TECHNICAL FIELD

The present invention relates to an activator of peroxisome proliferator-activated receptor α.

This application claims priority based on Japanese Patent Application No. 2017-220362 filed in Japan on Nov. 15, 2017 and Japanese Patent Application No. 2018-132701 filed in Japan on Jul. 12, 2018, of which the contents are incorporated herein by reference.

BACKGROUND ART

The peroxisome is an organelle found in cells of plants and animals, and its matrix contains various enzymes such as catalase. A peroxisome proliferator is a substance that induces proliferation of the peroxisome. Administration of therapeutic drugs for hyperlipidemia (fibrates), herbicides, phthalate plasticizers or the like is known to induce proliferation of the peroxisome and expression of genes such as catalase.

Isseman et al. have identified a nuclear receptor which is activated by the peroxisome proliferator and given a name of peroxisome proliferator-activated receptor (hereinafter, “PPAR”) (Non-Patent Document 1).

As PPAR, three subtypes such as PPARα, PPARγ, and PPARδ have been identified until now (Non Patent Document 2). It has been reported that among them, PPARα is highly expressed in organs such as kidney, liver, heart, and skeletal muscle that consume large amounts of fatty acids (Non Patent Document 3).

The above-mentioned fibrates have a ligand effect on the PPARα and show a strong serum TG (triglyceride) lowering effect, and thus are used as therapeutic drugs for hyperlipidemia.

As fibrates, for example, clinofibrate represented by the following formula (Patent Literature 1),

fenofibrate represented by the following formula (Patent Literature 2),

and bezafibrate represented by the following formula (Patent Literature 3)

are known.

Further, it has been reported that PPARα is related to, for example, arterial sclerosis or obesity, diabetes, metabolic syndrome, heart failure, and chronic kidney disease in addition to hyperlipidemia (Non Patent Literature 4), and is expected as a therapeutic/preventive drug for these diseases. Furthermore, these diseases are often accompanied by aciduria, and are known to increase the risk of urolithiasis, particularly uric acid calculi (Non Patent Literatures 5 and 6). However, it has also been reported that the fibrates have an effect of reducing aciduria (Non Patent Literature 7).

Incidentally, the present inventors have found that a derivative represented by the following formula inhibits reabsorption of uric acid via a uric acid transporter URAT1, and is useful as an agent for preventing or treating gout or hyperuricemia, and filed a patent application (Patent Literature 4):

in the formula, a dotted line represents a single bond or a double bond,Q represents CR8, NR9, or N,in a case where Q represents CR8, R3and R8are bonded to each other to form a naphthalene ring or a quinoline ring together with a ring formed of dotted lines,or a combination of R1and R2, R2and R8, or R3and R8are 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 together with two carbon atoms to which the combination is bonded, and the heteroaryl ring forms a fused ring together with the ring formed of dotted lines,where, the ring formed of dotted lines is a ring in which the number of double bonds in the ring is the maximum,in a case where Q represents N, R1and R2are bonded to each other to form a quinoline ring together with the ring formed of dotted lines,in a case where Q represents NR9, R3and R9or R2and R9are bonded to each other to form an imidazo[1,2-a]pyridine ring together with the ring formed of dotted lines,in a case where R1, R2, R3, and R8do not constitute a ring, R1, R2, R3, and R8may 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, a 3- to 7-membered cycloalkyl group, 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, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 12 carbon atoms, an alkyloxycarbonyl group in which the alkyl group has 1 to 8 carbon atoms, a hydroxy group, an amino group, a carboxyl group, a nitro group, a cyano group, CONR′R″, SR′, or SO2NR′R″,where, R′ and R″ may be the same as or different from each other and represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,in a case where R1, R2, R3, and R8constitute a ring, the ring may have 1 to 4 substituents which are the same as the substituent for R1in the case where R1, R2, R3, and R8do not constitute a ring, the substituents being the same as or different from each other,

A represents a phenyl group, a naphthyl group, a pyridyl group, a pyrimidyl group, a pyrazyl group, a pyridazyl group, a quinolyl group, or an isoquinolyl group which may have 1 to 5 substituents same as that of R1in the case where R1does not constitute a ring, the substituents may be the same as or different from each other, where, A is bonded to the ring formed of dotted lines through a carbon atom constituting the ring of the A group,

X represents NR11, an oxygen atom, or a sulfur atom, where, R11represents 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,where, the alkylene chain may be substituted with 1 to 4 same or different 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 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 3- to 7-membered cycloalkyl group, or a 4- to 7-membered saturated hetero ring having 1 or 2 heteroatoms, as a ring constituent element, selected from an oxygen atom, a sulfur atom, and a nitrogen atom,the alkylene chain may be a linear or branched alkylene chain, 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 the alkylene chain 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, and

