Title of Invention

ISOQUINOLINE COMPOUNDS AND PROCESS FOR PREPARING THE SAME

Abstract

The present invention relates to an isoquinoline compound represented by the following formula (1), an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof, as well as an agent for the prophylaxis and/or treatment of a disease caused by hyperreactivity of poly(ADP-ribose)polymerase, containing the compound, and a poly(ADP-ribose)polymerase inhibitor containing the compound. In addition, this compound is useful as an agent for the prophylaxis and/or treatment of cerebral infarction, particularly as an agent for the prophylaxis and/or treatment of acute cerebral infarction. Furthermore, this compound is useful as a prophylactic and/or therapeutic agent that improves neurological symptoms associated with cerebral infarction, particularly acute cerebral infarction.

Full Text

DESCRIPTION ISOQUINOLINE COMPOUNDS AND MEDICINAL USE THEREOF Technical Field The present invention relates to a novel isoquinoline compound and a pharmaceutical agent containing same as an active ingredient. Background Art Poly(ADP-ribose)polymerase, hereinafter sometimes to be abbreviated as ^PARP", is an intranuclear enzyme that utilizes nicotinamide nucleotide (NAD) as a substrate, cleaves the bond between nicotinamide and ribose, transfers ADP-ribose residue into a protein, and causes addition polymerization of plural ADP-ribose residues. This enzyme is attractive as an apoptosis-related enzyme, which is considered to be activated by recognizing the nick of DNA damaged by a free radical, such as nitrogen monoxide, active oxygen and the like, which is produced in the lesion during ischemia, and have a primary role to aid DNA repair. It is considered in recent years that the activation of PARP decreases intracellular NAD, a large amount of ATP is consumed to compensate for the decrease, as a result of which intracellular energy is depleted, and the cell is driven to death. In an experiment using a PARP knockout mouse, it has been clarified that a cultured neuronal cells show resistance to disorders due to excitatory amino acids, such as nitrogen monoxide, NMDA (N-methyl-D-aspartate) and the like, and that it shows a tremendous protective effect by inhibiting cerebral infarction caused by cerebral ischemia by not less than 80% (Eliasson MJL. et al., Nature Med., 3, 1089-95 (1997)). However, none of the reported PARP inhibitors to date has subjected to a clinical trial as a therapeutic agent for cerebral infarction. As the reported PARP inhibitors to date, for example, 5-substituted-3,4-dihydro-2H-isoquinoline derivatives (JP-A-H2-124874) , 1,llb-dihydrobenzopyrano [4.3.2-de]isoquinolin-3-one derivatives (W099/11645), 3,4-dihydro-5-[4-(1-piperidinyl)-butoxy]-1(2H)-isoquinoline (each of WO99/08680 and W099/11649), pyrimidine derivatives (WO00/42025), benzimidazole derivatives (each of WO00/64878 and WO00/68206), phthalazine derivatives (each of WO00/67734 and WOOO/44726) , quinazolinone derivatives (each of WO02/48117 and WO02/44157) and the like are known, but the PARP inhibitory activity thereof is not very strong. Moreover, JP-B-S46-12454 discloses isoquinoline derivatives having an analgesic action and a hypoglycemic action, US Patent Nos. 1174272 and 1062357 respectively disclose quinazoline derivatives having a hypotensive action, GB Patent Nos. 1174272 and 1062357 and DE Patent No. 2121031 respectively disclose quinazoline derivatives having a hypotensive action, US Patent No. 4808595 discloses furopyridine derivatives having an intraocular pressure lowering action, and JP-A-S64-42472 discloses quinazoline derivatives having a cerebral dysfunction improving action, but none of these takes note of the PARP inhibitory activity. [patent reference 1] JP-A-H2-124874 [patent reference 2] W099/11645 [patent reference 3] WO99/08680 [patent reference 4] W099/11649 [patent reference 5] WO00/42025 [patent reference 6] WO00/64878 [patent reference-7] WO00/68206 [patent reference 8] WO00/67734 [patent reference 9] WOOO/44726 [patent reference 10] WO02/48117 [patent reference 11] WO02/44157 [patent reference 12] JP-B-S46-12454 [patent reference 13] US Patent No. 1174272 [patent reference 14] US Patent No. 1062357 [patent reference 15] GB patent No. 1174272 [patent reference 16] GB patent No. 1062357 [patent reference 17] DE Patent No. 2121031 [patent reference 18] US Patent No. 4808595 [patent reference 19] JP-A-S64-42472 [non-patent reference 1] Eliasson MJL. et al., Nature Med., 3, 1089-95 M997) Disclosure of the Invention An object of the present invention is to provide a compound having a PARP inhibitory activity and useful as a therapeutic agent for cerebral infarction, particularly a therapeutic agent for acute cerebral infarction, and a compound useful as an intermediate. The present inventors have conducted intensive studies and found that an isoquinoline compound represented by the following formula (I), an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a water adduct thereof have potent PARP inhibitory activity, which resulted in the completion of the present invention. Accordingly, the present invention provides the following. (1) An isoquinoline compound represented by the following formula (I) : Rx is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoy1, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy; is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group; and is represented by the following formula (II) : X is CH or a nitrogen atom, provided that when Y is absent in the formula (I) , then X should be CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, . -*•■"■* alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 and R2' are the same or different and each is a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2' are taken together to form ketone, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. (2) The aforementioned isoquinoline compound of the formula (I), wherein R1 is a hydrogen atom or alkyl; Y is absent or an alkylene chain having 1 to 5 carbon atoms wherein an optional carbon atom may have a hydroxyl group; and R is represented by the formula (II), wherein, in the formula (II) , X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), then X should be CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atom or alkyl, R2 and R2' are the same or different and each is a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl or hydroxyalkyl, an optically active form thereof, a pharmaceutical^ acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (3) The aforementioned isoquinoline compound of the formula (I), wherein R1 is a hydrogen atom or methyl; Y is absent, methylene, ethylene, propylene or 2- hydroxypropylene; and R is represented by the formula (II), wherein, in the formula (II), X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), then X should be CK; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 3; t is an integer of 1 to* 4; when R3 is a hydrogen atom or methyl, R2 and R2' are the same or different and each is a hydroxyl group, hydroxymethyl or 2-hydroxyethyl; and when R3 is 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or 2-hydroxypropyl, R2 and R2' are the same or different and each is a hydrogen atom, hydroxyl group, methyl, hydroxymethyl or 2-hydroxyethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (4) The aforementioned isoquinoline compound, which is selected from (1) (R) -3-[2-(3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (2) 3-[1-(2-hydroxyethyl)piperidin-4-yl]-5-methyl~2H-isoquinolin-1-one (3) 3- [3- (3-hydroxypyrrolidin-l-yl) propyl] -2H-isoquinolin-l-one (4) 3-[3-(3-hydroxypyrrolidin-l-yl) propyl]-5-methyl~2H-isoquinolin-1-one (5) 3-[2-(3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (6) 3- [2- (3-hydroxypyrrolidin-l-yl) ethyl] -2H-isoquinolin-l-one (7) 3-[2-(2-hydr6xymethylpiperidin-l"yl)ethyl]-5-methyl-2H-isoquinolin-1-one (8) 3- [2- (2-hydroxymethylpiperidin-l-yl) ethyl]-2H-isoquinolin-1-one (9) 3-[l-(2-hydroxyethyl)piperidin-4-yl]-2H-isoquinolin-l-one (10) 3-[l- (3-hydroxypropyl)piperidin-4-yl]-2H*isoquinolin-l-one (11) 3-[l- (4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-l-one (12) 3-[2-hydroxy-3-(pyrrolidin-l~yl) propyl] -2H-isoquinolin-l-one (13) 3-[2-hydroxy-3- (pyrrolidin-l^yl) propyl] -5-methyl~2H-isoquinolin-1-one (14) (S)-3-[2-(2-hydroxymethylpyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-l-one (15) (S) -3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-2H-isoquinolin-1-one (16) (S)-3-[3-(2-hydroxymethylpyrrolidin-l-yl)propyi]-5-methyl~2H~isoquinolin~l-one (17) (S)-3-[3-(2-hydroxymethylpyrrolidin-l-yl)propyl]-2H- isoquinolin-1-one (18) (R)-3-[3-(2-hydroxymethylpyrrolidin-l-yl)propyl]-2H- isoquinolin-1-one (19) 3^[2^(4-hydroxypiperidin-l-yl)ethyl]-2H-isoquinolin^l-one (20) (R)-3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-2H-isoquinolin-1-one (21) 3-(l^methyl-2-hydroxymethylpiperidin-4-yl)-2H-isoquinolin-1-one (22) 3- [1- (3-hydroxy-2,2-dimethylpropyl) piperidin-4-yl] -2H-isoquinolin-1-one (23) 5-methy1-3- [l-(3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (24) 3-[l-(2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-l- one (25) 3-[2-(3-hydroxypiperidin-l-yl)ethyl]-5-methyl-2H- isoquinolin-1-one (26) (R)-3-[3- (2-hydroxymethylpyrrolidin-l-yl)propyl]-5-nethyl-2H-isoquinolin-l-one (27) 3- [2- (3-hydroxypiperidin-l-yl) ethyl] -2H-isoquinolin-l-one (28) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H- isoquinolin-1-one (29) 3-[l-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinolin-l" one (30) 5-methy1-3- [l-( 2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-qne (31) 5-methyl-3-[l-(4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-1-one (32) 3-[2-(3-hydroxypiperidin-l-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (33) 3-[l- (3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (34) (S) -3- [2- (3-hydroxypyrrolidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (35) (R)-3-[2- (3-hydroxypiperidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (36) (R) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-l-one (37) (-) -3- [i- (2-hydroxylethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one and (38) ( + ) -3- [1- (2-hydroxylethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one f an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a water adduct thereof. (5) The aforementioned isoquinoline compound of the formula (I) f wherein R1 is a hydrogen atom or methyl; Y is absent; and R is represented by the formula (II) , whereinr in the formula (II) , X is CH; W is a nitrogen atom; s is an integer of 1 or 2; t is an integer of 2; when R3 is methyl, R2 and R2' are the same or different and each is a hydroxyl group or hydroxymethyl; and when R3 is hydroxyethyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group or hydroxymethyl. an optically active form thereof, a pharmaceutical!^ acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (6) The aforementioned isoquinoline compound, which is selected from (2) 3-[1-(2-hydroxyethyl)piperidin-4-yl]-5-methyl-2H-isoquinolin-1-one (9) 3-[l-(2-hydroxyethyl)piperidin-4-yl]-2H-isoquinolin-l-one (10) 3-[1-(3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-l-one (11) 3-[1-(4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-l-one (21) 3-(l-methyl-2-hydroxymethylpiperidin-4-yl)-2H-isoquinolin-1-one (22) 3-[l-(3-hydroxy-2,2-dimethylpropyl)piperidin-4-yl]-2H-isoquinolin-1-one (23) 5-methyl-3-[l-(3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (24) 3-[1-(2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-l-one (28) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (29) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinolin-l-one (30) 5-methyl-3-[l-(2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (31) 5-methyl-3- [1-(4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-1-one (33) 3-[1-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (37) (-) -3- [1- (2-hydroxylethyl)pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one and (38) (+)-3-[1-(2-hydroxylethyl) pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (7) The aforementioned isoquinoline compound of the formula (I), wherein R1 is a hydrogen atom or methyl; Y is ethylene, propylene or 2-hydroxypropylene; and R is represented by the formula (II), wherein, in the formula (II) , X is a nitrogen atom; W is CH; s is an integer of 1 to 3; t is an integer of 1 to 4; R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl or hydroxymethyl; and R3 is a hydrogen atom, provided that when R2 is a hydrogen atom or alkyl, R2' is a hydroxyl group or hydroxymethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (8) The aforementioned isoquinoline compound, which is selected from (1) (R)-3-[2- (3-hydrbxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (3) 3-[3- (3-hydroxypyrrolidin-l-yl) propyl] -2H-isoquinolin-l-one (4) 3-[3- (3-hydroxypyrrolidin-l-yl) propyl]-5-methyl-2H-isoquinolin-1-one (5) 3-[2-(3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (6) 3- [2- (3-hydroxypyrrolidin-l-yl) ethyl] -2H-isoquinolin-l-one (7) 3- [2- (2-hydroxymethylpiperidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (8) 3- [2- (2-hydroxymethylpiperidin-l-yl) ethyl] -2H-isoquinolin-1-one (12) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -2H-isoquinolin-l- one (13) 3- [2-hydroxy-3-(pyrrolidin-l-yl) propyl] -5-methyl-2H-isoquinolin-1-one (14) (S)-3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methyl- 2H-isoquinolin-l-one (15) (S) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyl] -2H-isoquinolin-1-one (16) (S) -3-[3- (2-hydroxymethylpyrrolidin-l-yl) propyl]-5- methyl-2H~isoquinolin-l-one (17) (S)-3-[3- (2-hydroxymethylpyrrolidin-l-yl)propyl]-2H-isoquinolin-1-one (18) (R)-3-[3- (2-hydroxymethylpyrrolidin-l-yl)propyl]-2H-isoquinolin-1-one (19) 3-(2-(4-hydroxypiperidin-l-yl) ethyl]-2H-isoquinolin-l-one (20) (R)-3-[2- (2-hydroxymethylpyrrolidin-l-yl) ethyl]-2H-isoquinolin-1-one (25) 3-[2-(3-hydroxypiperidin-l-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (26) (R) -3-[3-(2-hydroxymethylpyrrolidin-l-yl)propyl]-5-methyl-2H-isoquinolin-l-one (27) 3-[2-(3-hydroxypiperidin-l-yl) ethyl]-2H-isoquinolin-l-one (32) 3-[2-(3-hydroxypiperidin-l-yl)ethyl]-5-methyl-2H- isoquinolin-1-one (34) (S)-3-[2-(3-hydroxypyrrolidin-l-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (35) (R) -3- [2- (3-hydroxypiperidin-l-yl) ethyl] -5-mezhyl-2H-isoquinolin-1-one and (36) (R) -3-[2-(2-hydroxymethylpyrrolidin-l-yl) ethyl] -5~methyl-2H-isoquinolin-l-one, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (9) The aforementioned isoquinoline compound of the formula (I), wherein R1 is a hydrogen atom or methyl; Y is absent or ethylene; R is represented by the formula (II) f wherein, in the formula (II) , when Y is present in the formula (I) , X is a nitrogen atom; when Y is absent in the formula (I) , X is CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 or -2; t is an integer of 1 to 3; when R3 is a hydrogen atom, R2 and R2' are each a hydroxyl group or hydroxymethyl; and when R3 is hydroxyethyl, R2 and R2' are each a hydrogen atom, a hydroxy1 group or hydroxymethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (10) The aforementioned isoquinoline compound which is selected from (1) (R) -3-[2-(3-hydroxypyrrolidin-l-yl)ethyl]-5-me^hyl-2H-isoquinolin-1-one (2) 3-[l-(2-hydroxyethyl)piperidin-4-yl]-5-methyl-2H-isoquinolin-1-one (5) 3-[2-(3-hydroxypyrrolidin-l-yl)ethyl]-5-methyl-2H- isoquinolin-i-one (28) 3-[l-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H- isoquinolin-1-one (34) (S)-3-[2-(3-hydroxypyrrolidin-l-yl)ethyl]-5-met±iyl-2H- isoquinolin-1-one (36) (R)-3-[2- (2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methy1-2H-isoquinolin-l-one (37) (-)-3-[i-(2-hydroxyethyl)pyrrolidin-3-yl]-5-mezhyl-2H-isoquinolin-1-one and (38) (+).-3-[l-(2-hydroxyethyl)pyrrolidin-3-yl]-5-me-hyl-2H-isoquinolin-1-one, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (11) The aforementioned isoquinoline compound of the formula (I), wherein, R1 is methyl; Y is absent; and R is represented by the formula (II), wherein X is CH; W is a nitrogen atom; S is 1 or 2; t is an integer of 2; R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group or hydroxyalkyl; and R3 is hydroxyethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (12) (2) 3-[l-(2-Hydroxyethyl)piperidin-4-yl]-5-methyl-2H-isoquinolin-1-one, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (13) (28) 3-[l-(2-Hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. (14) (37) (+)-3-[l-(2-Hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H- isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. (15) (38) (-)-3-[l-(2-Hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H- isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof, (16) The aforementioned isoquinoline compound of the formula (I), wherein R1 is methyl; Y is ethylene; R is represented by the formula (II), wherein, in the formula (II) , X is a nitrogen atom; W is CH; s is 1; t is an integer of 2 or 3; R2 and R2' are the same or different and each is a hydrogen atom, a hydroxy1 group or hydroxymethyl; and R3 is a hydrogen atom, provided that when R is a hydrogen atom, then R should be a hydroxyl group or hydroxymethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (1) (R) -3-[2-(3-Hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. (18) (5) 3-[2-(3-Hydroxypyrrolidin-l-yl)ethyl]]-5-methyl-2H-isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. (19) (34) (S)-3-[2- (3-Hydroxypyrrolidin-l-yl)ethyl]-5-methyl-2H-isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. ("20) (36) (R)-3-[2- (2-Hydroxymethylpyrrolidin-l-yl)ethyl]-5-methy1-2H-isoquinolin-l-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. (21) An agent for the prophylaxis and/or treatment of a-disease caused by hyperactivity of poly(ADP-ribose)polymerase, which comprises the aforementioned isoquinoline compound, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (22) The aforementioned agent used for the prophylaxis and/or treatment of cerebral infarction. (23) The aforementioned agent used for the prophylaxis and/or treatment of acute cerebral infarction. (24) The aforementioned agent used for the prophylaxisc and/or theratment, which improves neurological symptoms associated with cerebral infarction. (25) An agent for the prophylaxis and/or treatment of cerebral infarction, which comprises the aforementioned: isoquinoline compound, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (26) The aforementioned agent used for the prophylaxis and/or ireatment of acute cerebral infarction. (27). The aforementioned agent for the prophylacxis and/or theratment, which improves neurological symptoms associated tfith cerebral infarction. (28) A poly(ADP-ribose)polymerase inhibitor comprising the aforementioned isoquinoline compound, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (29) A compound selected from the following: (R) -3- (3-hydroxypyrrolidin-l-yl) -N-methyl-N-methoxypropanamide (R)-N,N-dierhyl-2-[4-(3-hydroxypyrrolidin-l-yl) -2-oxobutyl]-3-Tie thy Ibenz amide (R) -3- [2- (3-hydroxypyrrolidin-l-yl) ethyl]-5-methylisocoumarin (R) -3-(2-hydroxymethylpyrrolidin-l-yl)-N-methyl-N-raethoxypropanamide (R)-N,N-diethyl-2-[4- (2-hydroxymethylpyrrolidin-l-yl)-2-oxobutyl]-3-methylbenzamide (R) -3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methylisocoumarin and (R) -3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methylisocoumarin hydrochloride. (30) A method for producing a compound of the following is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N~dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy; is dialkylamino; is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), X is CH; W is CH or a nitrogen atom; provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atom, alkyl, amino", monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 and R2' are the same or different and each is a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkylf alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2' are taken together to form ketone, which comprises reacting a compound of the following formula R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbcnyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy; is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group; and is represented by the following formula (II) : X is CH or a nitrogen atom, provided that when Y is absent in the formula (I) , X is CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkvlsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 and R2' are the same or different and each is a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2'and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyi, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2' are taken together to form ketone,., which comprises using a compound of the following formula R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyi, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsuifamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy; is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group; and is represented by the following formula (II) : X is CH or a nitrogen atom, provided thar when Y is absent in the formula (I) f then X should be CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 and R2r are the same or different and each is a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2' are taken together to form ketone, hich comprises using a compound of the formula (16) : is a hydrogen atom, a halogen atom, alkyl, alkoxy, *haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio f alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyi or alkoxyalkyloxy; is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom, may have a hydroxy1 group; and is represented by the following formula (II) : X is CH or a nitrogen atom, provided that when Y is absent in the formula (I) , then X should be CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen" atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 and R2' are the same or different and each is a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2' are taken together to form ketone. (33) A method for producing the aforementioned isoquinoline compound, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof, which comprises the aforementioned steps. (34) A method for producing the aforementioned isoquinoline compound, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof, which comprises the aforementioned steps. Best Mode for Embodying the Invention The present invention is explained in detail in the 7 following. The compound of the formula (I) may be in the form of a tautomer shown by the following formula (III). The present Specific examples of the substituent for R1 are as follows, which substituent is on any carbon atom in the ring, halogen atom: fluorine atom, chlorine atom, bromine atom and iodine atom, with preference given to fluorine atom, chlorine atom and bromine atom. alkyl: linear or branched chain alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like, with preference given to methyl. alkoxy: alkoxyl consisting of alkyl (as defined above) and oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like, with preference given to methoxy. haloalkyl: alkyl (as defined above) substituted by one or more halogen atoms (as defined above), such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and the like, with preference given to trifluoromethyl. dialkylamino: dialkylamino wherein the alkyl moieties are the same or different and each independently alkyl (as defined above) and the alkyl moieties may form a ring. For example, dimethylamino, diethylamino, N-methyl-N-ethylamino, pyrrolidin-1-yl, piperidin-1-yl and the like can be mentioned, with preference given to dimethylamino. acyl: acyl having 1 to 4 carbon atoms in total, which consists of alkyl (as defined above) and carbonyl, such as formyl, acetyl, propionyl, 2-methylpropionyl, butyryl and the like. alkoxycarbonyl: ester consists of alkoxy (as defined above) and carbonyl, such as methoxycarbonylf ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like. N-alkylcarbamoyl: N-alkylcarbamoyl consisting of monoalkylanino having 1 to 4 carbon atoms and carbonylf such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl and the like. N,N-dialkyIcarbamoyl: NrN-dialkylcarbamoyl consisting of dialkylamino (as defined above) and carbonyl, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutyIcarbamoyl and the like. acylamino: acylamino consisting of acyl (as defined above) and amino, such as formylamino, acetylamino, propionylamino, butyrylamino and the like. diacylamino: diacylamino consisting of two acyls (as defined above) and amino, wherein the acyl moieties are independent and may be the same or different," such as N,N-diacetylamino, N,N~dipropionylamino, N,N-dibutyrylami*io and the like, alkylthio: alkylthio consisting of alkyl (as defined above) and sulfur atom, such as methylthio, ethylthio, propylthio, butylthio and the like, with preference given to methylthio. alkoxycarbonylamino: alkoxycarbonylamino consisting of alkoxycarbonyl (as defined above) and amino, such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like. N-alkylsulfamoyl: N-alkylsulfamoyl consisting of monoalkylamino (as defined above) and sulfon, such as N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-butylsulfamoyl and the like. N,N-dialkylsulfamoyl: N,N-dialkylsulfamoyl consisting of dialkylamino (as defined above) and sulfon, such as N,N-dimethylsu If amoyl, N, N-diethylsulf amoyl, N, N-dipropy Isulf amoyl, N,N-dibutyIsulfamoyl and the like. alkoxyalkyloxy: alkoxyalkyloxy consisting of alkoxy (as defined above), alkyl (as defined above) and oxygen, wherein alkoxy and alkyl are as defined above, such as methoxymethyloxy, ethoxymethyloxy and the like, with preference given to methoxymethyloxy. As the substitution site for R1, substitution at the 5-position or 7-position of isoquinoline ring is preferable, particularly the 5-position is preferable. Y is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxy 1 group. For example, (1) -CH(OH)CH2- (2) -CH2CH(OH)CH2-, (3) -CH2CH2CH(OH)CH2-, (4) -CH2CH2CH2CH (OH) CH2-, (5) -CH2CH2CH2CH2CH(OH)CH2-, (6) -CH2CH2CH2CH2CH2CH(OH)CH2-, (7) -CH2CH2CH2CH2CH2CH2CH (OH) CH2-, (8) -CH2CH(CH2OH)CH2-, (9) -CH2CH(CH2CH2OH)CH2~, and the like can be mentioned, with preference given to (2) . As the linear alkylene chain, ethylene and propylene are preferable. Specific examples of the substituent for R2 and R2' are as follows, which substituent is on any carbon atom in the ring. alkyl: as defined for alkyl for R1. hydroxyalkyl: hydroxyalkyl consisting of alkyl (as defined for alkyl for R1) and hydroxyl group, with preference given to hydroxymethyl. alkoxycarbonyl: alkoxycarbonyl consisting of alkoxy (as defined for alkoxy for R1) and carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like, with preference given to ethoxycarbonyl. dialkylaminoalkyl: dialkylaminoalkyl consisting of dialkylamino (as defined for dialkylamino for R1) and alkyl (as defined for alkyl for R1) , with preference given to dimethylaminomethyl. dialkylcarbamoyl: dialkylcarbamoyl consisting of dialkylamino (as defined for dialkylamino for R1) and carbonyl, with preference given to dimethylcarbamoyl. Specific examples of the substituent for R3 are as follows. alkyl: as defined for alkyl for R1, with preference given to methyl, ethyl, propyl and isobutyl, particularly preferably methyl. hydroxyalkyl: as defined for hydroxyalkyl for R2, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy-2- methylpropyl, 4-hydroxybutyl and the like, with preference given to hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxypropyl and 2,2-dimethyl-3-hydroxypropyl, particularly preferably hydroxymethyl and hydroxyethyl. monoalkylamino: as defined for monoalkylamino for Rx, with preference given to methylamino. dialkylamino: as defined for dialkylamino for R1, with preference given to dimethylamino. alkoxycarbonyl: as defined for alkoxycarbonyl for R1, with preference given to ethoxycarbonyl*. alkylsulfonyl: alkylsulfonyl consisting of alkyl (as defined for alkyl for R1) and sulfonyl, such as methanesulfonyl, ethanesulfonyl and the'like. acyl: as defined for acyl for R1. acylamino optionally having a substituent: as defined for acylamino for R1, a group consisting of acyl having 1 to 4 carbon atoms and amino group, which is selected from formylamino, acetylamino, propionylamino, 2- methylpropionylamino and butyrylamino. As the substituent, halogen atom (particularly fluorine atom) can be preferably mentioned. For example, trifluoroacetylamino can be mentioned. benzoylamino optionally having a substituent: as the substituent, those similar to the substituents for Rx can be mentioned. arylalkyl: arylalkyl consisting of aryl and alkyl (as defined for acylamino for R1) , such as benzyl, phenethyl and the like, with preference given to benzyl. alkylsulfonylamino: alkylsulfonylamino consisting of alkylsulfonyl (as defined above) and amino, such as . . methanesulfonylamino, ethanesulfonylamino and the like, with preference given to methanesulfonylamino. As the compound of the formula (I) and a pharmaceutically acceptable salt thereof, acid addition salts thereof with inorganic acids or organic acids can be mentioned. The compound of the formula (I) and a pharmaceutical^ acceptable salt thereof may be in a form of a water adduct, a hydrate or a solvate thereof, and these water adduct, hydrate and solvate are also encompassed in the present invention. When the compound of the formula (I) has an assymetric atom, at least two optical isomers are present. These optical isomers and mixtures thereof (including racemate) are encompassed in the present invention. The compounds encompassed in the formula (I) of the present invention can be synthesized according to the following methods. In the following reaction schemes, each symbol is as defined above unless particularly indicated. method is reacted with a compound of the formula (12) obtained by a known method, in the presence of a suitable base generally used in synthetic organic chemistry, such as n~ butyllithium, lithium diisopropylamide, lithium diethylamide, lithium bistrimethylsilylamide and the like, in a suitable solvent that does not inhibit the progress of the reaction, such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, an optionally mixed solvent thereof and the like, at -7 8°C to the reflux temperature of the solvent, preferably at -78°C to room temperature, for 0.1 (6 min) to 48 hr, preferably 1 hr to 24 hr to give a compound of the formula (13) . A compound of the formula (11') is reacted with a compound of the formula (14), wherein J3 is N-alkyl-N-alkoxyamino or dialkylamino (as defined for dialkylamino for R3 ) , with preference given to N~methyl-N-methoxyamino in the presence of a suitable base generally used in synthetic organic chemistry, such as n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium -diethylamide, lithium bistrimethylsilylamide and the like, in 1 a suitable solvent mentioned above that does not inhibit the progress of the reaction at -78°C to the reflux temperature of the solvent for 0.1 (6 min) to 48 hr to give a compound of the formula (15). The compound of the formula (15) is-reacted, in acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, or an optional mixed solvent thereof, at room temperature to the reflux temperature of the solvent for 0.1 (6 min) to 48 hr to give the compound of the formula (16) . The compound of the formula (16) is reacted with an ammonia source (e.g., ammonia salt generally used in synthetic organic chemistry such as ammonium acetate, ammonium carbonate, ammonium chloride, aqueous ammonia solution and the like) in a suitable solvent that does not inhibit the progress of the reaction (methanol, ethanol, n-propanol, isopropanol, 21-butanol, dimethoxyethane, 2-methoxyethanol, aceric acid, aqueous ammonia solution, an optional mixed solvent thereof and the like) at room temperature to the reflux temperature of the solvent for 0.1 (6 min) to 48 hr to give a compound of the formula (13). The compound of the present invention thus obtained can be isolated or purified according to a conventional method. The compound of the present invention encompassed in the formula (I) can be also synthesized using the intermediates shown in the following. For example, (R) -3-(2-hydroxymethylpyrrolidin-l-yl) propionitrile, (R)-3-(3-hydroxypyrrolidin-l-yDpropionitrile, (S) -3- (3-hydroxypy.rrolidin-l-yl)propionitrile, (R) -3- (3-hydroxypyrrolidin-l-yl)-N-methyl-N-methoxypropanamide, (R) -N,N-diethyl~2-[4-(3-hydroxypyrrolidin-l-yl) -2-oxobutyl]-3-methylbenzamide, (R)-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methylisocoumarin, (R)-3- (2-hydroxymethylpyrrolidin-1-yl) ~N-methyl-N-methoxypropanamide, (R)-N,N-diethyl-2-[4-(2-hydroxymethylpyrrolidin-l-yl) -2-oxobutyl]-3-methylbenzamide, (f?)-3-[2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin and (R) -3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methylisocoumarin hydrochloride are novel compounds, and are useful as intermediates for synthesizing, of the formula (I) of the present invention, (1) (R)-3-[2-(3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-l-one, (34) (S)-3-[2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-l-one and (36) (R) -3- [2- (2-hydroxymethylpyrrolidin-l-yl)ethyl]-5- Tiethyl-2H-isoquinolin-l-one. In addition, (1) (R)-3-[2-(3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-l-one, (34) (S)-3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-l-one and (36) (R) -3-[2- (2-hydroxymethylpyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-l-one of the formula (I) of the present invention can be synthesized by reacting (R)-3-(2-hydroxymethylpyrrolidin-l-yl)propionitrile, (R)-3- (3-hydroxypyrrolidin-1-yl)propionitrile or (S)-3- (3-hydroxypyrrolidin-l-yl)propionitrile with N,N-die"ihyl-2, 3-dimethylbenzamide or N,N-dimethyl-2 ,3-dime thy lbenz amide according to Synthesis Method 1. The compound of the formula (I) , an optical isomer and a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof obtained by the above-mentioned methods' have a potent PARP inhibitory activity, and are useful as agents for the prophylactic and/or therapeutic agents that improve cerebral infarction, particularly agents for the prophylaxis and/or treatment of acute cerebral infarction. Moreover, they are useful as prophylactic and/or therapeutic agents that improve neurological symptoms associated with cerebral infarction, particularly acute cerebral infarction. Moreover, the neurological symptoms associated with cerebral infarction, particularly acute cerebral infarction can be evaluated by scoring according to the NIH Stroke Scale (Brott T, et al.; Measurement of acute cerebral infarction: a clinical examination scale. Stroke vol. 20, pp. 864-870 (1989)) defined by the US National Institute of Health (NIH) . When the isoquinoline compound, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof according to the present invention is used as a pharmaceutical agent, the compound of the present invention can be orally or parenterally administered in the form of a pharmaceutical composition or a preparation (tablet, pill, capsule, granule, powder, syrup, emulsion, elixir, suspension, solution, injection, infusion, suppository and the like) obtained by admixing with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, corrigent, flavor, emulsifier, diluent, dissolution aids and the like). The pharmaceutical composition can be formulated according to a conventional method. In the present specification, parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, dripping and the like. A preparation for injection"can be prepared according to a method known in this field. The suppository for rectal administration can be produced by admixing the drug with a suitable excipient and the like. As the dosage form of a solid preparation for oral administration, those mentioned above such as powder, granule, tablet, pill, capsule and the like can be mentioned. As the liquid for oral administration, emulsion, syrup, elixir, suspension, solution and the like acceptable as a pharmaceutical agent can be mentioned. The dose is determined in consideration of age, body weight, general health condition, sex, diet, administration time, administration method, clearance rate, combination of drugs, the disease state of the patient then under treatment, and other factors. The compound of the present"invention, an optical isomer thereof and a pharmaceutically acceptable salt thereof are low toxic and can be used safely. While the daily dose varies depending on the condition and body weight of patient, the kind of the compound, administration route and the like, for example, it is desirably administered parenterally (subcutaneously, intravenously, intramuscularly or rectally) at about 0.01-50 mg/individual/day, preferably 0.01-20 mg/individual/day, and orally at about 0.01-150 mg/individual/day, preferably 0.1-100 mg/individual/day. Examples The present invention is explained in more detail in the following by referring to Examples, which are not to be construed as limitative as long as the spirit of the invention is not deviated. The unit of J is Hz. (R)-2-hydroxymethylpyrrolidine (Tokyo Kasei Kogyo Co., Ltd.) (50 g) was dissolved in methylene chloride (500 mL) f and acrylonitrile (36 mL) was added dropwise to the solution with stirring at room temperature. Subsquently, the mixture was stirred overnight at room temperature. After the completion of the reaction, the solvent was concentrated to give (R)-3-(2-hydroxymethylpyrrolidin-l-yl)propionitrile (76 g) . Hi-NMRtCDClsJS: 1.61-1.94 (5Hr m) , 2.33(1H, qf J*8Hs) , 2-53(2H, dd, J=6Hz, 8Hz) , 2.61-2.71(2Hf m) f 3.01-3.10 (1H, m) f 3.16-3.24(lHr m) , 3.37-3.46(lH, m) , 3.64(1H, dd, J=3Hz, 11Hz) Co., Ltd.) (50 g) and potassium carbonate (55.8 g) were dissolved in a mixed solvent of acetonitrile (500 mL) and water (100 mL) , and acrylonitrile (29 mL) was added dropwise to the solution at room temperature. Subsequently, the mixture was stirred overnight at room temperature. After the completion of the reaction, the solvent was concentrated, and the obtained residue was dissolved in water. Potassium carbonate was added to saturation. The mixture was extracted 3 times with chloroform, and the extract was dried over potassium carbonate. The solvent was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform:methano 1=10 :1) to give (R) -3- (3-hydroxypyrrolidin-l-yl)propionitrile (53 g) .' 