The tetrahydropyridine - or 4-hydroxypiperidine-alkylate or their physiologically acceptable salts, methods for their preparation and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new tetrahydropyridine - or 4-hydroxypiperidine-alkylation formula I, where R1, R2, R3and R6denote hydrogen, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, C1-C6-alkoxyl or two adjacent radicals can form precondensation benzene ring, And denotes the carbon atom, and the dotted line denotes an optional bond, or a denotes a carbon atom that is associated with a hydroxyl group (C-OH), and the dotted line indicates the absence of coupling, n = 2 to 6, Z1, Z2and Z3represent a nitrogen atom or a substituted carbon atom, or a physiologically favourable salts, which possess antipsychotic or anxiolytic activity. 8 C. and 2 h.p. f-crystals, 3 tables.

The invention relates to new 4-aryl-Tetra-hydropyridine and 4-aryl-piperidinyl connected with alkyl-azoles and having the General formula (I):

< / BR>
and their physiologically acceptable salts, to processes for their preparation, to their use as pharmaceuticals and to pharmaceutical compositions based on them.

Connection components is cnyh fusion products and to obtain drugs.

These compounds have a strong affinity for Sigma receptors and/or 5HTIA-type and, therefore, potentially suitable for the treatment of certain mental and neurological disorders in humans and other mammals.

There are cases in which the influence of Sigma receptors for the treatment of psychosis. Numerous atypical relating to the treatment of psychosis tools, such as rimcazole (Schwarcz G. and other Drug Dev. Res., 1985, 5, 387), remoxipride (Wadworth A. N. and other Drugs, 1990, 40, 863), Diospyros (Jain A. K. and other Int. Clin. Psychopharmacol., 1987, 2, 129), show a significant affinity for Sigma receptors.

On the other hand, studies on the biology and function of receptors Sigma-type show that coordination compounds with the receptor, the Sigma-type can be effective in the treatment of some motor disorders, particularly horei chorea, dystonia and Tourette's syndrome. The presence of receptors Sigma-type in black matter (brain) allows their use in the treatment of Parkinson's disease (Walker, J. M. and al., Pharmacological Reviews, 1990, 42, 355).

Some coordination compounds with the receptor, the Sigma-type is associated with modulation effects caused by the mediation of the NMDA receptor and act as antiischemic agents the of funds and in the treatment of epilepsy and convulsions (Kaiser S., Neurotransmissions VII, 1991).

It is known that the coordination compounds with the receptor, the Sigma-type have antiamnesic impact on animals used as models (and other Early Brain Research, 1991, 546, 281).

Coordination compounds of Sigma receptors type of effect on the levels of acetylcholine in animals used as models (Matsuno and other Brain Research, 1992, 575, 315) and, therefore, can be used to treat senile dementia, such as Alzheimer's disease.

Coordination compounds 5HTIA receptor-type, in particular agonists or partial agonists 5HTIA, are detectable anxiolytic and antidepressant activity (Glitz D. A., Drugs, 1991, 41, 11).

Therefore, agents that have a strong affinity to Sigma receptors and/or 5HTIA-type, can be used if one or more of these diseases.

The literature describes examples of 4-aryl-1,2,3,6-tetrahydro pyridines and 4-aryl-4-hydroxypiperidine, however, there is no description of the compounds in which these substructures are connected with the azole nitrogen nucleus by alkyl unsubstituted chain:

Davis L. Temple and others, U.S. patent 4320131: March 16, 1982; Richard A. Glennon, etc., J. Med. Chem. 1991, 34, 33ster and other , J. Med. Chem. 1993, 36, 3923-28; David J. Wustrow and others, BioMed. Chem. Lett., 1993, 3, 277-280; Shimazaki Norihiko and others Can. Pat. App., CA 2053475 AA.

The applicant has previously been described a number of N-alkylation connected with various nitrogen heterocycles to be used as dibenzodiazepine agents for the treatment of anxiety (European patents NN 382637, 497659 and 502786) for the treatment of other behavioral disturbances (European patents NN 429360 and 497658). In the above patent describes compounds of General formula (I) where And denotes the nitrogen atom, therefore, they are talking about piperazinovom kernel.

In the present invention pieperazinove core replace piperidinium or tetrahydropyridinium.

