Derivatives of n-allpolitical


(57) Abstract:

Usage: in medicine as compounds with antiamnesic, antihypoxic and anorectic effect, exhibiting low toxicity, improving learning ability and memory. The essence of the invention: derivatives of N-acyl-polydopamine General formula I

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where R1= (C1- C4)alkyl, cycloalkyl, aralkyl or aryl; R2= N, (C4- C5)alkyl, carbamicacid or carbalkoxy; R3= hydroxy, alkoxy, amino, alkylamino or dialkylamino; n = 0 to 3, with (a) when R1= phenyl, R2= hydrogen or isopropyl, and n = 0, R3= not methoxy; b) when R1= tertbutyl, R2= hydrogen and n = 0 or 1, R3= not methylamino; C) when R1= tert-butyl, R2= isobutyl, methyl, benzyl or carbamoylmethyl, and n = 0, R3= not methylamino, g) when R1= tert-butyl, R2= carbomethoxyamino, n = 0, R3= not isopropylamino. Compounds have low toxicity. The described compounds are obtained by condensing the desired acid in a homogeneous phase when the block is not reacts functional groups using condensing agents such as, for example, carbody the Wallpaper promising group of drugs. Known nootropic compounds include piracetam (N-urea-organic-2), which was widely introduced into medical practice in the early 80-ies. In the future, were synthesized N-substituted-2-pyrrolidone (for example, etirazetam, oksiratsetam, aniracetam, pramiracetam, rollerteam and others).

In U.S. patent N 4743616 Tanaka and others described N-arylpyrimidine connection with endopeptidase inhibitory activity and providing antiamnesic action. Unlike piracetam derivatives, compounds described by Tanaka and others, contain prolinnova group.

So Therefore, and R. Ostrovsky described (Chem.Pharmac. J., 1985, No. 11, pp. 1322-1329) biologically active N-terminal derivatives pyroglutamic acid having the formula

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In another source (I. A. Therefore and other Chem.Pharmac. J., 1988, N 3, pp. 271-2759) described biologically active compounds N-allpoly having the formula

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The need for highly toxic nootropic drugs that can be used to treat deterioration of mental abilities caused by various destructive factors, there is still. The present invention is directed to satisfying this need.

The infusion of the spine, in particular, antiamnesic, antihypoxic and anorectic effect.

According to the present invention proposed derivatives of N-allpolitical General formula I

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R1=(C4-C5)alkyl, cycloalkyl, aralkyl or aryl;

R2= H, (C1-C4)alkyl, carbamicacid or carbalkoxy;

R3= hydroxy, alkoxy, amino, alkylamino or dialkylamino;

n = 0-2;

if this

a) when R1=phenyl, R2=hydrogen or isopropyl, and n=0, R3not methoxy,

b) when R1=tert-butyl, R2=hydrogen and n=0 or 1, R3= not methylamino,

b) when R1=tert-butyl, R2= isobutyl, methyl, benzyl or carbimidoyl, and n=0, R3not methylamino,

g) when R1= tert-butyl, R2= carbomethoxyamino, n=0, R3not isopropylamino.

Derivatives of N-allpolitical can be a

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R1= isobutyl, pentyl, 1-substituted, phenyl, phenylmethyl or phenylpropyl

R3= OH, OC2H5, NH2, NHCH3N(CH3)2; or

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R1= phenylmethyl or phenyl;

R3= OC2H5or NH2; or

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diet to be selected from the following compounds:

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The compounds of formula I differ from the known neuroprotective drugs in that they contain in their structure the remainder of the natural amino acids L-Proline (instead of pyrrolidone), together with the remainder of the second natural amino acids. These N-acyl-L-prolinnova dipeptides have extremely low toxicity and high activity.

Examples of implementation of the invention can serve the following connections:

I N-phenacetin-L-polyglycitol ether

II N-phenacetin-L-polyglycine

III N-phenacetin-L-prolyl -- allanatrophy ether

IV N-phenylacetyl-L-prolyl-alanine

V N-phenylacetyl-L-prolyl-L-aspartic acid diethyl ester

VI N-phenylacetyl-L-prolyl-L-asparaginase

VII N-benzoyl-L-polyglycitol ether

VIII N-isovaleryl-L-polyglycitol ether

IX N-phenylacetyl-L-prolyl-L-validatedby ether

X N-benzoyl-L-prolyl-L-validatedby ether

XI N-benzoyl-L-prolyl -- allanatrophy ether

XII N-benzoyl-L-prolyl-alanine

XIII N-benzoyl-L-polyglycine

XIV N-phenylacetyl-L-polyglucin-N-methylamide

XV N-phenylacetyl-L-polyglycidylether

XVI N-phenylacetyl-L-prolyl-L-glutamic acid IER is cetyl-L-prolyl-GABA-methyl ester

XX N-phenylacetyl-L-prolyl-L-allanatrophy ether

XXI N-caproyl-L-polyglycitol ether

XXII N-(1-adamantyl)-L-polyglycitol ether

XXIII N-phenylbutyric-L-polyglycidyl ether

The present invention also aims at obtaining pharmaceutical compositions and methods of treatment that involve the use as active substances pharmaceutically effective amounts of N-allpolitical formula 1, as defined above, preferably a compound of General formula

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R1chosen preferably from the group consisting of isobutyl, penttila, L-adamantyl, phenyl, phenylmethyl and phenylpropyl; R3chosen preferably from the group consisting of NH2, NH CH3N(CH3)2, OH and OC2H5. More preferably in the pharmaceutical compositions and methods of treatment according to the invention include an effective dose of a compound of the formula

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Here "pharmaceutically effective amount" or "effective amount" means an amount capable of providing effective treatment of the syndrome, because of which the patient suffers.

Compounds according to the invention possess psychotropic activity, including the Academy of Sciences of the tion, aging and hypoxia. These compounds also have an anorectic effect, alcohol activity and reduce mental disorders prenatally alcoholic offspring.

The present invention relates to various methods of treating the sick people by introducing effective dose of the compounds according to the invention. Such methods include treatment of people suffering from mental drop caused by injury, aging, senile dementia, and mentally retarded children; obesity; disorders of the Central nervous system (CNS) as a result of chemical toxicity, mainly caused by saturnism; sickle cell anemia; withdrawal benzodiazepine, which manifests itself as aggression, anxiety, and seizures; and alcohol dependence.

Detailed description of the invention

The above compounds of formula 1 were obtained well-known methods of peptide synthesis. The usual process of obtaining the considered compounds is mixing and condensation of the required amino acids, usually in a homogeneous phase.

Condensation in homogeneous phase can be performed in the following about nesposobny group, with amino acid, which has a free amino group and protected other reactive groups, in the presence of a condensing agent, such as carbodiimide;

b) condensation of the amino acid having an activated carboxyl group and protected other reactive group, with an amino acid, which has a free amino group and protected other reactive groups;

C) condensation of an amino acid having a free carboxyl group and protected other reactive group, with an amino acid having an activated amino group and protected other reactive groups.

The carboxyl group can be activated by turning it into chloranhydride, azide, anhydrite group or activated ester, such as N-oxysuccinimide, N-OK-cyberstrategy, pentachlorophenoxy or paranitrophenol ether. The amino group can be activated by turning it into hospitalid or "povorotnym" method.

The most common for the above condensation reactions are: carbodiimide method; azide method; method of mixed anhydrides; the method of activated esters. These methods are described in "The Peptides". Vol.1. 1965 (Academic Press), E. Schroeder, attachment peptides of formula 1 are the method of mixed anhydrides or carbodiimide method. The condensation reaction carried out according to the method of mixed anhydrides, preferably carried out in compliance with the "Anderson" conditions (G. W. Anderson et al. J. Am. Chem. Soc, 89, 50-12-5017 (1967)). Carboxyl component (for formation of the mixed anhydride of N-allpoly preferably activate isobutylparaben. Can be used also ethylchloride and methylchloroform.

