Derivatives of 4-piperidinylalkylamine and pharmaceutical composition possessing antagonistic affect on muscarinic receptor

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

 

The present invention relates to the derivatives of benzocyclobutene General formula

in which

And represents-C(O)R4or-S(O)2R5;

R1is a (C1-C6)-alkyl or allyl;

R2and R3independently at each reference represent hydrogen, halogen, (C1-C6)-alkyl, halogen(C1-C6)-alkyl, -OR', -S(O)0-2R', -NR'r R", -NR'r COR", -NR'"CONR'R", -NR'r SO2R", -NR'"SO2NR'r R", -SO2NR'r R", -OSO2R', nitro, cyano, heteroaryl or aryl, the group heteroaryl or aryl are unsubstituted or substituted by one or more group selected from hydroxy, cyano, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen(C1-C6)-alkoxy, (C1-C6)-alkylthio, halogen, halogen(C1-C6)alkyl, hydroxy(C1-C6)-alkyl, nitro, (C1-C6)-alkoxycarbonyl, amino, mono - or di(C1-C6)-alkylamino, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulphonyl, mono - or di-(C1-C6)-alkylaminocarbonyl, (C1-C6)-alkylsulfonyl, mono - or di-(C1-C6)-alkylaminocarbonyl and (C1-C6)-alkylcarboxylic;

it is assumed that R2and R3at the same time not PR is astavliaut a hydrogen;

R', R" and R'" independently each reference represents hydrogen, (C1-C6)-alkyl or (C3-C6-cycloalkyl, halogen(C1-C6)-alkyl, diphenylmethyl, aryl or aryl-(C1-C6)-alkyl in which aryl group is unsubstituted or substituted by one or more group selected from hydroxy, cyano, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen(C1-C6)-alkoxy, (C1-C6)-alkylthio, halogen, halogen(C1-C6)alkyl, hydroxy(C1-C6)-alkyl, nitro, (C1-C6)-alkoxycarbonyl, amino, mono-or di-(C1-C6)-alkylamino, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulphonyl, mono - or di-(C1-C6)-alkylaminocarbonyl, (C1-C6)-alkylsulfonyl, mono - or di-(C1-C6)-alkylaminocarbonyl, (C1-C6)-alkylcarboxylic and phenyl; heterocyclyl, which is unsubstituted or substituted by one or more groups selected from hydroxy, oxo, cyano, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen(C1-C6)-alkoxy, (C1-C6)-alkylthio, halogen and halogen(C1-C6)-alkyl, heteroaryl, which is unsubstituted or substituted by one or more groups selected from (C1-sub> 6)-alkyl, (C1-C6)-alkoxy and halogen, or R' and R" together with the nitrogen atom to which they are attached, may form a 5-7-membered ring that may contain one additional heteroatom selected from O, N or S(O)0-2specified ring is unsubstituted or substituted by one or two groups (C1-C6)-alkyl;

R4is a (C1-C6)-alkyl, halogen(C1-C6)-alkyl, benzyloxy, diphenylmethyl,

-NRaRbin which Raand Rbare as defined in the proposal,

-Y-heterocyclyl, -Y-heteroaryl in which these groups heterocyclyl and heteroaryl are independently from each other unsubstituted or substituted by one or more groups selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, halogen(C1-C6)-alkyl, (C1-C6)-alkylsulfonyl, mono - or di-(C1-C6)-alkylaminocarbonyl and (C1-C6)-alkylsulfonyl, and the specified Y is a bond or (C1-3-alkylen;

Rarepresents hydrogen, (C1-C6)-alkyl, halogen(C1-C6)-alkyl, cycloalkyl or aryl, the group cycloalkyl or aryl, each independently of the other is unsubstituted or substituted one or more gr is POI, selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, halogen(C1-C6)-alkyl and alkyl(C1-C6)sulfonyl,

or Raand Rbtogether with the nitrogen atom to which they are attached, may form a 5-7-membered ring that may contain one additional heteroatom selected from O, N or S(O)0-2specified ring is unsubstituted or substituted by one or two groups (C1-C6)-alkyl;

Rbrepresents hydrogen or (C1-C6)-alkyl;

R5is a (C1-C6)-alkyl, halogen(C1-C6)-alkyl,

-NRaRbin which Raand Rbare as defined above, aryl or heteroaryl mentioned aryl or heteroaryl each independently of the other is unsubstituted or substituted by one or two groups selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen and (C1-C6)-alkylsulfonyl; and

p is 1 or 2;

or individual isomers, racemic and not racemic mixtures of isomers, or pharmaceutically acceptable salts or solvate.

It has been unexpectedly found that the compounds of formula I are antagonists of muscarinic receptor.

Acetylcholine (Ach). acetylcholine) is a major TRANS what Itter parasympathetic nervous system. The physiological effects of Ach is mediated through activation of either nicotinic receptors or muscarinic receptors. Both these class of receptors are heterogeneous: for example, a family of muscarinic receptors includes five subtypes (M1, M2, M3, M4and M5), each of which are encoded by different genes and has a unique pharmacological action and specific distribution.

Almost all of the muscle tissue Express as muscarinic M2 receptors, and muscarinic M3 receptors, both of these subspecies play a certain functional role. The number of M2 receptors exceeds the number of M3 receptors in the ratio of approximately 4 to 1. As a rule, M3 receptors are mediators of the direct contractile effect on the vast majority tissue of smooth muscles. On the other hand, M2 receptors indirectly cause contraction of smooth muscle through inhibition of relaxation involving sinteticheski active mediators (β-adrenergic receptors).

Compounds that have activity as antagonists at the muscarinic receptors, used to treat certain medical conditions associated with poor functioning of the smooth muscles, as well as for the treatment of cognitive and neurodegenerative disorders the disorders, such as Alzheimer's disease. Until recently, most of these compounds were selective with respect to the various subtypes of muscarinic receptors, leading to undesirable antiholinergicheskim side effects such as dry mouth, constipation, blurred vision, or tachycardia.

The most common of these side effects is dry mouth as a result of blocking muscarinic receptors in salivary glands. Recently created specific antagonists M2 and/or M3 receptors have been shown to have fewer side effects. Data confirm that the preferential blockade of M2 and/or M3 receptors in relation to the M5 receptor could be therapeutically effective in the treatment of painful conditions associated with a disturbed functioning of the smooth muscles.

In addition, antagonists of muscarinic receptor are the most modern therapies used as bronchodilatory agents in chronic obstructive pulmonary disease (COPD). I believe that the effectiveness of this class of compounds is carried out by means of antagonism in relation to the transmitters of natural origin (acetylcholine), manifested M3 receptors on smooth muscles of the Airways, and compounds of this class may have up to anitelea benefits in COPD by suppressing discharge of mucus, the mediator which can also be M3 receptors. Usual modern protivokashlevoe tool for the treatment of COPD is ipratropium (atrovent), which is administered in aerosol form 4 times a day. Later the company Boehringer-Ingelheim" was developed Tiotropium (Spiriva), as muscarinic antagonist of the second generation, and, as expected, this drug will be produced since 2002 (in cooperation with the company "Pfizer"). Tiotropium also administered in aerosol form, but it is long on the M3 receptor and as a result has a prolonged bronchodilatory action. Tiotropium injected once a day. Although Tiotropium have a high affinity to all subtypes of muscarinic receptors, it is a Quaternary ammonium compound that is poorly absorbed.

Developed a bit of selective antagonists M2 and/or M3 receptors. The present invention fills this need by providing the possibility of obtaining antagonists of this type, which can be used for the treatment of painful conditions associated with poor functioning of the smooth muscles and respiratory disorders.

Objects of the present invention is new derivatives of benzocyclobutene, individual isomers, racemic and not racemic mixtures of isomers, and pharmaceutically acceptable with the and or hydrates, which are particularly useful as antagonists of the muscarinic receptor. The present invention also relates to pharmaceutical compositions containing a therapeutically effective amount of at least one of the compounds of formula I, or individual isomers, racemic and not racemic mixture of isomers, pharmaceutically acceptable salt or solvate of these compounds in a mixture with at least one pharmaceutically acceptable carrier. Preferably the pharmaceutical compositions suitable for administration to a subject, in a painful condition that can be cured when exposed to the antagonist muscarinic receptor.

Another aspect of the present invention relates to a method for producing compounds of formula I, the method includes:

the interaction of compounds of General formula

in which R, R1, R2and R3are as defined above in the text of the application, with the compound of the formula R4C(O)L or R5S(O)2L, where L is tsepliaeva group, and R4and R5are as defined above in the text of the application, obtaining thus compounds of General formula

in which R1, R2, R3, p and a are as defined above in the tech what those applications.

Another aspect of the present invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one of the compounds of General formula I, or individual isomers, racemic or not racemic mixtures of isomers and their salts or solvate, in a mixture with at least one suitable carrier.

According to another aspect of the present invention relates to the use of compounds of formula I for the treatment of the patient, in this painful condition, which can be alleviated in the treatment of compounds having selective activity against muscarinic receptors. In particular, the patient may be in a condition, which includes disorders or disturbances of the functioning of the smooth muscles, preferably disorders or disorders of the activities of the genitourinary tract, disorders or disturbances of the functioning of the respiratory tract, disorders of the activity of the gastrointestinal tract; more preferably disorders or disturbances of activity of the urinary tract, such as increased activity of the bladder or overactive detrusor (sphincter) and their symptoms, such as changes, manifested as persistent urge to urinate, frequent urination, reduced bladder, urinary incontinence, and is such to them, changes urodynamically manifested in the change of volume of the bladder, incomplete urination, unstable bladder contraction, the sphincter spasticity and other symptoms, and the symptoms usually manifested by detrusor hyperreflexia (neurogenic bladder dysfunction, such as difficulty urinating, lack of urination, hypersensitivity pelvic or idiopathic conditions such as detrusor instability, and the like. In accordance with another preferred embodiment of the present invention the disease includes disorders or disturbances of the functioning of the respiratory tract, such as allergies or asthma. In accordance with another preferred embodiment of the present invention painful condition includes gastrointestinal disorders. According to another preferred variant implementation of the present invention painful condition includes cognitive and neurodegenerative disorders or disorders.

Unless otherwise stated, the following terms when used in the text of this application, including the description and claims have the meanings given below. It should be noted that when used in the description and the attached claims, the singular forms of Chi is La mean and plural forms, unless the context clearly to the contrary.

"(C1-C6)-alkyl"or "lower alkyl"or "alkyl" means the monovalent linear or branched saturated hydrocarbon radical containing from one to six carbon atoms, unless otherwise indicated. Examples of radicals are "lower alkyl" 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 radicals.

"Substituted (C1-C6)-alkyl" means a (C1-C6)-alkyl, which is defined in the proposal and includes from one to three substituents, preferably one Deputy, such as hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro or thiol. These groups can be attached to any carbon atom included in (C1-C6)-alkyl part. Examples of radicals substituted (C1-C6)-alkyl" include, but are not limited to, 2-methoxyethyl, 2-hydroxyethyl, dimethylaminocarbonylmethyl, 4-hydroxy-2,2-dimethyl-butyl, trifluoromethyl, triptorelin and similar radicals.

"(C1-C6)-alkoxy" means the radical-O-R, in which R represents a radical (C1-C6)-alkyl, as defined in the proposal. Examples of radicals "alkoxy" include, but are not limited to, methoxy, this is XI, isopropoxy and similar radicals.

"Aryl" means the monovalent aromatic carbocyclic radical consisting of one individual ring, or one or more condensed rings, among which at least one ring is aromatic, this radical may be optionally substituted by one or more, preferably one or two, substituents selected from hydroxy, cyano, lower alkyl, lower alkoxy, halogenoalkane, alkylthio, halogen, halogenoalkane, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylaminomethylene, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, if not specified otherwise. Alternatively, two adjacent atoms in the aryl ring can be substituted by methylendioxyphenyl or ethylenedioxythiophene. Examples of radicals "aryl" include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthrachinone, tert-butylphenyl, 1,3-benzodioxolyl and similar radicals.

"Aryl(C1-C6)-alkyl" means a radical R R"-, where R' is an aryl radical, which is defined in the proposal, and R" represents an alkyl radical, which is defined in the proposal. Examples were radical the "arylalkyl" include, but not limited to, benzyl, phenylethyl, 3-phenylpropyl and similar radicals.

"(C3-C10-Cycloalkyl" means a monovalent saturated carbocyclic radical consisting of one or more rings, preferably one or two rings containing from three to ten atoms each, this radical may be optionally substituted by one or more, preferably one or two, substituents selected from hydroxy, cyano, lower alkyl, lower alkoxy, halogenoalkane, alkylthio, halogen, halogenoalkane, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylaminomethylene, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, if not specified otherwise. Examples of radicals "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclohexyl, cyclopentyl, cycloheptyl, substituted and similar radicals.

"Heteroaryl" means a monovalent aromatic cyclic radical containing one or more ring, preferably one to three rings, containing from four to eight atoms each, such radical includes one or more heteroatoms in the ring, preferably one or two heteroatom (SEL is the R from nitrogen, oxygen or sulfur), this radical may be optionally substituted by one or more, preferably one or two substituents selected from hydroxy, cyano, lower alkyl, lower alkoxy, halogenoalkane, alkylthio, halogen, halogenoalkane, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylaminomethylene, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, unless otherwise noted. Examples of radicals "heteroaryl" include, but are not limited to, imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thienyl, furanyl, pyridinyl, chinoline, ethenolysis, benzofuran, benzothiazyl, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzopyranyl, indazoles, indolyl, isoindolyl, chinoline, ethenolysis, naphthyridine, benzosulfimide and similar radicals.

"Heterocyclyl" means a monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings containing from three to eight atoms each, such radical includes one or more heteroatoms within the ring (chosen from N, O or S(O)0-2), and the specified radical may be optionally substituted by one or more, predpochtitel is about one or two, substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, halogenoalkane, alkylthio, halogen, halogenoalkane, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylaminomethylene, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, unless otherwise noted. Examples of heterocyclic radicals include, but are not limited to, morpholinyl, piperazinil, piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiomorpholine and similar radicals.

"Halogen" means a fluorine radical, bromine, chlorine and/or iodine.

"Halogen(C1-C6)-alkyl" means a radical of the lower alkyl defined in the proposal, substituted at any position by one or more halogen atoms, which are defined in the proposal. Examples of radicals "halogenated" include, but are not limited to, 1,2-direcror, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-triptorelin, 2,2,2-trichlorethyl and similar radicals.

"Halogen(C1-C6)-alkoxy" means a radical-OR where R means halogenates, which is defined above.

"Hydroxy(C1-C6)-alkyl" means a radical of the lower alkyl defined in the proposal, substituted one or more guide what oxypropane. Examples of radicals "hydroxyalkyl" include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2-(hydroxymethyl)-3-hydroxypropyl and the like radicals.

"(C1-C6-alkoxycarbonyl or(C1-C6)-alkyl ester group" means a radical-C(O)-O-R, in which R represents a radical of the lower alkyl defined in the proposal. Examples of radicals "alkoxycarbonyl" include, but are not limited to, methoxycarbonyl, etoxycarbonyl, second-butoxycarbonyl, isopropoxycarbonyl and similar radicals.

"Aryloxyalkyl or aryl ester group" means a radical-C(O)-O-R, in which R represents an aryl radical, which is defined in the proposal. Examples of radicals "aryloxyalkyl" include, but are not limited to, phenyl ester group, afterbuy ester group and the like radicals.

"(C1-C6-alkylsulphonyl" (or "acyl"means a radical-C(O)-R in which R represents a radical of the lower alkyl defined in the proposal. Examples of radicals "alkylaryl" include, but are not limited to, acetyl, propio the sludge, n-butyryl, sec-butyryl, tert-butyryl, ISO-propionyl and similar radicals.

"(C1-C6-alkylaminocarbonyl" means the radical-C(O)NR'r R"in which R' represents lower alkyl, which is defined in the proposal, and R" represents hydrogen or lower alkyl, which is defined in the proposal. Examples of radicals alkylaminocarbonyl include, but are not limited to, methylaminomethyl, dimethylaminoethyl, tert-butylaminoethyl, n-butylaminoethyl, ISO-propylaminoethyl and similar radicals.

"(C1-C6)-alkylcarboxylic" means the radical-NC(O)R'in which R' represents lower alkyl, which is defined in the proposal. Examples of radicals of alkylcarboxylic include, but are not limited to, methylcobalamine, out-propylnitrosamine, tert-BUTYLCARBAMATE and similar radicals.

"(C1-C6)-alkylaminocarbonyl" means the radical-S(O)2NR'r R"in which R' represents lower alkyl, which is defined in the proposal, and R" represents hydrogen or lower alkyl, which is defined in the proposal. Examples of radicals alkylaminocarbonyl include, but are not limited to, methylaminomethyl, dimethylaminomethyl and similar radicals.

