Derivatives of n-(3-aminopropyl)-n-phenyl-5,6,7,8 - tetrahydronaphthalen-2-carboxamide, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

Derivatives of N-(3-aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-carboxamide formula I, where R1is a hydrogen atom, halogen, methyl or aloxi, R'1is hydrogen, halogen, R1- H or methoxy, R3- C1-3-alkyl, R4- 2,3-dihydro-1H-inden-2-yl, 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen-yl-, or R3and R4together with bearing the nitrogen atom form a 1,2,3,4-tetrahydroisoquinoline, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (other designations, see p. 1 f-crystals of the invention), in the form of a base or salt, in the form of pure isomers or mixtures of such isomers, are anti-ischemic activity. 6 C. and 1 C.p. f-crystals, 1 table.

The invention relates to derivatives of N-(3 - aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-carboxamide, their preparation and application in therapeutic practice.

According to the invention proposed derivatives of N-(3-aminopropyl)-N - phenyl-5,6,7,8-tetrahydronaphthalen-2-carboxamide of General formula (I)

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perhaps in the form of a pure optical isomer or mixture of such isomers,

where R1is a hydrogen atom or halogen, methyl group, or a C1-C4alkoxy group,

R1' UB> separately is C1-C3alkyl group,

R4separately is 2,3-dihydro-1H-inden-2-yl group, 2,3-dihydro-1H-inden-1-yl group or 1,2,3,4-tetrahydronaphthalen - 1-yl group, or an alternative

R3and R4together, and bearing with them the nitrogen atom, form a 1,2,3,4-tetrahydrothieno-2-yl group, 6,7-dimethoxy-1,2,3, 4-tetrahydrothieno-2-yl group, a 5,8-dimethoxy-1,2,3,4 - tetrahydrothieno-2-yl group, 1,2,3,4-tetrahydro-9H - pyrido[3,4-b] indol-2-yl influenza, 1,2,3,4-tetrahydro-9H-pyrido[4,3 - b] indol-3-yl influenza, 4, 5, 6, 7-tetrahydrothieno [2, 3-c] -pyrid-6-yl group, 2,3-dihydro-1H-isoindole-2-yl group, or 2,3,4,5 - tetrahydro-1H-3-benzazepin-3-yl group, corresponding formulas which have

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with the exception of compounds in which R1is alkoxygroup, R1' and R1" each is hydrogen, and R3and R4together with the nitrogen atom are substituted or unsubstituted 1,2,3,4 - tetrahydroisoquinoline-2-yl group,

in the form of a base or salt, obtained by joining acids.

Preferred compounds in which

R1is a halogen atom,

R1' is a hydrogen atom or halogen,

R1is a hydrogen atom is hydro-1H-inden-2-yl group, 2,3-dihydro-1H-inden-1-yl group or 1,2,3,4-tetrahydronaphthalen-1-yl group, or an alternative

R3and R4together, and bearing with them the nitrogen atom, form a 1,2,3,4-tetrahydrothieno-2-yl group, 6, 7-dimethoxy-1,2,3,4-tetrahydrothieno-2-yl group or a 5, 8-dimethoxy-1,2,3,4-tetrahydrothieno-2-yl group.

Among these compounds the most preferred are N-[3-[(2,3-dihydro-1H-inden-2-yl) methylamino] propyl] - N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide in the form of a base or salt, obtained by attaching acid;

N-[3-[(2,3-dihydro-1H-inden-1-yl)methylamino] propyl]-N- (3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide in the form of a pure optical isomer or mixture of such isomers and in the form of a base or salt, obtained by attaching acid; and

N-[3-[(1,2,3,4-tetrahydronaphthalen-1-yl) methylamino] propyl] -N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide in the form of a pure optical isomer or mixture of such isomers and in the form of a base or salt, obtained by joining acids.

According to the invention a method of obtaining the derivatives of N-(3-aminopropyl)-N-phenyl-5,6,7,8 - tetrahydronaphthalen-2-carboxamide of the formula (I), in which the benzene is have interaction with methyl ether 5,6,7,8-tetrahydronaphthalen-2-carboxylic acid of formula (III)

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with the formation of the amide of General formula (IV)

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which is then subjected to interaction with 1-bromo-3-chloro - propane of the formula (V)

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with the formation of chlorinated General formula (VI), which, finally, is subjected to the interaction with the amine of General formula HNR3R4in which R3and R4such as defined above.

According to the proposed invention is also a pharmaceutical composition exhibiting anti-ischemic activity, including active substance and excipient, characterized in that the active substance it contains the connection PP. 1-5 in number 1-1000 mg

Compounds according to the invention can exist in the form of bases or of salts, resulting from the accession of acids.

In addition, in the case when R4contains an asymmetric carbon atom, that is, R4is 2,3-dihydro-1H-inden-1-yl group or 1,2,3,4-tetrahydronaphthalen-1-yl group, the compounds can exist in the form of pure optical isomers or mixtures of such isomers.

Compounds corresponding to General formula (I) can be obtained by the reaction described by the following scheme:

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Benzolamide General formula (II), in kagitingan-2-carboxylic acid of formula (III), for example in the presence of sodium hydride and in a solvent such as dimethyl sulfoxide. The result is the amide of General formula (IV), which is then subjected to interaction with 1-bromo-3-chloropropane formula (V), for example in the presence of sodium hydride and in a solvent such as N,N-dimethylformamide.

