Agents against feeble-mindedness comprising derivatives of 2-aryl-8-oxodihydropurine as active component

FIELD: organic chemistry, neurology, medicine.

SUBSTANCE: invention relates to a new medicinal agent used in treatment of feeble-mindedness comprising a derivative of 2-aryl-8-oxodihydropurine, namely, a derivative of 2-aryl-8-oxodihydropurine that comprises acetamide group at position 7 or 9 of purine ring. Invention proposes compounds of formulae (Ia) and (Ib) wherein radicals X1, Y1, R12, R13, R22, R23, R32, R42 and R43 have the corresponding values, or their pharmaceutically acceptable acid-additive salt. Also, invention proposes using compounds of the formulae (Ia) and (Ib) or their pharmaceutically acceptable acid-additive salt for preparing a medicinal agent used in treatment or prophylaxis of feeble-mindedness wherein feeble-mindedness represents deterioration of the teaching process, dysmnesia, dysmnesia-based disorientation, mental dysfunction, Alzheimer's disease, cerebrovascular feeble-mindedness and/or senile feeble-mindedness, and in treatment or prophylaxis of higher cerebral dysfunction. Invention provides the development of a medicinal preparation for prophylaxis or treatment of feeble-mindedness symptoms associated with diseases that can induce feeble-mindedness and higher cerebral dysfunction.

EFFECT: valuable medicinal properties of agents.

12 cl, 3 tbl, 5 ex

 

The technical field to which the invention relates.

The present invention relates to a medicinal product for the treatment of dementia, containing a derivative of 2-aryl-8-oxopiperidine, more specifically, a derivative of 2-aryl-8-oxopiperidine, which has acetamide group in the 7 - or 9-position of the purine ring.

The level of technology

With the increase in the length of life of society, an increase in the number of patients suffering from dementia, which has become a social problem, with approximately 90% is dementia type Alzheimer's disease and cerebroside dementia. Regarding symptom of dementia, short - and long-term dysmnesia is the main and usually the Central symptom, therefore, it is believed that dementia consists of dysmnesia, disorientation caused by dysmnesia, and the associated increased dysfunction of the brain. In patients suffering from dementia, the functions of the various neurotransmission systems significantly reduced mainly in the cerebral cortex and endings, in addition, also decreased function of cerebral energy metabolism. Especially in patients with dementia type Alzheimer's disease detected hypofunction neurotransmission in cholinergic, glutamatergic, neuropeptidergic and monoaminergic with the system, and this suggests that the main cause of dementia type Alzheimer's disease is a dysfunction such neurotransmission systems [Coyle, J.. and others, Science,219, 1184-1190 (1983); Gottfries, C.G. and others, Psychopharmacology,86, 245-252 (1985)]. In addition, from the point of view of neurotoxicity caused by β-amyloid peptide, it is assumed that the loss of hippocampal neurons due to accumulation β-amyloid peptide in senile plaques on the surface of cells involved in the mechanism of the above diseases, and is one of the main causes of dementia type Alzheimer's disease [Selkoe D.J., Annu. Rev. Neurosci.,12, 463-490 (1989)].

On the basis of detection of the fact that a significant neural dysfunction associated with cholinergic system is the cause of dysmnesia with dementia, as suggested above, have been developed drugs to improve symptoms of dementia through activation of the cholinergic system. In addition, paying attention to the reduction of glutamatergic receptors of neurons and N-methyl-D-aspartic acid (hereinafter referred to as the "NMDA"), which are some of the receptors glutamic acid, were also developed a drug to activate the NMDA receptor.

Recently have also made some attempts to get agonists for receptors of the peripheral benzodiazepine type d is more optional referred to as "BZω 3") as a therapeutic agent to improve symptoms of dementia. For example, it was reported that N,N-di-n-hexyl-2-(4-forfinal)indole-3-ndimethylacetamide (hereinafter referred to as the "FGIN-1-27"), which is an agonist BZω3receptors, and some types of neurosteroids (for example, pregnenolone sulfate, allopregnanolone) have a weak improving actions in animal models when the difficulty of learning (active test evasion, radially-manual labyrinth test and water labyrinth test) [Flood, J.F., and others, Brain Res.,448, 178-181 (1988); Flood, J.F., and others, Proc. Natl. Acad. Sci. U.S.A.,89, 1567-1571 (1992); Romeo, E., and others, J. Pharmacol. Exp. Ther.,270, 89-96 (1994)].

To date, there have been many studies of the function BZω3receptors, and it has been shown that in the brain BZω3receptors are often present in the outer membrane of mitochondria in glial cells, while they are included in the capture of cholesterol in the inner membrane of the mitochondria, and then act on the biosynthesis of neurosteroids, such as pregnenolone and, therefore, allopregnanolone and allotetrahydrocortisone. It is believed that stimulation of BZω3receptor promotiom biosynthesis neurosteroids in the brain, and these neurosteroid contact neurosteroid-recognized site (a site other than the benzodiazepine receptor) in combination with receptor γaminobutyric acid (hereinafter optionally referred to as the "GABA-A") - benzodiazepine receptor - Cl-ion channel and influence the process of opening of the Cl-channel [Romeo, E., and others, J. Pharmacol. Exp. Ther.,262, 971-978 (1992)].

As agonists BZω3receptor modulate the function of GABA-A receptors by biosynthesis neurosteroids suggest that agonists BZω3the receptor can be used as tranquilizers, antidepressants, hypnotic tools, anti-epileptics, etc. for Example, WO 99/28320 describes derivatives of 2-aryl-8-oxopiperidine formula (I), which is selective and high affinity agonist BZω3receptor, i.e. useful as medicines for the treatment of, for example, diseases associated with anxiety and depression,

In addition, it was also reported that agonists BZω3receptor show trancvillizator actions, but it is unlikely it was reported that these agonists are improving effects when the difficulty of the training, except for the above message FGIN-1-27.

The invention

Agonists BZω3receptor have a mechanism of action different from the mechanism known medicines for dementia, and it seems that you can get a useful drugs against dementia with non-existing in the present is a time of drugs against dementia, if there were found among them a connection to potentially improve the action on dementia.

The inventors of the present invention conducted investigations for the detection of compounds with the potential to improve the action on dementia among the known agonist BZω3receptor, and found that derivatives of 2-aryl-8-oxopiperidine formula (I) and their pharmaceutically acceptable acid additive salts have unexpectedly high improves action to difficulties in learning and/or memory in animals, and these difficulties are caused by the systematic introduction of MK-801 [dizocilpine maleate; (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]Cycloheptane-5,10-einmaleins], which is a noncompetitive antagonist of the NMDA receptor and (-)-scopolamine hydrobromide (hereinafter referred "scopolamine"), which is a competitive antagonist of acetylcholine receptor. Based on the discoveries were made by the present invention.