"(C1-C6)-alkylsulfonyl" means the radical-NS(O)2 R'in which R' represents lower alkyl, which is defined in the proposal. Examples of radicals of alkylsulfonyl include, but are not limited to, methylsulfonylamino, propylsulfonyl and similar radicals.

"(C1-C6)-alkylsulfonyl" means the radical-S(O)2R, in which R represents a lower alkyl or substituted lower alkyl, which is defined in the proposal. Examples of the alkylsulfonyl radicals include, but are not limited to, methylsulphonyl, trifloromethyl, propylsulfonyl and similar radicals.

"(C1-C6)-alkylsulfonate" means the radical-OS(O)2R, in which R represents a lower alkyl or substituted lower alkyl, which is defined in the proposal. Examples of radicals of alkylsulfonate include, but are not limited to, methylsulfonylamino, tripterocalyx, propylsulfonyl and similar radicals.

"Optional" or "optionally" means that the end of this term event or circumstance may but need not necessarily, take place, and that the description includes examples of where such event or circumstance occurs and examples of when it doesn't. For example, the term "optional communication" means that the bond may be present, and Otsu is to act, and that the description includes single, double or triple bond.

"Tsepliaeva group" has the meaning generally accepted in synthetic organic chemistry, i.e. means an atom or group that can be substituted in the conditions of the alkylation reaction. Examples tseplyaesh groups include, but are not limited to, halogen, alkane - or arylsulfonate, such as methanesulfonate, econsultancy, thiomethyl, benzosulfimide, tosyloxy, titilate, dialoginterface, optionally substituted benzyloxy, isopropoxy, acyloxy and similar radicals.

"Protective group" means a group which selectively blocks one reactive center in the connection involving various functional groups, so that the chemical reaction can be selectively carried out in such a way that it will engage another unprotected reactive center; the term has the meaning generally accepted in synthetic chemistry. Specific methods according to the present invention, it is assumed that the protective groups are used for removing the reaction activity of oxygen atoms present in the reactants. Acceptable protective group for an alcohol or phenolic hydroxyl groups, such that they can be removed sequentially and selectively include group, a protected ACE the Atami, gelegenheitsarbeit, benzyl ester groups, alkylsilane ester groups, heterocyclyl ester groups, and metal or alkyl ester groups, and similar groups. Protective or blocking groups to carboxyl groups is similar to that described protective groups for hydroxyl groups, it is preferable that the ester group with tert-bullom, benzyl or stands. Examples of protective groups can be found at: .W.Greene et al., "Protective Groups in Organic Chemistry", J.Wiley, 2nded. 1991, in: Harrison et al., "Compendium of Synthetic Organic Methods", Vols.1-8 (J.Wiley and Sons, 1971-1996).

"Protective group for the amino group" means a protective group, which refers to organic groups intended to protect nitrogen atom from participating in unwanted reactions in the implementation of the methods of synthesis, this group includes benzyl, benzyloxycarbonyl (carbobenzoxy, Cbz), para-methoxybenzeneboronic, para-nitrobenzenesulfonyl, tert-butoxycarbonyl (Boc), TRIFLUOROACETYL, and the like groups. Preferably used as a protective group for an amino group or a Boc or Cbz due to the relative ease of their removal, for example, using an acid in the case of Boc, for example, by triperoxonane acid or chloroethanol acid in ethyl acetate; or rolled through the practical hydrogenation in the case of Cbz.

"Removing protection" means a process in which after completion of the selective reaction of the protective group is removed. Some of the protective group may be more desirable than others, due to ease of use or ease of removing the protection. Reagents designed to remove the protection in the case of a protected hydroxyl or carboxyl groups include the carbonates of potassium or sodium, alcohol solutions of lithium hydroxide, zinc in methanol, acetic acid, triperoxonane acid catalysts based on palladium or tribromide boron and similar substances.

The term "isomer" refers to compounds that have the same molecular formula but differ in the way or link order of their constituent atoms or the arrangement of their constituent atoms in space. Isomers that differ in the arrangement of their constituent atoms in space are called stereoisomers". Stereoisomers that are not mirror images of each other are termed "diastereomers"and stereoisomers that are incompatible in the space mirror images of each other, are called "enantiomers" or sometimes optical isomers. The carbon atom associated with four different substituents, is called a "chiral center".

"Chiral isomer" means is connected to the e with one chiral center. This connection has two enantiomeric forms with mirror-symmetric arrangement of the substituents and can exist either in the form of individual enantiomers, and mixtures thereof. A mixture containing equal amounts of each of the enantiomeric forms with mirror-symmetric arrangement of the substituents, is called a "racemic mixture". A compound that contains more than one chiral center, is 2n-1pairs of enantiomers, where n denotes the number of chiral centers. Compounds with more than one chiral center may exist in the form of individual diastereoisomer, or a mixture thereof, called "a mixture of diastereomers". In the case when there is one chiral center, stereoisomer can be characterized by the absolute configuration (R or S) of such a chiral center. The absolute configuration means the location in space of the substituents attached to the specified chiral center. The substituents attached to the considered chiral center are ranked in accordance with the rules of ordering Cana-Ingold-Prelog (Cahh et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, v.78, p.413; Cahn and Ingold, J.Chem. Soc. (London) 1951, 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

"Geometric isomers" means the diastereomers, which owe their existence to difficulties of the rotations is s around the double bonds. Such configurations are distinguished by different names, depending on the availability of the prefixes CIS - or TRANS-, or Z and E, which means that the groups are located on the same or on different sides of the double bond in accordance with the rules of Cahn-Ingold-Prelog.

"Tropicheskie isomers" refers to the isomers, owe their existence and rough rotation volume groups around a Central connection.

The term "essentially pure" means that the obtained at least about 80 molar percent, more preferably at least about 90 molar percent, and most preferably at least about 95 molar percent of the target enantiomer or stereoisomer.

The term "pharmaceutically acceptable" indicates a possible use for the manufacture of a pharmaceutical composition that is generally safe, non-toxic and acceptable biologically as well as in any other relationship and determines eligibility for veterinary use and for use in the treatment of people.

The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and which retain the desired pharmacological activity of the parent compound. Such salts include:

(1) salt - products recognize the value acid, formed with inorganic acids such as chloromethane acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like acids; or formed with organic acids such as acetic acid, benzolsulfonat acid, benzoic acid, camphorsulfonic acid, citric acid, econsultancy acid, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonate acid, Mukanova acid, 2-naphthalenesulfonate acid, propionic acid, salicylic acid, succinic acid, Dibenzoyl-L-tartaric acid, tartaric acid, para-toluensulfonate acid, trimethylhexane acid, triperoxonane acid and the like acids; or

(2) salts formed when a proton acid, present in the original compound either is replaced by a metal ion, for example an alkali metal ion, alkali earth metal ion or an aluminum ion; or forms a coordination compound with an organic or inorganic base. Suitable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanol the min, tromethamine and the like bases. Suitable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

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

It should be understood that in all cases, references to pharmaceutically acceptable salts include salts of the addition products of solvent (solvate and crystalline forms (polymorphic modifications), as defined in the proposal formed the same salt is the product of the merger acid.

"Crystalline form" (or polymorphic modifications) mean crystal structure, the formation of which the connection can crystallize with the formation of different types of crystal packing, each of which has the same elemental composition. Different crystalline forms are usually characterized by different x-ray diffraction, different infrared spectra have different melting points, density, hardness, crystal form, optical and electrical properties, stability, and solubility. Solvent for recrystallization, crystallization rate, temperature, x is anemia and other factors can cause the predominance of any one crystalline form.

"Solvate" refers to forms - addition products solvent, such forms contain either stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to capture solvent molecules in a fixed molar ratio, thus forming a solid crystalline state of the solvate. If water is the solvent, the resulting MES is a hydrate, if the solvent is alcohol, the resulting MES represents an anion. Hydrates are formed by the combination of one or more water molecules with one of the substances in which the water remains in the molecular state in the form of H2Oh, when such combinations can be formed of one or more hydrates.

"Prodrug" means a pharmacologically inactive form of the connection, which must undergo metabolism in vivo, for example, when exposed to biological fluids or enzymes of the patient, turning into a pharmacologically active form of the compound in order to produce the required pharmacological effect. The prodrug may be metabolized to absorption, during absorption, after absorption, or on the specific site. Although the metabolism of the majority of compounds occurs initially in the liver, almost all other tissues and organs in persons is nasty easy, capable, to varying degrees, involved in metabolism. Prodrug forms of the compounds can be used, for example, in order to increase the bioavailability, make connections more acceptable to the patient, for example, by masking or reducing the unpleasant characteristics of the connection, such as a bitter taste or irritation of the gastrointestinal tract, modify the solubility, for example, in the case of intravenous administration, to ensure the possibility of prolonged or sustained release or delivery, to facilitate preparation of the composition or to make possible the site-specific delivery connection. Prodrugs are described in: The Organic Chemistry of Drug Design and Drug Action, by Richard B.Silverman, Academic Press, Design of Prodrugs San Diego, 1992. Chapter 8: "Prodrugs and Drug delivery Systems", pp.352-401, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed. by E.B.Roche, American Pharmaceutical Association, Washington, 1977; and in: Drug Delivery Systems, ed. by R.L.Juliano, Oxford Univ.Press, Oxford, 1980.

The term "patient" means both mammals and non mammals. The term "mammal" refers to any representative of the class. Mammals, including, but not limited to, the person, and not non-human primates, such as chimpanzees and other representatives of the apes and not non-human primates such as chimpanzees and the other is e species of monkeys; as well as including farmed animals, such as cattle, horses, sheep, goats and pigs, domestic animals, such as rabbits, dogs and cats; laboratory animals including rodents, such as rats, mice, Guinea pigs and similar animals. Examples of mammals include, but are not limited to, birds, etc.

The term "therapeutically effective amount" means an amount of compound that when administered to a mammal for treating a disease, is sufficient to cause said treatment of the disease. "Therapeutically effective amount" will vary depending on the particular compound, disease and severity of symptoms, age and health of the patient, the route of administration and the form in which you enter the connection from the decision of the attending physician or veterinarian and other factors.

The term "pharmacological effect" when used in the text of the application indicates that the effect achieved when the impact on the patient in case of achieving the intended goals of therapy. In accordance with one embodiments of the present invention achieve a pharmacological effect means that the initial testimony, which had been subjected to treatment of the patient, resolved, alleviated or reduced. For example, pharmaco is agicheskii effect will this effect which provides for the prevention, alleviation or reduction of the primary indications in being treated patient. According to another preferred variant implementation of the present invention achieve a pharmacological effect means that disorders, disorders or symptoms matching the primary indications of the patient being treated, prevented, alleviated or reduced. For example, a pharmacological effect would be that effect, which ensures the prevention or reduction of the primary indications of the exposed treatment of the patient.

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

The term "treatment" of the disease condition includes:

(1) preventing the disease condition, i.e. treatment leads to the fact that patients do not develop clinical symptoms to the appearance or manifestation which predisposes to the disease, but which have not yet felt or not manifest as the symptoms of the disease;

(2) the suppression of painful conditions, i.e. suspension or weakening the development of a pathological state or its clinical symptoms; or

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

The term "ant who honest" means a molecule, for example, such as a molecule, compound, drug, inhibitor of an enzyme or hormone, which reduces or prevents the action of another molecule or portion of the receptor.

The term "disorder or disorders of the urinary tract" or "uropathy", used interchangeably with the term "symptoms of the urinary tract"means pathological changes in the urinary tract. Symptoms of urinary tract infections include increased activity of the bladder (also known as overactive detrusor), difficulty urinating, lack of urination, hypersensitivity of the pelvis.

The term "increased activity of the bladder" and "overactive detrusor" include, but are not limited to, changes that are manifested as persistent urge to urinate, frequent urination, reduced bladder, urinary incontinence, and the like; as well as changes urodynamically manifested in the change of volume of the bladder, incomplete urination, unstable bladder contraction, the sphincter spasticity and other symptoms, and include symptoms, usually manifested by detrusor hyperreflexia (neurogenic bladder dysfunction, such as difficulty urinating, lack of urination, hypersensitive shall be pelvic or idiopathic state, such as detrusor instability, and the like.

The term "difficulty urinating " includes, but is not limited to the above, benign hypertrophy of the prostate (national Department of standardization), urethral stricture, tumor and the like. Usually it symptomatically manifested as difficulty urinating (slow urination, difficulty starting urination, and the like) or irritation (persistent urination, suprapubic pain, etc.).

The term "failure urination" includes, but is not limited to the above, urethral hypermobility, or sphincter of urinary incontinence, due to various reasons. Symptomatically, this usually manifests as stress incontinence.

The term "hypersensitivity pelvic" includes, but is not limited to the above, pain in the pelvic organs, interstitial (elementary) cystitis, prostadynia, a chronic disease of the prostate, vulvadynia, urethritis, orchialgia etc. Symptomatically it usually manifests as pain, inflammation or discomfort in the pelvic organs and usually includes symptoms associated with increased activity of the bladder.

In the text of the application used abbreviations have the following meanings:

BnzBenzil
Boc (or boc)tert-butoxycarbonyl
National Department of standardizationbenign prostatic hypertrophy or

benign prostatic hyperplasia
DIAdiisopropylethylamine
DMFN,N-dimethylformamide
DMSOthe sulfoxide
EDCIhydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
EtOAcThe ethyl acetate
Halthe halogen or halide
HOBTthe hydrate of 1-hydroxybenzotriazole
Proprotective group
OF GHURreversed-phase liquid chromatography high
Resolution
TFUtriperoxonane acid
TFWanhydride triperoxonane acid
THFtetrahydrofuran

Nomenclature

The system of naming and numbering of atoms in the compounds according to the present invention are presented below:

Range is ur used in this application is based largely on a computer system "AUTONOM"™version 4, (the development of Beilstein Institute") to establish names for systematic IUPAC nomenclature. For example, the compound of General formula I, in which R2and R3mean methoxy, R1means propyl, R is 1, a represents-C(O)R4and R4means-N(CH3)2will be called "dimethylamide 4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid".

Among the compounds that are the subject of the present invention, some compounds of General formula I, or prodrugs, individual isomers, racemic or not racemic mixtures of isomers, or pharmaceutically acceptable salt or solvate of such compounds are preferred.

Especially preferred compounds of General formula I according to claim 1 claims, in which a represents a-C(O)R4or-S(O)2R5;

R1is a (C1-C6)-alkyl or allyl;

R2and R3independently at each reference represent hydrogen, halogen, (C1-C6)-alkyl, halogen(C1-C6)-alkyl, -OR', -S(O)0-2R', -NR'r R", -NR'r COR", -NR'"CONR'R", -NR'r SO2R", -NR'"SO2NR'r R", -SO2NR'r R", -OSO2R', nitro, cyano, heteroaryl or aryl, the group heteroaryl Il is aryl are optionally substituted by one or more groups, selected from hydroxy, cyano, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen(C1-C6)-alkoxy, (C1-C6)-alkylthio, halogen, halogen(C1-C6)alkyl, hydroxy(C1-C6)-alkyl, nitro, (C1-C6)-alkoxycarbonyl, amino, mono - or di(C1-C6)-alkylamino, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulphonyl, mono - or di(C1-C6)-alkylaminocarbonyl, (C1-C6)-alkylsulfonyl, mono-or di(C1-C6)-alkylaminocarbonyl and (C1-C6)-alkylcarboxylic, it is assumed that R2and R3at the same time does not mean hydrogen;

R', R" and R"' independently at each reference represents hydrogen, (C1-C6)-alkyl or (C3-C6-cycloalkyl, halogenated, aryl or aryl-(C1-C6)-alkyl, the aryl group is optionally substituted by one or more groups selected from hydroxy, cyano, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen(C1-C6)-alkoxy, (C1-C6)-alkylthio, halogen, halogen(C1-C6)alkyl, hydroxy(C1-C6)-alkyl, nitro, (C1-C6)-alkoxycarbonyl, amino, mono - or di(C1-C6)-alkylamino, (C1-C6)-alkylsulfonyl, (the 1-C6)-alkylsulphonyl, mono - or di(C1-C6)-alkylaminocarbonyl, (C1-C6)-alkylsulfonyl, mono - or di(C1-C6)-alkyl-aminocarbonyl and (C1-C6)-alkylcarboxylic, heterocyclyl specified group heterocyclyl is optionally substituted by one or more groups selected from hydroxy, oxo, cyano, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen(C1-C6)-alkoxy, (C1-C6)-alkylthio, halogen and halogen(C1-C6)-alkyl, heteroaryl specified group heteroaryl is optionally substituted by one or more groups selected from (C1-C6)-alkyl, (C1-C6)-alkoxy and halogen-free,

or R' and R" together with the nitrogen atom to which they are attached, may form a 5-7-membered ring that may contain one additional heteroatom selected from O, N or S(O)0-2specified ring is unsubstituted or substituted by one or two groups (C1-C6)-alkyl;

R4is a (C1-C6)-alkyl, halogen(C1-C6)-alkyl, benzyloxy, diphenylmethyl,

-NRaRbin which Raand Rbare as defined in the proposal,

-Y-heterocyclyl, -Y-heteroaryl in which these groups of heterocycle and heteroaryl are independently from each other unsubstituted or substituted by one or more groups, selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, halogen(C1-C6)-alkyl, (C1-C6)-alkylsulfonyl, mono - or di-(C1-C6)-alkylaminocarbonyl and (C1-C6)-alkylsulfonyl, and the specified Y is a bond or (C1-3-alkylen;

Rarepresents hydrogen, (C1-C6)-alkyl, halogen(C1-C6)-alkyl, cycloalkyl or aryl, the group cycloalkyl or aryl, each independently from each other are unsubstituted or substituted by one or more groups selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen, halogen(C1-C6)-alkyl and alkyl(C1-C6-sulfonyl,

or Raand Rbtogether with the nitrogen atom to which they are attached, may form a 5-7-membered ring that may contain one additional heteroatom selected from O, N or S(O)0-2specified ring is unsubstituted or substituted by one or two groups (C1-C6)-alkyl;

Rbrepresents hydrogen or (C1-C6)-alkyl;

R5is a (C1-C6)-alkyl, halogen(C1-C6)-alkyl,

-NRaRbin which Raand Rbare as defined above, aryl or heteroaryl is, these aryl or heteroaryl each independently of the other is unsubstituted or substituted by one or two groups selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen and (C1-C6)-alkylsulfonyl; and

p is 1 or 2;

or individual isomers, racemic and not racemic mixtures of isomers, or pharmaceutically acceptable salt or solvate of these compounds.

