Quinuclidine derivatives of (hetero) arylcycloheptane carboxylic acids as muscarine receptor antagonists

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) wherein R4 represents a group of formula (II) and R1, R2, R3, R5 and X are those as specified in the patent claim.

EFFECT: preparing the pharmaceutical composition applicable in treating chronic obstructive pulmonary disease and containing the compound of formula (I).

8 cl, 3 tbl, 39 ex

 

The present invention relates to cycloalkylcarbonyl alkilany esters polycyclic aminoalcohols, method of production thereof, to pharmaceutical compositions containing them, to a method for producing pharmaceutical compositions, to their use in therapy and to intermediate compounds used in obtaining them.

Muscarinic receptors are a family of receptors coupled with G protein (GPCR), including five members of a family of M1, M2, M3, M4and M5. Of the five muscarinic subtypes three (M1, M2and M3) is known as having a physiological effect on the fabric of the human lung.

Parasympathetic nerves are the main path for reflex bronchostenosis human respiratory and mediate the tone of the respiratory tract through the release of acetylcholine at muscarinic receptors. The tone of the Airways is increased in patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), and for this reason were developed antagonists of muscarinic receptors for use in the treatment of respiratory diseases. Antagonists of muscarinic receptors in clinical practice is often called antiholinergicakimi, is widespread in the treatment of perolini for individuals with COPD, and their use has been discussed in detail in the literature (e.g., Lee et al., Current Opinion in Pharmacology 2001, 1, 223-229).

When used for the treatment of respiratory disorders antagonists of muscarinic receptors is usually administered by inhalation. However, with the introduction by inhalation significant part of antagonists of muscarinic receptors is often absorbed into the systemic circulation, which leads to the described side effects such as dry mouth. In addition, most of muscarinic antagonists has a relatively short duration of action that requires their introduction several times a day. This mode multiple daily dosing is not only uncomfortable for the patient, but also creates a significant risk of inadequate treatment because of the non-patient treatment associated with the scheme involving frequent repetition dosing.

Therefore, there is still a need for new compounds that are able to block muscarinic receptors. In particular, there is a need for new the muscarinic antagonists, which have high efficiency and reduced systemic side effects when introduced through inhalation. In addition, there is a need for new the muscarinic antagonists, which have greater duration at doses is the formation through inhalation and which is suitable for dispensing or one, or twice a day.

In WO 98/04517 described arylcyclopropanes, arizonabuckeye, arylcyclohexylamine and arylcyclohexylamine carboxylic esters, antimuskarinovoe act occurs with activity against smooth muscle of the bladder.

The problem is solved in that the compound of formula (I):

where

R1and R2together with the carbon atom to which they are both directly attached form a 7-membered cycloalkyl ring which may be substituted by one or more substituents, independently selected from halogen, hydroxyl and C1-6of alkyl;

R3represents phenyl or 5-6-membered heteroaryl ring;

R4represents a group of formula (II)

where

Y represents-CH2CH2-replacement ring group (II) can occur in clauses 3 or 4;

R5represents a group of formula (IV)

where

w is 0 or 1;

R6represents a C1-4alkylen, possibly substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-6alkoxy, NH2, NH(C1-6alkyl) and N(C1-6alkyl)2;

if w is equal to 0, then 0; if w = 1, u is 0 or 1;

Q representation is employed, a Oh, -CONR8- or-C(O)O-;

R7is a cyclic group Cyc1or C1-4Akilova group, where C1-4the alkyl group may be substituted by one or more substituents, independently selected from a cyclic group of Cyc2and-OCyc2; and R7can additionally represent hydrogen;

each of Cyc1and Cyc2independently represents an aryl, heteroaryl or 3-8-membered aliphatic carbocyclic ring, each of which can be substituted by one or more substituents, independently selected from halogen, cyano, OR26, phenyl, and C1-6of alkyl, where the phenyl or C1-6the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl;

R8represents hydrogen;

R26represents hydrogen or C1-6alkyl, where C1-6the alkyl can be substituted by one or more substituents, independently selected from halogen and hydroxyl;

and where the heteroaryl group may be monocyclic and bicyclic and contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur;

and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

It is preferable soedinenie the invention, where R1and R2together with the carbon atom to which they are both directly attached form a 7-membered cycloalkyl ring, and R3represents phenyl.

Also preferred is a compound according to the invention, where R4represents a group of formula (IIa)

Also preferred is a compound according to the invention, where R5represents a

-C1-4alkylen-Q-R7;

where Q represents O, -CONH -, or-C(O)O-;

R7represents hydrogen, Cyc1or C1-4alkyl group, where C1-4the alkyl group may be substituted by one or more substituents, independently selected from phenyl, phenoxy, where phenyl and phenoxy can possibly be substituted by one or more substituents, independently selected from halogen, hydroxyl, cyano, C1-4alkoxy and OCF3; and

Cyc1represents phenyl or 5-6-membered heteroaryl ring, each of which can be substituted by one or more substituents, independently selected from halogen, C1-4alkoxy, phenyl, and C1-4of alkyl, where phenyl and C1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl.

More preferred is a compound according to izopet the tion, where R5represents a

-C1-4alkylen-Q-Cyc1;

where Q represents a-CONH-; and Cyc1is a 5-6-membered heteroaryl, possibly substituted by one or more substituents, independently selected from halogen, C1-4alkoxy, phenyl, and C1-4of alkyl, where phenyl and C1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl.

Even more preferred is a compound according to the invention, where R1and R2together with the carbon atom to which they are both directly attached form a 7-membered cycloalkyl ring, R3represents phenyl, and R5represents a

-C1-4alkylen-Q-Cyc1;

where Q represents a-CONH-; and Cyc1is a 5-6-membered heteroaryl, possibly substituted by one or more substituents, independently selected from halogen, C1-4alkoxy, phenyl, and C1-4of alkyl, where phenyl and C1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl.

Most preferred is a compound selected from

(3R)-1-methyl-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-(3-phenoxypropan)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[OTN X,

(3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-(4-terbisil)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-benzyl-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-[3-(triptoreline)benzyl]-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-(3,4-diferensial)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-(3-methoxybenzyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-(2-phenoxyethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-(benzyloxy)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-({[1-(2-thienyl)cycloheptyl]carbonyl}oxy)-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-oxo-2-(pyrazin-2-ylamino)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-oxo-2-(pyridazin-3-ylamino)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-{2-oxo-2-[(2-phenoxyethyl)amino]ethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-{2-[(5-methylisoxazol-3-yl)amino]-2-oxoethyl}-3-{[(1-Fe is illlogical)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-{2-[(6-chloropyridin-3-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-{2-[(3-forfinal)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-(2-naphthyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-(3-methoxyphenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-(5-methyl-2-thienyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]octane X,

(3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-{2-[3-(trifluoromethyl)phenyl]ethyl}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-(1,3-benzodioxol-5-yl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-(4-cyanophenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-{2-[(6-chloropyrazine-2-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-{[1-(4-chlorophenyl)cyclopropyl]methyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-{2-[(5-methylpyridin-2-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-(carboxymethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-(3-chlorphen is)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-(2-amino-2-oxoethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,

(3R)-1-[2-(3-chloro-4-methoxyphenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X, and

(3R)-1-{2-[(3-methylisoxazol-5-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X;

where X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

According to the invention is also proposed pharmaceutical composition for use in the treatment of chronic obstructive pulmonary disease containing a compound of the formula (I)as defined above together with a pharmaceutically acceptable auxiliary substance, diluent or carrier.

The compounds of formula (I) contain the anion X, associated with the positive charge on the Quaternary nitrogen atom. The anion X may be any pharmaceutically acceptable anion of a mono or polyvalent (e.g., divalent) acid. In one embodiment of the invention X may be an anion of an inorganic acid, for example chloride, bromide, iodide, sulfate, nitrate or phosphate; or the anion of a suitable organic acid, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, econsultant, para-toluensulfonate, bansilalpet or napadisylate (naphthalene-1,5-disulfonate) (for example, kaminpeletier).

Obviously, some compounds of the present invention may exist in solvated, for example hydrated, as well as resolutiony forms. It should be understood that the present invention encompasses all such solvated forms. Some compounds of formula (I) can exist in stereoisomeric forms. It is obvious that the invention encompasses all geometric and optical isomers of compounds of formula (I) and mixtures thereof, including racemates. The tautomers and their mixtures also form an aspect of the present invention.

In the context of the present description, the term "heteroaryl" means an aromatic cyclic system containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and includes monocyclic and bicyclic heteroaromatic rings. Examples 5-6-membered heteroaryl ring according to the present invention include thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, isoxazolyl, isothiazolin, pyrazolyl and triazolyl. Examples of the bicyclic heteroaromatic rings include a condensed bicyclic ring system, where both rings t is Auda aromatic or alternatively, one ring is aromatic and the other ring is non-aromatic. 6,6 - or 6,5-condensed bicyclic ring system where one ring is aromatic and the other ring is non-aromatic, such non-aromatic ring may be substituted by oxo (=O) so that the ring is formed ketone, amide, or urea functional group. Unless otherwise specified, the heteroaryl group may be linked via carbon or nitrogen. Examples 5-6-membered heteroaryl rings of the present invention include thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, isoxazolyl, isothiazolin, pyrazolyl and triazolyl. Examples of bicyclic heteroaromatic rings include indolyl, indazoles, chinoline, ethenolysis, hintline and honokalani.

The term "aliphatic heterocyclic ring" means a non-aromatic monocyclic and bicyclic rings containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. Examples 4-8-membered aliphatic heterocyclic rings of the present invention include pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, homopiperazine, homopiperazine and azetidines.