The result is chlorinated General formula (VI), which, finally, is subjected to the interaction with the amine of General formula HNR3R4in which R3and R4such as defined above, for example in the presence of potassium iodide and a base such as potassium carbonate, in a solvent such as N,N-dimethylformamide.

Benzolamide General formula (II) are commercially available and described in the literature, for example in applications EP-0144730 and ER-0300865, or can be obtained by methods described in the literature or known to experts.

Methyl ether 5,6,7,8-tetrahydronaphthalen-2-carboxylic acid is described in J. Amer. Chem. Soc. (1943), 65, 1097.

Amines of General formula (VII) in which R4is 2,3-dihydro - 1H-inden-2-yl group, described in J. Med. Chem. (1980), 23, 745.

Amines of General formula (VII) in which R4is 2,3-dihydro - 1H-inden-1-yl group, described in J. Amer. Chem. Soc. (1966), 88, 2233.

Amines of 459, in C. R. Hebd. Seances Acad. Sci. Ser. C. (1969), 268, 2225 and in J. Med. Chem. (1966), 9, 830.

1,2,3,4-tetrahydrothieno-2-silts, corresponding to the General formula (VII) are commercially available or described in the literature.

1, 2, 3, 4-tetrahydro-N-pyrido[3,4-b]indole, corresponding to the General formula (VII), described in Organic Synthesis (1971), 51, 136.

1,2,3,4-tetrahydro-N-pyrido[4,3-b] indole, corresponding to the General formula (VII), described in J. Chem. Soc. (1968), 1235.

4,5,6,7-tetrahydrothieno [2, 3-c]pyridine corresponding to General formula (VII), described in Arkiv. Kemi(1970), 13 (19), 217.

2,3-dihydro-1H-isoindole corresponding to General formula (VII), described in Organic Synthesis Coil. (1973), 5, 406.

2,3,4,5-tetrahydro-1H-3-benzazepin corresponding to General formula (VII), described in Helv. Chim. Acta (1935), 18, 1388.

The following examples illustrate in detail the production of several compounds according to the invention.

Elemental microanalysis and IR and NMR spectra confirm the structures of the obtained compounds.

Numbers given in parentheses in the titles of the examples correspond to the numbers in the 1st column in the table below.

Example 1 (Compound No. 2).

N-[3-[(2,3-dihydro-1H-inden-2-yl)methylamino] propyl] -N- (3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide "ptx2">

To a suspension 1,008 g (0,021 mol) of sodium hydride (content 50% in oil) in 8 ml of dimethyl sulfoxide in an argon atmosphere add one drop of methanol, the mixture is left to mix for 10 minutes, and then add 1,94 g (0.012 mol) of 3,4-dichlorobenzamide. The mixture is stirred for 15 minutes, then 2.0 g (0,0105 mol) methyl ester 5,6,7,8 - tetrahydronaphthalene-2-carboxylic acid, dissolved in 8 ml of dimethyl sulfoxide, is added dropwise, and then the stirring is continued at room temperature for 3 hours. Slowly add 150 ml of water, 50 ml of diethyl ether and 50 ml of ethyl acetate, the organic phase is separated, washed successively with 50 ml water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered, and the solvent is evaporated.

The residue is crystallized from a mixture of diethyl ether and hexane, with 2,09 g of product, which is used in the next stage.

1.2. N-(3-Chloropropyl)-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalen - 2-carboxamide.

To a solution of 2.05 g (0,0064 mol) of N-(3,4-dichlorophenyl)-5,6, 7,8-tetrahydronaphthalen-2-carboxamide 1 1 ml N, N-dimethylformamide in a nitrogen atmosphere is added slowly in small portions 0,369 g (0,0077 mol) of hydrobromide, the mixture is left to warm to room temperature and stirred for 4 hours.

The mixture is cooled, slowly add 50 ml of water and 50 ml of diethyl ether, the phases are separated and the aqueous phase is extracted with 50 ml diethyl ether. The organic phases are combined and successively washed twice with 50 ml water, 50 ml of 1N hydrochloric acid, twice with 50 ml water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent is evaporated.

Gain of 2.51 g of the product, which is used in the next stage.

1.3. N-[3-[(2,3-Dihydro-1H-inden-2-yl)methylamino]-propyl]- N-(3,4-dichlorophenyl)-5,6,7,8 - tetrahydronaphthalen-2-carboxamide tandikat (1: 1).

To a solution of 2.45 g (0,0062 mol) M-(3-chloropropyl)-N-(3, 4 - dichlorophenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide in 9 ml of N,N-dimethylformamide in an argon atmosphere add 1,71 g (0,0124 mol) of potassium carbonate and 1.03 g (0,0062 mol) of potassium iodide, and then, after 5 minutes of 1.14 g (0,0062 mol) N-methyl-2,3-dihydro - 1H-inden-2-amine hydrochloric acid, and the mixture is heated at 85oC for 4 hours.

The mixture is cooled, add 50 ml of water and 50 ml of diethyl ether, the phases are separated, and the aqueous phase is extracted with twice 50 ml of diethyl ether. The organic phase merge ritel evaporated.

Get totaling 3.04 g of oily product, which is then purified by chromatography on a column of silica gel, elwira a 97/3 mixture of dichloromethane/methanol.

Receive 0.930 g of pure reason in the form of butter.

Oxalate receive in 2-propanol by adding 0,165 g (0,0018 mol) of oxalic acid to 0.930 g (0,0018 mol) of the base, the product is isolated and recrystallized from ethyl acetate.

Finally obtain 0.64 g of oxalate in the form of white crystals.

Melting point: 140-141oC.

