S-substituted [(hetero)aryl]alkylisothioureas, production thereof, pharmaceutical composition, investigation of glutamatergic system, treatment methods (variants)

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

 

The SCOPE of the INVENTION

This invention relates to new derivatives of N,S,N’(N’)-three(Tetra)substituted estimacion possessing physiological activity. More specifically, the present invention relates to S-substituted N-1-[(hetero)aryl]alkyl-N’-1-[(hetero)aryl]allylisothiocyanate and their physiologically active salts and bases presented in the form of racemic mixtures or mixtures of stereoisomers or as individual optical isomers; to specific physiological activity of these compounds that can be used as a “molecular tools”; to pharmaceutical compositions containing these compounds; and to a method of treating and preventing various diseases, including neurodegenerative, for example, Alzheimer's disease (AD). The basis of the pharmacological effect of these compounds is their complex cognitive stimulation and neuroprotective action taken by affecting hemodialysis calcium channels in the membranes of nerve cells, in particular, regulated glutamate receptors of the Central nervous system (CNS).

BACKGROUND of INVENTION

Recently it was shown that potentiation (or positive modulation) of one of the subtypes of glutamate receptors, the so-called receptors “amino-3-hydrox the-5-methylisoxazole-4-propionic acid kainic acid (AMPA/KA receptors), leads to increased memory in experimental animals (.Yamada K.A. Modulating excitatory synaptic neurotransmission: potential treatment for neurological disease. - Neurobiological Dis., 1998, v.5, No.2, pp.67-80). In this regard, the search for compounds that can potentiate AMPA/KA receptors is a novel and promising approach to the development of new medicines for the treatment of ad and other diseases that cause impaired cognitive functions in humans. (Lynch, G. Memory and the brain: unexpected chemistries and a new pharmacology. - J. Neurobiol. Learn and Memory. 1998, v.70, n.1-2, pp. 82-100). In addition, they could be useful in situations that require significant strengthening memory and activation of the learning process, i.e. to serve as a cognitive stimulant.

On the other hand, it is known that a wide range of neurological diseases (such as BA, Huntington's chorea, amyotrophic lateral sclerosis, and ischemia of the brain), is associated with excitotoxicity the action of the excitatory neurotransmitter amino acids glutamate and aspartate (Doble A. The Role of Excitotoxicity in Neurodegenerative Disease: Memorandum for Therapy. Pharmacology and Therapeutics. 1999, v.81, no. 3, p.163-221). In accordance with this mechanism, the membrane depolarization of neurons during prolonged activation of glutamate receptors of the Central nervous system in the first place, receptors, N-methyl-D-aspartate (NMDA receptors), leads to disruption of calcium homeostasis in nerve cells and initiates a number of pathological processes that cause GI is spruce nerve cells (D.W.Choi, Neuron, 1988, v.1, p.623-634). Therefore, the search for selective antagonists of NMDA receptors in the brain that can protect nerve cells from the neurotoxic effects of excessive concentrations of calcium ions is a very promising approach to the development of new neuroprotective agents for the treatment and protection against a wide range of neurodegenerative diseases (Parsons C.G., Danysz W, Quack G. Glutamate in CNS Disorders as a Target for Drug Development: An Update. Drugs News Perspect, 1998, v.11, No. 9, p.523-580).

DETAILED description of the INVENTION

As a result of research aimed at finding compounds that are able to positively modulate AMPA/KA receptors, and with anti-NMDA activity, the inventors have discovered a broad group of S-substituted N-1-[(hetero)aryl]alkyl-N’-1-[(hetero)aryl]alkalization, which are characterized by a unique combination of these activities.

The present invention relates to novel S-substituted N-1-[(hetero)aryl]alkyl-N’-1-[(hetero)aryl]allylisothiocyanate in the form of free bases and salts with pharmacologically acceptable acids, as well as the individual optical isomers of these compounds or mixtures of the latter, which in the aggregate represented by the General formula (I):

in which:

Y and Z may be the same or different and independently represent a possibly substituted aryl or you can Sames the config (possibly partially or fully hydrogenated) heteroaryl;

sign (#) indicates the possible presence of chiral carbon atom;

R1and R2may be the same or different and independently represent H or lower alkyl;

R3represents lower alkyl, possibly substituted alkenyl, possibly substituted cycloalkyl, cycloalkenyl, aralkyl or a group of the General formula:

-(CH2)n-W

in which: n=1-4, and W is selected from the group consisting of:

possibly substituted aryl;

possibly replaced (possibly partially or fully hydrogenated) heteroaryl;

possibly substituted cycloalkyl;

Attila, optionally mono-or di-substituted lower alkyl;

group COOR5(in which R5represents H, lower alkyl, phenyl); group CH2OR5(in which R5has the values defined above); group NR6R7(in which R6and R7may be the same or different, and each independently represents: H; alkyl; cycloalkyl; aralkyl; one of the substituents R6or R7can represent acyl group C(O)R5in which R5has the values defined above; or in which R6and R7can work together to form does not necessarily substituted 1,4-butylene or 1,5-pentamethylene chain, and chain-CH2CH2-O-CH2CH2-); group N(R8)+X-(in which R8represents lower alkyl, and X represents the anion of a pharmacologically acceptable acid) N-phthalimidopropyl, possibly substituted in the benzene ring. R4represents H, lower alkyl, possibly substituted aryl, phenylethyl, possibly substituted in the phenyl ring, [(hetero)aryl]methyl or 1-[(hetero)aryl]ethyl; and:

and:

whenR3isthe lowestalkyl,R1, R2, R3notare simultaneously N;

in the form of bases or their salts with pharmacologically acceptable acids HX in the form of a racemate, individual stereoisomers or mixtures thereof.

Used in the above definitions and the subsequent description, the term "lower alkyl" means alkyl group with straight or branched chain, containing from 1 to 4 carbon atoms, examples of which are methyl, ethyl, isopropyl, butyl, sec-butyl, tert-butyl and similar.

The term "cycloalkyl" means a cyclic saturated hydrocarbon group with 5-7 ring carbon atoms, and its examples include cyclopentyl, cyclohexyl and similar.

The term "cycloalkenyl" means a cyclic unsaturated hydrocarbon group with 5-7 ring carbon atoms, and its examples include cyclopentenyl, cyclohexenyl and similar.

The term "aryl" means nez is displaced or substituted phenyl or naftalina group. Substituents of the phenyl group can be a halogen (e.g. fluorine, chlorine, and the like), lower alkyl groups (e.g. methyl, ethyl, isopropyl and the like), lower alkoxygroup (for example, methoxy, ethoxy, isopropoxy and similar), piano, nitro, trihalomethyl group (for example, trifluoromethyl and the like), optionally substituted amino (e.g. amino, dimethylamino, acetylamino, N-piperidino, N-phthalimido group and the like), acyl groups (e.g. formyl, acetyl, benzoyl and the like), carboxamide group (for example, N,N-diethylcarbamoyl group and the like), carboxypropyl, carbalkoxy and similar. Vice naftilos groups can be fluorine, chlorine, bromine, methyl and metoxygroup.

The term "aralkyl" means the above aryl, attached to an alkyl group as described above.

The term “heteroaryl” means 5 - or 6-membered N-, O-or S-hetero-aromatic cycle or benzo-derivative. Examples of suitable substituents include not necessarily substituted furan, thiophene, pyrrole, indole, pyridine, quinoline, etc.

Under used herein the term "halogen" refers to chlorine, bromine, fluorine or iodine.