Connection constituent objects of the invention correspond to General formula (I):

< / BR>
in which R1, R2and R3identical or different, represent each a hydrogen atom, halogen atom, linear or branched alkyl radical, perhalogenated radical, aryl or substituted aryl radical or CNS radical; moreover, two adjacent radicals can form an aromatic or saturated loop;

And denotes the carbon atom, and the dotted line denotes an optional bond, And or denotes the carbon atom, with n can have values from 2 to 6, preferably means 4;

Z1denotes a nitrogen atom or a substituted carbon atom, which may be denoted as C-R4;

Z2denotes a nitrogen atom or a substituted carbon atom, which may be denoted as C-R5;

Z4denotes a nitrogen atom or a substituted carbon atom, which may be denoted as C-R7;

R4, R5, R6and R7identical or different, denote a hydrogen atom, halogen atom, linear or branched alkyl radical, a hydroxyl radical, CNS radical, carboxyl radical, carboxamide radical, alkylcarboxylic radical, aryl or substituted aryl radical, or two adjacent radicals can form part of another cycle, aromatic or non-aromatic.

The invention also relates to physiologically acceptable salts of the compounds of General formula (I), in particular the salts of hydrochloric, Hydrobromic, sulfuric, phosphoric, acetic, lactic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic, salicylic acid and alkyl-, cycloalkyl - or aryl-sulphonic acids.

Radical

< / BR>

When R4, R5, R6and R7not form part of another aromatic or non-aromatic, loop, it is preferably about azole, in which one of Z1, Z2or Z4denotes the nitrogen atom, in particular, about pyrazole (Z1or Z4= N) or imidazole (Z2= N).

When R4, R5, R6or R7be part of another, an aromatic or not, cycle, "azole" component of the above-mentioned radical remains the main, i.e. it does not cover radicals, such as - or-carboline, pyrrolizidine, and radicals containing carbonyl functions, such as pyrazolones, imidazolone, benzimidazolone and generally heterocycles, including carbonyl function.

When R4, R5, R6or R7be part of another, an aromatic or not, cycle, the above-mentioned radical preferably denotes a bicyclic radical, in particular, indole, indazol, benzimidazole or benzotryazolyl radical.

Under linear or branched alkyl preferably realize lower alkyl with 1-6 C-atoms, in particular methyl, ethyl or propyl, and this definition also applies to the alkyl residues ALCO is) phenyl, if necessary substituted by one or more radicals selected among halogen and linear or branched alkyl radicals.

Under the halogen understand fluorine, chlorine or bromine, preferably chlorine.

Finally, under perhalogenated understand linear or branched alkyl radical, of which all hydrogen atoms are replaced by halogen atoms. Preferably we are talking about perforaciones radical, in particular about triptorelin radical.

New derivatives of General formula (I) can be obtained in the following ways:

METHOD AND

By interacting spiranovic derivative of General formula (II):

< / BR>
in which R1, R2, R3and a have the above meaning, "m" can have the values 0 to 4 and X represents a group to delete as chlorine, bromine, mesilate group or tosyloxy-group;

with a nitrogen-containing heterocycle of General formula (III):

< / BR>
in which Z1, Z2, Z4and R6have the above meaning.

The reaction is carried out in a solution of dimethylsulfoxide; dimethylformamide, alcohol, such as ethanol, aromatic hydrocarbons such as toluene, or aliphatic hydrocarbon, such as geonet potassium or triethylamine.

The reaction temperature varies from room temperature up to the boiling point of the used solvent.

Reaction time is 1-24 hours;

METHOD B

By simultaneous "one-stage" interaction between the derivative of General formula (IV), alkylating agent of General formula (V) and a nitrogen-containing heterocycle of General formula (III):

< / BR>
< / BR>
< / BR>
where R1, R2, R3, A, X, n, Z1, Z2, Z4and R6have the above meaning.

The reaction is carried out in a solution of dimethylsulfoxide, of dimethyl formamide, alcohol, such as ethanol, aromatic hydrocarbons such as toluene, or aliphatic hydrocarbon, such as hexane, or a simple ester, as dioxane. This reaction is carried out preferably in the presence of a base, for example potassium carbonate or triethylamine.

The reaction temperature ranges from room temperature up to the boiling point of the used solvent.

The reaction time is from 1 to 24 hours;

THE WAY IN

Obtaining compounds of General formula (I) can be achieved by cooperation in the alkylation of amines of General formula (IV):

< / BR>
in which R1, R2, R3and A have the/SUB> and R6have the above meaning.

The reaction is carried out in a solution of dimethylsulfoxide, dimethylformamide, alcohol, such as ethanol, aromatic hydrocarbons such as toluene, or aliphatic hydrocarbon, such as hexane, or simply ether, such as dioxane. This reaction is carried out preferably in the presence of a base like potassium carbonate or triethylamine.

