RU2297411C2 - Isoquinoline compounds, intermediate compounds, methods for their preparing and using - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, biochemistry, medicine.

SUBSTANCE: invention relates to novel isoquinoline compounds of the general formula (I):

wherein R¹ represents hydrogen atom, halogen atom or alkyl; Y is absent or represents alkylene chain comprising from 1 to 8 carbon atoms wherein arbitrary carbon atom can comprise hydroxyl group as a substitute; R represents the following formula (II):

wherein X represents -CH or nitrogen atom under condition that if Y absent in the formula (I) then X must represent -CH; W represents -CH or nitrogen atom under condition that if X represents -CH then W must represents nitrogen atom; s represents a whole number from 1 to 3; t represents a whole number from 1 to 3; if R³ represents hydrogen atom or alkyl then R² represents hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R^2' represents hydroxyl group or hydroxyalkyl, and if R³ represents hydroxyalkyl then R² and R^2' represent hydrogen atom. Also, invention relates to their optically active forms, pharmaceutically acceptable salts, aqueous adducts, hydrates and solvates. Compounds of the formula (I) elicit inhibitory effect on activity of poly-(ADP-ribose)-polymerase and can be used in prophylaxis of diseases associated with cerebral infarction.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

40 cl, 4 tbl, 55 ex

Description

FIELD OF THE INVENTION

The present invention relates to a novel isoquinoline compound and a pharmaceutical agent containing it as an active ingredient.

State of the art

Poly (ADP-ribose) polymerase, hereinafter sometimes abbreviated as "PARP", is an intranuclear enzyme that uses nicotinamide nucleotide (NAD) as a substrate, breaks the bond between nicotinamide and ribose, transfers the remainder of the ADP-ribose to the protein and causes polymerization by addition of numerous ADP-ribose residues. This enzyme is attractive as an enzyme associated with apoptosis, which is believed to be activated as a result of recognition of DNA damage by a free radical, such as nitrogen monoxide, active oxygen, etc., which occurs in the affected area during ischemia, and plays a major role in promoting DNA repair.

In recent years, it is believed that PARP activation reduces intracellular NAD, a significant part of ATP is used to compensate for this decrease, as a result of which intracellular energy is used, and this leads to cell death. In an experiment using mice with PARP shock loading, it was found that cultured neuronal cells show resistance to disorders associated with excitatory amino acids, such as nitric oxide, NMDA (N-methyl-D-aspartate), etc., and that this demonstrates a very significant protective effect by inhibiting cerebral infarction caused by cerebral ischemia by at least 80% (Eliasson MJL. et al., Nature Med. 3, 1089-95 (1997)).

However, none of the currently known PARP inhibitors have undergone clinical trials as a therapeutic agent for treating cerebral infarction. As for the PARP inhibitors known to date, for example, 5-substituted-3,4-dihydro-2H-derivatives of isoquinoline (JP-A-H2-124874), derivatives of 1,11b-dihydrobenzopyrano are known [4.3.2- de] isoquinolin-3-one (WO 99/11645), 3,4-dihydro-5- [4- (1-piperidinyl) butoxy] -1 (2H) -isoquinoline (each of WO 99/08680 and WO 99 / 11649), pyrimidine derivatives (WO 00/42025), benzimidazole derivatives (each of WO 00/64878 and WO 00/68206), phthalazine derivatives (each of WO 00/67734 and WO 00/44726), quinazolinone derivatives (each of WO 00/47726) 02/48117 and WO 02/44157) and the like, but their PARP inhibitory activity is not very high.

In addition, JP-B-S46-12454 discloses isoquinoline derivatives having an analgesic effect and hypoglycemic activity, US Pat. 1174272 and 1062357, respectively, quinazoline derivatives having antihypertensive activity are disclosed in GB patents No. 1174272 and 1062357 and in DE patent No. 2,121,031, respectively, in US Pat. 4808595 discloses furopyridine derivatives having the ability to lower intraocular pressure, and JP-A-S64-42472 discloses quinazoline derivatives that have the ability to correct cerebral dysfunction, but none of them indicated PARP inhibitory activity.

(patent reference 1) JP-A-H2-124874

(patent reference 2) WO 99/11645

(patent reference 3) WO 99/08680

(patent reference 4) WO 99/11649

(patent reference 5) WO 00/42025

(patent reference 6) WO 00/64878

(patent reference 7) WO 00/68206

(patent reference 8) WO 00/67734

(patent reference 9) WO 00/44726

(patent reference 10) WO 02/48117

(patent reference 11) WO 02/44157

(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 (1997)

SUMMARY OF THE INVENTION

An object of the present invention is to provide a compound having PARP inhibitory activity and useful as a therapeutic agent for treating cerebral infarction, especially a therapeutic agent for treating acute cerebral infarction, and a compound that can be used as an intermediate.

The inventors of the present invention conducted intensive studies and found that the isoquinoline compound represented by the following formula (I), its optical form, its pharmaceutically acceptable salt, its hydrate and its aqueous adduct possess effective PARP inhibitory activity, which led to the present invention. Accordingly, the present invention provides the following:

(1) An isoquinoline compound represented by the following formula (I):

Where

R ¹ represents a hydrogen atom, a halogen atom, an alkyl, alkoxy, haloalkyl, hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, acylamino, diacylamino alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N, N-dialkylsulfamoyl or alkoxyalkyloxy;

Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; and

R is represented by the following formula (II):

Where

X represents CH or a nitrogen atom, provided that if Y is not present in the formula (I), then X must represent CH;

W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom;

s represents an integer from 1 to 5;

t represents an integer from 1 to 5;

if R ³ represents a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, optionally containing a substituent, benzoylamino, optionally containing a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, then R ² and R ^{2 'are the} same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R ³ is hydroxyalkyl, then R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group, an alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R ² and R ^2' taken together form a ketone,

its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(2) The above isoquinoline compound of formula (I), wherein

R ¹ represents a hydrogen atom or alkyl;

Y is absent or represents an alkylene chain containing from 1 to 5 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; and

R is represented by formula (II),

where, in the formula (II),

X represents CH or a nitrogen atom, provided that if Y is not present in the formula (I), then X must represent CH;

W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom;

s represents an integer from 1 to 5;

t represents an integer from 1 to 5;

if R ³ represents a hydrogen atom or alkyl, then R ² and R ^{2 'are the} same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R ³ is hydroxyalkyl, then R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group, an alkyl or hydroxyalkyl,

its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(3) The above isoquinoline compound of formula (I), wherein

R ¹ represents a hydrogen atom or methyl;

Y is absent or is methylene, ethylene, propylene or 2-hydroxypropylene; and

R is represented by formula (II),

where, in the formula (II),

X represents CH or a nitrogen atom, provided that if Y is not present in the formula (I), then X must represent CH;

W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom;

s represents an integer from 1 to 3;

t represents an integer from 1 to 4;

if R ³ represents a hydrogen atom or methyl, then R ² and R ^{2 'are the} same or different, and each represents a hydroxyl group, hydroxymethyl or 2-hydroxyethyl; and

if R ³ is 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or 2-hydroxypropyl, then R ² and R ^{2 ′ are the} same or different and each represents a hydrogen atom, a hydroxyl group, methyl, hydroxymethyl or 2-hydroxyethyl,

its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate.

(4) The above isoquinoline compound, which is selected from the group consisting of

(1) (R) -3- [2- (3-hydroxypyrrolidin-1-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-1-yl) propyl] -2H-isoquinolin-1-one

(4) 3- [3- (3-hydroxypyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one

(5) 3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(6) 3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one

(7) 3- [2- (2-hydroxymethylpiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(8) 3- [2- (2-hydroxymethylpiperidin-1-yl) ethyl] -2H-isoquinolin-1-one

(9) 3- [1- (2-hydroxyethyl) piperidin-4-yl] -2H-isoquinolin-1-one

(10) 3- [1- (3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one

(11) 3- [1- (4-hydroxybutyl) piperidin-4-yl] -2H-isoquinolin-1-one

(12) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one

(13) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one

(14) (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(15) (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one

(16) (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one

(17) (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one

(18) (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one

(19) 3- [2- (4-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-one

(20) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one

(21) 3- (1-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-methyl-3- [1- (3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one

(24) 3- [1- (2-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one

(25) 3- [2- (4-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(26) (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one

(27) 3- [2- (3-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-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-1-one

(30) 5-methyl-3- [1- (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-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(33) 3- [1- (3-hydroxypropyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one

(34) (S) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(35) (R) -3- [2- (3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(36) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(37) (-) - 3- [1- (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,

their optically active forms, their pharmaceutically acceptable salts, their aqueous adducts, their hydrates and their solvates.

(5) The above isoquinoline compound of formula (I), wherein

R ¹ represents a hydrogen atom or methyl;

Y is absent; and

R is represented by formula (II),

where, in the formula (II),

X represents CH;

W represents a nitrogen atom;

s represents an integer of 1 or 2;

t represents an integer of 2;

if R ³ is methyl, then R ² and R ^{2 'are the} same or different, and each represents a hydroxyl group or hydroxymethyl; and

if R ³ is hydroxyethyl, then R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group or hydroxymethyl,

its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(6) The above isoquinoline compound, which is selected from the group consisting of

(2) 3- [1- (2-hydroxyethyl) piperidin-4-yl] -5-methyl-2H-isoquinolin-1-one

(9) 3- [1- (2-hydroxyethyl) piperidin-4-yl] -2H-isoquinolin-1-one

(10) 3- [1- (3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one

(11) 3- [1- (4-hydroxybutyl) piperidin-4-yl] -2H-isoquinolin-1-one

(21) 3- (1-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-methyl-3- [1- (3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one

(24) 3- [1- (2-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-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-1-one

(30) 5-methyl-3- [1- (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-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,

their optically active forms, their pharmaceutically acceptable salts, their aqueous adducts, their hydrates and their solvates.

(7) The above isoquinoline compound of formula (I), wherein

R ¹ represents a hydrogen atom or methyl;

Y represents ethylene, propylene or 2-hydroxypropylene; and

R is represented by formula (II),

where, in the formula (II),

X represents a nitrogen atom;

W represents CH;

s represents an integer from 1 to 3;

t represents an integer from 1 to 4;

R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group, an alkyl or hydroxymethyl; and

R ³ represents a hydrogen atom,

with the proviso that if R ² represents a hydrogen atom or alkyl, R ^{2 '} represents a hydroxyl group or hydroxymethyl,

its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(8) The above isoquinoline compound, which is selected from the group consisting of

(1) (R) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(3) 3- [3- (3-hydroxypyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one

(4) 3- [3- (3-hydroxypyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one

(5) 3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(6) 3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one

(7) 3- [2- (2-hydroxymethylpiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(8) 3- [2- (2-hydroxymethylpiperidin-1-yl) ethyl] -2H-isoquinolin-1-one

(12) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one

(13) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one

(14) (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(15) (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one

(16) (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one

(17) (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one

(18) (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one

(19) 3- [2- (4-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-one

(20) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one

(25) 3- [2- (4-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(26) (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one

(27) 3- [2- (3-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-one

(32) 3- [2- (3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(34) (S) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(35) (R) -3- [2- (3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one and

(36) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one,

their optically active forms, their pharmaceutically acceptable salts, their aqueous adducts, their hydrates and their solvates.

(9) The above isoquinoline compound of formula (I), wherein

R ¹ represents a hydrogen atom or methyl;

Y is absent or represents ethylene;

R is represented by formula (II),

where, in the formula (II),

if Y is present in formula (I), X represents a nitrogen atom; if Y is absent in formula (I), X represents CH;

W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom;

s represents an integer of 1 or 2;

t represents an integer from 1 to 3;

if R ³ represents a hydrogen atom, then R ² and R ^{2 '} each represents a hydroxyl group or hydroxymethyl; and

if R ³ represents hydroxyethyl, R ² and R ^{2 '} , each represents a hydrogen atom, a hydroxyl group or hydroxymethyl,

its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(10) The above isoquinoline compound, which is selected from the group consisting of

(1) (R) -3- [2- (3-hydroxypyrrolidin-1-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-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(28) 3- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one

(34) (S) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(36) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one

(37) (-) - 3- [1- (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,

their optically active forms, their pharmaceutically acceptable salts, their aqueous adducts, their hydrates and their solvates.

(11) The above isoquinoline compound of formula (I), wherein

R ¹ represents methyl;

Y is absent; and

R is represented by formula (II),

Where

X represents CH;

W represents a nitrogen atom;

S represents 1 or 2;

t represents an integer of 2;

R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group or hydroxyalkyl; and

R ³ represents hydroxyethyl,

its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(12)

(2) 3- [1- (2-hydroxyethyl) piperidin-4-yl] -5-methyl-2H-isoquinolin-1-one, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its MES.

(13)

(28) 3- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its MES.

(fourteen)

(37) (+) - 3- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate .

(fifteen)

(38) (-) - 3- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate .

(16) The above isoquinoline compound of formula (I), wherein

R ¹ represents methyl;

Y represents ethylene;

R is represented by formula (II),

where, in the formula (II),

X represents a nitrogen atom;

W represents CH;

s represents 1;

t represents an integer of 2 or 3;

R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group or hydroxymethyl; and

R ³ represents a hydrogen atom,

provided that if R ² represents a hydrogen atom, then R ^{2 '} must represent a hydroxyl group or hydroxymethyl,

its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(17)

(1) (R) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate .

(eighteen)

(5) 3- [2- (3-hydroxypyrrolidin-1-yl) ethyl]] - 5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(19)

(34) (S) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate .

