Acidified arylcycloalkylamins and their application as pharmaceutical drugs

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds -acidified arylcycloalkylamins of formula I in any of their stereoisomeric forms or in form of their mixture in any ratio, or their pharmaceutically acceptable salts, where in formula I : R1 represents aryl, not obligatory substituted with one or two similar or different substitutes, selected from group that includes C1-C6-alkyl and halogen; R2 represents aryl or heteroaryl, which represents residue of 5-6-member aromatic monocyclic heterocycle, containing 1-2 nitrogen atoms as heteroatom and/or 1 sulfur atom or oxygen atom, or residue of 9-10-member aromatic bicyclic heterocycle, containing 1-2 nitrogen atoms as heteroatom, each of which is unsubstituted or contains 1-3 similar or different substitutes, selected from group, consisting of halogens, NH2, unsubstituted C1-C10-alkyl, C1-C10 -alcoxy, C1-C10-alkylamino and di(C1-C10-alkyl)amino, and at least monosubstituted C1-C10-alkyl, etc., n represents 1, 2, 3 or 4. Invention relates to pharmaceutical composition, stimulating expression of endothelial NO synthase, based on said compounds, as well as application of compounds of formula I for production of medication for stimulating expression of endothelial NO-synthase and for treatment of such cardiovascular diseases as atherosclerosis, thrombosis, coronary artery disease, hypertension and impaired cardiac function.

EFFECT: invention ensures enhancing composition and treatment method efficiency.

9 cl, 2 tbl, 41 ex

 

This invention relates to acylated to arylcyclohexylamines formula I

in which R1, R2and n have the meanings specified below. The compounds of formula I are valuable pharmaceutically active compounds, which are applicable for the treatment of various painful conditions, including cardiovascular diseases such as atherosclerosis, thrombosis, coronary artery disease, hypertension and heart failure. They activate the expression of the enzyme endothelial synthase nitric oxide (NO synthase) and you can apply them to the States, when you want increased expression of the indicated enzyme or increased NO levels or normalization of low NO. In addition, the invention relates to methods of preparing compounds of the formula I, their use, specifically as active ingredients in pharmaceuticals and to pharmaceutical preparations containing these compounds.

Endothelial NO-synthase (eNOS, NOS-III) belongs to a group of three isoenzymes that produce nitric monoxide (NO) oxidation of arginine. Released endothelial NO plays a Central role in a number of major cardiovascular mechanisms. NO has a vasodilator and inhibits platelet aggregation, adhesion of leukocytes to indot is Leah and proliferation of intimal smooth muscle cells.

Endothelial NO-synthase is an object of the physiological and pathophysiological regulation both at the transcriptional and posttranscriptional level. The enzyme already present in the endothelium may be calcium-dependent and calcium-independent activation by phosphorylation of specific amino acids, as well as direct interactions with specific proteins. Stimulants specified release NO, usually short-term, are extracellular arginine, 17β-estrogen and mechanical stimulus that occurs because of the action of the blood flow (shear stress) on the endothelial surface of the lumen. The latter leads to additional regulation of eNOS onthe transcriptional level. For example, Sessaet al. (Circ. Research 74 (1994) 349)managed through training exercises and increase shear stress,associated with them, to get a noticeable increase in eNOS.

Definitely not proven whether the regulation at post-transcriptional level is significantin vivo. So,for example, after injection of a large dose of arginine is only a short term improvement endothelialization vasorelaxation in patients with coronary disease.

On the other hand the importance of increasing regulation of eNOS protein recognized by science. So, there are data showing that the tread properties Inga is itora HMG-CoA-reductase - simvastatin may be partly due, along with a hypolipidemic action, an increase in eNOS expressionin vivo[(Endres et al., Proc. Natl. Acad. Sci. USA 95 (1998) 8880)]. In addition, it is known that mutations at one point in the 5'-pakiruumi region of the gene for eNOS (eNOS promoter") and the reduction in the rate of transcription of the eNOS gene, caused them to be associated with increased risk of spasm of the coronary vessels of the Japanese population [(Nakayama et al., Circulation 99 (1999) 2864)].

A common assumption, therefore, is that transcriptional and posttranscriptional mechanisms regulating eNOS seriously violated in many diseases, especially cardiovascular diseases. Dysfunction of this type in the endothelium lining the blood vessels, is possible even at very early stages of many cardiovascular diseases that leads to the deficiency of bioactive NO, which is evident in the progression of the disease in the form of physiological and morphological changes that can be measured. Thus the crucial stage in the early stages of the development of accelerated atherosclerosis by reducing the release of endothelial NO, such as, for example, oxidation of low-density lipoprotein, the recruitment and accumulation of monocytes in an intim vessels and proliferation of intimal cells. A consequence of the development of atherosclerosis is the formation of plaques GNC the ri blood vessels, which can, in turn, cause additionalthe decrease in the release of endothelial NO (by reducing shear stress) and further deterioration of the disease. Because endothelial NO is a vasodilator factor, often a decrease also leads to hypertension, which may, as an independent risk factor to cause additional damage organs.

The purpose of therapeutic approach to the treatment of these diseases should therefore be to interrupt the specified chain of events by increasing the expression of endothelial NO. Experiments on gene transfer, whichin vitrolead to overexpression of NO synthase in previously damaged vessels, are really able to counteract the described processes and, thus, prove the correctness of this approach [(Varenne et al., Hum. Gene Ther. 11 (2000) 1329)].

The literature describes some low molecular weight compounds that can directly influence the transcription and expression of eNOS in cultured cells. Statins, which have already been mentioned, but are the only substances for which this increase in eNOSin vivocan be considered a side effect. But in the light of thesome known side effects of this class of substances is unclear,how strong this effect in the case of the AE dose safe from the point of view of toxicology.

Liao et al. claimed in WO 99/47153 and WO 00/03746 inhibitors rhoGTP and agents that affect the structure of the actin cytoskeleton to increase eNOS in endothelial cells and for the treatment of various diseases, such as stroke or pulmonary hypertension; without, however, specific ways of achieving those results.

In WO 02/064146, WO 02/064545, WO 02/064565 and WO 02/064546 described acylated benzododecinium cyclooctylamine that polysoude regulate the expression of eNOS in endothelial cells and are useful pharmaceutically active ingredients for the treatment of various diseases, but there is a constant need for additional enhancers expression of eNOS, with useful properties. This invention satisfies the specified need by providing the compounds of formula I and methods of their use.

This invention relates to acylated to arylcyclohexylamines formula I

in any of its stereoisomeric forms or mixtures thereof in any ratio, or its pharmaceutically acceptable salts, where in the formula I:

R1represents aryl or heteroaryl, each of which is unsubstituted or substituted by one or more identical or different substituents, selected the C group, consisting of C1-C6-alkyl, halogen, CF3C1-C6-alkoxy, C1-C6-allylmercaptan, -CN, COOR10, CONR11R12, NR13R14, S(O)mR15and S(0)2NR16R17;

R2represents aryl or heteroaryl, each of which is unsubstituted or contains one or more identical or different substituents selected from the group consisting of:

of halogen; -CN; NH2; unsubstituted and at least monosubstituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10the quinil, C1-C10-alkoxy, C1-C10-alkylamino and di(C1-C10-alkyl)amino, the substituents of which are selected from the group consisting of:

F, OH, Cl-C8-alkoxy, aryloxy, C1-C8-allylmercaptan, NH2C1-C8-alkylamino and di(C1-C8-alkyl)amino; C3-C5-Alcantara; phenyl; heteroaryl; or aryl-substituted heteroaromatic1-C4-alkyl; CF3; NO2; OH; phenoxy; benzyloxy; (C1-C10-alkyl)-COO -; - S(O)mR20; SH; phenylamino; benzylamino; (Cl-Cl0-alkyl)-CONH-; (C1-C10-alkyl)-CO-N(C1-C4-alkyl)-; phenyl-CONH-; phenyl-CON(C1-C4-alkyl)-; heteroaryl-CONH-; heteroaryl-CON(C1-C4-alkyl)-; (C1-C10-alkyl)-CO-; 'is-CO-; heteroaryl-CO-; CF3CO-; -OCH2O-; -OCF2O-; -OCH2CH2O-; -CH2CH2O-; COOR21; CONR22R23; C(NH)-NH2; SO2NR24R25; R26SO2NH-; R27SO2N(C1-C6-alkyl)-; and the remainder of saturated or at least monounsaturated aliphatic monocyclic 5-7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from the group consisting of N,O and S, and the heterocycle may be substituted by one or more substituents selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-alkoxy, OH, oxo and CF3where the heterocycle may optionally be condensed with the above aryl group or heteroaryl group representing R2;where all aryl, heteroaryl, phenyl, arylesterase, heterotrissocladius and phenylaziridine groups that are in the specified optional substituents mentioned aryl group or heteroaryl group representing R2,may be substituted by one or more substituents selected from the group consisting of halogen, -CN, C1-C3-alkyl, OH, C1-C3-alkoxy and CF3;

R10represents H, C1-C6-alkyl or benzyl in which the phenyl group mo is et to be substituted by one or more identical or different substituents, selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3;

R11selected from the group consisting of:

H; C1-C6-alkyl which can be substituted by phenyl; phenyl, indanyl and heteroaryl, where each aromatic group is unsubstituted or contains one or more identical or different substituents from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3;

R12represents H or C1-C6-alkyl;

R13selected from the group consisting of:

H, C1-C6-alkyl, and unsubstituted and substituted phenyl, benzyl, heteroaryl, phenyl-CO -, and heteroaryl-CO-, the substituents of which are selected from the group consisting of halogen free,-CN, C1-C3-alkyl, C1-C3-alkoxy and CF3which can be represented by one or more of these substituents;

R14represents H or C1-C6-alkyl;

R15selected from the group consisting of:

C1-C6-alkyl; CF3; and substituted and unsubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3which can be represented by one or more specified replace the;

R16regardless of R11is defined as R11;

R17regardless of R12is defined as R12;

R20selected from the group consisting of:

H; C1-C10-alkyl which may be substituted by one or more substituents selected from the group consisting of F, OH, C1-C8-alkoxy, aryloxy, C1-C8-allylmercaptan, C1-C8-alkylamino and di(C1-C8-alkyl)amino; CF3and substituted or unsubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3which can be represented by one or more of these substituents;

R21selected from the group consisting of:

H; C1-C10-alkyl which may be substituted by one or more substituents selected from the group consisting of F, C1-C8-alkoxy and di(C1-C8-alkyl)amino; aryl-(C1-C4-alkyl)- and heteroaryl-(C1-C4-alkyl)-, both of which can be substituted by one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy and di(C1-C6-alkyl)amino;

R22selected from the group consisting of:

H; C1-C10-alkyl, which may be amesen one or more substituents, selected from the group consisting of F, C1-C8-alkoxy, di(C1-C8-alkyl)amino and phenyl; phenyl; indanyl and heteroaryl; where each of the aromatic groups can be unsubstituted or contains one or more substituents selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3;

R23represents H or C1-C10-alkyl;

R24regardless of R22is defined as R22;

R25,regardless of R23is defined as R23;

R26regardless of R20is defined as R20;

R27,regardless of R20is defined as R20;

Heteroaryl represents the balance of 5-10-membered aromatic, monocyclic or bicyclic heterocycle containing one or more heteroatoms selected from the group consisting of N,O and S;

aryl represents phenyl, naphthas-1-yl or naphthas-2-yl;

m represents 0, 1 or 2;

n represents 1, 2, 3 or 4;

provided that if R1represents unsubstituted phenyl, R2can not be unsubstituted phenyl, 4-Bromphenol, 3-methoxyphenyl, chlorine substituted 4H-thieno[3,2-b]pyrrol-5-yl, unsubstituted tanila,naphthyridine, unsubstituted pyridinyl, 3-hydroxy-4-methoxypyridine-2-yl, 2,6-dichloro is iridin-4-yl or 3,4,5-trimethoxyphenyl.

