Substituted indole mannich bases

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

 

The present invention relates to substituted indole reasons manniche, to methods for their preparation, to medicines containing these compounds and to the use of these compounds to obtain drugs.

Pain is the main clinical symptoms. Despite the progress made, there remains a pressing need to develop effective treatment of pain. Urgent need for targeted, taking into account the individual characteristics of patients the treatment of chronic and nechanicky painful conditions, and refers to a successful and satisfactory for the patient's pain therapy, confirmed in numerous recently published scientific papers in the field of applied analgesics, respectively, in fundamental studies of nociception.

Classical opioids, such as morphine, are effective in the treatment of strong, including a very strong pain. However, their use is associated with undesirable side effects, such in particular as respiratory depression, vomiting, the need to use sedation, constipation and addiction.

A special place among the highly effective analgesics is tramadol hydrochloride, i.e. the (1RS, 2R8)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)C is clohexane, because this active substance possesses a strong ability to suppress pain, without causing any known side effects, inherent to opioids (Journ. Pharmacol. Exptl. Ther. 267, page 33 (1993)). The search and development of other suppress the pain of funds continue everywhere.

With regard to the foregoing, the present invention was based on the task to obtain new compounds are especially suitable for use as active substances in the relevant medicines. It was envisaged that these active substances shall be designed primarily for the treatment of pain and for the treatment of inflammatory and allergic reactions, drug and/or alcohol dependence, diarrhea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, shock, migraines, narcolepsy, obesity, asthma, glaucoma, hypokinetic syndrome, painful indifference (apathy), bulimia, anorexia, catalepsy, to suppress feelings of anxiety and fear (anxiolysis), to improve clarity of consciousness and/or to enhance libido.

This task is solved according to the invention thanks to substituted indole reasons manniche the following General formula I which have a pronounced analgesic effect, especially when chronic pain, and which also can be used for the treatment of inflammatory and allergic reactions, drug and/or alcohol dependence, diarrhea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, shock, migraines, narcolepsy, obesity, asthma, glaucoma, hypokinetic syndrome, painful indifference (apathy), bulimia, anorexia, catalepsy, to suppress feelings of anxiety and fear (anxiolysis), to improve clarity of consciousness and/or to enhance libido.

The object of the invention in accordance with this are substituted indole Mannich bases of the General formula I

in which R1denotes H, C1-C10alkyl or linked via C1-C6alkylenes aryl group or heteroaryl, preferably H, C1-C6alkyl or linked via C1-C2alkylenes aryl group, particularly preferably H or C1-C2alkyl,

R2denotes H, F, Cl, Br, CF3, CN, NO2, Other8, SR9, OR10, SO2NH2, SO2Other21, CO(OR11), CH2CO(OR12), COR19C1-C10alkyl, aryl, heteroaryl or linked via C1-C6alkylenes aryl group or heteroaryl, preferably H, Cl, F, NO2, OR10, CO(OR11), C1-C6alkyl l is Bo linked via C 1-C2alkylenes aryl group, particularly preferably H, C1-C2alkyl or unsubstituted phenyl,

R3denotes CH(R13)N(R14)(R15),

R4, R5, R6, R7can have identical or different meanings and denote H, F, Cl, Br, CF3, CN, NO2, Other8, SR9, OR10, SO2NH2, SO2Other21, CO(OR11), CH2CO(OR12), COR19C1-C10alkyl, aryl, heteroaryl or linked via C1-C6alkylenes aryl group or heteroaryl, preferably H, Cl, F, NO2, OR10, CO(OR11), aryl, C1-C6alkyl or linked via C1-C2alkylenes aryl group, particularly preferably H, NO2C1-C2alkyl or unsubstituted phenyl,

R8denotes H, COR16C1-C10alkyl or aryl, preferably C1-C6alkyl,

R9denotes H, C1-C10alkyl or aryl, preferably C1-C6alkyl or phenyl,

R10denotes H, COR17C1-C10alkyl, aryl or is linked via C1-C6alkylenes aryl group or heteroaryl, preferably H, C1-C6alkyl or linked via C1-C2alkylenes aryl group,

R11denotes H, C1-C10alkyl or aryl, before occhialino N or C 1-C6alkyl,

R12denotes H, C1-C10alkyl or aryl, preferably C1-C6alkyl,

R13denotes unsubstituted phenyl, or at least one-deputizing C1-C4the alkyl, C1-C3alkoxygroup, halogen, CF3, CN, O-phenyl or a phenyl, preferably unsubstituted phenyl, or at least one-deputizing the stands, tert-bootrom, a methoxy group, F, Cl, Br or CF3phenyl, particularly preferably unsubstituted phenyl or 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-were, 3-were, 4-were, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromo-2-forfinal, 2-chloro-4-forfinal, 2-chloro-5-forfinal, 2-chloro-6-forfinal, 4-bromo-2-forfinal, 3-bromo-4-forfinal, 3-bromo-2-forfinal, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimetilfenil, 2,4-dimetilfenil, 2,5-dimetilfenil, 2,3-acid, 2,4-acid, 2,5-acid, 3,4-acid, 3,4,5-trimethoxyphenyl, 2-triptoreline, 3-triptoreline or 4-triptoreline most preferably unsubstituted phenyl,

R14, R15can have identical or different meanings and denote unbranched or branched, feast upon the config or unsaturated, unsubstituted or at least one-deputizing C1-C6alkyl or unsubstituted or at least one-deputizing phenyl, benzyl or phenethyl, preferably saturated, unsubstituted or at least one-deputizing C1-C6alkyl, particularly preferably CH3or

R14, R15both together are (CH2)nwhere n denotes an integer from 3 to 6, or (CH2)2O(CH2)2preferably (CH2)nwhere n represents 4 or 5,

R16represents C1-C10alkyl, aryl or heteroaryl, preferably C1-C6alkyl,

R17represents C1-C10alkyl, preferably C1-C6alkyl,

R18represents C1-C10alkyl, aryl, heteroaryl or naphthyl, preferably C1-C6alkyl,

R19denotes H, NHNH2, Other20C1-C10alkyl, aryl, heteroaryl or linked via C1-C6alkylenes aryl group or heteroaryl, preferably C1-C6alkyl or linked via C1-C2alkylenes aryl group,

R20denotes H, C1-C10alkyl, aryl, heteroaryl or linked via C1-C6alkylenes aryl group or heteroaryl, preferably C1-C6alkyl or associated cher the C C 1-C2alkylenes aryl group,

R21denotes H, COR17C1-C10alkyl, aryl or is linked via C1-C6alkylenes aryl group or heteroaryl, preferably H, C1-C6alkyl or linked via C1-C2alkylenes aryl group,

and/or their racemates, the enantiomers, the diastereomers and/or the base and/or corresponding salts of physiologically acceptable acids, with the exception of the racemates of the compounds in which R3denotes CH(R13)N(R14)(R15), respectively, and R4-R7and R2denote N, R13denotes phenyl, R14and R15together denote (CH2)5and R1denotes N, CH3or benzyl or

R4-R7and R2denote N, R13denotes phenyl, R14, R15each represents CH3and R1denotes N, CH3or benzyl or

R4-R7and R1denote N, R13denotes 2-chlorophenyl, R14and R15each represents CH3or R14and R15together are (CH2)2O(CH2)2, R2means COOR11and R11represents C2H5and relevant hydrochloride or

R4-R7and R1denote N, R13denotes phenyl, R14 15together are (CH2)5, R2means COOR11and R11denotes CH3in the form of hydrochloride or

R4-R7and R2denote N, R13denotes phenyl, R14and R15together are (CH2)4, R1denotes N, CH3CH2-CH=CH2or 4-chlorbenzyl and when the value of R1CH3well as the corresponding hydrochloride of the compound or

R4-R7, R1and R2denote N, R13denotes phenyl, R14denotes phenyl and R15denotes 4-ethoxyphenyl or

R4-R7denote N, R13denotes 2,4,6-trimethoxyphenyl, R14and R15together are (CH2)2O(CH2)2, R1denotes CH3and R2denotes phenyl or

R4-R7and R1denote N, R13denotes phenyl, 2-hydroxyphenyl or 2-hydroxy-5-were, R14and R15together are (CH2)5and R2denotes CH3and a value of R13phenyl well as the corresponding hydrosulfate or

R4-R7and R1denote N, R13denotes phenyl, R14and R15together are (CH2)2O(CH2)2and R2denotes CH3as well as the corresponding GI is resultat connection or

R4-R7and R1denote N, R13denotes phenyl, R14and R15together are (CH2)5, R2means COOR11and R11denotes CH3in the form of hydrochloride or

R1, R4, R6, R7denote N, R2means COOR11, R11stands With2H5, R14and R15each represents CH3, R13denotes 2-chlorophenyl and R5denotes the ethyl ester of 3-[(2-chlorophenyl)dimethylaminomethyl]-5-methylene-1H-indole-2-carboxylic acid or ethyl ester of 3-[(2-chlorophenyl)dimethylaminomethyl]-5-hydrokit-1H-indole-2-carboxylic acid.

Under alkyl radicals are meant preferably at least one-deputizing halogen, HE, CN, CF3particularly preferably F, Cl, Br or HE hydrocarbons. If the alkyl radicals contain more than one substituent, these substituents may be identical or different. The alkyl radicals can be branched, unbranched or cyclic. Particularly preferred as the alkyl radicals methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, heptyl, nonyl or decenyl.

Under the aryl radicals are meant preferably at least od is zameshannye HE halogen, preferably F, Cl or Br, CF3CN, C1-C6the alkyl, C1-C6alkoxygroup or phenyl phenyl or naphthyl. Unsubstituted or substituted phenyl radicals may be condensed with other rings. To the preferred aryl radicals are 2-, 3-, 4-bromophenyl, 4-bromo-2-forfinal, 5-bromo-2-forfinal, 3-bromo-4-forfinal, 4-tert-butylphenyl, 2-chloro-4-forfinal, 2-chloro-6-forfinal, 4-cyanophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3-acid, 3,4-acid, 2,4-dimetilfenil, 2,5-dimetilfenil, 2-, 3-, 4-forfinal, 2-methoxyphenyl, 2-, 3-, 4-were 3-phenoxyphenyl, 2-, 4-triptoreline or 3,4,5-trimethoxyphenyl.

Under heteroaryl radicals are meant aromatic compounds, which contain at least one heteroatom, preferably nitrogen and/or oxygen and/or sulfur, particularly preferably nitrogen and/or oxygen, and which preferably may be substituted with halogen, CN, CF3or HE. The most preferred heteroaryl radical is substituted or unsubstituted thiophene, pyrrolyl or furfuryl.

