Mercaptoacetylamide derivatives, pharmaceutical composition containing the same, method for production thereof and method for treatment of cardiovascular condition

FIELD: pharmacology, medicine.

SUBSTANCE: invention relates to new mercaptoacetylamide derivatives, which represents angiotensine converting enzyme and neutral endopeptidase inhibitors and useful in treatment of cardiovascular condition. More particularly invention relates to derivatives of formula I , wherein R1 represents hydrogen or acyl; wherein R2 represents hydrogen or biphenylmethyl; { represents -(CH2)n (n = 1, integer); B1 and B2 are independently hydrogen; or pharmaceutically acceptable salts or stereomers thereof. Method for production of compounds of formula I and formula II, pharmaceutical composition on the base of formula I, method for production thereof and method for treatment of cardiovascular condition.

EFFECT: new derivatives having value biological properties.

14 cl, 3 tbl, 4 ex, 1 dwg

 

BACKGROUND of INVENTION

1. The technical field

The present invention relates to new compounds which inhibitory activity against angiotensin-converting enzyme, and inhibitory activity against neutral endopeptidase and to methods for their preparation. The present invention also relates to pharmaceutical compositions containing such compounds dual inhibitory actions or their pharmaceutically acceptable salts and to their use for obtaining medicines.

2. The level of technology

Angiotensinase enzyme (ACE) is patibilities, which catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II is a vasoconstrictor agent that also stimulates aldosterone secretion by the adrenal cortex. The ACE inhibition prevents the conversion of angiotensin I to angiotensin II, and metabolism of bradykinin, leading to reduced circulating angiotensin II and aldosterone and increased concentrations of bradykinin in the circulatory system. In addition to these neurohormonal changes observed decrease in peripheral vascular resistance and blood pressure, especially in individuals with high circulating renin. Other pharmacological effects connected is by inhibition of ACE, include regression of left ventricular hypertrophy, improvement of clinical symptoms in heart failure and reduce mortality in patients with congestive heart failure (CHF) or dysfunction of the left ventricle after myocardial infarction.

Neutral endopeptidase (NEP) is the enzyme responsible for the metabolism of atrial natriuretic peptide (PNP). Inhibition of NEP leads to increased concentrations of PNP, which in turn lead to natriuresis, diuresis and reduction in intravascular volume, venous outflow and blood pressure. EOR is secreted by atrial myocytes in response to stretch of the Atria or increase intravascular volume. It has been shown that increased concentrations of PNP in plasma represent a potential compensatory mechanism for various painful conditions, including congestive heart failure, renal failure, hypertension and cirrhosis.

Secretion EOR myocytes of the Atria causes the dilation of blood vessels, diuresis, nutrient and inhibition of renin release and secretion of aldosterone. In contrast, angiotensin II causes vasoconstriction, reabsorption of sodium and water and the production of aldosterone. These two hormonal systems interact oppositely directed in imoressive way maintaining normal physiological vascular and hemodynamic responses. U.S. patent 5430145 describes tricyclic derivatives mercaptoethylamine used as inhibitors of ACE and NEP. The present invention relates to specific compounds covered by the General description of the U.S. patent 5430145 that have unexpectedly superior properties of ARMA (absorption, distribution, metabolism, excretion) compared to the compounds represented in the examples.

BRIEF description of the INVENTION

Accordingly, the present invention relates to a compound of the formula I:

in which:

R1represents hydrogen, -CH2OS(O)C(CH3)3or acyl group;

R2represents hydrogen, -CH2O-C(O)C(CH3)3With1-C4is alkyl, aryl, aryl(C1-C4-alkyl) or diphenylmethyl;

X represents -(CH2)nwhere n is an integer of 0 or 1, -S-, -O-,

where R3represents hydrogen, C1-C4is alkyl, aryl or aryl(C1-C4-alkyl), and R4is-CF3With1-C10is alkyl, aryl or aryl(C1-C4-alkyl);

In1and In2each independently represents hydrogen, hydroxy or-OR5where R5is1-the 4is alkyl, aryl or aryl(C1-C4-alkyl), or In1and In2attached to adjacent carbon atoms so that the In1and In2taken together with the adjacent carbon atoms, form a benzene ring or methylenedioxy.

In one implementation of the present invention relates to a compound of formula I, in which R1is acetyl. In another implementation of the present invention relates to a compound of formula I, in which R1represents hydrogen. In the following implementation of the present invention relates to a compound of formula I, in which R2represents hydrogen. In the following implementation of the present invention relates to a compound of formula I, in which1and/or In2represent hydrogen. In yet another implementation of the present invention relates to a compound of formula I, in which X represents-CH2.

In one implementation of the present invention relates to a compound of formula IA:

in which R1is acetyl or hydrogen. The structure of preferred compounds according to the present invention are compounds of formulas IB and IC below:

The compounds of formula I, including compounds of formulas IA, IB and IC, are particularly useful as inhibit the s ACE and NEP double action.

The present invention relates, accordingly, to pharmaceutical compositions comprising effective for inhibition of ACE and/or NEP amount of the compounds of formula I in a mixture or in contact in any other way with one or more pharmaceutically acceptable carriers or excipients.

DETAILED description of the INVENTION

The term "C1-C4-alkyl", as used herein, refers to a saturated straight or branched monovalent hydrocarbon chain of one, two, three or four carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. The term "C1-C10-alkyl" refers to a saturated straight or branched monovalent hydrocarbon chain of from one to ten carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.

The term "aryl", as used herein, refers to phenyl or naftilos group, unsubstituted or substituted with one to three substituents selected from the group consisting of methylenedioxy, hydroxy, C1-C4-alkoxy, fluorine and chlorine. Included in the scope of the present invention, the term "aryl(C1-With4-alkyl" represents phenylmethyl (benzyl), phenylethyl, p-methoxybenzyl, p-tormentil and p-Chlorobenzyl.

The term "C1-C4-alkoxy", as used herein, refers to a monovalent Deputy, which consists of a straight or branched alkyl chain having from one to 4 carbon atoms, linked via an oxygen atom, a simple ester group and having a free valence bond of the oxygen a simple ester group, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy and the like.

The term "heterocycle", as used herein, refers to any group with a closed ring in which one or more ring atoms represent an element other than carbon, and includes, but is not limited to, piperidinyl, pyridinyl, isoxazolyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinil, benzimidazolyl, thiazolyl, thienyl, furanyl, indolyl, 1,3-benzodioxolyl, tetrahydropyranyl, imidazolyl, tetrahydrofuryl, pyranyl, dioxane, pyrrolyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, purinol, chinoline and ethenolysis.

The term "halogen" or "Hal", as used herein, refers to a family of fluorine, chlorine, bromine or iodine.

The term "aryl group"as used herein, refers to aliphatic and aromatic acyl groups, and to those to whom that is obtained from heterocyclic compounds. For example, the acyl group can be lower or (C1-C4)alkanoyloxy group, such as formyl or acetyl, aroline group, such as benzoyl or heterocyclic acyl group containing one or more heteroatoms O, N and S, such as a group

The term "stereoisomer"as used in this description is a General term used for all isomers of individual molecules that differ only in the orientation of their atoms in space. The term "stereoisomer" includes isomers mirroring (enantiomers), geometric (CIS/TRANS or E/Z isomers and isomers of compounds with more than one chiral center that are not mirror images of each other.