1.4. N-[3-[(2,3-Dihydro-1H-inden-2-yl)methylamino] propyl] - N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide (E)-2-butenedioate (1:1).

Fumarate receive in a mixture of 2-propanol and diisopropyl ether by the addition of 1.05 g (0,009 mol) of fumaric acid to 4,58 g (0,009 mol) of the Foundation; salt is isolated and recrystallized from a mixture of 2-propanol and diisopropyl ether.

Finally get to 4.28 g fumarata in the form of white crystals. Melting point: 160-161oC.

Example 2 (Compound No. 13).

N-(4-Chlorophenyl)-N-[3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl) propyl]-5,6,7,8-tetrahydronaphthalen-2-carboxamide tandikat.

2.1. N-(4-Chlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-carb is and in argon atmosphere add one drop of methanol, the mixture is subjected to stirring for 10 minutes and added 1.40 g (to 0.011 mol) of 4-chlorobenzenamine. The mixture is stirred for 15 minutes, added dropwise 1.8 g (0,0095 mol) of methyl-5,6,7,8-tetrahydronaphthalen - 2-carboxylate, dissolved in 7 ml of dimethyl sulfoxide and stirred at room temperature for 3 hours. Slowly add 150 ml of water, 50 ml of diethyl ether and 50 ml of ethyl acetate, the organic phase is separated, washed successively with 50 ml water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered, and the solvent is evaporated.

The residue is crystallized from diethyl ether and receive a 1.96 g of the product, which is used in the next stage.

2.2. N-(4 - Chlorophenyl)-N-(3-chlorpropyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide.

To a solution of 1.92 g (0,0067 mol) of N-(4-chlorophenyl)-5,6,7,8 - tetrahydronaphthalen-2-carboxamide in 11 ml of N,N-dimethylformamide in a nitrogen atmosphere is added slowly in small portions 0,384 g (0,0080 mol) of sodium hydride as a 50% suspension in oil, the mixture is cooled to 0oC, are added dropwise 1,325 g (0,0084 mol) 1-bromo-3-chloropropane, the mixture is left to warm to room temperature and stirred for 4 hours.

The mixture is cooling the gross ether. The organic phases are combined and successively washed twice with 50 ml water, 50 ml of 1 N hydrochloric acid, twice with 50 ml water and 50 ml saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, and the solvent is evaporated.

Get to 2.29 g of the product used in the next stage.

2.3. N-(4-Chlorophenyl)-N-[3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl)propyl]-5,6,7,8-tetrahydronaphthalen-2 - carboxamide tandikat.

The solution to 2.29 g (0,0063 mol) of N-(4-chlorophenyl)-N-(3 - chlorpropyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide in 9 ml of N, N-dimethylformamide in an argon atmosphere add 1,738 g (0,0126 mol) of potassium carbonate (potash) and 1.04 g (0,0063 mol) of potassium iodide, and then, after 5 minutes, 1.45 g (0,0063 mol) of hydrochloric acid 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the mixture is heated at 85oC for 4 hours.

After cooling the mixture there was added 50 ml of water and 50 ml of diethyl ether, the phases are separated and the aqueous phase is extracted with twice 50 ml of diethyl ether. The organic phases are combined and washed with 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent is evaporated.

The result is 3.1 g of oily product, which clean x is East of the base in the form of butter.

Oxalate receive in 2-propanol by adding 0,230 g (0,0025 mol) of oxalic acid to 1,32 g (0,0025 mol) of the base, the product is isolated and recrystallized from 2 - propanol.

Finally get 1.0 g of oxalate in the form of white crystals. Melting point: 162-163oC.

Example 3 (Compound N 17).

N-[3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2 - yl)propyl]-N - (4-were)-5,6,7,8-tetrahydronaphthalen-2-carboxamide tandikat.

3.1. N-(4-Were)-5, 6,7,8-tetrahydronaphthalen-2 - carboxamide.

To a suspension 0,912 g (0.019 mol) of sodium hydride (content 50% in oil) in 7 ml of dimethyl sulfoxide in an argon atmosphere add one drop of methanol, the mixture is stirred for 10 minutes and add 1,177 g (to 0.011 mol) 4-methylbenzamide. The mixture is stirred for 15 minutes, added dropwise 1.8 g (0,0095 mol) of methyl-5,6,7,8-tetrahydronaphthalen-2 - carboxylate, dissolved in 7 ml of dimethyl sulfoxide, and continue stirring at room temperature for 3 hours. Slowly add 150 ml of water, 50 ml of diethyl ether and 50 ml of ethyl acetate, the organic phase is separated, washed successively with 50 ml water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtrage at the next stage.

3.2. N-(3-Chloropropyl)-N-(4-were)-5,6,7,8-tetrahydronaphthalen - 2-carboxamide.

To a solution of 1.4 g (0,0053 mol) of N-(4-were)-5,6,7,8-tetrahydronaphthalen-2-carboxamide in 9 ml of N,N-dimethylformamide in a nitrogen atmosphere is added slowly, in small portions, 0,307 g (0,0064 mol) of sodium hydride as a 50% suspension in oil, the mixture is cooled to 0oC, are added dropwise 1,048 g (0,0066 mol) 1-bromo-3-chloropropane and after cooling to room temperature, the mixture is stirred for 4 hours.

The mixture is cooled, slowly add 50 ml of water and 50 ml of diethyl ether, the phases are separated and the aqueous phase is extracted with 50 ml diethyl ether. The combined organic phases are washed successively twice with 50 ml water, 50 ml of 1N hydrochloric acid, twice with 50 ml water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate, the solvent is evaporated.