According to a preferred variant implementation of the compounds of formula I according to the present invention are compounds in which a represents-C(O)R4.

In accordance with this preferred embodiment of the present invention a preferred group of compounds of formula I are compounds in which R4means-NRaRbmore preferably, in which R4means-NRaRband Rais a (C1-C6)-alkyl or aryl, and Rbrepresents hydrogen or (C1-C6)-alkyl, or Raand Rbtogether with the nitrogen atom to which they are attached, may form a 5-7-membered ring that may contain one additional heteroatom selected from O, N or S(O)0-2specified ring is unsubstituted or substituted by one or two groups (C1-C6)-alkyl./p>

Another preferred group of compounds included in the scope of this preferred variant implementation of the present invention, are compounds in which R4means-NRaRband Raand Rbtogether with the nitrogen atom to which they are attached, form piperidine, pyrolidine or pieperazinove ring system, these piperidino, pyrolidine or pieperazinove ring system are unsubstituted or substituted by one or two groups (C1-C6)-alkyl.

Another preferred group of compounds of formula I included in the scope of this preferred variant implementation of the present invention, are compounds in which R4means-NRaRband Raand Rbtogether with the nitrogen atom to which they are attached, form morpholino ring system specified Martinova ring system is unsubstituted or substituted by one or two groups (C1-C6)-alkyl.

According to another preferred variant implementation of the present invention preferred compounds of formula I, in which the fragment And means-C(O)R4and R4means (C1-C6)-alkyl or halo(C1-C6)-alkyl.

According to another preferred variant implementation of us who Otsego fragment of the invention And means-C(O)R 4and R4means-Y-heterocyclyl, or-Y-heteroaryl, and Y represents a relationship or (C1-3)alkylen. A preferred group of compounds within the scope of this variant implementation of the present invention are compounds, in which the heteroaryl group selected from furan, thiophene, isoxazol, oxazole or imidazole, and according to another variant implementation of the present invention a preferred group of compounds are those compounds in which heterocyclyl group is piperidino group, which is unsubstituted or substituted by one or more groups (C1-C6)-alkyl.

According to another preferred variant implementation of the compounds of formula I according to the present invention are compounds in which the fragment And means-S(O)2R5.

In this volume the preferred alternative implementation of the present invention a preferred group of compounds of formula I are compounds in which R5means (C1-C6)-alkyl or halo(C1-C6)-alkyl.

In this volume the preferred alternative implementation of the present invention a preferred group of compounds of formula I are compounds in which R5means-NRaRbmore preferably where R means-NRaRband Rais a (C1-C6)-alkyl or aryl, and Rbrepresents hydrogen or (C1-C6)-alkyl, or Raand Rbtogether with the nitrogen atom to which they are attached, may form a 5-7-membered ring that may contain one additional heteroatom selected from O, N or S(O)0-2specified ring is unsubstituted or substituted by one or two groups (C1-C6)-alkyl.

According to another preferred variant implementation of the present invention the fragment And means-S(O)2R5and R5represents aryl, more preferably R5represents phenyl, which is unsubstituted or substituted by one or more groups selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen and (C1-C6)-alkylsulfonyl.

According to another preferred variant implementation of the present invention the fragment And means-S(O)2R5and R5is heteroaryl, and even more preferably, if the specified heteroaryl chosen from the group comprising furan, thiophene, isoxazol, oxazole and imidazole, each representative group is unsubstituted or substituted by one or two groups (C1-C6)-alkyl.

According to another preferred variant implementation of the compounds of formula I according to the present invention are compounds in which R2and R3represent-OR', -NO2, -OSO2R', aryl or hydrogen, it is assumed that R2and R3at the same time do not represent hydrogen; more preferably R2and R3represents hydrogen or-OR', where R' means (C1-C6)-alkyl or halo(C1-C6)-alkyl, it is assumed that R2and R3are not simultaneously represent hydrogen.

According to another preferred variant implementation of the present invention the compounds of formula I are compounds in which R1is a (C1-C6)-alkyl; more preferably R1represents ethyl or propyl.

Examples of preferred compounds or individual isomers, racemic or narramissic mixtures of isomers, pharmaceutically acceptable salt or solvate of such compounds include:

(7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methanesulfonamido-4-ylmethyl)Propylamine;

(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)piperidine-4-ylmethanone;

(1-methanesulfonamido-4-ylmethyl)-(7-methoxy-1,2,3,4-tetrahydro Talin-2-yl)Propylamine;

dimethylamide 4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid;

(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanone;

(1-methanesulfonamido-4-ylmethyl)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine; and

(4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanol.

Compounds according to the present invention can be obtained by the methods indicated in the diagrams reactions of synthesis, which are given for illustration, these schemes are presented and described below.

Source materials and reagents used for obtaining such compounds are either commercially available from suppliers such as Aldrich Chemical Co.", or can be obtained by methods known to the person skilled in the art. The following methods are described in the sources listed as references such as Fieser and Fieser, "Reagents for Organic Synthesis"; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd, "Chemistry of Carbon Compounds", Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and in "Organic Reactions", Wiley & Sons: New York, 1991, Volumes 1-40. The following scheme of reactions of synthesis are only illustrations of some of the ways that can be obtained the compounds according to the present invention; it is possible that numerous modifications so the x schema reactions of synthesis, which will be obvious to a person skilled in the art, applied to the description provided in this application.

Source materials and intermediate products interactions can be isolated and purified, if the need arises, using well-known methods, including, but not limited to, filtration, distillation, crystallization, chromatography and the like methods. Such substances can be described using the well-known characteristics, including physical constants and spectral data analysis.

Unless otherwise stated, the reactions described in the text of the application is preferably carried out at atmospheric pressure in the temperature range from about -78°With up to approximately 150°S, more preferably from approximately 0°With up to approximately 125°and most preferably and conveniently at about room temperature (or ambient temperature), for example at about 20°C.

Scheme And

On the scheme And presents the General case of the method of obtaining compounds of General formula I, in which R1, R2, R3And R are as defined above in the text of the application.

The compound of formula (b) in the General case can be obtained through the interaction of the tetralone the formula (a) with the protected aminopiperidine General formula (e) under the reaction conditions of reductive amination. Suitable reaction conditions recovery include the presence of triacetoxyborohydride sodium, cyanoborohydride sodium, isopropoxide titanium and cyanoborohydride sodium, the presence of hydrogen and a metal catalyst, and agents as a vector of hydrogen, such as cyclohexane, formic acid and its salts, zinc and chloromethane acid or formic acid, or the presence of sulfide borane followed by treatment with formic acid. Suitable organic solvents for carrying out reactions include dichloromethane, 1,2-dichloroethane, tetrahydrofuran, alcohols or ethyl acetate, and similar substances. Preferably the reaction is carried out in basic medium in the presence of triacetoxyborohydride sodium in 1,2-dichloroethane. Methods of restoration amination described in the chemical literature. For example, in J. Org. Chem. 1996, 61, 3849 and in Tetrahedron Letters 1996, 37, 3977 describes how to use triacetoxyborohydride sodium as a reagent for reductive amination of aldehydes to obtain a wide class of amines.

The compound of formula (b) is further subjected to interaction in the reaction conditions, reductive amination, as described in the proposal, with appropriate carboxaldehyde, obtaining thus in the General case, the compound of formula (C), which after removal of the protection piperidino group in the us is the conditions, well-known specialist in the art, as described in the proposal, can undergo acylation, alkylation or sulfonation under the action of the acid chloride R4C(O)Cl, carbamoylated R4COCl, isocyanate R4WITH or sulphonylchloride R5S(O)2Cl, respectively, in the above formulas, R4and R5are as defined above in the text of the application, under conditions well known to the person skilled in the art to produce in General, compounds of formula I according to the present invention.

A well-known source of a substance specified on the scheme And are commercially available or can be easily synthesized by a person skilled in the technical field.

Compounds that act as antagonists at the muscarinic receptors, used to treat certain medical conditions related to insufficient activity of smooth muscles. Until recently, most of these compounds were selective towards different muscarinic receptors, leading to undesirable antiholinergicheskim side effects such as dry mouth, constipation, blurred vision, or tachycardia. The most common of these side effects is dry mouth as a result of blocking muscarinic receptors, slew the Noah cancer. Recently created specific antagonists M2 and/or M3 receptors have been shown to have fewer side effects. Data confirm that the preferential blockade of M2 and/or M3 receptors in relation to the M5 receptor could be therapeutically effective in the treatment of painful conditions associated with a disturbed functioning of the smooth muscles, such as disorders or disturbances of the functioning of the urinary tract, disorders of the functioning of the respiratory tract, disorders of the activity of smooth muscles and cognitive and neurodegenerative disorders.

Disorders or disturbances of the functioning of the urinary tract, for the treatment which it is possible to use the compounds according to the present invention, more specifically include increased activity of the bladder or overactive detrusor (sphincter) and their symptoms, such as changes symptomatically manifested as persistent urge to urinate, frequent urination, reduced bladder, urinary incontinence, and the like, changes urodynamically manifested in the change of volume of the bladder, incomplete urination, unstable bladder contraction, the sphincter spasticity and other symptoms, and the symptoms usually manifested PR is of detrusor hyperreflexia (neurogenic dysfunction of the urinary bladder), such as difficulty urinating, lack of urination, hypersensitivity pelvic or idiopathic conditions such as detrusor instability, etc.

Disorders or disorders of the gastrointestinal tract for the treatment of which it is possible to use the compounds according to the present invention, more specifically syndrome include increased irritability of the colon, diverticulosis, achalasia, hypermobility of the gastrointestinal tract and diarrhea.

Disorders or disturbances of the functioning of the respiratory tract for the treatment of which it is possible to use the compounds according to the present invention, more specifically include chronic obstructive pulmonary disease, including chronic bronchitis, emphysema, asthma and lung fibrosis.

Compounds that are selective against M2 muscarinic receptor, as has been shown, can also be used to treat cognitive and neurodegenerative diseases, such as Alzheimer's disease, which is described in the article: J. Med. Chem., 1993, v.36, n-3737. In US patent No. 6294554 described the muscarinic antagonist used for the treatment of cognitive impairments and disorders.

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

Compounds according to the present invention are antagonists of muscarinic receptor. The affinity of the studied compounds according to the present invention to muscarinic receptor can be determined using the methods of in vitro studies - the study of binding in which drug use cell membrane of the ovarian cells of Chinese hamsters expressing recombinant muscarinic receptors man (M1-M5), this technique is described in more detail in example 18.

Antagonistic properties of the compounds under study in relation to muscarinic receptors can be installed when conducting in vivo studies, which determine the inhibitory activity against muscarinic receptors are mediators of excretion of saliva in rats under anesthesia, this procedure is described in more detail for oxotremorine/pilocarpine-induced salivation (OIS/PIS) on the model I shot rats, example 19.

Antagonistic properties of the compounds under study in relation to muscarinic receptors can be installed when conducting in vivo studies, which determine the inhibitory activity against muscarinic receptors, which are mediators of bladder contractions at anesthesiology the rats, as described in more detail to study the inhibition induced entered by the volume contraction of the bladder, example 20.

Antagonistic properties of the compounds under study in relation to muscarinic receptors can be identified when conducting in vivo studies, which determine the inhibitory activity against muscarinic receptors, which are mediators of bladder contractions and salivation have shot dogs, described in more detail in example 21.

Antagonistic properties of the compounds under study in relation to muscarinic receptor using the compounds as bronchodilatory agents can be determined by conducting in vivo studies on shot rats, as described in more detail in example 22.

The present invention relates to pharmaceutical compositions comprising at least one compound according to the present invention, or a prodrug, or individual isomers, racemic and not racemic mixture of isomers, or pharmaceutically acceptable salt or solvate together with a pharmaceutically acceptable carrier and optionally other therapeutic or prophylactic ingredients.

As a rule, the compounds according to the present invention is introduced into terapeutiche the key effective amount, using any route of administration, adopted for the introduction of agents that are used for the same purposes. Suitable intervals dosages are usually 1-500 mg / day, preferably 1-100 mg / day, and most preferably 1-30 mg / day, depending on many factors such as the severity of symptoms to be treated, the age and relative health of the patient, the effectiveness of which connection to use, as a way of introduction and forms of used to introduce, as well as indications in respect of which is the introduction, and the preferences and experience of the attending physician. Specialist in the treatment of such diseases can without holding undue experimentation, based on existing knowledge and the disclosure of the invention in the description of this application, to install a therapeutically effective amount of the compounds according to the present invention that you want to use in this disease. As a rule, the compounds according to the present invention is administered in the form of pharmaceutical compositions, which are suitable for oral (including transbukkalno and sublingual), rectal, nasal, local, pulmonary, vaginal, transdermal or parenteral (including intramuscular, intraarterial, intratracheal, podkin the e and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred method of introduction, as a rule, is oral, using a common mode of daily dosages, which can be adjusted depending on the severity of the disease.

The compound or compounds according to the present invention, together with one or more conventional auxiliary agent, the carrier or diluent can be represented in the form of pharmaceutical compositions or unit dosage forms. The pharmaceutical composition or unit dosage forms may include conventional ingredients in conventional proportions, with or without additional active compounds or components, and unit dosage forms may contain any suitable effective amount of the active ingredient corresponding to the intended interval used daily dosages. The pharmaceutical compositions can be used in the form of solid dosage forms such as tablets or filled capsules, semi-products, powders, sustained-release or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal the CSOs introduction; or in the form of sterile injectable solutions intended for parenteral administration. Compositions containing approximately one (1) milligram of active ingredient, or more widely, from approximately 0.01 to approximately one hundred (100) milligrams of active ingredient per tablet, thus are suitable typical unit dosage forms.

Compounds according to the present invention can be included in the variety of dosage forms for oral maintenance. Pharmaceutical compositions and dosage forms may include as an active ingredient the compound or compounds according to the present invention or their pharmaceutically acceptable salts. Pharmaceutically acceptable carriers can be either solid or liquid. Drugs in the solid state include powders, tablets, pills, capsules, pills, suppositories and small granules. A solid carrier can be one or more substances, which can act as diluents, substances that enhance the taste and smell of solubilization, lubricants, suspendida agents, binders, preservatives, agents that promote raspadaemosti tablets, or may be a material of the capsules. In the case of powders, the carrier generally is a finely powdered solid, which is located in a mixture with finely ground active ingredient. In the case of tablets, the active ingredient, as a rule, are mixed in suitable proportions with the carrier that has the ability to bind, and pressed to obtain the desired shape and size. The powders and tablets preferably contain from about one (1) to approximately seventy (70) percent of the active compounds. Suitable carrier materials include, but are not limited to specified, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc. the Term "drug", as expected, includes the composition of the active compound with encapsulating material as a carrier, you get a capsule in which the active component with the carrier or without carriers, is surrounded by carrier, which is included in the composition. Similarly, the scope of the invention includes drops and lollipops. Tablets, powders, capsules, pills, drops and lozenges can be considered as solid forms suitable for oral administration.