Most preferred are the following substituted indole Mannich bases:

ethyl ester of 3-(dimethylaminomethyl)-1H-indole-2-carboxylic acid,

3-(dimethylaminophenyl)-1H-indole-2-carboxylic acid,

[(5-fluoro-1H-indol-3-yl)phenylmethyl]dimethylamine,

[(1-ethyl-2-phenyl-1H-indol-3-yl)phenylmethyl]dimethylamine,

[(5-methoxy-1H-indol-3-yl)phenylmethyl]dimethylamine,

3-(dimethylaminophenyl)-5-hydroxy-1H-indole-2-carboxylic acid,

dimethyl[(2-methyl-1H-indol-3-yl)phenylmethyl]Amin,

3-(dimethylaminophenyl)-1H-indol-4-ol,

dimethyl[(4-methyl-1H-indol-3-yl)phenylmethyl]Amin,

[(5-chloro-1H-indol-3-yl)phenylmethyl]dimethylamine,

[(5-benzyloxy-1H-indol-3-yl)phenylmethyl]dimethylamine,

3-(dimethylaminophenyl)-1H-indol-4-silt ether acetic acid,

{[2-(4-chlorophenyl)-1H-indol-3-yl]phenylmethyl}dimethylamine,

5-benzyloxy-3-(dimethylaminophenyl)-1H-indole-2-carboxylic acid,

dimethyl[(2-methyl-5-nitro-1H-indol-3-yl)phenylmethyl]Amin,

dimethyl[(2-methyl-6-nitro-1H-indol-3-yl)phenylmethyl]Amin,

[(6-fluoro-2-methyl-1H-indol-3-yl)phenylmethyl]dimethylamine,

{[2-(4-forfinal)-1H-indol-3-yl]phenylmethyl}dimethylamine,

{[2-(3-chloro-4-forfinal)-1H-indol-3-yl]phenylmethyl}dimethylamine,

[(7-ethyl-1H-indol-3-yl)phenylmethyl]dimethylamine,

3-(dimethylaminophenyl)-1H-indole-6-carboxylic acid,

dimethyl[(1-methyl-1H-indol-3-yl)phenylmethyl]Amin,

1-methyl-3-(morpholine-4-alpenlite)-1H-indole,

3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1-methyl-1H-indole,

1-ethyl-2-phenyl-3-(pyrrolidin-1-yl-o-trimethyl)-1H-indole,

3-[(2-chlorophenyl)piperidine-1-ylmethyl]-etyl-2-phenyl-1H-indole,

1-ethyl-2-phenyl-3-(phenylpyrrolidine-1-ylmethyl)-1H-indole,

1-ethyl-3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-2-phenyl-1H-indole,

2-phenyl-3-(pyrrolidin-1-yl-o-trimethyl)-1H-indole,

2-phenyl-3-(piperidine-1-yl-o-trimethyl)-1H-indole,

3-[(2-chlorophenyl)piperidine-1-ylmethyl]-2-phenyl-1H-indole,

dimethyl[(2-phenyl-1H-indol-3-yl)-o-trimethyl]Amin,

2-phenyl-3-(phenylpyrrolidine-1-ylmethyl)-1H-indole,

3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-2-phenyl-1H-indole,

4-methyl-3-(piperidine-1-yl-o-trimethyl)-1H-indole,

3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-4-methyl-1H-indole,

5-benzyloxy-3-(phenylpiperidine-1-ylmethyl)-1H-indole,

[(5-benzyloxy-1H-indol-3-yl)-o-trimethyl]dimethylamine,

7-ethyl-3-[(2-methoxyphenyl)morpholine-4-ylmethyl]-1H-indole,

3-[(2-methoxyphenyl)piperidine-1-ylmethyl]-2-phenyl-1H-indole,

5-chloro-3-[(2-methoxyphenyl)piperidine-1-ylmethyl]-1H-indole,

5-chloro-3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1H-indole,

5-benzyloxy-3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1H-indole,

[(2-methoxyphenyl)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine,

{[1-(4-methoxybenzyl)-1H-indol-3-yl]phenylmethyl}dimethylamine,

3-(phenylpiperidine-1-ylmethyl)-1H-indole,

1-methyl-3-(phenylpiperidine-1-ylmethyl)-1H-indole,

3 -(phenylpyrrolidine-1-ylmethyl)-1H-indole,

[(1H-indol-3-yl)phenylmethyl]dimethylamine,

5-benzyloxy-3-(phenylpyrrolidine-1-ylmethyl)-1H-indole,

[(5-bromo-2-forfinal)-(4-n the tro-1H-indol-3-yl)methyl]dimethylamine,

[(5-bromo-2-forfinal)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-bromophenyl)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine,

[(2-bromophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(3-bromophenyl)-(7-ethyl-1H-indol-3-yl)methyl]dimethylamine,

[(3-bromophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(4-tert-butylphenyl)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(4-tert-butylphenyl)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

[(4-tert-butylphenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-4-forfinal)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-4-forfinal)-(4-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

{(2-chloro-6-forfinal)-[2-(4-chlorophenyl)-1H-indol-3-yl]methyl}dimethylamine,

[(2-chloro-6-forfinal)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(3-chlorophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2,3-dichlorophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2,4-dichlorophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(4-tert-butylphenyl)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-4-fluoro who enyl)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2,3-acid)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine,

3-[(2,3-acid)dimethylaminomethyl]-4,7-dihydro-1H-indole-6-carboxylic acid,

3-[(2,3-acid)dimethylaminomethyl]-5-hydroxy-1H-indole-2-carboxylic acid,

[(3,4-acid)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine,

[[2-(4-chlorophenyl)-1H-indol-3-yl]-(3,4-acid)methyl]dimethylamine,

[(3,4-acid)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

[(3,4-acid)-(7-ethyl-1H-indol-3-yl)methyl]dimethylamine,

[(3,4-acid)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(3,4-acid)-[2-(4-forfinal)-1H-indol-3-yl]methyl]dimethylamine,

[[2-(3-chloro-4-forfinal)-1H-indol-3-yl]-(3,4-acid)methyl]dimethylamine,

[(5-chloro-1H-indol-3-yl)-(2-forfinal)methyl]dimethylamine,

[(4-forfinal)-(4-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(7-ethyl-1H-indol-3-yl)-(2-methoxyphenyl)methyl]dimethylamine,

dimethyl[(2-methyl-1H-indol-3-yl)-o-trimethyl]Amin,

[(7-ethyl-1H-indol-3-yl)-o-trimethyl]dimethylamine,

dimethyl[(1-methyl-1H-indol-3-yl)-o-trimethyl]Amin,

[(5-chloro-1H-indol-3-yl)-o-trimethyl]dimethylamine,

[(5-chloro-1H-indol-3-yl)-m-trimethyl]dimethylamine,

dimethyl[(2-methyl-1H-indol-3-yl)-n-trimethyl]Amin,

[(5-chloro-1H-indol-3-yl)-p-trimethyl]dimethylamine,

dimethyl[(2-methyl-1H-in the ol-3-yl)-(3-phenoxyphenyl)methyl]amine,

[(1-ethyl-2-phenyl-1H-indol-3-yl)-(3-phenoxyphenyl)methyl]dimethylamine,

[(7-ethyl-1H-indol-3-yl)-(3-phenoxyphenyl)methyl]dimethylamine,

dimethyl[(1-methyl-1H-indol-3-yl)-(3-phenoxyphenyl)methyl]amine,

[[2-(4-forfinal)-1H-indol-3-yl]-(3-phenoxyphenyl)methyl]dimethylamine,

[[2-(3-chloro-4-forfinal)-1H-indol-3-yl]-(3-phenoxyphenyl)methyl]dimethylamine,

dimethyl[(4-methyl-1H-indol-3-yl)-(3-phenoxyphenyl)methyl]amine,

[(5-chloro-1H-indol-3-yl)-(2-triptoreline)methyl]dimethylamine,

dimethyl[(2-methyl-1H-indol-3-yl)-(4-triptoreline)methyl]amine.

Another object of the invention are methods of obtaining substituted indole bases of manniche General formula I, which are characterized in that the aromatic aldehyde compounds of General formula II

where R13has the values stated for the General formula I,

in dissolved form, preferably in an organic solvent, particularly preferably in toluene in the presence of a base, preferably potassium carbonate or anhydride of boric acid, at a temperature preferably in the range from -10 to +110°subjected to interaction with secondary amines of General formula III

in which R14and R15have the meanings mentioned for the General formula I,

obtaining aminolink compounds of General formula IV

further, these analnye compounds of General formula IV without further purification under the action of the corresponding carboxylic acid, preferably acetylchloride, in absolute solvent, preferably in diethyl ether, turned into salt imine General formula V

then these salts imine General formula V without further purification in dissolved form, preferably in acetonitrile and/or toluene, is subjected to the interaction with the indole and/or substituted indole compounds of the General formula VI

in which R3denotes H, a R1, R2, R4-R12and R16-R21have the meanings mentioned for the General formula I,

and thus obtained indole Mannich bases of the General formula I is purified by washing and/or extraction, preferably by washing with acetone, and produce using conventional methods.

Another object of the invention are also alternative ways to get substituted indole bases of manniche General formula I, in which R1does not denote H, a R2-R21have the meanings mentioned for the General formula I, which are the modes differ in that the aromatic aldehyde compounds of General formula II

where R13has meant is I, above for General formula I,

in dissolved form, preferably in an organic solvent, particularly preferably in toluene in the presence of a base, preferably potassium carbonate or anhydride of boric acid, at a temperature preferably in the range from -10 to +110°subjected to interaction with secondary amines of General formula III

in which R14and R15have the meanings mentioned for the General formula I,

obtaining aminolink compounds of General formula IV

further, these analnye compounds of General formula IV without further purification under the action of the corresponding carboxylic acid, preferably acetylchloride, in absolute solvent, preferably in diethyl ether, turned into salt imine General formula V

then these salts imine General formula V without further purification in dissolved form, preferably in acetonitrile and/or toluene, is subjected to the interaction with the indole and/or substituted indole compounds of the General formula VI

in which R1and R3denote H, a R2, R4- R12and R16- R21have the meanings mentioned for the General formula I, and thus obtained compounds of the General formula VI, in which R1denotes H, a R2- R21have the meanings mentioned for the General formula I, in dissolved form, preferably in dimethyl sulfoxide, at a temperature preferably in the range from 10 to 150°in the presence of an appropriate base, preferably triethylamine or of potassium tert-butylate, are subjected to interaction with compounds of General formula XR22where R22represents a C1-C10alkyl or linked via C1-C6alkylenes aryl group or heteroaryl, preferably C1-C6alkyl or linked via C1-C2alkylenes aryl group, and X denotes Cl, Br or I, preferably Cl, and thus obtained compounds of General formula I, in which R1represents a C1-C10alkyl or linked via C1-C6alkylenes aryl group or heteroaryl, and the remaining radicals R2-R21have the meanings mentioned for the General formula I, purified by filtration, preferably through the resin-absorbent, particularly preferably by filtering through immobilized on the polymer of Tris(2-amino-ethyl)amine (firm Novabiochem, bad Soden) and/or 3-(3-mercaptophenyl)propanedinitrile (company Argonaut, Muttenz, Switzerland), and in the end produce using conventional methods.

The synthesis proposed in the image is the situation of substituted indole bases of manniche it is preferable to carry out for the following technologies in automated installation company Zymark, presented in figure 1 and 2.

Substituted indole Mannich bases of the General formula I according to the invention by known experts in the field of methods can be converted into their salts with physiologically acceptable acids, preferably hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. The formation of salts is preferably carried out in an appropriate solvent, particularly preferably in diethyl ether, diisopropyl ether, Akilova ether acetic acid, acetone and/or 2-butanone. It is most preferable to form a salt with trimethylchlorosilane in methylethylketone.

Proposed in the invention substituted indole Mannich bases of the General formula I toxicologically safe and can be applied so as pharmaceutically active substances.

Another object of the invention in accordance with this are also medicines that contain as active substance at least one substituted indole base manniche General formula I and neoba is consequently other active substances and/or excipients. In some cases the drug may preferably contain as active substance mixture of the enantiomers of at least one substituted indole Mannich bases of the General formula I, the enantiomers in the mixture are presented preferably in equimolar amounts. Particularly preferably, the relative proportion of one of the enantiomers is from 5 to 45 mol.%, most preferably from 10 to 40 mol.%, in terms of the total amount of the mixture of enantiomers.

Preferably the medicinal product according to the invention are intended for the treatment of pain, primarily for the treatment of chronic pain and/or inflammatory reactions and/or allergic reactions and/or drug addiction and/or alcohol addiction and/or diarrhoea and/or gastritis and/or various ulcers and/or cardiovascular disease and/or urinary incontinence and/or depression and/or shock and/or migraine and/or narcolepsy and/or overweight and/or asthma and/or glaucoma and/or hypokinetic syndrome and/or painful indifference (apathy) and/or bulimia and/or anorexia and/or catalepsy and/or for anxiolysis and/or to improve the clarity of consciousness and/or to enhance libido.

