Guanidine-containing compounds applicable as muscarinic receptor antagonists

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I

or its pharmaceutically acceptable salts wherein R1-3, R5-7, a, X, Y, Y', Y" and Z have the values specified in cl. 1 of the patent claim which are muscarinic receptor antagonists. The invention also refers to pharmaceutical compounds, methods for preparing and methods for using such compounds.

EFFECT: preparing the compounds applicable as muscarinic receptor antagonists.

25 cl, 18 ex

 

The prior art inventions

The present invention relates to guanidinium compounds possessing activity of antagonists of muscarinic receptors or anticholinergic activity. The invention relates also to pharmaceutical compositions containing these compounds, methods for their preparation and methods of use for treatment of pulmonary disorders.

Description of the prior art

Pulmonary or respiratory disorders such as chronic obstructive (seal) lung disease (CORD) and asthma, affect many millions of people around the world, and such violations are a major cause of morbidity and mortality.

It is known that antagonists of muscarinic receptors provide bronchosan actions, and therefore, such compounds are applicable for the treatment of respiratory disorders, such as CORD and asthma. If used for treatment of such disorders antagonists of muscarinic receptors is usually administered by inhalation. However, even with the introduction of inhalation significant amount of the antagonist of muscarinic receptor is often absorbed into the pulmonary circulation, leading to systemic side effects such as xerostomia, mydriasis and cardiovascular side effects.

In addition, many introduced by inhalation antagonists ICC is arenovich receptors have a relatively short duration of action, so you want to be entered multiple times a day. This regimen medications many times a day is not only inconvenient, but also creates a significant risk of inadequate treatment due to non-compliance of the patient circuit with the required frequency of dosing of the drug.

Accordingly there is a need for new antagonists of muscarinic receptors. In particular, there is a need for antagonists of muscarinic receptors with high activity and low systemic side effects with the introduction of inhalation and prolonged duration of action, thereby allowing you to enter the dose of a compound once a day or even once a week. In addition, there is a need for antagonists of muscarinic receptors with high affinity for the receptor and the long period of existence in the body. It is assumed that such compounds are particularly effective for the treatment of lung disorders, such as CORD and asthma, while reducing or eliminating side effects such as xerostomia and higher.

The invention

The present invention relates to new guanidinium compounds that have the activity of antagonists of muscarinic receptors or anticholinergic the banking activity. Discovered that among other properties, compounds of this invention have a high affinity binding for subtypes of muscarinic receptors hM2and hM3have a longer half-life, have more “therapeutic window” or have a higher activity compared with related compounds. Accordingly, it is expected that the compounds of the invention are applicable and suitable as therapeutic agents for the treatment of pulmonary disorders.

One aspect of the invention relates to compounds having the formula I

where

R1selected from C1-6of alkyl, -C2-6alkenyl, -C3-9cycloalkyl and heteroaryl; R2selected from aryl and heteroaryl; R3selected from H and-C0-1alkylene-OH or R3forms a double bond with R1; or-CR1R2R3together form a group of the formula

where A is selected from-O-, -S-, -CH2-, -CH=CH-, -CH2CH2-, -NH - and-N(CH3)-; and R4selected from H, halogen, -OH, -C1-8the alkyl and-C1-8alkoxy;

X is selected from-O - and-O-CH2-; when X is a bond, Y is-CH2-, Y' represents N and Y represents-CH2-; and, when X represents-O - or-O-CH2-, Y' performance, which defaults to a-CH-, Y is a bond and Y represents-CH2- or -(CH2)2or Y represents-CH2and Y represents-CH2-;

R5selected from fluorine and-C1-4of alkyl, and a is 0 or an integer from 1 to 3;

R6and R7independently selected from H and-C1-4the alkyl and, in addition, where one of R6or R7may be-NH2;

Z is selected from H, -C1-6of alkyl, -C1-3alkylene-Q, and-NH-C0-1alkylen-Q; Q is selected from C3-7cycloalkyl, aryl and heteroaryl and Q is optionally substituted by 1-5 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C0-2alkylene-COOH, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4of alkyl, -CONR8aR8b, -NH-C(O)-C1-4of alkyl, -N-di-C1-4the alkyl and-N+(O)O; R8aand R8bindependently selected from H and-C1-4of alkyl;

where R1and R2optionally substituted by 1-5 groups Raindependently selected from C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil, -C3-6cycloalkyl, cyano, halogen, -ORb, -C(O)ORb, -SRb, -S(O)Rb, -S(O)2Rb, -C(O)NRcRdand-NRcRd; each Rbindependently selected from H, -C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil and-C3-6cycloalkyl; each Rcand Rdindependently selected the C H -C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil and-C3-6cycloalkyl;

where each alkyl, Alchemilla, Alchemilla, Allenova and cycloalkyl group in Ra-d, R4-8and Z optionally substituted by 1-5 fluorine atoms; where each cycloalkyl in Ra-doptionally substituted by 1-3 substituents, independently selected from C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil, cyano, halogen, -O(C1-4the alkyl), -S(C1-4the alkyl), -S(O)(C1-4the alkyl), -S(O)2(C1-4the alkyl), -NH2, -NH(C1-4the alkyl) and-N(C1-4the alkyl)2where each alkyl, Alchemilla and Alchemilla group optionally substituted by 1-5 substituents fluorine atoms; and Allenova group within Z optionally substituted with 1-2 substituents independently selected from C1-2the alkyl and-OH; or their pharmaceutically acceptable salts.

Among the compounds of the formula I compounds of particular interest are compounds having a dissociation constant of inhibition (Kito associate with the receptor subtype M3less than or equal to 100 nm; in particular, with Kiless than or equal to 50 nm; more specifically, with Kiless than or equal to 10 nm; and more specifically, having a Ki of less than or equal to 1.0 nm.

Another aspect of the invention relates to pharmaceutical compositions, stereoseparation acceptable carrier and a compound of the invention. Such compositions may optionally contain other therapeutic agents such as steroidal anti-inflammatory agents (e.g. corticosteroids), agonists β2-adrenergic receptors, inhibitors of phosphodiesterase-4 and combinations thereof. Accordingly, in another aspect of the invention the pharmaceutical compositions contain a compound of the invention, the second active agent and a pharmaceutically acceptable carrier. Another aspect of the invention relates to the combination of active agents containing the compound of the invention and a second active agent. The compound of the invention can be made in the composition of the drug together with an additional agent(s) or separately from it. In the manufacture separately, the pharmaceutically acceptable carrier can include additional agent(s). Therefore, another aspect of the invention relates to a pharmaceutical combination compositions and combination contains a first pharmaceutical composition comprising a compound of the invention and a first pharmaceutically acceptable carrier, and a second pharmaceutical composition comprising a second active agent and a second pharmaceutically acceptable carrier. This invention relates also to a kit containing such pharmaceutical compositions, for example, where the first and second pharmaceutical compositions ablauts the separate pharmaceutical compositions.

Compounds of the invention have activity of antagonists at the muscarinic receptor, and therefore it is assumed that they are applicable as therapeutic agents for the treatment of patients suffering from disease or disorder that is treated by blocking the muscarinic receptor. Thus, one aspect of the invention relates to a method of inducing expansion of the bronchi of the patient, introducing the patient causes the bronchi number of compounds of the invention. The invention relates also to a method of treatment of pulmonary disorders such as chronic obstructive lung disease or asthma, containing the introduction to the patient a therapeutically effective amount of compounds of the invention. Another aspect of the invention relates to a method of creating antagonism against muscarinic receptor in a mammal, containing the introduction to the mammal generates antagonism against muscarinic receptor number of compounds of the invention.

Because compounds of the invention have activity of antagonists at the muscarinic receptor, such compounds are also used as research tools. Accordingly, one aspect of the invention relates to a method of applying the compounds of the invention as a means of research, p is item the method comprises conducting biological analysis using the compounds of the invention. Compounds of the invention can also be applied for the evaluation of new chemical compounds. Therefore, another aspect of the invention relates to a method for assessment of the test compounds in biological analysis, containing (a) conducting a biological assay with the use of the test compound to obtain a first magnitude analysis; (b) conducting the biological assay with the use of compounds of the invention for obtaining the second value analysis, where stage (a) is conducted either before, after, or simultaneously with the stage (b), and (C) compare the value of the first analysis stage (a) with the value of the second analysis stage (b). Examples of biological analyses include analysis of the binding of the muscarinic receptor and analysis of bronchospastic the mammal. Another aspect of the invention relates to a method of studying a biological system or sample containing muscarinic receptor, the method comprises (a) contacting the biological system or sample with a compound of the invention and (b) determining the effects caused by the action of the compound on the biological system or sample.

The invention relates also to methods and intermediate products, applicable for producing compounds of the invention. Accordingly, another aspect of the invention relates to a method for producing compounds of the invention containing (a) with the combination of the compounds (1) and compounds (2) in the conditions of formation of amide linkages and the removal of protection for the product with the formation of compound (3) or a combination of Mitsunobu or the interesterification reaction of the compound (1) and compounds (4) and removing protect the product with the formation of compound (5); (b) interaction of the compound (3) or compound (5) with compound (6) with the formation of compounds (7) and (C) the interaction of compounds (7) and compound (8) to obtain the compounds of formula I; where values of the compounds (1) to (9) are specified in the context. In other aspects the invention relates to products obtained by any of the methods in the context of methods.

Another aspect of the invention concerns the use of compounds of the invention for the manufacture of medicines, especially for the manufacture of the medicinal product applied for the treatment of pulmonary disorders or to induce antagonism against muscarinic receptor in a mammal. Another aspect of the invention concerns the use of compounds of the invention as a tool for research. Other aspects and embodiments of the invention described in this context.

Detailed description of the invention

In one aspect this invention relates to compounds having the formula I

or their pharmaceutically acceptable salts. This formula can also be indicated as

Used in context, the term “compound of the invention” includes all compounds encompassed by formula I, such as connections, Hacene formulas II-VIII. In addition, when the compound of the invention contains a basic or acidic group (for example, amino group or carboxyl group), the compound may exist as a free base, free acid or in the form of various salts. All such forms salts included in the scope of the invention. Accordingly, the person skilled in the art should understand that the reference to the connection in the context of, for example, reference to “a compound of the invention” or “compound of formula I includes a compound of formula I, and pharmaceutically acceptable salts of such compounds, unless otherwise specified. In addition, the scope of the invention included a solvate of the compounds of formula I.

Compounds of the invention can contain one or more chiral centers and therefore may exist in several stereoisomeric forms. When there are such chiral centers, this invention relates to racemic mixtures, pure stereoisomers (enantiomers or diastereomers, mixtures enriched with stereoisomer, and the like, unless otherwise specified. When the chemical structure is depicted without any stereochemistry, it is clear that all possible stereoisomers are included such structure. Thus, it is assumed that, for example, the term “compound of formula I” includes all possible stereoisomers sedimentologica this, when in the context shown or named stereoisomer, a specialist in this area should be clear that in the compositions of this invention may contain small amounts of other stereoisomers, unless otherwise specified, provided that the applicability of the composition as a whole is not excluded because of the presence of other isomers. Individual enantiomers can be obtained by numerous methods that are well known in the field, including chiral chromatography using a suitable chiral stationary phase or media, or chemical transformation of these diastereoisomers, separation of the diastereomers conventional means such as chromatography or recrystallization, then regeneration of the original enantiomers. In addition, when possible, all CIS-TRANS or E/Z-isomers (geometric isomers), tautomeric forms and topoisomerase forms of the compounds of the present invention is included in the scope of the present invention, unless otherwise stated.

In particular, the compounds of formula I contain a chiral center at the carbon atom indicated by the symbol * in the following partial formula (shown for clarity without the optional substituents), illustrated cycloalkyl R1that is cyclopentyl, aryl R2who is phenyl, and R3before the hat is HE:

In one embodiment of this invention, the carbon atom indicated by the symbol *has the (R)-configuration. In this embodiment, the compounds of formula I have the (R)-configuration at the carbon atom marked with *, or enriched stereoisomeric form having the (R)-configuration at this carbon atom. In another embodiment, the carbon atom indicated by the symbol *has the (S)-configuration. In this embodiment, the compounds of formula I have the (S)-configuration at the carbon atom marked with *, or enriched stereoisomeric form having the (S)-configuration at this carbon atom.

Compounds of the invention, as well as those compounds that are used in their synthesis, may include also labeled with isotopes compounds, i.e. compounds in which one or more atoms enriched with atoms having an atomic mass different from the atomic mass, predominantly found in nature. Examples of isotopes that can be incorporated into compounds of formula I, for example, include, but are not limited to,2H,3H,13C,14C,15N18O and17O.

Found that the compounds of the invention have activity of antagonists of muscarinic receptors. Discovered that among other properties, compounds of this innovation is about the invention have a high affinity binding for subtypes of muscarinic receptors hM 2and hM3have a longer half-life existence in the body and have a higher activity compared with related compounds, and it is assumed that such compounds are used as therapeutic agents for the treatment of pulmonary disorders.

The nomenclature used in the context for naming compounds of the invention, illustrated in the context of the examples. This item is installed using commercially available AutoNom software (MDL, San Leandro, California).

Representative embodiments of

Have in mind that the following substituents and number provide representative examples of various aspects and embodiments of the invention. It is assumed that these representative number further define and illustrate these aspects and embodiments of, and not assume that they exclude other ways to exercise or limit the scope of the invention. In this respect, the idea that a specific number or Deputy is preferred, in any case does not imply the exclusion of other numbers or deputies of the invention, unless otherwise specified.

R1may be-C1-6alkyl, -C2-6alkenylphenol, -C3-9cycloalkyl or heteroaryl group to which I is unsubstituted or substituted by 1-5 groups R a. Raindependently selected from C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil, -C3-6cycloalkyl, cyano, halogen, -ORb, -C(O)ORb, -SRb, -S(O)Rb, -S(O)2Rb, -C(O)NRcRdand-NRcRd. Each Rbindependently selected from H, -C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil and-C3-6cycloalkyl. Each group Rcand Rdindependently selected from H, -C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil and-C3-6cycloalkyl. In one embodiment, R1represents a C3-9cycloalkyl, in another embodiment, -C3-6cycloalkyl, i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and in another embodiment, R1represents a C5cycloalkyl, i.e. cyclopentyl. In one embodiment, R1represents a C1-6alkyl group such as-CH2CH(CH3)2. In another embodiment, R1represents a C2-6alkenylphenol group such as-CH2CHCH2. In one embodiment, R1is unsubstituted. In another embodiment, R1is heteroaryl, such as thiophenyl (including thiophene-2-yl and thiophene-3-yl).

Each alkyl, Alchemilla, Alchemilla, Allenova and cycloalkyl the group in R a, Rb, Rcand Rdmay be substituted by 1-5 fluorine atoms. In addition, each cycloalkyl in Ra-dmay be substituted by 1-3 substituents, independently selected from C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil, cyano, halogen, -O(C1-4the alkyl), -S(C1-4the alkyl), -S(O)(C1-4the alkyl), -S(O)2(C1-4the alkyl), -NH2, -NH(C1-4the alkyl) and-N(C1-4the alkyl)2where each alkyl, Alchemilla and Alchemilla group optionally substituted by 1 to 5 fluorine atoms.

R2may be an aryl group that is unsubstituted or substituted by 1-5 groups Rathat have the values specified above. In one embodiment, R2represents phenyl. In another embodiment, R2represents unsubstituted phenyl. In another embodiment, R2is heteroaryl, such as thiophenyl (including thiophene-2-yl and thiophene-3-yl).

R3can be H or-C0-1alkylene-OH or may form a double bond with R1that can be represented as

In one particular embodiment, R3represents-OH. In addition, -CR1R2R3together can form a group of the formula

where A represents a bond, -O-, -S-, -CH 2-, -CH=CH-, -CH2CH2-, -NH - or-N(CH3)and R4selected from H, halogen, -OH, -C1-8the alkyl and-C1-8alkoxy. The alkyl group in R4may be substituted by 1-5 fluorine atoms. In one particular embodiment,- CR1R2R3together form

In this embodiment, as shown, A represents-O -, and R4represents H.

In one embodiment, X is a bond, Y is-CH2-, Y' represents N and Y represents-CH2-you can submit as

In another embodiment, when X represents-O - or-O-CH2-, Y' represents-CH-, Y is a bond and Y represents-CH2- or -(CH2)2-you can submit as

respectively. In another embodiment, when X represents-O - or-O-CH2-, Y' represents-CH -, and both of Y and Y represents-CH2-that can be represented as:

R5selected from fluorine and-C1-4the alkyl. The number for a is 0 or an integer from 1 to 3. In one embodiment, a is 0. The alkyl group in R5may be substituted by 1-5 fluorine atoms.

R 6and R7independently selected from H and-C1-4the alkyl. In addition, one of R6or R7may be-NH2. In one embodiment, R6represents hydrogen or C1-4alkyl. In another embodiment, R7represents hydrogen. In one other embodiment, both of the R6and R7represent hydrogen. The alkyl group in R6and R7may be substituted by fluorine atoms. For example, R6and/or R7may be-CH3and-CFH2, -CF2H or-CF3.

Z is selected from hydrogen, -C1-6of alkyl, -C1-3alkylene-Q, and-NH-C0-1alkylen-Q. In another embodiment, Z represents-CH2-Q. In another embodiment, Z represents -(CH2)2-Q. in another embodiment, Z represents -(CH2)3-Q. in another embodiment, Z represents-NH-Q. in one another embodiment, Z represents-NH-CH2-Q. In another embodiment, Z represents hydrogen or C1-6alkyl. Examples of-C1-6alkyl groups include methyl, propyl, butyl and pentyl. Alkyl and alkylene group Z may be substituted by 1-5 fluorine atoms. In addition, Allenova group Z may be substituted by 1 or 2 substituents, together with the IMO selected from C 1-2the alkyl and-OH. For example, in one embodiment, Z represents-CH(CH3)-.

Q represents-C3-7cycloalkyl, aryl or heteroaryl group. Examples of-C3-7cycloalkyl groups include cyclopropyl, cyclohexyl and cycloheptyl. Examples of aryl groups include phenyl and naphthyl. In one embodiment, Q is a phenyl. Examples of heteroaryl groups include pyrrolidinyl, imidazolidinyl, thiazolidine, oxazolidine, fornillo, tiffaniejoy, triazolyl, pyrazolidine, isoxazolidine, isothiazolinone, pyridinoline, personilnya, pyridazinyl, pyramidalnou, triazinyl, indolenine, benzofuranyl, benzopyranyl, benzothiophene, benzoimidazole, benzothiazolyl, benzodioxolyl, pinolillo, izohinolinove, chinazolinei and khinoksalinona group. Especially interesting are thiazolidine (e.g., thiazol-2-yl and thiazol-4-yl), furazilina (e.g., furan-2-yl and furan-3-yl), teofilina (for example, thiophene-2-yl and thiophene-3-yl), pyrazolidine (for example, 1H-pyrazole-3-yl), pyridinoline (for example, pyridine-2-yl), indlela (for example, 1H-indol-2-yl, 1H-indol-4-yl and 1H-indol-5-yl), benzofuranyl (for example, benzofuran-5-yl), benzothiophene (for example, benzo[b]thiophene-2-yl and benzo[b]thiophene-5-yl) and benzodiox lilina (for example, benzo[1,3]dioxol-5-yl) group.

