Fused heterocyclic compound and medicinal use thereof

A prophylactic and/or therapeutic drug for a disease caused by functional promotion of poly(ADP-ribose) synthase, which comprises a fused heterocyclic compound represented by the formula (I):

• 90
• wherein
• a dotted line part
• is a single bond or a double bond;
• ring Ar is a benzene ring, a naphthalene ring or an aromatic heterocycle;
• x is a carbon atom optionally substituted by an alkyl, an aromatic heterocyclic group optionally having substituent(s) or a phenyl optionally having substituent(s), or a nitrogen atom;
• Y is
• —(CH2)m—,—(CH2)m—N(R4)—CO—(CH2)n—,—(CH2)m—CO—N(R4)—(CH2)n—,—(CH2)m—CO—O—(CH2)n—,—(CH2)m—O—CO—(CH2)n—,(CH2)m—O—(CH2)n— or—(CH2)m—CO—(CH2)n—
• wherein m and n are the same or different and each is 0 or an integer of 1-10, R4 is hydrogen or alkyl, and —(CH2)m— is linked with a parent-nucleus;
• R1 and R2 are the same or different and each is a hydrogen, a halogen, an alkyl, an alkoxy, a haloalkyl, a hydroxy, an amino, a dialkylamino, a nitro, a cyano, an acyl, a carboxy, an ester, a carbamoyl, an N-alkylcarbamoyl, an N,N-dialkylcarbamoyl, an acylamino, a diacylamino, a thiol, an alkylthio, an alkoxycarbonylamino, a sulfamoyl, an N-alkylsulfamoyl, an N,N-dialkylsulfamoyl or an alkoxyalkyloxy;
• and
• R is an amino, a monoalkylamino, a dialkylamino, a morpholino or a thiomorpholino, or represented by the following. formula (a)-(e):
• 91
• wherein a dotted line part is a single bond or a double bond, W is CH or a nitrogen atom, s is an integer of 1-4, t is an integer of 0-3, u is an integer of 1-3, R5 and R5′ are the same or different and each is hydrogen, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R5 and R5′ in combination form ketone, and R6 is hydrogen, amino, monoalkylamino, dialkylamino, alkyl, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, benzoylamino optionally having substituent(s), hydroxy, arylalkyl, sulfamoyl or alkylsulfonylamino, or represented by the following formula (f)-(i):
• 92
• wherein Y′ is as defined for Y above, Z′ is CH or a nitrogen atom, W′ is CH, a nitrogen atom or an oxygen atom, t′ is an integer of 1-3, u′ is an integer of 1-3, provided that when the above-mentioned formula (a) is piperazine, then R6 may be hydroxyalkyl, R7 is hydrogen, amino, monoalkylamino, dialkylamino, alkyl, alkoxycarbonyl, alkylsulfonyl, acyl, hydroxyalkyl, acylamino or benzoylamino optionally having substituent(s), provided that when W′ is an oxygen atom, then R7 should be absent, and R8 is hydrogen, alkyl or hydroxyalkyl,
• an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a water adduct thereof.

A prophylactic and/or therapeutic drug for a disease caused by functional promotion of poly(ADP-ribose) synthase, which comprises a fused heterocyclic compound represented by the formula (I):

