uric acid calculi.

4. The method according to claim 2, for treating renal disorder due to urolithiasis and uric acid calculi.

5. The method according to claim 1, wherein R.sup.3 and R.sup.8 are bonded to each other to form a benzene ring or a pyridine ring together with two carbon atoms to which R.sup.3 and R.sup.8 are bonded.

6. The method according to claim 1, wherein R.sup.3 and R.sup.8 are bonded to each other to form a 5-membered heteroaryl ring containing two heteroatoms, as a ring constituent element, selected from a nitrogen atom, an oxygen atom, and a sulfur atom, together with two carbon atoms to which R.sup.3 and R.sup.8 are bonded.

7. The method according to claim 1, wherein R.sup.3 and R.sup.8 are bonded to each other to form thiazole ring or isothiazole together with two carbon atoms to which R.sup.3 and R.sup.8 are bonded.

8. The method according to claim 1, wherein R.sup.1, R.sup.2, R.sup.6, and R.sup.7 may be the same as or different from each other and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or a cyano group.

9. The method according to claim 1, wherein R.sup.6 is a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or a cyano group.

10. The method according to claim 1, wherein W represents CH.

11. The method according to claim 1, wherein X represents an oxygen atom or a sulfur atom.

12. The method according to claim 1, wherein Y is represented by the following Formula (II), ##STR00026## in the formula, R.sup.a and R.sup.b may be the same as or different from each other and represent an alkyl group having 1 to 8 carbon atoms, or R.sup.a and R.sup.b are bonded to each other to form a 3- to 7-membered cycloalkane together with carbon atoms to which R.sup.a and R.sup.b are bonded, and “-” represents a bond.

13. The method according to claim 1, wherein Z represents CO.sub.2H.

14. The method according to claim 1, wherein the compound is selected from 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid, 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid, 2-[[6-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoic acid, 2-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-methylpropanoic acid, 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]-2-methyl propanoic acid, 2-[[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid, 2-[[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid, 1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclobutan-1-carboxylic acid, 2-methyl-2-[[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl]thio]propanoic acid, 2-[[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid, 1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclopentan-1-carboxylic acid, 2-[[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid, 2-[[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid, 1-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]cyclobutan-1-carboxylic acid, 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-ethylbutanoic acid, 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-3,3-dimethylbutanoic acid, and 1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclohexan-1-carboxylic acid.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1A is a diagram showing measurement results of plasma ALT as an indicator of liver damage in a test example.

(2) FIG. 1B is a diagram showing measurement results of liver TG level as an indicator of fatty liver in a test example.

(3) FIG. 2 is a diagram showing measurement results of urine pH as an indicator of diabetes in a test example.

DESCRIPTION OF EMBODIMENTS

(4) Subsequently, the present invention will be described in detail.

(5) In the present specification, examples of the alkyl group having 1 to 8 carbon atoms represented by R.sup.1 to R.sup.13, R.sup.a and R.sup.b include a methyl group, an ethyl group, a propyl group, an iso-propyl group, a butyl group, an iso-butyl group, a tert-butyl group, a pentyl group or a hexyl group, and preferably an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, and a propyl group.

(6) Examples of the alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms represented by R.sup.1 and R.sup.13 include the alkyl group substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom, preferably a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group or a 2-fluoroethyl group, and more preferably a trifluoromethyl group.

(7) Examples of the alkoxy group having 1 to 8 carbon atoms represented by R.sup.1 to R.sup.9 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an iso-butoxy group, a tert-butoxy group, a pentyloxy group or a hexyloxy group, and preferably a methoxy group, an ethoxy group, a propoxy group, and a butoxy group.

(8) Examples of the alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms represented by R.sup.1 to R.sup.9 include a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group or a tert-butoxy group, all of which are substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom, and preferably a trifluoromethoxy group, a chloromethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group or a 2-fluoroethoxy group.

(9) Examples of the alkylsulfanyl group represented by R.sup.1 to R.sup.9 include a linear or branched chain alkylsulfanyl group having 1 to 8 carbon atoms, such as a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, a butylsulfanyl group, an iso-butylsulfanyl group, and a tert-butylsulfanyl group, and preferably a methylsulfanyl group and an ethylsulfanyl group.

(10) Examples of the halogen atom represented by R.sup.1 to R.sup.9 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferably a fluorine atom and a chlorine atom.