Q may be substituted by 1-5 groups R8independently selected from halogen (such as Cl and F), -C1-4the alkyl (for example, -CH3), -C0-4alkylene-OH (e.g.,- OH and-CH2OH), cyano, -C0-2alkylene-COOH, -C(O)O-C1-4the alkyl (for example, -C(O)O-CH3), -O-C1-4of alkyl (e.g.,- OCH3), -S-C1-4of alkyl (e.g.,- S,-CH3), -CONR8aR8b, -NH-C(O)-C1-4of alkyl, -N-di-C1-4the alkyl and-N+(O)O, where R8aand R8bindependently selected from H and-C1-4the alkyl. Each alkyl and Allenova group in R8may be substituted by 1-5 fluorine atoms. For example, R8may be fluorinated C1-4alkyl group, such as-CF3or fluoro-substituted-O-C1-4alkyl group, such as-OCF3.

In one embodiment, Q is substituted with one R8selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4of alkyl, and -- CONR8aR8bwhere each alkyl group is optionally substituted by 1-3 fluorine atoms. In another embodiment, Q is substituted by two groups of R8who are halogen atoms (which may be the same or different). In one embodiment, Q is an unsubstituted-C3-7cycloalkyl group. In one embodiment, the implementation of whom tvline Q represents an unsubstituted aryl group. In another embodiment, Q represents an aryl group having one group R8selected from halogen, -C1-4of alkyl, cyano, -C0-2alkylene-COOH, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4of alkyl, -CONR8aR8bwhere each alkyl group is optionally substituted by 1-3 fluorine atoms. In one another embodiment, Q represents an aryl group having two groups of R8who are halogen atoms. In one embodiment, Q is an unsubstituted heteroaryl group. In another embodiment, Q is a heteroaryl group having one group R8that represents a C1-4alkyl group.

In one embodiment, the invention relates to compounds having the formula I, in which R1represents isobutyl, cyclopentyl or thiophenyl; R2represents phenyl or thiophenyl; R3represents-OH or-CR1R2R3together form a group of the formula

a is 0; R6represents H or-C1-4alkyl; R7represents H; and Z represents H, -C1-6alkyl, -C1-3alkylen-Q or-NH-C0-1alkylen-Q; Q represents cyclohexyl, cycloheptyl, phenyl, benzodioxolyl, benzofuranyl, anstifter, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2; and the alkyl groups in R8optionally substituted by 1-5 fluorine atoms.

In another embodiment, the invention relates to a compound having the formula II

or its pharmaceutically acceptable salts, where R1-3, R6-7and Z have the meanings indicated for formula I. In one particular embodiment, the invention relates to compounds of formula II, where R1is cyclopentyl or thiophenyl; R2represents phenyl or thiophenyl; R3represents-OH; R6represents H or-C1-2alkyl; R7represents H; and Z represents-C1-6alkyl, -C1-3alkylen-Q or-NH-C0-1alkylen-Q; Q represents cyclohexyl, cycloheptyl, phenyl, benzodioxolyl, benzofuranyl, benzothiophene, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2, the alkyl group in R 8optionally substituted by 1-5 fluorine atoms.

Another variant embodiment of the invention relates to compounds having formula IIa

or their pharmaceutically acceptable salts, where R6and Z have the meanings indicated for formula I. In one particular embodiment, the invention relates to compounds of formula IIa, where R6represents H or-C1-2alkyl; Z represents-C1-6alkyl, -C1-3alkylen-Q or-NH-C0-1alkylen-Q; Q represents cyclohexyl, cycloheptyl, phenyl, benzodioxolyl, benzofuranyl, benzothiophene, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2; and the alkyl groups in R8optionally substituted by 1-5 fluorine atoms.

Another aspect of the invention relates to compounds having the formula IIb

or their pharmaceutically acceptable salts, where Q has the meanings indicated for formula I. In one particular embodiment, the invention relates to compounds of formula IIb, where Q represents cyclohexyl, cycloheptyl, phenyl, benzodioxolyl, benzofuranyl, benzodi is phenyl, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2; and the alkyl groups in R8optionally substituted by 1 to 5 fluorine atoms. In another embodiment, the invention relates to compounds of formula IIb, where Q is furanyl or thiophenyl.

Another aspect of the invention relates to compounds having the formula IIc:

or their pharmaceutically acceptable salts, where Z has the meanings indicated for formula I. In one particular embodiment, the invention relates to compounds of formula IIc, where Q represents phenyl, furanyl or thiophenyl; and phenyl in Q is optionally substituted by 1-2 groups R8independently selected from halogen and-C0-4alkylene-OH.

In another embodiment, the invention relates to a compound having the formula III:

or its pharmaceutically acceptable salts, where R1-3, R6-7and Z have the meanings indicated for formula I. In one particular embodiment, the invention relates to compounds of formula III, where R1is cyclopentyl; R2isone phenyl; R3represents-OH; R6and R7represent H; Z represents-C1-3alkylen-Q; Q represents a phenyl, benzofuranyl, furanyl, pyridinyl or thiophenyl and phenyl in Q is optionally substituted by 1-2 groups R8independently selected from halogen and-C0-4alkylene-OH.

In another embodiment, the invention relates to a compound having the formula IV:

or its pharmaceutically acceptable salts, where R1-3, R6-7and Z have the meanings indicated for formula I. In one particular embodiment, the invention relates to compounds of the formula IV, where R1represents isobutyl or cyclopentyl; R2represents phenyl; R3represents-OH; R6and R7represent H; Z represents-C1-6alkyl or C1-3alkylen-Q; Q represents a phenyl, furanyl, pyridinyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH and-O-C1-4the alkyl, and the alkyl groups in R8optionally substituted by 1-5 fluorine atoms.

A specific group of compounds of formula I are the compounds described in the provisional application for U.S. patent No. 60/967914 registered on 7 September 2007. This group includes the connection is by means of formula (I'):

where R1selected from C1-6of alkyl, -C2-6alkenyl and-C3-9cycloalkyl; R2represents aryl; R3selected from H and-C0-1alkylene-OH or forms a double bond with R1or-CR1R2R3together form a group of the formula:

where A represents a bond, -O-, -S-, -CH2-, -CH=CH-, -CH2CH2-, -NH - or-N(CH3)and where R4selected from H, halogen, -OH, -C1-8the alkyl and-C1-8alkoxy; X represents a bond, -O - or-O-CH2-; when X is a bond, Y is-CH2-, Y' represents N and Y represents-CH2-; when X represents-O - or-O-CH2-, Y' represents-CH - and Y is a bond and Y represents-CH2- or -(CH2)2or Y represents-CH2and Y represents-CH2-; R5selected from a fluorine atom and a-C1-4the alkyl and a is 0 or an integer from 1 to 3; R6and R7independently selected from H and-C1-4of alkyl, and further where one of R6and R7may be-NH2; Z is selected from H, -C1-6of alkyl, -C1-3alkylene-Q, and-NH-C0-1alkylene-Q, where Q is selected from C3-7cycloalkyl, aryl or heteroaryl, optionally substituted by 1-5 groups R8independently selected from halogen, C 1-4of alkyl, -C0-4alkylene-OH, cyano, -C0-2alkylene-COOH, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4of alkyl, -CONR8aR8b, -NH-C(O)-C1-4of alkyl, -N-di-C1-4the alkyl and-N+(O)O, where R8aand R8bindependently selected from H and-C1-4of alkyl; R1and R2optionally substituted by 1-5 groups Raselected from C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil, -C3-6cycloalkyl, cyano, halogen, -ORb, -C(O)ORb, -SRb, -S(O)Rb, -S(O)2Rb, -C(O)NRcRdand-NRcRdwhere each Rbindependently selected from H, -C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil and-C3-6cycloalkyl and each of Rcand Rdindependently selected from H, -C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil and-C3-6cycloalkyl; where each alkyl, Alchemilla, Alchemilla, Allenova and cycloalkyl group in Ra-d, R4-8and Z optionally substituted by 1-5 fluorine atoms; where each cycloalkyl in Ra-doptionally substituted by 1-3 substituents, independently selected from C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil, cyano, halogen, -O(C1-4the alkyl), -S(C1-4the alkyl), -S(O)(C1-4the alkyl), -S(O)2(C1-4the alkyl), -NH2, -NH(C1-4the alkyl) and-N(C1-4the alkyl)2where each alkyl, Alchemilla and al is ininna group optionally substituted by 1 to 5 fluorine atoms and Allenova group within Z optionally substituted by 1 or 2 substituents, independently selected from C1-2the alkyl and-OH; or their pharmaceutically acceptable salts.

In addition, particular compounds of the invention that are of interest include the compounds shown below in the examples and their pharmaceutically acceptable salts.

Definition

When describing the compounds, compositions, methods, and methods of the invention used the following terms have the following meanings, unless otherwise indicated. In addition, applied in the context of the form in the singular include the appropriate forms in the plural, unless the context of use clearly does not dictate otherwise. Have in mind that the terms “comprising”, “including” and “having” are included in the context and means that there may be additional elements other than the listed elements. All numbers representing quantities of ingredients, properties such as molecular weight, reaction conditions and so forth used in the context, should be understood as modified in all instances by the term “about”, unless otherwise specified. According to the numbers presented in the context are approximate numbers, which may vary depending on the desired properties that are trying to get the present invention. At least not as attempts to restrict the label of the doctrine of equivalents to the scope of the claims, each number should be understood at least in the context of the significant digits and by applying ordinary rounding.

The term “alkyl” means a monovalent saturated hydrocarbon group, which may be unbranched or branched. Unless otherwise stated, such an alkyl group typically contains from 1 to 10 carbon atoms and includes, for example, -C1-2alkyl, -C1-4alkyl and-C1-6alkyl. Representative alkyl groups include as an example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

When the concrete used in the context of the term assumes a certain number of carbon atoms number of carbon atoms indicated before the term in the form of lower index. For example, the term “-C1-4alkyl” means an alkyl group having from 1 to 4 carbon atoms, and the term “-C5-9cycloalkyl” means cycloalkyl group having 5 to 9 carbon atoms, where the carbon atoms have any suitable configuration.

The term “alkylene” means a divalent saturated hydrocarbon group, which may be unbranched or branched. Unless otherwise stated, such alkylene groups typically contain from 0 to 10 atoms ug is erode and include, for example, -C0-1alkylene-, -C0-2alkylene-, -C0-4alkylene-, -C0-5alkylene-, -C1-4alkylene-, -C1-2alkylene-, -C2-4alkylene-, -C2-5alkylen and-C3-6alkylen-. Representative alkylene group include as an example, methylene, ethane-1,2-diyl (ethylene), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl and the like. It is clear that when the term alkylene includes zero carbon atoms, such as-C0-1alkylene - or-C0-5alkylene-, we mean that such terms include the absence of carbon atoms, i.e. Allenova group is missing, but there is a covalent bond, a linking group, divided alkilinity term.

The term “alkenyl” means a monovalent unsaturated hydrocarbon group, which may be unbranched or branched and which has at least one, and usually 1, 2 or 3 carbon-carbon double bond. Unless otherwise stated, such alkeneamine groups typically contain from 2 to 10 carbon atoms and include, for example, -C2-4alkenyl and-C2-6alkenyl. Representative alkeneamine group include as an example, ethynyl, n-propenyl, Isopropenyl, n-but-2-enyl, n-Gex-3-enyl and the like. The term “albaniles” means a divalent alkenylphenol group and approximate alkenyl the new groups include-C 2-3albaniles-.

The term “alkoxy” means a monovalent group of formula-O-alkyl, where alkyl is mentioned in the context of values. Unless otherwise noted, these alkoxygroup usually contain from 1 to 10 carbon atoms and include, for example, -C1-4alkoxy and-C1-8alkoxy. Representative alkoxygroup include as an example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy and the like.

The term “quinil” means a monovalent unsaturated hydrocarbon group, which may be unbranched or branched and which has at least one, and usually 1, 2 or 3 carbon-carbon triple bond. Unless otherwise agreed, such alkyline groups typically contain from 2 to 10 carbon atoms and include, for example, -C2-4quinil and-C2-6quinil. Representative alkyline group include as an example atenil, n-PROPYNYL, n-but-2-inyl, n-Gex-3-inyl and the like.

The term “aryl” means a monovalent aromatic hydrocarbon having a single ring (i.e. phenyl) or condensed rings (i.e. naphthalene). Unless otherwise stated, such aryl groups typically contain from 6 to 10 carbon atoms in the ring and include, for example, -C6-10aryl. Representative aryl groups include ina as an example, phenyl and naphthalene-1-yl, naphthalene-2-yl and the like.

The term “cycloalkyl” means a monovalent saturated carbocyclic hydrocarbon group. Unless otherwise stated, such cycloalkyl groups typically contain from 3 to 10 carbon atoms and include, for example, -C3-6cycloalkyl, -C3-7cycloalkyl and-C5-9cycloalkyl. Representative cycloalkyl group include as an example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term “divalent hydrocarbon group” means a divalent hydrocarbon group, which consists mainly of carbon atoms and hydrogen atoms and which optionally contains one or more heteroatoms. Such divalent hydrocarbon groups can be unbranched or branched, saturated or unsaturated, acyclic or cyclic, aliphatic or aromatic, or combinations thereof. Divalent hydrocarbon group can optionally contain heteroatoms included in the hydrocarbon chain or as substituents attached to the carbon chain.

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

Referring to that used in the context of the phrase “with the formula” or “having the structure” is not a limitation and it is used in the same sense of the Les, as usual use the term “containing”.

The term “heteroaryl” means a monovalent aromatic group having one ring or two condensed rings and containing in the ring at least one heteroatom (typically 1-3 heteroatoms)selected from nitrogen atom, oxygen or sulfur. Unless otherwise stated, such heteroaryl groups typically contain from 5 to 10 carbon atoms in the ring and include, for example, -C2-9heteroaryl. Representative heteroaryl groups include as an example pyrrolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolin, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, benzofuranyl, benzopyranyl, benzothiophene, benzoimidazole, benzothiazole, benzodioxolyl, hinely, ethanolic, hintline, honokalani and the like, where the place of attachment is at any available carbon atom or nitrogen ring.

The term “optionally substituted” means that the group can be unsubstituted or may be substituted one or more times, for example 1-3 times or 1-5 times. For example, an alkyl group which is optionally substituted” 1-5 fluorine atoms, may be unsubstituted or may contain 1, 2, 3, 4 or 5 fluorine atoms.

The term “pharmaceutical is viable” refers to the substance, which is not biologically or otherwise unacceptable when used in the invention. For example, the term “pharmaceutically acceptable carrier” refers to a substance that can be incorporated into the composition and to enter the patient without inducing unacceptable biological action or interaction in an unacceptable way with other components of the composition. Such pharmaceutically acceptable substances usually meet the required standards of Toxicological and manufacturing testing and include such substances identified as suitable inactive ingredients of the Department for quality control of food, drugs and cosmetics in the USA.

The term “pharmaceutically acceptable salt” means a salt derived from a base or acid, which is acceptable for administration to a patient such as a mammal (e.g., salts having acceptable security for a mammal with this regimen medicines). However, it is clear that you do not want the salt under consideration by the invention, were pharmaceutically acceptable salts, for example salts of intermediate compounds that are not intended for administration to the patient. Pharmaceutically acceptable salts can be obtained from pharmaceutically acceptable inorganic or organic is a mini-bases and from pharmaceutically acceptable inorganic and organic acids. In addition, when the compound of formula I contains both a basic portion and an acid portion may be formed zwitterionic, and they are included in the applied context, the term “salt”. Salts derived from pharmaceutically acceptable inorganic bases include salts of ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(III), manganese(II), potassium, sodium and zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamin, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polianinova resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine and the like. Salts derived from pharmaceutically acceptable inorganic acids include salts of boric, carbonic, halogenations (Hydrobromic, hydrochloric, hydrofluoric or idiscovered), nitric, phosphoric, sulfamic and sulfuric acids. With the Lee, derived from pharmaceutically acceptable organic acids include salts of aliphatic hydroxyacids (such as citric, gluconic, glycolic, lactic, lactobionic, malic and tartaric acids), aliphatic monocarboxylic acids (e.g. acetic, butyric, formic, propionic and triperoxonane acids), amino acids (such as aspartic and glutamic acids), aromatic carboxylic acids (e.g. benzoic, p-chlorobenzoyloxy, diphenyloxides, hentaimovi, the hippuric and triphenylarsine acids), aromatic hydroxy acids (for example, o-hydroxybenzoic, p-hydroxybenzoic, 1-hydroxynaphthalene-2-carbon and 3-hydroxynaphthalene-2-carboxylic acid), ascorbic acid, dicarboxylic acids (e.g., fumaric, maleic, oxalic and succinic acids), glucuronic, almond, mucus, nicotine, orotovoy, Paveway, Pantothenic, sulfonic acids (for example, benzosulfimide, camphorsulfonate, agisilaou, econsultancy, isetionate, methansulfonate, naphthalenesulfonates, naphthalene-1,5-disulfonate, naphthalene-2,6-disulfonate and p-toluensulfonate acids), xinafoate acid and the like.

The term “therapeutically effective amount” means an amount sufficient for treatment when administered to a patient in need of treatment is, i.e. the amount of drug required to obtain the desired therapeutic effect. For example, a therapeutically effective amount for the treatment of chronic obstructive lung disease (CORD) is the number of connections required, for example, to reduce, suppress, eliminate or prevent symptoms of CORD or to treat the causes underlying CORD. On the other hand, the “effective” amount is the amount necessary to obtain the desired result, which may not necessarily be therapeutically effective amount. For example, when studying the system, causing antagonism against muscarinic receptor, “effective amount” may be the amount needed to create antagonism against receptor.

The term “treatment”used in the context, means the treatment of diseases or conditions (such as COPD) patient such as a mammal (particularly a human)that includes (a) preventing the disease or diseased condition, i.e. prophylactic treatment of the patient; (b) reducing the intensity of the disease or diseased condition, i.e. the elimination of the disease or pathological state or the induction of reverse development of diseases or conditions in patie the same; (C) suppressing the disease or diseased condition, i.e. slowing or stopping the development of the disease or diseased condition of the patient, or (d) reduce the symptoms of diseases or conditions in a patient. For example, the term “treatment of COPD may include prevention of occurrence of COPD, reducing the intensity of COPD, the suppression of COPD and reduce the symptoms of COPD. It is assumed that the term “patient” includes such animals, for example people who need treatment or prevention of diseases which are currently subjected to treatment for the prevention or treatment of a particular disease or morbid condition, as well as test-subjects in which compounds of the invention appreciate or which are used in the analysis, for example, the animal model.

It is assumed that all other applicable in the context of the terms have their ordinary meaning understood by the average expert in the field to which they relate.

