WO2005113540A1

WO2005113540A1 - Isoquinoline compound and pharmaceutical use thereof

Info

Publication number: WO2005113540A1
Application number: PCT/JP2005/009120
Authority: WO
Inventors: Masakazu Fujio; Hiroyuki Satoh; Toshifumi Matsumoto; Takafumi Futamura
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2004-05-20
Filing date: 2005-05-19
Publication date: 2005-12-01

Abstract

Disclosed are an isoquinoline compound represented by the general formula (I) below, an optically active substance thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water addition product thereof and a solvate thereof which have a strong PARP inhibitory effect.

Description

Specification

Isoquinoline conjugates and their pharmaceutical uses

Technical field

The present invention relates to a novel isoquinoline conjugate and a drug containing the same as an active ingredient.

Background art

[0002] Poly (ADP-ribose) polymerase (hereinafter abbreviated as "PARP") breaks the bond between nicotinamide and ribose using nicotinamide nucleotide (NAD) as a substrate. It is a nuclear enzyme that transfers ADP-ribose residues to proteins and performs addition polymerization of multiple ADP-ribose residues. This enzyme has attracted attention as an apoptosis-related enzyme, and is activated by recognizing breaks in DNA damaged by free radicals such as nitric oxide and active oxygen produced at the site of disease during ischemia. However, the main role has been to assist in DNA repair.

[0003] In recent years, it has been considered that PARP activation causes a decrease in intracellular NAD, and that a large amount of ATP is consumed to compensate for this decrease, resulting in depletion of intracellular energy and death of the cell. . In experiments using PARP knockout mice, cultured neurons show resistance to disorders caused by excitatory amino acids such as nitric oxide and NMDA (N-methyl D-aspartate). Indeed, it was revealed that the cerebral infarction lesion exhibited an amazing protective effect of suppressing 80% or more (Non-Patent Document 1).

[0004] However, none of the PARP inhibitors reported so far has been provided to clinical trials as a therapeutic agent for cerebral infarction. Examples of the PARP inhibitors that have been reported to date include, for example, 5-substituted 1,3,4 dihydro-12H-isoquinoline derivatives (Patent Document 1), 1, lib dihydridobenzobenzopyrano [4.3.2-de] Isoquinolin-1-one derivatives (Patent Document 2), 3,4-dihydro-5- [4- (1-piberidyl) -butoxy] 1 (2H) -isoquinolinone (Patent Documents 3 and 4), pyrimidine Derivatives (Patent Document 5), benzimidazole derivatives (Patent Documents 6 and 7), phthalazine derivatives (Patent Document 8, Patent Documents 9 and 10), quinazolinone derivatives (Patent Documents 11 and 12), and the like. Known, but this Their PARP inhibitory activity is not very strong.

Patent Document 13 discloses an isoquinoline derivative having an analgesic effect and hypoglycemic effect, and Patent Document 14 discloses a method for producing a 3H-pyrazo-mouth [3,4-c] isoquinoline-5 (4H) one derivative. Literature 2 shows 2-methyl 4-dimethylaminomethylisoquinoline-one-on force Non-patent Document ₃ shows ₃ -amino- ₄ -acetyl-2H-isoquinoline-one-on force Patent Document 15 shows 4-dialkylaminomethyl 2H isoquinoline one-on derivative Patent Document 16 discloses fused isoquinolin-1-one derivatives, respectively. However, these compounds do not focus on PARP inhibitory action.

Patent document 1: EP355750 publication

Patent Document 2: WO 99/11645

Patent Document 3: WO99Z08680

Patent Document 4: WO 99/11649

Patent Document 5: WO00Z42025

Patent Document 6: WO00Z64878 Publication

Patent Document 7: WOOOZ68206

Patent document 8: WO00Z67734 publication

Patent Document 9: WO00Z44726

Patent Document 10: WOOlZ79184 Publication

Patent Document 11: WO02 / 48117

Patent Document 12: WO02Z44157

Patent Document 13: Japanese Patent Publication No. 46-12454

Patent Document 14: US Patent No. 4,113, 731

Patent Document 15: Japanese Patent Publication No. 52-156875

Patent Document 16: Japanese Patent Publication No. 54-84597

Non-patent document l: Eliasson MJL. Et. Al., Nature Med., 3, 1089-95 (1997) Non-patent document 2: Chemical & Pharmaceutical Bulletin (Chem. Pharm. Bull. Vol. 19 (11)) , 1971, p. 2414) Non-Patent Document 3: Pharmaceutical Journal (Vol. 91 (No. 12), p. 1279, 1971)

Disclosure of the invention

Problems to be solved by the invention

An object of the present invention is to provide a compound having PARP inhibitory activity and useful as a therapeutic drug for cerebral infarction, particularly as a therapeutic drug for acute phase of cerebral infarction.

Means for solving the problem

As a result of intensive studies, the present inventors have found that an isoquinoline conjugate represented by the following general formula (I), an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, The present inventors have found that a water adduct and a solvate thereof have a strong PARP inhibitory action, and have completed the present invention.

That is, the gist of the present invention is as follows.

(1) The following general formula (I)

[0009] [Formula 1]

[0010] [wherein, R ¹ is a hydrogen atom, a halogen atom, an alkyl, an alkoxy, a haloalkyl, a hydroxy, an alkylamino with an amino, a dialkylamino, a nitro, a hydroxyl with an acyl, a carboxyl, an alkoxycarbonyl, a carbamoyl, an N-alkyl And alkamoyl, N, N-dialkylcarbamoyl, acylylamino, diacylamino, thiol, alkylthio, sulfamoyl with alkoxycarbamyl, N-alkylsulfamoyl, N, N-dialkylsulfamoyl or alkoxyalkyloxy.

R ² represents alkyl.

R ³ represents a group selected from the following general formula (a) or (b). [0011] [Formula 2]

(a) (b)

X represents a C alkylene chain.

13

R ⁴ is a hydrogen atom, an alkyl, hydroxyalkyl, amino input Arukiruamino, Jiarukirua Mi input alkoxycarbonyl - le, alkylsulfonyl - le, Ashiru, Ashiruamino, optionally have a substituent Ariru, have a substituent Represents a heteroaryl, V having a substituent, or arylalkyl, or! /, Or! /, Heteroarylalkyl having a substituent. ]

Or an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof and a solvate thereof.

(2) —In general formula (I),

R ¹ represents a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, hydroxy or amino,

R ² represents alkyl,

R ³ represents a group selected from the general formula (a) or (b),

X represents a C anolexylene chain;

13

R ⁴ represents a hydrogen atom, alkyl or hydroxyalkyl, the isoquinoline compound according to the above (1), an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof and a solvent thereof. Japanese food.

(3) —In general formula (I),

R ¹ is a hydrogen atom, a halogen atom, C alkyl, C alkoxy, C haloal

1-4 1 -4 1-4 represents a kill, hydroxy or amino,

R ² represents C alkyl;

1-4

R ³ represents a group selected from the general formula (a) or (b),

X represents a C anolexylene chain; R ⁴ represents a hydrogen atom, C alkyl, or C hydroxyalkyl; (1) or (2)

1-4 1 -4

And the optically active isomers, pharmaceutically acceptable salts thereof, hydrates thereof, water adducts thereof, and solvates thereof.

(4) In general formula (I),

R ¹ represents a hydrogen atom or a halogen atom,

R ² represents C alkyl;

1-4

R ³ represents a group selected from the following general formula (a) or (b),

X represents a C anolexylene chain;

13

R ⁴ represents a hydrogen atom or a C alkyl, which is described in any of (1) to (3) above.

1-4

Sokinolini conjugates, optically active substances thereof, pharmaceutically acceptable salts thereof, hydrates thereof, water adducts and solvates thereof.

(5) —In general formula (I),

R ¹ represents a hydrogen atom or a halogen atom,

R ² represents methyl or ethyl,

R ³ represents a group selected from the general formula (a) or (b),

X represents a C anolexylene chain;

13

R ⁴ represents a hydrogen atom or a C alkyl, which is described in any of (1) to (4) above.

1-4

(6) —In general formula (I),

R ¹ represents a hydrogen atom, a fluorine atom or a chlorine atom,

R ² represents methyl or ethyl,

R ³ represents a group selected from the general formula (a) or (b),

X represents ethylene,

R ⁴ represents a hydrogen atom or a C alkyl, which is described in any of (1) to (5) above.

1-4

(7) —In general formula (I), R ¹ represents a hydrogen atom or a fluorine atom or a chlorine atom substituted at the 7-position,

R ² represents methyl or ethyl,

R ³ represents a group selected from the following general formula (a) or (b),

X represents ethylene,

R ⁴ represents a hydrogen atom, methyl or ethyl; the isocyanoline conjugate of any one of (1) to (6), an optically active form thereof, a pharmaceutically acceptable salt thereof, and a hydrate thereof. , Its water adducts and solvates thereof.

(8)

(1) 7 Fluoro-3-methyl-4- (1 ethoxycarbol-1,2,3,6-tetrahydrid pyridine-1--4-yl) 2H-isoquinoline-1-one

(2) 7 Fluoro-3-methyl-4- (1-methyl-1,2,3,6-tetrahydropyridine 4-yl) 2H-isoquinolin-1-one

(3) 7 Cloth 4- (1-ethoxycarbyl-1,2,3,6-tetrahydropyridine-1-yl) 3 Methyl 2H-isoquinolin-1-one

(4) 7 Cloth 4- (1,2,3,6-tetrahydropyridine-14-yl) 3-Methyl 2H Isoquinoline 1-on

(5) 7 Cloth 4- (1-methyl 1,2,3,6-tetrahydropyridine-1-yl) 3-Methyl 2H-isoquinolin-1-one

(6) 7 Black 1- 4- (1-Methylbiperidine 1-4-yl) 3-Methyl 2H-Isoquinolin-1on

(7) 7 4- (1-ethyl 1,2,3,6-tetrahydropyridine-1-yl) 3-methyl-2H-isoquinolin-1-one

(8) 7 1-methyl 4-H-isoquinolin-1-on

(9) 7 Fluoro-3-methyl 4- (1,2,3,6-tetrahydropyridine-1-yl) 2 H Isoquinoline

(10) 7 Cloth 4- (1-propyl-1,2,3,6-tetrahydropyridine-14-yl) -1-methyl-2H-isoquinolin-1-one (11) 7 Black 4- (1-propylpyridin-1-yl) 3-methyl-2H-isoquinolin-1-one

(12) 3-Methyl 4- (1-ethoxycarbol-1,2,3,6-tetrahydropyridine-14-yl) -1H-isoquinolin-1-one

(13) 3-Methyl-4-1 (1,2,3,6-tetrahydropyridine-4-yl) -1H-isoquinolin-1-one

(14) 3-Methyl 4- (piperidin-4-yl) 2H-isoquinolin-1-one

(15) 3-Methyl-4-1 (1-methyl-1,2,3,6-tetrahydropyridine-1-yl) 2 H Isoquinoline

(16) 3-Methyl-4- (1-ethyl-1,2,3,6-tetrahydropyridine-4-yl) -2H isoquinoline

(17) 3-methyl 4- (1-propyl-1,2,3,6-tetrahydropyridine-1-yl) -1H-isoquinoline

(18) 3-Methyl-4 (1-methylbiperidine-4-yl) 2H-isoquinoline-1-one

(19) 3-Methyl 4- (1-ethylpyperidin-1-yl) 2H-isoquinoline-1-one

(20) 7 Fluoro-3-methyl-4- (1-ethyl-1,2,3,6-tetrahydropyridine-4-yl) 2H-isoquinolin-1-one