The present invention is the development of drugs for treatment of dementia, containing a derivative of 2-aryl-8-oxopiperidine, which shows extremely high improving effect on learning and/or memory caused by hypofunction of the glutamatergic system or cholinergic system, and which is useful DL the treatment of dementia (for example, cognitive difficulty), such as dementia type Alzheimer's disease, cerebrosidase dementia and senile dementia. These and other objectives and advantages of the present invention will become clear to the expert in the art from the following description.

The present invention relates to a medicinal product for the treatment or prevention of dementia, containing a derivative of 2-aryl-8-oxopiperidine formula (I):

where:

W represents a hydrogen atom; C1-6alkyl group; a halogen atom; C1-6alkoxy group; amino group; mono - or di(C1-4alkyl)amino group; or a phenyl group which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro;

X represents a hydrogen atom; C1-6alkyl group; C3-8cycloalkyl-C1-4alkyl group; C1-4alkyl group, substituted phenyl group, which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro; With3-6alkenylphenol group; karbamoilnuyu group; di(C1-4alkyl)karbamoilnuyu group; what if a group of the formula [Q]:

where R1represents a C1-6alkyl group; C3-6alkenylphenol group; C3-8cycloalkyl group; C3-8cycloalkyl-C1-4alkyl group; or hydroxy-C1-4alkyl group;

R2represents a C1-6alkyl group; C3-8cycloalkyl group; phenyl group which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro; C1-4alkyl group, substituted phenyl group, which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro; or a monocyclic 5-or 6-membered heteroaryl group, or a bicyclic heteroaryl group comprising 5 - or 6-membered heteroaryl that have at least one heteroatom selected from a nitrogen atom, oxygen atom or sulfur atom, and optionally substituted C1-3the alkyl or trifluoromethyl; or R1and R2can be taken together with the neighboring nitrogen atom to education piperidino rings, pyrolidine ring, morpholino rings or piperazinovogo ring m which may be optionally substituted by 1 or 2 C 1-6alkilani respectively;

R3represents a hydrogen atom, a C1-6alkyl group or hydroxy-C1-4alkyl group;

Y represents a hydrogen atom; C1-6alkyl group; C3-8cycloalkyl group; C3-8cycloalkyl With1-4alkyl group; C3-6alkenylphenol group; C1-4alkyl group, substituted phenyl group, which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro; or a group of the formula [Q]:

where R1, R2and R3are as described above;

Rather it represents a phenyl group which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro; or a monocyclic 5 - or 6-membered heteroaryl group, or a bicyclic heteroaryl group comprising 5 - or 6-membered heteroaryl that have at least one heteroatom selected from a nitrogen atom, oxygen atom or sulfur atom, and optionally substituted C1-3the alkyl or trifluoromethyl;

provided that either X or Y of the above formula (I) PR is dstanley a group of the above formula [Q], and when X represents a group of the formula [Q], then Y is a hydrogen atom; C1-6alkyl group; C3-8cycloalkyl group; C3-8cycloalkyl-C1-4alkyl group; C3-6alkenylphenol group; or (C1-4alkyl group, substituted phenyl group, which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro, and Y represents a group of the formula [Q], then X is a hydrogen atom; C1-6alkyl group; C3-8cycloalkyl-C1-4alkyl group; C1-4alkyl group, substituted phenyl group, which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro; With3-6alkenylphenol group; karbamoilnuyu group; or a di(C1-4alkyl)karbamoilnuyu group; or its pharmaceutically acceptable acid additive salt (hereinafter referred to as the "compound of the present invention").

More specifically, the present invention relates to a medicinal product for the treatment or prevention of dementia type Alzheimer's disease, cerebrocortical dementia and/or senile is labaume, comprising as active ingredient a compound of the above formula (I).

Further, as an embodiment of improvements dysfunction, we offer drug for improving learning and/or memory in mammals (including humans).

Pharmaceutically acceptable acid additive salt of the compounds of formula (I) refers to a pharmaceutically acceptable acid additive salt of the compounds of formula (I), which has sufficient basicity for the formation of an acid additive salt, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate or phosphate, and organic acid salts such as maleate, fumarate, oxalate, citrate, tartrate, lactate, benzoate or methanesulfonate.

Compounds of the present invention and their acid additive salts of the formula (I) may not necessarily exist in the form of a hydrate and/or MES, and their hydrate and solvate included in the present invention.

The compounds of formula (I) can optionally have at least one asymmetric carbon atom, and don't have to have geometric isomers. Thus, the compounds of formula (I) may exist as two or more stereoisomers, the compounds of the present invention can include these stereoisomers, their mixtures and racemate.

Derivatives of 2-aryl-8-oxadi hydroporini of the present invention have values of the positions of the purine ring as shown in the following formula (I):

where A, W, X and Y are as above, and then the item based on the specified position value.

For terms used in this description, the following definitions are used.

C1-6alkyl group, and C1-6alkyl part may denote a linear or branched chain. Suitable examples of "C1-6alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl, preferably containing 1-4 carbon atoms. Suitable examples of "C1-6alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy. "C3-6Alchemilla group" includes groups having 3-6 carbon atoms containing one double bond in any position other than the 1 and 2 positions, such as allyl and 2-butenyl.

Suitable examples of "C3-8cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. "C3-8cycloalkyl-C1-4alkyl group" denotes an alkyl group having 1-4 carbon atoms, which is substituted defined above, With3-8cycloalkyl group, such as cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl. "Hydroxy-C1-4alkyl group" denotes a1-4alkyl group substituted by a hydroxy-group, such as hydro is simetal, 2-hydroxyethyl and 3-hydroxypropyl. "Halogen atom" refers to fluorine, bromine, chlorine and iodine. "Mono - or di(C1-4alkyl)amino group" means an amino group, substituted by 1 or 2 alkyl groups having 1-4 carbon atoms, such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino.

Suitable examples of the "phenyl group which may optionally have 1 or 2 substituent selected from halogen, C1-7of alkyl, C1-7alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro are phenyl; 2-, 3 - or 4-chlorophenyl; 2-, 3 - or 4-bromophenyl; 2-, 3 - or 4-forfinal; 2,4-dichlorophenyl; 2,4-dibromophenol; 2,4-differenl; 2-, 3 - or 4-were; 2-, 3 - or 4-methoxyphenyl; 2-, 3 - or 4-triptoreline; 2-, 3 - or 4-hydroxyphenyl; 2-, 3 - or 4-AMINOPHENYL; 2-, 3 - or 4-methylaminophenol; 2-, 3 - or 4-dimethylaminophenyl; 2-, 3 - or 4-cyanophenyl and 2-, 3 - or 4-nitrophenyl.