Z represents CO2H, CON(R12) (R13), CO2(R14), SO2N (R15) (R16) or a tetrazolyl group,where, R12, R14, and R15represent 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, R13and R16represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a phenyl group which may have a substituent, a pyridyl group which may have a substituent, a pyridazyl group, a pyrimidyl group or a pyrazyl group, 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 which may have a substituent, andwhere, in a case where R3and R8are bonded to each other to form a naphthalene ring together with the ring formed of dotted lines, X represents an oxygen atom, A represents a naphthalene, and the 1-position of A is bonded to the ring formed of dotted lines, the 2-position of A does not represent any of an alkoxy group having 1 to 8 carbon atoms, a hydroxy group, and ethyl 3-[[1-(2-fluorophenyl)naphthalen-2-yl]thio]propanoate.

However, the patent literatures do not clearly disclose that these compounds have an effect of activating peroxisome proliferator-activated receptor. Further, a uric acid excretion promoter having a mechanism of inhibition of URAT1 or the like has a risk of uric acid calculi because it promotes excretion of uric acid in urine, and there is a concern about the fact that the risk increases in the case of aciduria.

CITATION LIST

Patent Literature

Patent Literature 1: JP 48-54047 A

Patent Literature 2: JP 54-81244 A

Patent Literature 3: JP 51-12618 B

Patent Literature 4: WO 2016/108282 A

Non Patent Literature

Non Patent Literature 1: Nature, 347, p645-650, 1990

Non Patent Literature 2: Proc. Nati. Acad. Sci. USA, 91, p 7335-7359, 1994

Non Patent Literature 3: Endocrinology, 137, p354-366, 1996

Non Patent Literature 4: The Lipid, Vol. 27, No. 4, P336-371, 2016

Non Patent Literature 5: ACTA UROLOGICA JAPONICA, Vol. 57, No. 1, P 43-47, 2011

Non Patent Literature 6: Clin J Am Soc Nephrol, Vol. 5, P 1277-1281, 2010

Non Patent Literature 7: Gout and Nucleic Acid Metabolism, vol. 30, No. 2, P 211-215, 2006

SUMMARY OF INVENTION

Technical Problem

An object of the present invention is to provide an agent for treating or preventing a disease such as hyperlipidemia, dyslipidemia or diabetes which is mediated by a peroxisome proliferator-activated receptor α and having an excellent activating effect of peroxisome proliferator-activated receptor α.

Solution to Problem

The present inventors have conducted intensive studies and, as a result, have found that a compound having a URAT1 inhibitory activity disclosed in Patent Literature 4 has an excellent peroxisome proliferator-activated receptor α activating effect, and have completed the present invention.

That is, the present invention has the following aspects.

(1) An activator of peroxisome proliferator-activated receptor α including: 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 R1, R2, R3, and R8do not constitute a ring, in the formula, R1, R2, R3, R6, R7, and R8may 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,in a case where R1, R2, R3, and R8constitute a ring, a combination of R1and R2, R2and R8, or R3and R8are 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,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,

R4and R5are bonded to each other to form a benzene ring together with two carbon atoms to which R4and R5are bonded, or represent the same as that of R1,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 CR9or N,where, R9represents the same as that of R1,

X represents NR10, an oxygen atom or a sulfur atom,where, R10represents 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 CO2H, CO2R11, a tetrazolyl group, or SO2NR12R13,where, R11represents an alkyl group having 1 to 8 carbon atoms, and R12and R13may 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 with 1 to 3 halogen atoms,where, in a case where R3and R8are bonded to each other to form a benzene ring together with two carbon atoms to which R3and R3are bonded, X represents an oxygen atom, R4and R5are bonded to each other to form a benzene ring together with two carbon atoms to which R4and R5are bonded, R7represents neither an alkoxy group having 1 to 8 carbon atoms nor a hydroxy group.

(2) The activator of peroxisome proliferator-activated receptor α according to (1), including: the compound, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, where R3and R3are bonded to each other to form a benzene ring or a pyridine ring together with two carbon atoms to which R3and R3are bonded.

(3) The activator of peroxisome proliferator-activated receptor α according to (1), including: the compound, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, where R3and R8together with two carbon atoms to which R3and R8are bonded 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.

(4) The activator of peroxisome proliferator-activated receptor α according to (1) or (3), including: the compound; a tautomer or stereoisomer of the compound; or a pharmaceutically acceptable salt or solvate thereof, where R3and R8together with two carbon atoms to which R3and R8are bonded form thiazole ring or isothiazole.