The term "alkoxy" means the group AlkO-in which the alkyl part is as defined above alkyl group. Examples and what maxigrip include methoxy, ethoxy, butoxy and similar groups.

The term “acyl” means a group COR (where R* matter of H, alkyl, aryl and aralkyl defined above). Examples of acyl groups include formyl, acetyl, benzoyloxy, phenylacetylene and similar groups.

The term "pharmacologically acceptable acid" encompasses all pharmaceutically acceptable acids, both inorganic (e.g., hydrochloric, sulfuric, phosphoric, etc.); and organic (e.g., oxalic, citric, tartaric, maleic, succinic, metallinou, p-toluensulfonate etc.),

PREFERRED VARIANTS of the EMBODIMENT of the INVENTION

Among the compounds of formula (I)constituting one of the objects of the present invention, preferred are the following three subgroups of compounds which can be represented by the formulas (1.1), (1.2) and (1.3)below.

1.1. In particular, a first group of preferred compounds are: S-substituted N-[(hetero)aryl]-methyl-N’-1-[(hetero)aryl]alkalino-thiourea of General formula 1.1:

in which:

Y and Z have the meanings given above for formula I; sign (#) indicates the possible presence of chiral carbon atom;

R9represents H or lower alkyl;

R10represents lower alkyl, alkenyl, aralkyl or a group of the General formula:-(H 2)m-V

in which: m=1-2, and V is selected from the group consisting of: (m=1) maybe substituted aryl, possibly substituted cycloalkyl; Attila, optionally monosubstituted lower alkyl;

group COOR5(in which R5has the values defined above);

group CH2Or SIG5(in which R5has the values defined above);

diphenylphosphinyl group;

(when m=2) aryl;

group COOR5(in which R5has the values defined above);

N-piperidine; N-the research; N-pyrrolidino;

N-phthalimido group, possibly substituted in the benzene ring.

R11represents H, lower alkyl or 2-phenylethyl, possibly substituted in the phenyl ring.

and: when R10represents lower alkyl, R9, R11are not both N.

1.1.1. Within the group 1.1 the most preferred are S-substituted N-1-[(hetero)aryl]methyl-N’-1-(R,S)-phenylethylenediamine in the form of a racemic mixture (or additive mixture of stereoisomers) of the General formulae I.1.1:

in which:

A represents aryl, and heterocyclic Deputy, namely:

not necessarily substituted 2-or 3-furyl,

not necessarily substituted 2-or 3-thienyl,

not necessarily substituted 2-pyrrolyl,

not necessarily substituted 3-indolyl;

n is necessarily substituted 2-tetrahydrofurfuryl.

R10has the values defined above for formula I.1;

R11has the values defined above for formula I.1;

I.2. The second sub-group of preferred compounds among the substances corresponding to the formula I, are:

S-substituted N-[(hetero)aryl]-methyl-N’-[(hetero)aryl]metriso-thiourea of General formula I.2:

in which:

Y and Z have the meanings given above for formula I;

R10has the values defined above for formula I.1;

R11has the values defined above for formula I.1;

and: when R10represents lower alkyl, R11is not N.

I.2.1. Within the group I.2 most preferred are S-substituted N-[(hetero)aryl]methyl-N’-(heteroaryl)methylisothiazoline General formula I.2.1:

in which Het represents:

not necessarily substituted 2-or 3-furyl;

not necessarily substituted 2-or 3-thienyl;

not necessarily substituted 2-pyrrolyl;

not necessarily substituted 3-indolyl;

not necessarily substituted 2-tetrahydrofurfuryl.

And1is:

phenyl, (optional mono or di-substituted by such substituents as halogen, lower alkyl, methoxy, ethoxy, trifluoromethyl);

methylenedioxyphenyl;

2-furyl;

2-tetrahydrofurfuryl.

R 10has the values defined above for formula I.2.1;

R11has the values defined above for formula I.2.1;

Even more preferred in the range of estimacion formulae I.1.1 are two groups of compounds I.1.1.1 I.1.1.2 and:

1.1.1.1 S-substituted N-1[(hetero)aryl]methyl-N’-[1-R(+)-phenylethyl]ISO-thiourea of General formula 1.1.1.1:

in which:

And1has the values defined above for formula I.2.1.

R11has the values defined above for formula I.1;

R12selected from the group consisting of:

lower alkyl;

allyl; 2-penttila; 2-(etoxycarbonyl) ethyl;

cyclohexenyl; 2-N-phthalimidomethyl;

of benzyl, not necessarily substituted in the benzene ring;

I.1.1.2. S-substituted N-[(hetero)aryl]-methyl-N’-[1-S(-)-phenylethyl]estimacion General formula I.1.1.2:

in which:

And1has the values defined above for formula I.2.1

R11has the values defined above for formula I.1;

R12has the values defined above for formula I.1.1.1

The third sub-group of preferred compounds among estimacion corresponding to formula I is a group of diastereoisomeric compounds 1.3, represented by four subgroups: A, I.3b, S and I.3d:

A. S,N’-substituted N-[1-S(-)-phenylethyl]-N’-[(1-S(-)-f is niatel]-estimacion General formula I:

in which:

R13selected from the group consisting of:

lower alkyl;

allyl;

cyclohexenyl;

of benzyl, possibly substituted in the benzene ring;

2-(phenyl)ethyl;

R14represents lower alkyl, does not necessarily substituted benzyl, (heteroaryl)methyl or 2-phenylethyl;

I.3b. S,N’-substituted N-[1-S(-)-phenylethyl]-N’-[1-(R(+)-phenylethyl]-estimacion General formula I.3.b:

in which:

R13and R14have the meanings given above for formula I;

S. S,N-substituted N-[1-R(+)-phenylethyl]-N’-[1-S(-)-phenylethyl]-estimacion General formula I.3.c:

in which:

R13and R14have the meanings given above for formula I;

I.3d. S,N’-substituted N-[1-R(+)-phenylethyl]-N’-[1-R(+)-phenylethyl]-estimacion General formula I.3.d:

in which:

R13and R14have the meanings given above for formula A.

Most preferred are the following compounds of formula I (in the form of pharmacologically acceptable salts and/or free basis):

S-methyl-N-1-S(-)-phenylethyl-N’-1-S(-)-phenylethylenediamine and S-methyl-N-1-S(-)-phenylethyl-N’-(4-methoxy)benzyl-N’-1-S(-)-phenylethylenediamine.

Most preferred are the following with the organisations of the formula I.1. (in the form of pharmacologically acceptable salts and/or free bases): S-methyl-N-4-terbisil-N’-[1-S(-)-phenylpropyl]-N’-isobutyl-estimacion and S-methyl-N-4-terbisil-N’-[1-R(+)-phenylpropyl]-N’-isobutylacetophenone.

Most preferred is the following compound of the formulae I.1.1 (in the form of pharmacologically acceptable salts and/or free bases): S-methyl-N-4-methoxybenzyl-N’-3,4-dimethoxyphenyl-N’-1-phenylethylenediamine.

Most preferred are the following compounds of the formula I.2 (in the form of pharmacologically acceptable salts and/or free basis):

S-benzyl-N-benzyl-N’-benzisothiazolin, S-4-nitrobenzyl-N-benzyl-N’-benzisothiazolin, S-4-carboxymethyl-N-benzyl-N’-benzisothiazolin, S-allyl-N-benzyl-N’-benzisothiazolin, S-2-cyclohexenyl-N-benzyl-N’-benzisothiazolin, S-2-phenylethyl-N-benzyl-N’-benzisothiazolin, S-2-etoxycarbonyl-ethyl-N-benzyl-N’-benzisothiazolin.