Suitable examples of "C1-4alkyl group, substituted phenyl group, which may optionally have 1 or 2 substituent selected from halogen, C1-4of alkyl, C1-4alkoxy. trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro are benzyl; 2-, 3 - or 4-Chlorobenzyl; 2-, 3 - or 4-bromobenzyl; 2-, 3 - or 4-terbisil; 2,4-dichlorobenzyl; 2,4-dibromobenzyl; 2,4-diferensial; 2-, 3 - or 4-ethylbenzyl; 2-, 3 - or 4-methoxybenzyl; 2-, 3 - or 4-trifloromethyl; 2-, 3 - or 4-hydroxybenzyl; 2-, 3 - or 4-aminobenzyl; 2-, 3 - or 4-methylaminomethyl; 2-, 3 - or 4-dimethylaminobenzoyl; 2-, 3 - or 4-cyanobenzyl; 2-, 3 - or 4-nitrobenzyl; phenethyl and 2-(4-chlorophenyl)ethyl.

Examples the following formula [V]:

are the above "phenyl group which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro, and alkyl group having 1 and 2 carbon atoms, which is substituted by the above "phenyl group which may optionally have 1 or 2 substituent selected from halogen, C1-6of alkyl, C1-6alkoxy, trifloromethyl, hydroxy, amino, mono - or di(C1-4alkyl)amino, cyano and nitro, and represents preferably phenyl; 4 - or 3-chlorophenyl; 4 - or 3-bromophenyl; 4 - or 3-forfinal; 4-methoxyphenyl; 4-triptoreline; 4-hydroxyphenyl; benzyl; 2-, 3 - or 4-Chlorobenzyl; 4-bromobenzyl; 3 - or 4-terbisil; 4-methylbenzyl; 4-methoxybenzyl; 4-trifloromethyl; 4-hydroxybenzyl; phenethyl and 2-(4-chlorophenyl)ethyl.

Suitable examples of the "monocyclic 5-or 6-membered heteroaryl group or a bicyclic heteroaryl group comprising 5 - or 6-membered heteroaryl that have at least one heteroatom, selected from nitrogen atom, oxygen atom or sulfur atom, and optionally substituted C1-3the alkyl or trifluoromethyl are 2-, 3 - or 4-pyridyl; 5-methyl-2-pyridyl; 2 - or 3-thienyl; 2 - or 3-furyl; 2-, 4 - or 5-pyrimidinyl; 2 - or 3-pyrazinyl; 1-pyrazolyl; 2-imidazolyl; 2-thiazolyl; 3-isoxazolyl; 5-methyl-3-isoxazolyl; chenail and ethanolic.

Preferred are the compounds of formula (I)in which a represents a group of the formula [A']:

(where R4represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6alkoxygroup, triptorelin group, a hydroxy-group, amino group, mono - or di(C1-4alkyl)amino group, a cyano or a nitro-group, and R5represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6alkoxygroup or hydroxy-group), pyridyloxy group, thienyl group or follow group; and W, X and Y are as defined above, or their pharmaceutically acceptable acid additive salt.

More preferred are the compounds of formula (I)in which:

(a) X represents a group of the following formula [Qx]:

where R11represents a C1-6alkyl group, and R21represents a C1-6alkyl group or a group of forms of the crystals [In]:

where R6represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6alkoxygroup, triptorelin group, a hydroxy-group, amino group, mono - or di(C1-4alkyl)amino group, a cyano or a nitro-group; R7represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C1-6alkoxygroup or hydroxy-group; and m represents 0, 1, or 2, or

R11and R21can be taken together with the adjacent nitrogen atom with the formation of piperidino rings, pyrolidine ring, morpholino rings or piperazinovogo ring, which may optionally have 1 or 2 lower alkyl substituent, respectively; R31represents a hydrogen atom, a C1-6alkyl group or hydroxy-C1-4alkyl group,

Y represents a hydrogen atom or a C1-6alkyl group,

(b) X represents a hydrogen atom, a C1-6alkyl group or karbamoilnuyu group; Y represents a group of the formula [Qy]:

where R11, R21and R31are as described above;

A represents a group of the above formula [A'], pyridyloxy group, thienyl group or follow group;

W is as defined above, or Pharma is efticiency acceptable acid additive salt.

More preferred are the compounds of formula (I), where:

(c) X is a group as defined above in the formula [Qx] (where R11represents a methyl group; an ethyl group; various group; ISO-propyl group or boutelou group;

R21represents an ethyl group; various group; ISO-propyl group; boutelou group; phenyl group; a phenyl group substituted with halogen, methoxy, trifluoromethyl or hydroxy; benzyl group; a benzyl group substituted with halogen, methoxy, trifluoromethyl or hydroxy;

R31is as defined above;

Y represents a hydrogen atom, methyl group or ethyl group, or

(d) X represents a hydrogen atom, methyl group, ethyl group, through the group, isopropyl group or boutelou group;

Y represents a group of the above formula [Qy] (where R11represents a methyl group, ethyl group, through the group, isopropyl group or boutelou group;

R21represents an ethyl group; various group; ISO-propyl group; boutelou group; phenyl group; a phenyl group substituted with halogen, methoxy, trifluoromethyl or hydroxy; benzyl group; a benzyl group substituted with halogen, methoxy, trifter what etiam or hydroxy;

R31is as defined above;

A represents a group of the above formula [A'], pyridyloxy group, thienyl group or follow group;

W is as defined above; or pharmaceutically acceptable acid additive salt.

In addition, preferred are derivatives of 2-aryl-8-oxopiperidine formula (Ia):

where:

R12and R22are the same or different and represent an ethyl group, through group or boutelou group; or R12represents a metal group, ethyl group or sawn group, and R22represents a phenyl group, halogenfrei group, metoksifenilny group, benzyl group, halogenmethyl group or methoxybenzyloxy group;

R32represents a hydrogen atom, methyl group or ethyl group;

Y1represents a hydrogen atom, methyl group or ethyl group;

R42represents a hydrogen atom, halogen atom, methyl group, methoxy group, a nitrogroup, or triptorelin group; or the following formula (Ib):

where:

X1represents a hydrogen atom, methyl group, ethyl group, or through the group;

R 13and R23are the same or different and represent an ethyl group, through group or boutelou group; or R13represents a methyl group, ethyl group or sawn group, and R23represents a phenyl group, halogenfrei group, metoksifenilny group, benzyl group, halogenmethyl group or methoxybenzyloxy group;

R33represents a hydrogen atom, methyl group or ethyl group;

R43represents a hydrogen atom, halogen atom, methyl group, methoxy group, a nitrogroup, or triptorelin group;

or their pharmaceutically acceptable acid additive salt.

