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 a compound having the General formula I, where R1and R2means 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)1-3- CONR'R", -CONR'R", langroup, haloalkyl or nitro-group; or 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-alkyl, cycloalkyl, or R' and R" together with the nitrogen atom to which they are bound may also form a 5-7-membered ring that optionally includes an additional annular heteroatom selected from N, O or S(O)0-2; R3independently in each case, the means (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)quinil or cycloalkyl; or one of X, Y or Z means independently-O - or >N-R4other oscil, heteroaryl(C1-C6)alkyl, -(C1-C6)-CR'R'R', -COOR', -SO2R', -C(O)-R', -SO2(CH2)0-3NR'R", -CONR'R" R' and R" are as above; R denotes an integer from 1 to 3, inclusive; m indicates an integer from 0 to 3 inclusive; n means an integer from 1 to 6, inclusive; or individual isomers, racemic or nerezisca mixture of isomers, or pharmaceutically acceptable salt or solvate. Also describes a pharmaceutical composition having antagonistic activity against muscarinic receptors M2/M3 on the basis of the compounds of formula I and a method of producing compounds of the formula I. the Technical result obtained new compounds with useful biological properties. 3 N. and 19 C.p. f-crystals.

The present invention relates to compounds of General formula I,

where

R1and R2means 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)1-3-CONR'R", -CONR'R", langroup, haloalkyl or nitro-group; or

)alkyl, aryl, heterocyclyl, heteroaryl, aryl(C1-C3)-alkyl, heteroaryl(C1-C3)alkyl, heterocyclyl(C1-C3)alkyl, cycloalkyl-alkyl, cycloalkyl or R' and R" together with the nitrogen atom to which they are bound may also form a 5-7-membered ring that optionally includes an additional annular heteroatom selected from N, O or S(O)0-2;

R3independently in each case, the means (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)quinil or cycloalkyl; or

one of X, Y or Z means independently-S-, -O - or >N-R4other means-CH2-;

R4means 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)0-3NR'R", -CONR'R", or-PO(OR')2where R' and R" are as described above;

p means an integer from 1 to 3 inclusive;

m means an integer from 0 to 3 inclusive;

n means an integer from 1 to 6, inclusive;

or prodrugs, individual isomers, racemic or deracemization mixtures is of the compounds of formula I are selective antagonists of muscarinic receptors M2/M3.

Acetylcholine (Ach) is the primary mediator of the parasympathetic nervous system. The physiological action of Ach mediated by activation or nicotinic or muscarinic receptors. Both of these classes of receptors are heterogeneous: for example, a family of muscarinic receptors includes five subtypes (M1, M2, M3, M4and M5), each encoded by specific genes and has a unique pharmacology and distribution.

Almost all tissue smooth muscle Express muscarinic receptors M2 and M3, both of which play a functional role. Receptor M2about four times larger than the receptor M3. Usually the receptors M3help direct contractile effects of acetylcholine for a wide variety of tissue smooth muscle. Receptors M2contrast , cause smooth muscle contraction indirectly, simpaticeskii inhibiting relaxation, mediated by adrenergic receptors.

Compounds acting as antagonists at the muscarinic receptors, were used to treat some medical conditions related to improper functioning of the smooth muscles. Until recently the most part tactil anticholinergic side effects, as, for example, dry mouth, constipation, blurred vision, or tachycardia. The most common of these side effects is dry mouth caused by blockade of muscarinic receptors in the salivary gland. It was found that the recently developed specific antagonists M2 or M3 reduced side effects. The available data indicate that simultaneous blockade of receptors M2 and M3 could be therapeutically effective in the treatment of painful conditions associated with disorders of smooth muscle.

We developed a small number of selective antagonists M2/M3. This invention satisfies this need by providing the types of antagonists, useful for the treatment of painful conditions associated with improper functioning of the 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 the smooth muscle described Ehlert and others in the Life Sciences 1997, 61, 1729-1740. Hedge, etc.. Life Sciences 1999, 64, 419-428, refer to the subtypes of muscarinic receptors, modulating the contractility of the smooth muscle in the bladder. Eglen and others, Trends. Pharmacol. Sci. 1994, 15, 114-119, and Eglen and others, Pharmacol. Rev. 1996, 48, 531-is the study of selective muscarinic antagonists are described Nilverbrant and others, Life Sciences 1997, 60, 1129-1136; Alabaster, Life Sciences, 1997, 60, 1053-1060; Osayu, etc.. Drug Res. 1994, 44, 1242-1249, and Homma, etc., Neurourology and Urodynamics 1997, 345-346. Selective modulation of subtypes of muscarinic receptors is described Eglen and Hedge, 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. A certain classification of muscarinic acetylcholine receptors described Caulfield and others, Pharmacological Reviews 1998, 50(2), 279-290.

In the following literature describes compounds related to the compounds of General formula I. the US Patents No. 5,382,595, No. 5,177,089, No. 5,047,417 and No. 5,607,953 company Eisai Co., Ltd. refer to some derivatives butenova and acrylic acid. The US patent No. 4,748,182 firm Merrell Dow Pharm. Inc. describes some derivatives of aromatic 2-aminoalkyl-1,2-benzisothiazol-3(2H)one-1,1-dioxide and their use as anti-hypertensive and anxiolytics. The US patents No. 4,880,802 and No. 5,298,513 Bayer AG reveal some derivatives aminotetraline used for the treatment of Central nervous system, cardiovascular system or intestines. The US patent No. 4,584,293, Dr. Karl Thomae GmbH, presents some aminotetraline and their use for lowering the heart rate. Some derivative aminot the NT US No. 5,545,755 firm decision Upjohn Co. reveals some derivatives aminotetraline used for the treatment of disorders of the Central nervous system. International patent application WO 99/43657 company F. Hoffmann-La Roche AG refers to some derivatives of 2-arylaryl(piperidine-4-ylmethyl)amine as antagonists of muscarinic receptors. Some 2-aminomethylbenzoic having the ability to bind dopamine receptors D2, D3, and serotonin NT-1A, describes Homan and others in Bioorg. Med. Chem. 1999, 7(6), 1111-1121. Glennon, etc., J. Med. Chem. 1989, 32, 1921-1926, refer to N-telemedicine derivatives as serotonergic funds.

All quoted here above or below the publications, patents and patent applications are fully incorporated, thus, in the form of links.

Objects of the present invention are derivatives of benzocyclobutene formula I, prodrugs, individual isomers, racemic or nerezisca mixture of isomers and their pharmaceutically acceptable salts or hydrates. The invention also relates to pharmaceutical compositions containing an effective amount of at least one of the compounds of formula I, or prodrugs, individual isomers, racemic or deracemization mixtures of isomers, or their formatieren embodiment of the invention pharmaceutical compositions suitable for administration to a subject in a morbid condition, which is easier when processing an antagonist of muscarinic receptor M2/M3.

On the other hand, the invention relates to the use of such compounds in the treatment of the subject in a painful condition that is alleviated by treatment with an antagonist of muscarinic receptors M2/M3. In a preferred embodiment of the invention the subject is a painful condition, which includes disorders of smooth muscle, preferably disorders of the genitourinary tract, disorders of the respiratory tract, disorders of the gastrointestinal tract; more preferably, violations of the urinary tract, such as urinary bladder increased activity or hyperactivity of the detrusor and its symptoms, such as changes symptomatically manifested as extreme urgency of urination, frequency of urination, decreased bladder capacity, episodes of incontinence, and the like; changes urodynamically manifested as changes in bladder capacity, threshold urination, unstable contractions of the bladder, sphincter spasticity, and the like, and the symptoms usually manifested in the form of detrusor hyperreflexia (neurogenic bladder), in States, such as Sindh is aaniyah of unknown origin, as, for example, the mobility of the detrusor, and the like. In another preferred embodiment of the invention the disease includes disorders of the respiratory tract, such as allergies and asthma. In yet another preferred embodiment of the invention painful condition includes gastrointestinal disorders.

According to another aspect of the invention relates to a method for obtaining compounds of formula I, the method involves reacting compounds of General formula II

with a compound of General formula III

to obtain the compounds of formula I,

where R1, R2, R3, p, m, n, X, Y, and Z are as described here.

Unless specified otherwise, the following terms used in this application, including the description and the claims, have the following definitions. It should be noted that the reference in the description of the invention and the attached claims about something General or specific in the singular implies related to many objects provisions, unless the context clearly indicates otherwise.

"Lower alkyl" means a monovalent saturated hydrocarbon radical is different. Examples of the lower alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, 1-ethylpropyl, sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl and the like.

"Substituted lower alkyl" means lower alkyl, as is indicated here, including from one to three substituents, preferably one Deputy such as hydroxyl, alkoxygroup, amino group, aminogroup, carboxyl, acyl, halogen, lagrappe, nitrogroup, Tolna group. These groups can be attached to any carbon atom of the lower alkyl part. Examples of substituted lower alkyl radicals include, but are not limited to, 2-methoxyethyl, 2-hydroxyethyl, dimethylaminocarbonylmethyl, 4-hydroxy-2,2-dimethylbutyl, trifluoromethyl, triptorelin and the like.

"Alkylene" means a divalent unsaturated hydrocarbon radical with a straight or branched chain, containing from one to six, inclusive, carbon atoms, unless otherwise specified. Examples alkilinity radicals include, but are not limited to, methylene, ethylene, propylene, 2-methylpropene, butylene, 2-ethylbutyl and the like.

"Alkenyl" means a monovalent unsaturated hydrocarbon radical with Pleroma, if not stated otherwise. Examples alkenyl radicals include, but are not limited to, ethynyl, allyl, 1-propenyl, 2-butenyl and the like.

"Quinil" means a monovalent unsaturated hydrocarbon radical with a straight or branched chain containing the triple bond and containing from two to six, inclusive, carbon atoms, unless otherwise specified. Examples etkinlik radicals include, but are not limited to, ethinyl, 1-PROPYNYL, 2-butynyl, propargyl and the like.

"Alkoxygroup" means the radical-O-R, where R is a lower alkyl radical, as defined above. Examples of CNS radicals include, but are not limited to, a methoxy group, ethoxypropan, isopropoxy and the like.

"Aryl" means the monovalent aromatic carbocyclic radical consisting of one individual ring, or one or more condensed rings, in 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 a hydroxyl group, langroup, lower alkyl, (ness.)alkoxygroup, halogen(ness.)alkoxygroup, alkylthio, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylaminomethylene, alkylsulfonamides, arylsulfonamides, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, unless otherwise noted. Alternative two adjacent atoms of aryl ring can be substituted, methylendioxy or ethylenedioxythiophene. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, naphthyl, biphenyl, indanyl, anthrachinone, tert-butylphenyl, 1,3-benzodioxolyl and the like.

"Arylalkyl" means the radical R'R"-, where R' means aryl radical, as defined here, and R means an alkyl radical as defined here. Examples arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl and the like.

"Cycloalkyl" means a monovalent saturated carbocyclic radical consisting of one or more rings, preferably one or two rings containing from three to eight carbon atoms in the ring, which optionally may be substituted by one or more, preferably one or two substituents selected from a hydroxyl group, langroup, the lower and the La, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylaminomethylene, alkylsulfonamides, arylsulfonamides, alkylaminocarbonyl, arylenecarborane, alkylsulphonyl-amino group, arylcarboxamide, unless otherwise noted. Examples cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclohexyl, cyclopentyl, cycloheptyl and the like.

"Cycloalkenyl" means the radical R'R"-, where R' means cycloalkenyl radical, as here established, and R" denotes an alkyl radical, as installed here. Examples cycloalkyl radicals include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylmethyl and the like.

"Heteroaryl" means a monovalent aromatic cyclic radical containing one or more rings, preferably one to three rings, containing from four to eight atoms in the ring, including ring one or more heteroatoms, preferably one or two selected from nitrogen, oxygen or sulfur), which optionally may be substituted by one or more, preferably one who, halogen-(ness.)alkoxygroup, allylthiourea, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylaminomethylene, alkylsulfonyl-amino, arylsulfonamides, alkylaminocarbonyl, arylamino-carbonyl, alkylcarboxylic, arylcarboxamide, if not otherwise indicated. Examples of heteroaryl radicals include, but are not limited to, imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thienyl, furanyl, pyridinyl, chinoline, ethenolysis, benzofuran, benzothiophene, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzopyranyl, indazoles, indolyl, isoindolyl, naphthyridine, benzosulfimide and the like.

