β-lactamyl-substituted analogues of phenylalanine, cysteine and serine as vasopressin antagonists

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula , where A, Q, R1, R2, R3, R4, R5' are represented in i.1 of the formula, as well as to its hydrates, solvates and pharmaceutically acceptable salts, Also described are application of said compound and pharmaceutical composition, including such compound, for treatment of disease condition in mammals, which is sensitive to action of antagonists of vasopressin V1a, V1b or V2 receptors.

EFFECT: increase efficiency of compound application.

20 cl, 13 ex, 1 dwg

 

CROSS REFERENCES TO RELATED APPLICATIONS

For this application according to § 119(e) 35 U.S.C. claiming the priority of provisional patent application U.S. serial No. 60/700 673, filed on July 19, 2005, the contents of which in its entirety is incorporated into the present application by reference.

The technical FIELD

The present invention relates to 2-(azetidin-2-on-1-yl)-substituted alkanoyl acids, which are analogues of amino acids. In particular, the invention relates to such alkanoyl acids, which are analogues of phenylalanine, cysteine, homocysteine and homoserine, and their analogues and derivatives. In addition, the present invention relates to methods for treating mammals in need of getting rid of painful conditions associated with antagonism of receptors of vasopressin V1aV1band V2and sensitive to this antagonism.

BACKGROUND of the INVENTION

Arginine vasopressin (AVP) is neurohypophyseal a neuropeptide produced in the hypothalamus, and he is involved in a large number of biological processes in the circulatory system, the peripheral nervous system (PNS) and Central nervous system (CNS, Central nervous system). In particular, AVP acts as neurotransmitter in the brain. Identified several pharmacologically important subtypes of receptor vasopressin, including Retz who ptory vasopressin V 1aV1band V2. These receptors vasopressin involved in some psychiatric, psychological and behavioral painful conditions, including depression, anxiety, affective disorders and stress, as well as non-mediating tolerance of pain. Moreover, receptors of vasopressin is involved in several metabolic processes, including homeostasis of water metabolism, the activity of the kidneys, the mediating functions of the cardiovascular system, as well as regulating the body temperature of mammals.

For example, AVP plays an important role in causing depression, i.e. one of the most common serious disorders of the Central nervous system. In the number of potential targets for treatment of depression includes hypothalamo-pituitary-adrenal axis (HPA axis), which is impaired in many patients with depression, as well as with stress-induced affective disorders (see Scott and Dinam, 1998; Serradiel-Le Gal et al., 2002, and the content of these sources is incorporated into the present application by reference). Normalization of the activity of the HPA axis, apparently, is a prerequisite for sustained remission of depression symptoms with the use of drugs (see strengthen the team, et al., 1999, and the contents of the specified source is incorporated into the present application by reference).

One of the signs give the depression is elevated levels of cortisol and ACTH, associated with impaired regulation of the HPA axis (see Owens and Nemeroff, 1993; Plotsky et al.1998, and the content of these works incorporated into the present application by reference). Corticoliberin (CRH) and arginine vasopressin (AVP) are the two main stimulator of ACTH secretion, and modern preclinical and clinical studies have shown that AVP is important for mediating the release of ACTH during chronic psychological stress (see Scott and Dinan, 1997, 1998, and the content of the works included in the application as a reference). AVP is formed in neurons, localized in paraventrikulyarnoe nucleus of the hypothalamus, and activation of these neurons induces the release of AVP into the bloodstream in the system of the portal vein median Eminence. However, the secretion of cortisol in response to psychological stress in healthy volunteers, are anxious, apparently, is regulated by AVP, but not CRH (see Boudarene et al., 1999, and the content of work is incorporated into the present application by reference). Chronic psychological stress, followed by a malfunction in the regulation of the HPA axis may contribute to the etiology of affective disorders. It was found that many patients with major depression showed elevated levels of AVP, which is reduced by weakening the mental disorder (see van Londen et al., 1997&2000, and containing what their work is incorporated into the present application by reference).

In addition, AVP is transported to the anterior pituitary, where it can stimulate the release of ACTH by interacting with the receptor V1bon the cell membranes of corticotrophs. For example, rats, selectively bred to illustrate the behavior associated with high anxiety, demonstrate dysregulation of the HPA axis. Impact receptor antagonist V1bcan eliminate CRH-stimulated secretion of ACTH, showing the switch in the regulation of ACTH to CRH on AVP (see Keck et al., 1999, and the content of work is incorporated into the present application by reference). It was also demonstrated the presence of receptor V1bin a few departments of the Central nervous system of rats and the Central nervous system of mice. Therefore, it is believed that antagonists V1b, which penetrate into the Central nervous system, may have great therapeutic potential in affective disorders associated with stress. At the present time there is no antagonists of vasopressin, which can overcome the barrier the blood-brain (Serradeil-Le Gal et al., 2002). In addition, there is preclinical and clinical evidence that vasopressin, acting through the receptor V1bcontributes to the development of subtype of major depression associated with chronic stress and dysregulation of the HPA axis (see Boudarene et al., 1999; Griebel et al., 2002; Scott and Dinan, 1997, 1998, and the content of these works is clucene in this application by reference).

It was reported that cardiovascular disorders are a major cause of hospital admissions of people aged 65 years and older. It was shown that AVP contributes to the pathophysiology and the development of heart disease, including congestive heart failure (see Schrier & Abraham "Hormones and hemodynamics in heart failure," N. Engl. J. Med. 341:577-585 (1999); Thibonnier "Vasopressin receptor antagonists in heart failure," Curr. Op. Pharmacology 3:683-687 (2003); Lee et al., "Vasopressin: A new target for the treatment of heart failure," Am. Heart J. 146:9-18 (2003), and content of all these activities is included in this application by reference). In addition, coordinated renal physiology/the cardiovascular system promotes normal health and homeostasis of the heart. Thus, AVP also plays an important role in water and electrolyte balance, regulation of blood volume, the tone of smooth muscles of vessels, as well as the ability of the heart to contraction and cardiac metabolism. Each of these factors is among the main factors that affect the performance of the heart and its ability to meet the needs of the body. AVP affects all of the above factors, in particular, through the activation of receptor V1aand V2. Receptors of vasopressin V1alocalized in the smooth muscle of blood vessels and cardiomyocytes, respectively, contributing to the narrowing of soudo is, as well as protein synthesis and growth of cardiac cells. Receptors of vasopressin V2localized in the collecting ducts of the kidney nephrons, helping reverse the absorption of free water. Small changes in the osmolarity of plasma sensed by receptors in the hypothalamus that regulate neurosecretory selection AVP from the pituitary. When osmotic stimulation of the content of AVP in plasma can rise from an initial level 3-4 PG/ml to 9-10 PG/ml These moderate changes in the level of neurohormone AVP together with the renin-angiotensin-aldosterone system day-to-day regulate the balance of water and electrolytes in healthy subjects.

However, it was reported that the role of AVP in the physiology of the cardiovascular system healthy subjects is minimal, and for these people the necessary sverkhfizicheskoe dose of neurohormones to affect blood pressure, the heart's ability to contract and coronary blood flow. In contrast, AVP plays a major role in patients with heart failure. For example, it was observed that the basic levels of AVP in plasma is increased in patients with heart failure compared with healthy subjects (control), in particular those who have hyponatremia (see Goldsmith "Congestive heart failure: potential role of arginine vasopressin antagonists in therapy of heart failure," Congest. Heart Fail. 8:251-6 (2002); Schrier ad Ecder, (2001), and the data content of the works included in the present application by reference). Further, AVP associated reduced water diuresis in patients with congestive heart failure (CHF), leading to increased blood volume, hyponatremia, edema and weight gain. In heart failure the elevated levels of AVP in plasma leads to an increase in peripheral vascular resistance and jammed the pressure in the pulmonary capillaries at the minute reduction in cardiac output and stroke volume of the heart. In addition, additional data suggest that AVP contributes to the hypertrophic characteristics of the myocardium in heart failure (see Nakamura et al., "Hypertrophic growth of cultured neonatal rat heart cells mediated by vasopressin Via receptor," Eur J Pharmacol 391:39-48 (2000); Bird et al., A "Significant reduction in cardiac fibrosis and hypertrophy in spontaneously hypertensive rats (SHR) treated with a V1areceptor antagonist," (abstract) Circulation 104:186 (2001), and the content of these works incorporated into the present application by reference), and cellular/molecular studies have shown that, in addition, AVP initiates a signaling cascade that promotes fibrosis of the myocardium, as a rule, observed in the development of the disease.

Structural modification of vasopressin resulted in a number of vasopressin agonists (see Sawyer,Pharmacol.Reviews, 13:255(1961)). In addition, it was revealed several potent and selective PE tednik antagonists of vasopressin (see Lazslo et al., Pharmacological Reviews,43:73-108 (1991); Mah and Hofbauer,Drugs of the Future,12:1055-1070 (1987); Manning and Sawyer,Trends in Neuroscience,7:8-9 (1984)). Next were revealed new structural classes ones antagonists of vasopressin (see Yamamuraet al., Science,275:572-574 (1991); Serradiel-Le Galet al., Journal of Clinical Investigation,92:224-231 (1993); Serradiel-Le Galet al., Biochemical Pharmacology,47(4):633-641 (1994)). Finally, the General structural class 2(azetidin-2-on-1-yl)-substituted esters and amides of acetic acid is known as an intermediate of synthesis products when receiving β-lactamase antibiotics (see U.S. patent No. 4751299).

The INVENTION

It was found that some compounds included in the General class of 2-(azetidin-2-on-1-yl)-substituted alkanovykh acids and their derivatives are antagonists of vasopressin receptors, including the receptors of vasopressin V1aV1band V2. In the present application is described 2-(azetidin-2-on-1-yl)-substituted alcamovia acid, which are analogues of phenylalanine, cysteine, homocysteine and homoserine, as well as their analogues, homologues and derivatives. In addition, in the application described pharmaceutical compositions, which include therapeutically effective amounts of these alkanovykh acids intended for the treatment of diseases and disorders that are dependent on antagonism to one or more receptors of vasopressin, for example the recipe for the rum V 1aV1band V2. Advanced methods of treatment of diseases and medical conditions in mammals that are associated with violations functions of vasopressin and are dependent antagonism of the vasopressin receptors, such as receptors V1aV1band V2or combinations thereof. In addition, the described methods of obtaining 2-(azetidin-2-on-1-yl)-substituted alkanovykh acids, which are analogues of phenylalanine, cysteine, homocysteine and homoserine and their various analogs and derivatives.

In one of the illustrative embodiments of the present invention describes compounds of formula (I):

where Q represents oxygen, sulfur or oxidized sulfur, including group-S(O)- and-SO2-;

n represents 1 or 2;

A is an R5O, monosubstituted the amino group, the disubstituted amino group or optionally substituted nitrogen-containing heterocycle attached at the nitrogen atom;

R1represents hydrogen or C1-C6alkyl;

R2represents hydrogen, alkyl, including C1-C6alkyl, alkenyl, including C2-C6alkenyl, as, for example, vinyl, allyl, etc., quinil, including C2-C6quinil, as, for example, ethinyl, PROPYNYL and the like, alkoxy, including C1-C4alkoxy, alkisti is, including C1-C4alkylthio, halogen, halogenated, as, for example, trifluoromethyl, tryptophanate etc., cyano, formyl, alkylsulphonyl, including C1-C3alkylsulphonyl, alkoxycarbonyl or Deputy selected from the group consisting of-CO2R8, -CONR8R8'and-NR8(COR9);

R3represents optionally substituted amino, amido, acylamino or ureido group; or R3represents a nitrogen-containing heterocyclic group attached to a nitrogen atom;

R4represents alkyl, including C1-C6alkyl, alkenyl, including C2-C6alkenyl, quinil, including C2-C6quinil, cycloalkyl, including C3-C8cycloalkyl, cycloalkenyl, including C3-C9cycloalkenyl, as, for example, Limonar, pineal etc., alkylsulphonyl, including C1-C3alkylsulphonyl, optionally substituted aryl, optionally substituted arylalkyl, including aryl(C1-C4alkyl), optionally substituted arylalkyl, optionally substituted allakariallak, optionally substituted arylalkyl, including aryl(C2-C4alkenyl), optionally substituted arylalkenes or optionally substituted arylalkyl, including aryl(C2-C4quinil);

R5selected from hydrogen, alkyl is, including C1-C6of alkyl, cycloalkyl, including C3-C8cycloalkyl, alkoxyalkyl, including (C1-C4alkoxy)-(C1-C4the alkyl), optionally substituted arylalkyl, including aryl(C1-C4the alkyl), heterocyclyl, heterocyclyl(C1-C4the alkyl and R6R7N-(C2-C4of alkyl, where each of heterocyclyl independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinil, homopiperazine or hinokitiol; where these morpholinyl, pyrrolidinyl, piperidinyl, piperazinil, homopiperazine or hinokitiol optionally substituted on the nitrogen atom of C1-C4the alkyl or optionally substituted aryl(C1-C4by alkyl);

R5'selected from the group consisting of-SR15, -S(O)R15, -SO2R15C1-C6of alkyl, C3-C8cycloalkyl, (C1-C4alkoxy)-(C1-C4the alkyl), optionally substituted arylalkyl, including aryl(C1-C4the alkyl), heterocyclyl, heterocyclyl(C1-C4the alkyl and R6'R7'N-(C2-C4of alkyl, where each of heterocyclyl independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinil, homopiperazine or hinokitiol; where these morpholinyl, pyrrolidinyl, piperidinyl piperazinil, homopiperazine or hinokitiol optionally substituted on the nitrogen atom of C1-C4the alkyl or optionally substituted aryl(C1-C4by alkyl);

R6represents hydrogen or alkyl, including C1-C6alkyl, and R7represents alkyl, including C1-C6alkyl, cycloalkyl, including C3-C8cycloalkyl, optionally substituted aryl or optionally substituted arylalkyl, including aryl(C1-C4alkyl); or R6and R7together with the attached nitrogen atom form a heterocycle, such as, for example, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil and homopiperazine; where these piperazinil or homopiperazine optionally substituted on the nitrogen atom by a substituent R13;

R6'represents hydrogen or alkyl, including C1-C6alkyl, and R7'represents alkyl, including C1-C6alkyl, cycloalkyl, including C3-C8cycloalkyl, optionally substituted aryl or optionally substituted arylalkyl, including aryl(C1-C4alkyl); or R6'and R7'together with the attached nitrogen atom form a heterocycle, such as, for example, pyrrolidinyl, piperidinyl, morpholinyl, piperazinil and homopiperazine; where these piperazinil or homopiperazine optional substituted poetomu nitrogen substituent R 13';

each of the substituents R8and R8'in each case independently selected from hydrogen, alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; optionally substituted aryl or optionally substituted arylalkyl, including aryl(C1-C4alkyl); or R8and R8'together with the attached nitrogen atom form a heterocycle, such as, for example, optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinil and homopiperazine;

Deputy R9selected from hydrogen, alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; alkoxyalkyl, including (C1-C4alkoxy)-(C1-C4alkyl); optionally substituted aryl, optionally substituted arylalkyl, including aryl(C1-C4alkyl); optionally substituted heteroaryl, optionally substituted heteroaromatic, including heteroaryl(C1-C4alkyl); and R8R8'N-(C1-C4the alkyl);

R13and R13'independently selected from hydrogen, alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; alkoxycarbonyl, including C1-C4alkoxycarbonyl; optionally substituted aryloxyalkyl, optionally substituted arylalkyl, including aryl(C 1-C4alkyl); and optionally substituted of Ariola;

R15selected from the group consisting of C1-C6of alkyl, C3-C8cycloalkyl, (C1-C4alkoxy)-(C1-C4the alkyl), optionally substituted aryl(C1-C4the alkyl), Y'-, Y'-(C1-C4the alkyl and R6'R7'N-(C2-C4the alkyl); and

the hydrate, the solvate, and pharmaceutically acceptable salts of these compounds;

provided that when Q represents oxygen, n is 2 and R5'is not-SR15, -S(O)R15or-SO2R15.

Another illustrative variant implementation of the present invention relates to compounds of the formula (II):

where aryl is an optionally substituted monocyclic or polycyclic aromatic group;

m means 1,2,3 or 4; and

A, R1, R2, R3and R4consistent with the definition given in the description of formula (I); and hydrates, solvate and pharmaceutically acceptable salts of such compounds.

Another illustrative variant implementation of the present invention relates to compounds of the formula (III):

where aryl is an optionally substituted monocyclic or polycyclic aromatic group;

Q' Ave dstanley an oxygen, sulfur or-CH2-;

n' is 0, 1 or 2;

m' is 0, 1 or 2; and

A, R1, R2, R3and R4consistent with the definition given in the description of formula (I); and

the hydrate, the solvate, and pharmaceutically acceptable salts of these compounds;

provided that, if Q' represents oxygen, n' is 2; and if Q' represents a sulfur, n' is 1 or 2.

In one aspect the invention relates to compounds of formula (I)in which Q represents oxygen, and n represents 2. In another aspect of the invention describes compounds of formula (I)in which Q represents sulfur and n is 1 or 2. In another aspect the invention relates to compounds of formula (I)in which Q represents sulfur, n is 1 and R5'is alkyl or optionally substituted arylalkyl. In another aspect of the invention describes compounds of formula (I)in which Q is sulfur, n is 2 and R5'is alkyl or optionally substituted arylalkyl.

In one aspect, the compounds of formulas (II) and (III), the aryl represents optionally substituted phenyl, including phenyl, alkylphenyl, hydroxyphenyl, alkoxyphenyl, halogenfree, cyanophenyl and the like; optionally substituted pyridinyl, including 2-, 3 - and 4-pyridinyl, alkyl 2-, 3 - and 4-pyridinyl, halogen 2-, 3 - and 4-pyridinyl, and the like; and optionally alseny naphthyl, including 2 - and 3 - naphthyl, alkylated, hydroxynaphthyl, alkoxyaryl, halogenated etc.

It should be understood that various aspects of the formulas described in this application can be chosen in numerous combinations. Illustrative, for any of the compounds of formula (I), (II) or (III)choosing compounds in which R2represents hydrogen, R4is arylalkyl and A represents a mono - or disubstituted by an amino group or optionally substituted nitrogen-containing heterocycle. In various embodiments, choose connection, in which R2represents hydrogen or methyl, R4is arylalkyl and A represents a mono - or disubstituted by an amino group, or optionally substituted nitrogen-containing heterocycle. In another illustrative combinations of the compounds of formulas (I) and (III) R2represents hydrogen, R4is arylalkyl and Q and Q' represent sulfur atoms. In various embodiments, A represents a mono - or disubstituted by an amino group, or optionally substituted nitrogen-containing heterocycle, and n or n' is 1. In other embodiments, R1represents hydrogen and other alternatives R4more specifically is optionally substituted by ventilation. In addition, it should be understood that such variants can be combined is the next step to determine subsets selected from the compounds described in this invention.

In another embodiment, the present application describes pharmaceutical compositions, and these compositions include one or more of the compounds described in this application, including, but not limited to, compounds of formula (I), (II) or (III) and/or 2-(azetidin-2-on-1-yl)-substituted analogues of phenylalanine, cysteine, homocysteine and homoserine, as well as derivatives and analogs described in this application compounds, and combinations thereof. 2-(azetidin-2-on-1-yl)-substituted analogues of phenylalanine, cysteine, homocysteine and homoserine and their derivatives and analogs include compounds of formulas (I), (II) or (III). Described in this application, the pharmaceutical compositions also include one or more pharmaceutically acceptable carriers, diluents and/or excipients. In one illustrative aspects described pharmaceutical compositions, which show oral activity and/or oral bioavailability. In another illustrative aspect described pharmaceutical compositions, which allow 2-(azetidin-2-on-1-yl)-substituted analogues of phenylalanine, cysteine, homocysteine and homoserine, as well as their derivatives and analogues to penetrate the barrier the blood-brain.

In another embodiment, methods of treating painful the States in mammals, sensitive to antagonism to the receptors of vasopressin V1aV1band/or V2in case of need of such treatment. These methods include the stage of introduction of the mammal pharmaceutically effective amount of one or more compounds disclosed in this application, including, but not limited to, compounds of formula (I), (II) or (III) and/or 2-(azetidin-2-on-1-yl)-substituted analogues of phenylalanine, cysteine, homocysteine and homoserine, as well as their derivatives and analogs, are described in this application, as well as their combinations. In another embodiment, the methods include the stage of introduction to the mammal a composition containing a pharmaceutically effective amount of one or more 2-(azetidin-2-on-1-yl)-substituted analogues of phenylalanine, cysteine, homocysteine and homoserine, as well as their derivatives and analogs, are described in this application, and a pharmaceutically acceptable carrier, diluent or excipient.