The designations "R" and "S"as used in this description are commonly used in organic chemistry to denote a specific configuration of the chiral center. The term "R" (rectus - right) refers to the configuration of the chiral center with the location of the group order (from highest to second lowest) clockwise when viewed along the direction to the group of the lowest order. The term "S" (sinister - left) refers to the configuration of the chiral center with the location of the group order (from highest to second lowest) against chavoustie, if you look along the communication towards the group of the lowest order. The order of the groups is based on the rules of the sequence in which the assignment of priority is based, primarily, on the atomic number (in order of decreasing atomic number). List and discuss the priorities are in the book Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Mander, editors, Wiley-Interscience, John Wiley & Sons, Inc., New York, 1994.

In addition to the system of (R)-(S) in this description can also be used an older system D-L to denote the absolute configuration, particularly with respect to amino acids. In this system, the projection formula Fischer is oriented so that the carbon number 1 of the main chain was up. The prefix "D" is used to represent the absolute configuration of the isomer in which the functional (determines) the group is to the right of carbon chiral center, and the "L" isomer, in which it is located to the left.

The term "treatment"as used herein, means, but is not limited to, any treatment to alleviate symptoms, eliminate the causation of symptoms or on a temporary or on a permanent basis, or to prevent or slow down the symptoms and development of a specified disease, disorder or condition.

The term "patient"as defined herein, refers to talonro is a wounded animal, such as a mammal that is affected by a specific disease, disorder or condition. It is quite clear that Guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals in the volume of the meaning of the term.

The term "pharmaceutically acceptable salt", as used herein, is intended to apply to any salt, whether it is known or above open in the future, which is used by an experienced specialist in this field and which is non-toxic organic or inorganic salt additive which is suitable for use as a pharmaceutical agent. Examples of bases which form suitable salts include hydroxides of alkali and alkaline earth metals, such as hydroxides of sodium, potassium, calcium or magnesium; ammonia, and aliphatic, cyclic or aromatic amines, such as methylamine, dimethylamine, triethylamine, diethylamine, isopropylethylene, pyridine and picoline. Examples of acids which form suitable salts include inorganic acids such as, for example, hydrochloric, Hydrobromic, sulfuric, phosphoric and the like, and organic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, limo is owned, ascorbic, maleic, hydroxymaleimide and dihydroxytoluene, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, antanimena, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, almond and the like, and organic sulfonic acids, such as methanesulfonate and p-toluensulfonate acid.

The term "pharmaceutical carrier", as used herein, refers to well-known pharmaceutical excipients used for the preparation of pharmaceutically active compounds for the introduction, which are virtually non-toxic and does not cause sensitivity in conditions of use. The exact proportion of such excipients is determined by the solubility and chemical properties of the active compounds, selected by way of introduction, as well as conventional pharmaceutical practices.

CHEMICAL SYNTHESES

Compounds according to the present invention can be obtained as follows.

Tricyclic group of compounds of formula I can be obtained by using the well-known and available to those of ordinary skill techniques and methods. U.S. patent 5430145 describes examples of suitable techniques, and the content of which is incorporated in this description by reference. One of these methods, shown in the diagram And described below.

CX is MA AND

On stage and suitable derivative blocked by phthalimido (S)-phenylalanine structure 2 can be obtained by reaction of a suitable derivative (S)-phenylalanine structure 1 with phthalic anhydride in a suitable aprotic solvent such as dimethylformamide.

At stage b, the right derivative is blocked by phthalimido (S)-phenylalanine structure 2 can be converted into the corresponding acid chloride of the acid with the subsequent interaction with the appropriate methyl ester of the amino acid structure 3 by the reaction of the combination. For example, a suitable derivative blocked by phthalimido (S)-phenylalanine structure 2 can react with oxalylamino in a suitable aprotic solvent such as methylene chloride. The resulting acid chloride of the acid can then be combined with the appropriate methyl ester of the amino acid structure 3 using a suitable base, such as N-methylmorpholine, in a suitable aprotic solvent such as dimethylformamide, giving the corresponding derived methyl ester of 1-oxo-3-phenylpropylamine patterns 4.

On stage with hydroxymethylene functional group corresponding derived methyl EF is RA 1-oxo-3-phenylpropylamine patterns 4 can be oxidized to the corresponding aldehyde of structure 5 with the help of a well known and accepted in the practice of the methods of oxidation. For example, hydroxymethylene functional group corresponding to the derived methyl ester of 1-oxo-3-phenylpropylamine patterns 4 can be oxidized to the corresponding aldehyde of structure 5 by means of oxidation in Turn using oxalicacid and dimethylsulfoxide in a suitable aprotic solvent such as methylene chloride.

At stage d, the appropriate aldehyde of structure 5 can be cycletour in the corresponding enamine structure 6 by means of acid catalysis. For example, the appropriate aldehyde of structure 5 can be cycletour in the corresponding enamine structure 6 processing triperoxonane acid in a suitable aprotic solvent such as methylene chloride.

At stage e, the appropriate enamine of structure 6 can be converted into the corresponding tricyclic compound of structure 7 by acid catalyzed reaction Friedel -. For example, a suitable enamine of structure 6 can be converted into the corresponding tricyclic compound of structure 7 by treatment with a mixture triftormetilfullerenov acid and triperoxonane anhydride in a suitable aprotic solvent such as methylene chloride.

At stage e of the conditions of development may be necessary to peresterilizovali carboxyl functional group. For example, to obtain suitable is about diphenylmethylene ether can be used in the processing of the crude product by bromodiphenylmethane in a suitable aprotic solvent, such as dimethylformamide, together with dinucleophiles base, such as cesium carbonate.

At stage f talimena protective group of the appropriate tricyclic compound of structure 7 can be removed using methods and techniques well known in the art. For example, talimena protective group of the appropriate tricyclic compound of structure 7 can be removed using hydrazine monohydrate in a suitable proton solvent such as methanol, giving appropriate aminosidine patterns 8.

At the stage of g can be obtained from the corresponding (S)-acetate connection structure 10 by reaction of the corresponding amino compounds of structure 8 with the corresponding (S)-acetate of structure 9. For example, the corresponding aminosidine structure 8 can be introduced into reaction with the corresponding (S)-acetate compound of structure 9 in the presence of the agent combinations, such as EEDQ (1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (1,3-dicyclohexylcarbodiimide) or diethylthiophosphate, in a suitable aprotic solvent such as methylene chloride, to obtain the corresponding (S)-acetoxysilane structure 10.

At stage h (S)-acetate functional group of the corresponding amide compound of structure 10 can be hydrolyzed to the corresponding (S)-the Peart patterns 11 base such as lithium hydroxide, in a suitable solvent mixture such as tetrahydrofuran and ethanol.