The best solvents are a mixture of ethyl acetate with dimethylformamide, pure dimethylformamide and chloroform. Best tertiary bases are N-methylmorpholine, N-ethylmorpholine and triethylamine.

The condensation reaction carried out by carbodiimide method, preferably carried out in the presence of oxibendazole (W. Konig and R. Geiger, Chem. Ber., 103, 788-789 (1979)). Condensation on the carbodiimide method can also be carried out in the presence of other additives, such as paranitrophenol, pentachlorophenol or N-oxysuccinimide.

Reactive groups that should not participate in the condensation may be protected groups, which are easily removed, for example, by hydrolysis or recovery. Thus, the carboxyl group can be protected by ethicaly ethanol, methanol, tert-butanol, benzyl alcohol is x, aromatic, heterocyclic carboxylic acids, such as acetyl, benzoyl, pyridylcarbonyl, acid groups derived from carbonic acid, such as etoxycarbonyl, benzyloxycarbonyl, tertbutyloxycarbonyl; or an acid group derived from sulfonic acids such as para-talouselama.

The term "functional derivatives of the peptides of formula 1 are indicated:

1) N-acyl derivatives of aliphatic or aromatic acids;

2) esters derived from lower aliphatic alcohols;

3) amides, or monoalkyl-or dialkylamino amides, in which the alkyl groups have one or two C-atoms.

During the synthesis of the claimed polydopamine N-acyl derivatives preferably received using Proline which was previously azetilirovanie a suitable acyl group. This acyl group functioned also as a protective group in the further course of the synthesis. You can also enter the desired amino group after synthesis of peptides, allira dipeptides in the usual ways. Preferred N-acyl groups are N-phenylacetyl and N-benzoyl.

Esters of peptides according to formula 1 are preferably ispolzuemogo peptide. Preferably, the esters were derived from methanol or ethanol.

Amides of the peptides of formula 1 is obtained by ammonolysis of (i.e., by reaction with NH3) alkyl ester of the corresponding dipeptide or by reaction with an amino acid to form the desired amide. Amides of dipeptides can also be obtained by the introduction of amide groups in the corresponding dipeptide any suitable way, for example by treatment with amine in the presence of a condensing agent. Preferred unsubstituted amides, monomethyl and dimethylamide.

They studied the ability of compounds according to the invention to prevent memory impairment caused by maximal electroshock or receiving scopolamine. In contrast to N-arylpyrimidines compounds previously described by Tanaka and others , the compounds according to the invention are not designed for the suppression of the activity of polyangiitis. As described in the examples, the tested compounds exhibit antiamnesic activity (example 12). It was shown that the preferred compound having formula 1 (see tab. 1) that can facilitate different phases of memory formation: obtaining information, saving and restoring her memory in different procedures for passive and active escaped eduversum mental drop, caused by frontal lobectomy (example 15), prenatal alcoholism and prenatal hypoxia (example 16), aging (example 17). It also shows antihypoxic activity (example 18).

When watching piracetam cried some of the above effects, it was found that the level of active dose for it is 200-800 mg/kg In contrast, the claimed compounds produces the same effects at doses of approximately 0.1-0.5 mg/kg

Described here is the link 1 has an additional useful property that the anorectic action. In contrast to the known anorectic drug compound 1 does not cause adrenergic stimulation (agitation, increased blood pressure, and others). Connection 1, in addition, non-toxic (example 20) and is effective when administered orally (example 12). It is shown that compound 1 is able to reduce withdrawal symptoms when you cancel a benzodiazepine, reducing anxiety, aggressiveness and severity pentylenetetrazole of kindling (example 21).

The substances according to the invention can be used in any form which is suitable for oral administration, such as pills, tablets, coated tablets. These substances can be t active ingredient in combination with pharmaceutically acceptable carrier. The substances according to the invention can be used to treat patients with decreased mental abilities caused by a brain injury, intoxication, ageing, Korsakov's syndrome, Alzheimer's disease, organic brain syndrome, alcoholism, including prenatal alcohol damage, hypoxia , delayed mental development of children, obesity, stroke, cerebral disorders due to congenital disorders or genetic abnormalities, disorders of the Central nervous system as a result of chemical toxicity, including saturnism for treatment of substance abuse, including maintaining abstinence and cancellations, and some hematologic disorders, including sickle cell anemia. Preferably, these substances can be used in doses of 0.5-5.0 mg per day.

Hereinafter the invention is described with reference to various specific and preferred applications and will be described with reference to the following examples. It is obvious, however, that there are many expansion options, variations and modifications beyond the examples and detailed descriptions, but the relevant General inventive concept, design, and scope of the claims.

P sn - asparaginyl

Val - poured

Ala - alanyl

-Ala --alanyl

Leu - leucyl

Gly - glycyl

Glu - glutamyl

EtOH - ethanol

MeOH - methanol

DMF - dimethylformamide

DCC - dicyclohexylcarbodimide

DCU - dicyclohexylmethane

EtAC - ethyl acetate

BZ is benzoyl

Ad - 1-substituted

OHBt - 1-oxybenzoates

Et3N - triethylamine

Phac - phenylacetyl

TLC - thin layer chromatography

In the examples was used the following equipment:

the melting point was determined by sulfuric-acid apparatus in open capillaries without corrections;

specific rotation of the polarization plane of light were recorded on an automatic polarimeter Perkin-Elmer-241;

the spectra of nuclear magnetic resonance (NMR) were obtained on a spectrometer Bruker AC-250;

Chemical shifts were expressed in million-1regarding Me4Si.

To indicate resonance signals used the following abbreviations: s - singlet, d - doublet, t - triplet, g - quadruplet, m - multiplet.

Constants of spin-spin interaction are given in Hz.

Thin-layer chromatography (TLC) was performed on silikagelevye plates 60F254 Merck with the manifestation of iodine in the camera or ultraviolet OI approximately 180-220 g and/or male outbred mice albino weight of about 18-22,

In alcohol tests on living organisms used the offspring of alcoholic mothers of this type. Male rats albino Wistar rats at the age of 24-26 months used in the experiments associated with aging.

Example 1.

Synthesis of ethyl ester of N-phenylacetyl-L-propyl-glycine

N-Phac-L-Pro-Gly-O Et (1)

a) N-phenylacetyl-L-propyl, N-Phac-L-Pro-OH

To 5.75 g (0.05 mol) of L-Proline in 25 ml of 2N NaOH was added dropwise with stirring at a temperature below 10oC 12.5 ml 4N NaOH and 6.6 ml (0.05 mol) of N-phenylacetylide (tKip89 - 90oC/10 Torr). The reaction mixture was stirred 15 min, was extracted with EtAc to remove chloride, then acidified using 2N HCl to pH 3, extracted with chloroform, dried with sodium sulfate and evaporated. Was obtained 6.2 g of N-Phac-L-Pro-OH in the form of white crystals c: tPL150 - 152oC []2D0= -60,5o(c = 0.4, DMF), Rf= 0,66 (silica gel, dioxane-water 9:1).

1H-NMR spectrum in CDCl1/ (m-1): 1,77 - to 2.29 (m, CH2-CH2, Pro, 4H); 3.40 in - 3,63 (m, CH2, Pro, 2H); 3,63 and to 3.73 (each s, CH2-C6H5, 2H); 4,56 and to 4.38 (each dd, CH Pro, 1H); 7.18 in - 7,39 (m, CH2C6H5, 5H); 11,38 (user. s, COOH, 1H).

b) Ethyl ester of N-phenylacetyl-L-polyglycine

In a solution of 2.33 g (0.01 mol) of N-Phac-L-Pro-OH (tPL150 - 151oC) in 50 ml DMF was added with stirring at -10oC 1.39 ml (0.01 mol) Et3N and then of 1.34 ml (0.01 mol) of isobutylacetate. After 2 min to the reaction mixture was added dropwise over 25 min, 1.4 g (0.01 mol) of the hydrochloride glycinamido ether (tPL140 - 142oC) and a solution of 1.39 ml (0.01 mol) Et3N in 25 ml of DMF, to avoid temperature increase. Then the stirring was continued with cooling for 30 min and at room temperature for 1.5 hours the Precipitate was filtered and the filtrate evaporated in vacuo, the residue was dissolved in CHCl3the solution is washed with 5% NaHCO3, water, 1N HCl and again with water, dried with sodium sulfate and evaporated. Educated 1.66 g (54%) of the oil was mixed with ether to obtain white crystals: tPL96 - 97oC; []2D0= -120, c = 0.4 CHCl3), Rf= 0,80 (silica gel, dioxane-water 9:1).