1H-NMR(CDC13)8: 1. 68-1. 81 (1H, m) , 2 .04-2.10 (1H, m) , 2.13-2.27(1H, m) , 2.34-2.43(lH, m) , 2.51-2.63 Material Synthesis Example 1 using (S) -( + )-3-pyrrolidinol (Omega Corporation) (12.3 g) and acrylonitrile (10.2 mL) , (S)-3-(3-hydroxypyrrolidin-l-yl)propionitrile (53 g) was obtained. 1H-NMR(CDC13)5: 1.68-1.81(1H, m) , 2.04-2.10 (1H, m) , 2.13-2.27(1H, m) , 2.34-2.43(lH, m) , 2.51-2.63(3H, m), 2.72-2.84 N,0-dimethylhydroxylamine hydrochloride (198.6 g), sodium bicarbonate (620.9 g), methylene chloride (1.5 L) and water (1.1 L) were added, and acrylchloride (150 mL) was added dropwise to the mixture under ice-cooling. The mixture was stirred under ice-cooling for 4 hr, and the methylene chloride layer was separated. The organic layer was dried over magnesium sulfate, and the solvent was concentrated to give N-methyl-N-methoxyacrylamide (223.79 g) . This compound was used in the next step without further purification. 1H-NMR(CDC13)8: 3.27(3H, s) , 3.71(3H, s) , 5.76(1H, dd, J=2Hz, 11Hz) , 6.43 (1H, dd, J=2Hz, 17Hz) , 6.74 (1H, dd, J=llHz, 17Hz).. Starting Material Synthesis Example 5 (R)-(-)-3-pyrrolidinol hydrochloride (51.8 g) , potassium carbonate (69.6 g) , water (125 mL) and acetonitrile (500 mL) were added, and the mixture was stirred at room temperature for 1 hr. A solution (60 mL) of N-methyl-N-methoxyacrylamide (42 g) obtained in Starting Material Synthesis Example 4 in acetonitrile was added dropwise to the mixture, and the reaction was allowed to proceed overnight at room temperature. After the completion of the reaction, acetonitrile was concentrated under reduced pressure, and potassium carbonate was added to the residual aqueous layer to achieve oversaturation. The aqueous layer was extracted with chloroform, the extract was dried over magnesium sulfate and concentrated to give (R)-3- (3-hydroxypyrrolidin-l-yl) -li¬me thyl-N-methoxypropanamide (76.7 g) . 1H-NMR(CDC13)8: 1.65-1.75(1H, m) , 2.10-2.25(1H, m) r 2.36(1H, dd, J=8.79Hz, 15.2Hz), 2.60-2.70(4H, m), 2.75-2.80 tetrahydrofuran (90 raL) were added, and a solution (1,56 mol/L, 280 mL) of n-butyllithium in hexane was added dropwise to the mixture at -78°C. The mixture was stirred at 0°C for 30 min. The reaction mixture was cooled to -78°C and a solution (120 mL) of N,N-diethyl-2,3-dimethylbenzamide (42.5 g) in tetrahydrofuran was added dropwise to the mixture, and the mixture was stirred at -78°C for 1 hr. Then, a solution (120 mL) of (R) -3- (3-hydroxypyrrolidin-l-yl) -N-methyl-N-methoxypropanamide (38.6 g) obtained in Starting Material Synthesis Example 5 in tetrahydrofuran was added dropwise. The temperature was gradually risen to room temperature, and the reaction was allowed to proceed overnight. After the completion of the reaction, water (200 mL) was added, and tetrahydrofuran was concentrated under reduced pressure. The reaction mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated to give (R)-N,N-diethyl-2-[4- (3- hydroxypyrrolidin-1-yl) -2-oxobutyl] -3-methylbenzamide (79 .4 g) . 1H-NMR(CDC13)8: 1-04(3H, t, J=7.2Hz), 1.21(3H, t, J=7.2Hz), 1.65-1.80UH, m) , 2.10-2.30 (2H, m) , 2.2K3H, s) , 2.40-2.50 (1H, m) , 2.60-2.80(5H, m) , 2. 80-2. 95 (1H, m) , 3 ._00-3 . 20 (2H, m) , * -3.30-3.40UH, m) , 3.40-3.70(1H, m) , 3.70-4.00(2H, m) , 4.29-4.32(1H, m) , 7.01-7.07(1H, m) , 7.16-7.20(2H, m) Starting Material Synthesis Example 7 (R)-N,N-diethyl-2-[4-(3-hydroxypyrrolidin-l-yl)-2-oxobutyl]-3-methylbenzamide (124 g) obtained in Starting Material Synthesis Example 6 was dissolved in 25%(v/v) aqueous sulfuric acid solution (600 mL), and the solution was heated under reflux for 12 hr. After completion of the reaction, the reaction mixture was washed with chloroform, and the aqueous layer was alkalified with potassium carbonate. Chloroform was added and insoluble materials were removed by celite filtration. The aqueous layer was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated, and the precipitated crystals were washed with diethyl ether-ethyl acetate and collected by filtration by suction to give (R) -3- [2-(3-hydroxypyrrolidin-l-yl)ethyl]-5-methylisocoumarin (55.6 g) . ^-NMRfCDClaJS: 1.65-1. 80 (1H, m) , 2 . 1CX-2. 25 (1H, m) , 2.30-2.40(1H, m) , 2.46(3H, s) , 2. 56-2.61 (1H, mK 2. 74-2 .78 (1H, m) , 2.85-2.96(3H, m) , 4.32-4.36 (1H, m) r 6.43(1H, s) , 7.34(3H, t, J=7.5Hz), 7.51(1H, d, J=7.5Hz), 8.12(1H, d, J=7.5Hz) Starting Material Synthesis Example 8 D-prolinol (30 g) and tetrahydrofuran (300 mL) were added, and N-methyl-N-methoxyacrylamide (28.7 g) was added to the mixture with stirring at room temperature. After the completion of the reaction, the reaction mixture was concentrated to quantitatively cjive (R)-3-(2-hydroxymethylpyrrolidin-1-yl) -N-methyl-N-methoxypropanamide as an oil. ^-NMRfCDClsJS: 1.62-1.89(4H, m) , 2 . 22-2. 30 (1H, m) , 2.48- 2.80(4Hf m) , 3.16-3.48(6H, m) , 3.18(3H, s), 3.65-3.71(1H, m), Diisopropylamine (104 mL) and tetrahydrofuran (500 mL) were added, and a solution (457 mL, 1.56 mol/L) of n-butyllithium in hexane was added dropwise to the mixture with stirring at -78°C under a nitrogen stream. After the completion of the dropwise addition, the mixture was stirred at 0°C for 30 min, and cooled to -78°C again. A solution of N,N-diethy1-2,3-dimethylbenz amide (67.0 g) in tetrahydrofuran (150 mL) was added dropwise to the reaction mixture. After the completion of the dropwise addition, the mixture was further stirred at -78°C for 1 hr. A solution of (R)-3-(2-hydroxymethylpyrrolidin-1-yl) -N-methyl-N-methoxypropanamide (64 g) obtained in Starting Material Synthesis Example 8 in te-trahydrofuran (150 mL) was added dropwise. After the completion of the dropwise addition, the mixture was further stirred at -78°C for 1 hr. The mixture was gradually heated to room temperature. After the completion of the reaction, ice and water were added to the reaction mixture, and the organic layer was separated. The organic layer was concentrated, combined with the aqueous layer mentioned above, and the combined layer was extracted twice with chloroform. The organic layer was concentrated to give (R)-N,N-diethyl-2-[4-(2-hydroxymethylpyrrolidin-l-yl) -2-oxobutyl] -3-methylbenzamide as an oil. This compound was used in the next reaction without-further purification. ^-NMRfCDClaJS: 1.04(3H, t, J=7Hz) , 1.2K3H, t, J=7Hz) , 1.62-1.94(4H, m) , 2.12-2.22UH, m) , 2.2M3H, s) , 2.36-2.44 (1H, m) , 2.52-2.63(2Hf m) , 2.68-2.82(1H, m) , 2.97-3.24(5H, m) , 3.32-3.40(2H, m) , 3.62-3.90(4H, m) , 7.03-7.08(1H, m) , 7.16-7.20(2H, m) 35 Star-ting Material Synthesis Example 10 hydroxymethylpyrrolidin-1-yl) -2-oxobutyl]-3-methylbenzamide obtained in Starting Material Synthesis Example 9 was dissolved in cone, hydrochloric acid (250 mL) and water (250 mL) f and the solution was heated under reflux for 10 hr. After the completion of the reaction, the reaction mixture was cooled to room temperature and washed with toluene (200 mL). An aqueous solution of potassium carbonate (300 g) was added to the aqueous layer to basify the layer, and the layer was extracted twice with chloroform and the extract was dried over magnesium sulfate. The solvent was concentrated and acetone was added to the obtained" residue. The mixture was further concentrated to give (R) -3-[2-(2-hydroxymethylpyrrolidin-l-yl) ethyl]-5-methylisocoumarin (67 g). ^i-NMRICDClaJS: "1.66-1. 92(4Hf m) , 2 . 32-2 . 42 (1H, m) , 2.46(3H, s) , 2.65-2.70(4H, m), 3.12-3.28(2H, m) , 3.38(1H, dd, J=4Hz, 11Hz) , 3.64(1H, dd, J=4Hz, 11Hz), 6.43(1H, s) , 7.34(1H, t, J=8Hz), 7.51 (1H, d, J=8Hz), 8.12 (1H, d, J=8Hz)_ Using a known method, (J?) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin was converted to a hydrochloride to give (R)-3-[2- (2-hydroxymethylpyrrolidin-1-yl) ethyl]-5-methylisocoumarin hydrochloride. ^-NMRfDMSO-de) 5: 1.70-2.18 (4H, m) , 2.47(3H, s) r 3.08-3.22(3H, m) , 3.60-3.85(5H, m) , 5.51 Example 1 Diisopropylamine (122 mL) was dissolved in tetrahydrofuran (400 mL), and n-butyllithium (1.56 mol/L) (534 mL) was added dropwise to the solution under ice-cooling. The mixture was stirred under ice-cooling for 30 min, and then cooled to -78°C. A solution (150 mL) of N,N-diethyl-2,3-dimethylbenzamide (85.4 g) in tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at -78°C for 0.5 hr. The reaction mixture, was cooled to -78°C and a solution (150 mL) of (R)-1-(2-cyanoethyl)-3-hydroxypyrrolidine (53 g) in tetrahydrofuran was added dropwise to the mixture. The reaction mixture was warmed to room temperature. After the completion of the reaction, water was added to the reaction mixture and the organic layer was separated and concentrated. The residue was dissolved in chloroform and the solution was washed with saturated brine and dried over magnesium sulfate. The organic layer was extracted with IN hydrochloric acid, and the layer was basified. The aqueous layer was extracted with chloroform and the extract was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography to give (R)-3-[2-(3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-l-one (23.6 g). ^-NMRfCDClsJS: 1.83-1.96 (lHr m) , 2.21-2. 32 (1H, m) , 2.48(3Hf s) , 2.49-2.55(lH, m) , 2.72-2.79(3H, m), 2.81-2.92(3H, m) f 2.96-3.05(1H, m) , 4.42-4.49(lH, m) , 6.33(1H, s), 7.29(1H, t, J*8Hz) , 7.43 (1H, d, J=7Hz) , 8.22 (1H, d, J=8Hz) , 11.40(1H, brs) . MS(EI)272 (M+) Using a known method, (R) -3-[2-(3-hydroxypyrrolidin-l-yl)ethyl]-5-methyl-2H-isoquinolin-l-one was converted to a hydrochloride to give (R) -3- [2-(3-hydroxypyrrolidin-l-yl) ethyl] -5~methyl-2H-isoquinolin-l-one hydrochloride. ^-NMRfDMSO-dsJS: 1. 83-2.00 (1.5H, m) , 2.15-2.30 (0 . 5Hr m) , 2.48(3Hr m) , 2.96-3.10(2.5H, m)r 3.14-3.66(5.5H, m) , 4.37-4.50(1H, m), 5.55(1H, brs)r 6.52(0.5H, s), 6.54(0.5H, s) , 7.34(1H, t, J=8Hz), 7.53(1H, d, J=7Hz), 8.02(1H, d, J=8Hz) , 10.70(0.5H, brs) , 11.27 (0.5H, brs), 11.43(0.5H, brs), 11.46(0.5H, brs). MS (EI) 272 (M+) . [CC]D~-3.52° (C=1.15, MeOH) A different synthesis method of (R)-3-[2-(3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-l-one is shown in the following. Ammonium carbnate (65.3 g) was gradually added to acetic acid (165 mL) . After bubbling, (R) -3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methylisocoumarin (54.3 g) was added to the mixture, and the mixture was heated under reflux for 1 hr. After the completion of the reaction, the reaction mixture was cooled to room temperature and added to aqueous sodium hydroxide (115 g) solution (300 mL) (with heat generation and ammonia odor). The mixture was stirred at room temperature for 30 min. After the completion of the reaction, the mixture was extracted with chloroform, the extract was dried over magnesium sulfate, and concentrated. Ethyl acetat.e was added to the obtained residue and the suspension was washed. Collection by filtration gave (R) -3-[2-(3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-l-one (45.1 g) . Example 2 5-Methyl-3-(piperidin-4-yl)-2H-isoquinolin-l-one (1.0 g) , sodium bicarbonate (0.52 g) and 2-bromoethanol (0.67 g) were dissolved in acetonitrile (20 mL) and the solution was heated under reflux. After the completion of the reaction, the reaction mixture was concentrated and water was added to the obtained residue. The mixture was extracted with chloroform, and the extract was dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography to give 3-[l-(2-hydroxyethyl)piperidin-4-yl]-5-methyl-2H-isoquinolin-l-one (0.4 g). -NMRfCDClaJe: 1. 