Most preferred are the following compounds of formula I.2.1 (in the form of pharmacologically acceptable salts and/or free bases): S-methyl-N-2-tetrahydrofurfuryl-N’-5-methylfentanyl-N’-2-phenylethylenediamine and S-methyl-N-piperonyl-N’ -2-thienylmethyl-N’-isopropylideneuridine.

Most preferred are the following compounds of formula I.1.1.1 (in the form of pharmacologically PR is acceptable salts and/or free bases): S-methyl-N-benzyl-N’-1-R(+)-phenylethyl-N’-(cyclohex-3-enyl)methylisothiazoline and S-methyl-N-benzyl-N’-1-R(+)-phenylethyl-N’-2-phenylethylenediamine.

Most preferred are the following compounds of formula I.1.1.2 (in the form of pharmacologically acceptable salts and/or free bases): S-methyl-N-benzyl-N’-1-S(-)-phenylethyl-N’-(cyclohex-3-enyl)methylisothiazoline and S-methyl-N-benzyl-N’-1-S(-)-phenylethyl-N’-2-phenylethylenediamine.

Most preferred is the following connection formula A (in the form of pharmacologically acceptable salts and/or free basis):

Most preferred is the following connection formula I.3.b (in the form of pharmacologically acceptable salts and/or free basis):

S-methyl-N-[1-S(-)-phenylethyl]-N’-[1-R(+)-phenylethyl]-N’-isobutylacetophenone.

Most preferred is the following connection formula I.3.c (in the form of pharmacologically acceptable salts and/or free basis):

S-methyl-N-[1-R(+)-phenylethyl]-N’-[1-S(-)-phenylethyl]-N’-isobutylacetophenone.

Most preferred is the following connection formula I.3.d (in the form of pharmacologically acceptable salts and/or free basis):

S-methyl-N-[1-R(+)-phenylethyl]-N’-[1-R(+)-phenylethyl]-N’-isobutylacetophenone.

The compounds of formula I according to the invention is obtained using methods known in the art to obtain similar substances or new ways described below.

Intermediate thioureas forms of the crystals of TM, in which R1, R2, R4, (#), Y and Z have the above values are the values above are carried out by analogy with known reaction of amines with isothioscyanates. However, subsequent alkylation of N,N’(N’)-di(three)-substituted thioureas TM due to the strong steric interaction flows is ambiguous. In the course of developing the present invention was found selective methods of alkylation little reactive thioureas such structure, allowing to keep the optical activity of the compounds.

The basis for obtaining new compounds of the formula I according to the invention is the method lies in the fact that the thiourea of the formula TM

subjected to reaction with an equivalent amount or an excess (200%) of the appropriate alkylating agent of formula R3-G (in which R3defined above, a G is a leaving group such as halide, sulfate, alkylsulfonate, arylsulfonate, triplet, alkylsulfate, perchlorate, acetate, and also not necessarily substituted benzoate)may, in a polar inert solvent (such as alcohols, ethylene glycol, acetic acid, dimethylformamide, dimethylsulfoxide, sulfolane, acetone) at a temperature of from room temperature up to the boiling temperature of the reaction mixture.

According to further aspect of the invention, before the offers methods for obtaining compounds of formula I, characterized in that the process is performed under the action of microwave radiation in the mentioned solvents or in the form of a homogenized mixture of the source compounds without solvent.

The structure of the obtained compounds was confirmed by chemical data, spectral analysis and other physico-chemical characteristics; the melting temperature is not corrected. The PMR spectra taken on the instrument Bruker CXP-200 (200 MHz). The multiplicity of the observed signals are indicated in abbreviated form: (s) - singlet, (d) - doublet, (t) - triplet, (K) - quadruplet and (m) - multiplet.

The following examples illustrate but do not limit the invention.

Example 1. Hydroiodic S-methyl-N-(S)-(-)-α -methylbenzyl-N’-(S)-(-)-α -methylbenzeneethanamine. (Connection 1).

A solution of 1.63 g (0.01 mol) of (S)-(-)-α -methylbenzenesulfonate, to 1.21 g (0.01 mol) of (S)-(-)-α -methylbenzylamine in 50 ml of benzene was boiled for 4 hours. The solvent was evaporated, the resulting thiourea was added 1.7 g (0.012 mol) of methyliodide in 50 ml of methanol. The reaction mixture is boiled for 1.5 hours, the solvent and unreacted methyliodide was evaporated. The resulting oil was poured dry ether, the precipitated crystals were filtered.

Yield 2.1 g (49.2 percent), TPL 86-88° C.

Example 2. Hydroiodic S-methyl-N-(S)-(-)-α -methylbenzyl-N’-(4-methoxy)benzyl-N’-(S)-(-)-α -methylbenzeneethanamine. (Compound 2).

R is the target of 13.6 g (0.1 mol) of 4-methoxybenzaldehyde, 12.1 g (0.1 mol) of (S)-(-)-α -methylbenzylamine in 100 ml of toluene is boiled with a nozzle Dean-stark before the termination of the distillation of water. The reaction mixture is evaporated. The resulting Imin restore catalytic hydrogenation: Schiff base (20 g) in 50 ml of isopropanol and 2 g of 1%Pd/C is placed in the device to hydrogenation at atmospheric pressure. The restoration is carried out before the cessation of hydrogen absorption. The reaction mixture is cooled, filtered off the catalyst, evaporated the solvent. The oil obtained is distilled, selecting a fraction 168-172° C/1 mm Hg To 2,40 g (0.01 mol) of N-(4-methoxy)benzyl-N-(S)-(-)-α -methylbenzylamine in 50 ml of methanol was added 1.63 g (0,01M) (S)-(-)-α -methylbenzenesulfonate, boiled for 1.5 hours, add 1.7 g (0.012 mol) of methyliodide. The reaction mixture is boiled for 24 hours. The solvent is evaporated, the resulting oil zakristallizuetsya of dry ether, the crystals are filtered, recrystallized from 20 ml of isopropanol.

Yield 2.0 g (35.5%), and TPL 117-119°

Example 3. Hydroiodic S-methyl-N-4-terbisil-N’-[1-S(-)phenylpropyl]-N’-isobutylacetophenone. (Compound 3).

A solution of 13.5 g (0,1M) (S)-(-)-1-phenylpropylamine, 7.2 g (0,1M) samalanga aldehyde in 100 ml of toluene is boiled with a nozzle Dean-stark before the termination of the distillation of water. The solvent is evaporated. The resulting Imin restore catalytic hydrogenation: the Schiff base is (20 g) in 50 ml of isopropanol and 2 g of 1%Pd/C is placed in the device to hydrogenation at atmospheric pressure. The restoration is carried out before the cessation of hydrogen absorption. The reaction mixture is cooled, filtered off the catalyst, evaporated the solvent. The oil obtained is distilled, selecting a fraction wing 112-116°/1 mm RT. Art. It is 2.09 g (0.01 mol) of N-[1-S(-)-phenylpropyl]-N-isobutylamine in 50 ml of methanol was added to 1.79 g (0,01M) 4-fermentalization, boiled for 8 hours, add 1.7 g (0.012 mol) of methyliodide. The reaction mixture is boiled for 4 hours. The solvent is evaporated, the resulting oil zakristallizuetsya of dry ether, the crystals are filtered, recrystallized from 20 ml of isopropanol.

Yield 2.3 g (46,0%), TPL 111-113° C.

Example 4. Hydroiodic S-methyl-N-4-methoxybenzyl-N’-3,4-dimethoxy-phenethyl-N’-1-phenylethylenediamine. (Compound 4).