"Aryl" means an aromatic Carbo is ilycheskie ring, for example phenyl or naphthyl. The term "aliphatic carbocyclic ring" means a non-aromatic carbocyclic ring, as monocyclic and bicyclic. Examples 3-8-membered aliphatic carbocyclic rings are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkyl" means a saturated monocyclic carbocyclic ring. Cycloalkyl groups are monocyclic, such as cyclopentyl or cyclohexyl. Halogen is, for example, fluorine, chlorine or bromine.

Unless otherwise stated, in the context of this application alkyl groups and groups can be straight or branched chain and include, for example, methyl, ethyl, n-pupil, isopropyl or tert-butyl. The term "alkylene" means a bivalent alkyl group, for example-CH2-, -CH2CH2- , and-CH(CH3)CH2-. In the context of this application alkylene group may include cycloalkyl rings, for example, example, C4alkylene is

In the context of this application, when it is confirmed that the group may be substituted by one or more substituents, this group can be unsubstituted or substituted; in the case of substitution of the group is mainly substituted by one, two or three zamestitelyami. In General, the hydroxyl group is not connected is inane to the carbon atom, which is sosednim with the nitrogen atom.

In one embodiment of the invention R1and R2together with the carbon atom to which they are both directly attached form a group of the formula (VIII)

where q is equal to 0, 1, 2, 3, 4, 5 or 6; and each R independently represents halogen, hydroxyl and C1-4alkyl. If cycloalkyl ring substituted by more than one substituent R, the carbon atoms in cycloalkyl ring may have one or two deputies. In an additional aspect of this embodiment, q is 0, 1 or 2; and each R independently represents halogen, hydroxyl or C1-4alkyl. In another aspect of this embodiment, q is equal to 0.

In one embodiment of the invention R3represents phenyl or thienyl.

In one embodiment of the invention R3represents phenyl.

In one embodiment of this invention R1and R2together with the carbon atom to which they are both directly attached form a unsubstituted 7-membered cycloalkyl ring, and R3represents unsubstituted phenyl.

In one embodiment of the invention R4represents a group of formula (II), Y represents-CH2CH2-and the substitution on the ring in the group (II) is in position 3.

In one embodiment of the invention R4 represents a group of formula (IIa)

In one embodiment of the present invention features a compound of formula (IX), where R3represents phenyl or thienyl, and R5and X are such as defined in formula (I)

In the compounds of formula (I) R5represents a group of formula (IV)

In one embodiment of the invention w is equal to 0 and equal to 0.

In one embodiment of the invention w is equal to 1 and R6represents a C1-4alkylen.

In one embodiment of the invention w is equal to 1, R6represents a C1-4alkylen, and equal to 0.

In one embodiment of the invention w is equal to 1, R6represents a C1-4alkylen, equal to 1, and Q represents OH, -CONH -, or-C(O)O-.

In one embodiment of the invention w is equal to 1, R6represents a C1-4alkylen, equal to 1, and Q represents Oh or-CONH-.

In one embodiment of the invention w is equal to 1, R6represents a C1-4alkylen, equal to 1, and Q represents-CONH -, or-C(O)O-.

In one embodiment of the invention R7is a cyclic group Cyc1or group C1-4alkyl, possibly substituted cyclic group Cyc2.

In one embodiment of the invention Cyc1and Cyc2represent phenyl or 5-6-the feudal heteroaryl, with phenyl or a 5-6-membered heteroaryl may be substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, OCF3, phenyl, and C1-4the alkyl and phenyl, or With1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl. Examples 5-6-membered heteroaryl groups in this embodiment include isoxazolyl and furanyl.

In one embodiment of the invention Cyc1represents phenyl, naphthyl or a 5-6-membered heteroaryl, and phenyl, naphthyl, or 5-6-membered heteroaryl may be substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, OCF3, phenyl, and C1-4the alkyl and phenyl, or C1-4the alkyl can be substituted by one or more substituents, independently selected from halogen and hydroxyl. Examples 5-6-membered heteroaryl groups in this embodiment include isoxazolyl, pyrazinyl, pyridazinyl and furanyl.

In one embodiment of the invention Cyc2represents phenyl or 5-6-membered heteroaryl, and phenyl or 5-6-membered heteroaryl may be substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, OCF3, phenyl, and C-4 the alkyl and phenyl, or C1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl. Examples 5-6-membered heteroaryl groups in this embodiment include isoxazolyl and furanyl.

In one embodiment of the invention R5represents a C1-4alkyl, and C1-4the alkyl can be substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, phenyl, naphthyl, furanyl, teinila, phenoxy, and phenyl, naphthyl, furanyl, thienyl or group phenoxy may be substituted by one or more substituents, independently selected from halogen, cyano, C1-4alkoxy, OCF3and C1-4of alkyl, With1-4the alkyl can be substituted by one or more substituents, independently selected from halogen and hydroxyl.

In one embodiment of the invention R5represents a C1-4alkyl, and C1-4the alkyl can be substituted by one or more substituents, independently selected from phenyl, furanyl, phenoxy, and phenyl, furanyl or group phenoxy may be substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, OCF3and C1-4of alkyl, and C1-4the alkyl may be the ü substituted by one or more substituents, independently selected from halogen and hydroxyl.

In one embodiment of the invention R5represents a C1-4alkyl, and C1-4the alkyl can be substituted by phenyl, TuranAlem or phenoxy, and phenyl, furanyl or group phenoxy may be substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4of alkyl, OMe, CF3and OCF3.

In one embodiment of the invention R5represents a

-C1-4alkylen-Q-R7;

where Q represents O, or-CONH-, or-C(O)O-;

R7is a Cyc1or C1-4alkyl group, and C1-4the alkyl group may be substituted by one or more substituents, independently selected from phenyl, phenoxy, and phenyl, phenoxy may be substituted by one or more substituents, independently selected from halogen, hydroxyl, cyano, C1-4alkoxy and OCF3; and

Cyc1represents phenyl or 5-6-membered heteroaryl ring, each of which can be substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, phenyl, and C1-4the alkyl and phenyl, and C1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydrox the La.

In one embodiment of the invention R5represents a C1-4alkylen-Q-Cyc1;

where Q represents a-CONH-; and Cyc1is a 5-6-membered heteroaryl, possibly substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, phenyl, and C1-4the alkyl and phenyl, or C1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl. Examples 5-6-membered heteroaryl according to this embodiment include isoxazolyl, pyrazinyl and pyridazinyl.

In one embodiment of the invention R5represents-CH2-Q-Cyc1;

where Q represents a-CONH-; and Cyc1is a 5-6-membered heteroaryl, possibly substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, phenyl, and C1-4the alkyl and phenyl, or C1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl. Examples 5-6-membered heteroaryl according to this embodiment include isoxazolyl, pyrazinyl and pyridazinyl.

In one embodiment of the invention R5represents-CH2-Q-Cyc1;

where Q represents a-CONH-; and Cyc1is a 5-6-membered heteroaryl possibly substituted C 1-4the alkyl. Examples 5-6-membered heteroaryl according to this embodiment include isoxazolyl, pyrazinyl and pyridazinyl.

In one embodiment of the invention R5represents a C1-4alkylen-Q-Cyc1;

where Q represents a-CONH-; Cyc1represents a 5-membered heteroaryl, possibly substituted by one or more substituents, independently selected from halogen and C1-4the alkyl. Example 5-membered heteroaryl according to this embodiment is isoxazolyl.

In one embodiment of the invention R26represents hydrogen or C1-4alkyl, and C1-4the alkyl can be substituted by one or more substituents, independently selected from halogen and hydroxyl. In one embodiment of the invention R26represents hydrogen or C1-4alkyl.

In an additional aspect of the present invention proposed a compound of formula (X)

where q is 0, 1 or 2; each R independently represents halogen, hydroxyl or C1-4alkyl; R3represents phenyl; R5represents a C1-4alkyl, and C1-4the alkyl can be substituted by phenyl, TuranAlem or phenoxy, and phenyl, furanyl or group phenoxy may be substituted by one or more substituents, independently select nimi from halogen, hydroxyl, C1-4of alkyl, OMe and OCF3; and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

In an additional aspect of the present invention proposed a compound of formula (XI)

where q is 0, 1 or 2; each R independently represents halogen, hydroxyl or C1-4alkyl; R3represents phenyl;

R5represents a C1-4alkyl, and C1-4the alkyl can be substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, phenyl, naphthyl, furanyl, teinila, phenoxy, and phenyl, naphthyl, furanyl, thienyl or group phenoxy may be substituted by one or more substituents, independently selected from halogen, hydroxyl, cyano, C1-4alkoxy, OCF3and C1-4of alkyl, and C1-4the alkyl can be substituted by one or more substituents, independently selected from halogen and hydroxyl;

and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

In an additional aspect of the present invention proposed a compound of formula (XII)

where q is 0, 1 or 2; each R independently represents halogen, hydroxyl or C1-4alkyl; R3the submitted is phenyl; R5represents a C1-4alkylen-Q-Cyc1; where Q represents-CONH-; Cyc1represents a 5-membered heteroaryl, possibly substituted by one or more substituents, independently selected from halogen and C1-4of alkyl; and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

In an additional aspect of the present invention proposed a compound of formula (XIII)

where q is 0, 1 or 2; each R independently represents halogen, hydroxyl or C1-4alkyl; R3represents phenyl;

R5represents a C1-4alkylen-Q-R7;

Q represents OH, -CONH-;

R7represents hydrogen, Cyc1or C1-4alkyl group, and C1-4the alkyl group may be substituted by one or more substituents, independently selected from phenyl, phenoxy, and phenyl, phenoxy may be substituted by one or more substituents, independently selected from halogen, hydroxyl, cyano, C1-4alkoxy and OCF3; and

Cyc1represents phenyl or 5-6-membered heteroaryl ring, each of which can be substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-4alkoxy, phenyl, and C1-41-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl;

and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

Compounds according to the present invention, where R4represents a group of formula (IIa)contain a chiral center at position 3 hinkleyville ring, i.e. in the position marked with an asterisk (*) in the image of formula (IIa) in this description of the invention below

In one embodiment of the present invention R4represents a group of formula (IIa), where the stereochemical configuration at position 3 hinkleyville ring is a (R), in the designation according to the system Kan-Ingold-Prelog. (R)-Stereoisomer according to this embodiment can be represented in the form of a mixture of (S)-stereoisomer. For example, (R)-stereoisomer can be represented in the form of a racemic (1:1) mixture of (S)-stereoisomer. However, in an additional aspect of this embodiment features optically pure compound of formula (I), where R4represents a group of formula (IIa), and where the stereochemical configuration at position 3 hinkleyville ring represents (R).

