Isoquinoline compounds, intermediate compounds, methods for their preparing and using

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 R2' represents hydroxyl group or hydroxyalkyl, and if R3 represents hydroxyalkyl then R2 and R2' 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

 

The technical field to which the invention relates.

The present invention relates to a new isoquinoline compound-containing pharmaceutical agent as an active ingredient.

The level of technology

Poly(ADP-ribose)polymerase, hereinafter sometimes abbreviated hereinafter as "PARP is a nuclear enzyme that uses nicotinamide (NAD) as a substrate, breaks the link between nad and ribose, which shifts the balance of ADP-ribose in protein and causes polymerization attach multiple ADP-Robotnik residues. This enzyme an attractive as associated with apoptosis enzyme, which is reputed to be activated in the recognition of DNA damage by free radicals such as nitric monoxide, active oxygen, etc. that occurs in the affected area during ischemia, and plays a major role in promoting DNA repair.

In recent years, believe that the activation of PARP reduces intracellular NAD, a significant part of the ATP is consumed to compensate for this decrease, which increases intracellular energy, and this leads to cell death. In the experiment using mice with shock PARP, found that cultured neuronal cells exhibit resistance to violations associated with exciting am what narikotome, such as nitric monoxide, NMDA (N-methyl-D-aspartate), etc. and that it shows a very significant protective effect by inhibiting cerebral infarction caused by cerebral ischemia, not less than 80% (Eliasson MJL. et al., Nature Med., 3, 1089-95 (1997)).

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

In addition, in JP-B-S46-12454 disclosed derivatives of isoquinoline, analgesic action and hypoglycemic activity, U.S. patent No. 1174272 and 1062357, respectively, derivatives of hintline having hypotensive activity, are disclosed in GB patent No. 1174272 and 1062357 and in DE patent No. 2121031, respectively, in U.S. patent No. 4808595 disclosed derivatives of FSD is pyridine, having the ability to lower intraocular pressure, and in JP-A-S64-42472 disclosed derivatives hintline with the ability to correct cerebral dysfunction, but none of them had instructions on PARP-inhibitory activity.

(patent reference 1) and 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) U.S. Patent No. 1174272

(patent reference 14) U.S. 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) U.S. Patent No. 4808595

(patent reference 19) JP-A-S64-42472

(non-patent reference 1) Eliasson MJL. et al., Nature Med., 3, 1089-95 (1997)

The invention

The aim of the present invention is to provide compounds with PARP-inhibitory activity and useful as a therapeutic agent for the treatment of cerebral infarction, particularly a therapeutic agent for the treatment of acute cerebral infarction, and compounds that can be used as an intermediate with the unity.

The authors of the present invention have 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 water adduct have an effective PARP-inhibiting activity, which led to the present invention. Accordingly, the present invention proposed the following:

(1) Isoquinoline compound represented by the following formula (I):

where

R1represents a hydrogen atom, halogen atom, alkyl, alkoxy, halogenated, hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbarnoyl, N-allylcarbamate, N,N-dialkylamino, acylamino, diarylamino, thiol, alkylthio, alkoxycarbonyl, sulfamoyl, N-alkylsulfonyl, N,N-dialkylamino or alkoxyalkyl;

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

R represented by the following formula (II):

where

X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH;

W represents CH or nitrogen atom, provided that if Predstavljaet 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 R3represents a hydrogen atom, alkyl, amino, monoalkylamines, dialkylamines, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, optionally containing a Deputy, benzoylamine, optionally containing a Deputy, arylalkyl, sulfamoyl or alkylsulfonamides, then R2and R2'the same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'the same or different, and each represents a hydrogen atom, hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylamino, or R2and R2'taken together form a ketone,

its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(2) the Above isoquinoline compound of the formula (I), where

R1represents a hydrogen atom or alkyl;

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

R is represented by formula (II)

where, in the formula (II)

X represents CH or nitrogen atom, y is the condition, if Y is missing in the formula (I), then X must represent CH;

W represents CH or nitrogen atom, provided that if X is 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 R3represents a hydrogen atom or alkyl, then R2and R2'the same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'the same or different, and each represents a hydrogen atom, hydroxyl group, alkyl or hydroxyalkyl,

its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(3) the Above isoquinoline compound of the formula (I), where

R1represents a hydrogen atom or methyl;

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

R is represented by formula (II)

where, in the formula (II)

X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH;

W represents CH or nitrogen atom, provided that if X is 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 R3present is employed, a hydrogen atom or methyl, then R2and R2'the same or different, and each represents a hydroxyl group, hydroxymethyl or 2-hydroxyethyl; and

if R3represents 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or 2-hydroxypropyl, then R2and R2'the same or different, and each represents a hydrogen atom, hydroxyl group, methyl, hydroxymethyl or 2-hydroxyethyl,

its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

(4) the Above isoquinoline compound which is chosen from the group consisting of

(1) (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(2) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-5-methyl-2H-isoquinoline-1-he

(3) 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he

(4) 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he

(5) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(6) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he

(7) 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(8) 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-2H-isoquinoline-1-he

(9) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-2H-isoquinoline-1-he

(10) 3-[1-(3-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(11) 3-[1-(4-hydroxybutyl)piperidine-4-yl]-2H-isoquinoline-1-he

(12) 3-[2-hydroxy-3-(pyrrolidin-1-yl)impregnated is]-2H-isoquinoline-1-he

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

(14) (S)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(15) (S)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he

(16) (S)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he

(17) (S)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he

(18) (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he

(19) 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he

(20) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he

(21) 3-(1-methyl-2-hydroxyethylpiperazine-4-yl)-2H-isoquinoline-1-he

(22) 3-[1-(3-hydroxy-2,2-dimethylpropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(23) 5-methyl-3-[1-(3-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(24) 3-[1-(2-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(25) 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(26) (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he

(27) 3-[2-(3-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he

(28) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(29) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinoline-1-he

(30) 5-methyl-3-[1-(2-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(31) 5-methyl-3-[1-(4-hydroxybutyl)piperidine-4-yl]-2H-isoquinoline-1-he

(32) 3-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(34) (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(35) (R)-3-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(36) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(37) (-)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(38) (+)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

their optically active forms, their pharmaceutically acceptable salts, their water adducts, their hydrates and their solvate.

(5) the Above isoquinoline compound of the formula (I), where

R1represents 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 1 or 2;

t represents an integer 2;

if R3represents methyl, then R2and R2'the same or different, and each represents a hydroxyl group or hydroxymethyl; and

if R3is hydroxyethyl, then R2and R2'the same or different, and each represents a hydrogen atom, a hydroxyl group or hydroxymethyl,

its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(6) the Above isoquinoline compound which is chosen from the group consisting of

(2) 3-[1-(hydroxyethyl)piperidine-4-yl]-5-methyl-2H-isoquinoline-1-he

(9) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-2H-isoquinoline-1-he

(10) 3-[1-(3-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(11) 3-[1-(4-hydroxybutyl)piperidine-4-yl]-2H-isoquinoline-1-he

(21) 3-(1-methyl-2-hydroxyethylpiperazine-4-yl)-2H-isoquinoline-1-he

(22) 3-[1-(3-hydroxy-2,2-dimethylpropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(23) 5-methyl-3-[1-(3-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(24) 3-[1-(2-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(28) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(29) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinoline-1-he

(30) 5-methyl-3-[1-(2-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he

(31) 5-methyl-3-[1-(4-hydroxybutyl)piperidine-4-yl]-2H-isoquinoline-1-he

(33) 3-[1-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(37) (-)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(38) (+)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

their optically active forms, their pharmaceutically acceptable salts, their water adducts, their hydrates and their solvate.

(7) the Above isoquinoline compound of the formula (I), where

R1represents a hydrogen atom or methyl;

Y represents ethylene, propylene or 2-hydroxypropyl; and

R is represented by formula (II)

where, in the formula (II)

X represents a nitrogen atom;

W represents CH;

s represents an integer is number from 1 to 3;

t represents an integer from 1 to 4;

R2and R2'the same or different, and each represents a hydrogen atom, hydroxyl group, alkyl or hydroxymethyl; and

R3represents a hydrogen atom,

provided that if R2represents a hydrogen atom or alkyl, R2'represents a hydroxyl group or hydroxymethyl,

its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(8) the Above isoquinoline compound which is selected from the group including

(1) (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(3) 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he

(4) 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he

(5) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(6) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he

(7) 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(8) 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-2H-isoquinoline-1-he

(12) 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-2H-isoquinoline-1-he

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

(14) (S)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(15) (S)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he

(16) (S)-3-[3-(2-hydroxyethylpyrrolidine-1-ylpropyl]-5-methyl-2H-isoquinoline-1-he

(17) (S)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he

(18) (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he

(19) 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he

(20) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he

(25) 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(26) (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he

(27) 3-[2-(3-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he

(32) 3-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(34) (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(35) (R)-3-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(36) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

their optically active forms, their pharmaceutically acceptable salts, their water adducts, their hydrates and their solvate.

(9) the Above isoquinoline compound of the formula (I), where

R1represents 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 the formula (I), X represents a nitrogen atom; when Y is absent in the formula (I), X represents CH;

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

s represents an integer of 1 ili;

t represents an integer from 1 to 3;

if R3represents a hydrogen atom, then R2and R2'each represents a hydroxyl group or hydroxymethyl; and

if R3is hydroxyethyl, R2and R2'each represents a hydrogen atom, a hydroxyl group or hydroxymethyl,

its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(10) the Above isoquinoline compound which is selected from the group including

(1) (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(2) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-5-methyl-2H-isoquinoline-1-he

(5) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(28) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(34) (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(36) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(37) (-)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(38) (+)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

their optically active forms, their pharmaceutically acceptable salts, their water adducts, their hydrates and their solvate.

(11) the Above isoquinoline compound of the formula (I), where

R1is methyl;

Y is absent; and

R a represents the formula (II)

where

X represents CH;

W represents a nitrogen atom;

S represents 1 or 2;

t represents an integer 2;

R2and R2'the same or different, and each represents a hydrogen atom, a hydroxyl group or hydroxyalkyl; and

R3is hydroxyethyl,

its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(12)

(2) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-5-methyl-2H-isoquinoline-1-it, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(13)

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

(14)

(37) (+)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(15)

(38) (-)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(16) the Above isoquinoline compound of the formula (I), where

R1is methyl;

Y represents ethylene;

R is represented by formula (II)

where, in the formula (II)

X represents a nitrogen atom;

W represents CH;

p> s is 1;

t represents an integer 2 or 3;

R2and R2'the same or different, and each represents a hydrogen atom, a hydroxyl group or hydroxymethyl; and

R3represents a hydrogen atom,

provided that if R2represents a hydrogen atom, then R2'must represent a hydroxyl group or hydroxymethyl,

its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(17)

(1) (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(18)

(5) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(19)

(34) (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(20)

(36) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(21) the Agent for preventing and/or treating diseases caused by hyperactivity of poly(ADP-ribose)polymerase, which includes the above isoquinoline compound, its optically active form, its pharmaceutically als is salt, its water adduct, its hydrate and its MES.

(22) the Above agent used for the prevention and/or treatment of cerebral infarction.

(23) the Above agent used for the prevention and/or treatment of acute cerebral infarction.

(24) the Above agent used for the prevention and/or treatment, which improves neurological symptoms associated with cerebral infarction.

(25) the Agent for preventing and/or treating cerebral infarction, which includes the above isoquinoline compound, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(26) the Above agent used for the prevention and/or treatment of acute cerebral infarction.

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

(28) an Inhibitor of poly(ADP-ribose)polymerase, which includes the above isoquinoline compound, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

(29) a Compound selected from the group including:

(R)-3-(3-hydroxypyrrolidine-1-yl)-N-methyl-N-methoxypropane

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

(R)-3-[2-(3-hydroxypropy the Jn-1-yl)ethyl]-5-methylisoquinoline

(R)-3-(2-hydroxyethylpyrrolidine-1-yl)-N-methyl-N-methoxypropane

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

(R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline and

hydrochloride (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline.

(30) a Method for obtaining compounds of the following formula (15):

where

R1represents a hydrogen atom, halogen atom, alkyl, alkoxy, halogenated, hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbarnoyl, N-allylcarbamate, N,N-dialkylamino, acylamino, diarylamino, thiol, alkylthio, alkoxycarbonyl, sulfamoyl, N-alkylsulfonyl, N,N-dialkylamino or alkoxyalkyl;

J2is dialkylamino;

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

R represented by the following formula (II):

where

X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X represents CH;

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

s represents an integer 1 to 5;

t represents an integer from 1 to 5;

if R3represents a hydrogen atom, alkyl, amino, monoalkylamines, dialkylamines, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, not necessarily with the Deputy, benzoylamine, not necessarily with the Deputy, arylalkyl, sulfamoyl or alkylsulfonamides, then R2and R2'the same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'the same or different, and each represents a hydrogen atom, hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylamino, or R2and R2'taken together form a ketone,

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

where R1and J2have the above meanings, with a compound of the following formula (14):

where Y and R have the above values and the J3represents N-alkyl-N-alkoxyamino.

(31) a Method for obtaining compounds of the following formula (16):

where

R1represents a hydrogen atom, halogen atom, alkyl, alkoxy, halogenated, hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbarnoyl, N-allylcarbamate, N,N-dialkylamino, acylamino, diarylamino, thiol, alkylthio, alkoxycarbonyl, sulfamoyl, N-alkylsulfonyl, N,N-dialkylamino or alkoxyalkyl;

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

R represented by the following formula (II):

where

X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X represents CH;

W represents CH or nitrogen atom, provided that if X is 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 R3represents a hydrogen atom, alkyl, amino, monoalkylamines, dialkylamines, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, not necessarily with the Deputy, benzoylamine, not necessarily with the Deputy, arylalkyl, sulfamoyl or alkylsulfonamides, R2and R2'the same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'the same or different, and each represents a hydrogen atom, hydroxyl group, alkyl, shall hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylamino, or R2and R2'taken together form a ketone,

which includes the use of compounds of the following formula (15):

where J2is dialkylamino, and R1, Y and R have the above values.

(32) the Method of obtaining the compounds represented by the following formula (I):

where

R1represents a hydrogen atom, halogen atom, alkyl, alkoxy, halogenated, hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbarnoyl, N-allylcarbamate, N,N-dialkylamino, acylamino, diarylamino, thiol, alkylthio, alkoxycarbonyl, sulfamoyl, N-alkylsulfonyl, N,N-dialkylamino or alkoxyalkyl;

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

R represented by the following formula (II):

where

X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH;

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

s represents an integer is 1 to 5;

t represents an integer from 1 to 5;

if R3represents a hydrogen atom, alkyl, amino, monoalkylamines, dialkylamines, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, not necessarily with the Deputy, benzoylamine, not necessarily with the Deputy, arylalkyl, sulfamoyl or alkylsulfonamides, R2and R2'the same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'the same or different, and each represents a hydrogen atom, hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylamino, or R2and R2'taken together form a ketone,

which includes the use of compounds of formula (16):

where

R1represents a hydrogen atom, halogen atom, alkyl, alkoxy, halogenated, hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbarnoyl, N-allylcarbamate, N,N-dialkylamino, acylamino, diarylamino, thiol, alkylthio, alkoxycarbonyl, sulfamoyl, N-alkylsulfonyl, N,N-dialkylamino or alkoxyalkyl;

Y is absent or represents alkylenes chain containing 1 to 8 carbon atoms, where an arbitrary carbon atom may have to the number of substituent hydroxyl group; and

R represented by the following formula (II):

where

X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH;

W represents CH or nitrogen atom, provided that if X is 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 R3represents a hydrogen atom, alkyl, amino, monoalkylamines, dialkylamines, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, not necessarily with the Deputy, benzoylamine, not necessarily with the Deputy, arylalkyl, sulfamoyl or alkylsulfonamides, then R2and R2'the same or different, and each represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'the same or different, and each represents a hydrogen atom, hydroxyl group, alkyl, hydroxyalkyl, alkoxycarbonyl, dialkylaminoalkyl or dialkylamino, or R2and R2'taken together form a ketone.