A solution of 12.0 g (0.1m) of acetophenone, 18,1 g (0.1m) of 3,4-dimethoxyphenethylamine in 100 ml of toluene is boiled with a nozzle Dean-stark before the termination of the distillation of water. The solvent is evaporated. The resulting Imin restore catalytic hydrogenation: Schiff base (20 g) in 50 ml of isopropanol and 2 g of 1%Pd/C is placed in the device to hydrogenation at atmospheric pressure. The restoration is carried out before the cessation of hydrogen absorption. The reaction mixture is cooled, filtered off the catalyst, evaporated the solvent. The oil obtained is distilled, selecting a fraction 184-188° C/1 mm Hg To 3.03 g (0.01 mol) of N-3,4-dimethoxyphenethyl is-N-1-phenethylamine in 50 ml of methanol was added to 1.79 g (0,01M) 4-methoxyphenylethylamine, boil for 8 hours, add 1.7 g (0.012 mol) of methyliodide. The reaction mixture is boiled for 4 hours. The solvent is evaporated, the resulting oil zakristallizuetsya of dry ether, the crystals are filtered, recrystallized from 20 ml of isopropanol.

Yield 2.2 g (36,3%), TPL 121-123° C.

Example 5. Hydroiodic S-methyl-N-2-tetrahydrofurfuryl-N’-5-methylfentanyl-N’-2-phenylethylenediamine. (Compound 5).

A solution of 11.0 g (0,1M) 5-methylpyrrole, 12,1 g (0,1M) 2-phenethylamine in 100 ml of toluene is boiled with a nozzle Dean-stark before the termination of the distillation of water. The solvent is evaporated. The resulting Imin restore catalytic hydrogenation: Schiff base (20 g) in 50 ml of isopropanol and 2 g of 1%Pd/C is placed in the device to hydrogenation at atmospheric pressure. The restoration is carried out before the cessation of hydrogen absorption. The reaction mixture is cooled, filtered off the catalyst, evaporated the solvent. The oil obtained is distilled, selecting a fraction 132-137°/1 mm RT. Art. To 2,33 g (0.01 mol) of N-5-methylfentanyl-N-2-phenethylamine in 50 ml of methanol was added 1,43 g (0,01M) tetrahydrofurfurylamine, boiled for 8 hours, add 1.7 g (0.012 mol) of methyliodide. The reaction mixture is boiled for 4 hours. The solvent is evaporated, the resulting oil zakristallizuetsya of dry ether, the crystals are filtered, recrystallized from 20 ml of isopropanol.

You are the od 1.7 g (34,0%), TPL 105-107° C.

Example 6. Hydroiodic S-methyl-N-piperonyl-N’-2-thienylmethyl-N’-isopropylaminocarbonyl. (Compound 6).

A solution of 11.6 g (0,1M) thiophene-2-carbaldehyde, 6.5 g (0,11) Isopropylamine in 100 ml of toluene is boiled with a nozzle Dean-stark before the termination of the distillation of water. The solvent and unreacted amine evaporated. To a solution of the obtained imine in 100 ml of methanol with stirring in small portions was added 2 g (0,06M) sodium borohydride. Then the reaction mixture is boiled for 1 hour, the solvent evaporated, the residue is dissolved in 200 ml of methylene chloride and washed with water (3* 100 ml). The organic phase is separated, dried with potash, the solvent is evaporated. The oil obtained is distilled, selecting a fraction 135-140° C/10 mm Hg To about 1.75 g (0.01 mol) of N-2-thienyl-N-Isopropylamine in 50 ml of methanol was added 1,93 g (0,01M) piperonylpiperazine, boiled for 8 hours, add 1.7 g (0.012 mol) of methyliodide. The reaction mixture is boiled for 4 hours. The solvent is evaporated, the resulting oil zakristallizuetsya of dry ether, the crystals are filtered, recrystallized from 20 ml of isopropanol.

Yield 2.1 g (42,9%), TPL 91-93° C.

Example 7. Hydroiodic S-methyl-N-[1-S(-)-phenylethyl]-N’-[1-S(-)-phenylethyl]-N’-isobutylacetophenone. (Compound 7).

A solution of 12.1 g (0.1 m) (S)-(-)-1-phenethylamine, 7.2 g (0,1M) samalanga aldehyde in 100 ml of toluene is boiled with a nozzle Dean-stark is to stop the distillation of water. The solvent is evaporated. The resulting Imin restore catalytic hydrogenation: Schiff base (19 g) in 50 ml of isopropanol and 2 g of 1%Pd/C is placed in the device to hydrogenation at atmospheric pressure. The restoration is carried out before the cessation of hydrogen absorption.

The reaction mixture is cooled, filtered off the catalyst, evaporated the solvent. The oil obtained is distilled, selecting a fraction 152-155° C/10 mm Hg To 1,95 g (0.01 mol) of N-[1-S(-)-phenylethyl]-N-isobutylamine in 50 ml of methanol was added 1,49 g (0,01M) 1-S(-)-phenylethylenediamine, boiled for 8 hours, add 1.7 g (0.012 mol) of methyliodide. The reaction mixture is boiled for 4 hours. The solvent is evaporated, the resulting oil zakristallizuetsya of dry ether, the crystals are filtered, recrystallized from 20 ml of isopropanol.

Yield 1.8 g (47,3%), TPL 105-107° C.

A similar method based on the corresponding chiral 1-phenylethylamine received the following optically active estimacion:

Hydroiodic S-methyl-N-[1-S(-)-phenylethyl]-N’-[1-R(+)-phenylethyl]-N’-isobutylacetophenone. (Compound 8).

Yield 1.8 g (47,3%), TPL 107-109° C.

Hydroiodic S-methyl-N-[1-R(+)-phenylethyl]-N’-[1-R(+)-phenylethyl]-N’-isobutylacetophenone. (Compound 9).

Yield 1.7 g (35,2%), TPL 106-108° C.

Hydroiodic S-methyl-N-[1-R(+)-phenylethyl]-N’-[1-S(-)-phenylethyl]-N’-isobutylacetophenone. (Compound 0).

Yield 1.7 g (35,2%), TPL 105-107° C.

Example 8.

The hydrobromide S-benzyl-N-benzyl-N’-benzisothiazolin. (Compound 11).

To a solution of 10.7 g (0.1 mol) of benzylamine in 150 ml of ethanol was added 0.3 g of sulfur and 4.6 g (0.06 mol) of carbon disulfide. The mixture is heated on a water bath under reflux until complete cessation allocation of hydrogen sulfide. Sulfur is filtered off, part of the alcohol is evaporated under reduced pressure. After cooling, the precipitated N-benzyl-N’-benzyltoluene filtered off, recrystallized from 100 ml of isopropanol. To of 2.56 g (0.01 mol) obtained thiourea in 50 ml of acetone add 2,05 g (0.012 mol) of benzyl bromide. The reaction mixture was kept at a temperature of 50° With 24 hours. The precipitated crystals are filtered and recrystallized from 20 ml of isopropanol.

The yield of 3.3 g (77.3 per cent), TPL 145-147° C.

Calculated: 61,83%, N 5,42%, N 6,55%, C22H23BrN2S. Found: 61,48%, N 5,47%, N 6,35%.

Range PMR (DMSO-d6, ppm, δ ): 4,65 (2H, s, SCH2), AND 4.75 (2H, m, CH2Ph), of 4.95 (2H, m, CH2Ph), 7,10-7,55 (15 NM, m, Ph), 9,80 (1H, ushort, NH), 10,10 (1H, ushort, NH).