In the context of the present description, the term "optically pure" ODA is defined in terms of enantiomeric excess (EE), which is calculated from the ratio of the difference between the amounts of their respective present enantiomers and the sum of these quantities, expressed in percent. For illustration, a product containing 95% of one enantiomer and 5% of another enantiomer has an enantiomeric excess (EE) 90% [i.e. (95-5)/(95+5)×100]. Optically pure compound of the present invention has AI at least 90%. In one embodiment of the present invention optically pure compound has AI at least 95%. In an additional embodiment of the invention, the optically pure compound has AI at least 98%.

In an additional embodiment of the present invention proposed a compound of formula (IX)as defined above in this description of the invention, where the stereochemical configuration at position 3 hinkleyville ring represents (R). In an additional aspect of this embodiment the compound of formula (IX) is optically pure.

In an additional embodiment of the present invention proposed a compound of formula (X)as defined above in this description of the invention, where the stereochemical configuration at position 3 hinkleyville ring represents (R). In an additional aspect of this embodiment the compound of formula (X) is optically pure.

In an additional embodiment of the present invention is radlogin compound of formula (XI), as defined above in this description of the invention, where the stereochemical configuration at position 3 hinkleyville ring represents (R). In an additional aspect of this embodiment the compound of formula (XI) is optically pure.

In an additional embodiment of the present invention proposed a compound of formula (XII)as defined above in this description, where the stereochemical configuration at position 3 hinkleyville ring represents (R). In an additional aspect of this embodiment the compound of formula (XII) is optically pure.

In an additional embodiment of the present invention proposed a compound of formula (XIII)as defined above in this description, where the stereochemical configuration at position 3 hinkleyville ring represents (R). In an additional aspect of this embodiment the compound of formula (XIII) is optically pure.

In one embodiment of the present invention R5is not the stands.

In one embodiment of the present invention R5is not the stands or unsubstituted benzyl.

In one embodiment of the present invention R5is not the stands, unsubstituted benzyl or substituted benzyl.

Pharmaceutically acceptable anions according to this embodiment include the chloride, bromide and iodide.

In addition the sustained fashion aspect of the present invention, a method for producing compounds of formula (I), which includes the interaction of the compounds of formula (XIV)where R1, R2and R3such as defined in formula (I), or C1-6Olkiluoto ester, acid anhydride or gelegenheid acid,

with the compound of the formula (XV), where Y is as defined in formula (I), and hydroxyl group, (XV) is in position 3 or 4

obtaining the compounds of formula (Va)

where R1, R2and R3such as defined in formula 1, and then the interaction (Va) with a compound R5-LG, where LG represents a leaving group (e.g. halogen), and R5the same as defined in formula (I): and maybe

- the conversion of the compound into another compound of formula (I),

- formation of pharmaceutically acceptable salts with the anion of a mono or polyvalent acid.

The interaction of the compound (XIV) (or C1-6Olkiluoto ether) with compound (XV) can be conveniently carried out in the presence of a suitable solvent, such as heptane, toluene or dichloromethane, at a temperature in the range from 0 to 100°C. In one embodiment of the invention, the compound (XIV) may conveniently take the form of gelegenheid acid (e.g. the acid chloride), which can be obtained by reacting the acid with a suitable reagent (for the example, the thionyl chloride or oxalylamino) in a suitable solvent such as dichloromethane or toluene, at tempearture in the interval from 0 to 100°C.

The interaction of compounds (V) and R5-LG can be conveniently carried out in the presence of a suitable solvent, such as dichloromethane or acetonitrile, at a temperature in the range from 0 to 100°C.

The compounds of formula (XIV) can be conveniently obtained by adding the ORGANOMETALLIC compound R3Met (XVII), where R3the same as defined in formula (I), and Met represents a suitable metal, with a compound of formula R1R2C(=O) (XVIII), where R1and R2such as defined in formula (I), with the formation of the alcohol R1R2R3SON (XIX). Alcohol (XIX) can then be transformed into alkilany ether, and alkilany ether is then converted into the acid (XIV) by treatment Olkiluoto ether alkali metal and damping CO2. The acid (XIV) can be converted into its C1-6alkilany ester, acid anhydride or gelegenheid acid.

The interaction of compounds (XVII) and (XVIII) can be conveniently carried out in the presence of a suitable solvent, such as tetrahydrofuran or diethyl ether at a temperature in the range from -20°C to 100°C. the compounds of structure R3Met (XVII) Met may be a halide of lithium, sodium, potassium or magnesium. Making alcohol 1R2R3SON (XIX) in his alkilany ester can be conveniently accomplished by treatment of compound C1-6alkyl-LG, where LG represents a leaving group (e.g. halogen), in a suitable solvent, such as dichloromethane, tetrahydrofuran or acetonitrile with a suitable base, such as triethylamine, diisopropylethylamine or sodium hydride at a temperature in the range from 0°to 90°C. the Obtained alkilany ether can then be conveniently transformed into a structure of the formula (XIV) by treatment with a mixture of sodium and potassium in a solvent such as diethyl ether, at a temperature in the range from 0°C to -80°C and damping CO2. Can be performed additional processing of the acid with the formation of C1-6Olkiluoto ether by treatment With1-6the alcohol solvent such as methanol with an acid catalyst, such as toluensulfonate acid, or by treatment of the acid TMS-diazomethane or with diazomethane in a solvent mixture such as tetrahydrofuran/methanol. Can be carried out additional processing of the acid with the formation of the anhydride or gelegenheid acid by treatment with oxalylamino or sulphonylchloride in a solvent such as dichloromethane, at a temperature in the range from -20°C to 40°C.

Compound (XV) or are commercially available or can be obtained JV the ways, corresponding or similar to those described in the literature; see, for example, EP 188255, Leonard et. al. J. Org. Chem. 1963, 28, 1499 and US 005318977.

Specialists in the art it is obvious that the methods of the present invention certain functional groups such as hydroxyl, carboxyl or amino group in the source reagents or intermediate compounds may need to be protected with protective groups. Thus obtaining compounds of formula (I) may involve, at some point, removing one or more protective groups. Protection and removal to protect functional groups described in "Protective Groups in Organic Synthesis", 2nd edition, T.W.Greene and P.G.M. Wuts, Wiley-Interscience (1991) and "Protecting Groups", P.J.Kocienski, Georg Thieme Verlag (1994).

Compounds of the present invention exhibit useful pharmaceutical properties. For example, the compounds according to the invention exhibit higher activity than the analogous compounds containing cyclopentene, tsiklogeksilnogo and cyclooctane rings. In addition, the compounds also exhibit stronger binding to plasma proteins than similar compounds containing tsiklogeksilnogo and cyclopentene rings. Stronger binding to plasma proteins may be a useful property for connections introduced by inhalation, as it can reduce the impact of any systemic action, which is output may have a connection.

The compounds of formula (Va) has not been previously obtained. In addition, the data aquaternion compounds also show activity as anticholinergic agents and are of interest for use in the treatment of conditions of the urinary tract, such as overactive bladder. Accordingly, the present invention also suggested that the compound of formula (V) or its salt accession acid

where

R1and R2together with the carbon atom to which they are both directly attached form a 7-membered cycloalkyl ring which may be substituted by one or more substituents, independently selected from halogen, hydroxyl and C1-4of alkyl,

R3represents phenyl or 5-6-membered heteroaryl ring, R4represents a group of formula (VI)

where

Y represents-CH2CH2-and the substitution of the ring in the group (VI) can occur in positions 3 or 4.

For compounds of formula (V) embodiment of the invention include those in which each of R1, R2, R3and R4as defined in this description of the invention above in the embodiments of the invention related to compounds of formula (I).

Salt accession acid compounds of the formula (V) includes the ut salt is hydrochloride, the hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or n-toluensulfonate.

The compounds of formula (V) according to the present invention include.

(3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane,

(3R)-3-{[(1-tamiltamil)carbonyl]oxy}-1-azabicyclo[2.2.2]Octan

and their pharmaceutically acceptable salts accession acid.

