KR20000076342A - Substituted Isoquinoline Derivatives and Their Use as Anticonvulsants - Google Patents

Abstract

The present invention relates in particular to a compound of formula (I) or a pharmaceutically acceptable salt thereof effective for the treatment and prevention of epilepsy.

<Formula I>

Wherein Q is a monocyclic or bicyclic aryl or heteroaryl ring,

R ¹ is hydrogen, C _1-6 alkyl (optionally substituted with hydroxy or C _1-4 alkoxy), C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 alkylCO-, formyl, CF ₃ CO- or C _1-6 alkylSO ₂ —, R ² is hydrogen or halogen, NO ₂ , CN, N ₃ , CF ₃ O-, CF ₃ S-, CF ₃ CO-, trifluoro Methyldiazylinyl, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 perfluoroalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _{1 -4} alkyl-, C _1-6 alkylO-, C _1-6 alkylCO-, C _3-6 cycloalkylO-, C _3-6 cycloalkylCO-, C _3-6 cycloalkyl-C _1-4 AlkylO-, C _3-6 cycloalkyl-C _1-4 alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C _1-4 alkyl-, C _1-6 alkyl S-, C _1-6 alkyl SO ₂ -, (C _{1-4 alkyl) 2 NSO 2 -, (C} 1-4 alkyl) NHSO ₂ -, (C _1-4 alkyl) ₂ NCO-, (C _1-4 alkyl) NHCO-, or CONH Less than 3 substituents selected from the group consisting of ₂ ; Or -NR ³ R ⁴ , wherein R ³ is hydrogen or C _1-4 alkyl and R ⁴ is hydrogen, C _1-4 alkyl, formyl, -CO ₂ C _1-4 alkyl or -COC _1-4 alkyl Or two R ² groups together form a carbocyclic ring which is saturated or unsaturated and substituted or unsubstituted with —OH or ═O;

X is hydrogen, halogen, C _1-6 alkoxy, C _1-6 alkyl, amino or trifluoroacetylamino, except for compounds where R ² is 2-alkoxy when X is hydrogen, compounds when X is halogen N- (7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-benzoyl-2-methoxybenzamide, N- (7-iodo-1 , 2,3,4-tetrahydroisoquinolin-5-yl) -5-benzoyl-2-methoxybenzamide, N- (5-iodo-1,2,3,4-tetrahydroisoquinoline-7 -Yl) -5-benzoyl-2-methoxybenzamide, N- (5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methoxy-4-trifluoro Chloromethyldiazinylbenzamide, N- (5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methoxy-5-trifluoromethyldiazinylbenzamide , N- (7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl) -2-methoxy-5-trifluoromethyldiaziriinyl benzamide and N- (8-fluoro Rho-2-methyl-1,2,3,4-tetrahydrate Rooisoquinolin-5-yl) -4-t-butyl-2-methoxybenzamide is excluded.

Description

Substituted Isoquinoline Derivatives and Their Use as Anticonvulsants

The present invention relates to novel compounds, methods for their preparation and their use as therapeutic agents.

International Publication No. 97/48683 (Smithcline Misery), which was not published at the time of filing this application, describes N- (7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)- 5-benzoyl-2-methoxybenzamide, N- (7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-benzoyl-2-methoxybenzamide, N- (5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-benzoyl-2-methoxybenzamide, N- (5-iodo-1,2,3,4 -Tetrahydroisoquinolin-7-yl) -2-methoxy-4-trifluoromethyldiazinylylbenzamide, N- (5-iodo-1,2,3,4-tetrahydroisoquinoline-7 -Yl) -2-methoxy-5-trifluoromethyldiazylinylbenzamide, N- (7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl) -2-meth Methoxy-5-trifluoromethyldiaziriinylbenzamide and N- (8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -4-t-butyl- 2-alkoxy to the benzamide moiety, including 2-methoxybenzamide Tetrahydroisoquinolinyl benzamide with a time substituent is disclosed.

The present inventors now surprisingly find that the carboxamide compounds of formula (I) have antifungal activity and therefore are associated with anxiety, mania, depression, fear disorders and / or aggression, subarachnoid hemorrhage or nerve shock, cocaine, nicotine, alcohol and Withdrawal-related effects of substance abuse, such as benzodiazepines, traumatic epilepsy, including anti-treatable and / or preventable disorders such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases, for example , Huntington chorea, schizophrenia, OCD, neurological deficits associated with AIDS (acquired immune deficiency syndrome), sleep disorders (including circadian rhythm disorders, insomnia & sleep attacks), convulsions (eg, vagina Draturet syndrome), traumatic brain injury, tinnitus, neuralgia, especially tertiary neuralgia, neuropathy, toothache, cancer, diabetes, multiple sclerosis (MS) and motor neurons It has been found to be useful for the treatment and / or prevention of inappropriate neuronal activity, ataxia, myocardial cavity (convulsiveness), temporomandibular joint dysfunction and amyotrophic lateral sclerosis (ALS) that lead to neuropathic liver disease such as diseases. .

Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In the formula,

Q is a monocyclic or bicyclic aryl or heteroaryl ring,

R ¹ is hydrogen, C _1-6 alkyl (optionally substituted with hydroxy or C _1-4 alkoxy), C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 alkylCO-, formyl, CF ₃ CO- or C _1-6 alkylSO _2- ,

R ² is hydrogen, hydroxy or halogen, NO ₂ , CN, N ₃ , CF ₃ O-, CF ₃ S-, CF ₃ CO-, trifluoromethyldiaziriinyl, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 perfluoroalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl-, C _1-6 alkyl O- , C _1-6 alkylCO-, C _3-6 cycloalkylO-, C _3-6 cycloalkylCO-, C _3-6 cycloalkyl-C _1-4 alkylO-, C _3-6 cycloalkyl-C _1-4 alkylCO-, acetoxy, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C _1-4 alkyl-, C _1-6 alkyl S-, C _1-6 alkylSO _2- , (C _{1- 4} alkyl) ₂ NSO _2- , (C _1-4 alkyl) NHSO _2- , (C _1-4 alkyl) ₂ NCO-, (C _1-4 alkyl) NHCO- or CONH ₂ Substituents of; Or -NR ³ R ⁴ , wherein R ³ is hydrogen or C _1-4 alkyl and R ⁴ is hydrogen, C _1-4 alkyl, formyl, -CO ₂ C _1-4 alkyl or -COC _1-4 alkyl Or)

Two R ² groups together form a carbocyclic ring which is saturated or unsaturated and substituted or unsubstituted with —OH or ═O;

X is hydrogen, halogen, C _1-6 alkoxy, C _1-6 alkyl, amino or trifluoroacetylamino,

Excluding compounds where R ² is 2-alkoxy when X is hydrogen, compounds N- (7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinoline-5- when X is halogen Yl) -5-benzoyl-2-methoxybenzamide, N- (7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-benzoyl-2-methoxybenzamide , N- (5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-benzoyl-2-methoxybenzamide, N- (5-iodo-1,2, 3,4-tetrahydroisoquinolin-7-yl) -2-methoxy-4-trifluoromethyldiazinylylbenzamide, N- (5-iodo-1,2,3,4-tetrahydroiso Quinolin-7-yl) -2-methoxy-5-trifluoromethyldiazinylylbenzamide, N- (7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)- 2-methoxy-5-trifluoromethyldiaziriinyl benzamide and N- (8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -4-t -Butyl-2-methoxybenzamide is excluded.

Typical compounds of the invention are (tetrahydroisoquinolin-7-yl) carboxamides, in particular (tetrahydroisoquinolin-7-yl) benzamide. If substituent X is not hydrogen it may be at the 5, 6 or 8 position, especially the 5 position of the tetrahydroisoquinoline residue.

In general, ring system Q is optionally substituted phenyl or optionally substituted heteroaryl, typically thiophenyl or 3-isoxazolyl. When two R ² groups form a carbocyclic ring it is typically a 5 to 7 membered ring and Q is a naphthalene or indan or indanone ring system, or a bicyclic heteroaryl such as 5-dihydrobenzofura It may be neil.

In formula (I), alkyl groups, including alkyl groups, which are part of other residues such as alkoxy or acyl, may be straight or branched chains. Phenyl groups, including phenyl groups, which are part of other residues in R ² , are optionally substituted with one or more substituents independently selected from the group consisting of halogen or C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkylcarbonyl Can be. Suitable C _3-6 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Suitable halo substituents include fluoro, chloro, iodo and bromo.

Suitable groups of the compounds of the present invention are the formulas (IA) and (IB).

Examples of suitable groups of formula (I) are as follows.

R ¹ is hydrogen, methyl, ethyl, propyl, hydroxyethyl, methoxyethyl, formyl, acetyl, trifluoroacetyl or methanesulfonyl,

R ² is hydrogen or at least one methyl, ethyl, n-butyl, iso-propyl, iso-butyl, t-butyl, phenyl, methoxy, ethoxy, iso-propoxy, n-butoxy, cyclopropylmeth Oxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl, Trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl, trifluoromethyldiazinyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl, or

Two R ^{2 form} a benzene, cyclopentane or cyclopentanone ring;

X is hydrogen, chloro, bromo, iodo, fluoro, amino, trifluoroacetylamino.

Compounds of formula (I) in a preferred group are

R ¹ is hydrogen, methyl, methoxyethyl,

R ² is hydrogen or one or more methyl, n-butyl, t-butyl, iso-propyl, phenyl, methoxy, ethoxy, iso-propoxy, phenoxy, acetyl, nitro, cyano, bromo, chloro , Fluoro, iodo, pivaloyl, trifluoromethyl, azido, trifluoromethoxy,

X is hydrogen, iodo, chloro or trifluoroacetylamino.