A similar method of N-benzyl-N’-benzyltoluene and appropriate alkylhalogenide were obtained:

The hydrochloride of S-4-nitrobenzyl-N-benzyl-N’-benzisothiazolin. (Compound 12).

Yield 3.1 g (72.6 per cent), TPL 158-160° C.

Calculated: 61,75%, N 5,18%, N 9,82%, C22H22C1N302S. Found: 61,43%, N 5,27%, N Of 9.55%.

Range PMR (DMSO-d, ppm, δ ): 4,75 (2 is, d, CH2Ph), is 4.85 (2H, m, CH2Ph), of 4.95 (2H, s, SCH2), 7,10-7,30 (10H, m, Ph), 7,40-of 7.90 (4H, DD, Ph-N2), or 10.60 (1H, ushort, NH), 10,80 (1H, ushort, NH).

The hydrobromide S-4-carboxymethyl-N-benzyl-N’-benzisothiazolin. (Compound 13).

Yield 2.7 g (57,3%), TPL 137-139° C.

Calculated: 58,60%, N 4,92%, N 5,94%, C23H23BrN202S. Found: 58,43%, N 5,07%, N 5,59%.

Range PMR (DMSO-d6, ppm, δ ): 4,55 (2H, s, SCH2)AND 4.65 (2H, m, CH2Ph), 4,70 (2H, m, CH2Ph), 6,90-7,10 (10H, m, Ph), 7,20-of 7.70 (4H, DD, Ph-COOH), 10,00 (1H, ushort, NH), 10,10 (1H, ushort, NH).

The hydrobromide S-allyl-N-benzyl-N’-benzisothiazolin. (Compound 14).

Yield 2.5 g (66.3 per cent), TPL 81-83° C.

Calculated: 57,29%, N 5,61%, N 7,42%, C18H21BrN2S. Found: 57,48%, N 5,42%, N 7,35%.

Range PMR (DMSO-d6, ppm, δ ): 4,65 (2H, m, SCH2), AND 4.75 (2H, m, CH2Ph), is 4.85 (2H, m, CH2Ph), 5,10-of 5.40 (2H, m, =CH2), OF 5.75 (1H, m, =CH), 7,20 is 7.50 (10H, m, Ph), 9,80 (1H, ushort, NH), 10,10 (1H, ushort, NH).

The hydrobromide S-2-cyclohexenyl-N-benzyl-N’-benzisothiazolin. (Compound 15).

Yield 2.2 g (52.8%)and TPL 145-147° C.

Calculated: 60,43%, N 6,04%, N Of 6.71%, C21H25BrN2S. Found: 60,33%, N 5,91%, N 6,37%.

Range PMR (DMSO-d6, ppm, δ ): 1,55-2,10 (6N, m, SSNS), AND 4.75 (2H, m, CH2Ph), is 4.85 (2H, m, CH2Ph), the 4.90 (1H, m, SCH), THE 5.65 (1H, m, =CH), equal to 6.05 (1H, m, =CH),7,20-of 7.60 (10H, m, Ph), 10,00 (1H, ushort, NH), 10,10(1 H, ushort, NH).

The hydrobromide S-2-phenylethyl-N-benzyl-N’-benzisothiazolin. (Compound 16).

Yield 2.2 g (49.9 percent), TPL 78-80° C.

Calculated: 62,58%, N 5,71%, N 6,35%, C23H25BrN2S. Found: 62,48%, N 5.46 Percent, N 6,39%.

Range PMR (DMSO-d6, ppm, δ ): 2,80 (2H, t, CH2Ph), 3,70 (2H, m, SCH2) 4,55 (2H, d, CH2Ph), 5,00 (2H, m, CH2Ph), 7,10 to 7.75 (15 NM, m, Ph), 10,00 (1H, ushort, NH), 10,30 (1H, ushort, NH).

The hydrobromide S-2-etoxycarbonyl-ethyl-N-benzyl-N’-benzyl-estimacion. (Compound 17).

Yield 1.8 g (41,2%), TPL 95-97° C.

Calculated: 54,92%, N 5,76%, N 6,40%, C20H25BrN202S. Found: 54,61%, N 5,48%, N Of 6.31%.

Range PMR (DMSO-d6, ppm, δ ): 1,45 (3H, t, CH3), 3,30 (2H, t, SNS(O)), OF 3.60 (2H, q, ON), 3,70 (2H, m, SCH2), AND 4.75 (2H, m, CH2Ph), the 4.90 (2H, m, CH2Ph), 7,10-of 7.55 (10H, m, Ph), 10,10 (1H, ushort, NH), 10,30 (1H, ushort, NH).

As noted above, the compounds of formula I, according to the invention, have the ability to potentiate the response of AMPA/KA receptors and block the responses of the NMDA receptor, which is confirmed by the results of biological tests.

RESEARCH METHODS AND RESULTS

The authors used two alternative approaches to directed search for compounds that can potentiate the response of AMPA/KA receptors and cause the improvement of memory and cognitive functions in behavioral experiments in animals.

The first is the definition of a potentiating effect of new compounds on AMPA-, Kainat - induced transmembrane currents in Purkinje neurons of the cerebellum in rats and blockade of NMDA-induced currents in neurons of the cerebral cortex of rats;

The second proof in behavioral experiments, improve memory and cognitive functions in rats with deficiency of cholinergic neurons caused by exposure not what rotaxane f64, (and decrease as a consequence, the functions of memory and learning), as well as in intact rats.

Method of assessment potentiating AMPA/KA - induced currents and blocking NMDA-induced currents of connection properties.

The experiments were carried out by the method of patch-clamp on svezhesorvannyh Purkinje neurons isolated from the cerebellum of rats (14-16 day). To highlight used the modified method. Slices of cerebellum thickness of 400-600 microns was placed in a thermostatted chamber volume of 10 ml. of a Solution for isolation had the following composition (in mm): NaCl 150.0, KCl 5.0, CaCl22.0, MgSO4×7H2O 2.0, HEPES 10.0, glucose 15.0, pH 7.42. Slices were incubated in this solution for 60 minutes, after which the solution was replaced with a similar solution containing pronase (2 mg/ml) and collagenase (1 mg/ml)and were incubated for 70 minutes. After washing the initial solution for 20 minutes, the sections were placed in a Petri dish and pulled by mechanical means using a Pasteur pipette. The solution was continuously flushed with 100% O2when t° 34C° . The Purkinje neurons were placed in the working chamber with a volume of 0.6 ml of the working solution had the composition (in mm): NaCl 150.0, KCl 5.0, l22.6, MgSO4x7H20 2.0, HEPES 10.0, glucose 15.0, pH 7.36.

Similarly receive and process the cortical slices of rat brain with the only difference that the age of the rats was 7-8 is the time of incubation with enzymes was 14 minutes.

Transmembrane currents were caused by the activation of AMPA/KA receptors applique solutions agonist of these receptors-kainic acid and activation of NMDA receptors appliqué solutions agonist of these receptors N-methyl-D-aspartic acid (NMDA) method quick superfusion. Registration currents was performed using borosilicate microelectrodes (resistance 1.5-2.5 mω) filled with the following composition (in mm): KCl 100.0, EGTA 11.0, CaCl21.0, MgCl21.0, HEPES 10.0, ATR 5.0, pH 7.2.

For registration used ERS (NEKA, Germany). Write currents was carried out on the PC hard disk, Pentium-100 with program Pulse, also purchased in the company of NEKA. Processing of the results was carried out using Pulsefit (NEKA).