• 93
• wherein
• a dotted line part
• is a single bond or a double bond;
• ring Ar is a benzene ring, a naphthalene ring or an aromatic heterocycle;
• X is a carbon atom optionally substituted by an alkyl, an aromatic heterocyclic group optionally having substituent(s) or a phenyl optionally having substituent(s), or a nitrogen atom;
• Y is
• —(CH2)m—,—(CH2)mN(R4)—CO—(CH2)n—,(CH2)m—CO—N(R4)—(CH2)n—,—(CH2)mCO—O—(CH2)n— or—(CH2)m—O—(CH2)n—
• wherein m and n are the same or different and each is 0 or an integer of 1-10, R4 is hydrogen or alkyl, and —(CH2)m— is linked with a parent-nucleus;
• R1 and R2 are the same or different and each is a hydrogen, a halogen, an alkyl, an alkoxy, a haloalkyl, a hydroxy, an amino, a dialkylamino, a nitro, a cyano, an acyl, a carboxy, an ester, a carbamoyl, an N-alkylcarbamoyl, an N,N-dialkylcarbamoyl, an acylamino, a diacylamino, a thiol, an alkylthio, an alkoxycarbonylamino, a sulfamoyl, an N-alkylsulfamoyl or an N,N-dialkylsulfamoyl;
• and
• R is an amino, a monoalkylamino, a dialkylamino, a morpholino or a thiomorpholino, or represented by the following formula (a)-(e):
• 94
• wherein a dotted line part is a single bond or a double bond, W is CH or a nitrogen atom, s is an integer of 1-3, t is an integer of 0-3, u is an integer of 1-3, R5 and R5′ are the same or different and each is hydrogen, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R5 and R5′ in combination form ketone, and R5 is hydrogen, amino, monoalkylamino, dialkylamino, alkyl, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, benzoylamino optionally having substituent(s), hydroxy, arylalkyl, sulfamoyl or alkylsulfonylamino, or represented by the following formula (f)-(i):
• 95
• wherein Y′ is as defined for Y above, Z′ is CH or a nitrogen atom, W′ is CH or a nitrogen atom, t′ is an integer of 1-3, u′ is an integer of 1-3, R7 is hydrogen, amino, monoalkylamino, dialkylamino, alkyl, alkoxycarbonyl, alkylsulfonyl, acyl, hydroxyalkyl, acylamino or benzoylamino optionally having substituent(s), and R8 is hydrogen, alkyl or hydroxyalkyl,
• provided that (1) when Y is —(CH2)m— (m=0) and R is 4-methylpiperazin-1-yl, 1-piperidino, 4-morpholino or 4-(2-hydroxyethyl)piperazin-1-yl, then R1 should be halogen, alkyl, alkoxy, haloalkyl, hydroxy, amino, dialkylamino, nitro, cyano, acyl, carboxy, ester, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl or N,N-dialkylsulfamoyl, and (2) when X is a nitrogen atom and Y is —(CH2)m— (m=0), then R should be represented by any of the formulas (b)-(d) and Z should be CH,
• an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a water adduct thereof.

A poly(ADP-ribose) synthase inhibitor comprising a fused heterocyclic compound represented by the formula (I):

• 96
• wherein
• a dotted line part
• is a single bond or a double bond;
• ring Ar is a benzene ring, a naphthalene ring or an aromatic heterocycle;
• X is a carbon atom optionally substituted by an alkyl, an aromatic heterocyclic group optionally having substituent(s) or a phenyl optionally having substituent(s), or a nitrogen atom;
• Y is
• —(CH2)m—,—(CH2)m—N(R4)—CO—(CH2)n—,—(CH2)mCO—N(R4)—(CH2)n—,(CH2)m—CO—O—(CH2)n—,—(CH2)m—O—CO—(CH2)n—,—(CH2)m—O—(CH2)n— or—(CH2)m—CO—(CH2)n—
• wherein m and n are the same or different and each is 0 or an integer of 1-10, R4 is hydrogen or alkyl, and —(CH2)m— is linked with a parent-nucleus;
• R1 and R2 are the same or different and each is a hydrogen, a halogen, an alkyl, an alkoxy, a haloalkyl, a hydroxy, an amino, a dialkylamino, a nitro, a cyano, an acyl, a carboxy, an ester, a carbamoyl, an N-alkylcarbamoyl, an N,N-dialkylcarbamoyl, an acylamino, a diacylamino, a thiol, an alkylthio, an alkoxycarbonylamino, a sulfamoyl, an N-alkylsulfamoyl, an N,N-dialkylsulfamoyl or an alkoxyalkyloxy;
• and
• R is an amino, a monoalkylamino, a dialkylamino, a morpholino or a thiomorpholino, or represented by the following formula (a)-(e):
• 97
• wherein a dotted line part is a single bond or a double bond, W is CH or a nitrogen atom, s is an integer of 1-4, t is an integer of 0-3, u is an integer of 1-3, R5 and R5′ are the same or different and each is hydrogen, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R5 and R5∝ in combination form ketone, and R6 is hydrogen, amino, monoalkylamino, dialkylamino, alkyl, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, benzoylamino optionally having substituent(s), hydroxy, arylalkyl, sulfamoyl or alkylsulfonylamino, or represented by the following formula (f)-(i):
• 98
• wherein Y′ is as defined for Y above, Z∝ is CH or a nitrogen atom, W′ is CH, a nitrogen atom or an oxygen atom, t′ is an integer of 1-3, u′ is an integer of 1-3, provided that when the above-mentioned formula (a) is piperazine, then R6 may be hydroxyalkyl, R7 is hydrogen, amino, monoalkylamino, dialkylamino., alkyl, alkoxycarbonyl, alkylsulfonyl, acyl, hydroxyalkyl, acylamino or benzoylamino optionally having substituent(s), provided that when W′ is an oxygen atom, then R7 should be absent, and R8 is hydrogen, alkyl or hydroxyalkyl,
• an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a water adduct thereof.