Examples of compounds of formula (I) are

N- (1,2,3,4-tetrahydroisoquinolin-7-yl) -5-chlorothiophen-2-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-chlorothiophen-2-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chlorobenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-t-butylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-propoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-nitrobenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenylbenzamide,

N- (2-methyl-1,2.3,4-tetrahydroisoquinolin-7-yl) -3-methylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluorobenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyanobenzamide,

N- (2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) -3,4-dichlorobenzamide,

N- (2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) -4-iodobenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-bromobenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-nitrobenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-butylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-acetoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-trifluoromethylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2,4-difluorobenzamide,

N- (2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) -3,4-dimethoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-fluoro-4-trifluoromethyl benzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-chloro-3-nitrobenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-di-trifluoromethylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2,4-dichloro-5-fluorobenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluoro-5-trifluoromethyl benzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,4,5-trimethoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-trifluoromethoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-pivaloylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-iso-propoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-acetoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-cyclopentyloxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-cyclopropylmethoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-methoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-naphtamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -naphthalene-1-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-methoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-t-butoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-propoxybenzamide,

N- (2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) benzotriazole-5-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzothiazole-6-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2,3-dihydrobenzofuran-5-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methylbenzimidazole-5-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-ethoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-methoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-ethoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-iso-propoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-t-butylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-bromo-5-methoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-fluoro-3-methoxybenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -1-methylpyrazole-4-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-trifluoromethylpyrazole-3-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methylthiazole-4-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-methylisoxazole-3-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-t-butylisoxazole-3-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methoxyisoxazole-5-carboxamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) indole-2-carboxamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-iso-propylbenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-iso-propylbenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluoro-4-methoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-n-propoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-ethoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-n-propoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-iodo-4-methoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-propoxy-3-trifluoromethylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-chloro-3-methoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-propoxy-3-trifluoromethylbenzamide

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-t-butylbenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxybenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-fluoro-3-methylbenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-ethylbenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-propyl-3-trifluoromethylbenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethyl-3-trifluoromethylbenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-iso-propoxybenzamide hydrochloride,

N- (1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methyl-3-methylsulfonylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethyl-3-methylsulfonylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonyl-4-iso-propylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonyl-4-methoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-trifluoroacetylbenzamide, hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-pentafluoroethyl-benzamide hydrochloride,

N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide,

N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide,

N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propoxybenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-iso-butylbenzamide hydrochloride,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-butyl-3-fluoromethyl-benzamide hydrochloride,

N- (2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide,

N- (2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide,

N- (2-iso-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide,

N- (2-iso-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethoxy-3-methylsulfonylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-oxochroman-6-carboxamide hydrochloride,

N- (2-formyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide,

N- (2-hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide,

N- (2-hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethylbenzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenylmethoxy-3-trifluoromethyl benzamide,

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-hydroxy-3-trifluoromethyl benzamide,

N- (2-methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-iso-propoxybenzamide,

N- (2-methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propoxybenzamide,

N- (2-methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide,

N- (5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-azidobenzamide trifluoroacetate,

N- (2-methyl-5-trifluoroacetylamino-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methoxybenzamide,

N- (2-methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide,

N- (2-methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethylbenzamide.

In synthesis, these compounds are often in salt form, for example hydrochloride or trifluoroacetate, which salt forms also form part of the present invention. Such salts can be used to prepare pharmaceutically acceptable salts. This compound and its salts can be obtained as solvates, for example hydrates, which also form part of the invention.

The compounds listed above and their pharmaceutically acceptable salts, in particular hydrochloride, and their pharmaceutically acceptable solvent compounds, in particular hydrates, form preferred aspects of the invention.

Administration of such compounds to mammals can be by oral, parenteral, sublingual, nasal, rectal, topical or transdermal administration.

The amount effective to treat the disorder depends on the nature and depth of the disorder to be treated and general factors such as the weight of the mammal. However, unit dosages are usually from 1 to 1000 mg, suitably from 1 to 500 mg of active compound, for example 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg. Active compounds in an amount ranging from 2 to 400 mg. Unit dosages range from 1 to 1000 mg per adult body weight of 70 kg body weight, for example from 1 to 500 mg, ie from about 0.01 to 15 mg / kg per day, more typically from 0.1 to per day 6 mg / kg, for example in the range of 1 to 6 mg / kg per day, at least once per day, for example 1, 2, 3, 4, 5 or 6 times per day, more typically It will be administered 1 to 4 times per day.

It is highly preferred that the compound of formula (I) is administered in the form of unit dosage compositions, such as compositions for suboral, rectal, topical or parenteral (particularly intravenous) administration, including compositions for unit oral administration.

Such compositions are prepared by mixing and appropriately controlled for oral or parenteral administration, such as tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and injectable solutions, Or in suspension or suppository form. Compositions that can be administered orally, in particular shaped oral compositions, are preferred because they are generally more convenient for use.

Tablets and capsules for oral administration are typically provided in unit doses and include conventional excipients such as binders, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavors and wetting agents. Tablets may be coated according to methods well known in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar reagents. Suitable disintegrants include starch, polyvinylpyrrolidone, and starch derivatives such as starch sodium glycolate. Examples of suitable lubricants include magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

These solid oral compositions can be prepared by conventional methods such as blending, filling, tableting and the like. Repeated blending operations can be used to distribute the active agent throughout these compositions using large amounts of fillers. Such manipulation is of course common in the art.

Oral liquid formulations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be provided as a dry product for reconstitution with water or other suitable excipients prior to use. Such liquid preparations include conventional additives, for example suspending agents (eg, sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate or hydrogenated edible fats), emulsifiers (eg lecithin) Sorbitan monooleate or gum arabic); Non-aqueous excipients that may include edible oils (eg, almond oil, fractionally distilled coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol); Preservatives (eg, methyl or propyl p-hydroxybenzoate or sorbic acid); And if desired, conventional flavoring or coloring agents. Oral formulations also include conventional sustained release formulations, such as tablets or granules with enteric skin.

For parenteral administration, it is prepared in a fluid unit dosage form containing a compound and a sterile excipient. Excipients and concentration dependent compounds may be suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in excipients, sterilizing with a filter, and then filling and sealing the appropriate vial or ampoule. Advantageously, adjuvants such as local anesthetics, preservatives and buffers are also dissolved in excipients. To increase stability, the composition can be filled into vials, frozen and water removed in vacuo.

Parenteral suspensions are prepared in substantially the same manner except that the compounds are suspended in excipients instead of dissolving, sterilized by exposure to ethylene oxide and then suspended in sterile excipients. Advantageously, surfactants or wetting agents are included in the composition to promote uniform distribution of the compounds of the present invention.

As in conventional practice, a composition will usually be accompanied by written or printed instructions for use in the relevant medical treatment.

Thus, the present invention further provides anxiety, mania, depression, fear disorders and / or aggressiveness, comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvent compound thereof and a pharmaceutically acceptable carrier, Disorders associated with subarachnoid hemorrhage or nerve shock, withdrawal-related effects of substance abuse such as cocaine, nicotine, alcohol and benzodiazepines, treatable and / or preventable disorders such as traumatic epilepsy and epilepsy, Parkinson's disease, psychosis , Migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, OCD, neurological deficits associated with AIDS (acquired immunodeficiency syndrome), sleep disorders (circadian rhythm disorders) , Insomnia & sleep attacks), convulsions (eg, Gildra Tourette Syndrome), traumatic brain injury, tinnitus, neuralgia, especially tertiary neuralgia, neuropathy Impaired neuronal activity, ataxia, dysmenorrhea (convulsiveness), temporomandibular joint dysfunction and muscular dystrophy, resulting in neuropathy of diseases such as toothache, cancer, diabetes, multiple sclerosis (MS) and motor neuron disease Provided are pharmaceutical compositions for the treatment and / or prophylaxis of (ALS).

The invention also includes administering to a patient in need thereof an effective or prophylactic amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvent compound thereof, and / or ) Aggression, subarachnoid hemorrhage or disorders associated with nerve shock, withdrawal effects of substance abuse such as cocaine, nicotine, alcohol and benzodiazepines, treatable and / or preventable disorders such as traumatic epilepsy, and anti-treatment such as epilepsy, Parkinson's Illness, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, OCD, neurological deficits associated with AIDS (acquired immunodeficiency syndrome), sleep disorders (work Periodic rhythm disorders, including insomnia & sleep attacks, convulsions (eg, Gildra Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, Inadequate neuronal activity, ataxia, myocardiac (spasm), temporomandibular joints, leading to neuronal dystonia of diseases such as hepatic neuralgia, neuropathy, toothache, cancer, diabetes, multiple sclerosis (MS) and motor neuron disease Methods of treating and / or preventing dysfunction and amyotrophic lateral sclerosis (ALS) are provided.

In another aspect, the invention provides anxiety, mania, depression, fear disorders and / or aggressiveness, disorders associated with subarachnoid hemorrhage or nerve shock, withdrawal effects associated with substance abuse such as cocaine, nicotine, alcohol and benzodiazepines, traumatic Treatable and / or preventable disorders such as epilepsy, antiepileptic diseases such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases (eg, Huntington's chorea), schizophrenia, obsessive compulsive disorder (OCD), neurological deficits associated with AIDS (acquired immunodeficiency syndrome), sleep disorders (including circadian rhythm disorders, insomnia & sleep attacks), convulsions (eg, Gildra Tourette syndrome), traumatic brain injury, tinnitus, Improper neuronal activity leading to neuropathic liver disease, especially in diseases such as tertiary neuralgia, neuropathy, toothache, cancer, diabetes, decompensation (MS) and motor neuron disease, In the manufacture of a medicament for the treatment and / or prophylaxis of ataxia, dysmenorrhea (convulsive), temporomandibular joint dysfunction and amyotrophic lateral sclerosis (ALS), the compound of formula (I) or a pharmaceutically acceptable salt thereof or It provides the use of a solvent compound.