(33) the Method of obtaining the above isoquinoline compound, its optically active forms, its pharmaceutically acceptable salt, a water adduct, its hydrate or its MES, which includes the above mentioned stages.

(34) SP is a way to obtain the above isoquinoline compounds its optically active forms, its pharmaceutically acceptable salt, a water adduct, its hydrate or its MES, which includes the above mentioned stages.

The preferred embodiment of the invention

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 tautomer.

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

Specific examples of the substituents for R1following, the Deputy may be located at any one of the carbon atoms of the ring:

the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom, preferably fluorine atom, chlorine atom and bromine atom;

alkyl: 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, preferably methyl;

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

halogenoalkane: alkyl (as defined above), substituted by one or more of halogen atoms (as defined above), such as tormentil, deformity, trifluoromethyl, 2-foretel, 2,2-dottorati, 2,2,2-triptorelin and the like, preferably trifluoromethyl;

dialkylamino: dialkylamino, where the alkyl fragments are the same or different, and each independently represents alkyl (as defined above) and the alkyl fragments can be in the form of a ring. For example, you can specify dimethylamino, diethylamino, N-methyl-N-ethylamino, pyrrolidin-1-yl, piperidine-1-yl and the like, preferably dimethylamino;

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

alkoxycarbonyl: ester consists of alkoxy (as defined above) and carbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl etc.;

N-allylcarbamate: N-allylcarbamate consisting of monoalkylamines containing from 1 to 4 carbon atoms and carbonyl, such as N-methylcarbamoyl, N-ethylcarbazole, N-propellerblades, N-butylcarbamoyl etc.;

N,N-dialkylamino: N,N-dialkylamino consisting of dialkylamino (as defined above) and carbonyl, such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylamino, N,N-dibutylamino etc.;

acylamino: acylamino consisting of acyl (as defined, is Elena above) and amino, such as formylamino, acetylamino, propionamido, bucillamine etc.;

diarylamino: diarylamino consisting of two atilov (as defined above), amino, where the acyl fragments independent and may be the same or different, such as N,N-diatsetilamino, N,N-dipropylamino, N,N-dibutylamino etc.;

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

alkoxycarbonyl: alkoxycarbonyl consisting of alkoxycarbonyl (as defined above), amino, such as methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, butoxycarbonylamino etc.;

N-alkylsulfanyl: N-alkylsulfonyl consisting of monoalkylamines (as defined above) and a sulfone, such as N-methylcarbamoyl, N-ethylsulfonyl, N-propylsulfonyl, N-butylsulfonyl etc.;

N,N-dialkylamino: N,N-dialkylamino consisting of dialkylamino (as defined above) and a sulfone, such as N,N-dimethylsulphamoyl, N,N-diethylcarbamoyl, N,N-dipropylamino, N,N-dibutylamino etc.;

alkoxyalkanols: alkoxyalkanols consisting of alkoxy (as defined above), alkyl (as defined above) and oxygen, where the alkoxy and alkyl have the above values, such as methoxyethoxy, ethoxymethyl the si and the like, preferably methoxyethoxy.

Of the provisions of the substituent for R1preferably the substitution in the 5-position or 7-position of the isoquinoline ring, particularly preferably a substitution in the 5-position.

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

(1) -CH(OH)CH2-,

(2) -CH2CH(OH)CH2-,

(3) -CH2CH2CH(OH)CH2-,

(4) -CH2CH2CH2CH(OH)CH2-,

(5) -CH2CH2CH2CH2CH(OH)CH2-,

(6) -CH2CH2CH2CH2CH2CH(OH)CH2-,

(7) -CH2CH2CH2CH2CH2CH2CH(OH)CH2-,

(8) -CH2CH(CH2OH)CH2-,

(9) -CH2CH(CH2CH2OH)CH2-, and the like,

preferably (2). As for unbranched alkalinous chain, the preferred ethylene and propylene.

Specific examples of the substituents for R2and R2'are the following, with the Deputy may be located at any one of the carbon atoms of the ring:

alkyl: as defined above, the alkyl for R1;

hydroxyalkyl: hydroxyalkyl consisting of alkyl (as defined above alkyl for R1) and hydroxyl groups, preferably hydro is simetal;

alkoxycarbonyl: alkoxycarbonyl consisting of alkoxy (as defined above alkoxy for R1) and carbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like, preferably etoxycarbonyl;

dialkylaminoalkyl: dialkylaminoalkyl consisting of dialkylamino (as defined above dialkylamino for R1) and alkyl (as defined above alkyl for R1), and the preferred dimethylaminomethyl;

dialkylamino: dialkylamino consisting of dialkylamino (as defined above dialkylamino for R1) and carbonyl, preferably dimethylcarbamoyl.

Specific examples of the substituents for R3following:

alkyl: as defined above, the alkyl for R1, preferably methyl, ethyl, propyl and isobutyl, especially preferred methyl;

hydroxyalkyl: as defined above hydroxyalkyl for R2such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy-2-methylpropyl, 4-hydroxybutyl and the like, preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxypropyl 2,2-dimethyl-3-hydroxypropyl, especially preferred hydroxymethyl and hydroxyethyl;

monoalkylamines: as defined above, monoalkylamines for R1and preferred metiram the but;

dialkylamino: as defined above, dialkylamino for R1, preferably dimethylamino;

alkoxycarbonyl: as defined above alkoxycarbonyl for R1, preferably etoxycarbonyl;

alkylsulfonyl: alkylsulfonyl consisting of alkyl (as defined above alkyl for R1and sulfonyl, such as methanesulfonyl, econsultancy etc.;

acyl: as defined above for acyl R1;

acylamino, optional with Deputy: as defined above, acylamino for R1the group consisting of acyl containing from 1 to 4 carbon atoms and amino groups, which are selected from formylamino, acetylamino, propionamido, 2-methylpropionamide, bucillamine. As Vice-preferably you can specify the atoms of halogen (particularly fluorine atom). For example, you can specify triptoreline, benzoylamine, optional with Deputy: Deputy, you can specify those that are similar to those listed for R1;

arylalkyl: arylalkyl consisting of aryl and alkyl (as defined above acylamino for R1), such as benzyl, phenethyl and the like, preferably benzyl;

alkylsulfonamides: alkylsulfonamides consisting of alkylsulfonyl (as defined above), amino, such as methanesulfonamido, ethanolgasoline etc. and prepositionalphrase.

As the compounds of formula (I) and its pharmaceutically acceptable salts, you can specify salt accession of inorganic acids or organic acids.

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

Compounds described by formula (I) of the present invention, can be synthesized in accordance with the following methods. In the following schemes of the reactions of each of the symbols have the above values, if no special instructions.

The method of obtaining 1

The compound of the formula (11)obtained in a known manner, is subjected to the interaction with the compound of the formula (12)obtained in a known manner, in the presence of a suitable base, usually used in organic synthesis such as n-utility, sitedisability, litigating, liebestraumereien and the like, in a suitable solvent, such that no inhibits the course of the reaction, such as diethyl ether, diisopropyl levy ether, tetrahydrofuran, 1,4-dioxane, arbitrary mixtures, and the like, at temperatures from -78°C to the boiling point of the solvent under reflux, preferably at a temperature of from -78°C to room temperature over a period of time from 0.1 (6 min) up to 48 hours, preferably from 1 hour to 24 hours, receiving the compound of formula (13).

The method of obtaining 2

The compound of formula (13) can be obtained by synthesis by the way, opened the way to obtain 1, using the compound of the formula (11'), obtained in a known manner, where J2represents amino, monoalkylamines (as defined above monoalkyl for R3), or dialkylamino (as defined above dialkylamino for R3) and the compound of formula (12)obtained in a known manner.

The method of obtaining 3

The compound of the formula (11') is subjected to interaction with the compound of the formula (14), where J3represents N-alkyl-N-alkoxyamino or dialkylamino (as defined above dialkylamino for R3), preferably N-methyl-N-methoxyamino, in the presence of a suitable base, typically used in the processes of synthesis in organic chemistry, such as n-utility, second-utility, tert-utility, sitedisability, Letitia ilamed, liebestraumereien and the like, in a suitable solvent mentioned above, which did not inhibit the course of the reaction, at a temperature in the range from -78°C to the boiling point of the solvent under reflux for from 0.1 (6 min) up to 48 hours, receiving compound of the formula (15). The compound of formula (15) is subjected to reaction in acetic acid, triperoxonane acid, methanesulfonic acid, hydrochloric acid, sulphuric acid or in arbitrary mixtures 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, receiving compound of the formula (16). The compound of formula (16) is subjected to interaction with a source of ammonia (for example, a salt of ammonia, commonly used in the synthesis of organic chemicals, such as ammonium acetate, ammonium carbonate, ammonium chloride, aqueous ammonia, and the like) in a suitable solvent, such that no inhibits the course of the reaction (methanol, ethanol, n-propanol, isopropanol, n-butanol, dimethoxyethane, 2-methoxyethanol, acetic acid, aqueous ammonia, an arbitrary mixture of these solvents and the like)at a temperature in the range from room temperature to the boiling point of the solvent with reflux for from 0.1 (6 min) up to 48 hours, produces the compound of formula (13).

Thus obtained compound of the present invention can be selected or cleared in accordance with customary methods.

Compounds of the present invention described by formula (I)can also be synthesized using below the intermediate connection.

For example, (R)-3-(2-hydroxyethylpyrrolidine-1-yl)propionitrile, (R)-3-(3-hydroxypyrrolidine-1-yl)propionitrile, (S)-3-(3-hydroxypyrrolidine-1-yl)propionitrile, (R)-3-(3-hydroxypyrrolidine-1-yl)-N-methyl-N-methoxypropane, (R)-N,N-diethyl-2-[4-(3-hydroxypyrrolidine-1-yl)-2-oxobutyl]-3-methylbenzamide, (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methylisoquinoline, (R)-3-(2-hydroxyethylpyrrolidine-1-yl)-N-methyl-N-methoxypropane, (R)-N,N-diethyl-2-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-oxobutyl]-3-methylbenzamide, (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline hydrochloride and (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline 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-isoquinoline-1-she, (34) (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it (36) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it.

In addition, (1) (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-(4) (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (36) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he of the formula (I) of the present invention can be synthesized, through the interaction of (R)-3-(2-hydroxyethylpyrrolidine-1-yl)propionitrile, (R)-3-(3-hydroxypyrrolidine-1-yl)propionitrile or (S)-3-(3-hydroxypyrrolidine-1-yl)propionitrile with N,N-diethyl-2,3-dimethylbenzamide or N,N-dimethyl-2,3-dimethylbenzamide in accordance with the method of obtaining 1.

The compound of formula (I), its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and his MES obtained by the methods described above have an effective PARP-inhibiting activity and can be used as a prophylactic and/or therapeutic agents that facilitate the state of cerebral infarction, especially agents for the prevention and/or treatment of acute cerebral infarctions. In addition, they can be used as a prophylactic and/or therapeutic agents that weaken the neurological symptoms associated with cerebral infarction, especially the symptoms of acute cerebral infarction. In addition, neurological symptoms associated with cerebral infarction, especially acute cerebral infarction, can be estimated by counting in accordance with the scale of assessments of heart attacks NIH 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 National Institute of Health US National Institute of Health (NIH).

If kinolive connection, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and MES in accordance with the present invention 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 injections, infusions, suppositories and the like)obtained by mixing with pharmaceutically acceptable carrier (excipient, binder, baking powder, corrective agent, flavoring agent, emulsifying agent, diluent contributing to the dissolution of the agents and the like). The pharmaceutical composition may be created in accordance with customary methods. In the description of the methods of parenteral administration includes subcutaneous injection, intravenous injection, intraperitoneal injection, drip, etc. Preparations for injection can be prepared in accordance with well-known specialists of ways. Suppositories for rectal injection can be obtained by mixing the drug with suitable excipients, etc. as a dosage form of solid preparations intended for oral administration, you can specify such as powders, granules, tablets, pill is, capsules, etc. as liquid preparations for oral administration can specify emulsions, syrups, elixirs, suspensions, solutions, etc. applicable as pharmaceutical agents.

The dose is determined with respect to the age, body weight, General health, sex, diet, time of administration, route of administration, frequency of breeding, a combination of medication, the disease state to be treated of the patient, and other factors. Compounds of the present invention, their optical isomers and their pharmaceutically acceptable salts are of low toxicity and are safe to use. Although the magnitude of the daily dose varies depending on the condition and body weight of the patient, the type of connection, the route of administration and the like, for example, preferably parenteral enter (subcutaneously, intravenously, intramuscularly, or rectally) about 0.01-50 mg/individual/day, preferably 0.01 to 20 mg/individual/day, and oral about 0.01-150 mg/individual/day, preferably 0.1 to 100 mg/individual/day.

EXAMPLES

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

Getting the parent compounds. Example 1

(R)-2-hydroxyethylpyrrolidine (Tokyo Kasei Kogyo Co., Ltd. (50 g) dissolved in methylene chloride (500 ml), and to the solution are added dropwise Acrylonitrile (36 ml) under stirring at room temperature. Then the mixture is stirred over night at room temperature. After completion of the reaction the solvent is concentrated and receiving (R)-3-(2-hydroxyethylpyrrolidine-1-yl)propionitrile (76 g).

1H-NMR (CDCl3) δ: 1,61-of 1.94 (5H, m), 2,33 (1H, q, J=8 Hz), 2,53 (2H, DD, J=6 Hz, 8 Hz), 2,61-a 2.71 (2H, m), 3,01-3,10 (1H, m), 3,16-3,24 (1H, m), 3,37-of 3.46 (1H, m)to 3.64 (1H, DD, J=3 Hz, 11 Hz).

Getting the parent compounds. Example 2

Hydrochloride (R)-(-)-3-pyrrolidinone (Tokyo Kasei Kogyo Co., Ltd.) (50 g) and potassium carbonate (55.8 g) is dissolved in a mixed solvent consisting of acetonitrile (500 ml) and water (100 ml)and the solution added dropwise Acrylonitrile (29 ml) at room temperature. Then the mixture is stirred over night at room temperature. After completion of the reaction the solvent is concentrated and the resulting residue is dissolved in water. Potassium carbonate added until saturation. The mixture is extracted three times with chloroform, and the extract is dried over potassium carbonate. The solvent is concentrated and the resulting residue purified using a chromatographic column with silica gel (chloroform:methanol = 10:1)to give (R)-3-(3-hydroxypyrrolidine-1-yl)propionitrile (53 g).