(21) 7 Fluoro-3-methyl-4 (1-methylbiperidine-4-yl) -2H-isoquinoline-1one

(22) 7-Fluoro-3-methyl 41-ethylbiperidine 4-yl) 2H-isoquinoline-1 on

(23) 3-Methyl 4- (1-isopropyl-1,2,3,6-tetrahydropyridine-1-yl) —2H-isoquinolin-1-one

(24) 3-Methyl-4- (111-butyl-1,2,3,6-tetrahydropyridine-4-yl) 2H-isoquinoline 1one

(25) 3 ethyl 4- (1 ethoxycarbol 1,2,3,6-tetrahydropyridine 4-yl) 2H-isoquinoline 1 1-one

(26) 3ethyl 4- (1,2,3,6-tetrahydropyridine-1-yl) 2H-isoquinoline-1one

(27) 3-eth 4- (1-methyl 1,2,3,6-tetrahydropyridine-14-)-1H-isoquinolin-1-one, and

(28) 3 ethyl-4 (1-methylbiperidine-4-yl) 2H-isoquinoline 1-one

The isoquinoline compound according to any one of the above (1) to (7), whose optical power is also selected, its optically active substance, its pharmaceutically acceptable salt, its hydrate, its water adduct and its solvate.

(9)

(3) 7 Chloro 4- (1-ethoxycarbol-1,2,3,6-tetrahydropyridine-1-yl) 3 Methyl 2H-isoquinolin-1-one

(4) 7-chloro 4- (1,2,3,6-tetrahydropyridine-1-yl) 3-methyl 2H isoquinoline 1-on

(5) 7 Chloro 4- (1-methyl 1,2,3,6-tetrahydropyridin-4-yl) 3-methyl 2H-isoquinolin-1-one

(6) 7 Black 4- (1-methylbiperidine-1-yl) 3-methyl-2H-isoquinolin-1on

(7) 7 Chloro 4- (1-ethyl 1,2,3,6-tetrahydropyridine-1-yl) 3-methyl 2H-isoquinolin-1-one

(8) 7 Chloro 4- (1-ethylpyperidin-1-yl) 3-methyl 2H-isoquinolin-1-on

(9) 7 Fluoro-3-methyl 4- (1,2,3,6-tetrahydropyridine-1-yl) 2 H Isoquinoline 1 year old

(10) 7 Cloth 4- (1-propyl-1,2,3,6-tetrahydropyridine-14-yl) -1-methyl-2H-isoquinolin-1-one

(11) 7 4- (1-propylpiperidine-1-yl) 3-methyl-2H-isoquinolin-1-one

(13) 3-Methyl-4-1 (1,2,3,6-tetrahydropyridine-4-yl) -1H-isoquinolin-1-one

(14) 3-Methyl 4- (piperidin-4-yl) 2H-isoquinolin-1-one

(15) 3-Methyl-4-1 (1-methyl-1,2,3,6-tetrahydropyridine-1-yl) 2 H Isoquinoline

(16) 3-Methyl-4- (1-ethyl-1,2,3,6-tetrahydropyridine-4-yl) -2H isoquinoline

(17) 3-methyl 4- (1-propyl-1,2,3,6-tetrahydropyridine-1-yl) -1H-isoquinoline

(18) 3-Methyl-4 (1-methylbiperidine-4-yl) 2H-isoquinoline-1-one

(19) 3-Methyl 4- (1-ethylpyperidin-1-yl) 2H-isoquinoline-1-one

(20) 7 Fluoro-3-methyl-4- (1-ethyl-1,2,3,6-tetrahydropyridin-4-yl) 2H-isoquinolin-1-one

(21) 7 Fluoro-3-methyl-4 (1-methylbiperidine-4-yl) -2H-isoquinoline-1one

(22) 7-Fluoro-3-methyl 41-ethylbiperidine 4-yl) 2H-isoquinoline-1 on

(23) 3-Methyl 4- (1-isopropyl-1,2,3,6-tetrahydropyridine-1-yl) —2H-isoquinolin-1-one (24) 3-Methyl-4- (111-butyl-1,2,3,6-tetrahydropyridine-4-yl) 2H-isoquinoline 1 on, and

(25) 3 ethyl 4- (1 ethoxycarbol 1,2,3,6-tetrahydropyridine 4-yl) 2H-isoquinolin-1-one

The isoquinoline compound according to any one of the above (1) to (8), whose optical power is also selected, its optically active substance, its pharmaceutically acceptable salt, its hydrate, its water adduct and its solvate.

(10) The isoquinoline conjugate according to any one of (1) to (9) above, an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof, and a hydrate thereof. A prophylactic and / or therapeutic agent for a disease caused by hyperactivity of poly (ADP-ribose) synthase, which comprises a solvate.

(11) The preventive and / or therapeutic agent or the therapeutic agent according to the above (10), wherein the disease caused by hyperactivity of poly (ADP-ribose) synthase is cerebral infarction.

(12) The preventive and / or therapeutic agent or the therapeutic agent according to (10) above, wherein the disease caused by hyperactivity of poly (ADP-ribose) synthase is in the acute phase of cerebral infarction.

(13) The isoquinoline conjugate according to any one of (1) to (9) above, an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof, and a hydrate thereof. A poly (ADP-ribose) synthase inhibitor comprising a solvate.

The invention's effect

According to the present invention, a substance selected from the group consisting of an isoquinoline compound represented by the above general formula (I), a pharmaceutically acceptable salt, a hydrate, a water adduct and a solvate is used as an active ingredient. As a therapeutic agent for cerebral infarction.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

[0015] Each substituent in the general formula (I) will be described.

[0016] Specific examples of the substituents in R ¹ are as follows, also, R ¹ is substituted on any ring carbon atom.

Halogen atom: Fluorine atom, chlorine atom, bromine atom, iodine atom, fluorine atom, salt A fluorine atom and a chlorine atom are particularly preferable, in which a fluorine atom and a bromine atom are preferred.

Alkyl: C straight or branched chain alkyl, such as methyl, ethyl,

1-4

Mouth pill, isopropyl, butyl, isobutyl, tertiary butyl and the like are mentioned, and methyl and ethyl are particularly preferred, and methyl is particularly preferred.

Alkoxy: Alkoxy consisting of an alkyl (synonymous with alkyl in R ¹ ) and an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tertiary butoxy, with methoxy being preferred. U ,.

Haloalkyl: alkyl (same as alkyl in R ¹ ) substituted with one or more halogen atoms (same as halogen atom in R ¹ ), for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2 , 2-difluoroethyl, 2,2,2-trifluoroethyl and the like, with trifluoromethyl being preferred.

Alkylamino: an alkylamino having an alkyl (synonymous with alkyl in R ¹ ), such as methylamino, ethylamino, n-propylamido-containing isopropylamido-containing n-butylamino and the like.

Dialkylamino: alkyl portion are the same or different, dialkyl § amino having independent alkyl (alkyl as defined in R ^1), the alkyl portions may form a ring. For example, N-methyl-N-ethylamido-containing pyrrolidin-1-yl, dimethylamido-containing pyrimidine-1-yl, piperidin-1-yl and the like can be mentioned.

Acyl: an acyl having 1 to 4 carbon atoms, which is also composed of alkyl and carbohydrate, such as formyl, acetyl, propiol, 2-methylpropiol, and butyryl.

Alkoxycarbonyl - le: alkoxy (R ¹ alkoxy synonymous in) and carboxymethyl - composed Le alkoxycarbonyl - a le, for example, methoxycarbonyl - le, ethoxycarbonyl - le, propoxy carbo - le, isopropoxycarbonyl, butoxy And tert-butoxycarbol.

N-alkyl rubamoyl: N-alkyl composed of C alkylamino and carbohydrate

1-4

Alkylcarbamoyl, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl and the like. N, N-dialkyl-powered rubamoyl: N, N-dialkyl-powered rubamoyl composed of dialkylamino (synonymous with dialkylamino in R ¹ ) and carboxy, such as N, N-dimethylcarbamoyl, N, N —Getylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl and the like.

Ashiruamino: Ashiru a (Ashiru synonymous in R ¹⁾ and Aminoka also configured Ashiruamino, e.g. Horumiruami input Asechiruami input propionate - such Ruami input Buchiriruamino the like.

Jiashiruamino: a Jiashi Noreamino composed of two Ashiru and (Ashiru synonymous in R ¹⁾ Amino, Ashiru unit are independent and Yogu be the same or different for example N, N - Jiasechiruami entry N, N N, N-dibutyrylamino with dipropionylamido and the like.

Alkylthio: alkyl is § alkylthio composed of a (alkyl as defined in R ¹⁾ and a sulfur atom, such as methylthio, Echiruchio, propylthio, etc. butylthio and the like, methylthio is preferred.

Alkoxy carbamino: an alkoxycarbonylamino composed of an alkoxycarbol (synonymous with the alkoxycarbol in R ¹ ) and amino, such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino. And the like.

N - alkylsulfamoyl: alkylamino N- alkylsulfamoyl composed of (Arukiruamino synonymous in R ¹⁾ and scan sulfone, such as N- Mechirusurufa moil, N- E chill sulfamoyl, N- propylsulfamoyl Famoyl, N-butylsulfamoyl and the like.

N, N-dialkylsulfamoyl: N, N-dialkylsulfamoyl composed of dialkylamino (synonymous with dialkylamino in R ¹ ) and sulfone, such as N, N-dimethylsulfamoyl, N-getylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl and the like can be mentioned.

Alkoxyalkyloxy: Alkoxyalkyloxy consisting of alkoxy (same as alkoxy in R ¹ ), alkyl (same as alkyl in R ¹ ) and oxygen And methoxymethyloxy, ethoxymethyloxy, etc., and methoxymethyloxy is preferred.

[0017] R ¹ is preferably a hydrogen atom, a halogen atom, alkyl or alkoxy, particularly preferably a fluorine atom or a chlorine atom.

[0018] The position of the following is preferred as a replacement position of R ^1! / ,.

[0019] [Formula 3]

Alkyl in [0020] IT is the same meaning as the alkyl in R ^1, particularly preferably methyl Sig preferred is methyl or Echiru.

[0021] The alkylene chain of C in X represents methylene, ethylene, or propylene;

13

Is preferred.

Specific examples of the substituent for R ⁴ are as follows.

Alkyl: a force synonymous with alkyl in R ¹ Methyl, ethyl, propyl, butyl are preferred, and methyl is particularly preferred.

Hydroxyalkyl: alkyl is a hydroxyalkyl (alkyl as defined in R ¹⁾ and Ru is composed of hydroxy, for example 2-hydroxy E chill, 3-hydroxypropyl, 2-hydroxy 2-methylpropyl, etc. 4-hydroxy-butyl and the like, 2 hydroxamate Shetyl is preferred.