Illustrative painful conditions that are sensitive to antagonism of receptors of vasopressin V1aV1band/or V2and treatable described in the present application methods include various mental illnesses associated with stress, depression, anxiety, affective disorders, obsessive-compulsive disease, impulsivity, AG is assignee disorders and the like; diseases that affect water homeostasis, renal function, inhibition of the metabolism of the phosphatidyl-Inositol, temperature regulation, and the like; diseases associated with nausea, vomiting and pain; as well as various cardiovascular diseases, including congestive heart failure, disorders or conditions associated with platelet aggregation, etc. Additionally, this application describes how to treat other painful conditions that can be treated by, for example, the receptor antagonists of oxytocin, antagonists of the receptor tachykinin, receptor antagonists neirokinina 1, antagonists of the receptor neirokinina 2 and the like, and these methods include the stage of introduction of the patient, if necessary, get rid of such diseases or conditions, an effective amount of one or more 2-(azetidin-2-on-1-yl)-substituted analogues of phenylalanine, cysteine, homocysteine and homoserine, as well as their derivatives and analogs, are described in this application, including compounds of formulas (I), (II) or (III); or methods include the stage of introduction of the patient, if necessary, get rid of such diseases or conditions described in this application of the composition, and the composition includes an effective amount of one or more 2-(azetidin-2-on-1-yl)substituted the taxes phenylalanine, cysteine, homocysteine and homoserine, as well as their derivatives and analogs, are described in this application, including compounds of formulas (I), (II) or (III), and pharmaceutically acceptable carrier, diluent and/or excipient.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows an affinity for binding with human V1b(Ki=0.07 nm) compound of example 9B, defined in the study of competitive binding, made for CHO cells, transfected with the human receptor V1a.

DETAILED description of the INVENTION

General chemical terms used in the description of the formulas in this application, have their traditional values. For example, the term "alkyl" refers to linear or optionally branched saturated hydrocarbon, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl etc.

The term "cycloalkyl" refers to an unbranched or optionally branched saturated hydrocarbon, at least part of which forms a cycle, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentene, cyclohexyl, cycloheptyl, cyclooctyl etc.

The term "alkenyl" refers to a linear or optional times evlenme hydrocarbon, which contains at least one double bond, including, but not limited to, vinyl or ethynyl, allyl or propenyl, Isopropenyl, 2-butenyl, 2-methyl-2-propenyl, butadienyl etc.

The term "quinil" refers to a linear or optionally branched hydrocarbons that contain at least one triple bond, including but not limited to, ethinyl, PROPYNYL, 1-butynyl, Gex-4-EN-2-inyl etc.

The term "aryl" refers to aromatic cycle or heteroaromatic cycle and includes groups such as furyl, pyrrolyl, thienyl, pyridinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolin, imidazolyl, pyrazolyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, oxadiazolyl, naphthyl, indanyl, fluorenyl, chinoline, ethenolysis, benzodioxane, benzofuranyl, benzothiazol etc.

The term "optionally substituted" refers to substitution of one or more, for example, from one to about three, hydrogen atoms by one or more substituents. The number of substituents include, but is not limited to, groups such as C1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio, hydroxy, nitro, halogen, carboxy, cyano, C1-C4halogenated, C1-C4halogenoalkane, amino, carbarnoyl, carboxamido, amino, alkylamino, dialkylamino, and is cellkilling, C1-C4alkylsulfonamides etc.

The term "heterocycle" refers to non-aromatic cyclic structure, which includes one or more heteroatoms, such as nitrogen, oxygen, sulfur and the like, and the term includes such groups as tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinil, homopiperazine, hinokitiol etc.

The term "alkoxy" refers to alkyl or cycloalkyl Deputy attached to the rest of the molecule via an oxygen atom, and the term includes such groups as metoki, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy etc.

The term "acyl" includes terms such as "alkanoyl" and "aroyl", and refers to alkyl, alkenyl, quinil, aryl, etc. attached to the rest of the molecule via a carbonyl group. As an illustration, atilov includes formyl, acetyl, propanol, butanol, pentanol, cyclohexanol, optionally substituted benzoyl, etc.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "alkanoyloxy" encompasses groups such as formyloxy, acetoxy, n-propionoxy, n-butyrate, pivaloyloxy and similar lower alkanoyloxy group.

The terms "optionally substituted C1-C4alkyl", "optionally substituted C3-C8cycloalkyl" and "obazatelno substituted C 2-C4alkenyl" refer respectively to alkyl, cycloalkyl or alkenyl, optionally substituted Deputy, described in this application, including, but not limited to, a hydroxy-group, a protected hydroxy-group, the alkyl, protected carboxy, carbarnoyl, benzylthio, alkylthio etc.

The term "(C1-C4alkyl)", used, for example, in the names of "aryl(C1-C4alkyl)", "(C1-C4alkoxy)-(C1-C4alkyl)and the like, refers to a saturated linear or branched saturated divalent alkyl chain formed by one to four carbon atoms, including, for example, aryl, C1-C4alkoxy, etc. as Deputy, and this term refers to such groups as, for example, benzyl, phenetyl, inproper, α-methylbenzyl, methoxymethyl, ethoxyethyl etc.

The term "optionally substituted phenyl" means a phenyl radical, optionally substituted by one or more substituents, each of which is independently selected from groups such as C1-C4alkyl, C1-C4alkoxy, hydroxy, halogen, nitro, trifluoromethyl, sulfonamide, cyano, carbarnoyl, amino, mono(C1-C4alkyl)amino, di(C1-C4alkyl)amino, C1-C4alkylsulfonamides and enol-2-yl.

The term "protected amino group" relative to the tsya to the amino group, protected by a protective group which can be used to protect the nitrogen atom, as, for example, the nitrogen atom in the β-laktamovogo cycle, during synthesis or subsequent reactions. Examples of such groups are benzyl, 4-methoxybenzyl, 4-methoxyphenyl, trialkylsilyl, for example trimethylsilyl, etc.

The term "protected carboxypropyl" refers to carboxypropyl protected or blocked standard protective groups commonly used for the temporary blocking of acid carboxypropyl. Examples of such groups include lower alkali, for example tert-butyl, halogen-substituted lower alkali, for example 2-iodates and 2,2,2-trichloroethyl, benzyl and substituted benzyl, such as 4-methoxybenzyl and 4-nitrobenzyl, diphenylmethyl, alkenyl, for example allyl, trialkylsilyl, for example trimethylsilyl and tert-butyldimethylsilyl, and similar carboxyamide group.

It should be understood that in embodiments of the invention described in this application, illustrating a variation of the alkyl is C1-C6alkyl, for example methyl, ethyl, propyl, prop-2-yl and the like; an illustrative variation of alkenyl is C2-C6alkenyl, for example vinyl, allyl and the like; an illustrative variation of quinil is C2-C6quinil, as, for example, ethinyl, PROPYNYL and the like; an illustrative variation alkoxy is C1-C4 alkoxy, for example methoxy, Penta-3-oxy and the like; an illustrative variation of alkylthio is C1-C4alkylthio, for example, ethylthio, 3-methylbut-2-ylthio and the like; an illustrative variation of alkylcarboxylic is C1-C3alkylsulphonyl, for example acetyl, propanol and the like; an illustrative variation of cycloalkyl is C3-C8cycloalkyl; illustrative option cycloalkenyl is C3-C9cycloalkenyl, such as limonene, pinenes and the like; an illustrative variation optionally substituted arylalkyl is optionally substituted aryl(C1-C4alkyl); illustrative option optionally substituted arylalkyl is optionally substituted aryl(C2-C4alkenyl); illustrative option optionally substituted arylalkyl is optionally substituted aryl(C2-C4quinil); an illustrative variation of alkoxyalkyl is (C1-C4alkoxy)-(C1-C4alkyl); illustrative option optionally substituted heteroaromatic is optionally substituted heteroaryl(C1-C4alkyl); and illustrative option alkoxycarbonyl is C1-C4alkoxycarbonyl.

The term "antagonist" in the present description refers to complete or partial antagonist. Although it used the change of partial antagonist of any natural activity, partial antagonists as the following illustrations demonstrate not less than about 50% of the actions of the antagonist, or not less than about 80% of the actions of the antagonist. The term also encompasses compounds that are full antagonists of the receptor vasopressin V1b. Referring to that described in the present application is illustrative methods require therapeutically effective amounts of receptor antagonists vasopressin V1b; therefore, compounds exhibiting partial antagonism of the vasopressin receptor V1bcan be administered in higher doses to be sufficient antagonistic activity for the inhibition of the action of vasopressin or vasopressin agonist.

In one aspect of the compounds of formula (I) represents A monosubstituted the amino group, the disubstituted amino group or optionally substituted nitrogen-containing heterocycle attached at the nitrogen atom.

In another aspect of the invention describes compounds of formula (I)in which Q represents oxygen and n is 2. In another aspect of the invention describes compounds of formula (I)in which Q represents sulfur and n is 1 or 2. In another aspect of the invention describes compounds of formula (I)in which Q represents sulfur, n is 2 and R5'represents alkyl or optionally alseny arylalkyl. In another aspect of the invention describes compounds of formula (I)in which Q represents sulfur, n is 2 and R5'represents alkylthio or optionally substituted, arylalkyl.

In one aspect of the compounds of formulas (II) and (III) aryl represents optionally substituted phenyl, including phenyl, alkylphenyl, hydroxyphenyl, alkoxyphenyl, halogenfree, cyanophenyl and the like; optionally substituted pyridinyl, including 2-, 3 - and 4-pyridinyl, alkyl 2-, 3 - and 4-pyridinyl, halogen 2-, 3 - and 4-pyridinyl, and the like; and optionally substituted naphthyl, including 2 - and 3-naphthyl, alkylated, hydroxynaphthyl, alkoxyaryl, halogenated etc.

In another aspect of the invention describes compounds of formula (II), in which aryl represents optionally substituted phenyl, including phenyl, alkylphenyl, hydroxyphenyl, alkoxyphenyl, halogenfree, cyanophenyl and the like; optionally substituted pyridinyl, including 2-, 3 - and 4-pyridinyl, alkyl 2-, 3 - and 4-pyridinyl, halogen 2-, 3 - and 4-pyridinyl, and the like; and optionally substituted naphthyl, including 2 - and 3-naphthyl, alkylated, hydroxynaphthyl, alkoxyaryl, halogenated etc.

In another aspect of the invention describes compounds of formula (II)in which R5'represents an optionally substituted alkyl, including optionally substituted C1-C6alkyl, C1-C4alkyl and C1 -C2alkyl. In another aspect of the invention describes compounds of formula (II)in which R5'represents optionally substituted aryl(C1-C4alkyl), including phenyl(C1-C4alkyl) or optionally substituted aryl(C1-C2alkyl).

In another aspect of the invention describes compounds of formula (III), in which each of the symbols n' and m' denotes an integer of 1.

In another aspect of the invention describes compounds of formula (II) and (III)in which aryl represents optionally substituted phenyl. In another aspect of the invention describes compounds of formula (II) and (III), in which each of the symbols m and m' denotes an integer of 1.

In another aspect of the invention describes compounds of formula (I), (II) and (III)in which A is a monosubstituted the amino group. In another aspect of the invention describes compounds of formula (I)in which A represents the disubstituted amino group. In another aspect of the invention describes compounds of formula (I)in which A represents an optionally substituted nitrogen-containing heterocycle attached at the nitrogen atom.

In another aspect of the invention describes compounds of formula (I), (II) and (III)in which A represents an amino group of formula R14XN-; where R14selected from the group consisting of hydrogen, hydroxy, alkyl, including C1-C 6alkyl; alkoxycarbonyl, including C1-C4alkoxycarbonyl; and benzyl; and X is selected the group consisting of alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; alkoxyalkyl, including (C1-C4alkoxy)-(C1-C4alkyl); optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(C1-C4alkyl); and the group Y, Y-(C1-C4the alkyl), R6R7N and R6R7N-(C2-C4the alkyl), where Y is a heterocycle. In one embodiment, compounds of formula (I), (II) and (III), R14represents hydrogen.

In another aspect of the invention describes compounds of formula (I), (II) and (III)in which A represents heterocyclyl having the formula, R14XN-, where R14and X, together with the attached nitrogen atom, form a heterocycle, for example a heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinil and homopiperazine; and said heterocycle optionally substituted R10, R12, R6R7N or R6R7N-(C1-C4the alkyl, as defined above.

In one embodiment, the invention describes compounds of formula (I), (II) and (III)in which R14and X, together with the attached nitrogen atom, form PI is original, optionally substituted at 4-position hydroxy, alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; alkoxy, including C1-C4alkoxy; alkoxycarbonyl, including (C1-C4alkoxy)carbonyl; hydroxyalkyloxy, including (hydroxy(C2-C4alkyloxy))-(C2-C4alkyl); R6R7N-, R6R7N-alkyl, including R6R7N-(C1-C4alkyl); diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C1-C4by alkyl) or piperidine-1-yl(C1-C4by alkyl).

In another embodiment, the invention describes compounds of formula (I), (II) and (III)in which R14and X, together with the attached nitrogen atom, form a piperazinil, optionally substituted on the 4 position by alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(C1-C4alkyl); α-methylbenzyl, etc., N-alkyl ndimethylacetamide-2-yl, including N-(C1-C5alkyl)ndimethylacetamide-2-yl; N-(cycloalkyl)ndimethylacetamide-2-yl, including N-(C3-C8cycloalkyl)ndimethylacetamide-2-yl; R6R7N-, R6'R7'N - or alkoxycarbonyl, including (C1-C4alkoxycarbonyl).

In each the m variant of the invention describes compounds of formula (I), (II) and (III)in which A represents the disubstituted amino group having the formula, R14XN-, where R14and X together with the attached nitrogen atom form piperidinyl, optionally substituted on the 4 position by alkyl, including C1-C4alkyl; or heterocyclyl(C1-C4by alkyl).

In another embodiment, the invention describes compounds of formula (I), (II) and (III)in which A represents the disubstituted amino group having the formula, R14XN-, where R14and X together with the attached nitrogen atom form piperidinyl, optionally substituted on the 4 position piperidinyl(C1-C4by alkyl), piperazinil(C1-C4by alkyl) or pyrrolidinyl(C1-C4by alkyl).

In another aspect of the invention describes compounds of formula (I), (II) and (III)in which A is a monosubstituted the amino group. In another aspect of the invention describes compounds of formula (I), (II) and (III)in which A represents the disubstituted amino group. In another aspect of the invention describes compounds of formula (I), (II) and (III)in which A represents an optionally substituted nitrogen-containing heterocycle attached at the nitrogen atom.

In another aspect of the invention describes compounds of formula (I), (II) and (III)in which A is a monosubstituted the amino group of the formula XNH-; where X is selected from the group status is the present from alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; alkoxyalkyl, including (C1-C4alkoxy)-(C1-C4alkyl); optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(C1-C4alkyl); and the group Y, Y-(C1-C4the alkyl), R6R7N and R6R7N-(C2-C4the alkyl), where Y is a heterocycle.

In another aspect of the invention describes compounds of formula (I), (II) and (III)in which A represents the disubstituted amino group of the formula R14XN-; where R14selected from the group consisting of hydroxy, alkyl, including C1-C6alkyl; alkoxycarbonyl, including C1-C4alkoxycarbonyl; and benzyl; and X is selected from the group consisting of alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; alkoxyalkyl, including (C1-C4alkoxy)-(C1-C4alkyl); optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(C1-C4alkyl); and the group Y, Y-(C1-C4the alkyl), R6R7N and R6R7N-(C2-C4the alkyl), where Y is a heterocycle.

In another aspect of the invention describes compounds of formula (I), (II) and (III), in the which A represents optionally substituted heterocyclyl, having the formula R14XN-, where R14and X, together with the attached nitrogen atom, form a heterocycle, for example a heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinil and homopiperazine; and said heterocycle optionally substituted R10, R12, R6R7N or R6R7N-(C1-C4the alkyl, as defined above.

In another aspect of the invention describes compounds of formula (I), (II) and (III)in which R14and X, together with the attached nitrogen atom, form piperidinyl, optionally substituted at 4-position hydroxy, alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; alkoxy, including C1-C4alkoxy; alkoxycarbonyl, including (C1-C4alkoxy)carbonyl; hydroxyalkyloxy, including(hydroxy(C2-C4alkyloxy))-(C2-C4alkyl); R6R7N-, R6R7N-alkyl, including R6R7N-(C1-C4alkyl); diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C1-C4by alkyl) or piperidine-1-yl(C1-C4by alkyl).

In another aspect of the invention describes compounds of formula (I), (II) and (III)in which R14and X, together with the attached nitrogen atom, form a piperazinil, optional C is displaced 4-position by alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; optionally substituted aryl, optionally substituted arylalkyl, including optionally substituted aryl(C1-C4alkyl); α-methylbenzyl, etc., N-alkyl ndimethylacetamide-2-yl, including N-(C1-C5alkyl)ndimethylacetamide-2-yl; N-(cycloalkyl)ndimethylacetamide-2-yl, including N-(C3-C8cycloalkyl)ndimethylacetamide-2-yl; R6R7N-, R6'R7'N - or alkoxycarbonyl, including (C1-C4alkoxy)carbonyl).

Described illustrative compounds of formula (I), (II) and (III)in which A represents the disubstituted amino group having the formula, R14XN-, where R14and X together with the attached nitrogen atom form piperidinyl, optionally substituted on the 4 position by alkyl, including C1-C4alkyl; or heterocyclyl(C1-C4by alkyl).

Described illustrative compounds of formula (I), (II) and (III)in which A represents the disubstituted amino group having the formula, R14XN-, where R14and X together with the attached nitrogen atom form piperidinyl, optionally substituted on the 4 position piperidinyl(C1-C4by alkyl), piperazinil(C1-C4by alkyl) or pyrrolidinyl(C1-C4by alkyl).

Described illustrative compounds of formula (I), (II) and (III)in which R14and X with the together with the attached nitrogen atom form homopiperazine, optionally substituted on the 4 position by alkyl, including C1-C4alkyl; aryl, or aryl(C1-C4by alkyl).

Described illustrative compounds of formula (I), (II) and (III)in which A represents the disubstituted amino group having the formula, R14XN-, where R14and X together with the attached nitrogen atom form a heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl and 1,2,3,4-tetrahydroisoquinoline-2-yl.

In another aspect, compounds of formula (I), (II) or (III) R3represents a structure selected from the group consisting of:

where each of the substituents R10and R11independently selected from hydrogen, optionally substituted alkyl, including C1-C6alkyl; optionally substituted cycloalkyl, including C3-C8cycloalkyl; alkoxyalkyl, including C1-C4alkoxyalkyl; alkylcarboxylic, including C1-C5alkylcarboxylic, optionally substituted aryl, optionally substituted arylalkyl, including aryl(C1-C4alkyl); optionally substituted, arylalkyl, including aryl(C1-C4alkyloxy); optionally substituted, arylalkylamines, including aryl(C1-C4alkylcarboxylic); diphenylmethoxy and Triveni is methoxy; and

R12selected from hydrogen, alkyl, including C1-C6alkyl; cycloalkyl, including C3-C8cycloalkyl; alkoxycarbonyl, including C1-C4alkoxycarbonyl; optionally substituted aryloxyalkyl, optionally substituted arylalkyl, including aryl(C1-C4alkyl); and optionally substituted of Ariola.

In another aspect of the invention describes compounds of formula (I), (II) or (III)in which R3represents a structure selected from the group consisting of

where R10, R11and R12correspond to the definitions given in this application.

In another aspect of the invention describes compounds of formula (I), (II) or (III)in which R3represents a structure selected from the group consisting of

where R10, R11and R12correspond to the definitions given in this application.

In another aspect of the invention describes compounds of formula (I), (II) or (III)in which R3represents a structure selected from the group consisting of

where R10,R11and R12correspond to the definitions given in this application.

It should be understood that the above described in the present application, embodiments of the aspects and raznovidnost the present invention may be combined with each other in all possible ways to obtain additional embodiments, aspects and varieties. For example, in another aspect the invention relates to compounds of formula (I), (II) and (III)in which A represents the disubstituted amino group having the formula, R14XN-, where R14and X together with the attached nitrogen atom form piperidinyl, optionally substituted on the 4 position by alkyl, including C1-C4alkyl; or heterocyclyl(C1-C4by alkyl); and R3is a structure

where R10and R11correspond to the definitions given in this application.

