Substituted 1-aminoalkylated, pharmaceutical composition and the method of production thereof

 

(57) Abstract:

The invention relates to organic chemistry and can find application in medicine. Describes the connection of General formula I where R1, R2and R3means independently in each case hydrogen, halogen, (C1-C6)alkyl, -OR', -SR', -NR'R", -SOR', -SO2R',- COOR', -OCOR', -OCONR'R", -OSO2R', -OSO2NR'R';- NR'SO2R", -NR'COR", -SO2NR'R", -SO2(CH2)1-3CONR'R", -CONR'R", cyano, haloalkyl or nitro, or R1and R2if they are adjacent, together with the carbon atoms to which they are attached, may form a 5-7-membered aromatic, saturated or unsaturated cycle, optionally comprising one or two ring heteroatoms selected from N, S(O)0-2or O, and optionally substituted (C1-C6)alkyl, halogen, cyano or (ness.)alkoxy; R' and R ' denote, independently in each case hydrogen, (C1-C6)alkyl, substituted (C1-C6)alkyl, (C0-C3)alkylalkoxy, aryl, heterocyclyl, heteroaryl, aryl(C1-C3)alkyl, heteroaryl(C1-C3)alkyl, heterocyclyl(C1-C3)alkyl, cycloalkenyl, cycloalkyl or R' and R" together with the nitrogen atom, the local ring heteroatom, selected from N, O or S(O)0-2; R4means in each case (C1-C6)alkyl; R5means independently in each case, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil or cycloalkyl; one of X, Y or Z means independently-S-, -O-, -CH2or >N-R6other mean-OH2-; R6means hydrogen, (C1-C6)alkyl, haloalkyl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, -(C1-C6)-CRR'R', -COOR', -SO2R', -C(O)R', -SO2-(CH2)0-3-NR'R", -CONR'R", -C(O)OCH2OC(O)R, -C(O)O-CH2-S-C(O)R' or-PO(OR')2where R' and R" have the above meanings; m indicates an integer of 0-3; and n means an integer of 1-6, or individual isomers, racemic or nerezisca mixture of isomers, or pharmaceutically acceptable salt, or their solvate. Also describes a pharmaceutical composition having antagonistic activity against muscarinic receptors M2/MOH on the basis of the compounds of formula I and methods of making compounds of formula I. the Technical result obtained new compounds with useful biological properties. 4 N. and 17 C.p. f-crystals, 7 PL.

This izobreteniya in each case hydrogen, halogen, (C1-C6)alkyl, -OR', -SR', -NR'R", -SOR', -SO2R', -COOR', -OCOR', -OCONR'R", -OSO2R', -OSO2NR'R", -NR'SO2R", -NR'COR", -SO2NR'R", -SO2(CH2)1-3CONR'R", -CONR'R", cyano, haloalkyl or nitro, or

R1and R2if they are adjacent, together with the carbon atoms to which they are attached, can also form a 5-7 membered saturated or unsaturated cycle, optionally comprising one or two ring heteroatoms selected from N, S(O)0-2or O and optionally substituted (C1-C6)alkyl, halogen, cyano or (ness.)alkoxy;

R’ and R" denote independently in each case hydrogen, (C1-C6)alkyl, substituted (C1-C6)alkyl, (C0-C3)alkylalkoxy, aryl, heterocyclyl, heteroaryl, aryl(C1-C3)alkyl, heteroaryl(C1-C3)alkyl, heterocyclyl(C1-C3)alkyl, cycloalkenyl, cycloalkyl or

R' and R" together with the nitrogen atom to which they are attached, can also form a 5-7 membered cycle, optionally incorporating one additional ring heteroatom selected from N, O or S(O)0-2;

R4means independently in each case, (C1-C6)alkenyl, (C2-C6)quinil or cycloalkyl;

one of X, Y or Z means independently-S-, -O-, -CH2or >N-R6other means-CH2-;

R6means hydrogen, (C1-C6)alkyl, haloalkyl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, -(C1-C6)-CR'R'R', -COOR', -SO2R', -C(O)R', -SO2-(CH2)0-3-NR'R", -CONR'R", -C(O)OCH2OC(O)R', -C(O)O-CH2-S-C(O)R' or-PO(OR')2where R' and R" have the above meanings;

m means an integer of 0-3;

n means an integer of 1-6;

or prodrugs, individual isomers, racemic or nerezisca mixture of isomers, or pharmaceutically acceptable salt, or their solvate.

It has been unexpectedly found that the compounds of formula I are selective antagonists of muscarinic receptors M2/M3.

Acetylcholine (Ach) is the primary mediator of the parasympathetic nervous system. Physiological activity of Ach-mediated activation or nicotinic or muscarinic receptors. Both these class of receptors are heterogeneous, for example a family of muscarinic receptors includes five padti the Noah pharmacology and distribution.

Almost all tissue smooth muscle Express muscarinic receptors as M2 and M3, both of which play a functional role. The M2 receptors outnumber the M3 receptors in the ratio of approximately 4:1. Typically, the M3 receptors mediate the direct contractile effects of acetylcholine in the vast majority tissue smooth muscle. On the other hand, the M2 receptors causes contraction of smooth muscles indirectly, by inhibiting simpaticeskii ( -adrenoreceptors) mediated relaxation.

Compounds that act as antagonists at the muscarinic receptors, used to treat certain disease conditions associated with improper function of smooth muscles. Until recently, most of these compounds did not possess selectivity for different subtypes of muscarinic receptors, causing an unpleasant anticholinergic side effects such as dry mouth, constipation, blurred vision, or tachycardia. The most common of these side effects is dry mouth, resulting from the blockade of muscarinic receptors in the salivary gland. It is shown that the newly created specific antagonists M2 and the 3 could be therapeutically effective in the treatment of painful conditions, associated with damage to the smooth muscle.

Selective antagonists M2/M3 created a little bit. The present invention fills this need, providing these types of antagonists, applicable to the treatment of painful conditions associated with improper function of smooth muscles.

More information on subtypes of muscarinic receptors and their antagonists can be obtained from the following literature. Some subtypes of muscarinic receptors in smooth muscle described Ehlert and other, Life Sciences, 1997, 61, 1729-1740. Hedge and others, Life Sciences 1999, 64, 419-428, refer to the subtypes of muscarinic receptors, modulating the contraction of smooth muscles of the bladder. Eglen and others, Trends. Pharmacol. Sci. 1994, 15, 114-119, and Eglen and others, Pharmacol. Rev. 1996, 48, 531-565, refer to some subtypes of muscarinic receptors and the function of smooth muscle. Clinical studies of selective muscarinic antagonists described Nilvebrant and other, Life Sciences, 1997, 60, 1129-1136, Alabaster, Life Sciences, 1997, 60, 1053-1060; Osayu and others, Drug Res. 1994, 44, 1242-1249, and Homma, etc., Neurourology and Urodynamics 1997, 345-346. Selective modulation of subtypes of muscarinic receptors reported Eglen and Hegde, Emerging Drugs 1998, 3, 67-79. Eglen and others, Curr. Opin. Chem. Biol. 1999, 3, 426-432, refer to the ligands of muscarinic receptors and their therapeutic potential. Some of classific the x literary sources described compounds, related to compounds of General formula I. US Patent No. 5693630 from the company Astra Aktiebolag refers to some phenylethylamine and phenylpropylamine for the treatment of psychiatric disorders. The US patents No. 5382595, No. 5177089, No. 5047417 and No. 5607953 from the company Eisai Co., Ltd., refer to some derivatives butenova and propanolol acids. Some N-(4-amino-2-butenyl)-N-alkylcarboxylic applicable as stimulants depressants of the Central nervous system, described in US patents No. 3354178 and No. 4065471 from company Sterling Drug. Inc. The US patents No. 4087541 and No. 4038407 from the company Boehringer Ingelheim GmbH quote some 2-(aralkylamines)phthalimide applicable to slow heart rhythm. The US patent No. 4490369 from Dr. Karl Thomae GmbH reveals some derivatives benzazepine and their use as tools with bradycardia. The US patent No. 3054794 from US firms Vitamin & Pharmaceutical Co. refers to the method of obtaining 3-(aminoalkyl)oxazolidin-2,4-diones. Some derivatives of benzene for the treatment of coronary artery disease is described in US patent No. 5998452 from the company Chugai Seiyaku Kabushiki Kaisha. Benzodiazepinovye derivatives with Uralkalij substituents with vasodilator properties, are disclosed in US patent No. 4729994 from the company McNeilab Inc. The patent FR No. 2302733 from Dr. Karl Thomae GmbH quoted some arylalkylamine and EP 259793 from Dr. the basic 2-arylaryl(piperidine-4-ylmethyl)amine as antagonists of muscarinic receptors. Some 1-ethyl-3-(2-dialkylaminomethyl)hexahydropirimidine series-2-ones described Singh and others, Indian Journal of Chemistry 1976, 14, 528-531. Glozman and others, Khim.-Farm.Zh. 1996, 30(4), 11-14, I quote some of substituted 1-(dialkylaminoalkyl)-4-phenylpyrrolidine-2-ones.

All publications, patents and patent applications cited in the context of earlier or later, hereby incorporated by reference in its entirety.

Objects of the present invention are derivatives of heterocyclisation formula I, prodrugs, individual isomers, racemic and nerezisca mixture of isomers and their pharmaceutically acceptable salt, or their solvate. In addition, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one of the compounds of formula I, or prodrugs, individual isomers, racemic or narramissic mixtures of isomers, or pharmaceutically acceptable salt or solvate in a mixture of at least one suitable carrier. In a more preferred variant of embodiment of the invention pharmaceutical compositions suitable for introduction to the patient in a painful condition that is alleviated by treatment with an antagonist of muscarinic reciente, located in a painful condition, which is facilitated with the help of therapy, an antagonist of muscarinic receptors M2/M3. In a preferred variant embodiment of the invention the patient is a painful condition, which includes disorders associated with smooth muscles, preferably disorders of the genitourinary tract, disorders of the respiratory tract, disorders of the gastrointestinal tract, more preferably disorders of the genitourinary tract, such as increased activity of the bladder or overactive detrusor, and its symptoms, such as changes symptomatically manifested as urgency of urination, frequency, reduced ability to fill the bladder, incontinence, and the like; the symptoms manifested in the dynamics of the urinary tract, such as changes in the functional activity of the bladder, the threshold of the bladder, unstable bladder contractions, muscle spasticity sphincter and the like, and the symptoms usually manifested in the detrusor hyperreflexia (neurogenic bladder), in such States as obstruction of the expiration of nedostatocnosti expiration, increased pelvic sensitivity, or when idea is the embodiment of the invention the disease includes disorders of the respiratory tract, such as allergies and asthma. In another preferred variant of embodiment of the invention painful condition includes disorders of the gastrointestinal tract.

In another aspect, the invention relates to a method for obtaining compounds of formula I, the method which includes

(a) the interaction of compounds with the General formula II

with a compound of General formula III

with the aim of obtaining compounds of General formula I

where R1, R2, R3, R4, R5, m, n, X, Y, and Z have the meanings given in the context, or

(b) (i) interaction derived armetale having the General formula IV

where M means a metal or a magnesium halide,

with the compound of the formula V

where R is alkyl, aryl or arylalkyl and

Raand Rbdenote alkyl or alkoxy or

Raand Rbtogether with the nitrogen atom to which they are attached, form a loop, with the formation of the compounds of formula VI

and (ii) the recovery of the compounds of formula VI, followed by cyclization and processing a compound of formula R5L, where L means the formula VII and processing of compound of General formula II

with the aim of obtaining compounds of General formula I

where R1, R2, R3, R4, R5, m, n, X, Y, and Z have the meanings given in the context, or

(C) (i) the recovery of the compounds of formula VI

followed by cyclization, and

(ii) treating the compounds of formula VI, a compound of formula VIII

where L denotes a leaving group, and

(iii) recovering the product to obtain the compounds of formula IX

and (iv) alkylation of compounds of formula IX corresponding aldehyde or a compound of the formula R5L, where L is a leaving group, to obtain compounds of formula I

where R1, R2, R3, R4, R5X, Y, Z, m and n have the meanings described in the context.

Unless otherwise noted, the following terms used in this application, including the description and claims have the meanings given below. It should be noted that in the description and the attached claims definite and indefinite forms of the singular permit the use of the plural, unless the context cheapavodart radical, containing from one to six carbon atoms inclusive, unless otherwise noted. Examples (ness.)Akilov include, but without limitation, methyl, ethyl, propyl, isopropyl, 1-ethylpropyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.

The term “substituted (ness.)alkyl” means (ness.)alkyl, as defined in the context that contains 1-3 substituent, preferably one Deputy, such as hydroxy, alkoxy, amino, amido, carboxy, acyl, halogen, cyano, nitro, and thiol. These groups can be attached to any carbon atom in (ness.)alkyl part. Examples of substituted (ness.)alkyl radicals include, but without limitation, 2-methoxyethyl, 2-hydroxyethyl, dimethylaminocarbonylmethyl, 4-hydroxy-2,2-dimethylbutyl, trifluoromethyl, triptorelin and the like.

The term “alkylene” means a divalent linear or branched saturated hydrocarbon radical containing from one to six carbon atoms inclusive, unless otherwise noted. Examples alkilinity radicals include, but are not limited to, methylene, ethylene, propylene, 2-methylpropene, butylene, 2-ethylbutyl and the like.

The term “alkenyl” means the monovalent linear or branched nanasai not indicated otherwise. Examples alkenyl radicals include, but without limitation, ethynyl, allyl, 1-propenyl, 2-butenyl and the like.

The term “quinil” means the monovalent linear or branched unsaturated hydrocarbon radical containing a triple bond and two to six carbon atoms inclusive, unless otherwise noted. Examples etkinlik radicals include, but are not limited to, ethinyl, 1-PROPYNYL, 2-butynyl, propargyl and the like.

The term “alkoxy” means a radical-OR where R means (ness.)alkyl radical, as defined in the context. Examples of alkoxyalkyl include, but without limitation, methoxy, ethoxy, isopropoxy and the like.

The term “aryl” means the monovalent aromatic carbocyclic radical consisting of one individual ring, or one or multiple condensed rings, from which at least one ring is aromatic in nature, which optionally may be substituted by one or more, preferably one or two, substituents selected from hydroxy, cyano, (ness.)of alkyl, (ness.)alkoxy, halogen(ness.)alkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, (Ninoshvili, alkylsulfonamides, arylsulfonamides, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, unless otherwise noted. Alternatively, two adjacent atom of the aryl ring can be substituted, methylendioxy or ethylenedioxythiophene. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthrachinone, tert-butylphenyl, 1,3-benzodioxolyl and the like.

The term “arylalkyl” (or “aralkyl”) means the radical R'R"-, where R' means aryl radical, as defined in the context, and R" denotes an alkyl radical, as defined in the context. Examples arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl and the like.

The term “cycloalkyl” means a monovalent saturated carbocyclic radical consisting of one or more rings, preferably one or two rings, of three to eight carbon atoms on the ring, which optionally can be substituted by one or more, preferably one or two, substituents selected from hydroxy, cyano, (ness.)of alkyl, (ness.)alkoxy, halogen(ness.)alkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl, sulfonyl, alkylsulfonamides, arylsulfonamides, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, unless otherwise noted. Examples cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclohexyl, cyclopentyl, cycloheptyl and the like.

The term “cycloalkenyl” means the radical R'R"-, where R' means cycloalkyl radical, as defined in the context, and R" denotes an alkyl radical, as defined in the context. Examples cycloalkenyl radicals include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylmethyl and the like.

The term “heteroaryl” means a monovalent aromatic cyclic radical containing one or more rings, preferably one to three rings from 4 to 8 atoms in each ring including one or more heteroatoms, preferably one or two atoms in the ring (chosen from nitrogen, oxygen or sulfur), which optionally may be substituted by one or more, preferably one or two substituents selected from hydroxy, cyano, (ness.)of alkyl, (ness.)alkoxy, halogen(ness.)alkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, onila, alkylsulfonamides, arylsulfonamides, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, unless otherwise noted. Examples of heteroaryl radicals include, but without limitation, imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thienyl, furanyl, pyridinyl, chinoline, ethenolysis, benzofuran, benzothiophene, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzopyranyl, indazoles, indolyl, isoindolyl, chinoline, ethenolysis, naphthyridine, benzosulfimide and the like.

The term “heteroaromatic” (or “heteroaryl” means a radical of the formula R'R"-, where R' means a heteroaryl radical, as defined in the context, and R" denotes an alkyl radical, as defined in the context. Examples heteroarylboronic radicals include, but without limitation, 2-imidazolidinyl, 3-pyrrolidinyl and the like.

The term “heterocyclyl” means a monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings, from 3 to 8 atoms in each ring including one or more ring heteroatoms (chosen from N, O or S(O)0-2), which optionally can be substituted od is.)of alkyl, (ness.)alkoxy, halogen(ness.)alkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylaminomethylene, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, unless otherwise noted. Examples of heterocyclic radicals include, but are not limited to, morpholinyl, piperazinil, piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiomorpholine, hinokitiol and the like.

The term “heteroseksualci” (or “geterotsiklicheskikh” means a radical of the formula R'R"-, where R' means a heterocyclic radical as defined in the context, and R" denotes an alkyl radical, as defined in the context. Examples geterotsiklicheskikh radicals include, but without limitation, 1-piperazinylmethyl, 2-morpholinomethyl, and the like.

The term “halogen” means a fluorine atom, bromine, chlorine and/or iodine.

The term “haloalkyl” means (ness.)alkyl radical, which is defined in the context, substituted in any position by one or more halogen atoms, as defined in the context. Examples haloalkyl radicale.

The term “hydroxyalkyl” means (ness.)alkyl radical, which is defined in the context, substituted by one or more hydroxyl groups. Examples of hydroxyalkyl radicals include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2-(hydroxymethyl)-3-hydroxypropyl and the like.

The term “alkylthio” means a radical-SR where R means (ness.)alkyl, which is defined in the context. Examples of alkylthiomethyl include, but without limitation, methylthio, butylthio and the like.

The term “alkylamino” means a radical NR'R"-, where R' means (ness.)alkyl radical, as defined in the context, and R" denotes hydrogen or (ness.)alkyl radical, as defined in the context. Examples of acylaminoacyl include, but without limitation, methylamino, (1-methylpropyl)amino, dimethylamino, methylethylamine, diethylamine, hydroxyacetylamino, methoxyethylamine and the like.

The term “acyloxy” means the radical-OC(O)R, where R means (ness.)alkyl radical, as defined in the one.

The term “alkoxycarbonyl” or “alkilany ester” means a radical-C(O)-O-R, where R means (ness.)alkyl radical, as defined in the context. Examples alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, etoxycarbonyl, second-butoxycarbonyl, isopropoxycarbonyl and the like.

The term “aryloxyalkyl” or “aryl ester” means a radical-C(O)-O-R, where R is aryl radical, as defined in the context. Examples aryloxyalkyl radicals include, but without limitation, complex phenyl ether complex nattily ether and the like.

The term “arylethoxysilanes” or “complex arylalkylamine ether” means the radical-C(O)-O-RR', where R means (ness.)alkyl radical and R' means aryl radical, as defined in the context. Examples aryloxyalkyl radicals include, but without limitation, complex benzyl ether complex phenethyl ester and the like.