The reaction temperature ranges from room temperature up to the boiling point of the used solvent.

The reaction time is from 1 to 24 hours;

METHOD D

Compounds of General formula (I) can be obtained by reacting, in the conditions of alkylation, the compounds of General formula (VII):

< / BR>
in which R1, R2, R3, n and A have the above meaning, with a nitrogen-containing heterocycle of General formula (III):

< / BR>
in which Z1, Z2, Z4and R6have the above meaning.

The reaction is carried out in a solution of dimethylsulfoxide, dimethylformamide, alcohol, such as ethanol, aromatic hydrocarbons such as toluene, or aliphatic hydrocarbon, such as hexane, or simply ether, such as dioxane. This reaction is carried out the reaction varies in the range from room temperature up to the boiling point of the used solvent.

The reaction time is from 1 to 24 hours;

METHOD D

By dehydration of compounds of General formula (I)

< / BR>
in which R1, R2, R3, "n", Z1, Z2, Z4and R6have the above meaning; And indicates the carbon atom that is associated with a hydroxyl group (C-OH), and the dotted line indicates the absence of any additional communication.

The reaction is carried out in an acidic medium such as, for example, hydrochloric acid, triperoxonane acid, sulfuric acid or phosphoric acid, or by treatment with thionyl chloride in benzene.

The reaction temperature ranges from room temperature up to 180oC.

The reaction time varies from 1 to 14 hours;

METHOD E

By joining ORGANOMETALLIC reagents, for example finelite or phenylmagnesium, to compounds of General formula (VIII):

< / BR>
in which "n", Z1, Z2, Z4and R6have the above meaning.

The reaction is carried out in a solution of inert solvent, usually a simple ester, such as, for example, dimethoxyethane, tetrahydrofuran or diethyl ether.

The reaction temperature ranges from room temperature up to the boiling point opposite x is MANUAL W

By restoring the amide carbonyl group of compounds of General formula (IX):

< / BR>
in which R1, R2, R3, A, n, Z1, Z2, Z4and R6have the above meaning.

The reaction is carried out preferably in an inert organic solvent, such as diethyl ether or tetrahydrofuran, using reducing agents, as LiAlH4, AlH3or DIBORANE.

The reaction temperature ranges from room temperature up to the boiling point of the used solvent.

The reaction time is from 5 minutes to 24 hours;

METHOD 3

By reacting compounds of General formula (I) with non-toxic inorganic or organic acid in an appropriate solvent, which may be, for example, an alcohol, like methanol, ethanol or any propanolol or butanol; esters like ethyl acetate, or a nitrile as acetonitrile; and using conventional methods of deposition, crystallization, etc. receive appropriate salt.

Inorganic acid chosen among hydrochloric, Hydrobromic, sulfuric or phosphoric acids, and organic acid chosen among mono-, di - or tricarboxylic acids, such as acetic, monocapillary, cinnamic, salicylic acid and alkyl-, cycloalkyl or arylsulfonate.

You can get mono - or disale acids and their salts may be anhydrous or hydrated form.

The invention is illustrated in the following examples, which do not limit any specific conditions of the method or scope of protection of the invention.

METHOD AND

EXAMPLE 1

Getting 4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl) butyl]-1H-pyrazole

A mixture of 15.0 g (48 mmol) of 8-hydroxy-8-phenyl-5-asoni - Spiro-[4,5]-decane, 5.4 g (53 mmol) of 4-chloro-pyrazole and 13.2 g of potassium carbonate in 200 ml of dimethylformamide is refluxed for 20 hours. Then is evaporated to dryness under reduced pressure, dissolved again in chloroform and washed several times with water. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure to get crude product, which was suspended in diethyl ether, filtered cold and washed with diethyl ether. Obtain 12.4 g (37.1 mmol) of 4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl) butyl]-1H-pyrazole.

Melting point and spectroscopic data for the identification of this product are presented in Table 1.


A mixture of 8.6 g (35 mmol) of 4-hydroxy-4-(3-trifluoromethyl - phenyl)-1-piperidine, 7.68 g of 1,4-dibromo-butane and 13.8 g of potassium carbonate in 100 ml of dimethylformamide is refluxed for 4 hours. Then add 3.59 g (35 mmol) of 4-chloro-pyrazole and refluxed for 14 hours. Then is evaporated to dryness under reduced pressure, dissolved again in chloroform and washed several times with water. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure to get crude product, which was purified by chromatography on silica gel. Obtain 9.7 g (24.2 mmol) of 4-chloro-1-[4-[4-hydroxy-4-(3-triptoreline)-1 - piperidinyl] butyl]-1H-pyrazole.