Compounds described in the present invention include the structure of the nucleus of azetidinone, which contains asymmetric carbon atoms C(3) C(4), forming four stereoisomeric configuration, as shown by the following formulas:

Therefore, as described in this application, the compounds can exist as a single diastereoisomer, in the form of a racemic mixture or as a mixture of diastereomers. Assume that for some applications may be subject to certain stereoisomers or mixtures of stereoisomers, whereas in other applications can use other stereoisomers or mixtures of stereoisomers. In some embodiments, the implementation described one stereoisomer, for example, with the structure of the nucleus assetid is Nona, having diastereomers configuration (3S,4R).

In addition, it is assumed that the α-carbon atom bearing the substituent R1is chiral. In addition, the group selected as the substituents R1, R2, R3, R4and A, can also include chiral centers. For example, if R3represents a 4-substituted oxazolidin-2-he-3-yl, position 4 of this cycle is asymmetric. Further, if R3represents a 2,5-disubstituted of oxazolidin-4-one-3-yl or 1,2,5-triple-substituted imidazolidin-4-one-3-yl, each of the carbon atoms in positions 2 and 5 of these cycles is asymmetric. Finally, if R3represents succinimido, and one of the substituents R14and R15is hydrogen, carbon, having a non-hydrogen Deputy, is also asymmetric. Therefore, additional stereoisomers collectively represented by formula (I), (II) or (III). Although in the present description considered in connection, which includes all combinations of pure stereochemical isomers, whereas that in many cases in the above compounds, at least one of the above-described chiral centers may be present in the same absolute configuration. In one illustrative aspect described in the application connections have an absolute configuration of (αR,3S,4R) or as the zero configuration (αS,3S,4R).

Illustrative ways of compounds described in this invention, include classes of compounds of formula (I), (II) or (III)in which:

A is an R5O-;

A is an R5O-, and R5represents a C1-C6alkyl;

A is an R5O-, and R5represents optionally substituted aryl(C1-C4alkyl);

A is a monosubstituted the amino group of the formula XNH-;

A represents the disubstituted amino group having the formula, R14XN-;

A is XNH - or R14XN, and X represents an optionally substituted aryl(C1-C4alkyl);

A is XNH - or R14XN, and X is an R6R7N-(C1-C4alkyl);

A is XNH - or R14XN, X represents R6R7N-(C1-C4alkyl) and R6and R7together with the attached nitrogen atom form a heterocycle;

A is an R14XN, and R14and X together with the attached nitrogen atom form a heterocycle;

A is an R14XN, R14and X together with the attached nitrogen atom form a heterocycle, and the heterocycle optionally substituted optionally substituted heterocyclyl(C1-C4by alkyl);

A is an R14XN, R14and X together is about with the attached nitrogen atom form piperidinyl, and piperidinyl optionally substituted on the 4 position heterocyclyl(C1-C4by alkyl), including piperidinyl(C1-C4alkyl), piperazinil(C1-C4alkyl) and pyrrolidinyl(C1-C4alkyl);

A is XNH - or R14XN-, and X is an optionally substituted aryl(C1-C4alkyl);

A is XNH - or R14XN-, X represents an optionally substituted aryl(C1-C4alkyl), and aryl represents optionally substituted phenyl;

R1represents hydrogen;

R1represents a C1-C6alkyl;

R1represents a C1-C2alkyl;

R2represents hydrogen;

R2represents a C1-C2alkyl;

R2represents methyl;

R2represents methylthio;

R2represents cyano;

R3represents a 4-substituted oxazolidin-2-he-3-yl;

R3represents a 4,5-disubstituted of oxazolidin-2-he-3-yl;

R3represents a 2-substituted oxazolidin-4-one-3-yl;

R3represents a 2-substituted imidazolidin-4-one-3-yl;

R3is a 1,2-disubstituted imidazolidin-4-one-3-yl;

R3represents a 5-substituted imidazolidin-2-on-1-yl;

R3the present is the focus of a 4,5-disubstituted imidazolidin-4-one-1-yl;

R4represents an optionally substituted 2-Eilat-1-yl;

R4represents an optionally substituted 2-arylated-1-yl;

R5'represents a C1-C6alkyl;

R5'represents optionally substituted aryl(C1-C4alkyl).

Other illustrative variants of the compounds described in the present invention include classes of compounds of the formula (II)in which A, R5, X, R14, R1, R2, R3and R4correspond to the above definitions; and in which aryl represents phenyl, substituted phenyl or 4-substituted phenyl.

Have in mind that the above classes of compounds can be combined for more illustrative classes. Other combinations of the above classes of compounds described in this invention.

Other illustrative classes of compounds described by the following formula:

where Ar represents optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted furyl or optionally substituted thienyl; A represents a nitrogen-containing heterocycle attached at the nitrogen atom, which is optionally substituted heterocyclyl(C1-C4by alkyl); and R5'is not necessary C is displaced by arylalkyl, including aryl(C1-C4alkyl).

Other illustrative classes of compounds described by the following formulas:

where Ar represents optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted furyl or optionally substituted thienyl; A represents a nitrogen-containing heterocycle attached at the nitrogen atom, which is optionally substituted heterocyclyl(C1-C4by alkyl); and R5'is optionally substituted by arylalkyl, including aryl(C1-C4alkyl).

Other illustrative classes of compounds described by the following formula:

where Ar represents optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted furyl or optionally substituted thienyl; A represents a nitrogen-containing heterocycle attached at the nitrogen atom, which is optionally substituted heterocyclyl(C1-C4by alkyl); n is 1, 2 or 3; and aryl represents optionally substituted phenyl or optionally substituted naphthyl.

In another embodiment described in this application connections include a primary amino group. Such amines are capable of forming salts with many inorganic and organic is a slot with obtaining pharmaceutically acceptable acid additive salts. It is assumed that in those cases where the compounds described in this application formulas are oils, not solids, the ability of the compounds to form a solid salt additive is to facilitate the handling and introduction described in this application connections. Acids commonly used for the formation of such salts are inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, phosphoric acid, etc. and organic acids such as p-toluensulfonate acid, methanesulfonate acid, oxalic acid, p-bromophenylacetate acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc. Therefore, examples of such pharmaceutically acceptable salts are sulfates, pyrosulfite, bisulfate, sulfites, bisulfite, phosphates, monohydrogenphosphate, dihydrophosphate, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalates, malonate, succinate, suberate, Sabatini, fumarate, maleate, Butin-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalates, sulfonates, xylols lithonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartratami, methansulfonate, propanesulfonate, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelate etc. Preferred pharmaceutically acceptable salts are salts formed with hydrochloric acid, triperoxonane acid, maleic acid or fumaric acid.

Described in this application connections are applicable in the methods aimed at ensuring antagonism to receptors of vasopressin V1aV1band V2. This antagonism is effective in the treatment of several disorders and diseases associated with these receptors in mammals. As an illustration, mammal being treated by administration of compounds described in this application is the man.

In another embodiment, the present application describes compounds that penetrate the barrier the blood-brain. Have in mind that compounds that overcome the barrier the blood-brain may have wider application in the treatment of various painful conditions, which are sensitive to antagonists of vasopressin. For example, you need to understand that those currently recognized as different subtypes of depressive illness.

In another embodiment of the invention is worn to methods for producing compounds of formula (I), (II) or (III). In one aspect of the described method of producing compounds of the formula:

where W is a QR5'or aryl, according to definitions for the various embodiments in this application; Ar1represents optionally substituted aryl or optionally substituted heteroaryl; and R1, R2, R4n and A correspond to the definitions given for the various embodiments in this application. The methods include receiving stage of the interaction between the compounds of formula:

with the compound of the formula

where W' represents-QR5'or aryl, according to definitions for the various embodiments in this application, or W' is a protected form QR5'or aryl, which may be deprived of protection or turned into-QR5'or aryl. In one aspect of the described method, if Q represents oxygen, n is 2. In one embodiment, described is a method of obtaining compounds of the above formula in which R4represents an optionally substituted arylidene. This method includes a step of interaction between the compounds of formula (A) with the compound of the formula:

where W' represents-QR' or aryl, according to definitions for the various embodiments in this application, or W' is a protected form QR5'or aryl, which may be deprived of protection or turned into-QR5'or aryl. In one aspect of the described method, if Q represents oxygen, n is 2.

Esters and amides of 2-(azetidine-1-yl)acetic acids and their analogs and derivatives described in the present application, basically can be obtained known in the art methods of synthesis, and application of the various techniques described in this application. As shown for compounds of formula (I), (II) and (III)described in this application, the esters of 2-(azetidine-1-yl)alkalicarbonate acid can be obtained 2+2 cyclopentadiene appropriately substituted derivatives of acetic acid (i) and aminoethanol (ii) when processing base in a suitable solvent, as shown in the synthesis scheme I, where Z represents a hydroxyl or a leaving group, and an integer n, and the fragments A, R1, R2, R3and R4correspond to the above descriptions. The term "leaving group", as used hereinafter in the claims, refers to substituents, such as halogen, acyloxy, benzoyloxy and the like, associated with active carbon atom which may be substituted by a nucleophile. Helices what their reaction, shown in the synthesis scheme I, applicable to Eminem (ii)that contain fragments of esters, thioesters or amides.

The scheme of synthesis I

Obtaining the appropriate Eminov (ii), obtaining typical examples of the required acetylchloride or anhydrides (i) and methods of cycloaddition is basically described in U.S. patent No. 4665171 and 4751299, the contents of which are incorporated into the present application by reference. Have in mind that if Q in the compounds (ii-a) represents a sulfur or its oxidized form, for example, sulfoxide or sulfon, it may be incompatible with the conditions of some reactions. In these cases, to prevent undesirable reactions of the sulfur atom can be applied properly fitted protective group. Illustrative of the protective group to the sulfur atom described in the book Greene &Wuts “Protective Groups in Organic Synthesis, 2d Ed., John Wiley & Sons, New York, 1991, the contents of which are incorporated into the present application by reference.

In one illustrative embodiment, R3represents a 4-substituted oxazolidin-2-he-3-yl or 1,4,5-triple-substituted imidazolidin-2-he-3-yl. The compounds of formula (I), (II) and (III) require that R3was a 4-substituted oxazolidin-2-he-3-yl or 1,4,5-triple-substituted imidazolidin-2-he-3-yl, obtained from the corresponding (4-substituted, oxazo the one-2-one-3-yl) or (1,4,5-triple-substituted imidazolidin-2-he-3-yl)acetylchloride or anhydrides. Gelegenheid or acid anhydride can be obtained from an appropriately substituted glycine. This glycine at the first stage is converted into a carbamate and then restore to obtain the corresponding alcohol. Then the alcohol cyclist 4-substituted oxazolidin-2-it, which is then injected into the reaction of N-alkylation with ether halogenases acid. The ester hydrolyzing, and the resulting acid is converted into acetylsalicinic or anhydride (i). Illustrative examples of oxazolidinones that are used in this method of synthesis and subsequent synthesis methods described in this application include the following commercially available compounds.

R10R11R10R11
(4R)-methyl(5S)-phenyl(4S)-methyl(5R)-phenyl
(4R)-methyldiphenyl(4R)-phenyl(5S)-phenyl
(4S)-phenyl (5R)-phenyl(4S)-tert-butylH
(4S)-phenyldiphenyl(4S)-1H-indol-3-ylmethylH
(4S)-benzyldimethyl(4S)-benzylH
(4S)-tert-butyldiphenyl(4S)-diphenylmethylH
(4R)-benzylH(4S)-isopropylH
(4R)-isopropylH

Illustrative examples imidazolidinone and imidazolidinedione that are used in this method of synthesis and subsequent synthesis methods described in this application include the following commercially available compounds.

R10/sup> R11R12R10R11R12
HH2-methoxyphenylHHacetyl
HH4-methoxyphenylHHphenyl
HH2-were(4S)-phenyl(5R)-methylmethyl
HH3-wereHHmethyl
HH4-wereHHthe pet-butyl

R10R11R12
(2S)-tert-butyl(5S)-benzyl
(5S)-benzyldimethylmethyl
H(2R)-tert-butylmethyl

R10R12Q
methylphenylS

In another illustrative embodiment, R3represents a 2,5-disubstituted of oxazolidin-4-one-3-yl or 1,2,5-triple-substituted imidazolidin-4-one-3-yl. Compounds of formula (I), (II) and (III), which requires that R3was a 2,5-disubstituted of oxazolidin-4-one-3-yl or 1,2,5-triple-substituted imidazolidin-4-one-3-yl, obtained from the corresponding (2,5-disubstituted of oxazolidin-4-one-3-yl or 1,2,5-triple-substituted imidazolidin-4-one-3-yl)acetylchloride or anhydrides, respectively. The conditions of the reactions is, applicable for obtaining the compounds described in U.S. patent No. 4772694 included in the present application by reference. Briefly, the desired oxazolidinone or imidazolidinone receive, respectively, of the α-hydroxy acid or α-amino acids. Imidazolone get, transforming α-amino acid, i.e. R11)-CH(NH2)CO2H, amide-protected amino group, and then condensing this amide with an aldehyde, i.e. R10)-CHO, in the presence of acid to obtain a secure position 3 imidazolidin-4-it, where R10and R11correspond to the above definitions. In position 1 using a suitable reagent may be introduced functional group R12where R12this corresponds to the above definition, and position 3 can be unsecured. The cycle then imidazolidin-4-it alkylate ether halogenases acid, the ether is cleaved and the resulting substituted acetic acid is transformed into the corresponding gelegenheid or anhydride (i). Required oxazolidinone get a similar manner from the corresponding α-hydroxy acids, i.e. R11)-CH(OH)CO2H.

In another illustrative embodiment, R3is succinimide. Those compounds of formula (I), (II) and (III), which requires that R3represented succinimido, obtained from the corresponding 2-(succinimido)and is arilgalogenide or anhydrides. Methods of obtaining these reagents are described in U.S. patent No. 4734498 included in the present application by reference. Briefly, these compounds are obtained from tartaric acid or, if one of the substituents R10and R11is hydrogen, malic acid. Tartaric acid acelerou or O-alkylate, the corresponding diacyl or di-O-alkylvinyl acid is treated with acid anhydride to produce succinic anhydride and the reaction of succinic anhydride with a complex ester of glycine receive a first acyclic polyamides, which is then cyclist obtaining 3,4-disubstituted ester Succinimidyl acid. Split the ester group and convert the resulting acid to the corresponding gelegenheid or anhydride of the acid (i). Monosubstituted succinimidylester gelegenheid or anhydride derived from malic acid through the formation of succinic anhydride followed by the formation of succinimide, as described above.

In another illustrative embodiment, R3represents an N-substituted amine or N'-substituted urea. Those compounds of formula (I), (II) and (III), which requires that R3represented N-substituted amine or N'-substituted urea, can be obtained from the corresponding 3-amino analogues protected phthalimido. Talimena protective group can be removed using the receiving standard techniques, as, for example, by treatment with hydrazine, etc. After removing the protection of the amino group can be alkylated with one of a large number of alkyl and cycloalkyl halides and sulfates, such as methyliodide, isopropylamino, diethylsulfate, cyclopropanemethylamine, cyclopenthiazide etc. These amino groups can also be etilirovany the acid halides, acid anhydrides, isocyanates, isothioscyanates, such as acetylchloride, propionic anhydride, methyl isocyanate, 3-triftormetilfullerenov etc.

The Foundation, which must be applied in the synthesis scheme I, include, among others, tertiary aliphatic amines, such as trimethylamine and triethylamine, cyclic tertiary amines, for example N-methylpiperidine and N-methylmorpholine, aromatic amines such as pyridine and lutidine, and other organic bases, such as 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).

Solvents suitable for carrying out the reactions described in the synthesis scheme I, include, including, dioxane, tetrahydrofuran, diethyl ether, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, acetonitrile, dimethyl sulfoxide and N,N-dimethylformamide. It is assumed that with the use described in this application can be obtained in any desired stereochemical configuration of the target to connect the clusters by selecting the desired configuration at each chiral center from the number noted above. This choice can be made using optically pure starting compounds or by separation of mixtures of optical isomers at a suitable stage of the synthesis of compounds of the above two formulas using standard techniques.

In addition, can be obtained azetidinone cycle that does not contain all the necessary substituents R2, R3, R4or R1-substituted N-landiolol acid, or fragment alkoxyalkanols acid, but having substituents capable of further chemical transformations to transform into the same groups as described for compounds of formula (I), (II) and (III). Basically azetidinone can be obtained by N-C(4) cyclization, as, for example, cyclization arylhydroxamic (iv), in azetidinone intermediate compound (v)as shown in scheme II and demonstrated for compounds of formula (I), where R1, R2, R3, R4and A correspond to the above definitions, according to the method of Mattingly et al., inJ. Am. Chem.Soc. (1979), 101, 3983Accts. Chem. Res.(1986), 19, 49, and the content of these sources is included in the present description by reference. I mean what other hydroxamate, such as alkylhydroxylamines, arylhydroxamic, etc. are suitable for carrying out the cyclization.

The scheme of synthesis II

Next is e chemical transformations of alloxanthine (V), intended for insertion, for example, R1-substituted imine amino acids using standard techniques, illustrative lead to the formation of compounds of formula (I), (II) and (III).

Alternative cyclization to obtain the intermediate azetidinone, which can then be converted into compounds of formula (I), (II) and (III)may be carried out by oxidative cyclization arylhydroxamic (vi) to obtain the intermediate azetidinone (vii), as shown in the diagram synthesis III and demonstrated for compounds of formula (I), where R2and R3consistent with the data above, and L represents a leaving group such as halide, in accordance with the method Rajendra and Miller in J. Org. Chem. (1987), 52, 4471 and Tetrahedron Lett. (1985), 26, 5385, and the content of these works incorporated into the present application by reference. The group R in scheme III is an alkyl or aryl fragment is selected so that when subsequent transformations to ensure that the molecule substituent R4corresponding to the above definitions. For example, R may be a group ArCH2-where Ar represents an optionally substituted aryl group, as in the formula (vii-a), so that the oxidative elimination of HBr led to the desired substituent R4for example steriley group as in the formula (vii-b). There is in the Doo, the transformation R in R4not necessarily immediately after cyclization, and this reaction is conveniently carried out after other stages of the synthesis of compounds of formula (I), (II) and (III). In addition, mean that for the cyclization are suitable alternatives shown arylhydroxamic, such as alkylhydroxylamines, arylhydroxamic etc.

The scheme of synthesis III

Other applicable intermediate compounds such as derivatives azetidinone acid (x)can be converted into compounds of formula (I), (II) and (III), as shown for the case of synthesis of compounds of formula (I) in the scheme of synthesis of IV and demonstrated for compounds of formula (I), where R1, R2, R3, R4A and n correspond to the above definitions. The introduction of fragment R1and carboxylic acid derivative R5'-Q-(CH2)nin the compounds of formula (I) may be carried out by alkylation of the anion (x).

The scheme of synthesis IV

A derivative of acetic acid (x) deprotonated and then alkylate alkylhalogenide formula R1-Z, where Z is a leaving group, receiving the intermediate compound (xi-a). As an illustration, the anion of compound (xi-a) can be alkylated compound Z'-(CH2)nQR5'where Z' is a leaving group, to receive the of the compounds of formula (I).

The solution derived 2-(3,4-disubstituted of azetidin-2-on-1-yl)acetic acid (x) or (xi) in a suitable solvent, for example tetrahydrofuran, dioxane or diethyl ether, is treated dinucleophiles the basis for obtaining the anions of the compounds (x) or (xi), respectively. Suitable for this reaction includes diisopropylamide lithium 2,2,6,6-tetramethylpiperidine lithium or bis(trimethylsilyl)amide and lithium. Then, to obtain the desired compounds formed anion enter into interaction with a suitable electrophile. The use of illustrative electrophilic compounds represented by the formula aryl-(CH2)n-Z, leads to obtaining the appropriate connections.

Previous synthetic methods can be applied in most cases to obtain described in this application connections, including, but not limited to, analogs of serine, homoserine, cysteine, homocysteine, phenylalanine, homophenylalanine and other homologues of these compounds. In addition, the same methods of synthesis can be used to generate analogs and derivatives of these compounds, as, for example, analogues of tyrosine analogues, including naphthyl and substituted naphthyl, oxidized variants of serosoderjaschei compounds, disulfide variants of serosoderjaschei compounds, oxidized disulfide variant is in serosoderjaschei compounds, etc.

On the other hand, variants of compounds with disulfide fragment can be obtained from the analogues of serine and homoserine by conversion of the terminal hydroxyl group into a leaving group, for example halogen, alkyl or arylsulfonyl, aryloxy and the like, to obtain the compounds of formula (I) or (III)as shown in scheme V and demonstrated for compounds of formula (I).