80-1. 95 (2H, m) , 1. 96-2 .10 (2H, m) , 2.24-2.33(2H, m), 2.53(3H, s), 2.56-2.65(3H, m), 3.05-3.15(2H, m), 3.67(2H, t, J=5Hz), 6.44(1H, s), 7.34(1H, t, J=7Hz), 7.48(1H, d, J=7Hz) , 8.24 (1H, d, J=7Hz), 10.72(1H, brs) . MS(EI)286(M+) Example 3 By the reaction in the same manner as in Example 1, using N,N-diethyl-2-methylbenzamide (3.45 g) and 4-(3-hydroxypyrrolidin-l-yl)butyronitrile (1.5 g), 3-[3-{3-hydroxypyrrolidin-1-yl) propyl]-2H-isoquinolin-l-one (536.3 mg) was obtained, 1H-NMRtCDClaJS: 1.78-1.95 (2H, m) , 2 . 03-2 . 20 (2H, m) , 2.31-2.49(2H, m), 2.62-2.90(4H, m) , 3.09-3.30(2H, m) , 4.35-4.49 (1H, m) , 5.83 (lttf brs) , 6.32(1H, s) , 7.35-7.45(2H, m) , 7.56-7.62(1H, m), 8.34(1H, d, J=8Hz), 14.41(1H, brS) MS(EI)272(M+) Example 4 By the reaction in the same manner as in Example 1, using N,N-dimethyl-2,3-dimethylbenzamide (2.00 g) and 4-(3-hydroxypyrrolidin-l-yl)butyronitrile (0.8 g), 3-[3-(3-hydroxypyrrolidin-1-yl) propyl] -5-me thy l-2H-isoquinolin-l-one (157.5 mg) was obtained. ^-NMRfCDCla^: 1. 88-2 . 00 (2H, m) , 2 . 08-2 .19 (2H, m) , 2.36-2.42(2H, m), 2.50(3H, s) , 2 . 62-2.98(4H, m), 3.16-3.30(2H, m), 4.39-4.48(lH, ra) , 5.86(1H, brs), 6.43(1H, a), 7.27-7.32(IH, m) , 7.44(1H, b, J=7Hz), 8.22(1H, b, J=8Hz), 14.45(1H, brs) MS(EI)286(M+) Example 5 By the reaction in the same manner as in Example 1, using N,N-dimethyl-2,3-dimethylbenzamide (4.10 g) and 3-(3-hydroxypyrrolidin-1-yl)propionitrile (1.5 g), 3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-l-one (157.5 mg) was obtained. ^-NMRfCDClaJS: 1. 88-1. 99 (IH, m) , 2 . 22-2 . 38 (*1H, m) , 2.48-2.57(4H, m) , 2.71-2.95(6H, m) , 3.01-3.10(IH, m) , 3.51(1H, brs), 4.42-4.5K1H, m) , 6.34(1H, s) , 7.27-7. 31 (IH, m) , 7.43(1H, b, J=7Hz), 8.22(IH, b, J=8Hz), 11.42(IH, brs). MS(EI)272(M+) Example 6 By the reaction in the same manner as in Example 1.,. using N,N-diethyl-2,3-dimethylbenzamide (4.347 g) and 3-(3-hydroxypyrrolidin-l-yl)propionitrile (1.6 g) , 3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-2H-isoquinolin-l-one (397.6 mg) was obtained. ^-NMJMCDClaJB: 1. 84-1. 97 (IH, m) , 2 . 21-2 . 37 (IH, m) , 2.43-2.55(1H, m) , 2.70-2.82(3H, m), 2.82-2.95 (3H, m) , 3.00-3.11(IH, m), 4.44-4.50(lH, m) , 6.25(1H, s), 7.38-7.45(IH, m) , 7.57-7.62(IH, t, J=7Hz), 8.34 (IH, d, J=8Hz) , 11.41(IH, brs) MS(EI)258(M+) Example 7 By the reaction in the same manner as in Example 1, using N,N-dimethyl-2,3-dimethylbenzamide (3.17 g) and 3-(2-hydroxymethylpiperidin-l-yl)propionitrile (1.51 g) , 3-[2-(2-hydroxymethylpiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-l-one (268 mg) was obtained. ^-NMR (300MHz, CDC13) 8: 11.5 (brs, IH) , 8.24(d, J=8.1, IH) , 7.49(d, J-8.1, IH), 7.30(t, J=8.1, IH), 6.39(s, IH), 3.65- 3.80(m, 2H) , 3.30(brsr IH) , 3.10-3.30(m, IH), 3.00-3.10 (mr IH) , 2.85-3.00(m, IH) , 2.70-2.85(m, 2H) , 2.50(s, 3H) , 2.35-2.60 (m, 2H) , 1.30-1.75(mr 6H) .. MS (EI) 300 (M+) Example 8 By the reaction in the same manner as in Example 1, using N,N-diethyl~2-methylbenzamide (3.42 g) and 3-(2-hydroxymethylpiperidin-1-yl) propionitrile (1 ♦ 51 g) , 3- [2- (2-hydroxymethylpiperidin-1-yl) ethyl] 72H-isoquinolin-l-one (392 mg) was obtained. XH-NMR (300MHzf CDC13) 8: 11.5 (brsf IH), 8.36(d, J=7.8, IH) r 7.60(t, J=7.8, IH), 7.39-7.46(m, 2H) , 6.29(s, IH) , 3.65-3.85(m, 2H) , 3.30(brs, IH) , 3.10-3.30 (mr IH) , 3.00-3.10(m, IH) , 2.85-3.00(m, IH) f 2.70-2.80(m, 2H) r 2.45-2.60(m, IH) r 2.30-2.45(m, IH) , 1.30-1.75(m, 6H) . MS(EI)286(M+r * Example 9 By the reaction in the same manner as in Example 2, using 3- fpiperidin-4-yl) -2H-isoquinolin-l-one hydrochloride (1.1 g) and 2-bromoethanol (1.0 g) as starting materials, 3-[l-{2-hydroxyethyl)piperidin-4-yl]-2H-isoquinolin-l-one (0.39 g) was obtained. ^-NMRtCDClsJS: 1. 71-1.91(2H, m) , 2 . 00-2 .10 (2H, m) , 2.22-2.33(2H, m) , 2.50-2.65(3H, m) , 3.04-3.13(2H, m), 3.62-3.67(2H, m) , 6.34(1H, s), 7.42-7.52(2H, m), 7.61-7.67 (IH, m) , 8.34-8.38(1H, m) , 1Q.69UH, brs) . MS (EI) 272 (M+) Example 10 By the reaction in the same manner as in Example 2, using 3-(piperidin-4-yl)-2H-isoquinolin-l-one hydrochloride (500 mg) and 3-bromo-l-propanol (315 mg) , 3-[l-(3- hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-l-one (136 mg) was obtained. XH-NMR(270MHz, DMS0-d6)§: 1.79-1.91(4H, m) , 2.12-2.17 (2H, m), 2.69-3.02(5H, m) , 3.44-3.52(5H, m), 6.37(1H, s) , 7.42-7.4T(lH, m) , 7.66-7.7K2H, m) , 8.13(1H, d, J-7.8Hz), 11.31(1H, brS) . MS(EI)286(M+) Example 11 Bv the reaction in the same manner as in Example 21, using 3-(piperidin-4-yl)-2H-isoquinolin-l-one hydrochloride (500 mg) and 4-bromo-l-butanol (434 mg), 3-[l-(4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-l-one (50 mg) was obtained. 1H-NMR(270MHz, DMSO-d6)5: 1.44-1.47(4H, m) , 1.57-1.63 (2H, m) , 1.88-1.97(4H, m) , 2.27-2.41(3H, m) , 2.95-2.99 By the reaction in the same manner as in Example 1, using N,N-diethyl-2-methylbenzamide (1.91 g) and 3-hydroxy-4~ (pyrrolidin-l-yl)butyronitrile (1.54 g) , 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-2H-isoquinolin-l-one (0.089 g) was obtained. ^-NMRfCDClaJg: 1.75-1. 84 (4H, m) , 2 . 32-2 . 84 (8H, m) , 4.00-4.06(1H, m) , 6.26(1H, s), 7.39-7.46(2H, m), 7.61(1H, tf J=8Hz) , 8.36UH, d, J*8Hz) r 9.85(1H, brs) . MS (EI)272(M+) Example 13 By the reaction in the-same manner as in Example 1, using N,N-dimethyl-2,3-dimethylbenzamide (2.65 g) and 3-hydroxy-4-(pyrrolidin-l-yl)butyronitrile (2.31 g) , 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinolin-l-one (0 . 066 g) was obtained. ^-NMRtCDClaJe: 1.75-1. 84 (4Hr m) , 2 . 32-2 . 90 (8Hf m) , 2.39(3H, s) , 4.06-4.11(lHf m) , 6.36(1H, s) , 7.28(1H, t, J=8Hz) , 7.42(1H/ df J=8Hz), 8.19 (1H, d, J=8Hz), 10.00 (1H, brs). MS(EI)286(M+) Example 14 By the reaction in the same manner as in Example 1, using tf,N-dimethyl-2,3-dimethylbenzamide (4.60 g) and (S)-3-(2~ nydroxymethyl)pyrrolidin-l-yl)propionitrile (2.01 g) , (S)-3-[2- (2-hydroxymethylpyrrolidin-l-yl) ethyl] -5-methyl-2H-Lsoquinolin-1-one *(351 mg) was obtained. H-NMR (300MHz, CDC13) 8: 12.4(brs, 1H) , 8.23 (d, J-8.1, 1H) , 7.45(d, J-8.1, 1H) , 7.31(t, J-8.1, 1H) , 6.39(s, 1H) , 4.10 (brs, LH), 3.76(d, J=14.1, 1H), 3.56(df J-14.1, 1H), 3.35-3.50(m, LH) , 3.10-3.25(m, 1H), 2.85-2.95(m, 2H) , 2.70-2.80(m, 1H) , 2.60-2.70(m, IH) , 2.50(s, 3H), 2.40-2.45(m, IH), 1.80-2.00(m, 4H) . MS(EI)286(M+) Example 15 By the reaction in the same manner as in Example 1, using N,N-diethyl-2-methylbenzamide (4.96 g) and (S)-3-(2-hydroxymethyl)pyrrolidin-l-yl)propionitrile (2.00 g), (S)-3- [2-(2-hydroxymethylpyrrolidin-l-yl) ethyl]-2H-isoquinolin-l-one (515 mg) was obtained. XH-NMR (300MHz, CDC13) 5= 12.4 (brs, IH) , 8.35 (d, J=7.8, IH) , 7.59-7.64(m, IH), 7.35-7.50(m, 2H) , 6.28(s, IH), 4.06(brs, IH), 3.76(d, J-14.1, IH), 3.55(d, J-14.1, IH) , 3.35-3.45(m, IH), 3.10-3.25(m„ IH), 2.80-3.00(m, 2H), 2.65-2.80(m, IH), 2.55-2.65(m, IH), 2.35-2.45(m, IH), 1.70-2.00(m, 4H). MS(EI)272(M+) Example 16 By the reaction in the same manner as in Example 1, using N,N-dimethyl-2,3-dimethylbenzamide (4.84 g) and (S)-4-(2-hydroxymethyl)pyrrolidin-l-yl)butyronitrile (2.30 g), (S)-3- [3-(2-hydroxymethylpyrrolidin-l-yl)propyl]-5-methyl-2H-isoquinolin-1-one (363 mg) was obtained. XH-NMR (300MHz, CDC13) 8: 12.1 (brs, IH) , 8.23(d, J=8.1, IH) , 7.46(d, J=8.1, IH), 7.28-7.34(m, IH), 6.44(s, IH), 5.16(brs, IH) , 3.80(d, J-14.1, IH), 3.60(d, J-14.1, IH), 3.20-3.30 (m, IH), 2.80-3.00(m, 2H), 2.60-2.80(m, 2H), 2.51(s, 3H), 2.40-2.45(m, IH), 2.20-2.35(m, IH), 1.70-2.05(m, 6H). MS(EI)300(M+) Example 17 By the reaction in the same manner as in Example 1, using N,N-diethyl-2-methylbenzamide (5.23 g) and (S)-4-(2-hydroxymethyl)pyrrolidin-l-yl)butyronitrile (2.30 g), (S)-3-[3-(2-hydroxymethylpyrrolidin-l-yl) propyl]-2H-isoquinolin-l- one (331 mg) was obtained. XH-NMR (300MHz, CDC13) 8: 12.2(brs, IH), 8.34(d, J=8.1, IH), 7.59-7.64(m, IH), 7.39-7.48(m, 2H), 6.34(3, IH), 5.05(brs, IH), 3.80(d, J-14.1, IH), 3.60(d, J-14.1, IH), 3.15-3.20(m, IH), 2.70-2.85(m, 2H), 2.60-2.70(m, 2H), 2.40-2.55(m, IH), 2.20- 2.35(m, IH), 1.70-2.10(m, 6H) Example 18 By the reaction in the same mariner as in Example 1, using N,N-diet^yl-2,3-dimethylbenzamide (5.0136 g) and (R)-4-(2-hydroxymethylpyrrolidin-l-yl)butyronitrile (2.2 g) , (R)-3-[3-(2-hydroxymethylpyrrolidin-l-yl) propyl] -2H-isoquinolin-l-one (627.3 mg) was obtained. IN aqueous HCl solution (2.4 ml) was added thereto in an acetone solvent, and the precipitated crystals were collected by filtration to, give (R)-3-[3-(2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinclin-l-one hydrochloride (555.3 mg) . 1H-NMR(CD3OD)8: 1. 83-2.25 (7H, m) , 2 . 68-2 . 73 (2H, m) , 3.08-3.22(2H, m) , 3.43-3.70(4H, m) f 3.85-3.90 (IH, m) , 6.54(IH, s) , 7.45-7.50(IH, m) , 7.59(1H, d, J=8Hz) , 7.70(1H, t, J=8Hz), 8.24(1H, d, J=8Hz). MS(EI)286(M+) Example 19 By the reaction in the same manner as in Example 1, using N,N-diethyl-2,3-dimethylbenzamide (5.6017 g) and 3-(4-hydroxypiperidin-l-yl)propionitrile (2.26 g), 3-[2-(4-hydroxypi~peridin-l-yl) ethyl] -2H-isoquinolin-l-one (327 . 5 mg) was obtained. 1H-NMR(CDC13)8: 1. 63-1. 76 (2H, m) , 1. 84-2 . 02 (2H, m) , 2.22-2.39(2H, m) , 2 . 62-2 . 99 (6H, m) , 3 . 61-3 . 80 (2H, m) , 6.25(1H, s) , 7.36-7.46 (2H, m) , 7. 57-7. 62 (IH, m) , 8.30(1H, d, J=8Hz) , 11.37(1H, brs). MS(EI)272(M+) Example 20 By the reaction in the same manner as in Example 1, using N,N-diethyl-2r3-dimethylbenzamide (4.975 g) and (R)-3-(2-hydroxymethylpyrrolidin-l-yl)propionitrile (2.0 g) , (R)-3-[2-(2-hydroxymethylpyrrolidin-l-yl) ethyl] -2H-isoquinolin-l-one (408.4 mg) was obtained. 1H-NMR(CDC13)5: 1.75-2.00 (3H, m) , 2 . 36-2 . 48 (IH, m) , 2.59-2.78(2H, m) , 2.83-2.96(2H, m) , 3.11-3.23(IH, m) , 3.35-4.45(IH, m) , 3.50-3.62(lH, m), 3.71-3.81(IH, m) , 4.02(1H, brs), 6.29(lHf s) , 7.39-7.50(2H, m) , 7.58-7.64 (IH, m) , 8.35I1H, d, J=8Hz) , 12.41(1H, brs). MS(EI)272 (M+) Example 21 To 2-N-t-butoxycarbonyl-4-oxopipecolinic acid (7.96 g) was added dropwise ethyl chloroformate (3.45 ml) , in the presence of triethylamine, in tetrahydrofuran under ice-cooling to give a mixed acid anhydride. The precipitated salt was filtered and the filtrate was ice-cooled again. Ethanol (15 ml) was added and the mixture was stirred at room temperature. The reaction mixture was concentrated and ethyl acetate was added. The mixture was washed with C. 5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was concentrated to give ethyl 2-N-t-butoxycarbonyl-4-oxopipecolate (6.39 g). The obtained ethyl 2-N-t-butoxycarbonyl-4-cxopipecolate (6.39 g) was dissolved in 1,3-dimethyl-2-imidazoiidinone and ethanol. Tosylmethyl isocyanide (5.30 g) was added and the mixture was cooled to -78°C. Potassium t-butoxide (6.09 g) was carefully added not to raise the temperature of -^he reaction mixture, and the mixture was stirred at room temperature. The reaction mixture was concentrated, 10% aqueous citric acid solution was added and the mixture was extracted with chloroform. The chloroform layer was washed -with saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was concentrated. The residue was purified by column chromatography (n-hexane:ethyl acetate=4:l) to give ethyl 2-N-t-butoxycarbonyl-4-cyanopipecolate (1.21 g). The obtained ethyl 2-N-t-butoxycarbonyl-4-cyanopipecolate (1.21 g) was dissolved in tetrahydrofuran and the solution was water-cooled. Lithium borohydride (279 mg) was added and the mixture was stirred at room temperature for 21 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was concentrated to give (N-t-butoxycarbonyl-2-hydroxymrethyl-4-cyano) piperidine (961 mg) . By the reaction in the same manner as in Example 1, using (N-t-butoxycarbonyl-2-hydroxymethyl-4-cyano) piper idine (1.14 g) and N,N-diethyl-2-methylbenzamide (1.84 g) , 3-(l-t- butoxycarbonyl-2-hydroxymethylpiperidin-4-yl) -2H-isoquinolin-1-one (616 mg) was obtained. The obtained 3-(l-t-butoxycarbonyl-2-hydroxymethylpiperidin-4-yl)-2H-isoquinolin-l-one (616 mg) was dissolved in ethyl acetate, and 4N hydrogen chloride-ethyl acetate solution (2.0 ml) was added to the solution, and the mixture was stirred at room temperature for 6.5 hr. The reaction mixture was concentrated, and the precipitated crystals were washed with diethyl ether and dried under reduced pressure to give 3-(2-hydroxymethylpiperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (433 mg). The obtained 3- (2-hydroxymethylpiperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (433 mg) was dissolved in acetonitrile and water. 