A poly(ADP-ribose) synthase inhibitor comprising a fused heterocyclic compound represented by the formula (I):

• 99
• wherein
• a dotted line part
• is a single bond or a double bond;
• ring Ar is a benzene ring, a naphthalene ring or an aromatic heterocycle;
• X is a carbon atom optionally substituted by an alkyl, an aromatic heterocyclic group optionally having substituent(s) or a phenyl optionally having substituent(s), or a nitrogen atom;
• Y is
• —(CH2)m—,—(CH2)mN(R4)—CO—(CH2)n—,—(CH2)m—CO—N(R4)—(CH2)n—,—(CH2)m—CO—O—(CH2)n or—(CH2)m—O—(CH2)n—
• wherein m and n are the same or different and each is 0 or an integer of 1-10, R4 is hydrogen or alkyl, and —(CH2)m— is linked with a parent-nucleus;
• R1 and R2 are the same or different and each is a hydrogen, a halogen, an alkyl, an alkoxy, a haloalkyl, a hydroxy, an amino, a dialkylamino, a nitro, a cyano, an acyl, a carboxy, an ester, a carbamoyl, an N-alkylcarbamoyl, an N,N-dialkylcarbamoyl, an acylamino, a diacylamino, a thiol, an alkylthio, an alkoxycarbonylamino, a sulfamoyl, an N-alkylsulfamoyl or an N,N-dialkylsulfamoyl;
• and
• R is an amino, a monoalkylamino, a dialkylamino, a morpholino or a thiomorpholino, or represented by the following formula (a)-(e):
• 100
• wherein a dotted line part is a single bond or a double bond, W is CH or a nitrogen atom, s is an integer of 1-3, t is an integer of 0-3, u is an integer of 1-3, R5 and R5 are the same or different and each is hydrogen, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R5 and R5′ in combination form ketone, and R6 is hydrogen, amino, monoalkylamino, dialkylamino, alkyl, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, benzoylamino optionally having substituent(s), hydroxy, arylalkyl, sulfamoyl or alkylsulfonylamino, or represented by the following formula (f)-(i):
• 101
• wherein Y′ is as defined for Y above, Z′ is CH or a nitrogen atom, W′ is CH or a nitrogen atom, t′ is an integer of 1-3, u′ is an integer of 1-3, and R7 is hydrogen, amino, monoalkylamino, dialkylamino, alkyl, alkoxycarbonyl, alkylsulfonyl, acyl, hydroxyalkyl, acylamino or benzoylamino optionally having substituent(s), and R8 is hydrogen, alkyl or hydroxyalkyl,
• provided that (1) when Y is —(CH2)m— (m=0) and R is 4-methylpiperazin-1-yl, 1-piperidino, 4-morpholino or 4-(2-hydroxyethyl)piperazin-1-yl, then R1 should be halogen, alkyl, alkoxy, haloalkyl, hydroxy, amino, dialkylamino, nitro, cyano, acyl, carboxy, ester, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl or N,N-dialkylsulfamoyl, and (2) when X is a nitrogen atom and Y is —(CH2)m— (m=0), then R should be represented by any of the above formulas (b)-(d) and Z should be CH,
• an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a water adduct thereof.