The term “alkylaryl” (or “acyl” means a radical R-C(O)-, where R means (ness.)alkyl radical, as defined in the context. Examples alkylcarboxylic radicals include, but are not limited to, acetyl, propionyl, n-butyryl, in the-, where R is aryl radical, as defined in the context. Examples arylcarboxylic radicals include, but are not limited to, benzoyl, naphtol and the like.

The term “arylalkylamines” (or aralkylamines) means the radical R-C(O)-, where R is Aracely radical, as defined in the context.

Examples aralkylamines radicals include, but are not limited to, phenylacetyl and the like.

The term “heteroarylboronic” means the radical R-C(O)-, where R is heteroaryl radical, as defined in the context. Examples heteroarylboronic radicals include, but are not limited to, pyridinyl, 3-methylisoxazole, isoxazolyl, thienoyl, furoyl and the like.

The term “heterocalixarenes” (or “heterocyclicamines) means the radical R-C(O)-, where R is heterocyclyl radical, as defined in the context. Examples geterotsiklicheskikh radicals include, but are not limited to, piperazinyl, morpholinyl, pyrrolidinyl and the like.

The term “cycloalkylcarbonyl” means the radical R-C(O)-, where R is cycloalkyl radical, as defined in the context. Examples cycloalkylcarbonyl radicals include, but are without faceting” means the radical-C(O)NR'R" where R' means (ness.)alkyl, as defined in the context, and R" denotes hydrogen or (ness.)alkyl, as defined in the context. Examples alkylaminocarbonyl radicals include, but are not limited to, methylaminomethyl, dimethylaminoethyl, tert-butylaminoethyl, n-butylaminoethyl, isopropylaminocarbonyl and the like.

The term “allumination” means the radical-C(O)NR'R" R' means aryl, as defined in the context, and R" denotes hydrogen or aryl, as defined in the context. Examples arylaminomethylene radicals include, but are not limited to, phenylenecarbonyl, methoxyphenylalanine, diphenylmethanone, dimethoxyphenylacetone and the like.

The term “heteroarylboronic” means the radical-C(O)NR'R", where R’ denotes heteroaryl, as it is defined in the context, and R" denotes hydrogen or heteroaryl, as it is defined in the context. Examples heteroarylboronic radicals include, but are not limited to, pyridinylmethyl, tanyamiroshnik, furylmethanol and the like.

The term “alkylcarboxylic” means the radical-NC(O)R' R' means (ness.)alkyl, as defined in the context. Examples of alkylcarboxylic and the like.

The term “arylcarboxamide” means the radical-NC(O)R' R' means aryl, as defined in the context. Examples of arylcarbamoyl include, but without limitation, phenylcarbonylamino, anisochronous and the like.

The term “allylcarbamate” means the radical-OC(O)NR'R" R' means (ness.)alkyl, as defined in the context, and R" denotes hydrogen or (ness.)alkyl, as defined in the context. Examples alkylcarboxylic radicals include, but without limitation, methylcarbamoyl, ethylcarbitol and the like.

The term “arylcarbamoyl” means the radical-OC(O)NR'R" R' means aryl, as defined in the context, and R" denotes hydrogen or aryl, as defined in the context. Examples arylcarbamoyl radicals include, but without limitation, phenylcarbamoyl, afterburner and the like.

The term “arylalkylamines” means the radical-OC(O)NR'R" R' means (ness.)alkyl, as defined in the context, and R" means aryl, as defined in the context. Examples alkylcarboxylic radicals include, but without limitation, benzylcarbamoyl, phenylcarbamoyl and the like.

The term “alkylaminocarbonyl” means the radical-S(O)2

The term “arylamination” means the radical-S(O)2NR'R" R' means aryl, as defined in the context, and R" denotes hydrogen or aryl, as defined in the context. Examples killinaskully radicals include, but without limitation, phenylenesulfonyl, methoxybenzenesulfonyl and the like.

The term “heteroarylboronic” means the radical-S(O)2NR'R" R' means heteroaryl, as it is defined in the context, and R" denotes hydrogen or heteroaryl, as it is defined in the context. Examples heteroarylboronic radicals include, but without limitation, trilaminate, piperazineethanesulfonic, furylmethanol, imidazolidinone and the like.

The term “alkylsulfonyl” means the radical-NS(O)2R' R' means (ness.)alkyl, as defined in the context. Examples of alkylsulfonamides include, but without limitation, methylsulfonylamino, propylsulfonyl and the like.

The term “arylsulfonyl” means the radical-NS(O)2

The term “alkylsulfonyl” means the radical-S(O)2R, where R means (ness.)alkyl or substituted (ness.)alkyl, as defined in the context. Examples alkylsulfonyl radical include, but without limitation, methylsulphonyl, trifloromethyl, propylsulfonyl and the like.

The term “arylsulfonyl” means the radical-S(O)2R, where R is aryl as defined in the context. Examples arylsulfonyl radical include, but without limitation, phenylsulfonyl, toluensulfonyl, nitrophenyloctyl, methoxyphenylacetyl, 3,4,5-trimethoxyphenylacetic and the like.

The term “heteroarylboronic” means the radical-S(O)2R, where R is heteroaryl, as it is defined in the context. Examples heteroarylboronic radical include, but without limitation, thienylmethyl, furnisher, imidazolylalkyl, N-methylimidazolidine and the like.

The term “heterocyclisation” means the radical-S(O)2R, where R is heterocyclyl, as it is defined in the context. Examples heterocyclisation radical include, but without limitation, piperidinylcarbonyl, PIP is e R means (ness.)alkyl or substituted (ness.)alkyl, as it is defined in the context. Examples of alkylsulfonamides include, but without limitation, methylsulfonylamino, tripterocalyx, propylsulfonyl and the like.

The term “optional” or “optionally” means that the described subsequently, the event or event can occur, but it isn't necessary, and that the description includes instances where the event or incident occurs and instances in which it is not. For example, the term “optional communication” means that a relationship may exist or may not exist and that the description includes single, double, or triple bond.

The term “leaving group” means a group with a value normally associated with it in synthetic organic chemistry, i.e., an atom or a group substitutable in terms of alkylation. Examples of leaving groups include, but are not limited to, halogen, alkane - or arylsulfonate, such as methanesulfonate, econsultancy, thiomethyl, benzosulfimide, tosyloxy, titilate, dialogfactory, optionally substituted benzyloxy, isopropoxy, acyloxy and the like.

The term “protective group” or “blocking group” means a group Kotorska reaction may be selectively held at another unprotected reactive position, the group with a value normally associated with it in synthetic chemistry. Some of the ways in which this invention is based on the use of protective groups to block reactive oxygen atoms present in the reacting compounds. Acceptable protective group for an alcohol or phenolic hydroxyl, which can be easily and selectively removed, include groups that offer protection in the form of acetates, haloalkylthio, simple benzyl ethers, simple alkylsilane ethers, simple geterotsiklicheskikh esters and simple methyl or alilovic esters and the like. Protective or blocking groups for carboxy similar to those described for hydroxyl, preferably with the formation of tert-butyl, benzyl or methyl esters. Examples of protective groups can be found in T. W. Greene and others, Protective Groups in Organic Chemistry (J. Wiley, 2nd ed., 1991), and Harrison and others, Compendium of Synthetic Organic Methods, T. 1-8 (J. Wiley and Sons. 1971-1996).

The term “aminosidine group” means such a blocking group that is intended to protect the nitrogen atom against undesirable reactions during the synthesis, and includes, but without limitation, benzyl, benzyloxycarbonyl (carbobenzoxy, CBZ), n-methoxybenzyloxy is correctly applied or VOS, or CBZ as aminosidine group because of the relatively easy removal, for example, weak acids in the case of VOS, for example triperoxonane acid or hydrochloric acid in ethyl acetate, or by catalytic hydrogenation in the case of CBZ.

The term “hidroxizina group” means the blocking group protecting the hydroxyl, which otherwise would have been modified during some chemical reactions. Proper protection of the hydroxyl includes forming ethers groups, which can be easily removed after completion of all other stages of the reactions, such as benzyl or triticina group, optionally substituted on the phenyl ring. Other appropriate protection of the hydroxyl group includes, forming a simple alkalemia esters, tetrahydropyranyl, trialkylsilyl group and allyl group.

The term “removing protection” or “release” means a reaction which removes the protective group after completion of the interaction. Some of the protective group may be preferable to others because of the convenience, or the relative ease of their removal. Deblokiruyuschee reagents for protected hydroxyl or carboxyl groups on torakusu acid, palladium catalysts or tribromide boron, and the like.

The term “isomerism” means compounds that have identical molecular formulas but differ in the nature or sequence of atoms connecting them, or spatial arrangement of their atoms.

Isomers that differ in the spatial arrangement of their atoms, called “stereoisomers”. Stereoisomers that are not mirror images of each other, called “diastereoisomers” and stereoisomers that are not coincident with the imposition of mirrors, called “enantiomers” or sometimes optical isomers. The carbon atom bound to four non-identical substituents, referred to as “chiral center”.

The term “chiral isomer” means a compound with one chiral center. It has two enantiomers of opposite chirality and can exist either in the form of an individual enantiomer or as a mixture of enantiomers. A mixture containing equal number of individual enantiomeric forms of the opposite chirality, is called a “racemic mixture”. A compound that contains more than one chiral center, is 2n-1 is ntram can exist either as an individual diastereoisomer, or as a mixture of diastereomers, called “diastereomeric mixture”. If the connection there is one chiral center, stereoisomer can be characterized by the absolute configuration (R or S) of this chiral center. The absolute configuration refers to the spatial arrangement of the substituents connected to the chiral center. Deputies associated with the chiral center when considering feature in the series in accordance with rule sequence Kahn, Ingold and Prelog (Cahn and others, Angew. Chem. Inter. Edit. 1966, 5, 385; typo 511; Cahn and others, Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn and other Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

The term “geometric isomer” means that the diastereomers owe their existence and rough rotation around double bonds. These configurations differ in their names with the prefixes CIS and TRANS or Z and E, indicating that the groups are on the same side or on opposite sides of the double bond in the molecule in accordance with rule Cana-Ingold-Prelog.

The term “tropicheskie isomers” refers to the isomers, which owe their existence and rough rotation caused by the obstacle created when the enemy is at least about 80 mol.%, more preferably, at least about 90 mol.% and most preferably at least about 95 mol.%, the desired enantiomer or stereoisomer.

The term “pharmaceutically acceptable” means, as applicable, in the preparation of pharmaceutical compositions, i.e., generally safe, non-toxic and neither biologically nor otherwise not is undesirable and includes that which is acceptable for veterinary and pharmaceutical use in humans.

The term “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity of the parent compound. Such salts include

(1) acid additive salts formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or formed with organic acids such as acetic acid, benzolsulfonat acid, benzoic acid, camphorsulfonic acid, citric acid, econsultancy acid, fumaric acid, glucoheptonate sitesurvey acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonate acid, Mukanova acid, 2-naphthalenesulfonate acid, propionic acid, salicylic acid, succinic acid, Dibenzoyl-L-tartaric acid, tartaric acid, n-toluensulfonate, trimethylhexane acid, triperoxonane acid and the like, or

(2) salts formed when an acidic proton present in the original compound is replaced by a metal ion, for example an alkali metal ion, ion alkaline-earth metal or an aluminum ion; or forms coordination with organic or inorganic base.

Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Preferred pharmaceutically acceptable salts are salts formed from hydrochloric acid, triperoxonane acid, Dibenzoyl-L-tartaric acid and phosphoric acid.

It should be understood that all references to pharmaceutically acceptable acontext, the above-mentioned acid additive salt.

The term “crystalline form” (or polymorphs) means the crystal structure, in the form which the compound can crystallize in different location layout of crystals, all of which have the same elemental composition. Different crystalline forms usually have different x-rays, infrared spectra, melting points, density, configuration, crystal, optical and electrical properties, stability, and solubility. Recrystallization from a solvent, rate of crystallization, storage temperature, and other factors can cause the predominance of one crystalline form.

The term “solvate” means a solvent-additive form, which contain either stoichiometric or non-stoichiometric amount of solvent. Some compounds in the solid crystalline state have a tendency to catch the solvent molecules in a specific molar ratio, thereby forming a MES. If water is the solvent, the educated MES is a hydrate, if the solvent is alcohol, the educated MES is an alcoholate. Hydrates are formed by recognize the result as H2Oh, and this connection can form one hydrate or more.

The term “prodrug” means a pharmacologically inactive form of the compound, which after administration to a subject must be metabolized in vivo, for example, with biological fluids or enzymes in a pharmacologically active form of the compound to achieve the desired pharmacological effect. The prodrug can be metabolized before absorption, the absorption, after absorption, or in a specific area. And although many compounds originally metabolism occurs in the liver, almost all other organs and tissues, especially the lung, is capable of varying levels of metabolism. Proletarienne forms of the compounds can be used, for example, to improve bioavailability to improve for the subject of portability, for example, by masking or reducing the unpleasant characteristics, such as a bitter taste or irritation of the gastrointestinal tract, to change the solubility, for example, for intravenous administration, to provide prolonged or continuous release or delivery, to facilitate dosage form or to provide targeted delivery of the soybeans the livery Systems page 352-401; Design of Prodrugs, editor N. Bundgaard, Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs, editor E. B. Roche, American Pharmaceutical Association, Washington, 1977, and Drug Delivery Systems, editor R. L. Juliano, Oxford Univ. Press, Oxford, 1980.

The term “subject” means a mammal, and memleketim. Under mammal means any member of the class Mammalia, including, without limitation, humans, nonhuman primates, such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and Guinea pigs and the like. Examples of memleketim include, but without limitation, birds and the like.

The term “therapeutically effective amount” means an amount of compound that when administered to a subject to treat painful conditions is sufficient to make effective such treatment of the disease condition. therapeutically effective amount will vary depending on the compound, the disease condition being treated, the severity or nature of the disease, the age and relative healthy the doctor and other factors.

The term “pharmacological effect” as it is used in context, covers all the consequences caused by the subject that achieve the intended goals of therapy. In one preferred embodiment of the invention, a pharmacological effect means that the primary symptoms of the subject being treated, prevented, alleviated or reduced. For example, a pharmacological effect could be, which leads to the prevention, alleviation or reduction of the primary symptoms in the treated subject. In another preferred embodiment of the invention, a pharmacological effect means that breaches or symptoms the primary symptoms of the subject being treated, prevented, alleviated or reduced. For example, a pharmacological effect could be, which leads to the prevention or reduction of the primary symptoms in the treated subject.

The term “disease state” means any disease, condition, symptom or indication.

The term “treating” or “treatment” of the disease condition includes

(1) preventing the disease condition, i.e., the obstacle to the emergence of clinical symptoms of painful conditions in sarail its symptoms;

(2) the suppression of painful conditions, i.e., the termination of development of the disease condition or its clinical symptoms, or

(3) the weakening of painful conditions, i.e., induction of temporary or permanent regression of the disease condition or its clinical symptoms.

The term “antagonist” means a molecule, such as a compound, a drug, an inhibitor of the enzyme or hormone, which reduces or prevents the action of another molecule or receptor site.

The term “disorders of the urinary tract” or “uropathy”, used interchangeably with the term “symptoms of the urinary tract” means pathological changes in the urinary tract. The symptoms of the urinary tract include increased activity of the bladder (also known as hyperactivity of the detrusor), outlet obstruction, lack of outlet openings and increased pelvic sensitivity.

The term “increased activity of the bladder” or “hyperactive detrusor” includes, but without limitation, with such changes manifested by symptoms of urgency, urinary frequency, reduced bladder capacity, incontinence and comune, unstable bladder contractions, the sphincter spasticity, and the like, and symptoms, usually manifested by detrusor hyperreflexia (neurogenic bladder), in conditions such as obstruction of the outlet insufficiency outlet, increased pelvic sensitivity, or idiopathic conditions, the instability of the detrusor and the like.

The term “outlet obstruction” includes, but without limitation, benign hypertrophy of the prostate (national Department of standardization), urethral stricture disease, tumors and the like. This is usually manifested as obstructive symptom (low speed expiration difficulty in the initial stage of urination, and the like) or as an irritant (urgency, suprapubic pain, and the like).

The term “insufficiency outlet” includes, but without limitation, increased urethral mobility, congenital defect sphincter or mixed incontinence. This usually comes in the form of symptom of stress incontinence.

The term “increased pelvic sensitivity” includes, but without limitation, pain in the pelvic region, interstitial is income pain, inflammation or discomfort in the pelvis and usually includes symptoms of bladder with increased activity.

Nomenclature: the name and numbering of the compounds according to this invention, are illustrated below.

Generally, the nomenclature used in this application is based on AUTONOMTMcomputerized system Institute of Bilstein for education systematic IUPAC nomenclature. For example, the compound of formula I, where R1means econsultancy, R2and R3mean N, R4means methyl, R5means ethyl, n means 3, m is 2 and X, Y and Z denote CH2called 1-(4-{[2-(4-ethanolgasoline)-1-methylethyl]ethylamino}butyl)azepin-2-it.

Similarly the compound of formula I, where R1means chlorine, R2and R3mean N, R4means methyl, R5means propyl, n is 2, m is 1, X is N and Y and Z denote CH2called

1-[3-{[2-(4-chlorophenyl)-1-methylethyl]propylamino}propyl]tetrahydropyrimidin-2-it.

Similarly the compound of formula I, where R1means methanesulfonyl, R2and R3mean N, R4means methyl, R5means ethyl, n oznaczanie)-1-methylethyl]amino}butyl)-4-methanesulfonyl[1,4]diazepan-2-it.

Among the compounds of the present invention described in the summary of the invention, certain compounds of formula I, or prodrugs, individual isomers, racemic and nerezisca mixture of isomers, or pharmaceutically acceptable salt, or their solvate are preferred.

R1, R2and R3means independently in each case preferably hydrogen, halogen, (C1-C6)alkyl, alkoxy, alkylsulfonyl or alkylsulfonate and more preferably hydrogen, methoxy, methylsulphonyl or methylsulfonylamino.

Another preferred group includes the compounds where R1and R2if they are adjacent, together with the ring to which they are attached, form a 5 - or 6-membered monocyclic saturated or unsaturated cycle, optionally containing 0, 1 or 2 cyclic heteroatoms independently selected from nitrogen, oxygen or sulfur, more preferably R1and R2if they are adjacent, together with the ring to which they are attached, form a naphthalene, indole, 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxin, chroman, benzo[1,3]dioxole, benzo[1,3]oxathiolan, benzo[1,3]oxathiolane and even more preferably 2,3-Digi/SUB>)alkyl and more preferably methyl.

R5means independently in each case, preferably (C1-C6)alkyl, (ness.)alkenyl or (ness.)quinil, more preferably ethyl, propyl, isopropyl, allyl or propargyl and even more preferably ethyl or propyl;

m means preferably 0-3, more preferably 1-2, and even more preferably 2, and

n means preferably 1-6, more preferably 1-3, and even more preferably 3.

One of X, Y or Z means independently in each case, preferably-S-, -O-, -CH2or >N-R6most preferably-CH2or >N-R6and even more preferably >NH.

Especially preferred are the compounds of formula I, where R4means methyl. In a more preferred variant of embodiment R4means methyl and m is 0.

In another preferred variant of embodiment R4means methyl and m is 1. An example of such compound is 1-(2-{ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl)piperidine-2-it. In a more preferred variant of embodiment R4means methyl, m is 1 and Y represents >N-R6.

Examples of such connection

1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-methylpiperazin-2-he /

N-methyl-4-((S)-2-{[4-(2-oxopiperidin-1-yl)butyl]propylamino}propyl)benzosulfimide.