(twenty)

(36) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate .

(21) An agent for the prophylaxis and / or treatment of a disease caused by hyperactivity of a poly (ADP-ribose) polymerase, which includes the aforementioned isoquinoline compound, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(22) The above agent used to prevent and / or treat cerebral infarction.

(23) The above agent used to prevent and / or treat acute cerebral infarction.

(24) The above agent used for prophylaxis and / or treatment, which improves neurological symptoms associated with cerebral infarction.

(25) An agent for the prevention and / or treatment of cerebral infarction, which includes the aforementioned isoquinoline compound, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(26) The above agent used to prevent and / or treat acute cerebral infarction.

(27) The above agent for the prevention and / or treatment, which improves the neurological symptoms associated with cerebral infarction.

(28) An inhibitor of poly (ADP-ribose) polymerase, comprising the aforementioned isoquinoline compound, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate.

(29) A compound selected from the group including:

(R) -3- (3-hydroxypyrrolidin-1-yl) -N-methyl-N-methoxypropanamide

(R) -N, N-diethyl-2- [4- (3-hydroxypyrrolidin-1-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-1-yl) -2-oxobutyl] -3-methylbenzamide

(R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin; and

(R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin hydrochloride.

(30) A method for producing a compound of the following formula (15):

Where

R ¹ represents a hydrogen atom, halogen atom, alkyl, alkoxy, haloalkyl, hydroxy, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, acylamino, diatsilamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N, N-dialkylsulfamoyl or alkoxyalkyloxy;

J ² represents dialkylamino;

Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; and

R is represented by the following formula (II):

Where

X represents CH or a nitrogen atom, provided that if Y is not present in the formula (I), then X represents CH;

W represents CH or a nitrogen atom; provided that if X represents CH, then W must represent a nitrogen atom;

s represents an integer from 1 to 5;

t represents an integer from 1 to 5;

if R ³ represents a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, optionally having a substituent, benzoylamino, optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, then R ² and R ^{2 'are the} same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R ³ is hydroxyalkyl, then R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group, an alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R ² and R ^2' taken together form a ketone,

which includes the implementation of the interaction of the compounds of the following formula (11 '):

where R ¹ and J ² have the above meanings, with a compound of the following formula (14):

where Y and R are as defined above and J ³ is N-alkyl-N-alkoxyamino.

(31) A process for preparing a compound of the following formula (16):

Where

R ¹ represents a hydrogen atom, a halogen atom, an alkyl, alkoxy, haloalkyl, hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, acylamino, diacylamino alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N, N-dialkylsulfamoyl or alkoxyalkyloxy;

Y is absent or represents an alkylene chain containing 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; and

R is represented by the following formula (II):

Where

X represents CH or a nitrogen atom, provided that if Y is not present in the formula (I), then X represents CH;

W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom;

s represents an integer from 1 to 5;

t represents an integer from 1 to 5;

if R ³ represents a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, optionally having a substituent, benzoylamino, optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R ² and R ^{2 'are the} same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R ³ is hydroxyalkyl, then R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group, an alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R ² and R ^2' taken together form a ketone,

which includes the use of a compound of the following formula (15):

where J ² represents dialkylamino, and R ¹ , Y and R have the above meanings.

(32) A method for producing a compound represented by the following formula (I):

Where

R ¹ represents a hydrogen atom, a halogen atom, an alkyl, alkoxy, haloalkyl, hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, acylamino, diacylamino alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N, N-dialkylsulfamoyl or alkoxyalkyloxy;

Y is absent or represents an alkylene chain containing 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; and

R is represented by the following formula (II):

Where

X represents CH or a nitrogen atom, provided that if Y is not present in the formula (I), then X must represent CH;

W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom;

s represents an integer from 1 to 5;

t represents an integer from 1 to 5;

if R ³ represents a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, optionally having a substituent, benzoylamino, optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, R ² and R ^{2 'are the} same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R ³ is hydroxyalkyl, then R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group, an alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R ² and R ^2' taken together form a ketone,

which includes the use of a compound of formula (16):

Where

R ¹ represents a hydrogen atom, a halogen atom, an alkyl, alkoxy, haloalkyl, hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, acylamino, diacylamino alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N, N-dialkylsulfamoyl or alkoxyalkyloxy;

Y is absent or represents an alkylene chain containing 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; and

R is represented by the following formula (II):

Where

X represents CH or a nitrogen atom, provided that if Y is not present in the formula (I), then X must represent CH;

W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom;

s represents an integer from 1 to 5;

t represents an integer from 1 to 5;

if R ³ represents a hydrogen atom, alkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, optionally having a substituent, benzoylamino, optionally having a substituent, arylalkyl, sulfamoyl or alkylsulfonylamino, then R ² and R ^{2 'are the} same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R ³ is hydroxyalkyl, then R ² and R ^{2 'are the} same or different, and each represents a hydrogen atom, a hydroxyl group, an alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylcarbamoyl, or R ² and R ^2' taken together form a ketone.

(33) A process for preparing the aforementioned isoquinoline compound, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate, which comprises the above steps.

(34) A method for producing the above isoquinoline compound, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate, which comprises the above steps.

Preferred Embodiment

Further, the present invention is explained in more detail.

The compound of formula (I) may be in the form of tautomers represented by the following formula (III). The present invention covers both tautomers.

Specific examples of each of the groups of the above formula (I) are as follows:

Specific examples of substituents for R ^{1 are} as follows, wherein the substituent may be on any of the ring carbon atoms:

halogen atom: fluorine atom, chlorine atom, bromine atom and iodine atom, fluorine atom, chlorine atom and bromine atom being preferred;

alkyl: a linear or branched alkyl chain containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like, with methyl being preferred;

alkoxy: alkoxy consisting of alkyl (as defined above) and an oxygen atom such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like, with methoxy being preferred;

haloalkyl: alkyl (as defined above) substituted with one or more halogen atoms (as defined above) such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, etc. n., trifluoromethyl being preferred;

dialkylamino: dialkylamino where the alkyl moieties are the same or different and each independently represents alkyl (as defined above) and the alkyl moieties may be ring-shaped. For example, dimethylamino, diethylamino, N-methyl-N-ethylamino, pyrrolidin-1-yl, piperidin-1-yl and the like can be mentioned, with dimethylamino being preferred;

acyl: acyl containing only 1 to 4 carbon atoms, which consists of alkyl (as defined above) and carbonyl, such as formyl, acetyl, propionyl, 2-methylpropionyl, butyryl, etc .;

alkoxycarbonyl: the ester consists of alkoxy (as defined above) and a carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like;

N-alkylcarbamoyl: N-alkylcarbamoyl consisting of monoalkylamino having from 1 to 4 carbon atoms and carbonyl such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl and the like;

N, N-dialkylcarbamoyl: N, N-dialkylcarbamoyl consisting of dialkylamino (as defined above) and carbonyl such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl .P.;

acylamino: an 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, where the acyl moieties are independent and may be the same or different, such as N, N-diacetylamino, N, N-dipropionylamino, N, N-dibutyrylamino, etc. .;

alkylthio: alkylthio consisting of alkyl (as defined above) and a sulfur atom such as methylthio, ethylthio, propylthio, butylthio and the like, with methylthio being preferred;

alkoxycarbonylamino: alkoxycarbonylamino consisting of alkoxycarbonyl (as defined above) and an amino such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino and the like;

N-alkylsulfamoyl: N-alkylsulfamoyl consisting of monoalkylamino (as defined above) and sulfone 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 sulfone, such as N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl .P.;

alkoxyalkyloxy: alkoxyalkyloxy consisting of alkoxy (as defined above), alkyl (as defined above) and oxygen, where alkoxy and alkyl are as defined above, such as methoxymethyloxy, ethoxymethyloxy and the like, with methoxymethyloxy being preferred.

Of the substituent positions for R ¹ , substitution at the 5-position or 7-position of the isoquinoline ring is preferred, especially substitution at the 5-position is particularly preferred.

Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent. For example, you can specify

(1) -CH (OH) CH ₂ -,

(2) -CH ₂ CH (OH) CH ₂ -,

(3) -CH ₂ CH ₂ CH (OH) CH ₂ -,

(4) -CH ₂ CH ₂ CH ₂ CH (OH) CH ₂ -,

(5) -CH ₂ CH ₂ CH ₂ CH ₂ CH (OH) CH ₂ -,

(6) -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH (OH) CH ₂ -,

(7) -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH (OH) CH ₂ -,

(8) -CH ₂ CH (CH ₂ OH) CH ₂ -,

(9) -CH ₂ CH (CH ₂ CH ₂ OH) CH ₂ -, and the like,

more preferably (2). As for the straight chain alkylene chain, ethylene and propylene are preferred.

Specific examples of substituents for R ² and R ^{2 ′} are as follows, wherein the substituent can be located on any of the ring carbon atoms:

alkyl: as defined above, alkyl for R ¹ ;

hydroxyalkyl: hydroxyalkyl consisting of alkyl (as defined above for R ¹ alkyl) and a hydroxyl group, with hydroxymethyl being preferred;

alkoxycarbonyl: alkoxycarbonyl consisting of alkoxy (alkoxy as defined above for R ¹⁾ and a carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like, preferably ethoxycarbonyl;

dialkylaminoalkyl: dialkylaminoalkyl consisting of dialkylamino (as defined above dialkylamino for R ¹ ) and alkyl (as defined above alkyl for R ¹ ), with dimethylaminomethyl being preferred;

dialkylcarbamoyl: dialkylcarbamoyl consisting of dialkylamino (as defined above dialkylamino for R ¹ ) and carbonyl, with dimethylcarbamoyl being preferred.

Specific examples of substituents for R ^{3 are} as follows:

alkyl: as defined above, alkyl for R ¹ , with methyl, ethyl, propyl and isobutyl being preferred, methyl being particularly preferred;

hydroxyalkyl: as defined above, hydroxyalkyl for R ² such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy-2-methylpropyl, 4-hydroxybutyl and the like, with hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxypropyl and 2 being preferred , 2-dimethyl-3-hydroxypropyl; hydroxymethyl and hydroxyethyl are particularly preferred;

monoalkylamino: as defined above monoalkylamino for R ¹ , with methylamino being preferred;

dialkylamino: as defined above, dialkylamino for R ¹ , with dimethylamino being preferred;

alkoxycarbonyl: as defined above alkoxycarbonyl for R ¹ , with ethoxycarbonyl being preferred;

alkylsulfonyl: alkylsulfonyl consisting of alkyl (as defined above for R ¹ alkyl) and sulfonyl, such as methanesulfonyl, ethanesulfonyl and the like;

acyl: as defined above, acyl for R ¹ ;

acylamino optionally having a substituent: as defined above acylamino for R ¹ , a group consisting of acyl containing from 1 to 4 carbon atoms and an amino group selected from formylamino, acetylamino, propionylamino, 2-methylpropionylamino and butyrylamino. Preferred substituents include halogen atoms (especially a fluorine atom). For example, trifluoroacetylamino, benzoylamino, optionally having a substituent, may be indicated: as substituents, those similar to those listed for R ¹ may be indicated;

arylalkyl: an arylalkyl consisting of aryl and alkyl (as defined above for acylamino for R ¹ ), such as benzyl, phenethyl and the like, with benzyl being preferred;

alkylsulfonylamino: alkylsulfonylamino consisting of alkylsulfonyl (as defined above) and amino, such as methanesulfonylamino, ethanesulfonylamino and the like, with methanesulfonylamino being preferred.

As the compound of formula (I) and a pharmaceutically acceptable salt thereof, inorganic acid or organic acid addition salts may be mentioned.

The compounds of formula (I) and their pharmaceutically acceptable salts may be in the form of their aqueous adducts, hydrates or solvates, and these aqueous adducts, hydrates and solvates are also included in the scope of the present invention. If the compound of formula (I) has an asymmetric atom, then at least two optical isomers are present. These optical isomers and mixtures thereof (including racemates) are included in the scope of the present invention.

The compounds described by formula (I) of the present invention can be synthesized in accordance with the following methods. In the following reaction schemes, each of the symbols has the above meanings, unless otherwise indicated.

Production Method 1

The compound of formula (11) obtained in a known manner is reacted with a compound of formula (12) obtained in a known manner in the presence of a suitable base commonly used in organic synthesis, such as n-butyllithium, lithium diisopropylamide, lithium diethylamide, lithium bistrimethylsilylamide and the like. , in a suitable solvent, one that does not inhibit the course of the reaction, such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, arbitrary mixtures thereof and the like, at a temperature of from -78 ° C to the boiling point of refluxing agent, preferably at a temperature of from -78 ° C to room temperature, for a period of time from 0.1 (6 minutes) to 48 hours, preferably from 1 hour to 24 hours, obtaining a compound of formula (13).

The method of obtaining 2

The compound of formula (13) can be obtained by synthesis according to the method disclosed in production method 1, using the compound of formula (11 ') obtained in a known manner, where J ² is amino, monoalkylamino (as defined above monoalkyl for R ³ ), or dialkylamino (as defined above dialkylamino for R ³ ) and the compound of formula (12) obtained in a known manner.