"Heteroaromatic" (or "heteroaryl" means a radical of the formula R'R" R' means a heteroaryl radical, as here established, and R" means alkilinity radical, as installed here. Examples heteroarylboronic radicals include, but are not limited to, 2-imidazolidinyl, 3-pyrrolidinyl and the like.

"Heterocyclyl" means a monovalent saturated cyclic radical, consisting of one or more of the second one or more ring heteroatoms (chosen from N, O or S(O)0-2), and which optionally may be substituted by one or more, preferably one or two substituents selected from hydroxyl group, carbonyl group, langroup, lower alkyl, (ness.)alkoxygroup, halogen(ness.)alkoxygroup, alkylthio group, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylamino-sulfonyl, arylaminomethylene, alkylsulfonamides, arylsulfonyl-amino group, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic group, arylcarboxamide, if not otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, morpholinyl, piperazinil, piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiomorpholine, hinokitiol and the like.

"Heteroseksualci" (or "geterotsiklicheskikh" means a radical of the formula R'R" R' means a heterocyclic radical, as here established, and R" means alkilinity radical, as installed here. Examples geterotsiklicheskikh radicals include, but are not limited to, 1-piperazinylmethyl, 2-morpholino-methyl and the like.

"Halogen" means fluorine, Enen in any position by one or more halogen atoms, as installed here. Examples haloalkyl radicals include, but are not limited to, 1,2-direcror, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-triptorelin, 2,2,2-trichloroethyl and the like.

"Hydroxyalkyl" means a lower alkyl radical, as here established, 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-hydroxy-butyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, and the like.

"Alloctype" means the radical-O-C(O)-R, where R is a lower alkyl radical, as installed here. Examples of acyloxy include, but are not limited to, acetoxy, propionyloxy and the like.

"Alkoxycarbonyl" or "balance complex Olkiluoto ether" means the radical-C(O)-O-R, where R is a lower alkyl radical, as installed here. Examples alkoxycarbonyl radicals include, but are not limited to, methoxy-carbonyl, etoxycarbonyl, second-butoxycarbonyl, isopropoxycarbonyl e R is aryl radical, as installed here. Examples aryloxyalkyl radicals include, but are not limited to, remains difficult phenyl ester, complex neftianogo ether and the like.

"Arylethoxysilanes" or "balance complex arylalkyl ether" means the radical-C(O)-O-RR', where R is a lower alkyl radical and R' means aryl radical, as installed here. Examples aryloxyalkyl radicals include, but are not limited to, remains difficult benzyl ether complex phenethyl ester and the like.

"Alkylaryl" (or "acyl" means a radical R-C(O)-, where R is a lower alkyl radical, as installed here. Examples alkylcarboxylic radicals include, but are not limited to, acetyl, propionyl, n-butyryl, sec-butyryl, tert-butyryl, Isopropenyl and the like.

"Arylcarbamoyl" means the radical R-C(O)-, where R is aryl radical, as defined here. Examples arylcarboxylic radicals include, but are not limited to, benzoyl, naphtol and the like.

"Arylalkylamines" (or "aralkylamines") means the radical R-C(O)-, where R is arylalkyl radical, as defined here. Examples arylalkyl-carbonyl radicals, vkluchau)-, where R is heteroaryl radical, as defined here. Examples heteroarylboronic radicals include, but are not limited to, pyridinyl, 3-methylisoxazole, isoxazolyl, thienoyl, furoyl and the like.

"Heterocalixarenes" (or "heterocyclicamines") means the radical R-C(O)-, where R is heterocyclyl radical, as defined here. Examples geterotsiklicheskikh radicals include, but are not limited to, piperazinyl, morpholinyl, pyrrolidinyl and the like.

"Cycloalkylcarbonyl" means the radical R-C(O)-, where R is cycloalkyl radical, as defined here. Examples cycloalkylcarbonyl radicals include, but are not limited to, cyclobutanol, Cyclopentanol, cyclohexanol and the like.

"Alkylaminocarbonyl" means the radical-C(O)NR'R" R' means the lower alkyl, as here established, and R" denotes hydrogen or lower alkyl, as installed here. Examples of alkylaminocarbonyl include, but are not limited to, methylaminomethyl, dimethylaminoethyl, tert-butylaminoethyl, n-butyl-aminocarbonyl, isopropylaminocarbonyl and the like.

"Arliamentary" means a radical of the radical-C(O)NR'R", where R&noncarbonyl include, but not limited to, phenyl-aminocarbonyl, methoxyphenylalanine, diphenylmethanone, dimethoxy-phenylenecarbonyl and the like.

"Heteroarylboronic" means a radical of the radical-C(O)NR'R" R' means heteroaryl, as here established, and R" denotes hydrogen or heteroaryl, as defined here. Examples of heteroarylboronic include, but are not limited to, pyridinylmethyl, tanyamiroshnik, furanyl-aminocarbonyl and the like.

"Alkylcarboxylic" means the radical-N-C(O)-R' R' means the lower alkyl as installed here. Examples of alkylcarboxylic include, but are not limited to, medicalbilling, isopropyl-carbonylation, tert-BUTYLCARBAMATE and the like.

"Arylcarboxamide" means the radical-N-C(O)-R' R' means aryl, as installed here. Examples of arylcarboxylic include, but are not limited to, phenylcarbonylamino, totalcorporationt and the like.

"Allylcarbamate" means the radical-O-C(O)-NR'R" R' means the lower alkyl, as here established, and R" denotes hydrogen or lower alkyl, as installed here. Primer">"Arylcarbamoyl" means the radical-O-C(O)-NR'R" R' means aryl, as defined here, and R" denotes hydrogen or aryl, as defined here, Examples of arylcarbamoyl include, but are not limited to, phenylcarbamoyl, naphthyl-carbarnoyl and the like.

"Arylalkylamines" means the radical-O-C(O)-other'R" R' means the lower alkyl as defined here, and R" means aryl, as defined here. Examples of arylalkylamine include, but are not limited to, benzyl-carbarnoyl, phenylethanol and the like.

"Alkylaminocarbonyl" means the radical-S(O)2-NR'R" R' means the lower alkyl, as here established, and R" denotes hydrogen or lower alkyl, as defined here. Examples alkylaminocarbonyl include, but are not limited to, methylaminomethyl, dimethylaminomethyl and the like.

"Arylamination" means the radical-S(O)2-NR'R" R' means aryl, as defined here, and R" denotes hydrogen or aryl, as defined here. Examples arylaminomethylene include, but are not limited to, phenylamino-sulfonyl, methoxybenzenesulfonyl and the like.

"Heteroarylboronic" means the radical-S(O)2-NR'R"is R. Examples heteroarylboronic include, but are not limited to, trilaminate, piperazineethanesulfonic, furanyl-aminosulfonyl, imidazolidinone and the like.

"Alkylsulfonamides" means the radical-N-S(O)2-R' R' means the lower alkyl as defined here. Examples of alkylsulfonamides include, but are not limited to, methylsulfonylamino, propyl-sulfonylamino and the like.

"Arylsulfonamides" means the radical-N-S(O)2-R' R' means aryl, as defined here. Examples of arylsulfonamides include, but are not limited to, phenylcarbonylamino, naphtylcontaining and the like.

"Alkylsulfonyl" means the radical-S(O)2-R, where R is lower alkyl or substituted lower alkyl, as installed here. Examples alkylsulfonyl include, but are not limited to, methylsulphonyl, trifloromethyl, propylsulfonyl and the like.

"Arylsulfonyl" means the radical-S(O)2-R, where R is aryl as installed here. Examples arylsulfonyl include, but are not limited to, phenyl-sulfonyl, nitrophenyloctyl, methoxyphenyl)2-R, where R is heteroaryl as installed here. Examples heteroarylboronic include, but are not limited to, thienylmethyl, furnisher, imidazolylalkyl, N-methylimidazolidine and the like.

"Heterocyclisation" means the radical-S(O)2-R, where R is a heterocyclic residue, as installed here. Examples heterocyclisation include, but are not limited to, piperidinylcarbonyl, piperazinylcarbonyl and the like.

"Alkylsulfonate" means the radical-O-S(O)2-R, where R is lower alkyl or substituted lower alkyl, as installed here. Examples of alkylsulfonates include, but are not limited to, methylsulphonyl-oxygraph, triftormetilfullerenov, propylsulfonyl and the like.

"Arylsulfonamides" means the radical-O-S(O)2-R, where R is aryl as installed here. Examples of arylsulfonate include, but are not limited to, benzolsulfonate, 4-chlorobenzenesulfonamide and the like.

"Heteroarylboronic" means the radical-O-S(O)2-R, where R is heteroaryl as installed here. Examples ASS="ptx2">"Geterotsiklicheskikh" means the radical-O-S(O)2-R, where R is a heterocyclic residue, as installed here. Examples heterocyclyl-sulfonyloxy include, but are not limited to, 3,5-dimethylisoxazol-sulfonyloxy, pyrrolidinylcarbonyl and the like.

"Optional" or "optionally" means that the described event or circumstance may not occur and that the description includes instances when the event or circumstance occurs and instances when this is not the case. For example, "optional link means that the link may be present and may not be present and that the description includes single, double or triple bond.

"Leaving group" means a group that has a value, usually associated with it in synthetic organic chemistry, that is, an atom or group that can be substituted in the conditions of alkylation. Examples of leaving groups include, but are not limited to, halogen, alkane - or arylsulfonic, as, for example, methanesulfonamido, econsultancy, thiomethyl, benzolsulfonate, tailorshop and taylortype, digalog-phosphineoxide, not samli "protecting group" means a group which selectively blocks one reactive center in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive center as it is usually associated with it in synthetic chemistry. Some methods of the present invention rely on the protective group for blocking reactive oxygen atoms present in reacts substances. Suitable protective groups for the alcoholic or phenolic hydroxyl groups, which may be sequentially and selectively removed, include groups that protect in the form of acetates, haloalkylthio, simple benzyl ethers, simple alkyl-cyrilovich ethers, simple heterocyclyl esters or simple methyl, or alilovic esters, and the like. Protective or blocking groups for carboxyl groups such as those described for hydroxyl groups, preferably the protection is realized with the formation of complex tert-butyl, benzyl or methyl esters. Examples of protective groups can be found in T. W. Green and others in Protective Groups in Organic Chemistry (J. Wiley, 2nd ed., 1991) and Harrison and others in the Compendium of Synthetic Organic Methods, volumes 1-8 (J. Wiley and Sons, 1971-1996).

"Deprotection" or "removing protection" means the process by which a protective group is removed after the selective reaction. Some of the protective group may be preferable over the other, thanks to the convenience or the relative ease of their removal. Removed protection reagents for protected hydroxyl or carboxyl groups include the carbonates of potassium or sodium, lithium hydroxide in alcohol solution, the zinc in methanol, acetic acid, triperoxonane acid, palladium catalysts or trichromacy boron, and the like.

"Isomerism" means compounds having the same molecular formula, but differ in the nature or sequence of light the x atoms in space, called "stereoisomers". Stereoisomers that are not mirror images of each other, are referred to as "diastereoisomers" and stereoisomers that are not swarnalakshmi mirror images are called enantiomers or sometimes optical isomers. Carbon atom associated with four different substituents, is called a "chiral center".