In another preferred variant of embodiment R4means methyl and m is 2, more preferably R4means methyl, m is 2 and n means 3.

Examples of such compounds are the following:

1-(4-{ethyl-[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)azepin-2-he;

4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]oxazepan-3-one

or 4-(2-{ethyl-[4-(2-oxazepan-1-yl)butyl]amino}propyl)phenyl ether 1,1,1-triftormetilfullerenov acid.

Especially preferred are the compounds of formula I, where R4means methyl, m is 2 and one of X, Y or Z means >N-R6and other means-CH2-. Even more preferably, when R4means methyl, m is 2 and X is >N-R6. In another preferred variant of embodiment R4means methyl, m is 2 and Y represents >N-R6in another preferred variant of embodiment R4means methyl, m is 2 and Z means >N-R6.

Yes the>N-R6.

Examples of such compounds are the following:

1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-2-he;

1-(4-{ethyl-[(S)-1-methyl-2-(4-triptoreline)ethyl]amino}butyl)[1,4]diazepan-2-he /

1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-methyl[1,4]diazepan-2-it.

Especially preferred are also the compounds of formula I, where R4means methyl, m is 2 and Z means >N-R6.

Examples of such compounds are the following:

4-(4-{allyl-[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)[1,4]diazepan-5-he;

4-(4-{[2-(4-tert-butylphenyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-he;

ethyl ester 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo-[1,4]diazepan-1-carboxylic acid;

4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-he;

4-((S)-2-{[4-(7-oxo[1,4]diazepin-1-yl)butyl]propylamino}propyl)phenyl ether propane-2-sulfonic acid, or

4-(4-{[(S)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-methylethyl]propylamino}butyl)-[1,4]diazepan-5-he.

In another preferred variant of embodiment R4Osnach the finding include pharmaceutically acceptable salts of the compounds of the present invention, where the pharmaceutically acceptable salts formed from hydrochloric acid, 2,2,2-triperoxonane acid, Dibenzoyl-L-tartaric acid, sulfuric or phosphoric acid, more preferred salts formed from hydrochloric acid, 2,2,2-triperoxonane acid or phosphoric acid, or even more preferred salts formed from hydrochloric acid.

Compounds of the present invention can be obtained by the methods depicted in the illustrative schemes of synthesis reactions described below.

Starting materials and reagents that are used to obtain these compounds, as a rule, or obtained from commercial suppliers such as Aldrich Chemical Co., or synthesized by methods known to experts in this field, in accordance with the methods presented in references such as Fieser and Fieser (1991) Reagents or Organic Synthesis: Wiley & Sons: New York, volumes 1-15; Rodd (1989) Chemistry of Carbon Compounds, Elsevier Science Publishers, volumes 1-5 and Supplementals, and (1991) Organic Reactions, Wiley & Sons: New York, volumes 1-40. Subsequent schemes of synthesis reactions are merely an illustration of some of the ways that can be synthesized compounds of the present invention, and various modifications to these schemes of synthesis can be carrying the E.

Raw materials and intermediate compounds shown in schemes of synthesis, can be isolated and optionally purified using conventional techniques, including, but without limitation, filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized with conventional data, including physical constants and spectral data.

Unless otherwise stated, the reactions described in the context of, preferably carried out at atmospheric pressure at a temperature in the range of from about -78° C to about 150° C, more preferably 0-125° C and most preferably and conveniently at about room temperature (ambient temperature), for example about 20° C.

In General, the compounds of formula I can be obtained by methods described in the following diagrams reactions.

Scheme And

Scheme And mainly describes the method of obtaining the compounds of formula I, where X, Y, Z, R1, R2, R3, R4, R5, m and n have the meanings previously described.

The compound of formula I, as a rule, can be obtained by condensation of carboxaldehyde 1 phenylalkylamine 2 in terms of Vosstaniya sodium, laborgerate sodium, isopropoxide titanium and laborgerate sodium, hydrogen and a metal catalyst and transferring hydrogen agents, such as cyclohexane, formic acid and its salts, zinc and hydrochloric acid, formic acid or dimethylsulfide followed by treatment with formic acid.

Appropriate inert organic solvents for the reaction include dichloromethane, 1,2-dichloroethane, tetrahydrofuran, alcohols or ethyl acetate, and the like. Preferably the reaction is carried out under basic conditions with triacetoxyborohydride sodium in 1,2-dichloroethane.

Methods of restoration amination described in the chemical literature. For Example, J. Org. Chem. 1996, 61, 3849, Tetrahedron Letters 1996, 37, 3977, describe techniques that use triacetoxyborohydride sodium as a reagent for reductive amination of aldehydes using a large variety of amines. For Example, J. Am. Chem. Soc. 1971, 93, 2897, and Org. Synth. Coil. 1988, 6, 499, describe techniques that use Lamborgini sodium as a reagent for the reductive amination of carbonyl compounds.

Well-known starting materials of the circuit And are commercially available or izvestnymi (1), (2) and (3).

Scheme (1)

Carboxaldehyde 1, where X, Y, Z, m and n are as defined above values can be obtained by the interaction of aminogroup compounds and alkylating agent of the formula L(CH2)nCH=CH2where L is a leaving group such as halogen or methansulfonate, preferably chlorine, under basic conditions to obtain a compound b. The alkylation reaction is accompanied by the oxidation/decomposition of the end alkinoos group b in the aldehyde group with the aim of obtaining carboxaldehyde 1. A variety of oxidizing agents used for oxidation/cleavage of alkenes to aldehydes described in the chemical literature. For Example, J. Org. Chem. 1956, 21, 478, describes how, using osmium tetroxide and (meta)periodate sodium; Syn. Comm. 1982, 12, 1063, describes how, using potassium permanganate and (meta)periodate sodium; J. Org. Chem. 1987, 52, 3698, describes how, using potassium permanganate and silica gel; Chem. Rev. 1958, 58, 925, describes how using ozone; J. Org. Chem. 1986, 51, 3213, describes how, using only potassium permanganate; J. Org. Chem. 1987, 52, 2875, describes how, using (meta)periodate sodium and catalytic ruthenium. Preferably the reaction of p is Alternative carboxaldehyde 1, where X, Y, Z, m and n have the meanings described above, can be obtained by the interaction of the free amino compound and an alkylating agent of the formula L(CH2)nC(OR)2where R means (C1-C6)alkyl and L is a leaving group such as halogen, preferably bromine, to obtain a connection with. the alkylation Reaction is followed by hydrolysis acetamino group connection in acidic conditions to obtain carboxaldehyde 1.

Scheme (3)

Alternative carboxaldehyde 1, where X, Y, Z, m and n have the meanings described in the Executive summary of the invention can be obtained by the interaction of aminoacyl d, where R means (C1-C6)alkyl, with the corresponding allermuir agent such as allerease agent of the formula L(CH2)nCOL', or L(CH2)nL', or L(CH2)nN=C=O, where in each case the L' means a leaving group such as halogen, preferably chlorine, to obtain a connection that is, the acylation Reaction is accompanied by an internal N-alkylation of compounds e and subsequent hydrolysis acetamino group of compounds of f, to obtain carboxaldehyde 1.

For example, the original phenylalkylamine 2 can the S="ptx2">

Phenylalkylamine 2, where R1, R2, R3, R4and R5have the above meanings, can be obtained by the interaction of benzaldehyde g, c nitroalkane under the reaction conditions of Knowingly or Henry for obtaining compounds of h, then the restoration of the nitro group to the amino group and the restoration of alkinoos communication connection h to obtain compound i. Phenylalkylamine 2 can be obtained by subsequent reaction of the free amino group of compound i with an aldehyde RCHO under conditions of reductive amination or allermuir agent RCOL, then recovery (R means (C1-C6)alkyl group, where CH2R means R3), or with an alkylating agent R5L, where L is a leaving group such as halogen.

Scheme 5

Alternative phenylalkylamine 2, where R1, R2, R3, R4and R5have the meanings described in the Executive summary of the invention can be obtained by the interaction of bromine benzol j c metal magnesium and alkanolamides for connection k, then the ozonolysis of compound k to obtain compound 1. Phenylalkylamine 2 can be obtained by subsequent treatment of compound 1 with the primary amine is an amine 2 described in the chemical literature, for example, J. Med. Chem. 1973, 6, 480-483; J. Med. Chem. 1986, 29, 2009-2015, J. Med Chem. 1991, 34, 1662-1669.

Scheme (6)

Alternative phenylalkylamine 2, where R1, R2, R3, R4and R5have the meanings previously described, can be obtained by the coupling of compounds of General structure n, where R is alkyl, aryl or alkylaryl, more preferably R is benzyl, and Raand Rbdenote alkyl or alkoxy, or Raand Rbtogether with the nitrogen atom to which they are attached, form a cycle, more preferably Raand Rbform morpholinyl cycle, with a derivative of Arimathea, more preferably aryl Grignard reagent of the General structure m, to obtain a complex ether of carbamino acid of the General structure where R is alkyl, aryl or alkylaryl, more preferably R is benzyl. The weak recovery regenerating agent such as sodium borohydride or lithium or borane, preferably with sodium borohydride, followed by treatment with a base, such as potassium hydroxide or tert-butyl potassium, gives oxazolidin-2-it p. Oxazolidinone p can be alkilirovanii using alkyl, substituted leaving group, preferably alkylhalides, prourokinase, for example, with a salt of formic acid, preferably with ammonium formate and palladium on charcoal, to obtain the corresponding chiral amphetamines formula 2 or formula 2A.

Scheme B

Scheme B describes, in particular, the method of obtaining the compounds of formula I, where X, Y and Z mean every-CH2and R1, R2, R3, R4, R5, m and n have the meanings previously defined.

The compound of formula IA can be obtained by the reaction described in scheme B. Preferably the compound of formula IA can be obtained by the interaction of carboxaldehyde la, phenylalkylamines 2 under conditions of reductive amination, as described in scheme B.

Typical methods of preparing compounds of formula IA shown in example 1.

Schema

The schema describes, in particular, the method of obtaining the compounds of formula I, where X is >NR6, -O - or-S-; Y and Z mean every-CH2and R1, R2, R3, R4, R5, m and n have the meanings previously defined.

The compound of formula IB can be obtained by the reaction described in scheme C. Preferably the compound of formula IB can be obtained by the interaction of the carb is SS="ptx2">Typical methods of preparing compounds of formula IB shown in example 2.

Scheme G

Scheme G describes, in particular, the method of obtaining the compounds of formula I, where X and Z denote each-CH2-; Y represents >N-R6, -O - or-S -, and R1, R2, R3, R4, R5, R6, m and n have the previously described meaning.

The compounds of formula ICa, ICb or ICc can be obtained by the reactions described in scheme,

The compound of formula ICa, where Y denotes-O - or-S-, preferably may be obtained by interaction of carboxaldehyde 1C with phenylalkylamine 2 under conditions of reductive amination, as described in the diagram,

The alternate connection of the formula s, where Y represents >N-R6can also be obtained by condensation of the protected nitrogen carboxaldehyde 1d, where P denotes the corresponding N-protective group, with phenylalkylamine 2 under conditions of reductive amination, as described in scheme A. This reaction is accompanied by removal of the N-protective group of compound 3 under acidic conditions in order to obtain the compounds of formula ICb, where Y represents the >NH. Then the compound of formula ICb may further react with an appropriate alkylating agent is their formula ICC, where R6does not mean N.

Illustrative methods for obtaining the compounds of formula ICa, ICb or ICC are given in examples 3, 4 and 5.

Scheme D

Scheme D describes, in particular, the method of obtaining the compounds of formula I, where X and Y denote each-CH2-; Z denotes >N-R6, -O - or-S -, and R1, R2, R3, R4, R5, R6, m and n have the meanings described above.

The compound of the formula IDa, IDb and IDc can be obtained by reactions described in scheme D.

Preferably the compound of the formula IDa, where Z denotes-O - or-S-, can be obtained by the interaction of carboxaldehyde 1e under conditions of reductive amination, as described in scheme D.

The alternate connection of the formula IDc, where Z denotes >N-R6can be obtained by condensation of N-protected carboxaldehyde 1f, where f denotes the corresponding aminosidine group, with phenylalkylamine 2 under conditions of reductive amination, as described in scheme D. the Alternate connection 4 can be obtained from N-protected carboxaldehyde If condensation phenylalkylamines 2A, followed by reductive alkylation.

Removal of the N-protective group in which the formula IDb may further react with an appropriate alkylating agent, allermuir agent or sulfonylureas agent by methods known in the art, to obtain the compounds of formula IDc, where R6does not mean N.

Illustrative methods for obtaining the compounds of formula IDa, IDb and IDc are shown in examples 6, 7 and 8.

Scheme E

Scheme E describes, in particular, the alternative method of obtaining the compounds of formula I, where X, Y, Z, R1, R2, R3, R4, R5, m and n have the meanings given above.

The compound of the formula I can be obtained by using the reactions described in scheme E. the Alternate connection of the formula I can be obtained by alkylation of suitably protected oxazolidinone p compound of General formula r, where L is a leaving group, preferably halogen, giving N-alkilirovanny oxazolidinone 5. If X, Y or Z means N, the secondary amino group of compounds r is protected according to methods known in the art, as described above. This reaction is accompanied by the splitting oxazolidinones cycle in conditions of hydrogenolysis, for example, with a salt of formic acid in the presence of palladium hydroxide, giving the intermediate amine 6. Alkylation of the secondary amine in chain link and the corresponding alkylhalides give the desired product of formula I. If X, Y or Z means N, N-protective group can be removed under acidic conditions.

Illustrative methods for obtaining compounds of formula I by the method outlined in scheme E, is given in example 9.

The compounds of this invention are antagonists of muscarinic receptors. Compounds that act as antagonists at the muscarinic receptors, used to treat certain disease conditions associated with improper function of smooth muscles. Until recently, most of these compounds did not possess selectivity for different subtypes of muscarinic receptors, leading to unpleasant anticholinergic side effects such as xerostomia, constipation, blurred vision, or tachycardia, of which the most common is xerostomia, occurs when the blockade of the receptor in the salivary gland. It is shown that the recently created specific antagonists M2 or M3 have reduced side effects. The data suggest that competitive blockade of receptors M2 and M3 could be therapeutically effective in the treatment of painful conditions associated with disorders of smooth muscle, such as violations Mohapatra.

Disorders of the genitourinary tract, being treated with the compounds according to this invention include, in particular, increased activity of the bladder or the hyperactivity of the detrusor and their symptoms, such as changes manifested by symptoms of urgency, frequency of urination, decreased bladder capacity, episodes of incontinence, and the like; changes urodynamics, manifested as changes in bladder capacity, the threshold of the bladder, unstable bladder contractions, the sphincter spasticity, and the like, and the symptoms usually manifested as detrusor hyperreflexia (neurogenic bladder), with conditions, such as outlet obstruction, lack of outlet openings, increased pelvic sensitivity, or idiopathic conditions such as detrusor instability, and the like.

Disorders of the gastrointestinal tract, being treated with the compounds according to this invention, in particular, include irritable bowel syndrome, diverticular disease, achalasia, gastrointestinal hyperkinesia and diarrhea. Disorders of the respiratory tract, being treated with the compounds according to dibros.

These and other options for therapeutic applications described, for example, Goodman & Gilman (1996). The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, New York, Chapter 26, 601-616, and Coleman, R. A. (1994). Pharmacological Reviews, 46, 205-229.

The affinity of these compounds to muscarinic receptors can be identified by analysis of the binding of the receptor in vitro, which uses the product of the cell membrane of cancer cells Chinese hamster expressing recombinant human muscarinic receptors (M1-M5), and which is described in more detail in example 17.

The properties of the investigated compounds as muscarinic antagonists can be identified by analyzing in vivo, where it is determined the inhibitory activity against muscarinic receptor-mediated secretion of saliva in rats under anesthesia, and which are described in more detail on the model induced oxotremorine/pilocarpine (OIS/PIS) salivation in rats under anesthesia, example 18.

The properties of the investigated compounds as muscarinic antagonists can be identified by analyzing in vivo, where it is determined the inhibitory activity against muscarinic receptor-mediated response of the bladder, induced by its volume, example 19.

The properties of the investigated compounds as muscarinic antagonists can be identified by analyzing in vivo, where it is determined the inhibitory activity against muscarinic receptor-mediated contraction of the bladder and the secretion of saliva in dogs under General anesthesia, and which is described in more detail in example 20.

The present invention includes pharmaceutical compositions containing at least one compound of the present invention or a prodrug, individual isomers, racemic or prizemistuyu mixture of mezamero, or a pharmaceutically acceptable salt, or its MES along at least one pharmaceutically acceptable carrier and optionally other therapeutic and/or prophylactic ingredients.

In General, the compounds of the present invention will be administered in a therapeutically effective amount of any of the accepted ways of administration for agents that have similar beneficial properties. Acceptable dose ranges are usually 1-500 mg, preferably 1-100 mg per day and most preferably 1-30 mg / day, depending on numerous factors who want to make the used connection the path and dosage form for administration, the indication for which prescribed the introduction, and the choice and experience of the attending physician. Any of the usual specialists in the treatment of such diseases will be able to determine a therapeutically effective amount of the compounds of the present invention for a particular disease without undue experimentation and relying on our own knowledge and the disclosure of this application.

In General, the compounds of the present invention will be administered as a dosage form, including those applicable to oral administration (including buccal and sublingual), rectal, nasal, local, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous), or in a form suitable for administration by inhalation or insufflation. The preferred method of introduction, as a rule, is oral using a convenient daily dose mode, which can be adjusted in accordance with the severity of the disease.

The compound or compounds of the present invention together with one or more conventional auxiliary agents, carriers or diluents can Antartic doses can comprise conventional ingredients in known proportions, with additional active compounds or components, or without them, and a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be applied. The pharmaceutical compositions can be used in the form of solid dosage forms such as tablets or filled capsules, semi-solids, powders, mixtures with continuous release, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use, or in the form of suppositories for rectal or vaginal administration, or in the form of a sterile injectable solution for parenteral use. A mixture containing approximately 1 mg of active ingredient or, more broadly, from about 0.01 to about 100 mg per tablet, are accordingly acceptable representative forms of standard doses.

Compounds of the present invention can be designed in the form of a variety of dosage forms for oral administration. Pharmaceutical compositions and dosage forms may contain a compound or compounds of the present invention, the sludge which may be solid or, or liquid. Solid form preparations include powders, tablets, pills, capsules, kageki, suppositories, and dispersible granules. A solid carrier can be one or more substances that also act as diluents, flavoring agents, soljubilizatory, lubricants, suspendresume agents, binders, preservatives, agents for disintegration of tablets or encapsulating material. In powders, the carrier generally is a powdered solid substance that is mixed with powdered active ingredient. In tablets, the active ingredient, usually mixed with a carrier having the necessary binding capacity in appropriate proportions and pressed to the desired shape and size. The powders and tablets preferably contain from about 1 to about 70% of the active compounds. Appropriate carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, carboxymethylcellulose sodium form, low melting wax, cocoa butter and the like. It is implied that the term “drug” includes a composition of active compounds such encapsulates the Mat is eat, who associated with him. Likewise included in a wafer and pellet. Tablets, powders, capsules, pills, wafers and cakes can be as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid form preparations containing emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid forms of drugs, which, as implied, shortly before use must be turned into liquid form preparations. Emulsions can be prepared in solutions, for example aqueous solutions of propylene glycol, or may contain emulsifiers, such as lecithin, monooleate sorbitan or gum Arabic. Aqueous solutions can be prepared by dissolving the active component in water and adding the respective colorants, flavors, stabilizing and thickening agents. Aqueous suspensions can be prepared by dispersing powdered active component in water with viscous material such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose sodium form and other well-known suspendresume agents. Liquid forms of drugs flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

Compounds of the present invention can be developed in a form for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in the form of standard doses in ampoules, pre-filled syringes, containers with a small injection volume or mnogochasovykh containers with an added preservative. Songs can have such form as suspensions, solutions or emulsions in oily or aqueous fillers, such as solutions in aqueous polyethylene glycol. Examples of oil or non-aqueous carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (such as ethyl ester of oleic acid) and may contain included in the composition of agents, such as preservatives, moisturizing, emulsifying or suspendida, stabilizing and/or dispersing agents. Alternative active ingredient may be in powder form, obtained Septim with an appropriate filler, for example, with sterile water, not containing pyrogens.