The scheme of synthesis V

Analogues of serine and homoserine can be converted into compounds of formula (xii), where L is a leaving group, using standard methods. Then the compound (xii) can be converted into compound (xiii) by treatment of the sulfide anion, disulfide-anion, sulfoxide-anion or sulfonyl-anions, where R15corresponds to the data in this application definitions and m is 1 or 2. It is believed that other nucleophiles, including sulfonylurea, can also be used for substitution of the leaving group L in obtaining the compounds (xiii).

On the other hand, compounds with oxidized sulfur atoms can be synthesized by treatment of the resulting nucleophilic substitution thioesters or disulfide compounds oxidizing agent, such as an oxidizer based on peroxides, etc. In a typical oxidizing agents include hydrogen peroxide, other peroxides, peroxyacids, etc. In the case of oxidation of disulfides with udaetsya, the oxidation may be only one of the two sulfur atoms. In addition, it is believed that such conditions can be selectively oxidized sulfur atom, which is next to the group, which is a stronger donor electron density.

On the other hand, compounds with oxidized sulfur atoms can be synthesized by conventional treatment thioester or disulfide compounds described in this application, an oxidizer, such as oxidant on the basis of peroxides, etc. In a typical oxidizing agents include hydrogen peroxide, other peroxides, peroxyacids, etc. In the case of oxidation of disulfides is considered that oxidation may be only one of the two sulfur atoms. In addition, it is believed that such conditions can be selectively oxidized sulfur atom, which is next to the group, which is a stronger donor electron density.

The compounds obtained according to the synthesis schemes I-V, can be pure diastereoisomers, mixtures of diastereoisomers or racemates. The actual stereochemical composition of the compounds will be determined by the specific reaction conditions, the combination of the substituents and stereochemistry and optical activity of the applied reagents. It is believed that diastereomeric mixtures can be separated by chromatography or by fractional crystallization from gaining the m if desired, individual diastereomers, with the use of standard techniques. In particular, the reactions described in the schemes of synthesis II, III and IV, creates a new chiral center at the carbon atom bearing the substituent R1.

In addition, the described alternative methods of synthesis, including the synthesis of several representatives of the structural class of esters and amides of substituted 2-(azetidin-2-on-1-yl)acetic acid, to obtain β-lactamase antibiotics. See, for example, U.S. patent No. 4751299.

The following syntheses and examples provide additional information about the connections, which are indicative described in this application of the invention, including methods of synthesis of these compounds, but in respect of these syntheses and examples are not meant and should not assume that they whatever way limit the scope of the present invention. Unless otherwise stated, all reactions were carried out at room temperature, and evaporation of the reaction mixtures was carried out in vacuum. All the following compounds were characterized by standard analytical methods, including spectroscopy nuclear magnetic resonance (NMR) and mass spectral analysis (MS).

EXAMPLES

In each of the examples below range1H NMR was consistent with proposed structure. In addition, conducted m the SS-spectral analysis using FAB +for observation of the corresponding ion (M+H)+.

EXAMPLE 1A

(4(S)-phenyloxazolidine-2-he-3-yl)acetylchloride

A solution of 1.0 equivalent of (4(S)-phenyloxazolidine-2-he-3-yl)acetic acid (Evans, U.S. patent No. 4665171) and 1.3 equivalent of oxalicacid in 200 ml of dichloromethane was treated with a catalytic amount of anhydrous dimethylformamide (85 μl/milliequivalent derivative of acetic acid), which led to a vigorous evolution of gas. After 45 minutes the gas is completely stopped, and the reaction mixture was concentrated under reduced pressure, obtaining mentioned in the title compound in the form of not-quite-white solid after drying in vacuum for 2 hours

EXAMPLE 1B

4(R)-phenyloxazolidine-2-he-3-yl)acetylchloride

The compound was obtained by following the procedure of example 1A, except that he used (4(R)-phenyloxazolidine-2-he-3-yl)acetic acid instead of (4(S)-phenyloxazolidine-2-he-3-yl)acetic acid (see Evans & Sjogren, Tetrahedron Lett. 26:3783(1985)).

EXAMPLE 1C

2-(4(S)-phenyloxazolidine-2-he-3-yl)propanolol

A solution of 1 equivalent of the compound of example 3A and 1.3 equivalents of oxalicacid in 200 ml of CH2Cl2(150 ml/g of propionic acid derivative) was treated with a catalytic amount of anhydrous DMF (85 μl/mmol derived propionic acid), th is led to the rapid evolution of gas. After 45 min the gas is completely stopped, and the reaction mixture was concentrated under reduced pressure, obtaining mentioned in the title compound in the form of not-quite-white solid after drying in vacuum for 2 hours

EXAMPLE 2A

Methyl(4(S)-phenyloxazolidine-2-he-3-yl)acetate

Solution (4(S)-phenyloxazolidine-2-he-3-yl)acetic acid (1 g, to 4.52 mmol) (Evans in U.S. patent No. 4665171) in 20 ml of anhydrous methanol during each hour was treated with 5 equivalents of acetylchloride, using a total of 20 equivalents. The resulting solution was stirred over night. The residue obtained after evaporation of methanol, re-dissolved in 30 ml of CH2Cl2and was treated with 50 ml of a saturated aqueous solution of Na2CO3. The organic layer was evaporated and dried (MgSO4), getting mentioned in the title compound as a colourless oil (1,001 g, 94%);1H NMR (CDDl3): δ 3,37 (d, J=18,0 Hz, 1H), 3,69 (c, 3H), of 4.13 (t, J=8,3 Hz, 1H), 4,28 (d, J=18,0 Hz, 1H), 4,69 (t, J=8,8 Hz, 1H), 5,04 (t, J=8,4 Hz, 1H), 7,26-7,29 (m, 2H), was 7.36-7,42 (m, 3H).

EXAMPLE 2B

Methyl 2-(4(S)-phenyloxazolidine-2-he-3-yl)propanoate

A solution of the compound of example 2A (1 g, of 4.25 mmol) in 10 ml of anhydrous THF at -78°C was treated to 4.68 ml (4,68 mmol) of 1M solution of bis(trimethylsilyl)amide lithium in THF. The reaction mixture was stirred for 1 h at approximately -70°C and then added MeI (,59 ml, 25,51 mmol). After full conversion of azetidinone the reaction mixture was extinguished saturated aqueous NH4Cl and was distributed between EtOAc and water. The organic layer was sequentially washed with a saturated aqueous solution of sodium bisulfite and saturated aqueous NaCl. The resulting organic layer was dried (MgSO4) and was evaporated, getting mentioned in the title compound (mixture of diastereomers) as a white solid (1.06 g, 93%);1H NMR (CDCl3): δ 1,07/1,53 (d/d, J=7.5 Hz, 3H), 3,59/3,74 (c/c, 3H), 3,85/4,48 (kV/kV, J-7.5 Hz, 1H), 4,10-to 4.14 (m, 1H), 4,60-4,64/4,65-4,69 (m/m, 1H), 4,88-4,92/4,98-5,02 (m/m, 1H), 7.24 to 7,40 (m, 5H).

EXAMPLE 3A

2-(4(S)-phenyloxazolidine-2-he-3-yl)propanoic acid

To a solution of compound of example 2B (1 g, to 4.01 mmol) in 35 ml of MeOH was added at 0°C and 14.3 ml (12,04 mmol) 0,84M solution of LiOH in water. Then the reaction mixture was stirred for 3 h at room temperature. Upon completion of the hydrolysis of azetidinone MeOH was removed by evaporation, the crude residue was dissolved in CH2Cl2and was treated with saturated aqueous NaCl. The obtained organic layer was dried (MgSO4) and was evaporated, getting mentioned in the title compound (racemic mixture) as a white solid (0,906 g, 96%).1H NMR (CDCl3): δ 1,13/1,57 (d/d, J=7.5 Hz, 3H), 3.75 per 4,50 (kV/kV, J=7.5 Hz, 1H), 4,10-4,16 (m, 1H), to 4.62-4.72 in (m, 1H), 4.92 in-to 5.03 (m, 1H), 7,32-the 7.43 (m, 5H).

EXAMPLE 4

About the aja method for producing amides from activated ether derivatives

β-tert-Butyl ester α-(3-trifluoromethyl)benzylamine N-menthoxycarbonyl-L-aspartic acid. A solution of β-tert-butyl ester α-N-hydroxysuccinimidylN-menthoxycarbonyl-L-aspartic acid (1,95 g, with 4.64 mmol, Advanced ChemTech) in 20 ml of dry tetrahydrofuran was treated with 0.68 ml (4,74 mmol) 3-(trifluoromethyl)benzylamine. After completion of the reaction (TLC, 60:40 hexane/ethyl acetate) and the mixture was evaporated and the resulting oil was distributed between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was evaporated and receiving of 2.23 g (quantitative yield) specified in the title compound as a white solid.1H NMR (CDCl3): δ 1.39 in (c, 9H), 2,61 (DD, J=6,5 Hz, J=and 17.2 Hz, 1H), 2,98 (DD, J=3,7 Hz, J=17,0 Hz, 1H), to 4.41 (DD, J=5,9 Hz, J=15.3 Hz, 1H), 4,50-of 4.57 (m, 2H), 5,15 (c, 2H), 5,96 of 5.99 (m, 1H), 6,95 (c, 1H), 7,29-7,34 (m, 5H), 7,39-the 7.43 (m, 2H), of 7.48-7,52 (m, 2H).

EXAMPLE 5

General methods of hydrolysis of tert-butyl esters

A solution of tert butyl ether complex in formic acid, typically, 1 g in 10 ml) was stirred at room temperature until until the air was no longer detected by thin layer chromatography (dichloromethane to 95%/methanol 5%), with a typical reaction time was about 3 hours. Formic acid is evaporated under reduced pressure, the obtained solid residue was distributed between dichloromethane and saturated the one solution of bicarbonate. The organic layer was evaporated, getting not quite white solid, which can be used directly for further reactions or optionally be recrystallized from a solvent system.

EXAMPLE 6

A General method of obtaining the amides of the carboxylic acids

Shown for the case of obtaining β-tert-butyl ester α-(3-trifluoromethyl)benzylamineN-menthoxycarbonyl-D-aspartic acid. A solution of 1 g (at 2.93 mmol) monohydrate, β-tert-butyl ether N-menthoxycarbonyl-D-aspartic acid (Novabiochem) in 3-4 ml of dichloromethane was treated with sequential addition and 0.46 ml (3,21 mmol) 3-(trifluoromethyl)benzylamine, of 0.44 g (3,23 mmol) 1-hydroxy-7-benzotriazole and 0.62 g (3,23 mmol) of the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide. After at least a 12-hour incubation at room temperature, or after completion of the reaction according to thin-layer chromatography (eluent 95:5 dichloromethane/methanol) and the reaction mixture was then washed with saturated aqueous sodium bicarbonate solution and distilled water. The organic layer was evaporated and receiving of 1.41 g (quantitative yield) specified in the title compound in the form of not-quite-white solid.1H NMR (CDCl3): δ 1.39 in (c, 9H); 2,61 (DD, J=6,5 Hz, J=and 17.2 Hz, 1H); 2,98 (DD, J=4,2 Hz, J=and 17.2 Hz, 1H); to 4.41 (DD, J=5,9 Hz, J=15.3 Hz, 1H); 4,50-of 4.57 (m, 2H); 5,10 (c,2H); 5,96-6,01 (m, 1H); 6,91-7,00 (m, 1H); 7,30 and 7.36 (m, 5H); 7,39-the 7.43 (m, 2H); of 7.48-7,52 (m, 2H).

EXAMPLE 6A

N-tert-butoxycarbonyl-(S)-benzyl-D-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidine

N-tert-butyloxycarbonyl-(S)-benzyl-D-cysteine (0,289 g of 0.93 mmol) and 4-[2-(1-piperidyl)ethyl]piperidine (0,192 g, 0.98 mmol) were mixed in dichloromethane (20 ml) according to the method of example 6, receiving 0,454 g (quantitative yield) not quite white solid.1H NMR (CDCl3): δ 0,89-of 1.15 (m, 2H); 1,39-of 1.44 (m, 16H); 1,54-to 1.61 (m, 4H); 1,62-1,71 (m, 1H); 2.21 are to 2.35 (m, 5H); 2,49-of 2.58 (m, 2H); 2,66-to 2.74 (m, 1H); 2,79-of 2.97 (m, 1H); 3,67 is 3.76 (m, 3H); 4,48-4,51 (m, 1H); 4.72 in-the 4.75 (m, 1H); 5,41-5,44 (m, 1H); 7,19-7,34 (m, 5H).

EXAMPLE 7A

tert-Butyl ether N-[(9H-fluoren-9-yl)methoxycarbonyl]-O-benzyl-D-serine

N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-benzyl-D-serine (0,710 g, 1.70 mmol) in dichloromethane (8 ml) was treated with tert-butyl acetate (3 ml) and concentrated sulfuric acid (40 ml) in a sealed flask at 0°C. After completion of the communication (TLC), the reaction mixture was extinguished dichloromethane (10 ml) and saturated aqueous potassium bicarbonate (15 ml). The organic layer was washed with distilled water and evaporated. The obtained residue was column purified flash chromatography (98:2 dichloromethane/methanol)to give 0,292 g (77%) of colorless oil.1H NMR (CDCl3): δ 1,44 (c, 9H); 3,68 (DD, J=2,9 Hz, J=9,3 Hz, 1H); a 3.87 (DD, J=2,9 Hz, J=9,3 Hz, 1H); 4,22 (t, J=7,1 Hz, 1H); 4,30-4,60 (m, 5H); 5,64-5,67 (m, 1H); 7,25-7,39 (m, 9H); ,58-7,61 (m, 2H); 7,73-7,76 (m, 2H).

EXAMPLE 8A

tert-Butyl ether O-benzyl-D-serine

The compound of example 7A (0,620 g of 1.31 mmol) in dichloromethane (5 ml) was treated with Tris(2-amino-ethyl) - amine (2,75 ml) for 5 hours the mixture was twice washed in phosphate buffer (pH=5,5), once with saturated aqueous solution of potassium bicarbonate and evaporated, getting 0,329 g (quantitative yield) specified in the title compound in the form of not-quite-white solid.1H NMR (CD3OD): δ 1,44 (c, 9H); of 3.48 (DD, J=J'=4,2 Hz, 1H); 3,61 (DD, J=4.0 Hz, J=9,2 Hz, 1H); and 3.72 (DD, J=4,6 Hz, J=9,2 Hz, 1H); 4,47 (d, J=12.0 Hz, 1H); 4,55 (d, J=12.0 Hz, 1H); 7,26-7,33 (m, 5H).

EXAMPLE 9

A General method of obtaining 2-azetidinone of imine and acetylchloride

Stage 1: General method of obtaining the imine derived from amino acids. A solution of 1 equivalent of the ester or amide of an α-amino acid in dichloromethane was sequentially treated with 1 equivalent of an appropriate aldehyde and a dehydrating reagent, for example, magnesium sulfate or silica gel in an amount of about 2 g of dehydrating reagent per gram of the original ester or amide of an α-amino acids. The reaction mixture was stirred at room temperature until, until the original connection is not fully entered into the reaction, which was determined using thin-layer chromatography. As a rule, the reaction was completed within one hour. Then the reaction mixture was filtered, the of Adak on the filter was washed with dichloromethane, the filtrate was concentrated under reduced pressure and obtained the desired Imin, which was used in the subsequent stage without further purification.

Stage 2: General methods 2+2 cycloaddition imine and acetylchloride. The imine solution in dichloromethane (10 ml dichloromethane/1 g imine) was cooled to 0°C. To this chilled solution was added 1.5 equivalents of a suitable amine, as a rule, triethylamine, and then was added dropwise a solution of 1.1 equivalents of a suitable acetylchloride, for example, described in example 1A, in dichloromethane (10 ml dichloromethane/1 g suitable acetylchloride). The reaction mixture was allowed to warm to room temperature over 1 h and then was suppressed by the addition of saturated aqueous solution of ammonium chloride. The resulting mixture was distributed between water and dichloromethane. The layers were separated and the organic layer is successively washed with 1 N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue can be used directly in further reactions or, if desirable, can be cleaned by chromatography or recrystallization from a suitable solvent system.

EXAMPLE 9A

tert-Butyl (2R)-(benzoyloxymethyl)-2-[3(S)-(4(S)-penile Catholicon-2-he-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate

Imin obtained from 0,329 g (1,31 mmol) of tert-butyl methyl etherO-benzyl-D-serine (example 8A) and cinnamic aldehyde, was mixed with 2-(4(S)-phenyloxazolidine-2-he-3-yl)acetylchloride (example 1A) according to the method of example 9 and was obtained 0,543 g (73%) of product after purification column chromatography (90:10 hexane/ethyl acetate);1H NMR (CDCl3): δ 1.39 in (c, 9H); of 3.56 (DD, J=2.7 Hz, J=9.5 Hz, 1H); 3,82 (DD, J 4.8 Hz, J=9.5 Hz, 1H); 4,11 (t, J=8,3 Hz, 1H); 4,21-the 4.29 (m, 2H); 4,50-4,58 (m, 3H); 4,71-4,78 (m, 2H); to 6.19 (DD, J=9.1 Hz, J=16.0 Hz, 1H); of 6.49 (d, J=16.0 Hz, 1H); 7,07-7,11 (m, 1H); 7,19-7,40 (m, 14H).

EXAMPLE 9B

N-[4-[2-(piperid-1-yl)ethyl]piperidine-1-yl]amide of (2S)-(benzyldimethyl)-2-[3(S)-(4(S)-phenyloxazolidine-2-he-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid

Imin obtained from the dihydrochloride of (S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidine (example 11A, 0,417 g, 0.90 mmol) and cinnamic aldehyde in the presence of triethylamine (0.26 per ml, of 1.87 mmol), was introduced in the reaction with 2-(4(S)-phenyloxazolidine-2-he-3-yl)acetylchloride (example 1A) according to the method of example 9, receiving 0,484 g (76%) of product as not quite white solid after recrystallization from a mixture of dichloromethane/hexane.1H NMR (CDCl3): δ 0,89 was 1.06 (m, 2H); 1,40-of 1.44 (m, 5H); 1,57-to 1.67 (m, 6H); 2,25 is 2.43 (m, 6H); 2,45 at 2.59 (m, 2H); 2.71 to is 2.88 (m, 2H); 3,55-3,70 (m, 3H); 4,11-4,17 (m, 1H); 4,37-4,47 (m, 2H); 4,54-br4.61 (m, 1H); with 4.64-4,69 (m, 1H); 4,76-4,84 (m, 2H); 6,05-to 6.19 (m, 1H); 6,66-of 6.71 (m, 1H); 7,12-7,40 (m, 15H).

Connection EXAMPLES 9C-9AD, shown in clubusacasino, can also be obtained with the use described in this application techniques, by replacing the above-described derivatives of serine or cysteine derivatives corresponding to the compounds shown below.

9AD
ExampleAn'Q'm'
9C(3-triptorelin)amino2-O-1
9D4-(3-triptoreline)piperazine-1-Il2-O-2
9E4-(3-triptoreline)piperazine-1-Il2-O-1
9F4-cyclohexylpiperazine-1-yl2-O-2
9G4-(piperidine-1-ylmethyl)piperidine-1-yl2-O- 1
9H4-(piperidine-1-yl)piperidine-1-yl2-O-2
9I4-[2-(piperidine-1-yl)ethyl]piperidine-1-yl2-O-1
9J(3-triptorelin)amino1-S-2
9K4-(3-triptoreline)piperazine-1-Il1-S-1
9L4-(3-triptoreline)piperazine-1-Il1-S-2
9M4-cyclohexylpiperazine-1-yl1-S-1
9N4-(piperidine-1-ylmethyl)piperidine-1-yl1-S-2
9O4-(piperidine-1-yl)piperidine-1-yl 1-S-1
9P4-[2-(piperidine-1-yl)ethyl]piperidine-1-yl1-S-2
9Q(3-triptorelin)amino2-S-2
9R4-(3-triptoreline)piperazine-1-Il2-S-1
9S4-(3-triptoreline)piperazine-1-Il2-S-2
9T4-cyclohexylpiperazine-1-yl2-S-1
9U4-(piperidine-1-ylmethyl)piperidine-1-yl2-S-2
9V4-(piperidine-1-yl)piperidine-1-yl2-S- 1
9W4-[2-(piperidine-1-yl)ethyl]piperidine-1-yl2-S-2
9X(3-triptorelin)amino0-CH2-1
9Y4-(3-triptoreline)piperazine-1-Il0-CH2-2
9Z4-(3-triptoreline)piperazine-1-Il0-CH2-1
9AA4-cyclohexylpiperazine-1-yl0-CH2-2
9AB4-(piperidine-1-ylmethyl)piperidine-1-yl0-CH2-1
9AC4-(piperidine-1-yl)piperidine-1-yl0-CH2-2
4-[2-(piperidine-1-yl)ethyl]piperidine-1-yl0-CH2-1

EXAMPLE 10A

(2R)-(Benzoxazolyl)-2-[3(S)-(4(S)-phenyloxazolidine-2-he-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid

The compound of example 9A (0.16 g, 0.28 mmol) is hydrolyzed according to the method used in example 5, receiving 0,144 g (quantitative yield) not quite white solids;1H NMR (CDCl3): δ of 3.65 (DD, J=4.0 Hz, J=9.5 Hz, 1H); 3,82 (DD, J=5.5 Hz, J=9.5 Hz, 1H); 4,11 (DD, J=7.8 Hz, J=8,8 Hz, 1H); 4,33 (c, 2H); 4,50 (d, J=5.0 Hz, 1H); of 4.57 (t, J=9.0 Hz, 1H); of 4.67 (DD, J=4.0 Hz, J=5.0 Hz, 1H); 4,69 (DD, J=5.0 Hz, J=9.5 Hz, 1H); 4.75 V (t, J=8.0 Hz, 1H); 6,17 (DD, J=9,3 Hz, J=15,8 Hz, 1H); 6,55 (d, J=16.0 Hz, 1H); 7,09 for 7.12 (m, 2H); 7,19-7,42 (m, 13H).