Obtain 1.55 g of the product used in the next stage.

3.3. N-[3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl) propyl]-N-(4-were)-5,6,7,8-tetrahydronaphthalen-2 - carboxamide tandikat.

To a solution of 1.55 g (0,0045 mol) of N-(3-chloropropyl)-N-(4-were)- 5,6,7,8-tetrahydronaphthalen-2-carboxamide in 7 ml of N,N - dimethylformamide in an argon atmosphere on the 0,0045 mol) hydrochloric acid 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the mixture is heated at 85oC for 4 hours.

After cooling, to the mixture are added 50 ml of water and 50 ml of diethyl ether, the phases are separated, the aqueous phase is extracted with twice 50 ml of diethyl ether. The organic phases are combined and washed with 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent is evaporated.

Get 2,07 g of oily product, which is purified chromatographically on a column of silica gel, elwira a 97/3 mixture of dichloromethane/methanol.

Get 0,920 g of pure reason in the form of butter.

Oxalate receive in 2-propanol by adding rate £ 0.162 g (0,0018 mol) of oxalic acid to 0.9 g (0,0018 mol) of the base, the product is isolated and recrystallized from 2-propanol.

Finally get 0,797 g of oxalate in the form of white crystals.

Melting point: 159-160oC.

Example 4 (Compound No. 26).

N-[4-(2-Methylpropoxy)phenyl] -N-[3-(1,2,3,4-tetrahydro-N - pyrido[4,3-b] indol-3-yl) propyl]-5,6,7,8-tetrahydronaphthalen-2-carboxamide tandikat.

4.1. N-[4-(2-Methylpropoxy) phenyl]ndimethylacetamide.

To a solution of 23 g (0.15 mol) of N-(4-hydroxyphenyl) ndimethylacetamide in 124 ml of N, N-dimethylformamide add a 32.6 ml (0.3 mol) of 1-bromo-2-med cool, the solvent is evaporated and the residue is collected in 400 ml of diethyl ether and 200 ml of 1N sodium hydroxide. The organic phase is separated and washed successively three times with 50 ml of 1N sodium hydroxide, three times 100 ml of water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered, the solvent is evaporated.

Get 30,96 g of the product used in the next stage.

4.2. 4-(2-Methylpropoxy) benzolamide.

To a solution 30,35 g (0,146 mol) M-[4-(2-methylpropoxy) phenyl]ndimethylacetamide in 157 ml of ethanol type of 41.5 ml (0,309 mol) of 30% aqueous sodium hydroxide, the mixture is heated in a vessel under reflux for 5 hours.

The solvent is evaporated and the residue is collected in 400 ml of diethyl ether and 350 ml of water. The organic phase is separated and washed successively three times with 100 ml of water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered, the solvent is evaporated.

Get 23,64 g of product, which is then cleaned chromatography on a column of silica gel, elwira 7/3 mixture of cyclohexane/ethyl acetate.

Get 22,43 g of the product.

4.3. N-[4- (2-Methylpropoxy)phenyl] -5,6,7,8-tetrahydronaphthalen-2-carboxamide.

The residue is crystallized from a mixture of diethyl ether and hexane, get 3,10 g of the product used in the next stage.

4.4. N-(3-Chloropropyl)-N-[4-(2-methylpropoxy)phenyl]-5,6, 7,8-tetrahydronaphthalen-2-carboxamide.

To a solution of 2.5 g (0,008 mol) of N-[4-(2-methylpropoxy)phenyl]- 5,6,7,8-tetrahydronaphthalen-2-carboxamide in 13 ml of N,N-dimethylformamide in a nitrogen atmosphere is added slowly in small portions of 0.5 g (0,010 mol) of sodium hydride as a 50% suspension in oil, the mixture is cooled to 0oC, are added dropwise 1.6 g (0,010 mol) 1-bromo-3-chloropropane and after heating to room t the odes and 100 ml of diethyl ether, the phases are separated, and the aqueous phase extracted with 100 ml diethyl ether. The combined organic phases are washed successively twice with 50 ml water, 50 ml of 1N hydrochloric acid, twice with 50 ml water and 50 ml saturated aqueous solution of sodium chloride and dried over magnesium sulfate, the solvent is evaporated.

Obtain 3.13 g of the product used in the next stage.

4.5. N-[4-(2-Methylpropoxy)phenyl] -N-[3-(1,2,3,4-tetrahydro - 9H-pyrido[4,3-b] indol-3-yl) propyl] -5,6,7,8 - tetrahydronaphthalen-2-carboxamide tandikat.

To a solution of 3.13 g (0,008 mol) of N-(3-chloropropyl)-N-[4-(2 - methylpropoxy)phenyl] -5,6,7,8-tetrahydronaphthalen-2 - carboxamide in 11 ml of N,N-dimethylformamide in an argon atmosphere type of 2.21 g (0,016 mol) potassium carbonate and of 1.33 g (0,008 mol) of potassium iodide, and then, after 5 minutes, add 1,67 g (0,008 mol) of hydrochloric acid 1,2,3,4-tetrahydro-9H-pyrido[4,3 - b] indole and heating the mixture at 85oC for 4 hours.

After cooling, to the mixture was added 100 ml of water and 100 ml diethyl ether, the phases are separated and the aqueous phase is extracted with twice 50 ml of diethyl ether. The combined organic phases are washed with 100 ml saturated aqueous solution of sodium chloride and dried over magnesium sulfate, the solvent is evaporated.

the, luira 95/5 mixture of dichloromethane/methanol.