Compounds of the present invention can be designed in the form for the local introduction of the epidermis as ointments, creams or lotions, or as transdermal patches. Ointments and creams can be designed, for example, aqueous or oily base with the addition of the corresponding thickening and/or gelling agents. Lotions can be developed with water or oil based and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspendida agents, thickening agents, or coloring agents. Formulations suitable for topical introduction into the oral cavity include the pellet containing the active agent is a flavored basis, usually sucrose and gum Arabic or tragakant; lozenges comprising the active ingredient in an inert basis such as gelatin and glycerol or sucrose and gum Arabic, and liquid for rinsing the oral cavity, including an active ingredient and a suitable carrier liquid.

Compounds of the present invention can be developed in a form for administration as suppositories. Low-melting mohanna is dispersed, for example, by stirring. The molten homogeneous mixture is then poured into molds of suitable size, is allowed to cool and harden.

Compounds of the present invention can be designed in the form for nasal administration. Solutions or suspensions used directly in the nasal cavity using conventional means, such as a dropper, pipette or spray. The compositions may be provided in the form of a single dose or multiple doses. In the latter case, this can be achieved by introducing the patient from a dropper or pipette the appropriate, pre-determined volume of solution or suspension. In the case of a spray, this may be achieved, for example, by measuring the spray injection pump.

Compounds of the present invention can be designed in the form for aerosol administration, particularly in the respiratory tract, including intranasal administration. The connection usually will consist of particles of small size, for example, about 5 microns or less. A particle of this size can be obtained by methods known in the art, such as fine grinding. The active ingredient supply sealed packaging with sootle dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Typically, the aerosol may also contain a surfactant such as lecithin. The dose can be controlled with the aid of the measuring valve. Alternative active ingredients can be formulated in the form of a dry powder, for example, a powder mix of the compound with an appropriate powder base such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). Powder media in the nasal cavity will form a gel. Composition in powder form can be represented in the form of a standard dose of, for example, capsules or cartridges, for example, from gelatin or blister packs from which the powder may be introduced through the inhaler.

Compounds of the present invention can be designed in the form of transdermal or subcutaneous delivery of drug. These delivery systems are useful when you need continuous release of the connection and when the observation mode and a treatment regimen is crucial. Connection in transdermal delivery systems are often attached to prolipamy to the skin of the solid substrate. Secretariageral-2-one). Delivery system with continuous release is injected into the subcutaneous layer with the help of surgery or injections. Subcutaneous implants encapsulate the compound in the lipid soluble membrane, such as silicone rubber, or a biodegradable polymer, for example in policano acid.

Pharmaceuticals mainly manufactured in standard dosage forms. In such form the preparation is subdivided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, the package containing separate quantities of the drug, such as packs of tablets, capsules, and powders in vials or ampoules. In addition, a standard dosage form itself can be a capsule, tablet, wafer or bread or can be the appropriate number of any of them in Packed form.

Other appropriate pharmaceutical carriers and their formulations are described Remington, The Science and Practice of Pharmacy, 1995, editor E. W. Martin, Mack Publishing Company, 19th-oe edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing a compound of the present invention, described in examples 10-16.

Sleduyuscheego invention. They should not be regarded as limiting the scope of the invention but merely as illustrating and representing its essence.

Examples

Experience 1 (obtaining the compounds of formula 1)

4-(2-Oxazolin-1-yl)butyric aldehyde

To a stirred suspension of sodium hydride (0.9 g, 37.5 mmole) in dimethylformamide (50 ml) was added asokan-2-he (3,83 g, 30 mmol). The mixture was stirred at room temperature for 15 min, then was slowly added 5-bromo-1-penten (of 5.03 g, or 33.7 mmole). The reaction mixture was stirred at room temperature for 30 min, then at 80° C for 16 hours the Solvent was removed under reduced pressure and to the residue was added water. The mixture was extracted with ethyl ether, the organic phase is washed with water, dried (magnesium sulfate) and concentrated, obtaining 1-Penta-4-eilatan-2-he (5.53 g) in the form of oil.

The osmium tetroxide (17 mg, 0.07 mmole) was added to 1-Penta-4-eilatan-2-ONU (5,52 g, and 28.3 mmole) in a mixture of tetrahydrofuran (100 ml) and water (50 ml) under cooling in a water bath with the temperature of the environment. The mixture was stirred for 5 min and added portions of the solid periodate sodium (15,11 g, 70,65 mmole) for 15 minutes, the Reaction mixture was stirred teenietop. The organic phase was dried (magnesium sulfate) and concentrated. Purification by chromatography on silica gel, elution with chloroform gave 4-(2-oxazolin-1-yl)butyric aldehyde (4.72 in).

Similarly, following the method described above, but optionally replacing asokan-2-he other appropriate compounds of formula a and optionally replacing 5-bromo-1-penten other relevant alkylating agents of the formula L(CH2)nCH=CH2where L is a leaving group such as halogen, and using well-known specialists modification, received additional compounds of formula 1: 4-(5-oxo[1,4]oxazepan-4-yl)butyric aldehyde and tert-butyl ester 5-oxo-4-(4-oxobutyl)[1,4]diazepan-1-carboxylic acid.

Experience 2 (alternative obtaining the compounds of formula 1)

tert-Butyl ester 5-oxo-4-(4-oxobutyl)[1,4]diazepan-1-carboxylic acid

To a suspension of 60% sodium hydride in mineral oil (0.2 g, 5 mmol) in N,N-dimethylformamide (6 ml) was added tert-butyl ester 5-oxo[1,4]diazepan-1-carboxylic acid (1.0 g, 4,67 mmole). The reaction mixture was heated at 50° C for 5 min and then at room temperature for 15 minutes To the resulting solution were added dimethylether for 16 h the solvent was removed and the residue was distributed between water and ethyl acetate. The organic phase is washed with water, dried (magnesium sulfate) and concentrated. The residue was dissolved in diethyl ether, the suspension was filtered and the filtrate was concentrated. Purification by chromatography on silica gel with elution with 2% methanol in chloroform gave tert-butyl ester 4-(4,4-dimethoxymethyl)-5-oxo[1,4]diazepan-1-carboxylic acid (0.8 g) as a thick syrup.

1H-NMR (CDCl3, , M. D.): 1,49,, N; 2,64, m, 3H; 3,32, 3H; 4,37, m, 1H.

A solution of tert-butyl ester 4-(4,4-dimethoxymethyl)-5-oxo[1,4]diazepan-1-carboxylic acid (3 g, the remaining 9.08 mmole) in glacial acetic acid containing 0.5 ml of water (10 ml) was stirred at room temperature for 24 h the Solution was concentrated at 35° C under reduced pressure and the residue was distributed between saturated aqueous sodium bicarbonate and diethyl ether. The organic phase was dried (magnesium sulfate), concentrated and the residue was recrystallized from a mixture of diethyl ether/hexane, obtaining tert-butyl ester 5-oxo-4-(4-oxobutyl)[1,4]diazepan-1-carboxylic acid (0.85 grams), tPL86-87° C.

Experience 3 (alternative obtaining the compounds of formula 1)

(2-Oxopiperidin-1-yl)butyric aldehyde

To stir the mixture shall orangered 5-haralanov acid (1.55 g, 10 mmol). The reaction mixture was stirred at ambient temperature for 1 h Aqueous layer was separated and was extracted with ethyl acetate. The combined organic phase was washed with 1% hydrochloric acid and water, dried (magnesium sulfate) and concentrated. The oily residue was dissolved in tetrahydrofuran was added sodium hydride (60% in oil) (0.3 g, 7.5 mmole). The reaction mixture was heated at boiling for 1.5 h and filtered. The filtrate was concentrated, obtaining 1-(2,2-dimethoxymethyl)piperidine-2-he (1.06 g) as a pale yellow oil.

A mixture of 1-(2,2-dimethoxymethyl)piperidine-2-it (1.06 g, 5,67 mmole) in 5% aqueous tetrahydrofuran (20 ml) was heated at boiling for 1 h, the Mixture was dried over anhydrous magnesium sulfate, filtered and concentrated, obtaining (2-oxopiperidin-1-yl)acetaldehyde (0,69 g) as a pale yellow oil.

4-(2-Oxo[1,3]oxazolin-3-yl)butyric aldehyde

To ice of 1.93 M solution of phosgene in toluene (31 ml, 60 mmol) was added dropwise a solution of 5-chloro-1-pentanol (4.9 g, 40 mmol) and N,N-diethylaniline (5,97 g, 40 mmol) in toluene (40 ml). The reaction mixture was stirred at ambient temperature for 4 h the Mixture was filtered, the filtrate was concentrated. Oetelaar 4-amino aldehyde (7.09 in) 44 mmole) and triethylamine (4,45 g, 44 mmole) in ethyl acetate (60 ml). The reaction mixture was stirred at room temperature for 15 h, filtered and concentrated. Purification by chromatography on silica gel with elution with 10% ethyl acetate in hexane gave 5-harpertrophy ether (4,4-diethoxybutane)carbamino acid (11.4 g) in the form of oil.

To a solution of 5-globetronica ether (4,4-diethoxybutane)carbamino acid (11.4 g, 44 mmole) in N,N-dimethylformamide (100 ml) was added released from oil sodium hydride (1.01 g, of 42.3 mmole). The reaction mixture was stirred for 15 h at room temperature and then at 70° C for 3 hours the Mixture was diluted with water, was added a saturated aqueous solution of sodium chloride and was extracted with ether. The organic phase is washed with water, dried (magnesium sulfate) and concentrated. Purification by chromatography on silica gel gave 3-(4,4-diethoxybutane)[1,3]oxazolin-2-he (2,03 g) as a viscous oil.

A mixture of 3-(4,4-diethoxybutane)[1,3]oxazolin-2-she (2 g, 7.3 mmole) and 1.5 g of ion-exchange resin Dowex 50W2-200 in 3% aqueous solution of tetrahydrofuran (30 ml) was heated at boiling for 24 hours the Mixture was filtered, the filtrate was concentrated and dissolved in dichloromethane. The solution was dried over magnesium sulfate and the A.

3-(2-Oxotetrahydrothalifendine-1-yl)propionic aldehyde

To a stirred and cooled with ice to a solution of diethylacetal 3-aminopropionic aldehyde (5,88 g, 40 mmol) in diethyl ether (35 ml) was added dropwise 3-globabilization (4,78 g, 40 mmol). The reaction mixture was stirred at room temperature for 4 h the Mixture was concentrated and dissolved in N,N-dimethylformamide (40 ml). To this solution was added released from oil sodium hydride (0.96 g, 40 mmol). The reaction mixture was stirred at 70° C for 18 h, concentrated, and treated with diethyl ether (40 ml) and filtered. The filtrate was concentrated and purified by chromatography on silica gel with elution by the mixture hexane-ethyl acetate-methanol (10:9,7:0,3) to give 1-(3,3-diethoxypropane)tetrahydropyrimidin-2-he (9,05 g) in the form of oil.

A mixture of 1-(3,3-diethoxypropane)tetrahydropyrimidin-2-it (1 g, 4.35 mmole) and ion-exchange resin Dowex 50W2-200 in 3% aqueous solution of tetrahydrofuran (30 ml) was heated at boiling for 24 hours the Mixture was filtered, the filtrate was concentrated and the residue was dissolved in dichloromethane (30 ml), dried over magnesium sulfate, and concentrated, obtaining 3-(2-oxotetrahydrothalifendine-1-yl)propionic aldehyde (0,46 g).=methyl, R5=ethyl)

[(S)-2-(4-tert-Butylphenyl)-1-methylethyl]ethylamine

Step 1: benzyl ester [(S)-2-(4-tert-utility)-1-methyl-2-oxoethyl]carbamino acid (about)

To a suspension of 0.85 g (34,6 mmole) magnesium turnings in 25 ml of tetrahydrofuran was added 5 ml of a solution of 5 g (of 28.8 mmole) 1-bromo-4-tert-butylbenzoyl in 25 ml of tetrahydrofuran. Added one crystal of iodine and 1,2-dibromoethane (0.3 ml), the mixture was heated to boiling in order to initiate the reaction. Then was added dropwise a remainder of 1-bromo-4-tert-butylbenzene and the reaction mixture was stirred at room temperature for 1 h the Remaining magnesium was allowed to settle and the supernatant portions were added to the cooled, pre-prepared mixture of 8 g (a 27.4 mmole) benzyl ester ((S)-1-methyl-2-morpholine-4-yl-2-oxoethyl)carbamino acid n in 30 ml of tetrahydrofuran and 30 ml (60 mmol) of 2 M of isopropylacrylamide in diethyl ether. The reaction mixture was stirred at room temperature for 16 hours Then the mixture was added to a well stirred mixture of 100 ml of 5% hydrochloric acid and crushed ice. The mixture was extracted with two portions of 50 ml of ethyl acetate. The organic phase is washed with 25 ml saturated sodium chloride solution, dried-oxoethyl]carbamino acid on allocated in the form of solids, 9.2 grams, tPL156-158° C.

Step 2: (4S,5S)-5-(4-tert-butylphenyl)-4-methyloxazolidine-2-it (R)

To a solution of 9 g (of 26.5 mmole) of benzyl ester [(S)-2-(4-tert-butylphenyl)-1-methyl-2-oxoethyl]carbamino acid in 40 ml of toluene and 10 ml of 2-propanol was added dropwise a solution of 7 g (18,42 mmole) sodium borohydride in 2 ml of water containing 1 drop of 50% sodium hydroxide solution. The reaction mixture was stirred at room temperature for 15 hours, the Layers were separated and the organic layer washed with 25 ml of 10% sodium hydroxide solution. 2-Propanol was removed under reduced pressure, the remaining toluene solution was heated at boiling for 1 h the Solvent was removed under reduced pressure. The residue was recrystallized from a mixture of diethyl ether/hexane, obtaining the (4S,5S)-5-(4-tert-butylphenyl)-4-methyloxazolidine-2-he p, 3g; tPL199-200° C

Similarly, following the method described above, received the following connections:

(S)-5-(4-benzyloxyphenyl)-4-methyloxazolidine-2-it, tPL138-139° C;

(S)-4-methyl-5-(4-triptoreline)oxazolidin-2-it, tPL158-159° C, diethyl ether/hexane;

(S)-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-methyloxazolidine-2-it,

M+N=235, and

(S)-4-methyl-5-(-ethyloxazole-2-he (q)

To a solution of 1 g (4.3 mmole) of (4S,5S)-5-(4-tert-butylphenyl)-4-methyloxazolidine-2-it R in 10 ml of N,N-dimethylformamide was added 5.2 ml (5.2 mmole) of 1 M tert-butyl, potassium in tetrahydrofuran. To the resulting gel was added 4 ml (4.7 mmole) of iodata. The reaction mixture was heated at 70° C for 1 h was Added cold water (25 ml) and the mixture was extracted with 30 ml ethyl acetate. The organic phase was washed with two portions of 10 ml of water, dried (magnesium sulfate) and concentrated under reduced pressure. (4S,5S)-5-(4-tert-Butylphenyl)-4-methyl-3-ethyloxazole-2-it q was isolated in the form of a solid crystalline substance from a mixture of ethyl acetate/hexane, 1.06 g, M+N=261.

Similarly, following the method described above, received the following connection:

(S)-5-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-methyl-3-propylacetamide-2-it, M+N-277.

Step 4: (S)-2-(4-tert-butylphenyl)-1-methylethyl]ethylamine

A mixture of 1 g (a 3.83 mmole) of (4S,5S)-5-(4-tert-butylphenyl)-4-methyl-3-ethyloxazole-2-it, 2 g (31,74 mmole) of ammonium formate and 1 g of 10% palladium on coal in 20 ml of methanol was heated at boiling for 2 hours the Mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was distributed between 10 ml of a saturated aqueous solution of carbonate NAT is. S)-2-(4-tert-Butylphenyl)-1-methylethyl]ethylamine were isolated as hydrochloride of diethyl ether, 0,93 g, tPL169,4-171,0° C

Experience 5 (obtaining the compounds of formula 2)

(R1, R3and R5=H, R4=methyl, R2=tert - butyl)

(S)-2-(4-tert-Butylphenyl)-1-methylethylamine

A mixture of 1 g (4.3 mmole) of (4S,5S)-5-(4-tert-butylphenyl)-4-methyloxazolidine-2-it R (see experiments 4, phase 2), 2 g (31,74 mmole) of ammonium formate and 0.1 g of 10% palladium on coal in 25 ml of methanol was heated at boiling for 2 hours the Mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was distributed between 10 ml of 10% aqueous solution of sodium carbonate and 25 ml of ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The title compound was isolated as hydrochloride of diethyl ether, 0,93 g (95%), tPL259,5-261,3° C.

Example 1

(Obtaining the compounds of formula IA, as described in scheme B)

1-(2-{Ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl)azepin-2-he

A mixture of [2-(4-methoxyphenyl)-1-methylethyl]ethylamine (0.3 g, of 2.75 mmole), (2-oxazepan-1-yl)acetaldehyde (0.5 g, 3.2 mmole) and triacetoxyborohydride sodium (0.88 g, 4.1 mmole) in 1,2-dichloro between diethyl ether (50 ml) and nasystem aqueous solution of sodium bicarbonate (25 ml). The organic solution was extracted with 5% hydrochloric acid (20 ml), the aqueous acidic phase was washed with diethyl ether and brought the pH up to 12 25% sodium hydroxide solution. The mixture was extracted with dichloromethane, the organic phase was dried (sodium sulfate) and concentrated, obtaining 1-(2-{ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl)azepin-2-he 11 (0.84 g) as a viscous oil, which was turned into salt Dibenzoyl-L-tartaric acid.

Analysis: calculated for C38H46N2O10: 66,07; N. Of 6.71; N 4,06%; found: 64,69; H 6,5; N 3,0%.