The compound of example 10A was used for other derivatives of amides and esters, such as amides and esters represented by the group a in the compounds of formula (I), (II) and (III).

EXAMPLE 11A

The dihydrochloride (S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidylamine

During the night spent interaction of N-tert-butoxycarbonyl-(S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidine (0,453 g of 0.93 mmol) acetylchloride (0,78 ml, 13,80 mmol) in anhydrous methanol (15 ml). Specified in the title compound was obtained in the form of not quite white solid by evaporation of the reaction mixture DOS is ha (0,417 g, 97%).1H NMR (CD3OD): δ 0,94-of 1.29 (m, 2H); 1,49-of 1.57 (m, 1H); 1,62-of 1.95 (m, 10H); 2,65 is 2.80 (m, 2H); 2,81-of 2.97 (m, 4H); 3,01-3,14 (m, 2H); 3,50-3,60 (m, 3H); 3,81-to 3.92 (m, 2H); to 4.41-4,47 (m, 2H); 7,25-7,44 (m, 5H).

EXAMPLE 12A

tert-Butyl [3(S)-(4(S)-phenyloxazolidine-2-he-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate

Imin obtained from a 4.53 g (34.5 mmol) of tert-butyl ester of glycine and cinnamic aldehyde, was introduced in the reaction with 2-(4(S)-phenyloxazolidine-2-he-3-yl)acetylchloride (example 1A) using the procedure of example 9, receiving 5.5 g (30%) of the compound indicated in the title, in the form of colorless crystals after recrystallization from n-chlorobutane); MP 194-195°C.

EXAMPLE 13

The General procedure of alkylation and/or acylation (azetidin-2-on-1-yl)acetate

Solution (azetidin-2-on-1-yl)acetate in tetrahydrofuran (0.22 M for azetidinone), as in example 12A, cooled to -78°C and was treated with bis(trimethylsilyl)amidon lithium (2.2 equivalent). The resulting anion was treated with the appropriate alkyl or allelochemical (1.1 equivalent). After all, azetidine entered into the reaction, the reaction mixture was extinguished saturated aqueous ammonium chloride and distributed between ethyl acetate and water. The organic phase is successively washed with 1 N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The obtained organic layer was dried (sulf is tons of magnesium) and evaporated. The residue was purified by chromatography on silica gel using a suitable eluent, such as a mixture of 3:2 hexane/ethyl acetate.

This technique was used to obtain the compounds of formula (I), (II) and (III) an alternative method of synthesis of the common intermediate compounds, such as tert-butyl[3(S)-(4(S)phenyloxazolidine-2-he-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate and related compounds. In addition, this technique was used to obtain alkyl and acylated analogs described in this application compounds, for example compounds of formula (I), (II) and (III)in which the substituent R1different from hydrogen. Further, it is believed that this technique can be modified for the introduction of additional groups in azetidinone cycle with the aim of obtaining described in the present application are compounds in which the substituent R2different from hydrogen.

It is believed that epimer of these compounds on the carbon atom situated in the alpha position relative to azetidinone cycle, can also be obtained in accordance with the above-described methods by choosing the appropriate starting compounds. In addition, all other connections which are among the compounds of formula (I), (II) and (III)can also be obtained mainly by the methods of the preceding examples.

In another embodiment, compounds described in anastasimatarion, applicable as receptor antagonists of vasopressin V1aV1band V2in the treatment of patients suffering from diseases and morbid conditions that sensitive receptors vasopressin V1aV1band V2. To illustrate the methods described in the present invention include the stage of introduction to a subject or patient in need of such treatment, an effective amount of the compounds described by the formulae given in this application. Antagonism against different subtypes of receptors of vasopressin is accompanied by numerous physiological and therapeutic beneficial effects. These effects may appear due to antagonism at the receptor vasopressin both peripheral and Central nervous system. Applications related to the peripheral nervous system include the introduction of receptor antagonists of vasopressin V1aand/or V2as an aid in heart failure or as antithrombotic funds. Effect on the Central nervous system consists of the administration of receptor antagonists of vasopressin V1aand/or V1bi.e. compounds described in this application, for the treatment of obsessive-compulsive disorders, aggressive disorders, depression, tre is agnosti and other psychological and neurological disorders.

Illustrative painful conditions that are sensitive receptor antagonists vasopressin V2and may be subject to the treatment described in the present application methods include various cardiovascular disorders, including disorders or conditions associated with platelet aggregation, etc. in Addition, the present invention describes methods for treatment of other diseases or medical conditions that may be treated, for example, the receptor antagonists of oxytocin, antagonists of the receptor tachykinin, receptor antagonists neirokinina 1, antagonists of the receptor neirokinina 2, etc. where the method includes a step of introducing the patient, if necessary, facilitate such diseases or conditions, an effective amount of one or more compounds from among substituted 2-(azetidin-2-on-1-yl)alkalicarbonate acids, substituted 2-(azetidin-2-on-1-yl)hydroxyalkylated acids, substituted 2-(azetidin-2-on-1-yl)alkylamino acids and their analogs and derivatives described in this application.

EXAMPLE METHODS 1

Cells expressing the human receptor vasopressin V1b

cDNA of the human vasopressin receptor 1B (HV1B) (see Lolait et al., "Extrapituitary expression of the rat Vlb vasopressin receptor gene," Proc. Natl. Acad. Sci. USA. 92:6783-7 (1995); de Keyzer et al, "Cloning and characterization of the human V3(Vlb) pituitary vasopressin receptor" FEBS Lett. 356:215-20 (1994); Sugimoto et al., "Molecular cloning and functional expression of a cDNA encoding the human Vlb vasopressin receptor" J. Biol. Chem. 269:27088-92 (1994)) have been built into the expression vector mammalian cell PCI-neo (Promega) at the EcoR1 site. The recombinant plasmids carrying cDNA HV1B, was isolated from transformed clones of E. coli and used for transfection of cells of the Chinese hamster ovary (CHO-K1, ATCC). Two micrograms of DNA receptor HV1B was introduced in 105the CHO cells, cultured in 6-hole tablet, using the method of transfection mediated Fugene-6 (Boehringer Mannheim). Twenty-four hours after transfection cells were cultured in selection in G-418 (0.25 mg/ml), was added to the culture medium. Three days later conducted a limited dilution to obtain isolated cell clones in 96-well plates. After a 2-week period of growth monoclone were divided into two groups of 12-well plates. Upon reaching confluently one group of holes explored by the ability to bind tritium-labeled arginine-vasopressin (NEN). Were initially identified nine positive clones from among the 60 studied, and the clones that showed the highest binding AVP, kept as permanent cell lines for screening compounds Serenix the affinity to HV1B.

EXAMPLE METHODS 2

Cellular analysis of binding people the human or the rat receptor V 1aV1band/or V2

Cell lines V1aV1band/or V2(cells expressing human or rat receptor V1aV1band/or V2) were grown in medium alpha-MEM with the addition of 10% calf serum and 250 μg/ml G418 (Gibco, Grand Island, NY) in a flask with a volume of 75 cm3. For the competitive analysis of binding cells HV1b separated from each other by using not containing enzyme solution to separate cells on the basis of PSB (Speciality Media, Phillipursburg, NJ)following the manufacturer's instructions. The cells were placed in 12-hole culture plates in the number one flask for 18 tablets (quantity should be adjusted depending on the degree of confluently cells) and maintained in culture for 2-3 days. Then the culture medium was removed, cells were once washed with 2 ml of binding buffer (25 mm Hepes, 0.25% of BSA, 1xDMEM, pH=7.0) at room temperature. To each well was added to 990 μl of binding buffer containing 1 nm3H-AVP and then 10 μl of serially diluted test compounds or not labeled AVP (all solutions in DMSO). Each analysis was performed in triplicate and got curves of inhibition from the dosage consisting of points corresponding to the common binding (only DMSO) and 5 concentrations of 0.1, 1.0, 10, 1000, and 1000 nm) test compound or not labeled AVP, the coverage is non IC 50. Cells were incubated for 30 minutes at 37°C in a humidified incubator. Then the analytical mixture was removed and each well three times washed with PBS (pH=7,4). After washing was added 1 ml of 2% SDS in the hole and content of the tablets was allowed to settle for 15 min at room temperature. Gently knock on the tablets, to ensure the detachment of the destroyed cells. The contents of the wells completely transferred into vials for scintillation counting. Then each well was washed with 0.5 ml PBS and added to the appropriate bottle. Then add scintillation fluid (Ecoscint, National Diagnostics, Atlanta, Georgia) in an amount of 3 ml per vessel. Count of samples on the counter scintillation fluid (Beckman LS801). Calculated IC50and Kiusing the program Prism Curve to the curve at points.

In the above analysis using cells expressing the human receptor V1aor V1b, were tested compounds isolated examples. The values of the affinity for binding (IC50for illustrative compounds are given in the following table. In addition, the table shows the inhibition constants (Ki) illustrative compounds.

ExampleHuman. V1a,
the affinity for binding (IC50 (nm))
Human. V1a,
the affinity for binding (Ki(nm))
Human. V1b,
the affinity for binding (IC50(μm))
Human. V1b,
the affinity for binding (Ki(μm))
9B0,110,071,100,69

EXAMPLE METHODS 3

Inhibition of metabolism phosphatidylinositol-mediated receptor vasopressin V1bfunctional analysis of the activity of antagonists

Physiological actions of vasopressin mediated by specific receptors associated with G-protein. Receptors of vasopressin V1aV1band/or V2associated with G-protein, which is associated with cAMP. Agonistic or antagonistic nature described in this application connections can be identified by their ability to inhibit mediated by vasopressin metabolism phosphatidylinositol using standard techniques, including the techniques described in the following paragraphs.

Cells expressing human or rat receptor V1aV1band/or V2were grown in alpha-modifitsirovannoi minimum maintenance medium containing 10% calf serum and 0.25 is g/ml G418. Three days prior to analysis close to confluently culture was divided and were sown in 6-well plates to tissue cultures, and about 100 wells were seeded from each 75 cm3bulb (division equivalent ratio of 12:1). Each well contained 1 ml of growth medium with 2 mccoury [3H] myoinositol (American Radiolabeled Chemicals, St. Louis, MO).

All analyses were performed in triplicate, except the source and 10 nm AVP (for both n=6). Arginine vasopressin (AVP) was dissolved in 0.1 G. of acetic acid. The tested drugs were dissolved in DMSO on the day of the experiment and diluted in DMSO to 200 times, i.e. the end of the studied concentrations. Potential medicines and AVP (or the corresponding volume of DMSO) separately added in 5 μl of DMSO in a glass test tube h mm, containing 1 ml of analytical buffer (balanced salt solution Tyrode containing 50 mm glucose, 10 mm LiCl, 15 mm HEPES, pH of 7.4, 10 μm phosphoramidon and 100 μm bactracin). Incubation was performed in a random order. Incubation began with the removal of the medium containing the label, once washing the monolayer of 1 ml of 0.9% NaCl and adding content in a test tube for analysis. The plates were incubated for 1 h at 37°C. the Incubation was stopped by removing the incubation medium, add 500 ál of ice-cold 5% triperoxonane acid and leaving the mixture for 15 mine is.

Products incubation was divided into columns (BioRad Poly-Prep Econo-Columns filled with 0.3 ml formiates resin AG 1 X-8100-200. The resin was mixed with water in the ratio 1:1 and in each column was added 0.6 ml of the mixture. Then the column was washed with 10 ml water. Under each column was placed scintillation vessel (20 ml). The contents of each incubation, the wells was transferred into microcolony, after which the wells were washed with 0.5 ml distilled water, which was also added in microcolony. Then double-column washed with 5 ml of 5 mm myoinositol for elution of free Inositol. 1 ml aliquots of the resulting liquid was transferred into a new 20 ml scintillation vessels, was added 10 ml of Beckman Ready Protein Plus and made calculations. After washing myoinositol, empty scintillation vessels were placed under the column and suirable [3H]-containing insertspace three times by adding 1 ml of 0.5 M ammonium formate containing 0.1 G. of formic acid. The elution conditions were optimized to obtain the mono-, bis - and triphosphate Inositol, without elution is more metabolically inert tetrakis-, pentakis and hexacis phosphates. The samples were calculated on the multipurpose scintillation counter Beckman LS 6500 after adding 10 ml of scintillation fluid Tru-Count High Salt Capacity.

The content of Inositol lipids was measured by adding 1 ml of sodium dodecyl sulfate (DS) in each well, then gave the contents of the wells to settle for at least 30 minutes of Dissolved content of each well was transferred into a 20 ml scintillation vial. Added 10 ml of scintillation fluid Beckman Ready Protein Plus and made calculations of radioactivity.

Curves the concentration-response AVP curves and concentration-inhibition for the tested compounds compared with 10 nm AVP investigated the nonlinear method of least squares - fitting of curves relative to the 4-parameter logistic function. Varied parameters are the initial and maximum levels of insiteful, EC50or IC50and the hill coefficient to achieve the best match. In the process of fitting curves weights were chosen in accordance with the assumption that the standard deviation is proportional to the number of radioactive decays per minute. In each experiment built full curves of the concentration-response AVP and the value of the IC50were converted into values of Kiusing the equation of Cheng-Prusoff, based on the value EC50for AVP in the same experiment. The content of insiteful expressed as the number of disintegrations per minute on 106disintegrations per minute of total Inositol.

Experiments to determine the competitiveness of the tested compounds was in the village of the industry curve concentration-response AVP in the absence and presence of test compounds at two or more concentrations. Data were agreed with the following logistic equation describing competitive binding:

where Y represents the number of disintegrations per minute for Inozemtsev, B means the concentration of the original Inozemtsev, M represents the maximum increase in the concentration of insiteful, And the mean concentration of agonist (AVP), E represents EC50for agonist, D is the concentration of agonist, K represents the Kiagonist and Q means cooperatively (the hill coefficient).

Experiments to determine the competition of the tested compounds was to build the curves of the concentration-response AVP in the absence and presence of test compounds at least five concentrations. Values of Kithat reflected the activity of AVP antagonists in the formation of signaling molecule IP3, was calculated using the program PRISM on the basis of the equation of Cheng and Prusoff.

The EXAMPLE METHOD 4

Detection of seed Golden hamsters

It is believed that in certain conditions, the ability of hamsters to detect seeds may reflect the level of their anxiety. The described research methods ability to detect seeds in hamsters exposed to are described in this application connections, is an animal model of anxiety.

M is iskich individuals Syrian Golden hamsters ( Mesocricetus auratus) (120-130 g)obtained from the laboratory Harlan Sprague-Dawley Laboratories (Indianapolis, IN), were placed one by one into the cells of plexiglass (24 cm × 24 cm × 20 cm), contained in the reverse cycle light:dark (14:10; light included at 19:00) and provided food and water without restrictions. All tests were performed during the dark phase of the daily cycle in low red light. Before testing, all animals were starved for 20-24 hours. After 90 minutes after intraperitoneally (IP) injection SRX262 (n=10) or saline media (n=10) animals were removed from their permanent cells and placed in a temporary cage for 2 minutes. During their absence under the bedding in the corner of their permanent cells laid six sunflower seeds. Animals were placed in their permanent cell, randomly placing them head towards one of the empty corners of the cell and locking the delay time detection of seed during the five-minute observation period. Delay in detection of the seeds was decreased after administration of compounds described in this application, and the delay was comparable in magnitude with the delay in the introduction of fluoxetine, buspirone and hlordiazepoksida.

EXAMPLE METHODS 5

Social subordination in hamsters, the study of biochemical marker

There are a group of literary sources that describe the neuroendocrine and providences the e consequences of repeated social subordination in adult male Golden hamsters. Lesions in fights with other individuals and the transition to a lower social status cause of adult animals severe stress, leading to changes in the levels of adrenal and gonadally steroids, as well as changes in social behavior (Rose et al., 1975; Eberhart et al., 1980, 1983). Studies of adult male hamsters showed reduced levels of testosterone and increased levels of glucocorticoids after repeated defeats from dominant individuals of their own species (Huhman et al., 1991).

Male hamsters were placed and maintained as described above. For 30 minutes each day for 14 consecutive days, animals were subjected to the threat and attacked by the larger members of the species (n=14). After these daily episodes of traumatic stress, animals were left alone in their regular cells for 10 days. During this recovery period, the animals were injected compounds of the present invention (1 mg/kg/day) (n=7) or saline (n=7). At the end of injection the animals were killed by decapitation and collected blood from the body for holding radioimmune analysis of testosterone and cortisol. Testosterone levels hamsters that were in constant subjection, were very low, whereas baseline levels of cortisol were high. This neuroendocrine profile has changed under the action of the link is, described in this application. The collected data showed that blocking the receptor V1bcan improve recovery from traumatic stress, such as social subordination.

EXAMPLE METHODS 6

Social subordination in hamsters, the study of behavior, the selection of antidepressant activity

For example, hamsters was used the model of social subordination in the scheme of "resident intruder". Model of aggression resident/intruder is based on the motivation of the resident animal to chase and fight intruders falling on their territory (Miczek 1974). Smaller animals are placed in a permanent cell as residents in the ongoing clashes with the enemy will suffer defeat and become socially subordinate. Social subordination is a significant natural cause of stress in the animal Kingdom. Animals, defeated and subordinates in establishing a dominant hierarchy or territorial skirmishes, can be highly inclined to submit to future agonistic interactions.

For example, defeated the mouse demonstrates less aggression and more likely to subordinate behavior (Frishknecht et al., 1982; Williams and Lierle 1988). Rats, constantly suffering defeat from more aggressive species, demonstrate the oppressed behavior, Hara is terisolasi less social initiative and offensive aggression, as well as the strengthening of protective behaviors (Van de Poll et al., 1982). Repeatedly defeated male hamsters demonstrate subordinating reaction in collisions with nonaggressive intruders (Potegal et al., 1993), in addition, their normal reproductive behavior is suppressed, as shown by the delay time before mating with ready to fertilize the female. In addition, after repeated defeats from dominant individuals resident individual hamster demonstrates protective behaviour and fear of non-invasive intruders smaller (Potegal et al., 1993). Distribution of subordinating behavior on new, do not pose a threat to animals is an example of "due to destruction" (Potegal et al., 1993). The reason for the defeat is not permanent in adult hamsters, because the tendency to escape and protective behavior disappears in a few weeks. Animals, demonstrating the reason for the defeat, subjected to the action of the compounds according to the present invention, and watched return to normal aggressive and reproductive behavior.

In addition, social subordination is pronounced under the influence of neuroendocrinology animal. In adult animals, playing in the collision and suffered a decrease in social status, change levels and adrenal gonadally steroids (Rose at al. 1975; Eberhart et al., 1908, 1983). After repeated defeats from the dominant congeners adult male hamsters demonstrate decreased levels of testosterone and elevated levels of glucocorticoids (Huhman et al., 1991). Evaluated the restoration of normal levels of testosterone and cortisol in animals that were injected described in this application connections.