If groups or substituents in the compounds of formula I such as, for example, aryl, heteroaryl, alkyl, etc. can be represented several times, they all independently of one another have the specified values and can therefore in each case be identical or different from each other. As an example, mention can be made of di(C1-C10-alkyl)amino group in which the alkyl substituents may be the same or different. When the group in compounds of formula I may be at least monosubstituted, or when it contains one or more substituents, it can be substituted, for example, one, two, three, four, or five substituents. When the group is substituted by two or more substituents, the substituents may be the same or may differ from each other.

Alkyl, alkeline and alkyline residues may be linear or branched, acyclic or cyclic, this also applies to those cases where these residues are part of other groups, such as alkoxygroup, alkoxycarbonyl groups or substituted amino groups, or when they are replaced.

Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, n-isomers of these residues, isopropyl, isobutyl, isope the til, Deut-butyl,tert-butyl, neopentyl, 3,3-dimethylbutyl. The term alkylin this application specifically includes cycloalkyl group cycloalkylation group (i.e. an alkyl group, substituted cycloalkenyl), which contain at least three carbon atoms. Examples of such cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. All cycloalkyl group may be substituted by one or more identical or different C1-C4-alkyl residues, specifically the stands. Examples of substituted cycloalkyl residues are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclobutyl. In addition, unless otherwise indicated, the term alkyl in this application also includes unsubstituted alkyl residues, as well as alkyl residues, which are substituted by one or more, for example 1, 2, 3 or 4 identical or different residues, for example, aryl groups. In the substituted alkyl residues, for example arylalkyl, hydroxyalkyl, such as hydroxy-(C1-C3)-alkyl-, or alkoxyalkyl, for example, C1-C4-alkyl-O-(C1-C3)-alkyl, the substituents can be located in any desired position.

Examples alkenyl and etkinlik groups are vinyl, 1-propenyl, 2-propenyl (i.e. allyl), 2-butenyl, 2-m is Teal-2-propenyl, 3-methyl-2-butenyl, ethinyl, 2-PROPYNYL (i.e. propargyl), 2-butenyl or 3-butenyl. The term of alkenyl in this application specifically incorporates cycloalkenyl group and cycloalkenyl group (i.e. an alkyl group, substituted cycloalkenyl), which contain at least three carbon atoms. Examples cycloalkenyl residues are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctanol. All cycloalkenyl group may be substituted by one or more identical or different C1-C4-alkyl residues, specifically the stands. In addition, unless otherwise indicated, the terms of alkenyland quinil in this application also include unsubstituted alkeneamine and alkyline residues, as well as alkeneamine and alkyline residues, which are substituted by one or more, for example 1, 2, 3 or 4 identical or different residues, for example, aryl groups. In substituted alkenyl and etkinlik residues, for example, arylalkyl, hydroxyalkyl, such as hydroxy-(C2-C3)-alkenyl-or alkoxyalkanols, such as C1-C3-alkyl-O-(C2-C4alkenyl)-, the substituents can be located in any desired position.

Examples of C3-C5-elendilmir groups are group-CH2CH2CH2-,-CH2-CH(CH3)-,-CH2CH2CH2CH2- and-C 2CH2CH2CH2CH2-.

Unless otherwise stated, the above-mentioned phenyl residues, raftiline and indanamine residues and heterocyclic residues (including heteroaryl residues can be unsubstituted or contain one or more, for example 1, 2, 3, or 4 substituent mentioned in the above definition, which can be located in any desired position. If in the compounds of formula I have the nitro group as substituents, in the preferred embodiment of the present invention in the molecule of compound I contains not more than two nitro groups. In monosubstituted phenyl residues Deputy may be in the 2-position, 3-position and 4-position, in disubstituted phenyl residues, the substituents can be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisemester phenyl residues, the substituents can be in the 2,3,4-position, 2,3,5-position, 2,3,6-I, 2,4,5-position, 2,4,6-position or 3,4,5-I. In Tetra-substituted phenyl residues, the substituents can be in 2,3,4,5-position, 2,3,4,6-I or 2,3,5,6-position. Tolyl (that were) can be 2-tolila, 3-tailam or 4-tailam. Naphthyl may be 1-naphthyl or 2-naphthyl. In monosubstituted 1-naftalina residues Deputy may be in position 2, Polo is attachment 3, position 4, position 5, position 6, position 7 or position 8, in monosubstituted 2-naftalina residues Deputy may be in position 1, position 3, position 4, position 5, position 6, position 7 or position 8. In a more highly-substituted PCB naftalina residues, such as 1-naftalina residues or 2-naftalina residues, which contain two or three substituent, the substituents can be located in any desired position. Indanamine residues include indan-1-ilen residues and indan-2-ilen residues, which can be unsubstituted or contain one or more of these substituents. In the case of substituted indaily residues Deputy or deputies can be in any of the possible positions.

Unless otherwise stated, heteroaryl residues and heterocyclic residues are preferably derivatives of heterocycles containing 1, 2, 3 or 4 heteroatoms which may be the same or different; more preferably, if they are derivatives of heterocycles containing 1, 2 or 3, particularly 1 or 2 heteroatoms which may be the same or different. Unless otherwise indicated, the compounds may be monocyclic or polycyclic, for example, monocyclic, bicyclic and tricyclic. Preferably, if they are monocyclic or b is cyclic. The number of atoms in the cycle is preferably 5, 6, 8, 9 or 10. Separate the loops preferably represent a 5-membered, 6-membered or 7-Chennai cycles. Examples of monocyclic and bicyclic systems, of which the remains, found in the compounds of formula I, are pyrrole, furan, thiophene, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1,3-dioxole, 1,3-oxazol (i.e. oxazol), 1,2-oxazol (i.e. isoxazol), 1,3-thiazole (i.e. thiazole), 1,2-thiazole (i.e. isothiazol), tetrazole, pyridine, pyridazine, pyrimidine, pyrazin, Piran, thiopyran, 1,4-dioxin, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepin, 1,3-oxazepine, 1,3-diazepine, indole, benzothiophene, benzofuran, benzothiazole, benzoxazole, benzimidazole, benzodioxole, quinoline, isoquinoline, cinnoline, hinzelin, cinoxacin, phthalazine, thienothiophene, 1,8-naphthiridine and other naphthirydines, pteridine or phenothiazines, each of them rich in the form of a(targetform), or a partially unsaturated form (for example, in dihydrofuroor tetrahydrofurane) or maximally unsaturated form or aromatic form, provided that the respective forms are known and stable. The term "aryl" the term "heteroaryl", as used in this application include bicyclic residues, the cat is where both cycles are aromatic, and also bicyclic residues, in which only one cycle is aromatic. Suitable heterocycles include, for example, saturated heterocycles pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine. The degree of saturation of the heterocyclic groups mentioned in their individual definitions. Unsaturated heterocycles may contain, for example, 1, 2 or 3 double bonds in the cyclic system. Five-membered rings and 6-Chennai rings can in particular also be aromatic.

Residues, derivatives of these heterocycles may be linked via any suitable carbon atom. Residues, derivatives of nitrogen-containing heterocycles containing a hydrogen atom or substituents on the nitrogen atom of the ring, such as the remains of pyrrole, imidazole, pyrrolidine, research or piperazine may also be attached via the nitrogen atom of the ring, especially if the corresponding heterocyclic residue attached to the carbon atom. For example, thienyl residue may be represented as 2-tanila or 3-tanila, the remainder of Furie - 2-furil or 3-furil, the rest of pyridine in the form of 2-pyridinyl or 4-pyridinyl, the rest of piperidinyl - 1-piperidinyl balance (i.e. piperidino group), 2-piperidinyl residue, 3-piperidinyl residue or 4-piperidinyl residue, the residue (thio)morpholinyl - 2-(thio)morph is onlinego residue, 3-(thio)morpholinyl residue or 4-(thio)morpholinyl balance (i.e. thiomorpholine balance). The remainder derived 1,3-thiazole or imidazole, which is attached via a carbon atom, may be joined through the 2-position, 4-position or 5-position.

When the heterocyclic group is substituted, it may contain one or more, e.g. 1, 2, 3, or 4 substituent, the same or different. The substituents in the heterocyclic compounds may be in any desired positions, for example, 2-thienyl residue or 2-furilla the residue at the 3-position and/or 4-position and/or 5-position, 3-anilina residue or 3-furilla residue in the 2-position and/or 4-position and/or 5-position, 2-pyridinoline the residue at the 3-position and/or 4-position and/or 5- position and/or 6-position, 3-pyridinoline residue in the 2-position and/or 4-position and/or 5-position and/or 6-position, 4-pyridinoline residue in the 2-position and/or 3-position and/or 5-position and/or 6-position. Suitable nitrogen-containing heterocycles can also be present as N-oidov or in the form of Quaternary salts containing a counterion, which is derived from pharmaceutically acceptable acids. Pyridine groups, for example, can therefore be in the form of pyridine-N-oxides.

Halogen represents fluorine, chlorine, bromine or iodine, preference is sustained fashion fluorine or chlorine.