Similarly, following the procedure described above in example 1, but optionally replacing (2-oxazepan-1-yl)acetaldehyde corresponding compounds of formula 1A, optionally replacing [2-(4-methoxyphenyl)-1-methylethyl]ethylamine with other appropriate compounds of formula 2A and utilizing modifications known to specialists in this field, has received additional compounds of formula I, where X, Y and Z mean every-CH2Is:

Dibenzoyl-L-tartrate 1-(2-{ethyl-[2-(4-methoxyphenyl)-1-methylethyl] amino}ethyl)pyrrolidin-2-it, 12, analysis: calculated for C36H42N2O10: 65,24; N To 6.39; N to 4.23%; found: 64,75; N Between 6.08; N Of 3.97%;

Dibenzoyl-L-tartrate 1-(4-{[2-(4-bromo-2 is-L-tartrate 1-(2-{ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl)piperidine-2-she's 14, analysis: calculated for C37H44N2O10: 65,67; N 6,55; N 4.14%; found: 64,86; N 6,23; N To 3.92%;

Dibenzoyl-L-tartrate 1-(3-{ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino}propyl)piperidine-2-she's 15, analysis: calculated for C38H46N2O10·0.5 N2O: 65.22 Per; N 6,77; N 4,00%; found: 65,37; N 6,48; N 3,94%;

Dibenzoyl-L-tartrate 1-(2-{[2-(4-methoxyphenyl)-1-methylethyl]propylamino}ethyl)piperidine-2-she's 16, analysis: calculated for C38H46N2O10: 66,07; N. Of 6.71; N 4,06%; found: 65,10; N. Of 6.29; N, 3.71 per cent;

Dibenzoyl-L-tartrate 1-(2-{ethyl[2-(4-forfinal)-1-methylethyl]amino}ethyl)piperidine-2-she's 17, tPL95-96° C, M+N=307;

Dibenzoyl-L-tartrate 1-(2-{[2-(4-chlorophenyl)-1-methylethyl]ethylamino}ethyl)piperidine-2-she's 18, M+N=323;

Dibenzoyl-L-tartrate 1-(2-{ethyl[2-(4-trifloromethyl)-1-methylethyl]amino}ethyl)piperidine-2-she's 19, analysis: calculated for C37H41F3N2O10: 60,82; N To 5.66; N 3,83%; found 60,70; N 5,46; N 3,56%;

Dibenzoyl-L-tartrate 1-(4-{ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino}butyl)piperidine-2-she's 20, analysis: calculated for C39H48N2O10: 66,46; N 6,84; N of 3.97%; found: 66,29; N 6,69; N Of 4.04%;

Dibenzoyl-L-tartrate 1-(2-{ethyl[2-(4-isobutoxy)-1-methylethyl]amino}ATI; N 3,74%;

Dibenzoyl-L-tartrate 1-(2-{[2-(3-phenoxyphenyl)-1-methylethyl]propylamino}ethyl)piperidine-2-she's 22, analysis: calculated for C43H48N2O10: 68,60; N To 6.43; N 3,72%; found: From 67.56; H 6,23; N 3,48%;

Dibenzoyl-L-tartrate 1-(2-(isobutyl[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl)piperidine-2-she's 23, M+N=347;

Dibenzoyl-L-tartrate 1-{2-[2-naphthalene-2-yl)-1-methylethyl]propylamino}ethyl)piperidine-2-it 24 analysis: calculated for C41H46N2O9: 69,28; N. Of 6.52; N 3,94%; found: 67,58; N 6,16; N 3,48%;

hydrochloride 1-(2-{[2-(6-methoxynaphthalene-2-yl)-1-methylethyl]propylamino}ethyl)piperidine-2-she is 25, analysis: calculated for C24H351N2O9·0,4 H2O: 67,63; N. Of 8.47; N 6,69%; found: 67,42; N 8,30; N 6,63%;

Dibenzoyl-L-tartrate 1-(2-{[2-(4-chlorophenyl)-1-methylethyl]propylamino}ethyl)piperidine-2-she is 26, M+N=377;

Dibenzoyl-L-tartrate 1-(4-{[2-(4-chlorophenyl)-1-methylethyl]propylamino}butyl)piperidine-2-she's 27, M+N=365;

Dibenzoyl-L-tartrate 4-(2-{ethyl[2-(2-oxopiperidin-1-yl)ethyl]amino}propyl)phenyl ether diethylcarbamyl acid 28, M+N=404;

Dibenzoyl-L-tartrate 4-(2-{ethyl[2-(2-oxopiperidin-1-yl)ethyl]amino}propyl)phenyl ether dimethylcarbinol acid 29, M+N=321;

dibenz is=411;

Dibenzoyl-L-tartrate 1-(2-{ethyl[2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)piperidine-2-she's 31, M+H=305;

Dibenzoyl-L-tartrate 4-(2-{ethyl[2-(2-oxopiperidin-1-yl)ethyl]amino}propyl)phenyl ether isopropylcarbamate acid 32, M+H=390;

hydrochloride 1-(4-{[2-(3-triptoreline)-1-methylethyl]propylamino}butyl)piperidine-2-she is 33, M+N=399;

Dibenzoyl-L-tartrate 1-(6-{ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino)hexyl)piperidine-2-she's 34, M+N=375;

Dibenzoyl-L-tartrate 1-(4-{[2-(3-chlorophenyl)-1-methylethyl]propylamino}butyl)piperidine-2-she is 35, analysis: calculated for C39H47ClN2O9·0,8 N2O: 63,35; N. Of 6.65; N 3,79%; found: 63,64; N. Of 6.65; N 3,79%;

Dibenzoyl-L-tartrate 1-(4-{[2-(3-forfinal)-1-methylethyl]propylamino}butyl)piperidine-2-she is 36, M+H=349;

Dibenzoyl-L-tartrate 1-(4-{[2-(4-bromophenyl)-1-methylethyl]ethylamino}butyl)piperidine-2-she's 37, M+N=395;

hydrochloride of 1-(5-{ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino}of pentyl)piperidine-2-she is 38, M+N=361;

hydrochloride of 1-{4-[2-naphthalene-2-yl)-1-methylethyl]propylamino}butyl)piperidine-2-it 39 analysis: calculated for C25H37lN2O· 0,8 H2O: 69,60; N. Of 9.02; N of 6.49%; found: 69,69; N 8,80; N 6,70%;

hydrochloride 1-(4-{[2-(4-tert-butylphenyl the n-6-yl)-1-methylethyl]propylamino}butyl)piperidine-2-she's 41, M+N=389;

hydrochloride of 1-(4-{isopropyl[2-(3-triptoreline)-1-methylethyl]amino}butyl)piperidine-2-she's 42, M+N=377;

hydrochloride 1-(4-{[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]propylamino}butyl)piperidine-2-she is 43, M+N=373;

hydrochloride 1-(4-{[1-(4-chlorbenzyl)propyl]propylamino}butyl)piperidine-2-she's 44, M+N=379;

hydrochloride 1-(4-{[1-(3-methoxy-4-methylbenzyl)propyl]propylamino}butyl)piperidine-2-she is 45, M+N =389;

hydrochloride N-[3-(2-{[4-(2-oxopiperidin-1-yl)butyl]propylamino}propyl)phenyl]methanesulfonamide 46, M+N=424;

hydrochloride 1-{4-[(2-(1-benzopyran-6-yl-1-methylethyl)propylamino]butyl}piperidine-2-she's 47, M+N=387;

hydrochloride of 1-{4-[(2-benzo[1,3]dioxol-5-yl-1-methylethyl)ethylamino]butyl}piperidine-2-she is 48, M+N =361;

hydrochloride 1-(4-{[2-(3-chloro-4-forfinal)-1-methylethyl]propylamino}butyl)piperidine-2-she's 49, M+N=383;

hydrochloride 1-(4-{[2-(4-methylsulfinylphenyl)-1-methylethyl]propylamino}butyl)piperidine-2-she's 50, M+N=377;

hydrochloride of 1-(4-{isopropyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)piperidine-2-she's 51, M+N=409;

hydrochloride 1-(4-{[2-(1H-indol-5-yl)-1-methylethyl]isopropylamino}butyl)piperidine-2-she is 52, M+N=370;

hydrochloride 1-(4-{[2-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-furan-6-yl)-1-methylethyl]propylamino}butyl)piperidine-2-she's 54, analysis: calculated for C25H41ClN2O2: 68,70; N. Of 9.45; N 6,41%; found: 63,93; N 9,16; N 6,34%;

hydrochloride 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)piperidine-2-it 55, analysis: calculated for C22H37l2O3S· 1,5 H2O: 55,97; N 8,54; N 5,93%; found: 55,83; N 8,21; N 6,70%;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)piperidine-2-it 56, M+N=449;

hydrochloride 1-(4-{[2-(4-tert-butylphenyl)-1-methylethyl]ethylamino}butyl)piperidine-2-57 she, analysis: calculated for C24H41ClN2O· 0,65 H2O: 68,51; N 10,13; N 6,66%; found: 68,48; N 9,92, N 6,85%;

phosphate 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether propane-2-sulfonic acid 58, analysis: calculated for C25H45N2O8PS· l,75H2O: 47,05; N 7,46; N 4,39%; found: 46,96; N. Of 7.35; N 4,40%;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether 4-methysulfonylmethane acid 59, M+N=579;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ester benzosulfimide acid 60, M+H=510;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}p{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether butane-1-sulfonic acid 62, M+N=481;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether 4-chlorobenzenesulfonic acid 63, M+N=535;

2,2,2-triptorelin-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ester of 3,4-dimethoxybenzenesulfonamide acid 64, M+N=561;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether econsultancy acid 65, M+N=453;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether dimethylsulfonium kioti 66, M+N=468;

2,2,2-triptorelin 4-(2-{[2-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether methanesulfonate acid 67, M+N=439;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether 4-methoxybenzenesulfonamide acid 68, M+N=531;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether naphthalene-1-sulfonic acid 69, M+N=551;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether naphthalene-2-sulfonic acid 70, M+N=551;

2,2,2-triptorelin 4-(2-{[2-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether 4-nitrobenzenesulfonate KIS the pan-1-sulfonic acid 72, M+N=467;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ester thiophene-1-sulfonic acid 73, M+N=507;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether phenylmethanesulfonyl acid 74, M+N=515;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether 4-triftormetilfullerenov acid 75, M+N=585;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether 4-cyanobenzenesulfonyl acid 76, M+N=526;

2,2,2-triptorelin 4-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl ether 1,1,1-triftormetilfullerenov acid 77, M+N=493;

phosphate 4-(2-{[4-(2-oxazepan-1-yl)ethyl]propylamino}propyl)phenyl ether propane-2-sulfonic acid 78, analysis: calculated for C23H41N2O8PS: 51,48; N. Of 7.70; N 5,22%; found: 45,23; N 7,12, N 9,45%;

hydrochloride 4-methanesulfonyl-N-[3-(2-{[2-(2-oxazepan-1-yl)ethyl]propylamino}propyl)phenyl]benzamide 79, analysis: calculated for C28H40l3O4S· 0,7 N2O: 59,76; N 7,41; N 7,47%; found: 59,71; N 7,20; N 7,44%;

the hydrochloride of 4-methyl-N-[3-(2-{[2-(2-oxazepan-1-yl)ethyl]propylamino} the,44; N of 8.37; N 8,43%; found: 67,32; N 8,18; N, 8.43 per cent;

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)azepin-2-she's 81, tPL78-79° C, M+N=409;

hydrochloride 1-(4-{[2-(4-ethanolgasoline)-1-methylethyl]ethylamino}butyl)azepin-2-she is 82, M+N=423;

hydrochloride of 1-(4-{ethyl[2-(4-isopropylphenyl)-1-methylethyl]amino}butyl)azepin-2-she's 83, M+N=437;

4-tert-butyl-N-[3-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl]benzamide 84, analysis: calculated for C33H49N3O2: 76,26; N 9,50; N 8,08%; found: 76,32; N 9,39; N 8,19%;

hydrochloride 1-(4-{[2-(3-benzosulfimide)-1-methylethyl]ethylamino}butyl)azepin-2-she is 85, M+N=471;

hydrochloride 1-(4-{[2-(3,3-dimethyl-1,1-dioxo-2,3-dihydro-1H-1-benzo[b]thiophene-5-yl)-1-methylethyl]isopropylamino}butyl)azepin-2-she is 86, analysis: calculated for C26H37ClN2O3S: 62,56; N 8,68; N 5,61%; found: 58,09; N 8,16; N 5,26%;

hydrochloride 1-(4-{[2-(4-benzosulfimide)-1-methylethyl]ethylamino}butyl)azepin-2-she's 87, M+N=471;

hydrochloride of 1-(4-{ethyl[2-(4-(2-methylpropan-1-sulfonyl)phenyl)-1-methylethyl]amino}butyl)azepin-2-she is 88, M+N=451;

hydrochloride [2-methanesulfonyl-5-(2-{[4-(2-oxazepan-1-yl)butyl]propylamino}propyl)phenyl]amide benzo[1,3]dioxol; 6,40%; found: 56,79; N 6,98; N 6,40%;

hydrochloride 1-(4-{[2-(3,3-dioxo-2,3-dihydrobenzo[1,3]oxalyl-5-yl)-1-methylethyl]ethylamino}butyl)azepin-2-she is 90, M+N=423;

hydrochloride 1-(4-{[2-(2,3-dihydrobenzo[1,3]oxalyl-5-yl)-1-methylethyl]isopropylamino}butyl)azepin-2-she's 91, M+N=405;

hydrochloride of 1-(4-{ethyl[2-(3-methanesulfonyl)-1-methylethyl]amino}butyl)azepin-2-she is 92, M+N=409;

hydrochloride 1-(4-{[2-(3,3-dioxo-2,3-dihydrobenzo[1,3]oxalyl-5-yl)-1-methylethyl]isopropylamino}butyl)azepin-2-she's 93, M+N=437;

hydrochloride of 1-(4-{isopropyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)azepin-2-she's 94, M+N=423;

hydrochloride of 1-(4-{(1-ethylpropyl)[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)azepin-2-she 95, M+N=451;

hydrochloride 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)azepin-2-she's 96, M+N=423;

the hydrochloride of 4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)-N,N-dimethylbenzenesulfonamide 97, M+N=438;

hydrochloride 1-(3-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}propyl)azepin-2-it 98, M+N=409;

the dihydrochloride of 1-[4-(ethyl{2-[4-(4-methylpiperazin-1-sulfonyl)phenyl]-1-methylethyl}amino)butyl]azepin-2-it 99, M+N=493;

the hydrochloride of 4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)101, M+N-331;

hydrochloride 1-(4-{[2-(3-chloro-4-methanesulfonyl)-1-methylethyl]ethylamino}butyl)azepin-2-it 102, analysis: calculated for C22H36CL2O3S· 1.4 N2O: 52,35; N. Of 7.75; N 5,55%; found: 52,34; N. Of 7.36; N 5,65%;

the hydrochloride of 4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)benzosulfimide 103, M+N=410;

N-dimethylethyl-4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)benzosulfimide 104, M+N=466;

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)azepin-2-it 105, M+N=463;

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)azepin-2-it 106, M+N=431;

hydrochloride of 1-(4-{ethyl[2-(4-nitrophenyl)-1-methylethyl]amino}butyl)azepin-2-it 107, analysis: calculated for C21H34lN3ABOUT3·0,7 N2O: 59,41; N 8,40; N 9,90%; found: 59,48; N 8,21; N 9,92%;

the hydrochloride of 4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)phenyl ether 1,1,1-triftormetilfullerenov acid 108, M+N=479;

sodium salt of N-[4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)phenyl]-1,1,1-triftoratsetofenona 109, analysis: calculated for C22H34F3N3NaO3S: 55,33; N 7,18, N 8,80%; found: 51,96; N. Of 6.73;N 8,62%;

2,2,2-triptorelin 1-(2-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}ethyl)azepin-2-it 111, M+N=435;

hydrochloride of 1-[4-(ethyl{2-[4-(thiazol-2-sulfonyl)phenyl]-1-methylethyl}amino)butyl]azepin-2-it 112, analysis: calculated for C24H36lN3ABOUT3S2·1H2O: 54,17; N 7,20; N of 7.90%; found: 54,09; N 6,91; N 7,86%;

2,2,2-triptorelin 4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)-N-isopropylbenzenesulfonyl 113, M+N=452;

2,2,2-triptorelin 4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)-N-(2-hydroxyethyl)benzosulfimide 114, M+N=454;

2,2,2-triptorelin 4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)-N-(2-methoxyethyl)benzosulfimide 115, M+N=468;

2,2,2-triptorelin 1-[4-{ethyl(2-[4-(morpholine-4-sulfonyl)phenyl]-1-methylethyl}amino)butyl]azepin-2-it 116, M+H=480;

2,2,2-triptorelin 4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)-N-(2,2,2-triptorelin)benzosulfimide 117, M+N=492;

hydrochloride of 1-(4-{ethyl[2-(4-tert-butylphenyl)-1-methylethyl]amino)butyl)azepin-2-she 118, analysis: calculated for C25H43ClN2O· 0,45 H2O: 69,64; N 8,53 N 5,55%; calculated: 57,12; N To 8.41; N 5,61%, or

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)asokan N charged 8.52; N 5,43%.

Example 2

(Obtaining the compounds of formula IB as described in the diagram)

3-(4-{Ethyl[(S)-2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)[1,3]oxazine-2-he

To a suspension of the hydrochloride of ethyl[(S)-2-(4-methylsulfinylphenyl)-1-methylethyl]amine (0.25 g, 1 mmol) in 1,2-dichloroethane (10 ml) were added triethylamine (0.2 ml, 1.5 mmole). To this mixture was added 4-(2-oxo[1,3]oxazine-3-yl)butyric aldehyde (0.18 g, 1.05 mmole) and triacetoxyborohydride sodium (0.32 g, 1.5 mmole). The reaction mixture was stirred at room temperature for 15 h, concentrated and the residue was distributed between 5% solution of sodium hydroxide (5 ml) and diethyl ether (20 ml). The organic phase was dried (magnesium sulfate) and concentrated, obtaining 3-(4-{ethyl[(S)-2-(4-methylsulfinylphenyl)-1-methylethyl]amino}butyl)[1,3]oxazine-2-he (0.33 g) as a viscous oil.

It chilled with ice to a solution of 3-(4-{ethyl[(S)-2-(4-methylsulfinylphenyl)-1-methylethyl]amino}butyl)[1,3]oxazine-2-she (0.33 g, 0.9 mmole) in methanol (10 ml) was added a solution of peroxymonosulfate potassium (Oxon® ) (1.22 g, 1.98 mmole) in water (10 ml). The reaction mixture was stirred at room temperature for 5 hours Then was added a 1.5 M solution of sodium carbonate (10 ml) and the mixture ek was purified by chromatography on silica gel with 10% ethyl acetate in chloroform, getting 3-(4-{ethyl[(S)-2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)[1,3]oxazine-2-he 122, (0.17 g) as a colourless oil.

Analysis: calculated for C20H33ClN2O4S: 55,48; N. Of 7.68; N 6,47%; found: 52,32; N 7,42; N 5,97%.