1H-NMR spectrum (CD3)2SO, (m-1): of 1.18 (t, CH3CH2O 55% 5H); 1,17 (t, CH3CH2O, 45% of 3H); of 1.65 to 2.35 (m, CH2-CH2Pro , 4H); 3,2 - 3,4 (m, CH2, Pro, 2H); 3.40 in (s, CH2-C6H5UB>2Gly , 45% 2H); 4,08 (q, CH3CH2-O, 55% 2H); 4.09 to (q, CH3CH2-O, 45% 2H); 4,32 (dd, CH , Pro, 55% of 1H); 4,48 (dd, CH , Pro, 45% of 1H); a 7.1 to 7.6 (m, CH2C6H5, 5H); 8,29 (t, J = 5,9, NH Gly, 55% of 1H); 8,63 (t, J = 5,9 NH Gly, 45% of 1H).

Calculated for C17H22N4O4: C = 64,15; H=6,92; N=8,80.

Found: C=63,93; H=For 6.81; N=9,07.

Example 2.

Synthesis of N-phenylacetyl-L-polyglycolide Phac-L-Pro-Gly - NH2(II)

N-Phac-L-Pro-Gly-OEt (0,53 g; tPL96 - 97oC []2D0-122,0]2D0= 58,5(C = 0,2, CHCl3).

1H-NMR spectrum in CHCl3, (m-1) : 1.8 to 2.3 (m, CH2-CH2, Pro, 4H); 3,3 - 3,5 (m, CH2, Pro, 2H); 3,55 of 3.75 (m, AB part of ABX system, CH2Gly , 2H); 3,66 (s, CH2C6H5, 2H): 4,07 (dd, CH , Pro, 1H); 4,37 (t, NHGly, 1H); 5,63 and 7,86 (each s, NH2); to 7.2 to 7.4 (m, C6H5, 5H).

Calculated for C15H19N3O3: C=62,53; H=6,48; N=14,61.

Found: C=62,28; H=6,54; N=14,53.

Example 3.

Synthesis of ethyl ester of N-phenyl-L-prolyl-alanine

N-Phac-L-Pro -- Ala-OEt (III)

To a solution of 0.61 g (2.6 mmol) of N-phenylacetyl-L-Proline (tPL151oC []2DPL69-71oC) and of 0.29 ml of methylmorpholine in 4 ml of CHCl3. Stirring was continued with cooling for 40 min and then at room temperature for 2 hours, the Residue was filtered, and the solvent is evaporated on a rotating evaporator. The residue was dissolved in CHCl3and washed with 5% solution of NaHCO3, water, 1N HCl, water and then dried over sodium sulfate and evaporated. Output stood at 0.58 g or 98% N-Phac-L-Pro -- Ala-OEt, which is received in the form of a clear oil: Rf=0,52 (silica gel, CHCl3-MeOH, 9:1); Rf= 0,53 (silica gel, dioxane-water, 9:1); []2D0= 92,25o(C=0.3, and CHCl3).

1H-NMR spectrum (CD3)2SO, (m-1): 1,17 (t, CH3CH2-O, 68% of 3H); 1,13 (t, CH3CH2O, 32% of 3H); 1.7 to 2.2 (m, CH2-CH2, Pro, 4H); 2,42 (m, CH2-Ala, 2H); 3,2-3,3 (m, CH2, Pro, 2H); -3,40 (s, CH2-C6H5, 32% 2H) with HDO-signal; 3,66 (m, CH2-C6H5, 68% 2H); 4,01 (q, CH3CH2O, 32% 2H); Android 4.04 (q, CH3-CH2O 68% 2H); to 4.41 (m, CH2-Ala, 2H); is 4.21 (dd, CH, Pro, 1H); 7,1 and 7.36 (m, CH2-C6H5, 5H); to 7.93 (t, NH, 1H).

Designed SS="ptx2">

Synthesis of N-phenylacetyl-L-prolyl - alanine amide N-Phac-L-Pro -- Ala-NH2(IV)

For saturation ethanol solution (15 ml) 0.36 g of N-phenylacetyl-L-prolyl-alanine ethyl ester obtained in example 3 was barbotirovany gaseous ammonia. Settled in for the night, the solution evaporated, and the residue was purified in a chromatography column (silica gel) using CHCl3as eluent. Amide IV was obtained in the form of oil: exit 0,22 g (61%); Rf= 0,28 (silica gel, CHCl3- methanol, 9:1); []2D0= 22,8(C=0,33; CHCl3).

1H-NMR (Me2SO-d6), / (m-1); 1,69-2,2 (m, CH2-CH2Pro, 4H); 2,16-2,31 (m, CH2-Ala 2H); 3,1-3,3 (m, CH2, -Ala , 2H); 3,3-of 3.45 (m, CH2Pro, 2H); 3,66 (s, CH2-C6H5, 2H); 4,22 and to 4.41 (each dd, CH Pro, 1H); 6,84, was 7.36 and 6,86, 7,38 (each Shire. s, NH2, 2H); 7,12-7,35 (m, CH2C6H5, 5H); 7,89 and by 8.22 (each t, NH-Ala , 1H).

Calculated for C16H21N3O3: C=63,34; H=6,99; N=13,85.

Found: C=Expenses 63.81; H=7,03; N=14,01.

Example 5.

Synthesis of diethyl ether N-phenylacetyl-L-prolyl-L-aspartic acid N-Phac-L-Pro-L-Asp (OEt)2(V)

It is well displaced the Lina at -10oC. then sequentially added 0,57 ml (4.3 mmol) of ISO-BuOC(O)Cl, in 2-3 minutes - the mixture of 0.91 g (4.3 mmol) of L-Asp(OEt)2HCl; of 0.48 ml (4.3 mmol) of N-methylmorpholine and 15 ml of EtAc. Stirring was continued for 1 h at -10oC. After the mixture was defended for 1 hour, the residue was filtered off, the solution evaporated and the residue was dissolved in a mixture of ethanol and ether. The resulting solid residue was separated, the mother liquor is evaporated and the residue (1.65 g) was purified in a chromatography column (silica gel) using CHCl3and a mixture of CHCl3-EtOH as eluents. Diethylether N-phenylacetyl-L-prolyl-L-aspartic acid was obtained in the form of oil: Rf=0,87 (silica gel, CHCl3-EtOH, 9:3); []2D0= -38,0(C=2,2; CHCl3).

1H-NMR (Me2SO-d6), (m-1): of 1.23 (t, J=7,16 Hz, CH3CH2O 90% of 3H); to 1.24 (t, J=7,16, CH3CH2O, 10%, 3H); 4,10 (q, CH3CH2-O, 90% 2H); 4,12 (q, CH3CH2-O, 10% 2H); 1,25 (t, J=7,14, CH3CH2O 90% of 3H); 1.26 in (t, J=7,14, CH3CH2O, 10%, 3H); 4,19 (q, CH3CH2-O, 90% 2H); is 4.21 (q, CH3CH2O, 10% 2H); about 1.75-2.40 a (m, CH2-CH2Pro, 4H); 3.45 points-of 3.65 (m, CH2, Pro, 2H); 4,58 (dd, J=8,00; J=2,59; CH Pro, 1H); 2,78; 2,95 (dd, AB-the H2Asp, 10% 2H); to 4.81 (dt, J=CH, NH 8,50; CH Asp 1H); 7.5 (a, d, J=8,50; NH Asp, 90% of 1H); 7.03 is (d, J=8,40; NHAsp, 10% of 1H); 3,70 (s, CH2C6H5, 2H); 7,20 was 7.36 (m, C6H5, 5H).