In another aspect, the present invention is a therapeutic agent, specifically withdrawal of anxiety, mania, depression, fear disorders and / or aggression, disorders associated with subarachnoid hemorrhage or nerve shock, substance abuse such as cocaine, nicotine, alcohol and benzodiazepines Effects associated with traumatic epilepsy, treatable and / or preventable disorders such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia , Obsessive-compulsive disorder (OCD), neurological deficits associated with AIDS (acquired immune deficiency syndrome), sleep disorders (including circadian rhythm disorders, insomnia & sleep attacks), convulsions (eg, Gildra Tourette syndrome), traumatic brain Injury, tinnitus, neuralgia, especially tertiary neuralgia, neuropathy, toothache, cancer, diabetes, multiple sclerosis (MS) and neuronal dysfunction of diseases such as motor neuron disease A compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of inappropriate neuronal activity, ataxia, muscular dysfunction (convulsive), temporal mandibular joint dysfunction and amyotrophic lateral sclerosis (ALS) Or the use of a solvent compound.

Another aspect of the invention is to react a compound of formula (II) with a compound of formula (III) and, if desired, convert a R ^1A or R ^2A group to a R ¹ or R ² group, or R ¹ or R ² Formula (I) comprising converting a group to another R ¹ or R ² group, converting a salt product to a free base or another pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt. Provided is a process for the preparation of

In the formula,

R ^1A is the same as R ¹ as defined in formula (I) or a group which can be converted to R ¹ ,

X is as defined in claim 1,

Q is as defined in formula (I),

Y is Cl or OH,

R ^2A groups are independently the groups as defined in formula (I) or can be converted to R ² .

The reaction of the compound of formula (III) (Y = Cl) which is an acid chloride will directly produce a hydrochloride salt. Suitable solvents are ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine. If the compound of formula (III) is an aromatic acid (Y = OH), the components of the mixture of (dimethylaminopropyl) -ethyl-carbodiimide / hydroxybenzotriazole are reacted in a suitable solvent, for example dimethyl formamide. As such, conventional conditions for condensing aromatic acids with amines can be used.

The conversion of an R ^1A or R ^2A group to an R ¹ or R ² group typically occurs when a protecting group is needed during the coupling reaction or during the preparation of the reactants by the following method. Interconversion of R ¹ or R ² groups to another group typically results in the case where one compound of formula (I) is used as a direct precursor of another compound of formula (I), or a more complex or reactive substituent This occurs when it is easier to introduce at the end of the synthetic sequence.

The compound of formula (II), wherein X is hydrogen, is nitro-tetrahydroiso of formula (IV).

The compound of formula (II), wherein X is hydrogen, is reacted with a tosylate by reacting nitro-tetrahydroisoquinoline of formula (IV) with compound R ^1A Z (where Z is a leaving group such as halogen, in particular iodo) The intermediate of (V) can be obtained and prepared, for example, by reducing with tin (II) chloride and HCl, or with hydrogen and a palladium / activated carbon catalyst to obtain the amino-tetrahydroisoquinoline of formula (II). .

When the desired R ^1A group is methyl, the compound of formula (IV) can also be reacted with formic acid and formaldehyde to introduce the N-methyl group.

Nitro-tetrahydroisoquinolines of formula (IV) are described under Stokker, Tet. Lett., 1996, 37, 5453 2-trifluoroacetyl-nitro-tetrahydroisoquinoline obtained by reaction of N- (nitrophenyl) ethyl-trifluoroacetamide and paraformaldehyde using the method of. Can be prepared by hydrolysis. N- (nitrophenyl) ethyl-trifluoroacetamide can be prepared from readily available materials by reacting trifluoroacetic anhydride with rutidine and nitrophenethylamine hydrochloride, as illustrated in the description below. have.

Compounds of formula (II) also contain the corresponding amino-isoquinoline (or nitro-analogue thereof) of formula (VI) with compound R ^1A Z, wherein Z is a leaving group such as halogen, in particular iodo, or tosylate By reaction to obtain an intermediate of formula (VII), for example by reducing with sodium borohydride or by hydrogenation with hydrogen and a palladium / activated carbon catalyst to obtain tetrahydroisoquinoline of formula (II) Can be. When the compound of formula (VII) is substituted with nitro-isoquinoline, the nitro group is converted to an amino group in the hydrogenation step.

When the desired R ¹ is hydrogen, the N of tetrahydroisoquinoline or isoquinoline is usually before the coupling step to form the carboxamide of formula (I), for example t-butoxycarbonyl or trifluoro It is preferred to be protected by acetyl.

The amino / nitro-isoquinolines of formula (VI) and the reagents used are either commercially available or can be prepared from commercially available materials using conventional methods described in the literature.

If substituent X is not hydrogen, it may be introduced during any of the above processes, for example by conventional substitution of the aromatic ring of the compound of formula (IV), (V) or (iii), or in the process It may be present on commercially available starting materials. Most suitably, substituent X is introduced into the compound of formula (II) wherein X is hydrogen. For example, when X is halogen it can be introduced via an amino group using Sandmeyer chemistry as illustrated below.

Compounds of formula (III) can be prepared by further substitution of commercially available benzoic acid or thiophene carboxylic acid derivatives using conventional processes, or by oxidation of the corresponding substituted benzyl alcohols. Alternatively, benzoic acid can be prepared from the corresponding substituted phenols, for example, by forming acetate and converting to acetophenone followed by the desired acid.

If the intermediate is a novel compound, this also forms part of the present invention.

The process for the preparation of the compounds of the invention is further illustrated by the following description and examples. The utility of the compounds of the present invention is shown by the pharmacological data following the examples.

Description 1

N-2- (4-nitrophenyl) ethyl-trifluoroacetamide

At 0 ° C., a solution of a solution of trifluoroacetic anhydride (10.6 mL) in dichloromethane (100 mL) was diluted with 2,6-lutidine (17.44 mL) and 4-nitrophenethylamine hydrochloride (15.25 g, 75 mmol). ) A stirred solution was added dropwise. The mixture was stirred overnight at 25 ° C. under argon and then washed with dilute citric acid (× 2), brine and dried over Na ₂ SO ₄ . The title compound was obtained as a pale white yellow solid as a substance in the organic phase (19.04 g).

Description 2

7-nitro-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinoline

Nitro compound D1 (2.26 g, 9.15 mmol) and paraformaldehyde (0.45 g, 14.4 mmol) in acetic acid (10 mL) and concentrated H ₂ SO ₄ (15 mL) are described in GE Stokker., Tet. Lett., 1996, 37, 5453] was stirred for 20 minutes at 25 ℃. Finishing gave the title compound as a white solid (2.17 g).

Description 3

7-nitro-1,2,3,4-tetrahydroisoquinoline

At room temperature, trifluoroacetamide D2 (17.22 g, 63 mmol) was hydrolyzed using a solution of potassium carbonate (46.6 g) in 10% aqueous methanol (660 mL). Finishing with dichloromethane gave the title compound (11 g).

Description 4

2-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline

For 2 hours at 80 ° C., amine D3 (2.08 g, 11.7 mmol) was described in G.M. Carrera and D.S. Garvey, J. Het. Chem., 1992, 29, 847] were treated with 88% formic acid (3.45 mL) and 37% aqueous formaldehyde (5.88 mL). After basifying with 10% sodium hydroxide and finishing with ethyl acetate, an orange rubber was obtained (2.3 g). Chromatography on Kiesegel 60 in 0-3% methanol-ethyl acetate gave the title compound as an orange solid (1.7 g).

Description 5

7-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline

7-nitro compound D4 (0.25 g, 1.3 mmol) in methanol (40 mL) was hydrogenated over 10% palladium on carbon (100 mg) overnight at atmospheric pressure. The catalyst was filtered off with a pad of diatomaceous earth and concentrated in vacuo to afford the title compound as a white solid (213 mg).

Description 6

7-amino-2- (t-butyloxycarbonyl) -1,2,3,4-tetrahydroisoquinoline

At 25 ° C., di-butyl dicarbonate in 10% aqueous hydroxide in dioxane was used, followed by catalytic catalytic hydrogenation according to the process described in D5 to prepare the title compound from the compound of description D3.

Description 7

N- (2-t-butyloxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-chlorothiophen-2-carboxamide

For 30 minutes at room temperature, 5-chlorothiophene-2-carboxylic acid (214 mg, 1.3 mmol), ethyldimethylaminopropyl carbodiimide (250 mg, 1.3 mmol) and 1-hydride in anhydrous DMF (25 mL) Roxybenzotriazole (176 mg, 1.3 mmol) was stirred. A solution of N-boc amine D6 (300 mg, 1.21 mmol) in dichloromethane (5 mL) was added and the mixture was kept at room temperature overnight. Finishing afforded a pink rubber which was chromatographed on Kigelgel 60 in 30% acetate-hexanes. Appropriate fractions were combined to yield the title compound as a white solid (0.5 g).