This invention includes all stereoisomeric forms of the compounds of formula I. Asymmetric centers exist in the compounds of formula I, all independently of each other can have the S-configuration or R-configuration. This invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example, mixtures of enantiomers and/or diastereomers, in all ratios. Thus, the compounds according to this invention, which can exist as enantiomers may be in enantiomerically pure form, as levogyrate, and programalso antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. As for CIS/transitorie, which also takes place, for example, in cycloalkene ring of formula I and refers to the relative position of the residues R1and R2-CO-NH-, the invention includes both conforma and transform, as well as mixtures of these forms in all ratios, and all these forms are the object of the present invention. If you want, you can obtain the individual isomers separation of the mixture by conventional methods, for example, by chromatography or crystallization, the use of stereochemical pure starting substances for the synthesis or stereoselective synthesis. Obtaining derivatives, optionally, can be the implement to the separation of stereoisomers. Separation of a mixture of stereoisomers can be carried out at the stage of the compounds of the formula I or at the stage of intermediate compounds during the synthesis, or at the stage of starting compound. This invention also includes all tautomeric forms of compounds of formula I.

In the case of compounds of formula I containing one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically ortoxicologically acceptable salts, in particular pharmaceutically applicable salt. Thus, the compounds of formula I which contain acidic groups can be present on these groups and to apply for this invention, for example, in the form of salts of alkali metals, salts of alkaline earth metals or ammonium salts. Examples of such salts are sodium salts, potassium salts, calcium salts, magnesium salts or ammonium salts or salts of organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of formula I which contain one or more basic groups, i.e. groups which can be protonated,it is possible to apply this invention in the form of their additive salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric to the slot, nitric acid, methanesulfonate acid,p-toluensulfonate acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, Pavlinov acid, deathlessnoob acid, malonic acid, succinic acid, timelineview acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionate acid, gluconic acid, ascorbic acid, isonicotinoyl acid, citric acid, adipic acid, and other acids known to the experts in this field. If the molecule of the compounds of the formula I contains at the same time acidic and basic groups, the invention also includes, in addition to the above salt forms, inner salts or betaines (zwitterions). Salts of compounds of formula I can be obtained by conventional methods known to experts in the art, for example, by contact of the compounds of formula I with an organic or inorganic acid or base in a solvent or diluent, or by anion exchange or cation with other salts. This invention also includes all salts of the compounds of formula I, which due to low physiological compatibility, are not suitable for use directly in the farm is sitechecker means, but which can be used, for example, as intermediates for chemical reactions or to obtain pharmaceutically acceptable salts.

In addition, this invention also includes all of the solvate of the compounds of the formula I, for example hydrates, and the adducts with alcohols, active metabolites of compounds of formula I and derivatives and prodrugs of the compounds of the formula I which contain a physiologically-tolerated and able to split the group, for example, esters, amides and compounds in which the N-H group depicted in formula I, substituted N-alkyl group, such as N-methyl or N-acyl group, such as N-acetyl or N-argininemia groups, including pharmaceutically acceptable salts formed functional groups present in the N-acyl group.

In preferred embodiments of this invention, one or more structural fragments in the compounds of formula I, including the number of n groups of R1and R2and other groups present in the compounds of formula I, independently of one another have the following preferred values the preferred values, even more preferred values, or preferred values.

R1preferably represents a phenyl or monocyclic 5-membered or 6-members of the hydrated heteroaryl, which are unsubstituted or substituted by one or more identical or different substituents, for example, substituents selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, CF3, halogen and C1-C4-alkyl-S(O)m-. More preferably, if R1represents phenyl, thienyl or pyridinyl, in particular phenyl, all of which are unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of C1-C3-alkyl, CF3and Halogens.

R2preferably represents aryl or heteroaryl, which are unsubstituted or substituted by one or more identical or different substituents, for example, substituents selected from the group consisting of: halogen; -CN; NH2; unsubstituted or at least monosubstituted C1-C8-alkyl, C2-C8-alkenyl, C2-C8-quinil, C1-C8-alkoxy, C1-C8-alkylamino and di(C1-C8-alkyl)amino, the substituents of which are selected from the group consisting of F, OH, C1-C6-alkoxy, phenoxy, C1-C6-allylmercaptan, NH2C1-C6-alkylamino and di(C1-C6-alkyl)amino; C3-C5-Alcantara; phenyl; heteroaryl; FeNi is substituted or heteroarylboronic C 1-C2-alkyl; CF3; OH; phenoxy; benzyloxy; (C1-C6-alkyl)-COO; S(O)m-(C1-C6)-alkyl, which may optionally be substituted by OH or C1-C6-alkoxy; S(O)m-phenyl, S(O)m-heteroaryl; SH; phenylamino; benzylamino; (C1-C6-alkyl)-CONH-; (C1-C6-alkyl)-CON(C1-C4-alkyl)-; phenyl-CONH-; phenyl-CON(C1-C4-alkyl)-; heteroaryl-CONH-; heteroaryl-CON(C1-C4-alkyl)-; (C1-C6-alkyl)-CO-; phenyl-CO-; heteroaryl-CO-; CF3-CO-; -OCH2O-; -OCF2O-; -OCH2CH2O-; CH2CH2O-; COO(C1-C6-alkyl); -CONH2; -CONH(C1-C6-alkyl); -CON(di(C1-C6-alkyl)); C(NH)-NH2; -SO2NH2; -SO2NH(C1-C6-alkyl); -SO2NH(phenyl); -SO2N(di(C1-C6-alkyl)); C1-C6-alkyl-SO2NH-; and (C1-C6-alkyl)-SO2N(C1-C6-alkyl)-; phenyl-SO2NH-; phenyl-SO2N(C1-C6-alkyl)-; heteroaryl-SO2NH-; heteroaryl-SO2N(C1-C6-alkyl)-; and the remainder of saturated or at least monounsaturated aliphatic managername 5-7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, the heterocycle may be substituted by one or more substituents selected from the group consisting of the C halogen free, C1-C3-alkyl, C1-C3-alkoxy, OH, oxo and CF3where the heterocycle may optionally be condensed with the above aryl group or heteroaryl group representing R2; where all heteroaryl, phenyl, heterotrissocladius and phenylaziridine groups, which are optionally present in said substituents of the indicated aryl group or heteroaryl group,representing R2,may be substituted by one or more substituents selected from the group consisting of halogen, -CN, C1-C3-alkyl, OH, C1-C3-alkoxy and CF3.

More preferably, if R2represents phenyl or heteroaryl, which are unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of halogen; -CN; NH2; unsubstituted or at least monosubstituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-quinil, C1-C3-alkoxy, C1-C4-alkylamino and di(C1-C4-alkyl)amino, the substituents of which are selected from the group consisting of F, C1-C3-alkoxy, Cl-C3-allylmercaptan and NH2; C3-C5-Alcantara; phenyl; heteroaryl; phenylseleno or heteroaryl EDINOGO C 1-C2-alkyl; CF3; OH; (C1-C4-alkyl)-COO; S(O)m-(C1-C4)-alkyl, (C1-C4-alkyl)-CONH-;(C1-C4-alkyl)-CON(C1-C4-alkyl)-;(C1-C4-alkyl)-CO-; phenyl-CO-; heteroaryl-CO-; CF3-CO-; -OCH2O-; -OCF2O-; -OCH2CH2O-; -CH2CH2O-; COO(C1-C6-alkyl); -CONH2; -CONH(C1-C4-alkyl); -CON(di(C1-C4-alkyl)); C(NH)-NH2; -SO2NH2; -SO2NH(C1-C4-alkyl); -SO2NH(phenyl); -SO2N(di(C1-C4-alkyl)); and (C1-C4-alkyl)-SO2NH-; and (C1-C4-alkyl)-SO2N(C1-C4-alkyl)-;and the residue of a saturated or at least monounsaturated aliphatic monocyclic 5-7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, and the heterocycle may be substituted by one or more substituents selected from the group consisting of halogen, C1-C3-alkyl, C1-C3-alkoxy, OH, oxo and CF3where the heterocycle may optionally be condensed with the above phenyl group or heteroaryl group representing R2; where all heteroaryl, phenyl, heterotrissocladius and phenylaziridine groups that are not necessarily present in the substituents shown above phenyl group or heteroaryl group, representing R2may be substituted by one or more substituents selected from the group consisting of halogen, -CN, C1-C3-alkyl, OH, C1-C3-alkoxy and CF3.

Even more preferably, if R2represents phenyl or heteroaryl, which are unsubstituted or contain one or more identical or different substituents selected from the group consisting of: F; Cl; Br; C1-C3-alkyl, C1-C3-alkoxymethyl; 2-amino-3,3,3-cryptochrome-; CF3; C3-C5-Alcantara; phenyl; heteroaryl; benzyl; heteroaromatic-; OH; C1-C3-alkoxy; phenoxy; triptoreline; 2,2,2-triptoreline; (C1-C4-alkyl)-COO; Cl-C3-allylmercaptan; phenylmercaptan; C1-C3-alkylsulfonyl; phenylsulfonyl; NH2; C1-C4-alkylamino; di(C1-C4-alkyl)amino; (C1-C3-alkyl)-CONH-; (C1-C3-alkyl)-SO2NH-; and (C1-C3-alkyl)-CO-; phenyl-CO-; -OCH2O-; -OCF2O-; -CH2CH2O-; COO(C1-C4-alkyl); -CONH2; -CONH(C1-C4-alkyl); -CON(di(C1-C4-alkyl)); -CN; -SO2NH2; -SO2NH(C1-C4-alkyl); -SO2N(di(C1-C4-alkyl)); pyrrolidinyl; piperidinyl; morpholinyl and thiomorpholine; where all heteroaryl, phenyl,heterotrissocladius and phenylaziridine group, that may not necessarily present in the said substituents of the indicated phenyl group or heteroaryl group,representing R2may be substituted by one or more substituents selected from the group consisting of halogen, -CN, C1-C3-alkyl, OH, C1-C3-alkoxy and CF3;