Obtain 1.63 g of pure reason in the form of butter.

Oxalate receive in 2-propanol by adding 0,221 g (0,0025 mol) of oxalic acid to 1,32 g (0,0025 mol) of the base, the product is isolated and recrystallized from 2-propanol.

Finally get 1.0 g of oxalate in the form of white crystals.

Melting point: 121-122oC.

Example 5 (Compound No. 20).

N-(4-Methoxyphenyl)-N-[3-(1,2,3,4-tetrahydro-9H-pyrido [3, 4-b] indol-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen-2 - carboxamide tandikat.

5.1. N-(4-Methoxyphenyl)-5,6,7,8 - tetrahydronaphthalen-2-carboxamide.

To a suspension of 1.25 g (0,026 mol) of sodium hydride (content in oil - 50%) in 10 ml of dimethyl sulfoxide in an argon atmosphere add one drop of methanol, the mixture is stirred for 10 minutes and added 1.92 g (0.015 mol) of 4-methoxybenzylamine. The mixture is stirred for 15 minutes, added dropwise 2.5 g (0,013 mol) of methyl-5,6,7,8 - tetrahydronaphthalen-2-carboxylate dissolved in 10 ml of dimethyl sulfoxide and continue stirring at room temperature for 3 hours. Slowly add 200 ml of water, 100 ml of diethyl ether and 100 ml of ethyl acetate, the organic phase is separated and washed posledovatel is at over magnesium sulfate and filtered, and the solvent is evaporated.

Get to 3.34 g of the residue, the residue is crystallized from a mixture of diethyl ether and hexane.

Get 2,69 g of the product used in the next stage.

5.2. N-(3-Chloropropyl)-N-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen - 2-carboxamide.

To a solution 2,47 g (0,0088 mol) of N-(4 - methoxyphenyl)-5,6,7,8 - tetrahydronaphthalen-2-carboxamide in 14 ml of N,N-dimethylformamide in a nitrogen atmosphere is added slowly in small portions 0,506 g (0,0105 mol) of sodium hydride as a 50% oil suspension, the mixture is cooled to 0oC, are added dropwise 1.73 g (to 0.011 mol) of 1 - bromo-3-chloropropane, after returning the temperature of the mixture to room continue stirring for 4 hours. The mixture is cooled, slowly add 100 ml of water and 100 ml diethyl ether, the phases are separated, the aqueous phase is extracted with 100 ml diethyl ether. The combined organic phases are washed successively twice with 50 ml water, 50 ml of 1N hydrochloric acid, twice with 50 ml water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated.

Obtain 3.11 g of the product used in the next stage.

5.3. N-(4-Methoxyphenyl)-N-[3 -(1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole-2-LIH)-N-(4-methoxyphenyl) -5,6,7,8-tetrahydronaphthalen-2-carboxamide in 8 ml of N,N-dimethylformamide in an argon atmosphere add to 1.76 g (0,0128 mol) potassium carbonate and 1.06 g (0,0064 mol) of potassium iodide, and then, after 5 minutes, 1.1 g (0,0064 mol) of hydrochloric acid 1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole and heating the mixture for 4 hours at 85oC.

After cooling, to the mixture was added 100 ml of water and 100 ml diethyl ether, the phases are separated, the aqueous phase is extracted with twice 50 ml of diethyl ether. The combined organic phases are washed with 100 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent is evaporated.

Obtain 2.66 g of oily product, clean it chromatographic column on silica gel, elwira 97/3 mixture of dichloromethane/methanol.

Receive 0.930 g of pure reason in the form of butter.

Oxalate receive in 2-propanol by adding 0,170 g (0,0019 mol) of oxalic acid to 0.930 g (0,0019 mol) of the base, the product is isolated and recrystallized from 2-propanol.

Finally get 0,515 g of oxalate in the form of white crystals.

Melting point: 245oC.

Example 6 (Compound No. 28).

N-(4-Chlorophenyl)-N-[3-(2,3,4,5-tetrahydro-1H-3-benzazepin-3 - yl)propyl] -5,6,7,8-tetrahydronaphthalen-2-carboxamide tandikat.

6.1. N-(4-Chlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide.

To a suspension 0,912 g (0.019 mol) of Hydra the mixture is stirred for 10 minutes and added 1.40 g (to 0.011 mol) of 4-chlorobenzenamine. The mixture is stirred for 15 minutes, added dropwise 1.8 g (0,0095 mol) of methyl-5,6,7,8-tetrahydronaphthalen-2-carboxylate, dissolved in 7 ml of dimethyl sulfoxide and stirred the mixture at room temperature for 3 hours. Slowly add 150 ml of water, 50 ml of diethyl ether and 50 ml of ethyl acetate, the organic phase is separated and washed successively with 50 ml water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered, and the solvent is evaporated.

Obtain 2.5 g of the residue, the residue is crystallized from diethyl ether.

Get a 1.96 g of the product used in the next stage.

6.2. N-(4-Chlorophenyl)-N-(3-chlorpropyl)-5,6,7, 8-tetrahydronaphthalen - 2-carboxamide.

To a solution of 1.92 g (0,0067 mol) of N-(4-chlorophenyl)-5,6,7,8 - tetrahydronaphthalen-2-carboxamide in 11 ml of N,N-dimethylformamide in a nitrogen atmosphere is added slowly in small portions 0,384 g (0,008 mol) of sodium hydride as a 50% suspension in oil, the mixture is cooled to 0oC, are added dropwise 1,325 g (0,0084 mol) 1-bromo-3-chloropropane, after returning the temperature of the mixture to room continue stirring for 4 hours. The mixture is cooled, slowly add 50 ml of water and 50 ml of diethyl ether successively twice with 50 ml water, 50 ml of 1N hydrochloric acid, twice with 50 ml water and 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent is evaporated.