Description 8

7-nitro-2-n-propyl-1,2,3,4-tetrahydroisoquinoline

Nitro compound D3 (1.55 g, 8.7 mmol) and propionaldehyde (2.52 g, 43.5 mmol) in 1,2-dichloroethane (50 mL) were dissolved in sodium triacetoxyborohydride (0.28 g, 13.1 mmol) and glacial acetic acid (0.6 Ml, 9.0 mmol). The mixture was stirred at 25 ° C. over the weekend and then diluted with dichloromethane (50 mL). The mixture was washed with saturated NaHCO ₃ , dried (Na ₂ SO 4) and concentrated in vacuo. Chromatography on Kegel gel 60 in ethyl acetate gave the title compound.

Description 9

7-amino-2-n-propyl-1,2,3,4-tetrahydroisoquinoline

At 50 ° C., nitro compound D8 (0.73 g, 3.32 mmol) in ethanol (100 mL) was heated and treated with a solution of tin (II) chloride (2.57 g, 13.27 mmol) in concentrated HCl (10 mL) and for 3 h. Stirring was continued. The mixture was basified with 40% NaOH and the product was extracted to give dichloromethane. Finishing was chromatographed on Chigelgel 60 in 10% methanol: dichloromethane to afford the title compound as a viscous yellow solid (0.26 g, 41%).

Description 10

7-amino-2-iso-propyl-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared in 10% overall yield from D3 and acetone using methods similar to those described in Descriptions 8 and 9.

Description 11

7-amino-2-ethyl-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared in 14% overall yield from D3 and acetaldehyde using methods similar to those described in Descriptions 5 and 8.

Description 12

2-formyl-7-nitro-1,2,3,4-tetrahydroisoquinoline

For 15 minutes at 50 ° C., a mixture of acetic anhydride (1.4 mL) and formic acid (0.7 mL) was stirred. After cooling to 0 ° C., a solution of D3 (1.78 g) and 4-dimethylaminopyridine (0.1 g) in dichloromethane (30 mL) was added and stirring continued at 25 ° C. for 2 hours. The reaction mixture was washed with aqueous potassium carbonate, water and brine and dried (MgSO ₄ ). Evaporation in vacuo gave the title compound (2.4 g).

Description 13

7-amino-2-formyl-1,2,3,4-tetrahydroisoquinoline

Compound D12 (2.3 g) was dissolved in ethanol (50 mL) and shaken at 50 psi with hydrogen in the presence of 5% Pd / C catalyst (0.8 g) at room temperature. After filtration and evaporation the title compound was obtained as a white solid (1.6 g).

Description 14

2- (2-t-butyldimethylsilyloxyethyl) -7-nitro-1,2,3,4-tetrahydroisoquinoline

7-nitro-tetrahydroisoquinoline (5.0 g, 28.0 mmol) was dissolved in DMF (150 mL). This solution was treated with (2-bromoethoxy) -t-butyl-dimethylsilane (12.0 mL, 56.0 mmol) and stirred at 80 ° C overnight. The mixture was cooled to room temperature and the solvent was removed in vacuo. Purification by column chromatography via SiO ₂ eluting with 50% diethyl ether / petroleum ether gave the title compound (4.2 g, 44%).

Description 15

7-amino-2- (2-t-butyldimethylsilyloxyethyl) -1,2,3,4-tetrahydroisoquinoline

2- (2-t-butyldimethylsilyloxyethyl) compound D14 (2.88 g, 8.57 mmol) and 10% Pd / C (0.5 g, 60% paste in water) in methanol (100 mL) Similar to Description 5 Hydrogenation to afford the title compound (2.62 g).

Description 16

2- (2-t-butyldimethylsilyloxyethyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide

Triethylamine (0.112 mL, 0.81 mmol) and 3-bromo-4-ethoxybenzoyl chloride (193 mg, 0.73 mmol) were dissolved in dichloromethane (100 mL) with stirring. To this mixture was added D15 (204 mg, 0.67 mmol) compound. The mixture was stirred overnight and then evaporated in vacuo. The resulting residue was chromatographed on silica using 10% methanol: dichloromethane to give the title compound (123 mg, 35%).

Description 17

7-amino-2- (2-methoxyethyl) -1,2,3,4-tetrahydroisoquinoline

Description 18

5-iodo-7-nitro-1,2,3,4-tetrahydroisoquinoline

The nitro compound of description 3 (750 mg, 3.9 mmol) and N-iodosuccinimide (1.13 g) in triflic acid (5 mL) was stirred at 25 ° C. overnight. The mixture was carefully poured into saturated NaHCO ₃ and extracted with ether (2 ×). The combined organic extracts were washed with aqueous sodium thiosulfate, dried (MgSO ₄ ) and evaporated in vacuo to give a residue. Chromatography on Chigelgel 60 in 2% methanol-dichloromethane gave the title compound (650 mg).

Description 19

7-amino-5-iodo-1,2,3,4-tetrahydroisoquinoline

At 50 ° C., a solution of nitro compound D18 (650 mg, 2.14 mmol) in ethanol (20 mL) was treated with a solution of tin (II) chloride (1.42 g) in concentrated HCl (3 mL). The resulting yellow solution was basified with 10% aqueous sodium hydroxide and the product was extracted to produce dichloromethane. Flash chromatography on Kegel gel 60 (5% methanol-dichloromethane) gave the title compound (428 mg, 73%)

Description 20

7-amino-5-iodo-2- (t-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinoline

Iodoamine D19 (580 mg, 2.12 mmol) in DMF (30 mL) was treated with DMAP (20 mg) and di-t-butyl-dicarbonate (466 mg, 2.13 mmol) and the solution was stirred at rt overnight. . The reaction mixture was evaporated to dryness in vacuo. Chromatography on kigel gel 60 (2% methanol-dichloromethane) gave the title compound (745 mg, 94%).

Description 21

5,7-dinitro-1,2,3,4-tetrahydroisoquinoline

5-nitro-1,2,3,4-tetrahydroisoquinoline (1.0 g, 5.6 mmol) in concentrated sulfuric acid (3 mL) was treated with concentrated nitric acid (1 mL) and the mixture was stirred at rt for 1 h. The mixture was cooled, basified with 40% aqueous NaOH and finished with dichloromethane to give the title compound (1.1 4 g).

Description 22

5,7-dinitro-2-methyl-1,2,3,4-tetrahydroisoquinoline

Amine D21 (1.8 g) in formic acid (5 mL) and paraformaldehyde (7 mL) was reacted in a similar manner to Description 2 to give the title compound (1.74 g, 91%).

Description 23

5-amino-7-nitro-2-methyl-1,2,3,4-tetrahydroisoquinoline

In a similar manner to Description 19, dinitro compound D22 (1.7 g) was reduced to tin chloride (II) (5.42 g) to give the title compound (0.6 g).

Description 24

5-trifluoroacetylamino-7-nitro-2-methyl-1,2,3,4-tetrahydroisoquinoline

Treated with trifluoroacetic anhydride (1.1 equiv) with amine D23 (0.5 g) in dichloromethane (10 mL) and triethylamine (1.5 equiv) and the mixture was stirred at 25 ° C. for 3 h. After finishing with dichloromethane, the residue was chromatographed on Chigelgel 60 in 3% methanol-dichloromethane to give the title compound (0.7 g, 96%).

Description 25

7-amino-5-trifluoroacetylamino-2-methyl-1,2,3,4-tetrahydroisoquinoline

Nitro compound D24 (0.7 g, 2.28 mmol) in ethanol (20 mL) was hydrogenated over 10% Pd / C (70 mg). The catalyst was filtered off with celite and evaporated in vacuo to yield the title compound as a pale white solid (0.6 g, 93%).

Description 26

5-chloro-7-nitro-2-methyl-1,2,3,4-tetrahydroisoquinoline

At 0 ° C., 5-amino compound D23 (1.6 g, 7.7 mmol) in 5M HCl (25 mL) was treated with a solution of sodium nitrite (0.55 g, 8.0 mmol) in water (3 mL) over 5 minutes. The cold solution was added slowly to a solution of copper chloride (I) (1.0 g, 10 mmol) in 5M HCl (25 mL). The mixture was stirred at 25 ° C. for 30 minutes and then basified with 40% NaOH. After finishing treatment with dichloromethane (300 mL) flash chromatography on Kigelgel 60 (5% methanol: dichloromethane) gave the title compound as a yellow solid (1.1 g, 62%).

Description 27

7-amino-5-chloro-2-methyl-1,2,3,4-tetrahydroisoquinoline

Nitro D26 (0.80 g, 3.5 mmol) in ethanol (70 mL) and concentrated HCl (7 mL) was heated to 50 ° C. and tin (II) chloride (2.66 g, 14 mmol) was added. The mixture was heated and cooled for 15 minutes. Finishing in a similar manner to that described in Description 19 gave the title compound as a yellow oil (0.48 g).

Preparation Example 1

3-bromobenzyl TBMS ether

T-butyldimethylsilyl chloride in 1M solution in dichloromethane (28.0 mL) to a solution of 3-bromobenzyl alcohol (5.00 g, 0.027 mmol) in dichloromethane (30 mL) and Et ₃ N (4.2 mL, 0.03 mol) Was added dropwise. The mixture was stirred at rt overnight then water (30 mL) was added. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to give a red oil which was purified by flash chromatography on silica gel using 20% ether in hexane to give a colorless oil (8.0 g).