Compounds according to the invention have activity as pharmaceuticals, in particular as anticholinergic agents, including antagonists of muscarinic receptors (M1, M2 and M3), in particular antagonists of M3. Diseases and conditions that can be treated by the compounds, include:

1) respiratory tract: obstructive diseases of the respiratory tract, including asthma, including bronchial, allergic, hereditary, acquired, caused by stress, drugs (including those caused by aspirin and NSAIDs (non-steroidal anti-inflammatory drugs)and is caused by dust asthma, both intermittent and continuous, and of all degrees of severity, and other cases of hypersensitivity of the respiratory tract; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; allergic alveolitis and related diseases; hypercholesterol the th pneumonitis; the lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-tumor therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitis and thrombotic disorders of the vascular network of the lung, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the Airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medication, and vasomotor rhinitis; permanent and seasonal allergic rhinitis, including neurotic rhinitis (hay fever); nasal polyposis; acute a viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;

2) bones and joints: the skin lesions of rheumatic or gouty origin, associated with osteoarthritis/osteoarthrosis or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and pain in the neck and back; rheumatoid arthritis and of still's disease; seronegative of spondyloarthropathies, including ankylosing spondylitis, pariat the ical arthritis, reactive arthritis and undifferentiated spondarthritis; septic arthritis and other infection arthropathies and bone lesions, such as tuberculosis, including Pott disease and arthritis Ponce; acute and chronic crystal-induced synovitis including gout, a disease caused by deposition of calcium polyphosphate, and associated with the Apatite calcium, inflammation of the tendons, synovial bags and synovial inflammation; Behcet's disease; primary and secondary Sjogren syndrome; systemic sclerosis and limited scleroderma; systemic erythematous lupus, mixed disease of connective tissue, and undifferentiated disease of connective tissues; inflammatory myopathies including dermatomyositis and polymyositis; polymyalgia rheumatica; juvenile arthritis including idiopathic inflammatory skin lesion of rheumatic or gouty origin of any joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitis, including giant cell arteritis diagnostics, Takayasu's arteritis, syndrome Cerca-Strauss, polyarteritis polyarteritis, microscopic polyarteritis, and vasculitis associated with viral infection, allergic reactions, cryoglobulin and paraproteins; lumbar pain; familial Mediterranean fever, syndrome is Make wells, and family Irish fever, a disease of Kikuchi; medicinal arthralgia, tendancey and myopathy;

3) pain and reconstruction of connective tissue in bone and muscle damage due to injury [for example sports injury] or disease: skin lesion of rheumatic or gouty origin (for example, rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as degeneration of the intervertebral disc or degeneration of the temporomandibular joint), a disease of the bone reconstruction (such as osteoporosis, osteoporosis Paget's disease or osteonecrosis), polychondritis, scleroderma mixed disease of connective tissue, spondyloarthropathies or periodontal disease (such as periodontitis);

4) skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and hypersensitivity reactions of the delayed type; phyto - and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, red flat zoster, zoster sclerotic and atrophic, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, bullous bullosa, urticaria, disease Quincke, vasculitis, toxic erythema, dermal eosinophilia, alopecia areata, alopecia male type, sweet syndrome, syndrome Ve the EPA-Christian, erythema multiforme; cellulitis, both infectious and non-infectious; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic damage; disorder, induced by drugs, including drug resistant rash;

5) eyes: blepharitis; conjunctivitis, including permanent and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; chorioidea; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmic, including sympathetic ophthalmic; sarcoidosis; infections including viral, fungal, and bacterial;

6) gastrointestinal tract: glossitis, gingivitis, periodontitis; inflammation of the esophagus, including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, anal itching; coeliac disease, irritable bowel syndrome and food allergies which may have effects remote from the digestive tract (for example, migraine, rhinitis or eczema);

7) abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;

8) genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitially) cystitis and x is onicescu ulcer of the bladder; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);

9) allograft rejection: acute and chronic after, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or after blood transfusion; or chronic graft-versus-host;

10) CNS (Central nervous system): Alzheimer's disease and other Dement disorders including CJD disease Creutzfeld - Jakob) and nvCJD (atypical variant of the disease of Creutzfeldt-Jakob disease; amyloidosis; multiple sclerosis and other demyelinizing syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis diagnostics; asthenic bulbar paralysis; acute and chronic pain (acute, intermittent or constant, either Central or peripheral origin)including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint pain and bone pain, pain, caused by cancer and tumor invasion, neuropathic pain syndromes including diabetic, post herpetic, and HIV-associated neuropathy; neurosarcoidosis; complications of the Central and peripheral nervous system as a result of malignant, infectious or autoimmune processes;

11) on the other autoimmune and allergic disorders, including Hashimoto's thyroiditis, graves ' disease, Addison disease, diabetes mellitus, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, Hyper-IgE syndrome, antiphospholipid syndrome;

12) other disorders with an inflammatory or immunological component; including acquired immunodeficiency syndrome (AIDS), leprosy, syndrome Cesari and paraneoplastic syndromes;

13) cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocardia, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvular, and aortic, including infective (for example syphilitic); vasculitis; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14) Oncology: treatment of common types of cancer, including tumors of the prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain, and malignant development affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and recurrence of the tumor and paraneoplastic syndrome is;

15) gastrointestinal tract: coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, undifferentiated colitis, upset, irritable bowel, irritable bowel syndrome, non-inflammatory diarrhea, food allergies, which have the action removed from the digestive tract, for example migraine, rhinitis and eczema.

Accordingly, the present invention additionally proposed compound of formula (I)as defined above in this description of the invention, for use in therapy.

In another aspect of the invention proposed the use of the compounds of formula (I)as defined above in this description of the invention, in the manufacture of a medicinal product for use in therapy.

In the context of the present description, the term "therapy" also includes "prevention"if there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

In an additional aspect of the invention, a method for treatment of a painful condition of the mammal suffering from the specified disease or at risk for a specified disease, comprising the administration to a mammal in need of such treatment, a therapeutically effective amount with the organisations of the formula (I), as defined earlier in this specification.

The present invention also suggested that the compound of formula (I)as defined above in this description of the invention, for the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).

Also in the present invention proposed a compound of formula (I)as defined above in this description of the invention, for the treatment of asthma.

In the present invention has also proposed the use of the compounds of formula (I)as defined above in this description of the invention, in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).

The present invention also proposed the use of the compounds of formula (I)as defined above in this description of the invention, in the treatment of asthma.

The present invention also proposed the use of the compounds of formula (I)as defined above in this description of the invention, in the manufacture of a medicinal product for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).

The present invention also proposed the use of the compounds of formula (I)as defined above in this description of the invention, in the manufacture of a medicinal product for use in the treatment of asthma.

In addition, in the present invention is proposed pic is b chronic obstructive pulmonary disease (COPD) (such as irreversible COPD) in a warm-blooded animal, such as man, which comprises the administration to a mammal in need of such treatment, an effective amount of the compounds of formula (I)as defined above in this description.

In addition, in the present invention, a method for treating asthma in a warm-blooded animal, such as man, which comprises the administration to a mammal in need of such treatment, an effective amount of the compounds of formula (I)as defined above in this description.

In order to apply the compounds according to the invention for therapeutic treatment of warm-blooded animal, such as man, this ingredient is usually prepared in the form of a preparation according to conventional pharmaceutical practice as a pharmaceutical composition.

Therefore, in another aspect of the present invention proposed a pharmaceutical composition which contains a compound according to the invention, as defined above in this description of the invention, and a pharmaceutically acceptable excipient, diluent or carrier. In an additional aspect of the present invention, a method for obtaining this composition, which comprises mixing the active ingredient with a pharmaceutically acceptable auxiliary substance, diluent or carrier. Depending on the method of introducing farmace the political composition, for example, contains from 0.05 to 99% of the mass.(percent by weight), for example from 0.05 to 80 wt. -%, for example from 0.10 to 70 wt. -%, for example, 0.10 to 50 wt. -%, the active ingredient, where all weight percents based on the total composition.

The pharmaceutical compositions according to this invention can be activated by a method generally accepted for a painful condition, which is required to treat, for example through local (such as in the lungs and/or Airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention can be prepared in the form of the preparation methods known in the art, in the form of, for example, aerosols, dry powder compositions, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

A suitable pharmaceutical composition of the present invention is a composition suitable for oral administration in a standard dosage form, e.g. tablet or capsule which contains from 0.1 mg to 1 g of the active ingredient.

In another aspect the pharmaceutical composition according to the invention is a composition suitable for nutrional, subcutaneous or intramuscular injection. Each patient may receive, for example, intravenous, subcutaneous or intramuscular dose of 0.01 mg/kg to 100 mg/kg compound, for example in the range from 0.1 mg/kg to 20 mg/kg according to this invention, and the composition is administered 1 to 4 times per day. Intravenous, subcutaneous and intramuscular dose can be given by bolus injection. Alternatively, the intravenous dose can be given by continuous infusion over a period of time. Alternatively, each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, and the composition is administered 1 to 4 times per day.

Other suitable pharmaceutical composition according to this invention is a composition suitable for inhalation, as inhalation is a particularly useful method for the introduction of compounds according to the invention in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma. With the introduction by inhalation the compounds of formula (I) can be used effectively in doses that are in microgramma range, for example 0.1 to 500 μg, 0.1 to 50 μg, 0.1 to 40 μg, 0.1 to 30 μg, 0.1 to 20 μg, 0.1 to 10 mg, 5-10 mg, 5-50 μg, 5-40 µg, 5-30 µg, 5-20 mg, 5-10 mg, 10-50 mg, 10-40 mg, 10-30 10-20 mcg or µg active is ngredient.

In one embodiment of the invention features a pharmaceutical composition comprising a compound according to the invention, as defined above in this description of the invention together with a pharmaceutically acceptable auxiliary substance, diluent or carrier, prepared in the form of the drug for inhalation.