Arukiruamino: it is synonymous with Arukiruamino in R ^1.

Dialkylamino: the same meanings as dialkyl § Mino in R ^1.

Alkoxycarbonyl: The same as the alkoxycarbonyl for R ¹ .

Alkylsulfonyl which consists Le - (alkyl as defined in R ¹⁾ and sulfo: - alkylsulfonyl Le.

Ashiru: is synonymous with Ashiru in R ^1.

Ashiruamino: it is synonymous with Ashiruamino in R ^1.

Aryl: Examples of aryl include phenol and naphthyl, and phenol is particularly preferable. Heteroaryl: Examples of heteroaryl include furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine and the like. § reel alkyl: Ariru a group consisting from (for R ⁴ Ariru synonymous) and alkyl (Al kills synonymous in R ^1), such as benzyl, include full Nechiru, benzyl especially preferred.

Heteroalkyl § Reel alkyl: (Heteroariru synonymous in R ⁴⁾ Heteroariru and a group composed of from (alkyl as defined in R ¹⁾ and alkyl Le.

The aryl, heteroaryl, arylalkyl and heteroarylalkyl represented by R ⁴ may be substituted with a suitable substituent. Here, the “substituent” includes a halogen atom, an alkyl, an alkoxy, a haloalkyl, an alkylamino, a dialkylamino, an acyl, an alkoxycarbol, an N-alkylcarbamoyl, an N, N-dialkylcarbamoyl, Examples thereof include N-alkylsulfamoyl, N, N-dialkylsulfamoyl, and alkoxyalkyloxy containing acylamino, diacyamino, alkylthio, alkoxycarbonylamido.

R ⁴ is preferably a hydrogen atom, alkyl or hydroxyalkyl, particularly preferably a hydrogen atom or methyl or ethyl.

[0025] Examples of the compound of the general formula (I) and a pharmaceutically acceptable salt thereof include an acid addition salt with an inorganic acid or an organic acid.

[0026] The compound of the general formula (I) and a pharmaceutically acceptable salt thereof may exist as a hydrate, a water adduct and a solvate. The summaries are also included in the present invention. When the compound of the general formula (I) has an asymmetric atom, at least two types of optical isomers exist. These optical isomers and mixtures thereof (including racemates) are included in the present invention.

The compound of the present invention contained in the general formula (I) can be synthesized by the following method. In the following reaction formula groups, the definition of each symbol is as defined above unless otherwise specified.

General synthesis method [0028]

[0029] The compound of the general formula (2) should not inhibit the progress of the reaction! In a solvent (such as acetic acid, methanol, ethanol, chloroform, dichloroethane, water or any mixed solvent thereof), ice-cooled The compound of the general formula (3) can be obtained by reacting with a bromine atom at the reflux temperature of the solvent from below.

[0030] The compound of general formula (3) should not inhibit the progress of the reaction! Solvents (N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, methylethylketone, Toluene, benzene or any mixture thereof) in the presence of a suitable base used in organic chemistry (potassium carbonate, sodium carbonate, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, etc.) The compound of the general formula (13) (wherein R ⁵ represents an alkoxyalkyloxy, and the same as the alkoxyalkyloxy in the formula (13) can be mentioned at the reflux temperature of the solvent under ice-cooling). A leaving group commonly used in organic chemistry, such as a bromine atom or trifluoromethanesulfo-loxy). To give a compound of the general formula (5).

The compounds of the general formulas (4) and (5) may be used alone or as a mixture of A compound of the formula (6) (wherein J is a C trialkyltin group,

1-4 1 -4

May be substituted with a boronic ester or C alkyl !, may be! /, Cyclic boronic acid

1-4

Represents an ester. Specific examples are B (OH) or

2

[Formula 5]

[0033] and the like. Pro represents a basic nitrogen protecting group generally used in organic chemistry, such as methoxycarbol, ethoxycarbol, and tert-butoxycarbonyl. ), And each of the compounds of the general formulas (7) and (8) alone! / Can be obtained as a mixture thereof. Here, the reaction conditions when J represents a trialkyltin group are as follows: Journal “ob” Heterocyclic ”Chemistry (J. Het. Chem.), Vol. 28, pp. 191-198 (1991) Stille coupling conditions generally used in organic chemistry as shown in (1) can be used. On the other hand, when J represents a boronic ester, the reaction conditions are as follows: Tetrahedron 'Lett., Vol. 41, pp. 3705-3708 (2000). Suzuki coupling conditions that are generally used scientifically can be used.

[0034] The compound of the general formula (7) is subjected to an alkoxyalkyl group deprotection condition generally used in organic chemistry (preferably acidic conditions such as an organic solvent solution of trifluoroacetic acid, hydrochloric acid, hydrogen chloride or sulfuric acid). By reacting, a compound of the general formula (8) can be obtained.

[0035] The compound of the general formula (8) is subjected to suitable deprotection conditions for protecting groups (for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, tetrahydrofuran using potassium hydroxide and sodium hydroxide). , 1,4 dioxane, water or any mixed solvent thereof at room temperature to the reflux temperature of the solvent, or hydrochloric acid, sulfuric acid, acetic acid or any mixed solvent thereof at room temperature to the reflux temperature of the solvent. Deprotection can be carried out using a method such as a reaction method to obtain a compound of the general formula (12) (wherein R ⁴ is a hydrogen atom).

A compound of the general formula (12) (wherein R ⁴ is a hydrogen atom) and R ⁴ — Z (where Z is a salt) A leaving group generally used in organic chemistry such as a hydrogen atom, a bromine atom, an iodine atom, p-toluenesulfonyloxy, methanesulfonyloxy, etc., wherein R ⁴ is alkyl, hydroxyalkyl, alkoxycarbol, alkyl A sulfol, an acyl, a substituted or unsubstituted arylalkyl or a substituted or unsubstituted heteroarylalkyl compound) with a solvent (N, N In dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, acetone, methylethylketone, toluene, benzene, water or any mixture thereof, suitable bases used in organic chemistry (sodium hydrogencarbonate, hydrogencarbonate) Potassium, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide , In the presence of a such as sodium hydride), by reacting the ice at the reflux temperature of the solvent, the compound of the general formula (12) (wherein, R ⁴ and Al kill, hydroxyalkyl, alkoxycarbonyl - le, Compounds having an alkylsulfol, an acyl, or a substituted or unsubstituted or arylalkyl or a substituted or unsubstituted heteroarylalkyl) can be obtained.

Further, a compound represented by the general formula (12) (wherein R ⁴ is alkyl, arylalkyl which may have a substituent, or The compound which is arylalkyl) inhibits the progress of the reaction in the presence of the compound of the general formula (12) (wherein R ⁴ is a hydrogen atom) and aldehydes such as formaldehyde, acetate aldehyde and propionaldehyde. It is obtained by adding sodium cyanoborohydride and sodium triacetoxyborohydride in a suitable solvent that does not harm (acetonitrile, tetrahydrofuran, N, N dimethylformamide, dimethyl sulfoxide, etc.) and reacting at the reflux temperature of the solvent under ice cooling. You can do it.

[0038] The compound of general formula (8) should not inhibit the progress of the reaction! Solvents (methanol, ethanol, propanol, tetrahydrofuran, ethyl acetate, acetic acid, N, N dimethylformamide, water or any mixture thereof) Solvent, etc.) in the presence of a catalyst commonly used in organic chemistry hydrogenation reactions such as noradium-carbon, platinum dioxide, Raney-kel, rhodium carbon, etc., at atmospheric pressure or under pressure and reflux of the solvent from room temperature. By reacting at a temperature, a compound of the general formula (10) can be obtained.

Further, the compound of the general formula (10) does not inhibit the progress of the reaction from the compound of the general formula (7)! Methanol, ethanol, propanol, tetrahydrofuran, ethyl acetate, acetic acid, N, N-dimethylformamide, water or any mixture thereof), hydrogenation of organic chemicals such as noradium-carbon, platinum dioxide, Raney nickel, rhodium carbon After the compound of the general formula (9) is obtained by reacting from room temperature to the reflux temperature of the solvent under atmospheric pressure or pressure under the presence of a catalyst generally used in the reaction, it is generally used in organic chemistry. It can also be obtained by reacting under conditions for deprotection of an alkoxyalkyl group (preferably acidic conditions such as trifluoroacetic acid, hydrochloric acid, a solution of hydrogen chloride in an organic solvent or sulfuric acid).

[0040] The compound of the general formula (10) is subjected to a suitable deprotection condition for a protective group (methanol, ethanol, n-propanol, isopropanol, n-butanol, tetrahydrofuran, (4) Reaction in dioxane, water or any mixed solvent thereof at room temperature to the reflux temperature of the solvent, or reaction in hydrochloric acid, sulfuric acid, acetic acid or any mixed solvent thereof at room temperature to the reflux temperature of the solvent) To obtain a compound of the general formula (11) (wherein R ⁴ is a hydrogen atom).

[0041] A compound of the general formula (11) (wherein R ⁴ is a hydrogen atom) and R ⁴ — Z (wherein Z is a chlorine atom, a bromine atom, an iodine atom, and p-toluenesulfo-roxy) Or a leaving group generally used in organic chemistry such as methanesulfonyloxy, and R ⁴ may have an alkyl, hydroxyalkyl, alkoxycarbol, alkylsulfol, acyl, or substituent. , Arylalkyl or a compound having a substituent and which may be heteroarylalkyl) and a solvent which does not inhibit the progress of the reaction (N, N dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, acetone, methyl Suitable bases used in organic chemistry (sodium hydrogen carbonate, potassium bicarbonate, etc.) in ethyl ketone, toluene, benzene, water or any mixture thereof Sodium hydroxide, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, etc.) under ice cooling and at the reflux temperature of the solvent to give a compound of the general formula (11) (Wherein R ⁴ has an alkyl, a hydroxyalkyl, an alkoxycarbol, an alkylsulfol, an acyl, a substituent, or an arylalkyl or a substituent, Alternatively, a compound which is a heteroarylalkyl) can be obtained. In addition, a compound represented by the general formula (11) (wherein R ⁴ is alkyl, arylalkyl which may have a substituent, or The compound which is arylalkyl) inhibits the progress of the reaction in the presence of a compound of the general formula (11) (wherein R ⁴ is a hydrogen atom) and aldehydes such as formaldehyde, acetoaldehyde and propionaldehyde. Add sodium borohydride and sodium triacetoxyborohydride in a suitable solvent that does not harm (acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, etc.) and react under ice-cooling at the reflux temperature of the solvent. You can also get it.

The compound of the present invention thus obtained can be isolated and purified by a conventional method.

The salt, hydrate, water adduct and solvate of the isoquinoline compound represented by the general formula (I) can be produced by a method having a known isoquinoline compounding power.

[0045] The compound of the general formula (I), its optically active form, its pharmaceutically acceptable salt, its hydrate, its water adduct and its solvate obtained by the above method are potent PARP inhibitors. It has an effect and is useful as a therapeutic agent for cerebral infarction, especially for the acute stage of cerebral infarction.