35% Formalin (340 (j,l) and sodium triacetoxy borohydride (697 mg) were added to the solution, and the mixture was stirred at room temperature for 20 min. The reaction mixture was alkalified with 20% aqueous potassium carbonate solution and extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was concentrated. The precipitated crystals were washed with diethyl ether and dried under reduced pressure to give 3- (l-methyl-2-hydroxymethylpiperidin-4-yl) -2H-isoquinolin-l-one (146 mg) . XH~NMR (300MHz, DMS0-d6) 5: 11.1 (brsr 1H) , 8.12(d, J«7.8, 1H) , 7.55-7.70(m, 2H) , 7.44(t, J-7.8, 1H) , 6.39(s, 1H) , 4.48(brs, 1H), 3.55-3.75(m, 2H) , 2.60-2.80(m, 3H) , 2.40-2.60(m, 1H) , 2.42(s, 3H) , 1.70-2.00(m, 4H) . MS(EI)272(M+) Example 22 By the reaction in the same manner as in Example 2, using 3-(piperidin-4-yl)-2H-isoquinolin-l-one hydrochloride (510 mg) and 3-bromo-2,2-dimethyl-l-propanol (474 mg) , 3- [1- (3-hydroxy-2,2-dimethylpropyl)piperidin-4-yl]-2H-isoquinolin-l-one (92 mg) was obtained. ^-NMR (270MHz , DMSO-d6)8: 0.79 (6H, s) , 1. 54-1. 63 (2Hf m) , 1.89-1.93(2H, m) , 2.64-2.65UH, m) , 2 .70-3 . 00 (2H, m) , 3 .13-3 . 20 (2H, m) , 3.78-3.79(2H, m) , 4 .10-4 .14 (2Hr m) , 4 .14-4 . 60 (1H, m) , 6.38(1H, s) , 7.39-7.44(lH, m) , 7.57-7.65 (2H, m) „ 8.12(1H, d, J=8.1Hz), 11.25(1H, brS) . MS (EI)314(M+) Example 23 By the reaction in the same manner as in Example 2, using 5-methyl-3- (piperidin-4-yl)-2H-isoquinolin-l-one hydrochloride (1 g) and 3-bromo-l-propanol (751 mg), 5-methyl-3- [1- (3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-l-cne (221 mg) was obtained, melting point: 197-199°C, 1H-NMR( 270MHz, DMSO-d6)8: 1. 54-1.69(4H, m) , 1. 74-1. 96 (4H, m) , 2.33-2.38(2H, m) , 2.47-2.50(3H, m) , 2.96-3.00(2K , m) , 3.15-3.18UH, m) , 3.43-3.48(2H, m) , 4.48-4.49 (1H, m) , 6.35(1H, s) , 7.26-7.3K1H, m) , 7.49(1H, d, J=7.0Hz), 7.99(1H, d, J=7.8Hz), 11.24(1H, brS) . MS(EI)300(M+) " ' Example 24 By the reaction in the same manner as in Example 2, using 3-(piperidin-4-yl)-2H-isoquinolin-l-one hydrochloride (500 mg) and l-bromo-2-propanol (394 mg), 3-[l-(2- hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-l-one (87 mg) was obtained. ^-NMR (270MHz, DMSO-d6)5: 1.05 (3H, d, J=5.9Hz), 1. 61-1. 70 (2H, m) , 1.85-1.89(2H, m) , 2.03-2.09(2H, m) , 2.20-2.26(2H, m) , 2.40-2.50(2H, m), 2.94-2.98(1H, m), 3.75-3.76(1H, m), 4.26-4.28(1H, m) , 6.36(1H, s), 7.38-7.43 (1H, m) , 7.57-7.67 (2H, m) , 8.1K1H, d, J=7.8Hz), 11.20(1H, brS) . MS (EI) 286 (M+) Example 25 By the reaction in the same manner as in Example 1, using N,N-dimethyl-2,3-dimethylbenzamide (5.6095 g) and 3-(4-hydroxypiperidin-l-yl)propionitrile (2.44 g), 3-[2-(3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-l-one (418.2 mg) was obtained. ^-NMRfCDC^S: 1. 71-1. 91 (3H, m) , 2 . 01-2 .10 (2H, m) , 2.30- . . 2.42(2H, m), 2.49(3H, s), 2.71-2.79(4H, m), 2.89-2.98(2H, m), 3.78-3.85(lH, m) , 6.33(1H, s) , 7.26-7.30(1H, m) , 7.44(1H, b, J=7Hz), 8.24(1H, b, J=8Hz), 11.38(1H, brs) MS(EI)286(M+) Example 26 By the reaction in the same manner as in Example 1, using NfN-dimethyl«2f3-dimethylbenzamide (5.8040 g) and (R)-4-(2-hydroxymethylpyrrolidin-l-yl)butyronitrile (2.75 g), (R)-3-[3-(2-hydroxymethylpyrrolidin-l-yl)propyl]-5-methyl-2H-isoquinolin-1-one (344.1 mg) was obtained, melting point: 150.0-151.0°C, :H-NMR(300MHz, CDC13)8: 1.73-2.08(6H, m), 2.31-2.40(2H, m) , 2.49(3H, s) , 2.70-2.80 By the reaction in the same manner as in Example 1, using N,N-diethyl-2,3-dimethylbenzamide (5.2474 g) and 3-(3-hydroxypiperidin-l-yl)propionitrile (2.62 g) , 3-[2-(3-hydroxypiperidin-1-yl)ethyl]-2H-isoquinolin-l-one (888 - 2 mg) was obtained. melting point: 192.0-193.0°Cf ^-NMRfCDCL^S: 1.42-1.53 (1H, m) , 1. 63-1. 71 (1H, m) , 1.82-1.9M2H, m) , 2.39-2.40(2Hp m) , 2.61-2.76 (5H, m) , 2. 84-2 .91 (1H, m) , 3.19-3.2K1H, m) , 3.86-3 .98 (1H, m) , 6.23(1H, s) , 7.37-7.45(2H, m) , 8.33(1H,d, J=8Hz) , 11.25(1H, brs) Example 28 By the reaction in the same manner as in Example 2, using 5-methyl-3- (pyrrolidin-3-yl)-2H-isoquinolin-l-one hydrochloride (200 mg) and 2-bromoethanol (270 p.1) , 3-[l-(2-hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-l-one (39 mg) was obtained. XH-NMR (300MHz, CDC13) 8: 10.8 (brs, 1H) , 8.19(d, J=8.0f 1H) , 7.42(d, J-8.0, 1H), 7.28(t, J=8.0, 1H), 6.36(s, 1H), 3.70-3.85(m, 2H), 3.10-3.35(m, 2H), 3.05-3.20(m, 1H), 2.65-2.85(m, 2H) r 2.55-2.65(m, 1H) , 2.48(s, 3H) , 2.25-2.40(mf 2H) , 1.85-2.00(m, 1H). MS(ESI)273(M+1) Example 29 By the reaction in the same manner as in Example 2, using 3-(pyrrolidin-3-yl)-2H-isoquinolin-l-one hydrochloride (201 mg) and 2-bromoethanol (285 JJ.1) r 3-[l-(2-hydroxyethyl) pyrrolidin-3-yl] -2H-isoquinolin-l-one (58 mg) was obtained. XH-NMR (300MHz, CDC13) g: 10.8{brs, 1H) , 8.32(d, J=8.1, 1H) , 7.57-7.62(m, 1H) , 7.37-7.45 (m, 2H)., 6.27(s, 1H) , 3.70-3.80(m, 2H) , 3.15-3.30(m, 2H) , 3.05-3.15(m, 1H), 2.65-2.80(m, 2H), 2.55-2.65(m, 1H), 2.20-2.40(m, 2H) , 1.80-2.00(m, 1H) . MS(ESI) 259(M+l) Example 30 By the reaction in the same manner as in Example 2, using 5-methyl-3- (piperidin-4-yl)-2H-isoquinolin-l-one hydrochloride (1 g) and l-bromo-2-propanol (994 mg), 5-methyl-3-[1-(2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-l-one (147 mg) was obtained. 1H-NMR (270MHz, DMSO-d6)5: 1.05(3H, d, J=6.2Hz), 1.68-1.77(2H, m) , 1.85-1.89(2H, m) , 2.04-2.09 (2H, m) , 2.15-2.30(2H, m) , 2.39-2.50(4H, m), 2.95-2.99(2H, m), 3.77-3.78(1H, m), 4.23-4.25{1H, m) , 6.34(1H, s) , 7.26-7.32(1H, m) , 7.49(1H, d, J=7.0Hz), 7.99(1H, d, J=7.8Hz), 11.23(1H, brS). MS(EI)300(M+) Example 31 By the reaction in the same manner as in Example 2, using 5-methyl-3-(piperidin-4-yl)-2H-isoquinolin-l-one hydrochloride (1 g) and 4-bromo-l-butanol (433 mg) , 5-methyl-3- [1- (4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-l-one (201 mg) was obtained. 1H-NMR (270MHz, DMSO-d6)8: 1. 44-1. 47 (4H, m) , 1. 61-1. 74 (2H, m) , 1.74-1.97(4H, m) , 2.26-2.39(2H, m) , 2.43-2.49(4H, m) , 2.95-2.99(2H, m) , 3.33-3.42(2H, m), 4.37-4.54(1H, m) , 6.34(1H, s) , 7.26-7.32(lH, m), 7.49(1H, d, J=7.0Hz), 7.99(1H, d, J=8.1Hz), 11.24(1H, brS). MS (EI) 314 (M+) Example 32 By the reaction in the same manner as in Example 1, using N,N-dimethyl-2,3-dimethylbenzamide (5.1101 g) and 3-(3-hydroxypiperidin-l-yl)propionitrile (2.2 g), 3-[2-(3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-l-one (269.6 mg) was obtained, melting point: 184.0-185.0°C, XH-NMR(300MHz, CDCl3)8: 1.49-1.98(4H, m), 2.36-2.83(12H, m), 3.90-4.0K1H, m) , 6.33(1H, s) , 7.27-7.32 (1R, m) , 7.43(1H, b, J=7Hz), 8.22(IH, b, J=8Hz), 11.29(IH, brs). MS(EI)286(M+) Example 33 By the reaction in the same manner as in Example 2, using 5-methyl-3-(pyrrolidin-3-yl)-2H-isoquinolin-l-one hydrochloride (501 mg) and 3-bromo-l-propanol (991 ^1), 3-[l-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-l-one (216 mg) was obtained. XH-NMR (300MHz, CDC13) 6: 11.3 (brs, IH) , 8.21(d, J=7.8, IH) , 7.45(d, J-7.8, IH) , 7.26-7.33(m, IH) , 6.37 (s, IH) , 4.80-4.95(m, 2H) , 3.15-3.25(m, 2H) , 3.07(d, J=9.6, IH) , 2.80-2.90(m, IH) , 2.60-2.75(m, IH) , 2.50-2.60(m, IH), 2.50(s, 3H) , 2.20-2.40(m, 2H) , 1.75-1.95(m, 3H) . MS(EI)286(M+) Example 34 By the reaction in the same manner as in Example" 1, using N,N-diethyl-2,3-dimethylbenzamide (4.07 g) and (S)-l-(2-cyanoethyl)~3-hydroxypyrrolidine (1.6 g) , (S) -3-[2- (3-hydroxypyrrolidin-1-yl) ethyl]-5-methyl-2H-isoquinolin-l-one (0.228 g) was obtained, melting point: 176-178°C, ^-NMIMCDClaJS: 1. 83-1.96 (IH, m) , 2 . 21-2 . 32 (IH, m) , 2.48(3Hf s) , 2.49-2.55{lH, m), 2.72-2.79(3H, m) r 2.81-2.92(3H, m), 2.96-3.05-(lHr m) r 4.42-4.49(lH, m) , 6.33(1H, s) , 7.29(1H, t, J=8Hz) , 7.43(1H, d, J=7Hz), 8.22(lHr df J=8Hz), 11.40(lHf brs). MS(EI)272(M+) Example 35 By the reaction in the same manner as in Example 1, using N, N-dimethyl-2 ,3-dimethylbenzamide (1.41 g) and (R) -3- (3-hydroxypiperidin-l-yl)propionitrile (1.44 g) , (R)~3-[2-(3-hydroxypiperidin-1-yl) ethyl]-5-methyl-2H-isoquinolin-l-one (147 mg) was obtained, melting point: 180.0-181.0°C, Hi-NMRfCDClaJS: 1. 49-1. 98 (4Hf m) , 2 , 36-2 . 83 (12H, m) , 3.90-4.01(1H, m) , 6.33(1H, s) , 7.27-7.32 (IH, m) , 7.43(1H, b, J-7Hz) , 8.22(1H, b, J=8Hz) , 11.29(lHr brs) MS(EI)286 (M+) Example 36 By the reaction in the same manner as in Example 1, using N,N-diethyl-2,3-dimethylbenzamide (81.4 g) and (R)-3-(2-hydroxymethylpyrrolidin-l-yl)propionitrile (55.6 g) , (R)-3-[2- (2-hydroxymethylpyrrolidin-l-yl) ethyl ] -5-methyl-2H-isoquinolin-1-one (12.5 g) was obtained. 1H-NMR(CDC13)8: .1. 76-1.96 (4H, m) , 2.39-2.44(1H, m) , 2.50(3H, s) , 2.62-2.76(2H, m), 2.85-2.96(2H, m), 3.11-3.22(1", m), 3.38-3.46 (1H, m) , 3.55 (1H, dd, J=3Hz, 11Hz)',' 3.76(1H, dd, J=3Hz, 12Hz), 6.39(1H, s), 7.31(1H, t, J=8Hz), 7.55(1H, d, J=8Hz), 8.26(1H, d, J=8Hz), 12.43(1H, brs). MS (EI) 286 (M+) Using a known method, (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl) ethyl]-5-methyl-2H-isoquinolin-l-one was converted to a hydrochloride to give (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl) ethyl]-5-methyl-2H-isoquinolin-l-one hydrochloride dihydrate. 1H-NMR(DMSO-d6)6: 1.69-2:i4(4H, m) , 2.48(3H, s) , 2.94-3.44(4H, m) , 3.52-3.84(5H, m) , 5.48(1H, brs), 6.55(1H, s) , 7.34(lHf tr J-8Hz) , 7.53(1H, d, J«7Hz), 8.02 [a]D=+24.5° (c=1.009, MeOH) . A different synthesis method of (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-l-one is shown in the following. {R) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyl] -5-methylisocoumarin hydrochloride (62 g) and acetic acid (186 mL) were added and ammonium carbonate (74.4 g) was gradually added to the mixture with stirring. After bubbling, the reaction mixture was heated and stirred at 130°C for 2 hr with heating. After the completion of the reaction, the reaction mixture was cooled to room temperature and aqueous sodium hydroxide (140 g) solution (200 mL) was added. The mixture was stirred at 80°C, and after the completion of the reaction, the reaction mixture was concentrated. The methanol fraction was evaporated and the mixture was extracted twice s*ith chloroform. The organic layer was extracted twice with 3N hydrochloric acid (300 mL and 100 mL) , and potassium carbonate was added to the aqueous layer to basify the layer. The aqueous layer was extracted twice with chloroform, and the extract was dried over magnesium sulfate. The solvent was concentrated and ethyl acetate was added to the obtained residue. The mixture was further concentrated and the residue was dissolved in a small amount of ethyl acetate with heating. Diethyl ether was added to the solution and the precipitated crystals were collected by filtration to give (R) -3- [2- (2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methyl-2H-isoquinolin-l-one (41.5 g). Example 37 A solution (400 mL) of diisopropylamine (26.9 g) in tetrahydrofuran was cooled to -5°C and 1.57 M solution (154 ml) of n-butyllithium in hexane was added dropwise to the solution. After stirring at 0°C for 30 minf the mixture was cooled to -78°C and a solution (50 mL) of N,N-diethyl~2,3-dimethylbenzamide (45.1 g) in tetrahydrofuran was added dropwise. After stirring at -78°C for 1 hr, a solution (50 mL) of l-benzyl-3-cyanopyrrolidine (37.18 g) in tetrahydrofuran was added dropwise. After completion of the dropwise addition, the reaction mixture was heated to room temperature and the mixture was stirred overnight at room temperature. The mixture was further stirred under reflux for 1 hr and "the reaction mixture was concentrated to about half volume. Water and methylene chloride were added and the organic layer was partitioned, washed with water, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (ethyl acetate) to give (±)-3-(l-benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-l~one (66.38 g) . To the obtained (±)-3-(l-benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-l-one (66.38 g) was added D-tartaric acid (31.32 g) in methanol (1580 ml) f and the mixture was heated under reflux and cooled to room temperature to give precipitated (±) -3- (l-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one D-tartrate (44.56 g). This was further recrystallized twice from methanol to give (-) -3-(l-benzylpyrrolidin-3-yl) -5~methyl-2H-isoquinolin-1-one D-tartrate (27.06 g) . Subsequently, the crystals recovered from the mother liquor of the recrystallization was recrystallized three times from methanol to yield (11.74 g). (-) -3-(l-Benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-l-one D-tartrate (38.8 g) was stirred in methanol (150 ml)-methylene chloride (300 ml), IN aqueous sodium hydroxide solution (200 ml) and water (100 ml) were added dropwise to alkalify the solution. The methylene chloride layer was partitioned and washed with water, and then dried over magnesium sulfate and concentrated to give (-)-3-(l-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinoIin-l-one (27 . 