"Chiral isomer" means a compound with one chiral center. It is characterized by two enantiomers of opposite chirality, and it 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". The connection that has more than one chiral center, is 2n-1enantiomeric pairs, where n means the number of chiral centers. Compounds with more than one chiral center may exist or in the form of an individual diastereoisomer, or a mixture of diastereomers, called "diastereomeric mixture". When there is one chiral center, stereoisomer can be characterized by the absolute configuration (R or S) that hee with a chiral center. Deputies associated with this chiral center are classified in accordance with the Sequence Rule Cahn'a, Ingold'a and Prelog'and (Cahn and others, Angew. Chem. Inter. Edit. 1966, 5, 385; typos 511; Cahn and others, Angew. Chem.1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London). 612; Cahn and others, Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

The term "geometric isomers" means the diastereomers, which 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, which indicate that group in the molecule are located on the same or on different sides with respect to the double bond according to the rules of Cahn-Ingold-Prelog.

The term "atrophie isomers" refers to the isomers, owe their existence to a limited rotation due to restriction of rotation of large groups around a Central connection.

"Substantially pure" means that the compound is present 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.

"Pharmaceutically acceptable" means that which is useful for the preparation of pharmaceutical composition and includes, what is acceptable for pharmaceutical use in veterinary medicine, as well as for people.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable, as here described, 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, benzosulfimide, benzoic acid, camphorsulfonic, citric acid, econsultation, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic, lactic acid, maleic acid, malic acid, mandelic acid, methane-acid, Mukanova acid, 2-naphthalenesulfonate, propionic acid, salicylic acid, succinic acid, Dibenzoyl-L-tartaric acid, tartaric acid, p-toluensulfonate, trimethylhexane acid, triperoxonane acid and AI, either is replaced by a metal ion, for example, alkali metal ion, alkali earth metal ion or an aluminum ion, or forms a coordination bond with an 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.

You should assume that all references to pharmaceutically acceptable salts include the form with the accession of solvent (solvate) or crystal forms (polymorphs) as installed here, the same acid additive salt.

"Crystalline form" (or polymorphs) mean crystal structure, in which the substance can crystallize in different crystal packing, all of which have the same elemental composition. Different crystalline forms usually have different diffraction'hara the optical and electrical properties, stability and solubility. The solvent in the recrystallization, crystallization rate, storage temperature, and other factors may contribute to the dominance of one crystalline form.

"Solvate" means the form attached solvent, which contain either stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to capture a fixed molar ratio of the solvent molecules in the solid crystalline state, thus forming a MES. If water is the solvent, the resulting MES is a hydrate, when the solvent is alcohol, formed MES means alcoholate. Hydrates are formed by mixing one or more water molecules with one of the substances in which water is retained in the molecular state in the form of H2Oh, this combination is capable of forming one or more hydrates.

"Prodrug" means a pharmacologically inactive form of the connection, which must be metabolized by the subject in vivo, for example, with biological fluids or enzymes after administration of a pharmacologically active compound to produce the desired pharmacologists the Oia or in a particular place. Although the metabolism of many compounds occurs mainly in the liver, almost all other tissues and organs, especially the lung, is capable of various degrees of metabolism. Proletarienne forms of the compounds can be used, for example, to improve bioavailability, improve eligibility for the subject, as, for example, by masking or reducing undesirable 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 supported release or delivery, to improve the ease of preparation of the dosage form or provide site-specific delivery connection. Prodrugs describes Richard C. Silverman The Organic Chemistry of Drug Design and Drug Action, published by Academic Press, San Diego, 1992, Chapter 8: "Prodrugs and Drug delivery Systems", pages 352-401; Design of Prodrugs, edited by N. Bundgaard, published by Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs, ed E. C. Roche, American Pharmaceutical Association, Washington, 1977, and Drug Delivery Systems, edited by R. L. Juliano, published by Oxford Univ. Press, Oxford, 1980.

"Subject" means a mammal, and memleketim. Mammals mean any member of the class Mammalia, including, but not limited to the military animal, as, for example, cattle, horses, sheep, goats and pigs, 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 are not ogranichivayutsya them, birds and the like.

"Therapeutically effective amount" means an amount of compound that when administered to a subject to treat painful conditions sufficient to effect such treatment for the painful condition. "Therapeutically effective amount" will vary depending on the compounds and subjected to the treatment of painful conditions, from the severity undergoing treatment for the disease, the age and relative health of the subject, the route and form of administration, from the decision of the supervising practitioner or veterinarian, and other factors.

Used here, the term "pharmacological effect" covers the effects observed in the subject, which is achieved when conducted with the specific aim of the treatment. In one preferred variant of the invention, a pharmacological effect means that the primary symptoms at lichenologist to the prevention, relief or reduction of initial symptoms in the treated subject. In another preferred variant of the invention, a pharmacological effect means that disturbances or symptoms of primary readings have been subjected to treatment of the subject is prevented, alleviated or reduced. For example, the pharmacological effect is one that results in the prevention or reduction of the initial symptoms have been subjected to treatment of the subject.

"A painful condition" means any disease, condition, symptom or indication.

"Treating" or "treatment" of the disease condition includes:

(1) preventing the disease condition, that is, you need to ensure that the clinical symptoms of the disease condition did not develop the subject, which may be subjected to certain influence, or is prone to a painful condition, but had not experienced or has not manifested symptoms of painful conditions;

(2) the suppression of painful conditions, that is, inhibition of the development of a pathological state or its clinical symptoms, or

(3) relief of painful conditions, that is, the promotion time ILIT molecule, for example, substances, medicines, inhibitor of an enzyme or hormone, which reduces or prevents the action of another molecule or site of the receptor.

"Disorders of the urinary tract" or "uropathy", terms used interchangeably with "symptoms of urinary tract" means pathological changes in the urinary tract. Symptoms of urinary tract includes the bladder increased activity (also known as increased activity of the detrusor) syndrome infravesical obstruction, failure of expiration and increased pelvic sensitivity.

"The bladder increased activity or increased activity of the detrusor include, but are not limited to, changes symptomatically manifested as urgency of urination, frequency of urination, decreased bladder capacity, episodes of incontinence, and the like; changes shown urodynamically as changes in bladder capacity, threshold urination, unstable contractions of the bladder muscle spasms of the sphincter, and the like, and the symptoms usually manifested in detrusor hyperreflexia (neurogenic bladder), in the States, as, for example, the syndrome intravesically obstruc what I as, for example, the mobility of the detrusor, and the like.

"Syndrome infravesical obstruction" includes, but is not limited to, benign hypertrophy of the prostate (KIDDING) associated with urethral stenosis disease, cancer and similar diseases. He usually symptomatically manifested as impeding the passage (low speed expiration, difficulty in initiating urination and the like) or irritant (urgency of urination, suprapubic pain and similar symptoms).

"The failure of expiration" includes, but is not limited to this, urethral hypermobility, congenital sphincter insufficiency or incontinence mixed type. This is usually symptomatically manifested as urinary incontinence with tension.

"Increased pelvic sensitivity" includes, but is not limited to, pelvic pain, interstitial (cell) cystitis, prostadynia, prostatitis, vulvodynia, urethritis, testicular pain and the like. It is symptomatically manifested as pain, inflammation or discomfort related to the pelvic area, and usually includes symptoms of bladder increased activity.

Item: nasality, used in this application is based on AUTONOMTMcomputerized system Institute Beylshtein for the formation of the systematic IUPAC nomenclature. For example, the compound of formula I, where R1and R2mean metoxygroup, R3means propyl, R is 2, n is 3, m is 2, X and Y denote-CH2and Z denotes >NH, called: 4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he.

Among the compounds of the present invention, presented in the brief description of the invention, preferred are the compounds of formula I, or prodrugs, individual isomers, racemic or nerezisca mixture of isomers, or pharmaceutically acceptable salt or solvate.

R1and R2independently in each case means preferably hydrogen, halogen, (C1-C6)alkyl, alkoxygroup, alkylsulfonyl or alkylsulfonate group, and more preferably signify hydrogen, a methoxy group, methylsulphonyl or methylsulfonylamino.

R3means independently in each case, preferably lower alkyl, lower alkenyl or lower quinil, more preferably means ethyl, Priceline means hydrogen.

R means preferably a number from 1 to 3, more preferably from 1 to 2 and even more preferably 2.

m means preferably a number from 0 to 3, more preferably from 1 to

2 and even more preferably 2.

n means preferably a number from 1 to 6, more preferably from 1 to

3 and even more preferably 3.

One of X, Y or Z means independently in each case, preferably

-S-, -O - or >NR4most preferably >N-R4and even more

predpochtiteljno >NH.

Especially preferred compounds of General formula I, where R is 2. In another preferred embodiment of the invention R is 2, and one of X, Y or Z means >N-R4and the others are CH2-; in another embodiment of the invention p is 2, one X, Y or Z means >NR4and the others are CH2- where R4means hydrogen.

In another preferred embodiment of the invention p is 2 and m is 1. in another preferred embodiment of the invention p is 2, m is 1 and Y represents >N-R4and the other is-CH2-;

in one prepost is In another preferred embodiment of the invention R is 2, m is 1 and Z means >N-R4and the other is-CH2-; in another preferred embodiment of the invention p is 2, m is 1 and Z means >NH, a is-CH2-. An example of such compound is 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]-diazepan-5-he.

In another preferred embodiment of the invention p is 2 and m is 2; in another preferred embodiment of the invention p is 2, m is 2 and one of X, Y or Z means >N-R4and the other is-CH3- and in another preferred embodiment of the invention p is 2, m is 2 and one of X, Y or Z means >NH, and the other is-CH2-. In another preferred embodiment of the invention p is 2, m is 2 and X is >N-R4and the other is-CH2-.

In another preferred embodiment of the invention p is 2, m is 2 and Y represents >N-R4and the other is-CH2-. Examples of such compounds are:

1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he;

4-(2-dimethylaminoethanol)-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-propylen-2-it.

In another preferred embodiment of the invention p is 2, m is 2 and Z means >N-R4and the other is-CH2-; examples of such compounds are:

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethylisoxazol-4-sulfonic acids or

4-{5-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]pentyl}-[1,4]-diazepan-5-he.

In another preferred embodiment of the invention n is equal to 3, in another example embodiment of the invention n is equal to 3 and one of X, Y

or Z means >N-R4and the other is-CH2-.

In another example embodiment of the invention n is equal to 3 and p is 2, in another example embodiment of the invention n is 3, p is 2 and one of X, Y

or Z means >N-R4and the other is-CH2-; in another example embodiment of the invention n is 3, p is 2 and one of X, Y or Z means

>NH, and the other is-CH2-. In another preferred embodiment of the invention n is 3, p is 2, m is 2 and one of X, Y

or Z means >N-R4and the other is-CH2-; and in another preferred embodiment, Khujand is Cetelem embodiment of the invention n is equal to 3, p is 2, m is 2, Y represents >NH, and X and Z are CH2-. In another preferred embodiment of the invention n is 3, p is 2, m is 2, Z means >NH, and X and Y denote-CH2-.

In another preferred embodiment of the invention p is 2, m is 2, n means 3, one of X, Y or Z denotes-O-, and the other is-CH2-. The following are examples of such compounds are:

3-{4-[(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,3]oxazepan-2-he /

3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,3]oxazepan-2-it.

Other preferred compounds according to this invention include pharmaceutically acceptable salts of the compounds according to this invention, where the pharmaceutically acceptable salts formed from hydrochloric acid, 2,2,2-Cryptor-acetic acid, sodium salt Dibenzoyl-L-tartaric acid or phosphoric acid, more preferably salts formed from hydrochloric acid, 2,2,2-Cryptor-acetic acid.

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

Source materials and reagents, h Chemical Co., or synthesized using methods known to experts in this field, following the procedures set forth in references such as, for example, Fieser and Fieser, Reagents for Organic Synthesis, published by Wiley & Sons, new York, 1991, volumes 1-15; Rodd, Chemistry of Carbon Compounds, published by Elsevier Science Publishers, 1989, volumes 1-5 and Additions; and Organic Reactions, published by Wiley & Sons, new York, 1991, volumes 1-40. The following scheme of reactions of synthesis are only illustrate some of the ways which can be synthesized compounds of the present invention, and can be made various modifications to these schemes reactions of synthesis, and it is assumed that the experts in this field can reference the disclosure contained in this application.

Source materials and intermediate compounds of the schemes of synthesis reactions can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such substances may be characterized using conventional means, including physical constants and spectral data.