General synthetic methods

Compounds of the invention can be obtained from readily available starting compounds using the following General methods and procedures described in the examples, or by other methods, reagents and reference compounds, which are known to the average person skilled in the art. Although the following method is implemented to illustrate a particular embodiment of the invention, it is clear that similarly, we can obtain other embodiments of the invention use the same or similar methods or other methods, reagents and reference compounds known to the average person skilled in the art. It should also be clear that when you specify a typical or preferred conditions of the method (i.e. temperature, reaction time, molar ratio of reactants, solvents, pressures, etc), you can also apply other conditions of the method, unless otherwise specified. Although the optimum reaction conditions usually vary depending on various reaction parameters, such as specific reagents, solvents, and used the number, the average person skilled in the art can easily determine suitable reaction conditions, using the common methods of optimization.

In addition, as should be obvious to the person skilled in the art, to prevent the participation of some functional groups in adverse events may be necessary or desirable conventional protective group. The choice of suitable protective groups for specific functional groups, as well as suitable conditions and reagents for protection or exemption from the protection of such functional groups are well known in this field. Functional groups that can be protected, so mo is to prevent adverse reactions, include, as an example, carboxypropyl, amino group, hydroxyl group, tirinya group, carbonyl group and the like. Representative carboxyamide groups include, but are not limited to, ethers, such as methyl, ethyl, tert-butyl, benzyl (Bn), p-methoxybenzyloxy (RMV), 9-fluorenylmethyl (Fm), trimethylsilane (TMS), tert-butyldimethylsilyloxy (TBS), diphenylmethylene (benzhydryl, DPM) and the like; amides and hydrazides. Representative hydroxyamine groups include, but are not limited to, silyl groups, including three With1-6alkylsilane groups, such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) and the like; esters (acyl groups)including1-6alcoholnye groups, such as formyl, acetyl and the like; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (RMV), 9-fluorenylmethyl (Fm), diphenylmethyl (benzhydryl, DPM) and the like, and ethers. Representative protective group for tylnej groups include simple thioethers and complex thioethers. Representative protective groups for carbonyl groups include acetals and ketals. If desired, you can apply a protective group other than the group described in the context. For example, many who okislennye protective groups and their introduction and removal are described in the publication by T. W. Greene and G. M. Wuts,Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and cited in the references. More specifically, the following diagrams use the following abbreviations and reagents.

R represents “aminosidine group”, a term which is used in the context to indicate a protective group suitable for preventing undesired reactions at the amino group. Representative aminosidine groups include, but are not limited to, tert-butoxycarbonyl (VOS), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and the like. To delete a group, R1apply standard method of removing the protection. For example, to remove the protective N-BOC-group you can use this reagent as HCl or 4 M HCl in 1,4-dioxane.

Suitable bases used in these circuits include, as an illustration, but not limited to, potassium carbonate, calcium carbonate, sodium carbonate, triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA), sodium hydroxide, potassium hydroxide, tert-piperonyl potassium, and metal hydrides.

Suitable inert diluents or solvents used in these circuits include, as an illustration, but without limitation, tetr hydrofuran (THF), acetonitrile (MeCN), toluene, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), chloroform, carbon tetrachloride (CHCl3), 1,4-dioxane, methanol, ethanol, water and the like.

Suitable reagents for combination of carboxylic acid and amine include hydrate of 1-hydroxybenzotriazole (HOBt), hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium (Rubor), hexaflurophosphate O-(7-asobancaria-1-yl-N,N,N',N'-tetramethylurea (HATU), dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI), carbonyldiimidazole (CDI) and the like. Of combination reaction is carried out in an inert diluent in the presence of a base and in the conventional conditions of formation of amide linkages.

All reactions are usually carried out at a temperature in the range of from about -78°C. to 100°C., e.g. at room temperature. Monitoring of the reaction is usually carried out using thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and/or IHMS to complete the reaction. The reaction can be completed in minutes, or it may be necessary hours, usually from 1-2 hours up to 48 hours. After completion of the reaction the mixture can be further processed to obtain the desired product. For example, the mixture can be subjected to one or more of the following procedures: the process of evaporation or distribution (e.g. the R, between ethyl acetate and water, or between 5% THF in ethyl acetate and 1 M phosphoric acid); extraction (for example, ethyl acetate, CHCl3, DCM solution of KOH/chloroform); washing (for example, saturated aqueous NaCl, saturated NaHCO3, Na2CO3(5%), CHCl3, HCl or NaOH); drying (for example, over MgSO4or Na2SO4); the removal of solvent (e.g., in vacuum); filtering; concentration (e.g., in vacuum) and/or purification (e.g., chromatography on silica gel, flash chromatography or HPLC with reversed phase).

As an illustration, the compounds of formula I can be obtained in one or more of the following exemplary methods. All reagents are commercially available and/or can be easily synthesized by methods that are well known in this field.

Education of the head group in which X represents a bond

Connection (3) receive a combination of compounds (1) and (2) in the conventional conditions of formation of amide bond with the subsequent stage of the removal of protection.

Examples of the compound (1) include (R)-cyclopentylpropionate acid (R1is cyclopentyl, R2represents phenyl and R3represents hydroxy). Examples of the compound (2) include tert-butyl-1-piperidinecarboxylate (and avno 0, R1represents VOS).

Education of the head group in which X represents-O-

The compound (5) obtained by reaction of a combination of Mitsunobu (Mitsunobu and Yamada (1967) M.Bull. Chem. Soc. JPN. 40:2380-2382). The compound (1) and the compound (4) is subjected to reaction in the presence of phosphine catalyst such as triphenylphosphine, and azodicarboxylate, such as diethylazodicarboxylate or diisopropylethylamine, followed by a stage of removal of protection connection (5). The compound (5) can also be obtained by transesterification.

Examples of the compound (1) include (R)-cyclopentylpropionate acid (R1is cyclopentyl, R2represents phenyl and R3represents hydroxy). Examples of the compound (4) include tert-butyl ether (R)-3-hydroxypyrrolidine-1-carboxylic acid (0, R1represents the EGM, Y is a bond, Y' represents CH and Y represents-CH2-), tert-butyl ester 4-hydroxypiperidine-1-carboxylic acid (0, R1represents the EGM, Y is-CH2-, Y' represents CH and Y represents-CH2-or tert-butyl ester (R)-3-hydroxypiperidine-1-carboxylic acid (0, R1is The S, Y is a bond, Y' represents CH and Y represents -(CH2)2-).

Joining guanidino part to the head group - replacement 1thbenzotryazolyl part

DIPEA is added to the compound (3) or the compound (5) in a suitable solvent. Then add the compound (6), guanidinium agent and the reaction mixture was stirred at room temperature until completion of the reaction, usually within 30 minutes to several hours, thus obtaining the compound (7), which is used directly in the next stage. The compound (6) is easily obtained by the method described by Katritzky et al. (2000) J. Org. Chem. 65(23):8080-8082. An example of compound (6) is-(bisbenzimidazole-1-yl)Methylenebis (R6represents N).

Getting substituted guanidine

(Obtaining three - or Tetra-substituted guanidine)

Compound (7) is added to the compound (8) and the mixture was kept at room temperature or heated (~60°C) until completion of the reaction, usually about 14-24 hours. The reaction mixture is then cooled to room temperature, if necessary, and the solvent is removed. The crude substance is then purified, thus obtaining the compound of formula I. Examples of the compound (8) include 2-thiophenemethylamine, 4-hydroxybenzyl the min and benzylamine.

Additional details related to the specific reaction conditions, and other techniques for representative compounds of the invention or their intermediate products described in the examples below.

Utility

Compounds of the invention have activity of antagonists of muscarinic receptors and, in one embodiment, at nanomolar concentrations. In one embodiment, compounds of the invention are selective for inhibiting the activity of subtype muscarinic receptor M3compared with the inhibition activity of subtype muscarinic receptor M2. In another embodiment, compounds of the invention are selective for inhibiting the activity of subtypes of the muscarinic receptor M3and M2compared with inhibition activity subtypes of the muscarinic receptor M1, M4and M5. In addition, it is expected that the compounds of the invention possess the desired duration of action. Accordingly, in another specific embodiment, the invention relates to compounds having a duration greater than approximately 24 hours. In addition, it is also expected that compounds of the invention have reduced side effects such as xerostomia, PR is effective doses when administered by inhalation, in comparison with other known antagonists of muscarinic receptor entered by inhalation (such as tiotropy).

One indicator of the affinity of compounds against subtype receptor M3is the dissociation constant of inhibition (Kifor binding of the receptor. It is expected that the compounds of the invention have Kiin relation subtype receptor M3less than or equal to 100 nm, determined for example by analysis of the displacement of radioligand in vitro. Compounds of special interest includes compounds having the Kiless than or equal to 10 nm, and in another embodiment, the compounds have Kiless than or equal to 1.0 nm. Compounds, which are even more special interest includes compounds having the Kiless than or equal to 500 PM, and in another embodiment, the compounds have Kiless than or equal to 200 PM. It is noted that in some cases, compounds of the invention may have a weak activity of the antagonist of muscarinic receptor. In such cases, the person skilled in the art should understand that these connections are still applicable as a means of research.

Of particular interest are also compounds having ID50less than or equal to 100 mcg/ml after 24 hours on the Les dose, more specifically, compounds having ID50less than or equal to 30 μg/ml 24 hours after the dose.

The approximate analysis to determine properties of the compounds of the invention, such as the activity of the antagonist of muscarinic receptor described in the examples and include as an illustration, but not limited to, assays that measure the binding of muscarinic receptors hM1hM2hM3hM4and hM5(for example, as described in analysis 1). Applicable functional assays for determining the activity as an antagonist of muscarinic receptor compounds of the invention include as an illustration, but without limitation, assays that measure mediated by ligand changes in the content of intracellular cyclic monophosphate adenosine (camp)mediated ligand changes in the activity of the enzyme adenylylcyclase (which synthesizes camp), mediated by ligand changes in the incorporation of 5'-O-(γ-thio)triphosphate guanosine ([35S]γS) in the selected membrane catalyzed by receptor changes [35S]γS for GDF, mediated by ligand changes in free intracellular calcium ions (measured, for example, a tablet reader through fluorescent imaging or FLIPR®from Molecular Devices, Inc.) and t the th similar. The approximate analysis described in the analysis 2. It is expected that the compounds of this invention cause antagonism in relation to activation or reduce the activation of muscarinic receptors in any of the above tests, or assays of a similar nature and will usually be applied in these studies when the concentration of the component of approximately 0.1-100 nanomoles. Thus, the above analyses are applicable when determining therapeutic usefulness, for example bronchodilator activity, compounds of the invention.

Other properties and applicability of the compounds of the invention can be determined using various in vitro and in vivo are well known to the person skilled in the art. For example, the activity in vivo of the compounds of the invention can be measured in animal models, such as model Einthoven. In short, the bronchodilatory activity of the compounds evaluated in animal shot (Einthoven model) using pressure ventilation as a surrogate value of the resistance of the respiratory tract. See, for example, Einthoven (1892) Pfugers Arch. 51:367-445; and Mohammed et al. (2000) Pulm Pharmacol Ther.13(6): 287-92 and analysis 3, in which is described a rat model of Einthoven. In one embodiment, the compound of the invention, is introduced at a dose of 100 μg/ml in rat model Einthoven shows 35% or more than 35% inhibition of branches the surrounding reaction time at 24 hours and in another embodiment, shows 70% or more than 70% inhibition at the time of 24 hours. Other relevant analysis in vivo is the analysis of activism against stimulate salivation in rats (e.g., as described in the analysis 4).

It is expected that the compounds of the invention are applicable as therapeutic agents for the treatment of painful conditions mediated by muscarinic receptors. Therefore, it is assumed that patients suffering from disease or disorder that is treated by blocking muscarinic receptor, can be treated by introducing a therapeutically effective amount of an antagonist of muscarinic receptor of the invention. Such a painful condition include as an example, pulmonary disorders or diseases, including pulmonary disorders and diseases associated with reversible airway obstruction, such as chronic obstructive lung disease (e.g. chronic and stertorously bronchitis and emphysema), asthma, pulmonary fibrosis, allergic rhinitis, rhinorrhea, and the like. Other painful conditions that can be treated with antagonists of muscarinic receptors, are disorders of the genitourinary system, such as overactive bladder or increased activity of the detrusor and their symptoms; disorders of the gastrointestinal tract, such as irritable bowel syndrome, diverticular disease, achalasia, gastric is a rule-intestinal hypermotility disorders and diarrhea; cardiac arrhythmias, such as sinus bradycardia; Parkinson's disease; disorders of cognitive ability, such as Alzheimer's disease; dysmenorrhea and the like.

The amount of active agent, administered at the dose, or the total amount entered on the day, can be predetermined or can be determined for a particular patient based on numerous factors, including the nature and severity of the condition of the patient being treated, the condition, age, weight and General health of the patient, the tolerance of the patient to the active agent, route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the active agent, and any additional input (second) agents and the like. Treatment of a patient suffering from a disease or disease state (such as CORD), you can start with a predefined dose or dose determined by the attending physician, and continue during the period of time needed to treat, reduce, suppress or ameliorate symptoms of disease or conditions. Patients subjected to this treatment, usually subject to monitoring on an installed basis to determine the effectiveness of therapy. For example, in the treatment of CORD a significant improvement in the volume of the forced expiratory volume (measured per second) can be used to determine the effectiveness of treatment. Similar figures for other diseases and conditions described in the context of, well known to the person skilled in the art and readily available to the attending physician. Continuous monitoring by a physician, provides confidence that the optimal amount of active agent to be introduced at any given time, and also facilitates the determination of the duration of treatment. This is particularly important when introducing additional agents, as their choice, dose and duration of therapy may also require regulation. This way, the treatment regimen and the effect of medicines can be adjusted throughout the course of therapy, so as to introduce the least amount of active agent that exhibits the desired performance, and then this introduction continues only so long as is necessary for the successful treatment of diseases or conditions.

According to this, in one embodiment, compounds of the invention are applicable for treating disorders of the action of smooth muscles in mammals, including humans and their animal companions (e.g., dogs, cats etc). Such violations action of smooth muscles include as an illustration, overactive bladder, chronic obstructive pulmonary disease and syndrome irritable colon Ki is Ki. Suitable doses for the treatment of disturbances of action smooth muscle or other disorders mediated by muscarinic receptors will generally be in the range from approximately 0.14 mg/kg/day to about 7 mg/kg/day of active agent, including a dose of from about 0.15 μg/kg/day to about 5 mg/kg/day. For a person with an average weight of 70 kg, this dose can be from about 10 μg per day to about 500 mg per day of active agent.

In a particular embodiment, compounds of the invention are applicable for the treatment of pulmonary or respiratory disorders, such as CORD or asthma, in a mammal, including humans, by administration to the patient a therapeutically effective amount of the compounds. Dose for the treatment of pulmonary disorders usually will be about 10-1500 mg/day. The average person skilled in the art understands that the term “COPD” includes a variety of respiratory conditions including chronic obstructive bronchitis and emphysema and illustrated publications Barnes (2000) N. Engl. J. Med. 343:269-78, and cited them in links. When applying for the treatment of pulmonary disorders compounds of the invention optionally administered in combination with other therapeutic agents, such as agonist β2-adrenergic receptors; corticosteroid, non-steroidal of protiva sporitelny agent, or combinations thereof.

With the introduction of inhalation, the compounds of the invention typically have an effect on the bronchi. According to this in other aspects of the methods according to the invention the invention relates to a method of expansion of the bronchi of the patient, introducing the patient inducing bronchi number of compounds of the invention. A therapeutically effective dose to induce expansion of the bronchi is usually about 10-1500 mg/day.

In another embodiment, compounds of the invention are used for the treatment of overactive bladder. When applying for the treatment of overactive bladder typical dose is about 1.0 to 500 mg/day. In another embodiment, compounds of the invention are used to treat irritable bowel syndrome. If used for treatment of irritable bowel syndrome compounds of the invention are typically administered orally or rectally, and the usual dose is about 1.0 to 500 mg/day.

Since the compounds of this invention have activity of antagonists of muscarinic receptors, such compounds are also used as research tools for research or studying biological systems or samples containing muscarinic receptors. Any suitable biological system librates, contains muscarinic receptors M1, M2, M3, M4and/or M5you can apply for such studies, which can be carried out either in vitro or in vivo. Representative biological systems or samples that are suitable for such studies include, but are not limited to, cells, cell extracts, the plasma membrane, tissue samples, isolated organs, mammals (such as mice, rats, Guinea pigs, rabbits, dogs, pigs, people, and so forth), and the like, and of particular interest are mammals. In one specific embodiment of the invention antagonism against muscarinic receptor in a mammal cause the introduction of a number of compounds of the invention, the calling antagonism against muscarinic receptor. Compounds of the invention can also be used as research tools by conducting biological assays using such compounds.

When applied as a research tool a biological system or sample containing muscarinic receptor, usually in contact with a number of compounds of the invention, causing antagonism against muscarinic receptor. After the effect of the compound on the biological system or sample steps for creating antagonism in Rel is to muscarinic receptor determined using conventional techniques and equipment, for example, by measuring binding in the analysis of binding radioligand or mediated by ligand changes in functional analysis or determination of the degree of bronchospastic caused by the connection in the analysis of bronchospastic the mammal. The impact includes contacting cells or tissues with a compound introducing the compound to a mammal, such as intraperitoneal or intravenous injection, and so forth. This stage is the definition may contain the measurement of the reaction, i.e. quantitative analysis, or may include observation, i.e. qualitative analysis. Measurement of the reaction includes, for example, determining the action of the compound on the biological system or sample with the use of conventional techniques and equipment, such as analyses of the binding of radioligand and measurement mediated by ligand changes in functional assays. The results of the analysis can be applied to determine the level of activity and the number of connections required to achieve the desired result, i.e. the number, the caller's antagonism against muscarinic receptor. Stage definition usually involves identifying mediated by ligand action in relation to muscarinic receptors.

In addition, the compounds of the invention can be used as research tools for assessment of the key other chemical compounds and therefore, they are applicable also in screening assays to detect, for example, new compounds having activity of binding of muscarinic receptors. In this method, the compound of the invention used as a standard in the analysis to allow comparison of the results obtained with the test compound and the compounds of the invention to identify those test compounds that have about equal or better binding, if it exists at all. For example, data binding muscarinic receptors (defined, for example, in vitro displacement radioligand) for the test compound or group of test compounds is compared with the data binding muscarinic receptors for compounds of the invention to identify the compound that have the required properties, for example a compound having binding is approximately equal to or better than the compounds of the invention, if it exists at all. Alternatively, for example, bronchosan actions can be defined for the tested compounds and the compounds of the invention in the analysis of bronchospastic the mammal, and these data can be compared to identify test compounds that provide approximately equal to or better bronchosan actions. This aspects the invention includes as a separate embodiments as obtaining data for comparison (using appropriate assays), and data analysis tests to identify the interest of the tested compounds. So, the test compound can be evaluated in biological analysis method that contains the following stages: (a) conducting a biological assay with the test compound to get the size of the first analysis; (b) conducting the biological assay with a compound of the invention for obtaining a value of the second analysis, where the stage (a) is carried out either before or after, or simultaneously with the stage (b), and (C) compare the value of the first analysis stage (a) with the value of the second analysis stage (b). Examples of biological assays include assays of binding of muscarinic receptors.