5 g>. [ To the obtained (-)-3-(l-benzylpyrrolidin-3-yl)-5-methyl~ 2H-isoquinolin-l-one (27.5 g) were added 50% aqueous 10% palladium-carbon (6 g) and ethanol (400 ml) , and the mixture was stirred under a hydrogen atmosphere at 50°C for 6 hr. After celite filtration, the filtrate was concentrated and ethyl acetate was added to the obtained residue. The precipitated crystals were collected by filtration to give (-)-3-(pyrrolidin-3-yl)-5-methyl-2H~isoquinolin-l-one (16.8697 g). To the obtained {-) -3- (pyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one (3.0 g) were added bromoethar.ol (8.21 g) , sodium hydrogen-carbonate (5.6 g) , methyl ethyl ketone (84 ml) and water (8.4 ml) , and the mixture was stirred under reflux for 2 hr. The reaction mixture was concentrated, extracted with methylene chloride, and the extract was washed with water, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (methanol/ethyl acetate;2/5) and crystallized from ethyl acetate to give (-)-3-[1-(2-hydroxylethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (1.5425 g) . melting point: 137.3-138.6°Cf talD22 -53.1(01.005, CHC13) , XH-NMR(300MHz, CDC13)8: 1.85-2.01(1H, m) , 2.27-2.42 (2H, m) , 2.49(3H, s) , 2.55-2.64UH, m) , 2 . 69-2 . 85 (2H, m) , 3 .10-3 .16 (1H, m) , 3.20-3.3M2H, m) , 3 .74-3.88 (2H, m) , 6.35(1H, s) , 7.23-7.33(1H, m), 7.43(1H, d, J=7Hz), 8.20(1H, d, J=8Hz), 10.66(1H, brs) * -MS (EI)272 (M+) Example 38 The mother liquor obtained by optical resolution for (-)-3- (l-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-l-one D- tartrate in Example 37 was subjected to alkali treatment. Conversion to the L-tartrate by a method similar to the above-mentioned and 3 times of recrystallization from methanol gave (+)-3-(l-benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-l-one L-tartrate (38.99 g). Sebsequentlyr desalting, debenzylation and hydroxyethylation in the same manner as in the above gave (+)-3-[l-(2-hydroxylethyl)pyrrolidin-3-yl]~5-methyl-2H- isoquinolin-1-one. melting point: 137.0-138.6°C, [(X]D2Z+52.7 (C=1.004, CHC13) , 1H-NMR{ 300MHz, CDC13)8: 1. 85-2 . 01 (1H, m) , 2 . 27-2 . 42 (2H, m) , 2.49(3H, s) , 2.55-2.64(lH, m) , 2.69-2.85 (2H, m) , 3.10-3.16(1H, m) , 3.20-3.3K2H, m) , 3.74-3.88 (2H, m) , 6.35(1H, s) , 7.23- 7.33(1H, m) , 7.43UH, d, J=7Hz) , 8.20(1H, d, J=8Hz) , 10.66UH, brs) MS(EI)272(M+) The structural formula of the compound in each Example is shown in the following. The following numbers correspond to the above-mentioned Example numbers. Experimental Example PARP enzyme activity inhibitory action As an enzyme source, recombinant human PARP (4667-02X, Trevigen) was used. A poly ADP-ribosilation reaction was started by adding 3H-NAD (1.85 kBq, NAD [adenine-2, 8-3H], Daiichi Chemicals Co.f Ltd.) and activated DNA (0.02 mg/mL, 4667-03X, Trevigen) and then the enzyme source to an enzyme reaction buffer (10 mM Tris/HCl (pH 8.0), 1 mM iMgCl2, 28 mM KC1, 28 mM NaCl) . After incubation at 25°C for 15 min. , the reaction was stopped by adding 20% trichloroacetic acid, and the resulting acid insoluble fraction was adsorbed to a GF/B filter. The filter was washed several times with 5% trichloroacetic acid, and the radioactivity on the filter was measured with a liquid scintillation counter. The results are shown in Table 1. The PARP activity was determined by subtracting the radioactivity of an enzyme source non-addition sample as a blank value, and a 50% enzyme inhibitory value (IC50 value) of each test compound was calculated with the radioactivity of a compound non-addition sample as 100%. DPQ == 3,4-dihydro-5-[4-(l-piperidinyl)-butoxy]-l(2H)-isoquinolinone (can be synthesized according to Example 32 of JP-A-H2-124874, PARP inhibitor described in each of WO99/08680 and W099/11649) From these results, it has become clear that the compounds shown in Examples of the present invention have superior PARP inhibitory activity as compared to DPQ. Experimental Example 2 determination of stability Each compound was dissolved in physiological saline to give solutions having a concentration of 1.0 mg/mL or 10 mg/mL. They were preserved at room temperature, under shielding or non-shielding and the residual ratio at day 7 and day 11 was measured by HPLC. The results are shown in Table 2. column: Inertsil ODS3V (GL Science Inc.) Mobile phase: methanol: 0.01 mol/L aqueous ammonium acetate solution From these results, i€ has become clear that the compounds of the present invention are stable in aqueous solutions. Experimental Example 3 improving effect on neurological symptoms associated with cerebral infarction Cynomolgus monkey fasted in advance for 12 hr or more was anesthetized with intramuscular administration of ketamine hydrochloride (10 mg/kg) by injection and fixed on an operation table. Atropine sulfate (0.5 mg/body) was intramuscularly administered under pentobarbital anesthesia, and a small hole of about 5 mm was made with a dental drill near oval foramen and orbital fissure, and then dura matter and arachnoid were incised. Then, middle cerebral artery (MCA) near bifurcation of*internal carotid artery was exposed. The MCA near bifurcation of internal carotid artery was coagulated/occluded with a bipolar coagulator to form cerebral infarction. Thereafter a solvent or an Example drug was administered in a sustained manner at 3 mg/kg/hr for 6 hr. 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Industrial Applicability The compound of the above-mentioned formula (I) , an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a water adduct thereof are stable in aqueous solutions, have a potent PARP inhibitory activity as compared to known compounds, and are useful as a therapeutic drug of cerebral infarction, particularly acute cerebral infarction. In addition, (R)-3-(3-hydroxypyrrolidin-l-yl)-N-methyl-N-methoxypropanamide, (R) -N,N-diethyl-2-[4- (3-hydroxypyrrolidin-1-yl)-2-oxobutyl]-3-methylbenzamide, (R)-3-[2- (3-hydroxypyrrolidin-l-yl) ethyl]-5-methylisocoumarin, (R) -3-(2-hydroxymethylpyrrolidin-l-yl) -N-methyl-N-methoxypropanamide, (f?)-N,N-diethyl-2-[4-(2-hydroxymethylpyrrolidin-1-yl) -2-oxobutyl] -3-methylbenzamide, (R) -3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methylisocoumarin and (R) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyl]-5-methylisocoumarin hydrochloride are novel compounds and useful as intermediates for the synthesis of the compound of the formula (I) . This application is based on patent application Nos. 288833/2002, 340175/2002 and 109160/2003 filed in Japan, the contents of which are hereby incorporated by reference. 1. An isoquinoline compound represented by the following formula (I): 5 R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano f acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylaminof sulfamoyl , N-alkylsulfamoyl, N,N~dialkylsulfamoyl or alkoxyalkyloxy; is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group; and is represented by the following formula (II) : X is CH or a nitrogen atom, provided zhat when Y is absent in the formula (I)., .then X should be CH; W is CH or a nitrogen atom, provided uhat when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atomr alkylr amino, monoalkylamino , dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 is a hydrogen atom, an alkyl, a hydroxyl group or a hydroxyalkyl and R2' is a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2' are taken together to form ketone, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. 2. The isoquinoline compound of claim 1, which is represented by the formula (I), wherein R1 is a hydrogen atom or alkyl; Y is absent or an alkylene chain having 1 to 5 carbon atoms wherein an optional carbon atom may have a hydroxyl group; and R is represented by the formula (II) , wherein, in the formula (II), X is CH or a nitrogen atom, provided that when Y is absent in the formula (I) , then X should be CH; W is CH or a nitrogen atom, provided that when X is CH, .then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atom or alkyl, R2 is a hydrogen atom, a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl or hydroxyalkyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. 3. The isoquinoline compound of claim 1 or 2, which is represented by the formula (I) , wherein R1 is a hydrogen atom or methyl; Y is absent, methylene, ethylene, propylene or 2- hydroxypropylene; and R is represented by the formula (II), wherein, in the formula (II), X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), then X should be CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 3; t is an integer of 1 to 4; when R3 is a hydrogen atom or methyl, R2 is a hydrogen atom, methyl, ethyl, a hydroxyl group, hydroxymethyl or 2-hydroxymethyl and R2' is a hydroxyl group, hydroxymethyl or 2-hydroxyethyl; and when R3 is 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or 2-hydroxypropyl, R2 and R2. are the same or different and each is a hydrogen atom, hydroxyl group, methyl, hydroxymethyl or 2-hydroxyethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. 4. The isoquinoline compound of any of claims 1 to 3, which is selected from (1) (R) -3- [2- (3-hydroxypyrrolidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (2) 3-[L-(2-hydroxyethyl)piperidin-4-yl]-5-methyl-2H-isoquinolin-1-one (3) 3- [3- (3-hydroxypyrrolidin-l-yl) propyl] -2H~isoquinolin-l-one (4) 3- [3- (3-hydroxypyrrolidin-l-yl) propyl] -5-methyl-2H-isoquinolin-1-one (5) 3- [2- (3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (6) 3- [2- (3-hydroxypyrrolidin-l-yl) ethyl]-2H-isoquinolin-l-one (7) 3-[2- (2-hydroxymethylpiperidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (8) 3- [2- (2-hydroxymethylpiperidin-l-yl) ethyl] -2H-isoquinolin-1-one (9) 3-[l- (2-hydroxyethyl)piperidin-4-yl]-2H-isoquinolin-l-one (10) 3-[l- (3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-l- one (11) 3-[1- (4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-l-one (14) (S) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-l-one (15) (S) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyH -2H-isoquinolin-1-one (16) (S) -3- [3- (2-hydroxymethylpyrrolidin-l-yl) propyl] -5-methyl-2H-isoquinolin-l-one (17) (S) -3- [3- (2-hydroxymethylpyrrolidin-l-yl) propyl] -2H-isoquinolin-1-one (18) (R) -3- [3- (2-hydroxymethylpyrrolidin-l-yl) propyl]-2H-isoquinolin-1-one (19) 3- [2- (4-hydroxypiperidin-l-yl) ethyl] -2H-isoquinolin-l-one (20) (R) "3-[2-(2-hydroxymethyipyrrolidin-l-yl)ethyl]-2H-isoquinolin-1-one (21) 3-(l-methyl-2-hydroxymethylpiperidin~4-yl)-2H-isoquinolin-1-one (22) 3-[l-(3-hydroxy-2,2-dimethylpropyl)piperidin-4-yl]-2H-isoquinolin-1-one (23) 5-methyl-3-[l- (3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-1-one (24) 3-[l- (2-hydroxypropyl)piperidin-4-yl]-2H~isoquinolin-l-one (25) 3- [2- (3-hydroxypiperidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (26) (R) -3-[3- (2-hydroxymethylpyrrolidin-l-yl) propyl]-5-methyl-2H-isoquinolin-l-one (27) 3-[2- (3-hydroxypiperidin-l-yl) ethyl]-2H-isoquinolin-l-one (28) 3-[l-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (29) 3-[l-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinolin-l- one (30) 5-methyl-3-[l- (2-hydroxypropyl)piperidin-4~yl]-2H- isoquinolin-1-one (31) 5-methyl-3-[1-(4-hydroxybutyl)piperidin-4-yl] -2H-isoquinolin-1-one (32) 3- [2- (3-hydroxypiperidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-1-one . - (33) 3-[l-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (34) (S)-3-[2-(3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H- isoquinolin-1-one (35) (R) -3- [2-(3-hydroxypiperidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (36) (R) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyl] -5-methy 1-2H-isoquinolin-l-one (37) (-) -3-[l-(2-hydroxylethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one and (38) ( + )-3-[1- (2-hydroxylethyl)pyrrolidin-3-yl]-5-methyl~2H-isoquinolin-1-one, an optically active form thereof, a pharmaceutical^ acceptable salt thereof, a hydrate thereof or a water adduct thereof. 