Applique kainate calls in Purkinje neurons transmembrane incoming currents. Add in perfusely solution of compounds causes an increase in the amplitude of the currents. This increase depends on the connection, his concentration, the time that has passed after the start of application of the substance.

Application of NMDA causes the neurons of the cerebral cortex incoming currents. Add in perfusely solution compounds cause a decrease in the amplitude of the currents.

Example. The connection 16. The connection 16 at a dose of 20 μm causes an increase in Kainat-induced currents at 8-12% (average 10%).

Washing within 3-5 minutes comes the t of the response amplitude to the control value.

In neurons of the cerebral cortex connection 16 causes a reduction of NMDA-induced currents. At a concentration of 3 μm by 25-35% (average 30%), and at a dose of 10 μm - 100%. In other words, almost completely blocks these currents. The hillshade connection 16 for 3-6 minutes returns the amplitude of NMDA-induced currents to the control value.

The results obtained are presented in table 1. Connect is superior to standard activity substance Taken 1.0-2.0 times. However, they do not have a significant neurotoxic effects in the active interval of the studied doses, which makes them valuable for use in medicine, in the treatment and prevention of diseases, the mechanism of pathogenesis involving cholinergic neurotransmitter system and, especially, in the treatment of neurodegenerative diseases such as Alzheimer's disease.

Another aspect of the invention are compounds of General formula I, having the property to contribute (positively modulate) glutamate AMPA/KA receptors, and at the same time to block the transmembrane currents caused by activation of glutamate NMDA receptors.

Another aspect of the invention is a method of study glutamatergic system, which consists in the introduction of specific pharmacological markers as molecular tools, the quality of which use compounds of General formula I, due to their ability to potentiate AMPA/KA receptors and to block NMDA receptors.

Another aspect of the invention is a method for the treatment and prevention of neurological disorders and diseases associated with dysfunction glutamatergic nanoperiodic by affecting AMPA/KA and NMDA receptors by introducing an effective amount of compounds of General formula I.

Another aspect of the invention is a significant way of enhancing memory and activation of the learning process through positive modulation of AMPA/KA receptors introduction of effective amounts of compounds of General formula I.

Assigned to receive a dose of the active ingredient (compound of formula I or its pharmaceutically acceptable salts) varies depending on many factors, such as age, sex, weight of the patient, the symptoms and severity of the disease, specifically assigned to the connection, the route of administration, the form of the drug that is assigned to an active connection.

Usually, the total prescribed dose is from 1 to 200 mg per day. The total dose can be divided into several doses, for example, to receive from 1 to 4 times a day. During oral assignment interval total dose of active substance is between 10 to 200 mg per day, preferably from 15 to 150 mg of parenteral reception interval of doses ranging from 5 to 100 m the day, preferably, from 5 to 50 mg, and in intravenous injections of 1 to 50 mg per day, preferably from 1 to 25 mg. Exact dose can be selected by the treating physician.

As is commonly the case in medicine, the compounds of formula I according to the present invention is recommended to be applied in the form of compositions comprising respectively the next aspect of the invention.

The pharmaceutical composition according to the invention is prepared using generally accepted engineering techniques and includes a pharmacologically effective amount of the active agent compound of the formula I or its pharmaceutically acceptable salt (hereinafter referred to as "active compound"), which typically ranges from 5 to 30 wt.%, in combination with one or more pharmaceutically acceptable auxiliary additives, such as diluents, binders, loosening agents, absorbents, fragrances, flavoring agents. In accordance with known methods of the pharmaceutical compositions can be presented in various solid or liquid forms.

Examples of solid dosage forms include, for example, tablets, pills, gelatin capsules, etc.

Examples of liquid dosage forms for injection and parenteral administration include solutions, emulsions, suspensions, etc.

The compositions can usually get through the th standard procedures, providing a mixture of the active compound with a liquid or finely powdered solid carrier.

Compositions according to the invention in the form of tablets containing from 5 to 30% of the active compound and the filler(s) or carrier(s). As such for tablets are used: a)diluents: beet sugar, lactose, glucose, sodium chloride, sorbitol, mannitol, ethylene glycol, calcium phosphate disubstituted; b) binders: magnesium aluminum silicate, starch paste, gelatin, tragakant, methylcellulose, carboxymethylcellulose and polyvinylpyrrolidone; disintegrating agents: dextrose, agar, alginic acid or its salts, starch, twin.

EXAMPLE 1.

100 mg pills containing 15.0 mg of compound 17

Connection 17 15.0 mg

Lactose 40.0 mg

Alginic acid 20.0 mg

Citric acid 5.0 mg

Tragakant 20.0 mg

The tablet may be formed by pressing or moulding of the active ingredient with one or more additional ingredients.

Obtaining a CT is performed on a special installation. The active ingredient in free form, such as powder or granules, in the amount of 150 grams (the amount of matter required to obtain 10,000 tablets) is mixed with the binder - tragakant (200 g), mixed with the diluent is lactose (400 g), the mixture is added p is tricheuse substance - alginic acid (200 g) and odorant - citric acid (50 g).

For gelatin capsules are used optionally colorants and stabilizers. As the dyes used: tetrazine, Indigo; as stabilizers can be represented as: sodium metabisulfite, sodium benzoate. The proposed gelatin capsules contain from 1 to 20% of the active ingredient.

EXAMPLE 2.

500 mg capsules containing 50 mg of compound 18

The connection 18 50.0 mg

Glycerin 100.0 mg

Sugar syrup 290.0 mg

Mint oil 40.0 mg

Sodium benzoate 10.0 mg

Ascorbic acid 5.0 mg

The tetrazine 5.0 mg

500 g of the active substance (compound 18) (amount required for the preparation of 10,000 capsules) finely pulverized and mixed in a mixer with glycerol (1000 g) and sugar syrup (2900 mg). After stirring the mixture was added peppermint oil (400 g), sodium benzoate (100 g), ascorbic acid (50 g) and tetrazine (50 g). Gelatin capsules are prepared drip method. This method allows the simultaneous drip dosing of a solution of a medicinal substance and heated gelatinous mass (900 g of gelatin) in a chilled liquid paraffin. The result is the formation of seamless spherical gelatin capsules filled with a medicinal mixture, ready for use, containing 50 mg of active substance.

injectione forms of compositions preferably are isotonic solutions or suspensions. The above forms can be sterilized and may contain additives such as preservatives: sodium metabisulfite, benzoic acid, sodium benzoate, a mixture of methyl paraben and propyl paraben; stabilizers: apricot and Arabian gum, dextrin, starch paste, methyl cellulose, twin; salt, regulating the osmotic pressure (sodium chloride), or buffers. In addition, they can contain other therapeutically useful substances.

EXAMPLE 3.