Similarly, following the procedure described above in example 2, but optionally replacing 4-(2-oxo[1,3]oxazine-3-yl)butyric aldehyde with other appropriate compounds of formula 1b, and optionally replacing hydrochloride ethyl[(S)-2-(4-methylsulfinylphenyl)-1-methylethyl]amine corresponding compounds of formula 2, and utilizing modifications known in the art, received additional compounds of formula I where X is-O - or-S-:

hydrochloride 3-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)[1,3]oxazepan-2-it 123, analysis: calculated for C21H35ClN2O4S: 60,78; N. Of 8.50; N 6,75%; found: 52,82; N. Of 7.82; N Of 5.84%;

hydrochloride 3-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,3]oxazepan-2-she 124, analysis: calculated for C22H37ClN2O4S· 0,85 H2O: 55,47; N 8,19; N 5,88%; found: To 55.42; H 7,94; N Of 5.75%;

hydrochloride 3-(4-{isopropyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)[1,3]oxazepan-2-it 125, analysis: Vychisl">2,2,2-triptorelin 3-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)[1,3]oxazepan-2-it 126, M+N=465;

2,2,2-triptorelin 3-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)[1,3]oxazine-2-it 127, M+N=451;

hydrochloride 3-[4-(ethyl{2-[4-(propane-2-sulfanilyl)phenyl]-1-methylethyl}amino)butyl][1,3]oxazepan-2-it is 128, analysis: calculated for C24H41ClN2O4S· 0,85 H2O: 57,15; N 8,53 N 5,55%; found: 57,12; N To 8.41; N 5,61%;

hydrochloride 3-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)[1,3]oxazolin-2-it 129, analysis: calculated for C22H37ClN2O4S· 0,95 H2About: 55,26; N 8,20; N 5,86%; found: 55,26; N A 7.92; N Of 5.99%;

2,2,2-triptorelin 3-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)[1,3]oxazolin-2-it 130, M+N=479, or

hydrochloride 3-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)[1,3]diazinon-2-it 131, M+N=413.

Similarly, following the procedure described above in example 2, but optionally replacing 4-(2-oxo[1,3]oxazine-3-yl)butyric aldehyde with other appropriate compounds of formula 1b, and optionally replacing hydrochloride ethyl[(S)-2-(4-methylsulfinylphenyl)-1-methylethyl]amine other relevant sue the compounds of formula IB, where X is >N-R6:

Dibenzoyl-L-tartrate 1-[4-{ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino)butyl]tetrahydropyrimidin-2-it 134, analysis: calculated for C38H47N3ABOUT10: 64,67; N. Of 6.71; N 5,95%; found: 62,96; N 6,28; N 5,76%;

Dibenzoyl-L-tartrate 1-[4-{ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino)butyl]-3-methyltetrahydrofuran-2-it 135, analysis: calculated for C39H49N3ABOUT10·0,9 N2O: 63,64; N. Of 6.96; N 5,71%; calculated: 63,66; N Is 6.61; N 5,62%;

Dibenzoyl-L-tartrate 3-[4-{[2-(3-triptoreline)-1-methylethyl]propylamino)butyl]-1-methyltetrahydrofuran-2-it 136, analysis: calculated for C40H48F3N3O9: 62,25; N 6,27; N 5,44%; found: 60,64; N 6,05; N4,81%;

hydrochloride 1-[4-{[2-(3-triptoreline)-1-methylethyl]propylamino)butyl]tetrahydropyrimidin-2-it 137, analysis: calculated for C21H33lF3N3O9·0,8 N2O: 56,00; N 7,74; N was 9.33%; found: 56,00; N 7,45; N 9,11%;

hydrochloride 3-[4-{[2-naphthalene-2-yl-1-methylethyl]propylamino)butyl]-1-methyltetrahydrofuran-2-it 138, analysis: calculated for C25H38lN3O· 1.4 N2O: 65,67; N 8,99; N 9,19%; found: 65,64; N 8,99; N 9,19%;

hydrochloride 1-[3-{[2-(4-chlorophenyl)-1-MatiO· 1,15 H2O: 55,78; N 8,20; N 10,27%; found: 55,81; N. Of 7.93; N Of 10.25%;

hydrochloride of 1-(4-{ethyl[(S)-2-(4-methanesulfonyl)-l-methylethyl]amino}butyl)tetrahydropyrimidin-2-it 140, M+N=396;

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-3-methyl[1,3]diazepin-2-it 141, M+N=424;

hydrochloride 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,3]diazepin-2-it 142, M+N=424;

hydrochloride 1-[4-({2-[4-(the thiazole-2-sulfonyl)phenyl]-1-methylethyl}propylamino)butyl]tetrahydropyrimidin-2-it 143, analysis: calculated for C23H35lN4O3S2: 53,63; N 6,85; N 10,88%; found: 48,86; N, 6.42 Per; N 9,84%, or

hydrochloride of 1-[4-(ethyl{2-[4-(thiazol-2-sulfonyl)phenyl]-1-methylethyl}amino)butyl]tetrahydropyrimidin-2-it 144, analysis: calculated for C22H33lN4O3S2: 52,73; N 6,64; N 11,18%; found: 48,74; N. Of 6.31, N 10,33%.

Example 3

(Obtaining the compounds of formula Sa as described in scheme G)

4-[4-(Ethyl{(S)-2-[4-(thiazol-2-sulfonyl)phenyl]-1-methylethyl]amino)butyl][1,4]oxazepan-3-one

A mixture of ethyl{(S)-1-methyl-2-[4-(thiazol-2-sulfonyl)phenyl]-1-ethyl}amine (0,326 g of 1.02 mmole) and 4-(3-oxo[l,4]oxazepan-4-yl)butyric aldehyde (0,22 g, 1.2 mmole) and triacetoxyborohydride mudalali under reduced pressure and the residue was distributed between 50% hydrochloric acid and diethyl ether. The aqueous phase is brought to pH 12 with 25% solution of sodium hydroxide and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and concentrated, obtaining 4-(4-{ethyl[2-(4-thiazol-2-sulfanilyl)-1-methylethyl]amino}butyl)[1,4]oxazepan-3-one 145 in the form of oil.

Analysis: calculated for C23H34lN3O4S2·1H2O: 51,72; N 6,79; N 7,87%; found: 51,71; N. Of 6.49; N of 7.82%.

Similarly, following the procedure described above in example 3, but optionally replacing 4-(3-oxo[1,4]oxazepan-4-yl)butyric aldehyde with other appropriate compounds of formula 1c, and optionally replacing ethyl{(S)-1-methyl-2-[4-(thiazol-2-sulfonyl)phenyl]ethyl}amine with other appropriate compounds of formula 2, and utilizing modifications known to specialists in this field, has received additional compounds of formula Za, where Y denotes-O - or-S-:

hydrochloride 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl[1,4]oxazepan-3-one 146, analysis: calculated for C22H37ClN2O4S· 1,5 H2O: 54,14; H compared to 8.26; N 5,74%; found: From 54.19; H compared to 8.26; N 5,85%, or

2,2,2-triptorelin 4-(4-{ethyl[2-(4-triftormetilfullerenov) -1-methylethyl]amino}butyl)[1,4]oxazepan-3-one 147, M+N=465.

A mixture of the hydrochloride propyl[(S)-2-(4-methanesulfonyl)-1-methylethyl]amine (0.50 g, 1.7 mmole), tert-butyl ester 3-oxo-4-(4-oxobutyl)[1,4]diazepan-1-carboxylic acid (0.5 g, of 1.76 mmole), triethylamine (of 0.24 ml, 1.7 mmole) and triacetoxyborohydride sodium (0.54 g, 2.6 mmole) in 1,2-dichloroethane (20 ml) was stirred at room temperature for 17 hours, the Solvent was removed, the residue was distributed between ethyl acetate (30 ml) and 5% sodium carbonate solution (20 ml). The organic phase was dried (magnesium sulfate) and concentrated, obtaining tert-butyl ester 4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-3-oxo[1,4]diazepan-1-carboxylic acid (0,89 g) as a syrup.

1H-NMR (CDCl3), , M. D.: 0,82, t, 3H; 0,94, d, 3H; 1,46,, N; 3,05, s, 3H; of 7.36, d, 2H; 7,83, d, 2H.

A mixture of tert-butyl ester 4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-3-oxo[1,4]diazepan-1-carboxylic acid (0.9 g, 1.75 mmole) and 3 N. hydrochloric acid (4 ml) was heated to 50° C. the Reaction mixture was stirred at room temperature for 30 min, the pH was brought to 10 with saturated sodium carbonate solution, the organic phase was dried (magnesium sulfate) and concentrated. The residue was dissolved is, washed with diethyl ether and hexane and dried in vacuum, obtaining the dihydrochloride of 1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-2-it (0,49 g) 149, M+N=424.

Similarly, following the procedures described above in example 4, but not necessarily replacing tert-butyl ester 3-oxo-4-(4-oxobutyl)[1,4]diazepan-1-carboxylic acid with other appropriate compounds of formula 1d, and optionally replacing hydrochloride propyl[(S)-2-(4-methanesulfonyl)-1-methylethyl]amine with other appropriate compounds of formula 2, and utilizing modifications known to specialists in this field, has received additional compounds of formula ICb, where Y represents the >NH:

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)[1,4]diazepan-2-it 150, M+N=464;

hydrochloride of 1-(4-{ethyl[2-(4-thiazol-2-sulfanilyl)-1-methylethyl]amino}butyl)[1,4]diazepan-2-it 151, analysis: calculated for C23H35lN4O3S2·1,25 N2O: 48,12; N 6,76; N 9,76%; found: 48.10 Per; N. Of 6.52; N 9,81%;

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)piperazine-2-it 152, M+N=450;

the hydrochloride of N-methyl-4-(2-{[4-(2-oxopiperidin-1-yl)butyl]propylamino}proper)piperazine-2-it 154, M+N=410;

hydrochloride 1-(4-{[2-(4-the thiazole-2-sulfanilyl)-1-methylethyl]propylamino}butyl)piperazine-2-it 155, analysis: calculated for C25H35ClN4O3S2·1,5 H2O: 48,81; N 6,66; N 9,49%; found: 48,69; N Is 6.54; N, 9.64% Of;

hydrochloride 1-(4-{[2-(4-the thiazole-2-sulfanilyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-2-it 156, analysis: calculated for C24H36lN4O3S2·0,75 H2O: 49,78; N 6,88; N 9,67%; found: 49,74; N. Of 6.75; N RS 9.69%;

the dihydrochloride of N-methyl-4-(2-{[4-(2-oxo[1,4]diazepan-1-yl)butyl]propylamino}propyl)benzosulfimide 157, M+N=439;

1-[4-(ethyl{2-[4-(4-methoxybenzenesulfonyl)phenyl]-1-methylethyl}amino)butyl][1,4]diazepan-2-he 158, M+N=502;

4-[4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl}propylamino)butyl][1,4]diazepan-2-he 159, M+N=530;

hemihydrate of the dihydrochloride of 1-(4-{ethyl[2-(4-triptoreline)-1-methylethyl]amino}butyl)[1,4]diazepan-2-it 160, analysis: calculated for C21H33ClF3N3O· 0.5 H2O: 52,39; N 7,33; N 8,73%; found: 52,44; N To 7.32; N 8,58%, or

hydrochloride 1-(4-{[2-(4-tert-butylphenyl)-1-methylethyl]propylamino}butyl)piperazine-2-it 161, M+N=374.

Example 5

(Obtaining the compounds of formula ICC, as OPI

To a solution of 1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl-1,4-diazepin-2-she (0.08 g, is 0.19 mmole) in tetrahydrofuran (10 ml) were added triethylamine (3 drops) followed by triacetoxyborohydride sodium (0.06 g, 0.3 mmole) and 37% formaldehyde (0.1 ml, 1.2 mmole). The reaction mixture was stirred at room temperature for 16 hours the Reaction mixture was concentrated and the residue was distributed between 5% solution of sodium carbonate and chloroform. The organic phase was dried (magnesium sulfate) and concentrated, obtaining 1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-methyl[1,4]diazepan-2-it, which was isolated as the dihydrochloride of diethyl ether (hygroscopic) (0.07 g), 166, M+N=438.

Similarly, following the procedures described above in example 5, but optionally replacing 1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino)butyl-1,4-diazepin-2-he other free amino derivatives of formula ICb and optionally replacing formaldehyde other relevant allerease, alkylating or sulfanilimide agents and utilizing modifications known to specialists in this field, has received additional compounds of formula ICC, where Y represents >N-R6:

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-methanesulfonamide-2-it 168, M+N=474;

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(morpholine-4-carbonyl)piperazine-2-it 169, M+N=509;

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-methanesulfonyl[1,4]diazepan-2-it 170, M+N=488;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-methanesulfonyl-4-ethyl[1,4]diazepan-2-it 171, M+N=438;

1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-acetyl - [1,4]diazepan-2-he 172, M+N=466;

1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-propionyl[1,4]diazepan-2-he 173, M+H=480;

1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-pentanol[1,4]diazepan-2-he 174, M+N=508;

1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(3-cyclopentylpropionyl[1,4]diazepan-2-he 175, M+N=548;

1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(thiophene-2-carbonyl)[1,4]diazepan-2-he 176, M+N=534;

methyl ester 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-3-oxo[1,4]diazepan-1-carboxylic acid 177, M+N=482;

1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(thiophene-2-sulfonyl[1,4]diazepan-2-he 179, M+N=570;

isopropylated 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-3-oxo[1,4]diazepan-1-carboxylic acid 180, M+N=509;

butylamide 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-3-oxo[1,4]diazepan-1-carboxylic acid 181, M+N=523;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-benzoyl[1,4]diazepan-2-it 182, M+N=528;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-phenylacetyl[1,4]diazepan-2-it 183, M+N=542;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(3-phenylpropionyl[1,4]diazepan-2-it 184, M+N=556;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(pyridine-3-carbonyl)[1,4]diazepan-2-it 185, M+N=529;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(isoxazol-5-carbonyl)[1,4]diazepan-2-it 186, M+N=519;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(furan-2-carbonyl)[1,4]diazepan-2-it 187, M+N=518;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl the t 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(1-methyl-1H-imidazol-4-sulfonyl)[1,4]diazepan-2-it 189, M+N=568;

2,2,2-triptorelin methylamide 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-3-oxo[1,4] diazepan-1-carboxylic acid 190, M+N=481;

2,2,2-triptorelin of acylamide 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-3-oxo[1,4]diazepan-1-carboxylic acid 191, M+N=495;

2,2,2-triptorelin of phenylamide 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-3-oxo[1,4]diazepan-1-carboxylic acid 192, M+N=543;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-methanesulfonyl[1,4]diazepan-2-it 193, M+N=502;

hydrochloride 1-(4-{[2-(4-the thiazole-2-sulfanilyl)-1-methylethyl]propylamino}butyl)-4-methylpiperazin-2-it 194, analysis: calculated for C25H37lN4O3S2·1,8 H2O: 48,20; N 7,01; N 9,37%; found: 48,25; N 6,64; N 9,41%;

hydrochloride of 1-(4-{ethyl[2-(4-thiazol-2-sulfanilyl)-1-methylethyl]amino}butyl)-4-(pyridine-3-sulfonyl)piperazine-2-it 195, analysis: calculated for C27H36lN5O5S3·1,25 N2O: 46,25; N. Of 5.68; N 9,99%; found: 46,26; N. Of 5.68; N, 9.99%;

hydrochloride of 1-(4-{ethyl[2-(4-thiazol-2-sulfanilyl)-1-methylethyl]amino}butyl)-4-(pyridine-3-sulfonyl)[1,4]diazepan-2-it 196, analysis: the N 5,65; N 9,81%;

monohydrate hydrochloride 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)-4-(pyridine-3-sulfonyl)piperazine-2-it 197, M+N=511;

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)-4-methylpiperazin-2-it 198, M+N=464;

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(pyridine-3-sulfonyl)[1,4]diazepan-2-it 199, M+N=551;

monohydrate hydrochloride 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(pyridine-3-sulfonyl)piperazine-2-it 200, M+N=537;

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)-4-(pyridine-3-sulfonyl)[1,4]diazepan-2-it 201, M+N=605;

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-trifloromethyl[1,4]diazepan-2-it 202, analysis: calculated for C22H35lF3N4O5S· 0,75 H2O: 44,66; N 6,22; N 7,10%; found: 44,66; N Between 6.08; N, 6.96 per cent;

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-thiazole-2-ylmethyl[1,4]diazepan-2-it 203, analysis: calculated for C25H39lN4O3S2·0,85 H2O: 47,56; N 6,82; N 8,87%; found: 47,58; N 6,77; N 9,12%;

hydrochloride of 1-(4-{ethyl[2-(4-trif is lorid 1-(4-{ethyl[2-(3-triptoreline)-1-methylethyl]amino}butyl)-4-(pyridine-3-sulfonyl)piperazine-2-it 205, M+N=527;

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)-4-(1-methyl-1H-imidazol-4-sulfonyl)piperazine-2-it 206, M+N=594;

hydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2,2,2-TRIFLUOROACETYL)[1,4]diazepan-2-it 207, analysis: calculated for C23H37lF3N3O4S· 1,05 N2O: 49,25; 6,67 N; N 7,49%; found: 48,90; N 6,27; N 7,47%;

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)-4-(1-methyl-1H-imidazol-4-sulfonyl)[1,4] diazepan-2-it 208, M+N=608;

the dihydrochloride of 1-(4-{ethyl[2-(3-triptoreline)-1-methylethyl]amino}butyl)-4-(1-methyl-1H-imidazol-4-sulfonyl)piperazine-2-it 209, M+N=530;

the dihydrochloride of 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2,2,2-triptorelin)[1,4]diazepan-2-it 210, analysis:calculated for C23H38Cl2F3N3O3S· l,20H2O: 47,13; N 6,95; N 7,17%; found: 47.17; H 6,59; N 7,22%;

the dihydrochloride 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(2-dimethylaminoethanol)[1,4]diazepan-2-it 211, M+N=559;

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)-4-(1H-imidazol-4-ylmethyl)[1,4]diazepan-2-it 212, M+N=544;

hydrochloride 1-(4-{[2-(4-tert-butylphenyl)-1-methylethyl]ethylamino}butyl)-4-(1-methyl-1H-imidazol-4-sulfonyl)[1,4]diazepan-2-it 214, M+N=532;

hydrochloride of 1-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)-4-(2-methyl-1H-imidazol-4-sulfonyl)[1,4] diazepan-2-it 215, M+N=608;

hydrochloride 1-(4-{[2-(4-tert-butylphenyl)-1-methylethyl]ethylamino}butyl)-4-(2-methyl-1H-imidazol-4-sulfonyl)[1,4]diazepan-2-it 216, M+N=532;

hydrochloride 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(2-imidazol-1-retensioned)[1,4]diazepan-2-it 217, M+N=582;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(3-methoxybenzoyl)[1,4]diazepan-2-it 218, M+N=664;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(furan-2-carbonyl)[1,4]diazepan-2-it-219, and M+N=624;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino)butyl)-4-(thiophene-2-carbonyl)[1,4]diazepan-2-it 220, M+N=640;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(3-nitrobenzoyl)[1,4]diazepan-2-it 221, M+N=679;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-�-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(pyridine-4-carbonyl)[1,4]diazepan-2-it 223, M+N=635;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(isoxazol-5-carbonyl)[1,4]diazepan-2-it 224, M+N=625;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-benzoyl[1,4]diazepan-2-it 225, M+N=634;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(4-methoxybenzoyl)[1,4]diazepan-2-it 226, M+N-664;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(2-chloropyridin-4-carbonyl)[1,4]diazepan-2-it 227, M+N=670;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(3,4-dimethoxybenzoyl)[1,4]diazepan-2-it 228, M+N=694;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(5-methylisoxazol-3-carbonyl)[1,4]diazepan-2-it 229, M+N=639;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(thiophene-2-sulfonyl)[1,4]diazepan-2-it 230, M+N=676;

2,2,2-triptorelin of dimethylamine 4-[4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl}propylamino)butyl]-3-oxo[1,4]diazepan-1-sulfonic acid 231, M is solarpanel[1,4]diazepan-2-it 232, M+N=670;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-methanesulfonyl[1,4]diazepan-2-it 233, M+N=608;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(3-nitrobenzenesulfonyl)[1,4]diazepan-2-it 234, M+N=715;