(11) In a case where R.sup.1, R.sup.2, R.sup.3, and R.sup.8 constitute a ring, it is preferable that a combination of R.sup.3 and R.sup.8 be bonded to each other. In such a case, R.sup.3, R.sup.8, and two carbon atoms to which R.sup.3 and R.sup.8 are bonded to each other to form a 5-membered heteroaryl ring containing 1 to 3 heteroatoms, as a ring constituent element, selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and in that case, examples of the heteroaryl ring include thiazole, isothiazole, oxazole, isoxazole, and 2,1,3-thiadiazole, and preferably thiazole and isothiazole.

(12) In a case where R.sup.1, R.sup.2, R.sup.3, and R.sup.8 constitute a ring, examples of substituents on the benzene ring, the pyridine ring, and the heteroaryl ring include 1 to 4 same or different halogen atoms, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a hydroxy group, an amino group, a carboxyl group, a mercapto group, an alkylsulfanyl group having 1 to 8 carbon atoms, a nitro group or a cyano group, preferably, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a hydroxy group, an amino group, a carboxyl group, a mercapto group, a nitro group or a cyano group, and more preferably, an alkyl group having 1 to 8 carbon atoms, and an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

(13) Examples of substituents on the benzene ring which may be formed by bonding R.sup.4, R.sup.5, and two carbon atoms to which R.sup.4 and R.sup.5 are bonded include 1 to 4 same or different halogen atoms, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a hydroxy group, an amino group, a carboxyl group, a mercapto group, an alkylsulfanyl group having 1 to 8 carbon atoms, a nitro group or a cyano group, preferably a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a hydroxy group, an amino group, a carboxyl group, a mercapto group, a nitro group or a cyano group, and more preferably a halogen atom, an alkyl group having 1 to 8 carbon atoms, and a hydroxy group.

(14) Examples of the 3- to 7-membered cycloalkane represented by R.sup.a and R.sup.b bonded together with carbon atoms to which R.sup.a and R.sup.b are bonded include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring and a cyclohexane ring, and preferably a cyclobutane ring and a cyclopentane ring.

(15) Examples of the alkylene chain represented by Y include a linear or branched chain alkylene chain having 1 to 8 carbon atoms, such as methylene, ethylene, propylene, butylene, and iso-butylene, and preferably methylene, ethylene, and propylene.

(16) The alkenylene chain represented by Y means a linear or branched chain alkenylene chain having 2 to 6 carbon atoms and having 1 to 3 double bonds, and examples thereof include vinylene, allylene, 1-propenylene, isopropenylene, 1-, 2- or 3-butenylene, and 1,3-butadienylene, and preferably vinylene and allylene.

(17) Examples of substituents on the alkylene chain and alkenylene chain represented by Y include 1 to 4 alkyl groups having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and preferably an alkyl group having 1 to 8 carbon atoms.

(18) Further, the number of substituents is preferably 2.

(19) In the branched chain alkylene chain represented by Y, a 3- to 7-membered ring formed by side chains bonded to same carbon atom or different carbon atoms, together with the or each carbon atom to which the side chains are bonded is, for example, cyclopropane, cyclobutane or cyclopentane.

(20) Examples of a preferred aspect of the compound (I) used in the present invention include when W is CR.sup.9, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.7, and R.sup.9 are each a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a halogen atom, and a hydroxy group, R.sup.6 is a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and a cyano group, R.sup.3, R.sup.8, and two carbon atoms to which R.sup.3 and R.sup.8 are bonded to each other to form a 5-membered heteroaryl ring containing two heteroatoms, as a ring constituent element, selected from a nitrogen atom, an oxygen atom, and a sulfur atom, X is an oxygen atom or a sulfur atom, R.sup.a and R.sup.b in Y represent an alkyl group having 1 to 8 carbon atoms, and Z represents CO.sub.2H.

(21) Further, examples of a preferred aspect of the compound (I) used in the present invention include when W is CR.sup.9, R.sup.1, R.sup.4, R.sup.5, R.sup.7, and R.sup.9 are each a hydrogen atom, R.sup.2 is a hydrogen atom or a fluorine atom, R.sup.6 is a fluorine atom or a chlorine atom, a trifluoromethyl group, and a cyano group, a heteroaryl ring formed by joining R.sup.3, R.sup.8, and two carbon atoms to which R.sup.3 and R.sup.8 are bonded is a thiazole or isothiazole, X is a sulfur atom, R.sup.a and R.sup.b in Y represent an alkyl group having 1 to 3 carbon atoms, and Z represents CO.sub.2H.