Male Syrian Golden hamsters (Mesocricetus auratus) (120-130 g)obtained from the laboratory Harlan Sprague-Dawley Laboratories (Indianapolis, IN), were placed one by one into the cells of plexiglass (24 cm × 24 cm × 20 cm), contained in the reverse cycle light:dark (14:10; light included at 19:00) and provided food and water without restrictions. All tests were performed during the dark phase of the daily cycle in low red light. Each compound was tested at three doses (100 μg, 1 mg, and 10 mg/kg) plus saline media. Was studied twenty-four individuals (six per group). Animals were subjected to social subordination, placing them in permanent cell larger hamster every day for 30 minutes for 14 days in a row. Animals every day put to a variety of resident species, so that threats and attacks have been occurring constantly. After the termination of social subordination animals were allowed to recover in a calm state in their regular cells in the next two weeks. At then time them for one week was injected compounds described in this application, or media. At the end of this week, animals were tested for aggression towards smaller intruders placed in their permanent cage. Animals were fixed delay time before the bite, the number of bites and the time compression of the jaws. The next day in a constant cell of the animal was placed ready to fertilize the female and determined time prior to mating. At the end of a two-week period, animals were killed and analyzed blood from the body to testosterone and cortisol. All animals were killed in the first two hours of the dark phase of the cycle light:darkness to minimize diurnal changes in cortisol levels. The data for the different groups were compared using one-way model of ANOVA with subsequent post hoc tests of Bonferroni.

EXAMPLE METHODS 7

Elevated plus maze

Elevated plus maze was developed for the selection of medicines for anxiolytic and entries to the activity in rodents. This technique was confirmed by behavioral, physiologically and pharmacologically. Maze consists of two open branches and two closed branches. Rats and mice instinctively tend to make fewer visits to open branches than in the closed branch, and will be spending much less time in rytych branches. Forced to stay in open branches is much more disturbing behavior and higher levels of the stress hormone, than forced to stay in the closed branches. Clinically effective anxiolytic drugs, such as chlordiazepoxide or diazepam significantly increased the percentage time spent in open arms and the number of visits to open branches. On the contrary, entries compounds, for example, yohimbin or amphetamines reduce the number of entries into open arms and held them in time.

A group of male mice were kept in a normal cycle light:dark 12:12, and light included at 08:00 and supplied food and water without restrictions. Maze consisted of two open branches length 40 cm, width 6 cm without walls. Two closed branches had the same dimensions and wall height of 25 cm Each pair of branches was located in front of the other, forming a maze. The maze was raised to a height of 50 cm Each compound was tested at three doses (100 μg, 1 mg, and 10 mg/kg) plus saline media. Tested twenty-four individuals (six per group) cross the maze through 90 minutes after IP injection of drugs in the amount of approximately 0.1 ml At the beginning of the experiment, animals were placed in the end of one of the open branches. For whom the observation period has a duration of 5 minutes was determined delay time of entering an animal in a closed branch, the time spent in closed arms and the number of entries in open a branch after the first hit in a closed branch. The data for the different groups were compared using one-way model of ANOVA with subsequent post hoc tests of Bonferroni.

EXAMPLE METHODS 8

Impulsivity/inappropriate aggression

Impulsivity and/or inappropriate aggression can be defined using the standard analysis of animal behavior, including models resident intruder, models of aggression caused by isolation, and models of aggression between females and/or aggression between males. These studies can be performed for example mice, rats, and/or hamsters. Arginine vasopressin (AVP) are involved in the aggressive behavior of many species, including humans (see Coccaro et al., “Cerebrospinal fluid vasopressin levels: correlates with aggression and serotonin function in personality-disordered subjects” Arch. Gen. Psychiatry 55:708-14(1998)). It was shown that infusion of receptor antagonists vasopressin reduces aggression (see Ferris & Potengal “Vasopressin receptor blockade in the anterior hypothalamus suppresses aggression in hamsters” Physiol. Behav. 44:235-39 (1988)). The study vasopressin V1b-knocked out mice showed a decrease in aggressive behavior in these animals (see Wersinger et al., “Vasopressin V1breceptor knockout reduces aggressive behavior in male mice,” Mol. Psychiatry 7:975-84 (2002)).

In the experiment used adult male Syrian hamsters (Mesocricetus auratusCharles River Laboratories). Hamsters, which was supposed to be used as the residents were housed one at least 2 weeks prior to the start of the experiment. The subpopulation of males smaller size was used as intruders, and they were housed in groups (three animals/cage) to minimize the level of aggression. A pair of resident intruder had to have the difference in weight is at least 10, for Example, the mass range for residents was between 105 and 150 g, and the mass range of intruder between 95-140 g, although their absolute mass could change. Animals were placed in cages made of plexiglass (46,0×24,0×21,0 cm) bed of rods corn cobs in a room with controlled temperature (e.g., 69°F) and humidity, with unlimited access to food and water, and animals were kept under a light cycle of 14:10 light : dark with a light is switched off at 12:00 PM. The tests were carried out with the light red in the first three hours of the dark phase of the light / dark cycle. For all animals was carried out daily for 10 days prior to the study.

Every separate living hamster conducted a single test without the use of drugs for screening to determine initial levels of aggression in animals. In the testing of drugs used only resident males who performed at least one bite at a test session. Tests the connections, described in this application was performed within 48 h after sampling. After 25 minutes after drug injection residents moved into the testing room. Intruders were placed in cells resident in 5 minutes for 10-minute test. Each resident was not faced with intruders, which was used during the phase of selection. It should be understood that the protocols used in this experiment are consistent with the relevant rules of state and Federal regulations. The assessment included the time before the attack, time to bite the number of bites. Data were analyzed using one-way model of ANOVA, optionally with subsequent post hoc tests Newman-Keuls. Additional details of this study can be found in Blanchard et al., “AVP V1b selective antagonist SSR 149415 blocks aggressive behaviors in hamsters” Pharmacol., Biochem.Behav.80:189-94 (2005).

EXAMPLE METHODS 9

Binding and functional analysis of the human oxytocin

Oxytocin is known due to the fact that he plays the role of the hormone during childbirth and lactation. Agonists of oxytocin used in clinical practice to induce lactation; to cause or exacerbate the act of childbirth; to regulate postpartum atony of the uterus and uterine bleeding; to cause contraction of the uterus after cesarean section or other types of uterine surgery; and to cause therapeutic shall prekrashenie pregnancy. Acting as a neurotransmitter in the Central nervous system, oxytocin also plays an important role in the manifestation of the functions of the Central nervous system, such as maternal behavior, sexual behavior (including the erection of the penis, lordosis and copulatory behavior), yawning, mechanisms of tolerance and subordination, feeding, grooming, regulation of the cardiovascular system and thermoregulation (Argiolas and Gessa, Neuroscience and Biobehavioral Reviews, 15:217-231 (1991)). Antagonists of oxytocin find therapeutic application as a means to delay or prevent preterm birth, or to slow or stop delivery for a short period for other therapeutic interventions.

It is assumed that the compounds described in the present application, are also means influencing the oxytocin. Preparations of oxytocin and the number of oxytocin agonists are commercially available for therapeutic use. In recent years we have developed antagonists of oxytocin, weakening contractions, and assessed their potential applicability in the treatment of preterm labor and dysmenorrhea (Pavo et al.,J. Med. Chem., 37:255-259 (1994); Akerlund et al.,Br. J. Obstet. Gynaecol., 94:1040-1044 (1987); Akerlund et al.,Br. J.Obstet. Gynaecol., 86:484-487 (1979)). Antagonist of oxytocin atosiban was studied clinically and showed greater suppression of premature the birth pangs compared with placebo (Goodwin et al., Am. J. Obstet. Gynecol., 170:474 (1994)).

Was cloned and expressed human oxytocin receptor (Kimura et al., Nature, 356: 526-529 (1992)), which can be identified by the access number X64878. To demonstrate the affinity of the compounds described in this application to the human oxytocin receptor, investigated their binding, using a cell line expressing the human oxytocin receptor in 293 cells (hereinafter called cell line OTR), mainly following the method described by Morel et al. (Nature, 356:523-526 (1992)). Cell line 293 is a permanent line of primary renal embryonic human cells transformed with DNA devoid of the protein coat of the human adenovirus 5. Identification number ATCC CRL-1533.

Cell line OTR were grown in DMEM (Modified Daveco essential medium, Sigma, St.Louis, MO, USA) with addition of 10% serum of calves, 2mm L-glutamine, 200 mcg hygromycin (Sigma, St.Louis, MO, USA) and 250 μg/ml G418 (Gibco, Grand Island, NY, USA). To obtain cell membranes OTR grew up confluently 20 rotating bottles. The cells were divided in not containing enzymes environment for cell division (Specialty Media, Lavalette, NJ, USA) and centrifuged at 3200 rpm for 15 minutes. The precipitate is re-suspended in 40 ml of buffer Tris-HCl (hydrochloride Tris[hydroxymethyl] aminomethane) (50 mm, pH 7,4) and homoge who was seravalli for 1 minute using a Tekmar Tissumizer (Cincinnatti, OH USA). The suspension was centrifuged at 40000g for 10 minutes. The precipitate is re-suspended and centrifuged as described above. The resulting residue suspended in 80 ml of Tris-buffer pH 7.4 and kept in 4 ml aliquot at -80°C. For analysis of aliquots resuspendable analytical buffer and diluted to a concentration of 375 μg of protein per ml protein Concentration was determined by BCA analysis (Pierce, Rockford, IL, USA).

Analytical buffer consisted of 50 mm Tris-HCl (hydrochloride Tris[hydroxymethyl]aminomethane), 5 mm MgCl2and 0.1% bovine serum albumin at a pH of 7.4. Radioactive ligand for the study of binding was [3H]oxytocin ([tyrosyl-2,6-3H]oxytocin, 48,5 Curie/mmol, DuPont NEN, Boston, MA, USA). The components were added in the following order: 195 ál analytical buffer, 200 μl of membranes OTR (75 μg protein) in the analytical buffer, 5 μl of test compound in dimethyl sulfoxide (DMSO) or pure DMSO and 100 μl of [3H]oxytocin in analytical buffer (final concentration of 1.0 nm). Incubation was carried out for one hour at room temperature. Bound radioactive ligand was separated from unbound by filtration on the harvester with cells Brandel (Gaithersburg, MD, USA) through the filters glass fiber Whatman GF/B, which were soaked for 2 hours in 0.3% polyethylenimine. Filters were washed in ice-cold 50 mm Tris-HCl (pH of 7.7 at 25°C) and mugs filter is in placed in scintillation vials, which was then added 5 ml of scintillation fluid Ready Protein PlusTMand counted on a scintillation counter for liquids. Each incubation was performed in triplicate and got curves dose-inhibition, which included the points corresponding total binding and nonspecific binding (100 μm oxytocin, Sigma, St. Louis, MO, USA) and 6 or 7 concentrations of the tested compounds, covering the IC50. The total binding, as a rule, was approximately 1000 imp./min, and nonspecific binding is approximately 200 pulses/min. Value IC50was calculated by nonlinear least-squares fitting curves to a 4-parameter logistic models. Some compounds of formula (I) has demonstrated an affinity for the oxytocin receptor.

There are several bioassays to determine agonist or antagonist nature of the compounds showing affinity for the oxytocin receptor. One of these analyses are described in U.S. patent No. 5373089 included in the present application by reference. The specified bioanalysis based on the techniques described in the article Sawyer et al., (Endocrinology, 106:81 (1980)), which, in turn, based on the message Holton (Brit. J. Pharmacol., 3:328 (1948)). Methods of analysis for assessing pA2described by Schild (Brit. J. Pharmacol., 2:189 (1947)).

The EXAMPLE METHOD 10

Research is the study of functional activity of oxytocin

1. Animal material: used for the analysis 1.5 cm piece of the uterus unfertilized rats (Holtzman) during natural estrus.

2. Buffer/cuvette for analysis: Used buffer Munsiks. This buffer contained 0.5 mm of Mg2+. Through the buffer solution was continuously purged mixture of 95% oxygen/5% carbon dioxide, which gave a pH value of 7.4. The temperature of the analytical solution at 37°C. Used 10 ml cuvette for analysis, provided with a water jacket to maintain the temperature, and the input and output taps to add and remove buffer.

3. The recorder/sensor: Used to analyze a piece of tissue of the uterus is attached at one end and is connected to a sensor Statham Strain Gauge Force Transducer and the other end which, in turn, is attached to the recorder Grass Polygraph Model 79 for monitoring the compression of the fabric.

4. Protocol analysis:

(a) the Fabric is brought into equilibrium with the analytical solution, for 1 hour, by washing a new portion of the buffer every 15 minutes. During all this time supported tension fabric with a force of one gram.

(b) the Fabric is initially stimulated by oxytocin at a concentration of 10 nm for addiction tissue to the environment and 4 mm potassium chloride (KCl) to determine the maximum response of the compression.

(c) Then built a General curve dose-response to oxytocin and used the concentration of oxytocin, the equivalent of when is Erno 80% of the maximum response for assessing pA 2antagonist.

(d) the Fabric was subjected to the action of oxytocin (Calbiochemical, San Diego, CA) for one minute and remove it by washing. Before adding the next dose of the agonist or antagonist left three-minute pause. If tested antagonist, before the addition of agonist left a five-minute break. Agonist was added for one minute. All responses fabric integrated with application 7P10 Grass Integrator. To test antagonists used a concentration of oxytocin, equivalent to 80% of the maximum response. Used three different concentrations of the antagonist, and two of them were supposed to reduce the response to the action of the agonist less than 50% and one should reduce the response is more than 50% (in the ideal case, the ratio would be 25%, 50% and 75%). This was repeated three times for each dose of the antagonist for the three studied points.

(e) Calculations pA2for antagonists was calculated the ratio of the dose-response (DR) and built schedule shilda, putting the point in the coordinates Log(DR-1) - Log of the concentration of antagonist. Built line cheated by using regression analysis by the method of least squares. The value of pA2represents the concentration of antagonist at the point where the regression curve crosses the zero point of the ordinate Log(DR-1). pA2represents the negative logarithm Konz is Tracii antagonist, which reduces the response to the action of the agonist to one second.

EXAMPLE METHODS 11

Analysis of the binding of the receptor tachykinin

It is assumed that described in this application connections are the means influencing tachykinin. Tachykinins are a family of peptides that share a common amidinophenoxy carboxy-terminal sequence. Substance P was the first peptide of this family, which did not allocate, although its purification and determination of its primary sequence were not conducted until the early 1970 H. Between 1983 and 1984, several groups reported on the allocation of two new mammalian tachykinins, called currently neirokinina A (also known as substance K, neuromedin 1 and neurokinin α), and neirokinina B (also known as neuromedin K and neurokinin β). For a review of these findings, see J. E. Maggio,Peptides, 6 (Supplement 3): 237-243 (1985).

Antagonists of the receptor tachykinin useful in the treatment of a wide range of clinical conditions which are characterized by the presence of excess tachykinin. These clinical conditions may include disorders of the Central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the type Alzheim the RA, Alzheimer's disease, AIDS-associated dementia and down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis, and other neurotic diseases disorders such as peripheral neuropathy, for example diabetic neuropathy and neuropathy caused by chemotherapy, as well as post herpetic and other neuralgias; acute and chronic obstructive airway disease, such as respiratory distress syndrome adults, bronchopneumonia, bronchospasm, chronic bronchitis, cough drivers and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrosis, osteoarthritis and rheumatoid arthritis; disorders of the musculoskeletal system such as osteoporosis; allergies such as eczema and rhinitis; disorders associated with hypersensitivity, as, for example, dermatitis after contact with poison sumac; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, diffuse neurodermatitis, allergic rashes and other actinopodidae dermatitis; addictions, such as alcoholism; somatic disorders associated with stress; reflex sympathetic dystrophy such as shoulder syndrome; estimatesa disorders; not blagopriyatnye immunological reaction, such as rejection of transplanted tissues and disorders related to the enhancement or suppression of the immune system, such as systemic lupus erythematosis; gastrointestinal disorders or diseases associated with neural control organs of the abdominal cavity, such as ulcerative colitis, Crohn's disease, vomiting and irritable bowel syndrome; disorders of the activity of the bladder, such as hyperreflexia of the detrusor and incontinence; atherosclerosis; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; irritating symptoms of benign prostatic hypertrophy; disorders of blood flow caused by disease, widening and narrowing of the blood vessels, such as angina, migraine and disease , Raynaud's disease; and pain and nociception, for example, related to or associated with any of the previously mentioned conditions, particularly the spread of pain in migraine.

Tachykinin widely distributed in both the Central and peripheral nervous system. Released from nerves, they affect a number of biological processes, which, in most cases, depend on the activation of specific receptors expressed on the membrane of target cells. In addition, tachykinin produced nearby tissues not related to the nervous system. Tachykinin mammals, i.e. substa the tion P, neurokinin A and neurokinin B, there are three main subtypes of receptors, referred to as NK-1, NK-2 and NK-3, respectively. These receptors are present in various organs.

Believe that substance P, including those involved in neuropterida sensations of pain, including pain associated with migraine, headache and arthritis. These peptides are also involved in gastrointestinal disorders and diseases of the gastrointestinal tract, such as inflammatory bowel disease. In addition, tachykinin play a role in many other diseases, as discussed below.

Due to a substantial number of clinical disorders associated with an excess of tachykinins, development of receptor antagonists tachykinin should serve to strengthen control over these clinical conditions. The first of the identified receptor antagonists tachykinin were peptide derivatives. It turned out that these antagonists have limited pharmaceutical applicability due to their metabolic instability. In modern literature describes the new ones classes receptor antagonists tachykinin, which generally have a higher bioavailability when administered orally and metabolic stability compared to the previously open classes receptor antagonists tachykinin. Examples of such navigability receptor antagonists tachykinin can be found in European patent publication 591 040 A1, published on April 6, 1994; publication under the patent cooperation Treaty WO 94/01402, published January 20, 1994; publication under the patent cooperation Treaty WO 94/04494, published March 3, 1994; publication under the patent cooperation Treaty WO 93/011609 published January 21, 1993; publication under the patent cooperation Treaty WO 94/26735 published 24 November 1994. The tests are applicable for the evaluation of receptor antagonists tachykinin, well known in the art. See, for example, J. Jukicet al., Life Sciences,49:1463-1469 (1991); N. Kucharczyket al., Journal of Medicinal Chemistry,36:1654-1661 (1993); N. Rouissiet al., Biochemical and Biophysical Research Communications,176:894-901 (1991).

EXAMPLE METHODS 12

Analysis of the binding of the receptor NK-1

Antagonists of NK-1 is applicable in the treatment of pain, especially chronic pain, such as neuropathic pain, postoperative pain, migraine headaches, pain associated with arthritis, pain associated with cancer, chronic pain of the lower section of the back, histamine headaches, neuralgia associated with herpes, pain in the phantom limb, Central pain, dental pain, neuropathic pain, pain that is resistant to the action of opioids, pain of internal organs, surgical pain, pain caused by injury to the bones, pain during labor and delivery, pain due to burns, including sunburn, post partum pain, pain in angina and pain, tie is the R with the genitourinary tract, including cystitis.

In addition to the treatment of pain, antagonists of NK-1 is particularly applicable in the treatment and prevention of urinary incontinence; irritating symptoms of benign prostatic hypertrophy; disorders of motility of the gastrointestinal tract, such as irritable bowel syndrome; acute and chronic obstructive respiratory diseases, such as bronchospasm, pneumonia, asthma, and respiratory distress syndrome in adults; atherosclerosis; inflammatory conditions such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, Allergy, rhinitis, cough, dermatitis, allergic rashes, psoriasis, conjunctivitis, vomiting, caused irritation pupillary constriction; the rejection of transplanted tissues; the leakage of plasma, due to cytokine chemotherapy, etc.; spinal cord injury; stroke; stroke (ischemia); Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety and depression.

Study of the binding of radioactively labeled receptor was performed using a variant of a previously published Protocol. D.G. Payanet al., Journal of Immunology, 133:3260-3265 (1984). In this analysis an aliquot of IM9 cells (1x106cells/vial in medium RPMI 1604 with the addition of 10 fetal calf serum) were incubated with 20 PM 125I-labeled substance P in the presence of increasing concentrations of competing compounds for 45 minutes at 4°C.

Cell line IM9 is a well-studied cell line which is easily available for General use. See, for example,Annals of the New York Academy of Science,190:221-234 (1972);Nature (London),251:443-444 (1974);Proceedings of the National Academy of Sciences (USA),71:84-88 (1974). These cells were cultured according to standard methods in RPMI 1640 with the addition of 50 μg/ml gentamicin sulfate and 10% fetal calf serum.

The reaction was stopped by filtration through collecting system on the basis of glass fiber filter, using filters, pre-soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of the labeled substance P was determined in the presence of 20 mm unlabeled ligand.

EXAMPLE METHODS 13

Analysis of the binding of the receptor NK-2

Antagonists of NK-2 applicable in the treatment of urinary incontinence, bronchospasm, asthma, respiratory distress syndrome of adults, disorders of motility of the gastrointestinal tract, such as irritable bowel syndrome, and pain.