Unless otherwise specified herein described reaction is preferably run at atmospheric pressure within a temperature is about room temperature (or ambient temperature), for example, about 20°C.

Usually the compounds of formula I can be obtained by methods described in the following reaction schemes.

Scheme And

Scheme And, in General, describes a method of obtaining the compounds of formula I, where X, Y, Z, R1, R2, R3, R, m, and n are as described above.

The compound of the formula I can generally be obtained by the combination of carboxaldehyde 1 benzalkonium 2 under conditions of reductive amination. Suitable conditions for recovery include triacetoxyborohydride sodium, Lamborghini sodium, isopropoxide titanium and Lamborghini sodium, hydrogen and a metal catalyst and transferring hydrogen means, as, for example, cyclohexane, formic acid and its salts, zinc and hydrochloric acid, formic acid, or dimethyl sulfide boron followed by treatment with formic acid. Suitable 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 in basic conditions with triacetoxyborohydride sodium in 1,2-dichloroethane.

Methods of restoration amination described in hemicellulolytic sodium as a reagent for reductive amination of aldehydes using a wide variety of amines. For example, in J. Am. Chem. Soc. 1971, 93, 2897, in Org. Synth. Coll. 1988, 6, 499, describes how using Lamborghini sodium as a reagent for the reductive amination of carbonyl compounds.

Common educt for the scheme And are commercially available or known, or can easily be synthesized by an ordinary specialist in the field. For example, the source carboxaldehyde 1 can be easily synthesized, as shown in the following diagrams of reactions (1), (2) and (3).

Scheme (1)

Carboxaldehyde 1, where X, Y, Z, m and n are as described above, can be obtained by reaction of the amide group of the compound and alkylating agent of the formula L(CH2) nCH=CH2where L is a leaving group, such as halogen or methysulfonylmethane, preferably chlorine, in basic conditions with the formation of compound b.

After the alkylation reaction is followed by the oxidation/decomposition of the terminal alkinoos group of the compound b to the aldehyde group with the aim of obtaining carboxaldehyde 1. In the chemical literature describes various oxidizing agents used in the oxidation/cleavage of alkenes to aldehydes. For example, in J. Org. Chem. 1956, 21 the ways 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; in J. Org. Chem. 1987, 52, 2875, describes how, using (meta)periodate sodium and ruthenium as a catalyst. Preferably the reaction is carried out with the use of camerahouse osmium and (meta)periodate sodium or ozone.

Scheme (2)

Alternatively, carboxaldehyde 1, where X, Y, Z, m and n are as described above, can be obtained by reaction of the free amino compound and an alkylating agent of the formula L(CH2)nC(OR)2, where R is lower alkyl and L is a leaving group, such as halogen, preferably bromine, resulting in connection with. the reaction of alkylation followed by hydrolysis acetamino group connection in acidic conditions, leading to carboxaldehyde 1.

Scheme (3)

Alternatively, carboxaldehyde 1, where X, Y, Z, m and n are as described above, can be obtained by processing aminoacetate d, where R OSN 2)nCOL', or L(CH2)nOCOL', or L(CH2)nN=C=O, where in each case the L' is a leaving group, such as halogen, preferably chlorine, to obtain the compound that is the Reaction of acylation is accompanied by an internal N-alkylation of compounds e and subsequent hydrolysis acetamino group of compounds of f, leading to carboxaldehyde 1.

For example, the source benzonitrile 2 can be synthesized as shown in the following reaction scheme (4).

Scheme (4)

Benzonitrile 2, where R1, R2and R3are as described above, can be obtained by processing benzonitrile g primary amine of the formula R3NH2under conditions of reductive amination. In the chemical literature describes various methods for the synthesis of benzocyclobutene 2, for example, in J. Med. Chem. 1980, 23, 745-749; J. Med. Chem. 1981, 24, 429-434; J. Med. Chem. 1989, 32, 2128-2134; J. Org. chem. 1996, 61, 3849-3862, and in Bioorg. Med. Chem. Lett. 1997, 15, 1995-1998.

Scheme B

Scheme B, in particular, describes a method of obtaining the compounds of formula I, where X is >N-R4, -O - or-S -; each of Y and Z denotes-CH2and R1, R2, R3, R4, R, m, and n are as described above.

Examples of the compounds of formula IB shown in example 1.

Schema

The scheme, in particular, describes a method of obtaining the compounds of formula I, where X and Z denote each-CH2-, Y represents >N-R4, -O - or-S -, and R1, R2, R3, R4, R, m, and n are as described above.

Compounds of formula ICa, ICb or ICc can be obtained by methods described in scheme C.

Preferably the compound of formula I, where Y denotes-O - or-S-, can be obtained by the reaction of carboxaldehyde 1c with benzalkonium 2 under conditions of reductive amination, as described in scheme C.

Alternatively, the compound of formula I, where Y represents >N-R4can also be obtained by the combination of a protected nitrogen atom of carboxaldehyde 1d, where P is an appropriate protecting group for nitrogen, with benzalkonium 2 under the conditions described above. This reaction is accompanied by removal of the nitrogen protecting group of compound 3 in acidic conditions to obtain the compounds of formula Za, where Y is >NH. The compound of formula I, where Y represents the >NH, may be further subjected to a reaction with a suitable alkylating agent,organisations formula ICb, where Y represents >N-R4where R4is not hydrogen.

Examples of the compounds of formula ICa, ICb or ICC are given in examples 2, 3 and 4.

Scheme G

Scheme G describes, in particular, the method of obtaining the compounds of formula I, where X and Y denote each-CH2and Z denotes >N-R4, -O - or-S-, and R1, R2, R3, R4, R, m, and n are as described above.

Compounds of the formula IDa, IDb and IDc can be obtained as described in scheme G.

Preferably the compound of formula IDc, where Z denotes-O - or-S-, can be obtained by reaction of carboxaldehyde 1E with benzalkonium 2 under the conditions described in scheme,

Alternatively, the compound of formula I, where Z denotes >N-R4can be obtained by the combination of the protected nitrogen carboxaldehyde 1f, where f denotes a suitable nitrogen protecting group, with benzalkonium 2, as described above. This reaction is accompanied by removal of the protective group at the nitrogen compound 4 in acidic conditions and obtaining the compounds of formula IDa, where Z denotes >NH. Optional connection of the formula IDa may then be subjected to reaction with a suitable alkylating agent, atsiliruyuscimi IDb, where Z denotes >NR4where R4is not hydrogen.

Examples of the compounds of the formula IDa, IDb and IDc are shown in examples 5, 6 and 7.

Compounds of the present invention are antagonists of muscarinic receptors. Compounds acting as antagonists of muscarinic receptors have been applied for the treatment of severe painful conditions associated with improper functioning of the smooth muscles. Until recently, most of these compounds were selective for the different subtypes of muscarinic receptors, leading to unpleasant anticholinergic side effects, such as dry mouth, constipation, blurred vision, or tachycardia, the most common of which is dry mouth, which occurs as a result of the blockade of muscarinic receptors in the salivary gland. It was shown that the newly developed specific antagonists M2 or M3 showed a weakened side effects. The data obtained indicate that mechanically simultaneous blockade of receptors M2 and M3 over the M5 receptor could be therapeutically effective in the treatment of painful conditions associated with disorders of smooth muscle, such as violations of makepolo the ptx2">Violations of the urinary tract that can be treated using compounds according to this invention specifically include the bladder increased activity or increased activity of the detrusor and its symptoms, such as changes symptomatically manifested as urgency of urination, frequency of urination, decreased bladder capacity, episodes of incontinence, and the like;

changes shown urodynamically as changes in bladder capacity, threshold urination, unstable contractions of the bladder muscle spasms of the sphincter, and the like, and the symptoms usually manifested in detrusor hyperreflexia (neurogenic bladder), in the States, as, for example, the syndrome infravesical obstruction, failure of expiration, increased pelvic sensitivity, or in conditions of unknown origin, as, for example, the mobility of the detrusor, and the like.

Disorders of the gastrointestinal tract, can be subjected to treatment by the compounds according to the invention include irritable bowel syndrome, a disease related to the diverticulum, achalasia, disorders of gastrointestinal hyperkinesia and diarrhea. Violations onicescu obstructive pulmonary disease, asthma and pneumosclerosis.

These and other therapeutic applications are described, for example, in Goodman & Gilman, The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, new York 1996, Chapter 6, 601-616, and Coleman, R. A., Pharmacological Reviews 1994, 46, 205-229.

The affinity of these compounds to muscarinic receptors can be identified in the analysis of receptor binding in vitro, which uses the product of the cell membrane of cancer cells Chinese hamster expressing recombinant human muscarinic receptors (M1-M5), and further described in example 15.

The properties of the investigated compounds as muscarinic antagonists can be identified in the experiment in vivo, which determines inhibitory activity against mediated muscarinic receptor secretion of saliva have been subjected to the influence of narcosis in rats, described in more detail on the model induced oxotremorine/pilocarpine salivation (OIS/PIS) in rats exposed to anesthesia, example 16.

The properties of the investigated compounds as muscarinic antagonists can be identified in the analysis in vivo, which determines inhibitory activity against mediated muscarinic receptor sacramentary volume reductions, example 17.

The properties of the investigated compounds as muscarinic antagonists can be identified in the experiment in vivo, which determines inhibitory activity against mediated muscarinic receptor contraction of the bladder and the secretion of saliva from exposed to anesthesia dogs, this is described in more detail in example 18.

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

Usually the compounds according to this invention is administered in a therapeutically effective amount of any of the accepted methods of introduction for funds with a similar application. Suitable dose ranges are usually 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily depending on many factors, such as severity at treatment zabolevaniya, the indication for which it is intended the introduction, and the preference and experience of participating in the study physician. Normal versed in the treatment of such diseases specialist will be able without undue experimentation, relying on their own knowledge and the disclosure of this application, to install a therapeutically effective amount of the compounds of the present invention for this disease. Usually the compounds according to the present invention is administered in the form of finished pharmaceutical forms, including those suitable for oral (including buccal and sublingual), rectal, nasal, local, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred method of administration is generally oral, using a suitable daily dose mode, which can be set in accordance with the severity of the disease.

The compound or compounds of the present invention together with one or more conventional adjuvants, carriers or diluents can be placed in the doses can comprise conventional ingredients in conventional proportions, with or without additional active compounds or components, and shape as a standard doses may contain any suitable effective amount of the active ingredient, comparable with the value intended for use as a daily dose. The pharmaceutical compositions can be applied in the form of solid dosage forms, such as tablets or filled capsules, semi-solid forms, powders, finished dosage forms with a supported release, or in the form of 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 sterile injectable solutions for parenteral use. Finished dosage forms containing about 1 mg of active ingredient or, more broadly, from about 0.01 to about (100) milligrams per tablet, are accordingly suitable examples of forms with the standard dose.

Of the compounds of the present invention can be prepared dosage forms in the form of a large variety of dosage forms for oral administration. Pharmaceutical compositions and dosage forms may include the compound or compounds according to the present image is ositelu can be either solid, or liquid. Solid finished dosage forms include powders, tablets, pills, capsules, starch wafers, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, giving the fragrance means soljubilizatory, lubricants, suspendresume tools, binders, preservatives, means for raspadaemosti tablets or material for wrapping. In powders, the carrier is usually finely ground solids, mixed with finely ground active ingredient. In tablets, the active ingredient is usually mixed with a carrier with the necessary binding capacity in suitable proportions and pressed into a desired shape and size. The powders and tablets preferably contain from about one (1) to seventy (70) percent of the active compounds. Suitable carrier materials include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragant, methylcellulose, sodium carboxymethyl-cellulose, viscoplastic wax, cocoa butter and the like. Assume that the term "drug" includes ready Fortuny component carriers or without them, is surrounded by media who associated with him. Similarly includes starch wafers and cakes. Tablets, powders, capsules, starch wafers and cakes can be suitable as solid dosage forms for oral administration.