2,2,2-triptorelin 1-(4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl]propylamino}butyl)-4-(1-methyl-1H-imidazol-4-sulfonyl)[1,4]diazepan-2-it 235, M+N=674;

2,2,2-triptorelin (2-methoxyphenyl)amide 4-[4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl}propylamino)butyl]-3-oxo[1,4]diazepan-1-carboxylic acid 236, M+N=679;

2,2,2-triptorelin (3-methoxyphenyl)amide 4-[4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl} propylamino)butyl]-3-oxo[1,4]diazepan-1-carboxylic acid 237, M+N=679;

2,2,2-triptorelin (4-methoxyphenyl)amide 4-[4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl}propylamino)butyl]-3-oxo[1,4]diazepan-1-carboxylic acid 238, M+N=679;

2,2,2-triptorelin methylamide 4-[4-({2-[3-(benzo[1,3]dioxol-5-sulfonyl)phenyl]-1-methylethyl}propylamino)butyl]-3-oxo[1,4]diazepan-1-carboxylic acid 239, M+N=587;

2,2,2-triptorelin (3,4,5-trimethoxyphenyl)amide 4-[4-({2-[3-(benzo[1,3 ASS="ptx2">2,2,2-triptorelin 1-[4-(ethyl{2-[4-(4-methoxybenzenesulfonyl)phenyl]-1-methylethyl}amino)butyl]-4-(pyridine-3-carbonyl)[1,4]diazepan-2-it 241, M+N=607;

2,2,2-triptorelin 1-[4-(ethyl{2-[4-(4-methoxybenzenesulfonyl)phenyl]-1-methylethyl}amino)butyl]-4-benzoyl[1,4]diazepan-2-it 242, M+N=606;

2,2,2-triptorelin 1-[4-(ethyl{2-[4-(4-methoxybenzenesulfonyl)phenyl]-1-methylethyl}amino)butyl]-4-(1-methyl-1H-imidazol-4-sulfonyl)[1,4]diazepan-2-it 243, M+N=646;

the dihydrochloride of 1-(4-{ethyl[2-(4-triptoreline)-1-methylethyl]amino}butyl 4-(2-methyl-1H-imidazol-4-sulfonyl)[1,4]diazepan-2-it 244, analysis: calculated for C25H37lF3N5O3S· 1,0 H2O: 47,32; N 6.35mm; N 11,04%; found: C Is 47.24; H 6,11; N 11,21%;

hydrochloride 1-(4-{[2-(4-chlorophenyl)-1-methylethyl]ethylamino}butyl 4-(1-methyl-1H-imidazol-4-sulfonyl)[1,4]diazepan-2-it 245, M+N=510;

hydrochloride 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-chloromethanesulfonyl[1,4]diazepan-2-it 246, M+N=536;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]ethylamino}butyl)-4-(2-dimethylaminoethanol[1,4]diazepan-2-it 247, M+N=545;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-pyrrolidin-1-retensioned)[1,4]diazepan-21-retensioned)[1,4]diazepan-2-it 249, M+N=567;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-piperazine-1-retensioned)[1,4]diazepan-2-it 250, M+N=586;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-[2-(4-methylpiperazin-1-yl)econsultancy][1,4]diazepan-2-it 251, M+H=600;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]ethylamino}butyl)-4-(2-methylaminoethanol)[1,4]diazepan-2-it 252, M+N=531;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]ethylamino)butyl)-4-(2-Diethylaminoethanol)[1,4]diazepan-2-it 253, M+N=573;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]ethylamino}butyl)-4-(2-isopropylaminoethyl)[1,4]diazepan-2-it 254, M+N=559;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]ethylamino}butyl)-4-(2-benzylaminocarbonyl)[1,4]diazepan-2-it is 255, M+N=607;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]ethylamino}butyl)-4-(2-benzylaminocarbonyl)[1,4]diazepan-2-it is 256, M+N=621;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-[2-(2-methoxyethylamine)econsultancy][1,4]diazepan-2-it 257, M+N=575;

2,2,2-triptorelin metrokane acid 258, M+N=589;

2,2,2-triptorelin 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]ethylamino}butyl)-4-(2-aminoethanesulfonic)[1,4]diazepan-2-it 259, M+N-517;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-dimethylaminoethanol)piperazine-2-it 260, M+N=531;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-Diethylaminoethanol)piperazine-2-it 261, M+N=559;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-isopropylaminoethyl)piperazine-2-it 262, M+N=545;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-pyrrolidin-1-retensioned)piperazine-2-it 263, M+N=557;

2,2,2-triptorelin 1-(4-(ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-benzylaminocarbonyl)piperazine-2-it 264, M+N=593;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-benzylaminocarbonyl)piperazine-2-it 265, M+N=607;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-[2-(2-hydroxyethylamino)econsultancy]piperazine-2-it 266, M+N=547;

2,2,2-triptorelin 1-(4-(ethyl[2-(4-methanesulfonamido the acetate methyl ester{2-[4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-3-oxopiperidin-1-sulfonyl]ethylamino} acetic acid 268, M+N=575;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-piperazine-1-retensioned)piperazine-2-it 269, M+N=572;

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-[2-(4-methylpiperazin-1-yl)econsultancy]piperazine-2-it 270, M+N=586, or

2,2,2-triptorelin 1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-4-(2-aminoethanesulfonic)piperazine-2-it 271, M+N=503.

Example 6

(Obtaining the compounds of formula IDa, as described in scheme D)

4-(4-{[(S)-(4-Methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]oxazepan-5-he

To a mixture of [(S)-2-(4-methanesulfonyl)-1-methylethyl]Propylamine (0.2 g, 0,78 mmole) and 4-(5-oxo[1,4]oxazepan-4-yl)butyric aldehyde (0,22 g, 1.2 mmole) in 1,2-dichloroethane (8 ml) were added triacetoxyborohydride sodium (0.25 g at 1.17 mmole). The reaction mixture was stirred at room temperature for 15 hours, the Mixture was diluted with dichloromethane and washed with 5% sodium hydroxide solution. The organic phase was dried (magnesium sulfate) and concentrated, obtaining 4-(4-{[(S)-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]oxazepan-5-it, which was isolated as a hygroscopic hydrochloride in diet the 54,34; N of 8.25; N 5,76%; found: 54,32; N 8,03; N 5,98%.

Similarly, following the above procedure described in example 6, but optionally replacing 4-(5-oxo[1,4]oxazepan-4-yl)butyric aldehyde with other appropriate compounds of formula 1e, and optional replacing [(S)-2-(4-methanesulfonyl)-1-methylethyl]Propylamine with other appropriate compounds of formula 2, and utilizing modifications known to specialists in this field, has received additional compounds of formula IDa, where Z denotes-O - or-S-:

4-tert-butyl-N-[3-(2-{[4-(5-oxo[l,4]oxazepan-4-yl)butyl]propylamino}propyl)phenyl]benzamide 274, analysis: calculated for C32H47N3O3: 73,67; N Remaining 9.08; N 8,05%; found: 73,74; N 8,99; N 8,23%, or

2,2,2-triptorelin 4-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)[1,4]oxazepan-5-it 275, M+N=465.

Example 7

(Obtaining the compounds of formula IDb, as described in scheme D)

4-(4-{[(S)-2-(4-Methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-he

The mixture hydrochloride [(S)-2-(4-methanesulfonyl)-1-methylethyl]Propylamine (2,05 g, 7.03 is mmole), triethylamine (and 0.98 ml, 7 mmol), tert-butyl ester 5-oxo-4-(4-oxobutyl)[1,4]diazepan-1-carboxylic sour is Noah temperature for 15 hours The mixture was concentrated and the residue was distributed between diethyl ether and a saturated solution of sodium carbonate. The organic phase was dried (magnesium sulfate) and concentrated, obtaining tert-butyl ester 4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid (3.6 g) as a thick syrup. M+N=524. The hydrochloride was recrystallized from a mixture of acetone/diethyl ether, tPL156-158° C.

To tert-butyl ether, 4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid (3.7 g, 7,06 mmole) was added 6 N. hydrochloric acid (7 ml). The reaction mixture was heated at 50° C for 1 min, then stirred at room temperature for 30 minutes Brought the pH value of the reaction mixture to 10 with saturated solution of sodium carbonate and was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated, obtaining 4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it is in the form of a dihydrochloride (hygroscopic) of the diethyl ester (2.86 g) 277, M+N=424.

Similarly, following the procedure described above in example 7, but not necessarily replacing tert-butyl obazatelno replacing hydrochloride [(S)-2-(4-methanesulfonyl)-1-methylethyl]Propylamine with other appropriate compounds of formula 2, and utilizing modifications well-known experts in this field, has received additional compounds of formula IDb, where Z denotes >NH:

the hydrochloride of 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)[1,4]diazepan-5-it 278, M+N=410;

the hydrochloride of 4-(4-{ethyl[2-(4-triftormetilfullerenov)-1-methylethyl]amino}butyl)[1,4]diazepan-5-it 279, M+N=464;

2,2,2-triptorelin 4-(4-{[2-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-methylethyl]ethylamino}butyl)[1,4]diazepan-5-it 280, M+N=390;

2,2,2-triptorelin 4-(4-{[2-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 281, M+N=404;

hydrochloride 4-(4-{[2-(4-tert-butylphenyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 282, M+N=402;

hydrochloride 4-(4-{[2-(3-triptoreline)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 283, M+N=414;

hydrochloride 4-(4-{[2-(4-methoxyphenyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 284, M+N=376;

hydrochloride 4-(4-{[2-(4-tert-butylphenyl)-1-methylethyl]ethylamino}butyl)[1,4]diazepan-5-it 285, M+N=388;

hydrochloride 4-(4-{[2-(4-tert-butylphenyl)-1-methylethyl]isopropylamino}butyl)[1,4]diazepan-5-it 286, M+N=402;

hydrochloride 4-(4-{[2-(4-propanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 287, analysis: vechicle is 2">hydrochloride 4-[4-({2-[4-(propane-2-sulfonyl)phenyl]-1-methylethyl}propylamino)butyl][1,4]diazepan-5-it 288, analysis: calculated for C25H44lN3ABOUT3S· 0,95 N20: 54,03; N 8,51; N 7,56%; found: 54,05; N At 8.36; N, 7.55 per cent;

hydrochloride 4-(4-{[2-(4-ethanolgasoline)-1-methylethyl]propylamino}butyl[1,4]diazepan-5-it 289, analysis: calculated for C23H40lN3ABOUT3S: 54,11; N. Of 8.09; N 8,23%; found: 50,88; N A 7.85; N To 7.67%;

hydrochloride 4-(4-{[2-(4-naphthalene-2-yl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 290, M+N=396;

hydrochloride 4-(4-{[2-(4-the thiazole-2-sulfanilyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 291, analysis: calculated for C25H37lN4O3S2·1,35 H2O: 48,86; N 6,77; N to 9.91%; found: 48,89; N. Of 6.71; N 9,40%;

the hydrochloride of 4-(4-{allyl[2-(4-methanesulfonyl)-1-methylethyl] amino}butyl)[1,4]diazepan-5-it 292, analysis: calculated for C22H37lN3ABOUT3S· 0,8 H2O: 51,92; N. Of 7.65; N compared to 8.26%; found: 51,82; N. Of 7.48; N, 8.27 per cent;

hydrochloride 4-(4-{[2-(4-isobutoxy)-1-methylethyl] propylamino}butyl)[1,4]diazepan-5-it 293, M+N=418;

hydrochloride 4-[4-({2-[4-(2-methoxypropan-2-sulfonyl)phenyl]-1-methylethyl}propylamino)butyl][1,4]diazepan-5-it 294, M+N=452;

galore 4-(4-{[2-(4-AMINOPHENYL)-1-methylethyl]ethylamino}butyl)[1,4]diazepan-5-she 296, M+N=347;

the hydrochloride of 4-(4-{ethyl[2-(4-nitrophenyl)-1-methylethyl]amino}butyl)[1,4]diazepan-5-it 297, M+N==377;

hydrochloride 4-(4-{[2-(4-hydroxyphenyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 298, M+N=362;

hydrochloride 4-[4-(ethyl{2-[4-(thiazol-2-sulfonyl)phenyl]-1-methylethyl}amino)butyl][1,4]diazepan-5-it 299, analysis: calculated for C25H35lN4O3S2·1,80 N2O: 47,30; N 6,83; N 9,59%; found: 47,31; N To 6.43; N 9,45%;

the hydrochloride of the methyl ester of 4-(2-{ethyl[4-(7-oxo[1,4]diazepan-1-yl)butyl]amino}propyl)benzoic acid 300 analysis: calculated for C22H36ClN3ABOUT3·0,80 N2O: 55,41; N 8,16; N 8,81%; found: 55,38; N. Of 8.04; N 8,87%;

the hydrochloride of N-[4-(2-{ethyl[4-(7-oxo[1,4]diazepan-1-yl)butyl]amino}propyl)phenyl]methanesulfonamide 301, M+N=425;

N-ethyl-4-(2-{ethyl[4-(7-oxo[1,4]oxazepan-1-yl)butyl]amino}propyl)benzamide 302, analysis: calculated for C23H39ClN4O2: 58,10; N 8,48; N 11,78%; found: 52,73; N 8,10; N 10,80%;

hydrochloride 4-[4-(ethyl{2-[4-(pyrrolidin-1-carbonyl)phenyl]-1-methylethyl}amino)butyl][1,4]diazepan-5-it 303, analysis: calculated for C25H41ClN4O: 59,87; N 8,44; N 11,17%; found: 50,76; N. Of 7.95; N 9,52%;

hydrochloride 4-[4-(ethyl{2-[4-(2-oxoa-2-sulfonyl)phenyl]-1-methylethyl}amino)butyl][1,4]diazepan-5-it 305, analysis: calculated for C25H40lN5O3S· 0,3 H2O: 49,68; N 7,10; N 11,59%; found: 49,63; N 7,00; N Are 11.62%;

N,N-dimethyl-2-[4-(2-{[4-(7-oxo[1,4]diazepan-1-yl)butyl]propylamino}propyl)-benzazolyl]ndimethylacetamide 306, analysis: calculated for C25H43lN4O4S:52,90; N 7,81; N, 9.87%; found: 50,43; N 7,56; N 9,38%;

hydrochloride 4-[4-({2-[4-(the thiazole-2-yloxy)phenyl]-1-methylethyl}propylamino)butyl][1,4]diazepan-5-it 307, M+N=445;

hydrochloride 4-(2-{[4-(7-oxo[1,4]diazepan-1-yl)butyl]propylamino}propyl)phenyl ether propane-2-sulfonic acid 308, M+N=468;

hydrochloride 4-[4-({2-[4-(1,1-dioxothiazolidine-2-yl)phenyl]-1-methylethyl}ethylamino)butyl][1,4]diazepan-5-it 309, M+N=451, or

hydrochloride 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]prop-2-ynylamine}butyl)[1,4]diazepan-5-it 310, analysis: calculated for C22H34ClN3ABOUT3S: 53,65; N 7,16; N 8,53%; found: 49,57; N 6,83; N 7,84%.

Example 8

(Obtaining the compounds of formula IDc, as described in scheme D)

4-(4-{Ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino)butyl)-1-(isoxazol-5-carbonyl)[1,4]diazepan-5-he

To a mixture of the dihydrochloride of 4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan Nellore (0.04 g, at 0.31 mmole). The reaction mixture was stirred at room temperature for 4 h the Mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride, dried (magnesium sulfate) and was given concerts, getting 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-(isoxazol-5-carbonyl)[1,4]diazepan-5-it is in the form of hygroscopic hydrochloride (0.14 g) in a mixture of ethyl acetate/diethyl ether 316, M+N=505.

Similarly, following the procedures described above in example 8, but replacing the optional dihydrochloride 4-(4-{[(5)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it is other free amino derivatives of formula IDb and optionally replacing isoxazol-5-carbonylchloride other relevant allerease, alkylating or sulfanilimide agents and utilizing modifications known to specialists in this field, has received additional compounds of formula I, where Z means >N-R6:

the hydrochloride of 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-benzyl[1,4]diazepan-5-it 317, M+N=500;

the hydrochloride of 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-methanesulfonyl[1,4]diazepan-5-it 318, M+N=488;

2,2,2-triptorelin of dimethylamine 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 320, M+N=481;

2,2,2-triptorelin ethyl ester of 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino)butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 321, M+N=482;

2,2,2-triptorelin 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-(2-methoxyacetyl)[1,4]diazepan-5-it 322, M+N=482;

2,2,2-triptorelin 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-propionyl[1,4]diazepan-5-it 323, M+N=466;

2,2,2-triptorelin 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-(furan-2-carbonyl)[1,4]diazepan-5-it 324, M+N=504;

2,2,2-triptorelin 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-isobutyryl[1,4]diazepan-5-it 325, M+H=480;

2,2,2-triptorelin 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-benzoyl[1,4]diazepan-5-it 326, M+N=514;

2,2,2-triptorelin 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-cyclobutanecarbonyl[1,4]diazepan-5-it 327, M+N=492;

2,2,2-triptorelin 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-(morpholine-4-carbonyl)[1,4]diazepan-5-it 328, M+N-523;

2,2,2-triptorelin 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-cyclohexanecarbonyl[1,4]diazepan-5-it 330, M+N=520;

2,2,2-triptorelin of dimethylamine 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-5-oxo[1,4]diazepan-1-sulfonic acid 331, M+N=526;

2,2,2-triptorelin tert-butylamide 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 332, M+N=509;

2,2,2-triptorelin of phenylamide 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 333, M+N=529;

2,2,2-triptorelin (2-methoxyphenyl)amide 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 334, M+N=559;

2,2,2-triptorelin 4-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)-1-ethyl[1,4]diazepan-5-it 335, M+N=438;

hydrochloride 1-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-(isoxazol-5-carbonyl)[1,4]diazepan-5-it 336, M+N=519;

hydrochloride 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-1-methyl[1,4]diazepan-5-it 337, M+N=438;

hydrochloride 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-1-(2-amino-3-methylbutyl)-1-(2-dimethylaminoethanol)[1,4]diazepan-5-she 339, M+N=559;

hydrochloride phenyl ester 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 340, analysis: calculated for C29H42lN3O5S: 60,04; N 7,30; N 7,24%; found: 58,80; N To 7.84; N 6,57%;

hydrochloride tert-butyl ester 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4] diazepan-1-carboxylic acid 341, tPL156-158° C;

the hydrochloride of diethyl ether 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino]butyl}-5-oxo[1,4]diazepan-1-yl)phosphonic acid 342, M+N=560;

hydrochloride ethyl ester 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 343, tPL135-137° C;

hydrochloride 2-[4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carbonyl]phenyl ester of acetic acid 344, M+N=586;

hydrochloride 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-1-(2-hydroxybenzoyl)[1,4]diazepan-5-it 345, M+N=465;

hydrochloride propyl ester 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 346, tPL152-154° C;

hydrochloride from the lots 347, analysis: calculated for C27H46lN3O5S· 1,80 N2O: 57,89; N. Of 8.28; N 7,50%; found: 57,59; N 8,20; N 7,39%;

hydrochloride of 2,2-dimethylpropylene ether 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 348, M+N=538;

hydrochloride butyl ester 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 349, M+N=524;

hydrochloride 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carbaldehyde 350, M+N=452;

hydrochloride isopropyl ester 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]-propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 351, tPL142-143° C;

hydrochloride of 1-acetyl-4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 352, M+N=466;

hydrochloride 2-[4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carbonyl]benzyl ester of acetic acid 353, M+H=600;

hydrochloride 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-1-(4-trifloromethyl)[1,4]diazepan-5-it 354, M+N=582;

hydrochloride 4-[4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)lifeifei)-1-methylethyl]propylamino} butyl)-1-[2-(3-triptoreline)ethyl][1,4]diazepan-5-she 356, M+N=596;

hydrochloride of 1-[2-(4-chlorophenyl)ethyl]-4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it 357, M+N=562;

4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-1-(2-methoxyacetyl)[1,4]diazepan-5-he 358, M+N=496;

1-(2-isopropoxyphenyl)-4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-he 359, M+N=524;

benzoylmethylecgonine ether 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4] diazepan-1-carboxylic acid 360, M+N=618;

acetoxymethyl ether 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 361, tPL143-144° C;

2,2-dimethylphenylacetate ether 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4] diazepan-1-carboxylic acid 362, tPL129-130° C;

5-methyl-2-oxo[1,3]dioxol-4-ether ymetray 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4] diazepan-1-carboxylic acid 363, M+N=580;

acetylcholinesterase ether 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid 364, tPL142-144° C.