Other forms suitable for oral administration include medications, in liquid state, such as emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions or drugs in the solid state, which, as the pre is supposed, before use, can be quickly transferred to the drug is in a liquid state. To obtain emulsions can be used solutions, such as aqueous propylene glycol, or the emulsion may contain emulsifying agents such as lecithin, monooleate sorbitol or acacia. Aqueous solutions can be obtained by dissolving the active component in water with the addition of suitable coloring agent, substances that improve the taste and smell, stabilizer and thickener. Aqueous suspensions can be obtained by dispersing finely ground active component in water with viscous substances, such as natural or synthetic resins, polymers, methylcellulose, sodium carboxymethyl cellulose and other famous suspendresume agents. The liquid forms include solutions, suspensions and emulsions can contain, in addition to the active ingredient, tinted substances, substances that improve the taste and smell, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents, etc.

Compounds according to the present invention can be used in the composition for parenteral administration (e.g. by injection or continuous infusion) and may be what redstavleny as a single dosage form and placed in the ampoule, pre-filled syringes, small volume for infusion or can be in containers for repeated dosing with added preservatives. The composition can also be in the form of suspensions, solutions or emulsions in oily or aqueous base, for example in the form of solutions in aqueous polyethylene glycol. Examples of the oily or nonaqueous carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil)suitable for injectable organic esters (for example, etiloleat) and may contain auxiliary agents such as preservatives, agents for improving wettability, emulsifiers or suspendresume agents, stabilizers and/or dispersing agents. Alternatively the active ingredient may be in powder form, obtained by aseptic allocation of sterile solid or by lyophilization from solution, for preparation before use with a suitable filler, such as sterile pyrogen-free water.

Compounds according to the present invention can be used in the composition for local introduction to the epidermis as ointments, creams and lotions, or as a transdermal patch. Ointments and creams can be,for example, performed on an aqueous or oily base with the addition of suitable thickening and/or gelling agent. Lotions can be performed on a water or oil based and generally also contain one or more emulsifiers, stabilizers, dispersing agents, suspendida agents, thickeners or tinted substances. Compositions suitable for topical administration is the introduction through the mouth include lozenges, containing the active ingredient introduced into the base with a certain taste and smell, usually a resin of acacia or tragacanth gum; lozenges comprising the active ingredient, introduced in an inert basis such as gelatin and glycerin or sucrose and resin acacia; and liquid for gargling, including the active ingredient in a suitable liquid carrier.

Compounds according to the present invention can be used in the composition for administration in the form of suppositories. First soften the low-melting waxy base, such as a mixture of glycerides of fatty acids or cocoa butter, and then homogeneous dispersed active component, for example by stirring. Then the softened homogeneous mixture is then poured into molds of suitable size and allow to cool and harden.

Compounds according to the present invention can be used is s in the composition for nasal administration. Solutions or suspensions used for injection directly into the nasal cavity by conventional means, for example, using a pipette, dropper or spray. The compositions may be presented in a form for a single injection or multiple dosing. In the latter case, when using a dropper or pipette, this can be done by the patient with the introduction of a suitable pre-determined volume of solution or suspension. In the case of spray dosing can be carried out, for example, by a measuring device for spraying.

Compounds according to the present invention can be used in the composition for administration as an aerosol, in particular for introduction into the respiratory tract and including intranasal administration. The connection typically will be characterized by small particle size, for example of the order of five (5) microns or less. Particles of this size can be obtained by use of the means known from the prior art, for example, using micromilieu. The active ingredient is placed in a packaging under pressure and containing a suitable compressed fluid, such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or D. the natives suitable gas. The spray also may contain a surfactant such as lecithin. The dose of the drug can be regulated through a metering valve. Alternatively, the active ingredients can be represented in the form of a dry powder, for example in the form of a powder mixture of the compounds with a suitable powder base such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidine (PVP). The powder carrier in the nasal cavity will form a gel. Powder composition may be presented in unit dosage form, for example, capsules or cartridges, for example, from gelatin or in the form of blister packs from which the powder may be administered through an inhaler.

Compounds according to the present invention can be used in the composition for transdermal or subcutaneous injection using the introduction in the form of a delivery system for drugs. Such delivery systems drugs are preferred in cases when you want slow release compounds, and in the case when engaging the patient is a critical factor in determining the mode of administration. Connection systems transdermal often "stick" to go active is Vaudemont to the skin of solid media. Compound interest can be combined with a substance that facilitates the penetration of, for example, using azone(1-dodecylsulfate-2-one). System slow release of the injected subcutaneously into the subcutaneous layer by surgery or by injection. In the case of subcutaneous implants compound is administered in soluble in the lipid membrane, such as silicone rubber or a biodegradable polymer, such as polymer α-oxopropionate acid.

The pharmaceutical preparations are preferably in the form of unit dosage forms. In the manufacture of this form of composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a drug in the package; the package containing discrete doses of the drug, such as tablets per pack, capsules, and powders in vials or ampoules. The unit dosage form can be a capsule, tablet, dragee or a Lollipop or a suitable number of any of these forms in Packed form.

Other pharmaceutical carriers and compositions and their use are described in: Remington, The Science and Practice of Pharmacy, edited by E.W.Martin, Mack Publishing Company, 19th edition, 1995, Easton, Pennsylvania.

Typical pharmaceutical compositions that contain Asia connection according to the present invention, described in examples 11-17.

The following preparation examples and examples are given to a specialist in the art will be able to better understand and implement the present invention. These examples should not be construed as limiting the scope of the invention, they are only illustrative and are the most typical.

Example 1

Isopropylated 4-({ethyl-[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid

Step 1: tert-butyl ether 4-[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-ylamino)methyl] piperidine-1-carboxylic acid

To a solution of 7-nitro-3,4-dihydro-1H-naphthalene-2-she (600 mg, 2,98 mmol), obtained according J.Med.Chem., 1989, 32(9), 2128-34, and tert-butyl methyl ether 4-aminomethylpyridine-1-carboxylic acid (700 mg, 3.3 mmol) in dichloroethane (50 ml) under nitrogen atmosphere at once add triacetoxyborohydride sodium (1.4 g, 6.5 mmol, 2 EQ.). The reaction mixture was stirred at room temperature for 24 h the Reaction mixture was concentrated in vacuo and separated between EtOAc (100 ml) and 5%aqueous solution of KOH (50 ml). The aqueous layer was extracted twice using EtOAc (2×50 ml). The combined organic layers washed with saturated salt solution, dried over MgSO4, filtered and concentrated, thus obtaining a dark oily the e substance. After rapid chromatography on silica gel with elution with a mixture of 5% methanol/methylene chloride receive tert-butyl ester 4-[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-ylamino)methyl]piperidine-1-carboxylic acid as an oily substance (790 mg).

Step 2: tert-butyl ether 4-{[ethyl-(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl}piperidine-1-carboxylic acid

To a solution of tert-butyl ester 4-[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-ylamino)methyl]piperidine-1-carboxylic acid (485 mg, 1.25 mmol) and acetaldehyde (110 μl, 1,49 mmol) in dichloroethane (20 ml) under nitrogen atmosphere at once add triacetoxyborohydride sodium (530 mg, 2.49 mmol, 2 EQ.). The reaction mixture was stirred at room temperature for 24 h, then concentrated in vacuo. The remainder is divided between EtOAc (75 ml) and 5%aqueous solution of KOH (50 ml). The aqueous phase is extracted twice using EtOAc (2×30 ml). The combined organic layers dried over MgSO4, filtered and concentrated on silica gel (10 g). The resulting substance is placed on the column for rapid chromatography and elute using 20% acetone in hexane. The fractions containing the target substance are combined and concentrated, thus obtaining tert-butilovyi ether 4-{[ethyl-(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl}piperidine-1-carboxylic acid VI is e yellow oily substance (430 mg).

Step 3: tert-butyl ether 4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)-ethylamino]methyl}piperidine-1-carboxylic acid

To a solution of tert-butyl ester 4-{[ethyl-(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl}piperidine-1-carboxylic acid (490 mg, 1.2 mmol) in ethanol (30 ml) is added 10%palladium on carbon (50 mg). The solution is shaken using a shaker device Parra, within 24 h under hydrogen pressure of 55 pounds per square inch. The solution is filtered through celite and concentrated, thus obtaining tert-butyl ester 4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)-ethylamino]methyl}piperidine-1-carboxylic acid as an oily substance (405 mg), which was directly used in the next stage.

Stage 4: tert-butyl ether 4-({ethyl-[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid

To a solution of tert-butyl ester 4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)-ethylamino]methyl}piperidine-1-carboxylic acid (1.5 g, a 3.87 mmol) in EtOAc (50 ml) and 20%of the resultant aqueous solution of potassium carbonate (50 ml) was added dropwise 4-methysulfonylmethane (760 mg, 4.1 mmol) in EtOAc (75 ml). The reaction mixture was stirred at room temperature overnight and the layers separated. Layer with EtOAc concentrate on the specification of the barely and placed on a column for rapid chromatography. Column elute using 35% acetone in hexane. The fractions containing the substance are combined and concentrated, thus obtaining tert-butyl ester 4-({ethyl-[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid as a pale pink solid (1,33 g).

Stage 5: N-[7-(ethylpiperidine-4-ylmethyl-amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-4-methysulfonylmethane

To a solution of tert-butyl ester 4-({ethyl-[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid (1,33 g, 2.3 mmol) in methylene chloride (30 ml) under nitrogen atmosphere add triperoxonane acid (10 ml). The reaction mixture was stirred at room temperature for 30 min and concentrated in vacuo. The remainder is divided between EtOAc (50 ml) and 10%aqueous solution of KOH (50 ml), the organic layer is separated, dried over MgSO4, filtered and concentrated, thus obtaining N-[7-(ethylpiperidine-4-ylmethyl-amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-4-methysulfonylmethane (1,02 g). [M+H]+=470.

Stage 6: isopropylated 4-({ethyl-[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid

To a cooled in a bath with ice to a solution of N-[7-(ethylpiperidine-4-ileti the-amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-4-methysulfonylmethane (1.3 g, 2.3 mmol) in methylene chloride (40 ml) under nitrogen atmosphere at once added triethylamine (1.3 ml, 9.2 mmol, 4 equiv.) then isopropyltoluene (0.33 ml, 3.3 mmol, 1.4 EQ.). The reaction mixture is allowed to warm to room temperature and stirred for 24 h, the Reaction mixture was concentrated in vacuo and separated between EtOAc (75 ml) and 10%aqueous sodium hydroxide solution (40 ml). The aqueous layer was extracted using EtOAc (2×30 ml)and the combined layers with EtOAc dried over MgSO4filter and concentrate. After trituration with ether get isopropylated 4-({ethyl-[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid (1) as a light pink solid (1.1 g). [M+H]+=555.

In accordance with the procedure described above in example 1, but replacing at stage 6 isopropyltoluene to other suitable isocyanates are given the following connections:

N-(7-{ethyl[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methysulfonylmethane, (2), [M+H]+=583;

diethylamide-({ethyl[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (3), [M+H]+=569;

methylamide 4-({ethyl[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (4), [M+H]+=527;

enilemit 4-({ethyl[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (5), [M+H]+=589

amide 4-({ethyl[7-(4-methysulfonylmethane)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (6), [M+H]+=513.

Example 2

Isopropylated 4-({ethyl-[7-(4-perbenzoate)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid

Step 1: tert-butyl ether 4-({ethyl-[7-(2,2,2-triptoreline)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid

To a solution of tert-butyl ester 4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)ethylamino] methyl } piperidine-1-carboxylic acid (2.3 g, are 5.36 mmol) in methylene chloride (30 ml) under stirring in an inert atmosphere add pyridine (0.9 ml, about 10.7 mmol) and triperoxonane anhydride (1.0 ml, of 6.96 mmol) and the solution is kept under stirring at room temperature for 20 hours the Reaction mixture was concentrated in vacuo and separated between EtOAc and water. The organic layer was washed with a saturated solution of salt, dried (MgSO4) and concentrate. The crude reaction product is subjected to rapid chromatography on silica gel, elwira 20% acetone in hexane, obtaining thus tert-butyl ester 4-({ethyl-[7-(2,2,2-Cryptor-acetylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid as an orange oily substance (1.2 g).

Stage 2: N-[7-(typoberlin-4-ylmethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl]-2,2,2-triptorelin

To a solution of tert-butyl ester 4-({ethyl-[7-(2,2,2-Cryptor-acetylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid (800 mg, 1.7 mmol) in methylene chloride (20 ml) in an inert atmosphere add triperoxonane acid (5 ml) and leave the solution is mixed at room temperature for 1 h, the Reaction mixture was concentrated in vacuo and share between 10%KOH and EtOAc. The organic layer was washed with a saturated solution of salt, dried (MgSO4) and concentrated, thus obtaining N-[7-(ethylpiperidine-4-ylmethyl-amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-2,2,2-Cryptor-ndimethylacetamide in the form of an oily substance, which was directly used in the next stage.

Stage 3: isopropylated 4-({ethyl-[7-(2,2,2-Cryptor-acetylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid

To a solution of N-[7-(ethylpiperidine-4-ylmethyl-amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-2,2,2-Cryptor-ndimethylacetamide (1.7 mmol) in methylene chloride (20 ml) in an inert atmosphere added triethylamine (1.0 ml, 6.6 mmol) and isopropylidene (230 μl, 2.3 mmol). The reaction mixture is stirred for 20 h and then concentrated in vacuo. The resulting material is shared between 5%KOH and water. The organic layer is dried (MgSO4and concentrate, procapra this isopropylated 4-({ethyl-[7-(2,2,2-Cryptor-acetyl-amino)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid as a colorless oily substance (630 mg).

Stage 4: isopropylated 4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)-ethylamino]methyl}piperidine-1-carboxylic acid

To a solution of Isopropylamine 4-({ethyl-[7-(2,2,2-Cryptor-acetylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid (630 mg, 1.3 mmol) in methanol (20 ml) and water (10 ml) is added potassium carbonate (500 mg) and the reaction mixture is allowed to mix at room temperature for 24 h the Reaction mixture was concentrated in vacuo and separated between EtOAc and water. The organic layer was washed with a saturated solution of salt, dried (MgSO4) and concentrated, thus obtaining isopropylated 4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)-ethylamino]methyl}piperidine-1-carboxylic acid as a pale brown oily substance (464 mg).

Stage 5: isopropylated 4-({ethyl-[7-(4-fluoro-benzoylamine)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid

To a solution of Isopropylamine 4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)-ethylamino]methyl} piperidine-1-carboxylic acid (200 μl of 0.25 M solution in acetonitrile, 50 µmol) add 220 ál of 0.25 M solution of 4-tormentilla in dichloromethane and 30 μl of DIEA. The mixed solution is kept for 24 h at 25°C in an atmosphere of N2and concentrated in vacuo. End the product is separated by preparative liquid chromatography high resolution (OF GHWR, column YMC Combiprep ODS-A, 10-90% acetonitrile: water with 0.1% TFU)), while receiving isopropylated 4-({ethyl-[7-(4-fluoro-benzoylamine)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid (13.1 mg) 7, [M+H]+=495.

According to the method described above in example 2, step 5, but substituting 4-perbenzoate appropriate acid chloride or sulphonylchloride receive the following connections:

isopropylated 4-({ethyl[7-(4-triphtalocyaninine methyl)piperidine-1-carboxyl)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (8), [M+H]+=545;

isopropylated 4-[(ethyl{7-[(naphthalene-2-carbonyl)amino]-1,2,3,4-tetrahydronaphthalen-2-yl}amino)methyl]piperidine-1-carboxylic acid, (9), [M+H]+=527;

isopropylated 4-({ethyl[7-(4-methoxy-benzoylamine)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (10), [M+H]+=507;

isopropylated 4-[({7-[(biphenyl-4-carbonyl)amino]-1,2,3,4-tetrahydronaphthalen-2-yl}ethylamino)methyl]piperidine-1-carboxylic acid, (11), [M+H]+=553;

isopropylated 4-{[(7-diphenylacetylene-1,2,3,4-tetrahydronaphthalen-2-yl)ethylamino]methyl}piperidine-1-carboxylic acid, (12), [M+H]+=567;

isopropylated 4-({ethyl[7-(2-phenylbutyramide)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (13), [M+H]+=519;

isopropylated 4-[(ethyl{7-[2-(4-methoxyphenyl)-acetylamino]-12,3,4-tetrahydronaphthalen-2-yl}amino)methyl]piperidine-1-carboxylic acid, (14), [M+H]+=521;

isopropylated 4-({[7-(4-dimethylaminobenzylidene)-1,2,3,4-tetrahydronaphthalen-2-yl]ethylamino}methyl)piperidine-1-carboxylic acid, (15), [M+H]+=520;

isopropylated 4-({[7-(2,4-differentiating)-1,2,3,4-tetrahydronaphthalen-2-yl]ethylamino}methyl)piperidine-1-carboxylic acid, (16), [M+H]+=513;

isopropylated 4-({ethyl[7-(naphthalene-2-sulfonylamino)-1,2,3,4-tetrahydronaphthalen-2-yl] amino}methyl)piperidine-1-carboxylic acid, (17), [M+H]+=563;

isopropylated 4-({ethyl[7-(4-methoxy-benzosulfimide)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (18), [M+H]+=543;

isopropylated 4-{[ethyl(7-phenylmethanesulfonyl-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl}piperidine-1-carboxylic acid, (19), [M+H]+=527;

isopropylated 4-({ethyl[7-(4-triftormetilfullerenov)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (20), [M+H]+=597;

isopropylated 4-({ethyl[7-(4-forbindelseshandtering)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (21), [M+H]+=531;

isopropylated 4-({ethyl[7-(4-triftormetilfullerenov)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}methyl)piperidine-1-carboxylic acid, (22), [M+H]+=531;

isopropylated 4-({[7-(biphenyl-4-sulfonylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]ethylamino}methyl)piperidine-1-ka is oil acids, (23), [M+H]+=589; and

isopropylated 4-[(ethyl{7-[2-(4-isobutylphenyl)propionamido]-1,2,3,4-tetrahydronaphthalen-2-yl}amino)methyl]piperidine-1-carboxylic acid, (24), [M+H]+=589.