Spectroscopic data for the identification of this product are presented in Table 1.

THE WAY IN

EXAMPLE 14a

Obtaining 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydro-pyridinyl)]butyl] indole

A mixture of 4.8 g (30 mmol) 4-phenyl~1,2,3,6-tetrahydropyridine, 6.22 g of 1-(4-chlorobutyl) indole, 8.3 g of potassium carbonate in 100 ml of dimethylformamide is heated at 90oC for 3 hours. Then is evaporated to dryness under reduced pressure, dissolved again in chloroform and washed several times with water. The organic phase is dried over who have by chromatography on silica gel. Obtain 5.7 g (17.3 mmol) of 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl]indole. Spectroscopic identifying characteristics of this product are presented in Table II.

METHOD D

EXAMPLE 21A

Getting 4-chloro-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] propyl] -1H-pyrazole

To a suspension of 1.0 g of NaH in dimethylformamide was added dropwise a solution of 2.05 g (20 mmol) 4-chloro-pyrazole in dimethylformamide. The white suspension is heated for 30 minutes at 100oC. Cool and add 4.7 g (20 mmol) 1-(3-chloro-propyl)-4-phenyl-1,2,3,6-tetrahydropyridine, dissolved in dimethylformamide. Refluxed for 2 hours, then evaporated to dryness, the residue is extracted with chloroform, the solution washed with water and dried over sodium sulfate. The crude obtained product is purified by chromatography on silica gel. Obtain 5.2 g (17.2 mmol) of 4 - chloro-1-[4-[4-phenyl-1-(1,2,3,6 - tetrahydropyridine)]propyl]-1H-pyrazole.

Spectroscopic characterization (data) to identify this product are presented in Table II.

METHOD D

EXAMPLE 2A

Obtaining 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] -butyl] -1H-benzimidazole

A solution of 13.4 g (38.2 mmol) of 1-[4-(4-hydroxy-4-phenyl-1-PI is within 6 hours. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure to give crude product which is purified by chromatography on silica gel. Obtain 9.1 g (27.5 mmol) of 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H - benzimidazole.

Melting point and spectroscopic characteristics for identification of this product are presented in Table II.

METHOD E

EXAMPLE 11

Obtain 4,5-dichloro-1-[4-[4-hydroxy-4-(4-methyl-phenyl)-1-piperidinyl] butyl]-2-methyl-1H-imidazole

To a suspension of 1.08 g (11.4 mmol) MgCl2in 15 ml of anhydrous tetrahydrofuran at -40oC and under nitrogen atmosphere, add a solution of 1.0 g (3.3 mmol) of 4,5-dichloro-2-methyl-1-[4-(4-oxo-1-piperidinyl)butyl] -1H-imidazole in 10 ml of anhydrous THF. The mixture is stirred for 5 minutes, then at -40oC added 6.8 ml of a 1.0 M solution of 4-methylphenylethylamine. The resulting suspension is stirred for 15 minutes at -40oC and for 3 hours at room temperature. After that add an aqueous solution of ammonium chloride and tetrahydrofuran is evaporated. The resulting aqueous phase is extracted with chloroform. The chloroform phase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness, P1-[4-[4-hydroxy-4-(4-were)-1-piperidinyl]butyl]-2-methyl-1H-imidazole.

Spectroscopic identifying characteristics of this product are presented in Table 1.

WAY W

EXAMPLE 16A

Obtaining 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl]-1H-pyrazole

To a solution of 3.3 g (10 mol) of 1-[4-[4-phenyl-1-(1,2,3,6 - tetrahydropyridine)] -3-oxo-butyl] -1H-pyrazole in 25 ml THF added 2.0 g of LiAlH4. The resulting mixture was refluxed for 2 hours. The excess LiAlH4decompose by adding concentrated NaOH solution and water. The inorganic salt is filtered off and the THF is evaporated in vacuum, obtaining 2.6 g (8.2 mol) of 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl]-1H-pyrazole.

Melting point and spectroscopic characteristics for identification of this product are presented in Table 11.