Calculated for C21H28N2O6: C=62,35; H=6,99; N=6,92.

Found: C=62,63; H=7,01; N=6,74.

Example 6.

Synthesis of amide N-phenylacetyl-L-prolyl-L-asparagine


For saturation methanolic solution (25 ml) 0.5 g N-Phac-L-Pro-L-Asp(OEt)2obtained as in example 5, it was barbotirovany gaseous ammonia at 0oC. After settling overnight, the solution evaporated, the residue was dissolved in hot ethanol-chloroform to the residue was added pentane. The resulting residue was collected and dried; the yield was 0.45 g of amide N-phenylacetyl-L-prolyl - L-asparagine: tPL170 - 172oC; Rf= 0,24 (silica gel, CHCl3-EtOH, 9:3), []2D0= -55,7(C = 1,4 DMSO).

1H-NMR (Me2SO-d6), (m-1): 1,60 - 2,30 (m, CH2-CH2, Pro, 4H); 2,35 - of 2.50 (m, CH2, Asn, 2H) when the signal of the solvent; 3,63 (s, CH2=C6H5, 2H), 4,36 (m, CH Pro, 1H); 4,4 - 4,6 (m, CH Asn, 1H); 6,80 - of 7.60 (m, C>4O4: C = 58,94; H = 6,41; N = 16,16.

Found: C = 59,23; H = 6,66; N = 6,04.

Example 7.

Synthesis of ethyl ester of N-benzoyl-L-polyglycine, N-BZ-L-Pro-Gly-OEt (VII)

a) N-benzoyl-L-Proline

To a well stirred solution of L-Proline (5.75 g, 0.05 mol) in 2N NaOH (25 ml) was added drip from different drip funnels 4N NaOH (12.5 ml) and benzoyl chloride (5.8 ml, 0.05 mol), keeping the temperature around 0 - 4oC. the Mixture after 15 min was acidified using 1N HCl. The liberated oil was extracted with CHCl3combined organic extract was dried (MgSO4) and the solvent was removed. To the precipitate was added ether and the mixture was defended during the night when 0oC. the Separated crystals of N-benzoyl-L-Proline. Output were 3.42 g (60%), tKip152 - 154oC []2D0= -68,5, (C = 0.4; CHCl3); Rf= 0,13 (silica gel, CHCl3-CH3OH; 9:1).

Calculated for C12H13NO3: C = 65,73; H = 5,99; N = 6,39.

Found: C = 65,64; H = 6,03; N 6,54.

b) Ethyl ester of N-benzoyl-L-polyglycine

To a well stirred solution of N-benzoyl-L-Proline (2,19 g, 0.01 mol) in a mixture of absolute EtAc (50 ml) and DMF (10 ml) was added drip at -10oC N-methylmorphine (1,12 ml, 0.01 mol) and ISO-BuOC(O)Cl (of 1.34 ml, 0.01 mol). 2 is cozy mixing with cooling and hour and a half at room temperature the solvent was removed in vacuum. The residue was dissolved in chloroform, washed with 5% aqueous solution of NaHCO3, 1N HCl, water and then dried with Na2SO4. After filtration, the solvent evaporated, to the precipitate was added ether, and separating the resulting crystals from ether VII. The output rate of 1.67 g (76%); tKip63 - 65oC []2D0= 148,0(C = 0.4; CHCl3); Rf= 0,71 (silica gel, CHCl3-CH3OH; 9:1).

1H-NMR (Me2SO-d6) (m-1): of 1.18 (t, J=? 7.04 baby mortality, CH3CH2O 75% of 3H); of 1.09 (t, J=? 7.04 baby mortality, CH3CH2O, 25%, 3H); 1,73 - of 2.28 (m, CH2-CH2, Pro, 4H); 3,3 - 3,4 (m, CH2Pro, 2H); 3,60 and 3.74 (dd, J = by 5.87 and J = by 8.22; CH2Gly , 25% 2H); of 3.85 (d, J = by 5.87, CH2Gly , 75%, 2H); 4,10 (q, CH3CH2O), 75 % 2H); 4,13 (q, CH3CH2O, 25% 2H); 4,47 (dd, CH Pro, 25% of 1H); 4,48 (dd, CH Pro, 75% of 1H), 7,33 to 7.62 (m, C6H5, 5H); at 8.36 (t, J = by 5.87; NH, 75% of 1H); to 8.40 (t, J = by 5.87; NH, 25% of 1H).

Calculated for C16H20N2O4: C = 63,14; H = 6,16; N = 9,20.

Found: C = 63,56; H = 6,87; N = 9,48.

Example 8.

Synthesis of ethyl ester of N-isovaleryl-L-polyglycine

ISO-C4H9C(O)-LPro-Gly-Ot (VIII)

a) N-isovaleryl-L-Proline

To mix well Rast/SUP>C 4N-aq. NaOH (2.5 ml) and isovaleryl chloride (1.4 ml; 0.012 mol). After 15 min the mixture was acidified (pH 2 - 3) 1N HCl and was extracted with CHCl3. Mixed organic extract was dried using MgSO4and the solvent was removed. N-isovaleryl-L-Proline was obtained as oil. The yield of 0.85 g; Rf= 0,66 (silica gel, n-C4H9OH-AcOH-H2O, 5:1:2); []2D0= -129,3(C = 0,6; CHCl3).

1H-NMR (CDCl3), / (m-1): 0,99 (d, -CH(CH3)2, 6H); to 2.25 (m, CH(CH3)2, 1H); 2,3 (m, CH2CH(CH3)2, 2H); 1.9 to approximately 2.65 (m, CH2-CH2, 4H); 3.45 points - 3,70 (m, CH2Pro, 2H); cent to 8.85 (Shir. s, COOH, 1H).

Calculated for C10H17NO3: C = 60,27; H = 8,62; N = 7,02.

Found: C = 60,34; H = A Total Of 8.74; N = 7.23 Percent.

b) Ethyl ester of N-isovaleryl-L-polyglycine (VIII)

To a well stirred solution of N-isovaleryl-L-Proline (0.74 g; 0,0037 mol) in abs.EtAc (15 ml) was added N-ethylmorpholine (0.45 ml; 0,0037 mol) and ISO-BuOC(O)Cl (0.5 ml; 0,0037 mol). After 2 to 3 min drip was added at a temperature of from -10 to -5oC mixture of NH2CH2COOEt HCl (0.52 g; 0,0037 mol), N-ethylmorpholine (of 0.47 ml, 0,0037 mol) and DMF (10 ml). Stirring was continued for 30 min with cooling and 1.5 h the chloroform, washed with 5% aqueous solution of NaHCO3that water, IN aqueous HCl solution, water and then dried through MgSO4. After filtration the solvent is evaporated and the residue (0.6 g) is treated in a chromatographic column (silica gel) using CHCl3as eluent. Get 0,49 g (49%) of the ester VIII in the form of a clear oil, Rf= 0,55 (silica gel, CHCl3-MeOH 9:1), []2D0- to 113.4o(C 0,3; CHCl3), PMR spectrum in CDCl3, (M. D. ): 0,99 (d, J=5,97, CH(CH3)2, 6H): 2,22 (m, CH(CH3)2, 1H), 1.27mm (t, J=7,16, OCH2CH3, 3H), 4,18 (kV, OCH2CH3, 2H), 1,75-2,60 (m,CH2-CH2Pro,4H), 3,35-3,70 (m, CH2Pro 2H), 3.96 points and £ 4.02 (each DD, CH2Gly,2H), 3,85-4,10 (m, CH2CH(CH3)2), 6.50 and to 7.59 (each t, NHGly 1H).