At stage i (S)-alcohol functional group of the corresponding amide compound of structure 1A can be converted into the corresponding (R)-thioacetate or (R)-thiobenzoate patterns 12A. For example, the corresponding (S)-alcohol patterns 11a can be processed teoksessa acid under Mitsunobu reaction using triphenylphosphine and DIAD (diisopropylcarbodiimide) in a suitable aprotic solvent such as tetrahydrofuran.

On stage j (S)-alcohol functional group of the corresponding amide compound of structure 11a can be transformed into the corresponding (R)-alcohol patterns 11b. For example, the corresponding (S)-alcohol patterns 11a can be treated with acetic acid under Mitsunobu reaction using triphenylphosphine and DIAD in a suitable aprotic solvent such as tetrahydrofuran. The obtained (R)-acetate may then be hydrolyzed with a suitable base, such as lithium hydroxide.

At stage k (R)-alcohol functional group of the corresponding amide compound of structure 11b can be transformed into the corresponding (S)-thioacetate or (S)-thiobenzoate structure 12b. For example, the corresponding (R)-alcohol patterns 11b can be processed thioglucose acid under Mitsunobu reaction using the receiving of triphenylphosphine and DIAD in a suitable aprotic solvent, such as tetrahydrofuran.

As summarized in table 1, the groups R1and R2compounds of structures 12A and 12b may be replaced by using a well-known and available to those of ordinary skill methods and techniques, to obtain the corresponding compounds of structures 13A-14a and 13b-14b.

For example, diphenylmethylene ether functional group of the corresponding compounds of structure 12A can be removed using triperoxonane acid, giving the corresponding compound of carboxylic acid patterns 13A. Similarly, diphenylmethylene ether functional group of the corresponding compounds of structure 12b can be removed using triperoxonane acid, giving the corresponding compound of carboxylic acid patterns 13b.

(R)-thioacetate or (R)-thiobenzoate functional group of the respective connection patterns 13A can be removed by lithium hydroxide in a suitable solvent mixture such as tetrahydrofuran and ethanol, giving the corresponding (R)-tizaidine patterns 14a. Similarly, (S)-thioacetate or (S)-thiobenzoate functional group of the respective connection patterns 13b can be removed by lithium hydroxide in a suitable solvent mixture such as tetrahydrofuran and ethanol, giving the corresponding (S)-tizaidine patterns 14b.

Table 1
replacement groups R1and R2
ConnectionR1R2
13A and 13bCOCH3or COPhH
14a and 14bHH

Although the General methodology presented in the diagram shows the formation of compounds of the formula I, in which the group-COOR2has (S)-configuration, the compounds of formula I in which the group-COOR2has the (R)-configuration can be obtained by similar methods by replacing methyl ester (S)-amino acid patterns 3 stage b the corresponding methyl ether (R)-amino acids.

The source materials for use in the General methods of synthesis, presented in the diagram And are easily accessible to the average person skilled in the art. For example, some (R)- and (S)-carboxylate or benzoate source materials structure 9 can be obtained stereotypically restoring appropriate pyruvate compounds by allenbradley, as described in J.Org.Chem. 47, 1606 (1982), J.Org.Chem. 49, 1316 (1984) and SOC. 106, 1531 (1984), followed by treatment of the resulting alcohol with acetic anhydride or anhydride of benzoic acid to obtain the corresponding (R)- or (S)-carboxylate or benzoate the response patterns 9.

Alternatively, some tricyclic compounds of structure 7 can be obtained as described in the Application for the European patent EP A.

The present invention relates to a method for obtaining compounds of the above formula I, including:

the reaction of compounds of formula II

where R2, X, B1and B2are as defined above, and Hal represents halogen,

with the compound of the formula R1SH, where R1is the same as defined above, in the presence of a base such as a carbonate of an alkali metal.

The present invention relates further to a method for obtaining compounds of formula II, comprising the reaction of compounds of formula III

where R2, X, B1and B2are as defined above,

with the compound of the formula IV

where Hal represents halogen.

An alternative method of obtaining the compounds of formula I according to the present invention involves the reaction of the compounds of formula III

where R2, X, B1and B2are as defined above,

with the compound of the formula V

where R1is the same as defined above.

In the latter method, it is suitable aminosilane formula III can react with the corresponding (S)- or (R)-thioacetate formula V, giving, respectively, the corresponding (S)- or (R)-thioacetate formula I as described above for scheme a, step g.

The scheme offers another General method of synthesis of compounds of formula I.

SCHEMA

R1represents the PINES3, COPh,

X represents O, S, NH or (CH2)n

N is 0 or 1.

On stage and suitable aminosilane structure 28, in which X represents O, S, NH or (CH2)nwhere n is 0 or 1, is reacted with the appropriate (R)-bracelate patterns 33, giving the corresponding (R)-bromamide connection structure 34, in which X represents O, S, NH or (CH2)nwhere n is 0 or 1, in conditions similar to those described above for scheme a, step g.

Alternatively, a suitable aminosilane structure 28, in which X represents O, S, NH or (CH2)nwhere n is 0 or 1, is reacted with the appropriate (S)-bracelate, giving the corresponding (S)-bromamide, where X represents O, S, NH or (CH2)nwhere n is 0 or 1, or a suitable aminosilane structure 28, in which X represents O, S, NH or (CH2)nwhere n is 0 or 1, is reacted with the corresponding enantiomeric mixture of bracelet, giving appropriate diastereomer mixture bromamide, where X represents O, S, NH or (CH2)n where n is 0 or 1, as described above for scheme a, step g.

At the stage b (R)-bromochloro group of the corresponding (R)-bromamide connection structure 34, in which X represents O, S, NH or (CH2)nwhere n is 0 or 1, is transformed into the corresponding (S)-thioacetate or (S)-thiobenzoate structure 36, in which X represents O, S, NH or (CH2)nwhere n is 0 or 1.

Alternatively, (S)-bromochloro group of the corresponding (S)-bromamide, where X represents O, S, NH or (CH2)nwhere n is 0 or 1, is transformed into the corresponding (R)-thioacetate or (R)-thiobenzoate, where X represents O, S, NH or (CH2)nwhere n is 0 or 1.

For example, the appropriate (R)-bromamide connection structure 34, in which X represents O, S, NH or (CH2)nwhere n is 0 or 1, is reacted with thioglucose acid or Tolentino acid structure 35 in the presence of a base such as cesium carbonate or sodium. The reactants are typically contacted in a suitable organic solvent such as a mixture of dimethylformamide and tetrahydrofuran. The reactants are typically stirred together at room temperature over a period of time in the range from 1 to 8 hours. The obtained (S)-thioacetate or (S)-thiobenzoate structure 36, in which X represents O, S, NH or (CH2)nwhere n is 0 or 1, is recovered from the reaction zone met the DAMI extraction, known in this field. It can be purified by chromatography.

Alternatively, bromochlorophenol group suitable diastereomeric mixture bromamide described above, where X represents O, S, NH or (CH2)nwhere n is 0 or 1, turn to the appropriate diastereomer mixture thioacetate or thiobenzoate compounds where X is O, S, NH or (CH2)nwhere n is 0 or 1.