Most preferably, if R2selected from the group consisting of 4-ftoheia, 4-chlorphenyl, 4-bromophenyl, 4-(C1-C3-alkoxy)phenyl, 4-trifloromethyl, 2-bromo-4-ftoheia, 2-chloro-4-ftoheia, 3,4-dimetilfenil, 2,4-dimetilfenil, 4-chloro-2-methylphenyl, 2-hydroxy-4-methylphenyl, 2-hydroxy-4-ethoxyphenyl, 2-methoxy-4-methylphenyl, 4-phenoxyphenyl, 3-fluoro-4-methylphenyl, benzo[1,3]dioxol-5-yl, 2,2-debtorrent[1,3]dioxol-5-yl, 2,3-dihydrobenzofuran-5-yl, 1-(4-chlorophenyl)-5-trifluoromethyl-1H-pyrazole-4-yl, 1-(4-forfinal)for 3,5-dimethyl-1H-pyrazole-4-yl, 1H-benzotriazol-5-yl, 1H-indol-4-yl, 1H-indol-6-yl, 1-isopropyl-2-trifluoromethyl-1H-benzimidazole-5-yl, 1-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-6-silt, 1-phenyl-5-trifluoromethyl-1H-pyrazole-4-yl, 2-(2-hydroxypyridine-4-yl)-1H-benzimidazole-5-yl, 2-(4-cyanophenyl)-1H-benzimidazole-5-yl, 2,4-dimethyloxazole-5-yl, 2,4-dimethylpyrimidin-5-yl, 2,4-dimethylthiazol-5-yl, 2,5-dimethyl-1H-pyrrol-3-yl, 2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl, 2,5-dimethyl-1-(pyridine-4-ylmethyl)-1H-pyrrol-3-yl, 2,5-dimethyl-2H-Piras the l-3-yl, 2,6-dichloropyridine-3-yl, 2,6-dimethoxypyridine-3-yl, 2,6-dimethylpyridin-3-yl, 2-amino-4,6-dimethylpyridin-3-yl, 2-amino-6-chloropyridin-3-yl, 2-aminopyridine-3-yl, 2-chloro-6-methylpyridin-3-yl, 2-chloropyridin-4-yl, 2-cyclopropyl-4-methylthiazole-5-yl, 2-dimethylamino-4-methylthiazole-5-yl, 2-dimethylaminopyridine-4-yl, 2-ethyl-5-methyl-2H-pyrazole-3-yl, 2-hydroxy-6-methylpyridin-3-yl, 2-methyl-1H-benzimidazole-5-yl, 2-methyl-3H-benzimidazole-5-yl, 2-methylpyridin-3-yl, 2-methyl-6-triptorelin-3-yl, 2-methylthiazole-5-yl, 2-(morpholine-4-yl)pyridine-4-Il, 2-(morpholine-4-yl)pyrimidine-5-yl, 2-(pyrrolidin-1-yl)pyridine-4-yl, 3,5-dimethyl-1H-pyrazole-4-yl, 3-amino-5,6-dimethylpyrazine-2-yl, 3-amino-5-methylpyrazine-2-yl, 3-aminopyrazine-2-yl, 3-dimethylamino-4-methylphenyl, 3-dimethylaminophenyl, 3H-benzimidazole-5-yl, 1H-benzimidazole-5-yl, 3-methylsulfonylamino-2-methylphenyl, 3-methylsulfonylmethane, 3-methylisoxazol-4-yl, 3-(morpholine-4-yl)phenyl, 3 - (piperidine-1-yl)phenyl, 3-(pyrrolidin-1-yl)phenyl, 4-(2,2,2-triptoreline)phenyl, 4,6-dimethylpyridin-4-yl, 4-amino-2-ethylsulfonylimidazo-5-yl, 4-amino-2-methylpyrimidin-5-yl, 4-chloro-3-methylsulfonylmethane, 4-chloro-3-sulfamoylbenzoyl, 4-methyl-3-methylaminophenol, 4-methylthiazole-5-yl, pyridin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-amino-1-phenyl-1H-pyrazole-4-yl, 5-methylsulphonyl-2-methylphenyl, 5-methyl-1-phenyl-1H-pyrazole-4-yl, 5-methylisoxazol-3-yl, 5-methylp ridin-3-silt, 5-methylpyrazine-2-yl, 6-chloropyridin-3-yl, 6-cyano-3-yl, 6-dimethylaminopyridine-3-yl, 6-ethynylpyridine-3-yl, 6-methoxypyridine-3-yl, 6-methoxypyridine-3-yl, 6-methyl-2-methylaminomethyl-3-yl, 6-methylaminomethyl-2-yl, 6-methylpyridin-3-yl, 6-(morpholine-4-yl)pyridine-3-yl, 6(pyrrolidin-1-yl)pyridine-3-yl, imidazo[1,2a]pyridine-2-yl, 6-tigerlilies-3-yl, pyrimidine-4-yl, 4-methylsulfinylphenyl, 4-ethylsulfinyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 2-bromo-4-chlorphenyl, 2,3-dichlorophenyl, 3-chloro-4-(isopropylphenyl)thiophene-2-yl, 4-bromo-2-chlorphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 2-methylthiophene-3-yl, 3-chloro-4-methylthiophene-2-yl, 5-bromothiophene-2-yl, 5-chlorothiophene-2-yl, 5-methylthiophene-2-yl, 4-methylthiophene-2-yl, 3-methylthiophene-2-yl, 5-acetylthiophene-2-yl, pyridin-3-yl, pyridine-4-yl, 4-trifloromethyl, 4-ethylaminoethanol, 4-methylaminophenol, 2-AMINOPHENYL, 4-bromo-2-ftoheia, 2-chlorphenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 2-chloro-3-methylphenyl, 2-methylphenyl, 2-acetoxy-4-methylphenyl, 2-acetoxy-4-ethoxyphenyl, 2-acetoxy-4-methoxyphenyl, 4-triftormetilfullerenov, naphthalene-2-yl, 1,1-dietlinde-4-yl, 3-isobutylamine, 3-(2,2-dimethylpropanolamine)phenyl, 2-bromophenyl, 2-ftoheia, 3-bromo-5-methylthiophene-2-yl, 3-chloro-6-toranzo[b]tiof the h-2-yl and 3,4-dichlorobenzo[b]thiophene-2-Il.

Heteroaryl preferably represents the residue of a 5-10 membered aromatic monocyclic or bicyclic heterocycle containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, more preferably monocyclic 5-membered or 6-membered heterocycle containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S. more preferably, if a heterocycle selected from the group consisting of furil, pyrrolyl, teinila, thiazolyl, isothiazoline, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridazinyl, pyrazinyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, chinoline, ethenylene, khinoksalinona, heatline, indolyl, benzofuranyl, benzodioxolyl, benzothiophene, specifically from the group consisting of furil, pyrrolyl, teinila, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyrazinyl, pyridinyl and pyrimidinyl.

Aryl preferably represents phenyl.

m preferably represents 0 or 2.

n preferably represents 1 or 3, more preferably 1. That is, in the preferred embodiments of the invention the compounds of formula I are the acylated arylcyclohexylamine formula Ia (i.e acylated 2-arylcyclohexylamine) or formula Ib (i.e. acylated 2-Ariz chlopheniramine). In the compounds of formulas Ia and Ib residues R1and R2can have any of the usual and preferred meanings indicated above or below. In the compounds of formula Ia, R1and R2-CO-NH -, preferably located in the TRANS-position is obtained with respect to each other.

Preferred compounds of formula I are those compounds in which one, several or all of the structural fragments and groups contained therein, are the preferred values the preferred values, even more preferred meanings and preferred meanings defined above, all combinations of these preferred values, etc. and/or a specific value group, which is the object of the present invention. With respect to all preferred compounds of the formula I, the invention also includes all their stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.

The compound of formula I or its salt can be obtained, for example, by a method which comprises acylation of arylcyclohexylamine formula II carboxylic acid of formula R2-COOH or its derivative, this method is also an object of the present invention.

Suitable derivatives of carboxylic acids of formula R2-COOH ablauts is, for example, carboxylic acid anhydrides, esters, including C1-C4-alkalemia esters such as methyl ester or ethyl ester, optionally substituted akrilovye esters, such as phenyl esters or nitrophenolate esters or activated esters, or anhydrides or mixed anhydrides of the acids. In compounds of formula II and carboxylic acids of the formula R2-COOH and their derivatives group, R1and R2have the meanings indicated above, and the numbernhas the values specified above for compounds of formula I, or even other functional groups can be present in protected form or in the form of a precursor. For example, when you want to obtain the compound of formula I, which contains a carboxylic acid group or amino group, it may be necessary that the reaction of acylation of these groups were in protected form, for example, in the form of ester, such astert-butyl ether or benzyl ether, instead of the free carboxylic acid group, or acylated amino groups, such astert-butoxycarbonylamino or benzyloxycarbonylamino instead of a free amino group; and only after acylation and remove the protection you need for a finite group. Acceptable ways of introducing protective groups that can be used in the synthesis with the of dinani formula I, well-known experts in this field. An example of a group precursor functional group is a nitro-group, which can be converted into the amino group recovery, for example, catalytic hydrogenation after the acylation reaction.

The acylation reaction can be carried out in the usual conditions known to specialists in this field. In many cases the reaction is well carried out in an inert solvent or diluent, for example a hydrocarbon or chlorinated hydrocarbon, such as toluene, 1,2-dichloroethane or methylene chloride, simple ether, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, in alcohol, such as methanol, ethanol or isopropanol, amide, such as N,N-dimethylformamide or N-methylpyrrolidone, acetonitrile, water or a mixture of two or more solvents or diluents. Depending on the specific case, it may be advantageous to conduct the reaction in the presence of a base, for example, inorganic bases such as sodium hydroxide, sodium carbonate or sodium bicarbonate, or organic bases such as triethylamine, ethyldiethanolamine, N-ethylmorpholine or pyridine, and/or in the presence of an acylation catalyst such as 4-dimethylaminopyridine.

If for acylation of compounds of formula II, you must use a carboxylic acid of formula R2-COOH, the ACCS is advantageous to activate the acid or its salt condensing agent, or the agent of combination reaction, for example, an agent, such as those commonly used in the chemistry of peptides for the formation of amide bonds. Examples of suitable agents are carbodiimides, such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, TOTU, i.e. tetrafluoroborate O-((cyano(etoxycarbonyl)methylene)amino)-N,N,N',N'-tetramethylurea, HATU, i.e. hexaphosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium, the esters of Harborview acid, such ethylchloride or isobutylphthalate, tailhold, anhydride propylphosphonic acid or carbonyldiimidazole. Depending on the specific case, a suitable reaction temperature can vary in a wide interval. For example, when the acylation reaction using a carboxylic acid in the presence of the agent for the reaction of a combination or acid chloride of the carboxylic acid, the reaction is often carried out at room temperature.

After acylation, in addition to the above reactions remove protection from protected groups or transformation group of the precursor into the desired target group, it is possible to implement an optional reaction functionalization or modification of the compounds obtained, and appropriate functional groups can, for example, atrificial, lidirovat, peresterilizovali,to hydrolyze, alkilirovanii, sulfonylureas, to restore, to oxidize, turn in solely to type in other response.