When the isoquinoline compound of the present invention, its optically active form, its pharmaceutically acceptable salt, its hydrate, its water adduct and its solvate are used as a medicine, the compound of the present invention is pharmaceutically acceptable. Pharmaceutical compositions or preparations (tablets, pills, capsules) obtained by mixing with excipients (excipients, binders, disintegrants, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizing agents, etc.) Or granules, powders, syrups, emulsions, elixirs, suspensions, solutions, injections, drops, suppositories, etc.) orally or parenterally.

[0047] The pharmaceutical composition can be formulated according to a usual method.

[0048] In the present specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or infusion. Preparations for injection can be prepared by methods known in the art. Suppositories for rectal administration can be prepared by mixing the drug with an appropriate excipient and the like. Examples of solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills, and capsules. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions. No.

[0049] The dosage depends on age, body weight, general health condition, gender, diet, administration time, administration method, excretion rate, drug combination, degree of medical condition of the patient being treated at that time, and other factors. Is determined in consideration of the following factors.

[0050] The compound of the present invention, its optical isomer or its pharmaceutically acceptable salt, its hydrate, its water adduct and its solvate can be safely used with low toxicity, The dosage varies depending on the condition and weight of the patient, the type of compound, the route of administration, and the like.For example, parenterally, subcutaneously, intravenously, intramuscularly, or rectally, approximately 0.01 to 50 mg Z It is preferably administered daily, preferably 0.01 to 20 mgZ person Z days, and orally about 0.01 to 150 mgZ person / day, preferably 0.1 to: LOOmg / person / day.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples as long as the gist is not exceeded. The unit of the J value shown here is Hz.

[0052] Hereinafter, each raw material synthesis example synthesized in raw material synthesis examples 1 to 8 is shown. In the structural formula, MOM represents methoxymethyl.

[0053] [Formula 6]

[0054] Raw material synthesis example 1 Described in Synthetic Communications (Syn. Commun) Vol. 19, pp. 285-291 (1989) using 50.3 g of 1-ethoxycarbol-4 piperidone and 103 g of tri (n-butyl) tin hydride. The reaction was carried out according to the following method to obtain 48.7 g of (1 ethoxycarbol-1,2,3,6-tetrahydropyridine-14-yl) -tri (n-butyl) tin.

— NMR (CDC1) δ: 0.86—1.72 (30H, m), 2.20—2.32 (2H, m), 3.46

Three

—3.52 (2H, m), 3.88— 3.98 (2H, m), 4.15 (2H, q, J = 7 Hz), 5.74 (1H, brs).

[0055] Raw material synthesis example 2

8.4 g of 3-methyl 2H-isoquinolin-1-one was suspended in 80 mL of acetic acid, 3.3 mL of bromine was added at room temperature, and the mixture was stirred for 3 hours. After completion of the reaction, the precipitated crystals were collected by filtration and washed to quantitatively obtain 4-promo-3-methyl-2H-isoquinoline 1-one.

— NMR (DMSO d) δ: 2.41 (3Η, s), 7.50—7.56 (1H, m), 7.79— 7.

6

82 (2H, m), 8.20 (1H, d, J = 8 Hz), 11.71 (1H, brs).

[0056] Raw material synthesis example 3

Dissolve the entire amount of 4-bromo-3-methyl-2H-isoquinoline 11-one obtained in Raw Material Synthesis Example 2 in 120 mL of N, N dimethylformamide, add 3.5 g of sodium hydride (60%) under ice-cooling, and add And the mixture was ice-cooled again. 6.5 g of chloromethyl methyl ether was added to the reaction solution and reacted at room temperature. After completion of the reaction, ice, ImolZL hydrochloric acid and ethyl acetate were added to the reaction solution, and the precipitated crystals were collected to recover 6.8 g of 4-bromo-3-methyl-2H-isoquinoline-1-one. The ethyl acetate layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was concentrated. The obtained residue was purified by silica gel chromatography. The effluent of hexane: ethyl acetate = 4: 1 was concentrated to obtain 7.4 g of 4-bromo-2-methoxymethyl-3-methyl-2H-isoquinoline-one.

— NMR (CDC1) δ: 2.74 (3Η, s), 3.43 (3H, s), 5.64 (2H, s), 7.49 (1

Three

H, t, J = 8Hz), 7.73 (1H, t, J = 8Hz), 7.93 (1H, d, J = 8Hz), 8.41 (1H, d, J = 8Hz).

[0057] Raw material synthesis example 4

7 Fluoro-3-methyl-2H-isoquinolin-1-one 10.9 g is suspended in 220 mL of acetic acid. It became cloudy. After dropwise adding 3.35 mL of bromine, the mixture was stirred at room temperature overnight. After completion of the reaction, water was added and the crystals were collected by filtration and washed with isopropyl alcohol and ethyl acetate. The crystals were dried under reduced pressure to obtain 12.lg of 4-bromo-17-fluoro-3methyl 2H isoquinoline 1one.

— NMR (DMSO— d) δ: 2.39 (3Η, s), 7.60— 7.80 (1H, m), 7.85— 7.

6

90 (2H, m), 11.8 (1H, brs).

[0058] Raw material synthesis example 5 and raw material synthesis example 6

Under a nitrogen stream, 4-bromo-7-fluoro-3-methyl 2H isoquinoline 1-on 12.lg was suspended in 100 mL of N, N-dimethylformamide and the internal temperature was cooled to 10 ° C. 2.21 g of sodium hydride (60%) was added little by little, and the mixture was stirred at room temperature for 1.5 hours. After the reaction solution was ice-cooled again, a solution of 4.15 mL of chloromethyl methyl ether in 20 mL of N, N dimethylformamide was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated. The resulting residue was purified by silica gel column chromatography. The n-hexane: ethyl acetate = 10: 1 eluted and the n-hexane: ethyl acetate = 5: 1 eluted were each washed with n-hexane, and the crystals obtained by filtration were dried under reduced pressure. n-hexane: ethyl acetate = 10: 1 elution

4.37 g of 4-bromo-7fluoro-1-methoxymethyloxy-3-methylisoquinoline was obtained as crystals.

— NMR (CDC1) δ: 2.69 (3Η, s), 3.60 (3H, s), 5.72 (2H, s), 7.45— 7

Three

.52 (1H, m), 7.83- 7.87 (1H, m), 8.08- 8.13 (1H, m).

n-hexane: ethyl acetate = 5: 1 elution

5.49 g of 4-bromo-7fluoro-2-methoxymethyl-3-methyl-2H-isoquinoline 1one was obtained as crystals.

— NMR (CDC1) δ: 2.72 (3Η, s), 3.44 (3H, s), 5.63 (2H, s), 7.40— 7

Three

.47 (1H, m), 7.91-7.96 (1H, m), 8.04-8.08 (1H, m).

[0059] Raw material synthesis example 7

7 Raw material synthesis example 2 using 16.6 g of 3-methyl-2H-isoquinolin-1-one The reaction was carried out in the same manner as in the above to obtain 21.7 g of 4-bromo-7-methyl-3-methyl-2H-isoquinolin-1-one.

— NMR (DMSO d) δ: 2.40 (3Η, s), 7.80— 7.87 (2H, m), 8.12 (1H

6

, d, J = 2 Hz), 11.90 (1H, brs).

[0060] Raw material synthesis example 8

4-Bromo 7 1-g of 3-methyl-2H-isoquinolin-1-one was reacted in the same manner as in Raw Material Synthesis Example 5 and Raw Material Synthesis Example 6 using 18.6 g! 4-bromo-7-chloro-1-methoxymethyloxy 10 g of 1-3-methylisoquinoline was obtained.

— NMR (CDC1) δ: 2.69 (3Η, s), 3.61 (3H, s), 5.73 (2H, s), 7.66 (1

Three

H, dd, J = 2Hz, 9Hz), 8.05 (1H, d, J = 9Hz), 8.22 (1H, d, J = 2Hz).

[0061] Hereinafter, the compounds of the examples synthesized in Examples 1 to 28 are shown.

[0064] [Formula 9]

Example 1

a) 4-bromo-7-fluoro-2-methoxymethyl-3-methyl-2-H-isoquinoline 1one obtained in Raw Material Synthesis Example 5. 5.49 g, obtained in Raw Material Synthesis Example 1 (1 ethoxycarbonyl 1,2 9.38 g of 3,6-tetrahydropyridine-4-yl) -tri (n-butyl) tin, 978 mg of lithium chloride and 45.8 mg of 2,6-di-t-butyl 4-methylphenol 30 mL of N, N dimethylformamide , And 1.36 g of bis (triphenylphosphine) palladium (II) dichloride was added, and the mixture was reacted at 140 ° C. for 5 hours. After cooling the reaction solution to room temperature, water and ethyl acetate were added, and the mixture was filtered through celite. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. It was. Purify by silica gel column chromatography to obtain 7-fluoro-2-methoxymethine

4.51 g of 3-methyl 4- (1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine-14-yl) -1 2H-isoquinolin-1-one was obtained.

— NMR (CDC1) δ: 1.32 (3Η, t, J = 7Hz), 2.20— 2.35 (2H, m), 2.42 (

Three

3H, s), 3.45 (3H, s), 3.65— 3.75 (1H, m), 3.75— 3.90 (1H, m), 4.15 — 4.26 (4H, m), 5.56 (2H, s), 5.71 ( 1H, brs), 7.31-- 7.41 (2H, m), 8.

04- 8.08 (1H, m).

b) 7Fluoro-2-methoxymethyl-3-methyl 4- (1-ethoxycarbol-1,2,3,6-tetrahydropyridine-14-yl) 2H-isoquinolin-1-one 33.8 g and 170 mL of acetic acid The mixture was heated under reflux for 1 hour. The solvent was concentrated under reduced pressure, made alkaline with a 20% aqueous solution of potassium carbonate, and then cooled with water. After 8.7 mL of ethyl ethyl formate was added to the mixture and stirred at room temperature for 10 minutes, the form layer was separated, and the aqueous layer was further extracted with form. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography gave 29.8 g of 7-fluoro-3-methyl-4- (1-ethoxycarbonyl-1,2,3,6-tetrahydropyridin-1-yl) 2H-isoquinolin-1-one Was.

— NMR (CDC1) δ: 1.33 (3Η, t, J = 7Hz), 2.20— 2.32 (5H, m), 3.63

Three

—3.71 (1H, m), 3.82— 3.86 (1H, m), 4.10—4.27 (4H, m), 5.71 (1H, s), 7.33— 7.46 (2H, m), 8.04—8.08 (1H, m) , 11.1 (1H, brs).

Example 2

After dissolving 205 mg of 7-fluoro-3-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl) -2H-isoquinolin-1-one hydrochloride obtained in Example 9 in 6 mL of water and 3 mL of acetonitrile, 35 120 L of an aqueous formaldehyde solution was quenched and water-cooled. After adding 297 mg of sodium triacetoxyborohydride, the mixture was stirred at room temperature overnight. After completion of the reaction, a 20% aqueous potassium carbonate solution and water were added to make the solution alkaline, and the mixture was extracted with a solution of chloroform: methanol = 5: 1. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystals are collected by filtration, and 7-fluoro-3-methyl-4— (1-methyl-1,2,3,6-tetrahydropyridine-14-yl) 2H-isoquinoline-1 —On 154 mg was obtained.