The method of obtaining 3

A compound of formula (11 ') is reacted with a compound of formula (14) wherein J ³ is N-alkyl-N-alkoxyamino or dialkylamino (as defined above dialkylamino for R ³ ), with N-methyl-N-methoxyamino being preferred in the presence of a suitable base commonly used in synthesis processes in organic chemistry, such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium diethylamide, lithium bistrimethylsilylamide and the like, in a suitable solvent mentioned above, which does not inhibit the reaction, at temperament round in the range from -78 ° C to the boiling point of the solvent under reflux for 0.1 (6 min) to 48 hours, obtaining the compound of formula (15). The compound of formula (15) is reacted in acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid or in an arbitrary mixture of these solvents, in the temperature range from room temperature to the boiling point of the solvent under reflux, for a period of time from 0, 1 (6 min) up to 48 hours, obtaining a compound of formula (16). The compound of formula (16) is reacted with an ammonia source (e.g., an ammonia salt commonly used in organic chemistry synthesis processes, such as ammonium acetate, ammonium carbonate, ammonium chloride, aqueous ammonia, and the like) in a suitable solvent, such as which does not inhibit the course of the reaction (methanol, ethanol, n-propanol, isopropanol, n-butanol, dimethoxyethane, 2-methoxyethanol, acetic acid, aqueous ammonia, arbitrary mixture of these solvents, etc.), at a temperature in the range from room temperature temperature to the boiling point of the solvent under reflux for from 0.1 (6 min) to 48 hours, obtaining the compound of formula (13).

The compound of the present invention thus obtained can be isolated or purified in accordance with conventional methods.

The compounds of the present invention described by formula (I) can also be synthesized using the following intermediates.

For example, (R) -3- (2-hydroxymethylpyrrolidin-1-yl) propionitrile, (R) -3- (3-hydroxypyrrolidin-1-yl) propionitrile, (S) -3- (3-hydroxypyrrolidin-1-yl ) propionitrile, (R) -3- (3-hydroxypyrrolidin-1-yl) -N-methyl-N-methoxypropanamide, (R) -N, N-diethyl-2- [4- (3-hydroxypyrrolidin-1-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-1-yl) -2-oxobutyl] -3-methylbenzamide, (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin and (R) -3- [2- (2-hyd roxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin are new compounds and can be used as intermediates for the synthesis of compounds of formula (I) of the present invention, (1) (R) -3- [2- (3-hydroxypyrrolidine -1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (34) (S) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H- isoquinolin-1-one; and (36) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one.

In addition, (1) (R) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (34) (S) -3- [2 - (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one and (36) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5 The methyl-2H-isoquinolin-1-one of formula (I) of the present invention can be synthesized by reacting (R) -3- (2-hydroxymethylpyrrolidin-1-yl) propionitrile, (R) -3- (3-hydroxypyrrolidin-1 -yl) propionitrile or (S) -3- (3-hydroxypyrrolidin-1-yl) propionitrile with N, N-diethyl-2,3-dimethylbenzamide or N, N-dimethyl-2,3-dimethylbenzamide according to the production method one.

The compound of formula (I), its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate, obtained by the methods described above, have effective PARP inhibitory activity, and can be used as prophylactic and / or therapeutic agents that relieve cerebral infarction, especially agents for the prevention and / or treatment of acute cerebral infarction. In addition, they can be used as prophylactic and / or therapeutic agents that alleviate neurological symptoms associated with cerebral infarction, especially symptoms of acute cerebral infarction. In addition, neurological symptoms associated with cerebral infarction, especially acute cerebral infarction, can be assessed by counting according to the NIH infarction score scale (Stroke Scale) (Brott T, et al .; Measurement of acute cerebral infarction: a clinical examination scale. Stroke vol. 20, pp. 864-870 (1989)) established by the US National Institute of Health (NIH).

If the isoquinoline compound, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate in accordance with the present invention are used as a pharmaceutical agent, the compound of the present invention can be administered orally or parenterally in the form of a pharmaceutical composition or preparation (tablets , pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions, solutions, solutions for injection, infusion, suppositories, etc.) obtained by mixing with a pharmaceutical an eutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifying agent, diluent, dissolution promoting agents, and the like). The pharmaceutical composition can be created in accordance with conventional methods. In this description, parenteral administration methods include subcutaneous injections, intravenous injections, intraperitoneal injections, droppers, and the like. Injectable preparations can be prepared in accordance with methods known to those skilled in the art. Suppositories for rectal administration can be prepared by mixing drugs with suitable excipients and the like. As dosage forms of solid preparations for oral administration, such as powders, granules, tablets, pills, capsules, and the like can be mentioned. As liquid preparations for oral administration, emulsions, syrups, elixirs, suspensions, solutions, and the like, applicable as pharmaceutical agents can be mentioned.

The dose is determined taking into account age, body weight, general health, gender, diet, time of administration, route of administration, frequency of excretion, combination of drugs, disease state of the patient to be treated, and other factors. The compounds of the present invention, their optical isomers and their pharmaceutically acceptable salts have low toxicity and are safe to use. Although the daily dose varies depending on the condition and body weight of the patient, the type of compound administered, the route of administration, etc., for example, it is desirable to administer parenterally (subcutaneously, intravenously, intramuscularly or rectally) about 0.01-50 mg / individual / day, preferably 0.01-20 mg / individual / day, and orally about 0.01-150 mg / individual / day, preferably 0.1-100 mg / individual / day.

EXAMPLES

Further, the present invention is explained in more detail with reference to examples, which should not be construed as limiting within the scope of the invention. The value of J is expressed in Hz.

Obtaining the starting compounds. Example 1

(R) -2-hydroxymethylpyrrolidine (Tokyo Kasei Kogyo Co., Ltd.) (50 g) was dissolved in methylene chloride (500 ml), and acrylonitrile (36 ml) was added dropwise with stirring at room temperature. The mixture was then stirred overnight at room temperature. After completion of the reaction, the solvent was concentrated to obtain (R) -3- (2-hydroxymethylpyrrolidin-1-yl) propionitrile (76 g).

¹ H-NMR (CDCl ₃ ) δ: 1.61-1.94 (5H, m), 2.33 (1H, q, J = 8 Hz), 2.53 (2H, dd, J = 6 Hz, 8 Hz), 2.61-2.71 (2H, m), 3.01-3.10 (1H, m), 3.16-3.24 (1H, m), 3.37-3.46 (1H, m), 3.64 (1H, dd, J = 3 Hz, 11 Hz).

Obtaining the starting compounds. Example 2

(R) - (-) - 3-pyrrolidinol hydrochloride (Tokyo Kasei Kogyo Co., Ltd.) (50 g) and potassium carbonate (55.8 g) are dissolved in a mixed solvent consisting of acetonitrile (500 ml) and water ( 100 ml), and acrylonitrile (29 ml) was added dropwise to the solution at room temperature. The mixture was then stirred overnight at room temperature. After completion of the reaction, the solvent was concentrated, and the obtained residue was dissolved in water. Potassium carbonate is added until saturated. The mixture was extracted three times with chloroform and the extract was dried over potassium carbonate. The solvent was concentrated and the obtained residue was purified using a silica gel chromatography column (chloroform: methanol = 10: 1) to obtain (R) -3- (3-hydroxypyrrolidin-1-yl) propionitrile (53 g).

¹ H-NMR (CDCl ₃ ) δ: 1.68-1.81 (1H, m), 2.04-2.10 (1H, m), 2.13-2.27 (1H, m), 2 , 34-2.43 (1H, m), 2.51-2.63 (3H, m), 2.72-2.84 (3H, m), 2.91-2.99 (1H, m) 4.30-4.40 (1H, m).

Obtaining the starting compounds. Example 3

Carrying out the reaction similarly to the method of obtaining the starting compounds of example 1, using (S) - (+) - 3-pyrrolidinol (Omega Corporation) (12.3 g) and acrylonitrile (10.2 ml), (S) -3- (3 -hydroxypyrrolidin-1-yl) propionitrile (53 g).

¹ H-NMR (CDCl ₃ ) δ: 1.68-1.81 (1H, m), 2.04-2.10 (1H, m), 2.13-2.27 (1H, m), 2 , 34-2.43 (1H, m), 2.51-2.63 (3H, m), 2.72-2.84 (3H, m), 2.91-2.99 (1H, m) 4.30-4.40 (1H, m).

Obtaining the starting compounds. Example 4

N, O-dimethylhydroxylamine hydrochloride (198.6 g), sodium bicarbonate (620.9 g), methylene chloride (1.5 L) and water (1.1 L) were mixed and acryl chloride (150 ml) was added dropwise at ice cooling. The mixture was stirred under ice cooling for 4 hours and the methylene chloride layer was isolated. The organic layer was dried over magnesium sulfate and the solvent was concentrated to obtain N-methyl-N-methoxyacrylamide (223.79 g). This compound is used in the next step without further purification.

¹ H-NMR (CDCl ₃ ) δ: 3.27 (3H, s), 3.71 (3H, s), 5.76 (1H, dd, J = 2 Hz, 11 Hz), 6.43 (1H , dd, J = 2 Hz, 17 Hz), 6.74 (1H, dd, J = 11 Hz, 17 Hz).

Obtaining the starting compounds. Example 5

(R) - (-) - 3-pyrrolidinol hydrochloride (51.8 g), potassium carbonate (69.6 g), water (125 ml) and acetonitrile (500 ml) were mixed and the mixture was stirred at room temperature for 1 hour . A solution (60 ml) of N-methyl-N-methoxyacrylamide (42 g) in acetonitrile obtained in Example 4 for the preparation of the starting compounds was added dropwise to the mixture, and the reaction mixture was left overnight at room temperature. After completion of the reaction, acetonitrile was concentrated under reduced pressure, and potassium carbonate was added in excess to the remaining aqueous layer. The aqueous layer was extracted with chloroform, the extract was dried over magnesium sulfate and concentrated to give (R) -3- (3-hydroxypyrrolidin-1-yl) -N-methyl-N-methoxypropanamide (76.7 g).

¹ H-NMR (CDCl ₃ ) δ: 1.65-1.75 (1H, m), 2.10-2.25 (1H, m), 2.36 (1H, dd, J = 8.79 Hz , 15.2 Hz), 2.60-2.70 (4H, m), 2.75-2.80 (2H, m), 2.80-2.90 (3H, m), 3.18 ( 3H, s), 3.48 (1H, br s), 3.70 (3H, s), 4.33-4.35 (1H, m).

Obtaining the starting compounds. Example 6

In a stream of nitrogen, diisopropylamine (63.8 ml) and tetrahydrofuran (90 ml) 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 minutes. 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, the mixture was stirred at -78 ° C for 1 hour . Then, a solution (120 ml) of (R) -3- (3-hydroxypyrrolidin-1-yl) -N-methyl-N-methoxypropanamide (38.6 g) obtained in Example 5 for the preparation of the starting compounds in tetrahydrofuran was added dropwise. The temperature is gradually raised to room temperature and the reaction mass is left overnight. After 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) .

¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.2 Hz), 1.21 (3H, t, J = 7.2 Hz), 1.65-1.80 ( 1H, m), 2.10-2.30 (2H, m), 2.21 (3H, 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), 3.30-3.40 (1H, 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).

Obtaining the starting compounds. Example 7

(R) -N, N-diethyl-2- [4- (3-hydroxypyrrolidin-1-yl) -2-oxobutyl] -3-methylbenzamide (124 g) obtained in Example 6 for the preparation of the starting compounds is dissolved in 25% (vol./about.) an aqueous solution of sulfuric acid (600 ml) and the resulting solution is heated at the boil under reflux for 12 hours. After completion of the reaction, the reaction mixture was washed with chloroform and the aqueous layer was made alkaline with potassium carbonate. Chloroform is added and insoluble materials are removed by filtration through celite. 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 filtered under vacuum to obtain (R) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methylisocoumarin ( 55.6 g).

¹ H-NMR (CDCl ₃ ) δ: 1.65-1.80 (1H, m), 2.10-2.25 (1H, m), 2.30-2.40 (1H, m), 2 46 (3H, s), 2.56-2.61 (1H, m), 2.74-2.78 (1H, m), 2.85-2.96 (3H, m), 4.32 -4.36 (1H, m), 6.43 (1H, s), 7.34 (3H, t, J = 7.5 Hz), 7.51 (1H, d, J = 7.5 Hz) 8.12 (1H, d, J = 7.5 Hz).

Obtaining the starting compounds. Example 8

D-prolinol (30 g) and tetrahydrofuran (300 ml) were mixed and N-methyl-N-methoxyacrylamide (28.7 g) was added to the resulting mixture with stirring at room temperature. After completion of the reaction, the reaction mixture was concentrated, obtaining in quantitative yield (R) -3- (2-hydroxymethylpyrrolidin-1-yl) -N-methyl-N-methoxypropanamide as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.62-1.89 (4H, m), 2.22-2.30 (1H, m), 2.48-2.80 (4H, m), 3 , 16-3.48 (6H, m), 3.18 (3H, s), 3.65-3.71 (1H, m), 3.70 (3H, s).

Obtaining the starting compounds. Example 9

Diisopropylamine (104 ml) and tetrahydrofuran (500 ml) are mixed and a solution (457 ml, 1.56 mol / l) of n-butyllithium in hexane is added dropwise with stirring at -78 ° C in a stream of nitrogen. After completion of the dropwise addition, the mixture was stirred at 0 ° C for 30 minutes and cooled again to -78 ° C. A solution of N, N-diethyl-2,3-dimethylbenzamide (67.0 g) in tetrahydrofuran (150 ml) was added dropwise to the reaction mixture. After completion of the dropwise addition, the mixture was further stirred at −78 ° C. for 1 hour. A solution of (R) -3- (2-hydroxymethylpyrrolidin-1-yl) -N-methyl-N-methoxypropanamide (64 g) obtained in Example 8 for the preparation of the starting compounds in tetrahydrofuran (150 ml) was added dropwise. After completion of the dropwise addition, the mixture was further stirred at −78 ° C. for 1 hour. The mixture is gradually warmed to room temperature. After completion of the reaction, ice and water were added to the reaction mixture, and the organic layer was isolated. The organic layer was concentrated, combined with the aqueous layer obtained above, and the combined layers were extracted twice with chloroform. The organic layer was concentrated to give (R) -N, N-diethyl-2- [4- (2-hydroxymethylpyrrolidin-1-yl) -2-oxobutyl] -3-methylbenzamide as an oil. This compound is used in the next reaction without further purification.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7 Hz), 1.21 (3H, t, J = 7 Hz), 1.62-1.94 (4H, m) , 2.12-2.22 (1H, m), 2.21 (3H, s), 2.36-2.44 (1H, m), 2.52-2.63 (2H, 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).