Pharmaceutical compositions and preparations

Compounds of the invention are typically administered to the patient in the form of a pharmaceutical composition or drug. Such pharmaceutical compositions can enter the patient in any acceptable way of introduction, including but not limited to, inhalation, ingestion, local (including dermal and parenteral routes of administration. In addition, the compounds of the invention can be administered orally in the form of multiple doses per day as a single daily dose or a single dose weekly. It should be clear that any form compounds of the invention (i.e. the free base, the pharmaceutical is Eski acceptable salt, MES etc)that is appropriate for a particular way of introduction, can be applied in the discussed in the context of pharmaceutical compositions.

Accordingly, in one embodiment, the invention relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a compound of the invention. The composition may contain, if required, other therapeutic and/or used in the manufacture of the compositions of the agents. “Compound of the invention can also be called in the context of “active agent”.

The pharmaceutical compositions of this invention typically contain a therapeutically effective amount of a compound of the invention. However, the person skilled in the art should be understood that the pharmaceutical composition can contain more than a therapeutically effective amount, i.e. it can be in the form of compositions without packing (in bulk), or less than therapeutically effective amount, i.e. it can be in the form of single doses intended for numerous introductions to achieve therapeutically effective amount. In one embodiment, the composition will contain about 0.01 to 95 wt.% the active agent, including about 0.01 to 30 wt.%, for example, about 0.01 to 10 wt.%, moreover, the actual number depends on the Reparata, route of administration, dosing frequency, and so forth. In another embodiment, the composition is suitable for inhalation contains, for example, about 0.01 to 30 wt.% active agent, and in another embodiment, contains about 0.01 to 10 wt.% the active agent.

In the pharmaceutical compositions of the invention can be applied to any common carrier. The choice of the particular carrier, or excipient, or combinations of carriers or excipients will depend on the method of administration used for the treatment of a particular patient, or type of painful condition or pathological state. In this regard, getting the right composition for a particular method of introduction is quite within the competence of the specialist in the pharmaceutical field. In addition, carriers or excipients used in such compositions are commercially available. As an illustration, conventional methods of manufacturing are described in publications Remington: The Science and Practice of Pharmacy, 20thEdition, Lippincott Williams &White, Baltimore, Maryland (2000); and H. C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7thEdition, Lippincott Williams &White, Baltimore, Maryland (1999).

Representative examples of substances which can serve as pharmaceutically acceptable carriers include, but are not limited listed is, the following substances: sugar, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipients such as cocoa butter and waxes for suppositories; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as etiloleat and tillaart; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; water without pyrogens; isotonic saline; ringer's solution; ethyl alcohol; solutions of phosphate buffers; compressed gases as propellants such as chlorofluorocarbons and hydrofluorocarbons; and other non-toxic compatible substances used in pharmaceutical compositions.

Pharmaceutical compositions typically get a thorough mixing until smooth or mixing the active agent with a pharmaceutically acceptable carrier and one or more optional ingredients. Formed one the one mixed, the mixture can then be molded or download tablet, capsules, pills, containers, cartridges, transfer devices and the like using conventional methods and equipment.

In one embodiment, the pharmaceutical compositions are suitable for inhalation. Suitable compositions for inhalation are usually in the form of an aerosol or powder. Such compositions are typically administered using well-known devices for delivery, such as nebulizer-a nebulizer, an inhaler with a dry powder or a nebulizer with the filing of a dosed quantity, examples of which are described below.

In a specific embodiment of the invention the composition containing the active agent is administered by inhalation using inhaler-spray. Such devices for spraying usually form a stream of air with high speed, which causes the composition to be sprayed in the form of a mist, which is transferred to the respiratory tract of the patient. Accordingly, when the composition is manufactured for use in inhaler-spray, the active agent is typically dissolved in a suitable carrier to form a solution. Alternatively, the active agent can be ekranizirovat and be combined with a suitable carrier with the formation of a suspension of micronized particles with a size suitable for inhalation, where micronized agent will obyknovennoye as having particles at least about 90 percent of which have a mass mean diameter of less than approximately 10 microns. The term “mass average diameter” means the diameter at which half the mass of the particles contained in particles with a large diameter and half is contained in particles with a smaller diameter.

Suitable devices-sprayers include Respimat®Soft MistTMInhaler (Boehringer Ingelheim), the AERx®Pulmonary Delivery System (Aradigm Corp.) and the PARI LC PlusReusable Nebulizer (Pari GmbH). An exemplary composition for use in inhaler-nebulizer contains an isotonic aqueous solution containing from about 0.05 μg/ml to about 10 mg/ml compound of the invention. In one embodiment, such a solution has a pH of about 4-6.

In another specific embodiment, the composition containing the active agent is administered by inhalation using an inhaler with a dry powder (DPI). Such DPI is usually administered active agent in the form of a free flowing powder which is dispersed in the air flow during inhalation of the patient. To obtain a free flowing powder of the active agent is usually mixed with a suitable excipient, such as lactose, starch, mannitol, dextrose, polylactic acid, copolymer of polylactide and glycolide and combinations thereof. The active agent is usually micronizer and mixed with excipients for the floor is placed a mixture, suitable for inhalation. Accordingly, in one embodiment of the invention the active agent is micronized form. For example, a representative composition for use in DPI contains dry lactose having a particle size of between approximately 1 μm and approximately 100 μm (for example, dry milled lactose), and micronized particles of the active agent. Such a drug in the form of a dry powder can be produced, for example, by mixing lactose with the active agent and then dry mixing the components. Alternatively, if necessary, the active agent can be used to create excipients. The composition is then typically loaded into DPI, or in cartridges for inhalation, or capsules for use in DPI. DPI is well known to the average person skilled in the art, and many such devices are commercially available, and representative devices include Aerolizer®(Novartis), airmaxTM(IVAX), ClickHaler®(Innovata's Biomed), Diskhaler®(GlaxoSmithKline), Diskus®or Accuhaler (GlaxoSmithKline), Easyhaler®(Orion Pharma), EclipseTM(Aventis), FlowCaps®(Hovione), Handihaler®(Boehringer Ingelheim), Pulvinal®(Chiesi), Rotahaler®(GlaxoSmithKline), SkyeHalerTMor CertihalerTM(SkyePharma), Twisthaler (Schering-Plough), Turbuhaler®(AstraZeneca), Ultrahaler®(Aventis), and the like.

In another specific embodiment of the invention the computer is stand, containing the active agent is administered by inhalation using nebulizer, feeding a metered quantity (MDI). Such MDI typically produce a measured quantity of the active agent with the use of compressed gas as a propellant. Thus, drugs, feed metered quantity, usually contain a solution or suspension of the active agent in a liquefied propellant such as a chlorofluorocarbon, such as CCl3F or hydrofluroalkane (HFA), such as 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptathlon-n-propane (HFA 227), although the HFA is usually preferred due to the importance that the act chlorofluorocarbons on the ozone layer. Additional optional ingredients HFA include co-solvents such as ethanol or pentane, and surfactants, such as triolein sorbitan, oleic acid, lecithin and glycerin. See, for example, U.S. patent No. 5225183 name Purewal et al., EP 0717987 A2 (Minnesota Mining and Manufacturing Company), and WO 92/22286 (Minnesota Mining and Manufacturing Company). A representative composition for use in the MDI contains about 0.01 to 5 wt.% active agent, about 0-20 wt.% ethanol and about 0-5 wt.% surfactant, and the remainder of the composition is a propellant HFA. Such compositions are typically produced by adding chilled or compressed hydrofluroalkane coming in the second container, containing the active agent, ethanol (if used) and surfactant (if used). To obtain suspensions of the active agent micronizer and then combined with the propellant. The drug is then loaded into an aerosol container, which forms part of the MDI. MDI is well known to the average person skilled in the art, and many such devices are commercially available, and representative devices include AeroBid Inhaler System (Forest Pharmaceuticals), Atrovent Inhalation Aerosol (Boehringer Ingelheim), Flovent®(GlaxoSmithKline), Maxair Inhaler (3M), Proventil®Inhaler (Schering), Serevent®Inhalation Aerosol (GlaxoSmithKline), and the like. Alternatively, the drug is in suspension can be obtained by spray drying the coating of surfactant on micronized particles of the active agent. See, for example, WO 99/53901 (Glaxo Group Ltd.) and WO 00/61108 (Glaxo Group Ltd.).

Additional examples of methods of obtaining suitable for inhalation of particles and drugs and devices suitable for metered dose inhalation described in U.S. patent No. 5874063 name Briggner et al.; 5983956 name Trofast; 6221398 name Jakupovic et al.; 6268533 in the name of Gao et al.; 6475524 name Bisrat et al. and 6613307 in the name of Cooper.

In another embodiment, the pharmaceutical compositions are suitable for oral administration. Suitable compositions for oral administration can be in the form of capsules, tablets, pills, bread, sachets, pills, powders, granules; solutions or suspensions in aqueous or non-aqueous liquids; liquid emulsions of the type oil-in-water or water in oil; elixirs or syrups, and the like, and each form contains a predetermined quantity of active agent.

The composition is intended for oral administration in the form of solid dosage forms (i.e. in the form of capsules, tablets, pills and the like), typically contains an active agent and one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate. Solid dosage forms may also contain fillers or dry diluents, such as starch, microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or Arabian gum; humectants, such as glycerol; dezintegriruetsja agents, such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and/or sodium carbonate; agents, retarding dissolution such as paraffin; absorption accelerators, such as Quaternary ammonium compounds; wetting agents such as cetyl alcohol and/or glycerol monostearate; absorbents, such as Olin and/or bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and/or mixtures thereof; and coloring agents, and buffering agents.

In the pharmaceutical compositions can also contain release agents, wetting agents, agents that form coatings, sweeteners, gives taste and odor agents, preservatives and antioxidants. Examples of agents forming a coating on the tablets, capsules, pills and the like, include agents used for education intersolubility coatings, such as acetate-phthalate cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose, copolymers of methacrylic acid and methacrylic acid, acetate-trimellitate cellulose, karboksimetilcelljuloza, acetate-succinate of hydroxypropylmethylcellulose and the like. Examples of pharmaceutically acceptable antioxidants include : water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, metabisulfite sodium, sodium sulfite and the like; soluble in oils antioxidants, such as ascorbyl palmitate, bottled hydroxyanisol, bottled hydroxytoluene, lecithin, propylgallate, alpha-tocopherol, and the like, and chelating metals agents, such as citric acid, this is indiainteracts acid, sorbitol, tartaric acid, phosphoric acid and the like.

You can also make the composition to provide slow or controlled release of the active agent with the use, as an example, hydroxypropylmethylcellulose in varying proportions, or other polymer matrices, liposomes and/or microspheres. In addition, the pharmaceutical compositions of the invention may contain agents, giving them the opacity, and can be made so that they release the active agent only or preferably in a particular part of the gastrointestinal tract, optionally, the slow way. Examples of compositions filled, which can be used include polymeric substances and waxes. The active agent can also be in microencapsulated form, if you want one there are several above-described excipients.

Suitable liquid dosage forms for oral administration include, as an illustration, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms typically contain an active agent and an inert diluent, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl JV is RT, the benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuranyl alcohol, polyethylene glycols and fatty acid esters and sorbitan and mixtures thereof. Suspensions can contain suspendresume agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylenated and esters sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant and mixtures thereof.

When the pharmaceutical compositions of the invention are intended for oral administration, they are produced in the form of dosage forms. The term “dosage form” refers to physically discrete unit suitable for the metered introduction of the patient, i.e. each unit contains a predetermined quantity of active agent calculated to induce the desired therapeutic effect either this unit or in combination with one or more additional units. Such dosage forms can be capsules, tablets, pills and the like.

Compounds of the invention can also enter parenteral (e.g. subcutaneous, intravenous, intramuscular or intraperitoneal inj what Ktsia). For such an introduction of the active agent to provide a sterile solution, suspension or emulsion. Examples of the solvents to obtain such drugs include water, saline, alcohols with low molecular weight, such as propylene glycol, polyethylene glycol, vegetable oil, gelatin, fatty acid esters, such as etiloleat, and the like. Typical parenteral drug is a sterile aqueous solution of the active agent with a pH of 4-7. Parenteral preparations can also contain one or more of solubilization, stabilizers, preservatives, wetting agents, emulsifiers and dispersing agents. These drugs can be done with sterile sterile injectable medium, sterilizing agent, filtration, irradiation or heating.

Compounds of the invention can also enter transdermally using known systems for percutaneous delivery and excipients. For example, the compound can be mixed with penetration enhancers, such as propylene glycol, monolaurate of polyethylene glycol, azacycloheptan-2-ones and the like, and to include in the patch, or similar delivery system. If necessary, in such percutaneous compositions can be applied more excipients, including agents, transforming the composition into a gel, emulsifiers and buffers.

If required is to be the compounds of this invention can be introduced in combination with one or more other therapeutic agents. Thus, in one embodiment, compositions of the invention can optionally contain other medicines that are injected together with the compound of the invention. For example, the composition may further contain one or more drugs (also called “additional (second) agents”)selected from the group of other bronchodilatory means (e.g., PDE inhibitors3, modulators of adenosine 2b and agonists β2-adrenergic receptor); anti-inflammatory agents (e.g., steroidal anti-inflammatory agents such as corticosteroids and corticosteroids; non-steroidal anti-inflammatory agents (NSAID) and PDE inhibitors4); other antagonists of muscarinic receptors (i.e. anticholinergic agents); anti-infective agents (e.g., gram-positive and gram-negative antibiotics and antiviral agents; antihistamines; protease inhibitors; afferent blockers (e.g., agonists D2and modulators neirokinina) and their combinations. Numerous examples of such therapeutic agents are well known in this field, and examples of them are described below. Combination with the unity of invention with the additional agent can be achieved dual therapy, i.e. the activity of the antagonist of muscarinic receptor and the activity associated with an additional agent (e.g., agonist β1-adrenergic receptor), in some cases, the introduction of two compositions, and in some cases the introduction of a single composition containing the active agent and an additional agent. According to this another aspect of the invention the pharmaceutical composition contains a compound of the invention, the additional active agent and pharmaceutically acceptable carrier. The third, fourth, etc. active agents can also be introduced into the composition. For example, the composition may contain the compound of the invention, the second agent selected from a corticosteroid, agonists β2-adrenergic receptor; inhibitors of phosphodiesterase-4 and combinations thereof, and a pharmaceutically acceptable carrier. In a specific embodiment, the composition comprises a compound of the invention, the agonist β2-adrenergic receptor and steroid anti-inflammatory agent. When combined therapy of a number of compounds of the invention administered, and the number of second agents may be less than the number usually introduced when alone.

The compound of the invention can either physically mixed with the second agent with the formation of a composition containing both agents; or each agent to moreproductive in separate and distinct compositions, which is administered to the patient simultaneously or sequentially. For example, the compound of the invention can be mixed with a second active agent using conventional techniques and equipment with the formation of a combination of active agents containing the compound of the invention and a second active agent. In addition, the active agents can be mixed with a pharmaceutically acceptable carrier with the formation of the pharmaceutical composition containing the compound of the invention, the second active agent and a pharmaceutically acceptable carrier. In this embodiment, the components of the composition are typically mixed or stirred with obtaining physical mixture. The physical mixture was then administered in a therapeutically effective amount by any of the methods in the context of ways.

Alternatively, the active agents can be isolated or separated before the introduction of the patient. In this embodiment, the agents are not physically mixed together before introduction, but is administered simultaneously or at different time points in separate compositions. Such compositions can be packaged separately or can be packaged together in a set. With the introduction of different time points of the second agent is usually administered less than 24 hours after administration of the compounds of the invention. In other embodiments, implementation of the proximity of these BP the time points is less than 12 hours, less than 8 hours, less than 6 hours less than 4 hours, less than 3 hours, less than 1 hour, less than thirty minutes, less than ten minutes, less than one minute, or second agent is administered immediately after administration of the compounds of the invention. This also applies to the sequential implementation. Thus, the compound of the invention can be activated by inhalation simultaneously or sequentially with another active agent applying device for inhalation, which is used isolated compartments (e.g., blister packs) for each active agent, where the sequential introduction could mean the introduction immediately after the introduction of the compounds of the invention or after a predetermined time (for example, later on one hour or later than three hours). Alternatively, the combination can be entered with the use of different devices for delivery, i.e. using a single device for delivery for each agent. In addition, the agents can be delivered by different routes of administration, i.e. one inhalation and the other by oral administration.

In one embodiment, the kit contains a first dosage form containing a compound of the invention and at least one additional pharmaceutical form, containing one or more second agents specified in the context, in quantities DOS is enough for carrying out methods of the invention. The first dosage form and the second (or third etc) dosage form together contain therapeutically effective amounts of the active agents for the treatment or prevention of diseases or conditions in a patient.

The second agent(s)when it is included in the drug, present in a therapeutically effective amount, i.e. it is usually administered in an amount that produces a therapeutically beneficial effect when combined with the introduction of connection of the invention. The second agent may be in the form of pharmaceutically acceptable salts of MES, optically pure stereoisomer and so on. Thus, it is assumed that the second agent, listed below, include all such forms and are commercially available or can be obtained by using conventional procedures and reagents. Suitable doses for the second agent are usually in the range from about 0.05 μg/day to about 500 mg/day.

In a specific embodiment, the compound of the invention is administered in combination with an agonist β2-adrenergic receptor. Representative agonists β2-adrenergic receptor include, but are not limited to, albuterol, bitolterol, fenoterol, formoterol, indacaterol, isoetharine, levalbuterol, metaproterenol, pirbuterol, salbuta is l, salmefamol, salmeterol, terbutaline, and the like. Other antagonists β2-adrenergic receptor, which can be used in combination with the compounds of the invention include, but are not limited to, 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}-butyl)benzosulfimide and 3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}-propyl)benzosulfimide and related compounds described in WO 02/066422 (Glaxo Group Ltd.); 3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-imidazolidin-2,4-dione and related compounds described in WO 02/070490 (Glaxo Group Ltd.); 3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzosulfimide, 3-(4-{[6-({(2S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzosulfimide, 3-(4-{[6-({(2R/S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzosulfimide, N-(tert-butyl)-3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzosulfimide, N-(tert-butyl)-3-(4-{[6-({(2S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzosulfimide, N-(tert-butyl)-3-(4-{[6-({(2R/S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzosulfimide and related what's the connection described in WO 02/076933 (Glaxo Group Ltd.); 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol and related compounds described in WO 03/024439 (Glaxo Group Ltd.); N-{2-[4-((R)-2-hydroxy-2-phenylethylamine)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine and related compounds described in U.S. patent No. 6576793 in the name of Moran et al.; N-{2-[4-(3-phenyl-4-methoxyphenyl)AMINOPHENYL]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-chinoline-5-yl)ethylamine and related compounds described in U.S. patent 6653323 in the name of Moran et al. In a particular embodiment, the agonist β2-adrenergic receptors is a crystalline monohydrochloride salt of N-{2-[4-((R)-2-hydroxy-2-phenylethylamine)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine. Agonist β2-adrenergic receptors is usually administered in a quantity sufficient to provide about 0.05-500 μg per dose.