The object of the present invention is also the use of at least one substituted indole grounds plans is as General formula I according to the invention to obtain the corresponding medicinal product, intended for the treatment of pain, primarily for the treatment of chronic pain and/or inflammatory reactions and/or allergic reactions and/or drug addiction and/or alcohol addiction and/or diarrhoea and/or gastritis and/or various ulcers and/or cardiovascular disease and/or urinary incontinence and/or depression and/or shock and/or migraine and/or narcolepsy and/or overweight and/or asthma and/or glaucoma and/or hypokinetic syndrome and/or painful indifference (apathy) and/or bulimia and/or anorexia and/or catalepsy and/or for anxiolysis and/or to improve the clarity of consciousness and/or to enhance libido.

For the preparation of corresponding pharmaceutical compositions, along with at least one substituted indole base of manniche General formula I using carriers, fillers, solvents, diluents, dyes and/or binders. The choice of auxiliary substances depends on whether the drug for oral, intravenous, intraperitoneal, intradermal, intramuscular, nasal, buccal or topical application, for example, skin infections, infections of the mucous membranes and eye infections. For oral administration suitable compositions in the form of tablets, pills, capsules, granules, drops, tinctures and syrups,for parenteral, local and inhalation use can be solutions, suspensions, easily recoverable dry compositions, as well as aerosols. Suitable for intradermal injection compositions are proposed indole bases of manniche General formula I in depot form, in dissolved form or embedded in a plaster, optionally with the addition of tools to facilitate penetration. Used for oral or intradermal injection dosage forms offer compounds of General formula I can be released gradually slowed down, i.e. to have a prolonged action.

Pharmacological studies

1. Testing in vitro.

Extensive testing of the proposed invention indole bases of manniche on their effectiveness was carried out according to conventional methods of high-throughput, described John P. Devlin in High Throughput Screening, Izd-vo MarcEI Dekker Inc. (1997). Thus these methods are included in the present description by reference.

Effect of indole bases of manniche according to the invention is determined primarily by the degree of affinity to the family of NMDA receptors (N-methyl-D-aspartate receptors), it α-adrenergic and opioid receptors.

Research to identify the suppression of serotonin reuptake (the reuptake of 5-HT (5-hydroxytryptamine)) was performed using the of erodov, described M.Ch. Frink, H.-H.-Hennies, W. Englberger", M. Haurand and B. Wilffert in Arzneim.-Forsch./Drug. Res. 46 (III), 11, 1996, pp. 1029-1036. These methods included in the present description by reference.

To conduct these studies of the relevant sections of rat brain were isolated fresh synaptosome. In each case used the so-called P2-fraction, which was prepared according to the recommendations E.G. Gray and V.P. Whittaker described in Journ. Anat. 76, pages 79-88 [in Russian] (1962). This publication is included in this part of the present description by reference. To determine the reuptake of 5-HT these vesicular particles were isolated from the stem of the Department of brain and medulla oblongata (Pons and Medulla oblongata) male rats. For 5-HT vector identified the following characteristics:

reuptake 5-HT: Km=0,084±to 0.011 μm,

Vmax: 38,13±to 4.52 pmol/min/mg protein.

The results are shown respectively in the form of average values obtained in duplicate.

2. Research analgesia in mice in the test for pain.

In-depth study of the compounds according to the invention on their analgesic effectiveness was conducted in mice, studying their behavioural response in the test on pain induced by familienaam (modified method according to I.C. Hendershot and J. Forsaith, described in Journ. Pharmacol. Exp. Ther., volume 125, pages 237-240 (199)). For these purposes, as experimental animals used male NMRI mice weighing 25-30 g Groups of 10 animals each, were selected for testing one dose of the test substance in 10 min after intravenous injection of this substance was administered intraperitoneally injected at a dose of 0.3 ml/mouse of a 0.02%aqueous solution of finishinga (phenylbenzophenone, the company Sigma, Deisenhofen; preparation of the solution with the addition of 5% ethanol and the extract in a water bath at 45°). Animals were placed singly in a special cell to monitor and using a push-button counter in intervals from 5 to 20 minutes after administration of finishinga counted the number of induced pain extensor movements (so-called behavioral response to pain, i.e. in this case, the bowing of the body with stretching of the hind limbs). As control served as the animals, which were injected only with saline salt.

All substances were tested in a standard dose of 10 mg/kg, the Degree of suppression of the response to pain (% suppression) due to the introduction of the respective substance was calculated by the following formula:

Below the invention is explained in more detail by examples, which do not limit its scope.

Examples

General recommendations on the synthesis and analnyj compounds of General formula IV

General recommendations for the synthesis of 1

To 2.7 equivalent of a 40%aqueous solution of the corresponding secondary amine of General formula III slowly with stirring was added dropwise at 20°With 1.0 equivalent of the appropriate aromatic aldehyde compounds of General formula II. Then the solution was continued to stir for 30 min at 80°C, then cooled to room temperature and was mixed with 0.57 equivalent of potassium carbonate. It was formed two phases were separated, and the aqueous phase was extracted three times with 100 ml of acetic ether. The combined organic phases are dried over potassium carbonate and the solvent was removed. Thus obtained analnye compounds of General formula IV is then used without further purification in subsequent reactions.

General recommendations for the synthesis of 2

To a solution of 1.0 equivalent of the appropriate aromatic aldehyde compounds of General formula II in 80 ml of absolute toluene was added 1.6 per equivalent of the anhydride of boric acid. Then with vigorous stirring solution was added 2.4 equivalent of a secondary amine of General formula III in 85 ml of absolute toluene. The start of the reaction was accompanied by a marked increase in temperature. Next, the reaction solution was continued to stir for a further 2 hours at a temperature in the range from to 50° C. After cooling to room temperature the excess anhydride of boric acid was separated from the filtrate solvent was removed. Thus obtained analnye compounds of General formula IV without further purification was used in the subsequent reactions.

General recommendations for the synthesis of salts imine General formula V

General recommendations for the synthesis of 3

A solution of 1.0 equivalent acetylchloride in absolute diethyl ether is slowly under stirring was added dropwise to 1.0 equivalent ice solution, respectively suspensions obtained according to the guidelines for the synthesis of 1 or 2 Amidala General formula III. Then the reaction mixture continued to stir overnight at about 20°C. thus formed precipitate, which was filtered in a nitrogen atmosphere using a suction filter, and then dried in a vacuum generated by an oil pump. Thus obtained salt imine General formula V without further purification was used in the subsequent reactions.

General recommendations for the synthesis of indole bases of manniche General formula I

General recommendations for the synthesis of 4

The synthesis proposed in the invention of indole bases of mannia was performed using an automated installation company Zymark presented in figure 1 and 2.

Figure 1 shows the capping position (position 1) reacts the traditional tubes, robot 1 (item 2) and robot 2 (position 3), the first of which (the robot 1 moves the reaction tube, and the second (robot 2) pipethread reagents in the reaction tube, and is shown mounted on the work in the given temperature of the reactor module (item 4), the mixing modules (item 5) and the position of the filter (item 6), where the reaction solution is filtered.

Figure 2 also shows the robot 1 (position 1) and robot 2 (position 2)moving the vessel from the reaction products at the respective positions at which the products of synthesis obtained in the automated installation of figure 1, are subject to further processing. These products synthesis mixed with cyclone mixer (item 3) with acetone, stirred in a centrifugal reactor module (item 4) and finally acetone decanted.

For carrying out synthesis round bottom threaded tube of glass (diameter of 16 mm and a length of 125 mm) manually equipped with a stirrer and a capping position (position 1) was closed by a threaded cap with a membranous lining. This tube with the help of the robot 1 (item 2) were placed in the set to work in the temperature range of 0°reactor module. Robot 2 (item 3) were sequentially epatiroval the following reagents:

1) 1 ml of 0.1-molar solution of indole or substituted indole of the texts of General formula VI in acetonitrile and

2) in 1.2 ml of 0.1-molar solution of salt imine General formula V in acetonitrile.

Salt imine previously received according to the technology described in the following examples. Then the reaction mixture was stirred at 15°in one of the modules mixing (item 5) for 665 minutes After that, the reaction solution was filtered to position the filter (item 6). Next, the first in a vacuum centrifuge solvent was removed, and then the tripod with tubes manually moved in an automated processing plant (item 3), shown in figure 2, where the reaction mixture using a cyclone mixer was mixed with 2 ml of acetone. In a centrifugal reactor module (item 4) are thoroughly mixed for 10 min, after which the acetone decantation. This process was repeated three times and finally using a vacuum centrifuge solvent was removed.

General recommendations for the synthesis of N-alkyl indole bases of manniche General formula I

General recommendations for the synthesis of 5

A solution of 1.0 equivalent of indole Mannich bases of the General formula I, where R1denotes H, in absolute dimethylsulfoxide was treated for 15 min with 1.0 equivalent of potassium hydroxide, then mixed with 1.0 equivalent of the alkylating reagent (R12denotes Hal) and during the next 24 h was stirred at the temperature of the ome 20° C. Then, to this mixture was added 3.0 equivalent of 3-(3-mercaptophenyl)propanedinitrile, was kept for a further 3 h for the reaction of the components among themselves, was filtered from the PS-resin and the filtrate was concentrated in vacuum. The resulting residue was dissolved in a mixture of dichloromethane and water (ratio 1:1), stirred for 30 min, the phases were separated and the aqueous phase was extracted three times with 20 ml dichloromethane. The combined organic phases were dried over magnesium sulfate and finally the solvent was removed.

General recommendations for the synthesis of N-acylated indole bases of manniche General formula I

General recommendations for the synthesis of 6

A solution of 1.0 equivalent of indole Mannich bases of the General formula I, where R1denotes H, in absolute dimethylsulfoxide was treated for 15 min with 1.0 equivalent of potassium hydroxide, then mixed with 1.0 equivalent Alliluyeva reagent (R12denotes Hal) and during the next 24 h was stirred at a temperature of about 20°C. Then, to this mixture was added 3.0 equivalent immobilized on the polymer of Tris(2-amino-ethyl)amine, was kept for a further 3 h for the reaction of the components among themselves, was filtered from the PS-resin and the filtrate was concentrated in vacuum. The resulting balance of restore and in a mixture of dichloromethane and water (ratio 1:1), was stirred for 30 min, the phases were separated and the aqueous phase was extracted three times with 20 ml dichloromethane. The combined organic phases were dried over magnesium sulfate and finally the solvent was removed.

Example 1

ethyl ester of 3-(dimethylaminomethyl)-1H-indole-2-carboxylic acid

Stage 1

Benzylidenemalononitrile

The interaction of 32.0 ml (0,213 mole) of a solution of dimethylamine with 8.0 ml (0,079 mole) of benzaldehyde in accordance with the General recommendations for the synthesis of 1 and subsequent interaction with 4.7 ml (0.079 in mol) of acetylchloride in accordance with the General recommendations for the synthesis of 3 was obtained 9.5 g (corresponds to the output at 70.7% of theoretically calculated) benzylidenemalononitrile.

Stage 2

Ethyl ester of 3-(dimethylaminomethyl)-1H-indole-2-carboxylic acid

The specified connection was received in accordance with the General recommendations for the synthesis of 4 of the ethyl ester 1H-indole-2-carboxylic acid and benzylidenemalononitrile.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 323,2, 278,4 (M*).

Example 2

3-(dimethylaminophenyl)-1H-indole-2-carboxylic acid

The specified connection was received in accordance with the General recommendations for the synthesis of 4 of 1H-indole-2-carbon is th acid and benzylidenemalononitrile, obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 295,2, 250,4, to 206.6 (M*).

Example 3

[(5-fluoro-1H-indol-3-yl)phenylmethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-fluoro-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 313,3, 268,3, 224,6 (M*).

Example 4

[(1-ethyl-2-phenyl-1H-indol-3-yl)phenylmethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethyl-2-phenyl-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MC (EI)m/z: 310.5 to (M*).

Example 5

[(5-methoxy-1H-indol-3-yl)phenylmethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-methoxy-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 325,1, 280,3 (M*).