Starting compound to produce compounds of formula I are commercially available or can be obtained according to the methods described in the literature (or equivalent), for example, as described in [Aggarwal et al., Organic Letters 3 (2001) 2785; Wiehl et al., Chem. Ber. 119 (1986) 2668; Brown et al., Tetrahedron 43 (1987) 4071; US 6008240; or (Coutts et al., Cell. Mol. Neurobiol. 7 (1987) 271)].

All reactions for the synthesis of compounds of formula I, as such, are well known to the specialist and they can be carried out in the standard conditions according to the methods described in the literature (or equivalent), for example, in Houben-Weyl, Methods der Organischen Chemie (Methods of Organic Chemistry), Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley & Sons, New York. As indicated above, in order to avoid side reactions during the synthesis of compounds of formula I, at any stage, depending on the circumstances of a particular case, it may be necessary or advantageous to temporarily block functional groups by introducing protective groups and at a later stage of the synthesis to unprotect or to introduce functional groups into groups that preceded it, which turn into the target functional group at a later stage of the reaction. Such approaches to the synthesis, the protective group precursor, which is applicable in a particular case, well-known experts in this field. If required, the compounds of formula I can be cleaned by conventional methods of purification, for example, by recrystallization Il is chromatography.

The compounds of formula I are useful pharmaceutically active compounds that polysoude regulate the expression of endothelial NO-synthase and can be used as medicines for the treatment of various diseases. In the context of this invention, the treatment is understood as the actual treatment of disease, including the relief and cure, and prevention and prevention of disease, for example, preventing asthma symptoms or prevention of myocardial infarction and prevention of recurrent myocardial infarction in appropriate patients. Disease or symptoms of the disease may be acute or chronic.

Diseases that can be treated with compounds of formula I include, for example, cardiovascular diseases such as stable and unstable angina, coronary heart disease, Prinzmetal's angina(spasm), acute coronary syndrome, heart failure, myocardial infarction, stroke, thrombosis, occlusion of peripheral arteries (PAOD), endothelial dysfunction, atherosclerosis, restenosis, damage to the endothelium after PTCA, hypertension, including primary arterial hypertension, pulmonary arterial hypertension and secondary hypertension (renovascular hypertension, chronic glomerulonephritis), erectile dysfun the function and ventricular fibrillation. In addition, the compounds of formula I reduce the risk of cardiovascular disease in women in postmenopausal women and in women taking contraceptives. The compounds of formula I can also be used for treatment (i.e. treatment and prevention) diabetes and diabetic complications (nephropathy, retinopathy, angiogenesis, asthma, chronic renal failure, cirrhosis of the liver, osteoporosis, restricted ability to remember or limited ability to learn. The preferred readings are stable angina, coronary artery disease, hypertension, endothelial dysfunction, atherosclerosis and diabetic complications.

The compounds of formula I can be used in combination with other pharmaceutically active compounds, preferably compounds which can enhance the effect of the compounds of formula I. Examples of such other compounds include statins, ACE inhibitors, AT1 antagonists, inhibitors arginines, inhibitors of PDE V, calcium antagonists, alpha-blockers, beta-blockers, tiamazol (methimazole) and similar compounds, arginine, tetrahydrobiopterin, vitamins, in particular vitamin C and vitamin B6, Niacin.

The compounds of formula I and their pharmaceutically acceptable salts, optionally in combination with other pharmaceutically active compounds can enter the animal, preferably a mammal, and specifically human, as pharmaceuticals, as such, in mixtures with one another or in the form of pharmaceutical preparations. Additional objects of this invention are therefore compounds of the formula I and their pharmaceutically acceptable salts for use as pharmaceuticals, their use as promoters of transcription or boost regulators of endothelial NO-stasy, for example, in the States, when you want increased expression of the indicated enzyme or elevated levels of NO, or normalization of a reduced level of NO in a patient, and particularly their use in the treatment, therapy and prophylaxis of the abovementioned syndromes, as well as their application to obtain drugs for these purposes. In addition, an object of the present invention are also pharmaceutical preparations (or pharmaceutical compositions)which contain an effective dose of at least one of the compounds of formula I and/or pharmaceutically acceptable salts, and pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable substances-carriers or fillers and/or additives, or excipients.

The object of the present invention are those compounds of formula I, which are in themselves known and are excluded from from the dynany formula I, defined above, which are claimed as compounds themselves, and their pharmaceutically acceptable salts for use as promoters of transcription or boost regulators of endothelial NO-synthase, for use as pharmaceuticals for use in the treatment of the above diseases; pharmaceutical preparations which contain an effective dose of at least one of these excluded compounds and/or their pharmaceutically acceptable salts, and pharmaceutically acceptable carrier. All statements set forth above and hereinafter, referring, for example, to compounds of formula I for use as pharmaceuticals, specifically relate to the specified excluded compounds. Thus, for example, an object of the present invention are acylated arylcyclohexylamine formula I

in all their stereoisomeric forms and mixtures thereof in any ratio, and their pharmaceutically acceptable salts, where in the formula I:

R1represents aryl or heteroaryl, each of which is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of C1-C6-alkyl, halogen, CF3C1-C6-alkoxy, C1-C6-etkileri is that -CN, COOR10, CONR11R12, NR13R14, S(O)mR15and S(O)2NR16R17;

R2represents aryl or heteroaryl, each of which is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of halogen; -CN; NH2; unsubstituted and at least monosubstituted C1-C10-alkyl, C2-C10-alkenyl, C2-C10the quinil, C1-C10-alkoxy, C1-C10-alkylamino and di(C1-C10-alkyl)amino, the substituents of which are selected from the group consisting of F, OH, Cl-C8-alkoxy, aryloxy, C1-C8-allylmercaptan, NH2C1-C8-alkylamino and di(C1-C8-alkyl)amino; C3-C5-Alcantara; phenyl; heteroaryl; or aryl-substituted heteroaromatic1-C4-alkyl; CF3; NO2; OH; phenoxy; benzyloxy; (C1-C10-alkyl)-COO -; - S(O)mR20; SH; phenylamino; benzylamino; (Cl-Cl0-alkyl)-CONH-; (C1-C10-alkyl)-CO-N(C1-C4-alkyl)-; phenyl-CONH-; phenyl-CO-N(C1-C4-alkyl)-; heteroaryl-CONH-; heteroaryl-CO-N(C1-C4-alkyl)-; (C1-C10-alkyl)-CO-; phenyl-CO-; heteroaryl-CO-; CF3-CO-; -OCH2O-; -OCF2O-; -OCH2CH2O-; -CH2CH2O-; COOR21; CONR 22R23; C(NH)-NH2; SO2NR24R25; R26SO2NH-; R27SO2N(C1-C6-alkyl)-; and the balance of saturated and at least monounsaturated aliphatic monocyclic 5-7-membered heterocycle containing 1, 2 or 3 heteroatoms selected from the group consisting of N,O and S, and the heterocycle may be substituted by one or more substituents selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy, OH, oxo and CF3where the heterocycle may optionally be condensed with the above aryl group or heteroaryl group representing R2; where all aryl, heteroaryl, phenyl, arylesterase, heterotrissocladius and phenylaziridine groups that are in the specified optional substituents mentioned aryl group or heteroaryl group representing R2may be substituted by one or more substituents selected from the group consisting of halogen, -CN, C1-C3-alkyl, OH, C1-C3-alkoxy and CF3;

R10represents H, C1-C6-alkyl or benzyl, where the phenyl group may be substituted by one or more identical or different substituents from the group consisting of halogen, -CN, C1-C 3-alkyl, C1-C3-alkoxy and CF3;

R11selected from the group consisting of H, C1-C6-alkyl which can be substituted by phenyl; phenyl, indanyl and heteroaryl, where each aromatic group is unsubstituted or contains one or more identical or different substituents from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3;

R12represents H or C1-C6-alkyl;

R13selected from the group consisting ofH, C1-C6-alkyl, and unsubstituted and substituted phenyl, benzyl, heteroaryl, phenyl-CO -, and heteroaryl-CO-, the substituents of which are selected from the group consisting of halogen free,-CN, C1-C3-alkyl, C1-C3-alkoxy and CF3which can be represented by one or more of these substituents;

R14represents H or C1-C6-alkyl;

R15selected from the group consisting of C1-C6-alkyl, CF3and substituted and unsubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3which can be represented by one or more of these substituents;

R16regardless of R11is defined as R11;

R 17regardless of R12is defined as R12;

R20selected from the group consisting of C1-C10-alkyl which may be substituted by one or more substituents selected from the group consisting of F, OH, C1-C8-alkoxy, aryloxy, C1-C8-allylmercaptan, C1-C8-alkylamino and di(C1-C8-alkyl)amino; CF3; and substituted or unsubstituted phenyl and heteroaryl, the substituents of which are selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3which can be represented by one or more data deputies;

R21selected from the group consisting of H, C1-C10-alkyl which may be substituted by one or more substituents selected from the group consisting of F, C1-C8-alkoxy and di(C1-C8-alkyl)amino; aryl-(C1-C4-alkyl)- and heteroaryl-(C1-C4-alkyl)-, both of which can be substituted by one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-alkoxy and di(C1-C6-alkyl)amino;

R22selected from the group consisting of H, C1-C10-alkyl which may be substituted by one or more substituents selected from the group consisting of F, C1 8-alkoxy, di(C1-C8-alkyl)amino and phenyl; phenyl, indanyl and heteroaryl, in which each of the aromatic groups can be unsubstituted or contain one or more substituents selected from the group consisting of halogen, -CN, C1-C3-alkyl, C1-C3-alkoxy and CF3;

R23represents H or C1-C10-alkyl;

R24regardless of R22is defined as R22;

R25,regardless of R23is defined as R23;

R26regardless of R20is defined as R20;

R27,regardless of R20is defined as R20;

heteroaryl represents the balance of 5-10-membered aromatic, monocyclic or bicyclic heterocycle containing one or more heteroatoms selected from the group consisting of N,O and S;

aryl represents phenyl, naphthas-1-yl or naphthas-2-yl;

m represents 0, 1 or 2;

n represents 1, 2, 3 or 4;

for use as pharmaceuticals.

With regard to compounds of formula I for use as pharmaceutical agents, apply to them all the explanations given above directly to compounds of formula I as such. Thus, another object of the present invention are also the compounds of formula I is La use as pharmaceutical agents, in which one or more groups, one or more numbers, including all groups and the number in the definition of compounds are preferred values the preferred values, even more preferred values or preferred values.