In a specific embodiment, the compound of the invention is administered in combination with steroid anti-inflammatory agent. Representative steroidal anti-inflammatory agents include, but are not limited to, beclomethasone dipropionate; budesonide; butixocort propionate; 20R-16α,17α-[butylidene(oxy)]-6α,9α-debtor-11β-hydroxy-17β-(methylthio)androsta-4-EN-3-one (RPR-106541); ciclesonide; dexamethasone; S-formerely ester of 6α,9α-debtor-17α-(2-fornicator)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-thiocarbonic acid; S-formerely ester of 6α,9α-debtor-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxoandrosta-1,4-diene-17β-thiocarbonic acid; (S)-(2-oxitetraciclina-3S-silt) ester of 6α,9α-debtor-11β-hydroxy-16α-methyl-3-oxo-17α-propionylacetate-1,4-diene-17β-thiocarbonic acid; flunisolide; fluticasone propionate; methylprednisolone; mometasone furoate; prednisolone; prednisone; rofleponide; ST-126; triamcinolone acetonide, and the like. Steroid anti-inflammatory agent is usually injected in a quantity sufficient to provide about 0.05-500 μg per dose.

An example of a combination is a compound of the invention, added together with salmeterol as agonist β2-adrenergic receptor and fluticasone propionate as a steroid anti-inflammatory agent. Another example of a combination is a compound of the invention, added together with the crystalline monohydrochloride salt of N-{2-[4-((R)-2-hydroxy-2-phenylethylamine)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine as an agonist β2-adrenergic receptors and S-formationin ester, 6α,9α-debtor-17α-[(2-fornicator)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-thiocarbonic acid as steroid anti-inflammatory agent.

Other suitable combinations include, for example, other anti-inflammatory agents, for example, NSAIDs (such as sodium cromoglycate; nedocromil sodium; inhibitors of phosphodiesterase (PDE) (for example, theophylline, PDE4 inhibitors or mixed inhibitors of PDE3/PDE4); leukotriene antagonists (e.g., monteleukast); leukotriene synthesis inhibitors; iNOS inhibitors; protease inhibitors, such as inhibitors, tryptase and elastase; antagonists beta-2-integrin and agonists or antagonists of the adenosine receptor (e.g., agonists of the adenosine 2A); antagonists of cytokines (for example, chemokine antagonists, such as antibody interleukin (antibody (αIL), especially αIL-4 therapy and αIL-13-therapy or combination) or inhibitors of cytokine synthesis.

In a specific embodiment, the compound of the invention is administered in combination with inhibitors of phosphodiesterase-4 (PDE4) or mixed inhibitors of PDE3/PDE4. Representative PDE4 inhibitors or mixed inhibitors of PDE3/PDE4 include, but are not limited to, CIS-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-deformational)cyclohexane-1-he; CIS-[4-cyano-4-(3-cyclopropylmethoxy-4-deformational)cyclohexane-1-ol]; CIS-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid and the like or their pharmaceutically acceptable salts. Other representative PDE4 inhibitors is whether mixed inhibitors of PDE3/PDE4 include AWD-12-281 (elbion); NCS-613 (INSERM); D-4418 (Chiroscience and Schering-Plough); CI-1018 or PD-168787 (Pfizer); derivatives of benzodioxole described in WO99/16766 (Kyowa Hakko); K-34 (Kyowa Hakko); V-11294A (Napp); roflumilast (Byk-Gulden); derivatives of phthalazinone described in WO99/47505 (Byk-Gulden); pumafentrine (Byk-Gulden, now Altana); arofylline (Almirall-Prodesfarma); VM554/UM565 (Vernalis); T-440 (Tanabe Seiyaku) and T2585 (Tanabe Seiyaku).

In a specific embodiment, the compound of the invention is administered in combination with a muscarinic antagonist (i.e. anticholinergic agent). Representative muscarinic antagonists include, but are not limited to, atropine, atropine sulfate, atropine oxide, methylatropine nitrate, gomatropina hydrobromide, giostsiamina (d,l) hydrobromide, scopolamine hydrobromide, ipratropium bromide, oxytrope bromide, Tiotropium bromide, methantheline, propantheline bromide, anisotropine methyl bromide, clydine bromide, capirola (Robinul), isopropamide iodide, mepenzolate bromide, tridtsatiletie (Pathilone), exactly the methyl sulfate, cyclopentolate hydrochloride, Tropicamide, trihexyphenidyl hydrochloride, pirenzepine, telenzepine, AF-DX 116 and methoctramine and the like.

In a specific embodiment, the compound of the invention is administered in combination with antihistamine (i.e. an antagonist of N1-receptor). Representative antihistamines include, but are not limited to, ethanolamines, such as ka is unexamined maleate, clemastine fumarate, diphenylhydramine hydrochloride and dimenhydrinate; ethylendiamine, such as pyrilamine umlaut, tripelennamine hydrochloride and tripelennamine citrate; alkylamines followed, such as chlorpheniramine, acrivastine; piperazines such as hydroxyzine hydrochloride, hydroxyzine, pamoate, cyclizine hydrochloride, cyclizine lactate, meclizine hydrochloride and cetirizine hydrochloride; piperidine, such as astemizole, levocabastine hydrochloride, loratadine or its gtkaboutdialog, terfenadine and Fexofenadine hydrochloride; azelastina hydrochloride and the like.

The following preparations illustrate representative pharmaceutical compositions of the invention.

Examples of compositions for administration by DPI

The compound of the invention (0.2 mg) micronizing and then mixed with lactose (25 mg). This stirred mixture is then loaded into gelatin cartridge for inhalation. The contents of the cartridge is injected with the use of, for example, DPI.

Micronized compound of the invention (100 mg) is stirred with milled lactose (25 g) (for example, lactose, in which no more than approximately 85% of particles have a MMD from about 60 microns to about 90 microns and not less than 15% of particles have a MMD of less than 15 microns). This stirred mixture is then loaded into individual blisters blister packs with detachable externally the th sheath in number, sufficient to provide from about 10 μg to about 500 μg of the compound of the invention per dose. The contents of the blisters is injected with the use of DPI.

Alternatively, a micronized compound of the invention (1 g) is mixed with milled lactose (200 g) with the formation of the composition without packing (in bulk), with the mass ratio of the compounds and milled lactose of 1:200. The mixed composition is placed in a DPI capable of delivering between about 10 μg and about 500 μg of the compound of the invention per dose.

Alternatively, a micronized compound of the invention (100 mg) and micronized agonist β2-adrenergic receptor (500 mg) is mixed with milled lactose (30 g). The stirred mixture was then loaded into individual blisters blister packs with detachable outer shell in a quantity sufficient to provide from about 10 μg to about 500 μg of the compound of the invention per dose. The contents of the blisters is injected with the use of DPI.

Examples of compositions for use in MDI

Micronized compound of the invention (10 g) was dispersed in a solution obtained by dissolving lecithin (0.2 g) in demineralized water (200 ml). The resulting suspension is spray dried and then micronizer with the formation of the micronized compositions containing the hours of the Itza, having an average diameter less than about 1.5 microns. Micronized composition is then loaded into cartridges MDI containing compressed 1,1,1,2-Tetrafluoroethane in an amount sufficient to provide from about 10 μg to about 500 μg of the compound of the invention per dose at introduction by MDI.

Alternatively, a suspension containing 5 wt.% compounds of the invention, 0.5 wt.% lecithin and 0.5 wt.% trehalose, obtained by dispersing 5 g of the compound of the invention in the form of micronized particles with mean size less than 10 microns in colloidal solution obtained from 0.5 g of trehalose and 0.5 g of lecithin dissolved in 100 ml of demineralized water. The suspension is spray dried and the resulting mixture micronizer to obtain particles having an average diameter of less than 1.5 microns. Particles are loaded into the containers with pressurized 1,1,1,2-Tetrafluoroethane.

An example of a composition for use in inhaler-nebulizer

The compound of the invention (25 mg) dissolved in isotonic saline, buffered citrate (pH 5) (125 ml). The mixture is stirred and treated with ultrasound to dissolve the connection. Determine the pH of the solution and, if necessary, adjust to pH 5 by slow addition of aqueous 1 n sodium hydroxide. The solution is injected with the use of device-spray, which provides approx the tion 10 μg to about 500 μg of the compound of the invention per dose.

An example of hard gelatin capsules for oral administration

The compound of the invention (50 g), spray dried lactose (440 g) and magnesium stearate (10 g) are thoroughly mixed. The resulting composition is then loaded into hard gelatin capsules (500 mg of composition per capsule).

An example of a suspension for oral administration

The following ingredients are mixed with formation of a suspension containing 100 mg of the compound in 10 ml of suspension:

IngredientsNumber
The compound of the invention
Fumaric acid
Sodium chloride
Methylparaben
Propylparaben
Granulated sugar
Sorbitol (70% solution)
Wigan®(Silicate of magnesium-aluminum)
Corrigent
Coloring tools
Distilled water
1.0 g
0.5 g
2.0 g
0.15 g
0.05 g
25,5 g
is 12.85 g
1.0 g
a 0.035 ml
0.5 mg
as needed up to 100 ml

An example of an injectable drug for administration by injection

The compound of the invention (0.2 g) is stirred with 0.4 M buffer solution of sodium acetate (2.0 ml). the pH of the resulting solution adjust to pH 4 with application of 0.5 N. aqueous hydrochloric acid or 0.5 N. aqueous sodium hydroxide, if neo is absolutely essential, and then add sufficient water for injection to provide total volume of 20 ml of the Mixture was then filtered through a sterile filter (0.22 micron), while receiving a sterile solution suitable for administration by injection.

EXAMPLES

Following receipt and examples are provided to illustrate specific embodiments of the invention. However, it is assumed that these specific embodiments of in no way limit the scope of the invention unless otherwise indicated.

The following abbreviations have the following meanings, unless indicated otherwise, and any other abbreviations used and not defined in context, have their default value.

AUadenylylcyclase
BSAbovine serum albumin
camp3',5'-cyclic adenosine monophosphate
SNOthe Chinese hamster ovary
cm5the cloned receptor M5chimpanzees
DCMdichloromethane (i.e. methylene chloride)
DIPEAN,N-diisopropylethylamine
dPBSbuffered phosphate saline, Dulbecco
DMFN,N-dimethylformamide
EDCIN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
EDTAethylenediaminetetraacetic acid
EtOActhe ethyl acetate
FBSfetal calf serum
FLIPRfluorometrically tomographic tablet reader
HBSSbuffered salt solution Khanka
HEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
hM1the cloned receptor M1man
hM2the cloned receptor M2man
hM3the cloned receptor M3man
hM4 the cloned receptor M4man
hM5the cloned receptor M5man
HOBtthe hydrate of 1-hydroxybenzotriazole
MChmetilholin
Meonmethanol
TFAtriperoxonane acid
THFtetrahydrofuran

Any other abbreviations used but not defined in context, have their standard, generally accepted value. Unless otherwise noted, all materials, such as reagents, the starting materials and solvents were purchased from commercial suppliers (such as Sigma-Aldrich, Fluka Riedel-de Haën, and the like) and were used without additional purification. The reaction was performed in a nitrogen atmosphere unless otherwise stated. Monitoring the development of the reaction the reaction mixture was performed by thin-layer chromatography (TLC), analytical high performance liquid chromatography (anal. HPLC) and mass spectrometry, the details of which are given below and separately in the specific examples of the reactions. The reaction mixture was treated as described, in particular, in each reaction; the commonly their was purified by extraction and other methods of cleaning, such as temperature-dependent and solvent crystallization and precipitation. In addition, the reaction mixture, as usual, was purified preparative HPLC.

Getting 1

(R)-Cyclopentasiloxane acid

(2R,5R)-2-tert-butyl-5-phenyl-1,3-dioxolane-4-one (1A): (R)-almond acid (20 g, 130 mmol) was dissolved in anhydrous pentane (200 ml, 1.7 mol). Added pavlinovic aldehyde (13,6 g, 153 mmol) followed by the addition triftormetilfullerenov acid (488 μl, 5.4 mmol). The reaction mixture is boiled under reflux at 36°C in nitrogen atmosphere. After 5.5 hours the mixture was allowed to cool to room temperature before mixing with 200 ml of 8 wt.% solution of NaHCO3within 10 minutes. Excess pentane was removed by rotary evaporation. The solids were collected by filtration and washed (100 ml water) during vacuum filtration. The solids were dried overnight in high vacuum, thus obtaining the intermediate product (1A) as a white solid (23,8 g, purity 88%).

(2R,5S)-2-tert-Butyl-5-(1-hydroxycyclopent)-5-phenyl-1,3-dioxolane-4-one (1b): Hexamethyldisilazide lithium (0.8 g, 4.7 mmol; 4,7 ml of 1.0 M solution in hexano) was added to anhydrous THF (5.3 ml, 65 mmol) at -78°C. To the solution dropwise over 15 minutes was added to the intermediate product of the t (1A) (800 mg, 3.6 mmol) in 5.3 ml of anhydrous THF. After 30 minutes, dropwise over 1 minute was added Cyclopentanone (451 μl, 5.1 mmol). After 2 hours was added 0.8 ml of saturated aqueous Na2HPO4and the mixture was stirred at room temperature for 5 minutes. The mixture was added to 8 ml of saturated aqueous ammonium chloride. The aqueous layer was washed (2×80 ml EtOAc and the organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude product (780 mg) was purified flash chromatography (gradient of 5-15% EtOAc in hexano for 30 minutes), thus obtaining the intermediate product (1b).

(2R,5S)-2-tert-butyl-5-cyclopent-1-enyl-5-phenyl-1,3-dioxolane-4-one (1C): Intermediate (1b) (650 mg, 2.1 mmol) was dissolved in 6.8 ml of anhydrous THF and the solution was cooled to 0°C. was added dropwise thionyl chloride (436 μl, 6 mmol) followed by addition of pyridine (777 μl, 9.6 mmol). The mixture was stirred at 0°C for 1 hour. Was added a saturated aqueous ammonium chloride (14 ml) and the mixture was stirred for 5 minutes while heating to room temperature. The layers were separated and the aqueous layer was washed (2×100 ml EtOAc). The organic layers were combined, dried over Na2SO4was filtered and concentrated, thus obtaining the intermediate product (1C) as a pale yellow oil (540 mg), which was used in the next stage without additional cleaning is.

(S)-Cyclopent-1-energytransition acid (1d): Intermediate (1C) (540 mg, 1.9 mmol) was dissolved in Meon (927 μl, to 22.9 mmol). Was added water (1,84 ml, 102 mmol) followed by the addition of KOH (1.1 g, 18,8 mmol). The reaction mixture is boiled under reflux at 130°C for 3 hours. The mixture was diluted to 250 ml of saturated ammonium chloride, then washed (1×100 ml hexane). The remaining aqueous emulsion was washed (2×250 ml EtOAc). Layers combined EtOAc, washed with 50 ml saturated aqueous NaCl, dried over Na2SO4was filtered and concentrated, thus obtaining the intermediate product (1d) in the form of a brownish-yellow solid (290 mg).

The intermediate product (1d) (280 mg, 1.3 mmol) was dissolved in Meon (2,50 ml of 61.7 mmol) and the reaction vessel was rinsed with a stream of nitrogen before adding to a mixture of 28 mg of 10% Pd/C. the Mixture was stirred at room temperature under hydrogen pressure, 101325 PA (1 ATM) and reaction monitoring was performed HPLC until then, until it was consumed the original connection (~24 hours). The reaction vessel was rinsed with a stream of nitrogen, and then the mixture was filtered through celite and washed Meon. The filtrate was concentrated under vacuum, thus obtaining specified in the title compound as a pale yellow solid (284 mg).

Getting 2

(R)-2-Cyclopentyl-2-hydroxy-2-phenyl-1-piperazine-1-ylatason

To a stirred solution of (R)-cyclopentylpropionate acid (10.0 g, to 45.4 mmol) in DCM (200 ml) was added tert-butyl-1-piperidinecarboxylate (8.5 g, to 45.4 mmol). In the reaction mixture was added DIPEA (23,7 ml of 13.6 mmol), HOBt (10.4 g, 68,1 mmol) and then EDCI (10.4 g, to 54.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then washed with 1 N. NaOH (300 ml), 1 N. HCl (300 ml), then saturated aqueous NaCl (300 ml). The organic layer was then removed, dried over MgSO4and then filtered. The solvent was removed under reduced pressure. To the crude substance was added a 20% solution of TFA/DCM and the resulting mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure. Added DCM (300 ml) and the mixture was washed with saturated sodium bicarbonate (300 ml). The organic layer was then removed, dried over MgSO4and filtered. The crude substance was purified by chromatography on silica gel (10 wt.% Meon/1% NH3(water)), while receiving specified in the title compound as a white powder (9.0 g, and 31.2 mmol).

EXAMPLE 1

4-((R)-2-Cyclopentyl-2-hydroxy-2-phenylacetyl)-N-thiophene-2-iletileri-1-carboxamidine

To a stirred solution of (R)-2-cyclopentyl-2-hydroxy-2-phenyl-1-piperazine-1-ratanana (3,9 g, 13.7 mmol) in DMF (200 ml) was added DIPEA (4.8 ml, 27,3 mmol what) and then With(bisbenzimidazole-1-yl)Methylenebis (3.6 g, 13.7 mmol). The mixture was stirred at room temperature for 30 minutes followed by the addition of C-thiophene-2-ylmethylamino (2,8 ml and 27.3 mmol). The mixture was heated at 60°C for ~14 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude substance was purified HPLC with reversed phase, while receiving specified in the title compound as TFA salt (0.7 g, 1.3 mmol). MS m/z: [M+H]+calc. for C23H30N4O2S, 427,21; found 427,2.

Alternative synthesis

DIPEA (7.3 ml, to 41.6 mmol) was added to (R)-2-cyclopentyl-2-hydroxy-2-phenyl-1-piperazine-1-iletyou (6.0 g, to 20.8 mmol)dissolved in ethanol (90 ml, 2 mol). Added S-(bisbenzimidazole-1-yl)Methylenebis (6.0 g, is 22.9 mmol) and the mixture was stirred at room temperature for 30 minutes. Added With-thiophene-2-ylmethylamino (4.9 g, to 41.6 mmol) and the mixture was stirred over night at 55°C. the Mixture are condensed and the product was purified HPLC, while receiving specified in the title compound as TFA salt (7,3 g, purity 98%). MS m/z: [M+H]+calc. for C23H30N4O2S, 427,21; found 427,4.

EXAMPLE 2

4-((R)-2-Cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-hydroxybenzyl)piperazine-1-carboxamidine

To a stirred solution of (R)-2-cyclopentyl-2-hydroxy-2-phenyl-1-PIP the Razin-1-ratanana (5,00 g, 17.3 mmol; obtained as described in obtaining 1) in DMF (200 ml) was added DIPEA (to 10.6 ml of 60.7 mmol) and then With(bisbenzimidazole-1-yl)Methylenebis (5,48 g of 20.8 mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 4-hydroxybenzylidene (12.0 g, ml, 97 mmol). The mixture was heated at 60°C for ~14 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified HPLC with reversed phase, while receiving specified in the title compound as TFA salt (1.7 g, 3.1 mmol). MS m/z: [M+H]+calc. for C25H32N4O3, 437,25; found 437,2.