5. The isoquinoline compound of any of claims 1 to 4/which is represented by the formula (I) f wherein R1 is a hydrogen atom or methyl; Y is absent; and R is represented by the formula (II) , wherein, in the formula (II) , X is CH; W is a nitrogen atom; s is an integer of 1 or 2; t is an integer of 2; when R3 is methyl, R2 is a hydrogen atom, methyl, ethyl, a hydroxyl group or hydroxymethyl and R2' are the oamo or different and oaoh is a hydroxyl group or hydroxymethyl; and when R3 is hydroxyethyl, R2 and R2f are the same or different and each is a hydrogen atom, a hydroxyl group or hydroxymethyl, an optically active form thereof, a pharmaceutical^ acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. S. The isoquinoline compound of any of claims 1 to 5, which is selected from (2) 3-[l-(2-hydroxyethyl)piperidin-4-yl]-5-methyl-2H-isoquinolin-1-one (9) 3-[1-(2-hydroxyethyl)piperidin-4-yl]-2H-isoquinolin-l-one (10) 3-[1-(3-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-l-one (11) 3-[1-(4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-l-one (21) 3- (l-methyl-2-hydroxymethylpiperidin-4-yl) -2H-isoquinolin-1-one (22) 3-[l-(3-hydroxy-2,2-dimethylpropyl)piperidin-4-yl]-2H-isoquinolin-1-one (23) 5-methyl-3-[l- (3-hydfoxypropyl)piperidin-4-yl] -2H-isoquinolin-1-one (24) 3- [1- (2-hydroxypropyl)piperidin-4-yl]-2H-isoquinolin-l-one (28) 3-[l-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (29) 3- [1- (2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinolin-l-one (30) 5-methyl-3-[l- (2-hydroxypropyl)piperidin~4-yl]-2H-isoquinolin-1-one (31) 5-methyl-3-[1- (4-hydroxybutyl) piperidin-4-yl]-2H-isoquinolin-1-one (33) 3-[l-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one (37) (-) -3- [1- (2-hydroxylethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one and (38) ( + )-3-[1-(2-hydroxylethyl) pyrrolidin-3-yl]-5rmethyl-2H-isoquinolin-1-one , an optically active form thereof, a pharmaceuzically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. 7. The isoquinoline compound of any of claims 1 to 4, which is represented by the formula (I), wherein R1 is a hydrogen' atom or methyl; Y is ethylener or propylene or 0 hydroiiypropylcnc; and R is represented by the formula (II) , wherein, in the formula (II) , X is a nitrogen atom; W is CH; s is an integer of 1 to 3; t is an integer of 1 to 4; R2 is a hydrogen atom, an alkylf a hydroxyl group or a hydrogen atom,"a hydroxyl group,-■ alkyl or hydroxymethyl; and R3 is a hydrogen atom, provided that when R2 is a hydrogen atom or alkyl,, R2' is a hydroxyl group or hydroxymethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. 8. The isoquinoline compound of any of claims 1 to 4 or 7, which is selected from (1) (R) -3- [2- (3-hydroxypyrrolidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (3) 3-[3- (3-hydroxypyrrolidin-l-yl) propyl] -2H-isoquinolin-l-one (4) 3- [3- (3-hydroxypyrrolidin-l-yl) propyl}-5-methyl-2H-isoquinolin-1-one (5) 3-[2-(3-hydroxypyrrolidin-l-yl)ethyl]-5-me^hyl-2H-isoquinolin-1-one (6) 3-[2-(3-hydroxypyrrolidin-l-yl)ethyl]-2H~isoquinolin-l-one (7) 3- [2- (2-hydroxymethylpiperidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (8) 3- [2- (2-hydroxymethylpiperidin-l-yl) ethyl]-2H-isoquinolin-1-one (13) 3 [2 hydroiiy 3 (pyrrolidin 1 yl)propyl]—5 methyl 5H iooquinolin 1 one (14) (S) -3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methyl-2H-isoquinolin-l-one (15) (S) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyl] -2H-isoquinolin-1-one (16) (S) -3- [3- (2-hydroxymethylpyrrolidin-l-yl) propyl] -5-methyl-2H-isoquinolin-l-one (17) (S) -3- [3- (2-hydroxymethylpyrrolidin-l-yl) propyl] -2H-isoquinolin-1-one (18) (R) -3-[3-(2-hydroxymethylpyrrolidin-l-yl) propyl]-2H-isoquinolin-1-one (19) 3- [2- (4-hydroxypiperidin-l-yl) ethyl] -2H-isoquinolin-l-one (20) (R) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyl] -2H-isoquinolin-1-one (25) 3- [2- (3-hydroxypiperidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (26) (R) -3- [3- (2-hydroxymethylpyrrolidin-l-yl) propyl] -5-methyl-2H-isoquinolin-l-one (27) 3- [2- (3-hydroxypiperidin-l-yl) ethyl] -2H-isoquinolin-l-one (32) 3- [2- (3-hydroxypiperidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (34) (S) -3- £2^ (3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one (35) (R) -3- [2- (3-hydroxypiperidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-1-one and (36) (R) -3- [2- (2-hydroxymethylpyrrolidin-l-yl) ethyl]-5-methyl- 2H-isoquinolin-l-one, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. 9. The isoquinoline compound of any of claims 1 to 8, which is represented by the formula (I), wherein R1 is a hydrogen atom or methyl; Y is absent or ethylene; R is represented by the formula (II), wherein, in the formula (II) , when Y is present in the formula (I) , X is a nitrogen atom; when Y is absent in the formula *(1) , X is CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 or 2; t is an integer of 1 to 3; when R3 is a hydrogen atom, R2 is a hydrogen atom, a hydroxyl group or a hydroxymethyl and R2' aro oaohis a hydroxyl group or hydroxymethyl; and when R3 is hydroxyethyl, R2 and R2' are each a hydrogen atom, a hydroxyl group or hydroxymethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. 10. The isoquinoline compound of any of claims 1 to 9, which is selected from (1) (R) -3- [2- (3-hydroxypyrrolidin-l-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (2) 3- [1- (2-hydroxyethyl) piperidin-4-yl] -5-methyl-2H-isoquinolin-1-one (5) 3- [2- (3-hydroxypyrrolidin-l-yl) ethyl]-5-methyl-2H- isoquinolin-1-one (28) 3-[l-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H- isoquinolin-1-one (34) (S)-3-[2-(3-hydroxypyrrolidin-l-yl)ethyl] -5-methyl-2H~ isoquinolin-1-one (36) (R)-3-[2-(2-hydroxymethylpyrrolidin-l-yl) ethyl]-5-methyl-2H-isoquinolin-l-one (37) (-)-3-[l-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinolin-1-one and (38) ( + ) -3- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. 11. The isoquinoline compound of any of claims 1 to 6, 9 and - 10, which is represented by the formula (I) , wherein, R1 is methyl; Y is absent; and R is represented by the formula (II) , wherein X is CH; W is a nitrogen atom; S is 1 or 2; t is an integer of 2; R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group or hydroxyalkyl; and R3 is hydroxyethyl, an optically active form thereof, a, pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. (2) 3-[l-(2-Hydroxyethyl)piperidin-4-yl]-5-mechyl-2H-isoquinolin-1-one, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. 13. (28) 3-[l-(2-Hydroxyethyl)pyrrolidin-3-yl]-5-rriethyl»2H-isoquinolin-1-one, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. 14- (37) ( + ) -3- [1- (2-Hydroxyethyl) pyrrolidin-3-yl] -5-methyl~2H- isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. 15. (38) (-)-3- [1- (2-Hydroxyethyl) pyrrolidin-3-yl]-5-methyl-2H- isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. 16. The isoquinoline compound of any of claims 1 to 4 and 7 to 10, which is represented by the formula (I) , wherein R1 is methyl; Y is ethylene; R is represented by the formula (II) , wherein, in the formula til), X is a nitrogen atom; W is CH; s is 1; t is an integer of 2 or 3; R2 is a hydrogen atom, a hydroxyl group or hydroxymethyl and R2' a hydroxyl group or hydroxymethyl; and R" is a hydrogen atom, provided that when R2 is a hydrogen atom, then R2' should be a hydroxyl group or hydroxymethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof. 17. (1) (R) -3- [2- (3-Hydroxypyrrolidin-l-yl) ethyl] -5-methyl-2H- isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. 18. (5) 3-[2-(3-Hydroxypyrrolidin-l-yl) ethyl] J-5-methyl-2H- isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. 19. (34) (S) -3- [2- (3-Hydroxypyrrolidin-l-yl) ethyl] -5-methyl-2H- isoquinolin-1-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof. 20. (36) (R) -3-[2-(2-Hydroxymethylpyrrolidin-l-yl)ethyl]-5-methyl- 2H-isoquinolin-l-one, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a for the prophylaxis and/or treatment of a disease caused by hyperactivity of poly(ADP-ribose)polymerase. 33. The use of claim 32, wherein the disease is cerebral infarction. 34. The use of claim 32, wherein the disease is acute cerebraJ infarction. g=»35. A compound selected from the following: (R) -3- (3-hydroxypyrrolidin-l-yl) -N-methyl-N-me-hoxypropanamide (R)-N,N-diethyl-2-[4-(3-hydroxypyrrolidin-l-yl)-2-oxobutyl]-3- methylbenzamide (R) -3- [2- (3-hydroxypyrrolidin-l-yl) ethyl] -5-me-hylisocoumarin (R) -3- (2-hydroxymethylpyrrolidin-l-yl) -N-methyl-N- methoxypropanamide {R)-NrN-diethyl-2-[4-(2-hydroxymethylpyrrolidin-l-yl)-2- oxobutyl] -3-methylbenzamide (R) -3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methylisocoumarin and (R) -3-[2-(2-hydroxymethylpyrrolidin-l-yl)ethyl]-5-methylisocoumarin hydrochloride. R1 is a hydrogen atom, a halogen atom, alkyl, alJcoxy, haloalkyl, a hydroxy1 group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N ,N-dialkylcarbamoyl, acylamino, diacylamino , thiol, alkylthio , alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkylcxy; is dialkylamino; is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon aton may have a hydroxyl group; and is represented by the following fornvjla (II) : X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), X is CH; W is CH or a nitrogen atom; provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 is a hydrogen atom, an alkyl, a hydroxyl group or a hydroxyalkyl and R2'—arc the oamo is a hydroxyl group or hydroxyalkyl; and - - when R3 is hydroxyalkyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2r are taken together to form ketone, which comprises reacting a compound of the following formula R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylaminc, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio , alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, NfN-dialkylsulfamoyl or alkoxyalkyloxy; is absent or an alkylene chain having 1 to 8 carbon atoms wherein an optional carbon atom may have a hydroxyl group; and is represented by the following formula (II) : X is CH or a nitrogen atom, provided that when Y is absent in the formula (I), X is CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen aror.; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 is a hydrogen atom, an alkyl, a hydroxyl group or a hydroxyalkyl and R2' is a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2 and R2' are the same or different and each is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkylf alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2' are taken together to form ketone, R1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxy1 group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-diaikylcarbamoyl, acylamino r diacylamino, thiol, alkyl~hio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoylr NfN-dialkylsulfamoyl or alkoxyalkyloxy; is absent or an alkylene chain having 1 to 8*- carbon atoms wherein an optional carbon atom may have a hydroxyl group; and X is CH or a nitrogen atom, provided that when Y is absent in the formula (I) , then X should be CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; X is CH or a nitrogen atom, provided "hat when Y is absent in the formula (I) , then X should be CH; W is CH or a nitrogen atom, provided that when X is CH, then W should be a nitrogen atom; s is an integer of 1 to 5; t is an integer of 1 to 5; when R3 is a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino optionally having a substituent, benzoylamino optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R2 and R2' are the same or different and each is a hydroxyl group or hydroxyalkyl; and when R3 is hydroxyalkyl, R2 is a hydrogen atom, an alkyl, a hydroxyl group or a hydroxyalkyl and R2r is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R2 and R2' are taken together to form ketone. 39.- method for producing the isoquinoline compound of claim 1, an optically active form thereof, a pharmaceutically acceptable salt thereof, abater adduct thereof,* a hydrate thereof and a solvate thereof, which comprises the steps of any of claims 36 to 38 3440. A method for producing the isoquinoline compound of claim lr an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof or a solvate thereof, which comprises the steps of claims 36 to 38

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790-CHENP-2005 CLAIMS GRANTED.pdf

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