Preparation Example 2

3-pivaloylbenzyl alcohol TBDMS ether

At −78 ° C., n-butyllithium (2.80 mL, 7.00 mmol, 2.5 M in hexanes) was added slowly to a solution of Preparation 1 TBDMS ether (1.80 g, 6.0 mmol) in dry THF (10 mL) over 5 minutes. It was. At −78 ° C., the reaction mixture is kept under argon atmosphere for 1 hour, N, O-dimethylhydroxy pivaloyl amide (0.86 g, 6.60 mmol) in THF (2 mL) is added dropwise with stirring, NH ₄ Cl Quench with solution and warm to room temperature. The mixture was extracted with ether (2 × 50 mL) and the combined organics were dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the title compound as a colorless solid (1.75 g).

Preparation Example 3

3-pivaloylbenzyl alcohol

Preparative Example 2 (1.47 g, 4.80 mmol) of ether was dissolved in methanol (25 mL) and added with concentrated HCl (20 drop) and the whole was stirred at room temperature for 4 hours. Saturated NaHCO ₃ solution was added and the mixture was extracted with ether (2 × 50 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo to afford the title compound as a colorless oil (0.80 g).

Preparation Example 4

3-pivalobenzoic acid

3-pivaloylbenzyl alcohol (0.80 g, 4.16 mmol) was dissolved in dioxane (20 mL). A solution of KOH (0.35 g, 6.30 mmol) in water (5 mL) was added followed by KMnO ₄ (1.45 g, 9.17 mmol). The mixture was stirred at rt over the weekend. The solution was filtered through celite and extracted with ether. The aqueous phase was acidified with dilute HCl and extracted with ether (3 × 50 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (0.80 g).

Preparation Example 5

3-trifluoroacetylbenzoic acid

The title compound was prepared from diethyl trifluoroacetamide and 3-bromobenzyl TBDMS ether using methods similar to those described in Preparation Examples 1, 2, 3 and 4.

Preparation Example 6

Methyl 3-chloro-4-iso-propoxybenzoate

Treated methyl 3-chloro-4-hydroxybenzoate (5 g, 26.8 mmol) in DMF (45 mL) with potassium carbonate (7.41 g, 53.6 mmol), 2-iodopropane (3.85 mL, 40.2 mmol) Then stirred at 25 ° C. for 18 h. Finishing with ethyl acetate gave the title compound (6.1 g).

Preparation Example 7

3-Chloro-4-iso-propoxybenzoic acid

Methyl 3-chloro-4-iso-propoxybenzoate (5.5 g, 24.1 mmol) was hydrolyzed using 1M NaOH (36 mL) in methanol (80 mL). Extraction and finishing with ethyl acetate gave the title compound (4.3 g).

Preparation Example 8

3-Bromo-4-ethoxybenzoic acid

The title compound was prepared from 4-ethoxybenzoic acid in a similar manner to Process 1.

Preparation Example 9

3-Bromo-4-ethoxybenzoic acid

The title compound was prepared from 4-ethoxybenzoic acid.

Preparation Example 10

3-Cyano-4-iso-propylbenzoic acid

The title compound was prepared from 4-iso-propylbenzoic acid in a similar manner as described in step 5.

Preparation Example 11

4-methoxy-3-trifluoromethylbenzocin

The title compound was prepared from 3-bromo-4-methoxybenzoic acid and sodium trifluoroacetic acid in a similar manner to processes 3 and 4.

Preparation Example 12

4-methoxy-3-trifluoromethylbenzoyl chloride

At room temperature, 4-methoxy-3-trifluoromethylbenzoic acid was treated with oxalyl chloride and DMF in chloroform [D. Levin, Chem. Br., 1977, 20] followed by evaporation of the title compound in vacuo.

Preparation Example 13

Methyl 3-bromo-4-iso-propoxybenzoate

Treatment of methyl 3-bromo-4-hydroxybenzoate (2.5 g, 10.8 mmol) in DMF (35 mL) with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane (2.76 g, 21.6 mmol) Then stirred at 25 ° C. for 48 h. Finishing with ethyl acetate gave the title compound (3.0 g).

Preparation Example 14

Methyl 3-cyano-4-iso-propoxybenzoate

Methyl 3-bromo-4-iso-propoxybenzoate (2.0 g, 7.3 mmol) and copper cyanide (I) in N-methyl pyrrolidone (50 mL) were vigorously heated to reflux for 4 hours. Finishing with ethyl acetate gave the title compound (1.0 g).

Preparation Example 15

Methyl 3,5 dichloro-4-ethoxybenzoate

The title compound was prepared in 69% yield from 3,5-dichloro-4-hydroxybenzoic acid and iodoethane in a similar manner to Preparation Example 6.

Preparation Example 16

3-Methanesulfonyl-4-iso-propylbenzoic acid

At 75 ° C., 3-chlorosulfonyl-4-iso-propylbenzoic acid (2.62 g, 10 mmol) [prepared from 4-iso-propyl benzoic acid in a manner similar to that described in steps 7 and 8] was water (9 mL) It was added slowly to a slurry of NaHCO ₃ (2.52 g, 30 mmol) and Na ₂ SO ₃ (1.26 g, 10 mmol). The mixture was stirred for 1 hour and then treated with bromoacetic acid (2.08 g, 15 mmol) and NaOH (0.60 g, 15 mmol). The temperature was raised to 105 ° C and the mixture was heated to reflux for 24 hours. The mixture was cooled and acidified to pH 1, the resulting precipitate was collected, washed and dried to give the title compound (1.43 g, 59%).

Preparation Example 17

4-Methyl-3-methanesulfonylbenzoic acid

It was prepared in a total of 30% yield in a similar manner to Preparation Example 16.

Preparation Example 18

4-ethyl-3-methanesulfonylbenzoic acid

In a similar manner to Preparation 16, the preparation was carried out in a total 44% yield.

Preparation Example 19

3-methanesulfonyl-4-methoxybenzoic acid

In a similar manner to Preparation 16, the preparation was made in a total yield of 20%.

Preparation Example 20

4-ethoxy-3-methanesulfonylbenzoic acid

Prepared in 20% yield in a similar manner to Preparation Example 16.

Preparation Example 21

3-Chloro-4-ethoxybenzoic acid

Preparation Example 22

4-Iso-propyloxy-3-trifluoromethylbenzoic acid

Potassium trifluoroacetic acid (922 mg, 6.06 mmol), copper iodide (I) (1.15 g, in methyl 3-bromo-4-iso-propyloxybenzoate (828 mg, 3.03 mmol) in DMF (25 mL) 6.06 mmol) and toluene (50 mL). The resulting mixture was refluxed for 18 hours with heating at reflux for 1.5 hours with [Dean and Stark] removed and then cooled. The mixture was poured into Et ₂ O (100 mL) and H ₂ O (100 mL). The biphasic mixture was stirred at rt for 0.5 h and then filtered through celite. The two phases were separated and the aqueous phase further extracted with Et ₂ O (50 mL) and the organic extracts combined, washed with saturated aqueous Na ₂ S ₂ O ₃ , H ₂ O, saturated brine, dried (MgSO ₄ ) and vacuum Evaporation at gave a brown oil. It was dissolved in MeOH (about 20 mL) and treated with 2M NaOH (2 mL, 4 mmol) to heat the resulting solution for 3 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc and H ₂ O. The phases were separated and the aqueous phase was acidified to pH 1 with 2M HCl in the presence of EtOAc and the phases were separated. The aqueous phase was further extracted with EtOAC and the extracts were combined, washed with H ₂ O and saturated brine, dried (MgSO ₄ ) and evaporated to dryness in vacuo to give the title compound (671 mg, 89%) as a white solid.

Preparation Example 23

4-Ethyl-3-trifluoromethylbenzoic acid

Prepared from methyl 4-ethyl-3-bromobenzoate (1.10 g, 4.52 mmol) as described in Preparation 22 and isolated to give a white solid (923 mg, 93%).

Preparation Example 24

4-n-propoxy-3-trifluoromethylbenzoic acid

Prepared and isolated as described in Preparation 22 from methyl 3-bromo-4-n-propyloxybenzoate (1.43 g, 5.23 mmol) to give a white solid (1.18 g, 91%).

Preparation Example 25

4-t-butyl-3-trifluoromethylbenzoic acid

Prepared from methyl 3-bromo-4-n-propyloxybenzoate (2.46 g, 9.1 mmol) as described in Preparation 22 and isolated to give a white solid (1.55 g mg, 69%).

Preparation Example 26

4-oxochroman-6-carboxylic acid

Prepared according to the method of 3- (4-carboxyphenoxy) propionic acid (2.5 g) in concentrated sulfuric acid (20 mL) (J. Lichtenberger and R. Geyer. Bull. Soc. Chim. Fr., 1963 275). ) Was heated to 100 ° C. for 4 hours and then poured into crushed ice. The resulting precipitate was filtered and dried in vacuo to give the title compound (1.6 g).

Preparation Example 27

3-Bromo-4-iso-propoxybenzoic acid

The title compound was prepared using a method similar to Preparation Example 7.

Preparation Example 28

4-azidobenzoic acid

At 5 ° C., sodium nitrite (3.50 g) was added in portions to a solution of 4-aminobenzoic acid (2.00 g, 14.00 mmol) in trifluoroacetic acid (10 mL) and the mixture was stirred for 30 minutes. Sodium azide (3.77 g) was then added in portions and the mixture was stirred for 30 minutes at 0 ° C. The mixture was diluted with water and a white solid precipitated out. The solid was filtered, washed with cold water and precipitated to give the title compound (1.66 g, 73%).

Process 1

5-Bromo-2,4-dimethoxybenzoic acid

To a solution of 2,4-dimethoxybenzoic acid (4.0 g, 0.022 mol) in chloroform (60 ml) was added dropwise bromine (1.13 ml, 0.022 mol) in chloroform (20 ml). After stirring at room temperature overnight the precipitate was filtered off and dried to give the title compound as a white solid (2.87 g).