EXAMPLE 3

4-((R)-2-Cyclopentyl-2-hydroxy-2-phenylacetyl)-N-furan-2-iletileri-1-carboxamidine

(R)-2-Cyclopentyl-2-hydroxy-2-phenyl-1-piperazine-1-ylatason (2.0 g, 6,9 mmol) and S-(bisbenzimidazole-1-yl)Methylenebis (2.0 g, 7.6 mmol) was added to ethanol (40,0 ml, 685 mmol) followed by addition of DIPEA (2.4 ml, a 13.9 mmol). The resulting mixture was stirred at room temperature for about 1 hour to dissolve all solids, thus obtaining an intermediate product. Added furfurylamine (1.2 ml, a 13.9 mmol) and the reaction mixture was stirred at 35°C until completion of the reaction (approximately 22 hours). Purification preparative HPLC gave is shown in the title compound as TFA salt (329 mg, 6,9 mmol, purity of 97.5%). MS m/z: [M+H]+calc. for C23H30N4O3, 411,23; found 411,2.

EXAMPLE 4

According to the methods described in the previous examples, and with a suitable replacement of the original substances and reagents received connections from 4-1 to 4-52, having the following formula, as TFA salts.

Etc.ZQ
4-1-CH(CH3)-Qphenyl
4-2-CH2-Q3,4-differenl
4-3-CH2-Q4-methoxyphenyl
4-4-CH2-Qthiophene-3-yl
4-5-CH2-Qphenyl
4-6-CH2-Q3-forfinal
4-7-(CH2)2-Qphenyl
4-8 -CH2-Qpyridine-2-yl
4-9-CH2-Q3-hydroxyphenyl
4-10-CH2-Q4-forfinal
4-11-CH2-Q2-forfinal
4-12-CH2-Qcyclohexyl
4-13-CH2-Q3-methoxyphenyl
4-14-CH2-Q3,5-differenl
4-15-CH2-Qthe thiazole-2-yl
4-16-CH2-Q1H-pyrazole-3-yl
4-17-NH-Qphenyl
4-18-CH2-Qfuran-3-yl
4-19-CH2-Q2-methylthiazole-4-yl
-CH2-Qcut
4-21-CH2-Qbutyl
4-22-CH2-Qpencil
4-23-NH-Q2-forfinal
4-24-NH-Q2-chlorophenyl
4-25-NH-Q3-forfinal
4-26-NH-Q3-chlorophenyl
4-27-NH-Q4-were
4-28-NH-Q4-forfinal
4-29-NH-Q4-chlorophenyl
4-30-NH-Q4-methoxyphenyl
4-31-CH2-Qmethyl ester of 4-benzoic acid
4-321H-indol-2-yl
4-33-CH2-Qcycloheptyl
4-34-CH2-Q2-hydroxyphenyl
4-35-CH2-Q4-tittermatorter
4-36-CH2-Q4-AMINOPHENYL
4-37-CH2-Q4-hydroxymethylene
4-38-CH2-Q1H-indol-5-yl
4-39-CH2-Qbenzofuran-5-yl
4-40-CH2-Q4-were
4-41-CH2-Q4-methylsulfinylphenyl
4-42-CH2-Q3-cyanophenyl
4-43-CH2-Q4-44-CH2-Q2-were
4-45-CH2-Q3-were
4-46-CH2-Q1H-indol-4-yl
About 4-47-CH2-Q3-methylsulfinylphenyl
4-48-CH2-Qbenzo[b]thiophene-5-yl
4-49-CH2-Qbenzo[1,3]dioxol-5-yl
4-50-CH2-Qbenzo[b]thiophene-2-yl
4-51-CH2-Q1-methyl-1H-pyrazole-3-yl
4-52-CH2-Qcyclopentyl

(4-1) 4-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-((R)-1-phenylethyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H34N4O2, 435,27; found 435,2.

(4-2) 4-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(3,4-diferensial)is piperazin-1-carboxamidine. MS m/z: [M+H]+calc. for C25H30F2N4O2, 457,23; found 457,2.

(4-3) 4-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-methoxybenzyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H34N4O3, 451,26; found 451,2.

(4-4) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-thiophene-3-iletileri-1-carboxamidine. MS m/z: [M+H]+calc. for C23H30N4O2S, 427,21; found 427,4.

(4-5) N-benzyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C25H32N4O2, 421,25; found UAH 421,2.

(4-6) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(3-terbisil)piperazine-1-carboxamidine. MS m/z: [M+H]+vices. for C25H31FN4O2, 439,24; found 439,2.

(4-7) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-penetentiary-1-carboxamidine. MS m/z: [M+H]+calc. for C26H34N4O2, 435,27; found 435,2.

(4-8) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-pyridin-2-iletileri-1-carboxamidine. MS m/z: [M+H]+calc. for C24H31N5O2, 422,25; found 422,2.

(4-9) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(3-hydroxybenzyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C25H32N4O3, 437,25; found 437,2.

(4-10) 4-((R)-2-cyclopentyl-2-hydrox the-2-phenylacetyl)-N-(4-terbisil)piperazine-1-carboxamidine. MS m/z: [M+H]+vices. for C25H31FN4O2, 439,24; found 439,2.

(4-11) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(2-terbisil)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C25H31FN4O2, 439,24; found 439,2.

(4-12) N-cyclohexylmethyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C25H38N4O2, 427,30; found 427,2.

(4-13) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(3-methoxybenzyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H34N4O3, 451,26; found 451,2.

(4-14) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(3,5-diferensial)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C25H30F2N4O2, 457,23; found 457,2.

(4-15) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-thiazol-2-iletileri-1-carboxamidine. MS m/z: [M+H]+calc. for C22H29N5O2S, 428,20; found 428,2.

(4-16) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(1H-pyrazole-3-ylmethyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C22H30N6O2, 411,24; found 411,2.

(4-17) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(phenylamino)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C24H31N5O2, 422,25; found 422,2.

(4-18) 4-((R-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-furan-3-iletileri-1-carboxamidine. MS m/z: [M+H]+calc. for C23H30N4O3, 411,23; found 411,2.

(4-19) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(2-methylthiazole-4-ylmethyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C23H31N5O2S, 442,22; found 442,2.

(4-20) N-butyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C22H34N4O2, 387,27; found 387,2.

(4-21) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-pentylpyridine-1-carboxamidine. MS m/z: [M+H]+calc. for C23H36N4O2, 401,28; found 401,2.

(4-22) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-hexylpyridine-1-carboxamidine. MS m/z: [M+H]+calc. for C24H38N4O2, 415,30; found 415,2.

(4-23) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(2-forfinal)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C24H30FN5O2, 440,24; found 440,2.

(4-24) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(2-chlorophenyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C24H30ClN5O2, 456,21; found 456,2.

(4-25) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(3-forfinal)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C24H30FN5O2, 440,24; found 440,2.

(4-26) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)N-(3-chlorophenyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C24H30ClN5O2, 456,21; found 456,2.

(4-27) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-were)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C25H33N5O2, 436,26; found 436,2.

(4-28) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-forfinal)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C24H30FN5O2, 440,24; found 440,2.

(4-29) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-chlorophenyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C24H30ClN5O2, 456,21; found 456,2.

(4-30) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-methoxyphenyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C25H33N5O3, 452,26; found 452,2.

(4-31) Methyl ester of 4-({[4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxyethyl]amino}methyl)benzoic acid. MS m/z: [M+H]+calc. for C27H34N4O4, 479,26; found 479,2.

(4-32) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(1H-indol-2-ylmethyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C27H33N5O2, 460,26; found 460,2.

(4-33) N-cycloheptylmethyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H40N4O2, 441,32; neid is but 441,2.

(4-34) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(2-hydroxybenzyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C25H32N4O3, 437,25; found 437,2.

(4-35) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-cryptomaterial)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H31F3N4O3, 505,24; found 505,2.

(4-36) 4-({[4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxyethyl]amino}methyl)benzamide. MS m/z: [M+H]+calc. for C26H33N5O3, 464,26; found 464,2.

(4-37) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-hydroxymethylbenzene)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H34N4O3, 451,26; found 451,2.

(4-38) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(1H-indol-5-ylmethyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C27H33N5O2, 460,26; found 460,2.

(4-39) N-benzofuran-5-ylmethyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C27H32N4O3, 461,25; found 461,2.

(4-40) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-methylbenzyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H34N4O2, 435,27; found 435,2.

(4-41) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(4-matilal universal)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H34N4O2S, 467,24; found 467,2.

(4-42) N-(3-cyanobenzyl)-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H31N5O2, 446,25; found 446,2.

(4-43) 3-({[4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxyethyl]amino}methyl)benzamide. MS m/z: [M+H]+calc. for C26H33N5O3, 464,26; found 464,2.

(4-44) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(2-methylbenzyl)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C26H34N4O2, 435,27; found 434,2.

(4-45) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(3-methylbenzyl)piperazine-1-carboxamidine. MC m/z: [M+H]+calc. for C26H34N4O2, 435,27; found 435,2.

(4-46) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(1H-indol-4-ylmethyl)piperazine-1-carboxamidine. MC m/z: [M+H]+calc. for C27H33N5O2, 460,26; found 460,2.

(About 4-47) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(3-methylsulfonylbenzoyl)piperazine-1-carboxamidine. MC m/z: [M+H]+calc. for C26H34N4O2S, 467,24; found 467,2.

(4-48) N-benzo[b]thiophene-5-ylmethyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxamidine. MC m/z: [M+H]+calc. for C27H32N4O2S, 477,22; found 477,2.

<> (4-49) N-benzo[1,3]dioxol-5-ylmethyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxamidine. MC m/z: [M+H]+calc. for C26H32N4O4, 465,24; found 465,2.

(4-50) N-benzo[b]thiophene-2-ylmethyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)piperazine-1-carboxamidine. MC m/z: [M+H]+calc. for C27H32N4O2S, 477,22; found 477,2.

(4-51) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-(1-methyl-1H-pyrazole-3-ylmethyl)piperazine-1-carboxamidine. MC m/z: [M+H]+calc. for C23H32N6O2, 425,26; found 425,2.

(4-52) 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-cyclopentylpropionate-1-carboxamidine. MC m/z: [M+H]+calc. for C24H36N4O2, 413,28; found 413,2.

EXAMPLE 5

According to the methods described in the previous examples, and with replacement suitable source of chemicals and reagents were obtained connections, 5-1 and 5-2, having the following formula, as TFA salts.

(5-1) N-benzyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N'-methylpiperazin-1-carboxamidine (R6=-CH3). MS m/z: [M+H]+calc. for C26H34N4O2, 435,27; found 435,2.

(5-2) N-benzyl-4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N'-ethylpiperazin-1-carboxamidine (R6=-CH2CH3). MS m/z: [M+H]+calc. for C27H36N4O2 , 449,28; found 449,2.

Getting 3

tert-Butyl ether (R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetate)pyrrolidin-1-carboxylic acid

At room temperature diisopropylsalicylic (980 μl, 5 mmol) was slowly added to a mixture of (R)-cyclopentylpropionate acid (1.1 g, 5 mmol), tert-butyl ester (R)-3-hydroxypyrrolidine-1-carboxylic acid (1.0 g, 5.5 mmol) and triphenylphosphine (1.3 g, 5 mmol) in 10 ml of THF. The reaction mixture was then stirred at room temperature over night.

The solvent was removed and added to 100 ml of EtOAc. The organic layer was washed with sodium bicarbonate solution (50 ml × 3), then saturated aqueous NaCl and dried over sodium sulfate. The solvent was removed to obtain 4 g of the crude product, which was purified flash chromatography (EtOAc/hexane), while receiving specified in the title compound (1.5 g, purity 99%).

Getting 4

(R)-pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid

tert-Butyl ether (R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetate)pyrrolidin-1-carboxylic acid (1.3 g) in 8 ml of 1,4-dioxane was added to 4 ml of 4 M HCl in 1,4-dioxane and stirred at room temperature over night, while receiving specified in the title compound as HCl salt (1G).

EXAMPLE 6

(R)-1-(N-benzylcarbamoyl)pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid

tert-Butyl ether (R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetate)pyrrolidin-1-carboxylic acid (97,5 mg, 0.3 mmol) in 3 ml DMF was added DIPEA (130 μl, 750 mmol) followed by addition of C-(bisbenzimidazole-1-yl)methanamine (87 mg, 330 μmol). The reaction mixture was stirred at room temperature for 2 hours followed by the addition of benzylamine (39 μl, 360 μmol). The reaction mixture was stirred at room temperature over night. The solvent was removed and the dissolved substance was purified by chromatography with reversed phase, while receiving specified in the title compound as TFA salt (to 78.2 mg, 99.5%purity). MS m/z: [M+H]+Vychisl. for C25H31N3O3, 422,24; found 422,2.

EXAMPLE 7

According to the methods described in the previous examples, and with a suitable replacement of the original substances and reagents received connections from 7-1 to 7-18, having the following formula, in the form of the TFA salt:

Etc.Q
7-1phenyl
7-2 thiophene-2-yl
7-32-hydroxyphenyl
7-43-hydroxyphenyl
7-54-hydroxyphenyl
7-6furan-2-yl
7-7furan-3-yl
7-82-forfinal
7-93-forfinal
7-104-forfinal
7-112,6-differenl
7-123,4-differenl
7-133,5-differenl
7-144-triptoreline
7-155-methylfuran-2-yl
7-16pyridine-2-yl
7-17-(CH2)2-phenyl
7-18-CH2-phenyl

(7-1) 1-(N-benzylcarbamoyl)pyrrolidin-3-silt e is Il (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H31N3O3, 422,24; found 422,4.

(7-2) (R)-1-(N-thiophene-2-iletilerimde)pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C23H29N3O3S, 428,19; found 428,4.

(7-3) (R)-1-[N-(2-hydroxybenzyl)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H31N3O4, 438,23; found 438,5.

(7-4) (R)-1-[N-(3-hydroxybenzyl)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H31N3O4, 438,23; found 438,5.

(7-5) (R)-1-[N-(4-hydroxybenzyl)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H31N3O4, 438,23; found 438,3.

(7-6) (R)-1-(N-furan-2-iletilerimde)pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C23H29N3O4, 412,22; found 412,2.

(7-7) (R)-1-(N-furan-3-iletilerimde)pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C23H29N3O4, 412,22; found 412,2.

(7-8) (R)-1-[N-(2-terbisil)carbamimidoyl]pyrrolidin-3-silt ether (R)-C is kleintierpraxis acid MS m/z: [M+H] +calc. for C25H30FN3O3, 440,23; found 440,3.

(7-9) (R)-1-[N-(3-terbisil)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H30FN3O3, 440,23; found 440,4.

(7-10) (R)-1-[N-(4-terbisil)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H30FN3O3, 440,23; found 440,4.

(7-11) (R)-1-[N-(2,6-diferensial)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H29F2N3O3, 458,22; found 458,2.

(7-12) (R)-1-[N-(3,4-diferensial)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H29F2N3O3, 458,22; found 458,2.

(7-13) (R)-1-[N-(3,5-diferensial)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H29F2N3O3, 458,22; found 458,2.

(7-14) (R)-1-[N-(4-cryptomaterial)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C26H30F3N3O4, 506,22; found 506,2.

(7-15) (R)-1-[N-(5-methylfuran-2-ylmethyl)carb is imidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C24H31N3O4, 426,23; found to 426.2.

(7-16) (R)-1-(N-pyridin-2-iletilerimde)pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C24H30N4O3, 423,23; found 423,2.

(7-17) (R)-1-[N-(3-phenylpropyl)carbamimidoyl]pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C27H35N3O3, 450,27; found 450,2.

(7-18) (R)-1-(N-penicillinbinding)pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C26H33N3O3, 436,25; found 436,2.

EXAMPLE 8

According to the methods described in the previous examples, and with a suitable replacement of the original substances and reagents received connections from 8-1 to 8-13, having the following formula, in the form of the TFA salt:

Etc.Q
8-1phenyl
8-2thiophene-2-yl
8-3furan-2-yl
8-4furan-3-yl
8-52-hydroxyphenyl
8-63-hydroxyphenyl
8-74-hydroxyphenyl
8-83-methoxyphenyl
8-92-forfinal
8-103-forfinal
8-114-forfinal
8-12pyridine-2-yl
8-13benzofuran-5-yl

(8-1) 1-(N-benzylcarbamoyl)piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C26H33N3O3, 436,25; found 436,5.

(8-2) 1-(N-thiophene-2-iletilerimde)piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C24H31N3O3S, 442,21; found 442,4.

(8-3) 1-(N-furan-2-iletilerimde)piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C24H31N3O4, 426,23; found to 426.2.

(8-4) 1-(N-furan-3-iletilerimde)piperidine-4-silt ether (R)-cyclopentylmethyl is phenylacetic acid. MS m/z: [M+H]+calc. for C24H31N3O4, 426,23; found to 426.2.

(8-5) 1-[N-(2-hydroxybenzyl)carbamimidoyl]piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C26H33N3O4, 452,25; found 452,2.

(8-6) 1-[N-(3-hydroxybenzyl)carbamimidoyl]piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C26H33N3O4, 452,25; found 452,2.

(8-7) 1-[N-(4-hydroxybenzyl)carbamimidoyl]piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C26H33N3O4, 452,25; found 452,2.

(8-8) 1-[N-(3-methoxybenzyl)carbamimidoyl]piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C27H35N3O4, 466,26; found 466,2.

(8-9) 1-[N-(2-terbisil)carbamimidoyl]piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C26H32FN3O3, 454,24; found 454,2.

(8-10) 1-[N-(3-terbisil)carbamimidoyl]piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C26H32FN3O3, 454,24; found 454,2.

(8-11) 1-[N-(4-terbisil)carbamimidoyl]piperidine-4-silt ether (R)-Cyclopentasiloxane is acetic acid. MS m/z: [M+H]+calc. for C26H32FN3O3, 454,24; found 454,2.

(8-12) 1-(N-pyridin-2-iletilerimde)piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C25H32N4O3, 437,25; found 437,2.

(8-13) 1-(N-benzofuran-5-iletilerimde)piperidine-4-silt ether (R)-cyclopentylpropionate acid. MS m/z: [M+H]+calc. for C28H33N3O4, 476,25; found 476,4.

EXAMPLE 9

According to the methods described in the previous examples, and with replacement suitable source of chemicals and reagents were also obtained (R)-(N-benzylcarbamoyl)piperidine-3-silt ether (R)-cyclopentylpropionate acid in the form of the TFA salt:

MS m/z: [M+H]+calc. for C26H33N3O3, 436,25; found 436,5.

EXAMPLE 10

According to the methods described in the previous examples, and with replacement suitable source of chemicals and reagents were obtained 1-[N-(3-phenylpropyl)carbamimidoyl]piperidine-4-silt ether (R)-cyclopentylpropionate acid in the form of the TFA salt:

MS m/z: [M+H]+calc. for C28H37N3O3, 464,28; found 464,4.