With the introduction of through inhalation can be used inhalation dosing device for introducing active ingredient dispersed in a suitable propellant and in the presence or in the absence of additional excipients such as ethanol, a surfactant, moving or stabilizing agents. Suitable propellants include hydrocarbons, harperperennial and hydrofluroalkane (for example, heptapteridae) propellants or mixtures of any of such propellants. Preferred propellants are RA and R, each of which can be used alone or in combination with other propellants and/or surfactants and/or other excipients. You can also use a sprayed aqueous suspension or, preferably, solutions with adjustment or no adjustment to a suitable pH and/or toychest either as a single dose or parenteral multi-dose compositions.

Inhalers dry powder you can use the introduction of the active ingredient, alone or in combination in a pharmaceutically acceptable carrier, in the latter case, either in the form of fine powder or in the form of an ordered mixture. The dry powder inhaler can be a single dose or mnogochasovym and it is possible to use dry powder or containing powder capsule.

Device: dosing inhaler, nebulizer and inhaler dry powder is well known, and there are many such devices.

In addition, the invention relates to combination therapies, where the connection according to the invention, or pharmaceutical composition or drug containing the compound according to the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents for the treatment of one or more of the listed conditions.

In particular, for the treatment of inflammatory disorders, such as (but not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel disease, the compounds according to the invention can be mixed with the agents listed below.

Nonsteroidal anti-inflammatory agents (below NSAID)including non-selective cyclo-oxygenase inhibitors MOR-1/SOH-2, applied topically or systemically (such as peroxy the am, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, Ketoprofen and ibuprofen, fenamate, such as marennikova acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective inhibitors MOR-2 (such as meloxicam, celecoxib, rofecoksib, valdecoxib, lumiracoxib, parecoxib, etoricoxib); inhibiting cyclooxygenase donors of nitric oxide (CINOD); glucocorticosteroids (entered local, oral, intramuscular, intravenous or intra-articular routes); methotrexate; Leflunomide; hydroxychloroquine; D-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular tools, such as derivatives of hyaluronic acid; and dietary supplements, such as glucosamine.

In addition, the present invention relates to combinations of compounds according to the invention together with a cytokine or agonist or antagonist function of cytokines (including agents that act on the signaling pathway of cytokine, such as modulators system SOCS), including alpha-, beta - and gamma-interferons; insulin-like growth factor type 1 (IGF-1); interleukins (IL), including IL-17, and antagonists or inhibitors of interleukin, such as anakinra; inhibitors of tumor necrosis factor alpha (TNF-α, such as monoclonal anti-TNF antibodies (for example infliximab; adalimumab, and CDP-870), and antagonists of the receptor, TNF, including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxifylline.

In addition, the invention relates to combinations of compounds according to the invention together with B-lymphocytes targeted with monoclonal antibodies (such as CD20 (rituximab), MRA-aIL16R and T-lymphocytes, CTLA4-Ig, HuMax Il-15).

In addition, the present invention relates to combinations of compounds according to the invention with a modulator of the function of the chemokine receptor, such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for a family of S-C); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for a family of C-X-C) and CX3CR1 for a family of C-X3-S.

In addition, the present invention relates to combinations of compounds according to the invention with an inhibitor of matrix metalloprotease (DFID), i.e. stromelysins, collagenases and gelatinases and aggrecanases; mainly collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 (MMP-11 and MMP-9 and MMP-12, including agents, such as doxycycline.

In addition, the present invention relates to combinations of compounds according to the invention and an inhibitor of leukotriene biosynthesis, an inhibitor of 5-lipoxygenase (5-LO) or ant is onista protein, activates 5-lipoxygenase (FLAP), such as zileuton; ABT-761; Finlayson; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylbenzothiazole; methoxyacridine, such as Zeneca ZD-2138; the compound SB-210661; pyridinylamino 2-cyanonaphthalene connection, such as L-739,010; 2-cyanohydrine connection, such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY×1005.

In addition, the present invention relates to combinations of compounds according to the invention and antagonist receptor leukotriene (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of phenothiazines-3-silts, such as L-651,392; amidinopropane, such as CGS-25019c; benzoxazepine, such as ontazolast; benzoperoxide, such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP A) and BAY×7195.

In addition, the present invention relates to combinations of compounds according to the invention and an inhibitor of phosphodiesterase (PDE), such as methylxanthines, including theophylline and aminophylline; selective inhibitor of PDE isoenzyme, including PDE4 inhibitor, an inhibitor of the isoform PDE4D, or a PDE5 inhibitor.

In addition, the present invention relates to combinations of compounds according to the invention and antagonist of histamine receptor type 1, such as Ceti is ISIN, loratadin, desloratadin, fexofenadin, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine or mizolastine; applied orally, topically or parenterally.

In addition, the present invention relates to combinations of compounds according to the invention and proton pump inhibitors (such as omeprazole) or gastroprotective antagonist histamine receptor type 2.

In addition, the present invention relates to combinations of compounds according to the invention and antagonist of histamine receptor type 4.

In addition, the present invention relates to combinations of compounds according to the invention and vasoconstrictor sympathomimetic agent-based agonists of adrenergic receptors, alpha-1/alpha-2, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, nafazolina hydrochloride, Oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, Xylometazoline hydrochloride, tramazoline hydrochloride or Ethylmorphine hydrochloride.

In addition, the present invention relates to combinations of compounds according to the invention and agonists of beta-adrenergic receptors (including beta-receptor subtypes 1-4), such as izoprenalin, salbutamol, formoterol, salmeterol, terbutaline, ortsiprenalin, bitolterol mesilate, pirbuterol or indacaterol or his Herald the second enantiomer.

In addition, the present invention relates to combinations of compounds according to the invention and chromone, such as sodium cromoglycate or nedocromil sodium.

In addition, the present invention relates to combinations of compounds according to the invention with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

In addition, the present invention relates to combinations of compounds according to the invention with an agent that modulates hormonal nuclear receptors such as PPAR.

In addition, the present invention relates to combinations of compounds according to the invention together with immunoglobulin (Ig) or Ig drug or an antagonist or antibody modulating the function Ig, such as anti-IgE (e.g. omalizumab).

In addition, the present invention relates to combinations of compounds according to the invention, and other systemic or locally applied anti-inflammatory agent, such as thalidomide or its proizvodnoe, retinoid, dithranol or calcipotriol.

In addition, the present invention relates to combinations of compounds according to the invention and combinations of aminosalicylates and sulfapiridina, such as sulfasalazin, mesalazine, balsalazide and olsalazine; and immunomodulatory agents, such as thiopurine, and to corticoste is rodam, such as budesonide.

In addition, the present invention relates to combinations of compounds according to the invention together with an antibacterial agent such as a derivative of penicillin, tetracycline, macrolide, beta-covenants, fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; nucleoside reverse transcriptase inhibitors, such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitors such as nevirapine or efavirenz.

In addition, the present invention relates to combinations of compounds according to the invention and a cardiovascular agent such as a calcium channel blocker, blocker beta-adrenergic receptors, angiotensin-converting enzyme inhibitor (ACE), antagonist of angiotensin receptor-2; lipid-lowering agent such as a statin or fibrate; modulator morphology of blood cells, such as pentoxifylline; thrombolytic or anticoagulative means, such as an inhibitor of platelet aggregation.

In addition, the present invention relates to combinations of compounds according to the invention and the agent the CNS, such as an antidepressant (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-DOPA, ropinirole, pramipexol, inhibitor IAIA (monoamine oxidase), such as selgin, rasagiline, inhibitor comP, such as tasmar And-2-inhibitor, the inhibitor of the reuptake of dopamine antagonist of the NMDA (N-methyl-D-aspartate), agonist nicotine, dopamine agonist or inhibitor of neuronal nitric oxide synthase), or drugs against Alzheimer's disease, such as donepezil, rivastigmine, taken, inhibitor SOH-2 (cyclooxygenase-2), propentofylline or metrifonate.

In addition, the present invention relates to combinations of compounds according to the invention and the agent for the treatment of acute or chronic pain, such as Central or peripheral analgesic actions (for example, opioid or its derivative), carbamazepine, phenytoin, sodium valproate, amitryptiline or other antidepressant agents, paracetamol or non-steroidal anti-inflammatory agent.

In addition, the present invention relates to combinations of compounds according to the invention together with applied parenterally or topically (including inhalation) a local anesthetic agent such as lignocaine or its derivative.

The compound of the present invention can also be used in combination with antistia oronym agent, including hormonal agent such as raloxifene, or biphosphonate, such as alendronate.