Preferred are compounds of formulas (Ia) and (Ib), where both R32and R33each are hydrogen atoms.

Specific examples of the compounds of formulas (Ia) and (Ib) are as follows:

N-(4-methoxyphenyl)-7,8-dihydro-7-methyl-N-methyl-8-oxo-2-phenyl-N-purine-9-ndimethylacetamide (test the connection, And as defined below);

N-benzyl-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-7H-purine-7-ndimethylacetamide (test connection as defined below); and

N-benzyl-7-ethyl-N-ethyl-7,8-dihydro-8-oxo-2-phenyl-N-purine-9-ndimethylacetamide (test compound D as described below),

or their pharmaceutically acceptable acid additive salt.

Especially pre is respectful examples are the following compounds:

N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purine-7-ndimethylacetamide (test connection as defined below); and

N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-N-purine-9-ndimethylacetamide (test the connection, as specified below),

and their pharmaceutically acceptable acid additive salt.

Suitable examples of compounds of formula (I) are compounds according to the examples in WO 99/28320 (connection Examples 1-206).

The compounds of formula (I) can be obtained, for example, by the method described in WO 99/28320.

The best option of carrying out the invention

The suitability of the compounds of the present invention as a drug for the treatment and prevention of dementia is shown in the test results of typical compounds of the present invention, but are not limited to.

WO 99/28320 describes the actions of the compounds of formula (I) BZω3receptor, where it is shown that the compounds of formula (I) possess selectivity and high affinity for the BZω3the receptor.

Test compounds were used for the following connections.

Test compound a: N-(4-methoxyphenyl)-7,8-dihydro-7-methyl-N-methyl-8-oxo-2-phenyl-N-purine-9-ndimethylacetamide (the compound of Example 163, WO 99/28320).

Test compound: N-benzyl-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-7H-purine-7-ndimethylacetamide (the compound of Example 54 in WO 99/28320).

Fathers-in-law who has been created connection To: N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purine-7-ndimethylacetamide (the compound of Example 1 in WO 99/28320).

The test compound D: N-benzyl-7-ethyl-N-ethyl-7,8-dihydro-8-oxo-2-phenyl-N-purine-9-ndimethylacetamide (compound of Example 150 in WO 99/28320).

Test the connection, E: N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-N-purine-9-ndimethylacetamide (the compound of Example 146 in WO 99/28320).

Scopolamine is described, for example, in the Merck Index, 12th Edition, 8550 (1996), and is commercially available (for example, Sigma Aldrich Japan).

MK-801 is described, for example, in the Merck Index, 12th Edition, 3451 (1996), and is commercially available (for example, Sigma Aldrich Japan).

FGIN-1-27 can be obtained by a method described in JP-A-6-501030 (=WO 93/00334).

Difficulty learning/memory in animals are typically caused by systematic introduction of MK-801 (non-competitive antagonist of the NMDA receptor, which is a subtype of receptor glutamic acid) and scopolamine (a competitive antagonist of acetylcholine receptor), or intracerebral injection β-amyloid peptide [Stephanie, D. and others, Eur. J. Pharmacol.,319, 1-4 (1997)].

Experiment 1. The improving effects on spatial memory disorder caused by scopolamine.

A test of spatial memory using Y-labyrinth of the apparatus, is a test that uses behavioral characteristics of animals to enter through the new passage, avoiding the pass in which they were before (alternative behavior). This method is often used to study the spatial the working memory.

This experiment is carried out in accordance with the methodology Itoh, J., and others [Eur. J. Pharmacol.,236, 341-345 (1993)].

In the experiment using Std-ddY male mice weighing 25-30 g (8 mice in one group). The solution of scopolamine in physiological salt solution (concentration: 0.06 mg/ml) was subcutaneously administered to mice in a volume of 0.1 ml/10 g of body weight, i.e., 0.6 mg/kg to Mice in the group test compounds orally administered the test compound suspended in 0.5% solution of tragakant in a volume of 0.1 ml/10 g body weight 1 hour before injection of scopolamine, whereas animals in the control group with amnesia and a comparative control group injected with 0.5% solution of tragakant the way described above. However, a comparative control group administered with physiological saline solution instead of scopolamine. After 30 minutes after administration of scopolamine mice are placed in the end And pass the Y-labyrinth system, which consists of three black acrylic trapezoid passes (bottom width: 3 cm side height: 12 cm, width of the open ceiling: 10 cm, length: 40 cm), where the three passage is connected with one end of each passage with the formation of Y-shaped and the other ends are closed and three pass different names a, b and C, respectively, and allow you to freely search the maze for 8 minutes. When the mouse is difficult to enter the passage at length not less than 10 cm from the entrance of the passage, the name of the pass (a, b or C) record. It is considered the right choice when the mouse selects a different three passes in sequence, and count the number of alternative behaviors, that is, the number of correct choices. When the total number of inputs in the passage was less than 10 [maximum number of alternative behavior (the number obtained by subtracting 2 from the total number of inputs in the passage) is less than 8], the data obtained do not use and re-test, because the ability to learn sometimes may not reflect the alternative behavior. For the final data to determine the ratio of the number of alternative behaviors to the number of inputs (obtained by subtracting 2 from the total number of inputs in the aisles) as the rate of alternative behaviors.

When a statistical analysis of the rate of alternative behaviors in the control group with amnesia is compared with the speed in the comparative control group ecparameters test total number Wilcoxon (Wilcoxon) and it indicates whether caused significant amnesia in the control group with amnesia. Next, calculate the efficiency of the tested compounds compared to the control group with amnesia and a group of test compounds ecparameters multiple comparative test Dunnett (Dunnett). Statistical calculations Prov is completed using the SAS system version 6.12 (SAS Institute Japan Ltd.). Table 1 shows the minimum effective dose (MED), in which there is a significant improving effect of test compounds on scopolamine-induced spatial memory disorder at 5% level of significance rate of alternative behaviors. The rate of alternative behaviors in the control group with amnesia with scopolamine significantly reduced to 40-47%, whereas prior 61-70% in the comparative control group, and therefore, this confirms that hypofunction of the cholinergic system causes the disorder of spatial memory.

Table 1
Test connectionDose rate (mg/kg)
And3
In3
0,01
D3
E1
FGIN-1-2710

Test compounds a-E are higher improving effects (EDR <=3 mg/kg)than FGIN-1-27, especially more than just test connection rate=0.01 mg/kg).

Experiment 2. The improving effects on the disorder of the subject memory induced by scopolamine.

The test of the detected object is a test method using the property where the animal is Ralitsa to search for a new object. This method is often used to study the retention and recall of episodic memory.