Example 6

3-(dimethylaminophenyl)-5-hydroxy-1H-indole-2-carboxylic acid

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-hydroxy-1H-indole-2-carboxylic acid and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 310,6, 266,4, 222,5 (M*).

Example 7

dimethyl-[(2-methyl-1H-indol-3-yl)phenylmethyl] Amin

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methyl-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 220,5 (M*).

Example 8

3-(dimethylaminophenyl)-1H-indol-4-ol

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-hydroxy-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 267,1, 222,5 (M*).

Example 9

dimethyl[(4-methyl-1H-indol-3-yl)phenylmethyl]Amin

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-methyl-1H-indole and benzylidenemalononitrile received in accordance with the use of the om 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 220,5 (M*).

Example 10

[(5-chloro-1H-indol-3-yl)phenylmethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-chloro-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 240,6 (M*).

Example 11

[(5-benzyloxy-1H-indol-3-yl)phenylmethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-benzyloxy-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MC(EI) m/z: 312,4 (M*).

Example 12

3-(dimethylaminophenyl)-1H-indol-4-silt ether acetic acid

The specified connection was received in accordance with the General recommendations for the synthesis of 4 of 1H-indole-4-silt ester of acetic acid and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 264,3, 222,5 (M*).

Example 13

{[2-(4-chlorophenyl-1H-indol-3-yl]phenylmethyl}dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-(4-chlorophenyl)-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MC (EI) m/z: 316,3(M*).

Example 14

5-benzyloxy-3-(dimethylaminophenyl)-1H-indole-2-carboxylic acid

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-benzyloxy-1H-indole-2-carboxylic acid and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 401,1, 356,3, 312,4 (M*).

Example 15

dimethyl[(2-methyl-5-nitro-1H-indol-3-yl)phenylmethyl]Amin

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methyl-5-nitro-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC(ESI):

MS (EI) m/z: 265,4, 235,6 (M*).

Example 16

dimethyl[(6-nitro-1H-indol-3-yl)phenylmethyl]Amin

The specified connection was received in accordance with the General recommendations for the synthesis of 4 of 6-nitro-1H-indole, benzylideneamino is ignored, obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MC (EI) m/z: 251,4(M*).

Example 17

[(6-fluoro-1H-indol-3-yl)phenylmethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 of 6-fluoro-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 224,4 (M*).

Example 18

{[2-(4-forfinal)-1H-indol-3-yl]phenylmethyl}dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-(4-forfinal)-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 300,5, 224,5 (M*).

Example 19

{[2-(3-chloro-4-forfinal)-1H-indol-3-yl]phenylmethyl}dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-(3-chloro-4-forfinal)-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 334,4 (M*).

Example 20

[(7-ethyl-1H-indol-3-yl)phenylmethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 7-ethyl-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 234,5 (M*).

Example 21

3-(dimethylaminophenyl)-1H-indole-6-carboxylic acid

The specified connection was received in accordance with the General recommendations for the synthesis of 4 of 1H-indole-6-carboxylic acid and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 264,4, 250,5 (M*).

Example 22

dimethyl[(1-methyl-1H-indol-3-yl)phenylmethyl]Amin

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methyl-1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 265,1 (M*).

Example 23

1-methyl-3-(morpholine-4-alpenlite)-1H-indole

Stage 1

4-Benzylideneamino-4-ignored

The interaction of 17.9 ml (0,200 mole) of the research and 10.1 ml (0,100 mol) of benzaldehyde in the CE is provided with General guidelines for the synthesis of 2 and subsequent reaction with 6.0 ml (0,100 mol) acetylchloride in accordance with the General recommendations for the synthesis of 3 got a 10.1 g (corresponds to a yield of 48% from theoretically calculated) 4-benzylideneamino-4-ignored.

Stage 2

1-Methyl-3 -(morpholine-4-alpenlite)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methyl-1H-indole and 4-benzylideneamino-4-ignored.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 220,4 (M*).

Example 24

3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1-methyl-1H-indol

Stage 1

1-(2-Methoxybenzylidene)pyrrolidinedione

The interaction of 6.9 ml (0,084 mole) of pyrrolidine and 4.8 g (or 0.035 mole) of 2-methoxybenzaldehyde in accordance with the General recommendations for the synthesis of 2 and subsequent reaction with 2.1 ml (or 0.035 mole) of acetylchloride in accordance with the General recommendations for the synthesis of 3 was obtained 6.2 g (corresponding to a yield of 78% of theoretical) of 1-(2-methoxybenzylidene)pyrrolidinedione.

Stage 2

3-[(2-Methoxyphenyl)pyrrolidin-1-ylmethyl]-1-methyl-1H-indol

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methyl-1H-indole and 1-(2-methoxybenzylidene)pyrrolidinedione.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 250,4 (M*).

Example 25

1-ethyl-2-phenyl-3-(pyrrolidin-1-yl-o-trimethyl)-1H-indole

Stage 1

1-(2-Methylbenzylidene)pyrrolidinedione

The interaction of 8.2 ml (0,100 is Olya) pyrrolidine and 7.0 g (0,050 mole) of 2-methylbenzaldehyde in accordance with the General recommendations for the synthesis of 2 and subsequent reaction with 3.9 g (0,050 mole) of acetylchloride in accordance with the General recommendations for the synthesis of 3 received 6,6 g (corresponds to a yield of 63% from theoretically calculated) 1-(2-methylbenzylidene)pyrrolidinedione.

Stage 2

1-Ethyl-2-phenyl-3-(pyrrolidin-1-yl-o-trimethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethyl-2-phenyl-1H-indole and 1-(2-methylbenzylidene)pyrrolidinedione.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 324,4 (M*).

Example 26

3-[(2-chlorophenyl)piperidine-1-ylmethyl]-1-ethyl-2-phenyl-1H-indol

Stage 1

1-(2-Chlorobenzylidene)piperidinedione

The interaction of 8.5 g (0,100 mol) of piperidine and 7.0 g (0,050 mole) of 2-chlorobenzaldehyde in accordance with the General recommendations for the synthesis of 2 and subsequent reaction with 3.9 g (0,050 mole) of acetylchloride in accordance with the General recommendations for the synthesis of 3 received 7,1 g (corresponds to a yield of 58% from theoretically calculated) 1-(2-chlorobenzylidene)piperidinedione.

Stage 2

3-[(2-Chlorophenyl)piperidine-1-ylmethyl]-1-ethyl-2-phenyl-1H-indol

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethyl-2-phenyl-1H-indole and 1-(2-chlorobenzylidene)piperidinedione.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: to 344.4 (M*).

Example 27

1-ethyl-2-phenyl-3-(penile Raiden-1-ylmethyl)-1H-indole

Stage 1

1-Benzylideneaniline

The interaction of 16.4 ml (0,200 mole) of pyrrolidine and 10.1 ml (0,100 mol) of benzaldehyde in accordance with the General recommendations for the synthesis of 2 and subsequent reaction with 6.0 ml (0,100 mol) acetylchloride in accordance with the General recommendations for the synthesis of 3 received 14.1 g (corresponding to a yield of 72% from theoretically calculated) 1-benzylidenemalononitrile.

Stage 2

1-Ethyl-2-phenyl-3-(phenylpyrrolidine-1-ylmethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethyl-2-phenyl-1H-indole and 1-benzylidenemalononitrile.

Characteristics of the compounds were identified by registration MC (ESI):

MC (EI) m/z: 310.5 to (M*).

Example 28

1-ethyl-3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-2-phenyl-1H-indol

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethyl-2-phenyl-1H-indole and 1-(2-methoxybenzylidene)pyrrolidinedione obtained in accordance with example 24.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 340,4 (M*).

Example 29

2-phenyl-3-(pyrrolidin-1-yl-o-trimethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-phenyl-1H-indole and 1-(2-methylbenzyl the Yong)pyrrolidinedione, obtained in accordance with example 25.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 296,5 (M*).

Example 30

Stage 1

1-(2-Methylbenzylidene)piperidinedione

The interaction of 9.5 ml (0,096 mole) of piperidine and 4.7 ml (0,040 mole) of 2-methylbenzaldehyde in accordance with the General recommendations for the synthesis of 2 and subsequent reaction with 2.4 ml (0,040 mole) of acetylchloride in accordance with the General recommendations for the synthesis of 3 was obtained 5.8 g (corresponding to a yield of 65% of theoretically calculated) 1-(2-methylbenzylidene)piperidinedione.

Stage 2

2-Phenyl-3-(piperidine-1-yl-o-trimethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-phenyl-1H-indole and 1-(2-methylbenzylidene)piperidinedione.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 296,5 (M*).

Example 31

3 -[(2-chlorophenyl)piperidine-1-ylmethyl] -2-phenyl-1H-indol

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-phenyl-1H-indole and 1-(2-chlorobenzylidene)piperidinedione obtained in accordance with example 26.

Characteristics of the compounds were identified by registration MC (ESI):

MC (EI) m/z: 316,5 (M*).

Example 32

<> dimethyl[(2-phenyl-1H-indol-3-yl)-o-trimethyl]Amin

Stage 1

Dimethyl(2-methylbenzylidene)ammoniacal

The interaction of 14.0 ml (to 0.108 mole) of a solution of dimethylamine and 4.6 ml (0,040 mole) of 2-methylbenzaldehyde in accordance with the General recommendations for the synthesis of 1 and subsequent reaction with 2.4 ml (0,040 mole) of acetylchloride in accordance with the General recommendations for the synthesis of 3 received 5.3g (corresponds to a yield of 73% from theoretically calculated) dimethyl(2-methylbenzylidene)ameriglide.

Stage 2

Dimethyl[(2-phenyl-1H-indol-3-yl)-o-trimethyl]Amin

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-phenyl-1H-indole and dimethyl(2-methylbenzylidene)ameriglide.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 296,6 (M*).

Example 33

2-phenyl-3-(phenylpyrrolidine-1-ylmethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-phenyl-1H-indole and 1-benzylidenemalononitrile obtained in accordance with example 27.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: of 282.5 (M*).

Example 34

3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-2-phenyl-1H-indol

The specified connection was received in accordance with the General recom is presented for the synthesis of 4 from 2-phenyl-1H-indole and 1-(2-methoxybenzylidene)pyrrolidinedione, obtained in accordance with example 24.

Characteristics of the compounds were identified by registration MC (ESI):

MC (EI) m/z: 312,3(M*).

Example 35

4-methyl-3-(piperidine-1-yl-o-trimethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-methyl-1H-indole and 1-(2-methylbenzylidene)piperidinedione obtained in accordance with example 30.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 234,5 (M*).

Example 36

3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-4-methyl-1H-indol

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-methyl-1H-indole and 1-(2-methoxybenzylidene)pyrrolidinedione obtained in accordance with example 24.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 250,4 (M*).

Example 37

5-benzyloxy-3-(phenylpiperidine-1-ylmethyl)-1H-indole

Stage 1

1-Benzylideneaniline

The interaction of 19.8 ml (0,200 mole) of piperidine and 10.1 ml (0,100 mol) of benzaldehyde in accordance with the General recommendations for the synthesis of 2 and subsequent reaction with 6.0 ml (0,100 mol) acetylchloride in accordance with the General recommendations for the synthesis of 3 received 11,7 g (corresponds to a yield of 56% of the t of theoretically calculated) 1-benzylidenemalononitrile.

Stage 2

5-Benzyloxy-3-(phenylpiperidine-1-ylmethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-benzyloxy-1H-indole and 1-benzylidenemalononitrile.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 397,3, 312,5 (M*).

Example 38

[(5-benzyloxy-1H-indol-3-yl)-o-trimethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-benzyloxy-1H-indole and dimethyl(2-methylbenzylidene)ameriglide obtained in accordance with example 32.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 326,5 (M*).