Cells CHO-hNK-2R, representing cell line derived from CHO cells, transformed to produce human receptors NK-2, and expressing approximately 400,000 molecules of these receptors on the cell were grown in flasks volume is m 75 cm 3or rotating the bottles in the minimum support environment (alpha modification) with the addition of 10% fetal bovine serum. The genetic sequence of the human receptor NK-2 are given in the work of N. P. Gerard et al., Journal of Biological Chemistry, 265:20455-20462 (1990).

To obtain membranes confluent culture of 30 rotating vials were separated by washing each rotating vial with 10 ml of saline solution with phosphate buffer, Delbeke (PBS) without calcium and magnesium, followed by addition of 10 ml containing no enzyme solution for the separation of cells (based on PBS, from Specialty Media, Inc.). After another 15 minutes separated cells were collected and centrifuged at 1000 rpm for 10 minutes in a clinical centrifuge. Membranes were obtained by homogenization of the sediment cells in 300 ml of 50 mm Tris-buffer, pH to 7.4 using a TEKMAR homogenizer®within 10-15 seconds, followed by centrifugation at 12,000 rpm (20000g) for 30 minutes using a rotor BECKMAN JA-14®. The precipitate once washed by the method described above and received after this precipitate resuspendable 100-120 ml of 50 mm TRIS buffer, pH 7.4 and 4 ml aliquots of the resulting suspension was stored frozen at -70°C. the protein Concentration in these preparations was 2 mg/ml

To analyze the binding of the receptor, one 4-ml aliquot of the preparation of the membranes of CHO-hNK-2R suspended in 40 ml of the Academy of Sciences of the lytic buffer, containing 50 mm Tris, pH of 7.4, 3 mm magnesium chloride, 0.02% bovine serum albumin (BSA) and hemostatis 4 µg/ml For a single sample used volume of 200 ál of homogenate (40 µg protein). Radioactive ligand was [125I]yudhister-neurokinin A (New England Nuclear, NEX-252), 2200 Curie/mmol. Preparing the preparation of the ligand in the analytical buffer with a concentration of 20 curies per 100 μl; final concentration in the analysis time was 20 PM. Nonspecific binding was determined using 1 μm eledoisin. To plot a standard curve concentration-response used ten concentrations eledoisin from 0.1 to 1000 nm.

All samples and standards were added to the incubation mixture for 10 ál dimethylsulfoxide (DMSO) in the selection (one dose) or 5 ál of DMSO to determine the values IC50. The order of addition of components in the mixture for incubation was as follows: 190 or 195 ál analytical buffer, 200 μl of the homogenate, 10, or 5 ál of sample in DMSO, 100 μl of the radioactive ligand. Samples were incubated for 1 h at room temperature and then filtered on the harvester with cells through filters that were pre-soaked for two hours in 50 mm Tris buffer, pH of 7.7, containing 0.5% BSA. The filter three times washed with approximately 3 ml of cold 50 mm Tris buffer, pH of 7.7. Then from the filter kicked the slices, put them in tubes of the policy is irola 12×75 mm and counted on the meter gamma radiation.

EXAMPLE METHODS 14

Treatment for vomiting

In addition to the above indications to the treatment described in this application, the compounds can be used in the treatment of vomiting, including a strong, slow and anticipated in advance emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and changes in intracranial pressure. In particular, the compounds described in this application formulas can find application in the treatment of vomiting induced antineoplastics (cytotoxic) means, including the means which are commonly used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, such nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action, such as nitrosamine, cisplatin and dacarbazine; antimetabolites, such as folic acid antagonists of purine or pyrimidine; inhibitors of mitosis, for example, Vinca alkaloids and derivatives podofillotoksina; and cytotoxic antibiotics.

Specific examples of chemotherapeutic agents are described, for example, in D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances (Ed. by J.Kucharczyk et al. 1991, pp. 177-203. Commonly used chemical is terapevticheskii tools include cisplatin, the dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustin (CCNU), doxorubicin, daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, and chlorambucil. R. J. Grallaet al., Cancer Treatment Reports, 68:163-172 (1984).

Compounds described in this application formulas can also find application in the treatment of vomiting caused by radiation, including radiation therapy, for example, in the treatment of cancer or radiation sickness; and in the treatment of postoperative nausea and vomiting.

EXAMPLE METHODS 15

Inhibition of platelet aggregation

In addition to the above it is known that receptors of vasopressin V2mediate platelet aggregation. Agonists of the receptor vasopressin cause platelet aggregation, whereas receptor antagonists vasopressin V2inhibit the aggregation of platelets deposited under the action of vasopressin or antagonists of vasopressin. The degree of antagonistic activity of the compounds described in this application may be determined using conventional methods, including the analysis described in the following paragraphs.

In healthy volunteers the blood was collected through a puncture in Vienna and was mixed with heparin (60 ml of blood was added to 0.4 ml of saline solution with heparin 4 mg of heparin per ml of saline solution)). Received platelet-rich plasma (PRP), centrifuger whole blood (150g) and PRP was added indomethacin (3 μm) to block mediated platelet reactions release. PRP was continuously stirred at 37°C, and after addition of arginine vasopressin (AVP) (30 nm) to initiate aggregation, followed by the change in optical density. Compounds were dissolved in 50% dimethyl sulfoxide (DMSO) and were added to the plasma (10 µl/415 μl PRP) before the addition of AVP. Measured the inhibition percentage AVP-induced aggregation and hoped IC50.

In a study using washed platelets, 50 ml of whole blood was mixed with 10 ml citrate/heparin (85 mm sodium citrate, 64 mm citric acid, 111 mm glucose, 5 u/ml heparin) and separated PRP as described above. Then PRP was centrifuged (150g) and platelets resuspendable in physiological buffer solution (10 mm HEPES, 135 mm sodium chloride, 5 mm potassium chloride and 1 mm magnesium chloride)containing 10 mm indomethacin. Before aggregation induced by AVP (30 nm), which was described above, to stir the platelets were added to human fibrinogen (0.2 mg/ml) and calcium chloride (1 mm).

EXAMPLE METHODS 16

The behavior in Golden hamsters associated with tagging items side surface of the body

Obsessive-compulsive disease occur Bo is Isom diversity of characteristics and symptoms, mainly associated with uncontrolled desire of the patient to make unnecessary conditional actions. External characteristics of this disease are the actions associated with shopping, tidying, cleaning, etc. beyond any reasonable needs or reasonable justification. The subject is afflicted by severe, be unable to do anything other than perform conditional actions dictated by the disease. Obsessive-compulsive disease in all its varieties are the preferred target for treatment by the methods and compositions of the present invention as an additional therapy. The applicability of the compounds of formula (I) in the treatment of obsessive-compulsive disorder was demonstrated in a follow-up study.

Especially the stereotypical behavior of Golden hamsters, namely tagging items side surface of the body, can be caused by microinjection of vasopressin (10-100 nl, 1-100 μm) in the anterior hypothalamus (Ferris et al.,Science, 224, 521-523 (1984); Albers and Ferris,Regulatory Peptides, 12, 257-260 (1985), Ferris et al.,European Journal of Pharmacology, 154, 153 to 159 (1988)). After settling the stimulus described behavior begins with grooming, licking and scratching large sebaceous glands in the dorsolateral part of the lateral surface of the body. restapi grooming lateral glands can be so intense, the hair on the side becomes matted and soaked with saliva. After grooming hamsters exhibit behavior associated with tagging items side surface of the body, which is a form of scent marking associated with olfactory information transfer (Johnston,Physio. Behav., 51, 437-448 (1985); Ferris et al.,Physio. Behav., 40, 661-664 (1987)), manifested in the arching of the back and vigorous friction lateral glands on any vertical surface. Caused by vasopressin tagging lateral surface of the body usually begins within minutes after microinjection (Ferriset al., Science, 224, 521-523 (1984)). This behavior is specific to vasopressin, whereas microinjection of other neuropeptides, excitatory amino acids and catecholamines do not cause the described labeling (Ferriset al., Science, 224, 521-523 (1984); Albers and Ferris,Regulatory Peptides, 12, 257-260 (1985)). Moreover, the marking of the lateral surface of the body-specific receptor vasopressin V1because this behavior is selectively inhibited by antagonists of the receptor V1and is activated by agonists of the receptor V1(Ferris et al.,Neuroscience Letters, 55, 239-243 (1985); Alberset al., Journal of Neuroscience, 6, 2085-2089 (1986); Ferriset al., European Journal of Pharmacology, 154, 153 to 159 (1988)).

All animals used in this study were adult male Golden hamsters (Mesocricetus auratus) weighing about 160, Before Vvedenskii animal tests were performed stereotaxic surgery and allowed to recover. Hamsters kept under reversed light cycle (14 h light, 10 h dark, lights on at 19:00) in the cells of plexiglass and gave food and water without restrictions.

Stereotaxic surgery was performed under anesthesia by pentobarbital. Stereotaxic coordinates were as follows: 1.1 mm ahead of the crown, 1.8 mm to the side of the median sagittal suture at an angle of 8° from the vertical line, and 4.5 mm below the Dura mater. Sock was placed at the level of the line connecting the ears. One, the guide catheter No. 26 was lowered to the desired area and was attached to the skull with dental cement. The guide catheter was closed obturator No. 33, going beyond the guiding catheter 1 mm Inner catheter used for microinjection goes beyond the guide 3 mm to achieve the anterior hypothalamus.

Hamsters were microinjection 1 μm vasopressin in volume of 150 nl. Vasopressin was administered as a cocktail with 200 mm, 20 mm, 2 mm test compounds or by itself, in the media, i.e. dimethyl sulfoxide. As vasopressin, and the test compounds were dissolved in 100% dimethyl sulfoxide. All injections were performed in the anterior hypothalamus. Counted the number of mechani wall side surface of the body of animals within 10 minutes in a clean cage.

EXAMPLE METHODS 17

The application in which the combination with inhibitors of serotonin reuptake

Another aspect of the present invention is the use of compounds of formula (I) in combination with inhibitors of reuptake of serotonin to treat obsessive-compulsive disorders, aggressive behavior or depression. Compounds used as inhibitors of serotonin reuptake include, but are not limited to the above:

Fluoxetine, i.e. N-methyl-3-(p-triptoreline)-3-phenylpropylamine, arrives on the market in the form of a hydrochloride in the form of a racemic mixture of two enantiomers. For the first time this connection was mentioned in U.S. patent No. 4314081. Robertson and coJ. Med. Chem., 31, 1412 (1988) described the separation of R and S enantiomers of fluoxetine and showed that activity as inhibitors of serotonin reuptake enantiomers are similar to each other. In this application the word "fluoxetine" will be used to refer to any acid additive salt or free base and will include either a racemic mixture, or any of the R and S enantiomers;

DULOXETINE, i.e. N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, usually introduced in the form of hydrochloride and (+)enantiomer. First described in U.S. patent No. 4956388, which shows its high efficiency. The word "DULOXETINE" will be used in this application to refer to any acid additive salt or molecules of the free base;

Venlafaxine is known in the literature, and the method of its synthesis and activity as an inhibitor of serotonin uptake and norepinephrine described in U.S. patent No. 4761501. Venlafaxine in this patent is defined as "compound A";

Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxylic) described in U.S. patent No. 4478836 where milnacipran obtained in example 4. Obtained in this patent the compound is described as antidepressants. Moret and collaborators inNeuropharmacology, 24, 1211-19 (1985) describe its pharmacological activity as an inhibitor of reuptake of serotonin and norepinephrine;

Citalopram, i.e. the 1-[3-(dimethylamino)propyl]-1-(4-forfinal)-1,3-dihydro-5-isobenzofurandione, disclosed in U.S. patent No. 4136193 as an inhibitor of serotonin reuptake. Its pharmacology has been disclosed Christensen and co-authors ofEur. J. Pharmacol., 41, 153 (1977), and reports of its clinical effectiveness for depression can be found in Dufour et. al.,Int. Clin. Psychopharmacol., 2, 225 (1987), and Timmerman et. al., see above, 239;

Fluvoxamine, ie 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone-O-(2-amino-ethyl)oxime described in U.S. patent No. 4085225. Scientific articles about this drug were published Claassen et. al.,Brit. J. Pharmacol., 60, 505 (1977); De Wilde et. al.J Affective Disord., 4, 249 (1982); and Benfield and et. al.Drugs, 32, 313 (1986);

Paroxetine, i.e. TRANS-(-)-3-[(1,3-benzodioxol-5-yloxy)IU is Il]-4-(4-forfinal)piperidine may be found in U.S. patent No. 3912743 and 4007196. Reports of drug activity connection: Lassen,Eur. J. Pharmacol., 47, 351 (1978); Hassan et al.,Brit. J. Clin.Pharmacol., 19, 705 (1985); Laursen et al.,Acta Psychiat. Scand., 71, 249 (1985); and Battegay et al.,Neuropsychobiology, 13, 31 (1985); and

Sertraline, i.e. hydrochloride, (1S-CIS)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphtylamine, representing an inhibitor of serotonin reuptake, disclosed in U.S. patent No. 4536518, sold in the market as an antidepressant.

All of the above patents is incorporated into the present application by reference.

Additional therapy for a particular aspect of the present invention is carried out by administration of receptor antagonists vasopressin V1adescribed in this application, together with the inhibitor of serotonin reuptake, in any manner which provides effective levels of the compounds in the body at the same time. All these connections are available in the form of oral dosage forms and usually are introduced orally, and therefore, oral administration of an additional combination is preferred. The compounds can be administered together in a single dosage form or separately.

This aspect of the present invention provides improvements to reduce the observed concentrations of vasopressin as a result of the introduction of the receptor antagonist of the vasopressin V1bdue to the introduction of inhibi the ora serotonin reuptake. The described aspect of the present invention is particularly suitable for use in the treatment of depression and obsessive-compulsive disorder. Such disorders often may not be amenable to treatment with inhibitors of serotonin reuptake applied separately.

Although there is the possibility of introducing the compounds used in the methods described in this application directly, without the use of any of the pharmaceutical compositions, the compounds are usually administered in the form of pharmaceutical compositions comprising pharmaceutically acceptable carrier and at least one active ingredient. These compositions can introduce various ways, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds used in the methods described in this application, is effective in the form of compositions for injection, or for oral administration. Such compositions produced by methods well known in pharmaceutical technology, and they include at least one active connection. See, for example, Remington''s Pharmaceutical Sciences (16thed. 1980).

Upon receipt of the pharmaceutical compositions used in the methods described in the present invention, the active ingredient is usually mixed with an excipient, diluted by the diluent or p is meshaut in such media, which may take the form of a capsule, sachet, paper or other container. If the excipient serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a carrier or medium for the active ingredient. For example, the compositions can take the form of tablets, pills, powders, diamond-shaped tablets, sachets, those capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in a liquid medium), ointments containing for example up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

When preparing the compositions may be necessary to grind a valid network connection to provide the appropriate particle size prior to mixing with other ingredients. If the current connection is mostly insoluble, it is usually crushed to particle size less than 200 mesh (resp./inch). If the current connection is mainly soluble in water, the particle size is usually leveled by grinding to ensure mainly homogeneous distribution in the composition, for example about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum Arabic, calcium phosphate, alginates, tragakant, gelatin, silica is Alicia, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents, such as talc, magnesium stearate and mineral oil; a means of facilitating wetting; emulsifying and suspendresume means; preservatives, for example methyl and propylhydroxybenzoate; sweeteners and flavoring means. The compositions described in this application can be designed to provide rapid, prolonged or delayed release of active ingredient after administration to the patient by applying known in the art methods.

The described compositions are preferably manufactured in the form dosage forms, each dosage contains from about 0.05 to about 100 mg, more often from about 1.0 to about 30 mg of active ingredient. The term "dosage form" refers to physically separate units, useful as single doses to humans and other mammals, each unit contains a predetermined quantity of active ingredient calculated to obtain the desired therapeutic effect, in combination with a suitable pharmaceutical excipient.

Existing connections are mainly effective in a wide range of dosages. For example, on eunie dose usually fall in the range from about 0.01 to about 30 mg/kg of body weight. In the illustrative embodiment, the daily dose can range from about 0.02 to about 10 mg/kg of body weight, in the range from about 0.02 to about 1 mg/kg of body weight or in the range from about 0.02 to about 0.1 mg/kg of body weight. Such ranges of dosages applicable for treating any patient or mammal. Additionally, in the case of treatment of adults, illustrative doses are in the range of about 0.02 to about 15 mg/kg of body weight, or in the range from about 0.1 to about 10 mg/kg/day, in single or multiple doses. However, it should be understood that actually enter the number of connections shall be determined by the physician based on material circumstances, including being treated with the state of the chosen route of administration, the specific input connection or connections, age, weight and response of the individual patient and the severity of its symptoms, and therefore, the above ranges of dosages are intended to serve as illustrations and should not be interpreted to be understood as limiting the present invention in any way. In some cases, more than may be appropriate dosage, which is below the lower limit of the above ranges, whereas in other cases it can be applied even bol is high dosages without any harmful side effects. It is believed that such large doses at first to be divided into several small doses for administration throughout the day.

The type of composition used for administration of the compounds according to the methods described in this application may be determined by the specific applied connections, type the pharmacokinetic profile desired for the route of administration and the connection (connection), as well as the patient's condition.

EXAMPLE COMPOSITION 1

Received gelatin capsules containing the following ingredients:

IngredientQuantity (mg/capsule)
The compound of formula (I)30
Starch305,0
Magnesium stearate5,0

The above ingredients are mixed and fill the mixture in an amount of 340 mg hard gelatin capsules.

EXAMPLE COMPOSITION 2

Received the tablet, using the following ingredients:

IngredientQuantity (mg/tablet)
The compound of formula (I)25,0
Microcrystalline cellulose200,0
Colloidal silicon dioxide10,0
Stearic acid5,0

The components were mixed and extruded to obtain pellets weighing 240 mg each.

An example of a STRUCTURE of 3

Got a dry powder for administration via nebulizer containing the following components:

IngredientMass %
The compound of formula (I)5
Lactose95

The active compound was mixed with the lactose and the mixture is added to the apparatus for Invalidovna dry powders.

EXAMPLE of PART 4

Received the tablets of the following composition, each of which contained 30 mg of active ingredient:

IngredientsQuantity (mg/tablet)
The compound of formula (I)30.0 mg
Starch45.0 mg
Microcrystalline cellulose35,0 mg
Polyvinylpyrrolidone (as 10% solution in water)4.0 mg
The sodium carboxymethyl starch4.5 mg
Magnesium stearate0.5 mg
Talc1.0 mg
Total120 mg

The active ingredient, starch and cellulose were sieved through sieve No. 20 mesh U.S. and thoroughly mixed. The solution of polyvinylpyrrolidone were mixed with the obtained powder was then screened through a sieve of 16 mesh U.S. thus Obtained granules were dried at 50-60°C and sieved through a sieve of 16 mesh U.S. Then to the granules was added sodium carboxymethyl starch, magnesium stearate and talc, previously passed through sieve No. 30 mesh U.S., and the resulting mixture is extruded on the machine to obtain tablets, getting a tablet weight of 120 mg each.

EXAMPLE of PART 5

Capsules, each of which contained 40 mg of the drug was obtained in the following way:

IngredientQuantity (mg/capsule)
The compound of formula (I)40,0 mg
Starch109,0 mg
Magnesium stearate1.0 mg
Total150,0 mg

The active ingredient, cellulose, starch and magnesium stearate were mixed, sieved through sieve No. 20 mesh U.S. and filled hard gelatin capsule mixture in the amount of 150 mg.

EXAMPLE of compound 6

Suppositories, each of which contained 25 mg of active ingredient was obtained in the following way:

IngredientAmount (mg)
The compound of formula (I)25 mg
Glycerides of saturated fatty acids to2000 mg

The active ingredient was sieved through sieve No. 60 mesh U.S. and suspended in the glycerides of saturated fatty acids, pre-melted at the lowest possible temperature. The mixture is then poured into a mold to obtain suppositories normal capacity of 2.0 g and allowed to harden.

EXAMPLE of compound 7

Suspension containing 50 mg of the drug per dose is 5.0 ml, received the following way:

IngredientAmount (mg)
The compound of formula (I)50.0 mg
Xanthan gum4.0 mg
Sodium carboxymethyl cellulose (11%)
Microcrystalline cellulose (89%)
50.0 mg
Sucrose1.75 mg
Sodium benzoate10.0 mg
Flavoring additive and dyeas needed
Purified water5.0 ml

Drug, sucrose and xanthan resin were mixed, passed through sieve No. 10 mesh U.S. and then mixed with a previously obtained solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavoring additive and dye was diluted in a little water and added with stirring. Then add sufficient water to obtain the desired volume.