Although the scheme is proposed to obtain the compounds of formula I, in which the tricyclic group has a 4-carboxybenzoyl group (S)-configuration, when, for example, X represents-CH2the compounds of formula I, in which carboxyfullerene the group has the (R)-configuration can be obtained by replacing the corresponding amino compounds of structure 28 (4R)-carboxyhemoglobinemia, the receipt of which is described in scheme A.

EXPERIMENTAL PART

The following examples present typical syntheses as described in scheme C. it is Clear that these examples are only illustrative and are not intended in any way to limit the scope of the present invention. As used in this description, the following notations have the following meanings: "g" means grams, "mmol" means mmol, "ml" means milliliters, "°C" means degrees Celsius.

EXAMPLE 1

Obtaining (R)-2-bromo-3-IU albuminoidal acid (structure 33)

To a cooled solution of D-valine (12.7 g, 100 mmol) in 100 ml 2,5N sulfuric acid and 49% HBr (33 g, 200 mmol) at -10°C was added sodium nitrite (6,90 g, 100 mmol) in 50 ml of water for 30 minutes. Stirring in the temperature range between -5°and -10°With continued advanced for 3 hours. The reaction mixture was extracted with methylene chloride (2×150 ml), dried over MgSO4and concentrated, obtaining a light yellow oil (9.7 g, 50%, 53.6 mmol).

EXAMPLE 2

Getting diphenylmethylene ether [4S-[4α,7α(S),12bβ]]-7-[[2(S)-acetylthio-3-methyl-1-oxobutyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1a][2]benzazepine-4-carboxylic acid

Scheme, stage a: diphenylmethylene ether [4S-[4α,7α(S),12bβ]]-7-[[2(S)-bromo-3-methyl-1-oxobutyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1a][2]benzazepine-4-carboxylic acid

(R)-2-Bromo-3-methylbutanoic acid (900 mg, 5.0 mmol) and diphenylmethylene ether [4S-[4α,7α(S),12bβ]]-7-(amino)-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1a][2]benzazepine-4-carboxylic acid (1,76 g, 4.0 mmol) was dissolved in dry methylene chloride (5 ml) and was treated with EDC (1.0 g, 5,0 mmol) at 25°C for 2 hours. After 18 hours only traces diphenylmethylene ether [4S-[4α,7α(S),12bβ]]-7-(amino)-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1a][2]benzazepine-4-carboxylic acid. The mixture was diluted with methylene chloride (75 ml), washed with 10% chloride is hydrogen acid and saturated sodium bicarbonate. Then the mixture was dried (MgSO4), concentrated in vacuo, and purified flash chromatography, receiving specified in the header of the compound (C33H35N2O4Br) (2.4 g, 4.0 mmol).

Scheme, stage b: diphenylmethylene ether [4S-[4α,7α(S),12bβ]]-7-[[2(S)-acetylthio-3-methyl-1-oxobutyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1a][2]benzazepine-4-carboxylic acid

Toluxury acid (456 mg, 6.0 mol) and cesium carbonate (325,8 mg, 3.0 mmol) was dissolved in methanol (5 ml) under nitrogen atmosphere and was evaporated to dryness. To the mixture was added one stripped off the product from step a (4.0 mmol)dissolved in 5 ml of dry dimethylformamide, followed by stirring in a nitrogen atmosphere for 2 hours. The mixture was distributed between ethyl acetate (100 ml) and brine, washed with 10% hydrochloric acid and saturated sodium bicarbonate, dried (MgSO4), filtered and concentrated give crude product (2.2 g) as a pale yellow foam. The product was dissolved in methylene chloride and purified by chromatography (25% ethyl acetate/hexane) in 200 ml of silica using 20% ethyl acetate. Fractions were combined and concentrated, obtaining specified in the header of the ether compound (2.15 g).

EXAMPLE 3

Getting [4S-[4α,7α(S),12bβ]]-7-[[2(S)-acetylthio-3-methyl-1-oxobutyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1a][2]benzazepine-4-carboxylic acid

Raw p is oduct, obtained in example 2 (3.5 mmol), was dissolved in methylene chloride (6.0 ml) and anisole (1.0 ml), cooled to -50°and processed triperoxonane acid (6.0 ml). The mixture was allowed to warm to 25°and was stirred for 2 hours, concentrated in vacuo and purified by chromatography (1:1 ethyl acetate/hexane + 1% acetic acid), receiving specified in the header of the connection

Molecular weight = 432,54

Molecular formula = C22H28N2O5S

Data1The h and13C-NMR for MDL107688 (DMSO-d6, 300K, the numbering is not in accordance with the IUPAC nomenclature):

Position13(Ppm)1N (ppm)
1171,79-
1-COOH-12,07
250,534,99 m
324,982,21 m, 1,69 m
416,931.67 m, 1,67 m
524,692,38 m 1,92 m
649,78the ceiling of 5.60
7171,37-
848.10 perthe ceiling of 5.60
935,603,22 DD, 2,97 DD
10136,72-
11136,89-
12124,837,19 d
13125,217,08 t
14126,677.13 t
15130,107,07 d
16-8,33 d
17169,11-
1853,824,12 d
1930,692,14 m
20*20,180,99 d
21*19,290,94 d
24194,36-
2530,342.36 with
*: there is no clear difference between positions 20 and 21

EXAMPLE 4

Getting [4S-[4α,7α(S),12bβ]]-7-[[3-methyl-1-oxo-2(S)-dibutyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1a][2]benzazepine-4-carboxylic acid

The product obtained in example 3 (75 mg, 0,17 mmol) was dissolved in 1.0 ml of degassed methanol under nitrogen atmosphere and treated with lithium hydroxide (0.4 ml of 1 n solution). After stirring at 25°C for 1.5 hours the solution was concentrated in vacuum, diluted with water (2 ml) and acidified with hloristovodorodnykh (0.5 ml of 1 N. solution). The obtained product was filtered and dried in vacuum, obtaining mentioned in the title compound as a white solid (55 mg, 0.14 mmol, 83%).

Molecular weight = 390,50

Molecular formula = C20H26N2O4S

Data1The h and13C-NMR for MDL108048 (DMSO-d6, 300K, the numbering is not in accordance with the IUPAC nomenclature):

Positionδ(13C)m13C)δ(1N)nJCH
1171,86-1,68
250,63dto 4.98the ceiling of 5.60, 1,68
325,04t2,23, 1,684,98, 1,65
417,00t1,654,98, 1,91, 1,68, (5,60)
524,77t2,38, 1,91the ceiling of 5.60, 1,65
649,95dthe ceiling of 5.607,19, 4,98, 1,91
7171,55-5,63, 3,25, 2,97
847,89d5,6323,25, 2,97
936,05t3,25, 2,977,07, 5,63
10136,86*-3,25, 2,97, 5,63, 7,19
11138,82*-5,63, 7,08, 3,25, 2,97
12124,87d7,1857,13, 5,60, (3,25), (2,97)
13125,31d7,0847,07, (3,25), (2,97)
14126,70d7,1277,19
15130,11d7,0737,08, 3,25, 2,97
16NH-8,305,63
17171,29-8,30, 3,33, 1,94
1848,85d3,3261,94, 0,98, 0,94
1932,46d1,9363,33, 0,99, 0,94
2019,32kV0,9870,94, 1,94, 3,33
2120,58kV0,9440,99, 1,94, 3,33
*: there is no clear difference between positions 20 and 21

Connection is according to the present invention can be used for the treatment of warm-blooded animals or mammals, including mice, rats, and people suffering from painful conditions such as, but not limited to them, hypertension, congestive heart failure, cardiac hypertrophy, renal failure, and/or cirrhosis.