Found, % : C 58,78; H, a total of 8.74; N 9,87 C14H24H2O4< / BR>
Calculated, % : C 59,12; H Charged 8.52; N 9,85.

Example 9.

Ethyl ester of N-phenylacetyl - L - prolyl - L-valine,

N - Phac - L - Pro - L - Val - OC2H5(IX)

Obtained in the conditions of example 1 from 2,33 g (0.01 m) N - phenylacetyl - L-Proline and 1.8 g (0.01 mol) of the hydrochloride of the ethyl ester of L-valine with the release of 72% in the form of oil, Rf= 0,64 (silica gel, dioxane-water 9:1), []2D
H(CH3)2Val 90% 6H); to 0.89 and 0.95 (each d, J=6,9, CH(CH3)2Val, 10% 6H); 1.27mm (t, CH3-CH2-O, 90% of 3H), 1.28 (in t, CH3-CH2-O, 10%, 3H); 1,7-2,5 (m,CH2-CH2Pro,4H) to 2.25 (m,CH Val,1H); 3,4-3,7 (m,CH2Pro,2H); 3,7 (s, CH2Ar, 2H); 4,18 (kV, CH3CH2-O, 2H); to 4.38 (D. D.,CHVal,J=8,4, J= 4,9, 90% of 1H); 4,54 (D. D., CH Val,10% of 1H);4,68(D. D. CHPro1H); 7,28 (m, C6H5, 5H); 7,44 (D., J=8,4; NH 90% of 1H); 6.48 in (d, NH, 10% of 1H).

Found, %: C 66,58; H 7,74; N a 7.85 C20H28N2O4< / BR>
Calculated, %: C 66,63; H To 7.84; N 7,76.

Example 10.

Ethyl ester of N-benzoyl - L-prolyl - L-valine,

N-Bz-L-Pro-L-Val-OEt (X)

Obtained under the conditions of example 1, 2.2 g (0.01 mol) of N-benzoyl-L-Proline and 1.8 g (0.01 mol) of the hydrochloride of the ethyl ester of L-valine. Yield 2.6 g (72,3%), so pl. 96-97oC (from ether); Rf=0,61 (silica gel, dioxane-water 9:1), Rf0,86 (silica gel, CHCl3-C2H5OH 3:1); []2D0= -103,1o(C = 0.4; CHCl3).

PMR spectrum in CDCl3, (M. D. ) : to 0.92 and 0.96 (each d, J=6,9 Hz, CH(CH3)2Val6H); of 1.28 (t, CH3CH2O, 3H); 1,75-2,7 (m,CH2-CH2Pro4H), of 2.21 (m,CH Val,1H), 3,36-3,70 (m, CH2D), of 7.3 and 7.6 (m, C6H5and NH 5H + 95% of 1H).

Found, %: C 65,54; H 7,47; N 8,21, C19H26N2O4< / BR>
Calculated,% : C 65,86; H 7,58; N 8,08.

Example 11.

N-benzoyl - L-propyl -- laminatefloor ether.

N-BZ-L-PrO--Ala-Ot (XI)

To a solution in DMF (25 ml), 0.9 g (6 mmol) -Ala-OtHCl, 1.3 g (6 mmol) of N-BZ-L-Pro-OH and 0.87 g (6.4 mmol) of N-hydroxybenzotriazole added 0,83 ml (6,01 mmol) of triethylamine. The mixture was cooled to 3oC, and to it was added 1.54 g (7.5 mmol) of DCC. The mixture was defended in 3oC overnight and at room temperature for 1.5 hours, and then cooled to -15oC. Obtained DCU was removed by filtration. To filter added aqueous potassium bicarbonate and received the remainder. It was filtered, washed with water and bicrystalline from a mixture of ethanol with water. The hard part is filtered, washed and dried. Obtained 1.5 g (78,9%) of product: tPL88-98oC []2D0= -114,0, (C = 0.5; CHCl3); Rf= 0,86 (silica gel, CHCl3- C2H5OH, 9:1).

H-NMR spectra of DMSO-d6, (m-1: of 1.03 and 1.07 (each t, CH3-CH2O, 3H); 1,6-2,3 (m,CH2-CH2Pro4H); 2,45 (t,CH2-Ala,2H); 4.04 the (g, CH3CHO, 2H); 3,14 and 3.40 (each m, CH2); 8,02 and 8.00 (each, t, NH, 1H).

Calculated for C17H22N2O6: C = 64,15; H = 6,92; N 8,80

Found: C=64,23; H=7,03; N=8,91

Example 12.

Amide N-benzoyl-L-prolyl-alanine,

N-BZ-L-Pro -- Ala-Nh2(XII).

obtained in the conditions of example 2 of the ethyl ester of N-benzoyl-L-prolyl --/ alanine with the release of 72%, so pl. 135-137oC (from ether); Rf=0.21 in (silica gel, CHCl3-C2H5OH 9:1); []2D0= 41,6o(c = 0.45, and CHCl3). PMR spectrum (CD3)2SO (M. D. ) : 1,68 - of 2.20 (m,CH2-CH2Pro,4H); 2,24(t, CH2--Ala, 2H); 3,21 (D. T. , J NH = 5.4 Hz, CH2--Ala, 70% 2H), 3,10 (D. T., CH2Ala30%2H), 3,3-3,68 (m,CH2Pro,2H), 4,39 (D. D., CHPro,70% of 1H), 4,11 (D. D., CHPro , 30% of 1H), 6,86-7,22 (m,C6H5and NH2, 7H), 7,98 (t, NH, 70%, 1H), 7,87 (t, NH, 30%, 1H).

Found, %: C 62,31; H 6,70; N 14,58 C15H19N3O3< / BR>
Calculated, %: C 62,28, H 6,57, N 14,53.

Example 13.

Amide N-benzoyl-T-propylalanine, N-Bz-L-Pro-Gly-NH2(XIII)

Obtained in the conditions of example 4 from ethyl ester of N-benzoyl-L-polylysine with a yield of 75%, so pl. 64-74oC (gegr.), Rf=0,54 (silica gel, CHCl3-C2H5OH, 3: 1), Rf=0,3 (silica gel
SO, (M. D.): 1,68-2.0 and 2,05-2,30 (m,CH2-CH2Pro,4H), 3,3-of 3.45 (m, CH2under NGOs, 2H), 3,53 of 3.75 (m,CH2-Gly,2H), 4,20 and 4,40 (each, m CHPro 1H and 90% of 1H), 6,95-the 7.65 (m, C6H5and NH2, 7H), 8,05 and 8.41 (each t, NH, 10% 1H + 90% of 1H),

Found, %: C 61,32, H of 6.31, N15,21

C14H17N3O3< / BR>
Calculated,%: C 61,09 H 6,20, N 15,27

Example 14.


N-Phac-L-Pro-Gly-NHMe (XIV)

A solution of 1.6 g (5 mol) of N-Phac-L-Pro-Gly-OEt in 50 ml of ethanol was cooled to 0oC, then for 30 min through the solution was barbotirovany monomethylamine (dried by passing through a column with NaOH). The solution was left for 5 hours at room temperature. The ethanol evaporated in vacuo. To the precipitate was added ether, and the solid part was filtered and dried in vacuum at 25oC. Obtained 1.6 g (99%) of product: tpl185-186,5oC []2D0= -36,00 (C = 0.5; CHCl3); Rf= 0,66 (silica gel, dioxane-water, 9:1).

1H-NMR spectrum in DMSO-d6, (m-1): 1,66-of 2.24 (m,CH2CH2Pro,4H); 2,49 (d, NHCH385% of 3H); 2,60 (d, NHCH315% of 3H); 3,61 and 3,63 (each m, CH2Gly, 85% 2H); 3,52 and 3,62 (each m,CH2Gly 15% of 4.44 (dd,CHPro 15% 1H); 7,16 and 7.36 (m, C6H5, 5H); 7,58 (q, NH-CH385% of 1H); 7,84 (q, NHCH315% of 1H); scored 8.38 (t, NHGly, 85% of 1H); at 8.36 (t, NHGly, 15% of 1H).