Obtaining the starting compounds. Example 10

The entire amount of (R) -N, N-diethyl-2- [4- (2-hydroxymethylpyrrolidin-1-yl) -2-oxobutyl] -3-methylbenzamide obtained in Example 9 for the preparation of the starting compounds is dissolved in concentrated hydrochloric acid ( 250 ml) and water (250 ml) and the resulting solution was heated at the boil under reflux for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and washed with toluene (200 ml). To alkalize the layer, an aqueous solution of potassium carbonate (300 g) was added to the aqueous layer and the resulting layer was extracted twice with chloroform, the extract was dried over magnesium sulfate. The solvent was concentrated, and acetone was added to the resulting residue. The mixture was further concentrated to give (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin (67 g).

¹ H-NMR (CDCl ₃ ) δ: 1.66-1.92 (4H, 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 = 4 Hz, 11 Hz), 3.64 (1H, dd, J = 4 Hz , 11 Hz), 6.43 (1H, s), 7.34 (1H, t, J = 8 Hz), 7.51 (1H, d, J = 8 Hz), 8.12 (1H, d, J = 8 Hz).

Using a known method, (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin is converted to the hydrochloride to give the hydrochloride of (R) -3- [2- (2-hydroxymethylpyrrolidin-1- il) ethyl] -5-methylisocoumarin.

¹ H-NMR (DMCO-d ₆ ) δ: 1.70-2.18 (4H, m), 2.47 (3H, s), 3.08-3.22 (3H, m), 3.60 -3.85 (5H, m), 5.51 (1H, br.s), 6.82 (1H, s), 7.47 (1H, t, J = 8 Hz), 7.69 (1H, d, J = 7 Hz), 7.99 (1H, d, J = 8 Hz), 10.31 (1H, br.s).

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 minutes, 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 hour. 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 completion of the reaction, water was added to the reaction mixture, the organic layer was isolated and concentrated. The residue was dissolved in chloroform, the solution was washed with brine and dried over magnesium sulfate. The organic layer was extracted with 1N. hydrochloric acid and the resulting layer is alkalinized. 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 using a silica gel chromatography column to obtain (R) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (23.6 d).

¹ H-NMR (CDCl ₃ ) δ: 1.83-1.96 (1H, m), 2.21-2.32 (1H, m), 2.48 (3H, s), 2.49-2 55 (1H, m), 2.72-2.79 (3H, m), 2.81-2.92 (3H, m), 2.96-3.05 (1H, m), 4.42 -4.49 (1H, m), 6.33 (1H, s), 7.29 (1H, t, J = 8 Hz), 7.43 (1H, d, J = 7 Hz), 8.22 (1H, d, J = 8 Hz), 11.40 (1H, br.s).

MS (EI) 272 (M +).

Using a known method, (R) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one is converted to the hydrochloride to give (R) -3- [2 hydrochloride - (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one.

¹ H-NMR (DMCO-d ₆ ) δ: 1.83-2.00 (1.5H, m), 2.15-2.30 (0.5H, m), 2.48 (3H, m) 2.96-3.10 (2.5H, m), 3.14-3.66 (5.5H, m), 4.37-4.50 (1H, m), 5.55 (1H, broad c), 6.52 (0.5H, s), 6.54 (0.5H, s), 7.34 (1H, t, J = 8 Hz), 7.53 (1H, d, J = 7 Hz), 8.02 (1H, d, J = 8 Hz), 10.70 (0.5H, br.s), 11.27 (0.5H, br.s), 11.43 (0 5H, broad s), 11.46 (0.5H, broad s).

MS (EI) 272 (M +).

[α] _D = -3.52 ° (c = 1.15, MeOH).

The following is another method for the preparation of (R) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one.

Ammonium carbonate (65.3 g) was gradually added to acetic acid (165 ml). After completion of the gas evolution, (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 hour. After completion of the reaction, the reaction mixture was cooled to room temperature and sodium hydroxide (115 g) was added to an aqueous solution (300 ml) (heat was released and an ammonia smell appeared). The mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was extracted with chloroform, the extract was dried over magnesium sulfate and concentrated. Ethyl acetate was added to the obtained residue, and the resulting suspension was washed. As a result of filtration, (R) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (45.1 g) was collected.

Example 2

5-Methyl-3- (piperidin-4-yl) -2H-isoquinolin-1-one (1.0 g), sodium bicarbonate (0.52 g) and 2-bromoethanol (0.67 g) are dissolved in acetonitrile ( 20 ml) and the solution is heated at the boil under reflux. After 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 using a silica gel chromatography column to obtain 3- [1- (2-hydroxyethyl) piperidin-4-yl] -5-methyl-2H-isoquinolin-1-one (0.4 g).

¹ H-NMR (CDCl ₃ ) δ: 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 = 5 Hz), 6, 44 (1H, s), 7.34 (1H, t, J = 7 Hz), 7.48 (1H, d, J = 7 Hz), 8.24 (1H, d, J = 7 Hz), 10 72 (1H, broad s).

MC (EI) 286 (M +).

Example 3

By carrying out the reaction according to the method of example 1, using N, N-diethyl-2-methylbenzamide (3.45 g) and 4- (3-hydroxypyrrolidin-1-yl) butyronitrile (1.5 g), 3- [3- (3- hydroxypyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one (536.3 mg).

¹ H-NMR (CDCl ₃ ) δ: 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 (1H, br.s), 6 32 (1H, s), 7.35-7.45 (2H, m), 7.56-7.62 (1H, m), 8.34 (1H, d, J = 8 Hz), 14, 41 (1H, broad s).

MS (EI) 272 (M +).

Example 4

By carrying out the reaction according to the method of example 1, using N, N-dimethyl-2,3-dimethylbenzamide (2.00 g) and 4- (3-hydroxypyrrolidin-1-yl) butyronitrile (0.8 g), 3- [3 - (3-hydroxypyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one (157.5 mg).

¹ H-NMR (CDCl ₃ ) δ: 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 (1H, m), 5.86 (1H, br.s), 6.43 (1H, s), 7.27-7.32 (1H, m), 7.44 (1H, br, J = 7 Hz), 8.22 (1H , br., J = 8 Hz), 14.45 (1H, br. c).

MC (EI) 286 (M +).

Example 5

By carrying out the reaction according to the method of 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-1-one (157.5 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.88-1.99 (1H, m), 2.22-2.38 (1H, m), 2.48-2.57 (4H, m), 2 , 71-2.95 (6H, m), 3.01-3.10 (1H, m), 3.51 (1H, br.s), 4.42-4.51 (1H, m), 6 34 (1H, s), 7.27-7.31 (1H, m), 7.43 (1H, br, J = 7 Hz), 8.22 (1H, br, J = 8 Hz) 11.42 (1H, broad s).

MC (EI) 272 (M +).

Example 6

By carrying out the reaction according to the method of example 1, using N, N-diethyl-2,3-dimethylbenzamide (4.347 g) and 3- (3-hydroxypyrrolidin-1-yl) propionitrile (1.6 g), 3- [2- ( 3-hydroxypyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one (397.6 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.84-1.97 (1H, m), 2.21-2.37 (1H, m), 2.43-2.55 (1H, m), 2 70-2.82 (3H, m), 2.82-2.95 (3H, m), 3.00-3.11 (1H, m), 4.44-4.50 (1H, m) 6.25 (1H, s), 7.38-7.45 (1H, m), 7.57-7.62 (1H, t, J = 7 Hz), 8.34 (1H, d, J = 8 Hz), 11.41 (1H, broad s).

MC (EI) 258 (M +).

Example 7

By carrying out the reaction according to the method of example 1, using N, N-dimethyl-2,3-dimethylbenzamide (3.17 g) and 3- (2-hydroxymethylpiperidin-1-yl) propionitrile (1.51 g), 3- [2 - (2-hydroxymethylpiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (268 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 11.5 (br s, 1H), 8.24 (d, J = 8.1, 1H), 7.49 (d, J = 8.1 , 1H), 7.30 (t, J = 8.1, 1H), 6.39 (s, 1H), 3.65-3.80 (m, 2H), 3.30 (br s, 1H ), 3.10-3.30 (m, 1H), 3.00-3.10 (m, 1H), 2.85-3.00 (m, 1H), 2.70-2.85 (m , 2H), 2.50 (s, 3H), 2.35-2.60 (m, 2H), 1.30-1.75 (m, 6H).

MC (EI) 300 (M +).

Example 8

By carrying out the reaction according to the method of 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] -2H-isoquinolin-1-one (392 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 11.5 (br s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7, 8 Hz, 1H), 7.39-7.46 (m, 2H), 6.29 (s, 1H), 3.65-3.85 (m, 2H), 3.30 (br.s, 1H ), 3.10-3.30 (m, 1H), 3.00-3.10 (m, 1H), 2.85-3.00 (m, 1H), 2.70-2.80 (m , 2H), 2.45-2.60 (m, 1H), 2.30-2.45 (m, 1H), 1.30-1.75 (m, 6H).

MC (EI) 286 (M +).

Example 9

Carrying out the reaction according to the method of example 2, using 3- (piperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (1.1 g) and 2-bromoethanol (1.0 g) as starting compounds, 3- [1- (2-hydroxyethyl) piperidin-4-yl] -2H-isoquinolin-1-one (0.39 g).

¹ H-NMR (CDCl ₃ ) δ: 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 (1H, m), 8.34-8.38 (1H, m), 10.69 (1H, br.s).

MC (EI) 272 (M +).

Example 10

By carrying out the reaction according to the method of example 2, using 3- (piperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (500 mg) and 3-bromo-1-propanol (315 mg), 3- [1- ( 3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one (136 mg).

¹ H-NMR (270 MHz, DMCO-d ₆ ) δ: 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), 7.42-7.47 (1H, m), 7.66-7.71 (2H, m ), 8.13 (1H, d, J = 7.8 Hz), 11.31 (1H, br s).

MC (EI) 286 (M +).

Example 11

By carrying out the reaction according to the method of example 2, using 3- (piperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (500 mg) and 4-bromo-1-butanol (434 mg), 3- [1- ( 4-hydroxybutyl) piperidin-4-yl] -2H-isoquinolin-1-one (50 mg).

¹ H-NMR (270 MHz, DMCO-d ₆ ) δ: 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 (2H, m), 3.40-3.42 (2H, m), 4.55-4.65 (1H, m), 6.36 (1H, s), 7.38-7.43 (1H, m), 7.57-7.65 (2H, m), 8.12 (1H, d, J = 7.8 Hz), 11.20 (1H, br s).

MC (EI) 300 (M +).

Example 12

By carrying out the reaction according to the method of example 1, using N, N-diethyl-2-methylbenzamide (1.91 g) and 3-hydroxy-4- (pyrrolidin-1-yl) butyronitrile (1.54 g), 3- [2 -hydroxy-3- (pyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one (0.089 g).

¹ H-NMR (CDCl ₃ ) δ: 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, t, J = 8 Hz), 8.36 (1H, d, J = 8 Hz), 9 85 (1H, broad s).

MC (EI) 272 (M +).

Example 13

By carrying out the reaction as in Example 1, using N, N-dimethyl-2,3-dimethylbenzamide (2.65 g) and 3-hydroxy-4- (pyrrolidin-1-yl) butyronitrile (2.31 g), 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one (0.066 g).

¹ H-NMR (CDCl ₃ ) δ: 1.75-1.84 (4H, m), 2.32-2.90 (8H, m), 2.39 (3H, s), 4.06-4 11 (1H, m), 6.36 (1H, s), 7.28 (1H, t, J = 8 Hz), 7.42 (1H, d, J = 8 Hz), 8.19 (1H d, J = 8 Hz), 10.00 (1H, br.s).

MC (EI) 286 (M +).

Example 14

Carrying out the reaction according to the method of example 1, using N, N-dimethyl-2,3-dimethylbenzamide (4.60 g) and (S) -3- (2-hydroxymethyl) pyrrolidin-1-yl) propionitrile (2.01 g) give (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (351 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 12.4 (br s, 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 (br s, 1H), 3.76 (d, J = 14.1 , 1H), 3.56 (d, J = 14.1, 1H), 3.35-3.50 (m, 1H), 3.10-3.25 (m, 1H), 2.85-2 95 (m, 2H), 2.70-2.80 (m, 1H), 2.60-2.70 (m, 1H), 2.50 (s, 3H), 2.40-2.45 (m, 1H), 1.80-2.00 (m, 4H).

MC (EI) 286 (M +).