Example 3

Methylamide 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid

Step 1: tert-butyl ether 4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)methyl]piperidine-1-carboxylic acid

To a solution of 7-methoxy-3,4-dihydro-1H-naphthalene-2-she (1.0 g, 5,67 mmol) and tert-butyl methyl ether 4-aminomethylpyridine-1-carboxylic acid (1,34 g, 6,23 mmol) in dichloroethane (50 ml) under nitrogen atmosphere at once add triacetoxyborohydride sodium (3.0 g, of 14.2 mmol, 2.5 EQ.). The reaction mixture was stirred at room temperature for 24 h the Reaction mixture was concentrated in vacuo and separated between EtOAc (100 ml) and 5%aqueous solution of KOH (50 ml). The aqueous layer was extracted twice using ethyl acetate (2×50 ml). The combined organic layers washed with saturated salt solution, dried over MgSO4filter and concentrate. After rapid chromatography on silica gel with elution with a mixture of 5% methanol/methylene chloride receive tert-butyl ester 4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)methyl]piperidine-1-carboxylic acid in the form of an oily material (2.1 g).

Article is Diya 2: tert-butyl ether 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid

To a solution of tert-butyl ester 4-[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)methyl]piperidine-1-carboxylic acid (2.1 g, 5.6 mmol) and propionic aldehyde (0.45 ml, 6,23 mmol) in dichloroethane (20 ml) under nitrogen atmosphere at once add triacetoxyborohydride sodium (3,09 g, 14,15 mmol, 2.5 EQ.). The reaction mixture was stirred at room temperature for 24 h, then concentrated in vacuo. The remainder is divided between EtOAc (75 ml) and 5%aqueous solution of KOH (50 ml). The aqueous phase is extracted twice using EtOAc (2×30 ml). The combined organic layers dried over MgSO4, filtered and concentrated on silica gel (10 g). The resulting substance is placed on the column for rapid chromatography and elute using 20% acetone in hexane. The fractions containing the target substance are combined and concentrated, thus obtaining tert-butyl ester 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid (2.4 g).

Stage 3: (7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidine-4-iletildigini

To a solution of tert-butyl ester 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid (2.4 g, 4,56 mmol) in methylene chloride (30 ml) under nitrogen atmosphere add triperoxonane acid (10 ml). actionnow the mixture is stirred at room temperature for 30 min and concentrated in vacuo. The remainder is divided between EtOAc (50 ml) and 10%aqueous solution of KOH (50 ml). The organic layer is separated, dried over MgSO4, filtered and concentrated, thus obtaining (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidine-4-ylmethyl-Propylamine (1,62 g).

Stage 4: methylamide 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid

To a solution of (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidine-4-iletilammina (200 μl of 0.25 M solution in dichloromethane, 50 µmol) add 220 ál of 0.25 M solution of methyl isocyanate in acetonitrile and 30 μl of DIEA. The mixed solution is kept for 24 h at 25°C in an atmosphere of N2and then concentrated in vacuo. The final product is separated by preparative OF GHUR (column YMC Combiprep ODS-A, 10-90% acetonitrile:water with 0.1% TFU)), while receiving methylamide 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid (17,1 mg), 25 [M+H]+=374.

In accordance with the procedure described above in example 3, stage 4, but replacing the methyl isocyanate with a suitable isocyanate, sulphonylchloride, carbamoylation or acid chloride, receive the following connections:

adamantane-1-alamid 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (26), [M+H]+=494;

isopropyl the d 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (27), [M+H]+=402;

(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanol, (28), [M+H]+=430;

diethylamid 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (29), [M+H]+=416;

diisopropylamide 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (30), [M+H]+=444;

(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)pyrrolidin-1-ylmethanone, (31), [M+H]+=414;

dimethylamide 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (32), [M+H]+=388;

methylphenylene 4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (33), [M+H]+=450;

(1-benzosulfimide-4-ylmethyl)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine, (34), [M+H]+=457;

(1-methanesulfonamido-4-ylmethyl)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine, (35), [M+H]+=395;

7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-[1-(propane-2-sulfonyl)piperidine-4-ylmethyl]Propylamine, (36), [M+H]+=423;

[1-(2-chlorobenzenesulfonyl)piperidine-4-ylmethyl]-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine, (37), [M+H]=491;

(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-[1-(1-methyl-1H-imidazol-4-sulfonyl)piperidine-4-ylmethyl]the cuts is n, (38), [M+H]+=461;

1-(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-2,2-DIMETHYLPROPANE-1-(39), [M+H]+=401;

1-(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-3-methylbutane-1-he, (40), [M+H]+=401;

(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)thiophene-2-ylmethanol, (41), [M+H]+=427;

isoxazol-5-yl-(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)methanon, (42), [M+H]+=412;

1-(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-2,2-diphenylethanol, (43), [M+H]+=511;

1-(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-Etalon, (44), [M+H]+=359; and

(1-methanesulfonamido-4-yl)-(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)methanon, (45), [M+H]+=506.

In accordance with the procedure described above in example 3, but replacing in stage 1 7-methoxy-3,4-dihydro-1H-naphthalene-2-he-6-methoxy-3,4-dihydro-1H-naphthalene-2-it and using the appropriate acid chlorides, sulphonylchloride, carbamylcholine or isocyanates in stage 4, you receive the following connections:

adamantane-1-alamid 4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (46), [M+H]+=494;

(2-chlorophenyl)amide 4-{[(6-methoxy-1,2,3,4-tetrahydro Talin-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (47), [M+H]+=470;

tert-butylamide 4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (48), [M+H]+=416;

isopropylated 4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (49), [M+H]+=402;

methylamide 4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (50), [M+H]+=374;

(4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanol, (51), [M+H]+=430;

diethylamide-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (52), [M+H]+=416;

diisopropylamide 4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (53), [M+H]+=444;

(4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)pyrrolidin-1-ylmethanone, (54), [M+H]+=414;

dimethylamide 4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid (55), [M+H]+=388;

methylphenylene 4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid (56), [M+H]+=450;

(1-benzosulfimide-4-ylmethyl)-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine, (57), [M+H]+=457;

(1-methanesulfonamido-4-ylmethyl)-(6-methoxy-1,2,3,4-tetr hydronephrosis-2-yl)Propylamine, (58), [M+H]+=395;

(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-[1-(propane-2-sulfonyl)piperidine-4-ylmethyl]Propylamine, (59), [M+H]+=423;

[1-(2-chloro-benzazolyl)piperidine-4-ylmethyl]-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine, (60), [M+H]+=491;

(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-[1-(1-methyl-1H-imidazol-4-sulfonyl)piperidine-4-ylmethyl]Propylamine, (61), [M+H]+=461;

1-(4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-2,2-DIMETHYLPROPANE-1-(62), [M+H]+=401;

1-(4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-3-methylbutane-1-(63), [M+H]+=401;

(4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)thiophene-2-ylmethanol, (64), [M+H]+=427;

isoxazol-5-yl-(4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)methanon, (65), [M+H]+=412;

1-(4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-2,2-diphenylethanol, (66), [M+H]+=511;

1-(4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)Etalon, (67), [M+H]+=359

(1-methanesulfonamido-4-yl)-(4-{[(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)methanon, (68), [M+H]+=506.

In accordance with the procedure described above in example 3, but replacing 7-methoxy-3,4-dihydro-1H-naphthalene-2-he 6,7-di is ethoxy-3,4-dihydro-1H-naphthalene-2-he is in stage 1 and using the appropriate acid chlorides, sulphonylchloride, carbamylcholine or isocyanates in stage 4, you receive the following connections:

benzyl ether of 4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid (69), [M+H]+=481;

(4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)furan-2-ylmethanol, (70), [M+H]+=441;

(4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)thiophene-2-ylmethanol, (71), [M+H]+=457;

1-(4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-2-thiophene-2-ylatason, (72), [M+H]+=471;

1-(4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-Etalon, (73), [M+H]+=389;

(4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)-(3,5-dimethylisoxazol-4-yl)methanon, (74), [M+H]+=470;

(4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanol, (75), [M+H]+=460;

diethylamid 4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (76), [M+H]+=446;

(4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)pyrrolidin-1-ylmethanone, (77), [M+H]+=444;

dimethylamide 4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid (78), [MN] +=418;

(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methanesulfonamido-4-ylmethyl)Propylamine, (79), [M+H]+=425;

dimethylamide 4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-sulfonic acid, (80), [M+H]+=454;

(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propyl-(1-triftormetilfullerenov-4-ylmethyl)Amin, (81), [M+H]+=479;

(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propyl-[1-(thiophene-2-sulfonyl)piperidine-4-ylmethyl]amine, (82), [M+H]+=479;

methylamide 4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, (83), [M+H]+=404

[1-(5-chlorothiophene-2-sulfonyl)piperidine-4-ylmethyl]-(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine, (84), [M+H]+=527.

Example 4

N-{7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-yl}isobutyramide

Stage 1: (7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)piperidine-4-ylmethyl-Propylamine

To a solution of tert-butyl ester 4-{[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, obtained according to example 1. (1.12 g, 2,60 mmol) in methylene chloride (30 ml) under nitrogen atmosphere add triperoxonane acid (10 ml). The reaction mixture was stirred at room temperature for 30 min and concentrate the vacuum. The remainder is divided between EtOAc (50 ml) and 10%aqueous solution of KOH (50 ml). The organic layer is separated, dried over MgSO4, filtered and concentrated, thus obtaining (7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)piperidine-4-iletildigini (845 mg).

Stage 2: (1-methanesulfonamido-4-ylmethyl)-(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine, (122)

To a cooled in a bath with ice to a solution of (7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)piperidine-4-iletilammina (420 mg, 1.3 mmol) and pyridine (154 μl, 1.5 mmol, 1.2 EQ.) in methylene chloride (30 ml) in an inert atmosphere is added dropwise methanesulfonanilide (154 μl, 1.9 mmol, 1.5 EQ.). The reaction mixture is allowed to warm to room temperature and stirred for 24 hours the Reaction is stopped by the addition of water and separated layer with methylene chloride, dried (MgSO4) and concentrated, thus obtaining (1-methanesulfonamido-4-ylmethyl)-(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine in the form of a grayish-yellow solid (454 mg).

Stage 3: N-(1-methanesulfonamido-4-ylmethyl)-N-propyl-1,2,3,4-tetrahydronaphthalen-2,7-diamine

To a solution of (1-methane sulfanilimide-4-ylmethyl)-(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine (490 mg, 1.20 mmol) in ethanol (30 ml) is added 10%palladium on carbon (50 mg). R is the target shaken, using a shaking device Parra, within 24 h under hydrogen pressure of 55 pounds per square inch. The solution is filtered through celite and concentrated, thus obtaining N-(1-methane sulfanilimide-4-ylmethyl)-N-propyl-1,2,3,4-tetrahydronaphthalen-2,7-diamine (400 mg), (85), [M+H]+=380, which is directly used in the next stage.

Stage 4: N-{7-(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-yl}isobutyramide

To a solution of N2-(1-methanesulfonamido-4-ylmethyl)-N2-propyl-1,2,3,4-tetrahydronaphthalen-2,7-diamine (200 μl of 0.25 M solution in dichloromethane, 50 µmol) add 220 ál of 0.25 M solution of Isobutyraldehyde in dichloromethane and 30 μl of DIEA. The mixed solution is kept for 72 h at 25°C in an atmosphere of N2and then concentrated in vacuo. The final product is separated by preparative OF GHUR (column YMC Combiprep ODS-A"", 10-90% acetonitrile:water with 0.1% TFU)), thus obtaining N-{7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-yl}isobutyramide (10.4 mg), (86). [M+H]+=450.

In accordance with the procedure described above in example 4, stage 4, but replacing isobutyramide on a suitable acid chloride, sulphonylchloride or carboxaldehyde receive the following connections:

N-{7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-those whom raidernation-2-yl}-2,2-dimethylpropanamide, (87), [M+H]+=464;

N-{7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-yl}methanesulfonamide, (88), [M+H]+=458;

3-{7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-yl}-N-dimethylbenzenesulfonamide, (89), [M+H]+=487;

{7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-yl}amide pyrrolidin-1-sulfonic acid, (90), [M+H]+=513;

1-{7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-yl}-3-methyl-urea, (91), [M+H]+=437;

1-isopropyl-3-{7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-yl}urea, (92), [M+H]+=465;

1-tert-butyl-3-{7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-yl}urea, (93), [M+H]+=479

N2-ISO-butyl-N2-(1-methanesulfonamido-4-ylmethyl)-N2-propyl-1,2,3,4-tetrahydronaphthalen-2,7-diamine, (94) [M+H]+=436.

Example 5

N-(7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl] propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)isobutyramide

Stage 1: morpholine-4-yl-(4-{[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)methanon

It chilled in a bath with ice to a solution of (7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)piperidine-4-iletilammina, obtained according to the but example 4 (400 mg, 1.2 mmol), and triethylamine (170 μl, 1.4 mmol, 1.2 EQ.) in methylene chloride (40 ml) in an inert atmosphere is added dropwise morpholine-4-carbonylchloride (170 μl, 1.4 mmol). Remove the ice bath and the reaction mixture was stirred at room temperature for 4 h the Mixture with methylene chloride twice washed with water (30 ml), dried (MgSO4), filtered and concentrated, thus obtaining the morpholine-4-yl-(4-{[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)methanon in the form of a colorless oily substance (540 mg).

Stage 2: (4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanol

To a solution of morpholine-4-yl-(4-{[(7-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)methanone (540 mg, 1.2 mmol) in ethanol (30 ml) is added 10%palladium on carbon (50 mg). The solution is shaken using a shaker device Parra, within 24 h under hydrogen pressure of 55 pounds per square inch. The solution is filtered through celite and concentrated, thus obtaining (4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanol (432 mg), (95), [M+H]+=415, which is directly used in the next stage.

Stage 3: N-(7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)isobutyramide

To a solution of (4-{[(7-amino-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanone (200 μl of 0.25 M solution in dichloromethane, 50 µmol) add 220 ál of 0.25 M solution of Isobutyraldehyde in dichloromethane and 30 μl of DIEA. The mixed solution is kept for 72 h at 25°C in an atmosphere of N2and then concentrated in vacuo. The final product is separated by preparative OF GHUR (column YMC Combiprep ODS-A, 10-90% acetonitrile:water with 0.1% TFU)), thus obtaining N-(7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)isobutyramide (8.6 mg), (96), [M+H]+=485.

In accordance with the procedure described above in example 5, step 3, but replacing isobutyramide appropriate acid chloride, sulphonylchloride, carbamoylation or carboxaldehyde receive the following connections:

2,2-dimethyl-N-(7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)-propionamide, (97), [M+H]+=499;

N-(7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)methanesulfonamide, (98), [M+H]+=493;

N-(7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)-N,N-dimethylbenzenesulfonamide, (99), [M+H]+=522;

(7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)amide, pyrrolidin-1-AlfaNova acid, (100), [M+H]+=548;

1-isopropyl-3-(7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)urea, (101), [M+H]+=500;

1-tert-butyl-3-(7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-yl)urea, (102), [M+H]+=514

(4-{[(7-isobutylamino-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanol, (103), [M+H]+=471.