In addition, the present invention relates to combinations of compounds according to the invention together with (1) a tryptase inhibitor; (2) an antagonist of platelet activating factor (PAF); (3) inhibitor INTERLAKOKRASKA enzyme (ICE); (4) IMPDH inhibitor; (5) inhibitors of adhesion molecules, including antagonist VLA-4; (6) a cathepsin; (7) a kinase inhibitor such as an inhibitor tyrosinemia kinase (such as Btk, Itk, Jak3 or MAP, for example gefitinib or imatinib mesilate), serine/ser / thr kinases (such as the MAP kinase inhibitor, for example R, JNK, protein kinase a, b or C, or IKK), or a kinase involved in cell cycle regulation (such as cyclin-dependent kinase); (8) an inhibitor of glucose-6-phosphate-dehydrogenase; (9) an antagonist of kinin-B1 and-B2-receptor; (10) protivoogogove agent, for example colchicine; (11) an inhibitor of xanthine oxidase, for example allopurinol; (12) an agent that promotes the excretion of uric acid, such as probenicid, sulfinpirazonom or benzbromarone; (13) agent, amplifying secretion growth hormone; (14) transforming growth factor (TGFβ); (15) platelet-derived growth factor (PDGF); (16) a growth factor, fibroblast, such as the main growth factor of the fibroblast (bFGF); (17) granulocyte-macrophage colonystimulating the factor (GM-CSF); (18) capsaicinoid cream; (19) receptor antagonist tachykinin NK1 or NK3, such as NKP-608C, SB-233412 (talnetant) or D-4418; (20) elastase inhibitor such as UT-77 or ZD-0892; (21) an inhibitor of TNF-alpha converting enzyme (TACE); (22) inhibitor of the inducible nitric oxide synthase (iNOS); (23) molecules homologous chemoattractant receptors expressed in T cells (such as a CRTH2 antagonist); (24) inhibitor R; (25) agent modulating the function of Toll-like receptors (TLR); (26) agent modulating the activity of purinergic receptors such as RH; or (27) inhibitor activation of transcription factors such as NFkB, API, or STATS.

The connection according to the invention can also be used in combination with existing therapeutic agent for the treatment of cancer, for example, suitable agents include:

(1) antiproliferative/antineoplastic drug or combination that is used in medical Oncology, such as alkylating agent (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan or nitrosoanatabine); an antimetabolite (for example, antifolate, such as ftorpirimidinov 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); antitumor antibiotics (for example, tricyclin, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubitsin, mitomycin-C, dactinomycin or mithramycin); antimitoticescoe agent (for example, a Vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or taxoid, such as Taxol or Taxotere); or a topoisomerase inhibitor (e.g., epipodophyllotoxins, such as etoposide, teniposide, amsacrine, topotecan or computerin);

(2) cytotoxic agent, such as an antiestrogen (e.g., tamoxifen, toremifene, raloxifene, droloxifene or idoxifene), a negative regulator of estrogen receptors (e.g., fulvestrant), an antiandrogen (for example, bikalutamid, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist (releasing factor, luteinizing hormone or LHRH agonist (for example goserelin, laprolan or buserelin), a progestogen (for example, megestrol acetate), aromatase inhibitor (for example, anastrozole, letrozole, varsol or exemestane) or an inhibitor of 5α-reductase such as finasteride;

(3) an agent which inhibits the invasion of cancer cells (for example, the inhibitor of metalloproteinases, such as marimastat, or the inhibitor of the function of the receptor activator of plasminogen urokinase type);

(4) the inhibitor function of the growth factor, for example an antibody to a growth factor (for example the anti-erbb2 antibody trastuzumab or the anti-erbb1 antibody C is taximan [S]), inhibitor farnesyltransferase, a tyrosine kinase inhibitor or inhibitor of serine/trionychinae, inhibitor family of epidermal growth factors (for example, the inhibitor tyrosinekinase family of EGFR, such asN-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)hinzelin-4-amine (erlotinib, OSI-774) or 6-acrylamide-M-(3-chloro-4-forfinal)-7-(3-morpholinopropan)hinzelin-4-amine (CI 1033)), an inhibitor of a family of growth factors, platelets or inhibitor of a family of growth factor hepatocyte;

(5) an antiangiogenic agent such as an agent that inhibits the effects of vascular endothelial growth factor (for example, an antibody to vascular endothelial growth factor bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example, linomide, an inhibitor of the function of integrin αvβ3 or angiostatin);

(6) the agent, damaging blood vessels, such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;

(7) an agent used in antisense therapy, for example aimed at one of the targets listed above, such as ISIS 2503, an anti-ras antisense;

(8) an agent used in a gene therapeutic method such as a method of replacing the s aberrant genes, such as aberrant p53 or aberrant BRCA1 or BRCA2, method, GDEPT (gene-directed enzyme proletarienne therapy), for example, using citizendiumat, timedancing or bacterial enzyme nitroreductase, and methods of increasing tolerance of the patient to chemotherapy or radiotherapy such as gene therapy multilocational resistance; or

(9) an agent used in immunotherapy method, for example, in ex vivo and in vivo methods of enhancing the immunogenicity of tumor cells of the patient, such as transferowania cytokines, such as interleukin 2, interleukin 4 or colony-stimulating factor granulocyte and macrophages, methods of reducing anergy of T cells, methods of using transfetsirovannyh immune cells, such as cytocentrifugation dendritic cells, methods of using cytocentrifugation lines of tumor cells and methods of using antiidiotypic antibodies.

In an additional embodiment of the present invention is proposed pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I)as described above in this description of the invention, and at least one additional active ingredient selected from the

- phosphodiesterase inhibitor,

agonists β2-adrenale is aptara,

modulator functions of chemokine receptors

inhibitor of kinase function,

- protease inhibitor

- steroid of the glucocorticoid receptor agonist and

- non-steroidal agonist of the glucocorticoid receptor.

Pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and additional active ingredients in the mixture. Alternatively, the pharmaceutical product may, for example, contain the first and additional active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate introduction of the patient who needs it. Pharmaceutical product according to this embodiment is particularly applicable in the treatment of respiratory diseases such as asthma, COPD or rhinitis.

Examples of the phosphodiesterase inhibitor that can be used in the pharmaceutical product according to this embodiment include a PDE4 inhibitor, such as an inhibitor of the isoform PDE4D, an inhibitor of PDE3 and PDE5 inhibitor. Examples include the following compounds:

(Z)-3-(3,5-dichloro-4-pyridyl)-2-[4-(2-inanimate-5-methoxy-2-pyridyl]propanenitrile,

N-[9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepine-3(R)-yl]pyridine-3-carboxamide (Cl-1044),

3-(benzyloxy)-1-(4-terbisil)-N-[3-(methylsulphonyl)phenyl-1H-indole-2-carboxamide,

(1S-Exo)-5-[3-(bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]tetrahydro-2(1H)-pyrimidinone (Atizoram),

N-(3,5,dichloro-4-pyridinyl)-2-[1-(4-terbisil)-5-hydroxy-1H-indol-3-yl]-2-oxoacetate (AWD-12-281),

β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide (CDC-801),

N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepine-3(R)-yl]pyridine-4-carboxamide (Cl-1018),

CIS-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid (Cilomilast),

8-amino-1,3-bis(cyclopropylmethyl)xanthine (Cipamfylline),

N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-chinainternational (D-4418),

5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-aminothiazoline-4-one (Darbufelone),

2-methyl-1-[2-(1-methylethyl)pyrazolo[1,5-and]pyridine-3-yl]-1-propanone (Ibudilast),

2-(2,4-dichlorophenylethyl)-3-breidenthal-6-yl methanesulfonate (Lyrikill),

(-)-(R)-5-(4-methoxy-3-propoxyphenyl)-5-methyloxazolidine-2-he (Mizoram),

(-)-CIS-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4A, 10b-hexahydro-6-(4-diisopropylaminoethyl)-benzo[C][1,6]naphthiridine (Pumafentrine),

3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(deformedarse)benzamide (Roflumilast),

N-oxide Roflumilast,

5,6-diethoxybenzoic[b]thiophene-2-carboxylic acid (Teenlust),

2,3,6,7-tetrahydro-2-(mesitylene)-9,10-dimethoxy-3-methyl-4H-pyrimido[6,1-a]isoquinoline-4-one (trequinsin) and

3-[[3-(cyclopentyloxy)-4-methoxyphenyl]methyl]-N-ethyl-8-(1-methylethyl)-3H-purine-6-amine (V-11294A).

Examples of agonist β2-adrenergic receptors, which can be used in the pharmaceutical product according to this embodiment include metaproterenol, isoproterenol, izoprenalin, albuterol, salbutamol (e.g. as the sulphate), formoterol (e.g. as fumarata), salmeterol (e.g. as xinafoate), terbutaline, ortsiprenalin, bitolterol (e.g. nelfinavir), pirbuterol or indacaterol. Agonist β2-adrenergic receptors in this embodiment may be a β2-long acting agonists, such as salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarata), bambuterol (e.g. as hydrochloride), carmoterol (TA 2005, chemically identified as 2(1H)-hinolan, 8-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]monohydrochloride, [R-(R*,R*)], also identified under the registration number Chemical Abstract Service 137888-11-0 and disclosed in the patent US 4579854), indacaterol (CAS No. 312753-06-3; QAB-149), derivatives of formanilide, for example 3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)-benzosulfimide, as disclosed in WO 2002/76933, derivatives benzosulfimide, for example 3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)Hexi is]oxy}butyl)benzosulfimide, as disclosed in WO 2002/88167, allanalmovies receptor agonists, as disclosed in WO 2003/042164 and WO 2005/025555, indole derivatives as disclosed in WO 2004/032921 and US 2005/222144, and connections GSK 159797, GSK 159802, GSK 597901, GSK and GSK 642444 678007.

Examples of the modulator functions of chemokine receptors, which can be used in the pharmaceutical product according to this embodiment include the CCR1 receptor antagonist.

Examples of an inhibitor of kinase function, which can be used in the pharmaceutical product according to this embodiment include the kinase inhibitor R and IKK inhibitor.

Examples of protease inhibitors that can be used in the pharmaceutical product according to this embodiment, include an inhibitor of neutrophil elastase or inhibitor MMR.