The pharmaceutical agents according to this invention can be administered orally, for example in the form of pills, tablets, coated tablets, tablets, sugar coated, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, such as suppositories. The introduction can also be parenterally, for example subcutaneously, intramuscularly or intravenously, in the form of solutions for injection or infusion. Other suitable forms of introduction are, for example, the introduction through the skin or externally (topically), for example, in the form of ointments, tinctures, spray, transdermal therapeutic systems or the introduction of inhalation in the form of nasal sprays or aerosol mixtures or, for example, in the form of microcapsules, implants or rods. The preferred form of the introduction depends, among other factors, on the condition being treated and the severity of the disease.

The amount of the compounds of formula I and/or pharmaceutically acceptable salts in pharmaceutical preparations the Ah is usually from about 0.2 to about 800 mg, preferably from about 0.5 to about 500 mg, particularly from about 1 to about 200 mg per dose, but depending on the type of pharmaceutical drug quantity can also be more. The pharmaceutical preparations generally contain from about 0.5 to about 90% (mass) of the compounds of the formula I and/or their pharmaceutically acceptable salts. Manufacture of pharmaceutical preparations may be carried out by way of essentially known. For this purpose, one or more compounds of the formula I and/or their pharmaceutically acceptable salts together with one or more solid or liquid pharmaceutical carriers and/or additives (or auxiliary substances) and, if required, in combination with other pharmaceutically active compounds having therapeutic or prophylactic action, get an acceptable form for administration, which can then be used as a pharmaceutical product for human or veterinary use.

For the production of pills, tablets, tablets, sugar coated and hard gelatin capsules can be used, for example, lactose, starch, for example, maize starch or starch derivatives, talc, stearic acid or its salts, etc. Soft gelatin capsules and suppositories can contain, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable substances-carriers or solvents to obtain solutions, such as solutions for injection, or of emulsions or syrups are, for example, water, physiological solution of sodium chloride, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. May also be lyophilizate the compounds of formula I and their pharmaceutically acceptable salts and use the resulting lyophilizate, for example, to obtain preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

In addition to the compound or compounds according to this invention and substances, carriers of the pharmaceutical preparations can also contain additives, such as fillers, disintegrant, binders, lubricants, moisturizers, stabilizers, emulsifiers, dispersing agents, preservatives, sweeteners, substances that give color and flavor, flavorings, thickeners, diluents, buffer substances, solvents, soljubilizatory, the agents to achieve a depot, salts to change the osmotic pressure of the substance to cover or antioxidants.

The dosage for administration of the compounds of formula I and/or pharmaceutically acceptable salts depends on who the best and for optimum effect dose should as usual, to adapt to specific conditions. Therefore, the dose depends on the nature and severity of the disease, which is subject to treatment, as well as gender, age, weight and individual response of the person or animal being treated, the effectiveness and duration of action of the compounds used, the use of the compound for the treatment of acute or chronic diseases or for prevention, enter any other active compounds, in addition to compounds of the formula I. in General, the daily dose is from about 0.01 to about 100 mg/kg, preferably from about 0.1 to about 10 mg/kg, specifically from about 0.3 to about 5 mg/kg (in each case mg per kg of body weight), suitable for the introduction of an adult weighing about 75 kg to obtain the expected results. The daily dose can be administered once or, especially with the introduction of larger quantities, it can be divided into several parts, for example two, three or four separate doses. In some cases, depending on the individual reactions of the specified daily dose may be necessary to increase or decrease the specified daily dose.

The compounds of formula I can also be used for purposes other than the purposes mentioned above. Non-limiting examples include diagnostic purposes, such as applying for the examination of samples of cells and tissue is th, use as biochemical tools and use as intermediates for additional compounds, such as pharmaceutically active compounds.

Examples

A General method of acylation of arylcyclohexylamines

TOTU (304 mg, 0,928 mmol, 1.05 equivalents) and 323 μl of ethyldiethanolamine (sm 1,857 mmol, 2.1 equivalents) was added to 0,973 mmol (1.0 equivalent) of the corresponding carboxylic acid in 2 ml of absolute dimethylformamide at 0°C and the mixture stirred for 20 min at 0°C. Then add 0,884 mmol (1.0 equivalent) of the corresponding hydrochloride arylcyclohexylamine dissolved in 2 ml of absolute dimethylformamide, and the mixture is stirred for 30 min at 0°C and for 24 h at room temperature. The reaction mixture is filtered, the layer on the filter is washed with 20 ml of ethyl acetate and the resulting solution was washed with 20 ml of 5% aqueous sodium hydrogen carbonate solution and 20 ml of 5% aqueous solution of sodium chloride. The organic phase is dried over Chromabond XTR and evaporated. The resulting crude product was then purified preparative HPLC (RP-18, acetonitrile/water + 0.1% of triperoxonane acid).

With the aforementioned method of racemic TRANS-2-phenylcyclopropane and the corresponding carboxylic acid of formula R2-COOH get N-(TRANS-2-vinylcyclopropyl)carboxamide formula Ic, perejil is installed in the table 1.

In table 1, shows, in addition to the remainder R2the mass number of the peak (M+H)+in the mass spectra (MC), recorded for the obtained compounds, and the retention time (RT HPLC (in minutes).

Method HPLC

Column: YMC J SphereODSH80, 33 x 2 mm, 4 μm; temperature 30°C; flow rate of 1000 ml/min; eluent A: acetonitrile + 0.05% of HCOOH; eluent B: water + 0.05% of HCOOH; gradient: time 0,00 min: 10% eluent A + 90% eluent B, time 2,50 min: 95% eluent A + 5% eluent B, time 3,30 min: 95% eluent A + 5% eluent B, the time at 3.35 min: 10% eluent A + 90% eluent B.

Method HPLC B

Column: Merck Purospher Star, 55 x 2 mm, 3 μm; room temperature; flow rate of 0.45 ml/min; eluent A: acetonitrile + 0.1% of HCOOH; eluent B: water + 0.1% of HCOOH; gradient: time 0,00 min: 5% eluent A + 95% eluent B, the time of 5.00 min: 95% eluent A + 5% eluent B, time 7,00 min: 95% eluent A + 5% eluent B, time 8,00 min: 5 % eluent A + 95 % eluent B.

Method HPLC C

Column: YMC J SphereODS H80,33 × 2 mm, 3 μm; room temperature; flow rate 1000 ml/min; eluent A: acetonitrile; eluent B: water + 0.05% of triperoxonane acid; gradient: time 0,00 min: 10% eluent A + 90% eluent B, time 2,50 min: 95% eluent A + 5% eluent B, time 3,30 min: 95% eluent A + 5% eluent B.

td align="center"> And
Table 1
Examples of compounds of formula Ic
When Mer

No.
Rsup> 2MS (M+N)+HPLC RT (min)Method HPLC
12,4-dimethyloxazole-5-yl2571,999And
23-amino-5-methylpyrazine-2-yl (a)2674,55In
32-cyclopropyl-4-methylthiazole-5-yl2994,51In
42,6-dimethylpyridin-3-yl2661,119In
53-amino-5,6-dimethylpyrazine-2-yl (a)2834,73In
66-methylaminomethyl-2-yl2692,057And
73 methylsulfonylamino-4-were3454,18In
83-methylsulfonylmethane3312,057And
96-(morpholine-4-yl)pyridine-3-yl3231,902And
105,6,7,8-tetrahydroquinolin-3-yl (a)2933,30In
116-methoxypyridine-3-yl (a)2694,22In
12/td> 2-methylthiazole-5-yl259as 4.02In
133-(pyrrolidin-1-yl)phenyl (a)3075,04In
143-(piperidine-1-yl)phenyl (a)3213,63In
153-(4-methylpiperazin-1-yl)phenyl3361,437And
163-morpholine-4-yl)phenyl (a)3234,36In
172,5-dimethyl-1-(thiophene-2-ylmethyl)-1H-pyrrol-3-yl3515,04In
182-methyl-3H-benzimidazole-5-yl2921,300And
193-chloro-4-isopropylacetanilide-2-yl3842,396And
205-methyl-1-phenyl-1H-pyrazole-4-yl318at 2,324And
211-phenyl-5-trifluoromethyl-1H-pyrazole-4-yl3722,508And
222,5-dimethyl-1-(pyridine-4-ylmethyl)-1H-pyrrol-3-yl3462,679And
232,4-dimethylthiazol-5-yl2732,050
242-aminopyridine-3-yl2541,137And
256-methylpyridin-3-yl2531,611And
262-chloro-6-methylpyridin-3-yl2872,084And
276-methoxypyridine-3-yl (a)2833,80In
283-aminopyrazine-2-yl2552,168And
291H-indol-6-yl277of 4.44In
301H-indol-5-yl2774,35In
311H-indol-4-yl2774,35In
323-dimethylaminophenyl2812,149And
332-amino-4,6-dimethylpyridin-3-yl2822,84In
342,3-dichlorophenyl3064,88In
352,4-dimetilfenil2664,84In
362,4-differenl2742,73 In
375-methylthiophene-2-yl258to 4.68In
385-chlorothiophene-2-yl2784,95In
394-forfinal2562,32

(a) Connection receive in the form of a salt with triperoxonane acid.

Example 40

4-Fluoro-N-(TRANS-2-vinylcyclopropyl)benzamide (Enantiomer 1)

Racemic 4-Fluoro-N-(TRANS-2-vinylcyclopropyl)benzamid (the compound of example 39) is separated into the enantiomers preparative HPLC on chiral phase (Chiralpak AD; eluent: acetonitrile/isopropanol (120/5) + 0.1% diethylamine).

MS: m/e=256(M+H)+. HPLC: RT=4,07 min (column Daicel Chiralpak AD, 250 × 4.6 mm, 10 micron; eluent: acetonitrile/isopropanol (120/5) + 0.1% diethylamine; the flow rate of 1,000 ml/min).

Example 41

4-Fluoro-N-(TRANS2-vinylcyclopropyl)benzamide (Enantiomer 2).

Specified in the header of the get connection, as described in example 40, the separation of racemic 4-fluoro-N-(TRANS-2-vinylcyclopropyl)benzamide.

MS: m/e = 256 (M+H)+. HPLC: RT = 4,47 min (column Daicel Chiralpak AD, 250 x 4.6 mm, 10 μm; eluent: acetonitrile/isopropanol (120/5) + 0.1% diethylamine; the flow rate of 1,000 ml/min).