(22) The salt of the Formula (I) is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples thereof include a salt with a mineral acid such as hydrochloric acid or sulfuric acid; a salt with an organic carboxylic acid such as formic acid, acetic acid, citric acid, trichioroacetic acid, trifluoroacetic acid, fumaric acid or maleic acid; an acid addition salt such as a salt with a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid or naphthalenesulfonic acid; a salt with an alkali metal such as lithium, sodium or potassium; a salt with an alkaline earth metal such as calcium or magnesium; an ammonium salt; and a base addition salt such as a salt with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine or N,N′-dibenzylethylenediamine.

(23) Further, the compound (I) may have stereoisomers such as cis-trans isomers, optically active isomers, and racemic isomers, all of which can be used in the present invention.

(24) Furthermore, the compound (I) may be a tautomer, a hydrate, a solvate with an organic solvent such as alcohol, a derivative substituted with a stable isotope such as deuterium, or a prodrug.

(25) The compound (I) used in the present invention can be produced by the method described in Patent Literature 4.

(26) The compound (I) or a salt thereof can be used as an activator of peroxisome proliferator-activated receptor α to formulate a composition together with a pharmaceutically acceptable carrier for oral administration or the like in solid or liquid form.

(27) Examples of solid formulations for oral administration include capsules, tablets, pills, powders, and granules. In preparing the solid formulations, the compound of the present invention is generally admixed with at least one inert diluent, for example, sucrose, lactose or starch. For the formulations or the usual formulation process, additional substances other than the inert diluent, such as lubricants (e.g., magnesium stearate), may be used. In the case of capsules, tablets, and pills, a buffer may be further used. Tablets and pills may be provided with an enteric coating.

(28) Examples of liquid formulations for oral administration include inert diluents commonly used by those skilled in the art, e.g., pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing water. In addition to such inert diluents, the composition can also include adjuvants such as wetting agents, emulsifying agents, and suspensions; and sweetening, flavoring, and perfuming agents.

(29) The dose of the compound (I) of the present invention depends on the nature of the compound to be administered, the route of administration, the desired duration of treatment, and other factors, and is generally about 0.1 to 1000 mg/kg, and particularly preferably about 0.5 to 100 mg/kg per day for adults. If desired, the daily dose can be divided and administered in 2 or 4 doses.

EXAMPLES

(30) Subsequently, the present invention will be described in more detail with reference to test examples, but the present invention is not limited thereto.

(31) (Test Example 1)

(32) (1) Measurement of Agonist Activity against PPARα

(33) For the measurement of agonist activity against PPARα, the absorbance was measured according to the kit protocol using EnBio RCAS for PPARα kit (PPARA-CBP, Fujikura Kasei Co., Ltd.). A sample was dissolved in dimethylsulfoxide and added to a 96-well plate so as to have an evaluation concentration of 10 μM. GW7647 was added to a maximal response well so as to have a concentration of 0.5 μM. Dimethylsulfoxide was added to background wells. After subtracting the absorbance of the background well from the absorbance of each sample addition well, the ratio of each sample addition well to the maximal response well was calculated to evaluate the agonist activity (Binding ratio, %) against PPARα. Note that the sample addition wells and the background wells were duplicated, and the maximal response well was quadruplicated. As a positive control, 10 μM of a known PPARα agonist; Fenofibric acid (Tokyo Chemical Industry Co., Ltd.) was used.

(34) Based on the above test, (COMPOUND 1) to (COMPOUND 17) in [Table 1-1] and [Table 1-2] were evaluated for agonist activity against PPARα.