— NMR (DMSO— d) δ: 2.15 (3H, s), 2.15— 2.25 (2H, m), 2.40 (3H

6

, s), 2.70-2.80 (2H, m), 3.10-3.20 (2H, m), 5.65 (1H, s), 7.49-7.61 (2H, m), 7.80-7.84 (1H, m), 11.4 (1H, s) .MS (ESI): 273 (M + 1)

Example 3

10 g of 4-bromo 7-cloth 1-methoxymethyloxy 3-methylisoquinoline obtained in Raw Material Synthesis Example 8 and 10 g of (1 ethoxycarbol-1,2,3,6-tetrahydropyridine obtained in Raw Material Synthesis Example 1 — 4- (yl) -tri (n-butyl) tin The reaction was carried out in the same manner as in Example 1-a) using 15.4 g of 7-chloro-1--4- (1-ethoxycarbol-1,2,2). 2.3 g of 3,6-tetrahydropyridin-4-yl) 3-methyl2H-isoquinolin-1-one was obtained.

— NMR (CDC1) δ: 1.33 (3Η, t, J = 7Hz), 2.20— 2.32 (2H, m), 2.32 (

Three

3H, s), 3.62—3.71 (1H, m), 3.75—3.90 (1H, m), 4.15—4.26 (4H, m), 5.71 (1H, brs), 7.37 (1H, d, J = 9Hz), 7.57 (1H, dd, J = 2Hz, 9Hz), 8.38 (1H, d, J = 2Hz), 10.83 (1H, brs).

Example 4

0.8 g of 7-chloro-1- (1,2-ethoxycarbol-1,2,3,6-tetrahydropyridine-14-yl) 3-methyl-2H-isoquinolin-1-one obtained in Example 3 The mixture was dissolved in 5 mL of concentrated hydrochloric acid and 5 mL of acetic acid, and heated under reflux for 9 hours. After completion of the reaction, the solvent was concentrated to give acetone. The precipitated crystals were collected by filtration to obtain 0.69 g of 7-chloro-4- (1,2,3,6-tetrahydropyridin-1-yl) 3-methyl-2H-isoquinolin-1-one hydrochloride.

— NMR (DMSO— d) δ: 2.19 (3Η, s), 2.25— 2.42 (2H, m), 3.25— 3.

6

45 (2H, m), 3.64-3.75 (2H, m), 5.70 (1H, s), 7.65-7.71 (2H, m), 8.10 (1H, s), 9.52 (2H, brs), 11.56 ( 1H, brs). MS (El): 274, 276 (M +).

Example 5

In the same manner as in Example 2 using 0.49 g of 7-chloro-4- (1,2,3,6-tetrahydropyridin-4-yl) 3-methyl-2H-isoquinolin-1-one hydrochloride obtained in Example 4 Anti And then react to the 7-chloro-1--4- (1-methyl-1,2,3,6-tetrahydropyridine-14-yl)

0.29 g of —3 methyl 2H-isoquinolin-1-one hydrochloride was obtained.

— NMR (DMSO d) δ: 2.16 (1.5Η, s), 2.23 (1.5H, s), 2.31 (1H, m

6

), 2.60-2.88 (4H, m), 3.28-- 3.64 (2H, m), 3.70-- 3.92 (2H, m), 5.70 (1H, s), 7.44 (0.5H, d, J = 8Hz), 7.64 (0.5H, dd, J = 2Hz, 9Hz), 7.71 (0.5H, dd, J = 2Hz, 9Hz), 8.10 (1H, dd, J = 2Hz, 9Hz), 11.16 (1H, b rs) , 11.53 (0.5H, brs), 11.56 (0.5H, brs). MS (El): 288, 290 (M +;). Example 6

a) 7-Chloro-4- (1 ethoxycarbol-1,2,3,6-tetrahydropyridine-1-yl) obtained in Example 3 3-Methyl 2H-isoquinolin-1-one 3.Og Was dissolved in 3 OmL of acetic acid, 0.1 g of platinum dioxide was added, and the mixture was vigorously stirred at room temperature and normal pressure for 5 hours under a hydrogen stream. After removing the catalyst by filtration, the reaction solution was concentrated and subjected to the same reaction again. The reaction was carried out again, and the catalyst was removed by filtration when the ratio of the raw material to the product reached 30:46. Concentrate the reaction mixture and add 7-methyl-1-4- (1-ethoxycarbol-1,2,3,6-tetrahydropyridin-1-4-inole) 3-methylinole 2H-isoquinolin-1-one and 7-chloro A mixture of 4- (1-ethoxycarbonylbiperidine 4-yl) 3 methyl 2H-isoquinoline 1-one was obtained.

b) 2 mL of dimethyl sulfoxide and 30 mL of 6 mol ZL hydrochloric acid were added to this mixture, and the mixture was heated to reflux. After completion of the reaction, the solvent was concentrated, and the precipitated crystals were collected by filtration. 7-chloro-4- (1,2,3,6-tetrahydropyridine-14-yl) 3-methyl-2H-isoquinoline-1- 0.9 g of a mixture of on-hydrochloride and 7-chloro-4- (piperidin-1-yl) 3-methyl 2H-isoquinolin-1-one hydrochloride was obtained. Further, 0.5 g of filtrate was obtained. It was used for the next reaction without further purification.

c) 7-Chloro-1- (1,2,3,6-tetrahydropyridine-4-inole) 3-methinole 2H-isoquinolin-1-one-hydrochloride and 7-chloro-4- (piperidine-1-inole) 3-methyl The reaction was carried out in the same manner as in Example 2 using 0.6 g of a mixture of 12H-isoquinolin-1-one hydrochloride, and the mixture was purified by silica gel chromatography. Clos form: methanol = 20: From 1 effluent 7 Clos 4- (1-methyl 1, 2, 3, 6-tetrahydropyridine 1-4) 0.13 g of 1-3-methyl-2H-isoquinolin-1-one was obtained, and the form of methanol: methanol = 10: 1 5: 1 from the effluent of 7-chloro 4- (1-methylbiperidin-1-yl) 3- 0.25 g of methyl-1H-isoquinolin-1-one was obtained.

7 Black 4— (1-Methylbiperidine-1-yl) 3-Methyl 2H—Isoquinoline 1-one

— NMR (CDC1) δ: 1.60-1.75 (2Η, m), 2.04— 2.12 (2H, m), 2.34

Three

-2.50 (2H, m), 2.36 (3H, s), 2.48 (3H, s), 2.84-- 3.10 (3H, m), 7.5 5 (1H, d, J = 9Hz), 8.04 (IH, m), 8.43 (1H, d, J = 3Hz), 11.21 (IH, brs)

Example 7 and Example 8

7-chloro-4- (1,2,3,6-tetrahydropyridine-4-yl) obtained in Example 6-b) —3methyl-2H-isoquinoline-1-one hydrochloride and 7-chloro-1-4 (piperidine 4-yl) 7) The reaction was carried out in the same manner as in Example 2 using 0.3 g of a mixture of 3-methyl-2-H-isoquinolin-1-one hydrochloride and acetoaldehyde, and the purification was carried out in the same manner as in Example 6-c). Black 4- (1-ethyl 1,2,3,6-tetrahydropyridine-1-yl) 3-methyl-2H-isoquinolin-1-one 62 mg and 7-chloro 4- (1-ethylpyperidin-1-yl) 3 Thus, 0.12 g of —methyl 2H—isoquinolin-1-one was obtained.

[0072] 7 4- (1-ethyl 1,2,3,6-tetrahydropyridine-14-)-1-methyl-2-H-isoquinolin-1-one

— NMR (CDCl) δ: 1.20 (3Η, t, J = 7Hz), 2.20— 2.40 (2H, m), 2.32 (

Three

3H, s), 2.60 (2H, q, J = 7Hz), 2.72-2.79 (2H, m), 3.10-3.24 (2H, m), 5.69 (1H, s), 7.47-7.57 (2H, m), 8.36 (1H, d, J = 2Hz), 10.22 (1H, brs).

[0073] 7-chloro 4- (1-ethylpyperidin-1-yl) 3-methyl 2H-isoquinoline

1 ON

— NMR (CDC1) δ: 1.15 (3Η, t, J = 7Hz), 1.60—1.75 (2H, m), 2.00

Three

-2. 16 (2H, m), 2.25— 2.54 (4H, m), 2.47 (3H, s), 2.86—3.02 (1H, m), 3.08-3.21 (2H, m), 7.56 (1H, dd, J = 2Hz, 9Hz), 8.05 (1H, m), 8.43 (1H, d, J = 2Hz), 10.78 (1H, brs ).

Example 9

7-Fluoro 2-methoxymethyl-3-methyl 4- (1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine-1-yl) 2H-isoquinoline-1-one obtained in Example 1-a) 1. To Olg, 15 mL of acetic acid and 15 mL of concentrated hydrochloric acid were heated under reflux for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the precipitated crystals were washed twice with acetone by decanting. Further, the crystals were collected by filtration with acetone, dried under reduced pressure, and dried under reduced pressure to give 7-fluoro-3-methyl-4- (1,2,3,6-tetrahydropyridine-14-yl) 2H-isoquinoline-1-one. 537 mg of hydrochloride was obtained o

— NMR (DMSO— d) δ: 2.19 (3Η, s), 2.30— 2.50 (2H, m), 3.25— 3.

6

45 (2H, m), 3.70-3.80 (2H, m), 5.70 (1H, s), 7.51-7.58 (1H, m), 7.70-7.75 (1H, m), 7.80-7.85 (1H, m ), 9.52 (2H, brs), 11.50 (1H, brs) ₀

Example 10 and Example 11

7-Chloro-4- (1,2,3,6-tetrahydropyridine-4-yl) obtained in Example 6-b) —3methyl-2H-isoquinoline-l-one hydrochloride and 7-chloro-l-4 (piperidine 4-yl) The reaction was carried out in the same manner as in Example 2 using 0.5 g of a mixture of l) -3-methyl-2H-isoquinolin-1-one hydrochloride and propionaldehyde, followed by purification in the same manner as in Example 6-c). 4- (1-Propyl-1,2,3,6-tetrahydropyridine-4-yl) 3-methyl-2H-isoquinolin-1-one 0.12g and 7-Port 4- (1-propylpi (Lysine-4-yl) 3-methyl-2H-isoquinolin-1-one 0.26 g was obtained.

[0076] 7 1- (4-propynolee 1,2,3,6-tetrahydropyridine-1-yl) 3-methyl 2H-isoquinolin-1-one

— NMR (CDCl) δ: 0.97 (3Η, t, J = 7Hz), 1.56— 1.70 (2H, m), 2.23

Three

-2.36 (2H, m), 2.34 (3H, s), 2.45-- 2.50 (2H, m), 2.68-- 2.74 (2H, m), 3.12-3.20 (2H, m), 5.68 (1H, s) , 7.47— 7.57 (2H, m), 8.37 (1H , d, J = 2 Hz), 10.83 (IH, brs).