1H-NMR (CDCl3) δ: 1,68-of 1.81 (1H, m), 2,04-2,10 (1H, m), 2,13-of 2.27 (1H, m), 2,34 is 2.43 (1H, m), of 2.51 2.63 in (3H, m), 72-2,84 (3H, m), 2.91 in-2,99 (1H, m), 4,30-and 4.40 (1H, m).

Getting the parent compounds. Example 3

Carrying out a reaction similar to the method of obtaining the starting compounds of example 1, using (S)-(+)-3-pyrrolidino (Omega Corporation) (12.3 g) and Acrylonitrile (10,2 ml), get (S)-3-(3-hydroxypyrrolidine-1-yl)propionitrile (53 g).

1H-NMR (CDCl3) δ: 1,68-of 1.81 (1H, m), 2,04-2,10 (1H, m), 2,13-of 2.27 (1H, m), 2,34 is 2.43 (1H, m), of 2.51 2.63 in (3H, m), 2,72-2,84 (3H, m), 2.91 in-2,99 (1H, m), 4,30-and 4.40 (1H, m).

Getting the parent compounds. Example 4

Mix hydrochloride of N,O-dimethylhydroxylamine (198,6 g), sodium bicarbonate (620,9 g), methylene chloride (1.5 l) and water (1.1 l) and to the mixture are added dropwise acrylamid (150 ml) under cooling with ice. The mixture is stirred under ice cooling for 4 hours and methylenchloride layer emit. The organic layer is dried over magnesium sulfate and the solvent is concentrated and receiving N-methyl-N-ethoxyacrylate (223,79 g). This connection is used in the next stage without additional purification.

1H-NMR (CDCl3) δ: of 3.27 (3H, c), 3,71 (3H, c), USD 5.76 (1H, DD, J=2 Hz, 11 Hz), to 6.43 (1H, DD, J=2 Hz, 17 Hz), 6,74 (1H, DD, J=11 Hz, 17 Hz).

Getting the parent compounds. Example 5

Mix hydrochloride (R)-(-)-3-pyrrolidinone (51.8 g), potassium carbonate (69,6 g), water (125 ml) and acetonitrile (500 ml) and the mixture paramesh what happens at room temperature for 1 hour. To the mixture is added dropwise a solution (60 ml) of N-methyl-N-methoxyethylamine (42 g) in acetonitrile obtained in example 4 to obtain the starting compounds and the reaction mass is kept over night at room temperature. After completion of the reaction, the acetonitrile concentrated under reduced pressure and the potassium carbonate is added in excess to the remaining water layer. The aqueous layer was extracted with chloroform, the extract is dried over magnesium sulfate and concentrated, obtaining (R)-3-(3-hydroxypyrrolidine-1-yl)-N-methyl-N-methoxypropane (76,7 g).

1H-NMR (CDCl3) δ: of 1.65 and 1.75 (1H, m), 2,10-of 2.25 (1H, m), a 2.36 (1H, DD, J=8,79 Hz, 15.2 Hz), 2,60-2,70 (4H, m), 2,75 is 2.80 (2H, m), 2,80-2,90 (3H, m), 3,18 (3H, s), 3,48 (1H, USS), 3,70 (3H, s), 4,33 is 4.35 (1H, m).

Getting the parent compounds. Example 6

In a stream of nitrogen add Diisopropylamine (63,8 ml) and tetrahydrofuran (90 ml) and the solution (1.56 mol/l, 280 ml) n-utility in hexane are 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 to the mixture are added dropwise a solution (120 ml) of N,N-diethyl-2,3-dimethylbenzamide (42.5 g) in tetrahydrofuran, the mixture was stirred at -78°C for 1 hour. Then added dropwise a solution (120 ml) of (R)-3-(3-hydroxypyrrolidine-1-yl)-N-methyl-N-methoxypropylamine (38,6 g)obtained in example 5 to obtain the original compounds, Tetra is drofuran. The temperature is gradually increased to room temperature and the reaction mass leave for the night. After completion of the reaction, water is added (200 ml) and tetrahydrofuran concentrated under reduced pressure. The reaction mixture is extracted with chloroform. Chloroformate layer is dried over anhydrous magnesium sulfate and concentrated, obtaining (R)-N,N-diethyl-2-[4-(3-hydroxypyrrolidine-1-yl)-2-oxobutyl]-3-methylbenzamide (79,4 g).

1H-NMR (CDCl3) δ: was 1.04 (3H, t, J=7.2 Hz), to 1.21 (3H, t, J=7.2 Hz), of 1.65 and 1.80 (1H, m), 2,10-of 2.30 (2H, m), of 2.21 (3H, s), 2.40 a-2,50 (1H, m), 2,60 is 2.80 (5H, m), 2,80-2,95 (1H, m)3,00-3,20 (2H, m), 3,30 is 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).

Getting the parent compounds. Example 7

(R)-N,N-diethyl-2-[4-(3-hydroxypyrrolidine-1-yl)-2-oxobutyl]-3-methylbenzamide (124 g)obtained in example 6 to obtain the original compounds, 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 alkalinized with potassium carbonate. Add chloroform and insoluble matter is removed by filtering through celite. The aqueous layer was extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and concentrated and precipitated precipitated crystals are washed secludedly ether-ethyl acetate and filtered off with suction, receiving (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methylisoquinoline (55,6 g).

1H-NMR (CDCl3) δ: of 1.65 and 1.80 (1H, m), 2,10-of 2.25 (1H, m), 2,30-to 2.40 (1H, m), the 2.46 (3H, s), 2,56-2,61 (1H, m), 2,74-2,78 (1H, m), 2,85-2,96 (3H, m), 4,32 is 4.36 (1H, m), to 6.43 (1H, s), 7,34 (3H, t, J=7.5 Hz), 7,51 (1H, d, J=7.5 Hz), to 8.12 (1H, d, J=7.5 Hz).

Getting the parent compounds. Example 8

Mix D-prolinol (30 g) and tetrahydrofuran (300 ml) and to the resulting mixture is added N-methyl-N-ethoxyacrylate (28,7 g) under stirring at room temperature. After completion of the reaction, the reaction mixture was concentrated, receiving from a quantitative yield of (R)-3-(2-hydroxyethylpyrrolidine-1-yl)-N-methyl-N-methoxypropane in the form of oil.

1H-NMR (CDCl3) δ: 1,62-1,89 (4H, m), 2,22-of 2.30 (1H, m), 2,48 is 2.80 (4H, m), 3,16-of 3.48 (6H, m), 3,18 (3H, c), 3,65-3,71 (1H, m), 3,70 (3H, c).

Getting the parent compounds. Example 9

Mix Diisopropylamine (104 ml) and tetrahydrofuran (500 ml) and the mixture added dropwise a solution of (457 ml, 1.56 mol/l) n-utility in hexane under stirring at -78°C in a stream of nitrogen. After completion of adding dropwise, the mixture is stirred at 0°C for 30 min and again cooled to -78°C. To the reaction mixture is added dropwise a solution of N,N-diethyl-2,3-dimethylbenzamide (67,0 g) in tetrahydrofuran (150 ml). After completion of adding dropwise, the mixture is stirred for d is more at a temperature of -78° C for 1 hour. Added dropwise a solution of (R)-3-(2-hydroxyethylpyrrolidine-1-yl)-N-methyl-N-methoxypropylamine (64 g)obtained in example 8 to obtain the source compounds in tetrahydrofuran (150 ml). After completion of adding dropwise, the mixture is stirred further at a temperature of -78°C for 1 hour. The mixture is gradually warmed to room temperature. After completion of the reaction, to the reaction mixture add ice and water and the organic layer isolated. The organic layer is concentrated and combined with the above water layer and merged the layers twice extracted with chloroform. The organic layer is concentrated and receiving (R)-N,N-diethyl-2-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-oxobutyl]-3-methylbenzamide in the form of oil. This connection is used in the next reaction without further purification.

1H-NMR (CDCl3) δ: was 1.04 (3H, t, J=7 Hz), to 1.21 (3H, t, J=7 Hz), 1,62-of 1.94 (4H, m), 2,12-2,22 (1H, m), of 2.21 (3H, c), 2,36 is 2.44 (1H, m), 2,52-2,63 (2H, m), 2,68-2,82 (1H, m), 2,97-3,24 (5H, m), 3,32 is 3.40 (2H, m), 3,62-are 3.90 (4H, m), 7.03 is-was 7.08 (1H, m), 7,16-7,20 (2H, m).

Getting the parent compounds. Example 10

All the amount of (R)-N,N-diethyl-2-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-oxobutyl]-3-methylbenzamide obtained in example 9 to obtain the original compounds, dissolved in concentrated hydrochloric acid (250 ml) and water (250 ml) and the resulting solution nagrevaete boiling under reflux for 10 hours. After completion of the reaction, the reaction mixture is cooled to room temperature and washed with toluene (200 ml). For alkalizing layer to the aqueous layer add an aqueous solution of potassium carbonate (300 g) and the resulting double-layer is extracted with chloroform, the extract is dried over magnesium sulfate. The solvent is concentrated and to the resulting residue add acetone. The mixture is then concentrated, obtaining (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline (67 g).

1H-NMR (CDCl3) δ: 1,66-of 1.92 (4H, m), 2,32-to 2.42 (1H, m), 2,46 (3H, c), 2,65-2,70 (4H, m), 3,12 of 3.28 (2H, m)to 3.38 (1H, DD, J=4 Hz, 11 Hz), to 3.64 (1H, DD, J=4 Hz, 11 Hz), to 6.43 (1H, c), 7,34 (1H, t, J=8 Hz), 7,51 (1H, d, J=8 Hz), to 8.12 (1H, d, J=8 Hz).

Using the known method, (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline converted into the hydrochloride, getting hydrochloride (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline.

1H-NMR (DMCO-d6) δ: 1,70-to 2.18 (4H, m), 2,47 (3H, c), is 3.08-up 3.22 (3H, m), 3,60-of 3.85 (5H, m), the 5.51 (1H, USS), PC 6.82 (1H, c), 7,47 (1H, t, J=8 Hz), 7,69 (1H, d, J=7 Hz), to 7.99 (1H, d, J=8 Hz), 10,31 (1H, USS).

Example 1

Diisopropylamine (122 ml) dissolved in tetrahydrofuran (400 ml) and the solution added dropwise n-utility (1.56 mol/l) (534 ml) under cooling with ice. The mixture is stirred under ice cooling for 30 min, then cooled to a temperature of -78°C. a Solution (150 ml) N,N-diethyl-2,3-dimethylbenzamide (85,4 g) in tetrahydrofuran until the NML added to the reaction mixture and the mixture was stirred at -78° C for 0.5 hours. The reaction mixture was cooled to -78°C and to the mixture are added dropwise a solution (150 ml) of (R)-1-(2-cyanoethyl)-3-hydroxypyrrolidine (53 g) in tetrahydrofuran. The reaction mixture is heated to room temperature. After completion of the reaction, to the reaction mixture, water is added, the organic layer is isolated and concentrated. The residue is dissolved in chloroform, the solution washed with saturated saline and dried over magnesium sulfate. The organic layer is extracted with 1N. hydrochloric acid and the resulting layer is alkalinized. The aqueous layer was extracted with chloroform and the extract is dried over magnesium sulfate. The solvent is concentrated and the resulting residue purified using a chromatographic column filled with silica gel, obtaining (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (23,6 g).

1H-NMR (CDCl3) δ: 1,83 is 1.96 (1H, m), 2,21 of-2.32 (1H, m), 2,48 (3H, c), 2,49 is 2.55 (1H, m), 2,72-and 2.79 (3H, m), 2,81 of 2.92 (3H, m), 2,96 was 3.05 (1H, m), 4,42 figure-4.49 (1H, m), 6,33 (1H, c), 7,29 (1H, t, J=8 Hz), the 7.43 (1H, d, J=7 Hz), by 8.22 (1H, d, J=8 Hz), 11,40 (1H, USS).

MC(EI) 272(M+).

Using the known method, (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he is transformed into the hydrochloride, getting hydrochloride (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it.

1H-NMR (DMCO-d6) 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), of 5.55 (1H, USS), 6,52 (0,5H,c), 6,54 (0,5H, c), 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, USS), 11,27 (0,5H, USS), 11,43 (0,5H, USS), 11,46 (0,5H, USS).

MC(EI) 272(M+).

[α]D=-3,52° (c=1,15, MeOH).

The following is another way to obtain (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it.

Ammonium carbonate (65,3 g) is gradually added to acetic acid (165 ml). After completing the allocation of gas to the mixture of (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methylisoquinoline (54,3 g) and the mixture is heated at the boil under reflux for 1 hour. After completion of the reaction, the reaction mixture is cooled to room temperature and added to aqueous solution (300 ml) of sodium hydroxide (115 g) (when it is warm and smells of ammonia). The mixture is stirred at room temperature for 30 minutes After completion of the reaction, the mixture is extracted with chloroform, the extract is dried over magnesium sulfate and concentrated. To the obtained residue is added ethyl acetate, and the resulting suspension is washed. The result of the filter collect (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (45.1 g).

Example 2

5-Methyl-3-(piperidine-4-yl)-2H-isoquinoline-1-he (1.0 g), sodium bicarbonate (0.52 g) and 2-bromoethanol (0,67 g) dissolved in acetonitrile (20 ml) and the solution is heated at the boil under reflux. After completion of the reaction, the reaction mixture will contentresult and to the obtained residue, add water. The mixture is extracted with chloroform and the extract is dried over magnesium sulfate. The solvent is concentrated and the resulting residue purified using a chromatographic column filled with silica gel, receiving 3-[1-(2-hydroxyethyl)piperidine-4-yl]-5-methyl-2H-isoquinoline-1-he (0.4 g).

1H-NMR (CDCl3) δ: 1,80-of 1.95 (2H, m), 1,96 is 2.10 (2H, m), 2,24 is 2.33 (2H, m), 2,53 (3H, c), 2,56-to 2.65 (3H, m), 3,05 is 3.15 (2H, m)to 3.67 (2H, t, J=5 Hz), 6,44 (1H, c), 7,34 (1H, t, J=7 Hz), of 7.48 (1H, d, J=7 Hz), 8,24 (1H, d, J=7 Hz), of 10.72 (1H, USS).

MC(EI) 286(M+).

Example 3

Carrying out reaction according to the method of example 1, using N,N-diethyl-2-methylbenzamide (3,45 g) and 4-(3-hydroxypyrrolidine-1-yl)butyronitrile (1.5 g), obtained 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he (536,3 mg).

1H-NMR (CDCl3) δ: 1,78-of 1.95 (2H, m), 2,03-of 2.20 (2H, m), 2,31-2,49 (2H, m), 2,62-2,90 (4H, m), 3,09-3,30 (2H, m), 4.35 the figure-4.49 (1H, m), of 5.83 (1H, USS), 6,32 (1H, c), 7,35-7,45 (2H, m), 7,56 to 7.62 (1H, m), a 8.34 (1H, d, J=8 Hz), 14,41 (1H, USS).

MC (EI) 272(M+).

Example 4

Carrying out reaction according to the method of example 1, using N,N-dimethyl-2,3-dimethylbenzamide (2.00 g) and 4-(3-hydroxypyrrolidine-1-yl)butyronitrile (0.8 g), obtained 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he (157,5 mg).