Example 39

7-ethyl-3-[(2-methoxyphenyl)morpholine-4-ylmethyl]-1H-indole

Stage 1

4-(2-Methoxybenzylidene)morpholine-4-ignored

Interaction 18.8 ml (0,216 mole) of the research and 12.4 g (of 0.09 mole) of 2-methoxybenzaldehyde in accordance with the General recommendations for the synthesis of 2 and subsequent reaction with 5.3 ml (0,110 mole) acetylchloride in accordance with the General recommendations for the synthesis of 3 got to 7.61 g (corresponds to the output in 38% of theoretical) of 4-(2-methoxybenzylidene)morpholine-4-ignored.

Stage 2

7-Ethyl-3-[(2-methoxyphenyl)morpholine-4-ylmethyl]-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 7-ethyl-1H-indole and 4-(2-methoxybenzylidene)morpholine-4-ignored.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 264,3 (M*).

Example 40

3-[(2-methoxyphenyl)piperidine-1-ylmethyl]-2-phenyl-1H-indol

Stage 1

1-(2-Methoxybenzylidene)piperidinedione

The interaction of 18.4 g (0,216 mole) of piperidine and 25.9 g (0,090 mole) of 2-methoxybenzaldehyde in accordance with the General recommendations for the synthesis of 2 and subsequent reaction with 5.3 ml of 0.11 mol) of acetylchloride in accordance with the General recommendations for the synthesis of 3 got a 13.4 g (corresponds to a yield of 62% from theoretically calculated) 1-(2-methoxybenzylidene)piperidinedione.

Stage 2

3-[(2-Methoxyphenyl)piperidine-1-ylmethyl]-2-phenyl-1H-indol

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-phenyl-1H-indole and 1-(2-methoxybenzylidene)piperidinedione.

Characteristics of the compounds were identified by registration MC (ESI):

MC (EI) m/z: 312,3(M*).

Example 41

5-chloro-3-[(2-methoxyphenyl)piperidine-1-ylmethyl] -1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-chloro-1H-indole and 1-(2-methoxybenzylidene)piperidinedione obtained in accordance with example 40.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 355,0, 270,3 (M*).

Example 42

p>

5-chloro-3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl]-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-chloro-1H-indole and 1-(2-methoxybenzylidene)pyrrolidinedione obtained in accordance with example 24.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 340,9, 270,2 (M*).

Example 43

5-benzyloxy-3-[(2-methoxyphenyl)pyrrolidin-1-ylmethyl] -1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-benzyloxy-1H-indole and 1-(2-methoxybenzylidene)pyrrolidinedione obtained in accordance with example 24.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 412,9, 342,3 (M*).

Example 44

[(2-methoxyphenyl)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine

Stage 1

(2-Methoxybenzylidene)dimethylammoniumchloride

The interaction of 17.0 ml (is 0.135 mole) of a solution of dimethylamine and 6.8 g ml (0,050 mole) of 2-methoxybenzaldehyde in accordance with the General recommendations for the synthesis of 1 and subsequent reaction with 3.0 ml (0,050 mole) of acetylchloride in accordance with the General recommendations for the synthesis of 3 was obtained 4.8 g (corresponds to the output in 48% of theoretical) of 2-methoxybenzylideneamino

Stage 2

[(2-Methoxyphenyl)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methyl-1H-indole and 2-methoxybenzylidene)dimethylammoniumchloride.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 250,3 (M*).

Example 45

{[1-(4-methoxybenzyl)-1H-indol-3-yl]phenylmethyl}dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 and 5 of 1H-indole, benzylidenemalononitrile and 4-methoxybenzylamine.

Characteristics of the compounds were identified by registration MC (ESI):

MS (EI) m/z: 327,1 (M*).

Example 46

[(1H-indol-3-yl)phenylmethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1H-indole and benzylidenemalononitrile obtained in accordance with example 1.

The structure was identified by13C-NMR: δ = 144,35; 136,73; 128,30; 127,89; 126,55; 126,28; 123,32; 121,20; 119,96; 118,75; 111,72; 69,67; 44,49 part./million

Example 47

3-(phenylpyrrolidine-1-ylmethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1H-indole and 1-benzylidenemalononitrile obtained in accordance with the tvii with example 27.

The structure of the compounds were determined using MC (ESI): mass calculated 276,38 g/mol, found mass M+H = 276,9 g/mol.

Example 48

1-methyl-3-(phenylpiperidine-1-ylmethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methyl-1H-indole and 1-benzylidenemalononitrile obtained in accordance with example 37.

The structure of the compounds were determined using MC (ESI): mass calculated 304,44 g/mol, found mass M+H = 304,8 g/mol.

Example 49

3-(phenylpiperidine-1-ylmethyl)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1H-indole and 1-benzylidenemalononitrile obtained in accordance with example 37.

The structure of the compounds were determined using MC (ESI): mass calculated 290,41 g/mol, found mass M+H = 290,9 g/mol.

Example 50

5-Benzyloxy-3-(vinylpyrrolidone)-1H-indole

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-benzyloxyindole and benzylidenemalononitrile obtained in accordance with example 27.

Example 51

[(5-Bromo-2-forfinal)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-neither is rondalla and (5-bromo-2-formanilide)dimethylammoniumchloride, obtained in accordance with example 24 from 5-bromo-2-forventelige and dimethylamine.

Example 52

[(5-Bromo-2-forfinal)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methylindole and (5-bromo-2-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 5-bromo-2-forventelige and dimethylamine.

Example 53

[(2-Chloro-6-forfinal)-(2-phenyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-phenylindole and (2-chloro-6-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 2-chloro-6-forventelige and dimethylamine.

Example 54

[(2-Chloro-6-forfinal)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethylindole and (2-chloro-6-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 2-chloro-6-forventelige and dimethylamine.

Example 55

[(2-Chloro-6-forfinal)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-nitroindole and (2-chloro-6-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 2-chloro-6-FPO is benzaldehyde and dimethylamine.

Example 56

[(2-Chloro-6-forfinal)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methylindole and (2-chloro-6-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 2-chloro-6-forventelige and dimethylamine.

Example 57

[(2-Bromophenyl)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-nitroindole and (2 brabanthallen)dimethylammoniumchloride obtained in accordance with example 24 from 2-bromobenzaldehyde and dimethylamine.

Example 58

[(2-Bromophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methylindole and (2 brabanthallen)dimethylammoniumchloride obtained in accordance with example 24 from 2-bromobenzaldehyde and dimethylamine.

Example 59

[(3-Bromophenyl)-(7-ethyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 7-ethylindole and (3-bromobenzylamine)dimethylammoniumchloride obtained in accordance with example 24 3-bromobenzaldehyde and dimethylamine.

Example 60

[(3-Bromophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in compliance and General recommendations for the synthesis of 4 from 1-methylindole and (3-bromobenzylamine)dimethylammoniumchloride, obtained in accordance with example 24 3-bromobenzaldehyde and dimethylamine.

Example 61

[(4-tert-Butylphenyl)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methylindole and (4-tert-butylbenzamide)dimethylammoniumchloride obtained in accordance with example 24 4-tert-butylbenzaldehyde and dimethylamine.

Example 62

[(4-tert-Butylphenyl)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethyl-2-phenylindole and (4-tert-butylbenzamide)dimethylammoniumchloride obtained in accordance with example 24 4-tert-butylbenzaldehyde and dimethylamine.

Example 63

[(4-tert-Butylphenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methylindole and (4-tert-butylbenzamide)dimethylammoniumchloride obtained in accordance with example 24 4-tert-butylbenzaldehyde and dimethylamine.

Example 64

[(2-Chloro-4-forfinal)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-nitroindole and (2-chloro-4-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 2-chloro-4-CFT is benzaldehyde and dimethylamine.

Example 65

[(2-Chloro-4-forfinal)-(4-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-methylindole and (2-chloro-4-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 2-chloro-4-forventelige and dimethylamine.

Example 66

[(2-Chloro-6-forfinal)-(2-phenyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-phenylindole and (2-chloro-6-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 2-chloro-6-forventelige and dimethylamine.

Example 67

{(2-Chloro-6-forfinal)-[2-(4-chlorophenyl)-1H-indol-3-yl]methyl}dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-(4-chlorophenyl)indole and 2-chloro-6-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 2-chloro-6-forventelige and dimethylamine.

Example 68

[(2-Chloro-6-forfinal)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methylindole and (2-chloro-6-formanilide)dimethylammoniumchloride obtained in accordance with example 24 from 2-chloro-6-forventelige and dimethylamine.

Example 69

[(3-Chlorophenyl)-(1-methyl-1H-indol-3-the l)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methylindole and (3-chlorobenzylidene)dimethylammoniumchloride obtained in accordance with example 24 3-chlorobenzaldehyde and dimethylamine.

Example 70

[(2,3-Dichlorophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methylindole and (2,3-dichlorobenzamide)dimethylammoniumchloride obtained in accordance with example 24 from 2,3-dichlorobenzaldehyde and dimethylamine.

Example 71

[(2,4-Dichlorophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methylindole and (2,4-dichlorobenzamide)dimethylammoniumchloride obtained in accordance with example 24 of 2,4-dichlorobenzaldehyde and dimethylamine.

Example 72

[(4-tert-Butylphenyl)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethyl-2-phenyl-1H-indole and (4-tert-butylbenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 4-tert-butylbenzaldehyde and dimethylamine.

Example 73

[(2-Chloro-4-forfinal)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations is on the synthesis of 4 from 2-methyl-1H-indole and 2-chloro-4-formanilide)dimethylammoniumchloride, obtained in accordance with example 44 from 2-chloro-4-forventelige and dimethylamine.

Example 74

[(2-Chloro-6-forfinal)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methyl-1H-indole and 2-chloro-6-formanilide)dimethylammoniumchloride obtained in accordance with example 44 from 2-chloro-6-forventelige and dimethylamine.

Example 75

[(2,3-Acid)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 of 4-nitro-1H-indole and (2,3-dimethoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 2,3-dimethoxybenzaldehyde and dimethylamine.

Example 76

3-[(2,3-Acid)dimethylaminomethyl]-4,7-dihydro-1H-indole-6-carboxylic acid

The specified connection was received in accordance with the General recommendations for the synthesis of 4 of 1H-indole-6-carboxylic acid (2,3-dimethoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 2,3-dimethoxybenzaldehyde and dimethylamine.

Example 77

3-[(2,3-Acid)dimethylaminomethyl]-5-hydroxy-1H-indole-2-carboxylic acid

The specified connection was received in accordance with the General recommendations for the synthesis of 4 of 1H-indole-5-hydroxy-2-carboxylic acid (2,3-dimethoxy siligen)dimethylammoniumchloride, obtained in accordance with example 44 from 2,3-dimethoxybenzaldehyde and dimethylamine.

Example 78

[(3,4-Acid)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methyl-1H-indole and (3,4-dimethoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3,4-dimethoxybenzaldehyde and dimethylamine.

Example 79

[[2-(4-Chlorophenyl)-1H-indol-3-yl]-(3,4-acid)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-(4-chlorophenyl)-1H-indole and (3,4-dimethoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3,4-dimethoxybenzaldehyde and dimethylamine.

Example 80

[(3,4-Acid)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethyl-2-phenyl-1H-indole and (3,4-dimethoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3,4-dimethoxybenzaldehyde and dimethylamine.

Example 81

[(3,4-Acid)-(7-ethyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 7-ethyl-1H-indole and (3,4-dimethoxybenzamide)dimethylammoniumchloride obtained in the accordance with example 44 from 3,4-dimethoxybenzaldehyde and dimethylamine.

Example 82

[(3,4-Acid)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methyl - 1H-indole and (3,4-dimethoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3,4-dimethoxybenzaldehyde and dimethylamine.

Example 83

[(3,4-Acid)-[2-(4-forfinal)-1H-indol-3-yl]methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-(4-forfinal)-1H-indole and (3,4-dimethoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3,4-dimethoxybenzaldehyde and dimethylamine.