Effective inhibiting ACE and NEP number of the compounds of formula I is a quantity which is effective for inhibition of ACE and NEP, which gives, for example, anti-hypertensive effect.

Effective inhibiting ACE and NEP dose of the compounds of formula I can be readily determined using conventional techniques and observation of results obtained in similar circumstances. When determining the effective dose takes into account a number of factors, including but not limited to them, kind of animal, the size of the animal, the age and General health, specific disease, the degree of development or the severity of the disease, the individual reaction of the patient, specific input connection, the selected dosage regimen and the use of concomitant treatment.

Effective inhibition and ACE and NEP number of the compounds of formula I should usually vary from about 0.01 mg per kilogram of body weight per day (mg/kg/day) to about 20 mg/kg/day. Preferred is a daily dosage from about 0.1 mg/kg to about 10 mg/kg

For effective treatment of the patient, the compounds of formula I can is to be entered in any form or by any means, which makes the compound bioavailable in effective amounts, including oral and parenteral methods. For example, the compound can be administered orally, subcutaneously, intramuscularly, intravenous, transdermal, nasal, rectal, and the like. Usually it is preferable to oral administration. An experienced specialist in the field of preparation preparative forms can easily choose a suitable form and route of administration depending on the disease condition that should be treated, the stage of the disease and other taken in consideration of the circumstances.

PREPARATIVE FORM.

The compounds of formula I can be introduced in the form of pharmaceutical compositions or medicaments which are obtained by combining the compounds of formula I with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the chosen route of administration and conventional pharmaceutical practices.

The present invention relates to pharmaceutical compositions comprising an effective amount of the compounds of formula I in the mixture or connected otherwise with one or more pharmaceutically acceptable carriers or excipients.

The pharmaceutical composition or the medicinal product prepared is well known in the pharmaceutical way. The media may be the solid, semi-solid, or liquid material which can serve as a carrier or medium for the active ingredient. Suitable carriers or excipients are well known in this field. The pharmaceutical composition may be intended for oral or parentline use and can be administered to the patient in the form of tablets, capsules, pessaries, suppositories, solutions, suspensions or the like. Suitable pharmaceutical carriers and methods for the preparation of medicines can be found in standard handbooks, such as Remington: The Science and Practice of Pharmacy, 19thedition, Volumes 1 and 2, 1995, Mack Publishing Co., Easton, Pennsylvania, USA, which is included in this description by reference.

The pharmaceutical compositions can be administered orally, for example, with an inert diluent or with an edible carrier. They can be Packed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration compounds of formula I can be introduced into a carrier and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of the compounds of formula I, as active ingredient, but may vary depending on the particular form and may typically contain from 4% to about 70% by weight of the standard dose. Quantity is STV active ingredient, present in the composition is such that was received standard dosage form suitable for injection.

Tablets, pills, capsules, lozenges and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, resin tragakant or gelatin; excipients such as starch or lactose; disintegrating agents such as alginic acid, Primojel®, corn starch and the like; lubricants such as magnesium stearate or Sterotex®; glidants, such as colloidal silicon dioxide; and can be added sweeteners, such as sucrose or saccharin, flavoring agents such as peppermint, methyl salicylate or orange flavoring. If the standard dosage form is a capsule, it may contain in addition to materials of the above type, a liquid carrier such as polyethylene glycol or fatty oil. Other standard dosage forms can contain various other materials which modify the physical form of standard dosage forms, such as coating. Thus tablets or pills may be coated with sugar, shellac or other intersolubility coatings. A syrup may contain, in addition to the active ingredient, sucrose as a sweetens the La and some preservatives, dyes and tinted agents and flavoring. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the quantities used.

For purposes of parenteral administration the compounds of formula I can be introduced into the solution or suspension. These preparations should contain at least 0.1% of the compounds according to the invention, but can vary and can include from 0.1 to about 50% of their mass. The amount of active ingredient present in such compositions is such to provide the desired dose.

The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl paraben, antioxidant, such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of toychest, such as sodium chloride or dextrose. The parenteral preparation can be Packed in ampoule, syringe-tubes or mnogorazovye vessels, made of a stack is and or plastic.

It is understood of course that the compounds of formula I can exist in multiple isomeric configurations, including structural and stereoisomers. Further, it is clear that the present invention covers compounds of formula I in each of their various structural and stereoisomeric configurations, individual isomers and mixture of isomers.

BIOLOGICAL METHODS AND RESULTS

The new compounds of formula I possess prolonged intensive antihypertensive effect. In addition, in patients with heart failure the compounds of formula I increase cardiac output, lower end-diastolic pressure of the left ventricle (LVEDP) and increase coronary blood flow. Exceptionally strong activity of the compounds of the formula I is demonstrated pharmacological data, summarized in the drawing.

The results presented in the drawing show that there is a significantly improved lowering mean arterial blood pressure (SBP) at each of the injected doses compared with the same oral doses of MDL 100 240.

The data obtained in models of rats with congestive heart failure, also showed that the compounds of formula I have a much more beneficial effect on cardiac function in comparison with known compounds. For example, in studies, which which MDL 100 240 and MDL 107 688 tested on rats with heart failure, similar efficacy was found when MDL 107 688 used at half the dose MDL 100 240.

1. The compound of the formula I

in which R1represents hydrogen or acyl group;

R2represents hydrogen or diphenylmethyl;

X represents -(CH2)nwhere n is an integer 1;

B1and In2each independently represents hydrogen,

or its pharmaceutically acceptable salts or stereoisomers.

2. The compound according to claim 1, where R1is acetyl or hydrogen.

3. The compound according to claim 2, which is diphenylmethylene ether [4S-[4α,7α(S),12bβ]]-7-[[2(R)-acetylthio-3-methyl-1-oxobutyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1A][2]benzazepine-4-carboxylic acid.

4. The compound according to claim 2, which is diphenylmethylene ether [4S-[4α,7α(S),12bβ]]-7-[[2(S)-acetylthio-3-methyl-1-oxobutyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1A][2]benzazepine-4-carboxylic acid.

5. The compound according to claim 2, where R2represents hydrogen.

6. The compound according to claim 5, which is [4S-[4α,7α(S),12bβ]]-7-[[2(S)-acetylthio-3-methyl-1-oxobutyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1A][2]benzazepine-4-carboxylic acid.

7. The compound according to claim 5, which is [4S-[4α,7α(S),12bβ]]-7-[3-methyl-1-oxo-2(S)-dibutyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-occupied[2,1A][2]benzazepine-4-carboxylic acid.

8. The method of obtaining the compounds of formula I

in which R1represents hydrogen or acyl group;

R2represents hydrogen or diphenylmethyl;

X represents -(CH2)nwhereninteger 1;

B1and In2each independently represents hydrogen,

comprising the reaction of compounds of formula II

in which Hal represents halogen, and X, R2B1and In2such as defined above,

with the compound of the formula R1SH, where R1is the same as defined above, in the presence of a base.