Example 9

(Alt is unsulfonated)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid

Step 1: tert-butyl ether 4-{4-[5-(4-methanesulfonyl)-4-methyl-2-oxoacridine-3-yl]butyl}-5-oxo[1,4]diazepan-1-carboxylic acid

To a chilled mixture of 2.5 g of 5-(4-methanesulfonyl)-4-methyloxazolidine-2-she and 7.5 ml of N-methylpyrrolidone was slowly added 5 g of a 25% solution of tert-Aminata potassium in toluene. The mixture was stirred, then cooled and added 4.5 g of tert-butyl ester 4-(4-iodobutyl)-5-oxo[1,4]diazepan-1-carboxylic acid. The mixture was stirred at ambient conditions for 6 hours water was Added and the mixture was stirred. The precipitated product was collected and dried to yield about 3.5 g of tert-butyl methyl ether 4-{4-[5-(4-methanesulfonyl)-4-methyl-2-oxoacridine-3-yl]butyl}-5-oxo[1,4]diazepan-1-carboxylic acid.

Step 2: tert-butyl ether 4-{4-[2-(4-methanesulfonyl)-1-methylethylamine]butyl}-5-oxo[1,4]diazepan-1-carboxylic acid

A mixture of 10 g of tert-butyl methyl ether 4-{4-[5-(4-methanesulfonyl)-4-methyl-2-oxoacridine-3-yl]butyl}-5-oxo[1,4]diazepan-1-carboxylic acid, 1 g of 20% Pd/C, 10 ml of water and 90 ml of isopropanol was stirred and heated to 50-60° C. was Slowly added a solution of 3.5 g of potassium formate in 5 ml of water. The mixture was stirred for 3 h, then cooled and filtered.l}-5-oxo[1,4]diazepan-1-carboxylic acid.

Step 3: tert-butyl ether 4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid

A mixture of sodium borohydride (0.55 g) and tetrahydrofuran (40 ml) was stirred and slowly added a mixture of acetic acid (2,62 g) and tetrahydrofuran (10 ml) while cooling to maintain the temperature below the ambient temperature. The mixture permissively within a few hours. Preparing a solution of tert-butyl methyl ether 4-{4-[2-(4-methanesulfonyl)-1-methylethylamine]butyl}-5-oxo[1,4]diazepan-1-carboxylic acid (7.0 g) and propionic aldehyde (0.85 grams) in tetrahydrofuran (25 ml). The solution was slowly added with stirring to borhydride mixture. The mixture is stirred for several hours, followed by slow addition of 25% solution of sodium hydroxide (14 g). The upper organic layer was distilled in a vacuum. The residue was dissolved in toluene and washed with water. The organic layer was distilled in vacuum, obtaining 7.5 g of tert-butyl ester 4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid in the form of oil.

Example 10

The ingredients were mixed and lapradelle capsules containing about 100 mg each; about ienty combined and granulated, using such a solvent as methanol. The mixture is then dried and formed into tablets (containing about 20 mg of active compound), with appropriate teletrauma machine.

Example 12

The ingredients were mixed, forming a suspension for oral administration.

Example 13

The active ingredient was dissolved in parts of water for injection. Then under stirring was added sodium chloride in a quantity sufficient to make the solution isotonic. The solution is brought up to the desired number by using the remaining water for injection, filtered through a membrane filter with a pore size of 0.2 microns and Packed in sterile conditions.

Example 14

The ingredients were melted and mixed in a steam bath and poured into molds containing 2.5 g total mass.

Example 15

All ingredients, except water, are combined and heated to about 60° C under stirring. Then with vigorous stirring at about 60° With the added amount of water, sufficient to emulsify the ingredients, and then water was added to approximately 100 g

Example 16

The compositions on the organisations, as compositions for nasal spray. The compositions optionally contain inactive ingredients, such as, for example, microcrystalline cellulose, carboxymethylcellulose sodium form, dextrose and the like. Hydrochloric acid may be added to regulate pH. Compositions for nasal spray can be delivered using a pump with measured nazalnam spray, usually delivers about 50-100 ál of the mixture to run. The typical dosage is 2-4 spray every 4 to 12 hours

Example 17

Studies of the binding of radioactive ligand

Inhibitory activity in vitro of the compounds of this invention was determined using a modification of the method described Hegde, S. S., and others, Br. J. Pharmacol. 1997, 120, 1409-1418.

Used cell membrane ovary cells Chinese hamster expressing recombinant human muscarinic receptors (m1 -m5). Analyses were performed with the radioactive ligand [3H]N-methylscopolamine (0.4 nm, specific activity 84 CI/mmol) in a final volume of 0.25 ml of Tris-buffer Krebs. Nonspecific binding was defined with 1 μm atropine. The tests were carried out using the method of scinti is soedinenii, and analyzed using the iterative approximation curve to chetyrehmetrovuyu logistic equation. Values pIC50(-log IC50) were converted into values pKi using the equation of Cheng-Prusova.

Inhibitory activity (expressed as pKi values) in relation to muscarinic receptors of some given as examples, compounds of the present invention, see table. 7.

Example 18

The model induced oxotremorine/pilocarpine salivation (OIS/PIS) have shot rats

Female rats line Sprague-Dawley (Charles River, 200-300 g) were anestesiologi with urethane (1.5 g/kg subcutaneously) and subjected to tracheotomy. One femoral vein was Coulibaly for drug injection. After an hour stabilization period, rats pre-treated with methoctramine (for OIS), to counteract the bradycardia mediated receptor M2. Each animal was injected intravenously a single dose of filler or compound-standard. Ten minutes later pre-weighed cotton pads were placed in the oral cavity of animals, after this they entered the filler and the profound in the fifth minute after treatment with oxotremorine/pilocarpine and collected saliva for an additional 5 minutes Then cotton pads (5 - and 10-minute period) was again weighed to determine the amount of saliva secreted during the 10-minute period.

All groups treated with oxotremorine/pilocarpine were compared using univariate analysis of variance. A pairwise comparison was performed using criterion Dannetta. Ordered data (nonparametric method) or the actual levels of data (parametric method) was used in the analysis depending on the results of the test of Bartlett, which analyzes the homogeneity of the dispersion. The group treated filler/oxotremorine and filler/pilocarpine, compared with the group treated filler/filler, using the criterion of rank sum Wilcoxon signed. Received assessment ID50for each connection in relation to the 10-minute total Sekretareva mass for each animal. Sigmoidal model is presented in the form of dependencies:

Response=min+(max-min)/(1+(dose/ID50)**N),

where ID50mean dose to achieve the half maximal response, and N denotes the curvature parameter and max indicates the maximum response curve for the response to the dose. Minimum and active.

Example 19

The inhibition induced by volume reductions in rats

Inhibitory activity of compounds of this invention in relation to muscarinic receptors in vivo was determined in rats using a modification of the method described Hegde, S. S., and others, Proceedings of the 26th Annual Meeting of the International Continence Society 1996 (27-30 August), abstract 126.

Female rats line Sprague-Dawley was anestesiologi urethane and podgotavlival to intravenous drugs, and in some cases to measure arterial pressure and the pressure inside the bladder. The influence of the studied compounds on the induced volume contraction of the bladder were determined in separate groups of animals.

Induced displacement of reflex bladder contractions evoked by filling the bladder with saline. The compounds were administered intravenously in a cumulative way with 10-minute intervals. Atropine (0.3 mg/kg intravenously) was administered at the end of the study as a positive control.

In this assay, compounds of this invention were active.

Example 20

Antimuskarinovoe act occurs activity have shot dogs

Dogs-females breed Beagle (from Marshall Farms, North Rose, NY) were subjected to starvation for 18 h before the experiment with free access to water. On the day of the experiment the dogs were given anesthesia and maintained on phenobarbital (first 36 mg/kg intravenously, then 5-10 mg/kg intravenously for support). Intravenous fluid was administered to dogs during the remaining part of the experiment. The dogs were artificial lung ventilation via endotracheal tube with a Harvard respirator (model 613). As the femoral vein and a femoral artery were Coulibaly for drug administration and blood pressure respectively. Blood pressure was measured using sensor Gould (model 332XL) and recorded on the recording device Gould (model 3400). Was made sublingual incision to expose the left mandibular canal, which was then kemuliaan to collect saliva in a pre-weighed test tube. Left salivary gland was exposed through a submandibular incision. Allocated chordally the lingual nerve and put on him a bipolar electrode for stimulation. Trial response to the stimulation of chordal hirurgicheskogo intervention were infusion of physostigmine (180 µg/kg· h intravenously) during the remaining part of the experiment. After an hour stabilization period conducted two control stimulation hartalega lingual nerve at 12 Hz, 10 V and a duration of 0.5 msec (Grass S48). Hardly the lingual nerve was stimulated for 20 sec and 2 min, respectively, with a minimum 10-minute interval between each series of stimulation. After receiving two compatible control response dose filler or compound-standard was introduced in a cumulative way, for 3 min before each stimulation hartalega lingual nerve. Experiments in which a compatible response salivation were not received, is not included in the analysis. Atropine (1.0 mg/kg intravenously) was given as a positive control at the end of the study.

Mean arterial pressure was calculated as diastolic blood pressure + (systolic blood pressure - diastolic blood pressure)/3. Heart rate was obtained in the measurement of arterial pulse pressure. Saliva was collected in pre-weighed tubes and weighed after each selection, to determine the amount of secretiruemy saliva. Inhibition of the responses of salivary gland exp is the maximum percent inhibition of salivation estimation of parameters was performed using a nonlinear mixed model. The method was carried out using the original PROC NLIN and re PROC MIXED. This procedure assumes the following sigmoidal model the dose-response:

where the response indicates the percentage of maximum inhibition of bladder contractions at the highest point, x=log10dose treatment and 4 parameters are: log10ED50( ), the maximum and minimum response (Max and Min) and the curvature ( ). It was assumed that the minimum response is 0%. This technique provided the symmetry of the connection covariational patterns. It was a re-curve, which explains the dependence between multiple measurements obtained from the same animal, and estimate the required parameters and their confidence intervals by clarifying erroneous calculations to be responsible for the correlation within a subject.

Comparison with baseline

To compare each dose with a control baseline for each variable, held a two-dimensional analysis of variance ANOVA with main effects of subject and treatment, accompanied by paired t-test at each dose level. If the overall treatment effect was not significant (meaning the first dose.

The compounds of this invention were active in this assay.

Although the present invention is described with reference to specific variants of its incarnations, specialists should be clear that it can be made various changes and equivalents may be substituted without departing from the true nature and scope of the invention. In addition, can be done many modifications to adapt a particular situation, material, composition of matter, method, stage or stages of the way to the goal, the nature and scope of the present invention. It is implied that all such modifications are included in the scope of the attached claims.

1. Substituted 1-aminoalkylated General formula I,

where R1, R2and R3means independently in each case hydrogen, halogen, (C1-C6)alkyl, -OR', -SR', -NR'R", -SOR', -SO2R', -COOR', -OCOR', -OCONR'R", -OSO2R', -OSO2NR'R';- NR'SO2R", -NR'COR", -SO2NR'R", -SO2(CH2)1-3CONR'R", -CONR'R", cyano, haloalkyl or nitro; or

R1and R2if they are adjacent, together with the carbon atoms to which they are attached, may form a 5-7-membered aromatics is N, S(O)0-2or O, and optionally substituted (C1-C6)alkyl, halogen, cyano or (ness.)alkoxy;

R' and R ' denote, independently in each case hydrogen, (C1-C6)alkyl, substituted (C1-C6)alkyl, (C0-C3)alkylalkoxy, aryl, heterocyclyl, heteroaryl, aryl(C1-C3)alkyl, heteroaryl(C1-C3)alkyl, heterocyclyl(C1-C3)alkyl, cycloalkenyl, cycloalkyl, or

R' and R" together with the nitrogen atom to which they are attached, can also form a 5-7 membered cycle, optionally incorporating one additional ring heteroatom selected from N, O or S(O)0-2;

R4means independently in each case, (C1-C6)alkyl;

R5means independently in each case, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil or cycloalkyl;

one of X, Y or Z means independently-S-, -O-, -CH2or >N-R6other means-CH2-;

R6means hydrogen, (C1-C6)alkyl, haloalkyl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, -(C1-C6)-CR'R'R', -COOR', -SO2R', -C(O)R', -SO<" have the above meanings;

m means an integer of 0-3;

n means an integer of 1-6;

or individual isomers, racemic or nerezisca mixture of isomers, or pharmaceutically acceptable salt, or their solvate.

2. Connection on p. 1, where R1, R2and R3means independently in each case hydrogen, halogen, (C1-C6)alkyl, -OR', -SR', -NR'R", -SOR', -SO2R', -COOR', -OCOR', -OCONR'R", -OSO2R', -OSO2NR'R';- NR'SO2R", -NR'COR", -SO2NR'R", -SO2(CH2)1-3CONR'R", -CONR'R", cyano, haloalkyl or nitro; or R1and R2if they are adjacent, together with the carbon atoms to which they are attached, may form a 5-7-membered aromatic, saturated or unsaturated cycle, optionally comprising one or two ring heteroatoms selected from N, S(O)0-2or O, and optionally substituted (C1-C6)alkyl, halogen, cyano or (ness.)alkoxy;

R' and R ' denote, independently in each case hydrogen, (C1-C6)alkyl, substituted (C1-C6)alkyl, aryl, heterocyclyl, heteroaryl, aryl(C1-C3)alkyl, heteroaryl(C1-C3)alkyl, heterocyclyl(C1-C3)alkyl, cycloalkyl the th cycle, optionally containing one additional ring heteroatom selected from N, O or S(O)0-2; R4means independently in each case, (C1-C6)alkyl; R5means independently in each case, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)quinil or cycloalkyl; one of X, Y or Z means independently-S-, -O-, -CH2or >N-R6other means-CH2-; R6means hydrogen, (C1-C6)alkyl, haloalkyl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, -(C1-C6)-CR'R'R', -COOR', -SO2R', -C(O)R', -SO2-(CH2)0-3-NR'R", -CONR'R", or-PO(OR')2where R' and R" have the above values of m means an integer of 0-3; and n means an integer of 1-6; or individual isomers, racemic or nerezisca mixture of isomers, or pharmaceutically acceptable salt, or their solvate.

3. Connection under item 1 or 2, where n means 3.

4. Connection under item 1 or 2, where R4means methyl.

5. Connection on p. 4, where m is 0.

6. Connection on p. 4, where m means 1.

7. Connection on p. 6, where Y represents >N-R6.

8. Connection on p. 7, l)piperazine-2-it;

1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-methylpiperazin-2-it; or

N-methyl-4-((S)-2-{[4-(2-oxopiperidin-1-yl)butyl]propylamino}propyl)-benzosulfimide.

9. Connection on p. 3 or 4, where m means 2.

10. Connection on p. 9, which is selected from the group consisting of

1-(4-{ethyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)azepin-2-it;

4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]oxazepan-3-one; or

4-(2-{ethyl[4-(2-oxazepan-1-yl)butyl]amino}propyl)phenyl ether 1,1,1-triftormetilfullerenov acid.

11. Connection on p. 9, where one of X, Y or Z means >NR6and other means-CH2-.

12. Connection on p. 11, where X is >NR6.

13. Connection on p. 11, where Y represents >NR6.

14. Connection on p. 13, which is selected from the group consisting of

1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-[1,4]diazepan-2-it;

1-(4-{ethyl[(S)-1-methyl-2-(4-triptoreline)ethyl]amino}butyl)[1,4]diazepan-2-it; or

1-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-4-methyl-[1,4]diazepan-2-it.

15. Connection on p. 11, where Z allyl[2-(4-methanesulfonyl)-1-methylethyl]amino}butyl)[1,4]diazepan-5-it;

4-(4-{[2-(4-tert.-butylphenyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it;

ethyl ester 4-(4-{[2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)-5-oxo[1,4]diazepan-1-carboxylic acid;

4-(4-{[(S)-2-(4-methanesulfonyl)-1-methylethyl]propylamino}butyl)[1,4]diazepan-5-it;

4-((S)-2-{[4-(7-oxo[1,4]diazepin-1-yl)butyl]propylamino}propyl)phenyl ether propane-2-sulfonic acid; or

4-(4-{[(S)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-methylethyl]propylamino}butyl)-[1,4]diazepan-5-it.

17. Connection on p. 3 or 4, where one of X, Y or Z denotes-O - or-S -, and other means-CH2-.

18. Pharmaceutical composition having antagonistic activity against muscarinic receptors M2/M3, comprising a therapeutically effective amount of one or more compounds according to any one of paragraphs.1-17 in a mixture with a pharmaceutically acceptable carrier.

19. The method of obtaining the compounds of formula I on p. 1, which includes (i) interaction derived armetale General formula IV,

where M means a metal or mineraloid with the compound of the formula V,

where R is alkyl, aryl or arylalkyl;

Ra

(ii) the recovery of the compounds of formula VI, followed by cyclization and processing a compound of formula R5L, where L is a leaving group, to obtain compounds of formula VII

(iii) recovering the compound of formula VII to obtain the compounds of formula III

followed by treatment of the compounds of formula III with the compound of General formula II

with the formation of compounds of General formula I

where R1, R2, R3, R4, R5, m, n, X, Y, and Z have values under item 1.

20. The method of obtaining the compounds of formula I on p. 1, which includes

(i) the recovery of the compounds of formula VI

accompanied by cyclization,

(ii) treating compound of formula VI with the compound of formula VIII

where L denotes a leaving group,

(iii) recovering the product with the formation of the compounds of formula IX

and (iv) alkylation of compounds of formula IX corresponding aldehyde or a compound of the formula R5L, where L is a leaving group, to obtain compounds of FOP.1.

21. The compound according to any one of paragraphs.1-17, when it was not received by the method stated in paragraph 19 or 20.

Priority points and features:

25.05.2000 - PP.2 and 3 (signs), p. 4 (signs), p. 5 (signs), p. 6 (signs), PP.8 and 9 (signs), PP.10 and 14 (signs), PP.16, 18, 19;

09.02.2001 - PP.1 and 3 (signs), p. 4 (signs), p. 5 (signs), p. 6 (signs), p. 7 (signs), p. 9 (signs), PP.17 and 20;

16.05.2001 - p. 7 (signs), PP.11, 12, 13, 14 (signs), p. 15.



 

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