Example 84

[[2-(3-Chloro-4-forfinal)-1H-indol-3-yl]-(3,4-acid)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-(3-chloro-4-forfinal)-1H-indole and (3,4-dimethoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3,4-dimethoxybenzaldehyde and dimethylamine.

Example 85

[(5-Chloro-1H-indol-3-yl)-(2-forfinal)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-chloro-1H-indole and 2-formanilide)dimethylammoniumchloride obtained in accordance with example 44 from 2-forventelige and dimethylamine.

Example 86

[(4-Perfe who yl)-(4-methyl-1H-indol-3-yl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-methyl-1H-indole and (4-formanilide)dimethylammoniumchloride obtained in accordance with example 44 4-forventelige and dimethylamine.

Example 87

[(7-Ethyl-1H-indol-3-yl)-(2-methoxyphenyl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 7-ethyl-1H-indole and 2-methoxybenzylidene)dimethylammoniumchloride obtained in accordance with example 44 from 2-methoxybenzaldehyde and dimethylamine.

Example 88

Dimethyl[(2-methyl-1H-indol-3-yl)-o-trimethyl]Amin

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methyl-1H-indole and 2-methylbenzylidene)dimethylammoniumchloride obtained in accordance with example 44 from 2-methylbenzaldehyde and dimethylamine.

Example 89

[(7-Ethyl-1H-indol-3-yl)-o-trimethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 7-ethyl-1H-indole and 2-methylbenzylidene)dimethylammoniumchloride obtained in accordance with example 44 from 2-methylbenzaldehyde and dimethylamine.

Example 90

Dimethyl[(1-methyl-1H-indol-3-yl)-o-trimethyl]Amin

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methyl-1H-indole and 2-methylbenzylidene)d is mediamonitoring, obtained in accordance with example 44 from 2-methylbenzaldehyde and dimethylamine.

Example 91

[(5-Chloro-1H-indol-3-yl)-o-trimethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-chloro-1H-indole and 2-methylbenzylidene)dimethylammoniumchloride obtained in accordance with example 44 from 2-methylbenzaldehyde and dimethylamine.

Example 92

[(5-Chloro-1H-indol-3-yl)-m-trimethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-chloro-1H-indole and (3-methylbenzylidene)dimethylammoniumchloride obtained in accordance with example 44 from 3-methylbenzaldehyde and dimethylamine.

Example 93

Dimethyl[(2-methyl-1H-indol-3-yl)-n-trimethyl]Amin

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methyl-1H-indole and (4-methylbenzylidene)dimethylammoniumchloride obtained in accordance with example 44 4-methylbenzaldehyde and dimethylamine.

Example 94

[(5-Chloro-1H-indol-3-yl)-n-trimethyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-chloro-1H-indole and (4-methylbenzylidene)dimethylammoniumchloride obtained in accordance with example 44 4-methylbenzaldehyde and dimethylamine.

Example 95

Dimethyl[(2-methyl-1H-indol-3-yl)-(3-phenoxide who yl)methyl]amine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methyl-1H-indole and (3-phenoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3-phenoxybenzaldehyde and dimethylamine.

Example 96

[(1-Ethyl-2-phenyl-1H-indol-3-yl)-(3-phenoxyphenyl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-ethyl-2-phenyl-1H-indole and (3-phenoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3-phenoxybenzaldehyde and dimethylamine.

Example 97

[(7-Ethyl-1H-indol-3-yl)-(3-phenoxyphenyl)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 7-ethyl-1H-indole and (3-phenoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3-phenoxybenzaldehyde and dimethylamine.

Example 98

Dimethyl[(1-methyl-1H-indol-3-yl)-(3-phenoxyphenyl)methyl]amine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 1-methyl-1H-indole and (3-phenoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3-phenoxybenzaldehyde and dimethylamine.

Example 99

[[2-(4-Forfinal)-1H-indol-3-yl]-(3-phenoxyphenyl)methyl]dimethylamine

The specified connection was received in accordance with the General advice is through publications on the synthesis of 4 from 2-(4-forfinal)-1H-indole and (3-phenoxybenzamide)dimethylammoniumchloride, obtained in accordance with example 44 from 3-phenoxybenzaldehyde and dimethylamine.

Example 100

[[2-(3-Chloro-4-forfinal)-1H-indol-3-yl]-(3-phenoxyphenyl)methyl]amine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-(3-chloro-4-forfinal)methyl-1H-indole and (3-phenoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3-phenoxybenzaldehyde and dimethylamine.

Example 101

Dimethyl[(4-methyl-1H-indol-3-yl)-(3-phenoxyphenyl)methyl]amine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 4-methyl-1H-indole and (3-phenoxybenzamide)dimethylammoniumchloride obtained in accordance with example 44 from 3-phenoxybenzaldehyde and dimethylamine.

Example 102

[(5-Chloro-1H-indol-3-yl)-(2-triptoreline)methyl]dimethylamine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 out of 5-chloro-1H-indole and 2-triphtalocyaninine)dimethylammoniumchloride obtained in accordance with example 44 from 2-triftormetilfullerenov and dimethylamine.

Example 103

Dimethyl[(2-methyl-1H-indol-3-yl)-(4-triptoreline)methyl]amine

The specified connection was received in accordance with the General recommendations for the synthesis of 4 from 2-methyl-1H-indole and (4-triphtalocyaninine)dimethylammoniumchloride received in accordance with paragraph what iMER 44 4-triftormetilfullerenov and dimethylamine.

Pharmacological studies

1. Testing in vitro.

The testing proposed in the invention of indole bases of manniche on their effectiveness conducted in the manner described above. The research results confirm the possibility of using compounds of General formula I as ligands α2-subtype human α-adrenergic receptors, plays an important role in pain perception.

The affinity of the compounds according to the invention to this α2-subtype α-adrenergic receptors was determined in a test using antigenic complex that protects the stroma, which is the test described by John P. Devlin in High Throughput Screening, Izd-vo MarcEI Dekker Inc., 1997, pp. 307-316. This publication is included in this part of the present description by reference. The affinity of the compounds according to the invention was determined in each case at a concentration of 10 ám.

Some studies presented in the following table 1

52
Table 1
Example No.Inhibition (%) α2 (human), 10 µm
3667
5051
3495
3040
768
1540
5143
37
5338
5455
5549
5639
5764
5882
5937
6066
6163
6251
6360
6448
6542
6644
6736
6888
6975
7063
7150

The research proposed in the invention compounds showed further their ability to inhibit the reuptake of serotonin.

The results of some studies identifying the specified suppress serotonin reuptake presented in the following table 2.

Table 2
Example No.The suppression of the reuptake of 5-HT in %
4448
7260
7341
7472
7539
7642
Example No.The suppression of the reuptake of 5-HT in %
7738
7873
7950
8042
8168
8242
8339
8444
8544
8641
8750
8862
8945
9044
9149
9246
9378
9464
9570
9655
9779
9866
9942
10048
10141
10242
10374

2. Research analgesia in mice in the test for pain.

In-depth study proposed in the invention compounds for their analgesic effectiveness is Yunosti conducted in the test for pain, induced familienaam, by the method described above. The obtained data showed that the compounds according to the invention have an analgesic effect.

Some studies test pain syndrome is presented in the following table 3.

Table 3
Example No.Suppression of response to pain in the %
2239
2375
4641
4757
Example No.Suppression of response to pain in the %
486
4982

1. Substituted indole Mannich bases of the General formula I

in which R1denotes H, C1-C6alkyl or linked via C1-C2alkylenes group unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R2denotes H, F, Cl, Br, CF3CN, OR10, CO(OR11), CH2CO(OR12), COR19With1-C6alkyl, unsubstituted or at least one-deputizing HE, g is lagena, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R3denotes CH(R13)N(R14)(R15),

R4, R5, R6, R7can have identical or different meanings and denote H, F, Cl, Br, CF3, CN, NO2, OR10, CO(OR11), CH2WITH(OR12), COR19With1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R10denotes H, COR17With1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl, which is connected through With1-C2alkylenes group unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R11denotes H, C1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R12denotes H, C1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN,C 1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R13denotes unsubstituted phenyl, or at least one-deputizing1-C4by alkyl, halogen, CF3CN HE or phenyl,

R14, R15can have identical or different meanings and refer to a branched or unbranched1-C6alkyl or

R14and R15together are (CH2)nwhere n denotes an integer from 3 to 6, or (CH2)2O(CH2)2,

R17stands With1-C6alkyl,

R19means other20With1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R20denotes H, C1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

and/or their racemates, the enantiomers, the diastereomers and/or the base and/or corresponding salts of physiologically acceptable acids, with the exception of the racemates of compounds in which

R3denotes CH(R13)N(R14)(R15and respectively

R 4-R7and R2denote H, R13denotes phenyl, R14and R15together denote (CH2)5and R1denotes N, CH3or benzyl or

R4-R7and R2denote N, R13denotes phenyl, R14, R15each represents CH3and R1denotes N, CH3or benzyl or

R4-R7and R1denote N, R13denotes 2-chlorophenyl, R14and R15each represents CH3or R14and R15together are (CH2)2O(CH2)2, R2means COOR11and R11stands With2H5and relevant hydrochloride or

R4-R7and R1denote N, R13denotes phenyl, R14and R15together are (CH2)5, R2means COOR11and R11denotes CH3or

R4-R7and R2denote N, R13denotes phenyl, R14and R15together are (CH2)4, R1denotes N, CH3or 4-chlorbenzyl and when the value of R1=CH3well as the corresponding hydrochloride of the compound or

R4-R7and R1denote N, R13denotes phenyl, 2-hydroxyphenyl or 2-hydroxy-5-were, R14and R 15together are (CH2)5and R2denotes CH3and a value of R13phenyl well as the corresponding hydrosulfate or

R4-R7and R1denote N, R13denotes phenyl, R14and R15together are (CH2)2O(CH2)2and R2denotes CH3and the corresponding hydrosulfate connection or

R4-R7and R1denote N, R13denotes phenyl, R14and R15together are (CH2)5, R2means COOR11and R11denotes CH3in the form of hydrochloride.

2. Substituted indole Mannich bases according to claim 1, wherein R1represents H, a R2-R7, R10-R15, R17, R19, R20have the meanings indicated in claim 1.

3. Substituted indole Mannich bases according to claim 1, wherein R1represents a C1-C6alkyl, preferably1-C2alkyl, and R2-R7, R10-R15, R17, R19, R20have the meanings indicated in claim 1.

4. Substituted indole Mannich bases according to claim 1, wherein R1is an associated through With1-C2alkylenes group unsubstituted or at least one-deputizing is H, halogen, CF3CN, C1-C6the alkyl, C1-C6alkoxygroup phenyl or naphthyl, a R2-R7, R10-R15, R17, R19, R20have the meanings indicated in claim 1.

5. Substituted indole Mannich bases according to any one of claims 1 to 4, wherein R2represents H, a R3-R7, R10-R15, R17, R19, R20have the meanings indicated in claim 1.

6. Substituted indole Mannich bases according to any one of claims 1 to 4, wherein R2represents a C1-C6alkyl, preferably1-C2alkyl, a R3-R7, R10-R15, R17, R19, R20have the meanings indicated in claim 1.

7. Substituted indole Mannich bases according to any one of claims 1 to 4, wherein R2represents phenyl, a R3-R7, R10-R15, R17, R19, R20have the meanings indicated in claim 1.

8. Substituted indole Mannich bases according to any one of claims 1 to 4, wherein R2represents Cl or F, and the remaining radicals R3-R7, R10-R15, R17, R19, R20have the meanings indicated in claim 1.

9. Substituted indole Mannich bases according to any one of claims 1 to 4, wherein R2is a OR10and the remaining radicals R3-R , R10-R15, R17, R19, R20have the meanings indicated in claim 1.

10. Substituted indole Mannich bases according to any one of claims 1 to 4, wherein R2represents CO(OR11), and the remaining radicals R3-R7, R10-R15, R17, R19, R20have the meanings indicated in claim 1.