(35) TABLE-US-00001 TABLE 1-1 Compound Structural Compound Nos. formula name COMPOUND 1 2-[[7-(4- cyanophenyl)benzo[d]thiazol-6- yl]thio]-2-methylpropanoic acid COMPOUND 2 2-[[7-(4- cyanophenyl)benzo[d]isothiazol-6- yl]thio]-2-methylpropanoic acid COMPOUND 3 2-[[6-(4- cyanophenyl)benzo[d]thiazol-5- yl]oxy]-2-methylpropanoic acid COMPOUND 4 0 2-[[1-(4-cyanophenyl)naphthalen-2- yl]thio]-2-methylpropanoic acid COMPOUND 5 2-[[7-(4-cyanophenyl)-3- methylbenzo[d]isothiazol-6- yl]thio]-2-methyl propanoic acid COMPOUND 6 2-[[7-(4-cyanophenyl)-2- (trifluoromethyl)benzo[d]thiazol-6- yl]thio]-2-methylpropanoic acid COMPOUND 7 2-[[7-(4-cyanophenyl)-2- methylbenzo[d]thiazol-6-yl]thio]-2- methylpropanoic acid COMPOUND 8 1-[[7-(4- cyanophenyl)benzo[d]isothiazol-6- yl]thio]cyclobutan-1-carboxylic acid COMPOUND 9 2-methyl-2-[[7-[4-(tri- fluoromethyl)phenyl]benzo[d]iso- thiazol-6-yl]thio]propanoic acid

(36) TABLE-US-00002 TABLE 1-2 Compound Structural Compound Nos. formula name COMPOUND 10 2-[[7-(4-cyanophenyl)-4- fluorobenzo[d]isothiazol-6- yl]thio]-2-methylpropanoic acid COMPOUND 11 1-[[7-(4- cyanophenyl)benzo[d]isothiazol-6- yl]thio]cyclopentan-1-carboxylic acid COMPOUND 12 2-[[7-(4- chlorophenyl)benzo[d]isothiazol-6- yl]thio]-2-methylpropanoic acid COMPOUND 13 2-[[7-(4-cyano-3- methylphenyl)benzo[d]isothiazol-6- yl]thio]-2-methylpropanoic acid COMPOUND 14 0 1-[[7-(4-cyanophenyl)-3- methylbenzo[d]isothiazol-6- yl]thio]cyclobutan-1-carboxylic acid COMPOUND 15 2-[[7-(4- cyanophenyl)benzo[d]isothiazol-6- yl]thio]-2-ethylbutanoic acid COMPOUND 16 2-[[7-(4- cyanophenyl)benzo[d]isothiazol-6- yl]thio]-3,3-dimethylbutanoic acid COMPOUND 17 1-[[7-(4- cyanophenyl)benzo[d]isothiazol-6- yl]thio]cyclohexan-1-carboxylic acid Fenofibric acid (*1) 2-[4-(4-chlorobenzoyl)phenoxy]-2- methylpropionic acid (*1) Fenofibric acid is an active metabolite of fenofibrate.
(2) Test Results

(37) Table 2 shows the test results.

(38) TABLE-US-00003 TABLE 2 Binding ratio (%) Compound Nos. @ 10 μM 1 49.17 2 69.85 3 16.04 4 52.63 5 41.83 6 24.71 7 47.03 8 29.87 9 86.96 10 71.35 11 21.66 12 92.56 13 20.76 14 26.50 15 58.96 16 11.79 17 13.51 Fenofibric acid 50.46

(39) From the above results, it was confirmed that the compounds used in the present invention had an excellent PPARα activating effect.

(40) (Test Example 2)

(41) (1) Evaluation Using Non-Alcoholic Fatty Liver Disease (NAFLD) Model Rats Induced by Methionine/Choline-Deficient Diet

(42) As a NAFLD model, rats fed with a methionine/choline-deficient (MCD) diet were used to perform experiments. The MCD diet-fed model is widely used as a model for NAFLD/NASH.

(43) Wistar rats (male, 8 weeks old, Charles River Laboratories Japan, Inc.) were fed with an MCD diet (A02082002B, Research Diets, Inc.) for 5 weeks. From the time of feeding the above diet for 1 week, the rats were divided into a Vehicle group, a COMPOUND 2 (50 mg/kg) group, and a Fenofibrate (100 mg/kg) group so that there was no difference in body weight between the groups (n=4 in each of the groups). The Normal group was fed with an MCS diet as a control diet for the MCD diet (A02082003B, Research Diets, Inc.) for the same period. The administration volume was 10 mL/kg, a 1% methylcellulose solution was repeatedly orally administered to the Vehicle group and the Normal group, and a COMPOUND 2 solution and a Fenofibrate solution were repeatedly orally administered to the COMPOUND 2 group and the Fenofibrate group, respectively, once a day for 4 weeks.