Process 2

5-Bromo-4-iso-propyl-2-methoxybenzoic acid

Bromine in chloroform (20 mL) was added dropwise to a solution of 2-methoxy-4-iso-propyl benzoic acid (7.0 g, 36.0 mmol) in chloroform (100 mL). The reaction was stirred at rt overnight. Evaporation in vacuo gave an oil (9.27 g).

Process 3

Methyl 5-bromo-4-iso-propyl-2-methoxybenzoate

5-Bromo-4-iso-propyl-2-methoxybenzoic acid (9.268 g, 34.0 mmol) was dissolved in methanol (250 mL) and concentrated H ₂ SO ₄ (2 mL) was added. The mixture was refluxed for 5 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate and water and the organic layer was dried (MgSO ₄ ). Concentration in vacuo gave an oil which was purified by Biotage column chromatography on silica gel using 10% ether in hexanes to give an oil (5.5 g).

Process 4

2,4-dimethoxy-5-trifluoromethylbenzoic acid

Under argon atmosphere, 2,4-dimethoxy-5-bromobenzoic acid ethyl ester (1.5 g, 5.4 mmol) in DMF (25 mL) and toluene (8 mL) was added potassium trifluoroacetate (1.53 g, 10.1 mmol). And copper (I) iodide (2.1 g, 10.9 mmol). The mixture was heated to 170 ° C. with water removal (dine / stark) and then held at 155 ° C. overnight. The mixture was cooled, poured into ether and water and filtered over diatomaceous earth. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a brown oil. At 50 ° C., 60 chromatography on Kegel gels using 1: 1 ether / gasoline to give a solid (1.03 g) which was hydrolyzed in 1: 1 methanol: aqueous NaOH (50 mL). Finishing afforded the title compound as a white solid (1 g).

Process 5a

A solution of copper cyanide (I) (550 mg, 6 mmol) in methyl 2-methoxy-5-bromo-4-iso-propylbenzoate (861 mL) in N-methyl-2-propylidone (30 mL) Was added. The mixture was stirred under argon atmosphere and boiled under reflux for 4 hours. The mixture was cooled, poured into excess ice / water and ethyl acetate and filtered. The organic phase was separated, washed with water and brine and dried (MgSO ₄ ). The crude brown solid obtained by evaporation was purified by chromatography on silica gel eluting with ethyl acetate / n-hexane (1: 4). The product was obtained as a white solid (523 mg).

Process 5b

2-methoxy-5-cyano-4-iso-propylbenzoic acid

2N NaOH (1.25 mL) was added to a solution of methyl ester P5a (490 mg) in methanol (10 mL). The solution was stirred at rt overnight. The solution was then diluted with water, concentrated in vacuo and washed with ethyl acetate. The aqueous phase was then acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and evaporated to dryness to afford the product as a white solid (418 mg).

Process 6a

Ethyl 2-ethoxy-4-iso-propyl-5-cyanobenzoate

Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (1.2 g, 3.8 mmol) was added to the copper cyanide (I) in N-methyl-2-pyrrolidone (40 mL) described in step 5. 628 mg, 7.6 mmol) to give the title compound (400 mg) as an oil.

Process 6b

2-Ethoxy-4-iso-propyl-5-cyanobenzoic acid

Ester P6a (370 mg, 1.41 mmol) was dissolved in methanol (5 mL) and 1N NaOH (2.1 mL, 2.1 mmol) was added over 24 hours. The solution was concentrated in vacuo, diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and evaporated to afford the title compound acid (306 mg).

Process 7

4-Ethoxy-2-methoxy-5-methylsulfonylbenzoic acid

M.W. Harrold et al., J. Med. Chem., 1989, 32 874] gave 4-ethoxy-2-methoxy-5-chlorosulfonyl benzoic acid in 49% yield. This process is described in R.W. Brown, J. Org. Chem., 1991, 56, 4974, to yield the title compound in a yield of 19%.

Process 8

4-Iso-propyl-2-methoxy-5-methylsulfonylbenzoic acid

C. Hansch, B. Schmidhalter, F. Reiter, W. Saltonstall. J. Org. Chem., 1956, 21, 265], to prepare intermediate 5-chlorosulfonyl-4-isopropyl-2-methoxybenzoic acid and convert to the title compound using the method of step 7.

Example 1

N- (1,2,3,4-tetrahydroisoquinolin-7-yl) -5-chlorothiophen-2-carboxamide monotrifluoroacetate

N-boc amine D7 (0.48 g, 1.22 mmol) in dichloromethane (25 mL) containing trifluoroacetic acid (2 mL) was maintained at 25 ° C. for 18 h. After evaporation in vacuo, the residue was crystallized from ethyl acetate-ether to give pale white crystals (0.46 g, 92%). Melting point 153 to 155 ° C.

Example 2

N- (2-Methyl-tetrahydroisoquinolin-7-yl) -5-chlorothiophene-2-carboxamide

The compound of Example 1 (200 mg, 0.5 mmol), 98% formic acid (0.4 mL) and aqueous formaldehyde (0.6 mL) were treated according to the procedure of description 4. Chromatography on Kegel gel 60 in methanol-ethyl acetate followed by crystallization from ethyl acetate-ether gave an off-white powder. Melting point 138 to 140 ° C.

Example 3

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzamide

N-methyl amine D5 in dichloromethane (25 mL) containing triethylamine (0.5 mL) was treated with benzyl chloride and the mixture was kept at 25 ° C. for 18 h. Normal finishing and chromatography on Kegel gel 60 eluting with a gradient in ethyl acetate: hexanes. Appropriate fractions were collected to afford the title compound.

The following example was prepared using a method similar to the above method.

Example 4

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chlorobenzamide

Example 5

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-t-butylbenzamide

Example 6

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-propoxybenzamide

Example 7

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenoxybenzamide

Example 8

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-nitrobenzamide

Example 9

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenylbenzamide

Example 10

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylbenzamide

Example 11

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluorobenzamide

Example 12

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyanobenzamide

Example 13

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,4-dichlorobenzamide

Example 14

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iodobenzamide

Example 15

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-bromobenzamide

Example 16

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methylbenzamide

Example 17

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-nitrobenzamide

Example 18

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethoxybenzamide

Example 19

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-butylbenzamide

Example 20

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-acetoxybenzamide

Example 21

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-trifluoromethylbenzamide

Example 22

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2,4-difluorobenzamide

Example 23

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,4-dimethoxybenzamide

Example 24

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-fluoro-4-trifluoromethyl benzamide

Example 25

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-chloro-3-nitrobenzamide

Example 26

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-di-trifluorobenzamide

Example 27

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2,4-dichloro-5-fluorobenzamide

Example 28

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluoro-5-trifluoromethyl benzamide

Example 29

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methoxybenzamide

Example 30

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,4,5-trimethoxybenzamide

Example 31

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-trifluoromethoxybenzamide

Example 32

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-pivaloylbenzamide hydrochloride

The acid of Preparation 5 (200 mg, 1.0 mmol) and oxalyl chloride (140 mg, 1.1 mmol) in dichloromethane (10 mL) containing DMF (5 drops) was stirred at 25 ° C. for 1 hour and then in vacuo. Evaporated to dryness. The residue in dichloromethane was treated with amine D5 (162 mg, 1.0 mmol) and kept at 25 ° C. overnight. Finishing similar to Example 2 gave the title compound (110 mg). Melting point 197-210 ° C. (from methanol: ether).

Example 33

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-iso-propoxybenzamide

Example 34

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-acetoxybenzamide

Example 35

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-cyclopentyloxybenzamide

Example 36

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-cyclopropylmethoxybenzamide

Example 37

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-methoxybenzamide

Example 38

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-naphtamide

Example 39

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methylbenzamide

Example 40

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -naphthalene-1-carboxamide

Example 41

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-methoxybenzamide

Example 42

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-t-butoxybenzamide

Example 43

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-propoxybenzamide

Example 44

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzotriazole-5-carboxamide

Example 45

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzothiazole-6-carboxamide

Example 46

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2,3-dihydrobenzofuran-5-carboxamide

Example 47

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methylbenzimidazole-5-carboxamide

Example 48

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propoxybenzamide

Example 49

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide

Example 50

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-ethoxybenzamide

Example 51

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide

Example 52

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-methoxybenzamide

Example 53

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-ethoxybenzamide

Example 54

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-iso-propoxybenzamide

Example 55

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonylbenzamide

Example 56

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-t-butylbenzamide

At 25 ° C., a solution of amine D5 (162 mg, 1.0 mmol) and 3-bromo-4-t-butylbenzoic acid (257 mg, 1.0 mmol) in anhydrous N, N-dimethylformamide (7 mL) was added 1-. Treated with hydroxybenzotriazole (135 mg, 1.0 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (192 mg, 1.0 mmol). The mixture was shaken for 48 hours before the product was extracted with dichloromethane and washed with 10% aqueous NaHCO ₃ and water followed by brine. The organic layer was dried over MgSO ₄ and evaporated in vacuo to give 373 mg (93% yield) of the title compound.

Example 57

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-bromo-5-methoxybenzamide

Example 58

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-fluoro-3-methoxybenzamide hydrochloride

Example 59

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -1-methylpyrazole-4-carboxamide

Example 60

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-trifluoromethylpyrazole-3-carboxamide

Example 61

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methylpyrazole-4-carboxamide

Example 62

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-methylisoxazole-3-carboxamide

Example 63

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-t-butylisoxazole-3-carboxamide

Example 64

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methoxyisoxazole-5-carboxamide hydrochloride

Example 65

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) indolin-2-carboxamide

D5 was converted to the title compound by reaction with indole-2-carboxylic acid in a manner similar to the process of description 7.