Determination of the activation of transcription of eNOS

Activation of transcription of eNOS determine, as described in detail in Liet al. "Activation of protein kinase C alpha and/or epsilon enhances reduced of the human endothelial nitric oxide synthase gene", Mol. Pharmacol. 53 (1998) 630.

In a few words, a fragment of the 5' (length of 3.5 KBP) of the start codon of eNOS gene clone, is sequenced and clone into expression plasmids luciferase of Firefly to control the activation of the eNOS promoter activity of the reporter gene. For testing connections using the line of human vascular endothelial cells, stably transperineal and expressing this construction of the promoter-reporter. Cells are incubated with compounds for 18 hours

All compounds are dissolved in sterile dimethyl sulfoxide (DMSO). In a full environment Pets final concentration of 0.5% DMSO. In these cells measure the induction of the expression of the reporter gene using standard analysis system luciferase (Promega, Cat. No E150) according to the manufacturer's instructions.

The induction of luciferase in cells incubated in the investigated compounds, compared with cells incubated only with the solvent. The attitude of both activities (transcription/induction, TIR) is depicted as a function of concentration of the compound. Usually the values of TIR at low concentrations starting from 1, indicating the absence of the action of compounds and increases to maximum values TIR, TIR(max), which indicates an increase in transcription of eNOS. The values of EC50relations induction of the transcription as a function of the concentration of the emission of compounds determined graphically.

The effects of compounds on transcription of eNOS confirmed by a second analysis based on the detection of eNOS protein. Primary endothelial cells from umbilical vein human (HUVEC) isolated and cultured by standard methods. Confluent cells incubated with compounds for 18 h and the effect of compounds on the expression of eNOS protein determined quantitatively by the method of "Western blotting". After incubation with the compounds HUVEC are lysed in ice-cold lisinop buffer containing 10 mmol Tris-HCl (pH 8.0), 1% SDS and protease inhibitors. The lysate is subjected to a standard denaturing electrophoresis in polyacrylamide gel and perform blotting on nitrocellulose membranes. Using specific primary monoclonal antibodies (Transduction Laboratories, UK) and alkaline phosphatase labeled secondary antibodies (Jackson Labs), visualize the characteristic band of eNOS protein and determined quantitatively based on the detection of chemiluminescence.

The results are shown in table 2.

Table 2
Relations eNOS transcription for induction
Compound of example No.EC50(µm)
118
2to 0.060
30,30
40,33
50,16
60,32
71,8
82,0
93,5
105,1
110,78
1210
131,3
1411
1559
1632
17<0,01
180,33
190,45
200,11
210,24
2224
230,60
240,95
251,1
260,29
274,3
280,43
290,10
300,10
310,47
321,8
3312
341,2
350,062
360,31
370,26
380,23
39 0,19
401,5
410,18

The effect of the compounds of this invention can also be examined on the following animal models (experiments on animals carried out in accordance with the German law on animal protection and regulations on the use of experimental animals, as described in the instructions for the care and use of laboratory animals of the National institutes of health, USA).

Animals and treatment (Experiments A-C)

Using ApoE-deficient and eNOS-deficient mice (C57BL/6J phenotype, Jackson Laboratory, Bar Harbor, Me). The age of all animals is 10-12 weeks, and weight - 22-28, three days prior to surgery, mice are divided into 4 groups (control ApoE, n=10-12; ApoE with the tested compounds, n=10-12; control samples, n=10-12; eNOS with the tested compounds, n=10-12), the animals receive either a standard rodent diet containing 4% fat and 0.001% of cholesterol, then such animals are referred to as the placebo group), or a standard rodent diet plus the test compound (10 or 30 mg/kg/day orally (p.o.)).

A. Antihypertensive effects in mice with a knockout in APOE"

Blood pressure in mice, in consciousness, is determined using the computerized system of "tail-cuff" (Visitech Systems, Apex, Nc). After processing the test compounds ApoE-deficient and eNOS-deficient m is our blood pressure compared with the results obtained in the treatment with placebo.

B. Inhibition of education neointima and atherogenesis (cuff femoral artery)

After 3 days of treatment ApoE-deficient mice the corresponding compound (10 mg/kg/day, put in food animals analiziruyut intraperitoneal injection of phenobarbital (60 mg/kg), then intramuscularly administered xylazine (2 mg/kg) and impose the cuff around the femoral artery, as described in [Moroi et al. (J. Clin.Invest. 101 (1998) 1225)]. In short: open the left femoral artery, placed around the artery leaking polyethylene cuff (2 mm), made of tube PE-50 (inner diameter of 0.56 mm, outer diameter 0,965 mm, Becton Dickinson, Mountain View, Ca) and attach to post with two 7-0 suture threads. The right femoral artery isolated from the surrounding tissue, but the cuff does not impose. Processing corresponding connection continued for 14 days after the operation. Then kill animals. The aorta is used to determine the expressions of eNOS vessels quantitative method "Western blotting". Both femoral arteries removed, fixed in formalin and placed in paraffin. Cut 20 transverse sections (10 μm) of the left femoral artery with a cuff and from the corresponding segment of the right femoral artery. The slices are then paint as usual with hematoxylin and eosin. Morphometric analyses carried out with POM is using the computer program image analysis. (LeicaQWin, Leica Imaging Systems, Cambridge, GB). For each slice to determine the area ofclearance, neointima and media (middle layer). To this end neointima defined as the areabetween the lumen and the internal elastic membrane, media is defined as the areabetween the internal and external elastic membrane. The ratio of the area neointima and square media is denoted as neointima/media ratio. The results obtained in the group of mice that were treated with the test compound compared with the results obtained in the placebo group.

C. preventing the formation of atherosclerotic plaques after prolonged treatment

ApoE-deficient mice treated for 16 weeks corresponding compound introduced with food, and ultimately kill mice. From each mouse remove aorta, fixed them in formalin and conclude in paraffin. Plaque formation is assessed according to thethe formation of lipid damage in aorta (from aortic arch to the diaphragm) and analyzed by staining with oil red O. For the quantitative determination of the respective compounds on the expression of eNOS in blood vessels in this experiment, use the femoral artery. The results obtained in the group of mice that were injected compounds are compared with the results in the placebo group.

D. Improving coronary function in sick the ApoE-deficient mice

In experiments using older mice-maleswild-type C57BL/6J (Charles River Wiga GmbH, Sulzfeld)and ApoE-deficient mice (C57BL/6J phenotype, Jackson Laboratory, Bar Harbor, Me) 6-monthage and weight 28-36,Mice are divided into 3 groups (C57BL/6, n=8; control group ApoE-deficient mice, n=8; group of ApoE-deficient mice,which enter the appropriate connection, n=8),within 8 weeks the animals receive or normal rodent diet (containing 4% fat and 0.001% cholesterol), or a standard rodent diet plus the test compound (30 mg/kg/day orally). Anaesthetize mice by pentobarbitone sodium (100 mg/kg intraperitoneally), hearts rapidly excised and placed in ice-cold buffer perfusion. The aorta kanyoro and combined with the apparatus for perfusion (Hugo Sachs Electronics, Freiburg, Germany), which immediately runs at a constant perfusion pressure of 60 mm Hg Heart perfusion a retrograde fashion, modified bicarbonate buffered Krebs, balanced 95% O2and 5% CO2and maintained at a temperature of 37.5°C.

A small tube with a beveled edge (PE 50) pass through the pulmonary vein into the left ventricle and push through the wall of the ventricle, is fixed at the top globcover end and attached to the tip of micromanometer (Millar 1.4 French). The left atrium kanyoro through the same pulmonary vein and is the heart switches to the operating mode with constant pressure preload 10 mm Hg and pressure posterski 60 mm HgThe outflow from the aorta and flow in the atrium continuously measured using an ultrasonic probe (HSE/Transonic Systems Inc.). Coronary flow is calculated as the difference between the flow in the ventricle and outflow from the aorta. All hemodynamic data is obtained in digital form from the speed selection of 1000 Hz and recorded on a PC using special software (HEM, Notocord).

Hearts allow to stabilize for 30 minutes each functional hemodynamic data measured during steady state and during exercise pressure and volume load. Curves for the function of the left ventricle build, varying the pressure preload. To get the curves preload postnagruzku set to 60 mm Hg and adjust the preload in steps of 5 mm Hg in the range of from 5 to 25 mm Hg Hearts give the opportunity to stabilize to its initial state between the pressure and volume load.

1. The compound of the formula I

in any of its stereoisomeric forms or mixtures thereof in any ratio, or its pharmaceutically acceptable salt, where in formula I: R1represents aryl, optionally substituted by one or two identical or different substituents selected from the group comprising C1-C6and the keel and halogen;

R2represents aryl or heteroaryl, representing the balance of 5-6-membered aromatic monocyclic heterocycle containing 1-2 nitrogen atom as heteroatoms and/or 1 sulfur atom or oxygen, or the remainder of the 9-10-membered bicyclic aromatic heterocycle containing 1-2 nitrogen atom as heteroatoms, each of which is unsubstituted or contains 1-3 identical or different substituents selected from the group consisting of:

halogen, NH2, unsubstituted With1-C10-alkyl, C1-C10-alkoxy, C1-C10-alkylamino and di(C1-C10-alkyl)amino, and at least monosubstituted C1-C10-alkyl, the substituents of which are selected from the group consisting of HE, C1-C8-alkoxy, phenyl; heteroaryl(C1-C4-alkyl), which is a 5-6-membered ring containing as heteroatoms 1 atom of nitrogen or sulfur; CF3; S(O)mR20; R26SO2NH; R27SO2N(C1-C6-alkyl)-; and a residue of a saturated aliphatic monocyclic 5-6-membered heterocycle containing 1 or 2 heteroatoms selected from the group comprising N and O, and the heterocycle may be substituted by one or more substituents, a represents C1-C3-alkyl,

R20 represents a C1-C10-alkyl,

R26regardless of R20is defined as R20;

R27regardless of R20is defined as R20;

aryl represents phenyl, naphthas-1-yl or naphthas-2-yl;

m represents 2;

n represents 1, 2, 3 or 4;

provided that if R1represents unsubstituted phenyl, R2can not be unsubstituted phenyl, 4-Bromphenol, 3-methoxyphenyl, unsubstituted tanila, naphthyridine, unsubstituted pyridinyl, 2,6-dichloropyridine-4-yl or 3,4,5-trimethoxyphenyl.

2. The compound of formula I according to claim 1 in any of its stereoisomeric forms or mixtures thereof in any ratio, or its pharmaceutically acceptable salt, where in formula I the remainder R1represents unsubstituted phenyl.