2 ml vials containing 20 mg of compound 17

Connection 17 20.0 mg

Sodium chloride 0.9% solution of 1.6 ml

Benzoic acid 10.0 mg

Methyl cellulose 10.0 mg

Mint oil 0.4 ml

For the preparation of injectable active compound 17 (20 g; number needed to produce 1000 capsules) finely pulverized and mixed in a mixer with peppermint oil (400 ml), then add methyl cellulose (10 g)is mixed with 0.9% sodium chloride solution (1600 ml) and added benzoic acid (10 g). The resulting solution was Packed in ampoules of 2 ml and sterilized by steam for 30 minutes

1. S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkyl-estimacion General formula I

in which

Y and Z may be the same or different and independently represent a possibly substituted aryl or possibly replaced (possibly partially and fully hydrogenated) heteroaryl; sign (#) indicates the possible presence of chiral carbon atom;

R1and R2may be the same or different and independently represent H or lower alkyl;

R3represents lower alkyl, possibly substituted alkenyl, possibly substituted cycloalkyl, cycloalkenyl, aralkyl or a group of General formula

in which n =1-4, and W is selected from the group consisting of a possibly substituted aryl, possibly substituted by a (possibly partially or fully hydrogenated) heteroaryl; possibly substituted cycloalkyl;

Attila, optionally mono-or di-substituted lower alkyl;

group COOR5(in which R5represents H, lower alkyl, phenyl);

group CH2OR5(in which R5has the values defined above);

group NR6R7in which R6and R7may be the same or different, and each independently represents H; alkyl; cycloalkyl; aralkyl; one of the substituents R6or R7can represent acyl group C(O)R5in which R5has the values defined above; or in which R6and R7may together form an optionally substituted 1,4-butylene or 1,5-pentamethylene chain, and the chain-CH2CH2-O-C 2-CH2-;

group N(R8)3+X-in which R8represents lower alkyl, and X represents the anion of a pharmacologically acceptable acid;

N - phthalimidopropyl, possibly substituted in the benzene ring,

R4represents H, lower alkyl, possibly substituted aryl, phenylethyl, possibly substituted in the phenyl ring, [(hetero)aryl]methyl or 1-[(hetero)aryl]ethyl;

moreover, when R3represents lower alkyl, R1,R2,R3are not both N;

in the form of bases or their salts with pharmacologically acceptable acids HX in the form of a racemate, individual stereoisomers or mixtures thereof.

2. Compounds according to claim 1, represents the S-substituted N-[(hetero)aryl]-methyl-N'-1-[(hetero)aryl]alkylenediamine General formula

in which Y and Z have the meanings given above for formula I; sign (#) indicates the possible presence of chiral carbon atom, R9represents H or lower alkyl;

R10represents lower alkyl, alkenyl, aralkyl or a group of General formula

where m =1-2, and V is selected from the group consisting of (when m =1) maybe substituted aryl, possibly substituted cycloalkyl; Attila, optional monogamists what about the lower alkyl; group COOR5in which R5has the values defined above;

group CH2OR5in which R5has the values defined above; diphenylphosphinyl group; (m=2) aryl; group COOR5in which R5has the values defined above; N-piperidine; N-the research; N-pyrrolidine; N-phthalimidopropyl, possibly substituted in the benzene ring;

R11represents H, lower alkyl or 2-phenylethyl, possibly substituted in the phenyl ring,

moreover, when R10represents lower alkyl, R9, R11are not both N.

3. Compounds according to claim 2, representing the derivatives of S-substituted N-[(hetero)aryl]methyl-N’-1-(R,S)-phenylethylenediamine in the form of a racemate, individual stereoisomers or mixtures thereof of the General formulae I.1.1:

in which a represents aryl, and heterocyclic Deputy, namely, optionally substituted 2 - or 3-furyl, optionally substituted 2 - or 3-thienyl, optionally substituted 2-pyrrolyl, optionally substituted 3-indolyl; optionally substituted 2-tetrahydrofurfuryl;

R10has the values defined above for formula I.1;

R11has the values defined above for formula I.1.

4. Compounds according to claim 1, represents the S-substituted N-[(hetero)aryl]-ethyl-N'-[(hetero)aryl]methylisothiazoline General formula I.2

in which Y and Z have the meanings given above for formula I;

R10has the values defined above for formula I.1;

R11has the values defined above for formula I.1, in addition: when R10represents lower alkyl, R11is not N.

5. Compounds according to claim 4, representing the S-substituted N-[(hetero)aryl]methyl-N'-(heteroaryl)methylisothiazoline General formula I.2.1:

in which Het represents:

not necessarily substituted 2 - or 3-furyl;

not necessarily substituted 2 - or 3-thienyl;

not necessarily substituted 2-pyrrolyl;

not necessarily substituted 3-indolyl;

not necessarily substituted 2-tetrahydrofurfuryl,

And1is:

phenyl, (not necessarily mono - or disubstituted by such substituents as halogen, lower alkyl, methoxy, ethoxy, trifluoromethyl);

methylenedioxyphenyl; 2-furyl;

2-tetrahydrofurfuryl;

R10has the values defined above for formula I.1;

R11has the values defined above for formula I.1.

6. Compounds according to claim 3, representing the S-substituted N-[(hetero)aryl]methyl-N'-[1-R(+)-phenylethyl]estimacion General formula I.1.1.1:

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in which And1has the values defined above for formula I.2.1, R11has the values defined above for formula I.1;

R12selected from the group consisting of:

lower alkyl;

allyl;

cyclohexenyl;

of benzyl, not necessarily substituted in the benzene ring;

2-phenylethyl;

2-(etoxycarbonyl)ethyl;

2-N-phthalimidomethyl.

7. Compounds according to claim 3, representing the S-substituted N-[(hetero)aryl]-methyl-N'-[1-S(-)-phenylethyl]estimacion General formula I.1.1.2:

in which And1has the values defined above for formula I.2.1,

R11has the values defined above for formula I.1,

R12has the values defined above for formula I.1.1.1.

8. Compounds according to claim 1, represents S,N'-substituted N-[1-S(-)-phenylethyl]-N'-[(1-S(-)-phenylethyl]estimacion General formula I:

in which R13selected from the group consisting of lower alkyl; allyl; cyclohexenyl; benzyl, possibly substituted in the benzene ring; 2-(phenyl)ethyl;

R14represents lower alkyl, optionally substituted benzyl, (heteroaryl)methyl or 2-phenylethyl.

9. Compounds according to claim 1, represents S,N'-substituted N-[1-S(-)-phenylethyl]-N'-[1-(R(+)-unilater]estimacion General formula I.3.b:

in which R13and R14have the meanings given above for formula A.

10. Compounds according to claim 1, represents S,N'-substituted N-[1-R(+)-phenylethyl]-N'-[1-S(-)-phenylethyl]estimacion General formula Is:

in which R13and R14have the meanings given above for formula A.

11. Compounds according to claim 1, represents S,N'-substituted N-[1-R(+)-phenylethyl]-N'-[1-R(+)-phenylethyl]estimacion General formula I.3.d:

in which R13and R14have the meanings given above for formula A.

12. Compounds according to claim 1, represents the S-methyl-N-1-S(-) -phenylethyl-N'-1-S(-)-phenylethylenediamine and S-methyl-N-1-S(-)-phenylethyl-N'-(4-methoxy)benzyl-N'-1-S(-)-phenylethylenediamine in the form of a base or in the form of pharmacologically acceptable salts with HX.

13. Compounds according to claim 2, representing S-methyl-N-4-terbisil-N'-[1-S(-)-phenylpropyl]-N'-isobutylacetophenone and S-methyl-N-4-terbisil-N'-[1-R(+)-phenylpropyl]-N'-isobutylacetophenone in the form of a base or in the form of pharmacologically acceptable salts with HX.

14. The compound according to claim 3, representing S-methyl-N-4-methoxybenzyl-N'-3,4-dimethoxyphenyl-N'-1-phenylethylenediamine in the form of a base or in the form of pharmacologically acceptable salts with HX.

15. Joint who according to claim 4, representing S-methyl-N-benzyl-N'-benzisothiazolin, S-ethyl-N-benzyl-N'-benzisothiazolin, S-benzyl-N-benzyl-N'-benzisothiazolin, S-4-nitrobenzyl-N-benzyl-N'-benzisothiazolin, S-4-carboxymethyl-N-benzyl-N'-benzisothiazolin, S-allyl-N-benzyl-N'-benzisothiazolin, S-2-cyclohexenyl-N-benzyl-N'-benzisothiazolin, S-2-phenylethyl-N-benzyl-N'-benzisothiazolin, S-2-etoxycarbonyl-ethyl-N-benzyl-N'-benzisothiazolin in the form of a base or in the form of pharmacologically acceptable salts with HX.