9. The method of obtaining the compounds of formula II

in which R2represents hydrogen or diphenylmethyl;

X represents -(CH2)nwhere n is an integer 1;

B1and In2each independently represents hydrogen,

comprising the reaction of compounds of formula III

in which R2, X1and In2such as defined above,

with the compound of the formula IV

where Hal represents halogen.

10. A method of treating cardiovascular bresnen the condition, includes introduction to the patient in need of such treatment, a therapeutically effective for inhibiting angiotensin converting enzyme and neutral endopeptidase number of compounds according to claim 1.

11. The method according to claim 10, where the painful condition is hypertension.

12. The method according to claim 10, where the painful condition is congestive heart failure.

13. The pharmaceutical composition inhibiting angiotensinase enzyme and neutral endopeptidase, including one or more of the compounds defined in claim 1, and a pharmaceutically acceptable carrier.

14. A method of obtaining a pharmaceutical composition comprising the stage of combining one or more of the compounds defined in claim 1 with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, medicine, veterinary science, pharmacy.

SUBSTANCE: invention relates to derivatives of tetrahydropyranyl-cyclopentyl-tetrahydropyridopyridine of the formula (1): , wherein R3 means oxygen atom or absent; R8 is chosen from: (a) hydrogen atom; (b) (C1-C3)-alkyl that can be unsubstituted or substituted with 1-6 fluorine atoms; (c) -O-(C1-C3)-alkyl; (d) fluorine atom, and (e) hydroxy-group, and their pharmaceutically acceptable salts and separate diastereomers. These compounds are modulators of activity of chemokine receptors. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), method for modulation of activity of chemokine receptors in humans and animals and a method for preparing a medicinal agent. Invention provides preparing novel modulators of chemokine receptors activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinoquinoline of the formula (II): or their tautomers, or their pharmaceutically acceptable salts wherein ring A represents ortho-condensed phenyl and monosubstituted with R4 wherein R4 means halogen atom; R1 represents -(CH2)nL wherein n means a whole number from 1 to 6; L is chosen from unsubstituted phenyl or its benzo-derivative, or L is chosen from phenyl or its benzo-derivative and substituted with one or two groups chosen from -CN, -CF3, (C1-C4)-alkyl, or L is chosen from -OH, -OCOR', -SOmR' wherein m means 0, 1 or 2, -NR'R'' under condition that -NR'R'' differs from -NH2, -NR'COR'', or L is chosen from heterocycle or heteroaryl wherein in each abovementioned case any group from R' or R'' is chosen from hydrogen atom, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, phenyl, phenyl-(C1-C4)-alkyl and wherein any group from R' or R'' is unsubstituted or substituted 1, 2 or 3 times with phenyl, -OH, O-(C1-C4)-alkyl at carbon atoms wherein in any abovementioned case heterocycle is chosen from five- or six-membered heterocyclic ring comprising 1, 2 or 3 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) atoms or its condensed benzo-derivative, indicated heterocycle wherein carbon atom is disubstituted to form (C5-C7)-spiro-group and indicated heterocycle wherein carbon atom © is substituted for oxygen atom (O) to form carbonyl group and wherein in any case heteroaryl is chosen from unsubstituted thiophene, furan, imidazole, triazole, tetrazole. Compounds of the formula (II) are antagonists of glycine-receptors and can be used in preparing pharmaceutical agents designated for treatment or prophylaxis of ischemic disease.

EFFECT: valuable medicinal properties of compounds.

5 cl, 8 tbl, 148 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to the substituted pyrazoles, pharmaceutical compositions comprising these compounds and methods for their using in treatment of autoimmune diseases wherein cathepsin S is their mediating agent. Described substituted pyrazoles represent compounds of the formula (I): wherein a dotted line is placed near the group -C-R6 or absent, or it represents a bond; Y represents nitrogen atom or -CR20; Z represents nitrogen atom or -CR21; T represents nitrogen atom or -CR2; S represents nitrogen atom or -CR3 under condition that from 0 to 3 among S, T, Y and Z represent nitrogen atom, and additionally under condition that one among S, T, Y and Z can represent the group =N+-O- if other three are not nitrogen atom; R20 is chosen from hydrogen, halogen atom, hydroxy-, cyano-group, 4-7-membered heterocycle comprising nitrogen and oxygen atom; R21 represents hydrogen atom; R2 is chosen from hydrogen, halogen atom and hydroxy-group; R3 is chosen from hydrogen, halogen atom, (C1-C5)-alkoxy-group, (C1-C5)-alkyl, cyano-group, -RgRhN, 4-7-membered heterocyclyl comprising nitrogen and oxygen atom and -R17OC=O; R5 and R6 represent hydrogen atom; R7 and R8 can be combined in common and form optionally substituted 5-7-membered carbocylic or heterocyclic ring comprising nitrogen atom and wherein the indicated ring can be unsaturated or aromatic and this ring is substituted optionally with -Rt(C=O)- or -RtSO2; Rt represents (C1-C6)-alkyl; Rg, Rh and R17 represent (C1-C5)-alkyl; G represents (C3-C6)-alkanediyl; Ar represents monocyclic aryl ring optionally substituted from 1 to 3 substitutes chosen independently from halogen atom, (C1-C5)-alkyl and (C1-C5)-halogenalkyl; R32 represents hydrogen atom, (C1-C5)-alkyl, cyano-group, C1-C5)-hydroxyalkyl, -(C=O)NRvRx, -CHO or (C1-C6)-alkoxycarbonyl wherein each from Rv and Rx is chosen independently from hydrogen atom (H), (C1-C5)-alkyl, (C1-C5)-hydroxyalkyl, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom-(C1-C5)-alkylene, (C1-C5)-aminoalkylene; Q represents -NR33, sulfur (S) or oxygen (O) atom; R33 represents hydrogen atom, (C1-C5)-alkyl, (C2-C5)-heterocyclyl comprising oxygen atom-(C1-C5)-alkylene, -R35OC=O and -R35OC=O; R35 represents (C1-C5)-alkyl, or their pharmaceutically acceptable salts, amides and esters, or their stereoisomeric forms.

EFFECT: improved for inhibition, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

25 cl, 3 tbl, 135 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to derivatives of carboline of the general formula (I): wherein R3 means hydrogen atom (H), hydroxyl (OH), -O-(C1-C6)-alkyl; R4 means -N(R17)2 wherein R17 means hydrogen atom (H), (C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -S(O)y-R14 wherein y = 0, 1 or 2; R14 means (C1-C6)-alkyl, phenyl substituted with halogen atom; or R means amino-group (-NH2), -NH-C(O)-R15 wherein R15 means pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxaline, thiophene possibly substituted with -CF3 or (C1-C6)-alkyl; (C3-C7)-cycloalkyl, -N(R13)2 wherein R12 means hydrogen atom (H) or phenyl under condition that -N(R13)2 doesn't mean -NH2; phenyl possibly substituted with (C1-C6)-alkyl, -CF3 if two substituted at phenyl form dioxalane ring; R5 means hydrogen atom (H), or R and R5 in common with nitrogen atom (N) form a heterocycle. Also, invention describes a method for their preparing. Compounds of the formula (I) are suitable for preparing medicinal agents used in prophylaxis and treatment of diseases wherein the enhanced activity of 1 κB is involves.