3. The compound of formula I according to any one of claims 1 and 2 in any of its stereoisomeric forms or mixtures thereof in any ratio, or its pharmaceutically acceptable salt, where in formula I the number n represents 1.

4. The compound of formula I according to any one of claims 1 to 3, in any of its stereoisomeric forms or mixtures thereof in any ratio, or its pharmaceutically acceptable salt, where in formula I the number n represents 3.

5. The compound of formula I according to any one of claims 1 to 3 in any of its stereoisomeric forms or in VI is e mixtures thereof in any ratio, or its pharmaceutically acceptable salt, where in formula I the remainder R2represents phenyl or heteroaryl, representing the balance of 5-6-membered aromatic monocyclic heterocycle containing 1-2 nitrogen atom as heteroatoms and/or 1 sulfur atom or oxygen, or the remainder of the 9-10-membered bicyclic aromatic heterocycle containing 1-2 nitrogen atom as heteroatoms, each of which is unsubstituted or contains 1-3 identical or different substituents selected from the group comprising F; Cl; Br, C1-C3-alkyl; C1-C3-alkoxymethyl; CF3; phenyl; heteroaromatic-representing a 5-6-membered ring containing as heteroatoms 1 atom of nitrogen or sulfur, With1-C3-alkoxy, C1-C3-alkylsulfonyl; NH2;1-C4-alkylamino; di(C1-C4-alkyl)amino; and (C1-C3-alkyl)-SO2NH-; -SO2NH(C1-C4-alkyl); pyrrolidinyl; piperidinyl and morpholinyl, each of these heterocycles can be substituted by one or more substituents, a represents C1-C3-alkyl.

6. The compound of formula I in any of its stereoisomeric forms or mixtures thereof in any ratio, or its pharmaceutically acceptable salt according to any one of claims 1 to 5, for use as farmacevticheskoj the means to stimulate the expression of endothelial NO synthase.

7. Pharmaceutical composition for stimulating the expression of endothelial NO synthase containing an effective amount of at least one of the compounds of formula I in any of its stereoisomeric forms or mixtures thereof in any ratio, and/or its pharmaceutically acceptable salt according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

8. The use of the compounds of formula I in any of its stereoisomeric forms or mixtures thereof in any ratio, and/or its pharmaceutically acceptable salt according to any one of claims 1 to 5 for the manufacture of drugs to stimulate the expression of endothelial NO-synthase.

9. The use of the compounds of formula I in any of its stereoisomeric forms or mixtures thereof in any ratio, and/or its pharmaceutically acceptable salt according to any one of claims 1 to 5 for the manufacture of a medicine for treatment of cardiovascular disease, stable and unstable angina, coronary artery disease, acute coronary syndrome, heart failure, myocardial infarction, stroke, thrombosis, peripheral arterial occlusive disease, endothelial dysfunction, atherosclerosis, restenosis, damage to the endothelium after RTSA, hypertension, primary arterial hypertension, pulmonary hypertension, secondary arterial hypertension, renovascular hypertension, chronic is wow glomerulonephritis, erectile dysfunction, diabetes, diabetic complications, nephropathy, retinopathy, angiogenesis, asthma, chronic renal failure, osteoporosis, limited ability to remember or limited ability to learn.



 

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11 cl, 29 ex

FIELD: organic chemistry, agriculture, insecticides.

SUBSTANCE: invention relates to a substituted anilide derivative of the formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2; Z represents oxygen atom; Q means a substitute represented by any of the following formulae: Q1-Q3, Q6, Q8-Q12, Q14-Q19, Q21 and Q23 (wherein each among Y1 that can be similar or different represents halogen atom, (C1-C6)-alkyl group, and so on); Y2 represents (C1-C6)-alkyl group or halogen-(C1-C6)-alkyl group; Y3 represents (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl group or substituted phenyl group; p represents a whole number from 1 to 2; q represents a whole number from 0 or 2; r represents a whole number from 0 to 2. Also, invention proposes a chemical for control of pests of agricultural and fruit crops. The chemical comprises substituted anilide derivative of the formula (I) as an active component and represents insecticide, fungicide or acaricide. Also, invention proposes a method for addition of the chemical for control of pests of agricultural and fruits crops. Also, invention proposes aniline derivative represented by the general formula (II): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2. Invention provides the development of anilide derivative as insecticide, fungicide and acaricide against pests of agricultural and fruit crops.

EFFECT: valuable properties of compound.

5 cl, 6 tbl, 27 ex

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

where it is:

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

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

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

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

The invention relates to compounds of formula (I)

in which f represents phenylenebis radical, a represents the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; R11represents a hydrogen atom, an unbranched or branched alkyl radical having from 1 to 6 carbon atoms, or the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; b is a thiophene; W is absent or represents an Association or S; X represents a bond or a radical -(CH2)k-NR16-, -O-, -CO-, -NR16-CO-, and so forth, and k is 0 or 1; Y represents a bond or a radical selected from the radicals -(CH2)m-, -(CH2)m-O-(CH2)n, -(CH-Q-(CH2)n; and Q represents pieperazinove radical, m and n are equal to integers from 0 to 6; R16, R17, R18represent independently a hydrogen atom, or a salt of the compounds

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.

EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.

19 cl, 2 tbl, 2 dwg, 130 ex

FIELD: organic chemistry, medicine, biology.

SUBSTANCE: invention relates to novel derivatives of thiazole that are strong antagonists, agonists or partial agonists of cannabinoid CB1 receptors. Compounds show the general formula (I): wherein R and R1-R4 have values given in the invention claim. Also, invention relates to using compounds of the formula (I) or their stereoisomers for preparing a pharmaceutical composition. Also, invention relates to intermediate compounds of the formula (V): wherein R2 and R8 have values given in the invention claim.

EFFECT: valuable medicinal and biological properties of compounds.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.

EFFECT: valuable medicinal properties of compounds.

53 cl, 78 tbl, 17 ex

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

SUBSTANCE: invention relates to derivatives of aminodicarboxylic acids of the general formula (I) and a medicinal agent able to stimulate activity of soluble guanylate cyclase being independently of the presence of the heme group comprising in it and able to cause relaxation of vessels and comprising at least one compound of the general formula (I). Agent is designated for treatment of cardiovascular diseases and for treatment of the central nervous system diseases characterizing by disorder of the system NO/cGMP, and shows high bioavailability and effectiveness.

EFFECT: improved and valuable medicinal properties of agent.

7 cl, 232 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new derivatives of 2-arylimino-2,3-dihydrothiazoles of the general formula (I): wherein radical values R1, R2, R3 and R4 are given in the claim invention. New compounds are useful in treatment of pathological states or diseases wherein one or some somatostatin receptors are implicated, for example, acromegaly, hypophysis adenomas or gastroenteropancreatic endocrine tumors with carcinoid syndrome and gastroenteric bleedings.

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

14 cl, 2825 ex

FIELD: organic chemistry, agriculture, insecticides.

SUBSTANCE: invention relates to a substituted anilide derivative of the formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2; Z represents oxygen atom; Q means a substitute represented by any of the following formulae: Q1-Q3, Q6, Q8-Q12, Q14-Q19, Q21 and Q23 (wherein each among Y1 that can be similar or different represents halogen atom, (C1-C6)-alkyl group, and so on); Y2 represents (C1-C6)-alkyl group or halogen-(C1-C6)-alkyl group; Y3 represents (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl group or substituted phenyl group; p represents a whole number from 1 to 2; q represents a whole number from 0 or 2; r represents a whole number from 0 to 2. Also, invention proposes a chemical for control of pests of agricultural and fruit crops. The chemical comprises substituted anilide derivative of the formula (I) as an active component and represents insecticide, fungicide or acaricide. Also, invention proposes a method for addition of the chemical for control of pests of agricultural and fruits crops. Also, invention proposes aniline derivative represented by the general formula (II): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2. Invention provides the development of anilide derivative as insecticide, fungicide and acaricide against pests of agricultural and fruit crops.

EFFECT: valuable properties of compound.

5 cl, 6 tbl, 27 ex

The invention relates to carbamoyloximes General formula I

< / BR>
where R1selected from the group comprising alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl; R2represents alkyl, and R1and R2together with the nitrogen atom associated with R2and SO2the group associated with R1may form a heterocyclic or substituted heterocyclic group; R3represents hydrogen, and when R2does not form a heterocyclic group with R1then R2and R3together with the nitrogen atom associated with R2and the carbon atom bound to R3may form a heterocyclic or substituted heterocyclic group; R5represents -(CH2)x-Ar-R5'where R5'selected from the group comprising-O-Z-NR8R8'and-O-Z-R12where R8and R8'independently selected from the group comprising hydrogen, alkyl, substituted alkyl, heterocyclyl, and where R8and R8'combined with the formation of the heterocycle or substituted heterocycle, R12selected from the group comprising heterocycle substituted heteroaryl, x is an integer from 1 to 4; Q represents-C(X)NR7- where R7represents hydrogen, and X represents oxygen; and its pharmaceutically acceptable salts; the compounds of formula IA, where instead of the hydroxyl group on the C-end - radical R6that represents alkoxy, substituted alkoxy, cycloalkane, or-NH-substituted; two pharmaceutical compositions, having the ability to block or inhibit cell adhesion, containing as active ingredient a compound I or compound IA; method binding VLA-4 in a biological sample, and the method of treating inflammatory conditions in a patient is a mammal

The invention relates to new compounds having formula I or formula II:

< / BR>
< / BR>
where R1represents H, lower alkylthio or R1together with R2form a-CH2-; each of R2and R3independently represents H or lower alkyl; R4represents Oh or H2; R5is H, unsubstituted lower alkyl, cyclohexyl - lower alkyl; each of R6and R7independently represents hydrogen, phenyl, naphthyl, -C(O)-NHCHR13CO2R14or substituted phenyl, where the Deputy represents halogen, lower alkyl, lower alkoxy, hydroxy, or phenyl - lower alkoxy; R8represents H or lower alkyl; R9represents H or lower alkyl; R12is NR9or S; R13is lower alkylthio; R14represents H or lower alkyl; or their pharmaceutically acceptable salts, with the exception of 4,5-bis(4-methoxyphenyl)-2-(4-thiazolidinediones)thiazole and its hydrochloride

The invention relates to a new polymorphic forms of 2-(3-cyan-4-isobutylphenyl)-4-methyl-5-thiazolecarboxamide acid

The invention relates to new compounds for combating pests, in particular derivatives carbanilide and fungicide-insecticidal tool based on them

FIELD: medicine, pharmacy.

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

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

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