1H-NMR (CDCl3) δ: 1,88 is 2.00 (2H, m), 2,08-2,19 (2H, m), a 2.36-to 2.42 (2H, m)of 2.50 (3H, c), 2,62 are 2.98 (4H, m), 3,16-3,30 (2H, m), 4,39-4,48 (1H, m), 5,86 (1H, OSS), to 6.43 (1H, c), 7,27-to 7.32 (1H, m), 7,44 (1H, ush., J=7 Hz), by 8.22 (1H, ush., J=8 Hz), accounted for 14.45 (1H, USS).

MC(EI) 286(M+).

Example 5

Carrying out the reaction as SPO the teaching of example 1, using N,N-dimethyl-2,3-dimethylbenzamide (4,10 g) and 3-(3-hydroxypyrrolidine-1-yl)propionitrile (1.5 g), obtained 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (157,5 mg).

1H-NMR (CDCl3) δ: 1,88 of 1.99 (1H, m), 2,22-of 2.38 (1H, m), 2,48-to 2.57 (4H, m), 2.71 to 2,95 (6H, m), 3,01-3,10 (1H, m), 3,51 (1H, USS), 4,42-4,51 (1H, m), 6,34 (1H, c), 7,27-7,31 (1H, m), the 7.43 (1H, ush., J=7 Hz), by 8.22 (1H, ush., J=8 Hz), 11,42 (1H, USS).

MC(EI) 272(M+).

Example 6

Carrying out reaction according to the method of example 1, using N,N-diethyl-2,3-dimethylbenzamide (4,347 g) and 3-(3-hydroxypyrrolidine-1-yl)propionitrile (1.6 g), obtained 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he (397,6 mg).

1H-NMR (CDCl3) δ: 1,84-of 1.97 (1H, m), 2.21 are is 2.37 (1H, m), 2,43 is 2.55 (1H, m), 2,70-2,82 (3H, m), 2,82-2,95 (3H, m), 3.00 and-3,11 (1H, m), of 4.44 ñ 4.50 (1H, m), and 6.25 (1H, c), 7,38 was 7.45 (1H, m), EUR 7.57 to 7.62 (1H, t, J=7 Hz), 8.34 per (1H, d, J=8 Hz), 11,41 (1H, USS).

MC(EI) 258(M+).

Example 7

Carrying out reaction according to the method of example 1, using N,N-dimethyl-2,3-dimethylbenzamide (3,17 g) and 3-(2-hydroxyethylpiperazine-1-yl)propionitrile (1.51 g), obtained 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (268 mg).

1H-NMR (300 MHz, CDCl3) δ: 11,5 (USS, 1H), 8,24 (d, J=8,1, 1H), 7,49 (d, J=8,1, 1H), 7,30 (t, J=8,1, 1H), 6,39 (c, 1H), 3,65-of 3.80 (m, 2H), 3,30 (USS, 1H), 3,10-3,30 (m, 1H), 3.00 and-3,10 (m, 1H), 2,85-3,00 (m, 1H), 2,70-2,85 (m, 2H), 2,50 (c, 3H), 2,35-2,60 (m, 2H), 1.30 and a 1.75 (m, 6H).

MC(EI) 300(M+).

Example 8

Carrying out reaction according to the method of example 1, using N,N-diethyl-2-methylbenzamide (3.42 g) and 3-(2-g is proximitybased-1-yl)propionitrile (1.51 g), receive 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-2H-isoquinoline-1-he (392 mg).

1H-NMR (300 MHz, CDCl3) δ: 11,5 (USS, 1H), at 8.36 (d, J=7.8 Hz, 1H), 7,60 (t, J=7.8 Hz, 1H), 7,39-7,46 (m, 2H), 6,29 (c, 1H), 3,65-of 3.85 (m, 2H), 3,30 (USS, 1H), 3,10-3,30 (m, 1H), 3.00 and-3,10 (m, 1H), 2,85-3,00 (m, 1H), 2,70-2,80 (m, 2H), 2,45-2,60 (m, 1H), 2,30 at 2.45 (m, 1H), 1.30 and a 1.75 (m, 6H).

MC(EI) 286(M+).

Example 9

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

1H-NMR (CDCl3) δ: 1,71 is 1.91 (2H, m), 2.00 in of 2.10 (2H, m), 2,22 is 2.33 (2H, m), 2,50-to 2.65 (3H, m), 3.04 from-3,13 (2H, m), 3,62-to 3.67 (2H, m), 6,34 (1H, c), 7,42-7,52 (2H, m), to 7.61-to 7.67 (1H, m), 8.34 per is 8.38 (1H, m), 10,69 (1H, USS).

MC(EI) 272(M+).

Example 10

Carrying out reaction according to the method of example 2, using the hydrochloride of 3-(piperidine-4-yl)-2H-isoquinoline-1-she (500 mg) and 3-bromo-1-propanol (315 mg), obtained 3-[1-(3-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he (136 mg).

1H-NMR (270 MHz, DMCO-d6) δ: 1,79 is 1.91 (4H, m), 2,12-2,17 (2H, m), 2,69-to 3.02 (5H, m), 3,44-to 3.52 (5H, m), 6,37 (1H, c), 7,42-7,47 (1H, m), 7,66-7,71 (2H, m), 8,13 (1H, d, J=7.8 Hz), to 11.31 (1H, USS).

MC(EI) 286(M+).

Example 11

Carrying out reaction according to the method of example 2, using the hydrochloride of 3-(piperidine-4-yl)-2H-isoquinoline-1-she (500 mg) and 4-bromo-1-butanol (434 mg), obtained 3-[1-(4-hydroxybutyl)piperidine-4-yl]-2H-isoquinoline-1-he (50 mg).

1H-NMR (270 MHz, DMCO-d6 ) δ: of 1.44 to 1.47 (4H, m), 1,57-to 1.63 (2H, m), 1,88-of 1.97 (4H, m), 2,27-to 2.41 (3H, m), 2.95 and-2,99 (2H, m), 3,40-of 3.42 (2H, m), 4,55 with 4.65 (1H, m), 6,36 (1H, c), 7,38-the 7.43 (1H, m), EUR 7.57-the 7.65 (2H, m)to 8.12 (1H, d, J=7.8 Hz), 11,20 (1H, USS).

MC(EI) 300(M+).

Example 12

Carrying out 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), obtained 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-2H-isoquinoline-1-he (0,089 g).

1H-NMR (CDCl3) δ: 1,75-of 1.84 (4H, m), 2,32-2,84 (8H, m), 4,00-4,06 (1H, m), of 6.26 (1H, c), 7,39-7,46 (2H, m), to 7.61 (1H, t, J=8 Hz), at 8.36 (1H, d, J=8 Hz), 9,85 (1H, USS).

MC(EI) 272(M+).

Example 13

Carrying out reaction according to the method of example 1, using N,N-dimethyl-2,3-dimethylbenzamide (2.65 g) and 3-hydroxy-4-(pyrrolidin-1-yl)butyronitrile (2,31 g), obtained 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he (of 0.066 g).

1H-NMR (CDCl3) δ: 1,75-of 1.84 (4H, m), 2,32-2,90 (8H, m), 2,39 (3H, c), 4,06-4,11 (1H, m), 6,36 (1H, c), 7,28 (1H, t, J=8 Hz), 7,42 (1H, d, J=8 Hz), 8,19 (1H, d, J=8 Hz), 10,00 (1H, USS).

MC(EI) 286(M+).

Example 14

Carrying out 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), get (S)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (351 mg).

1H-NMR (300 MHz, CDCl3) δ: 12,4 (USS, 1H), 8,23 (d, J=8,1, 1H), 7,45 (d, J=8,1, 1H), 7,31 (t, J=8,1, 1H), 6,39 (c, 1H), 4,10 (USS, 1H), 3,76 (d, J=14,1, 1H), of 3.56 (d, J=14,1, 1H), 3,35-to 3.50 (m, 1H), 3,10-of 3.25 (m, 1H), 2,85-2,95 (m, 2H), 2.70 height is 2.80 (m, 1H), 2,60-2,70 (m, 1H), 2,50 (c, 3H), 2.40 a at 2.45 (m, 1H), 1,80-2,00 (m, 4H).

MC(EI) 286(M+).

Example 15

Carrying out 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-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he (515 mg).

1H-NMR (300 MHz, CDCl3) δ: 12,4 (USS, 1H), 8,35 (d, J=7,8, 1H), to 7.59-to 7.64 (m, 1H), 7,35 is 7.50 (m, 2H), 6,28 (c, 1H), 4,06 (USS, 1H), 3,76 (d, J=14,1, 1H), 3,55 (d, J=14,1, 1H), 3,35 is-3.45 (m, 1H), 3,10-of 3.25 (m, 1H), 2,80-3,00 (m, 2H), 2,65 is 2.80 (m, 1H), 2,55-to 2.65 (m, 1H), 2,35 at 2.45 (m, 1H), 1.70 to 2,00 (m, 4H).

MC(EI) 272(M+).

Example 16

Carrying out 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), get (S)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he (363 mg).

1H-NMR (300 MHz, CDCl3) δ: 12,1 (USS, 1H), 8,23 (d, J=8,1, 1H), 7,46 (d, J=8,1, 1H), 7,28-7,34 (m, 1H), 6,44 (c, 1H), 5,16 (USS, 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), of 2.51 (c, 3H), 2.40 a at 2.45 (m, 1H), measuring 2.20 to 2.35 (m, 1H), 1.70 to 2.05 is (m, 6H).

MC(EI) 300(M+).

Example 17

Carrying out 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-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he (331 mg).

1H-NMR (300 MHz, CDCl3) δ: 12,2 (USS, 1H), 8.34 per (d, J=8,1, 1H), to 7.59-to 7.64 (m, 1H), 7,39-of 7.48 (m, 2H), 6,34 (c, 1H), of 5.05 (USS, 1H, of 3.80 (d, J=14,1, 1H), 3,60 (d, J=14,1, 1H), 3,15-3,20 (m, 1H), 2,70-to 2.85 (m, 2H), 2,60-2,70 (m, 2H), 2.40 a is 2.55 (m, 1H), measuring 2.20 to 2.35 (m, 1H), 1.70 to 2,10 (m, 6H).

Example 18

Carrying out reaction according to the method of example 1, using N,N-diethyl-2,3-dimethylbenzamide (5,0136 g) and (R)-4-(2-hydroxyethylpyrrolidine-1-yl)butyronitrile (2.2 g), receive (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he (627,3 mg). This type 1H. an aqueous solution of HCl (2.4 ml) in acetone solvent and precipitated precipitated crystals are filtered off, getting hydrochloride (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-it (555,3 mg).

1H-NMR (CD3OD) δ: 1,83-of 2.25 (7H, m), 2,68-by 2.73 (2H, m), is 3.08-up 3.22 (2H, m), 3,43-3,70 (4H, m), 3,85-are 3.90 (1H, m), is 6.54 (1H, c), 7,45 is 7.50 (1H, m), to 7.59 (1H, d, J=8 Hz), of 7.70 (1H, t, J=8 Hz), 8,24 (1H, d, J=8 Hz).

MC(EI) 286(M+).

Example 19

Carrying out reaction according to the method of example 1, using N,N-diethyl-2,3-dimethylbenzamide (5,6017 g) and 3-(4-hydroxypiperidine-1-yl)propionitrile (of 2.26 g), obtained 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he (327,5 mg).

1H-NMR (CDCl3) δ: of 1.63 to 1.76 (2H, m), 1,84-2,02 (2H, m), 2,22-2,39 (2H, m), 2,62-2,99 (6H, m), 3,61-of 3.80 (2H, m), and 6.25 (1H, c), of 7.36-7,46 (2H, m), EUR 7.57 to 7.62 (1H, m), 8,30 (1H, d, J=8 Hz), 11,37 (1H, USS).

MC(EI) 272(M+).

Example 20

Carrying out reaction according to the method of example 1, using N,N-diethyl-2,3-dimethylbenzamide (4,975 g) and (R)-3-(2-hydroxyethylpyrrolidine-1-yl)propionitrile (2.0 g), receive (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-the n (408,4 mg).

1H-NMR (CDCl3) δ: 1,75-2,00 (3H, m), a 2.36-2,48 (1H, m), 2,59-2,78 (2H, m), 2,83-2,96 (2H, m), 3,11-of 3.23 (1H, m), 3,35 is 4.45 (1H, m), 3,50-3,62 (1H, m), 3,71-3,81 (1H, m), was 4.02 (1H, USS), of 6.29 (1H, c), 7,39-to 7.50 (2H, m), 7,58-to 7.64 (1H, m), 8,35 (1H, d, J=8 Hz), 12,41 (1H, USS).

MC(EI) 272(M+).

Example 21

To 2-N-tert-butoxycarbonyl-4-oxopiperidine acid (of 7.96 g) added dropwise ethylchloride (3,45 ml) in the presence of triethylamine in tetrahydrofuran under ice cooling, receiving a mixed anhydride of the acid. Precipitated precipitated salt is filtered off and the resulting filtrate is again cooled with ice. Add ethanol (15 ml) and the mixture is stirred at room temperature. The reaction mixture was concentrated and add ethyl acetate. The mixture was washed with 0,5h. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate. The drying agent is filtered off and the solvent is concentrated and getting ethyl 2-N-tert-butoxycarbonyl-4-oxopiperidin (6,39 g).

The obtained ethyl 2-N-tert-butoxycarbonyl-4-oxopiperidin (6,39 g) dissolved in 1,3-dimethyl-2-imidazolidinone and ethanol. Add dosimetrician (5.30 g) and the mixture is cooled to a temperature of -78°C. Carefully add tert-piperonyl potassium (6,09 g), so that did not increase the temperature of the mixture and the mixture is stirred at room temperature. The reaction mixture was concentrated, add Aut 10% aqueous citric acid solution and the mixture extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the solvent concentrated. The residue is purified using a chromatographic column with silica gel (n-hexane:ethyl acetate = 4:1)to give ethyl 2-N-tert-butoxycarbonyl-4-cyanobiphenyl (1,21 g).

The obtained ethyl 2-N-tert-butoxycarbonyl-4-cyanobiphenyl (1,21 g) dissolved in tetrahydrofuran and the solution is cooled with water. Add lithium borohydride (279 mg) and the mixture is stirred at room temperature for 21 hours. To the reaction mixture, water is added and the mixture extracted with ethyl acetate, the extract washed with saturated saline and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the solvent is concentrated and receiving (N-tert-butoxycarbonyl-2-hydroxymethyl-4-cyano)piperidine (961 mg).

Carrying out 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), receive 3-(1-tert-butoxycarbonyl-2-hydroxyethylpiperazine-4-yl)-2H-isoquinoline-1-he (616 mg).

The obtained 3-(1-tert-butoxycarbonyl-2-hydroxyethylpiperazine-4-yl)-2H-isoquinoline-1-he (616 mg) was dissolved in ethyl acetate and to the solution was added 4n. a solution of hydrogen chloride in ethyl acetate (2.0 ml) and the mixture was stirred at room tempera what ur in for 6.5 hours. The reaction mixture was concentrated and precipitated precipitated crystals are washed with diethyl ether and dried under reduced pressure, obtaining the hydrochloride of 3-(2-hydroxyethylpiperazine-4-yl)-2H-isoquinoline-1-it (433 mg).