Found: C 63,61; H Of 6.75; N 14,01.


Calculated: 63,34; 6,93; N 13,86.

Subsequent products were prepared according to example 1.

Example 15.

Dimethylamide N-phenylacetyl-L-polyglycine

Dipeptide of formula N-Phac-L-Pro-Gly-NMe2(XV), yield 78%; oil; Rf= 0,68; silica gel, dioxane: water 9:1);

[]2D0= -147,1o(C=0,1; CHCl3).

H-NMR spectrum in DMSO-d6(m-1):1,71-to 2.06(m,CH2Pro,4H) 2,83, 2,93, and 2,84 2,96 (each s, N(CH3)2, 6H); 3,3-3,6 (m, CH2Pro, 2H); to 3.67 (s, CH2C6H52H); 3.89 and 3,95 (each d, CH2Gly 2H); 4,37 and to 4.52 (dd, for every CH Pro, 1H); 7,15-7,34 (m, C6H5, 5H); 7,88 and 8,24 (each t , NH, 1H).

Found: C = 64,53; H = Of 7.48; N = 13,01.

WITH17H23H3O3< / BR>
Calculated: C = 64,32; H = 7,32; N = 13,23.

Example 16.

Diethyl ether N-phenylacetyl-L-prolyl-L-glutamic acid.

Dipeptide of the formula: N-Phac-L-Pro-L-Glu(OEt)2(XVI) yield 69%, oil; Rf = 0,9 (silica gel, dioxane: in1H-NMR spectrum in CDCl3(m-1; and 1,25 1,27 (each t, 2 CH3-CH2-O, 6H); 1,76-2,49 (m, CH2CH2,Pro,CH2Gly, 8H); 3,39-to 3.92 (m,CH2Pro,2H); 3,71 (s, CH2-C6H5, 2H); of 4.13 and 4.19 (each q, 2 CH3-CH2-O, 4H); 4.35 the and of 4.49 (each m, CHGly, 1H); 4,49 and br4.61 (each dd, HPro, 1H); 7,15-7,38 (m, C6H5, 5H); 7.30 and 7,43 (each d, NH Clu 1H);

Found: C=63,24; H=7,11; N=For 6.81.

C22H30N2O6< / BR>
Calculated: C=63,13; H= 7,24; N=6,69.

Example 17.


Dipeptide of formula N-Phac-L-Pro-L-Leu-NH2(XVII), yield 83%; tPL174-175oC, Rf= 0.5 (silica gel, CHCl3: EtOH, 9:1); []2D0= -101,4o(C=0.4; CHCl3).

1H-NMR spectrum in DMSO-d6, (m-1; of 0.82 and 0.88 (each d, CH (CH3)2Leu, 6H); 1.50 in (m, CH Leu, 1H); 1,31-1,93 and 1.7-2,40 (each m, CH2-CH2Pro, 4H); 3.43 points-to 3.67 (m, CH2Pro 2H); of 3.69 (s, CH2-C6H5, 2H); 4,17 and 4.34 (each m, CH Leu 1H); 4,28 and 4,58 (each dd CHPro, 1H), 7.0 and 7,13 (each s, NH2); 7,15-7,35 (m, C6H5, 5H); 7,10 was 7.45 (m, two s, C6H5and NH2); 7,86 and of 8.27 (each is P> Found: C=64,13; H=7,70; N=11,95.

Example 18.


N-Phac-L-Pro-Gly-OH (XVIII)

A suspension of 1.06 g (3.5 mmol) of ethyl ester of N-phenylacetyl-L-ProLogicII (example 1) in 5 ml of 1N NaOH was stirred at room temperature for 3 hours to obtain the solution. Then it was acidified using 2N HCl to pH 3. The solution was evaporated in vacuo to obtain an oil, which was dissolved in 15 ml of chloroform. Nerastvorim part was filtered, the filtrate was evaporated. To the precipitate was added ether, the solid part was filtered and dried in vacuum at room temperature: received, 0.9 g (89,9%) of product: tPL159-160oC (subl.); Rf= 0,54 (silica gel, dioxane-water, 9:1); []2D0= -85,8o(C=0.5; CHCl3).

1H-NMR spectrum in DMSO-d6, (m-1): 1,80-of 2.25 (m, CH2CH2, Pro, 4H); 3,36-3,63 (m, CH2Pro, 2H); 3,64 and 3,68 (each s, CH2-C6H5, 2H); 3,86; 4,00 3,83 and; was 4.02 (each dd, CH2Gly, 2H); 4,57 and of 4.44 (each dd CH Pro, H); 7,11-7,38 (m, C6H5, 5H); 7,52 and 7,32 (each t, NH, 1H) 12,06 (Shir. s, COOH, 1H).

Found: C=62,11; H=6,26; N=To 10.09.

C15H18N2O4< / BR>
Calculated: C=62,04; H=6,22; N= For 9.64.

Example 19.

1H-NMR spectrum in DMSO - d6(m-1); and 1.63 (m, CH GABA 2H); 1,65-of 2.15 (m, CH2-CH2Pro, 4H); to 2.29 (m, CH2GABA, 2H), 3,05 (m, CH2GABA, 2H), 3,2-3,4 (m, CH2Pro HDO 2H); to 3.58 (s, OCH33H); 3,66 (s, CH2-C6H5, 2H); 4,20 and 4,40 (each dd, CH Pro, 1H); 7,02-7,37 (m, C6H55H); 7,85 and to 8.20 (each t, NH, 1H).

Found: C=65,37; H=7,41; N=8,28.

C18H24N2O4< / BR>
Calculated: C=65,03; H=7,29; N=8,42.

Example 20.

Ethyl ester of N-phenylacetyl-L-prolyl-L-alanine

N-Phac-L-Pro-L-Ala-OEt (XX)

Obtained in the conditions described in example 1, yield 78%, so pl. 58-51oC, Rfof 0.75 (silica gel, dioxane-water 10:1) []2D0- 99,2o(c 0,6 CHCl3)

1H-NMR spectrum in DMSO-d6, (m-1): of 1.16 (t, CH3-CH2-O, 3H) of 1.27 and 1.31 (each d, CH3Al, 3H); 1,68-of 2.27 (m, CH2-CH2Pro, 4H); 3.46 in-3,61 (m, CH2Pro, 2H); the 3.65 (s, CH2-C6H5, 2H); 3,98-to 4.14 (q, CH3-CH2-O, 2H); 4,19 and the 4.29 (each dq, C

Found: C=65,07; H=7,32; N=8,45.

C18H24N2O4< / BR>
Calculated: C=65,03; H=7,29; N=8,42.

Example 21.

Ethyl ester of N-caproyl-L-polyglycine

< / BR>
Obtained in the conditions described in example 1. Yield 54%, oil, Rf of 0.8 (silica gel, dioxane-water 9:1), []2D0- -216o(c 0,2, CHCl3).

1H-NMR spectrum in DMSO-d6, (m-1): 0,90 and of 0.91 (each CH3-(CH2)4, 3H); 1,19 (t, CH3-CH2-O, 3H); 1,27, of 1.50 and 2.25 ( two m and t, CH3-(CH2)4, 8 H), 1.70 to of 2.20 (m, CH2-CH2Pro, 4H); 3,35 - 3,50 (m, CH2Pro, 2H); 3,78 and 3,82 (each d, CH2/Gly, 2H); 4,08 (I, CH3-CH2-O, 2H); 4,30 and 4,36 (each dd, CH Pro, 1H); 8,15 and at 8.36 (each t, NH Gly, 1H).

C15H26N2O4< / BR>
Found: C = 60,35; H = 8,84; N 9,31.

Calculated: C = 60,39; H = 8,78; N = 9,38.

Example 22.