(5) The activator of peroxisome proliferator-activated receptor α according to any one of (1) to (4), including: the compound; a tautomer or stereoisomer of the compound; or a pharmaceutically acceptable salt or solvate thereof, where R1, R2, R6, and R7may 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.

(6) The activator of peroxisome proliferator-activated receptor α according to any one of (1) to (5), including: the compound, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, where R6is a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or a cyano group.

(7) The activator of peroxisome proliferator-activated receptor α according to any one of (1) to (6), including: the compound, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, where W represents CH.

(8) The activator of peroxisome proliferator-activated receptor α according to any one of (1) to (7), including: the compound, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, where X represents an oxygen atom or a sulfur atom.

(9) The activator of peroxisome proliferator-activated receptor α according to any one of (1) to (8), including: the compound, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof,where Y is represented by the following Formula (II),

in the formula, Raand Rbmay be the same as or different from each other and represent an alkyl group having 1 to 8 carbon atoms, or Raand Rbare bonded to each other to form a 3- to 7-membered cycloalkane together with carbon atoms to which Raand Rbare bonded, and “−” represents a bond.

(10) The activator of peroxisome proliferator-activated receptor α according to any one of (1) to (9), including: the compound, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof, where Z represents CO2H.

(11) A method for treating and/or preventing a disease mediated by a peroxisome proliferator-activated receptor α, including administering a therapeutically effective amount of the compound according to any one of (1) to (10) or a salt thereof to a patient in need thereof.

(12) The treating and/or preventing method according to (11), where the disease mediated by the peroxisome proliferator-activated receptor α represents hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, non-HDL-cholesterolemia, hyper-VLDL-cholesterolemia, lipoprotein dysfunction, low levels of apolipoprotein A-I in the blood, atherosclerosis, atherosclerotic disease, coronary artery disease, cerebrovascular disorder, peripheral vascular disorder, metabolic syndrome, syndrome X, obesity including visceral fat obesity, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complication, heart failure, myocardial infarction, cardiomyopathy, hypertension, chronic kidney disease, fatty liver, non-alcoholic steatohepatitis, thrombus, Alzheimer's disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, abnormal hair growth, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, pancreatitis, and cancer including colon cancer, bowel cancer, skin cancer, breast cancer, prostate cancer, ovarian cancer, and lung cancer.

(13) The treating and/or preventing method according to (11) or (12), where the disease mediated by the peroxisome proliferator-activated receptor α represents various types of dyslipidemias, metabolic syndrome, obesity including visceral fat obesity, atherosclerosis and related diseases thereof or diabetes.

(14) Use of the compound or a salt thereof according to any one of (1) to (10), for treating and/or preventing the disease mediated by the peroxisome proliferator-activated receptor α.

(15) The use according to (14), where the disease mediated by the peroxisome proliferator-activated receptor α represents hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, non-HDL-cholesterolemia, hyper-VLDL-cholesterolemia, lipoprotein dysfunction, low levels of apolipoprotein A-I in the blood, atherosclerosis, atherosclerotic disease, coronary artery disease, cerebrovascular disorder, peripheral vascular disorder, metabolic syndrome, syndrome X, obesity including visceral fat obesity, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complication, heart failure, myocardial infarction, cardiomyopathy, hypertension, chronic kidney disease, fatty liver, non-alcoholic steatohepatitis, thrombus, Alzheimer's disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, abnormal hair growth, inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, pancreatitis, and cancer including colon cancer, bowel cancer, skin cancer, breast cancer, prostate cancer, ovarian cancer, and lung cancer.

(16) The use according to (14) or (15), where the disease mediated by PPAR represents various types of dyslipidemias, metabolic syndrome, obesity including visceral fat obesity, atherosclerosis and related diseases thereof or diabetes.

(17) A method for improving aciduria including administering an effective amount of the compound or a salt thereof according to (1) to (10) for improving aciduria associated with the disease mediated by the peroxisome proliferator-activated receptor α.

(18) Use of the compound or a salt thereof according to (1) to (10), for improving aciduria associated with the disease mediated by the peroxisome proliferator-activated receptor α.

(19) The method according to (17), for treating and/or preventing urolithiasis and uric acid calculi.

(20) The method according to (18), for treating and/or preventing urolithiasis and uric acid calculi.

(21) The method according to claim (17) or (19), for treating and/or preventing renal disorder due to urolithiasis and uric acid calculi.

(22) The use according to claim (18) or (20), for treating and/or preventing renal disorder due to urolithiasis and uric acid calculi.