Example 6

(7 Ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methanesulfonamido-4-ylmethyl)Propylamine

Stage 1: (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine

To a solution of 7-methoxy-3,4-dihydro-1H-naphthalene-2-she (6.0 g, and 39.7 mmol) in dichloroethane (130 ml) under inert atmosphere at once added Propylamine (3.4 ml, of 41.7 mmol, of 1.05 equiv.) and then triacetoxyborohydride sodium (21 g, 99,3 mmol, 2.5 EQ.). The reaction mixture is left under stirring at room temperature for 24 h the Mixture was concentrated in vacuo and separated between EtOAc (200 ml) and 5%aqueous NaOH solution (100 ml). The aqueous layer was extracted twice using EtOAc (2×70 ml). The combined organic layers washed with saturated salt solution (100 ml), dried over MgSO4filter and concentrate. The residue is placed in ether (125 ml) and treated with 1N HCl solution in ether. The salt is filtered off and dried, while e is ω hydrochloride (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine as a yellow-brown solid (5.0 g).

Stage 2: 2,2,2-Cryptor-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide

To a solution of (7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine (3.0 g, 11.7 mmol) in dichloromethane (100 ml) under inert atmosphere add pyridine (2.4 ml, of 29.3 mmol, 2.5 EQ.). To the resulting solution was added triperoxonane anhydride (1.8 ml, 12.9 mmol, 1.1 EQ.) and the mixture is left under stirring at room temperature for 24 h, the Reaction mixture was poured into 1M HCl, the organic layer is separated and concentrated in vacuo. The compound obtained is subjected to rapid chromatography on silica gel, elwira using 30% acetone in hexane, thus obtaining 2,2,2-Cryptor-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide in the form of oily substance (3.4 g).

Stage 3: 2,2,2-Cryptor-N-(7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide

To a cooled to -78°With a solution of 2,2,2-Cryptor-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide (3.4 g, 10.9 mmol) and tetrabutylammonium (4,43 g, 12,0 mmol) in dichloromethane (200 ml) in an inert atmosphere is added dropwise to trichloride boron (1M, 27,2 ml). The reaction mixture is heated to room temperature and stirred for 2.5 hours the Reaction is stopped by slowly adding water. The organic layer is separated and sosialt (MgSO 4). The resulting substance concentrate on silica gel (15 g) and placed on a column for rapid chromatography. After chromatography using 30% acetone in hexane as eluent get 2,2,2-Cryptor-N-(7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide in the form of a foamed substance (3.1 g).

Stage 4: N-(7-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2-Cryptor-N-propylacetamide

To a solution of 2,2,2-Cryptor-N-(7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide (1.0 g, of 3.32 mmol) in DMSO (30 ml) in an inert atmosphere add a suspension of tert-butoxide potassium (392 mg, 3,49 mmol, of 1.05 equiv.) in DMSO (10 ml). The reaction mixture was stirred at room temperature for 30 min and then added dropwise to ethyliodide (0,32 ml, 3,98 mmol, 1.2 EQ.). The reaction mixture was stirred for 2 h, the reaction is stopped with water and extracted using EtOAc (2×50 ml). The combined organic layers dried over MgSO4, filtered and concentrated on silica gel (10 g). The resulting substance is placed on the column for rapid chromatography and elute using 20% acetone in hexane, obtaining thus N-(7-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2-Cryptor-N-propylacetamide in the form of oily substance (660 mg).

Stage 5: (7 ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine

A solution of N-(7-ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2-Cryptor-N-propylacetamide (660 mg, 2.0 mmol) in methanol (30 ml) and 1N NaOH (30 ml) was stirred at room temperature for 30 hours, the Reaction mixture is concentrated and the residue separated between EtOAc (40 ml) and water (40 ml). The aqueous layer was extracted twice using EtOAc (2×30 ml). The combined organic layers washed with saturated salt solution (30 ml), dried (MgSO4) and concentrated, thus obtaining (7 ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine.

Stage 6: (7 ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methanesulfonamido-4-ylmethyl)Propylamine

To the solution obtained (7 ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine (200 μl of 0.25 M solution in 1,2-dichloroethane, 50 mmol) is added 220 μl solution of 1-(methylsulphonyl)-4-piperidinecarboxylate (0.25 M in 1,2-dichloroethane), then 30 μl of DIEA and 300 μl of 0.25 M suspension triacetoxyborohydride sodium in 1,2-dichloroethane. The solution is shaken at 25°C for 48 h in an atmosphere of N2. The reaction is stopped by adding 1 ml of 2%aqueous NaOH, and the mixture is transferred together with 0.5 ml of N2O and EtOAc working in the flask. The flask is shaken, the mixture is allowed to settle and the aqueous phase is removed and destroyed. The organic phase is washed with water, transferred into a test tube and concentrated in vacuo. The final product is separated pre is arational Of GHUR (column YMC Combiprep ODS-A, 10-90% acetonitrile:water with 0.1% TFU)), thus obtaining (7 ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methanesulfonamido-4-ylmethyl)Propylamine (8 mg), 104, [M+H]+=409.

In accordance with the procedure described above in example 6, step 1, but replacing 7-methoxy-3,4-dihydro-1H-naphthalene-2-he-6-methoxy-3,4-dihydro-1H-naphthalene-2-it, get the following connection:

(6 ethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methanesulfonamido-4-ylmethyl)Propylamine, (105), [M+H]+=409.

Example 7

7-{[1-(Morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid

Stage 1: 7 propylamino-5,6,7,8-tetrahydronaphthalen-2-ol

A solution of 2,2,2-Cryptor-N-(7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacetamide (340 mg, of 1.03 mmol) in methanol (30 ml) and 1N NaOH (30 ml) was stirred at room temperature for 30 hours, the Reaction mixture was concentrated and the residue separated between EtOAc (40 ml) and water (40 ml). The aqueous layer was extracted twice using EtOAc (2×30 ml). The combined organic layers washed with saturated salt solution (30 ml), dried (MgSO4) and concentrated, thus obtaining 7-propylamino-5,6,7,8-tetrahydronaphthalen-2-ol (240 mg).

Step 2: tert-butyl ether 4-{[(7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid

To a solution of 7-propylamino-5,6,7,8-tetrahydronaphthalen-2-ol (937 mg, 4.6 mmol) and tert-butyl methyl ether 4-formylpiperidine-1-carboxylic acid (1,46 g, 6,9 mmol) in dichloroethane (40 ml) in one step add triacetoxyborohydride sodium (2.1 g, 10,12 mmol). The reaction mixture is left under stirring at room temperature for 24 h the Reaction mixture was concentrated in vacuo and separated between EtOAc (75 ml) and 5%aqueous solution of KOH (75 ml). The organic layer is dried (MgSO4), filtered and concentrated, thus obtaining tert-butyl ester 4-{[(7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid (1,37 g).

Step 3: tert-butyl ether 4-{[propyl-(7-tripterocalyx-1,2,3,4-tetrahydronaphthalen-2-yl)amine]methyl}piperidine-1-carboxylic acid

It chilled in a bath with ice to a solution of tert-butyl ester 4-{[(7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid (300 mg, 0.75 mmol) in methylene chloride (30 ml) in an atmosphere of nitrogen was added triethylamine (0.16 ml, 1,125 mmol), then triftormetilfullerenov (0,08 ml, 0.78 mmol). The reaction mixture was stirred in an ice bath for 30 min and then added to water (60 ml). The organic layer is separated, dried over MgSO4, filtered and concentrated. After chromatography with 40% acetone in hexane receive tert-butyl ester 4-{[propyl-(7-tripterocalyx-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl}piperidine-1-carboxylic acid (220 mg).

Stage 4: 7-(piperidine-4-ylmethyl-propylamino)-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid

To a solution of tert-butyl ester 4-{[propyl-(7-tripterocalyx-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl}piperidine-1-carboxylic acid (220 mg, 0.41 mmol) in methylene chloride (5.0 ml) under inert atmosphere add triperoxonane acid (1.0 ml). The reaction mixture was stirred at room temperature for 1 h, the Reaction mixture was concentrated in vacuo and share between 1 N NaOH (20 ml) and EtOAc (30 ml). The organic layer is separated, dried (MgSO4) and concentrated, thus obtaining 7-(piperidine-4-ylmethyl-propylamino)-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid (114 mg).

Stage 5: 7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid

To a solution of 7-(piperidine-4-ylmethyl-propylamino)-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid (200 μl 0,19 M solution in acetonitrile, 36 µmol) add 220 ál of 0.2 M solution of morpholine-4-carbonylchloride in dichloromethane and 30 μl of DIEA. The mixed solution is kept for 48 h at 25°C in an atmosphere of N2and then concentrated in vacuo. The final product is separated by preparative OF GHUR (column YMC Combiprep ODS-A, 10-90% acetonitrile:water with 0.1% TFU)), thus obtaining 7-{[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid (12,8 mg) (106), [M+H]+=548.

In accordance with the procedure described above in example 7, step 5, but substituting morpholine-4-carbonylchloride appropriate acid chloride, carbamoylation or sulphonylchloride receive the following connections:

7-{[1-(isoxazol-5-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid (107), [M+H]+=530;

7-[(1-dimethylcarbamoyl-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid, (108), [M+H]+=506;

7-[(1-methanesulfonamido-4-ylmethyl)propylamino]-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid, (109), [M+H]+=513

7-{[1-(1-methyl-1H-imidazol-4-sulfonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ether triftormetilfullerenov acid, (110), [M+H]+=579.

Example 8

[7-(3-AMINOPHENYL)-1,2,3,4-tetrahydronaphthalen-2-yl]-(1-methanesulfonamido-4-ylmethyl)Propylamine

<> Stage 1: (7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine

To a solution of 7-bromo-3,4-dihydro-1H-naphthalene-2-it, obtained as described in J.Med.Chem. 1993, 36, 2279-2291, (5,2 g, 23 mmol) in 1,2-dichloroethane (30 ml) was added Propylamine (1.63 g, 28 mmol), then triacetoxyborohydride sodium (7,3 g, 34.5 mmol). The reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 24 h, after which the mixture was concentrated in vacuo. The obtained solid is divided between 1 M sodium hydroxide solution and ethyl acetate. Layer with ethyl acetate, washed with saturated salt solution, dried over magnesium sulfate and filtered, thus obtaining (7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine (2,75 g).

Stage 2: (7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methane sulfanilimide-4-ylmethyl)Propylamine

To a solution of (7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine (536 mg, 2 mmol) and 1-methanesulfonamido-4-carboxaldehyde (458 mg, 2,47 mmol) in dichloroethane (10 ml) add triacetoxyborohydride sodium (551 mg, 2.6 mmol) in one step. The reaction mixture was stirred at room temperature for 24 h the Reaction mixture was concentrated in vacuo and separated between EtOAc (75 ml) and 5%aqueous solution of KOH (75 ml). The organic layer is dried (MgSO4), fil the shape and concentrate, while receiving (7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methanesulfonamido-4-ylmethyl)Propylamine (857 mg), (111), [M+H]+=444.

Stage 3: [7-(3-AMINOPHENYL)-1,2,3,4-tetrahydronaphthalen-2-yl]-(1-methanesulfonamido-4-ylmethyl)Propylamine

In a test tube containing 2-3 mg of catalyst Pd(PPh3)4add 1 ml of the solution of (7-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methane sulfanilimide-4-ylmethyl)Propylamine (25 mmol DMA), then 120 μl of a solution of 3-aminophenylarsonic acid (30 mmol per DMA) and 200 ál of 1 N aqueous NaOH solution. The solution is shaken at 80°C for 4 h, concentrated and purified by chromatography, thus obtaining

[7-(3-AMINOPHENYL)-1,2,3,4-tetrahydronaphthalen-2-yl]-(1-methanesulfonamido-4-ylmethyl)Propylamine, (112), [M+H]+=456.

In accordance with the procedure described above in example 8, step 3, but replacing 3-aminophenylalanine a suitable acid derivative Bronevoy acid, receive the following connections:

[7-(4-methanesulfonyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-(1-methane sulfanilimide-4-ylmethyl)Propylamine, (113), [M+H]+=519;

(7-furan-2-yl-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methanesulfonamido-4-ylmethyl)Propylamine, (117), [M+H]+=431;

(7-furan-3-yl-1,2,3,4-tetrahydronaphthalen-2-yl)-(1-methanesulfonamido-4-ylmethyl)Propylamine, (118), [M+H]+=431;

(1-IU is analpenetration-4-ylmethyl)propyl-(7-pyridin-3-yl-1,2,3,4-tetrahydronaphthalen-2-yl)amine, (119), [M+H]+=442;

(1-methanesulfonamido-4-ylmethyl)propyl-[7-(1H-pyrrol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-amine, (120), [M+H]+=430

(1-methanesulfonamido-4-ylmethyl)propyl-(7-pyridin-4-yl-1,2,3,4-tetrahydronaphthalen-2-yl)Amin, (120), [M+H]+=420.

Example 9

7-{[1-(piperidine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethylisoxazol-4-sulfonic acid

Step 1: tert-butyl ether 4-({[7-(3,5-dimethylisoxazol-4-sulfonyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]propylamino}methyl)piperidine-1-carboxylic acid

To a cooled in a bath with ice to a solution of tert-Botafogo ether 4-{[(7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid, obtained as described in example 8 (1.0 g, 2.48 mmol), and triethylamine (0.52 in ml, by 2.73 mmol) in methylene chloride (75 ml) under inert atmosphere added dropwise 3.5 dimethylisoxazol-4-sulphonylchloride (535 mg, 2,73 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 24 hours the Reaction is stopped by the addition of water, the layer containing methylene chloride, separated, dried (MgSO4) and concentrated, thus obtaining tert-butyl ester 4-({[7-(3,5-dimethylisoxazol-4-sulfonyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl] propylamino}methyl)piperidine-1-karbonvansty (1,16 g).

Stage 2: 7-(piperidine-4-ylmethyl-propylamino)-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethyl-isoxazol-4-sulfonic acid

To a solution of tert-butyl ester 4-({[7-(3,5-dimethyl-isoxazol-4-sulfonyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]propylamino}methyl)piperidine-1-carboxylic acid (1,16 g, 2.1 mmol) in methylene chloride (30 ml) under nitrogen atmosphere add triperoxonane acid (10 ml). The reaction mixture was stirred at room temperature for 30 min and concentrated in vacuo. The remainder is divided between EtOAc (50 ml) and 10%aqueous solution of KOH (50 ml). The organic layer is separated, dried over MgSO4, filtered and concentrated, thus obtaining 7-(piperidine-4-ylmethyl-propylamino)-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethylisoxazol-4-sulfonic acid (847 mg).

Stage 3: 7-{[1-(piperidine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethylisoxazol-4-sulfonic acid

In an inert atmosphere mix 7-(piperidine-4-iletilammina)-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethylisoxazol-4-sulfonic acid (400 mg, 0.87 mmol), mono-tert-butyl ether piperidine-1,4-dicarboxylic acid (199 mg, 0.87 mmol, 1 EQ.), EDCI (166 mg, 0.87 mmol, 1 EQ.), the triethylamine (0.25 ml, to 1.79 mmol, 2 EQ.) and dichlormid is n (35 ml). The mixture is stirred at room temperature for 48 h and then concentrated in vacuo. The residue is placed in EtOAc (50 ml) and washed with water (30 ml), 1 N NaOH solution (30 ml), saturated salt solution (30 ml) and then dried (MgSO4). The solution is filtered and concentrated, thus obtaining a yellow oily substance. The obtained oily substance is subjected to rapid chromatography on silica gel, elwira using 20% acetone in hexane, obtaining thus protected amine in the form of a foamed substance (447 mg), which is removed using triperoxonane acid, as described in the proposal, while receiving 7- {[1-(piperidine-4-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethylisoxazol-4-sulfonic acid (320 mg), 114, [M+H]+=609.

Alternatively, by acylation of 7-(piperidine-4-iletilammina)-5,6,7,8-tetrahydronaphthalen-2-silt ester 3,5-dimethylisoxazol-4-sulfonic acid, obtained as described above in stage 2, using 1-methylpiperidin-4-carbonylchloride in conditions that are described in the text of the application example 5, get 7-{[1-(4-methylpiperazin-1-carbonyl)piperidine-4-ylmethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2-silt ester of 3,5-dimethylisoxazol-4-sulfonic acid, (115), [M+H]+=624.