EXAMPLE 11

According to the methods described in the previous examples, and with substitution of appropriate source the chemicals and reagents were obtained connections 11-1 and 11-2, having the following formula, in the form of the TFA salt:

(11-1) (R)-1-(N-methylcarbamoylmethyl)pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid (Z=-CH3). MS m/z: [M+H]+calc. for C19H27N3O3, 346,21; found 346,2.

(11-2) (R)-1-(N-butylcarbamoyl)pyrrolidin-3-silt ether (R)-cyclopentylpropionate acid (Z=-(CH2)3CH3). MS m/z: [M+H]+calc. for C22H33N3O3, 388,25; found 388,2.

EXAMPLE 12

According to the methods described in the previous examples, and with replacement suitable source of chemicals and reagents were obtained 1-carbamimidoyl-4-silt ether (R)-cyclopentylpropionate acid in the form of the TFA salt:

MS m/z: [M+H]+calc. for C19H27N3O3, 346,21; found 346,1.

EXAMPLE 13

According to the methods described in the previous examples, and with replacement suitable source of chemicals and reagents were obtained connections 13-1 and 13-2, having the following formula, in the form of the TFA salt:

(13-1) (R)-1-(N-benzylcarbamoyl)pyrrolidin-3-silt ester 2-hydroxy-4-methyl-2-phenylpentane acid (Q=phenyl). MS m/z: [M+H]+calc. for C24H31N3O3, 410,24; found 410,2.

(13-2) (R)-1-[N-(4-hydroxybenzyl)carbamine the oil]pyrrolidin-3-silt ester 2-hydroxy-4-methyl-2-phenylpentane acid (Q=4-hydroxyphenyl). MS m/z: [M+H]+calc. for C24H31N3O4, 426,23; found to 426.2.

EXAMPLE 14

According to the methods described in the previous examples, and with a suitable replacement of the original substances and reagents received connections from 14-1 to 14-4, having the following formula, in the form of the TFA salt:

Etc.Q
14-1phenyl
14-2thiophene-2-yl
14-34-hydroxyphenyl
14-4furan-2-yl

(14-1) N-benzyl-4-(2-hydroxy-2,2-dateopen-2-ylacetic)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C22H24N4O2S2, 441,13; found 441,0.

(14-2) 4-(2-hydroxy-2,2-dateopen-2-ylacetic)-N-thiophene-2-iletileri-1-carboxamidine. MS m/z: [M+H]+calc. for C20H22N4O2S3, 447,09; found 447,0.

(14-3) N-(4-hydroxybenzyl)-4-(2-hydroxy-2,2-dateopen-2-ylacetic)piperazine-1-carboxamidine. MS m/z: [M+H]+calc. for C22H24N4O3S2, 457,13; found 457,0.

(14-4) N-furan-2-ylmethyl-4-(2-hydroxy-2,2-dateopen-2-ylacetic)piperazin the-1-carboxamidine. MS m/z: [M+H]+calc. for C20H22N4O3S2, 431,11; found 431,0.

EXAMPLE 15

According to the methods described in the previous examples, and with replacement suitable source of chemicals and reagents were also obtained compound 15-1 and 15-2, having the following formula, in the form of the TFA salt:

(15-1) 1-[N-(3-phenylpropyl)carbamimidoyl]piperidine-4-silt ester 9H-xanthene-9-carboxylic acid (Z=-(CH2)3-phenyl). MS m/z: [M+H]+calc. for C29H31N3O3, 470,24; found 470,4.

(15-2) (R)-1-(N-benzylcarbamoyl)pyrrolidin-3-silt ester 9H-xanthene-9-carboxylic acid (Z=-CH2-phenyl). MS m/z: [M+H]+calc. for C26H25N3O3, 428,19; found 428,5.

EXAMPLE 16

According to the methods described in the previous examples, and with replacement suitable source of chemicals and reagents were also obtained (S)-1-carbamimidoyl-3-ymetray ester 9H-xanthene-9-carboxylic acid in the form of the TFA salt:

MS m/z: [M+H]+calc. for C21H23N3O3, 366,17; found 366,2.

EXAMPLE 17

According to the methods described in the previous examples, and with replacement suitable source of chemicals and reagents were also obtained (R)-1-carbamimidoyl-3-ymetray ester 9H-xanthene-9-carboxylic acid in the form of the TFA salt:

MS m/z: [M+H]+calc. for C20H21N3O3, 352,16; found 352,2.

EXAMPLE 18

According to the methods described in the previous examples, and with replacement suitable source of chemicals and reagents were obtained 1-carbamimidoyl-4-ymetray ester 9H-xanthene-9-carboxylic acid in the form of the TFA salt:

MS m/z: [M+H]+calc. for C21H23N3O3, 366,17 found 366,2.

Analysis 1

Analysis of the binding of radioligand

Obtaining membranes from cells expressing subtypes of muscarinic receptors hM1hM2hM3and hM4

Cell line Cho stably expressing cloned subtypes of muscarinic receptors hM1hM2hM3and hM4accordingly, grew almost to the level of confluently in a medium consisting of HAM's F-12, supplemented with 10% FBS and 250 μg/ml of geneticin. Cells were grown in an incubator with 5% CO2at 37°C and raised to the surface 2 mm EDTA in dPBS. Cells were collected in 5 minute centrifugation at 650 × g, and the precipitate of cells in the test tube after centrifugation or kept frozen at -80°C or immediately received a membrane. To obtain membranes sediment cells again suspended in buffer for lysis and homogenized tissue disintegrator transmitter station PT-2100 (Kinematica AG; 20 Sekou is d × 2 switching on). Crude membranes were centrifuged at 40,000 × g for 15 minutes at 4°C. the Precipitate membranes then re-suspended in the buffer to resuspendable and again homogenized tissue disintegrator transmitter station. The protein concentration of the suspension of the membranes was determined by the method described by Lowry, O. et al., Journal of Biochemistry 193:265 (1951). All membranes were stored frozen in aliquot at -80°C or used immediately. Aliquots of the obtained membrane receptor hM5bought directly from Perkin Elmer and kept at -80°C until use.

Analysis of the binding of radioligand with subtypes hM1hM2hM3hM4and hM5muscarinic receptor

Analyses linking radioligand was performed in 96-well titration the microplates in a total volume for the analysis of 1000 µl. Membranes of CHO cells stably expressing any subtype of muscarinic receptor hM1hM2hM3hM4or hM5diluted in buffer for analysis to the following specific concentrations of target protein (µg/well): 10 mcg for hM1, 10-15 mcg for hM2, 10-20 μg for hM3, 10-20 μg for hM4and 10-12 mcg for hM5. Membrane homogenized in a short period of time with the use of tissue disintegrator transmitter station (10 seconds) before adding to the analytical tablet. Study saturating binding for the determining the values of K Dradioligand was performed using methyl chloride L-[N-methyl-N3H]scopolamine ([3H]-NMS) (TRK666, 84,0 CI/mmol, Amersham Pharmacia Biotech, Buckinghamshire, England) at concentrations that comprise from 0.001 nm to 20 nm. Analyses of displacement to determine the values of Kithe tested compounds was performed with [3H]-NMS at 1 nm and eleven different concentrations of the tested compounds. Compound was initially dissolved to a concentration of 40 μm in a buffer for cultivation and then serially diluted 5× buffer for dilution to the final concentration factor of 400 FM to 4 μm. The order and the volume added to the analytical tablets were as follows: 825 μl of buffer for analysis with 0.1% BSA, 25 μl of radioligand, 100 μl of diluted test compound and 50 μl of membranes. Analytical plates were incubated for 6 hours at 37°C. binding assays were completed by rapid filtration through the filtration tablets with a glass fiber GF/B (Perkin Elmer Inc., Wellesley, MA), pre-treated with 0.3% polyethylenimine (PEI). Filtering the tablets were washed three times with buffer (10 mm HEPES) to remove unbound radioactivity. The tablets are then dried in the air and to each well was added 50 μl of scintillation fluid Microscint-20 liquid (PerkinElmer Inc., Wellesley, MA). Counting of radioactivity tablets then conducted in a scintillation counter PerkinElmer Topcount (PerkinElmer Inc.,Wellesley, MA). Data binding were analyzed by nonlinear regression analysis using the software package GraphPad Prism (GraphPad Software, Inc., San Diego, CA) using a single-site model competition. Values of Kifor test compounds were calculated from the observed values of the IC50and value of KDradioligand using the equation of Cheng-Prusoff (Cheng Y; W.H. Prusoff Biochemical Pharmacology22(23):3099-108 (1973)). Values of Kiturned in value pKito determine the geometric means and 95% confidence intervals. These summary statistics were then converted back to values of Kito represent the data.

In this assay, a lower value of Kiindicates that the test compound has a higher affinity of binding to the tested receptor. It was found that examples of the compounds of the invention that were tested in this analysis, a value of Kiless than approximately 100 nm for the subtype of muscarinic receptor M3in this analysis. It was found that these compounds usually have more values of Kiless than approximately 50 nm, and some compounds have values of Kiless than about 10 nm, or less than about 1.0 nm.

Analysis 2

Analyses of the functional activity of muscarinic receptors

Analgesia is mediated by agonist inhibition of the accumulation of camp

In this analysis the functional activity of the test compounds is determined by measuring the ability of test compounds to block the inhibition by oxotremorine mediated by Forskolin accumulation of camp in cells CHO-K1 expressing the receptor hM2.

Analyses of camp carried out in a radioimmunoassay format using the analysis system activation adenylylcyclase Flashplate with125I-camp (NEN SMP004B, PerkinElmer Life Sciences Inc., Boston, MA) according to manufacturer's instructions.

Cells are washed once with dPBS and raise to the surface with a solution of trypsin-EDTA (0.05% trypsin/0.53 mm EDTA)as described in assay 1. The separated cells are washed twice by centrifugation at 650 × g for five minutes in 50 ml of dPBS. Debris then re-suspended in 10 ml of dPBS and counting the radioactivity of the cells is performed by Coulter counter Z1 Dual Particle (Beckman Coulter, Fullerton, CA). The cells are again centrifuged at 650 × g for five minutes and then suspended in stimulation buffer to a concentration for the analysis of 1.6×106and 2.8×106cells/ml

The test compound is first dissolved to a concentration of 400 μm in a buffer for cultivation (dPBS, supplemented with 1 mg/ml BSA (0.1 per cent) and then serially diluted with buffer for dilution to a final molar concentrations of the components of from 100 μm to 0.1 nm. Oxotremorine diluted in the same way.

To measure inhibition is oxotremorine activity AC 25 ál of Forskolin (final concentration 25 μm after dilution in dPBS), 25 μl of the diluted oxotremorine and 50 μl of cells added to the wells for analysis of agonist. To measure the ability of test compounds to block inhibited by oxotremorine activity AC 25 ál of Forskolin and oxotremorine (final concentration 25 μm and 5 μm, respectively, after dilution in dPBS), 25 μl of diluted test compound and 50 MK cells added to the remaining wells for analysis.

The reaction mixture is incubated for 10 minutes at 37°C and the reaction stopped by the addition of 100 μl of ice buffer for detection. Tablets sealed, incubated over night at room temperature and counting radioactivity spend the next morning on the scintillation counter, PerkinElmer TopCount (PerkinElmer Inc., Wellesley, MA). The amount of biogas produced camp (pmol/well) is calculated by counting the radioactivity observed for samples and standards of camp as described in the user manual for the manufacturer. Data analyze nonlinear regression analysis with the software package GraphPad Prism (GraphPad Software, Inc., San Diego, CA) using nonlinear regression, single-site competition equations. The equation of Cheng-Prusoff used to calculate the Kiusing EU50curve concentration oxotremorine-response and concentration analysis oxotremorine as KD and [L] respectively. Values of Kiturn in the magnitude of the pKito determine the geometric means and 95% confidence intervals. These summary statistics were then converted back to values of Kito represent the data.

In this assay, a lower value of Kiindicates that the test compound has a higher functional activity of the tested receptors. It is assumed that examples of the compounds of the invention have a value of Kiless than approximately 100 nm to block inhibition by oxotremorine mediated by Forskolin accumulation of camp in cells Cho-K1 expressing the receptor hM2.

Blocking mediated by agonist binding [35S]TγS

In the second functional analysis functional activity of the tested compounds can be determined by measuring the ability of compounds to block driven oxotremorine binding of [35S]TγS in cells CHO-K1 expressing the receptor hM2.

During the application of the frozen membranes are thawed and then diluted in buffer for analysis with a final protein concentration of the target tissue 5-10 μg per well. Membrane homogenized in a short period of time with the use of tissue disintegrator transmitter station PT-2100 and then add in the analytical tablets.

Led the rite EC 90(effective concentration for 90% of the maximum response) to stimulate the binding of [35S]TγS agonist-oxotremorine determined in each experiment.

To determine the ability of test compounds to inhibit stimuliruemoe oxotremorine binding of [35S]TγS in each well of 96-well plates add the following: 25 μl of buffer for analysis with [35S]TγS (0.4 nm), 25 μl oxotremorine (EC90) and GDF (3 μm), 25 μl of diluted test compound and 25 μl of membranes of CHO cells expressing the receptor hM2. Analytical tablets then incubated at 37°C for 60 minutes. Contents analytical tablets filtered through pre-treated with a 1% BSA filters GF/B using 96-well harvester PerkinElmer. Tablets washed with ice buffer for washing for 3 × 3 seconds and then dried in air or in vacuum. To each well add scintillation fluid Microscint-20 (50 μl) and each plate is sealed and radioactivity counted on a topcounter (PerkinElmer). Data analyze nonlinear regression analysis with the software package GraphPad Prism (GraphPad Software, Inc., San Diego, CA) using nonlinear regression, single-site competition equations. The equation of Cheng-Prusoff used to calculate the Kiusing values IC50curve to ncentrate-response to the test compound and the concentration oxotremorine in the analysis as K Dand [L]the concentration of ligand, respectively.

In this assay, a lower value of Kiindicates that the test compound has a higher functional activity of the test receptor. It is assumed that examples of the compounds of the invention have a value of Kiless than approximately 100 nm to block driven oxotremorine binding of [35S]TγS in cells Cho-K1 expressing the receptor hM2.

Blocking mediated agonist of calcium release, as determined by analyses FLIPR

Subtypes of muscarinic receptors (receptors M1, M3and M5), which combines with protein Gqactivate the path of phospholipase C (PLC) after the binding of agonist to the receptor. As a result of this activated PLC hydrolyzes phosphatidylinositides (PIP2) into diacylglycerol (DAG) and phosphatidyl-1,4,5-trisphosphate (IP3), which, in turn, generates the release of calcium from intracellular reserves, i.e. endoplasmic and sarcoplasmic reticulum. Analysis of the FLIPR (Molecular Devices, Sunnyvale, CA) is based on the increase in intracellular calcium through the use of sensitive calcium dye (Fluo-4AM, Molecular Probes, Eugene, OR), which is fluorescent when binds free calcium. This event fluorescence measured in real the amount of time the way FLIPR, which detects the change in fluorescence from the monolayer of cells, cloned receptors M1and M3man and receptor M5chimpanzees. The activity of the antagonist can be identified by the ability of antagonists to inhibit mediated agonist increase in intracellular calcium.

For analyses stimulation of FLIPR calcium CHO cells, stably expressing the receptor hM1hM3and cM5, seeded in 96-well tablets FLIPR overnight before analysis. Seeded cells are washed twice using Cellwash (MTX Labsystems, Inc.) with FLIPR buffer (10 mm HEPES, pH of 7.4, 2 mm calcium chloride, 2.5 mm probenecid in HBSS without calcium and magnesium) to remove culture medium and receive 50 µl/well of FLIPR buffer. Cells are then incubated with 50 μl/well of 4 μm FLUO-4AM (you get 2× solution) for 40 minutes at 37°C and 5% carbon dioxide. After a period of incubation with the dye, the cells washed twice with FLIPR buffer, leaving a final volume of 50 µl/well.

To determine the activity of the antagonist first determine the dose-dependent stimulation of the release of intracellular CA2+for oxotremorine, so that later can be measured stimulation compared with stimulation oxotremorine at concentrations EU50. Cells are first incubated with buffer for cultivation connection for 20 minutes to follow them the addition of the agonist, performed by FLIPR. The value of EC90for oxotremorine receive according to the method described in detail in the measurement FLIPR, and the following section, data reduction, together with a formula ECF=((F/100-F)^1/H)*EC50. The concentration oxotremorine 3 × ECFreceived the tablets of stimulation, so that the concentration of EU90oxotremorine can be added to each well in tablets analysis of inhibition by the antagonist.

To conduct FLIPR apply the following settings: exposure time of 0.4 seconds, the laser power of 0.5 Watt, wavelength excitation 488 nm and the wavelength of emission of 550 nm. The baseline is determined by measuring changes in fluorescence during the 10 seconds before the addition of agonist. After agonist stimulation method FLIPR continuously measure the change in fluorescence every 0.5-1 second for 1.5 minutes to detect the maximum of the fluorescence changes.

The change in fluorescence is expressed as the maximum fluorescence fluorescence minus baseline for each hole. The raw data analyzed in dependence of the logarithm of drug concentration by nonlinear regression with GraphPad Prism (GraphPad Software, Inc., San Diego, CA) using the model of a sigmoidal curve dose-response. Values of Kiantagonist determine Prism use value EC 50oxotremorine as KDand EC90oxotremorine for the concentration of ligand according to the equation of Cheng-Prusoff (Cheng &Prusoff, 1973).

In this assay, a lower value of Kiindicates that the test compound has a higher functional activity of the test receptor. It is assumed that examples of the compounds of the invention have a value of Kiless than approximately 100 nm to block mediated by agonist of calcium release in cells SNO expressing the receptor hM3.

Analysis 3

Analysis Einthoven rats

This analysis used for in vivo evaluation bronchospastic action of the tested compounds, active antagonist of muscarinic receptor.

All compound diluted in sterile water and the dose of the compound is administered via a route inhalation (IH). Rats (Sprague-Dawley, male, 250-350 g) is exposed to aerosol generated from an LC Star Nebulizer Set and promoted by the gas mixture (5% CO2/95% atmospheric air). The solution of each test compound is sprayed over a period of time of 10 minutes in the chamber of the dispensing in the form of a disk, capable of containing six rats. In a pre-defined time points after inhalation connections analyze Einthoven.

Thirty minutes before pulmonary evaluation animals aneste irout inaction (thiobutabarbital, 120 mg/kg, intraperitoneally). Cervical vein catheterized filled with saline polyethylene catheters (PE-50) and used for infusion of MCh. The trachea then dissected and kanyoro a 14G needle and is used for ventilation of rats during pulmonary evaluation. After surgery, rats subjected to ventilation with the use of a piston respirator set at a stroke volume of 1 ml/100 g body weight, but not exceeding the volume of 2.5 ml, and the speed of 90 strokes per minute.