Example 15

Carrying out the reaction according to the method of example 1, using N, N-diethyl-2-methylbenzamide (4.96 g) and (S) -3- (2-hydroxymethyl) pyrrolidin-1-yl) propionitrile (2.00 g), get (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one (515 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 12.4 (br s, 1H), 8.35 (d, J = 7.8, 1H), 7.59-7.64 (m, 1H ), 7.35-7.50 (m, 2H), 6.28 (s, 1H), 4.06 (br s, 1H), 3.76 (d, J = 14.1, 1H), 3.55 (d, J = 14.1, 1H), 3.35-3.45 (m, 1H), 3.10-3.25 (m, 1H), 2.80-3.00 (m , 2H), 2.65-2.80 (m, 1H), 2.55-2.65 (m, 1H), 2.35-2.45 (m, 1H), 1.70-2.00 (m, 4H).

MC (EI) 272 (M +).

Example 16

Carrying out the reaction according to the method of example 1, using N, N-dimethyl-2,3-dimethylbenzamide (4.84 g) and (S) -4- (2-hydroxymethyl) pyrrolidin-1-yl) butyronitrile (2.30 g) give (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one (363 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 12.1 (br s, 1H), 8.23 (d, J = 8.1, 1H), 7.46 (d, J = 8.1 , 1H), 7.28-7.34 (m, 1H), 6.44 (s, 1H), 5.16 (br s, 1H), 3.80 (d, J = 14.1, 1H ), 3.60 (d, J = 14.1, 1H), 3.20-3.30 (m, 1H), 2.80-3.00 (m, 2H), 2.60-2.80 (m, 2H), 2.51 (s, 3H), 2.40-2.45 (m, 1H), 2.20-2.35 (m, 1H), 1.70-2.05 (m , 6H).

MC (EI) 300 (M +).

Example 17

Carrying out the reaction according to the method of example 1, using N, N-diethyl-2-methylbenzamide (5.23 g) and (S) -4- (2-hydroxymethyl) pyrrolidin-1-yl) butyronitrile (2.30 g), get (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one (331 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 12.2 (br s, 1H), 8.34 (d, J = 8.1, 1H), 7.59-7.64 (m, 1H ), 7.39-7.48 (m, 2H), 6.34 (s, 1H), 5.05 (br s, 1H), 3.80 (d, J = 14.1, 1H), 3.60 (d, J = 14.1, 1H), 3.15-3.20 (m, 1H), 2.70-2.85 (m, 2H), 2.60-2.70 (m , 2H), 2.40-2.55 (m, 1H), 2.20-2.35 (m, 1H), 1.70-2.10 (m, 6H).

Example 18

Carrying out the reaction according to the method of example 1, using N, N-diethyl-2,3-dimethylbenzamide (5.0136 g) and (R) -4- (2-hydroxymethylpyrrolidin-1-yl) butyronitrile (2.2 g), get (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one (627.3 mg). To this add 1N. an aqueous solution of HCl (2.4 ml) in an acetone solvent and the precipitated crystals are filtered off to obtain (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one hydrochloride ( 555.3 mg).

¹ H-NMR (CD ₃ OD) δ: 1.83-2.25 (7H, m), 2.68-2.73 (2H, m), 3.08-3.22 (2H, m), 3.43-3.70 (4H, m), 3.85-3.90 (1H, m), 6.54 (1H, s), 7.45-7.50 (1H, m), 7, 59 (1H, d, J = 8 Hz), 7.70 (1H, t, J = 8 Hz), 8.24 (1H, d, J = 8 Hz).

MC (EI) 286 (M +).

Example 19

By carrying out the reaction according to the method of example 1, using N, N-diethyl-2,3-dimethylbenzamide (5.6017 g) and 3- (4-hydroxypiperidin-1-yl) propionitrile (2.26 g), 3- [2 - (4-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-one (327.5 mg).

¹ H-NMR (CDCl ₃ ) δ: 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 (1H, m), 8.30 (1H, d, J = 8 Hz), 11.37 (1H, br.s).

MC (EI) 272 (M +).

Example 20

By carrying out the reaction according to the method of example 1, using N, N-diethyl-2,3-dimethylbenzamide (4.975 g) and (R) -3- (2-hydroxymethylpyrrolidin-1-yl) propionitrile (2.0 g), (R ) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one (408.4 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.75-2.00 (3H, m), 2.36-2.48 (1H, m), 2.59-2.78 (2H, m), 2 83-2.96 (2H, m), 3.11-3.23 (1H, m), 3.35-4.45 (1H, m), 3.50-3.62 (1H, m) , 3.71-3.81 (1H, m), 4.02 (1H, broad s), 6.29 (1H, s), 7.39-7.50 (2H, m), 7.58 -7.64 (1H, m), 8.35 (1H, d, J = 8 Hz), 12.41 (1H, br.s).

MC (EI) 272 (M +).

Example 21

Ethyl chloroformate (3.45 ml) was added dropwise to 2-N-tert-butoxycarbonyl-4-hydroxypipecolic acid (7.96 g) in the presence of triethylamine in tetrahydrofuran under ice-cooling to give mixed acid anhydride. The precipitated salt is filtered off and the resulting filtrate is again cooled with ice. 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 is washed with 0.5n. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was concentrated to obtain ethyl 2-N-tert-butoxycarbonyl-4-oxopipecolate (6.39 g).

The resulting ethyl 2-N-tert-butoxycarbonyl-4-oxopipecolate (6.39 g) was dissolved in 1,3-dimethyl-2-imidazolidinone and ethanol. Tosylmethylisocyanide (5.30 g) was added and the mixture was cooled to -78 ° C. Potassium tert-butoxide (6.09 g) was carefully added so that the temperature of the mixture did not rise 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 brine and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the solvent is concentrated. The residue was purified using a silica gel chromatography column (n-hexane: ethyl acetate = 4: 1) to obtain ethyl 2-N-tert-butoxycarbonyl-4-cyanopipecolate (1.21 g).

The resulting ethyl 2-N-tert-butoxycarbonyl-4-cyanopipecolate (1.21 g) was dissolved in tetrahydrofuran and the solution was cooled with water. Lithium borohydride (279 mg) was added and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the extract was washed with brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was concentrated to obtain (N-tert-butoxycarbonyl-2-hydroxymethyl-4-cyano) piperidine (961 mg).

By carrying out the reaction according to the method of example 1, using (N-tert-butoxycarbonyl-2-hydroxymethyl-4-cyano) piperidine (1.14 g) and N, N-diethyl-2-methylbenzamide (1.84 g), 3- (1-tert-butoxycarbonyl-2-hydroxymethylpiperidin-4-yl) -2H-isoquinolin-1-one (616 mg).

The resulting 3- (1-tert-butoxycarbonyl-2-hydroxymethylpiperidin-4-yl) -2H-isoquinolin-1-one (616 mg) was dissolved in ethyl acetate and 4N was added to the solution. a solution of hydrogen chloride in ethyl acetate (2.0 ml) and the mixture was stirred at room temperature for 6.5 hours. The reaction mixture was concentrated and the precipitated crystals were washed with diethyl ether and dried under reduced pressure to obtain 3- (2-hydroxymethylpiperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (433 mg).

The resulting 3- (2-hydroxymethylpiperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (433 mg) was dissolved in acetonitrile and water. 35% formalin (340 μl) and sodium triacetoxyborohydride (697 mg) were added to the solution, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was made basic with a 20% aqueous potassium carbonate solution and extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the solvent is concentrated. The precipitated crystals were washed with diethyl ether and dried under reduced pressure to obtain 3- (1-methyl-2-hydroxymethylpiperidin-4-yl) -2H-isoquinolin-1-one (146 mg).

¹ H-NMR (300 MHz, DMCO-d ₆ ) δ: 11.1 (br s, 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 (br s, 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).

MC (EI) 272 (M +).

Example 22

Carrying out the reaction according to the method of example 2, using 3- (piperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (510 mg) and 3-bromo-2,2-dimethyl-1-propanol (474 mg), 3- [1- (3-hydroxy-2,2-dimethylpropyl) piperidin-4-yl] -2H-isoquinolin-1-one (92 mg).

¹ H-NMR (270 MHz, DMCO-d ₆ ) δ: 0.79 (6H, s), 1.54-1.63 (2H, m), 1.89-1.93 (2H, m), 2.64-2.65 (1H, m), 2.70-3.00 (2H, m), 3.13-3.20 (2H, m), 3.78-3.79 (2H, m) ), 4.10-4.14 (2H, m), 4.14-4.60 (1H, m), 6.38 (1H, s), 7.39-7.44 (1H, m), 7.57-7.65 (2H, m), 8.12 (1H, d, J = 8.1 Hz), 11.25 (1H, br.s).

MC (EI) 314 (M +).

Example 23

Carrying out the reaction according to the method of example 2, using 5-methyl-3- (piperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (1 g) and 3-bromo-1-propanol (751 mg), 5- methyl-3- [1- (3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one (221 mg).

Melting point: 197-199 ° C.

¹ H-NMR (270 MHz, DMCO-d ₆ ) δ: 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 (2H, m), 3.15-3.18 (1H, m), 3.43-3.48 (2H, m), 4.48-4.49 (1H, m), 6.35 (1H, s), 7.26-7.31 (1H, m), 7.49 (1H, d, J = 7.0 Hz), 7.99 (1H, d, J = 7.8 Hz), 11.24 (1H, br.s).

MC (EI) 300 (M +).

Example 24

Carrying out the reaction according to the method of example 2, using 3- (piperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (500 mg) and 1-bromo-2-propanol (394 mg), 3- [1- ( 2-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one (87 mg).

¹ H-NMR (270 MHz, DMCO-d ₆ ) δ: 1.05 (3H, d, J = 5.9 Hz), 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), 8.11 (1H, d, J = 7.8 Hz), 11.20 (1H, br.s).

MC (EI) 286 (M +).

Example 25

By carrying out the reaction according to the method of example 1, using N, N-dimethyl-2,3-dimethylbenzamide (5.6095 g) and 3- (4-hydroxypiperidin-1-yl) propionitrile (2.44 g), 3- [2 - (4-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (418.2 mg).

¹ H-NMR (CDCl ₃ ) δ: 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 (1H, m), 6.33 (1H, s), 7.26-7.30 (1H, m), 7.44 (1H, br, J = 7 Hz), 8.24 (1H, br, J = 8 Hz), 11 38 (1H, broad s).

MC (EI) 286 (M +).

Example 26

Carrying out the reaction according to the method of example 1, using N, N-dimethyl-2,3-dimethylbenzamide (5.8040 g) and (R) -4- (2-hydroxymethylpyrrolidin-1-yl) butyronitrile (2.75 g), get (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one (344.1 mg).

Melting point: 150.0-151.0 ° C.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.73-2.08 (6H, m), 2.31-2.40 (2H, m), 2.49 (3H, s), 2, 70-2.80 (2H, m), 2.85-2.95 (2H, m), 3.75-3.87 (1H, m), 6.34 (1H, s), 7.27- 7.32 (1H, m), 7.44 (1H, br, J = 7 Hz), 8.23 (1H, br, J = 8 Hz), 11.43 (1H, br. C).

Example 27

By carrying out the reaction according to the method of example 1, using N, N-diethyl-2,3-dimethylbenzamide (5.2474 g) and 3- (3-hydroxypiperidin-1-yl) propionitrile (2.62 g), 3- [2 - (3-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-one (888.2 mg).

Melting point: 192.0-193.0 ° C.

¹ H-NMR (CDCl ₃ ) δ: 1.42-1.53 (1H, m), 1.63-1.71 (1H, m), 1.82-1.91 (2H, m), 2 , 39-2.40 (2H, m), 2.61-2.76 (5H, m), 2.84-2.91 (1H, m), 3.19-3.21 (1H, m) 3.86-3.98 (1H, m), 6.23 (1H, s), 7.37-7.45 (2H, m), 8.33 (1H, d, J = 8 Hz), 11.25 (1H, broad s).

Example 28

By carrying out the reaction according to the method of example 2, using 5-methyl-3- (pyrrolidin-3-yl) -2H-isoquinolin-1-one hydrochloride (200 mg) and 2-bromoethanol (270 μl), 3- [1- ( 2-hydroxyethyl) pyrrolidin-3-yl-5-methyl-2H-isoquinolin-1-one (39 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.8 (br s, 1H), 8.19 (d, J = 8.0, 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), 2.55-2.65 (m, 1H), 2.48 (s, 3H ), 2.25-2.40 (m, 2H), 1.85-2.00 (m, 1H).

MC (ESI) 273 (M + 1).

Example 29

By carrying out the reaction according to the method of example 2, using 3- (pyrrolidin-3-yl) -2H-isoquinolin-1-one hydrochloride (201 mg) and 2-bromoethanol (285 μl), 3- [1- (2-hydroxyethyl) is obtained pyrrolidin-3-yl] -2H-isoquinolin-1-one (58 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.8 (br s, 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).

MC (ESI) 259 (M + 1).

Example 30

Carrying out the reaction according to the method of example 2, using 5-methyl-3- (piperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (1 g) and 1-bromo-2-propanol (994 mg), 5- methyl-3- [1- (2-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one (147 mg).

¹ H-NMR (270 MHz, DMCO-d ₆ ) δ: 1.05 (3H, d, J = 6.2 Hz), 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 = 7.0 Hz), 7.99 (1H, d, J = 7.8 Hz), 11.23 (1H, br.s).

MS (EI) 300 (M +).

Example 31

Carrying out the reaction according to the method of example 2, using 5-methyl-3- (piperidin-4-yl) -2H-isoquinolin-1-one hydrochloride (1 g) and 4-bromo-1-butanol (433 mg), 5- methyl-3- [1- (4-hydroxybutyl) piperidin-4-yl] -2H-isoquinolin-1-one (201 mg).