The obtained hydrochloride 3-(2-hydroxyethylpiperazine-4-yl)-2H-isoquinoline-1-it (433 mg) was dissolved in acetonitrile and water. To the solution was added 35% formalin (340 μl) and triacetoxyborohydride sodium (697 mg) and the mixture is stirred at room temperature for 20 minutes, the Reaction mixture was alkalinized with 20% aqueous potassium carbonate solution and extracted with chloroform. Chloroformate layer was washed with saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate. The drying agent is filtered off and the solvent concentrated. Precipitated precipitated crystals are washed with diethyl ether and dried under reduced pressure, obtaining 3-(1-methyl-2-hydroxyethylpiperazine-4-yl)-2H-isoquinoline-1-he (146 mg).

1H-NMR (300 MHz, DMCO-d6) δ: 11,1 (USS, 1H), 8,12 (d, J=7,8, 1H), 7,55-of 7.70 (m, 2H), 7,44 (t, J=7,8, 1H), 6,39 (c, 1H), 4,48 (USS, 1H), 3,55 of 3.75 (m, 2H), 2,60 is 2.80 (m, 3H), 2,40-2,60 (m, 1H), 2,42 (c, 3H), 1.70 to 2,00 (m, 4H).

MC(EI) 272(M+).

Example 22

Carrying out reaction according to the method of example 2, using the hydrochloride of 3-(piperidine-4-yl)-2H-isoquinoline-1-she (510 mg) and 3-bromo-2,2-dimethyl-1-propanol (474 mg), obtained 3-[1-(3-hydroxy-2,2-dimethylpropyl)Piperi the Jn-4-yl]-2H-isoquinoline-1-he (92 mg).

1H-NMR (270 MHz, DMCO-d6) δ: of 0.79 (6H, c), and 1.54-and 1.63 (2H, m), 1,89-of 1.93 (2H, m), 2,64-to 2.65 (1H, m), 2.70 height is 3.00 (2H, m), 3,13-3,20 (2H, m), 3,78-with 3.79 (2H, m), 4,10-to 4.14 (2H, m), 4,14-4,60 (1H, m), 6,38 (1H, c), 7,39-7,44 (1H, m), EUR 7.57-the 7.65 (2H, m)to 8.12 (1H, d, J=8.1 Hz), 11,25 (1H, USS).

MC(EI) 314(M+).

Example 23

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

Melting point: 197-199°C.

1H-NMR (270 MHz, DMCO-d6) δ: 1,54 was 1.69 (4H, m), 1,74 is 1.96 (4H, m), 2,33-of 2.38 (2H, m), 2,47-of 2.50 (3H, m), 2,96-of 3.00 (2H, m), 3,15-3,18 (1H, m), 3.43 points-of 3.48 (2H, m), 4,48 figure-4.49 (1H, m), 6.35mm (1H, c), 7,26-7,31 (1H, m), 7,49 (1H, d, J=7,0 Hz), to 7.99 (1H, d, J=7.8 Hz), 11,24 (1H, USS).

MC(EI) 300(M+).

Example 24

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

1H-NMR (270 MHz, DMCO-d6) δ: of 1.05 (3H, d, J=5,9 Hz), 1,61 is 1.70 (2H, m), 1.85 to 1.89 respectively (2H, m), 2,03-of 2.09 (2H, m), 2,20-of 2.26 (2H, m), 2.40 a-2,50 (2H, m), 2,94 are 2.98 (1H, m), 3.75 to is 3.76 (1H, m), 4.26 deaths-to 4.28 (1H, m), 6,36 (1H, c), 7,38-7,43 (1H, m), EUR 7.57-to 7.67 (2H, m), 8,11 (1H, d, J=7.8 Hz), 11,20 (1H, USS).

MC(EI) 286(M+).

Example 25

Carrying out reaction according to the method of example 1, using N,N-dimethyl-2,3-dimethylbenzamide (5,6095 g) and 3-(4-hydroxypiperidine-1-yl)propionitrile (2,44 g), obtained 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-5-IU the Il-2H-isoquinoline-1-he (418,2 mg).

1H-NMR (CDCl3) δ: 1,71 is 1.91 (3H, m), 2,01 is 2.10 (2H, m), 2,30-to 2.42 (2H, m), 2.49 USD (3H, c), 2,71-and 2.79 (4H, m), 2,89 are 2.98 (2H, m), 3,78-of 3.85 (1H, m), 6,33 (1H, c), 7,26-7,30 (1H, m), 7,44 (1H, ush., J=7 Hz), 8,24 (1H, ush., J=8 Hz), 11,38 (1H, USS).

MC(EI) 286(M+).

Example 26

Carrying out reaction according to the method of example 1, using N,N-dimethyl-2,3-dimethylbenzamide (5,8040 g) and (R)-4-(2-hydroxyethylpyrrolidine-1-yl)butyronitrile (2,75 g)get (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he (344,1 mg).

Melting point: 150,0-151,0°C.

1H-NMR (300 MHz, CDCl3) δ: 1,73-of 2.08 (6H, m), 2,31-to 2.40 (2H, m), 2.49 USD (3H, c), 2,70 is 2.80 (2H, m), 2,85-2,95 (2H, m), 3.75 to a 3.87 (1H, m), 6,34 (1H, c), 7,27-to 7.32 (1H, m), 7,44 (1H, ush., J=7 Hz), 8,23 (1H, ush, J=8 Hz), 11,43 (1H, USS).

Example 27

Carrying out reaction according to the method of example 1, using N,N-diethyl-2,3-dimethylbenzamide (5,2474 g) and 3-(3-hydroxypiperidine-1-yl)propionitrile (2,62 g), obtained 3-[2-(3-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he (888,2 mg).

Melting point: 192,0-193,0°C.

1H-NMR (CDCl3) δ: 1,42-of 1.53 (1H, m), 1,63-1,71 (1H, m), 1,82 is 1.91 (2H, m), 2,39-to 2.40 (2H, m), 2,61 was 2.76 (5H, m), 2,84-only 2.91 (1H, m), 3,19-is 3.21 (1H, m), 3,86-3,98 (1H, m), 6,23 (1H, c), 7,37 was 7.45 (2H, m), with 8.33 (1H, d, J=8 Hz), 11,25 (1H, USS).

Example 28

Carrying out reaction according to the method of example 2, using the hydrochloride of 5-methyl-3-(pyrrolidin-3-yl)-2H-isoquinoline-1-she (200 mg) and 2-bromoethanol (270 μl), receive 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl-5-methyl-2H-isoquinoline-1-he (39 mg).

1H-NMR (300 is Hz, CDCl3) δ: 10,8 (USS, 1H), 8,19 (d, J=8,0, 1H), 7,42 (d, J=8,0, 1H), 7,28 (t, J=8,0, 1H), 6,36 (c, 1H), 3,70-of 3.85 (m, 2H), 3,10-to 3.35 (m, 2H), 3,05-3,20 (m, 1H), 2,65-to 2.85 (m, 2H), 2,55-to 2.65 (m, 1H), 2,48 (c, 3H), 2,25-to 2.40 (m, 2H), 1.85 to 2,00 (m, 1H).

MC(ESI) 273(M+1).

Example 29

Carrying out reaction according to the method of example 2, using the hydrochloride of 3-(pyrrolidin-3-yl)-2H-isoquinoline-1-she (201 mg) and 2-bromoethanol (285 μl), receive 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinoline-1-he (58 mg).

1H-NMR (300 MHz, CDCl3) δ: 10,8 (USS, 1H), 8,32 (d, J=8,1, 1H), EUR 7.57 to 7.62 (m, 1H), 7,37 was 7.45 (m, 2H), 6,27 (c, 1H), 3,70-of 3.80 (m, 2H), 3,15-3,30 (m, 2H), 3,05 is 3.15 (m, 1H), 2,65 is 2.80 (m, 2H), 2,55-to 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 reaction according to the method of example 2, using the hydrochloride of 5-methyl-3-(piperidine-4-yl)-2H-isoquinoline-1-it (1 g) and 1-bromo-2-propanol (994 mg), get 5-methyl-3-[1-(2-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he (147 mg).

1H-NMR (270 MHz, DMCO-d6) δ: of 1.05 (3H, d, J=6.2 Hz), 1,68-to 1.77 (2H, m), 1.85 to 1.89 respectively (2H, m), 2,04-of 2.09 (2H, m), 2,15-of 2.30 (2H, m), 2,39-of 2.50 (4H, m), 2.95 and-2,99 (2H, m), of 3.77-of 3.78 (1H, m), 4,23-of 4.25 (1H, m), 6,34 (1H, c), 7,26-7,32 (1H, m), 7,49 (1H, d, J=7,0 Hz), to 7.99 (1H, d, J=7.8 Hz), 11,23 (1H, USS).

MC(EI) 300(M+).

Example 31

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

1H-NMR (270 MHz, DMCO-d6) δ: of 1.44 to 1.47 (4H, m), 1,61-of 1.74 (2H, m),1,74-of 1.97 (4H, m), and 2.26-2,39 (2H, m), 2,43-2,49 (4H, m), 2.95 and-2,99 (2H, m), 3.33 and-of 3.42 (2H, m), 4,37-of 4.54 (1H, m), 6,34 (1H, c), 7,26-to 7.32 (1H, m), 7,49 (1H, d, J=7,0 Hz), to 7.99 (1H, d, J=8.1 Hz), 11,24 (1H, USS).

MC(EI) 314(M+).

Example 32

Carrying out reaction according to the method of example 1, using N,N-dimethyl-2,3-dimethylbenzamide (5,1101 g) and 3-(3-hydroxypiperidine-1-yl)propionitrile (2.2 g), obtained 3-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (269,6 mg).

Melting point: 184,0-to 185.0°C.

1H-NMR (300 MHz, CDCl3) δ: 1,49-to 1.98 (4H, m), a 2.36-2,83 (12H, m), 3,90-4,01 (1H, m), 6,33 (1H, c), 7,27-to 7.32 (1H, m), the 7.43 (1H, ush., J=7 Hz), by 8.22 (1H, ush., J=8 Hz), of 11.29 (1H, USS).

MC(EI) 286(M+).

Example 33

Carrying out reaction according to the method of example 2, using the hydrochloride of 5-methyl-3-(pyrrolidin-3-yl)-2H-isoquinoline-1-it (501 mg) and 3-bromo-1-propanol (991 mm), receive 3-[1-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he (216 mg).

1H-NMR (300 MHz, CDCl3) δ: 11,3 (USS, 1H), 8,21 (d, J=7,8, 1H), 7,45 (d, J=7,8, 1H), 7,26-7,33 (m, 1H), 6,37 (c, 1H), 4.80 to of 4.95 (m, 2H), 3.15 and is 3.25 (m, 2H), of 3.07 (d, J=9,6, 1H), 2,80-2,90 (m, 1H), 2,60-of 2.75 (m, 1H), 2,50-2,60 (m, 1H), 2,50 (c, 3H), 2,20-2,40 (m, 2H), 1,75-of 1.95 (m, 3H).

MC(EI) 286(M+)

Example 34

Carrying out 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), get (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (0,228 g).

Melting point: 176-178°C.

1H-NMR (CDCl3) δ: 1,83 is 1.96 (1H, m), 2,21 of-2.32 (1H, m), 48 (3H, c), 2,49 is 2.55 (1H, m), 2,72-and 2.79 (3H, m), 2,81 of 2.92 (3H, m), 2,96 was 3.05 (1H, m), 4,42 figure-4.49 (1H, m), 6,33 (1H, c), 7,29 (1H, t, J=8 Hz), the 7.43 (1H, d, J=7 Hz), by 8.22 (1H, d, J=8 Hz), 11,40 (1H, USS).

MC(EI) 272(M+).

Example 35

Carrying out reaction according to the method of example 1, using N,N-dimethyl-2,3-dimethylbenzamide (1,41 g) and (R)-3-(3-hydroxypiperidine-1-yl)propionitrile (1.44 g), receive (R)-3-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (147 mg).

Melting point: 180,0-181,0°C.

1H-NMR (CDCl3) δ: 1,49-to 1.98 (4H, m), a 2.36-2,83 (12H, m), 3,90-4,01 (1H, m), 6,33 (1H, c), 7,27-to 7.32 (1H, m), the 7.43 (1H, ush., J=7 Hz), by 8.22 (1H, ush., J=8 Hz), of 11.29 (1H, USS).

MC(EI) 286(M+).

Example 36

Carrying out reaction according to the method of example 1, using N,N-diethyl-2,3-dimethylbenzamide (81,4 g) and (R)-3-(2-hydroxyethylpyrrolidine-1-yl)propionitrile (55,6 g)get (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (12.5 g).

1H-NMR (CDCl3) δ: 1,76 is 1.96 (4H, m), 2,39 is 2.44 (1H, m)of 2.50 (3H, c), 2,62 was 2.76 (2H, m), 2,85-2,96 (2H, m), 3,11-up 3.22 (1H, m), 3,38-of 3.46 (1H, m), 3,55 (1H, DD, J=3 Hz, 11 Hz), 3,76 (1H, DD, J=3 Hz, 12 Hz), to 6.39 (1H c), 7,31 (1H, t, J=8 Hz), 7,55 (1H, d, J=8 Hz), compared to 8.26 (1H, d, J=8 Hz), 12,43 (1H, USS).

MC(EI) 286(M+).

Using the known method, (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he is transformed into the hydrochloride, getting dihydrate hydrochloride (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it.

1H-NMR (DMCO-d6) δ: 1,69-2,14 (4H, m), 2,48 (3H, c), 2,94-3,44 (4H, m), 3,52-a-3.84 (5H, m), 5,48 (1, OSS), 6,55 (1H, c), 7,34 (1H, t, J=8 Hz), 7,53 (1H, d, J=7 Hz), 8,02 (1H, d, J=8 Hz), 10,29 (1H, USS), 11,47 (1H, USS).

MC(EI) 286(M+).

[α]D=+24,5° (c=with 1.009, MeOH).

Below is another way to obtain (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it.

Mix hydrochloride (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline (62 g) and acetic acid (186 ml)to the mixture with stirring, gradually add ammonium carbonate (74,4 g). After cessation of gas evolution, the reaction mixture is heated and stirred at a temperature of 130°C for 2 hours under heating. After completion of the reaction, the reaction mixture is cooled to room temperature and added dropwise an aqueous solution (200 ml) of sodium hydroxide (140 g). The mixture is stirred at a temperature of 80°C and after completion of the reaction, the reaction mixture was concentrated. The methanol fraction is evaporated and the mixture is twice extracted with chloroform. The organic layer is extracted twice 3h. hydrochloric acid (300 ml and 100 ml) and the aqueous layer add potassium carbonate, for alkalizing the resulting layer. The aqueous layer was twice extracted with chloroform and the extract is dried over magnesium sulfate. The solvent is concentrated and to the residue is added ethyl acetate. The mixture is then concentrated and the residue is dissolved in a small amount of ethyl acetate under heating. To rest the Roux add diethyl ether and precipitated precipitated crystals are filtered off, receiving (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he (41.5 g).