EXAMPLE of compound 8

The capsules contain Asia 15 mg drug was obtained in the following way:

IngredientQuantity (mg/capsule)
The compound of formula (I)15,0 mg
Starch407,0 mg
Magnesium stearate3.0 mg
Total425,0 mg

The active ingredient, cellulose, starch and magnesium stearate were mixed, sieved through sieve No. 20 mesh U.S. and was filled with the obtained composition in the amount of 425 mg hard gelatin capsules.

EXAMPLE of compound 9

Composition for intravenous administration can be obtained in the following way:

IngredientsAmount (mg)
The compound of formula (I)250.0 mg
Isotonic saline1000 ml

An example of a COMPOSITION of 10

The composition for topical application can be obtained in the following way:

IngredientAmount (mg)
The compound of formula (I)1-10 g
Emulsifying wax30 g
Liquid paraffin20 g
Soft white paraffinto 100 g

Soft white paraffin wax was heated to melting. Made of liquid paraffin and emulsifying wax and stirred until dissolution. Added active ingredient and continued mixing until its dispersion. The mixture is then cooled to a solid state.

EXAMPLE of compound 11

Sublingual or buccal tablets containing 10 mg of active ingredient, can be obtained in the following way:

IngredientQuantity (mg/tablet)
The compound of formula (I)10.0 mg
Glycerin210,5 mg
Water143,0 mg
Sodium citrate4.5 mg
Polyvinyl alcohol : 26,5 mg
Polyvinylpyrrolidone 15,5 mg
Total410,0 mg

Mixed glycerin, water, sodium citrate, polyvinyl alcohol and polyvinylpyrrolidone with continuous stirring, maintaining a temperature of about 90°C. Then the solution was injected into the polymer, the resulting solution was cooled to about 50-55°C and slowly added drug. The homogeneous mixture was poured into molds made of inert material to obtain a diffuse matrix containing a drug and having a thickness of about 2-4 mm, Then this diffuse matrix cut, getting a single tablet, having a suitable size.

An example of a STRUCTURE of 12

In the methods described in this application, another illustrative composition is used in the media transdermal delivery ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion described in this application connections in regulated quantities. The operation and use of transdermal patches designed for delivery of pharmaceutical agents is well known in the art. See, for example, U.S. patent No. 5023252, issued June 11, 1991, is incorporated into the present application by reference. You can develop a similar patch that provides continuous, p is lerouxel delivery of drugs or delivery as needed.

EXAMPLE of compound 13

It is often desirable or necessary, directly or indirectly, to enter the pharmaceutical composition to the brain. The technique of direct injection include the placement of a catheter for introducing medicines into the ventricular system of the patient to bypass the barrier the blood-brain. One such implantable delivery systems used for transfer of biological agents in a specific anatomical region of the body, is described in U.S. patent No. 5011472, which is incorporated into the present application by reference.

EXAMPLE of compound 14

Indirect methods, which are mostly preferred, as a rule, include the creation of compositions in which the translation of medicinal compounds in a latent form by transformation of hydrophilic drugs into lipid-soluble drugs or prodrugs. Translation in the hidden form is achieved by blocking hydroxy, carbonyl, sulfate, and primary amine groups present in the molecule drugs to make the drug more lipid soluble and able to overcome the barrier the blood-brain. On the other hand, the delivery of hydrophilic drugs can be improved intra-arterial infusion of hypertonic solutions, which can be briefly open the barrier the blood-brain.

Although in the preceding description of the research Institute of the invention has been illustrated and described in detail, these pictures and descriptions should be interpreted as approximate and generic in nature, and it is understood that were shown and described is only illustrative embodiments of protected and that all changes and modifications that correspond to the essence of the described invention.

1. The compound of the formula

where Q represents sulfur;
n represents 1 or 2;
But is an optionally substituted nitrogen-containing heterocycle attached at the nitrogen atom, where the nitrogen-containing heterocycle is morpholinyl, pyrrolidinyl, piperidinyl, piperazinil, homopiperazine or hinokitiol, each of which is optionally substituted by groups R10, R12, R6R7N-, or R6R7N-(C1-C4alkyl); or a nitrogen-containing heterocycle is a 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl or 1,2,3,4-tetrahydroisoquinoline-2-yl;
R1represents hydrogen or C1-C6alkyl;
R2represents hydrogen;
R3selected from the group consisting of:

where each of the substituents R10and R11independently selected from hydrogen, optionally substituted C1-C6the alkyl, optionally substituted C3-C8cycloalkyl; C1-C4 alkoxyl1-C4of alkyl; C1-C6alkylcarboxylic; optionally substituted aryl, optionally substituted aryl(C1-C4the alkyl); optionally substituted aryl(C1- C4alkyloxy); optionally substituted aryl(C1-C4alkylcarboxylic); diphenylmethoxy, triphenylmethane; and
R12selected from hydrogen, C1-C6of alkyl; C3-C8cycloalkyl; C1-C4alkoxycarbonyl; optionally substituted aryloxyalkyl, optionally substituted aryl (C1-C4the alkyl); and optionally substituted of Ariola;
R4represents an optionally substituted of Steril;
R5'represents optionally substituted phenyl(C1-C4alkyl);
R6represents hydrogen or C1-C6alkyl, and R7represents a C1-C6alkyl, C3-C8cycloalkyl, optionally substituted aryl or optionally substituted aryl(C1-C4alkyl); or R6and R7together with the attached nitrogen atom form a heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinil and homopiperazine; where these piperazinil or homopiperazine optionally substituted on the nitrogen atom by a substituent R13;
13selected from the group consisting of hydrogen, C1-C6of alkyl, C3-C8cycloalkyl,1-C4alkoxycarbonyl, optionally substituted aryloxyalkyl, optionally substituted aryl(C1-C4the alkyl and optionally substituted of Ariola; and hydrates, solvate and pharmaceutically acceptable salts of these compounds;
where each of the above optionally substituted groups in each case stands for a group that carries from one to three substituents independently selected from the group consisting of C1-C4of alkyl, C1-C4alkoxy, C1-C4alkylthio, hydroxy, nitro, halogen, carboxy, cyano, C1-C4halogenoalkane,1-C4halogenoalkane, amino, carbamoyl, carboxamido, amino, alkylamino, dialkylamino, alkylamino and C1-C4alkylsulfonamides; and
where in each of the above aryl groups are independently selected from the group consisting of furil, pyrrolyl, teinila, pyridinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazoline, imidazolyl, pyrazolyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, oxadiazolyl, naphthyl, indanyl, fluorenyl, chinoline, izochinolina, benzodioxane, benzofuranyl and benzothieno.

2. The compound according to claim 1, in which Q represents sulfur and legal 1.

3. The compound according to claim 1, in which Q represents sulfur and n is 2.

4. The compound according to any one of claims 1 to 3, in which R5'represents optionally substituted phenyl(C1-C2alkyl).

5. The compound according to any one of claims 1 to 3, in which R5'represents benzyl.

6. The compound according to any one of claims 1 to 3, where a represents a substituted heterocycle where the heterocycle is selected from the group consisting of pyrrolidinyl, piperidinyl and piperazinil.

7. The compound according to any one of claims 1 to 3, in which the fragment represents piperidinyl or piperazinil and where the fragment And substituted in the 4 position by pyrrolidinium, piperidinium, piperazinil, homopiperazine, pyrrolidinyl (C1-C4by alkyl), piperidinyl (C1-C4by alkyl), piperazinil (C1-C4by alkyl) or homopiperazine (C1-C4by alkyl).

8. The compound according to any one of claims 1 to 3, where R5'represents phenyl (C1-C2)alkyl.

9. The compound according to any one of claims 1 to 3, where R3represents a

10. The connection according to claim 9, where R3represents a

11. The compound according to any one of claims 1 to 3, where R5'represents optionally substituted benzyl.

12. The compound according to claim 1 of the formula

or pharmaceuticas is acceptable salt.

13. Pharmaceutical composition comprising a compound according to any one of claims 1 to 3, and pharmaceutically acceptable carrier, diluent, excipient or combination thereof; where the compound is present in an amount effective for the treatment of painful conditions in mammals that are sensitive to the effects of receptor antagonists of vasopressin V1aV1bor V2when the need for such treatment.

14. The pharmaceutical composition according to item 13, where the painful condition is a mental illness associated with stress, depression, anxiety, affective disorders, obsessive-compulsive disease, impulsivity, aggressive disorders, diseases affecting the water homeostasis, renal function, inhibition of the metabolism of the phosphatidyl-Inositol or temperature regulation, diseases associated with nausea, vomiting and pain; or cardiovascular disease, congestive heart failure or disorder associated with platelet aggregation, or a combination thereof.

15. The use of compounds according to any one of claims 1 to 3 for the preparation of a medicinal product comprising an effective amount of the compounds for the treatment of painful conditions in mammals that are sensitive to the effects of receptor antagonists of vasopressin V1aV1bor V 2when the need for such treatment.

16. The application indicated in paragraph 15, where the composition further includes a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

17. The application indicated in paragraph 15, where the painful condition is a mental illness associated with stress, depression, anxiety, affective disorders, obsessive-compulsive disorder, impulsivity, aggressive disorder, a disorder affecting water homeostasis, renal function, inhibition of the metabolism of the phosphatidyl-Inositol or temperature regulation, a disease associated with nausea, vomiting and pain; or cardiovascular disease, congestive heart failure or disorder associated with platelet aggregation, or a combination thereof.

18. The application 17, where the disease state is an obsessive-compulsive disorder, anxiety, depression, and combinations thereof.

19. The application 17, where the disease is a anxiety.

20. The application 17, where the disease is a depression.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention is a 6-10-member aryl selected from phenyl, naphthyl, tetrahydronaphthalenyl, indanyl or a 6-member heteroaryl containing 1-2 N atoms, selected from pyridyl or pyrimidinyl, where the aryl and heteroaryl groups can be unsubstituted or substituted with 1-3 substitutes selected from a group consisting of C3-6-cycloalkyl, phenyl, phenyloxy, benzyl, benzyloxy, halogen atom, C1-7-alkyl, C1-7-alkoxy, oxazolyl, piperidin-1-yl, or C1-7-alkyl, substituted with a halogen atom, or represents phenyl, where at least one hydrogen atom is substituted with deuterium or tritium; R2 is a hydrogen atom, C1-7-alkyl or is benzyl, unsubstituted or substituted C1-7-alkoxy or halogen atom; or R1 and R2 together with a N atom with which they are bonded form 2,3-dihydroindol-1-yl or 3,4-dihydro-1quinolin-1-yl. The invention also relates to a method of producing compounds of formula and to a pharmaceutical composition having high affinity for the TAAR1 receptor.

EFFECT: compounds of formula (I), having high affinity for the TAAR1 receptor.

29 cl, 4 dwg, 1 tbl, 183 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are produced new diazepane substituted compounds representing various heterocyclic systems, including condensed, pharmaceutical compositions containing said compounds.

EFFECT: producing the compounds and compositions for preventing and treating neurological and mental disorders and diseases with involved orexin receptors.

13 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel cyanoisoquinoline derivatives of formula I , where R is selected from a group comprising hydrogen and C1-C10 alkyl, R1, R2, R3 and R4 are independently selected from a group comprising hydrogen, halogen, hydroxy, C1-C10 alkyl, substituted with 1-3 halogen atoms or C6-C14 acryl, C6-C14 aryl, -OR7, -SR7 and -SO2R7, where R7 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14 aryl, C3-C10 cycloalkyl, C6-C14 aryl and C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are optionally substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino and C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, and R5 and R6 are independently selected from a group comprising hydrogen and C1-C3 alkyl, or pharmaceutically acceptable salts thereof. The invention also relates to novel cyanoquinoline derivatives of formula II , where R31, R32, R33 and R34 are independently selected from a group comprising hydrogen, hydroxy, halogen, C1-C10 alkyl substituted with 1-3 halogen atoms or with C6-C14 aryl, C6-C14 aryl, -OR37, -SR37 and -SO2R37, where R37 is selected from a group comprising C1-C10 alkyl, C1-C10 alkyl substituted with C6-C14aryl, C3-C10 aryl, C7-C8 heteroaryl containing 1-2 heteroatoms selected from a group comprising N, O and S, where C6-C14 aryl and C7-C8 heteroaryl are substituted with 1-3 substitutes selected from a group comprising halogen, C1-C6 alkoxy, C1-C10 alkyl, C1-C6 dialkylamino C4 heterocyclyl containing 2 heteroatoms selected from a group comprising nitrogen and oxygen, R35 denotes hydrogen or methyl, or pharmaceutically acceptable salts thereof. The invention also relates to specific cyanoisoquinoline compounds, a pharmaceutical composition based on the compound of formula I, a hypoxia-inducible factor (HIF) hydroxylase inhibiting method, a method of treating, preventing or slowing down development of a condition associated with hypoxia-inducible factor (HIF), a condition associated with erythropoietin (EPO), anaemia, based on use of the compound of formula I.

EFFECT: obtaining novel cyanoisoquinoline compounds having useful biological properties.

42 cl, 1 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I): wherein n means 1 or 2, X means an oxygen atom, a sulphur atom or NH, R1 means a side group of natural α-amino acid or its homologues or isomers specified in hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methyl-propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxy-ethyl, carboxymethyl, 2-carboxyethyl, carbamoyl-methyl, 2-carbamoyl ethyl a, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 3-guanidinopropan-1-yl, benzyl or 4-hydroxybenzyl, R2 means hydrogen or methyl, R3 means hydrogen, or R1 and R3 are coupled together by the group (CH2)3- or (CH2)4- and together with nitrogen and carbon atoms whereto attached form a five- or six-member ring, as well to their salts, solvates and salt solvates.

EFFECT: preparing compounds for treating and/or preventing the diseases, first of all thromboembolic diseases.

2 cl, 2 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine of formula (I) in which R1 denotes a methyl group, R2 denotes a R21NR22 group, where R21 denotes an ethyl group which is substituted with an ethoxycarbonyl group, and R22 denotes a pyridin-2-yl group, R3 denotes an n-hexyloxycarbonyl group, where at step (a) phenyldiamine of formula (II) where R1 and R2 assume values given for formula (I), which reacts with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, to obtain a product of formula (III) where R1 and R2 assume values given for formula (I), which is hydrogenated at temperature from 30 to 60°C at hydrogen pressure from 1 to 10 bar, over palladium on activated charcoal (Pd/C) in a mixture of tetrahydrofuran and water, and then, without any preliminary extraction of the hydrogenation product, the obtained compound of formula (I), in which R3 denotes hydrogen, in the presence of potassium carbonate reacts with a compound of formula (IV) R3-X (IV), where R3 assumes values given for formula (I), and X denotes a suitable splitting group.

EFFECT: simple method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine.

3 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula , where R1 denotes OH, OPO3H2 or OCOR5; R2 denotes H, OH or OPO3H2; A denotes N or CR6; R3 denotes fluorine; R4 denotes H, C1-3alkyl or C3-6cycloalkyl; R5 denotes an alanine residue; R6 denotes H, C1-6alkoxy group or halogen; and n=0 or 1; and to pharmaceutically acceptable salts of compounds of formula I. The invention also relates to a pharmaceutical composition having antibacterial activity, and to use of compounds of formula I to obtain a medicinal agent for preventing or treating bacterial infections.

EFFECT: compounds of formula I, having antibacterial activity.

14 cl, 3 dwg, 2 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I), its optical isomer or pharmaceutically acceptable salt, R is specified in cl.1 of the patent claim. The compounds may be presented both as an optical isomer, and as a racemic substance, and may be used for mental disorders, such as schizophrenia.

EFFECT: higher efficacy of using the compounds.

8 cl, 4 tbl, 3 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention offers compounds presented by general formula (I): or their pharmaceutically acceptable salts wherein R1, R2, R3 and R4 are presented in the description and exhibit substantial COMT inhobotory activity. Besides, the present invention described pharmaceutical compositions inhibiting catechol-O-transferase activity which contain the compound or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.

EFFECT: there are declared pharmaceutical combinations for treatment or prevention of Parkinson's disease which contain (1) the pharmaceutical composition containing the compound under any cl 1-8 or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier, and (2) at least one compound specified in L-dope or carbidole.

10 cl, 9 ex, 17 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (VI): or its pharmaceutically acceptable salts; wherein n is equal to 0, 1, 2 or 3; R1 means -OH, H; R2a means OH, -CH3, provided at least one of R1 and R2a means -OH;R3 means Cl, Br, cyclopropyl, branched C3-5alkyl R4a means H; R8 means H; wherein the fragment: may be one of the groups B8, B35, B36, B37, B38, B39, B40, B41, B42, B43, B45, B46, B48, B54, B56, B58, B59, B61, B62, B71, B72, B74, B75, B76, B77, B78, B79, B80, B81, B82, B84, B86, B87, B88, B89, B90, B91, B93, B94, B95, B96, B97, B98, B99, B100 and B101 wherein the values are disclosed in the patent claim 1.

EFFECT: compounds show Hsp90 inhibitory activity that enables using them for treating the diseases caused by abnormal cell growth in mammals.

26 cl, 8 dwg, 2 tbl, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine-3-yl derivatives of formula (I)

wherein A represents *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-, or wherein asterisks specify a link which binds with a pyridine group of formula (I); R1 represents hydrogen, C1-4alkyl or chlorine; R2 represents C1-5alkyl or C1-4alkoxy group; R4 represents hydrogen or C1-4alkyl; R4 represents hydrogen, C1-4alkyl; C1-4alkoxy group or halogen; R5 represents -CH2-(CH2)n- CONR51R52, -CO-NHR51, 1-(3-carboxyazetidinyl)-2-acetyl, hydroxy group, hydroxyC2-5alkoxy group, di-(hydroxy C1-4alkyl) C1-4alkoxy group, 2,3-dihydroxypropoxy group, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxy group, -OCH2-CH(OH)-CH2-NR51R52 or -OCH2-CH(OH)-CH2-NHCOR54; R51 represents hydrogen, C1-3alkyl, 2-hydroxyetyl, 2-hydroxy-1-hydroxymethyletyl or 2,3-dihydropropyl; R52 represents hydrogen; R54 represents hydroxymethyl; n represents 0 or 1; and R6 represents hydrogen, C1-4alkyl or halogen; and a salt of said compound. Also the invention describes a pharmaceutical composition for prevention or treatment of diseases or conditions associated with activated immune system, on the basis of the compound of formula I and application of said compounds for preparing said pharmaceutical composition.

EFFECT: there are produced and described new compounds which are especially active as immunomodulatory agents.

18 cl, 92 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound with formula (I): where the values of radicals Q, R1, R2, R3, R4, X and Y are as specified in Clause 1 of the patent claim or to a pharmaceutically acceptable salt of such compound or a compound ether hydrolysed in vivo provided such compound is not: {(3S)-1-[5-(adamantan-1-ylcarbamoyl)pyridine-2-yl] piperidine-3-yl} acetic acid or {(3S)-1-[5-(cyclohexylcarbamoyl)-6-(piperazine-1-yl) pyridine-2-yl] piperidine-3-yl} acetic acid or a pharmaceutically acceptable salt thereof or a compound ether hydrolysed in vivo. Additionally, the invention relates to a pharmaceutical composition containing a compound with formula I for treatment of metabolic syndrome, Type II diabetes, adiposity etc and to application of such compound with formula I for manufacture of a medication to be applied for causing an inhibition effect with regard to 11βHSD1 with a homoiothermal animal.

EFFECT: produced and described is a new compound possessing inhibition activity with regard to Type 1 human 11-β-hydroxisteroiddehydrohenase enzyme (11βHSD1).

15 cl, 187 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formulae (I) and (III), as well as isomers or pharmaceutically acceptable salts thereof: where the values of radicals are given in claim 1 and 5. The invention also relates to a pharmaceutical composition based on said compounds, which has vanilloid receptor antagonist activity, use of said compounds to produce a medicinal agent for preventing or treating a condition which is associated with aberrant expression and/or aberrant activation of the vanilloid receptor. Described also is a method of producing a compound of formula III.

EFFECT: novel compounds which can be used as vanilloid receptor antagonists, for preventing or treating diseases are obtained and described.

40 cl, 281 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I): where: X denotes CH2-, -CH2CH2- ; Y denotes -CH2- or O; Y1 denotes -CH2- or O; where at least on of Y and Y1 denote -CH2-; R1 denotes H; R2 and R3 independently denote hydrogen; or one of them denotes H2 and the other denotes a branched or straight C1-6alkyl; where the said C1-6alkyl is possibly substituted with one amino, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C3-6cycloalkyl, phenyl; where any phenyl is possibly substituted with one CN; R4 denotes H; R5 denotes halogen; or its pharmaceutically acceptable salt.

EFFECT: compounds inhibit cholesterol absorption, which enables their use in treating and preventing atherosclerosis.

12 cl, 15 ex

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