Example 66

N- (2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-iso-propylbenzamide hydrochloride

Example 67

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-iso-propylbenzamide hydrochloride

Example 68

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluoro-4-methoxybenzamide

Example 69

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-n-propoxybenzamide

Example 70

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-ethoxybenzamide

Example 71

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-n-propoxybenzamide

Example 72

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethylbenzamide

Example 73

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-iodo-4-methoxybenzamide

Example 74

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-propoxy-3-trifluoromethylbenzamide

Example 75

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-chloro-3-methoxybenzamide

Example 76

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-propoxy-3-trifluoromethylbezamide

Example 77

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-t-butylbenzamide hydrochloride

Example 78

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxybenzamide hydrochloride

In a manner similar to that described in Example 3, D5 was reacted with 4-methoxy benzoyl chloride to convert to 95% yield of the title compound.

Example 79

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-chloro-3-methylbenzamide hydrochloride

Example 80

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propylbenzamide

Example 81

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-ethylbenzamide hydrochloride

Example 82

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-propyl-3-trifluoromethylbenzamide hydrochloride

Example 83

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethyl-3-trifluoromethylbenzamide hydrochloride

Example 84

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-iso-propoxybenzamide hydrochloride

Example 85

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide

Example 86

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methyl-3-methylsulfonylbenzamide

Example 87

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethyl-3-methylsulfonylbenzamide

Example 88

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonyl-4-iso-propylbenzamide

Example 89

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonyl-4-methoxybenzamide

Example 90

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-trifluoroacetylbenzamide hydrochloride

Example 91

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-pentafluoroethylbenzamide hydrochloride

Example 92

N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide

Example 93

N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide

Example 94

N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propoxybenzamide

Example 95

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-iso-butylbenzamide hydrochloride

Example 96

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-butyl-3-trifluoromethylbenzamide hydrochloride

Example 97

N- (2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide

Example 98

N- (2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide

Example 99

N- (2-iso-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide

Example 100

N- (2-iso-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy--3trifluoromethylbenzamide

Example 101

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethoxy-3-methylsulfonylbenzamide

Example 102

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-oxochroman-6-carboxamide hydrochloride

Example 103

N- (2-formyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide

Following the procedure of Example 3, 7-amino-2-formyl-1,2,3,4-tetrahydroisoquinoline (0.176 g) was reacted with 4-methoxy-3-trifluoromethylbenzoyl chloride to give the title Converted to compound. The product was isolated as a white solid (0.035 g).

Example 104

N- (2-hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide

Compound D16 (115 mg, 0.22 mmol) was dissolved in THF with stirring and tetrabutylammonium fluoride (1M in THF, 0.126 mmol) was added. The reaction was stirred overnight and the mixture was purified by column chromatography passing through SiO, eluting with 10% methanol: dichloromethane. Trituration with petroleum ether gave the title compound (48 mg, 49%).

Example 105

N- (2-hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethylbenzamide

The total 40% yield of the title compound was prepared from D15 in a similar manner to Description 16 and Example 106.

Example 106

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenylmethoxy-3-trifluoromethylbenzamide

Example 107

N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-hydroxy-3-trifluoromethylbenzamide

Example 108

N- (2-methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-iso-propoxybenzamide

Example 109

N- (2-methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propoxybenzamide

Example 110

N- (2-methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide

Example 111

(a) N- (2-t-butyloxycarbonyl-5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-azidobenzamide

The title compound was prepared in 81% yield from the acid and amine D6 of Acid Preparation 28.

(b) N- (5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-azidobenzamide trifluoroacetate

The title compound was prepared in 91% yield using a method similar to Example 1.

Example 112

N- (2-methyl-5-trifluoroacetylamino-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methoxybenzamide

The title compound (0.66 g) was prepared from D25 (0.50 g) and 3-bromo-4-methoxybenzoic acid (0.63 g) using a process similar to Description 7.

Example 113

N- (2-methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide

Example 114

N- (2-methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethylbenzamide

Pharmacological data

1. Binding Analysis Method

International Publication No. 92/22293 (Smithline Misery) includes in particular the compound trans-(+)-6-acetyl-4S- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H Compounds having true activity are disclosed, including -1-benzopyran-3R-ol (hereinafter referred to as compound A). It has been found that the compound of International Publication No. 92/22293 binds to a novel receptor that can be obtained from the rat whole brain tissue as described in International Publication No. 96/18650 (Smithline Misery). The affinity of the test compound for the new receptor site was assessed as follows:

Way

Whole whole brain tissue was obtained from rats. Tissues were first homogenized in buffer (usually 50 mM Tris / HCl, pH 7.4). Homogenized tissue was washed by centrifugation and resuspension in the same buffer and stored at -70 ° C until use.

To perform radioligand binding assays, aliquots of the prepared tissues (usually 1-2 mg / ml concentration of protein) were mixed with an aliquot of [3H] -Compound A dissolved in buffer. The final concentration of [3 H] -Compound A in the mixture is usually 20 nM or less. The mixture was incubated for 1 hour at room temperature. [3H] -Compound A bound to the tissue was then separated from unbound [3H] -Compound A by filtration with Whatman GF / B glass fiber filters. The filter was then quickly washed with ice cold buffer. A liquid scintillation cocktail was added to the filter and then counted in a liquid scintillation counter to determine the amount of radioactivity bound to the tissue trapped in the filter.

To determine the amount of "specific" binding of [3H] -Compound A, parallel analysis was performed when [3H] -Compound A and tissues were incubated together in the presence of unlabeled Compound A (usually 3 μΜ). Was carried out as follows. The amount of binding of [3H] -compound A remaining in the presence of this radiolabeled compound was defined as "nonspecific binding". The amount of "specific" binding of [3H] -Compound A to the novel position by subtracting this amount from the amount of total binding of the [3H] -Compound A amount (ie, present in the absence of a radiolabeled compound) Got.

The binding affinity of the test compound to the new site can be assessed by incubating [3H] -Compound A and tissue together in the presence of a range of concentrations of the compound to be tested. Schematically points to a decrease in the level of binding of specific [3H] -Compound A as a result of competing by increasing the concentration of the compound during the test, followed by a non-linear regression analysis of the resulting curve to assess the affinity of the compound of pKi It was used to.

result

Compounds of the invention were active in this test. For example, Examples 1, 4, 5, 6, 7, 10, and 13 had a pKi value of 7 or more.

2. MEST test

The maximum electric shock seizure threshold (MEST) test in rats was particularly sensitive to detecting the possibility of mycelial characteristics ¹ . In this model, antispasmodic raised the threshold to an electrically induced seizure, while the convulsant precursor lowered the seizure threshold.

Method for Mouse Model

Mice (male, Charles River, UK, CD-1 species, 25-30 g) were randomly assigned to groups 10-20, and various doses of compounds (0.3-300 mg / kg) or excipients Was administered orally or intraperitoneally in a dose volume of 10 ml / kg. 30 or 60 minutes after administration, the rats were then subjected to a single electric shock (0.1 sec, 50 Hz, sine wave form) through the corneal electrode. The average current and standard error (CC ₅₀ ) required to induce tonic seizures in 50% of rats in a particular treatment group was determined by the Dixon and Mood up and down method (1948) ² It was. Statistical comparisons between excipient treatment groups and drug treatment groups were made using the method of Litchfield and Wilcoxon (1943) ³ .

CC ₅₀ of control animals was usually 14-18 mA. The first animal in the control group received a current of 16 mA. If tonic seizures are not involved, then currents are increased in rats. If tonic seizures occur, the current is then reduced and all animals in the group tested.

The study was carried out using a Hugo Sachs Electronik Constant Current Shock Generator with global variable control of shock levels from 0 to 300 mA and steps of 2 mA.

result

Compounds of the invention tested 10 mg / kg by the oral route as suspensions in methyl cellulose and tested 1 hour after administration have been shown to increase seizure thresholds. For example, the compounds of Examples 4, 5, 6 and 7 increased by 24%, 36%, 90% and 23%, respectively.

Method for rat model

In male rats (Sprag Dawley, 80-150 g, 6 weeks of age), the threshold for maximum (tensile Fuji kidney) electric shock seizures was changed to constant current (0.3 second period, 1 to 300 mA in 5-20 mA steps). Was measured with a Hugo Sarks electronic stimulator delivering. The procedure is similar to the procedure outlined in the above mice and the details are as described in the publication of Upton et al. ⁴ .

The percentage of decrease or increase in CC ₅₀ of each group compared to the control was calculated.

The drug was suspended in 1% methyl cellulose.

result

Oral administration of the compounds of Examples 48, 49, 51 and 67 at the dose of 2 mg / kg at 2 hours showed an increase of 389%, 325%, 545% and 303%, respectively.

references

Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145-181

2. Dixon, W.J. and Mood, A. M. (1948). J. Amer. Stat. Assn., 43, 109-126

3. Litchfield, J.T. and Wilcoxon, F. (1949). J. Pharmacol. exp. Ther., 96, 99-113

4. N. Upton, T. P. Blackburn, C. A. Campbell, D. Cooper, M. L. Evans, H. J. Evans, H. J. Herdon, P. D. King, A.M.Ray, T.O.Stean, W.N.Chan, J.M.Evans and M.Thompson. (1997). B. J. Pharmacol., 121, 1679-1686.