Example 37

Solution (400 ml) Diisopropylamine (26,9 g) in tetrahydrofuran is cooled to -5°C and the solution added dropwise 1,57M solution (154 ml) n-utility in hexane. After stirring at 0°C for 30 min, the mixture is cooled to -78°C and added dropwise a solution (50 ml) of N,N-diethyl-2,3-dimethylbenzamide (45,1 g) in tetrahydrofuran. After stirring at a temperature of -78°C for 1 hour, added dropwise a solution (50 ml) of 1-benzyl-3-cyanopyrrolidine (37,18 g) in tetrahydrofuran. After completion of adding dropwise, the reaction mixture is heated to room temperature and the mixture is stirred over night at room temperature. The mixture is further stirred at the boil under reflux for 1 hour and the reaction mixture is concentrated to approximately half volume. Add water and methylene chloride and the organic layer separated, washed with water, dried over magnesium sulfate and concentrated. The resulting residue is purified using a chromatographic column with silica gel (ethyl acetate), obtaining (±)-3-(1-benzylpyrrolidine-3-yl)-5-methyl-2H-isoquinoline-1-he (66,38 g).

To the resulting (±)-3-(1-benzylpyrrolidine-3-yl)-5-methyl-2H-isoquinoline-1-ONU (66,38 d) add D-tartaric acid (31,32 g) in methanol (1580 ml), the mixture is heated under CI is the situation under reflux and cooled to room temperature, getting dropped in sediment D-tartrate (±)-3-(1-benzylpyrrolidine-3-yl)-5-methyl-2H-isoquinoline-1-it (44,56 g).

Then twice recrystallized from methanol, receiving D-tartrate (-)-3-(1-benzylpyrrolidine-3-yl)-5-methyl-2H-isoquinoline-1-it (27,06 g).

Then the crystals separated from the mother liquor upon recrystallization, again recrystallized three times from methanol, receiving (11,74 g). D-tartrate (-)-3-(1-benzylpyrrolidine-3-yl)-5-methyl-2H-isoquinoline-1-it (38,8 g) is stirred in a mixture of methanol (150 ml) - methylene chloride (300 ml) and added dropwise 1N. an aqueous solution of sodium hydroxide (200 ml) and water (100 ml) for alkalizing solution. Methylenchloride layer is isolated and washed with water, then dried over magnesium sulfate and concentrated, obtaining (-)-3-(1-benzylpyrrolidine-3-yl)-5-methyl-2H-isoquinoline-1-he (27.5 g).

[α]D22-101,8 (C=is 0.998, CHCl3).

To the resulting (-)-3-(1-benzylpyrrolidine-3-yl)-5-methyl-2H-isoquinoline-1-ONU (27.5 g) add 50% water 10% palladium-on-coal (6 g) and ethanol (400 ml) and the mixture is stirred in hydrogen atmosphere at a temperature of 50°C for 6 hours. After filtration through celite, the filtrate concentrated and to the residue is added ethyl acetate. Precipitated precipitated crystals are filtered off, obtaining (-)-3-(pyrrolidin-3-yl)-5-methyl-2H-isoquinoline-1-he (16,8697 g).

To the resulting (-)-3-(pyrrolidin-3-yl)-5-methyl-2H-isoquinoline-1-the well (3.0 g) add 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 washed with water, dried over magnesium sulfate and concentrated. The resulting residue is purified using a chromatographic column with silica gel (methanol/ethyl acetate; 2/5) and crystallized from ethyl acetate, obtaining (-)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he (1,5425 g).

Melting point: 137,3-138,6°C.

[α]D22-53,1 (C=1,005, CHCl3).

1H-NMR (300 MHz, CDCl3) δ: 1,85 for 2.01 (1H, m), 2,27-to 2.42 (2H, m), 2.49 USD (3H, c), 2,55-of 2.64 (1H, m), 2,69-to 2.85 (2H, m), 3,10 -, and 3.16 (1H, m), 3,20-and 3.31 (2H, m), 3,74-3,88 (2H, m), 6.35mm (1H, c), 7.23 percent-7,33 (1H, m), the 7.43 (1H, d, J=7 Hz), to 8.20 (1H, d, J=8 Hz), 10,66 (1H, USS).

MC(EI) 272(M+).

Example 38

The mother liquor obtained in the optical separation of the D-tartrate, (- )- 3-(1-benzylpyrrolidine-3-yl)-5-methyl-2H-isoquinoline-1-she in example 37, is treated with alkali. The result of turning it into an L-tartrate in a manner analogous to the above, and after a three-fold recrystallization from methanol receive L-tartrate of (+)-3-(1-benzylpyrrolidine-3-yl)-5-methyl-2H-isoquinoline-1-it (38,99 g). As a result of subsequent desalting, dibenzylamine and gidroksietilirovaniya ways, similar to the above, receive (+)-3-[1-(2-HYDR shall xylitol)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-it.

Melting point: 137,0-138,6°C.

[α]D22+52,7 (C=1,004, CHCl3).

1H-NMR (300 MHz, CDCl3) δ: 1,85 for 2.01 (1H, m), 2,27-to 2.42 (2H, m), 2.49 USD (3H, c), 2,55-of 2.64 (1H, m), 2,69-to 2.85 (2H, m), 3,10 -, and 3.16 (1H, m), 3,20-and 3.31 (2H, m), 3,74-3,88 (2H, m), 6.35mm (1H, c), 7.23 percent-7,33 (1H, m), the 7.43 (1H, d, J=7 Hz), to 8.20 (1H, d, J=8 Hz), 10,66 (1H, USS).

MC(EI) 272(M+).

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

Experimental example

Inhibitory activity against PARP enzyme activity

As a source of enzymes using recombinant human PARP (4667-02X, Trevigen). The reaction of poly ADP-ribosylate start by adding a3H-NAD (of 1.85 kBq, NAD [adenine-2, the 83H], Daiichi Chemicals Co., Ltd.) and activated DNA (0.02 mg/ml, 4667-03X, Trevigen) and then the source of enzyme for the enzymatic reaction buffer (10 mm Tris/HCl (pH 8.0), 1 mm MgCl2, 28 mm KCl, 28 mm NaCl). After incubation at a temperature of 25°C for 15 min the reaction is stopped by adding 20% trichloroacetic acid and the resulting insoluble in the acid fraction adsorb onto GF/B filter. The filter is washed several times with 5% trichloroacetic acid,and the radioactivity on the filter is measured, using scintillation counter.

The results obtained are presented in table 1. The activity of PARP determined by subtracting the radioactivity of the sample, which was not added source of enzymes, as a comparative value and the value of the 50% inhibitory ability of the enzyme (value IR50for each of the test compounds is calculated using the amount of radioactivity connection, taking as 100% the value for the sample in which the compound was not added.

Table 1
Test connectionPARP-inhibiting activity

IR50(nm)
Test connectionPARP-inhibiting activity

IR50(nm)
Example 139Example 2835
Example 217Example 3434
Example 446Example 3629
Example 550Example 3720
Example 944Example 3829
Control medication(DPQ)1000
DPQ = 3,4-dihydro-5-[4-1-piperidinyl)butoxy]-1(2H)-athinaikon (can be synthesized in accordance with example 32 JP-A-H2-124874, PARP inhibitor disclosed in each of WO 99/08680 and WO 99/11649)

Based on these results, it becomes apparent that the compounds presented in the examples of the present invention have excellent PARP-inhibiting activity in comparison with the DPQ.

Experimental example 2

Determination of stability

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

Column: Inertsil ODS3V (GL Science Inc.)

Mobile phase: methanol: 0.01 mol/l aqueous solution of ammonium acetate

Determination wavelength: 254 nm

Volumetric flow rate: 1.0 ml/min

Table 2
Test connectionConcentrationResidual ratio (%) in the darkResidual ratio (%) in the light
mg/mlAfter 7 daysAfter 11 daysAfter 7 daysAfter 11 days
Example 11,0100 100100100
10100100100100
Example 21,0100100100100
10100100100100
Example 361,0100100100100
10100100100100

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

Experimental example 3

A positive effect on neurological symptoms associated with cerebral infarction

Cynomolgus monkeys, which before the study were not given food for 12 hours or more, anaesthetize by intramuscular injection of cetomimidae (10 mg/kg) and fixed on the operating table. Intramuscularly injected tropicalfete (0.5 mg/kg of body weight) during anesthesia pentobarbital and make a small hole (about 5 mm), using a dental Bur, near the oval canal and orbital fissures, then cut the Dura and arachnoid membrane. Then expose the middle cerebral artery (MCA) near the bifurcation of the internal carotid artery. MCA near the bifurcation of the internal carotid artery coagulated/occluders using bipolar coagulator, which leads to cerebral infarction. After that, the solvent or drug sample is injected continuously at a rate of 3 mg/kg/hour for 6 hours.

Neurological symptoms associated with cerebral infarction, see for 26 hours after MCA occlusion.

Neurological symptoms assessed in accordance with the 5-point scale, as follows, in relation to consciousness, paralysis and mobility.

1. The level of consciousness

Assessment 5: there is almost no reaction on d is to achieve/activity surrounding people and the noise.

Assessment 4: although the observed response to motion/activity surrounding people and the noise, the animals quickly return to a state characterized by the absence of responses.

Assessment 3: although there is a response to motion/activity surrounding people and the noise, this reaction is short-lived.

Assessment 2: extended response to motion/activity surrounding people and the noise.

Assessment 1: a long response to motion/activity surrounding people and noise, accompanied by corresponding facial expressions.

Score 0: normal response to motion/activity surrounding people and the noise.

2. Paralysis

Score 5: the complete immobility of the limbs with hemiplegic side.

Assessment 4: random involvement of the extremities with hemiplegic side without compression/power.

Assessment 3: although there is the involvement of the extremities with hemiplegic side, capture the pieces of food are not obvious.

Score 2: a relatively free movement of the limbs with hemiplegic side, but the capture of the pieces of food are not obvious.

Assessment 1: free movement of the limbs with hemiplegic side and the apparent capture of pieces of food.

Score 0: normal limb movement with hemiplegic side.

3) Mobility

Assessment 5: maintaining a sitting posture.

Assessment 4: from time to time the output of the sitting poses is, then walk around the circle.

Assessment 3: from time to time climb on the walls of the cell.

Assessment 2: frequent walking in a circle.

Assessment 1: frequent climb on the walls of the cell.

Score 0: normal behavior.

Table 3
Group namenScore
The group, which was injected solvent414,8±0,3
The group, which was administered medicine sample58,6±1,9 (P<0,05)

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

Industrial applicability

Compounds of the above formula (I), their optical isomers, pharmaceutically acceptable salts, their hydrates and their water adducts are stable in aqueous solutions, have an effective PARP-inhibiting activity in comparison with the known compounds, and can be used as a therapeutic drug in the treatment of cerebral infarction, especially acute cerebral infarction. In addition, (R)-3-(3-hydroxypyrrolidine-1-yl)-N-methyl-N-methoxypropane, (R)-N,N-diethyl-2-[4-(3-hydroxypyrrolidine the-1-yl)-2-oxobutyl]-3-methylbenzamide, (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methylisoquinoline, (R)-3-(2-hydroxyethylpyrrolidine-1-yl)-N-methyl-N-methoxypropane, (R)-N,N-diethyl-2-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-oxobutyl]-3-methylbenzamide, (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline hydrochloride and (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline are new compounds and can be used as intermediates 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 content of which is included here for reference.

Additional examples

Example 1

(a) Diisopropylamine (5,48 ml) dissolved in tetrahydrofuran (13 ml) under nitrogen atmosphere and the temperature was decreased to -78°C. a Solution of n-utility (1,58 mol/l, to 23.8 ml) in n-hexane are added dropwise to the reaction mixture and the mixture is stirred at a temperature of 0°C for 30 minutes the Solution diisopropylamide lithium again cooled to -78°and slowly added dropwise a solution of N,N-diethyl-3-fluoro-2-methylbenzamide (3,41 g) in tetrahydrofuran (15 ml). After the addition, the reaction mixture was stirred at -78°C for one hour and slowly added dropwise a solution of (R)-3-(2-hydroxyethylpyrrolidine-1-yl)-N-methoxy-N-methylpropanamide (3,53 g) in tetrahydrofuran (15 ml). The reaction mixture is heated to anatoy temperature and stirred overnight (18 h). After completion of the reaction, to the reaction mixture add water to extinguish the reaction. The tetrahydrofuran is removed under reduced pressure and the resulting aqueous layer is extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and filtered. The chloroform is evaporated under reduced pressure to obtain (R)-N,N-diethyl-3-fluoro-2-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-oxobutyl]benzamide (5,94 g), which is used in the next reaction without further purification.

(b) To (R)-N,N-diethyl-3-fluoro-2-[4-(2-hydroxyethylpyrrolidine-1-yl)-2-oxobutyl]benzamide (5,94 g) is added concentrated hydrochloric acid (35 ml) and the resulting mixture is heated at the boil under reflux for 5 hours After completion of the reaction, the reaction mixture was alkalinized by adding powdered potassium carbonate and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and filtered. The chloroform is evaporated under reduced pressure to obtain (R)-5-fluoro-3[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-isocoumarin (4,01 g), which is used in the next reaction without further purification.

(C) (R)-5-fluoro-3[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-isocoumarin (4,01 g) dissolved in acetic acid (12 ml) and the resulting mixture heated to 70°C. Add arbonet ammonium (4,90 g) and the mixture is heated at the boil under reflux for 1 h The reaction mixture is cooled to room temperature and added to aqueous solution (30 ml) of sodium hydroxide (8 g). The mixture is stirred at room temperature for 30 min and diluted with water, extracted with chloroform, washed with saturated saline, dried over anhydrous magnesium sulfate and filtered. The chloroform is evaporated under reduced pressure to obtain oil, which is purified using a chromatographic column with silica gel (chloroform→chloroform:methanol=20:1→10:1). The obtained crude crystals were washed with ethyl acetate and collected by filtration to obtain (R)-5-fluoro-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-it (595 mg).

1H-NMR (CDCl3) δ: 1,70-2,00 (4R, m), 2,35 at 2.45 (1H, m), 2,55 is 2.75 (2H, m), 2,80-3,00 (2H, m), 3,10-of 3.25 (1H, m), 3,30 is 3.40 (1H, m), 3,50-3,60 (1H, m), 3,70-of 3.80 (1H, m), 3,85 (1H, USS), of 6.49 (1H, s), 7,26-7,38 (2H, m), 8,13 (1H, d, J=7,2 Hz), and 12.6 (1H, USS).

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

Example 2

Carrying out reaction according to the method of example 1, using N,N-ethyl-3-chloro-2-methylbenzamide (3,35 g) and (R)-3-(2-hydroxyethylpyrrolidine-1-yl)-N-methoxy-N-methylpropane (3,22 g)get (R)-5-chloro-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he (645 mg).

1H-NMR (CDCl3) δ: 1,70-2,00 (411, m), 2,35 at 2.45 (1H, m), 2,55 is 2.75 (2H, m), 2,80-3,00 (2H, m), 3,10-of 3.25 (1H, m), 3,30 is 3.40 (1H, m), 3,50-3,60 (1H, m), 3,70-of 3.80 (1H, m), of 6.65 (1H, s), 7,30-to 7.35 (1H, m), to 7.67 (1H, d, J=8.1 Hz), of 8.28 (1H, d, J 8.1 Hz), 12.7mm (1H, USS).

MS (EI) 307(M+1).