Other forms suitable for oral administration include liquid finished dosage forms, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid finished dosage forms that shortly before use, turn them into finished liquid dosage forms. Emulsions can be prepared in solutions, for example, in solutions of aqueous propylene glycol, or may contain emulsifying agents, such as lecithin, complex monoether of anhydromannitol and oleic acid or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing means and thickeners. Aqueous suspensions can be prepared in dispersion of micronized active component in water with viscous substance, such as, for example, natural or synthetic resinous substances, resins, methylcellulose, sodium carboxymethylcellulose and friends and emulsions can contain, in addition to the active component, colorants, flavorings, stabilizers, buffers, unnatural and natural sweeteners, dispersing agents, thickeners, solubilizing means and the like.

Compounds of the present invention can be prepared in dosage forms for parenteral administration (e.g. by injection, for example, by injection loading dose of a substance, or by continuous infusion) and may be presented in the form of standard doses in ampoules, pre-filled syringes, containers for small volume infusion or in containers with large doses of added preservative. The composition may submit such forms as suspensions, solutions or emulsions in oily or aqueous solvents, for example, a solution 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 complex organic esters (for example, etiloleat), and may include facilities for the preparation of ready-made forms, such as preserving, moisturizing, emulsifying or suspendida, stabilizing and/or dispersing setsticky conditions of sterile solid or by lyophilization from solution, for mixing before use with a suitable filler, for example, sterile pyrogen-free water.

Compounds of the present invention can be prepared in dosage forms for topical application to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be prepared in an aqueous or oily base with the addition of suitable thickening agents and/or contributing to the gel means. Lotions can be prepared in water or oil based and usually also contain one or more emulsifying means, stabilizing means, dispersing funds, suspendida agents, thickeners or dyes. Finished dosage forms suitable for topical application in the mouth include pellet, consisting of active substances in a flavored basis, usually sucrose and acacia or tragana; lozenges comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia, and liquid for rinsing the mouth, consisting of an active ingredient in a suitable liquid carrier.

Of the compounds of the present invention can be prepared latestgeneration fatty acids or cocoa butter, and homogeneous dispersed active component, for example, with stirring. The molten homogeneous mixture is then poured into molds to normal size, the mixture is allowed to cool and harden.

Of the compounds of the present invention can be prepared dosage forms for nasal application. The solution or suspension is injected directly into the nasal cavity using conventional methods, for example, a dropper, pipette or spray. Finished dosage forms can be represented in a form with a single dose or multiple doses. In the latter case, when using a dropper or pipette, the patient is administered an appropriate, pre-determined amount of solution or suspension. In the case of aerosol introduction can be carried out, for example, using the dosing grinding spray pump.

Of the compounds of the present invention can be prepared dosage forms for aerosol administration, particularly in the respiratory tract and including intranasal administration. The connection typically has particles of small size, for example, about five (5) microns or less. This particle size can be obtained using known in the field of methods, such as the nd package with a suitable gas displacer, as, for example, chlorofluorocarbon (CFC), for example, DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Aerosol can usually also contain a surfactant, such as lecithin. Medication dose may be regulated by a metering valve. Alternatively, the active ingredients can be represented in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base, such as, for example, lactose, starch, starch derivatives, for example, hydroxypropylmethyl-cellulose and polyvinylpyrrolidine (PVP). Powdered media forms a gel in the nasal cavity. Powder composition may be presented in the form of a single dose, for example, capsules or ampoules of, for example, gelatin or blister packs from which the powder may be entered using the inhaler.

Of the compounds of this invention can be prepared dosage forms for percutaneous or subcutaneous delivery of drugs. These delivery systems are useful when you need a supported release of the connection and when that patient mode and a treatment regimen is crucial. Connection vresse connection can also be combined with an activator penetration, for example, Azone (1-dodecyl-azacycloheptan-2-one). Delivery system with a supported release are inserted subcutaneously into the subcutaneous layer surgically or by injection. Subcutaneous implants encapsulate the connection soluble in the lipid membrane, for example, silicone rubber or biodegradable polymer, for example, polylactic acid.

The pharmaceutical preparations are preferably in the forms with the standard dose. In such form the preparation is subdivided into standard doses containing appropriate quantities of the active component. Containing the standard dose form may represent the product in the package containing discrete quantities of preparation, such as, for example, wrapped in packages, tablets, capsules, and powders in vials or ampoules. The form with the standard dose may itself present a capsule, tablet, starch wafer or wafer, or in a package can be the appropriate number of any of these forms.

Other suitable pharmaceutical carriers and finished dosage forms with them are described in Remington, The Science and Practice of Pharmacy, 1995, editor E. W. Martin, published by Mack Publishing Company, 19th-oe edition, Easton, Pennsylvania. Samples pharmaceutical

The following experiments to obtain and examples are provided in order to allow experts to better understand and implement the present invention. These experiments and examples should not be considered limiting the scope of the invention, but only to illustrate and create the idea of the invention.

Experience 1 (obtaining the compounds of formula 1)

4-(5-Oxo-[1,4]oxazepan-4-yl)butyric aldehyde

To a stirred suspension of sodium hydride (0.9 g, 37.5 mmol) in dimethylformamide (50 ml) was added 1,4-oxazepan-2-he (30 mmol). The mixture was stirred at room temperature for 15 minutes and 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 minutes, and then 16 hours at 80°C. the Solvent was removed in vacuo and to the residue was added water. The mixture was extracted with diethyl ether, the organic phase is washed with water, dried (magnesium sulfate) and concentrated, received 1-Penta-4-relaxation-2-he (5.5 g) in the form of oil.

Were added cityregional osmium (17 mg, 0.07 mmole) for 1-Penta-4-relaxation-2-ONU (5.5 g, 28.3 mmol) in a mixture of tetrahydrofuran (100 ml) and water (50 ml) under cooling in a water bath with the pace of the sodium (15,11 g, 70,65 mmol). The reaction mixture was stirred for 3 hours and filtered. The filtrate was concentrated, saturated with solid sodium chloride and was extracted with methylene chloride. The organic phase was dried (magnesium sulfate) and concentrated. Purification via chromatography on silica gel with elution by chloroform led to 4-(2-oxoacetate-1-yl)oil aldehyde (4.6 g).

Similarly, following the method described above, but optionally replacing 1,4-oxazepan-2-he other appropriate compounds of formula a and optionally replacing 5-bromo-1-penten other suitable alkylating means of the formula L(CH2)nCH=CH2where L is a leaving group, such as halogen, and applying well-known experts in this field modifications received additional compounds of formula 1, for example, 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 what the temperature. To the resulting solution were added dimethylacetal 4-bromacleanse aldehyde (0,99 g, 5 mmol). After stirring the reaction mixture for 16 hours at room temperature 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 and the suspension was filtered, and the filtrate was concentrated. Purification via chromatography on silica gel with elution with 2% methanol in chloroform led to tert-butyl ether, 4-(4,4-dimethoxymethyl)-5-oxo-[1,4]diazepan-1-carboxylic acid (0.8 g) as a viscous syrup. NMR: (CDCl3, M. D.) 1,49, s (N); 2,64, m (3H); 3,32, s (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 mmol) in glacial acetic acid containing 0.5 ml of water (10 ml) was stirred at room temperature for 24 hours. 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 diethyl ether/hexane, got tert-b is an alternative obtaining the compounds of formula 1)

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

It is cooled to the temperature of the ice to a solution of 1.93 M 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 hours.

The mixture was filtered and the filtrate was concentrated. The residue was treated with ethyl acetate, filtered and the solution was added dropwise to a cooled to the temperature of the frozen solution diethylacetal 4-amino aldehyde (7,09 g, 44 mol) and triethylamine (4,45 g, 44 mmole) in ethyl acetate (60 ml). The reaction mixture was stirred 15 hours at room temperature, filtered and concentrated. Purification via chromatography on silica gel with elution with 10% ethyl acetate in hexane resulted in 5-hlorfenilovogo 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 fat-free sodium hydride (1.01 g, of 42.3 mmole). The reaction mixture was stirred 15 hours at room temperature and then for 3 hours at 70°C. the Mixture was diluted with water, probably the Ali water, was dried (magnesium sulfate) and concentrated. After purification by chromatography on silica gel was obtained 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 mmol) and 1.5 g of ion-exchange resin Dowex 50W2-200 in 3% aqueous tetrahydrofuran (30 ml) was boiled under reflux for 24 hours. The mixture was filtered and the filtrate was concentrated and dissolved in dichloromethane. The solution was dried over magnesium sulfate and concentrated, received 4-(2-oxo-[1,3]oxazolin-3-yl)butyric aldehyde (1.45 g) as a viscous oil, which was hardened.

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

To a stirred and cooled to the temperature of the frozen solution 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 hours. The mixture was concentrated and dissolved in N,N-dimethylformamide (40 ml). To this solution was added subjected to obespylivaniju sodium hydride (0.96 g, 40 mmol). The reaction mixture was stirred 18 hours at 70°C, concentrated, mixed with diethyl ether (40 ml) and filtered what ethanol (10:9,7:0,3), received 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 1.0 g of ion-exchange resin Dowex 50W2-200 in 3% aqueous tetrahydrofuran (30 ml) was boiled under reflux for 24 hours. The mixture was filtered, the filtrate was concentrated and the residue was dissolved in dichloromethane (30 ml), dried with magnesium sulfate and concentrated, was obtained 3-(2-oxotetrahydrothalifendine-1-yl)-propionic aldehyde (0,46 g).

Experience 3 (obtaining the compounds of formula 2)

(R1, R2=H, R3=propyl, R=2)

Propyl(1,2,3,4-tetrahydronaphthalen-2-yl)Amin

To a solution of 3,4-dihydro-1-H-naphthalene-2-it (5 g, 34 mmole) in 1,2-dichloroethane (250 ml) was added Propylamine (2.8 ml, 34 mmole), and then triacetoxyborohydride sodium (22 g, 102 mmole). The reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 24 hours, concentrated in vacuum. The remaining solid residue was distributed between 1M sodium hydroxide and ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate and filtered. The filtrate was acidified using 1M hydrochloric acid in ether and collected 6.3 g propyl(1,2,3,4-tetrahydronaphthalen-2-yl)amine scheme B)

3-{4-[(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,3]oxazine-2-he (19)

To a solution of 7-methoxy-3,4-dihydro-1-H-naphthalene-2-she (5.0 g, of 28.4 mmole) and Propylamine (2.8 ml, 34 mmole, 1.2 EQ.) in 1,2-dichloroethane (150 ml) in an atmosphere of inert gas was added at once triacetoxyborohydride sodium (15 g, 71 mmol, 2.5 EQ.). The reaction was stirred at room temperature for 20 hours, then concentrated in vacuo. The residue was distributed between 10% aqueous potassium hydroxide (150 ml) and ethyl acetate (75 ml). The organic layer was washed with brine, dried and concentrated. The resulting substance was dissolved in diethyl ether (100 ml) and was treated with 1M Hcl in ether (28.4 ml). The solid residue was collected and dried in vacuum, received 6,23 g (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine in the form of a hydrochloric salt.

To (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine (about 13 mg, 50 mcmole) was added 440 μl solution of 4-(2-oxo-[1,3]oxazine-3-yl)butyric aldehyde (0.125 M in 1,2-dichloroethane), 30 μl of diisopropylethylamine (DIEA) and 300 μl of 0.25 M suspension triacetoxyborohydride sodium in 1,2-dichloroethane. The reaction mixture was shaken at room temperature for 48 hours. After dilution with 2 ml of onicescu phase was washed, was dried and concentrated. Purification by chromatography gave 3-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-yl)propylamino]butyl}-[1,3]oxazine-2-ONU 19, Mass spectrum (MS): 375 ([M+H]+).