METHOD 3

EXAMPLE 11a

Obtain 4,5-dichloro-2-methyl-1-[4-[4-phenyl-1-(1,2,3,6 - tetrahydropyridine)]butyl]-1H-imidazole-hydrochloride

To a solution of 7.4 g (20.3 mmol) of 4,5-dichloro-2-methyl-1-[4- [4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-imidazole in 15 ml of absolute ethanol, cooled in an ice bath, add 2.5 ml of 8.4 n solution of hydrogen chloride in ethanol. After a few minutes a precipitate appears, which is filtered off, washed with who-1H-imidazole-hydrochloride.

Melting point and spectroscopic data (characteristics) to identify this product are presented in Table II.

Used in tables abbreviations;

s. = singlet (C.)

d. = doublet (doctor)

t. = triplet (so)

m. = multiplet (m)

quin. = quintet

Hz = Hertz (Hz)

syst. = system

DMSO = DMSO (dimethyl sulfoxide)

b.a. = absorption band (and.p.)

a.c. = - centered absorption band (C.p.)

BIOLOGICAL TESTS

Binding to the serotonin receptor (5HT1A)

Use homogenizate of rat hippocampus according to modification of the method of S. J. Peroutka, J. of Neurochem., 47 (2), 529- 540 (1986). As radiocomunicaciones connection using [3H]8-OH-DPAT and to measure nonspecific use serotonin. The incubation time is 15 minutes at a temperature of 37oC. Radiocomunicaciones the connection associated with the protein is separated by filtration through filters made of fiberglass and determine the radioactivity retained on the filter by liquid scintillation. The inhibition constants (Ki, nm) calculated by analysis of nonlinear regression, using the EBDA/LIGAND (Munson and Rodbard, Analytical Biochemistry, 107, 220 (1980)).

Linking R is eficacia method L. Radesca, etc., J. Med. Chem., 34, 3058-3065 (1991). As radiocomunicaciones connections use [3H] (+)-3-PPP and to measure non-specific use of haloperidol. The incubation period is 120 minutes at a temperature of 25oC. Radiocomunicaciones the connection associated with the protein is separated by filtration through filters made of fiberglass and determine the radioactivity retained on the filter by liquid scintillation. The inhibition constants (Ki, nm) calculated by analysis of nonlinear regression, using the EBDA/LIGAND (Munson and Rodbard, Analytical Biochemistry, 107, 220 (1980)).

Daily dose for humans is 1 to 500 mg of compound 1, which can be entered for one or more of the techniques. Prepare compositions in the form of such preparative forms that are acceptable for the method used to introduce, as for example in the form of tablets, pills, capsules, suppositories, solutions or suspensions. These compositions are prepared by known methods, and they contain from 1 to 60 wt.% current beginning (compounds of General formula (I) and 40 to 99 wt.% corresponding pharmaceutical excipient compatible with the active principle and the physical form of the compositions used. In the example below, the formula table is EPA 11a - 5 mg

lactose 60 mg

crystalline cellulose 25 mg

povidone K 90 5 mg

pre gelatinising starch 3 mg

colloidal silicon dioxide 1 mg

magnesium stearate 1 mg

the total mass is 100 MHI

1. The tetrahydropyridine - or 4-hydropiperoides-alkylate General formula I

< / BR>
in which R1, R2and R3identical or different, represent each a hydrogen atom, halogen atom, linear or branched alkyl radical1-C6, perferably radical WITH1-C6, CNS radical WITH1-C6or two adjacent radicals can form precondensation benzene ring;

And denotes the carbon atom, and the dotted line denotes an optional bond, or a denotes a carbon atom that is associated with a hydroxyl group (- OH), and the dotted line indicates the absence of additional communication;

n can have a value of 2-6, preferably denotes 4;

Z1denotes a nitrogen atom or a substituted carbon atom, which may be represented as R4,

Z2denotes a nitrogen atom or a substituted carbon atom, which may be represented as C-R5,

Z4carts R5, R6and R7identical or different, denote a hydrogen atom, halogen atom, linear or branched alkyl radical WITH1-C6, hydroxyl radical, CNS radical WITH1-C6, phenyl or halogenhydrines radical, or two adjacent radicals selected from R4, R5, R6and R7, can form precondensation benzene ring with getting bicyclic radical,

or their physiologically acceptable salts, with the exception of 1-[3-(1H-benzimidazole-1-yl)propyl]-4-(4-chlorophenyl)-4-piperidinol.