16. Compounds according to claim 5, representing S-methyl-N-2-tetrahydrofurfuryl-N'-5-methylfentanyl-N'-2-phenylethylenediamine and S-methyl-N-piperonyl-N'-2-thienylmethyl-N'-isopropylethylene in the form of a base or in the form of pharmacologically acceptable salts with HX.

17. Compounds according to claim 6, representing S-methyl-N-benzyl-N'-1-R(+)-phenylethyl-N'-(cyclohex-3-enyl)methylisothiazoline and S-methyl-N-benzyl-N'-R(+)-phenylethyl-N'-2-phenylethylenediamine in the form of a base or in the form of pharmacologically acceptable salts with HX.

18. Compounds according to claim 7, representing S-methyl-N-benzyl-N'-1-S(-)-phenylethyl-N'-(cyclohex-3-enyl)methylisothiazoline and S-methyl-N-benzyl-N'-S(-)-phenylethyl-N'-2-phenylethylenediamine in the form of a base or in the form of pharmacologically acceptable salts with HX.

19. The connection of claim 8, representing S-methyl-N-[1-S(-)-phenylethyl]-N'-[1-S(-)-phenylethyl]-N'-isobutylidene the urea in the form of a base or in the form of pharmacologically acceptable salts with HX.

20. The connection according to claim 9, representing S-methyl-N-[1-S(-)-phenylethyl]-N'-[1-R(+)-phenylethyl]-N'-isobutylacetophenone in the form of a base or in the form of pharmacologically acceptable salts with HX.

21. The connection of claim 10, representing S-methyl-N-[1-R(+)-phenylethyl]-N'-[1-S(-)-phenylethyl]-N'-isobutylacetophenone in the form of a base or in the form of pharmacologically acceptable salts with HX.

22. Connection to item 11, representing S-methyl-N-[1-R(+)-phenylethyl]-N'-[1-R(+)-phenylethyl]-N'-isobutylacetophenone in the form of a base or in the form of pharmacologically acceptable salts with HX.

23. The method of obtaining salts of compounds of formula I, namely, that the thiourea of the formula TM

in which R1, R2, R4, (#), Y and Z have the above meanings, is subjected to reaction with an equivalent amount or an excess (200%) of the appropriate alkylating agent of formula R3-G in which R3defined above, a G is a leaving group such as halide, sulfate, alkylsulfonate, arylsulfonate, triplet, alkylsulfate, perchlorate, acetate, and optionally substituted benzoate, perhaps, in a polar inert solvent, such as alcohols, ethylene glycol, acetic acid, dimethylformamide, dimethylsulfoxide, sulfolane, acetone, at temperatures from room temperature up to the boiling temperature of the reaction mixture.

24. The method according to item 23, wherein the process is carried out under the action of microwave radiation in the mentioned solvents or in the form of a homogenized mixture of the source compounds without solvent.

25. Compounds of General formula I according to any one of claims 1 to 22, with the ability to potentiate glutamate AMPA/KA receptors and at the same time to block the transmembrane currents caused by activation of glutamate NMDA receptors.

26. Way of learning glutamatergic system, which consists in the introduction of specific pharmacological markers as molecular tools, which use compounds of General formula I according to any one of claims 1 to 22, in connection with their ability to potentiate the AMPA/KA receptors and to block NMDA receptors.

27. Compounds of General formula I according to claims 1-22, can potentiate glutamate AMPA/KA receptors and to block NMDA receptors and therefore, having the properties of stimulants for cognitive functions and specific neuroprotection.

28. Compounds of General formula I according to any one of claims 1 to 22, intended for the treatment and prevention of neurodegenerative diseases associated with dysfunction glutamatergic neuropterida.

29. The compounds of formula I according to any one of claims 1-22, designed to significantly enhance memory and activation of the learning process, i.e. as cognit the main stimulants.

30. Compounds of General formula I according to any one of claims 1 to 22, as the active substance for the manufacture of pharmaceutical compositions intended for the treatment and prevention of neurodegenerative diseases associated with dysfunction glutamatergic neuropterida, as well as a cognitive stimulant.

31. Pharmaceutical composition containing compounds of General formula I according to any one of claims 1 to 22, intended for the treatment and prevention of neurodegenerative diseases associated with dysfunction glutamatergic neuropterida, as well as a cognitive stimulant.

32. Method for the treatment and prevention of neurological disorders and diseases associated with dysfunction glutamatergic nanoperiodic by affecting AMPA/KA and NMDA receptors by introducing an effective amount of compounds of General formula I according to any one of claims 1 to 22.

33. How significant enhance memory and enable the learning process through positive modulation of AMPA/KA receptors introduction of effective amounts of compounds of General formula I according to any one of claims 1 to 22.



 

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FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thien-3-yl-sulfonylamino(thio)carbonyl-triazolin(thi)ons of general formula I

(wherein Q represents oxygen or sulfur; R1 represents unsubstituted alkyl; R2 represents hydrogen, halogen, unsubstituted alkyl; R3 represents hydrogen, halogen, alkyl optionally substituted with alkoxy, alkoxy or arylthio, optionally substituted with alkoxy or halogen, unsubstituted cycloalkyl or cycloalkyloxy, or unsubstituted arylalkoxy or aryloxy; R4 represents unsubstituted alkyl, alkoxy, dialkylamino, cycloalkyl) and their salts. Compounds of present invention are useful as herbicide agents. Also disclosed is herbicide composition and new synthetic intermediates for compounds of formula I.

EFFECT: new compounds and intermediates thereof with herbicide activity.

16 cl, 13 tbl, 67 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to organic chemistry and can find application in medicine

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to new derivatives of amidine General formula (I’)

where it is:

in which R1, R2and R3HE or1-C6alkyl, C1-C6alkoxy, R4- H1-C6alkyl, R5- H1-C6alkyl or the radical:

where R10, R11and R12- OH or H, R13- H1-C6alkyl; or the radical:

where R18, R19and R20- H, HE, C1-C6alkyl, R21and R22- H, C1-C6alkyl, or R21-alkylsulfonyl, alkylsulfonyl, alkylaryl, and R22- H or the radical:

where T is -(CH2)k-, k = 1, 2, R27- H, C1-C6alkyl

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

The invention relates to new chemical compounds of the heterocyclic series, with pronounced anticalcium activity, which may find application in medical practice in the treatment and prevention of cardiovascular diseases and represent derivatives of 2-N-1-benzopyran-2-it General formula I

where R and R1have the meanings indicated in the claims

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to the field of chemistry of heterocyclic compounds and relates, in particular, a new chemical compound 2-isopropyl-4-[(furyl-2)metalinox] methylene-1,3-dioxolane exhibiting the properties of activator germination of wheat seeds and increases the resistance of seedlings to water stress

The invention relates to new compounds of the class of cetomacrogol and semisolids, potential intermediates in obtaining new macrolide and asamenew antibiotics, as well as the way they are received and intermediate compounds for their production

The invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds
The invention relates to the field of chemistry and can be used in industry as vulcanizing agents and vulcanization accelerators

The invention relates to new chemical substances, which can be a fungicidal active substance means, in particular to Amida alkoxybenzenes acid, fungicidal tool and method of controlling fungal diseases of plants
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