Example 10

(4-{2-[((R)-7-Methoxy-1,2,3,4-t is traditonally-2-yl)propylamino]-ethyl}piperidine-1-yl)piperidine-4-ylmethanol

Stage 1: ((R)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-(2-piperidine-4-retil)Propylamine

To a solution of (R)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine (510 mg, 2.0 mmol) and tert-butyl ester 4-(2-oxoethyl)piperidine-1-carboxylic acid (500 mg, 2.2 mmol) in dichloroethane (40 ml) was added triethylamine (0.3 ml, 2.2 mmol) and triacetoxyborohydride sodium (1.0 g, of 4.75 mmol). The reaction mixture was stirred at room temperature for 24 h the Reaction mixture was concentrated in vacuo and separated between EtOAc (75 ml) and 5%aqueous solution of KOH (75 ml). The organic layer is dried (MgSO4), filtered and concentrated, thus obtaining oily substance (716 mg). After removing protection using 10 ml triperoxonane acid, as described in the proposal, receive ((R)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-(2-piperidine-4-yl-ethyl) - Propylamine.

Stage 2: (4-{2-[(R)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]ethyl}piperidine-1-yl)piperidine-4-ylmethanol

In an inert atmosphere mix ((R)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-(2-piperidine-4-yl-ethyl) - Propylamine (200 mg, 0.61 mmol), mono-tert-butyl ether piperidine-1,4-dicarboxylic acid (139 mg, 0.61 mmol), EDCI (117 mg, 0.61 mmol), HOBT (82 mg, 0.61 mmol), triethylamine (0.17 ml, 1.2 mmol) and dichloromethane (35 ml). The mixture premesis the Ute at room temperature for 48 h and then concentrated in vacuo. The residue is placed in EtOAc (50 ml) and washed with water (30 ml), 1 N NaOH solution (30 ml), saturated salt solution (30 ml) and dried (MgSO4). The solution is filtered and concentrated, thus obtaining an oily substance. The obtained oily substance is subjected to rapid chromatography on silica gel, elwira 20% acetone in hexane, obtaining thus protected amine (260 mg), which is removed using a 10 ml triperoxonane acid, as described in the proposal, obtaining (4-{2-[((R)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]-ethyl} piperidine-1-yl)piperidine-4-ylmethanone (200 mg), (116), [M+N]+=478.

Example 11

Composition for oral administration

Ingredient% wt./wt.
The active ingredient20,0%
Lactose79,5%
Magnesium stearate0,5%

The ingredients are mixed and fill the mixture in the capsule, approximately 100 mg in each capsule, one capsule is equivalent total daily dose.

Example 12

Composition for oral administration

Ingredient% wt./wt.
The active ingredient20,0%
Stearate is Agnes 0,5%
Sodium salt croscarmellose2,0%
Lactose76,5%
PVP (polyvinylpyrrolidine)1,0%

The ingredients are combined and granularit using a solvent such as methanol. The composition is then dried to form tablets (containing about 20 mg of active compound) in an appropriate device for the manufacture of tablets.

Example 13

Composition for oral administration

IngredientNumber
Active connection1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar25,5 g
Sorbitol (70%solution)is 12.85 g
"Veegum K (manufactured Vanderbilt Co.")1.0 g
A substance that improves the taste and smella 0.035 ml
Tinted substance0.5 mg
Distilled waterA quantity sufficient to bring the volume to 100 ml

Ingredients mesilat, receiving a suspension for oral administration.

Example 14

Composition for parenteral (IV)

Ingredient% wt./wt.
The active ingredient0.25 g
Sodium chlorideA quantity sufficient to make the solution isotonic
Water for injection100 ml

The active ingredient is dissolved in parts of water for injection. Then with stirring, add sufficient sodium chloride to make the solution isotonic. The solution is brought to the required mass, using the remaining water for injection, filtered through a membrane filter (0.2 microns) and packaged under sterile conditions.

Example 15

Composition for the manufacture of suppositories

Ingredient% wt./wt.
The active ingredient1,0%
Polyethylene glycol 100074,5%
Polyethylene glycol 400024,5%

The ingredients are melted and stirred on the steam bath, then poured into molds, 2.5,

Example 16

Composition for local use

Ingredients
grams
Active connection0,2-2
"Span 60"2
Twin 60 (Tween 60")2
Mineral oil5
Petrolatum10
Methylparaben0,15
Propylparaben0,05
BHA (bottled hydroxyanisol)0,01
WaterA quantity sufficient to bring the weight of the composition to 100 g

All ingredients, except water, are combined and heated with stirring to about 60°C. Then, with vigorous stirring, a sufficient amount of water at a temperature of about 60°With, in order to emulsify the ingredients, and then add water in a quantity sufficient to bring the weight of the composition to about 100 g

Example 17

Composition for nasal spray

As compositions for nasal spray was prepared several water suspensions containing approximately of 0.025-0.5% of active compound. The compositions optionally contain inactive ingredients such as microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose and the like ingredi the options. For adjustment of pH can be added chloromethane acid. Compositions for nasal spray can be delivered using a metering pump, usually upon delivery of approximately 50-100 microliters composition for one injection. The usual dosage regimen includes a 2-4 sprayed funds every 4-12 hours.

Example 18

Study of the binding of radioactive ligand

Inhibitory activity of the compounds according to the present invention in vitro was determined using a modification of techniques described in the article: Hegde, S.S. et al., Br.J.Pharmacol, 1997, v.120, p.1409-1418.

Use of the cell membrane of the ovarian cells of Chinese hamsters expressing recombinant muscarinic receptors man (m1-m5). The study was conducted with the use of radioactive ligand [3H]N-methylscopolamine (0.4 nm, specific activity 84 Curie·mmol-1) in a final volume of 0.25 ml of Tris-buffer Krebs. The nonspecific binding determined using 1 μm atropine. The study was conducted using the methodology developed by the closeness of the scintillations. Curves of competitive exclusion to build 10 concentrations of the studied compounds and analyzed using an iterative approximations of a curve, a given four-parameter logistic equation. Values pIC50(otricatelniy the logarithm value of the IC 50) translate in the pKi values, using the equation of Cheng-Prusoff.

Inhibitory activity against muscarinic receptors (expressed as the value pKi) for some of the compounds are given below:

StructureConnection # Examplem2m3
21to 7.32of 5.92
727,98to 6.19
2537,606,99
8547,89of 6.78
9558,28of 6.73
7037,376,48
10467,797,33
10777,796,83
11786,856,22
116108,608,29
11498,97,29
11597,667,17

Example 19

Model oxotremorine/pilocarpine-induced salivation (OIS/PIS) have shot rats

Female rats of the line "Sprague-Dawley" ("Charles River", weighing 200-300 g) is subjected to anesthesia with urethane (1.5 g/kg, subcutaneously) and tracheotomy. One femoral vein type cannula for injection of a medicinal product. After the stabilization period duration of 1 hour in rats subjected to preliminary processing methoctramine (only for the case of induction by oxotremorine (OIS)in order to initiate bradycardia, antagonist which is M2the receptor. Each animal intravenously injecting a measured dose of the filler or the specified connection. Ten minutes into the mouth of the animal has preliminarily placed the weighted strip of cotton, then the animal is injected metered quantity of filler or oxotremorine (0.1 mg/kg, intravenously)/pilocarpine (1 mg/kg, intravenously). 5 minutes after the introduction of oxotremorine/pilocarpine put fresh pads of cotton and collect saliva additional 5 minutes. Strip of cotton (after 5 - and 10-minute period) then again weighed to determine the amount of saliva released during the 10-minute period.

All received oxotremorine/pilocarpine group is comparatively using one-way analysis of variance. Pairwise comparison is performed with the use of the criterion Dannette (Dunnett). In the analysis using ordered data (nonparametric method) or data such as received (parametric methods), when selecting use the criterion of Bartlett (Bartlett), which determines the homogeneity of the dispersion. Groups filler/oxotremorine and filler/pilocarpine compare with the group of filler/filler, using the criteria rank-sum Wilcox (Wilcox). Determine the value of ID50for each connection in relation to the weight corresponding to the 10-minute total secretion for each animal. The sigmoid model is:

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

where ID50represents the dose required to ensure that visualreality, the value of which corresponds to half of the maximum response, N is the curve parameter, and max indicates the maximum of the response curve of the dependence of dose-response. Minimum response recorded on the model at time 0.

According to the study of the compounds according to the present invention have activity.

Example 20

The inhibition induced by an imposed displacement of bladder contractions in rats

The active compounds according to the present invention in relation to inhibition of muscarinic receptor is determined on rats using a modification of techniques described in: Hegde, S.S. et al., Proceedings of the 26th Annual Meeting of the International Continence Society, 1996 (August 27th - 30th), Abstract 126.

Female rats of the line "Sprague-Dawley" subjected to anesthesia with urethane and prepare the apparatus for intravenous administration of drugs and in some cases, the measurement of blood pressure, heart rate and vnutriepreserdna pressure. The effect of test compounds on depending on the injected volume capacity of the bladder define separate groups of animals. Induced entered displacement of the reflex contraction of the bladder cause by filling the bladder with saline. The compounds injected with cumulative 10-minutes is diversified intervals. Atropine (0.3 mg/kg, intravenously) administered at the end of the study as a positive control.

According to the study of the compounds according to the invention have activity.

Example 21

Antimuskarinovoe act occurs activity models have shot dogs

The active compounds according to the present invention in relation to inhibition of muscarinic receptor determine on dogs, using a modification of the method described in: Newgreen, D.T. et al., J.Urol, 1996, v.155 (Suppl.5), 1156.

Female dogs (Marshall Farms, North Rose, NY) no food for 18 hours before the experiment, provide water without restrictions. On the day of the experiment the dogs subjected to anesthesia and injected pentobarbital (36 mg/kg, intravenously, initially, then 5-10 mg/kg, intravenously, to maintain). Prior to the completion of the experiment, the dogs also injected fluid. Dogs subjected to artificial ventilation through an endotracheal tube using a respirator "Harvard" (Model 613). In both femoral vein and femoral artery enter the cannula for the introduction of drugs and blood pressure measurement, respectively. Blood pressure is measured using the sensor "Gould" (model P23XL) and recorded using a chart recorder "Gould" (model 3400). Perform sublingual incision, in order to open the duct of the left lower jaw, in which the use is m place the cannula for collection of saliva in pre-weighed vials. Left salivary gland naked through a submandibular incision. Chord-lingual nerve is isolated and placed on him the bipolar electrode for stimulation. Define the investigated reaction to the stimulation chord-lingual nerve, to confirm the correct location of the electrode.

After surgery infusion administered physostigmine (180 µg/kg/h intravenously) (a cholinesterase inhibitor) prior to the completion of the experiment. After a stabilization period of one hour spend two control stimulation chord-lingual nerve at 12 Hz, 10 V, with a duration of 0.5 milliseconds (Grass S48"). Chord-lingual nerve is stimulated for 20 s and 2 min, respectively, with a minimum of 10 minute intervals between each stimulation session. After you have received two consecutive control reaction, gradually introduce the filler or the specified connection, cumulative, for 3 minutes before each stimulation chord-lingual nerve. Experiments in which there was obtained the reaction salivation, do not include in subsequent analysis. Atropine (1.0 mg/kg, intravenously) is used as an intravenous control at the end of the study.

The average arterial blood pressure is calculated as (diastolic blood pressure)+(istoricheskoe blood pressure - diastolic blood pressure)/3. Heart rate is determined by the pulse. Saliva collected in pre-weighed vials and weighed after each collection in order to determine the weight of excreted saliva. Inhibition of the reaction of the salivary glands expressed as a percentage of the effect of atropine (1 mg/kg, intravenously).

Evaluation of the ED50

To determine the % of the maximum inhibition of salivation estimating parameters using nonlinear mixed models. When implementing this method at the start, use the subroutine PROC NLIN and iterations - routine PROC MIXED. This method involves the justice following sigmoid model of the process under investigation for ratio of dose - response:

where Response = % of maximum inhibition of bladder contractions at maximal impact, x=log10dose of treatment, and 4 parameters are: log10ED50(μ), maximum and minimum response (Max and Min) and curvature (σ). As a minimum take the 0%. This method assumes overall symmetry covariance structure. The correlation between the results of several measurements for the same animal is calculated using the method of iterative approximations of the curve, and this method estimate the desired parameters and limits them to ritalinic intervals, so that possible errors were within the respective interval.

Compared with baseline values

In order to compare the response to each dose with a reference value for each variable, spend two-factor analysis of variance for main effects (ANOVA), whereas the patient and the treatment, followed by checking for each dosage is taken into account by student's criterion. If the total effect processing according to analysis of variance (ANOVA) was not significant (p-value >0.05), and for each dose using the adjusted method Bonferroni (Bonferroni) p-values as p-values to test for paired by student's criterion.

According to the study of the compounds according to the present invention have activity.

Example 22

In vivo: activity antimuskarinovoe act occurs when bronchoconstrictive

Evaluate the antagonistic activity against methacholine induced bronchoconstriction and bradycardia on the model I shot rats in accordance with the methodology described in the article: Hirose et al, J.Pharm. Exp.Ther., 2001, v.297, p.790-797. Compounds are administered intravenously, orally or by intratracheal infusion to intravenous methacholine. As indicators of bronchoconstrictive use lung resistance and dynamic is such compliance.

Although in the description of the present invention presents various specific embodiments of the invention, a specialist in the art it will be clear that in accordance with the inventive concept within the scope of the present invention may be implemented in various modifications and equivalents used. In addition, can be implemented with various modifications, to adapt a particular situation, material, composition, method, stage or stages of the method in accordance with the purpose, intent and scope of the present invention. As expected, all such modifications are within the scope of the invention, which is defined by the attached claims.

1. Compounds of General formula

in which

And represents-C(O)R4or-S(O)2R5;

R1is a (C1-C6)-alkyl;

R2and R3independently in each case represent hydrogen, -OR', -NR'r R", -NR'r COR", -NR'"CONR'R", -NR'r SO2R", -NR'"SO2NR'r R", -OSO2R', heteroaryl representing pyrrolyl, pyridinyl, furanyl, where these groups heteroaryl are unsubstituted phenyl, substituted with one group selected from amino, (C1-C6)-alkylsulfonyl;

provided that R2The R 3both represent hydrogen;

R', R" and R'" independently in each case represent hydrogen, (C1-C6)-alkyl, halogen(C1-C6)-alkyl, diphenylmethyl, naphthyl, phenyl, phenyl-(C1-C6)-alkyl, the latter two groups, the phenyl group is unsubstituted or substituted by one or two groups selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen(C1-C6)-alkoxy, halogen, halogen(C1-C6)-alkyl, di-(C1-C6)-alkylamino, (C1-C6)-alkylsulfonyl and phenyl; isoxazolyl substituted by one or two groups (C1-C6)-alkyl, or R' and R" together with the nitrogen atom to which they are attached, may form a pyrolidine ring;

R4is a (C1-C6)-alkyl, benzyloxy, diphenylmethyl, -NRaRbwhere

Raand Rbare as defined below,

-Y-heteroaryl where heteroaryl is thienyl, furanyl, pyridinyl, isoxazolyl,

-Y-heterocyclyl where heterocyclyl is morpholinyl, pyrrolidinyl, piperazinil, piperidinyl,

where these groups heterocyclyl or heteroaryl are independently from each other unsubstituted or substituted by one or two groups selected from (C1-C )-alkyl, (C1-C6)-alkylsulfonyl; and the specified Y is a bond or (C1-C3-alkylen;

Rarepresents hydrogen, (C1-C6)-alkyl, (C3-C10-cycloalkyl or phenyl, unsubstituted or substituted with halogen,

Rbrepresents hydrogen or (C1-C6)-alkyl;

R5is a (C1-C6)-alkyl, halogen(C1-C6)-alkyl, -NRaRbwhere Raand Rbare as defined above, phenyl, imidazolyl, thiophenyl, where each independently of the other is unsubstituted or substituted by one group selected from (C1-C6)-alkyl, halogen; and

p is 1 or 2;

or their individual isomers or their pharmaceutically acceptable salts.