¹ H-NMR (270 MHz, DMCO-d ₆ ) δ: 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 (1H, m), 7.49 (1H, d, J = 7.0 Hz), 7.99 (1H, d, J = 8.1 Hz), 11.24 (1H, br.s).

MC (EI) 314 (M +).

Example 32

By carrying out the reaction according to the method of example 1, using N, N-dimethyl-2,3-dimethylbenzamide (5.1101 g) and 3- (3-hydroxypiperidin-1-yl) propionitrile (2.2 g), 3- [2 - (3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (269.6 mg).

Melting point: 184.0-185.0 ° C.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.49-1.98 (4H, m), 2.36-2.83 (12H, m), 3.90-4.01 (1H, m ), 6.33 (1H, s), 7.27-7.32 (1H, m), 7.43 (1H, br, J = 7 Hz), 8.22 (1H, br, J = 8 Hz), 11.29 (1H, broad s).

MC (EI) 286 (M +).

Example 33

By carrying out the reaction according to the method of example 2, using 5-methyl-3- (pyrrolidin-3-yl) -2H-isoquinolin-1-one hydrochloride (501 mg) and 3-bromo-1-propanol (991 μl), 3- [1- (3-hydroxypropyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one (216 mg).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 11.3 (br s, 1H), 8.21 (d, J = 7.8, 1H), 7.45 (d, J = 7.8 , 1H), 7.26-7.33 (m, 1H), 6.37 (s, 1H), 4.80-4.95 (m, 2H), 3.15-3.25 (m, 2H ), 3.07 (d, J = 9.6, 1H), 2.80-2.90 (m, 1H), 2.60-2.75 (m, 1H), 2.50-2.60 (m, 1H), 2.50 (s, 3H), 2.20-2.40 (m, 2H), 1.75-1.95 (m, 3H).

MC (EI) 286 (M +)

Example 34

Carrying out the reaction according to the method of example 1, using N, N-diethyl-2,3-dimethylbenzamide (4.07 g) and (S) -1- (2-cyanoethyl) -3-hydroxypyrrolidine (1.6 g), receive ( S) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (0.228 g).

Melting point: 176-178 ° C.

¹ H-NMR (CDCl ₃ ) δ: 1.83-1.96 (1H, m), 2.21-2.32 (1H, m), 2.48 (3H, s), 2.49-2 55 (1H, m), 2.72-2.79 (3H, m), 2.81-2.92 (3H, m), 2.96-3.05 (1H, m), 4.42 -4.49 (1H, m), 6.33 (1H, s), 7.29 (1H, t, J = 8 Hz), 7.43 (1H, d, J = 7 Hz), 8.22 (1H, d, J = 8 Hz), 11.40 (1H, br.s).

MC (EI) 272 (M +).

Example 35

By carrying out the reaction according to the method of example 1, using N, N-dimethyl-2,3-dimethylbenzamide (1.41 g) and (R) -3- (3-hydroxypiperidin-1-yl) propionitrile (1.44 g), receive (R) -3- [2- (3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (147 mg).

Melting point: 180.0-181.0 ° C.

¹ H-NMR (CDCl ₃ ) δ: 1.49-1.98 (4H, m), 2.36-2.83 (12H, m), 3.90-4.01 (1H, m), 6 , 33 (1H, s), 7.27-7.32 (1H, m), 7.43 (1H, br, J = 7 Hz), 8.22 (1H, br, J = 8 Hz) 11.29 (1H, broad s).

MC (EI) 286 (M +).

Example 36

Carrying out the reaction according to the method of example 1, using N, N-diethyl-2,3-dimethylbenzamide (81.4 g) and (R) -3- (2-hydroxymethylpyrrolidin-1-yl) propionitrile (55.6 g), get (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (12.5 g).

¹ H-NMR (CDCl ₃ ) δ: 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 (1H, m), 3.38-3.46 (1H, m), 3.55 (1H, dd, J = 3 Hz, 11 Hz), 3.76 (1H, dd, J = 3 Hz, 12 Hz), 6.39 (1H, s), 7.31 (1H, t, J = 8 Hz), 7.55 (1H, d, J = 8 Hz), 8.26 (1H, d, J = 8 Hz), 12.43 (1H, br.s).

MC (EI) 286 (M +).

Using the known method, (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one is converted to the hydrochloride to give the hydrochloride dihydrate (R) -3- [ 2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one.

¹ H-NMR (DMCO-d ₆ ) δ: 1.69-2.14 (4H, m), 2.48 (3H, s), 2.94-3.44 (4H, m), 3.52 -3.84 (5H, m), 5.48 (1H, br.s), 6.55 (1H, s), 7.34 (1H, t, J = 8 Hz), 7.53 (1H, d, J = 7 Hz), 8.02 (1H, d, J = 8 Hz), 10.29 (1H, br.s), 11.47 (1H, br.s).

MC (EI) 286 (M +).

[α] _D = + 24.5 ° (c = 1.009, MeOH).

The following is another method for the preparation of (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one.

(R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin hydrochloride (62 g) and acetic acid (186 ml) are mixed, ammonium carbonate (74.4 is added gradually with stirring) d). After gas evolution ceased, the reaction mixture was heated and stirred at 130 ° C for 2 hours with heating. After completion of the reaction, the reaction mixture was cooled to room temperature and an aqueous solution (200 ml) of sodium hydroxide (140 g) was added. The mixture was stirred at 80 ° C and, after completion of the reaction, the reaction mixture was concentrated. The methanol fraction was evaporated and the mixture was extracted twice with chloroform. The organic layer was extracted twice with 3N. hydrochloric acid (300 ml and 100 ml) and potassium carbonate is added to the aqueous layer to alkalize the resulting 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 resulting 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 filtered off to obtain (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (41.5 g )

Example 37

A solution (400 ml) of diisopropylamine (26.9 g) in tetrahydrofuran was cooled to −5 ° C. and a 1.57 M solution (154 ml) of n-butyllithium in hexane was added dropwise to the solution. After stirring at 0 ° C for 30 minutes, 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 hour, a solution (50 ml) of 1-benzyl-3-cyanopyrrolidine (37.18 g) in tetrahydrofuran was added dropwise. After completion of the dropwise addition, the reaction mixture was warmed to room temperature and the mixture was stirred overnight at room temperature. The mixture was further stirred at reflux for 1 hour, and the reaction mixture was concentrated to about half the volume. Water and methylene chloride were added and the organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. The resulting residue was purified using a silica gel column chromatography (ethyl acetate) to obtain (±) -3- (1-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one (66.38 g).

To the obtained (±) -3- (1-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one (66.38 g) is added D-tartaric acid (31.32 g) in methanol (1580 ml), the mixture is heated at the boil under reflux and cooled to room temperature, obtaining the precipitated D-tartrate (±) -3- (1-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one (44.56 g).

It was then recrystallized twice from methanol to give (-) - 3- (1-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one D-tartrate (27.06 g).

Then, crystals recovered from the mother liquor by recrystallization are again recrystallized three times from methanol to obtain (11.74 g). D-tartrate (-) - 3- (1-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one (38.8 g) is stirred in a mixture of methanol (150 ml) - methylene chloride (300 ml) and 1N was added dropwise. an aqueous solution of sodium hydroxide (200 ml) and water (100 ml) to alkalize the solution. The methylene chloride layer was isolated and washed with water, then dried over magnesium sulfate and concentrated to give (-) - 3- (1-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one (27.5 g).

[α] _D ²² -101.8 (C = 0.998, CHCl ₃ ).

To the obtained (-) - 3- (1-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one (27.5 g), 50% aqueous 10% palladium-on-carbon (6 g) was added and ethanol (400 ml) and the mixture was stirred in an atmosphere of hydrogen at a temperature of 50 ° C for 6 hours. After filtration through celite, the filtrate was concentrated and ethyl acetate was added to the resulting residue. The precipitated crystals are filtered off to obtain (-) - 3- (pyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one (16.8697 g).

To the resulting (-) - 3- (pyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one (3.0 g) was added bromoethanol (8.21 g), sodium bicarbonate (5.6 g) , methyl ethyl ketone (84 ml) and water (8.4 ml), the mixture was stirred at the boil under reflux for 2 hours. The reaction mixture was concentrated, extracted with methylene chloride and the extract was washed with water, dried over magnesium sulfate and concentrated. The resulting residue was purified using a silica gel chromatography column (methanol / ethyl acetate; 2/5) and crystallized from ethyl acetate to give (-) - 3- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H -isoquinolin-1-one (1.5425 g).

Melting point: 137.3-138.6 ° C.

[α] _D ²² -53.1 (C = 1.005, CHCl ₃ ).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.85-2.01 (1H, m), 2.27-2.42 (2H, m), 2.49 (3H, s), 2, 55-2.64 (1H, m), 2.69-2.85 (2H, m), 3.10-3.16 (1H, m), 3.20-3.31 (2H, m), 3.74-3.88 (2H, m), 6.35 (1H, s), 7.23-7.33 (1H, m), 7.43 (1H, d, J = 7 Hz), 8 20 (1H, d, J = 8 Hz); 10.66 (1H, br.s).

MC (EI) 272 (M +).

Example 38

The mother liquor obtained by optical separation of (-) - 3- (1-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one D-tartrate in Example 37 is treated with alkali. By converting it to L-tartrate in a manner analogous to the above, and after triple recrystallization from methanol, L-tartrate (+) - 3- (1-benzylpyrrolidin-3-yl) -5-methyl-2H-isoquinolin-1-one is obtained (38.99 g). Subsequent desalting, debenzylation and hydroxyethylation by methods similar to the above give (+) - 3- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one.

Melting point: 137.0-138.6 ° C.

[α] _D ²² +52.7 (C = 1.004, CHCl ₃ ).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.85-2.01 (1H, m), 2.27-2.42 (2H, m), 2.49 (3H, s), 2, 55-2.64 (1H, m), 2.69-2.85 (2H, m), 3.10-3.16 (1H, m), 3.20-3.31 (2H, m), 3.74-3.88 (2H, m), 6.35 (1H, s), 7.23-7.33 (1H, m), 7.43 (1H, d, J = 7 Hz), 8 20 (1H, d, J = 8 Hz); 10.66 (1H, br.s).

MC (EI) 272 (M +).

The following are structural formulas of the compounds of each of the examples. The numbers indicated correspond to the above numbering of examples.

Experimental example

Inhibitory effect against PARP enzyme activity

Recombinant human PARP (4667-02X, Trevigen) is used as an enzyme source. The reaction of poly ADP-ribosylation started by adding ³ H-NAD (1,85 kBq, NAD [ adenine-2, 8- ³ H], Daiichi Chemicals Co., Ltd. ) and activated DNA (0.02 mg / ml, 4667 -03X, Trevigen) and then the enzyme source to the enzymatic reaction buffer (10 mM Tris / HCl (pH 8.0), 1 mM MgCl ₂ , 28 mM KCl, 28 mM NaCl). After incubation at 25 ° C for 15 min, the reaction is stopped by adding 20% trichloroacetic acid and the resulting acid-insoluble fraction is adsorbed on a GF / B filter. The filter is washed several times with 5% trichloroacetic acid, the radioactivity on the filter is measured using a scintillation counter.

The results are presented in table 1. The PARP activity is determined by subtracting the radioactivity of the sample in which the enzyme source was not added, as the comparative value and the value of the 50% inhibitory ability of the enzyme (IC ₅₀ value) for each of the test compounds is calculated using the value of the radioactivity of the compound taking as 100% the value for the sample in which the compound was not added.

Table 1 Test connection PARP inhibitory activity
IR ₅₀ (nm) Test connection PARP inhibitory activity
IR ₅₀ (nm) Example 1 39 Example 28 35 Example 2 17 Example 34 34 Example 4 46 Example 36 29th Example 5 fifty Example 37 twenty Example 9 44 Example 38 29th Reference Medication (DPQ) 1000 DPQ = 3,4-dihydro-5- [4- (1-piperidinyl) butoxy] -1 (2H) -isoquinolinone (can be synthesized according to example 32 JP-A-H2-124874, a PARP inhibitor is disclosed in each of WO 99/08680 and WO 99/11649)

Based on these results, it becomes apparent that the compounds provided in the examples of the present invention have superior PARP inhibitory activity compared to DPQ.

Experimental Example 2

Determination of stability

Each of the compounds is dissolved in physiological saline, obtaining solutions with concentrations of 1.0 mg / ml or 10 mg / ml. They are stored at room temperature, in the dark or in the light, and the residual ratio on days 7 and 11 is measured using HPLC. The results are shown in table 2.

Column: Inertsil ODS3V (GL Science Inc.)

Mobile phase: methanol: 0.01 mol / L ammonium acetate aqueous solution

Determination at a wavelength: 254 nm

Volumetric flow: 1.0 ml / min

table 2 Test connection Concentration Residual ratio (%) in the dark Residual ratio (%) in the light mg / ml In 7 days In 11 days In 7 days In 11 days Example 1 1,0

100

one hundred

one hundred

one hundred

one hundred 10

one hundred

one hundred

one hundred

one hundred Example 2 1,0

one hundred

one hundred

one hundred

one hundred 10

one hundred

one hundred

one hundred

one hundred Example 36 1,0

one hundred

one hundred

one hundred

one hundred 10

one hundred

one hundred

one hundred

one hundred

Based on these results, it becomes apparent that the compounds of the present invention remain stable in aqueous solutions.