2. Compounds of General formula I on p. 1, which are

1) 4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl)-1H-pyrazole,

2) 4,5-dichloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)-butyl)-2-methyl-1H-imidazole,

3) 1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-benzimidazole,

4) 1-[4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-1,2,4-triazole,

5) 4-chloro-1-[4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]butyl]-1H-pyrazole,

6) 4,5-dichloro-1-[4-[4-hydroxy-4-(4-chlorophenyl)-1-piperidinyl]butyl]-2-methyl-1H-imidazole,

7) 4-chloro-1-[4-[4-hydroxy-4-(3-triptoreline)-1-piperidinyl]butyl] -1H-pyrazole,

8) 4,5-dichloro-1-[4-[4-hydroxy-4-(3-triptoreline)-1-piperidinyl)b>/BR>10) 1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]indole,

11) 4,5-dichloro-1-[4-[4-hydroxy-4-(4-were)-1-piperidinyl]butyl]-2-methyl-1H-imidazole,

12) 1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole,

13) 1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-indazol,

14) 2-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-2H-indazol,

15) 4-chloro-1-[4-[4-hydroxy-4-(4-were)-1-piperidinyl] butyl]-1H-pyrazole,

16) 4-chloro-1-[4-[4-hydroxy-4-(4-methoxyphenyl)-1-piperidinyl)butyl] -1H-pyrazole,

17) 1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-2-phenyl-1H-imidazole,

18) 1-[4-(4-hydroxy-4-(4-were)-1-piperidinyl] -butyl] -1H-benzimidazole,

19) 4,5-diphenyl-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-imidazole,

20) 4-chloro-1-[4-[4-hydroxy-4-(1-naphthyl)-1-piperidinyl] butyl]-1H-pyrazole,

21) 4-chloro-1-[4-[4-hydroxy-4-(2-naphthyl)-1-piperidinyl] butyl]-1H-pyrazole,

22) 4-chloro-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-pyrazole,

23) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl)-1H-benzimidazole,

24) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-1,2,4-triazole,

25) 4-chloro-1-[4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridine)]butyl] -1H-pyrazole,

26) 4,5-dichloro-1-[4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridine)] butyl]-2-methyl-1H-imidazole,

27 is reformational)-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-imidazole,

29) 4-chloro-1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)]butyl] -1H-pyrazole,

30) 4,5-dichloro-1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] butyl]-2-methyl-1H-imidazole,

31) 4,5-dichloro-1-[4-[4-(phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl]-2-methyl-1H-imidazole,

32) 4,5-dichloro-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-2-methyl-1H-imidazole-hydrochloride,

33) 4,5-dichloro-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-2-methyl-1H-imidazol-dichlorhydrate,

34) 1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)]butyl]indole,

35) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]indole,

36) 4,5-dichloro-2-methyl-1-[4-[4-(4-were)-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-imidazole,

37) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-pyrazole,

38) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-imidazol,

39) 2-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-2H-imidazol,

40) 4-chloro-1-[4-[4-(4-were)-1-(1,2,3,6-tetrahydropyridine)]butyl] -1H-pyrazole,

41) 4-chloro-1-[4-[4-(4-methoxyphenyl)-1-(1,2,3,6-tetrahydropyridine)] butyl]-1H-pyrazole,

42) 4-chloro-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] propyl] -1H-pyrazole,

43) 4,5-dichloro-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] propyl]-2-methyl-1H-imidazole,

44) 2-phenyl-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyrido is 4,5-diphenyl-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl]-1H-imidazole (R4, R5, R6and R7not form part of another, possibly aromatic cycle),

47) 4-chloro-1-[4-[4-(1-naphthyl)-1-(1,2,3,6-tetrahydropyridine)] butyl]-1H-pyrazole,

48) 4-chloro-1-[4-[4-(2-naphthyl)-1-(1,2,3,6-tetrahydropyridine)] butyl]-1H-pyrazole,

49) 1-[2-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] ethyl] -1H-benzimidazole,

50) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl]-1H-benzimidazole-hydrochloride,

51) 1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-benzimidazole,

52) 1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-benzimidazole-hydrochloride,

53) 4,5-dichloro-2-methyl-1-[4-[4-(3-triptoreline)-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-imidazole-hydrochloride,

54) 4-chloro-1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)]butyl] -1H-pyrazole-hydrochloride,

55) 1-[4-[4-(4-phenyl)-1-(1,2,3,6-tetrahydropyridine)] butyl] -1H-indazol-hydrochloride,

56) 4,5-dichloro-1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] butyl]-2-methyl-1H-imidazole-hydrochloride,

57) 4-(4-chlorophenyl)-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl] -1H-pyrazole-hydrochloride,

58) 4-(4-chlorophenyl)-2-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl] -1H-pyrazole,

59) 1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] butyl] -1H-triazole-hydrochloride,