11. Substituted indole Mannich bases according to any one of claims 1 to 10, characterized in that at least one of the radicals R4, R5, R6or R7represents N and the remaining radicals R4, R5, R6or R7and R10-R15, R17, R19, R20have respectively the values specified in claim 1.

12. Substituted indole Mannich bases according to any one of claims 1 to 10, characterized in that at least one of the radicals R4, R5, R6or R7represents a C1 or F, and the remaining radicals R4, R5, R6or R7and R10-R15, R17, R19, R20have respectively the values specified in claim 1.

13. Substituted indole Mannich bases according to any one of claims 1 to 10, characterized in that at least one of the radicals R4, R5, R6or R7represents a C1-C6alkyl, preferably1-C2alkyl, and the remaining radicals R4, R5, R6or 7and R10-R15, R17, R19, R20have respectively the values specified in claim 1.

14. Substituted indole Mannich bases according to any one of claims 1 to 10, characterized in that at least one of the radicals R4, R5, R6or R7represents NO2and the remaining radicals R4, R5, R6or R7and R10-R15, R17, R19, R20have respectively the values specified in claim 1.

15. Substituted indole Mannich bases according to any one of claims 1 to 10, characterized in that at least one of the radicals R4, R5, R6or R7is a OR10and the remaining radicals R4, R5, R6or R7and R10-R15, R17, R19, R20have respectively the values specified in claim 1.

16. Substituted indole Mannich bases according to any one of claims 1 to 10, characterized in that at least one of the radicals R4, R5, R6or R7represents CO(OR11), and the remaining radicals R4, R5, R6or R7and R10-R15, R17, R19, R20have respectively the values specified in claim 1.

17. Substituted indole Mannich bases according to any one of claims 1 to 10, characterized in that at least one of the radicals R4, R5, R6or R7p is ecstasy an unsubstituted or at least one-deputizing HE halogen, CF3CN, C1-C6the alkyl, C1-C6alkoxygroup phenyl or naphthyl, and the remaining radicals R4, R5, R6or R7, R10-R15, R17, R19, R20have respectively the values specified in claim 1.

18. Substituted indole Mannich bases according to any one of claims 1 to 17, wherein R10represents H, a R11-R15, R17, R19, R20have the meanings indicated in claim 1.

19. Substituted indole Mannich bases according to any one of claims 1 to 17, wherein R10represents a C1-C6alkyl, a R11-R15, R17, R19, R20have the meanings indicated in claim 1.

20. Substituted indole Mannich bases according to any one of claims 1 to 17, wherein R10is an associated through With1-C2alkylenes group unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl, C1-C6alkoxygroup phenyl or naphthyl, a R11-R15, R17, R19, R20have the meanings indicated in claim 1.

21. Substituted indole Mannich bases according to any one of claims 1 to 20, characterized in that R11represents H, a R12-R15, R17, R19, R20have the meanings indicated in claim 1.

22. Substituted indole OS is Finance, manniche according to any one of claims 1 to 20, wherein R11represents a C1-C6alkyl, a R12-R15, R17, R19, R20have the meanings indicated in claim 1.

23. Substituted indole Mannich bases according to any one of claims 1 to 22, characterized in that R12represents a C1-C6alkyl, a R13-R15, R17, R19, R20have the meanings indicated in claim 1.

24. Substituted indole Mannich bases according to any one of claims 1 to 23, characterized in that R13represents unsubstituted phenyl, or at least one-deputizing the stands, tert-bootrom, F, Cl, Br or CF3phenyl, preferably unsubstituted phenyl or 2-were, 3-were, 4-were, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-bromo-2-forfinal, 2-chloro-4-forfinal, 2-chloro-5-forfinal, 2-chloro-6-forfinal, 4-bromo-2-forfinal, 3-bromo-4-forfinal, 3-bromo-2-forfinal, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimetilfenil, 2,4-dimetilfenil, 2,5-dimetilfenil, 2-triptoreline, 3-triptoreline or 4-triptoreline, particularly preferably unsubstituted phenyl, a R14, R15, R17, R19, R20have the meanings indicated in claim 1.

25. Substituted indole Mann Foundation the ha according to any one of claims 1 to 24, characterized in that at least one of the radicals R14or R15represents a branched or unbranched1-C6alkyl, preferably CH3and the other radical R14or R15respectively, and R17, R19, R20have the meanings indicated in claim 1.

26. Substituted indole Mannich bases according to any one of claims 1 to 24, characterized in that R14and R15together are (CH2)nwhere n represents 4 or 5, a R17, R19, R20have the meanings indicated in claim 1.

27. Substituted indole Mannich bases according to any one of claims 1 to 26, characterized in that R17represents a C1-C6alkyl, and R19, R20have the meanings indicated in claim 1.

28. Substituted indole Mannich bases according to any one of claims 1 to 27, characterized in that R19represents a C1-C6alkyl, and R20matter specified in claim 1.

29. Substituted indole Mannich bases according to any one of claims 1 to 28, characterized in that R20represents a C1-C6alkyl.

30. Substituted indole Mannich bases according to claim 1 of the group, including

ethyl ester of 3-(dimethylaminomethyl)-1H-indole-2-carboxylic acid,

3-(dimethylaminophenyl)-1 H-indole-2-carboxylic acid,

[(5-fluoro-1H-indol-3-yl)FeNi is methyl]dimethylamine,

[(1-ethyl-2-phenyl-1H-indol-3-yl)phenylmethyl]dimethylamine,

[(5-methoxy-1H-indol-3-yl)phenylmethyl]dimethylamine,

3-(dimethylaminophenyl)-5-hydroxy-1H-indole-2-carboxylic acid,

dimethyl[(2-methyl-1H-indol-3-yl)phenylmethyl]Amin,

3-(dimethylaminophenyl)-1H-indol-4-ol,

dimethyl[(4-methyl-1H-indol-3-yl)phenylmethyl]Amin,

[(5-chloro-1H-indol-3-yl)phenylmethyl]dimethylamine,

[(5-benzyloxy-1H-indol-3-yl)phenylmethyl]dimethylamine,

3-(dimethylaminophenyl)-1H-indol-4-silt ether acetic acid,

{[2-(4-chlorophenyl)-1H-indol-3-yl]phenylmethyl}dimethylamine,

5-benzyloxy-3-(dimethylaminophenyl)-1H-indole-2-carboxylic acid,

dimethyl[(2-methyl-5-nitro-1H-indol-3-yl)phenylmethyl]Amin,

dimethyl[(2-methyl-6-nitro-1H-indol-3-yl)phenylmethyl]Amin,

[(6-fluoro-2-methyl-1H-indol-3-yl)phenylmethyl]dimethylamine,

{[2-(4-forfinal)-1H-indol-3-yl]phenylmethyl}dimethylamine,

{[2-(3-chloro-4-forfinal)-1H-indol-3-yl]phenylmethyl}dimethylamine,

[(7-ethyl-1H-indol-3-yl)phenylmethyl]dimethylamine,

3-(dimethylaminophenyl)-1H-indole-6-carboxylic acid,

dimethyl[(1-methyl-1H-indol-3-yl)phenylmethyl]Amin,

1-methyl-3-(morpholine-4-alpenlite)-1H-indole,

1-ethyl-2-phenyl-3-(pyrrolidin-1-yl-o-trimethyl)-1H-indole,

3-[(2-chlorophenyl)Piperi the Jn-1-ylmethyl]-1-ethyl-2-phenyl-1H-indole,

1-ethyl-2-phenyl-3-(phenylpyrrolidine-1-ylmethyl)-1H-indole,

2-phenyl-3-(pyrrolidin-1-yl-o-trimethyl)-1H-indole,

2-phenyl-3-(piperidine-1-yl-o-trimethyl)-1H-indole,

3-[(2-chlorophenyl)piperidine-1-ylmethyl]-2-phenyl-1H-indole,

dimethyl[(2-phenyl-1H-indol-3-yl)-o-trimethyl] Amin,

2-phenyl-3-(phenylpyrrolidine-1-ylmethyl)-1H-indole,

4-methyl-3-(piperidine-1-yl-o-trimethyl)-1H-indole,

5-benzyloxy-3-(phenylpiperidine-1-ylmethyl)-1H-indole,

[(5-benzyloxy-1H-indol-3-yl)-o-trimethyl]dimethylamine,

{[1-(4-methoxybenzyl)-1H-indol-3-yl]phenylmethyl}dimethylamine,

3-(phenylpiperidine-1-ylmethyl)-1H-indole,

1-methyl-3-(phenylpiperidine-1-ylmethyl)-1H-indole,

3-(phenylpyrrolidine-1-ylmethyl)-1H-indole,

[(1H-indol-3-yl)phenylmethyl]dimethylamine,

5-benzyloxy-3-(phenylpyrrolidine-1-ylmethyl)-1H-indole,

[(5-bromo-2-forfinal)-(4-nitro-1H-indol-3-yl)methyl]dimethyl amine,

[(5-bromo-2-forfinal)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-bromophenyl)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine,

[(2-bromophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(3-bromophenyl)-(7-ethyl-1H-indol-3-yl)methyl]dimethylamine,

[(3-bromophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(4-tert-butylphenyl)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(4-tert-butylphenyl)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

[(4-tert-butylphenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-4-forfinal)-(4-nitro-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-4-forfinal)-(4-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

{(2-chloro-6-forfinal)-[2-(4-chlorophenyl)-1H-indol-3-yl]methyl}dimethylamine,

[(2-chloro-6-forfinal)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(3-chlorophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2,3-dichlorophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2,4-dichlorophenyl)-(1-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(4-tert-butylphenyl)-(1-ethyl-2-phenyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-4-forfinal)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(2-chloro-6-forfinal)-(2-methyl-1H-indol-3-yl)methyl]dimethylamine,

[(5-chloro-1H-indol-3-yl)-(2-forfinal)methyl]dimethylamine,

[(4-forfinal)-(4-methyl-1H-indol-3-yl)methyl]dimethylamine,

dimethyl[(2-methyl-1H-indol-3-yl)-o-trimethyl]Amin,

p num="881"> [(7-ethyl-1H-indol-3-yl)-o-trimethyl]dimethylamine,

dimethyl[(1-methyl-1H-indol-3-yl)-o-trimethyl]Amin,

[(5-chloro-1H-indol-3-yl)-o-trimethyl]dimethylamine,

[(5-chloro-1H-indol-3-yl)-m-trimethyl]dimethylamine,

dimethyl [(2-methyl-1H-indol-3-yl)-p-trimethyl]Amin,

[(5-chloro-1H-indol-3-yl)-n-trimethyl]dimethylamine,

[(5-chloro-1H-indol-3-yl)-(2-triptoreline)methyl]dimethylamine,

dimethyl[(2-methyl-1H-indol-3-yl)-(4-triptoreline)methyl]amine.

31. The method of obtaining indole bases of manniche General formula I according to any one of claims 1 to 30, characterized in that the aromatic aldehyde compounds of General formula II

where R13has the values stated for the General formula I according to claim 1,

in dissolved form in the presence of an appropriate base at a temperature preferably in the range from -10 to +110°subjected to interaction with secondary amines of General formula III

in which R14and R15have the meanings mentioned for the General formula I according to claim 1,

obtaining aminolink compounds of General formula IV

then these analnye compounds of General formula IV without further purification under the action of the corresponding acid chloride to the slots in absolute solvent turned into salt imine General formula V

these salts imine General formula V without further purification in dissolved form, preferably in acetonitrile and/or toluene, is subjected to the interaction with the indole or substituted indole compounds of the General formula VI

in which R3denotes N, and R1, R2-R7, R10-R15, R17, R19, R20have the meanings mentioned for the General formula I,

and thus obtained substituted indole Mannich bases of the General formula I according to any one of claims 1 to 30 purified by extraction and/or washing, preferably by washing with acetone, and was isolated by the usual methods.