(44) The day after the end of the final administration, blood was collected from the posterior vena cava under non-fasting conditions and isoflurane inhalation anesthesia, and plasma was collected. Further, the liver was removed and a part thereof was cryopreserved. Plasma ALT was measured by the JSCC standardized method. Triglyceride (TG) in the liver was extracted from the liver with a chloroform/methanol mixed solution (2:1, v/v), evaporated to dryness, and dissolved in 2-propanol, and then the amount was measured using Triglyceride E Test Wako. The results were each expressed as a mean value±standard deviation. Significant difference was tested between the Normal group and the Vehicle group using the Welch's t test (unpaired) (#: p<0.05 and ###: p<0.001), and significant difference was tested among the Vehicle group and the test substance administration groups using the Dunnett's test (*: p<0.05, **: p<0.01, and ***: p<0.001).

(45) (2) Test Results

(46) The test results are shown in FIGS. 1A and 1B. Plasma ALT as an indicator of liver damage increased significantly in the Vehicle group fed with the MCD diet, compared to the Normal group fed with the MCS diet. On the other hand, the COMPOUND 2 group and the Fenofibrate group showed significantly lower values than the Vehicle group (FIG. 1A). Further, the liver TG level as an indicator of fatty liver increased significantly in the Vehicle group as compared to the Normal group, but was significantly lower in the COMPOUND 2 group and the Fenofibrate group than in the Vehicle group (FIG. 1B).

(47) From these results, it was found that after repeated oral administration of the compound of the present invention to rats fed with the MCD diet, a decrease in plasma ALT and liver TG level was observed, and the compound had a NAFLD pathological ameliorating effect.

(48) (Test Example 3)

(49) (1) Evaluation Using Diabetic Models, Zucker Diabetic Fatty (ZDF) Rats

(50) In this example, the low urinary pH improving effect of COMPOUND 2 was evaluated using diabetic model animals; ZDF rats with low urinary pH. Verinurad; a known URAT1 inhibitor was evaluated as a comparative control compound (the PPARα activating effect of Verinurad was evaluated by the method described in Test Example 1, and as a result, the binding ratio at an evaluation concentration of 10 μM was 3.80%, and no effect was confirmed).

(51) ZDF (Lepr.sup.fa/Lepr.sup.fa) rats (male, 7 weeks old at the start of administration, Charles River Laboratories Japan, Inc.) were divided into a Vehicle group, a COMPOUND 2 (25 mg/kg) group, a COMPOUND 2 (50 mg/kg) group, and a Verinurad (50 mg/kg) group so that there was no difference in body weight between the groups (n=5 in each of the groups). As a Lean group, ZDF (Lean) rats, i.e., control animals of ZDF (Lepr.sup.fa/Lepr.sup.fa) rats, were used (n=5). The administration volume was 10 mL/kg, a 1% methylcellulose solution was repeatedly orally administered to the Vehicle group and the Lean group, and a COMPOUND 2 solutions and a Verinurad solution were repeatedly orally administered to the COMPOUND 2 groups and the Verinurad group, respectively, once a day for 15 days.

(52) During the administration period, the pH of a urine sample obtained by urine collection was measured using a compact pH meter (B-712, Horiba, Ltd.). Urine collection was performed 6 days before the start of administration (pre), on the 1st day, 7th day and 14th day of administration, and urine was collected in a metabolic cage for 24 hours. The results were each expressed as a mean value±standard deviation. At each time point, significant difference was tested between the Lean group and the Vehicle group using the Student's t test (unpaired) (###: p<0.001). After one-way analysis of variance, significant difference was tested among the Vehicle group and the test substance administration groups using the Dunnett's test (*: p<0.05, **: p<0.01, and ***: p<0.001).

(53) (2) Test Results

(54) FIG. 2 shows the test results. The Vehicle group had significantly lower urine pH than the Lean group throughout the test period from the start of administration, and exhibited low urinary pH. In the COMPOUND 2 groups, the urine pH was significantly increased from the 7th day of administration in the case of (25 mg/kg) and the urine pH was significantly increased from the 1st day of administration in the case of 50 mg/kg, compared to the Vehicle group, and this showed a dose-dependent low urinary pH improving effect. On the other hand, in the Verinurad group, no low urinary pH improving effect was observed throughout the administration period.

(55) These results indicate that the compound of the present invention has a low urinary pH improving effect when orally administered to ZDF rats with low urinary pH.