Example 3

Carrying out reaction according to the method of example 1, using N,N-ethyl-3-fluoro-2-methylbenzamide (of 3.46 g) and (R)-3-(3-hydroxypyrrolidine-1-yl)-N-methoxy-N-methylpropane (3,36 g)get (R)-5-fluoro-3-[2-(3-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he (1.19 g).

1H-NMR (DMSO-d6) δ: 1,45-to 1.60 (1H, m), 1.85 to a 2.00 (1H, m), 2,35-to 2.40 (1H, m), 2.40 a is 2.55 (1H, m), 2,60-2,80 (6N, m), 4,16-4,20 (1H, m), 4,70 (1H, d, J=4, 2 Hz), of 6.45 (1H, s), 7,37-7,44 (1H, m), 7,49-of 7.55 (1H, m), of 7.96 (1H, d, J=7.8 Hz), and 11.5 (1H, USS).

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

Example 4

Carrying out reaction according to the method of example 1, using N,N-diethyl-3-chloro-2-methylbenzamide (3,43 g) and (R)-3-(3-hydroxypyrrolidine-1-yl)-N-methoxy-N-methylpropane (is 3.08 g), receive (R)-5-chloro-3-[2-(3-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he (102 mg).

1H-NMR (DMSO-d6) δ: 1,45-to 1.60 (1H, m), 1.85 to a 2.00 (1H, m), 2,35-to 2.40 (1H, m), 2.40 a is 2.55 (1H, m), 2,60-2,80 (6N, m), 4,19 (1H, USS), 4,74 (1H, USS), 6,56 (1H, s), 7,38-the 7.43 (1H, m), 7,81 (1H, d, J=7.5 Hz), to 8.12 (1H, d, J=7.5 Hz), and 11.6 (1H, USS).

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

Pharmacological data for compounds in which R1represents a halogen atom.

Enzymatic analysis is performed according to "Inhibitory effect against PARP enzyme activity"described in Experimental example of the present application.

Example No.R1PARP-inhibiting asset is awn, IR50(nm)
1F125
2Cl140
3F160
4Cl130

1. Isoquinoline compound represented by the formula (I)

where R1represents a hydrogen atom, halogen atom or alkyl;

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

R represented by the following formula (II):

where X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH;

W represents CH or nitrogen atom, provided that if X is 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 R3represents a hydrogen atom or alkyl, then R2represents a hydrogen atom, alkyl, a hydroxyl group, or hydroxyalkyl, R2'represents a hydroxyl group or hydroxyalkyl,

if R3is hydroxyalkyl, then R2The R 2'represent hydrogen, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

2. Isoquinoline compound according to claim 1, which is represented by formula (I), where R1represents a hydrogen atom or alkyl; Y is absent or represents alkylenes chain containing from 1 to 5 carbon atoms, where an arbitrary carbon atom may have as a substituent a hydroxyl group; R is represented by formula (II)where in the formula (II), X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH; W represents CH or nitrogen atom, provided that if X is CH, then W must represent a nitrogen atom; s is an integer from 1 to 3; t is an integer from 1 to 3; if R3represents a hydrogen atom or alkyl, then R2represents a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl, and R2'represents a hydroxyl group or hydroxyalkyl; if R3is hydroxyalkyl, then R2and R2'represent a hydrogen atom, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

3. Isoquinoline compound according to claim 1 or 2, which is represented by formula (I), where R1represents the hydrogen atom is or methyl; Y is absent or represents methylene, ethylene, propylene or 2-hydroxypropyl; R is represented by formula (II)where in the formula (II), X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH; W represents CH or nitrogen atom, provided that if X is CH, then W must represent a nitrogen atom; s is an integer from 1 to 3; t is an integer from 1 to 3; if R3represents a hydrogen atom or methyl, then R2represents a hydrogen atom, alkyl, a hydroxyl group, hydroxymethyl or 2-hydroxyethyl, and R2'represents a hydroxyl group, hydroxymethyl or 2-hydroxyethyl; and if R3represents 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl or 2-hydroxypropyl, then R2and R2'represent a hydrogen atom, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

4. Isoquinoline compound according to claim 1 or 2, which is chosen from the group consisting of

(1) (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(2) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-5-methyl-2H-isoquinoline-1-he,

(3) 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he,

(4) 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he,

(5) 3-[2-(3-hydro is superolein-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(6) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(7) 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(8) 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-2H-isoquinoline-1-he,

(9) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(10) 3-[1-(3-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(11) 3-[1-(4-hydroxybutyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(12) 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-2H-isoquinoline-1-he,

(13) 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he,

(14) (S)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(15) (S)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(16) (S)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he,

(17) (S)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he,

(18) (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he,

(19) 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(20) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(21) 3-(1-methyl-2-hydroxyethylpiperazine-4-yl)-2H-isoquinoline-1-he,

(22) 3-[1-(3-hydroxy-2,2-dimethylpropyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(23) 5-methyl-3-[1-(3-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(24) 3-[1-(2-hydroxypropyl)PIP is ridin-4-yl]-2H-isoquinoline-1-he,

(25) 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(26) (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he,

(27) 3-[2-(3-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(28) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

(29) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinoline-1-he,

(30) 5-methyl-3-[1-(2-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(31) 5-methyl-3-[1-(4-hydroxybutyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(32) 3-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(33) 3-[1-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

(34) (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(35) (R)-3-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(36) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(37) (-)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(38) (+)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

their optically active forms, their pharmaceutically acceptable salts, their water adducts, their hydrates and their solvate.

5. Isoquinoline compound according to claim 1 or 2, which is represented by formula (I), where R1represents a hydrogen atom or methyl; Y is absent; and R is represented by formula (II), where in is ormula (II) X represents CH; W represents a nitrogen atom; s is the integer 1 or 2; t represents an integer 2; if R3represents methyl, then R2represents a hydrogen atom, methyl, ethyl, hydroxyl group or hydroxymethyl and R2'represents a hydroxyl group or hydroxymethyl; and if R3is hydroxyethyl, then R2and R2'represent a hydrogen atom, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

6. Isoquinoline compound according to claim 1 or 2, which is chosen from the group consisting of

(2) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-5-methyl-2H-isoquinoline-1-he,

(9) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(10) 3-[1-(3-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(11) 3-[1-(4-hydroxybutyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(21) 3-(1-methyl-2-hydroxyethylpiperazine-4-yl)-2H-isoquinoline-1-he,

(22) 3-[1-(3-hydroxy-2,2-dimethylpropyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(23) 5-methyl-3-[1-(3-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(24) 3-[1-(2-hydroxypropyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(28) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

(29) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinoline-1-he,

(30) 5-methyl-3-[1-(2-hydroxypropyl)piperidine--yl]-2H-isoquinoline-1-he,

(31) 5-methyl-3-[1-(4-hydroxybutyl)piperidine-4-yl]-2H-isoquinoline-1-he,

(33) 3-[1-(3-hydroxypropyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

(37) (-)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(38) (+)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

their optically active forms, their pharmaceutically acceptable salts, their water adducts, their hydrates and their solvate.

7. Isoquinoline compound according to claim 1 or 2, which is represented by formula (I), where R1represents a hydrogen atom or methyl; Y represents ethylene, propylene; 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 is an integer from 1 to 3; R2represents a hydrogen atom, alkyl, a hydroxyl group or hydroxymethyl; R2'represents a hydroxyl group or hydroxymethyl; and R3represents a hydrogen atom; provided that if R2represents a hydrogen atom or alkyl, R2'represents a hydroxyl group or hydroxymethyl, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

8. Isoquinoline compound according to claim 7, which is selected from the group including

(1) (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-ithin the Lin-1-he,

(3) 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he,

(4) 3-[3-(3-hydroxypyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he,

(5) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(6) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(7) 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(8) 3-[2-(2-hydroxyethylpiperazine-1-yl)ethyl]-2H-isoquinoline-1-he,

(12) 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-2H-isoquinoline-1-he,

(13) 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he,

(14) (S)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(15) (S)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(16) (S)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he,

(17) (S)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he,

(18) (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-2H-isoquinoline-1-he,

(19) 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(20) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(25) 3-[2-(4-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(26) (R)-3-[3-(2-hydroxyethylpyrrolidine-1-yl)propyl]-5-methyl-2H-isoquinoline-1-he,

(27) 3-[2-(3-hydroxypiperidine-1-yl)ethyl]-2H-isoquinoline-1-he,

(32) 3-[2-(3-HYDR shall keepered-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(34) (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(35) (R)-3-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he

(36) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

their optically active forms, their pharmaceutically acceptable salts, their water adducts, their hydrates and their solvate.

9. Isoquinoline compound according to claim 1 or 2, which is represented by formula (I), where R1represents 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 the formula (I), X represents a nitrogen atom; when Y is absent in the formula (I), X represents JV; W represents CH or nitrogen atom, provided that if X is CH, then W must represent a nitrogen atom; s is the integer 1 or 2; t represents an integer from 1 to 3; if R3represents a hydrogen atom, then R2represents a hydrogen atom, a hydroxyl group or hydroxymethyl, R2'represents a hydroxyl group or hydroxymethyl; and if R3is hydroxyethyl, R2and R2'each represents a hydrogen atom, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

10. Isoquinoline compound according to claim 1 or 2, which selects the C group, including

(1) (R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(2) 3-[1-(2-hydroxyethyl)piperidine-4-yl]-5-methyl-2H-isoquinoline-1-he,

(5) 3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(28) 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

(34) (S)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(36) (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-he,

(37) (-)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he

(38) (+)-3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-he,

their optically active forms, their pharmaceutically acceptable salts, their water adducts, their hydrates and their solvate.

11. Isoquinoline compound of claim 10, which is represented by formula (I), where R1is methyl; Y is absent; and R is represented by formula (II), where X represents CH; W represents a nitrogen atom; s is the integer 1 or 2; t represents an integer 2; R2and R2'represent a hydrogen atom; and R3is hydroxyethyl, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

12. (2) 3-[1-(2-Hydroxyethyl)piperidine-4-yl]-5-methyl-2H-isoquinoline-1-it, its optically active form, its pharmaceutically acceptable with the l, its water adduct, its hydrate or its MES.

13. (28) 3-[1-(2-Hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-it, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

14. (37) (+)-3-[1-(2-Hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

15. (38) (-)-3-[1-(2-Hydroxyethyl)pyrrolidin-3-yl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

16. Isoquinoline compound according to claim 7, which is represented by formula (I), where

R1is 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 an integer of 1;

t represents an integer 2 or 3;

R2represents a hydrogen atom, a hydroxyl group or hydroxymethyl;

R2'represents a hydroxyl group or hydroxymethyl; and

R3represents a hydrogen atom,

its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

17. (1) (R)-3-[2-(3-Hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, its in the hydrated adduct, its hydrate and its MES.

18. (5) 3-[2-(3-Hydroxypyrrolidine-1-yl)ethyl]]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

19. (34) (S)-3-[2-(3-Hydroxypyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

20. (36) (R)-3-[2-(2-Hydroxyethylpyrrolidine-1-yl)ethyl]-5-methyl-2H-isoquinoline-1-it, its pharmaceutically acceptable salt, water adduct, its hydrate and its MES.

21. Isoquinoline compound represented by the formula (I'):

where Ra1represents a hydrogen atom or methyl;

Y' represents ethylene, propylene or 2-hydroxypropyl;

Ra is represented by the formula (II'):

where in the formula (II'),

X' represents a nitrogen atom;

W' is CH;

s' represents an integer from 1 to 3;

t' represents an integer from 1 to 3;

if Ra3represents a hydrogen atom, then Ra2represents a hydrogen atom or alkyl, and Ra2'represents a hydroxyl group or hydroxymethyl;

its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

22. Isoquinoline compound according to item 21,which is represented by formula (I'), where Ra1is methyl; Y' represents ethylene; Ra represented by the following formula (II'), where in formula (II') X' represents a nitrogen atom; W' is CH; and s' is 1; t' represents an integer 2 or 3; if Ra3represents a hydrogen atom, then Ra2represents a hydrogen atom, and Ra2'must represent a hydroxyl group or hydroxymethyl, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

23. Isoquinoline compound which is selected from the

(12) 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-2H-isoquinoline-1-it

(13) 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-5-methyl-2H-isoquinoline-1-it,

their optically active forms, their pharmaceutically acceptable salts, their water adducts, their hydrates or their solvate.

24. Agent for prevention and/or treatment of diseases caused by hyperactivity of poly(ADP-ribose)polymerase, which includes the isoquinoline compound according to any one of claims 1 to 23, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

25. The agent at point 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.

Art 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. Agent for prevention and/or treatment of cerebral infarction, which includes the isoquinoline compound according to any one of claims 1 to 23, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

29. Agent p, which is used for the prevention and/or treatment of acute cerebral infarction.

30. Agent p and 29, which improves neurological symptoms associated with cerebral infarction.

31. Inhibitor of poly(ADP-ribose)polymerase, including the isoquinoline compound according to any one of claims 1 to 23, its optically active form, its pharmaceutically acceptable salt, water adduct, its hydrate or its MES.

32. The use of isoquinoline compounds according to any one of claims 1 to 23, its optically active forms, its pharmaceutically acceptable salt, a water adduct, its hydrate or its MES to obtain an agent for prevention and/or treatment of diseases caused by hyperactivity of poly(ADP-ribose)polymerase.

33. Use p, where the disease is cerebral infarction.

34. Use p, where the disease is acute cerebral infarction.

35. A compound selected from the group including:

(R)-3-(3-hydroxypyrrolidine-1-the l)-N-methyl-N-methoxypropane,

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

(R)-3-[2-(3-hydroxypyrrolidine-1-yl)ethyl]-5-methylisoquinoline,

(R)-3-(2-hydroxyethylpyrrolidine-1-yl)-N-methyl-N-methoxypropane,

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

(R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline hydrochloride and (R)-3-[2-(2-hydroxyethylpyrrolidine-1-yl)ethyl]-5-methylisoquinoline.

36. The method of obtaining the compounds of formula (15):

where R1represents a hydrogen atom, halogen atom or alkyl;

J2is dialkylamino;

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

R is represented by formula (II):

where

X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X is CH;

W represents CH or a nitrogen atom; provided that if X is 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 R3represents a hydrogen atom or a the keel, then R2represents a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl, and R2'represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'represent a hydrogen atom,

including the interaction of the compounds of formula (11')

where R1and J2have the above meanings, with a compound of formula (14)

where Y and R have the above values, and J3represents N-alkyl-N-alkoxyamino.

37. The method of obtaining the compounds of formula (16)

where R1represents a hydrogen atom, halogen atom or alkyl;

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

R is represented by formula (II):

where X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X is CH;

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

s represents an integer from 1 to 3;

t is predstavljaet an integer from 1 to 3;

if R3represents a hydrogen atom or alkyl, then R2represents a hydrogen atom, alkyl, a hydroxyl group or hydroxyacyl and R2'represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'represent a hydrogen atom, including the intramolecular cyclization of the compounds of formula (15)

where J2is dialkylamino, and R1, Y and R have the above values,

in the presence of a base in an anhydrous solvent or in the presence of acid.