60) 1-[4-[Il)] butyl]-2-methyl-1H-benzimidazole,

62) 1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] butyl] -1H-indazol,

63) 2-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] butyl] -2H-indazol,

64) 2-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] butyl] -2H-benzotriazol-hydrochloride,

65) 2-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] butyl] -2H-benzotriazol,

66) 1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] butyl] -1H-benzotriazol-hydrochloride,

67) 1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)] butyl] -1H-benzotriazol,

68) 4-chloro-1-[4-[4-(4-forfinal)-1-(1,2,3,6-tetrahydropyridine)]butyl] -1H-pyrazole-hydrochloride,

69) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl] -1H-pyrazole-hydrochloride,

70) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl] -1H-triazole-hydrochloride,

71) 2-phenyl-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl]-1H-imidazole-hydrochloride,

72) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)] butyl] -1H-pyrrole hydrochloride,

73) 1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-pyrrol,

74) 4-(4-chlorophenyl)-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl] -1H-pyrazole,

75) 1-[4-[4-(4-forfinal)-4-hydroxy-1-piperidinyl]-butyl]-1H-benzimidazole,

76) 4-chloro-1-[4-[4-hydroxy-4-(3-triptoreline)-1-piperidinyl]butyl] -1H-pyrazole,

77) 1-[4-[ 4-(4-forfinal)-4-hydroxy-1-is(4-forfinal)-4-hydroxy-1-piperidinyl] -butyl] -2H-benzotriazol,

80) 1-[4-[4-(4-forfinal)-4-hydroxy-1-piperidinyl] -butyl] -2H-benzotriazol,

81) 3-chloro-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-indazol,

82) 3-chloro-1-[4-[4-phenyl-1-(1,2,3,6-tetrahydropyridine)]butyl]-1H-indazol-hydrochloride.

3. The method of obtaining compounds of General formula I according to any one of paragraphs.1 or 2, characterized in that interoperate connection spiranovic type General formula II

< / BR>
in which R1, R2, R3and a have the meanings specified in paragraph 1;

m may have a value of 0-4;

X denotes a group to delete as chlorine, bromine, mesilate or tailorshop,

with nitrogen-containing heterocyclic compound of the formula III

< / BR>
in which Z1, Z2, Z4and R6have the above values.

4. Method of producing compounds of the formula I according to any one of paragraphs.1 or 2, characterized in that takes place simultaneously in one stage, the reaction between the derivative of General formula IV, alkylating agent of formula V and a nitrogen-containing heterocyclic compound of the formula III

< / BR>
< / BR>
< / BR>
where R1, R2, R3, A, X, n, Z1, Z2, Z4and R6have the above values,

5. Method of producing compounds of the formula I p IV

< / BR>
in which R1, R2, R3and a have the above value, B denotes H or a group -(CH2)n-X, with derivative of General formula VI

< / BR>
in which Z1, Z2, Z4, R6have the above meaning;

B' matter, provided that when a represents a carbon atom directly connected to a hydroxyl group, b means a group -(CH2)n-X, and' means N.

6. Method of producing compounds of the formula I according to any one of paragraphs.1 and 2, characterized in that carry out the dehydration of compounds of formula I

< / BR>
in which R1, R2, R3, n, Z1, Z2, Z4and R6have the above meaning;

And indicates the carbon atom that is associated with a hydroxyl group (- OH), and the dotted line indicates the absence of additional communication.

7. Method of producing compounds of the formula I according to any one of paragraphs. 1 and 2, characterized in that carry out the reaction of the accession of ORGANOMETALLIC reagents such as finelite or phenylmagnesium to compounds of General formula VIII

< / BR>
in which n, Z1, Z2, Z4and R6have the above meaning.

8. The method of obtaining compounds of formula I is where R1, R2, R3And, "n", Z1, Z2, Z4and R6have the above meaning.

9. Compounds of General formula I or their physiologically acceptable salts according to any one of paragraphs. 1 or 2, with activity towards the Sigma receptors and/or NTA-type.

10. Pharmaceutical composition having activity towards the Sigma receptors and/or NTA-type, characterized in that it contains in addition to the pharmaceutically acceptable excipient at least one compound of General formula I or one of its physiologically acceptable salts according to any one of paragraphs. 1 or 2.