[0077] 7 Cloth 4- (1-propylpiperidine-1-yl) 3-methyl-2H-isoquinolin-1-on

— NMR (CDCl) δ: 0.95 (3Η, t, J = 7Hz), 1.50—1.75 (4H, m), 2.00

Three

-2.13 (2H, m), 2.25— 2.50 (4H, m), 2.49 (3H, s), 2.85—3.00 (1H, m), 3.04-3.20 (2H, m), 7.54 (IH, dd, J = 2Hz, 9Hz), 8.05 (IH, m), 8.37 (1H, d, J = 2Hz), 11.42 (1H, brs).

Example 12

a) The reaction was carried out in the same manner as in Example 1-a) using 7.4 g of 4-bromo-2-methoxymethyl 3-methyl 2H isoquinolin-1-one obtained in Starting Material Synthesis Example 3 to give 2-methoxymethyl-3 Methyl 4- (1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine-14-yl) 2H-isoquinolin-1-one 5.Og was obtained.

— NMR (CDC1) δ: 1.32 (3Η, t, J = 7Hz), 2.20— 2.32 (2H, m), 2.49 (

Three

3H, s), 3.45 (3H, s), 3.62— 3.70 (1H, m), 3.78— 3.89 (1H, m), 4.23 (2H, q, J = 7Hz), 4.08—4.26 (2H, m), 5.56-- 5.69 (3H, m), 7.38 (IH, d, J = 8Hz), 7.44 (IH, dt, J = lHz, 8Hz), 7.60-- 7.66 (IH, m), 8.43 (1H, d, J = 8Hz).

b) 2-Methoxymethyl-3-methyl-4- (1 ethoxycarbonyl-1,2,3,6-tetrahydropyridine-1-yl) 2H-isoquinolin-1-one 5. Performed using Og The reaction was carried out in the same manner as in Example 1-b), and 3-methyl-4- (1 ethoxycarbol-1,2,3,6-tetrahydropyridine-1-yl) 2H-isoquinolin-1-one 3.8 g Got.

— NMR (CDC1) δ: 1.33 (3Η, t, J = 7Hz), 2.20— 2.43 (2H, m), 2.32 (

Three

3H, s), 3.62-3.72 (1H, m), 3.83-3.93 (1H, m), 4.08-4.20 (2H, m), 4.23 (2H, q, J = 7Hz), 5.71 (IH, s), 7.40-7.47 (2H, m), 7.64 (1H, t, J = 8Hz), 8.42 (1H, d, J = 8Hz), 10.64 (1H, brs).

Example 13

Example 3 Using 1.8 g of 3-methyl 4- (1-ethoxycarbol-1,2,3,6-tetrahydridopyridine-14-yl) 2H-isoquinolin-1-one obtained in Example 12 Like 4, The reaction was performed to obtain 1.6 g of 3-methyl 4- (1,2,3,6-tetrahydropyridin-4-yl) 2H-isoquinolin-1-one hydrochloride.

— NMR (DMSO— d) δ: 2.19 (3Η, s), 2.30— 2.40 (2H, m), 3.30— 3.

6

44 (2H, m), 3.62-3.80 (2H, m), 5.68 (1H, s), 7.41-7.46 (1H, m), 7.61-7.68 (2H, m), 8.17 (1H, d , J = 8Hz), 9.56 (2H, brs), 11.32 (1H, brs). MS (EI): 240 (M +) _o

Example 14

a) 3-Methyl 4- (1-ethoxycarbol-1,2,3,6-tetrahydropyridin-4-yl) 2H-isoquinolin-1-one obtained in Example 12 After dissolving in 10 mL, 0.2 g of platinum dioxide was added, and the mixture was stirred at 60 ° C for 5 hours under a hydrogen stream. After completion of the reaction, the catalyst was removed by filtration, and the solvent was concentrated to obtain 3-methyl-4- (1-ethoxycarbo-rubiperidin-4-yl) 2H-isoquinoline 1-one. It was used for the next reaction without further purification.

b) 3-Methyl 4- (1-ethoxycarbo-rubiperidin-1-yl) 2H-isoquinoline 1-one whole amount was dissolved in 10 mL of acetic acid and 10 mL of concentrated hydrochloric acid, and heated under reflux. After the reaction was completed, the solvent was concentrated. Ethanol and acetone were added to the resulting residue, and the precipitated crystals were collected by filtration. 3-Methyl 4- (piperidin-1-yl) 2H-isoquinolin-1-one hydrochloride . .46 g was obtained.

— NMR (DMSO— d) δ: 1.65— 1.78 (2Η, m), 2.35 (3H, s), 2.40— 2.

6

65 (2H, m), 3.00-3.14 (2H, m), 3.20-3.40 (3H, m), 7.43 (1H, t, J = 8Hz), 7.67 (1H, t, J = 8Hz), 8.17 (1H , d, J = 8 Hz), 8.23 (1H, d, J = 8 Hz), 8.70-9.10 (2H, m), 11.17 (1H, brs).

Example 15

Same as Example 2 using 0.5 g of 3-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl) -2H-isoquinolin-1-one hydrochloride obtained in Example 13 Then, 0.25 g of 3-methyl 4- (1-methyl 1,2,3,6-tetrahydropyridin-1-yl) 2H-isoquinolin-1-one was obtained.

— NMR (CDC1) δ: 2.24-2.38 (2Η, m), 2.33 (3H, s), 2.46 (3H, s), 2.66-2.75 (2H, m), 3.08-- 3.26 (2H, m), 5.68-- 5.74 (1H, m), 7.42 (1H, dt, J = lHz, 8Hz), 7.52 (1H, d, J = 8Hz) , 7.62 (1H, dt, J = 1 Hz, 8Hz), 8.41 (1H, d, J = 8Hz), 10.31 (1H, brs). MS (EI): 254 (M +).

Example 16

Using 0.5 g of 3-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl) -2H-isoquinolin-1-one hydrochloride and 0.5 g of acetoaldehyde obtained in Example 13 The reaction was carried out in the same manner as in Example 2 to obtain 0.25 g of 3-methyl 4- (1-ethyl 1,2,3,6-tetrahydropyridin-1-yl) 2H-isoquinolin-1-one. .

— NMR (CDC1) δ: 1.20 (3Η, t, J = 7Hz), 2.20— 2.42 (2H, m), 2.33 (

Three

3H, s), 2.60 (2H, q, J = 7Hz), 2.68-2.78 (2H, m), 3.11-3.22 (2H, m), 5.68-5.72 (1H, m), 7.42 (1H, t, J = 8Hz), 7.53 (1H, d, J = 8Hz), 7.62 (1H, dt, J = 1Hz, 8Hz), 8.40 (1H, d, J = 8Hz), 10.09 (1H, brs). MS (EI) : 268 (M +) ₀

Example 17

Using 0.1 g of 3-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl) -2H-isoquinolin-1-one hydrochloride obtained in Example 13 and 0.5 g of propionaldehyde The reaction was carried out in the same manner as in Example 2 to obtain 27 mg of 3-methyl-4- (1-propyl 1,2,3,6-tetrahydridopyridine 4-yl) 2H isoquinoline-one.

— NMR (CDC1) δ: 0.97 (3Η, t, J = 7Hz), 1.59— 1.71 (2H, m), 2.24

Three

-2.38 (2H, m), 2.33 (3H, s), 2.45― 2.51 (2H, m), 2.70― 2.82 (2H, m), 3.12-3.26 (2H, m), 5.68― 5.72 (1H, m), 7.42 (1H, t, J = 8Hz), 7.53 (1H, d, J = 8Hz), 7.62 (1H, t, J = 8Hz), 8.40 (1H, d, J = 8Hz), 10.0 9 (1H, brs). MS (EI): 282 (M +) ₀

Example 18

A reaction was carried out in the same manner as in Example 2 using 0.4 g of 3-methyl-4- (piperidin-4-yl) 2H-isoquinolin-1-one hydrochloride obtained in Example 14, and 3-methyl-4- ( 96 mg of 1-methylbiperidine 4-yl) 2H isoquinoline-one was obtained.

— NMR (CDC1) δ: 1.60-1.74 (2Η, m), 2.02— 2.15 (2H, m), 2.36 ( 3H, s), 2.37-2.58 (2H, m), 2.48 (3H, s), 2.86-3.05 (3H, m), 7.43 (IH, t, J = 7Hz) , 7.60-7. 68 (1H, m), 8.09 (1H, m), 8.48 (IH, d, J = 7 Hz), 10.69 (IH, brs). MS (EI): 256 (M +).

Example 19

The reaction was carried out in the same manner as in Example 2 using 0.4 g of 3-methyl-4- (piperidin-4-yl) 2H-isoquinolin-1-one hydrochloride obtained in Example 14 and acetoaldehyde, and 0.14 g of methyl 4- (1-ethylbiperidine 4-yl) 2H-isoquinolin-1-one was obtained.

— NMR (CDC1) δ: 1.15 (3Η, t, J = 7Hz), 1.66— 1.82 (2H, m), 2.00

Three

-2. 12 (2H, m), 2.24- 2.53 (7H, m), 2.88- 3.18 (3H, m), 7.43 (1H, t, J = 7Hz), 7.62 -7. 68 (1H, m), 8.09 (1H, m), 8.47 (1H, dd, J = lHz, 7Hz), 10.43 (IH, brs) .MS (EI): 270 (M + ).

[0086] Example 20

Example 2 using 204 mg of 7-fluoro-3-methyl-4- (1,2,3,6-tetrahydropyridine 4-yl) 2H-isoquinoline 1-on hydrochloride obtained in Example 9 and 76.8 μL of acetoaldehyde 164 mg of 7-fluoro-3-methyl 4- (1-ethyl-1,2,3,6-tetrahydropyridine-14-yl) 2Η-isoquinolin-11-one as crystals Was.

— NMR (DMSO d6) δ: 1.00—1.20 (3Η, m), 2.16 (3H, s), 2.16—2.35 (2H, m), 2.51—2.83 (4H, m), 3.17-3.38 (2H, m), 5.65 (1H, s), 7.54-7.56 (2H, m), 7.80-7.83 (1H , m), 11.4 (1H, s). MS (ESI): 287 (M + 1).

Example 21

a) 7-Fluoro-3-methyl-4-1 (1 ethoxycarbol-1,2,3,6-tetrahydropyridine-1-yl) 2H-isoquinolin-1-one obtained in Example l-b) 2.26 g The reaction was carried out in the same manner as in Example 14-a) to obtain 1.72 g of 7-fluoro-1-methyl-4- (1-ethoxycarbo-rubiperidin-4-yl) 2H isoquinoline-1-one as crystals. It was subjected to the next reaction without further purification. b) The reaction was carried out in the same manner as in Example 14-b) using 1.72 g of 7-fluoro-3-methyl-4- (1-ethoxycarboxy-rubiperidin-4-yl) -2H-isoquinolin-1-one, and 7 Fluoro-3-methyl-4- (piperidine-1-yl) 2H-isoquinoline-11-one hydrochloride (1.54 g) was obtained. It was subjected to the next reaction without further purification.

c) The reaction was carried out in the same manner as in Example 2 using 769 mg of 7-fluoro-3-methyl-4- (piperidin-1-yl) 2H-isoquinolin-11-one hydrochloride. (1-Methylbiperidin-1-yl) 2H-isoquinolin-11-one was obtained as crystals to obtain 171 mg.