Similarly, following the method described above, but optionally replacing 4-(2-oxo-[1,3]oxazine-3-yl)butyric aldehyde with other appropriate compounds of formula 1b, and optionally replacing (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-Propylamine with other appropriate compounds of formula 2, and utilizing modifications known to specialists in this field were obtained additional compounds of formula I where X is-O-, in the form of salts with triperoxonane acid:

3-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,3]oxazepan-2-20, MS: 389 ([M+H]+);

3-{4-[(6,7-dimethoxy-1,2,3,4-tetr Aeronavale-2-yl)propylamino]butyl}-[1,3]oxazepan-2-he's 28, MS: 419 ([M+H]+);

3-{4-[(6,7-dimethoxy-1,2,3,4-tetr Aeronavale-2-yl)propylamino]butyl}-[1,3]oxazine-2-he's 29, MS: 405 ([M+H]+);

3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalene-2-yl)propylamino]butyl}-[1,3]oxazolin-2-31 he, MS: 403 ([M+H]+);

3-{4-[(5,7-debtor-1,2,3,4-tetr Aeronavale-2-yl)propylamino]butyl}-[1,3]oxazine-2 he 57, MS: 381 ([MM+N]+);

3-{4-[(5,7-debtor-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl}-[1,3]oxazolin-2-he 60, MS: 409 ([M+H]+);

3-{4-[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,3]oxazepan-2-he 69, MS: 404 ([M+H]+);

3-{4-[(7-nitro-1,2,3,4-tetr Aeronavale-2-yl)propylamino]butyl}-[1,3]oxazine-2-he's 70, MS: 390 ([M+H]+);

3-{4-[(7-ethoxy-1,2,3,4-tetr Aeronavale-2-yl)propylamino]butyl}-[1,3]oxazine-2-he 118, MS: 389 ([M+H]+);

3-{4-[(6-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,3]oxazepan-2-he 145, MS: 403 ([M+H]+);

3-{4-[(6-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,3]oxazine-2-he 147, MS: 389 ([M+H]+);

3-{4-[(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl} -[1,3]oxazine-2-he 161, MS: 425 ([M+H]+);

3-{4-[(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl} -[1,3]oxazepan-2-he 162, MS: 439 ([M+H]+or

3-{4-[(6,7-dimethoxy-1,2,3,4-tetr Aeronavale-2-yl)propylamino]butyl}-[1,3]oxazepan-2-he 174, MS: 419 ([M+H]+).

EXAMPLE 2

(Obtaining the compounds of formula Za, as described in the diagram)

1-{4-[(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he (3)

To (500 mg, 2 mmole, 1 EQ.), triethylamine (0.3 ml, 2.2 mmole, 1.1 EQ.) in 1,2-dichloroethane (20 ml) in an atmosphere of inert gas was added tert-butyl ester 3-oxo-4-(4-oxobutyl)-[1,4]diazepan-1-carboxylic acid (550 mg, 2 mmole, 1 EQ.) in one portion, and then triacetoxyborohydride sodium (650 mg, 3 mmole, 1.5 EQ.). The reaction mixture was stirred at room temperature for 20 hours, concentrated in vacuo and then distributed between 10% KOH (40 ml) and ethyl acetate (75 ml). The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Purification using chromatography led to 858 mg tert-butyl ester 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-3-oxo-[1,4]diazepan-1-carboxylic acid.

To a solution of tert-butyl ester 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-3-oxo-[1,4]diazepan-1-carboxylic acid (858 mg, of 1.64 mmole) in methylene chloride (25 ml) was added at once triperoxonane acid (5 ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture is evaporated to dryness in vacuo, dissolved in water and treated with a 15% aqueous solution of potassium hydroxide. The solution was extracted with ethyl acetate, washed with brine, dried over) and was treated with 1M HCl/ether (3.4 ml). The solid is collected and dried in vacuum, received the product 3 in the form of a dihydrochloride (767 mg, yield 98%), MS:374 ([M+H]+.

Similarly, following the procedures described above, but optionally substituting tert-butyl ester 3-oxo-4-(4-oxobutyl)-[1,4]diazepan-1-carboxylic acid with other appropriate compounds of formula 1d, and optionally replacing (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine appropriate compounds of formula 2, and applying well-known experts in this field modifications were obtained additional compounds of formula I, where Y represents the >NH:

1-{4-[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl}-[1,4]diazepan-2-it 1, MS: 388 ([M+H]+);

1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}piperazine-2-12, MS: 374 ([M+H]+);

1-{4-[ethyl(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he's 15, MS: 374 ([M+H]+);

1-{3-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]propyl}-[1,4]diazepan-2-he's 23, MS: 374 ([M+H]+);

1-{4-[(7-methanesulfonyl-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he's 25, MS: 418 ([M+H]+);

1-{4-[(7-isopropoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylene]butyl}piperazine-2-he is 54, MS: 480 ([M+H]+);

1-{4-[(5,7-debtor-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he is 63, MS: 394 ([M+H]+);

1-{4-[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he's 72, MS: 403 ([M+H]+);

1-{3-[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] propyl}-[1,4]diazepan-2-he is 74, MS: 389 ([M+H]+);

1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}piperazine-2-he 89, MS: 374 ([M+H]+);

1-{4-[(R)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he's 92, MS: 388 ([M+H]+);

1-{4-[(8)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he 93, MS: 388 ([M+H]+);

1-{4-[(7-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl} piperazine-2-he 111, MS: 388 ([M+H]+);

1-{4-[(7-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he 112, MS: 402 ([M+H]+);

1-{4-[(6-isopropoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}piperazine-2-he 114, MS: 402 ([M+H]+);

1-{4-[(6-ethoxy - 1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl }piperazine-2-he 148, MS: 388 ([M+H]+);

1-{5-[(6,7-dimethoxy-1,2,3,4-tetr Aeronavale-2-yl)propylamino]pentyl}-piperazine-2-about the an-2-he 155, MS: 432 ([M+H]+);

1-{4-[(6,7-dimethoxy-1,2,3,4-tetr Aeronavale-2-yl)propylamino]butyl}-[1,4]diazepan-2-he 156, MS: 418 ([M+H]+);

1-{4-[(6,7-dimethoxy-1,2,3,4-tetr Aeronavale-2-yl)propylamino]butyl}-piperazine-2-he 166, MS: 404 ([M+H]+);

1-{4-[(7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he 171, MS: 436 ([M+H]+).

EXAMPLE 3

(Alternative obtaining the compounds of formula ICb, as described in the diagram)

4-(2-Dimethylaminoethanol)-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he (64)

The hydrochloride (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine (150 mg, 0.3 mmole) and triethylamine (0.2 ml, 1.3 mmole) in methylene chloride (10 ml) was added in an atmosphere of inert gas 2-chloroethanesulfonate one (0.03 ml, 0.3 mmole). The reaction mixture was allowed to mix at room temperature for 1 hour and mixed with 2% sodium carbonate. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuum, received 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-3-oxo-[1,4]diazepan-1-sulphonylchloride in the form of a yellow oil.

To 4-{4-[(7-methoxy-1,2,3,4-Tetra the La) in methylene chloride (15 ml) was added in an atmosphere of inert gas dimethylamine in the form of a 2M solution in THF (0.17 ml, 0,34 mmole). The reaction mixture was allowed to mix at room temperature for 20 hours, then concentrated in vacuo. The remaining oil was purified on silica gel, received a clear oil, which was dissolved in diethyl ether (10 ml) and was treated with 1M Hcl in ether. The solid residue was collected and dried in vacuum, received 4-(2-dimethyl-aminoethanesulfonic)-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4] diazepan-2-it is in the form of hydrochloride (83 mg) 64, MS: 523 ([M+H]+).

Similarly, following the method described above, but optionally replacing 1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-he other compounds of formula S with a free amino group, and optionally replacing 2-chloroethanesulfonate other appropriate allerease, alkylating or sulfanilimide means, and applying well-known experts in this field modifications received additional compounds of formula ICb, where Y represents >N-R4:

4-(2-dimethylaminoethanol)-1-{4-[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-it 2, MS: 523 ([M+H]+);

4-(4-perbenzoic)-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)impregnated ronfalin-2-yl)propylamino]butyl}piperazine-2-he 122, MS: 458 ([M+H]+);

4-isobutyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-piperazine-2-he 123, MS: 444 ([M+H]+);

1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-4-(thiophene-2-carbonyl)piperazine-2-he 124, MS: 484 ([M+H]+);

diethylamid 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-3-oxopiperidin-1-carboxylic acid 125, MS: 473 ([M+H]+);

dimethylamide 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-3-oxopiperidin-1-carboxylic acid 126, MS: 445 ([M+H]+);

4-acetyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-piperazine-2-he 127, MS: 416 ([M+H]+);

4-(3,5-dimethylisoxazol-4-carbonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}piperazine-2-he 128, MS: 497 ([M+H]+);

1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-4-(thiophene-2-sulfonyl)piperazine-2-he 129, MS: 520 ([M+H]+);

1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl}-4-triftormetilfullerenov-2-he 130, MS: 506 ([M+H]+);

4-benzazolyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino-butyl}piperazine-2-he 131, MS: 514 ([M+H]+);

phenylamide 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-3-oxopiperidin-1-carboxylic acid 133, MS: 493 ([M+H]+);

tert-butylamide 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]-butyl}-3-oxopiperidin-1-carboxylic acid 134, MS: 473 ([M+H]+);

methylamide 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-3-oxopiperidin-1-carboxylic acid 135, MS: 431 ([M+H]+);

1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-4-thiophene-2-iletileri-2-he 136, MS: 470 ([M+H]+);

4-ethyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine]butyl}-piperazine-2-he 137, MS: 470 ([M+H]+);

4-(1-methanesulfonamido-4-ylmethyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-yl)propylamino]butyl}piperazine-2-he 138, MS: 549 ([M+H]+or

4-methanesulfonyl-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]-butyl}piperazine-2-he 139, MS: 452 ([M+H]+).

EXAMPLE 4

(Obtaining the compounds of formula ICC, as described in the diagram)

4-{4-[(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl}-[1,4]oxazepan-3-one (17)

To (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-PII)butyric aldehyde (0.125 M in 1,2-dichloroethane), 30 μl aminobutiramida-ethylamine (DIEA) and 300 μl of 0.25 M suspension triacetoxyborohydride sodium in 1,2-dichloroethane. The reaction mixture was shaken at room temperature for 48 hours. After dilution with 2 ml of 2% sodium hydroxide, the reaction mixture is passed together with 0.5 ml of water and ethyl acetate in a flask for processing. The organic phase is washed, dried and concentrated. Purification by chromatography gave 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]oxazepan-3-ONU 17, MS: 389([M+H]+).

Similarly, following the method described above, but optionally replacing 4-(2-oxo-[1,4]oxazepan-4-yl)butyric aldehyde with other appropriate compounds of formula 1C, and optionally replacing (7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-yl)Propylamine with other appropriate compounds of formula 2, and applying well-known experts in this field modifications were obtained additional compounds of formula ICC, where Y represents-O-:

4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]oxazepan-5-he's 27, MS: 419 ([M+H]+);

4-{4-[(5,7-debtor-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl}-[1,4]oxazepan-3-one 55, MS: 395 ([M+H]+);

1-{4-[(7-methoxy-1,2,3,4-tetrahydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]oxazepan-3-one 144, MS: 403 ([M+H]+).

EXAMPLE 5

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

4-{4-[(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he (5)

To a solution of (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine obtained as described in example 1 (800 mg, 3.3 mmole, 1 EQ.) in 1,2-dichloroethane (40 ml), was added in an atmosphere of inert gas in the form of one portion tert-butyl ester 5-oxo-4-(4-oxobutyl)-[1,4]diazepan-1-carboxylic acid (1.0 g, 3.6 mmole, 1.1 EQ.), and then triacetoxyborohydride sodium (1.7 g, of 8.25 mmole, 2.5 EQ.). The reaction mixture was stirred at room temperature for 20 hours, concentrated in vacuo and then distributed between 10% potassium hydroxide (50 ml) and ethyl acetate (100 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated. Purification via chromatography on silica gel resulted in 1.1 g of tert-butyl ester 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-5-oxo-[1,4]diazepan-1-carboxylic acid.