38. The method of obtaining the compound represented by formula (I)

where R1represents a hydrogen atom, halogen atom or alkyl;

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

R is represented by formula (II)

where X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH;

W represents CH or nitrogen atom, provided that if X is 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 R3represents a hydrogen atom or alkyl, then R2represents a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl and R2'represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'represent a hydrogen atom,

including the interaction of the compounds of formula (16)

where R1represents a hydrogen atom, halogen atom or alkyl;

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

where X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH;

W represents CH or nitrogen atom, provided that if X is 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 R3represents a hydrogen atom or alkyl, then R2represents a hydrogen atom, alkyl, a hydroxyl group or a Hydra is xilatyl and R 2'represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'represent a hydrogen atom,

with a source of ammonia in a suitable solvent, such that no inhibits the course of the reaction to obtain compounds of formula (I).

39. The method of obtaining the compound represented by formula (I)

where R1represents a hydrogen atom, halogen atom or alkyl;

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

R is represented by formula (II)

where X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH;

W represents CH or nitrogen atom, provided that if X is 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 R3represents a hydrogen atom or alkyl, then R2represents a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl and R2'represents a hydroxyl group or hydroxyalkyl; and

including intramolecular cyclization of compounds of formula (15)

where J2is dialkylamino, and R1, Y and R have the above values,

in the presence of a base in an anhydrous solvent or in the presence of acid to obtain the compounds of formula (16)

where R1, Y and R have the above values,

and the interaction of the compounds of formula (16) with a source of ammonia in a suitable solvent, such that no inhibits the course of the reaction to obtain compounds of formula (I).

40. The method of obtaining the compound represented by formula (I)

where R1represents a hydrogen atom, halogen atom or alkyl;

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

R is represented by formula (II)

where X represents CH or nitrogen atom, provided that when Y is absent in the formula (I), then X must represent CH;

W represents CH or atom is the monk, provided that if X is 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 R3represents a hydrogen atom or alkyl, then R2represents a hydrogen atom, alkyl, a hydroxyl group or hydroxyalkyl and R2'represents a hydroxyl group or hydroxyalkyl; and

if R3is hydroxyalkyl, then R2and R2'represent a hydrogen atom,

including the interaction of the compounds of formula (11'):

where R1and J2have the above meanings, with a compound of formula (14)

where Y and R have the above values, and J3represents N-alkyl-N-alkoxyamino, obtaining the compounds of formula (15)

where J2is dialkylamino, and R1, Y and R have the above values,

intramolecular cyclization of compounds of formula (15) in the presence of a base in an anhydrous solvent or in the presence of acid to obtain the compounds of formula (16)

where R1, Y and R have the above values,

and interaction connection Faure the uly (16) with a source of ammonia in a suitable solvent, such that no inhibits the course of the reaction to obtain compounds of formula (I).



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to novel derivatives of imidazolidine and describes compound of the formula (I): wherein R1 is chosen from the group consisting of (C1-C9)-alkyl, (C1-C2)-alkyl-Ar; R2 is chosen from the group consisting of phenyl, (C1-C4)-alkyl-Ar', -NC(O)R4, (C2-C4)-alkyl-NR3R4, (C1-C3)-alkyl-C(O)-Ar'; R3 is chosen from the group consisting of hydrogen atom (H), (C1-C2)-alkyl-Ar and Ar; R4 represents R3, or R4 can be taken in common with R3 and nitrogen atom to which they are bound for formation of morpholinyl; Ar is chosen from the group consisting of phenyl that can be optionally substituted with one, two or three substitutes chosen from the group consisting of F, Cl, Br and J; Ar' is chosen from the group consisting of phenyl, biphenyl, benzofuranyl and benz[b]thiophene that can be optionally substituted with one, two or three substitutes chosen from the group consisting of (C1-C6)-alkyl, -(CH2)0-5CO2R1, F, Cl, Br, J and COOH; A is chosen from -C(O)NHOH or -N(CHO)OH; X means -NH if Y means -C(O), or its pharmaceutically acceptable salt. Also, invention describes a method for treatment of bacterial infection based on compounds of the formula (I). Invention provides preparing novel compounds possessing the useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds.

4 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide of the formula (I): . Method involves: (A) contacting compound of the formula (II) with transient-base metal as a catalyst, hydrogen source and a base in solvent medium to form compound of the formula (III): wherein R1 represents -XR wherein X represents oxygen atom (O), sulfur atom (S) or selenium atom (Se), or R1 represents -NR2R3 wherein each R2 and R3 represents independently alkyl, cycloalkyl, arylalkyl or aryl, or R2 and R3 taken in common represent -(CH2)4-, -(CH2)5-, -(CH(R4)-CH2)3-, -(CH(R4)-CH2)4-, -(CH(R4)-(CH2)2-CH(R4)-, -(CH(R4)-(CH2)3-CH(R4)-, -CH2-CH2-A-CH2-CH2-, -CH(R4)-CH2-A-CH2-CH2-, -CH(R4)-CH2-A-CH2-CH(R4)- wherein R4 represents alkyl comprising of from one to four carbon atoms; A represents oxygen atom (O), sulfur atom (S), -NH or -NR wherein R represents alkyl, aryl, arylalkyl or heteroaryl; (b) conversion of compound of the formula (III) wherein R1 is given above to compound of the formula (IV) with using a base in an aqueous methanol medium, and (c) contacting compound of the formula (IV) with acid in solvent medium to form compound of the formula (I). Invention provides the development of safety and effective method for synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide for the large-scale production.

EFFECT: improved preparing method.

13 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzofuran of the formula (1): wherein R represents L; R1 represents 2-R2-5-R3-pyrrol-1-yl-carbonyl, -CON(C2H5)2, -CON(CH2C6H5)2, -CON[CO2C(CH3)2]2; L represents bromine atom (Br); R2 and R3 in each case and independently of one another represent alkyl comprising 1-6 carbon (C)-atoms, and to their salts also. These compounds are intermediate substances used in synthesis of medicinal preparations showing effect on the central nervous system, for example, 1-[4-(5-cyanoindole-3-yl)butyl]-4-carbamoylbenzofuran-5-yl)piperazine. Invention provides synthesis if new intermediate compounds allowing synthesis of medicinal preparations such as 1-[4-(5-cyanoindole-3-yl)butyl]-4-carbamoylbenzofuran-5-yl)piperazine by the available method.

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

4 cl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

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

7 cl, 47 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new type of compounds representing crown-containing styryl dyes with ammonium group at N-substitute of heterocyclic residue that can be used as photo- and thermosensitive compounds. Invention describes new crown-containing styryl dyes with ammonium group at N-substitute of a heterocyclic residue. Also, invention describes two variants of the method for their preparing. The first method is based on the interaction of a heterocyclic base quaternary salt with formyl derivative of the corresponding crown-compound, and the second method involves quaternization reaction of crown-containing heteroarylphenylethylene at heterocycle nitrogen atom. Proposed crown-containing styryl dyes are prepared from available raw with high yield and represent compounds of the new type able to stereospecific reactions [2 + 2], i. e. photocyclo-addition and possessing thermochromism properties.

EFFECT: improved preparing methods, valuable properties of dyes.

4 cl, 4 dwg, 16 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

Antibacterial agent // 2269525

FIELD: organic chemistry, veterinary science, pharmacy.

SUBSTANCE: invention relates to N-[1S-4-benzo[1,3]dioxol-5-ylmethylpiperazin-1-carbonyl)-2,2-dimethylpropyl]-2R-cyclopentylmethyl-3-(formylhydroxyamino)propionamide of the formula: or its pharmaceutically acceptable and acceptable in veterinary salt, hydrate or solvate. Also, invention proposes pharmaceutical or veterinary composition possessing antibacterial activity comprising the indicated compound in common with pharmaceutically acceptable or acceptable in veterinary vehicle. Invention provides a derivative of hydroxamic acid possessing an antibacterial activity.

EFFECT: valuable properties of agent.

3 cl, 9 tbl, 96 ex

Muscarinic agonists // 2269523

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.

EFFECT: valuable medicinal properties of agonists.

14 cl, 2 tbl, 101 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel tricyclic compounds, their pharmaceutically acceptable salts and solvates useful for inhibition of activity of farnesyl-protein-transferase. Invention describes compound of the formula (1.0): or its pharmaceutically acceptable salt or solvate wherein one among a, b, c and d means nitrogen atom (N) or -N+O-, and other a, b, c and d mean carbon atom and wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; or all a, b, c and d mean carbon atom wherein each carbon atom comprises radical R1 or R2 bound to indicated carbon atom; broken line (- - -) means optional binds; X means N or -CH when optional bond is absent, and it means carbon atom (C) when optional bond presents; when optional bond between carbon atom 5 and carbon atom 6 presents then only a single substitute A presents bound with carbon atom 5, and only a single substitute B presents bound with carbon atom 6, and A and B fifer from hydrogen atom (H); if optional bind between carbon atom 5 and carbon atom 6 is absent then two substitutes A present bound with carbon atom 5, and two substitutes B bound with carbon atom 6 wherein at least one of two substitutes A or one among two substitutes B mean H and wherein at least one of two substitutes A or one of two substitutes B has value distinct from H, and other radical are described in the invention claim. Also, invention disclosed a pharmaceutical composition comprising such compounds, a method for inhibition of anomalous growth of cells and methods for treatment of proliferative diseases as cancer.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

52 cl, 2 tbl, 505 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I): or its pharmaceutically acceptable salt wherein X is chosen from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S) atoms; Z represents nitrogen atom (N); Y is chosen from the group consisting of =O, =S or their tautomers; SPU means a spacer element providing distance d between Z and N atom wherein -SPU- represents bi-radical -(CR6R7)n- wherein n means 1, 2, 3, 4 or 5; N atom in common with R1 and R2 forms heterocyclic ring wherein indicated heterocyclic ring is chosen from the group consisting of piperidine and 8-azabicyclo[3.2.1]octane and wherein heterocyclic ring is substituted with one or more substitutes R4 chosen from the group consisting of hydrogen atom, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkylidene, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkyloxyimino-group each of them is substituted optionally with a substitute R5 and wherein at least with one of indicated substitutes R4 is represented by R4' chosen from the group consisting of (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkylidene wherein each of them is substituted optionally with a substitute R5 wherein R5 is chosen from the group consisting of hydrogen, halogen atom, hydroxy-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl; RX can absent or can be chosen from the group consisting of hydrogen atom and optionally substituted (C1-C8)-alkyl; R3 can be represented in 0-4-fold range and chosen from the group consisting of halogen atom, optionally substituted (C1-C8)-alkyl and (C1-C8)-alkoxy-group; each R6 and R7 is chosen optionally and independently among the group consisting of hydrogen atom, hydroxy-group and optionally substituted (C-C8)-alkyl. Also, invention relates to a pharmaceutical composition possessing the selective activity with respect to M and/or M4-subtypes of muscarinic receptors and antagonism with respect to D2-dopamine receptors and comprising compound of the formula (I) by claim 1 in common with pharmaceutically acceptable carriers or excipients. Also, invention relates to a method for enhancing activity of cholinergic receptor comprising interaction of cholinergic receptor and system comprising cholinergic receptor with the effective amount of at least one compound of the formula (I) by claim 1. Also, invention relates to using the compound according to any claim among 1-11 or its pharmaceutically acceptable salt, or pharmaceutical composition containing any base for preparing a medicinal preparation used in prophylaxis aim or treatment of psychosis or for attenuation of symptoms associated with psychosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivative of pyridine of the general formula (I): wherein each symbol has the following values: R1 and R2 mean hydrogen, halogen atoms, lower alkyl, lower alkoxy-group; R3 and R4 mean hydrogen atom, lower alkyl, halogen atom; R5 means hydrogen atom, lower alkyl; n = 0 or 1, or its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition based on compounds of the formula (I) and intermediates substances used in synthesis. Compounds possess inhibitory effect on activity of phosphodiesterase of type 4.

EFFECT: valuable medicinal and biochemical properties of derivatives.

9 cl, 13 tbl, 147 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

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

7 cl, 47 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (1): and their pharmaceutically acceptable salts wherein represents a double bond; Z1 represents nitrogen atom (N), -CR5 wherein R5 represents hydrogen atom (H), (C1-C6)-alkyl, hydroxy-group (OH),(C1-C6)-alkoxy-group or halogen atom; Z2 at position 2 represents CR1 and at position it represents CA wherein each R1 means independently (C1-C6)-alkyl; A represents -Wi-COXjY wherein Y means -COR2 wherein R2 means -OR, -NR2, -NRNR2 or -NROR wherein each R represents independently hydrogen atom (H), (C1-C6)-alkyl, or (C5-C6)-heteroaryl comprising one or two heteroatoms in ring chosen from atoms N, O and S wherein each of them is substituted with one or some groups chosen from -NR'2, -OR', -COOR', (C1-C6)-alkyl, -CN, =O, and -SR' wherein each R' represents hydrogen atom (H) or (C1-C6)-alkyl and wherein two R or R' jointed to the same nitrogen atom (N) can form 3-8-membered ring chosen from the group comprising piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring and wherein indicated ring can be substituted additionally with (C1-C6)-alkyl or -COO-(C1-C6)-alkyl; X represents unsubstituted (C1-C6)-alkylene, or Y means imidazole substituted with methyl group; i = 0; j = 0 or 1; R7 means hydrogen atom (H) or (C1-C6)-alkyl, -SOR, -SO2R, -RCO, -COOR, (C1-C6)-alkyl-COR, -CONR2, -SO2NR2,-CN, -OR, (C1-C6)-alkyl-SR, (C1-C6)-alkyl-OCOR, (C1-C6)-alkyl-COOR, (C1-C6)-alkyl-CN, or (C1-C6)-alkyl-CONR2 wherein each R represent independently hydrogen atom (H), (C1-C6)-alkyl or aryl that is substituted optionally with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; or R7 represents methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R3 represent independently halogen atom, (C1-C6)-alkyl, -OR, -SR or -NR2 wherein R represents hydrogen atom (H) or (C1-C6)-alkyl; n = 0-3; L1 means -CO; L2 means (C1-C4)-alkylene optionally substituted with one or two groups of (C1-C4)-alkyl; each R4 is chosen independently from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2, -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl; or R4 represents =O; m = 0-4; Ar means aryl group substituted with from 0 to 5 substitutes chosen from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2 and -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl. Compounds of the formula (I) possess the inhibitory activity with respect to p38-α kinase that allows their using as components of the pharmaceutical composition.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

63 cl, 3 tbl, 9 sch, 16 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula II , wherein X, Y represent N; Z O; Ar1 represents 2-piridyl; Ar2 represents phenyl and at least one from Ar1 and Ar2 is substituted by at least one residue selected from group comprising of -F, -Cl, -Br, -I, -SR, -CN, -C(O)R, -CH(OR)R', -CH2(OR), -CF3, C1-C10-alkyl and aryl, wherein R of R' are H, -CF3, C1-C10-alkyl and aryl or together form a ring, except for 3-(2-piridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole or 3-(2-piridyl)-5-[3-(trifluotomethyl)phenyl]-1,2,4-oxadiazole; or to new compounds as defined in specification; as well as pharmaceutical composition having activity in relation to metabothrophic glutamate receptors based on the same and method for modulating of metabothrophic glutamate receptors.

EFFECT: new compounds useful as modulators of metabothrophic glutamate receptors.

14 cl, 10 ex, 1 dwg

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