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

6 cl, 2 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydropyridine of the formula (I): wherein (a) means unsubstituted phenyl group or phenyl group substituted with 1, 2 or 3 substitutes chosen independently among (C1-C4)-alkoxy-group, or (b) means unsubstituted indolyl group; R1 and R2 are similar or different and mean hydrogen atom, (C1-C4)-alkyl or phenyl group; X means alkylene group with a direct chain comprising 5, 6, 7 carbon atoms, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to HDAC based on these compounds. Invention provides new compounds and pharmaceutical composition based on thereof for aims the stimulation of anti-proliferative effect in warm-blooded animals, such as humans.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 1 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing substituted imidazopyridine of the general formula (1): wherein R1 means (C1-C6)-alkoxy-group or -NH2. Method involves interaction of compound of the formula (2): with 3-halogen-2-butanone in cyclohexanone medium at temperature 80-100°C. Using cyclohexanone as a solvent allows reducing the process period and to enhance the yield of the end product.

EFFECT: improved preparing method.

9 cl, 19 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutically active compound 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (risperidone) of the formula (I): that possesses the neuroleptic properties. Method involves the condensation reaction of (2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)acetaldehyde of the formula (II): with (6-fluoro-3-piperidinyl)-1,2-benzisoxazole of the formula (IV): to yield intermediate enamine representing 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]vinyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of the formula (III): and the following reduction of this enamine in the presence of hydride. Also, invention claims intermediate compounds of the formula (II) and formula (III) and describes a method for preparing compound of the formula (II) comprising oxidation of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one of the formula (X): Method is characterized by high reproducibility in large-scale manufacturing and represents the unique combination of the synthesis simplicity, decreased cost, safety and protection of the environment.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, chemical technology, virology.

SUBSTANCE: invention relates to a new method for synthesis of a novel compound - 3,6-diazahomoadamantane of the formula: . Compounds of 3,6-diazahomoadamantane class possess an antiviral effect comparable with antiviral effect of aminoadamantane, elicit strychnine-like activity and show bactericidal, fungicide and algicidal properties and can be used as an antiviral preparation. Method for synthesis of 3,6-diazahomoadamantane involves interaction of 1-phenylthio-3,6-diazahomoadamantane-9-one with 65-66% hydrazine hydrate at boiling to form 1-phenylthio-3,6-diazahomoadamantane-9-one hydrazone that is subjected for reduction in Kizhner-Wolf reaction by alloying with alkali and then 1-phenylthio-3,6-diazahomoadamantane is desulfurized with Raney nickel in isopropyl alcohol at boiling.

EFFECT: improved method of synthesis.

2 cl, 1 ex

FIELD: organic chemistry, medicine, veterinary science, pharmacy.

SUBSTANCE: invention relates to derivatives of tetrahydropyranyl-cyclopentyl-tetrahydropyridopyridine of the formula (1): , wherein R3 means oxygen atom or absent; R8 is chosen from: (a) hydrogen atom; (b) (C1-C3)-alkyl that can be unsubstituted or substituted with 1-6 fluorine atoms; (c) -O-(C1-C3)-alkyl; (d) fluorine atom, and (e) hydroxy-group, and their pharmaceutically acceptable salts and separate diastereomers. These compounds are modulators of activity of chemokine receptors. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), method for modulation of activity of chemokine receptors in humans and animals and a method for preparing a medicinal agent. Invention provides preparing novel modulators of chemokine receptors activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 13 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a whitening composition comprising: (a) monomeric ligand or catalyst with transient metal of ligand of the formula (I): wherein R represents hydrogen atom; R1 and R2 are chosen independently from (C1-C4)-alkyl, pyridine-2-yl-methyl and (C2-C4)-alkylmethyl; X represents -C=O; R3 and R4 are similar and represent -(CH2)nC(O)O-(C1-C4)-alkyl; n = 0-4, and (b) equilibrating carriers and additional components. This composition is useful for catalytic whitening substrates with atmosphere oxygen. Also, invention describes a method for whitening the substrate involving applying step of the whitening composition on substrate in aqueous medium.

EFFECT: valuable properties of substances, improved whitening method.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinoquinoline of the formula (II): or their tautomers, or their pharmaceutically acceptable salts wherein ring A represents ortho-condensed phenyl and monosubstituted with R4 wherein R4 means halogen atom; R1 represents -(CH2)nL wherein n means a whole number from 1 to 6; L is chosen from unsubstituted phenyl or its benzo-derivative, or L is chosen from phenyl or its benzo-derivative and substituted with one or two groups chosen from -CN, -CF3, (C1-C4)-alkyl, or L is chosen from -OH, -OCOR', -SOmR' wherein m means 0, 1 or 2, -NR'R'' under condition that -NR'R'' differs from -NH2, -NR'COR'', or L is chosen from heterocycle or heteroaryl wherein in each abovementioned case any group from R' or R'' is chosen from hydrogen atom, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, phenyl, phenyl-(C1-C4)-alkyl and wherein any group from R' or R'' is unsubstituted or substituted 1, 2 or 3 times with phenyl, -OH, O-(C1-C4)-alkyl at carbon atoms wherein in any abovementioned case heterocycle is chosen from five- or six-membered heterocyclic ring comprising 1, 2 or 3 heteroatoms chosen from oxygen (O), nitrogen (N) or sulfur (S) atoms or its condensed benzo-derivative, indicated heterocycle wherein carbon atom is disubstituted to form (C5-C7)-spiro-group and indicated heterocycle wherein carbon atom © is substituted for oxygen atom (O) to form carbonyl group and wherein in any case heteroaryl is chosen from unsubstituted thiophene, furan, imidazole, triazole, tetrazole. Compounds of the formula (II) are antagonists of glycine-receptors and can be used in preparing pharmaceutical agents designated for treatment or prophylaxis of ischemic disease.

EFFECT: valuable medicinal properties of compounds.