To tert-butyl ether 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-propylamino]butyl}-5-oxo-[1,4]diazepan-1-carboxylic acid (800 mg, of 1.64 mmole) in methylene chloride (15 ml) premavatar within 30 minutes. The mixture is evaporated to dryness in vacuo, dissolved in water (40 ml) and was treated with 15% aqueous solution of potassium hydroxide (20 ml). The solution was extracted with ethyl acetate, washed with brine, dried (magnesium sulfate) and concentrated in vacuum. The free base (636 mg, of 1.64 mmole) was dissolved in diethyl ether (30 ml) and was treated with 1M Hcl in diethyl ether (3.3 ml). The solid precipitate was collected and dried in vacuum, received 732 mg of 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-5 in the form of dichlorhydrate, MS: 374 ([M+H]+).

Similarly, following the method described above, but optionally substituting tert-butyl ester 5-oxo-4-(4-oxobutyl)-[1,4]diazepan-1-carboxylic acid with other appropriate compounds of formula 1f, and optionally replacing (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine with other appropriate compounds of formula 2, and applying well-known experts in this field modifications were obtained additional compounds of formula IDa, where Z denotes >NH:

4-{4-[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-4, MS:388([M+H]+);

N-(2-{ethyl[4-(7-oxo-[1,4]diazepan-1-yl)butyl]amino} indan-5-yl)-4-methanesulfonyl-benzo)-[1,4]diazepan-5-he 8, MS: 505 ([M+H]+);

4-{4-[ethyl-(5-methoxyindol-2-yl)amino]butyl}-[1,4]diazepan-5-he 9, MS:360 ([M+H]+);

4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he 10, MS:418([M+H]+);

4-[4-(atiendan-2-ylamino]butyl]-[1,4]diazepan-5-he 11, MS: 330 ([M+H]+);

1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}piperazine-2-he 13, MS: 374 ([M+H]+);

4-{4-[ethyl(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]butyl}-[1,4]diazepan-5-he's 16, MS: 374 ([M+H]+);

4-{4-[(7-isopropoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he's 22, MS: 416 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt broadcast methansulfonate 38, MS: 452 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt broadcast econsultancy 39, MS: 466 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether propane-1-sulfonic 40, MS: 480 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether propane-2-sulfonic 41, MS: 480 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan>);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt broadcast benzosulfimide 43, MS: 514 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ester thiophene-2-sulfonic 44, MS: 520 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt broadcast phenylmethanesulfonyl 45, MS: 528 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethylisoxazol-4-sulfonic 46, MS: 533 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether 4-methoxybenzenesulfonamide 47, MS: 544 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether 4-chlorobenzenesulfonate 48, MS: 548 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether 3-chlorobenzenesulfonate 50, MS: 548 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether dimethylsulfonium acid 51, MS: 481 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5P-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl}-[1,4]diazepan-5-he's 61, MS: 494 ([M+H]+);

4-{4-[(7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl}-[1,4]diazepan-5-he's 65, MS: 374 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether 1-methyl-1H-imidazole-4-sulfonic 66, MS: 518 ([M+H]+);

4-{4-[(7-phenoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he's 67, MS: 450 ([M+H]+);

triperoxonane acid; 4-{4-[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he's 71, MS: 403 ([M+H]);

4-{5-[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]pentyl}-[1,4]diazepan-5-he is 73, MS: 417 ([M+H]+);

4-{4-[(7-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he 75, MS: 402 ([M+H]+);

N-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)propionamide 76, MS: 429 ([M+H]);

(7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)amide cyclopropanecarbonyl acid 77, MS: 441 ([M+H]+);

N-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)isobutyramide 78, MS: 443 ([M+H]+);

2,2-dimethyl-N-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)PR is hydronephrosis-2-yl)butyramide 80, MS: 457 ([M+H]+);

(7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)amide, pyrrolidin-1-sulfonic acids 81, MS: 506 ([M+H]+);

4-(4-{[7-(2,2-dimethylpropylene)-1,2,3,4-tetrahydronaphthalen-2-yl]propylamino}-butyl)-[1,4]diazepan-5-he's 82, MS: 443 ([M+H]+);

4-{4-[(7-cyclohexylamino-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he is 83 MS: 455 ([M+H]+);

1-isopropyl-3-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl] propylamino}-5,6,7,8-Tetra-hydronephrosis-2-yl)urea 84, MS: 458 ([M+H]+);

1-tert-butyl-3-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-Tetra-hydronephrosis-2-yl)urea 85, MS: 472 ([M+H]+);

1-benzoyl-3-(7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydro-naphthalene-2-yl)urea 86, MS: 520 ([M+H]+);

4-{4-[(S)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he's 87, MS: 388 ([M+H]+);

4-{5-[(R)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he's 88, MS: 402 ([M+H]+);

4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl}-[1,4]diazepan-5-he's 90, MS: 388 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-5,6,7,8-tetrahydronaphthalen-2-silt ether propane-2-sulfonic 95, MS: 466 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt broadcast benzosulfimide 96, MS: 514 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt broadcast phenylmethanesulfonyl 97, MS: 528 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether 4-methoxybenzenesulfonamide 98, MS: 544 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether 2-chlorobenzenesulfonate 99, MS: 548 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether pyrrolidin-1-sulfonic 100, MS: 507 ([M+H]+);

6-{[4-(7-oxo-[1,4] diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt broadcast methansulfonate 101, MS: 452 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether propane-1-sulfonic 102, MS: 480 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt broadcast triftoratsetata 103, MS: 506 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl] - cuts is 4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ester thiophene-2-sulfonic 105, MS: 520 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethylisoxazol-4-sulfonic 106, MS: 533 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether 4-chlorobenzenesulfonate 107, MS: 548 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether 3-chlorobenzenesulfonate 108, MS: 548 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether dimethylsulfonium acid 109, MS: 548 ([M+H]+);

4-{4-[(7-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he 110, MS: 402 ([M+H]+);

4-{4-[(6-isopropoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he 113, MS: 416 ([M+H]+);

6-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]-propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt live trifloromethyl-acid 140, MS: 508 ([M+H]+);

4-{4-[(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-he 141, MS: 436 ([M+H]+);

4-{5-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]pentyl}-[1,4]diazepan-5-he 142, MS: 402 ([M+H]+);

4{5-[(6-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]pentyl}-[1,4]diazepan-5-he 152, MS: 416 ([M+H]+);

4-{3-[(6-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]propyl}-[1,4]diazepan-5-he 153, MS: 388 ([M+H]+);

4-{5-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]pentyl}-[1,4]diazepan-5-he 157, MS: 436 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether dimethylcarbinol acid 167, MS: 445 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether morpholine-4-carboxylic acid 168, MS: 487 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether isopropylcarbamate acid 169, MS: 459 ([M+H]+);

7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether propellerbuying acid 170, MS: 459 ([M+H]+or

4-{5-[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]pentyl}-[1,4]diazepan-5-he 172, MS: 432 ([M+H]+).

EXAMPLE 6

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

1-(2-Dimethylaminoethanol)-4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-yl)propylamino]butyl}-[1,4]diazepan-5-he (24)

To a solution of dihydrochloride in example 1, triethylamine (to 0.78 ml, 5.6 mmol) in methylene chloride (20 ml) in an atmosphere of inert gas was added 2-chloroethanesulfonate (0.17 ml, 1.6 mmole). The reaction mixture was allowed to mix at room temperature for 4 hours and then added 2% solution of sodium carbonate. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuum to obtain chloroethyl-sulfonamida in the form of a yellow oil.

To chloroethylamide (1.6 mmole) and triethylamine (0.5 ml, 3.6 mmole, of 2.25 EQ.) in methylene chloride (30 ml) was added in an atmosphere of inert gas dimethylamine hydrochloride (148 mg, 1.8 mmole). The reaction mixture was allowed to mix at room temperature for 20 hours, then concentrated in vacuo. The remaining oil was chromatographically on silica gel and obtained the free base as a clear oil. The free base (215 mg, 0,41 mmole) was dissolved in diethyl ether and treated with 1M Hcl in diethyl ether (0,82 ml). The solid is collected and dried in vacuum, was obtained 1-(2-dimethylamino-econsultancy)-4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]-butyl}-[1,4]diazepan-5-he 24 in the form of hydrochloride (238 mg). (M+N)+=523.

Similarly, the following described what about]butyl}-[1,4]diazepan-5-it is the other representing the free amine compounds of the formula IDa and optionally replacing chlorethylene other appropriate allerease, alkylating or sulfanilimide means, and applying well-known experts in this field modifications were obtained additional compounds of formula IDb, where Z denotes >N-R4for example, 1-(2-dimethylaminocarbonylmethyl)-4-{4-[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-5-6 he, MS: 523 ([M+H]+).

EXAMPLE 7

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

4-{4-[(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]oxazepan-5-he (18)

To (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine (about 13 mg, 50 mcmole), obtained as described in example 1, was added 440 μl solution of 4-(6-oxo-[1,4]oxazepan-4-yl)butyric aldehyde (0.125 M solution in 1,2-dichloroethane), 30 μl of diisopropylethylamine (DIEA) and 300 μl of 0.25 M suspension triacetoxyborohydride sodium in 1,2-dichloroethane. The reaction mixture was shaken at room temperature for 48 hours After mixing with 2 ml of 2% aqueous solution of sodium hydroxide, the reaction mixture is passed together with 0.5 ml of water and ethyl acetate in a flask for processing. The organic phase is washed, dried and concentrated. After purification using chromatography was obtained 4-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2 the th above in example 7 method but optionally replacing 4-(6-oxo-[1,4]oxazepan-4-yl)butyric aldehyde with other appropriate compounds of formula 1e, and optionally replacing (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine with other appropriate compounds of formula 2, and applying well-known experts in this field modifications were obtained additional compounds of formula IDc, where Z denotes-O-:

4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]oxazepan-5-he's 26, MS: 419 ([M+H]+);

4-{4-[(7-isopropoxy-1,2,3,4-tetrahydro-naphthalene-2-yl)propylamino] butyl}-[1,4]oxazepan-5-he's 34, MS: 417 ([M+H]+);

4-{4-[(5,7-debtor-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]oxazepan-5-he is 56, MS: 395 ([M+H]+);

4-{4-[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino] butyl}-[1,4]oxazepan-5-he's 68, MS: 404 ([M+H]+);

4-{4-[(7-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]oxazepan-5-he 116, MS: 403 ([M+H]+);

4-{4-[(6-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]oxazepan-5-he 143, MS: 403 ([M+H]+or 4-{4-[(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-propylamino]butyl}-[1,4]oxazepan-5-he 160, MS: 439 ([M+H]+).

EXAMPLE 8

Composition for oral primer capsule should contain approximately the full daily dose.

EXAMPLE 9

The composition for oral administration

The ingredients are mixed and granularit using a solvent, e.g. methanol. Prepared form then dried and turned into tablets (containing about 20 mg of active compound) using the appropriate teletrauma machine.

EXAMPLE 10

The composition for oral administration

The ingredients are mixed to form a suspension for oral administration.

EXAMPLE 11

Finished dosage form for parenteral administration (intravenous)

The active ingredient is dissolved in a portion of water for injection. Then add with stirring a sufficient amount of sodium chloride to make the solution isotonic. The solution is brought to the desired volume balance water for injection, filtered through a membrane filter with a pore size of 0.2 μm and packaged under sterile conditions.

EXAMPLE 12

Finished dosage form in the form of suppositories

The ingredients are melted together and mixed by heating on the steam bath and poured into molds containing 2.5 g of the total mass.

EXAMPLE 1 with the exception of water, mixed and heated to about 60°C under stirring. Then add sufficient amount of water with a temperature of about 60°C under vigorous stirring to emulsify the ingredients, and then add water in sufficient quantity to about 100 g

EXAMPLE 14

Finished dosage forms for nasal spray

Some aqueous slurry containing from about 0.025 to 0.5% of active substance is obtained in the form of dosage forms for nasal spray. Finished dosage forms optionally contain inactive ingredients, such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose and the like. Can be added hydrochloric acid to establish a pH. Dosage forms for nasal spray can be delivered through the metering pump nasal spray, usually feed about 50-100 ál of dosage forms with one click. A typical application is 2-4 spray every 4-12 hours.