Examples of steroid agonist of the glucocorticoid receptor, which can be used in the pharmaceutical product according to this embodiment include budesonide, fluticasone (e.g. as propionate ether), mometazon (for example, in the form of furoate ether), beclomethasone (e.g. as 17-propionate or 17, 21-dipropionate esters), ciclesonide, loteprednol (as, for example, etabonate), etiprednol (as, for example, cycloacetal), triamcinolone (e.g. as acetonide), flunisolide, suticase, flumoxed, rofleponide, butixocort (for example, in the form of propionate ether), prednis the LON, prednisone, tipredane, Sterol esters, for example 6α,9α-debtor-17α-[(2-fornicator)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate S-formerely ester, 6α,9α-debtor-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioate S-(2-oxitetraciclina-3S-yl)new ester and 6α,9α-debtor-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioate S-formerely ester, steroid esters according to DE 4129535, steroids according to WO 2002/00679, WO 2005/041980 or steroids GSK 870086, GSK 685698 and GSK 799943.

Examples of the modulator of non-steroidal glucocorticoid receptor agonist, which can be used in the pharmaceutical product according to this embodiment include the modulators described in WO 2006/046916.

The present invention is further illustrated by the following non-limiting Examples.

In the examples, the NMR spectrum was determined on spectrophotometer Varian Unity Inova at a frequency of protons at 300 or 400 MHz. MS-Spectrum (mass spectrum) were determined or spectrophotometer Agilent 1100 MSD G1946D or spectrophotometer Hewlett Packard HP1100 MSD G1946A. Separation by preparative HPLC was performed using a column Waters Symmetry®or Xterra®using as eluent a mixture of 0.1% aqueous triperoxonane acid : acetonitrile, 0.1% aqueous solution of ammonia : acetonitrile or 0.1% ammonium acetate : acetonitrile. CX and NH 2-ion-exchange resin was purchased from Varian Incorporated. The IUPAC names were generated using a computer program ACDLabs Name.

Example 1: (3R)-3-{[(1-Phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]Octan

a) 1-Phenylcyclohexanol

To magnesium (1.2 g) in anhydrous tetrahydrofuran (60 ml) under nitrogen atmosphere was added a crystal of iodine, then brobinson (a 7.85 g) with such a rate as to maintain the reaction mixture at a constant reflux distilled. The reaction mixture was stirred for 20 minutes, then carefully added Cyclopentanone (4,48 g). After stirring for 10 minutes was added a saturated aqueous solution of ammonium chloride (10 ml) and the reaction mixture was separated between water (100 ml) and isohexane (100 ml). The organic layer was dried (MgSO4) and was evaporated to obtain specified in the subtitle compound (7.6 g) in the form of oil.

1H NMR (299,946 MHz, CDCl3) δ 7.53-7.47 (m, 2H), 7.36-7.29 (m, 2H), 7.26-7.19 (m, 1H), 2.07 (ddd, 2H), 1.97-1.50 (m, 11H).

b) 1-Methoxy-1-phenylcyclohexane

1-Phenylcyclohexanol (Example 1A) (7.6 g) was dissolved in tetrahydrofuran (100 ml) was added sodium hydride (60% in oil, 2.0 g). The reaction mixture was stirred at 60°C for 5 minutes and added logmean (7,1 g). The mixture was maintained at 60°C overnight and then added an additional amount of sodium hydride (6% in oil, 2.0 g) and iodomethane (7,1 g)and the reaction mixture was heated under reflux for 70 hours. The reaction mixture was separated between water (100 ml) and isohexane (100 ml) and the organic layer was separated, dried (MgSO4) and was evaporated to obtain specified in the subtitle compound (11,31 g).

1H NMR (299,946 MHz, CDCl3) δ 7.43-7.37 (m, 2H), 7.37-7.30 (m, 2H), 7.24-7.19 (m, 1H), 2.98 (s, 3H), 2.12-1.88 (m, 4H), 1.88-1.45 (m, 8H).

C) 1-Phenylcyclohexylamine acid

Potassium (2,62 g) and sodium (0.52 g) were heated together at 120°C in mineral oil in a nitrogen atmosphere for 30 minutes and then cooled to room temperature. The oil was removed and replaced with ether (100 ml)was added 1-methoxy-1-phenylcyclohexane (Example 1B) (4.9 g) and the reaction mixture was stirred in nitrogen atmosphere overnight at room temperature. The reaction mixture was cooled to -78°C and added with stirring solid carbon dioxide (~20 g). Gave the opportunity to the reaction mixture to warm to room temperature and carefully in an atmosphere of nitrogen was added water (150 ml). The aqueous layer was separated, neutralized with concentrated hydrochloric acid and was extracted with diethyl ether (150 ml). The organic layer was dried (MgSO4) and was evaporated to obtain specified in the subtitle compound (4.15 g) in the form of oil.

1H NMR (299,946 MHz, CDCl3) δ 7.40-7.20 (m, 5H), 2.49-2.35 (m,2H), 2.16-2.03 (m, 2H), 1.76-1.47 (m, 8H).

g) Methyl-1-phenylcyclohexanecarboxylic

1-Feniltiosemicarbazona acid (Example 1B) (4.15 g) was boiled under reflux in methanol (150 ml) and concentrated hydrochloric acid (5 ml) for 24 hours. The solvent is evaporated and the residue was dissolved in ether, which was washed with water (100 ml), saturated sodium bicarbonate (50 ml) and water (100 ml), dried (MgSO4) and was evaporated to obtain specified in the subtitle compound (3.5 g) as oil.

1H NMR (299,946 MHz, CDCl3) δ 7.37-7.18 (m, 5H), 3.63 (s, 3H), 2.47-2.35 (m, 2H), 2.08-1.97 (m, 2H), 1.70-1.48 (m, 8H).

Example 1 (3R)-3-{[(1-Phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]Octan

Methyl-1-phenylcyclohexanecarboxylic (Example 1 g) (1.0 g) and (R)-Hinkley-3-ol (commercially available from Acros Organics)1, (0.39 g) was boiled under reflux in heptane (50 ml)containing sodium (~5 mg), in the office of Dean-stark within 24 hours. Heptane (20 ml) was replaced by toluene (20 ml) and boiling under reflux was continued for 3 days. The reaction mixture was separated between water (50 ml) and ether (50 ml) and the ether layer was separated, dried (MgSO4) and was evaporated. The crude product was purified by column chromatography with silica gel, elwira a mixture of ethyl acetate/triethylamine (99/1) to obtain specified in C is the coupling head (0,83 g) in the form of butter. 1The number of minor (S)-isomer present in the (R)-Hinkley-3-Ola, which was estimated using chiral HPLC, should be less than 0.5%.

m/e 328 [M+H]+

1H NMR (299,946 MHz, CDCl3) δ 7.35-7.27 (m, 4H), 7.23-7.16 (m, 1H), 4.78-4.71 (m, 1H), 3.12 (ddd, 1H), 2.79-2.32 (m, 7H), 2.16-1.98 (m, 2H), 1.91-1.80 (m, 1H), 1.70-1.34 (m, 12H).

Example 2: (3R)-1-methyl-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane iodide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0,78 g) in acetonitrile (30 ml) was added iodomethane (0.8 ml). After maturation during the night the solvent was removed and the residue was dried in high vacuum, then triturated with ether to obtain specified in the connection header (847 mg).

m/e 342 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 7.39-7.29 (m, 4H), 7.28-7.21 (m, 1H), 5.07-4.99 (m, 1H), 3.83 (ddd, 1H), 3.44-3.19 (m, 4H), 3.19-3.04 (m, 1H), 2.94 (s, 3H), 2.46-2.24 (m, 2H), 2.23-2.08 (m, 2H), 2.03-1.76 (m, 3H), 1.75-1.41 (m, 10H).

Example 3: (3R)-1-(3-phenoxypropan)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.15 g) in acetonitrile (2 ml) was added 3-phenoxypropylamine (0,197 g). The reaction mixture was stirred at 80°C for 36 hours and the acetonitrile was removed. The solid is triturated twice with a mixture of ethyl acetate/isohexane, filter is Ali and dried to obtain specified in the title compound (140 mg).

m/e 462 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 7.45-7.19 (m, 7H), 7.03-6.90 (m, 3H), 5.07 (s, 1H), 4.02 (t, 2H), 3.96-3.82 (m, 1H), 3.54-3.27 (m, 3H), 3.19 (d, 1H), 3.12-2.92 (m, 1H), 2.45-2.25 (m, 4H), 2.24-1.79 (m, 7H), 1.78-1.41 (m, 10H).

Example 4: (3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

a) 2-bromo-N-isoxazol-3-yl-ndimethylacetamide

3-Aminoethoxy (1,14 g) was dissolved in dichloromethane (50 ml) was added sodium carbonate (3,74 g). Slowly, with stirring, was added bromocatechol (1,12 ml) and the suspension was stirred over night. The reaction mixture was washed with water (2×50 ml), dried and evaporated. The product was recrystallized from a mixture of dichloromethane/isohexane obtaining specified in the subtitle compound (2.3 g).

1H NMR (299,946 MHz, CDCl3) δ 8.94 (s, 1H), 8.34 (s, 1H), 7.06 (s, 1H), 4.03 (s, 2H).

b) (3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-{[(1-phenylcyclohexyl)-carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.12 g) in acetonitrile (3 ml) was added 2-bromo-N-isoxazol-3-yl-ndimethylacetamide (Example 4A) (75 mg). The reaction mixture was stirred at room temperature overnight and the acetonitrile was removed under reduced pressure. The solid is recrystallized twice from ethyl acetate, filtering the Ali and dried to obtain specified in the title compound (140 mg).

m/e 452 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 11.76 (s, 1H), 8.90 (dd, 1H), 7.44-.21 (m, 5H), 6.90 (s, 1H), 5.12 (t, 1H), 4.42 (s, 2H), 4.17-4.05 (m, 1H), 3.73-3.50 (m, 4H), 3.47-3.21 (m, 1H), 2.44-2.26 (m, 2H), 2.26-2.07 (m, 2H), 2.07-1.85 (m, 2H), 1.83-1.69 (m, 1H), 1.68-1.41 (m, 10H).