Claims (7)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. <Formula I> In the formula, Q is a monocyclic or bicyclic aryl or heteroaryl ring, R ¹ is hydrogen, C _1-6 alkyl (optionally substituted with hydroxy or C _1-4 alkoxy), C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 alkylCO-, formyl, CF ₃ CO- or C _1-6 alkylSO _2- , R ² is hydrogen, hydroxy or halogen, NO ₂ , CN, N ₃ , CF ₃ O-, CF ₃ S-, CF ₃ CO-, trifluoromethyldiaziriinyl, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 perfluoroalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl-, C _1-6 alkyl O- , C _1-6 alkylCO-, C _3-6 cycloalkylO-, C _3-6 cycloalkylCO-, C _3-6 cycloalkyl-C _1-4 alkylO-, C _3-6 cycloalkyl-C _1-4 alkylCO-, acetoxy, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C _1-4 alkyl-, C _1-6 alkyl S-, C _1-6 alkylSO _2- , (C _{1- 4} alkyl) ₂ NSO _2- , (C _1-4 alkyl) NHSO _2- , (C _1-4 alkyl) ₂ NCO-, (C _1-4 alkyl) NHCO- or CONH ₂ Substituents of; Or -NR ³ R ⁴ , wherein R ³ is hydrogen or C _1-4 alkyl and R ⁴ is hydrogen, C _1-4 alkyl, formyl, -CO ₂ C _1-4 alkyl or -COC _1-4 alkyl Or) Two R ² groups together form a carbocyclic ring which is saturated or unsaturated and substituted or unsubstituted with —OH or ═O; X is hydrogen, halogen, C _1-6 alkoxy, C _1-6 alkyl, amino or trifluoroacetylamino, Excluding compounds where R ² is 2-alkoxy when X is hydrogen, compounds N- (7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinoline-5- when X is halogen Yl) -5-benzoyl-2-methoxybenzamide, N- (7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-benzoyl-2-methoxybenzamide , N- (5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-benzoyl-2-methoxybenzamide, N- (5-iodo-1,2, 3,4-tetrahydroisoquinolin-7-yl) -2-methoxy-4-trifluoromethyldiazinylylbenzamide, N- (5-iodo-1,2,3,4-tetrahydroiso Quinolin-7-yl) -2-methoxy-5-trifluoromethyldiazinylylbenzamide, N- (7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)- 2-methoxy-5-trifluoromethyldiaziriinyl benzamide and N- (8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -4-t -Butyl-2-methoxybenzamide is excluded. A compound of formula (IA) or (IB) <Formula IA> <Formula IB> Wherein R ¹ , R ² and X are as defined in claim 1. N- (1,2,3,4-tetrahydroisoquinolin-7-yl) -5-chlorothiophen-2-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-chlorothiophen-2-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chlorobenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-t-butylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-propoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) 4-phenoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-nitrobenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenylbenzamide, N- (2-methyl-1,2.3,4-tetrahydroisoquinolin-7-yl) -3-methylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluorobenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyanobenzamide, N- (2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) -3,4-dichlorobenzamide, N- (2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) -4-iodobenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-bromobenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-nitrobenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-butylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-acetoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-trifluoromethylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2,4-difluorobenzamide, N- (2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) -3,4-dimethoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-fluoro-4-trifluoromethyl benzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-chloro-3-nitrobenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-di-trifluoromethylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2,4-dichloro-5-fluorobenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluoro-5-trifluoromethyl benzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,4,5-trimethoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-trifluoromethoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-pivaloylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-iso-propoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-acetoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-cyclopentyloxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-cyclopropylmethoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-methoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-naphtamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -naphthalene-1-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-methoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-t-butoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-propoxybenzamide, N- (2-methyl-l, 2,3,4-tetrahydroisoquinolin-7-yl) benzotriazole-5-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzothiazole-6-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2,3-dihydrobenzofuran-5-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methylbenzimidazole-5-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-ethoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-methoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-ethoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3,5-dichloro-4-iso-propoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-t-butylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-bromo-5-methoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-fluoro-3-methoxybenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -1-methylpyrazole-4-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-trifluoromethylpyrazole-3-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methylthiazole-4-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-methylisoxazole-3-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-t-butylisoxazole-3-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methoxyisoxazole-5-carboxamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) indole-2-carboxamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-iso-propylbenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-iso-propylbenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-fluoro-4-methoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-n-propoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-ethoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-n-propoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-iodo-4-methoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-propoxy-3-trifluoromethylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-chloro-3-methoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-n-propoxy-3-trifluoromethylbenzamide N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-t-butylbenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxybenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-fluoro-3-methylbenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-ethylbenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-propyl-3-trifluoromethylbenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethyl-3-trifluoromethylbenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-iso-propoxybenzamide hydrochloride, N- (1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methyl-3-methylsulfonylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethyl-3-methylsulfonylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonyl-4-iso-propylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-methylsulfonyl-4-methoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-trifluoroacetylbenzamide, hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-pentafluoroethyl-benzamide hydrochloride, N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide, N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide, N- (2-n-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propoxybenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-cyano-4-iso-butylbenzamide hydrochloride, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-iso-butyl-3-fluoromethyl-benzamide hydrochloride, N- (2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide, N- (2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide, N- (2-iso-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide, N- (2-iso-propyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-ethoxy-3-methylsulfonylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-oxochroman-6-carboxamide hydrochloride, N- (2-formyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide, N- (2-hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide, N- (2-hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethylbenzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-phenylmethoxy-3-trifluoromethyl benzamide, N- (2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-hydroxy-3-trifluoromethyl benzamide, N- (2-methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-iso-propoxybenzamide, N- (2-methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-iso-propoxybenzamide, N- (2-methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide, N- (5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -4-azidobenzamide trifluoroacetate, N- (2-methyl-5-trifluoroacetylamino-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-methoxybenzamide, N- (2-methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethoxybenzamide, N- (2-methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-bromo-4-ethylbenzamide. Disorders associated with anxiety, mania, depression, fear disorders and / or aggressive, subarachnoid hemorrhage or nerve shock, comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvent compound thereof, Withdrawal-related effects of substance abuse such as cocaine, nicotine, alcohol and benzodiazepines, traumatic epilepsy and other anti-treatable and / or preventable disorders such as epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other Degenerative diseases such as Huntington's chorea, schizophrenia, OCD, neurological deficits associated with AIDS (acquired immunodeficiency syndrome), sleep disorders (including circadian rhythm disorders, insomnia & sleep attacks), convulsions (E.g., Gildra Tourette Syndrome), traumatic brain injury, tinnitus, neuralgia, especially tertiary neuralgia, neuropathy, toothache, cancer, diabetes, multiple sclerosis (MS) and Use in the treatment and / or prevention of inadequate neuronal activity, ataxia, myocardial cavity (convulsiveness), temporal mandibular joint dysfunction and amyotrophic lateral sclerosis (ALS) leading to neuropathic liver disease of diseases such as sinus neuron disease Pharmaceutical composition for. Anxiety, mania, depression, fear disorders, comprising administering to a patient in need thereof an effective or prophylactic amount of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvent compound thereof; (Or) treatable and / or preventable disorders such as aggression, subarachnoid hemorrhage or disorders associated with nerve shock, withdrawal effects of substance abuse such as cocaine, nicotine, alcohol and benzodiazepines, traumatic epilepsy and epilepsy , Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, OCD, neurological deficits associated with AIDS (acquired immunodeficiency syndrome), sleep disorders (Including circadian rhythm disorders, insomnia & sleep attacks), convulsions (eg, Gildra Tourette syndrome), traumatic brain injury, tinnitus, nerves Inappropriate neuronal activity, ataxia, myopia (convulsiveness), temporomandibular bones, especially causing tertiary neuralgia of diseases such as tertiary neuralgia, neuropathy, toothache, cancer, diabetes, multiple sclerosis (MS) and motor neuron disease Methods of treating and / or preventing joint dysfunction and amyotrophic lateral sclerosis (ALS). Anxiety, mania, depression, fear disorders and / or aggression, disorders associated with subarachnoid hemorrhage or nerve shock, withdrawal-related effects of substance abuse such as cocaine, nicotine, alcohol and benzodiazepines, traumatic epilepsy, and antiepileptic diseases such as epilepsy Treatable and / or preventable disorders, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, OCD, AIDS (acquired immunodeficiency syndrome) ) Neurological deficits, sleep disorders (including circadian rhythm disorders, insomnia & sleep attacks), convulsions (eg, Gildra Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially tertiary neuralgia, neuropathy Impaired neuronal activity, ataxia, muscle spasms (convulsive), leading to neuropathic liver disease of diseases such as toothache, cancer, diabetes, multiple sclerosis (MS) and motor neuron disease In the manufacture of a medicament for the treatment and / or prophylaxis of temporomandibular joint dysfunction and amyotrophic lateral sclerosis (ALS), the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvent compound thereof. Use of If the following reaction with a compound of formula (Ⅱ) formula (Ⅲ) a compound of, and demand, R ^1A or R ^2A group R ¹ or R ² to switch groups, or, R ¹ or R ² groups other R ¹ or R Any one of claims 1 to 3 comprising converting to the ^second group, converting the salt product to a free base or another pharmaceutically acceptable salt, or converting the free base product to a pharmaceutically acceptable salt. Process for the preparation of a compound according to the invention. <Formula II> <Formula III> In the formula, R ^1A is the same as R ¹ as defined in formula (I) or a group which can be converted to R ¹ , X is as defined in claim 1, Q is as defined in formula (I), Y is Cl or OH, R ^2A groups are independently the groups as defined in formula (I) or can be converted to R ² .