EXAMPLE 15

Studies on the binding of radioactive ligand

Inhibitory activity of compounds of this invention in vitro was determined using a modification of the ska 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 Ki·mmol-1) in a final volume of 0.25 ml of Tris-Krebs buffer. Nonspecific binding was determined using 1 μm atropine. Analyses were carried out using close scintillation analysis technology. Curves of competition-substitution was obtained using 10 concentrations of the studied compounds, the curves were analyzed by iterative approximation of a four-parameter logistic equation. Values pIC50(-log IC50) (IC50- concentration of substance that causes 50% inhibition) were transferred to the pKi values, using the equation of Cheng - Prusoff.

Inhibitory activity against muscarinic receptors (expressed in terms pKi) some samples of the compounds according to the invention was as follows (see the end of the description).

EXAMPLE 16

The model induced oxotremorine/pilocarpine salivation (OIS/PIS) subjected to the action of narcosis in rats

Females rats Sprague-Dawley (Charles Rivers, 200-300 g) were given anesthesia in the form of urethane (1.5 g/kg, subcutaneously) and p is the organization within one hour of rats pre-treated with methoctramine (for OIS), to counteract mediated by receptor M2bradycardia. Each animal was injected intravenously a single dose of filler or compounds selected for comparison. After ten minutes of pre-weighed cotton pads were placed in the mouth of the animal, after which the animals were injected filler or oxotremorine (0.1 mg/kg, intravenously)/pilocarpine (1 mg/kg, intravenously). Fresh cotton pads were placed in 5 minutes after administration oxotremorine/pilocarpine and collected saliva 5 more minutes. Cotton strip (5 - and 10-minute period) then re-weighed to determine the amount of saliva that is allocated for a period of 10 minutes.

All treated oxotremorine/pilocarpine groups were compared using univariate analysis of variance. Pairwise comparisons were made using the test Dannetta. Ordered data (nonparametric method) or the actual levels of data (parametric method) used in the analysis depending on the results of the test of Bartlett determining the homogeneity of variances. The group treated filler/oxotremorine, and the group treated filler/pilocarpine, compared with the group polucha each connection in relation to the total weight of the secret of 10 minutes for each animal. Sigmoidal model is presented in equation

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 depending on the dose. The minimum response was taken as 0 in this model.

Compounds of the present invention showed activity in this study.

EXAMPLE 17

Suppression induced by volume reductions in rats

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

Female rats Sprague-Dawley were anesthetized with urethane and used devices for intravenous medications and, in some cases, to measure blood pressure, heart rate and 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 amount is rum. The studied compounds were injected intravenously cumulative way with 10-minute intervals. As a positive control at the end of the study were administered atropine (0.3 mg/kg, intravenously).

Compounds according to the invention showed activity in this assay.

EXAMPLE 18

Antimuskarinovoe act occurs activity in exposed anesthesia dogs

Inhibitory activity of the compounds according to the invention in relation to muscarinic receptors in vivo was determined in dogs, using a modification of the method described Newgreen, D. T. et al. in J. Urol., 1996, 155 (Supplement 5), 1156.

Female Beagle (from the farm Marshall, North Rose, NY) were subjected to fasting for 18 hours prior to the experiment, water was allowed in any quantity. On the day of the experiment the dogs were given anesthesia and supported pentobarbital (36 mg/kg, initially intravenously, then 5-10 mg/ kg, intravenously to maintain). Intravenous fluid was administered to the dog during the rest of the experiment. The dogs were artificial ventilation through an endotracheal tube by using a Harvard respirator (model 613). In both femoral vein and the femoral artery was inserted catheters for introduction lekarzy P23XL) and recorded using a recording device Gould (model 3400). Did sublingual incision for exposure of the left mandibular duct, which was then inserted a catheter to collect saliva in a pre-weighed vials. Left salivary gland was exposed using a submandibular incision. Allocated chordally the lingual nerve and put on it for bipolar stimulation electrode. Analyzed the response to the stimulation hartalega lingual nerve was obtained to confirm the correct connection of the electrode.

After completion of the surgical intervention in the rest of the experiment was poured physostigmine (180 µg/kg/h intravenously) (cholinesterase inhibitor). After continuing one hour stabilization period were carried out two control stimulation hartalega lingual nerve at 12 Hz, 10 V, duration of 0.5 MS (Grass S48). Hardly the lingual nerve was stimulated for 20 seconds and 2 minutes, respectively, with a minimum interval of 10 minutes between each series of stimulation. After receiving two consistent control responses filler or selected for comparison, the compound was administered defined doses stacked, three minutes before each stimulation hartalega lingual nerve. The experiments could not be on the e positive control was given atropine (1.0 mg/kg, intravenous).

Mean arterial blood pressure was calculated as diastolic blood pressure + (systolic blood pressure - diastolic blood pressure)/3. Heart rate was derived pulse fluctuations of blood pressure. Saliva was collected in pre-weighed tubes and weighed after each collection to determine the amount of saliva. Suppression of the response of the salivary glands expressed as a percentage of the effect of atropine (1 mg/kg, intravenously).

Evaluation of the ED50

For maximum % suppression of salivary flow parameter estimation was using nonlinear mixed model. The method was implemented using techniques PROC NLIN first and PROC MIXED iteratively. This method involves the following sigmoidal sensitive to the dose model:

where answer = % maximum suppress bladder contractions at the peak, x=log10doses used in the treatment, and 4 parameter model: log10ED50(), the maximum and minimum response (Max and Min) and the curvature (). The minimum was taken as 0%. This method assumed a complex symmetry covariance structure. Using iterationtag and the same animal were evaluated desired parameters and their confidence intervals values by refiners calculated errors so to be able to explain the correlation within the object.

Comparison with respect to the zero line

To compare each dose with respect to the zero control for each variable was carried out two-dimensional analysis of variance ANOVA with consideration of the effects of subject and treatment, followed by paired t-test for each dose level. If the overall treatment effect was not significant (p value>0.05) in ANOVA, used the specification of the values of p on Bonferroni for the value of p paired t-test for each dose.

Compounds according to this invention showed activity in this study.

At that time, as the present invention is described with reference to specific variations in its implementation, specialists in this field should understand that can be done various modifications and equivalent substitutions, without going beyond the true essence and scope of the invention. In addition, can be implemented many modifications for adaptation to a particular situation, material, composition of substances, method, stage or stages of the method, to the purpose, nature, and scope of the present invention.

It is assumed that all such modifications lie within the scope of the claim CLASS="ptx2">where R1and R2means 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)1-3- CONR'R", -CONR'R", langroup, haloalkyl or a nitro-group, where 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-alkyl, cycloalkyl or R' and R" together with the nitrogen atom to which they are bound may also form a 5-7-membered ring that optionally includes an additional annular heteroatom selected from N, O or S(O)0-2;

R3independently in each case, the means (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)quinil or cycloalkyl;

one of X, Y or Z means independently-O - or >N-R4other means-CH2-;

R4means hydrogen, (C1-C6)alkyl, haloalkyl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, -(C1-C

p = 1, 2, or 3;

m = 0-3, integer;

n = 1-6, an integer;

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

2. Connection on p. 1, where p = 2.

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

4. Connection on p. 2 or 3, where one of X, Y or Z means >N-R4and other means-CH2-.

5. Connection on p. 2, where one of X, Y or Z means >N-R4and other means-CH2- where R4means hydrogen.

6. Connection on p. 2, where one of X, Y or Z means >N-R4and other means-CH2- and where m = 1.

7. Connection on p. 6, where Y represents >N-R4and X and Z are CH2-.

8. Connection on p. 6, where Z denotes >N-R4and X and Z are CH2-.

9. Connection on p. 8, a 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-yl)propylamino]butyl}-[1,4]diazepan-5-he.

10. Connection on p. 2, where m = 2.

11.Connection on p. 10, where one of X, Y or Z means >N-R4and other means-CH2-.

12. Connection on p. 11, where R4means hydrogen.

13. Connection on p. 10,UP> and X and Z are CH2-.

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

1-{4-[(7-methoxy-1.2,3,4 tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-it;

4-(2-dimethylaminoethanol)-1-{4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-propylamino]butyl}-[1,4]diazepan-2-or

1-{4-[(7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,4]diazepan-2-it.

16. Connection on p. 10, where Z denotes >N-R4and X and Y denote-CH2-.

17. Connection on p. 16, which is selected from the group consisting of 7-{[4-(7-oxo-[1,4]diazepan-1-yl)butyl]propylamino}-5,6,7,8-traditonally-2-silt ester 3,5-dimethylisoxazol-4-sulfonic acids or 4-{5-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]pentyl}[1,4]diazepan-5-it.

18. Connection on p. 2, where m = 2, n = 3, one of X, Y or Z denotes-O -, and other means-CH2-.

19. Connection on p. 18, which is selected from the group consisting of 3-{4-[(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}[1,3]oxazepan-2-or 3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]butyl}-[1,3]oxazepan-2-it.

20. Pharmaceutical composition having antagonistically action against muskarinovoe of PP.1-19 in a mixture with a pharmaceutically acceptable carrier.

21. A method of obtaining a connection on p. 1, including the interaction of the compounds of General formula II

with a compound of General formula III

to obtain the compounds of formula I

where R1, R2, R3, p, m, n, X, Y, and Z are as specified in paragraph 1.

22. The compound according to any one of paragraphs.1-19, obtained by the method according to p. 21.

Priority items:

25.05.2000 on PP.1-3;

09.02.2001 on PP.4-7, 9-12, 14, 15, 17-22;

17.05.2001 on PP.8,13 and 16.



 

Same patents:

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to new and nitrate salts of compounds of formulas (I) to(VI), which can be used in medicine for the treatment of bone disorders such as abnormalities in bone and joints
The invention relates to a method for producing 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole the hydrochloride by hydrochlorination 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole of concentrated hydrochloric acid in the environment of ethyl alcohol at 20-35With target product is separated from the reaction mixture by dilution with water, heating to 75-80With that clarification of the resulting solution activated carbon, cooling the clarified solution to 0-2With, then the selected product is filtered, washed with alcohol and dried at 70C in vacuum (120 mm RT.CT.) get 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole hydrochloride with a melting point 292-294C (with decomposition) and mass fractions of the main substance of at least 99.8%, the product yield is 80% on the original basis

The invention relates to compounds of formula (I)

in which f represents phenylenebis radical, a represents the radical

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

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

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to a method for producing 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] methoxy] benzyl] thiazolidin-2,4-dione of formula (1), including the restoration of the compounds of formula (2'), where R is a (C1-C4)alkyl group, with the use of Raney Nickel or magnesium and, optionally, re-esterification using sulfuric acid in the temperature range from 0 to 60oWith obtaining the compounds of formula (3'), which is subjected to hydrolysis to obtain the acid of formula (4), the condensation of the acid of formula (4) with N-methyl-anthranilamide formula (7) without any pre-activation of the acid to obtain the compounds of formula (1), which is optionally transformed into a pharmaceutically acceptable salt

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to organic chemistry and can find application in medicine

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV with connection inflectional acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI:

e) acid hydrolysis oxazolidinone ring compounds of the formula VI to obtain the compounds of formula I

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to omega-Amida N-arylsulfonamides formula I

and/or stereoisomeric forms of the compounds I and/or physiologically acceptable salts of the compounds I where R1means phenyl, phenyl, substituted once with halogen, the rest of the heterocycle of the following groups: morpholine, pyrrolidine; R2means N; R3means -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

moreover, in formula IIa, IIe q indicates an integer of zero or 1, Z denotes the carbon atom or a covalent bond, and R8means a hydrogen atom or halogen, or R3means -(C1-C4)-alkyl-C(O)-Y, where Y means the remainder of the formula IIC or IId

moreover, in formulas IIc and IId, R8means H or halogen, R9means H, or R3means -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above values, means the integer 2 and R is substituted by-O-, And means covalent bond, B means -(CH2)m- where m is zero, X is-CH=CH-

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to an efficient and economical methods of producing intermediates for the synthesis of HIV protease inhibitors, related nelfinavir-mesilate and including nelfinavir-mesilate
Up!