 

Same patents:

The invention relates to novel triazole compounds of the General formula (1), where a denotes a linear or branched C1-C18-alkylenes group which may comprise at least one group which is selected from O, S, CONH, COO,3-C6-cycloalkene or double or triple bond; In denotes the radical of formula (a), (b) or (C); R1denotes H, NH2WITH3-C6-cycloalkyl or1-C8-alkyl, which is not substituted or substituted OS1-C8-alkyl; R2denotes H, HE, C1-C8-alkyl, C3-6-cycloalkyl, CF3, CN, NR3R4, SR3or CO2R3where R3denotes N or C1-C8-alkyl, a R4denotes H, C1-C8-alkyl, or COR3where R3stands WITH1-C8-alkyl; Ar represents naphthyl, phenyl with 1-2 substituent selected from C1-C8-alkyl, CF3, CHF2, NO2, SR3, SO2R3where R3means1-C8-alkyl; and pyridyl, pyrimidyl or triazinyl, which have from 1 to 3 substituents selected from C1-C8-alkyl, C2-C6-alkenyl, C2-C6-quinil, halogen, CN, CF3, OR4where R43-C6-lalouche possibly condensed, phenylalkylamine or 5-membered aromatic heterocycle with 1 to 2 nitrogen atoms, which may be condensed with a benzene ring

The invention relates to new N-substituted azaheterocyclic carboxylic acids f-crystals (I) or their salts, in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy: Y is the grouporin which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C= O)-, -O-CH2-, -(C= O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl; z = 1, 2, or 3; m = 1 or 2, n = 1 when m = 1 and n = 0 when m = 2; R4and R5each represents a hydrogen atom or, when m = 2, can both work together to develop a bond; R6is hydroxyl or C1-C8-alkoxygroup, or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-(3-carbomethoxy-1-piperidyl) propyl) phenothiazines and 10-(3-(3-carborexics-1-piperidyl) propyl) phenothiazines

The invention relates to Hinayana and hinokitiol, compositions containing them, and methods of producing these compounds

The invention relates to the derivatives of diphenylbutylpiperidine formula I where n is 1 or 2, or pharmaceutically acceptable salts

The invention relates to new derivatives of benzylpiperidine formula I, where R1denotes H or Hal, R2is unsubstituted or substituted Gal in the aromatic ring of the benzyl group in the 2 -, 3-or 4-position piperidino ring, provided that R2doesn't mean 4-benzyl when X represents-CO-, Y -, and Z represent CH2and R1- N; R3denotes H or A , X IS-CO-, Y is --CH2-, -NH - or-O-, Z is-CH2- or connection, And - alkyl WITH1-6In - OH, H+, HE, Hal Is F, Cl, Br or I, and their salts

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, in particular fungicidal activity, and more particularly to a derivative triazolyl, the way they are received and fungicidal tool

The invention relates to new 4-aryl-1-phenylalkyl-1,2,3,6-tetrahydropyridine F.-ly (I), where Y is CH or N; R1-H, halogen, CF3; R2-H, halogen, (C3- C4)alkyl or (C1- C4)alkoxy; R3and R4- H or (C1- C3)alkyl; X represents: (a) (C3- C6)alkyl, (C3- C6)alkoxy or (C1- C4)alkoxycarbonyl(C3- C6)alkoxy, (b), (C3- C7)cycloalkyl or c) Deputy chosen from the group comprising phenyl, phenoxybenzyl, their salts, solvate or Quaternary ammonium salts

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to new compounds 1,2,5,6-tetrahydropyridine number of General formula

(I) where Z is oxygen or sulfur;

R is hydrogen or C1-3-alkyl; when Z stands for oxygen, R1is a halogen, amino group, acetylamino or-O-R2where R2is4-6-alkyl or C6-quinil; Z, meaning sulfur, R1is halogen, C1-8-alkyl, C6-alkenyl straight chain, cyclopropylmethyl, benzyloxypropionic, morpholino-, 4-methylpiperidino - or 4-hexylamino or a group-O-R2where R2linear or branched C3-6alkenyl,3-6-quinil, cyclopropylmethyl, -R3-O-R4or-R3-O-R4-O-R5where each of R3, R4and R5means1-4-alkyl, or R1represents a group S-R2where R2linear C2-8-alkyl, or their pharmaceutically acceptable salts

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

The invention relates to new 3-intellipedia formula I, where R1, R2, R3and R4denote H, A, OH, OA, F, Cl, Br, J, CN, CF3, COOH, CONH2, CONHA, CONA2or COOA, or R1and R2and R3and R4together denote methylenedioxy, R5Is H or OH, R6- H or R5and R6together denote a bond, And represents C1- C6-alkyl, n denotes a number from 2 to 6, and their physiologically acceptable salts
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