This experiment is carried out in accordance with a partially modified method Bartolini, L. and others [Pharmacol. Biochem. Behav.,53, 277-283 (1996)].

In the experiment using Std-ddY male mice weighing 25-30 g (six mice in one group). Scopolamine, dissolved in physiological saline (concentration: 0.04 mg/ml), injected subcutaneously to mice in a volume of 0.1 ml per 10 g of body weight, i.e., 0.4 mg/kg For group studying the test compound suspended in 0.5% solution of tragakant, orally administered in a volume of 0.1 ml per 10 g of body weight within 30 minutes after administration of scopolamine, and for the control group with amnesia and a comparative control group injected with 0.5% solution of tragakant in the same way as described above. However, for comparative control group instead of scopolamine injected with physiological saline solution. After 30 minutes after administration of scopolamine conduct the first test within 5 minutes, and 1 hour after the first test, a second test within 5 minutes. In the first test two objects of the same shape [red adapters in the form of a funnel of a truncated cone, made of silicone (bottom diameter: 6.1 cm, ceiling diameter: 4.5 cm, height: 3.5 cm)] are placed in the two right corners of the box to dough made from brown and the Rila (length: 22.5cm, width: 24.5 cm, height: 11 cm), and measure the time for which the mouse will examine each object. In the second test object (typically: F), which was higher than the study in the first test left, while the other object in the first test was replaced by a new object [new: N, red life ring (outer diameter: 7.5 cm, inner diameter: 2.5 cm, thickness: 2.0 cm)] in the same position, and then measured the time exploring each object. The improvement rate of the subject memory is found by the formula: (N-F)/(N+F) as an index of discrimination, and conduct a comparison between comparative control group and the control group with amnesia, and between the control group with amnesia and a group of test compounds on the basis of the specified index of discrimination.

Statistical analysis the comparison between comparative control group and the control group with amnesia conduct test t Student and it shows, called major amnesia. The effectiveness of the test compounds is evaluated on the basis of comparison between the control group with amnesia and a group of test compounds parametric multiple comparative test of Dunnett. The statistical calculation is performed using the SAS system version 6,12 (SAS Institute Japan Ltd.). Table 2 shows the minimum effective dose (MED)at which a significant difference is their in the index of discrimination, as the improving effects of test compounds on scopolamine-induced memory loss of the object at 5% level of significance.

The discrimination index in the group with scopolamine-induced amnesia significantly reduced to 0.00-0.07 respectively, whereas he is 0.49-0,71 in comparative control group, and therefore, this confirms that hypofunction of the cholinergic system is the deterioration of the subject's memory.

Table 2
Test connectionDose rate (mg/kg)
0,01
E0,1
FGIN-1-27>30

Test the connection, E shows a significantly improved effect at the dose of 0.1 mg/kg and test the connection With exhibits significantly improved activity at low dose of 0.01 mg/kg, However, FGIN-1-27 does not show significant improved action at the dose of 30 mg/kg

Experiment 3. The improving effects on the deterioration of the memory location of the object caused by MK-801.

Test the memory location of the object is a test method that uses the property where the animals like to seek novelty, caused by the change of location of the object. This method is often used to study the ability of memory they are situated the object. This method is closely related to hypofunction of the glutamatergic system and selectively causes the deterioration of memory locations without compromising the subject of memory, which is caused by hypofunction of the cholinergic system.

This experiment is carried out in accordance with a partially modified method Sophie L. Dix, and others [Behav. Brain Res., M, 191-200 (1999)].

In the experiment using Std-ddY male mice weighing 25-30 g (six mice in one group). A solution of MK-801 in physiological salt solution (concentration: 0.005 mg/ml) injected subcutaneously in a volume of 0.1 ml per 10 g of body weight, i.e., 0.05 mg/kg For a group of test compounds orally administered the test compound suspended in 0.5% solution of tragakant in the amount of 0.1 ml per 10 g of body weight, 30 minutes before the injection of MK-801, and for the control group with amnesia and a comparative control group injected with 0.5% solution of tragakant in the same way as described above. However, for comparative control group instead of MK-801 injected with physiological saline solution. After 30 minutes after administration of MK-801 first test should be performed within 5 minutes, and 1 hour after the first test, a second test within 5 minutes. In the first test two objects of the same shape [red adapters in the form of a funnel of a truncated cone, made of silicone (bottom diameter: 6.1 cm, ceiling diameter: 4.5 cm, height: 3.5 cm)] placed the t respectively in the center and one corner of the test box, made of brown acrylic (length: 22.5 cm width: 24.5 cm, height: 11 cm), and measure the time for which the mouse study object. In the second test object moved object:), which was in the centre in the first test, move in the opposite angle relative to another object (neprimetny object: NGOs), and then measure the time for which the mouse will examine each object. Calculate the difference in time study and NGOs respectively between the first test and the second test, and conduct a comparison between comparative control group and the control group with amnesia, and between the control group with amnesia and a group of test compounds.

In the statistical analysis is performed a comparison between comparative control group and the control group with amnesia using Student t test and confirms it, is invoked if a significant deterioration of the memory location of the object. The effectiveness of the test compounds evaluated by comparing the control group with amnesia with a group of test compounds using the parametric multiple comparative test Dunnett. Statistical calculations performed SAS system version 6.12 (SAS Institute Japan Ltd.). Table 3 shows the minimum effective dose (MED), in which there is a significant improving effect on MK-801-induced don is the memory location of the object at 5% level of significance.

In addition, in the comparative control group study NGOs in the second test time is reduced study clearly larger than the study of NGOs. This result shows that the change in location of the object has novelty and animals often study the object with new. On the other hand, in the control group with amnesia with MK-801, study time for NGOs and noticeably decreases. These results confirm that MK-801 impairs not the memory object, and impairs memory location of the object.

Table 3
Test connectionDose rate (mg/kg)
0,1
E0,01
FGIN-1-2710

Test the connection With exhibits significantly superior effect at the dose of 0.1 mg/kg and test the connection, E shows significantly improved activity at low dose of 0.1 mg/kg, moreover, are effective at a dose of FGIN-1-27 less than 1/100.

Experiment 4. Acute toxicity

The experiment tested the connection is performed using Std-ddY male mice weighing 25-30 g (10 mice per group). The test compound suspended in 0.5% solution of tragakant, orally administered at the dose of 2000 mg/kg, and see the death of the mice within 7 days of the donkey in the introduction. In the mice treated with the test compound With, not die.

Experiment 5. Acute toxicity 2

Experiment with a test compound E is carried out using an Std-ddY male mice weighing is 22.9-25.6 g (5 mice per group) and Std-Wistar male rats weighing 126,6-136,6 g (5 rats per group). The test compound suspended in 0.5% solution of tragakant, orally and intraperitoneally administered to mice at the dose of 2000 mg/kg, and see the death of the mice within 7 days after injection. In the mice treated with the test compound E, do not die.