Get to 2.29 g of the product used in the next stage.

6.3. N-(4-Chlorophenyl)-N-[3-(2,3,4,5-tetrahydro-1H-3 - benzazepin-3-yl)propyl]-5,6,7,8-tetrahydronaphthalen-2 - carboxamide tandikat.

To a solution of 2.5 g (0,0069 mol) of N-(4-chlorophenyl)-N-(3 - chlorpropyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide in 9 ml of N, N-dimethylformamide in an argon atmosphere add to 1.9 g (0,0138 mol) potassium carbonate and 1.14 g (0,0069 mol) of potassium iodide, and then, after 5 minutes, add 1.26 g (0,0069 mol) of hydrochloric acid 2,3,4,5-tetrahydro-1H-3-benzazepine and heating the mixture at 85oC for 4 hours.

After cooling, to the mixture are added 50 ml of water and 50 ml of diethyl ether, the phases are separated and the aqueous phase is extracted with twice 50 ml of diethyl ether. The organic phases are combined and washed with 50 ml saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent is evaporated.

Get totaling 3.04 g of oily product, which is purified chromatographically on a column of silica gel, elwira 97/3 mixture of dichloromethane/methanol.

Obtain 1.18 g of pure base is to 1.18 g (0,0025 mol) of the Foundation, the product is isolated and recrystallized from 2-propanol.

Finally obtain 1.04 g of the oxalate in the form of white crystals.

Melting point: 180oC.

Example 7 (Compound No. 27).

N-(4-Chlorophenyl)-N-[3-(4,5,6,7-tetrahydrothieno-[2,3-c] pyrid-6-yl)propyl] -5,6,7,8-tetrahydronaphthalen-2-carboxamide tandikat (1:1).

To a solution of 2.37 g (0,0065 mol) of N-(4-chlorophenyl)-N-(3 - chlorpropyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide in 10 ml of N, N-dimethylformamide in an argon atmosphere add 2,69 g (0,0195 mol) potassium carbonate and 1.1 g (0,0065 mol) of potassium iodide, and then, after 5 minutes, 1,49 g (0,0065 mol) of 4,5,6,7 - tetrahydrothieno [2,3-c] pyridine oxalate and heating the mixture at 85oC for 4 hours.

After cooling, to the mixture are added 50 ml of water and 50 ml of diethyl ether, the phases are separated and the aqueous phase is extracted with twice 50 ml of diethyl ether. The organic phases are combined and washed with 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate, the solvent is evaporated.

Obtain 3.0 g of oily product, which is then purified chromatographically on a column of silica gel, elwira 97/3 mixture of dichloromethane/methanol.

Gain of 1.16 g of pure reason in the form of butter.

Finally get 1,09 g of oxalate in the form of white crystals.

Melting point: 164-165oC.

Example 8 (Compound No. 31).

N-(4-Chlorophenyl)-N-[3-(2,3-dihydro-1H-isoindole-2-yl) propyl] -5,6,7,8-tetrahydronaphthalen-2-carboxamid (E)-2-butenedioate (1:1).

To a solution of 2.0 g (0,0055 mol) of N-(4-chlorophenyl)-N-(3-chlorpropyl)- 5,6,7,8-tetrahydronaphthalen-2-carboxamide in 10 ml of N,N - dimethylformamide in an argon atmosphere add to 1.15 g (0,0083 mol) potassium carbonate and 0.92 g (0,0055 mol) of potassium iodide, and then, after 5 minutes, 0.66 g (0,0055 mol) of 2,3-dihydro-1H-isoindole, the mixture is heated at 85oC for 4 hours.

After cooling, the mixture was added 50 ml of water and 50 ml of diethyl ether, the phases are separated and the aqueous phase is extracted with twice 50 ml of diethyl ether. The organic phases are combined and washed with 50 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate, the solvent is evaporated.

Obtain 2.8 g of oily product, which is purified chromatographically on a column of silica gel, elwira 97/3 mixture of dichloromethane/methanol.

Get 0,82 g of pure reason in the form of butter.

Fumarate receive a 2-ol is kristallisoituu from 2-propanol.

Finally get 0,43 g fumarata in the form of white crystals.

Melting point: 141-142 oC.

Example 9 (Compound 44).

()-N-[3-[(2, Z-Dihydro-1H-inden-1-yl)methylamino] - propyl]-N-(3,4-dichlorophenyl) -5,6,7,8-tetrahydronaphthalen-2 - carboxamide tandikat (1:1).

To a solution of 3 g (0,0075 mol) of N-(3-chloropropyl)-N-(3,4-dichlorophenyl)- 5,6,7,8-tetrahydronaphthalen-2-carboxamide in 12 ml of N,N - dimethylformamide in an argon atmosphere add 2,07 g (0.015 mol) of potassium carbonate and 1.25 g (0,0075 mol) of potassium iodide, and then, after stirring for 5 minutes, add to 1.37 g (0,0075 mol) of hydrochloric acid N-methyl-2,3-dihydro-1H-inden-1-amine, the mixture is heated at 85oC for 3 hours and 30 minutes.