5 cl, 8 tbl, 148 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to the substituted pyrazoles, pharmaceutical compositions comprising these compounds and methods for their using in treatment of autoimmune diseases wherein cathepsin S is their mediating agent. Described substituted pyrazoles represent compounds of the formula (I): wherein a dotted line is placed near the group -C-R6 or absent, or it represents a bond; Y represents nitrogen atom or -CR20; Z represents nitrogen atom or -CR21; T represents nitrogen atom or -CR2; S represents nitrogen atom or -CR3 under condition that from 0 to 3 among S, T, Y and Z represent nitrogen atom, and additionally under condition that one among S, T, Y and Z can represent the group =N+-O- if other three are not nitrogen atom; R20 is chosen from hydrogen, halogen atom, hydroxy-, cyano-group, 4-7-membered heterocycle comprising nitrogen and oxygen atom; R21 represents hydrogen atom; R2 is chosen from hydrogen, halogen atom and hydroxy-group; R3 is chosen from hydrogen, halogen atom, (C1-C5)-alkoxy-group, (C1-C5)-alkyl, cyano-group, -RgRhN, 4-7-membered heterocyclyl comprising nitrogen and oxygen atom and -R17OC=O; R5 and R6 represent hydrogen atom; R7 and R8 can be combined in common and form optionally substituted 5-7-membered carbocylic or heterocyclic ring comprising nitrogen atom and wherein the indicated ring can be unsaturated or aromatic and this ring is substituted optionally with -Rt(C=O)- or -RtSO2; Rt represents (C1-C6)-alkyl; Rg, Rh and R17 represent (C1-C5)-alkyl; G represents (C3-C6)-alkanediyl; Ar represents monocyclic aryl ring optionally substituted from 1 to 3 substitutes chosen independently from halogen atom, (C1-C5)-alkyl and (C1-C5)-halogenalkyl; R32 represents hydrogen atom, (C1-C5)-alkyl, cyano-group, C1-C5)-hydroxyalkyl, -(C=O)NRvRx, -CHO or (C1-C6)-alkoxycarbonyl wherein each from Rv and Rx is chosen independently from hydrogen atom (H), (C1-C5)-alkyl, (C1-C5)-hydroxyalkyl, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom-(C1-C5)-alkylene, (C1-C5)-aminoalkylene; Q represents -NR33, sulfur (S) or oxygen (O) atom; R33 represents hydrogen atom, (C1-C5)-alkyl, (C2-C5)-heterocyclyl comprising oxygen atom-(C1-C5)-alkylene, -R35OC=O and -R35OC=O; R35 represents (C1-C5)-alkyl, or their pharmaceutically acceptable salts, amides and esters, or their stereoisomeric forms.

EFFECT: improved for inhibition, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

25 cl, 3 tbl, 135 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to bicyclic heterocyclic substituted phenyloxazolidinones that represent compounds of the formula (I): wherein R is taken from the group consisting of -OH, O-heteroaryl, -N3, -OSO2R'', -NR'''R'''', or the formula: wherein: (ii) R'' represents direct or branched alkyl comprising up to 5 carbon atoms; (iii) R''' and R'''' are taken independently from the group consisting of hydrogen atom (H), -CO2-R1, -CO-R1, -CS-R1 and -SO2-R4 wherein R1 is taken among the group consisting of cycloalkyl comprising from 3 to 6 carbon atoms and direct or branched alkyl comprising up to 6 carbon atoms; R4 is taken from direct or branched alkyl comprising up to 4 carbon atoms; and R4a represents -CN or -NO2; R4b represents -SR4c, amino-group, -NHR4c or -NR4cR4d wherein R4c and R4d are taken independently from hydrogen atom (H) or alkyl; X represents from 0 to 4 members taken independently from the group consisting of halogen atom; and Y represents radical of the formula (II): or (III): wherein R5, R6, R7 and R8 represent independently hydrogen atom (H), or R and R6 and/or R7 and R8 form in common oxo-group; R9 and R10 represent independently hydrogen atom (H); A, B, C and D are taken from carbon atom (C) and nitrogen atom (N) to form phenyl ring or 5-6-membered heteroaromatic ring wherein the indicated heteroaromatic ring comprises from 1 to 4 members taken from the group consisting of nitrogen atom (N); Z is taken from alkyl, heteroaryl comprising nitrogen atom (N); and m represents 0 or 1. These compounds are useful as antibacterial agents and can be used for treatment of patient with the state caused the bacterial infection or with the bacterial infection caused by S. aureus and E. faecium.

EFFECT: valuable medicinal properties of compounds.

45 cl, 1 tbl, 50 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to derivatives of carboline of the general formula (I): wherein R3 means hydrogen atom (H), hydroxyl (OH), -O-(C1-C6)-alkyl; R4 means -N(R17)2 wherein R17 means hydrogen atom (H), (C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -S(O)y-R14 wherein y = 0, 1 or 2; R14 means (C1-C6)-alkyl, phenyl substituted with halogen atom; or R means amino-group (-NH2), -NH-C(O)-R15 wherein R15 means pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxaline, thiophene possibly substituted with -CF3 or (C1-C6)-alkyl; (C3-C7)-cycloalkyl, -N(R13)2 wherein R12 means hydrogen atom (H) or phenyl under condition that -N(R13)2 doesn't mean -NH2; phenyl possibly substituted with (C1-C6)-alkyl, -CF3 if two substituted at phenyl form dioxalane ring; R5 means hydrogen atom (H), or R and R5 in common with nitrogen atom (N) form a heterocycle. Also, invention describes a method for their preparing. Compounds of the formula (I) are suitable for preparing medicinal agents used in prophylaxis and treatment of diseases wherein the enhanced activity of 1 κB is involves.

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

6 cl, 2 tbl, 83 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydropyridine of the formula (I): wherein (a) means unsubstituted phenyl group or phenyl group substituted with 1, 2 or 3 substitutes chosen independently among (C1-C4)-alkoxy-group, or (b) means unsubstituted indolyl group; R1 and R2 are similar or different and mean hydrogen atom, (C1-C4)-alkyl or phenyl group; X means alkylene group with a direct chain comprising 5, 6, 7 carbon atoms, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to HDAC based on these compounds. Invention provides new compounds and pharmaceutical composition based on thereof for aims the stimulation of anti-proliferative effect in warm-blooded animals, such as humans.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 1 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing substituted imidazopyridine of the general formula (1): wherein R1 means (C1-C6)-alkoxy-group or -NH2. Method involves interaction of compound of the formula (2): with 3-halogen-2-butanone in cyclohexanone medium at temperature 80-100°C. Using cyclohexanone as a solvent allows reducing the process period and to enhance the yield of the end product.

EFFECT: improved preparing method.

9 cl, 19 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutically active compound 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (risperidone) of the formula (I): that possesses the neuroleptic properties. Method involves the condensation reaction of (2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)acetaldehyde of the formula (II): with (6-fluoro-3-piperidinyl)-1,2-benzisoxazole of the formula (IV): to yield intermediate enamine representing 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]vinyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of the formula (III): and the following reduction of this enamine in the presence of hydride. Also, invention claims intermediate compounds of the formula (II) and formula (III) and describes a method for preparing compound of the formula (II) comprising oxidation of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one of the formula (X): Method is characterized by high reproducibility in large-scale manufacturing and represents the unique combination of the synthesis simplicity, decreased cost, safety and protection of the environment.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used in arresting syndrome of systemic inflammatory response. Agent comprises, mg: diphosphopyridine nucleotide, 0.3-100 and inosine, 40.0-1200. Proposed medicinal agent can comprise additionally inhibitor of angiotensin-converting enzyme, mainly, lisinopril, 2.5-100 and cardiac glycoside, mainly, digoxin, 0.07-0.3. The new medicinal agent possesses the capacity for arresting syndrome of systemic inflammatory response being independently of etiology of its rise, and allows obtaining the expressed and stable curative effect for short times.

EFFECT: improved and valuable properties of medicinal agent.

5 cl, 4 tbl, 4 ex

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