In contrast to the above results, the compounds of formula (I) exhibit extremely high improving effect in the deterioration of learning and/or memory, is caused by systematic introduction of MK-801 (non-competitive antagonist of the NMDA receptor subtype of glutamate receptors) and scopolamine (a competitive antagonist of acetylcholine receptors) even at a low dose and also have low toxicity, and therefore, the compounds may be useful as a drug for the treatment and prevention of deterioration of learning and/or memory in mammals (including humans), as well as for treatment and prevention of dementia. More specifically, the compounds of formula (I) can be useful as a drug for treatment and prevention is hudsonia the learning process, dysmnesia, disorientation, based on dysmnesia and intellectual dysfunction, which is the main symptom of dementia. Intellectual dysfunction refers not only dysmnesia, but also the condition in which reduced computational ability, the ability to think abstractly, linguistic function and prudence, in which the subject is unable to lead a normal life and social life.

In addition, the compounds of formula (I) can be useful as a drug for the treatment and prevention of dementia, such as dementia type Alzheimer's disease, cerebrocortical dementia and/or senile dementia, as these compounds exhibit high improving effect on learning and/or memory.

Further, the compounds of formula (I) can be useful as a drug for the treatment and prevention of higher brain dysfunction due to their high improving actions with the deterioration of learning and/or memory. High brain dysfunction refers to brain dysfunction, included in perception, attention, learning, memory, concept formation, postulating, prudence, speech, abstract thinking, action, cognition and behavior, etc. that are accompanied by dementia, aphasia, apraxia, agnosia, dyslexia, shall is ronim spatial neglect, dysmnesia, disorder, attention etc.

In addition, the compounds of formula (I) can be useful as a drug for the treatment and prevention of deterioration of the learning process, dysmnesia, disorientation, based on dysmnesia, and the associated higher brain dysfunction, due to their high improving actions when the deterioration of the learning process and/or dysmnesia. For example, the compounds of formula (I) can be useful as a drug for treatment and prophylaxis of the symptoms of dementia-related diseases that can cause dementia (such as Alzheimer's disease Peak, Huntington's disease, Parkinson's disease, down syndrome, schizophrenia, spinal degeneration, multiple cerebral infarction, intracerebral hemorrhage, disease Binswanger, normal hydrocrane pressure, chronic subdural hematoma, brain tumor, hypothyroidism, encephalitis, meningitis, abstinence syndrome, a disease of Creutzfeldt-Jakob disease, head trauma), as these compounds have a high improving effect on the deterioration of the learning process and/or dysmnesia.

The compounds of formula (I) can be administered orally, parenterally and intrarectal. Their dose may vary depending on the type of connections, routes of administration, symptoms/age of the patients, etc. but it is usually from 0.01 to 50 mg/kg/day, preferably 0.03 to 5 mg/kg/day.

The compounds of formula (I) are generally administered in the form of a pharmaceutical composition, which is obtained by mixing conventional and pharmaceutically acceptable carrier or diluent. Pharmaceutically acceptable carrier may be conventional media, which is widely used in the pharmaceutical field and does not react with the compounds of formula (I).

Suitable examples are lactose, Inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch, partially gelatinizing starch, sucrose, magnesium aluminosilicate, synthetic aluminum silicate, crystalline cellulose, carboxymethylcellulose sodium, hydroxypropyltrimonium starch, carboxymethylcellulose calcium, ion-exchange resins, methylcellulose, gelatin, gum Arabic, hydroxypropylcellulose, nizkozameshhennoj hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, weak anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, a fatty acid ester of sorbitol, sodium lauryl sulphate, glycerin, glycerin fatty acid ester purified lanolin, glycoregulation, Polysorbate, macrogol, vegetable oil, wax, propylene glycol, water, ethanol, polyoxyethylenesorbitan castor oil(GCF), sodium chloride, sodium hydroxide, hydrochloric acid, dibasic sodium phosphate, monotony sodium phosphate, citric acid, glutamic acid, benzyl alcohol, methyl p-oxybenzoic, ethyl p-oxybenzoic etc.

Suitable examples of dosage forms are tablets, capsules, granules, powders, syrups, suspensions, suppositories, injectable preparations, etc., These pharmaceutical preparations can be obtained in the usual way. Liquid preparations may be in the form that dissolves or suspendered in water or other suitable medium to use. In addition, pills and granules can be coated in the usual way. Preparations for injection can usually be obtained by dissolving the compounds of formula (I) in water, optionally using isotonic agent or solubilizer, and there may also optionally be added to the agent regulating the pH buffer agent and a preservative.

These drugs usually can contain a compound of the formula (I) in an amount of at least 0.01 percent, preferably 0.1 to 70%. These drugs may optionally contain other therapeutically effective ingredients.

Examples of formulations of medicines for the treatment and prevention of dementia in accordance with the present invention are shown in the following compositions.

Composition 1. The reception of tablets:

N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-
phenyl-N-purine-9-ndimethylacetamide1 g
Lactose84 g
Corn starch30 g
Crystalline cellulose25 g
Hydroxypropylcellulose3 g

The above components are mixed and granularit, and to the mixture weak anhydrous silicic acid (0.7 g) and magnesium stearate (1.3 g) and then pressed to obtain 1000 tablets (each tablet: 145 mg).

Part 2. The capsules:

N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-
N-phenyl-7H-purine-7-ndimethylacetamide2 g
Lactose165 g
Corn starch25 g
Hydroxypropylcellulose3.5 g
Weak anhydrous silicic acid1.8 g
Magnesium stearate2.7 g

The above components are mixed and granularit in the usual way, and the obtained granules are placed in a capsule with getting 1000 capsules (each 200 mg).

Part 3. The composition of the powders:

N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-

N-purine-9-ndimethylacetamide10 g
Lactose960 g
Hydroxypropylcellulose25 g
Weak anhydrous silicic acid5 g

The above components are mixed to obtain the desired powder in the usual way.

Industrial applicability

As explained above, the compounds of formula (I) exhibit extremely high superior deteriorating effect on the learning process and/or dysmnesia caused by hypofunction of the neuronal glutamate or acetylcholine neurons, and, therefore, it is expected that they will have a strong superior effect when intellectual dysfunction, which is the Central symptom of dementia, such as dementia type Alzheimer's disease and cerebroside dementia, that is, the deterioration of the learning process and/or dysmnesia, disorientation caused by dysmnesia and associated higher brain dysfunction, and they are useful for the treatment or prevention of dementia, such as dementia type of Alzheimer's disease, cerebrosidase dementia and senile dementia.