After cooling, to the mixture are added 50 ml of water and separated brown precipitate by filtration, washed with water and dried.

Receive 3.58 g of product, which is purified chromatographically on a column of silica gel, elwira 96/4 mixture of dichloromethane/methanol.

Obtain 1.12 g of pure reason.

To obtain the oxalate 0.73 g (0,0014 mol) and 0.13 g (0,0014 mol) of oxalic acid dissolved in 10 ml of 2-propanol, the mixture is heated under reflux until such time as the materials will not dissolve, the OHL which are square of 0.58 g of the oxalate.

Melting point: 142-143oC.

Example 10 (Compound No. 45).

()-N-[3-[(1,2,3,4-Tetrahydronaphthalen-1-yl) methylamino] propyl] -N-(3,4-dichlorophenyl)-5,6,7, 8-tetrahydronaphthalen-2 - carboxamide tandikat (1: 1).

To a solution of 3 g (0,0075 mol) of N-(3-chloropropyl)-N-(3,4-dichlorophenyl)- 5,6,7,8-tetrahydronaphthalen-2-carboxamide in 12 ml of N,N-dimethylformamide in an argon atmosphere add 2,07 g (0.015 mol) of potassium carbonate and 1.25 g (0,0075 mol) of potassium iodide, and then, after 5 minutes, add 1.48 g (0,0075 mol) of hydrochloric acid N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine, the mixture is heated at 85oC for 3 hours and 30 minutes.

After cooling, add 50 ml of water and separated by filtration yellow precipitate, washed with water and dried.

Get 4,32 g of product, which is purified chromatographically on a column of silica gel, elwira 96/4 mixture of dichloromethane/methanol.

Gain of 1.34 g of pure reason in the form of butter.

To obtain the oxalate of 1.34 g (0,0026 mol) and 0.23 g (0,0026 mol) of oxalic acid dissolved in 15 ml of 2-propanol, the mixture is heated under reflux until complete dissolution of the solids and the solvent is evaporated. The residue is recrystallized from a large volume S="ptx2">

Melting point: 116-117oC.

The table below illustrates the chemical structures and physical properties of a few compounds according to the invention. In the column "salt" "-" denotes a compound in the form of a Foundation, "the oaks." denotes the oxalate or tandikat, "FUM." indicates fumarate or (E)-2-butenedioate, "CIT." denotes citrate or 2-hydroxy - 1,2,3-propanetricarboxylate and "Meuse" means mesotartaric or 2,3-dihydroxybutanedioate; the value given in parentheses is the molar ratio of acid: base.

Compounds according to the invention were subjected to various tests which have demonstrated their therapeutic potential.

So, they were tested in the test for total cerebral ischemia in mice. Ischemia occurs due to cardiac pause caused by rapid intravenous injection of magnesium chloride. In this test measure the "survival time", representing the interval between the moment of introduction of magnesium chloride and the last observed respiratory movement of each mouse. This last movement is considered a sign of the end of the functioning of the Central nervous system.

Respiratory arrest occurs in approximately 19 seconds after rim access to food and water. Survival time is measured 10 minutes after the intraperitoneal administration of the compounds according to the invention. The results are presented as the difference between survival time, measured in a group of 10 mice which received the connection, and the survival time measured in a group of 10 mice that received the solvent. Correlation between changes in survival time and the doses of the compounds appear graphically in the form of a semi-log curve.

This curve allows you to calculate a "3-second effective dose" (era elements), indicating dose (mg/kg), which provides a 3 - second increase in time of survival relative to the control group of 10 untreated mice.

This 3-second increase in time of survival is both statistically significant and repeatable.

Era elements compounds according to the invention ranges from 0.1 to 30 mg/kg intraperitoneal injection.

Compounds according to the invention was also the object of study voltage-dependent ("voltage-dependent") barium chloride currents by the so-called technique of "patch-clamp".

Barium currents running through potential-dependent calcium channels, measured on the preparations of the cells of the cerebral cortex that is ostatnie currents, which include the L, N and P channels, as described in the Soc. Neurosci. Abstr. (1989), 15, 823.

Measuring cell with a volume of 800 µl containing cells of the cerebral cortex, is placed on the table Olympus TM - 2TMinverted microscope and observe the cells at 400x magnification. Cells continuously perfusionist (4-5 ml/min) using a device for the distribution of solutions with 9 inputs (dead volume of < 50 μl), only the output of which consisting of a polyethylene tube with an aperture of 500 μm, is less than 3 mm from the studied cells. The advantage of this device is that it allows you to quickly change the solution in the target cells.

Used the patch-clamp" method described in Pfluegers Archives (1981), 391, 85-100. Axopatch - 1DTMthe amplifier is connected to the computer AT 386-33 MHz with PCLAMPTMsoftware, Axon InstrumentsTMused for stimulation of the cells, data collection and analysis results. To register barium chloride currents pipettes of borosilicate glass is fixed in the vicinity of the cells by Narishige WR 60TMhydraulic micromanipulator. The ends of the pipettes filled out the appropriate intracellular solution having the following composition (in mm): CsCI (attend our 14th the configuration of the "whole cell", this cell perfusion so-called tea - bereavem solution having the following composition: Thea-C1 (144), BaCI2(5), MgCl2(2), CsCI (3), glucose (10), Hepes (10), Tris-OH (pH 7,4).

The solution makes it possible to measure calcium current (similar to barium current passing through the potential-dependent calcium channels), while at the same time it is independent of sodium and potassium currents.