Measure changes in pressure that occur with every breath. Collect baseline values for at least 2.5 minutes, then rats subjected decumulative effects with 2-divisible incremental increases in the number bronchostenosis MCh funds (5, 10, 20, 40 and 80 µg/ml). MCh is administered by infusion over a 2.5 minute from a syringe pump at a speed of 2 ml/kg/min Animals asteniziruth after completion of studies.

Changes in pressure ventilation (see H2O) in treated animals expressed as % inhibition of the reaction MCh relative to control animals. In this analysis the higher the value of % inhibition indicates that the test compound possesses bronchosan action. It is assumed that the exemplary compounds of the invention, which are experienced in this analysis at the dose of 100 µg/ml, exhibit b is more than 35% inhibition, it is assumed that some of them show more than 70% inhibition, and it is assumed that some of them show more than 90% inhibition.

Definition ID501.5 hours

Standard muscarinic antagonists were evaluated in the analysis Einthoven rats 1.5 hours after a dose. Has determined that the order of activity (ID50for five of the tested standards is as follows: pretorium (4,4 µg/ml) > Tiotropium (6 µg/ml) > desmethyldiazepam (12 µg/ml) > glycopyrrolate (15 µg/ml) > LAS 34237 (24 µg/ml). The activity of the test compounds similarly define 1.5 hours after a dose.

Definition ID50after 6 and 24 hours

Standards Tiotropium and ipratropium were also evaluated after 24 hours and/or 6 hours after administration of doses in rats analysis of Einthoven. Ipratropium (10 and 30 μg/ml) was approximately 3 times less active after 6 hours after injection of the dose compared to its activity 1.5 hours. The observed loss of activity at this time point (6 h) is consistent with its relatively short duration of action in the clinic. Tiotropium found the slow emergence of action, with peak pongsawat achieved within 6 hours after the dose. Its value activity after 6 h and 24 h was not significantly different from each other and were about 2 the Aza compared with its activity value after 1.5 hour. Similarly determine the onset of action of the test compound, and the amount of activity after 6 and 24 hours.

Analysis 4

Analysis of the decrease or inhibit salivary flow in rats

Rats (Sprague-Dawley, male, 250-350 g) were administered a dose of the drug, was anestesiology and Coulibaly as described for analysis 3. In a pre-defined time points after surgery, animals are placed on their dorsal side at 20° tilt their heads down. Pre-weighed gauze pad is inserted into the mouth of an animal and injected him muscarinic agonist pilocarpine (PILO) (3 mg/kg, intravenously). Saliva formed within 10 minutes after administration PILO, measure the gravimetric method of determining the mass of gauze pads before and after the introduction of PILO. Actions that reduce or inhibit salivation, expressed as % inhibition of salivary flow relative to control animals.

Definition ID50after 1, 6 and 24 hour

Analysis of the decrease or inhibit salivary flow in rats was developed to identify system impacts and calculating the index of selectivity in respect of the lungs (LSI) of the tested compounds. Standard, Tiotropium, was evaluated in this model after 1, 6 and 24 hours after dose. It was found that Tiotropium is the most potent is ri the inhibition of pilocarpine-induced salivation later, 6 hours after the dose. This discovery is consistent with the peak action observed in the analysis of Einthoven.

This model is a modified version of the techniques described in Rechter, "Estimation of anticholinergic drug effects in mice by antagonism against pilocarpine-induced salivation" Ata Pharmacol Toxicol 24:243-254 (1996). Calculate the average mass of saliva the treated filler of animals in each pre-processed and used to calculate % inhibition of salivation at the appropriate time pre-processing for each dose.

It is assumed that examples of the compounds of the invention that were tested in this assay, show value ID50less than 100 µg/ml (measured after 24 hours), it is assumed that some compounds exhibit values ID50less than 30 µg/ml, some less than 20 μg/ml and some less than 15 mcg/ml

Relationship ID50for actions against salivation to ID50action bronchospastic used to calculate the true index of selectivity for the lungs of the test compounds. Generally preferred are compounds having a true index of selectivity for light more than about 5.

Although the present invention has been described with reference to certain aspects or variants of implementation, the average person skilled in the art should understand that they can be made by various changes, or they may be replaced by equivalents, not beyond the nature and scope of the invention. In addition, to the extent allowable by applicable statuses and reglamentirovannyj patent, all cited in the context of publications, patents and patent applications hereby incorporated by reference in their entirety to the same extent as if each document was separately included in the context as a reference.

1. The compound of the formula I

where
R1selected from C1-6of alkyl, -C3-9cycloalkyl and thiophenyl;
R2selected from phenyl and thiophenyl;
R3selected from H and-C0-1alkylene-OH; or-CR1R2R3together form a group of the formula

where A represents-O-, and R4represents H;
X is selected from-O - and-O-CH2-; when X is a bond, Y is-CH2-, Y' represents N and Y represents-CH2-; and, when X represents-O - or-O-CH2-, Y' represents-CH-, Y is a bond and Y represents-CH2- or -(CH2)2or Y represents-CH2and Y represents-CH2-;
a=0;
R6and R7independently selected from H and-C1-4of alkyl;
Z is selected from C1-3alkylene-Q, and-NH-C0-1alkylen-Q; Q is selected from C3-7cycloalkyl, phenyl, benzodioxole the La, benzofuranyl, benzothiophene, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl and thiophenyl; and Q is optionally substituted by 1-5 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2;
where R1and R2optionally substituted by 1-5 groups Raindependently selected from C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil, -C3-6cycloalkyl, cyano, halogen, -ORb, -C(O)ORb, -SRb, -S(O)Rb, -S(O)2Rb, -C(O)NRcRdand-NRcRd; each Rbindependently selected from H, -C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil and-C3-6cycloalkyl; each Rcand Rdindependently selected from H, -C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil and-C3-6cycloalkyl;
where each alkyl, Alchemilla, Alchemilla, Allenova and cycloalkyl group in Ra-d, R4-8and Z optionally substituted by 1-5 fluorine atoms; where each cycloalkyl in Ra-doptionally substituted by 1-3 substituents, independently selected from C1-4of alkyl, -C2-4alkenyl, -C2-4the quinil, cyano, halogen, -O(C1-4the alkyl), S(C1-4the alkyl), -S(O)(C1-4the alkyl), -S(O)2(C1-4the alkyl), -NH2, -NH(C1-4the alkyl) and-N(C1-4the alkyl)2 where each alkyl, Alchemilla and Alchemilla group optionally substituted by 1-5 substituents, fluorine atoms; and Allenova group within Z optionally substituted with 1-2 substituents independently selected from C1-2the alkyl and-OH;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1represents isobutyl, cyclopentyl or thiophenyl.

3. The compound according to claim 1, where R3represents-OH or-CR1R2R3together form

4. The compound according to claim 1, where R6represents H or-C1-4alkyl; and R7represents H.

5. The compound according to claim 1, where Q represents cyclohexyl, cycloheptyl, phenyl, benzodioxolyl, benzofuranyl, benzothiophene, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl or thiophenyl.

6. The compound according to claim 1 where Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2.

7. The compound according to claim 1, where R1represents isobutyl, cyclopentyl or thiophenyl; R3represents-OH or-CR1R2R3together form a group of the formula

and is O; R6represents H or-C1-4alkyl; R7not only is em a H; Q represents cyclohexyl, cycloheptyl, phenyl, benzodioxolyl, benzofuranyl, benzothiophene, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2; and the alkyl groups in R8optionally substituted by 1-5 fluorine atoms.

8. The compound according to claim 1, having the formula

9. The connection of claim 8, where R1is cyclopentyl or thiophenyl; R3represents-OH; R6represents H or-C1-2alkyl; R7represents H; Q represents cyclohexyl, cycloheptyl, phenyl, benzodioxolyl, benzofuranyl, benzothiophene, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2; and the alkyl groups in R8optionally substituted by 1-5 fluorine atoms.

10. The compound of claim 8 having the formula

11. The connection of claim 10, where R6represents H or-C1-4alkyl; Q represents a cyclohexyl, cyclohepta is l, phenyl, benzodioxolyl, benzofuranyl, benzothiophene, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, -C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2; and the alkyl groups in R8optionally substituted by 1-5 fluorine atoms.

12. The compound of claim 8 having the formula

13. The connection section 12, where Q represents cyclohexyl, cycloheptyl, phenyl, benzodioxolyl, benzofuranyl, benzothiophene, furanyl, indolyl, pyrazolyl, pyridinyl, thiazolyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH, cyano, C(O)O-C1-4of alkyl, -O-C1-4of alkyl, -S-C1-4the alkyl and -- CONH2; and the alkyl groups in R8optionally substituted by 1-5 fluorine atoms.

14. The connection indicated in paragraph 13, where Q is furanyl or thiophenyl.

15. The connection 14, selected from
4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-furan-2-iletileri-1 carboxamidine and
4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-thiophene-2-iletileri-1 carboxamidine.

16. The compound according to claim 1, having the formula

17. Connection P16, where R1presented yet cyclopentyl; R2represents phenyl; R3represents-OH; R6and R7represent H; Z represents-C1-3alkylen-Q; Q represents a phenyl, benzofuranyl, furanyl, pyridinyl or thiophenyl; and phenyl in Q is optionally substituted by 1-2 groups R8independently selected from halogen and-C0-4alkylene-OH.

18. The compound according to claim 1, having the formula

19. Connection p, where R1represents isobutyl or cyclopentyl; R2represents phenyl; R3represents-OH; R6and R7represent H; Z represents-C1-3alkylen-Q; Q represents a phenyl, furanyl, pyridinyl or thiophenyl; Q is optionally substituted by 1-2 groups R8independently selected from halogen, -C1-4of alkyl, -C0-4alkylene-OH and-O-C1-4of alkyl; and alkyl groups in R8optionally substituted by 1-5 fluorine atoms.

20. A method of obtaining a compound according to any one of claims 1 to 19, including
(a) the combination of the compounds (1) and compounds (2) in the conditions of formation of amide linkages and the removal of protection for the product with the formation of compound (3)

or a combination of Mitsunobu or the interesterification reaction of the compound (1) and compounds (4) and remove the protection of the product with the formation of compound (5)
where R represents aminosidine group;
(b) interaction of the compound (3) or compound (5) with compound (6) with the formation of compound (7)

and
(c) the interaction of compounds (7) and compound (8) to obtain the compounds of formula I

21. The compound obtained by the method according to claim 20.

22. Pharmaceutical composition having antagonistic activity against Makarieva receptor containing the compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier.

23. The use of compounds according to any one of claims 1 to 20 for the manufacture of a medicinal product, which has antagonistic activity against Makarieva receptor.

24. The application of item 23, where the medicinal product is applicable for the treatment of chronic obstructive pulmonary disease or asthma.

25. The application of item 23, where the drug is effective to induce expansion of the bronchi.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a method of producing a phenylpropionic acid derivative of general formula: or salt thereof, where R2a is a methoxy group or ethoxy group; R3b is a cyclopentyl group and R5 is a methyl group which can be substituted with one or more phenyl groups, or an oxygen-containing heterocyclic group used as an intermediate compound during synthesis of 3-{5-[4-(cyclpentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid (T-5224), having anti-arthritic action and osteoclast inhibitory action. One of the versions of the method involves reaction of a benzophenol derivative of general formula: 3 , where R2a and R3b are as described above, or salts thereof with a 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-one derivative of general formula: , where R5 is as described above, and X is a halogen atom. The disclosed method can be used as a method for simple and safe synthesis of T-5224 with high output. The invention also relates to methods of producing intermediate compounds and novel intermediate compounds.

EFFECT: high efficiency of the composition.

28 cl, 23 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new improved method for preparing derivatives of 3,3-diarylpropylamines of the general formula (I) and sterically highly pure stable intermediate substances and their using for preparing pharmaceutical compositions. Method for preparing 3,3-diarylpropylamines of the general formula (I) wherein R means hydrogen atom, linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl; R' and R'' can be similar or different and mean linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl. Method involves condensation of cinnamic acid with compound of the general formula (1) to form compound of the general formula (2a) and the following reaction of the latter with chiral tertiary amine - cinchonidine to yield the corresponding salt of compound of the general formula (2b): and then from this compound the crystalline form of compound of the formula (3): is isolated followed by its either direct reduction with equivalent excess of hydride to yield lactol of the formula (5a) or via intermediate step by formation of corresponding acid chloroanhydride to form ester with alcohols of type R-OH wherein R is given above and the following conversion to compound of the formula (4): and the latter is hydrogenated with diisobutylaluminum-hydride or tri-tert.-butoxyaluminum-hydride to yield lactol of the formula (5) . Prepared lactols of the formula (5a) or (5) after reductive amination with secondary amine form compounds of the formula (I).

EFFECT: improved preparing method.

10 cl, 1 sch, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing amines and/or alkanolamines mainly containing mono- and diamine alkanols, alkyldiamines and triamines and cyclic amines by reacting glycerine with hydrogen and an aminating agent selected from the group: ammonia, methylamine and diethylamine, in the presence of a catalyst which contains a metal selected from Cu, Co, Ni, Mn, Mo, Cr, Zr, or a mixture thereof, at temperature ranging from 150°C to 300°C and pressure ranging from 20 to 300 bar, followed by separation of the end product. The process is carried out until 40-80% conversion of glycerine. The invention also relates to a method of producing amines and/or alkanolamines mainly containing mono- and diamine alkanols, alkyldiamines by reacting glycerine with hydrogen and aminating agent selected from ammonia, methylamine and diethylamine, in the presence of a catalyst which contains iridium, at temperature ranging from 150°C to 300°C and pressure ranging from 20 to 300 bar.

EFFECT: method enables efficient and full utilisation of glycerine as a starting material and obtain products with high output.

11 cl, 2 tbl, 32 ex

FIELD: medicine, pharmaceutics.

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

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing piperazinophenols, involving reaction of piperazine, N-(β-aminoethyl)piperazine, N-(β-benzylaminoethyl)piperazine or N,N1-bis-(piperazinoethyl)ethylenediamine with a Mannich base in an aqueous medium at temperature 90-110°C in molar ratio of piperazine, N-(β-aminoethyl)piperazine, N-(β-benzylaminoethyl)piperzine:Mannich base equal to 1:0,8-2, N,N1-bis-(piperazinoethyl)ethylenediamine:Mannich base equal to 1:2 or 1:4 until release of dimethylamine stops; as well as aminomethylation of piperazine or N-(β-aminoethyl) piperazine with diphenylol propane (DPP) in the presence of formaldehyde (FA) in an aqueous medium with molar ratio piperazine: FA: DPP equal to 1:1:1 or 1:2:2 at temperature 50-90°C for 4-10 hours. Reactants react in the presence of a surfactant in amount of 2-6% of the weight of the starting piperazine, and the surfactant used is neonol, OP-7, OP-10.

EFFECT: ensuring fire safety of the process, high output of the end product which can be used as antioxidant phenol stabilisers.

1 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) which is selected from gentisate, maleate, citrate, fumarate and semitartrate salts, which possess improved properties in their application, in particular higher stability.

EFFECT: invention also relates to method of obtaining acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) and to pharmaceutical composition, containing them, for treatment and prevention of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive lung disease, benign prostate gland hypertrophy and diseases of lower urinary tract.

11 cl, 30 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of novel 4-(azacycloalkyl)phthalonitriles. Novel 4-(azacycloalkyl)phthalonitriles of general formula

are obtained. The method of obtaining said compounds involves nucleophilic substitution of the bromine atom in 4-bromophthalonitrile (BPN) with N,N-cycloalkyleneamines.

.

The reaction takes place in the presence of a deprotonation agent K2CO3 and a catalytic complex Cul/dipyridyl formed in situ at temperature 90-95°C for 12 hours. Molar ratio of reactants BPN: amine: Cul: dipyridyl: K2CO3=1:1.2:0.1:0.1:1.5. After the reaction, the mixture is cooled and filtered. The filtered residue is washed with water and recrystallised.

EFFECT: obtaining novel 4-(azacycloalkyl)phthalonitriles using a method which is safe for this class of compounds.

2 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: invention refers to a deuterium-enriched α-ketoamide compound of formula wherein: D means a deuterium atom; the values R1-R5 are presented in cl.1 of the patent claim, and to a based pharmaceutical composition.

EFFECT: method improvement.

32 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula l , where a and b are independently equal to 0-5; R1 and R2 independently denote -C1-4alkyl, CN, halogen, -ORa, -CH2OH, Ra independently denotes H, C1-4alkyl; R3 denotes -C(O)NR3aR3b, -CN; R3a and R3b denote H; R5 denotes -C1-6alkyl; Q denotes -C0-5-alkylene-Q'-C0-1alkylene-, Q' denotes -CH2-, -CH=CH-, -C≡C-, -O-, -S-, -S(O)-, -SO2-, -C(O)-, -OC(O)-, -C(O)O-, -NRQ1C(O)-, -C(O)NRQ1-, -NRQ2-C(O)-NRQ3-, -C=N-O-, -S-S- and -C(=N-O-RQ4)-, RQ1 denotes H; RQ2 and RQ3 denote H; RQ4 denotes -C1-4alkyl, benzyl; e equals 0-5; R6 independently denotes halogen, -C1-4alkyl, -C0-4alkylene-OH, CN, -C (O)O-C1-4alkyl, -O-C1-4alkyl, -S-C1-4alkyl, -NH-C(O)-C1-4alkyl, -N (C1-4alkyl)2 and -N+(O)O; where the alkyl group in R6 is optionally substituted with 1-5 F atoms; one -CH2- group in Q is optionally substituted with one -OH; or a pharmaceutically acceptable salt or zwitterion form thereof.

EFFECT: compounds exhibit antagonistic activity towards muscarinic receptors, which enables their use to produce pharmaceutical compositions for treating lung diseases such as chronic obstructive pulmonary disease and asthma.

32 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of novel 4-(azacycloalkyl)phthalonitriles. Novel 4-(azacycloalkyl)phthalonitriles of general formula

are obtained. The method of obtaining said compounds involves nucleophilic substitution of the bromine atom in 4-bromophthalonitrile (BPN) with N,N-cycloalkyleneamines.

.

The reaction takes place in the presence of a deprotonation agent K2CO3 and a catalytic complex Cul/dipyridyl formed in situ at temperature 90-95°C for 12 hours. Molar ratio of reactants BPN: amine: Cul: dipyridyl: K2CO3=1:1.2:0.1:0.1:1.5. After the reaction, the mixture is cooled and filtered. The filtered residue is washed with water and recrystallised.

EFFECT: obtaining novel 4-(azacycloalkyl)phthalonitriles using a method which is safe for this class of compounds.

2 cl, 4 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),

(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.

EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.

7 cl, 19 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of ethylenediamine derivatives (4), having a halogenated carbamate group and an acyl group, involving catalytic hydrogenation of aminonitrile with a halogen-substituted carbamate group in the presence of an acid and then acylation of the formed amino derivative. The initial aminonitrile may be obtained with high output by reacting an amino acid amide with a halogen-substituted carbamating agent in the presence of water and then reacting the formed amide, which has a halogen-substituted carbamate group, with a reducing agent such as a Wilsmeyer reagent.

EFFECT: high yield.

22 cl, 45 ex

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