32. The method of obtaining substituted indole bases of manniche General formula I according to any one of claims 1 to 30, characterized in that the aromatic aldehyde compounds of General formula II

in which R13has the values stated for the General formula I,

in dissolved form in the presence of an appropriate base at a temperature of preferably from -10 to +110°subjected to interaction with secondary amines of General formula III

in which R14and R15have the meanings mentioned for the General formula I,

obtaining aminolink compounds of General formula IV

then these analnye compounds of General formula IV without further purification under the action of the corresponding carboxylic acid is transformed into salt imine General formula V

these salts imine General formula V without further purification in dissolved form, preferably in acetonitrile and/or toluene, is subjected to the interaction with the indole or substituted indole compounds of the General formula VI

in which R1and R3each represents H, a R2, R4-R7, R10-R15, R17, R19, R20have the meanings mentioned for the General formula I,

thus obtained compounds of General formula I, in which R1denotes H, a R2-R7, R10-R15, R17, R19, R20have the meanings mentioned for the General formula I, in dissolved form is subjected to interaction with compounds of General formula XR22where R22represents a C1-C6alkyl or linked via C1-C2alkylenes group unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl, C1-C6alkoxygroup phenyl or naphthyl, and X denotes Cl, Br or I, at a temperature of p is edocfile from 10 to 150° In the presence of an appropriate base and the thus obtained compounds of General formula I, in which R1represents a C1-C6alkyl or linked via C1-C2alkylenes group unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl, C1-C6alkoxygroup phenyl or naphthyl, and the remaining radicals R2-R7, R10-R15, R17, R19, R20have the meanings mentioned for the General formula I, purified by filtration and was isolated by conventional methods.

33. The method according to p, characterized in that the interaction with compounds of General formula XR22carried out in dimethyl sulfoxide.

34. The method according to p or 33, characterized in that X denotes Cl.

35. The method according to any of PP-34, wherein R22represents a C1-C6alkyl or linked via C1-C2alkylenes group unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl, C1-C6alkoxygroup phenyl or naphthyl.

36. The method according to any of PP-35, characterized in that the interaction with compounds of General formula XR22carried out in the presence of potassium hydroxide as the base.

37. The method according to any of PP-36, characterized in that the connection of the texts of General formula I is purified by filtering through the resin-absorbent, preferably by filtering through immobilized on the polymer of Tris(2-amino-ethyl)amine and/or 3-(3-mercaptophenyl)propane-megametropolis.

38. The method according to any of PP-37, characterized in that the aromatic aldehyde compounds of General formula II is subjected to the organic solvent, preferably in toluene, interaction with secondary amines of General formula III.

39. The method according to any of p-38, characterized in that the aromatic aldehyde compounds of General formula II is subjected to reaction in the presence of potassium carbonate and/or anhydride of boric acid as a base.

40. The method according to any of p-39, characterized in that analnye compounds of General formula IV interaction with acetylchloride turn in salt imine General formula V.

41. The method according to any of p-40, characterized in that analnye compounds of General formula IV are converted into absolute diethyl ether in salt imine General formula V.

42. Drugs having analgesic activity, containing as active substance at least one substituted indole base manniche General formula I

in which R1denotes H, C1-C6alkyl or linked via C1-C2alkylenes group unsubstituted or n is at least one-deputizing HE halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R2denotes H, F, Cl, Br, CF3CN, OR10, CO(OR11), CH2CO(OR12), COR19C1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R3denotes CH(R13)N(R14)(R15),

R4, R5, R6, R7can have identical or different meanings and denote H, F, Cl, Br, CF3, CN, NO2, OR10, CO(OR11), CH2CO(OR12), COR19C1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R10denotes H, COR17C1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl, which is connected through C1-C2alkylenes group unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R11denotes H, C1-C6alkyl, n is replaced or at least one-deputizing HE halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R12denotes H, C1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R13denotes unsubstituted phenyl, or at least one-deputizing C1-C4by alkyl, halogen, CF3CN HE or phenyl,

R14, R15can have identical or different meanings and refer to a branched or non-branched C1-C6alkyl, or

R14and R15together are (CH2)nwhere n denotes an integer from 3 to 6, or (CH2)2O(CH2)2,

R17represents C1-C6alkyl,

R19means other20C1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl,

R20denotes H, C1-C6alkyl, unsubstituted or at least one-deputizing HE, halogen, CF3CN, C1-C6the alkyl or C1-C6alkoxygroup phenyl or naphthyl, and/or their racemates, the enantiomers, the diastereomers and/or sootvetstvuyushie base and/or corresponding salts of physiologically acceptable acids and optionally other active substances and/or auxiliary substances.



 

Same patents:

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new 5-aryl-1-phenyl-4-heteroyl-3-hydroxy-3-pyrroline-2-ones of the formula:

wherein (1) X means sulfur atom (S); R means (CH3)2CH; (2) X means sulfur atom (S); R means (CH3)3C; (3) X means oxygen atom (O); R means (CH3)3C. Compounds of the formula (I) are prepared by interaction of the corresponding heteroylpyruvic acid methyl ester with mixture of aniline and aromatic aldehyde in acetic acid medium at short-time heating. Compounds elicit an anti-bacterial activity with value MIC = 3.9-7.8 mcg/ml as compared with 62-1000 mcg/ml for analogue.

EFFECT: valuable properties of compounds.

1 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

New compounds // 2258703

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I):

wherein R1 is taken among phenyl or pyridinyl and wherein each phenyl ring R1 or pyridinyl ring R1 can be substituted additionally and independently with chlorine, fluorine, bromine and iodine atom at any position of indicated ring, and also to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical composition based on these compounds eliciting δ-agonistic activity and to a method for pain treatment. Invention provides preparing new compounds of the formula (I) used in applying for pain treatment and for manufacturing drugs for this purpose.

EFFECT: valuable medicinal properties of new compounds.

8 cl, 3 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide that involves conversion of methylcyano acetate to the end compound for 8 or less stages. Also, invention relates to value intermediate compounds that are synthesized as result of realization of above indicated stages of the claimed method. 5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide is a value intermediate compound used in synthesis of the drug atorvastatin calcium that is used as hypolipidemic and/or hypocholesterolemic agent. Proposed method allows avoiding usage of expensive chiral parent substances and to reduce the synthesis process time.

EFFECT: improved preparing method.

12 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

The invention relates to new imidazole compounds of the formula I:

where R1represents hydrogen, hydroxy, protected hydroxy, or aryl, optionally substituted with a suitable(and) substituent(s) selected from the group consisting of halogen(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy, optionally substituted aryl, and lower alkyl, optionally substituted by hydroxy or protected carboxy; R2represents hydrogen or lower alkyl; R3is hydroxy or protected hydroxy; R4represents cyano, (hydroxy)minamino(lower)alkyl, carboxy, protected carboxy, N-containing heterocyclic group, optionally substituted amino, or carbarnoyl, optionally substituted with a suitable(s) of the substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl, amidoamine(lower)alkyl, optionally substituted by hydroxy; and-And - is-Q -, or-O-Q-, where Q is a single bond or lower alkylene, or its salt, provided when R2is the lowest Ala the substituent(s), the above, and also provided that the compound of formula I is not 1-(hydroxyethyl)-4-(etoxycarbonyl)imidazole or anilide 1-(2-hydroxyethyl)imidazole-4-carboxylic acid

The invention relates to the use of compounds of formula I to obtain medical drug suitable for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 1-aziridino-1-hydroxyiminomethyl of the general formula (I):

wherein R means a single bond or organic radical that can bind aziridinoxime groups by a covalent bond and taken among the group including saturated or unsaturated alkanes with normal or branched chain and comprising up to 6 carbon atoms, substituted azino-group -(R')C=N-N=C(R'') wherein R' and R'' represent independently of one another hydrogen atom or lower alkyl, heterocyclic compounds comprising from 3 to 6 atoms in ring and up to 4 heteroatoms taken among -N- and -O-, and aromatic compounds comprising up to 8 atoms in ring; R1 and R2 mean independently of one another -H, -COOH, -COOCH3, -COOC2H5 or -CONH2; n means a whole number 2 or 3; with exception the compound wherein R represents a single bond and R1 and R2 are both hydrogen atom, and also with exception the compound wherein R represents a single bond and one of substitutes is hydrogen atom among the group R1 and R2. Also, invention describes a method for their preparing and medicinal preparations comprising these compounds that possess an antitumor effect.

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

7 cl, 3 tbl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 3 tbl, 20 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to the improved method for preparing (R)-5-(2-benzenesulfonylethyl)-3-N-methylpyrrolidine-2-ylmethyl)-1H-indole of the formula (I): or its pharmaceutically acceptable salt. Method involves hydrolysis of compound of the formula (II): that is prepared by catalytic reduction of compound of the formula (III): . The claimed method excludes formation of dimer in the end product used in medicine.

EFFECT: improved method for preparing.

18 cl, 3 sch, 3 ex

Indole derivatives // 2256659

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (I): wherein R1 means phenyl substituted or unsubstituted radical R2 and/or R4; R2, R4 R5 and R6 in each case and independently of one another mean Hal; R3 mean substituted or unsubstituted radical R5 and/or R6 or means Het wherein Het means 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; Hal means fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J), and their physiologically acceptable salts and solvates also. Compounds of the formula (I) are prepared by interaction of compound of the formula (I): wherein L means Cl, Br, J or free or reactive functional modified group OH; R3 has value indicated in the formula (I) with compound of the formula (III): . Compounds of the formula (I) show affinity to 5-HT2A receptors that allow their using in the pharmaceutical composition.

EFFECT: valuable medicinal and pharmacological properties of compounds.

4 cl, 10 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to N-(indolcarbonyl)piperazine derivatives of general formula I

, wherein R1 is optionally substituted phenyl or naphthyl; R2 and R3 are independently Hal or Het1, A, OA, CN; R4 is H, CN, acyl, Hal, CONH2, CONHA or CONA; R1 is H; or R4 and R5 together form C3-C5-group; Het1 is aromatic heterocyclic ring, optionally substituted with one or two halogen atoms and containing 1-3 similar or different heteroatoms such as nitrogen, sulfur and oxygen, A-(C1-C6)-alkyl; Hal is F, Cl,Br, and J; and indole ring may be substituted with isatin, except for (1H-indole-5-yl)-(4-phenethylpiperazine-1-yl)-methanone and 1-((5-methoxy-1H-indole-7-yl)-carbonyl)-4-(2-phenethyl)-piperazine. Claimed compounds are potent 5-HT2A antagonists and are useful in treatment of psychosis, schizophrenia, depression, neurological diseases, dismepodia, Parlinson's disease, Alzheimer's disease, Hungtington's disease, amyotrophic lateral sclerosis, bulimia or anorexia, premenstrual syndrome, and/or in alleviation of hypomania.

EFFECT: new pharmaceutical agents.

9 cl, 10 ex, 1 tbl

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for production of 4-(heteroarylmethyl)halo-1-(2H)-phthalazinones, particularly 4-(4-pyridylmethyl)-1-(2H)-phthalazinone. Claimed method includes interaction between substituted phthalidyl-3-triphenylphosphonium and aldehyde of formula Ar-CHO, wherein Ar is pyridine, pyrazine, or pyrimidine, in presence of base followed by reaction with hydrazine hydrate optionally under acidic conditions.

EFFECT: environmental friendly and safe method.

4 cl, 1 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted 1-pyridyl-2-azolyl-1-(2-phenylethenyl)ethan-1-ols having general formula I:

where Py denotes 2-, 3-, or 4-pyridyl, Z nitrogen atom or CH group, and R1 and R2, independently from each other, are hydrogen or halogen atom, or trifluoromethyl group. Claimed compounds are applied as agricultural, industrial, medical, or veterinarian fungicides for controlling harmful fungi.

EFFECT: enhanced fungi control efficiency.

2 cl, 3 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

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