— NMR (CDC1) δ: 1.61— 1.70 (2Η, m), 2.05— 2.12 (2H, m), 2.36

Three

—2.45 (8H, m), 2.80—3.00 (1H, m), 3.02—3.06 (2H, m), 7.33—7.43 (1H, m), 8.08—8.12 (2H, m), 10.4 (1H, brs) .MS (ESI): 275 (M + 1)

Example 22

The reaction was carried out in the same manner as in Example 2 using 769 mg of 7-fluoro-3-methyl-4- (piperidine-4-yl) 2H isoquinoline 1-on hydrochloride obtained in Example 21-b) and 440 L of acetoaldehyde. By performing this, 221 mg of 7-fluoro-3-methyl-4- (1-ethylpyperidin-4-yl) -1 2H-isoquinolin-1-one was obtained as crystals.

— NMR (CDC1) δ: 1.12 (3H, t, J = 7Hz), 1.55— 1.80 (2H, m), 2.01

Three

—2.08 (2H, m), 2.39— 2.57 (7H, m), 2.80— 3.05 (1H, m), 3.05—3.20 (2H, m), 7.30— 7.50 (1H, m), 8.05— 8.20 ( 2H, m), 11.1 (1H, brs). MS (ESI): 289 (M + 1).

Example 23

3-methyl-4- (1,2,3,6-tetrahydropyridin-4-yl) -2H-isoquinolin-1-one hydrochloride obtained in Example 13 185 mg, potassium carbonate 187 mg, water 5 mL, acetonitrile The solution was dissolved in 2 mL of ril, and a solution of 141 mg of isopropyl oxide in 3 mL of acetonitrile was collected and stirred at 80 ° C. for 12.5 hours. After the completion of the reaction, a 20% aqueous potassium carbonate solution was added, and the reaction solution was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystals are collected by filtration, and 3-methyl-4- (1-isopro Pyr-1,2,3,6-tetrahydropyridin-1-yl) 2H-isoquinolin-1-one was obtained as crystals in an amount of 94 mg.

— NMR (CDCl) δ: 1.15 (6Η, d, J = 7Hz), 2.20— 2.45 (5H, m), 2.74

Three

-2.91 (3H, m), 3.28-- 3.32 (2H, m), 5.69 (1H, s), 7.40-- 7.45 (1H, m), 7.53-7.56 (1H, m), 7.60-- 7.65 (1H, m) , 8.40 (1H, d, J = 8 Hz), 10.4 (1H, brs). MS (ESI): 283 (M + 1).

Example 24

Using 185 mg of 3-methyl-4- (1,2,3,6-tetrahydropyridine-4-yl) -2H-isoquinoline-1-one hydrochloride obtained in Example 13 and 99.9 mg of n-butyraldehyde. And reacted in the same manner as in Example 2 to obtain 3-methyl 4- (1-n-butyl 1,2,3,6-tetrahydropyridine-14-yl) 2H-isoquinolin-1-one as a crystal. 95.7 mg was obtained.

— NMR (CDC1) δ: 0.97 (3Η, t, J = 7Hz), 1.35— 1.43 (2H, m), 1.57

Three

-1.62 (2H, m), 2.20— 2.45 (5H, m), 2.48— 2.54 (2H, m), 2.65—2.80 (2H, m), 3.10— 3.30 (2H, m), 5.67 (1H, s), 7.40-7.45 (1H, m), 7.52-7.55 (1H, m), 7.60-7.65 (1H, m), 8.41 (IH, d, J = 8Hz), 10.5 (IH, brs). MS (ESI): 297 (M + l) o

[0091] Example 25

a) The reaction was carried out in the same manner as in Raw Material Synthesis Example 2 using 16.6 g of 3-ethyl-2H-isoquinolin-1-one to obtain 22.8 g of 4-bromo-3-ethyl-2H-isoquinolin-1-one.

— NMR (DMSO— d) δ: 1.20 (3Η, t, J = 8Hz), 2.75 (2H, q, J = 8Hz), 7

6

.52-7.57 (1H, m), 7.79- 7.86 (2H, m), 8.21 (IH, d, J = 8Hz), 11.72 (IH, brs).

b) Using 22.8 g of 4-bromo-3-ethyl 2H-isoquinolin-1-one, the reaction was carried out in the same manner as in Example 3 to obtain 15.5 g of 4-bromo-3-ethyl-2-methoxymethyl-2H-isoquinolin-1-one. Was.

— NMR (CDC1) δ: 1.29 (3Η, t, J = 8Hz), 3.15 (2H, q, J = 8Hz), 3.45

Three

(3H, s), 5.65 (2H, s), 7.50 (IH, dt, J = lHz, 8Hz), 7.73 (1H, dt, J = 1H z, 7Hz), 7.95 (1H, d, J = 8Hz), 8.41 (1H, dd, J = lHz, 8Hz).

c) 4-bromo-3-ethyl 2-methoxymethyl-2H-isoquinolin-1-one 15.5 g, 2- (1-ethoxycarbon-1,2,3,6-tetrahydropyridine-1-yl) 4,4 , 5,5-Tetramethyl- [1,3,2] dioxaborolane 14.6g, diclo-mouth [1,1,1-bis (diphenylphosphino) phene] palladium (II) 'dichloromethane solvate 2.5g and carbon dioxide 21.5 g was dissolved in 150 mL of N, N-dimethinolehonolemamide, and the mixture was heated and heated at 80 ^° C for 11 hours. After completion of the reaction, the reaction solution was poured into ice water, ethyl acetate was added, and the mixture was filtered through celite. The organic layer was separated, washed with water and saturated saline, dried over magnesium sulfate, and the solvent was concentrated. The obtained residue was purified by silica gel column chromatography. Hexane: ethyl acetate = 2: 1 to 1: 1 is concentrated and concentrated to 3ethyl 2-methoxymethyl 4- (1 ethoxycarbonyl-1,2,3,6-tetrahydropyridine-14-yl) 2H-isoquinolyl 12-g was obtained as an oil.

— NMR (CDC1) δ: 1.20-1.35 (6Η, m), 2.25— 2.36 (2H, m), 2.60

Three

—2.70 (1H, m), 2.81— 2.92 (1H, m), 3.45 (3H, s), 3.57— 3.70 (1H, m), 3.79— 3.90 (1H, m), 4.02—4.26 (4H, m) , 5.43-5.50 (1H, m), 5.68-5.78 (2H, m), 7.37 (1H, d, J = 8 Hz), 7.44 (1H, dt, J = 1 Hz, 8 Hz), 7.59-7.65 (1H , m), 8.43 (1H, dd, J = lHz, 8Hz).

d) Example 1-b) using 12 g of 3-ethyl-2-methoxymethyl-4- (1 ethoxycarbonyl-1,2,3,6-tetrahydropyridine 4yl) 2H isoquinoline-one-on. The reaction was carried out in the same manner to obtain 8.7 g of 3-ethyl-4- (1 ethoxycarbol-1,2,3,6-tetrahydropyridine-14-yl) 2H-isoquinolin-1-one.

— NMR (CDC1) δ: 1.27-1.35 (6Η, m), 2.18— 2.43 (2H, m), 2.53

Three

-2.70 (2H, m), 3.57— 3.68 (1H, m), 3.82— 3.95 (1H, m), 4.05—4.30 (4H, m), 5.72 (1H, m), 7.41— 7.48 (2H, m), 8.43 (1H, d, J = 8 Hz), 10.59 (1H, brs).

Example 26

3-Ethyl 4- (1 ethoxycarbol 1,2,3,6-tetrahydropyridine-14-yl) obtained in Example 25-d) 2H-isoquinolin-1-one 2. Using Og Example 4 and The reaction was carried out in the same manner to obtain 1.8 g of 3-ethyl 4- (1,2,3,6-tetrahydropyridin-1-yl) -2H-isoquinolin-1-one hydrochloride.

— NMR (DMSO d) δ: 1.16 (3Η, t, J = 8Hz), 2.29— 2.57 (2H, m), 3

6

.30-3.50 (2H, m), 3.63-3.80 (2H, m), 5.71 (IH, m), 7.41-7.47 (IH, m), 7.61-7.69 (2H, m), 8.18 (1H, d, J = 8Hz), 9.53 (2H, m), 11.29 (IH, brs). MS (EI): 254 (M +).

[0093] Example 27

3-ethyl-4- (1,2,3,6-tetrahydropyridin-4-yl) -2H-isoquinolin-1-one hydrochloride obtained in Example 26 1. In the same manner as in Example 2 using Og The reaction was carried out to obtain 0.57 g of 3-ethyl-4- (1-methyl-1,2,3,6-tetrahydropyridine-4-yl) -1H-isoquinolin-1-one.

— NMR (CDC1) δ: 1.16 (3Η, t, J = 8Hz), 2.29— 2.57 (2H, m), 3.30

Three

-3.50 (2H, m), 3.63— 3.80 (2H, m), 5.71 (IH, m), 7.41— 7.47 (1H, m), 7.61-7.69 (2H, m), 8.18 (1H, d, J = 8Hz), 9.53 (2H, m), 11.29 (IH, brs). MS (EI): 254 (M +) ₀

[0094] Example 28

a) 3-ethyl-4- (1 ethoxycarbol-1,2,3,6-tetrahydropyridine-1-yl) 2H-isoquinolin-1-one obtained in Example 25-d) using 2.Og The reaction was carried out in the same manner as in Example 14-a) to give 3-ethyl-4- (1-ethoxycarbo-rubiperidin-4-yl) 2H-isoquinoline 1one. It was used for the next reaction without further purification.

b) The reaction was carried out in the same manner as in Example 14-b) using the entire amount of 3-ethyl-4- (1-ethoxycarborubiperidine-4-yl) 2H-isoquinoline! 0.93 g of — (piperidin-1-yl) 2H-isoquinolin-1-one hydrochloride was obtained.

— NMR (DMSO d) δ: 1.16 (3Η, t, J = 7Hz), 1.61— 1.72 (2H, m), 2

6

.25-- 3.45 (9H, m), 7.44 (IH, t, J = 8Hz), 7.61-- 7.67 (1H, m), 8.24 (IH, dd, J = lHz, 8Hz), 8.29 (1H, m), 9.05 (2H, brs), 11.17 (1H, brs). MS (EI): 256 (M +). c) The reaction was carried out in the same manner as in Example 2 using 0.85 g of 3-ethyl-4- (piperidin-4-yl) 2H-isoquinoline-1-one hydrochloride to give 3-ethyl-4- (1-methylbiberidin-1-yl) 2H. —0.33 g of isoquinolin-1-one was obtained.