Experimental Example 3

Positive effect on neurological symptoms associated with cerebral infarction

Cynomolgus monkeys who were given no food for 12 hours or more before the study are anesthetized by intramuscular injection of ketamine hydrochloride (10 mg / kg) and fixed on the operating table. Atropinsulfate (0.5 mg / kg body weight) is injected intramuscularly with pentobarbital anesthesia and a small hole (approximately 5 mm) is made using a dental drill near the oval canal and orbital cleft, then the dura mater and arachnoid are excised. Then, the middle of the cerebral artery (MCA) is exposed near the bifurcation of the internal carotid artery. MCA near the bifurcation of the internal carotid artery coagulate / occlude using a bipolar coagulator, which leads to cerebral infarction. After that, the solvent or drug of the example is administered continuously at a rate of 3 mg / kg / hour for 6 hours.

Neurological symptoms associated with cerebral infarction are observed within 26 hours after MCA occlusion.

Neurological symptoms are assessed according to a 5-point rating scale, as indicated below, in relation to consciousness, paralysis and mobility.

1. Level of consciousness

Score 5: there is almost no reaction to the movements / activity of people around and to noise.

Score 4: although there is a reaction to the movements / activity of people around and to noise, animals quickly return to a state characterized by the absence of reactions.

Assessment 3: although there is a reaction to the movements / activity of people around and to noise, this reaction is short-lived.

Grade 2: Long-term response to movement / activity of people around and noise.

Grade 1: A prolonged reaction to the movements / activity of people around and to noise, accompanied by appropriate facial expressions.

Score 0: normal response to movement / activity of people around and noise.

2. Paralysis

Grade 5: total limb immobility on the hemiplegic side.

Grade 4: accidental involvement of the limbs from the hemiplegic side without compression / strength.

Grade 3: Although there is hemiplegic involvement of the extremities, grabbing food pieces is not obvious.

Score 2: relatively free movement of the limbs from the hemiplegic side, but the capture of pieces of food is not obvious.

Grade 1: free movement of the limbs from the hemiplegic side and the obvious capture of pieces of food.

Score 0: normal limb movement on the hemiplegic side.

3) Mobility

Grade 5: maintaining a sitting posture.

Grade 4: Occasionally exiting a sitting position, then walking in a circle.

Grade 3: from time to time climbing the walls of the cell.

Grade 2: Frequent walking in a circle.

Grade 1: Frequent climbing on cell walls.

Score 0: normal behavior.

Table 3 Group name n Rating Solvent group four 14.8 ± 0.3 The example drug group 5 8.6 ± 1.9 (P <0.05)

Based on these results, it becomes apparent that the compounds of the present invention have a positive effect on the neurological symptoms associated with cerebral infarction.

Industrial applicability

The compounds of the above formula (I), their optical isomers, their pharmaceutically acceptable salts, their hydrates and their aqueous adducts are stable in aqueous solutions, have effective PARP inhibitory activity compared to known compounds, and can be used as therapeutic drugs in the treatment of cerebral heart attack, especially acute cerebral infarction. In addition, (R) -3- (3-hydroxypyrrolidin-1-yl) -N-methyl-N-methoxypropanamide, (R) -N, N-diethyl-2- [4- (3-hydroxypyrrolidin-1-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-1-yl) -2-oxobutyl] -3-methylbenzamide, (R) -3- [2- (2-Hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin and (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin hydrochloride are new compounds, and can be used as intermediates units for the synthesis of compounds of formula (I).

This application is based on patent applications No. 288833/2002, 340175/2002 and 109160/2003, filed in Japan, the contents of which are incorporated here by reference.

Additional examples

Example 1

(a) Diisopropylamine (5.48 ml) is dissolved in tetrahydrofuran (13 ml) in a nitrogen atmosphere and lowering the temperature to -78 ° C. A solution of n-butyllithium (1.58 mol / L, 23.8 ml) in n-hexane was added dropwise to the reaction mixture, and the mixture was stirred at 0 ° C for 30 minutes. The lithium diisopropylamide solution was again cooled to −78 ° C. and a solution of N, N-diethyl-3-fluoro-2-methylbenzamide (3.41 g) in tetrahydrofuran (15 ml) was slowly added dropwise. After complete addition, the reaction mixture was stirred at -78 ° C for one hour and a solution of (R) -3- (2-hydroxymethylpyrrolidin-1-yl) -N-methoxy-N-methylpropamide (3.53 g) in tetrahydrofuran (15 ml). The reaction mixture was warmed to room temperature and stirred overnight (18 h). After completion of the reaction, water is added to the reaction mixture to quench the reaction. Tetrahydrofuran was removed under reduced pressure and the resulting aqueous layer was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. Chloroform was evaporated under reduced pressure to obtain (R) -N, N-diethyl-3-fluoro-2- [4- (2-hydroxymethylpyrrolidin-1-yl) -2-oxobutyl] benzamide (5.94 g), which was used in the next reaction without further purification.

(b) To (R) -N, N-diethyl-3-fluoro-2- [4- (2-hydroxymethylpyrrolidin-1-yl) -2-oxobutyl] benzamide (5.94 g) was added concentrated hydrochloric acid (35 ml) and the resulting mixture was heated at the boil under reflux for 5 hours. After completion of the reaction, the reaction mixture was made alkaline by adding powdered potassium carbonate and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered. Chloroform was evaporated under reduced pressure to obtain (R) -5-fluoro-3 [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] isocoumarin (4.01 g), which was used in the next reaction without further purification.

(c) (R) -5-Fluoro-3 [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] isocoumarin (4.01 g) was dissolved in acetic acid (12 ml) and the resulting mixture was heated to 70 ° C. . Ammonium carbonate (4.90 g) was added and the mixture was heated at the boil under reflux for 1 h. The reaction mixture was cooled to room temperature and sodium hydroxide (8 g) was added to an aqueous solution (30 ml). The mixture was stirred at room temperature for 30 minutes and diluted with water, extracted with chloroform, washed with brine, dried over anhydrous magnesium sulfate and filtered. Chloroform was evaporated under reduced pressure to give an oil, which was purified using a silica gel chromatography column (chloroform → chloroform: methanol = 20: 1 → 10: 1). The resulting crude crystals were washed with ethyl acetate and collected by filtration to obtain (R) -5-fluoro-3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one (595 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.70-2.00 (4R, m), 2.35-2.45 (1H, m), 2.55-2.75 (2H, m), 2 , 80-3.00 (2H, m), 3.10-3.25 (1H, m), 3.30-3.40 (1H, m), 3.50-3.60 (1H, m) 3.70-3.80 (1H, m), 3.85 (1H, br.s), 6.49 (1H, s), 7.26-7.38 (2H, m), 8.13 (1H, d, J = 7.2 Hz), 12.6 (1H, br s).

MS (ESI): 291 (M + 1).

Example 2

Carrying out the reaction according to the method of example 1, using N, N-ethyl-3-chloro-2-methylbenzamide (3.35 g) and (R) -3- (2-hydroxymethylpyrrolidin-1-yl) -N-methoxy-N- methylpropamide (3.22 g), (R) -5-chloro-3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one (645 mg) is obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.70-2.00 (411, m), 2.35-2.45 (1H, m), 2.55-2.75 (2H, m), 2 , 80-3.00 (2H, m), 3.10-3.25 (1H, m), 3.30-3.40 (1H, m), 3.50-3.60 (1H, m) , 3.70-3.80 (1H, m), 6.65 (1H, s), 7.30-7.35 (1H, m), 7.67 (1H, d, J = 8.1 Hz ), 8.28 (1H, d, J-8.1 Hz), 12.7 (1H, br.s).

MS (ESI) 307 (M + 1).

Example 3

Carrying out the reaction according to the method of example 1, using N, N-ethyl-3-fluoro-2-methylbenzamide (3.46 g) and (R) -3- (3-hydroxypyrrolidin-1-yl) -N-methoxy-N- methylpropamide (3.36 g), (R) -5-fluoro-3- [2- (3-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one (1.19 g) is obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.60 (1H, m), 1.85-2.00 (1H, m), 2.35-2.40 (1H, m) 2.40-2.55 (1H, m), 2.60-2.80 (6H, m), 4.16-4.20 (1H, m), 4.70 (1H, d, J = 4.2 Hz), 6.45 (1H, s), 7.37-7.44 (1H, m), 7.49-7.55 (1H, m), 7.96 (1H, d, J = 7.8 Hz), 11.5 (1H, br.s).

MS (ESI): 277 (M + 1).

Example 4

Carrying out the reaction according to the method of example 1, using N, N-diethyl-3-chloro-2-methylbenzamide (3.43 g) and (R) -3- (3-hydroxypyrrolidin-1-yl) -N-methoxy-N- methylpropamide (3.08 g), (R) -5-chloro-3- [2- (3-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one (102 mg) is obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.60 (1H, m), 1.85-2.00 (1H, m), 2.35-2.40 (1H, m) 2.40-2.55 (1H, m), 2.60-2.80 (6H, m), 4.19 (1H, br.s), 4.74 (1H, br.s), 6 56 (1H, s), 7.38-7.43 (1H, m), 7.81 (1H, d, J = 7.5 Hz), 8.12 (1H, d, J = 7.5 Hz), 11.6 (1H, br s).

MS (ESI): 293 (M + 1).

Pharmacological data of the compound in which R ¹ represents a halogen atom.

Enzyme analysis is carried out according to the method "Inhibitory effect against PARP enzyme activity" described in the Experimental example section of this application.

Example No. R ¹ PARP inhibitory activity, IR ₅₀ (nm) one F 125 2 Cl 140 3 F 160 four Cl 130

Claims (40)

1. The isoquinoline compound represented by formula (I)

where R ¹ represents a hydrogen atom, a halogen atom or an alkyl; Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; R is represented by the following formula (II):