2. Compounds of General formula I according to claim 1, in which

And represents-C(O)R4or-S(O)2R5;

R1is a (C1-C6)-alkyl;

R2and R3independently in each case represent hydrogen, -OR', -NR'r R", -NR'r COR", -NR'"CONR'R", -NR'r SO2R", -NR'"SO2NR'r R", -OSO2R', heteroaryl representing pyrrolyl, pyridinyl, furanyl, where these groups heteroaryl are unsubstituted phenyl, substituted with one group selected from amino, (C1-C 6)-alkylsulfonyl;

provided that R2and R3both represent hydrogen;

R', R" and R'" independently in each case represent hydrogen,

(C1-C6)-alkyl, halogen(C1-C6)-alkyl, naphthyl, phenyl, phenyl-(C1-C6)-alkyl, the latter two groups, the phenyl group is unsubstituted or substituted by one or two groups selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen(C1-C6)-alkoxy, halogen, halogen(C1-C6)-alkyl, di-(C1-C6)-alkylamino, (C1-C6)-alkylsulfonyl;

isoxazolyl substituted by one or two groups (C1-C6)-alkyl, or R' and R" together with the nitrogen atom to which they are attached, may form a pyrolidine ring;

R4is a (C1-C6)-alkyl, benzyloxy, diphenylmethyl, -NRaRbwhere Raand Rbare as defined below,

-Y-heteroaryl where heteroaryl is thienyl, furanyl, pyridinyl, isoxazolyl,

-Y-heterocyclyl where heterocyclyl is morpholinyl, pyrrolidinyl, piperazinil, piperidinyl,

where these groups heterocyclyl or heteroaryl are independently from each other unsubstituted or substituted is passed one or two groups selected from (C1-C6)-alkyl (C1-C6)-alkylsulfonyl; and

where Y represents a bond or (C1-C3-alkylen;

Rais a (C1-C6)-alkyl, (C3-C10-cycloalkyl or phenyl, unsubstituted or substituted with halogen,

Rbrepresents hydrogen or (C1-C6)-alkyl;

R5is a (C1-C6)-alkyl, halogen(C1-C6)-alkyl, -NRaRbwhere Raand Rbare as defined above, phenyl, imidazolyl, thiophenyl, where each independently of the other is unsubstituted or substituted by one group selected from (C1-C6)-alkyl, halogen; and

p means an integer from 1 to 2;

or individual isomers or their pharmaceutically acceptable salts.

3. The compounds of formula I according to claim 1 or 2, in which a represents-C(O)R4.

4. The compounds of formula I according to claim 3 in which R4represents-NRaRb.

5. The compounds of formula I according to claim 4, in which R3is a (C1-C6)-alkyl or phenyl, and R13represents hydrogen or (C1-C6)-alkyl.

6. The compounds of formula I according to claim 3 in which R4is a (C1-C6)-alkyl.

7. The compounds of formula I, p is 3, in which R4represents a-Y-heterocyclyl or-Y-heteroaryl, in which Y represents a bond or (C1-C3-alkylen.

8. The compounds of formula I according to claim 7, in which heteroaryl selected from the group consisting of furan, thiophene, isoxazol.

9. The compounds of formula I according to claim 7, in which heterocyclyl is piperidinyl group, which is unsubstituted or substituted by one or two groups (C1-C6)-alkyl.

10. The compounds of formula I according to claim 1 or 2, in which a represents-S(O)2R5.

11. The compounds of formula I of claim 10, in which R5is a (C1-C6)-alkyl or halo(C1-C6)-alkyl.

12. The compounds of formula I of claim 10, in which R5represents-NRaRb.

13. The compounds of formula I indicated in paragraph 12, in which Rais a (C1-C6)-alkyl or phenyl, and Rbrepresents hydrogen or (C1-C6)-alkyl.

14. The compounds of formula I of claim 10, in which R5represents phenyl, which is unsubstituted or substituted (C1-C6)-alkyl, halogen.

15. The compounds of formula I of claim 10, in which R5represents thiophene and imidazole, which are unsubstituted or substituted by one group (C1-C6)-alkyl.

16. The compounds of formula Po one of claims 1, 2, 4-9, 11-15, in which R2and R3represent-OR', -OSO2R', phenyl, substituted by one group selected from amino, (C1-C6)-alkylsulfonyl or hydrogen, provided that R2and R3both signify hydrogen.

17. The compounds of formula I according to clause 16, in which R2and R3represent hydrogen or-OR', where R' represents a (C1-C6)-alkyl or halo(C1-C6)-alkyl, provided that R2and R3both signify hydrogen.

18. The compounds of formula I according to one of claims 1, 2, 4-9, 11-15, 17, in which R' represents a (C1-C6)-alkyl.

19. The compounds of formula I according p, in which R' represents ethyl or propyl.

20. The compounds of formula I according to claim 1, which is selected from the group consisting of

(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)piperidine-4-ylmethanone;

(1-methanesulfonamido-4-ylmethyl)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine;

dimethylamide 4-{[(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-carboxylic acid;

(4-{[(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanone;

(1-methanesulfonamido-4-ylmethyl)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)Propylamine; and

(4-{[(6,7-dimethoxy-1,2,3,4-tetrahed naphthalin-2-yl)propylamino]methyl}piperidine-1-yl)morpholine-4-ylmethanol.

21. The compounds of formula I according to claim 1, intended for use in the treatment and prevention of diseases susceptible to treatment with an antagonist of muscarinic receptor.

22. Pharmaceutical composition having antagonistic activity against muscarinic receptors M2 and/or M3, comprising a therapeutically effective amount of the compounds of formula I according to claim 1 in a mixture with an acceptable carrier.

23. The pharmaceutical composition according to item 22, in which the compound suitable for administration to the patient in such a painful condition that can be alleviated in the treatment of an antagonist of muscarinic receptor.



 

Same patents:

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinone of the general formula (VI): wherein R1, R2, R3 and R4 are chosen independently from group consisting of hydrogen atom (H) and halogen atom; each R5 means independently (C1-C12)-alkyl; R6 means -NR8-(CH2)mR9, -NR10R11 under condition that from 1 to 4 groups -CH2- can be substituted optionally with -OH; R8 means H; R9 means -NR10R11 wherein R10 and R11 mean (C1-C12)-alkyl, or R10 and R11 in common with nitrogen atom to which they are bound can form a heterocyclic group chosen from morpholinyl, pyrrolidinyl and piperidinyl under condition that the heterocyclic group can be substituted optionally with morpholino-group; J means -NH; L means carbon atom (C), and group -C(O)R6 is bound with L; K and M means -CR5; m = 1, 2, 3 or 4; p = 2. Method for synthesis of these compounds involves the addition reaction of compound of the general formula (III): wherein R* means R with compound of the formula (IV): wherein values R1, R2, R3 and R4 are given above with amine of the general formula (V): HR6 (V) wherein R6 is given above to form indolinone of the general formula (VI). Method provides synthesis of indolinone derivatives with the yield 25-85%.

EFFECT: improved method of synthesis.

20 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of inhibition, improved method of synthesis of compounds.

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes compound of the formula (I): wherein B represents oxygen atom (O) or -NR1; J represents 5-membered heteroaromatic ring representing group of the formula (J-1): optionally substituted with 1-2 radicals R5 wherein Q represents -NR5; each X, Y and Z represents independently nitrogen atom (N), -CH or - CR5; B1 represents O; R2 represents hydrogen atom (H) or (C1-C6)-alkyl optionally substituted with one halogen atom, or (C2-C6)-alkynyl; or R1 and R2 taken in common form a binding chain consisting of 2-3 members and comprising at least one carbon atom, optionally comprising one carbon atom as -C(=O), optionally substituted with R3 wherein R3 represents (C1-C2)-alkyl; each R represents independently H, (C1-C6)-alkyl, halogen atom or -CN; each R5 represents independently (C1-C6)-halogenalkyl or halogen atom, or each ring is substituted with one R6; each R6 represents independently halogen atom; n represents a whole number 1 or 2. Also, invention describes a composition used for control of insects and comprising the biologically effective dose of compound of the formula (I) and at least one additional component chosen from group comprising surface-active substances, solid and liquid diluting agents, and methods for control of insects with using compositions based on compounds of the formula (I) and compounds of the formula (I). Proposed compounds of the formula (I) possess insecticide activity and can be used in agriculture.

EFFECT: valuable insecticide properties of compounds and compositions.

11 cl, 26 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel oxazolidinones of the general formula (I): , their pharmaceutically acceptable salts, hydrates and salt hydrates that inhibit factor Xa selectively and possess anti-thrombosis effect. Also, invention relates to a method for synthesis of these compounds (variants) and using the known substituted oxazolidinones of the general formula (A): as agent inhibiting factor Xa selectively and possessing anti-thrombosis effect, and to a medicinal agent based on at least one compound of the formula (I) or at least one compound of the general formula (A). Values of substitutes R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are given in the invention claim.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and agent.

10 cl, 2 tbl, 252 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (1): and their salts wherein values R1, k, Ar, n, j, Y, R and R2 are determined in the invention claim. Novel compounds are able to modulate activity of chemokine receptors. Also, invention relates to using indicated compounds for treatment of human immunodeficiency virus or feline immunodeficiency virus and to a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 100 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention relates to derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide represented by the general formula (I): wherein R represents (C1-C6)-alkyl group that can be substituted with one or some halogen atoms; R1 represents hydrogen atom, (C1-C6)-alkyl group that can be substituted with one or some substituted chosen from group of substitutes A, (C2-C6)-alkenyl group or acyl group; X represents group of the formula -C-R2 or nitrogen atom; each among R2 and R3 represents independently hydrogen atom, halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from group of substitutes A, (C3-C7)-cycloalkyl group, (C2-C6)-alkenyl group, (C3-C7)-cycloalkenyl group, formyl group, group of the formula: -CH=NOR4 (wherein R4 represents hydrogen atom or (C1-C6)-alkyl group, cyano-group, phenyl group that can be substituted with one or some substitutes chosen from group of substitutes B, 5- or 6-membered heterocyclic group (heterocycle comprising 1-2 heteroatoms that are similar and chosen from nitrogen atom), (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or phenoxy-group. The group of substitutes A represents group consisting of halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, cyano-group and phenyl group. The group of substitutes B represents group consisting of halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from above given group of substitutes A, (C1-C6)-alkoxy-group that can be substituted with one or some substitutes chosen from above given group of substitutes A, or its salt. Also, invention relates to insecticide comprising a derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide or its salt as an active component and a carrier optionally. Also, invention relates to a method for synthesis of derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide. Invention provides synthesis of derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide possessing the high insecticide activity.

EFFECT: improved method of synthesis, valuable properties of derivatives.

18 cl, 3 tbl, 91 ex

FIELD: chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds of the general formula (I): wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents hydrogen atom, -CO-R3 wherein R3 represents (C2-C6)-alkyl substituted optionally with halogen atom, -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom or (C1-C4)-alkyl; R5 represents (C1-C8)-alkyl, (C2-C8)-alkenyl and others; Y represents compound of the formula: wherein R7 represents hydrogen atom or (C1-C4)-alkyl; R8 represents (C5-C8)-alkyl, (C4-C8)-cycloalkyl and others; X represents oxygen atom or sulfur atom and others. Also, invention relates to pharmaceutically acceptable salts of these compounds. Compounds of the formula (I) possess hypoglycemic and/or hypolipidemic activity and can be used in medicine in treatment of diabetes mellitus, hyperlipidemia, hyperglycemia, diseases caused by resistance to insulin and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 3 tbl, 131 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II): wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R1, R2 or R3; Ar means naphthyl; X means (C5-C8)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C1-C4)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C1-C6)-alkyls or group -CONH2, (C1-C6)-alkyl, nitrile, hydroxy-group, (C1-C6)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C1-C3)-alkyl or (C1-C5)-alkoxyalkyl, tetrahydrofuranyl-(C1-C3)-alkyl, nitrile-(C1-C3)-alkyl, carboxamide-(C1-C3)-alkyl; R1 means independently in each case (C1-C10)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C3-C6)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R2 means branched or unbranched (C1-C6)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C1-C4)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C1-C6)-alkoxy-group, hydroxy-group, mono- or di-(C1-C4)-alkyl-amino-group, group -OR6, nitro-group or group mono- or di-(C1-C4)-alkyl-amino-S(O)2 that is optionally partially or completely halogenated, or group -H2NSO2; R3 in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C1-C4)-alkynyl group or branched or unbranched (C1-C6)-alkoxy-group wherein each of them is optionally partially halogenated, -OR18 or (C1-C6)-alkyl optionally substituted with group -OR18, amino-group or mono- either di-(C1-C5)-alkyl-amino-group, (C2-C6)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C1-C4)-alkyl groups; R6 means (C1-C4)-alkyl that is optionally partially or completely halogenated; in each case R18 means independently hydrogen atom, (C1-C4)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

12 cl, 1 tbl, 38 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel oxazolidinones of the general formula (I): , their pharmaceutically acceptable salts, hydrates and salt hydrates that inhibit factor Xa selectively and possess anti-thrombosis effect. Also, invention relates to a method for synthesis of these compounds (variants) and using the known substituted oxazolidinones of the general formula (A): as agent inhibiting factor Xa selectively and possessing anti-thrombosis effect, and to a medicinal agent based on at least one compound of the formula (I) or at least one compound of the general formula (A). Values of substitutes R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are given in the invention claim.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and agent.

10 cl, 2 tbl, 252 ex

FIELD: organic chemistry, chemical technology, insecticides.

SUBSTANCE: invention relates to derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide represented by the general formula (I): wherein R represents (C1-C6)-alkyl group that can be substituted with one or some halogen atoms; R1 represents hydrogen atom, (C1-C6)-alkyl group that can be substituted with one or some substituted chosen from group of substitutes A, (C2-C6)-alkenyl group or acyl group; X represents group of the formula -C-R2 or nitrogen atom; each among R2 and R3 represents independently hydrogen atom, halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from group of substitutes A, (C3-C7)-cycloalkyl group, (C2-C6)-alkenyl group, (C3-C7)-cycloalkenyl group, formyl group, group of the formula: -CH=NOR4 (wherein R4 represents hydrogen atom or (C1-C6)-alkyl group, cyano-group, phenyl group that can be substituted with one or some substitutes chosen from group of substitutes B, 5- or 6-membered heterocyclic group (heterocycle comprising 1-2 heteroatoms that are similar and chosen from nitrogen atom), (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or phenoxy-group. The group of substitutes A represents group consisting of halogen atom, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group, cyano-group and phenyl group. The group of substitutes B represents group consisting of halogen atom, (C1-C6)-alkyl group that can be substituted with one or some substitutes chosen from above given group of substitutes A, (C1-C6)-alkoxy-group that can be substituted with one or some substitutes chosen from above given group of substitutes A, or its salt. Also, invention relates to insecticide comprising a derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide or its salt as an active component and a carrier optionally. Also, invention relates to a method for synthesis of derivative of N-heteroaryl-4-(halogenalkyl)nicotinamide. Invention provides synthesis of derivatives of N-heteroaryl-4-(halogenalkyl)nicotinamide possessing the high insecticide activity.

EFFECT: improved method of synthesis, valuable properties of derivatives.

18 cl, 3 tbl, 91 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted indoles or its pharmaceutically acceptable salts of the formula (I): , wherein R1 means hydrogen (H) atom, halogen atom, -CN, nitro-group, -SO2R4, -OH, -OR4, -SO2NR5R6, -CONR5R6, -COOH, -COOCH3, -NR5R6, phenyl, naphthyl or (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atom, -OR8 and -NR5R6 wherein x = 2; R2 means (C1-C7)-alkyl; R3 means phenyl, naphthyl or heteroaryl and each of them is possibly substituted with one or more substitutes chosen independently from H, halogen atom, -CN, -OH, -SO2R4, -OR4, -SO2NR5R6, -CONR5R6, phenyl, naphthyl, (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atoms, -OR8 and -NR5R6, -S(O)xR7 wherein x = 2; R4 means (C1-C6)-alkyl; R5 and R6 mean independently H, (C1-C6)-alkyl, or R5 and R6 in common with nitrogen atom to which they are bound can form 6-membered saturated heterocyclic ring comprising one atom chosen from -NR16; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; R16 means H, -COY-(C1-C4)-alkyl wherein Y means oxygen atom (O) and wherein alkyl group in the substitute group can be direct, branched or cyclic, and wherein heteroaryl means 5-6-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or means 6,6-condensed bicyclic aromatic ring system comprising one nitrogen atom. Compounds of the formula (I) can be used in production of a medicinal agent used in treatment of asthma and chronic obstructive disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

FIELD: chemistry of heterocyclic organic compounds, medicine.

SUBSTANCE: invention relates to a novel heterocyclic derivative of the formula (I'): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents-CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R5 represents (C2-C8)-alkenyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; R20 represents phenyl substituted with unsubstituted (C1-C6)-alkyl, (C1-C6)-alkyl substituted with fluorine atom, (C1-C4)-alkoxy-group, phenyl-(C1-C4)-alkoxy-group, hydroxyl group, halogen atom, nitro-group, unsubstituted amino-group or amino-group substituted with (C1-C4)-alkyl; n means a whole number from 1 to 4, or to its pharmaceutically acceptable salt. Also, invention relates to heterocyclic derivative of the formula (I): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R represents (C4-C8)-alkyl or (C2-C8)-alkenyl or -CO-C≡C-R6 wherein R6 represents (C1-C8)-alkyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; n means a whole number from 1 to 4, or its pharmaceutically acceptable salt. Compounds of the formulas (I') and (I) are effective as a hypoglycemic agent, hypolipidemic agent, agent improving resistance to insulin, therapeutic agent in treatment of diabetes mellitus, therapeutic agent in treatment of diabetes mellitus complications, agents enhancing tolerance to glucose, anti-arteriosclerotic agent, agents against obesity or agent for X syndrome.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 2 tbl, 56 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

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