1. Drug for treatment or prevention of dementia, containing a derivative of 2-aryl-8-oxopiperidine formula (Ia)

12and R22are the same or different and represent an ethyl group, through group or boutelou group, or R12represents a methyl group, ethyl group or through group and R22represents a phenyl group, halogenfrei group, metoksifenilny group, benzyl group, halogenmethyl group or methoxybenzyloxy group;

R32represents a hydrogen atom, methyl group or ethyl group;

Y1represents a hydrogen atom, methyl group or ethyl group;

R42represents a hydrogen atom, halogen atom, methyl group, methoxy group, a nitrogroup, or triptorelin group,

or its pharmaceutically acceptable acid additive salt.

or a derivative of 2-aryl-8-oxopiperidine formula (Ib)

where X1represents a hydrogen atom, methyl group, ethyl group, or through the group;

R13and R23are the same or different and represent an ethyl group, through group or boutelou group, or R13represents a methyl group, ethyl group or through group and R23represents a phenyl group, halogenfrei the th group, metoksifenilny group, benzyl group, halogenmethyl group or methoxybenzyloxy group;

R33represents a hydrogen atom, methyl group or ethyl group;

R43represents a hydrogen atom, a methyl group, a methoxy group, a nitrogroup, or triptorelin group,

or its pharmaceutically acceptable acid additive salt.

2. Drug for treatment or prevention of dementia according to claim 1, where the specified derivative is an N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purine-7-ndimethylacetamide or its pharmaceutically acceptable acid additive salt.

3. Drug for treatment or prevention of dementia according to claim 1, where the specified derivative is an N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-N-purine-9-ndimethylacetamide or its pharmaceutically acceptable acid additive salt.

4. Drug for treatment or prevention of dementia according to claim 1, where the specified derivative is a compound according to any one of claims 1 to 3, or its pharmaceutically acceptable acid additive salt.

5. Drug for treatment or prevention of dementia according to claim 1, where the specified derivative is a compound according to any one of claims 1 to 3, and where dementia is dementia type illness Alice the measure, cerebrosidase dementia and/or senile dementia.

6. Drug for the treatment or prophylaxis of higher brain dysfunction, containing a compound according to any one of claims 1 to 3, or its pharmaceutically acceptable acid additive salt.

7. Drug for treatment or prevention of the symptoms of dementia-related diseases that can cause dementia, containing a compound according to any one of claims 1 to 3, or its pharmaceutically acceptable acid additive salt.

8. The use of derivative described in any one of claims 1 to 3, or its pharmaceutically acceptable acid salt additive to obtain drugs for treatment or prevention of dementia.

9. The use of claim 8, where dementia is the deterioration of the learning process, dysmnesia, disorientation, based on dysmnesia, or intellectual dysfunction.

10. The use of claim 8, where dementia is Alzheimer's disease, cerebrosidase dementia and/or senile dementia.

11. The use of derivative described in any one of claims 1 to 3, or its pharmaceutically acceptable acid salt additive to obtain drugs for treatment or prophylaxis of higher brain dysfunction.

12. The use of derivative described in any one of claims 1 to 3, or its farmatsevticheskii acid additive salt for a medicinal product for the treatment or prevention of symptoms of dementia associated with diseases that can cause dementia.



 

Same patents:

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention proposes compound of the formula (1) in free form or as a salt wherein R1, R2, R3, R4 and R5 have values given in the invention claim. The claimed compounds are selective inhibitors of enzyme PDE-5 and show the high selectivity in inhibition of activity of 3',5'-cycloguanosine monophosphate phosphodiesterase being activity of PDE-5 first of all.

EFFECT: valuable biochemical properties of derivatives.

6 cl, 3 tbl, 87 ex

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

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

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

20 cl, 5 tbl, 149 ex

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

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

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

20 cl, 5 tbl, 149 ex

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

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

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

20 cl, 5 tbl, 149 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new compounds - purine derivatives of the general formula (I): in free form or salt wherein X means oxygen or sulfur atom or group NR5; R1 means alkyl, alkenyl, cycloalkyl, benzocycloalkyl, cycloalkylalkyl or aralkyl group that can be substituted optionally with hydroxy-, carboxy-group or alkoxycarbonyl; or if X means NR5 then R1 can mean alternatively heterocyclic group taken among benzylpiperidyl or the formula: ; or group of the formula (II): ; R2 means hydrogen atom, alkyl or alkoxy-group; R3 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, alkoxycarbonyl, -N(R9)R10, (C1-C4)-alkylene-SO2N(R11)R12 or -CON(R13)R14; or if two substitutes R2 and R3 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-10 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen and sulfur atom; R4 means hydrogen atom, alkoxy-, carboxy-group, carboxyalkyl, -SO2N(R11)R12, -N(R9)R10 or -CON(R13)R14; or if two substitutes R3 and R4 are joined to adjacent carbon atoms in indicated benzene ring then in common with carbon atoms to which they are joined they mean heterocyclic group comprising 5-6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen, oxygen or sulfur atom; R5 means hydrogen atom or alkyl; R6, R7 and R8 mean hydrogen atom, or one of these radicals means -SO2NH2, -N(CH3)COCH3, -CONH2 and two others mean hydrogen atom; R9 means hydrogen atom or alkyl; R10 means hydrogen atom, -COR15 wherein R15 means alkyl, alkoxy-group; or R9 and R10 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R11 means hydrogen atom or alkyl; R12 means hydrogen atom, alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonylalkyl; or R11 and R12 in common with nitrogen atom to which they are joined mean heterocyclic group comprising 5 or 6 ring atoms among them one or two atoms mean heteroatoms taken among nitrogen and oxygen atom; R13 and R14 each and independently of one another means hydrogen atom or alkyl with exception of 2-(para-n-butylanilino)-6-methoxypurine, 2-(para-n-butylanilino)-6-(methylthio)purine, 2,6-di-(phenylamino)-purine, 2,6-di-(para-tolylamino)-purine and 2-(para-tolylamino)-6-(phenylamino)-purine.

EFFECT: valuable biochemical properties of compounds.

11 cl, 4 tbl, 221 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing 1,3-oxathiolan nucleosides or a method for preparing derivatives of 1,3-oxathiolanyl-5-one that involve effective methods for formation of 1,3-oxathiolan ring followed by condensation of 1,3-oxathiolan with pyrimidine or purine base. Using indicated methods these compounds can be synthesized as separate enantiomers with high selectivity.

EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to the derivatives of purine, which has antiviral activity against human cytomegalovirus and human immunodeficiency virus type 1, of General formula:

where n = 0 to 4; m = 0 to 3; R1= N, HE or NH2; R2= HE, NH2, acetylamino or benzoylamine; R3= H or lower alkyl (C1-C4; R4= H, lower alkyl (C1-C4or phenyl; X = CH2, O, S, NH or C(O)O; and Y = CH2, CH=CH, C(O), or ordinary communication; Ar = phenyl, pyridyl, naphthyl or substituted phenyl of the formula

where independently R5-R9= alkyl1-C8cycloalkyl C5-C6, 1-substituted, allyl, phenyl, benzyl, F, Cl, Br, J, trifluoromethyl, alkoxy, C1-C5phenoxy, benzyloxy, benzoyloxy, cyano, carboxy, acetyl, or nitro, antiviral effect of the most active compounds against human cytomegalovirus in vitro manifests itself in concentrations of 0.01-0,0005M and is characterized by selectivity 1-400 thousand

FIELD: medicine, neurology, therapy, pharmacy.

SUBSTANCE: invention relates to pharmaceutical preparations used in treatment of neurological disorders. Preparations comprise eicosapentaenoic acid and arachidonic acid and shoes at least 90% of purity and taken as components of the preparation in the ratio from 1:1 to 20:1. Also, invention relates to methods for treatment of neurological disorders. Invention discloses the positive effect of the preparation on pathological neurodegenerative process. Invention provides the combined using eicosapentaenic and arachidonic acids in treatment of neurological disorders.

EFFECT: valuable medicinal properties of preparation.

11 cl, 3 tbl, 1 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: claimed method includes blending of active base and auxiliary ingredients to form tablet corn, representing composition of sugar powder, monocrystalline cellulose, vinylpyrrolidone and calcium stearate; humidifying of obtained mixture; drying of obtained granules; dry granulation through granulator with standardized holes; pelletization of standardized granules to produce tablet corn; and coating. Mixture is humidified with 5-7 % starch mucilage in starch mucilage/humidifying mixture mass ratio of 1:25-30, wherein mixture is blending with starch mucilage for homogeneous distribution wet in whole mass.

EFFECT: tablets with increased hardness and enhanced pharmacological activity.

2 cl, 2 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a new agent with expressed selective activity with respect to central muscarinic acetylcholine receptors belonging to subtype M1. Agent represents 1-phenyl-1-(1'-methylcyclopentyl)-4-piperidino-2-butyne-1-ol hydrochloride of the formula (1) known early as low toxic cholinolytic. Agent expands a set of ligands used in research of mechanisms of the central nervous system function. Agent shows high capacity for penetration through blood-brain barrier, low toxicity and high effectiveness.

EFFECT: valuable medicinal properties of agent.

1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-hydroxypiperidine of the general formula (I): wherein R means (a): -C(O)(CH2)nC(O)OH; (b): wherein R1 means -N(R2)(R3); each R2 and R3 means hydrogen atom, lower alkyl or cyclic tertiary amine; (c): -P(O)(OH)2 or (d): -C(O)(CH2)n and -NHC(O)(CH2)nN(R2)(R3) wherein n means a whole number 1-4. Indicated compounds can be used as prodrugs in preparing medicinal agents used in treatment of diseases associated with blocking agents for receptors of subtype NMDA.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 1 tbl, 20 ex

FIELD: medicine, pediatrics, psycho-neurology.

SUBSTANCE: the present innovation deals with applying preparation that normalize energy exchange. For this purpose it is necessary to introduce L-carnitine at the dosage of 20-30 mg/kg/d in three stages, coenzyme Q10 at the dosage of 30-60 mg/d once and limontar at the dosage of 10 mg/kg/d once during the first half of the day for 2 mo twice annually. The present innovation provides improved values for nervous-psychic development due to correcting mitochondrial alterations.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: organic chemistry of heterocyclic compounds, biology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines of the general formula (1): or (2): or their pharmaceutically acceptable salts, N-oxides or hydrate possessing physiologically active properties, in particular, eliciting ability to induce apoptosis in tumor cells causing their death. In the general formula (1) or (2) X represents sulfur or oxygen atom; Y represents sulfur atom, group -SO, group -SO2, group -NH or group -NR6; R1 represents aryl, substituted aryl, heteroaryl; R2 and R5 represent hydrogen atom, alkyl, allyl, substituted benzyl, group -CH2-C(O)R3, group -CH2-C(O)NR3R4 wherein R3, R4 and R6 represent inert substitute. Also, invention relates to new combinatory libraries for search compound-leaders and candidates for medicinal compounds preparing by screening the combinatory libraries.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 9 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: medicine, psychiatry, neurology.

SUBSTANCE: the present innovation deals with treating affected amnestic functions in women after uterine and adnexal extirpation. For this purpose, after a 7-d-long introduction of estradiol as suppositories at curative dosage of 8-20 mcg/kg body weight patients should be additionally injected with galanthamine intramuscularly once daily for 7-10 d at the dosage 5 mg, moreover, decreasing the number of estradiol injections up to once/3 d. The innovation suggested provides high antiamnestic effect at decreased dosage of preparations due to their agonistic action.

EFFECT: higher efficiency of therapy.

FIELD: medicine, gerontology.

SUBSTANCE: the present innovation deals with rehabilitation therapy of cerebrovascular diseases. One should introduce microcirculators and nootropic preparations to conduct training neuropsychological procedures. Moreover, microcirculatory and nootropic preparations should be introduced as intravenous infusions for 10 d, ten during 1 mo it is necessary to introduce tableted forms of the same preparations at simultaneous neuropsychological training directed to improving household skills valuable for a patient that deal with memorizing different names, important dates, names of medicinal preparations and location of domestic articles. On achieving a success the tasks should be complicated. Training should last for 30 min carried out thrice weekly: therapy course includes 12 trainings. The innovation widens the number of preparations for treating elderly and senile patients at discirculatory encephalopathy stage III and coarse cognitive deficiency.

EFFECT: higher efficiency of therapy.

3 ex, 1 tbl

Neuroprotector // 2268715

FIELD: medicine, pharmacology.

SUBSTANCE: claimed agent represents N-isopropylamide-2-(1-phenylethyl)-aminoethanesulfonic acids and is useful in treatment of various brain and spinal cord lesions.

EFFECT: new neuroprotector having no toxic effect.

6 dwg, 7 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: method involves applying antiherpetic therapy using Phamcyclovir. Then, Trental is sequentially introduced during 5 days with 2-5 ml of cerebrolysin being concurrently intratissularly introduced behind mastoid process tip. Mexidol is administered for 10 days. The treatment is finished by introducing Polyoxydonium.

EFFECT: combined microcirculation improvement; high neurotrophic and antioxidant activity; secondary immune deficiency adjustment; eliminated labyrinth hydrops.

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