Ethyl ester of N-(1-adamantyl)-L-prolyl-glycine

N-Ad-C(O)-L-Pro-Gly-OEt (XXII), yield 81%, tPL177 - 179oC, Rf= 0,93 (silica gel, CHCl3EtOH, 2:3); []2D0= = -66,2o(C = 0,6 CHCl3).

1H-NMR spectrum in DMSO-d6(m-1): of 1.18 (t, CH3-CH2-O, 3H); 1,66, of 1.88 and 1.96 (m, Ad); 1,6 - 2 the initial dd, CH2, Gly, J = 16.5, and 2H); 4,08 (q, CH3CH2-O, 2H); 4,39 (mEXT.CH Pro, 1P); 8,07 (tEXT.NH Gly, 1H).

Found: C = 66,49; H = At 8.36; N = 8,13.

C20H30N2O4< / BR>
Calculated: C = 66,28; H = 8,33; N = 7,73.

Example 23.

Ethyl ester of N-phenylbutyric-L-polyglycine N-C2H5(CH2)3C(O)-t-Pro-Gly-OEt (XXIII) obtained in the conditions of example 1, yield 84%, oil; Rf= 0,87 (silica gel, dioxane: water, 9:1); Rf= 0,75 (silica gel, CHCl3; EtOH, 9:1) []2D0= -90,1o(C = 0.8, the CHCl3);

1H-NMR spectrum in DMSO-d6, (m-1): of 1.18 (t, CH3-CH2-O-, 3H); 1,64 - of 2.23 (m, CH2-CH2Pro, 4H); 1,79, 2,28, and at 2.59 (m, two t, -(CH3)3, 6H); 3,2 - 3,6 (m, CH2Pro, 2H); 3,78 and 3,81 (each d, CH2Gly, 2H); 4,07 and 4.09 to (each q, CH3-CH2- O, 2H); 4,33 and 4,36 (each dd, CH Pro, 1 H);? 7.04 baby mortality - 7,35 (m, C6H5, 5H); 8,18 and of 8.47 (each t, NH Gly, 1H).

Calculated for C19H26N2O3: C = 69,05; H = 7,95; N = OF 8.47

Found: C = 69,21; H = 7,99; N = Charged 8.52.

Example 24.

The claimed compounds, including substances described in examples 1 to 23, was evaluated by the ability to prevent the passive avoidance (passive avoidance reaction) by example (setting Laffaette Co, USA). The experiments described here (examples 12, 13, 15 and 19) were carried out on male outbred rats albino weighing 180 - 220 g Each substance was administered intraperitoneally at a dose of 0.1 mg/kg 15 min before the end of the passive avoidance reaction. Amnesia caused transcorneal mesh immediately after training or scopolamine (1 mg/kg, subcutaneously), administered 30 min before training. Preservation reflex was determined after 24 h by measuring the latent period of transition in a dark chamber.

The degree of antiamnesic activity was assessed by the modified formula of Battler:

< / BR>
The higher this index, the more antiamnesic activity.

In the control group of animals MES as scopolamine caused amnesia: a significant decrease in the latent period during the transition in a dark chamber.

The claimed compounds caused significant antiamnesic effect: the increase of the latent period and index antiamnesic activity (AA) (PL. 1,2).

Given the excellent antiamnesic effect of compound 1 in both types of amnesia, and was chosen for further studies.

It was shown that its effectiveness is maintained after oral administration; in the experiments with m the dose (table. 3).

Positive amnestic effect was detected also in terms of reducing the intensity of exercise to develop the reflex of passive avoidance. Relieving effect of compound 1 was demonstrated in the case of its introduction 15 minutes before the test, immediately after, or 15 min prior to testing of memory reconstruction (table. 4).

The connection I can ease all the main phases of memory formation:

introduction information, consolidation and recovery.

Piracetam did not facilitate recovery in these experiments.

Example 25.

The effect of compound I on the learning of active avoidance was investigated in the Shuttle test chamber (Ugo Basil, Italy). Conditional reflex active avoidance (AVOIDANCE) was developed for 5 days with 50 daily samples for each rat. The learning task consisted in the fact that rats avoided the shock caused through the floor of the cell, directly after the beep. Rats could avoid the shock by moving to another compartment of the cell, but only at the time when you hear the signal (3c).

Compound I (0.1 mg/kg, daily, intraperitoneally), administered within 14 days before the training and daily during training, probabilidade active avoidance was broken simultaneous audio signal and electroshock (in the limbs) in five experiments. The connection I prevent deterioration avoidance (PL. 6).

Example 26.

The effect of compound I on a sharp decline locomotor activity was evaluated by the reduction of movement within 30 minutes the Experiments were performed on male outbred mice albino (18 - 22g), which were placed in groups of 10 animals in the registration cell (Optovarimex, Colomb., USA).

Introduction for 15 minutes before check-in doses ranging in size from 0.05 to 5.0 mg/kg compound 1 showed an increase in the degree of addiction ("the absorption of negative skill) without changing the initial locomotor activity (table. 7).

Example 27.

The deterioration of learning and memory was also reached frontal lobectomy, which was made after studying passive or active avoidance. Introduction of compound I started with the first postoperative day and was finished on the 9th laziness. Testing was performed on the 4-th and 9-th day. In the control group (false operation) training passive and active avoidance was not changed. The consequence of frontal lobectomy was reduced latent period of transition in a dark compartment; the connection I restored the passive avoidance reaction (table. 8).

Lamictalonline on the 9th day. Introduction of compound I increased the percentage of animals exhibiting active avoidance response and retention rates (table. 8).

Example 28.

The deterioration of trainability offspring of rats caused by prenatal alcohol or prenatal hypoxia. Prenatal alcohol was achieved by oral administration of 5 g/kg / day (25% solution) ethanol paronym to female rats throughout the period of prognosti. To achieve prenatal hypoxia rats on the 15th day of prognosti rats were placed in a pressure chamber with a large negative pressure ("rise" to a height of 8500 m; speed 2 h).

Treatment of young produced the 8th to the 20th day. Compound I was administered subcutaneously at a dose of 0.1 mg/kg/day. Testing was performed on a two-month rats.

It is established that both types of lesions (alcoholism, hypoxia) caused the violation of trainability test active avoidance (AVOIDANCE). Earlier postnatal introduction of compound I restored the ability to learn (table 9).

It has been shown that prenatal alcohol reduces the degree of habituation in the open space. Permanent postnatal introduction of compound I restored the normal course of habituation (table 10).

Check locomotor activity in multi-channel analyzer Optovarimex showed that compound 1 was increased, at constant introduction, the initial horizontal activity. Testing activity within 5 min showed a reduction in mobility due to acute addiction (the"assimilation of negative skill). This test is suitable for studying the nootropics. In the control group, the ratio of addiction amounted to 0.29. In animals that had previously been compound 1 revealed more pronounced addictive factor of 0.03 (table. 11).

The continuous introduction connections 1 facilitated the persistence of memory after 24 h and especially 14 days after participation in the passive avoidance test (table. 11). From these experiments it is evident that compound 1 can improve mental function in old rats.

Example 30.

Antihypoxic action of compound 1 was evaluated using a barometric chamber by means of "lifting" besporodnyh mice albino (18-22 g) at a height of 11000 m with a speed of 1000 m/min. in an hour extracts the number of the pre-brabolocoli this value to 43.7%.

Example 31.

The effect of compound 1 by weight and food consumption were studied in experiments on besporodnyh rats. The substance injected intraperitoneally for 3 weeks at a dose of from 0.1 mg/kg/day, slowed down the dynamics of weight gain compared to control: the increase in weight (% initial) was treated group 12% and in the control of 24%. The amount of consumed food, checked between the 19th and 21st days was lower in the treated animals (39.5 g/day/animal) than in controls (68,6 g/day/animal). Obtained data confirm the anorectic action of compound 1.

Example 32.