— NMR (CDC1) δ: 1.30 (3Η, t, J = 8Hz), 1.61— 1.82 (2H, m), 2.05

Three

-2. 16 (2H, m), 2.36 (3H, s), 2.50-- 3.09 (7H, m), 7.41 (1H, t, J = 8Hz), 7.52-7.64 (1H, m), 8.17 (1H , m), 8.47 (1H, dd, J = lHz, 8Hz), 1 0.60 (1H, brs). MS (EI): 270 (M +).

[0095] Pharmacological experiment PARP enzyme activity inhibitory action

Recombinant human PARP (4667-02X, Trevigen) was used as the enzyme source. The poly ADP ribosylation reaction is carried out by adding ³ H—NAD (1.85 kBq ゝ NAD) to an enzyme reaction buffer (10 mM TrisZHCl (pH 8.0), ImM MgCl, 28 mM KC1, 28 mM NaCl).

2

2 was initiated 8- ³ H] Daiichi Pure Chemicals Co., Ltd.) and activated DNA (0.02mgZmL, 4667- 03X, Trevigen) the Ka卩E, by adding the enzyme source. After incubation at 25 ° C for 15 minutes, the reaction was terminated with 20% trichloroacetic acid, and the resulting acid-insoluble fraction was adsorbed on a GFZB filter. Thereafter, the filter was washed several times with 5% acetic acid at a trichloride, and the radiation dose on the filter was measured with a liquid scintillation counter.

[0096] The results are shown in Table 1. PARP activity was measured by subtracting the radiation dose of the sample without enzyme source as a blank value.The 50% enzyme inhibition value (IC value) of each test compound was

50

The radiation dose of the non-added sample was calculated as 100%.

[0097] [Table 1]

[0098] DPQ = 3,4 dihydro-5- [4- (1-piberidyl) -butoxy] 1 (2H) -isoquinolinone (PARP inhibitor described in WO99Z08680 and WO99Z11649) From these results, it was evident that all of the conjugates shown in Examples of the present invention had superior PARP inhibitory activity as compared with known compounds.

Industrial applicability

[0099] The compounds of the above general formula (I), their optical isomers, their pharmaceutically acceptable salts, their hydrates, their water adducts and their solvates are stable in aqueous solutions and are known in the art. It has a stronger PARP inhibitory effect than compounds, and is useful as a therapeutic agent for cerebral infarction, especially for the acute phase of cerebral infarction.

[0100] This application is based on a Japanese patent application filed on May 20, 2004 (Japanese Patent Application No. 2004-150961), which is incorporated by reference in its entirety.

Claims

Claims The following general formula (I)

[Chemical 1]

(I)

[Wherein R ¹ is a hydrogen atom, a halogen atom, an alkyl, an alkoxy, a haloalkyl, a hydroxy, an alkylamino, a dialkylamino, a nitro, an acyl, a carboxyl, an alkoxycarbonyl, a carbamoyl, an N-alkyl carbamoyl, N, N-dialkylcarbamoyl, acylamino, diasilamino, thiol, alkylthio, sulfamoyl with alkoxycarbamyl, N-alkylsulfamoyl, N, N-dialkylsulfamoyl or alkoxyalkyloxy.

R ² represents alkyl.

R ³ represents a group selected from the following general formula (a) or (b).

[Formula 2]

X represents a C anorealkylene chain.

13

Or an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof and a solvate thereof. [2] In the general formula (I),

R ² represents alkyl,

R ³ represents a group selected from the general formula (a) or (b),

X represents a C anolexylene chain;

13

The isoquinoline compound according to claim 1, wherein R ⁴ represents a hydrogen atom, alkyl, or hydroxyalkyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof, and a solvate thereof. object.

[3] In the general formula (I),

R ¹ is a hydrogen atom, a halogen atom, C alkyl, C alkoxy, C haloal

1-4 1 -4 1-4 represents a kill, hydroxy or amino,

R ² represents C alkyl;

1-4

R ³ represents a group selected from the general formula (a) or (b),

X represents a C anolexylene chain;

13

R ⁴ represents a hydrogen atom, C alkyl or C hydroxyalkyl.

1-4 1 -4

And the pharmaceutically acceptable salts, hydrates, hydrates, and solvates thereof.

[4] In the general formula (I),

R ¹ represents a hydrogen atom or a halogen atom,

R ² represents C alkyl;

1-4

R ³ represents a group selected from the following general formula (a) or (b),

X represents a C anolexylene chain;

13

^4. The isoform according to claim 1, wherein R ⁴ represents a hydrogen atom or C alkyl.

1-4

A quinoline conjugate, an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof, and a solvate thereof.

[5] In the general formula (I),

R ¹ represents a hydrogen atom or a halogen atom, R ² represents methyl or ethyl,

R ³ represents a group selected from the general formula (a) or (b),

X represents a C anolexylene chain;

13

The isoform according to any one of claims 1 to 4, wherein R ⁴ represents a hydrogen atom or C alkyl.

1-4

[6] In the general formula (I),

R ¹ represents a hydrogen atom, a fluorine atom or a chlorine atom,

R ² represents methyl or ethyl,

R ³ represents a group selected from the general formula (a) or (b),

X represents ethylene,

R ⁴ represents a hydrogen atom or C alkyl;

1-4

[7] In the general formula (I),

R ¹ represents a hydrogen atom or a fluorine atom or a chlorine atom substituted at the 7-position,

R ² represents methyl or ethyl,

R ³ represents a group selected from the following general formula (a) or (b),

X represents ethylene,

The isoquinoline conjugate according to any one of claims 1 to 6, wherein R ⁴ represents a hydrogen atom, methyl or ethyl, an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a water form thereof. Adducts and solvates thereof.

[8] (1) 7 Fluoro-3-methyl 4- (1-ethoxycarbol-1,2,3,6-tetrahydrid pyridine-1-yl) 2H-isoquinolin-1-one

(3) 7 Cloth 4- (1-ethoxycarbyl-1,2,3,6-tetrahydropyridine-14-yl) 3 Methyl 2H-isoquinolin-1-one (4) 7 1- (1,2,3,6-tetrahydropyridine-4-yl) 3-methyl 2H isoquinoline 1-on

(6) 7 Black 1- 4- (1-Methylbiperidine 1-4-yl) 3-Methyl 2H-Isoquinolin-1on

(8) 7 1-methyl 4-H-isoquinolin-1-on

(9) 7 Fluoro-3-methyl 4- (1,2,3,6-tetrahydropyridine-1-yl) 2 H Isoquinoline

(11) 7 4- (1-propylpiperidine-1-yl) 3-methyl-2H-isoquinolin-1-one

(13) 3-Methyl-4-1 (1,2,3,6-tetrahydropyridine-4-yl) -1H-isoquinolin-1-one

(14) 3-Methyl 4- (piperidin-4-yl) 2H-isoquinolin-1-one

(15) 3-Methyl-4-1 (1-methyl-1,2,3,6-tetrahydropyridine-1-yl) 2 H Isoquinoline

(16) 3-Methyl-4- (1-ethyl-1,2,3,6-tetrahydropyridine-4-yl) -2H isoquinoline

(17) 3-methyl 4- (1-propyl-1,2,3,6-tetrahydropyridine-1-yl) -1H-isoquinoline

(18) 3-Methyl-4 (1-methylbiperidine-4-yl) 2H-isoquinoline-1-o N

(19) 3-Methyl 4- (1-ethylpyperidin-1-yl) 2H-isoquinoline-1-one

(21) 7 Fluoro-3-methyl-4 (1-methylbiperidine-4-yl) -2H-isoquinoline-1one

(22) 7-Fluoro-3-methyl 41-ethylbiperidine 4-yl) 2H-isoquinoline-1 on

(26) 3ethyl 4- (1,2,3,6-tetrahydropyridine-1-yl) 2H-isoquinoline-1one

(27) 3 ethynole 4- (1-methynole 1,2,3,6-tetrahydropyridine-14-inole) -1H-isoquinolin-1-one, and

(28) 3 ethyl-4 (1-methylbiperidine-4-yl) 2H-isoquinoline 1-one

The isoquinoline compound according to any one of claims 1 to 7, which is selected from the group consisting of an optically active isomer, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof, and a solvate thereof.

(2) 7 Fluoro-3-methyl 4- (1-methyl 1,2,3,6-tetrahydropyridine-1-yl) 2H-isoquinolin-1-one

(3) 7 1- (1-ethoxycarbol-1,2,3,6-tetrahydropyridine-1 4 -Yl) 3 methyl 2H-isoquinolin-1-one

(4) 7 Cloth 4- (1,2,3,6-tetrahydropyridine-14-yl) 3-Methyl 2H Isoquinoline 1-on

(6) 7 Black 1- 4- (1-Methylbiperidine 1-4-yl) 3-Methyl 2H-Isoquinolin-1on

(8) 7 1-methyl 4-H-isoquinolin-1-on

(9) 7 Fluoro-3-methyl 4- (1,2,3,6-tetrahydropyridine-1-yl) 2 H Isoquinoline

(11) 7 4- (1-propylpiperidine-1-yl) 3-methyl-2H-isoquinolin-1-one

(13) 3-Methyl-4-1 (1,2,3,6-tetrahydropyridine-4-yl) -1H-isoquinolin-1-one

(14) 3-Methyl 4- (piperidin-4-yl) 2H-isoquinolin-1-one

(15) 3-Methyl-4-1 (1-methyl-1,2,3,6-tetrahydropyridine-1-yl) 2 H Isoquinoline

(16) 3-Methyl-4- (1-ethyl-1,2,3,6-tetrahydropyridine-4-yl) -2H isoquinoline

(17) 3-methyl 4- (1-propyl-1,2,3,6-tetrahydropyridine-1-yl) -1H-isoquinoline (18) 3-Methyl-4 (1-methylbiperidine-4-yl) 2H-isoquinoline-1-one

(19) 3-Methyl 4- (1-ethylpyperidin-1-yl) 2H-isoquinoline-1-one

(21) 7 Fluoro-3-methyl-4 (1-methylbiperidine-4-yl) 2H-isoquinoline-1one

(22) 7-Fluoro-3-methyl 41-ethylbiperidine 4-yl) 2H-isoquinoline-1 on

(24) 3-Methyl-4- (111-butyl-1,2,3,6-tetrahydropyridine-4-yl) 2H-isoquinoline 1 on, and

The isoquinoline compound according to any one of claims 1 to 8, an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof, and a solvate thereof.

[10] An isoquinoline conjugate according to any one of claims 1 to 9, an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof, and a solvate thereof. A prophylactic and / or therapeutic agent for a disease caused by hyperactivity of poly (ADP-ribose) synthase, which is characterized in that Z or a therapeutic agent is used.

[11] The disease caused by hyperactivity of poly (ADP-ribose) synthase is cerebral infarction.

10. The prophylactic and / or Z or therapeutic agent according to 10.

[12] The preventive and / or therapeutic agent or therapeutic agent according to claim 10, wherein the disease caused by hyperactivity of poly (ADP-ribose) synthase is in the acute phase of cerebral infarction.

[13] The isoquinoline conjugate according to any one of claims 1 to 9, an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof, and a solvate thereof. To do A poly (ADP-ribose) synthase inhibitor characterized by the following.