The total potential-dependent barium currents produced by the application depolarizing potential duration of 250 MS, which moves the membrane potential from -80 to 0 mV. The stimulation frequency is 0.25 Hz.

Compounds according to the invention are dissolved in a TEA-barium environment and is applied after the amplitude of the barium current is stabilized. After obtaining a stable inhibitory effect of the cage again perfusion control TEM-bereavem solution in order to observe the cancellation effect.

The magnitude of the obtained effect comparable to the effect size of 100 μm cadmium solution. The inhibition potential-dependent barium current varies as a function of the doses of the compounds under study and, for the most active compounds, is about 49% at a concentration of 1 μm and 83% when the con is n vitro they have antagonistic properties with respect to neural calcium, a in vivo they possess neuroprotective and anti-ischemic properties.

These results confirm that the compounds can be used for the treatment and prevention of cerebral disorders, such as, for example, seizures, coronary disease, cardiac arrest or respiratory, cerebral embolism or thrombosis, for the treatment of cerebral aging, dementia, following the multiple heart attacks, dementia, such as Alzheimer's disease or sickness Maximum, to ensure oligometastases atrophy and other neurodegenerative diseases, such as Huntington's chorea and amitrofanova lateral sclerosis, for the treatment of cranial or spinal injuries, for the prevention of neural disorders, post-convulsive States, for the treatment of certain cancers, for the treatment of neurological disorders caused by AIDS, and for the prevention and treatment of diabetic retinopathy, macular degeneration optic nerve and retinopathy associated with glaucoma, and in General, for the treatment of any pathology associated with dysfunction of neural homeostasis of calcium.

Thus, the compounds can be used in all the pharmaceutical forms suitable for interlineable, coated with sugar, gelatin capsules, capsules-those capsules, suppositories or solutions or suspensions for drinking or injections, which are dosed in such a way that allow you to enter from 1 to 1000 mg of active substance per day.

1. Derivatives of N-(3-aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-carboxamide of General formula I

< / BR>
perhaps in the form of a pure optical isomer or mixture of such isomers,

where R1is a hydrogen atom or halogen, methyl group or1-C4-alkoxygroup;

R'1is a hydrogen atom or halogen;

R1is a hydrogen atom or a methoxy group;

R3separately - FROM1-C3is an alkyl group;

R4- separately - 2,3-dihydro-IH-inden-2-yl group, 2,3-dihydro-1H-inden-1-yl group or 1,2,3,4-tetrahydronaphthalen-1-yl group,

or alternatively R3and R4along with carrying their nitrogen atom form a 1,2,3,4-tetrahydrothieno-2-yl group, 6,7-dimethoxy-1,2,3,4 - tetrahydrothieno-2-yl group, a 5,8-dimethoxy-1,2,3,4-tetrahydrothieno-2-yl group, 1,2,3,4-tetrahydro-N-pyrido[3,4-b]indol-2-yl group, 1,2, 3,4-tetrahydro-N-pyrido[4,3-b] indol-3-yl group, 4,5,6,7-tetrahydrothieno[2,3-C] pyrid-6-yl group, 2,3-dihydro-1H-isoindole-2-yl group or 2,3,4,5-tetrahydro-1 is x R1is alkoxygroup, R'1and R1every -, and R3and R4together with the nitrogen atom are substituted or unsubstituted 1,2,3,4-tetrahydroisoquinoline-2-yl group, in the form of a base or salt, obtained by joining acids.

2. Connection on p. 1, where R1is a halogen atom, R'1- the atom of hydrogen or halogen, R1is a hydrogen atom, R3separately - FROM1-C3is an alkyl group, R4separately - 2,3-dihydro-1H-inden-2-yl group, 2,3-dihydro-1H-inden-1-yl group or 1,2,3,4-tetrahydronaphthalen-1-yl group, or alternatively R3and R4along with carrying their nitrogen atom form a 1,2,3,4-tetrahydrothieno-2-yl group, 6,7-dimethoxy-1,2,3,4-tetrahydrothieno-2-yl group or 5,8-dimethoxy-1,2,3,4-tetrahydrothieno-2-yl group.

3. N-(3-[(2,3-Dihydro-1H-inden-2-yl)methylamino] propyl)-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydronaphthalen-2-carboxamide in the form of a base or salt, obtained by joining acids.

4. N-[3-[(2,3-Dihydro-1H-inden-1-yl)methylamino] propyl] -N-(3,4-dichlorophenyl )-5,6,7,8-tetrahydronaphthalen-2-carboxamide in the form of a base or salt, obtained by the addition of acids.

5. N-[3-[(1,2,3,4-Tetrahydronaphthalen-1-yl)methylamino]propyl]-N-(3,4-dichlorophenyl)-5,6,7,8-Tania or salt, received by the accession acid.

6. The method of obtaining derivatives of N-(3-aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-carboxamide under item 1, characterized in that benzolamide General formula II

< / BR>
in which R1, R'1and R1defined in paragraph 1,

subjected to interaction with the methyl ether 5,6,7,8-tetrahydronaphthalen-2-carboxylic acid of the formula III

< / BR>
with the formation of the amide of General formula IV

< / BR>
which is then subjected to interaction with 1-bromo-3-chloro-propane of the formula (V)

< / BR>
with the formation of chlorinated General formula VI

< / BR>
which is subjected to interaction with the amine of General formula HNR3R4in which R3and R4defined in paragraph 1.

7. The pharmaceutical composition exhibiting anti-ischemic activity, including active substance and excipient, characterized in that the active substance it contains the connection PP.1-5 in number 1-1000 mg

 

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