We studied the effect of compound 1 on total (free) behavior and its acute toxicity. In experiments on outbred male mice-albinos (18-22 g) compound 1 at a dose in the range 1 - 10 mg/kg (intraperitoneally) was not increased and not decreased spontaneous motor activity, and not increased the stimulatory effect of amphetamine on it. In these doses connection 1 also did not change rectal temperature. At the dose of 25 mg/kg compound 1 decreased the stimulatory effect of amphetamine.

Increasing the dose to 500 mg/kg did not modify the motor coordination test (rotating shaft) and did not destroy the s 1 did not cause death of the animals within 24 hours At the dose of 100 mg/kg it was stirring in 50% of animals. At the dose of 5000 mg/kg (intraperitoneally) connection caused the death of 50% of the animals. Compounds according to the invention can be classified as low-toxic.

Example 33.

The effect of compound 1 on the withdrawal symptoms caused by termination of continuous administration of benzodiazepine tranquilizer phenazepam (T. A. Voronina and others , Phenazepam; A. C. Bogatsky, publishing house "Naukova Dumka", Kiev, 1982; C. 67-169) was studied in experiments on male rats albino weighing 190 - 200 g at the beginning of the experiment and 300 - 350 g at the end of the experiment.

Phenazepam (2 mg/kg intraperitoneally) or nat. R-R (control group rats) was administered to the animals daily for 57 days. The syndrome is manifested at 24-72 h after the last injection. The main manifestations of the syndrome were: "anxiogenic-like" status, aggression and accelerated development of kindling caused by pentylenetetrazole. Compound 1 was administered to rats which was the abolition, in doses of 0.5 mg/kg intraperitoneally 15 min prior to the test.

To assess the level of anxiety of rats used test conflicts (JR. Vogel, Psychopharmcologia, 21 1-7. (1971)). This experiment was predvaritelnykh passed an electric current of 0.5 mA. A conflict situation created by the collision of two different reflexes (drinking and self-defense).

Within 24 hours after termination of continuous testing of rats, which cancelled phenazepam, they have a marked decrease in the frequency of drinking compared with the control group. This behavior in the test conflicts can be seen as "anxiogenic-like". Compound 1 reacted "anxiogenic-like" reaction to the abolition of benzodiazepine and increased frequency of drinking in a conflict situation (table. 12).

In the experiment on rats was determined threshold of aggressive behavior (R. Tedeshi et. al. J. pharmacol. Exp. Ther. 125 28 - 34 (1959)). A couple of rats were placed on the floor, connected to the electrical circuit; registered amperage, which provoked a fight.

In rats with canceled fenazepam observed a reduction of the wrinkle. Connection 1 with the introduction of 2 h after the abolition of phenazepam increased the threshold for aggressive reactions (table. 13).

Researched convulsive reactions in rats using chemical kindling (Mason C. R. et. al Epilepsia, 13, 663-674 (1972); R. M. Post, Handbook of Biological Psychiatry, Part IV, N 7, Mapcel-Dekker (1981), p.p. 609-651) caused by small doses pentalen-tetrazole (35 mg/kg, intraperitoneally), enter lsii (2 points); clonic convulsions (3 points); tonic seizures and death (4 points).

Our experiments revealed that seizures caused pentalen-tetrazolo, were more pronounced in rats, which cancelled phenazepam than in the control. Compound 1 reduces the degree of kindling caused pentalen-tetrazole (PL. 14).

From these experiments it is evident that compound 1 is able to reduce withdrawal symptoms benzodiazepine: it reduces anxiety, aggressiveness and kindling caused by pentylenetetrazole.

1. Derivatives of N-allpolitical General formula I

< / BR>
where R1= (C4-C5)alkyl, cycloalkyl, aralkyl or aryl;

R2= H, (C1-C4)alkyl, carbamicacid or carbalkoxy;

R3= hydroxy, alkoxy, amino, alkylamino or dialkylamino;

n = 0-3,

when you do this:

a) when R1= phenyl, R2= hydrogen or isopropyl, and n = 0, R3= not methoxy;

b) when R1= tert-butyl, R2= hydrogen and n = 0 or 1, R3= not methylamino;

b) when R1= tert-butyl, R2= isobutyl, methyl, benzyl or carbamoylmethyl, and n = 0, R3not methylamino;

g) when R1= tert-butyl, R2= carbomethoxyamino, n = 0, R
< / BR>
where R1= isobutyl, pentyl, 1-substituted, phenyl, phenylmethyl or phenylpropyl;

R3= OH or OC2H5, NH2, NHCH3N(CH3)2< / BR>
3. Derivatives of N-allpolitical General formula I on p. 1, representing

< / BR>
where R1= phenylmethyl or phenyl, R3= OC2H5or NH2.

4. Derivatives of N-allpolitical under item 1, representing:

< / BR>
where R1= phenylmethyl or phenyl.

5. The derived N-allpolitical under item 1, representing

< / BR>
6. The derived N-allpolitical under item 1, representing

< / BR>
7. The derived N-allpolitical under item 1, representing

< / BR>
8. The derived N-allpolitical under item 1, representing

< / BR>
9. The derived N-allpolitical under item 1, representing

< / BR>
10. The derived N-allpolitical under item 1, representing

< / BR>
11. The derived N-allpolitical under item 1, representing


Same patents:

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

The invention relates to the derivatives of pyrrolidine formula (I) in which either R is methylene, ethyleneglycol, >SO, >SO2group or a sulfur atom; R1means pyridinyl, furyl, thienyl, optionally substituted by one or more alkyl groups, naphthyl, indolyl or phenyl, optionally substituted by one or more substituents selected from halogen atoms, alkyl-, alkoxy-, hydroxy - and dialkylamino; R5means a hydrogen atom; or R is methylene, R1is a hydrogen atom and R5means phenyl; or R is a group > CHR6, R1and R5mean a hydrogen atom; R2means alkoxycarbonyl, cycloalkyl-alkyloxy-carbonyl -, etc., R3means indolyl - or phenylaminopropyl, the phenyl nucleus of which is substituted by one or more substituents selected from a range that contains the halogen atom, the alkyl-, alkoxy-, alkylthio group and others; R4means a hydrogen atom and alkylaryl; R6means phenyl radical in the form of iamiceli mixture or enantiomers and their salts

The invention relates to heterocyclic amines of formula I:


in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

The invention relates to medicine, namely to the way the pharmacological treatment of acute respiratory viral infections and influenza using an inducer of endogenous interferon-Dibazol

The invention relates to new N-(-substituted pyridinyl)caronel-dipeptides, which have activity as inhibitors of the enzyme that promotes the conversion of angiotensin

The invention relates to medicine, namely to compounds having immunomodulatory properties

The invention relates to medicine, particularly cardiology, and can be used for the treatment and prevention of the consequences and complications of ischemia and reperfusion injury of the heart

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to applying compounds of the formula (I) for preparing an antibacterial composition and veterinary composition eliciting with the enhanced activity.

EFFECT: valuable properties of agents.

4 cl, 3 tbl, 78 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

EFFECT: valuable biochemical and medicinal properties of peptides.

106 cl, 9 tbl, 61 ex

FIELD: organic chemistry, medicine, pharmacy.

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

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry and drugs.

SUBSTANCE: New class of compounds of general formula 1, where R has formula 2 or 3; other residues are as described in claim of invention is disclosed. Said compounds are interleikyn-1β converting enzyme (ICE) inhibitors and have specific structural and physicochemical properties. Invention also relates to pharmaceutical composition containing said compounds. Compounds and composition of present invention are particularly useful in ICE activity inhibition and thereby can be used as drug for treating of diseases mediated by IL-1, apoptosis, IGIF and IFN-γ, as well as inflammations, autoimmune diseases, bone-destructive disorder, infections, disorder associated with cell proliferation, degenerative and necrotic disorders. Uses of claimed compounds and compositions as well as methods for production of N-acylamino compounds also are disclosed.

EFFECT: effective interleikyn-1beta converting enzyme inhibitors.

64 cl, 35 ex, 35 tbl, 21 dwg