where X represents CH or a nitrogen atom, provided that if Y is absent in formula (I), then X must represent CH; W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer from 1 to 3; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom or alkyl, then R ² represents a hydrogen atom, an alkyl, hydroxyl group, or hydroxyalkyl, R ^{2 '} represents a hydroxyl group or hydroxyalkyl, if R ³ is hydroxyalkyl, then R ² and R ^{2 ′} are hydrogen, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate. 2. The isoquinoline compound according to claim 1, which is represented by formula (I), where R ¹ represents a hydrogen atom or an alkyl; Y is absent or represents an alkylene chain containing from 1 to 5 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; R is represented by formula (II), where in formula (II) X represents CH or a nitrogen atom, provided that if Y is not present in formula (I), then X must represent CH; W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer from 1 to 3; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom or alkyl, then R ² represents a hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R ^{2 '} represents a hydroxyl group or hydroxyalkyl; if R ³ is hydroxyalkyl, then R ² and R ^{2 ′} are a hydrogen atom, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate, or its solvate. 3. The isoquinoline compound according to claim 1 or 2, which is represented by formula (I), where R ¹ represents a hydrogen atom or methyl; Y is absent or is methylene, ethylene, propylene or 2-hydroxypropylene; R is represented by formula (II), where in formula (II) X represents CH or a nitrogen atom, provided that if Y is not present in formula (I), then X must represent CH; W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer from 1 to 3; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom or methyl, then R ² represents a hydrogen atom, an alkyl, hydroxyl group, hydroxymethyl or 2-hydroxyethyl, and R ^{2 ′} represents a hydroxyl group, hydroxymethyl or 2-hydroxyethyl; and if R ³ is 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or 2-hydroxypropyl, then R ² and R ^{2 '} represent a hydrogen atom, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its MES. 4. The isoquinoline compound according to claim 1 or 2, which is selected from the group consisting of (1) (R) -3- [2- (3-hydroxypyrrolidin-1-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-1-yl) propyl] -2H-isoquinolin-1-one, (4) 3- [3- (3-hydroxypyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one, (5) 3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (6) 3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one, (7) 3- [2- (2-hydroxymethylpiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (8) 3- [2- (2-hydroxymethylpiperidin-1-yl) ethyl] -2H-isoquinolin-1-one, (9) 3- [1- (2-hydroxyethyl) piperidin-4-yl] -2H-isoquinolin-1-one, (10) 3- [1- (3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one, (11) 3- [1- (4-hydroxybutyl) piperidin-4-yl] -2H-isoquinolin-1-one, (12) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one, (13) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one, (14) (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one (15) (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one, (16) (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one, (17) (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one, (18) (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one, (19) 3- [2- (4-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-one, (20) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one, (21) 3- (1-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-methyl-3- [1- (3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one, (24) 3- [1- (2-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one, (25) 3- [2- (4-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (26) (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one, (27) 3- [2- (3-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-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-1-one, (30) 5-methyl-3- [1- (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-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (33) 3- [1- (3-hydroxypropyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one, (34) (S) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (35) (R) -3- [2- (3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (36) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (37) (-) - 3- [1- (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, their optically active forms, their pharmaceutically acceptable salts, their aqueous adducts, their hydrates and their solvates. 5. The isoquinoline compound according to claim 1 or 2, which is represented by formula (I), where R ¹ represents a hydrogen atom or methyl; Y is absent; and R is represented by formula (II), where in formula (II) X represents CH; W represents a nitrogen atom; s represents an integer of 1 or 2; t represents an integer of 2; if R ³ represents methyl, then R ² represents a hydrogen atom, methyl, ethyl, hydroxyl group or hydroxymethyl, and R ^{2 '} represents a hydroxyl group or hydroxymethyl; and if R ³ is hydroxyethyl, then R ² and R ^{2 '} represent a hydrogen atom, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate, or its solvate. 6. The isoquinoline compound according to claim 1 or 2, which is selected from the group consisting of (2) 3- [1- (2-hydroxyethyl) piperidin-4-yl] -5-methyl-2H-isoquinolin-1-one, (9) 3- [1- (2-hydroxyethyl) piperidin-4-yl] -2H-isoquinolin-1-one, (10) 3- [1- (3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one, (11) 3- [1- (4-hydroxybutyl) piperidin-4-yl] -2H-isoquinolin-1-one, (21) 3- (1-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-methyl-3- [1- (3-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-one, (24) 3- [1- (2-hydroxypropyl) piperidin-4-yl] -2H-isoquinolin-1-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-1-one, (30) 5-methyl-3- [1- (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-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, their optically active forms, their pharmaceutically acceptable salts, their aqueous adducts, their hydrates and their solvates. 7. The isoquinoline compound according to claim 1 or 2, which is represented by formula (I), where R ¹ represents a hydrogen atom or methyl; Y represents ethylene, propylene; and R is represented by formula (II), where in formula (II) X represents a nitrogen atom; W represents CH; s represents an integer from 1 to 3; t represents an integer from 1 to 3; R ² represents a hydrogen atom, an alkyl, hydroxyl group or hydroxymethyl; R ^{2 ′} represents a hydroxyl group or hydroxymethyl; and R ³ represents a hydrogen atom; with the proviso that if R ² represents a hydrogen atom or alkyl, R ^{2 '} represents a hydroxyl group or hydroxymethyl, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate. 8. The isoquinoline compound according to claim 7, which is selected from the group including (1) (R) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (3) 3- [3- (3-hydroxypyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one, (4) 3- [3- (3-hydroxypyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one, (5) 3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (6) 3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one, (7) 3- [2- (2-hydroxymethylpiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (8) 3- [2- (2-hydroxymethylpiperidin-1-yl) ethyl] -2H-isoquinolin-1-one, (12) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one, (13) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one, (14) (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (15) (S) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one, (16) (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one, (17) (S) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one, (18) (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one, (19) 3- [2- (4-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-one, (20) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -2H-isoquinolin-1-one, (25) 3- [2- (4-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (26) (R) -3- [3- (2-hydroxymethylpyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one, (27) 3- [2- (3-hydroxypiperidin-1-yl) ethyl] -2H-isoquinolin-1-one, (32) 3- [2- (3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (34) (S) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (35) (R) -3- [2- (3-hydroxypiperidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one and (36) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, their optically active forms, their pharmaceutically acceptable salts, their aqueous adducts, their hydrates and their solvates. 9. The isoquinoline compound according to claim 1 or 2, which is represented by formula (I), where R ¹ represents a hydrogen atom or methyl; Y is absent or represents ethylene; R is represented by formula (II), where in formula (II), if Y is present in formula (I), X represents a nitrogen atom; if Y is absent in formula (I), X represents SP; W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer of 1 or 2; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom, then R ² represents a hydrogen atom, a hydroxyl group or hydroxymethyl, R ^{2 '} represents a hydroxyl group or hydroxymethyl; and if R ³ is hydroxyethyl, R ² and R ^{2 ′} each represents a hydrogen atom, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate, or its solvate. 10. The isoquinoline compound according to claim 1 or 2, which is selected from the group including (1) (R) -3- [2- (3-hydroxypyrrolidin-1-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-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (28) 3- [1- (2-hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one, (34) (S) -3- [2- (3-hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (36) (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, (37) (-) - 3- [1- (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, their optically active forms, their pharmaceutically acceptable salts, their aqueous adducts, their hydrates and their solvates. 11. The isoquinoline compound of claim 10, which is represented by formula (I), wherein R ¹ is methyl; Y is absent; and R is represented by formula (II), where X is CH; W represents a nitrogen atom; s represents an integer of 1 or 2; t represents an integer of 2; R ² and R ^{2 '} represent a hydrogen atom; and R ³ is hydroxyethyl, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate, or its solvate. 12. (2) 3- [1- (2-Hydroxyethyl) piperidin-4-yl] -5-methyl-2H-isoquinolin-1-one, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate. 13. (28) 3- [1- (2-Hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate. 14. (37) (+) - 3- [1- (2-Hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or his solvate. 15. (38) (-) - 3- [1- (2-Hydroxyethyl) pyrrolidin-3-yl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or his solvate. 16. The isoquinoline compound according to claim 7, which is represented by formula (I), where R ¹ represents methyl; Y represents ethylene; R is represented by formula (II), where, in the formula (II), X represents a nitrogen atom; W represents CH; s represents the integer 1; t represents an integer of 2 or 3; R ² represents a hydrogen atom, a hydroxyl group or hydroxymethyl; R ^{2 ′} represents a hydroxyl group or hydroxymethyl; and R ³ represents a hydrogen atom, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate. 17. (1) (R) -3- [2- (3-Hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and his solvate. 18. (5) 3- [2- (3-Hydroxypyrrolidin-1-yl) ethyl]] - 5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and its solvate. 19. (34) (S) -3- [2- (3-Hydroxypyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and his solvate. 20. (36) (R) -3- [2- (2-Hydroxymethylpyrrolidin-1-yl) ethyl] -5-methyl-2H-isoquinolin-1-one, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate and his solvate. 21. The isoquinoline compound represented by the formula (I ′):

where Ra ¹ represents a hydrogen atom or methyl; Y 'represents ethylene, propylene or 2-hydroxypropylene; Ra is represented by formula (II '):

where in the formula (II '), X 'represents a nitrogen atom; W 'represents CH; s' represents an integer from 1 to 3; t 'represents an integer from 1 to 3; if Ra ³ represents a hydrogen atom, then Ra ² represents a hydrogen atom or alkyl, and Ra ^{2 '} represents a hydroxyl group or hydroxymethyl; its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate. 22. The isoquinoline compound according to claim 21, which is represented by formula (I '), wherein Ra ¹ is methyl; Y 'represents ethylene; Ra is represented by the following formula (II ′), wherein in the formula (II ′), X ′ represents a nitrogen atom; W 'represents CH; s' represents 1; t 'represents an integer of 2 or 3; if Ra ³ represents a hydrogen atom, then Ra ² represents a hydrogen atom, and Ra ^{2 '} must represent a hydroxyl group or hydroxymethyl, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate. 23. The isoquinoline compound, which is selected from (12) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -2H-isoquinolin-1-one and (13) 3- [2-hydroxy-3- (pyrrolidin-1-yl) propyl] -5-methyl-2H-isoquinolin-1-one, their optically active forms, their pharmaceutically acceptable salts, their aqueous adducts, their hydrates or their solvates. 24. An agent for the prevention and / or treatment of a disease caused by hyperactivity of a poly (ADP-ribose) polymerase, which comprises an isoquinoline compound according to any one of claims 1 to 23, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate. 25. The agent according to paragraph 24, which is used for the prevention and / or treatment of cerebral infarction. 26. The agent according to any one of paragraph 24 or 25, which is used for the prevention and / or treatment of acute cerebral infarction. 27. The agent according to any one of paragraph 24 or 25, which is used for the prevention and / or treatment of symptoms associated with cerebral infarction. 28. An agent for the prevention and / or treatment of cerebral infarction, which includes an isoquinoline compound according to any one of claims 1 to 23, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate. 29. The agent according to p. 28, which is used for the prevention and / or treatment of acute cerebral infarction. 30. An agent according to claims 28 and 29, which improves the neurological symptoms associated with cerebral infarction. 31. An inhibitor of poly (ADP-ribose) polymerase, comprising the isoquinoline compound according to any one of claims 1 to 23, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate, or its solvate. 32. The use of the isoquinoline compound according to any one of claims 1 to 23, its optically active form, its pharmaceutically acceptable salt, its aqueous adduct, its hydrate or its solvate for the preparation of an agent for the prophylaxis and / or treatment of a disease caused by poly hyperactivity (ADP- ribose) polymerase. 33. The application of clause 32, where the disease is cerebral infarction. 34. The application of clause 32, where the disease is acute cerebral infarction. 35. A compound selected from the group including: (R) -3- (3-hydroxypyrrolidin-1-yl) -N-methyl-N-methoxypropanamide, (R) -N, N-diethyl-2- [4- (3-hydroxypyrrolidin-1-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-1-yl) -2-oxobutyl] -3-methylbenzamide, (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin and (R) -3- [2- (2-hydroxymethylpyrrolidin-1-yl) ethyl] -5-methylisocoumarin hydrochloride . 36. A method of obtaining a compound of formula (15):

where R ¹ represents a hydrogen atom, a halogen atom or an alkyl; J ² represents dialkylamino; Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; R is represented by formula (II):

Where X represents CH or a nitrogen atom, provided that if Y is absent in formula (I), then X represents CH; W represents CH or a nitrogen atom; provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer from 1 to 3; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom or alkyl, then R ² represents a hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R ^{2 '} represents a hydroxyl group or hydroxyalkyl; and if R ³ represents hydroxyalkyl, then R ² and R ^{2 '} represent a hydrogen atom, comprising the interaction of the compounds of formula (11 ')

where R ¹ and J ² have the above meanings, with a compound of formula (14)

where Y and R are as defined above, and J ³ is N-alkyl-N-alkoxyamino. 37. A method of obtaining a compound of formula (16)

where R ¹ represents a hydrogen atom, a halogen atom or an alkyl; Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; R is represented by formula (II):

where X represents CH or a nitrogen atom, provided that if Y is absent in formula (I), then X represents CH; W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer from 1 to 3; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom or alkyl, then R ² represents a hydrogen atom, alkyl, hydroxyl group or hydroxylakyl and R ^{2 '} represents a hydroxyl group or hydroxyalkyl; and if R ³ is hydroxyalkyl, then R ² and R ^{2 ′} are a hydrogen atom comprising the intramolecular cyclization of a compound of formula (15)

where J ² represents dialkylamino, and R ¹ , Y and R have the above meanings, in the presence of a base in an anhydrous solvent or in the presence of an acid. 38. A method of obtaining a compound represented by formula (I)

where R ¹ represents a hydrogen atom, a halogen atom or an alkyl; Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; R is represented by formula (II)

where X represents CH or a nitrogen atom, provided that if Y is absent in formula (I), then X must represent CH; W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer from 1 to 3; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom or alkyl, then R ² represents a hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl and R ^{2 '} represents a hydroxyl group or hydroxyalkyl; and if R ³ represents hydroxyalkyl, then R ² and R ^{2 '} represent a hydrogen atom, comprising the interaction of the compounds of formula (16)

where R ¹ represents a hydrogen atom, a halogen atom or an alkyl; Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; R is represented by formula (II)

where X represents CH or a nitrogen atom, provided that if Y is absent in formula (I), then X must represent CH; W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer from 1 to 3; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom or alkyl, then R ² represents a hydrogen atom, alkyl, hydroxyl group or hydroxylakyl and R ^{2 '} represents a hydroxyl group or hydroxyalkyl; and if R ³ represents hydroxyalkyl, then R ² and R ^{2 '} represent a hydrogen atom, with a source of ammonia in a suitable solvent, one that does not inhibit the course of the reaction to give a compound of formula (I). 39. A method of obtaining a compound represented by formula (I)

where R ¹ represents a hydrogen atom, a halogen atom or an alkyl; Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; and R is represented by formula (II)

where X represents CH or a nitrogen atom, provided that if Y is absent in formula (I), then X must represent CH; W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer from 1 to 3; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom or alkyl, then R ² represents a hydrogen atom, an alkyl, a hydroxyl group or hydroxyalkyl and R ^{2 '} represents a hydroxyl group or hydroxyalkyl; and if R ³ represents hydroxyalkyl, then R ² and R ^{2 '} represent a hydrogen atom, including intramolecular cyclization of the compounds of formula (15)

where J ² represents dialkylamino, and R ¹ , Y and R have the above meanings, in the presence of a base in an anhydrous solvent or in the presence of an acid to give a compound of formula (16)

where R ¹ , Y and R have the above meanings, and reacting a compound of formula (16) with an ammonia source in a suitable solvent, such that does not inhibit the course of the reaction, to produce a compound of formula (I). 40. A method of obtaining a compound represented by formula (I)

where R ¹ represents a hydrogen atom, a halogen atom or an alkyl; Y is absent or represents an alkylene chain containing from 1 to 8 carbon atoms, where an arbitrary carbon atom may have a hydroxyl group as a substituent; and R is represented by formula (II)

where X represents CH or a nitrogen atom, provided that if Y is absent in formula (I), then X must represent CH; W represents CH or a nitrogen atom, provided that if X represents CH, then W must represent a nitrogen atom; s represents an integer from 1 to 3; t represents an integer from 1 to 3; if R ³ represents a hydrogen atom or alkyl, then R ² represents a hydrogen atom, an alkyl, a hydroxyl group or hydroxyalkyl and R ^{2 '} represents a hydroxyl group or hydroxyalkyl; and if R ³ represents hydroxyalkyl, then R ² and R ^{2 '} represent a hydrogen atom, comprising the interaction of the compounds of formula (11 '):

where R ¹ and J ² have the above meanings, with a compound of formula (14)

where Y and R are as defined above, and J ³ is N-alkyl-N-alkoxyamino to give a compound of formula (15)

where J ² represents dialkylamino, and R ¹ , Y and R have the above meanings, intramolecular cyclization of a compound of formula (15) in the presence of a base in an anhydrous solvent or in the presence of acid to obtain a compound of formula (16)

where R ¹ , Y and R have the above meanings, and reacting a compound of formula (16) with an ammonia source in a suitable solvent, such that does not inhibit the course of the reaction, to produce a compound of formula (I).