Example 5: (3R)-1-(4-terbisil)-3-{[(1-phenylcyclohexyl)carbonyl]-oxy}-1-azoniabicyclo[2.2.2]octane bromide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.1 g) in acetonitrile (5 ml) was added 4-forbindelse (0.15 ml). The reaction mixture was stirred at room temperature overnight and the acetonitrile was removed under reduced pressure. The solid is recrystallized from a mixture of ethyl acetate/isohexane, was filtered, washed with a mixture of ethyl acetate/isohexane and dried to obtain specified in the title compound (120 mg).

m/e 436 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 7.55 (dd, 2H), 7.42-7.18 (m, 7H), 5.11-5.00 (m, 1H), 4.51 (d, 1H), 4.45 (d, 1H), 3.87-3.73 (m, 1H), 3.47-3.21 (m, 3H), 3.20-3.08 (m, 1H), 3.08-2.90 (m, 1H), 2.42-2.19 (m, 2H), 2.18-2.03 (m, 2H), 2.01-1.76 (m, 2H), 1.75-1.61 (m, 1H), 1.61-1.39 (m, 10H).

Example 6: (3R)-1-benzyl-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.1 g) in acetonitrile (5 ml) was added benzylbromide (0.15 ml). The reaction mixture was stirred at room temperature overnight and acetonic the sludge was removed under reduced pressure. The solid is recrystallized from a mixture of ethyl acetate/isohexane, was filtered off, washed with a small amount of the mixture of ethyl acetate/isohexane and dried to obtain specified in the title compound (145 mg).

m/e 418 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 7.60-7.45 (m, 5H), 7.37-7.13 (m, 5H), 5.12-4.98 (m, 1H), 4.51 (d, 1H), 4.44 (d, 1H), 3.88-3.76 (m, 1H), 3.48-3.26 (m, 3H), 3.18 (d, 1H), 3.10-2.93 (m, 1H), 2.40-2.19 (m, 2H), 2.18-2.03 (m, 2H), 2.01-1.77 (m, 2H), 1.76-1.61 (m, 1H), 1.61-1.43 (m, 10H).

Example 7: (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-[3-(triptoreline)benzyl]-1-azoniabicyclo[2.2.2]octane bromide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.1 g) in acetonitrile (5 ml) was added 3-cryptomaterial (0.15 ml). The reaction mixture was stirred at room temperature overnight and the acetonitrile was removed under reduced pressure. The solid is recrystallized from a mixture of ethyl acetate/isohexane, was filtered, washed with a mixture of ethyl acetate/isohexane and dried to obtain specified in the subtitle compound (160 mg).

m/e 502 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 7.44 (t, 1H), 7.36-7.17 (m, 3H), 7.17-7.01 (m, 5H), 5.12-5.02 (m, 1H), 4.49 (d, 1H), 4.43 (d, 1H), 3.92-3.78 (m, 1H), 3.51-3.28 (m, 3H), 3.20 (d, 1H), 3.12-2.94 (m, 1H), 2.46-2.20 (m, 2H), 2.19-2.05 (m, 2H), 2.04-1.80 (m, 2H), 1.78-1.62 (m, 1H), 1.61-1.45 (m, 10H).

Example 8: (3R)-1-(3,4-diferensial)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]is ktana bromide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.1 g) in acetonitrile (5 ml) was added 3,4-differenziale (0.15 ml). The reaction mixture was stirred at room temperature overnight and the acetonitrile was removed under reduced pressure. The solid is recrystallized from a mixture of ethyl acetate/isohexane, was filtered, washed with a mixture of ethyl acetate/isohexane and dried to obtain specified in the title compound (100 mg).

m/e 454 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 7.70-7.55 (m, 2H), 7.42-7.19 (m, 6N), 5.11-5.03 (m, 1H), 4.51 (d, 1H), 4.47 (s, 1H), 3.86-3.74 (m, 1H), 3.48-3.25 (m, 3H), 3.15 (d, 1H), 3.10-2.95 (m, 1H), 2.44-2.21 (m, 2H), 2.19-2.05 (m, 2H), 2.03-1.76 (m, 2H), 1.75-1.60 (m, 1H), 1.61-1.44 (m, 10H).

Example 9: (3R)-3-{[(1-Phenylcyclohexyl)carbonyl]oxy}-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1-azoniabicyclo[2.2.2]octane bromide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.1 g) in acetonitrile (2.5 ml) was added 2-trifluoromethyl-5-bromomethylphenyl (0,12 ml). The reaction mixture was stirred at room temperature overnight and the acetonitrile was removed under reduced pressure. The solid is recrystallized from a mixture of ethyl acetate/isohexane, was filtered, washed with a mixture of ethyl acetate/isohexane and dried to obtain specified in the subtitle compound (47 mg).

m/e 476 [M]+/sup>

1H NMR (299,947 MHz, DMSO-D6) δ 7.43-7.39 (m, 1H), 7.37-7.20 (m, 5H), 7.06 (d, 1H), 5.10-5.02 (m, 1H), 4.69 (s, 2H), 3.94-3.82 (m, 1H), 3.51-3.27 (m, 3H), 3.22 (d, 1H), 3.16-2.99 (m, 1H), 2.43-2.22 (m, 2H), 2.21-2.07 (m, 2H), 2.04-1.80 (m, 2H), 1.79-1.65 (m, 1H), 1.64-1.38 (m, 10H).

Example 10: (3R)-1-(3-methoxybenzyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.1 g) in acetonitrile (5 ml) was added 3-methoxybenzylamine (0.15 ml). The reaction mixture was stirred at room temperature overnight and the acetonitrile was removed under reduced pressure. The residue was dissolved in ethyl acetate and precipitated with isohexanol, and the supernatant containing unreacted benzylbromide, carefully separated. The residue was dried to obtain specified in the subtitle compound (52 mg).

m/e 448 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 7.44 (t, 1H), 7.36-7.17 (m, 5H), 7.17-7.01 (m, 3H), 5.12-5.02 (m, 1H), 4.49 (d, 1H), 4.43 (d, 1H), 3.92-3.78 (m, 1H), 3.80 (s, 3H), 3.51-3.28 (m, 3H), 3.20 (d, 1H), 3.12-2.94 (m, 1H), 2.46-2.20 (m, 2H), 2.19-2.05 (m, 2H), 2.04-1.80 (m, 2H), 1.78-1.62 (m, 1H), 1.61-1.45 (m, 10H).

Example 11: (3R)-1-(2-phenoxyethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabi is yclo[2.2.2]octane (Example 1) and 2-phenoxyethylamine.

m/e 448 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 7.45-7.12 (m, 7H), 7.10-6.90 (m, 3H), 5.14-4.99 (m, 1H), 4.49-4.33 (m, 2H), 4.09-3.92 (m, 1H), 3.81-3.64 (m, 1H), 3.63-3.44 (m, 2H), 3.23-3.05 (m, 1H), 2.4-2.22 (m, 4H), 2.22-2.06 (m, 2H), 2.04-1.82 (m, 4H), 1.79-1.65 (m, 2H), 1.65-1.41 (m, 8H).

Example 12: (3R)-1-[2-(benzyloxy)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and [(2-bromoethoxy)methyl]benzene.

m/e 462 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.41-7.28 (m, 9H), 7.26-7.21 (m, 1H), 5.09-5.02 (m, 1H), 4.51 (s, 2H), 3.98-3.88 (m, 2H), 3.87-3.74 (m, 1H), 3.52-3.46 (m, 2H), 3.45-3.37 (m, 2H), 3.16-3.04 (m, 1H), 2.41-2.23 (m, 3H), 2.19-2.08 (m, 2H), 2.03-1.80 (m, 4H), 1.77-1.63 (m, 2H), 1.63-1.41 (m, 8H).

Example 13: (3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-({[1-(2-thienyl)cycloheptyl]carbonyl}oxy)-1-azoniabicyclo[2.2.2]octane bromide

a) 1-[5-(trimethylsilyl)-2-thienyl]cycloheptanol

To 1,4-dibromothiophene (8,46 g) in ether (125 ml) was added utility in hexane (14 ml of 2.5 M solution) at -78°C under nitrogen atmosphere. After 15 minutes, was added chlorotrimethylsilane (3.8 g). The reaction mixture was left to warm to room temperature, was stirred for 30 minutes and again cooled to -78°C. was Added utility in hexane (14 ml of 2.5 M solution) and after 15 minutes add the Lyali cycloheptanone (3,93 g). The reaction mixture was left to warm to room temperature and was stirred overnight. Was added water (50 ml) and product was extracted with isohexane (2×250 ml), which was dried and evaporated to obtain 1-[5-(trimethylsilyl)-2-thienyl]cycloheptanol (9.4 g).

1H NMR (299,946 MHz, CDCl3) δ 7.08 (d, 1H), 7.03 (d, 1H), 2.21-1.98 (m, 4H), 1.90 (s, 1H), 1.85-1.40 (m, 8H), 0.30 (s, 9H).

b) [5-(1-Methoxycyclohexyl)-2-thienyl](trimethyl)silane

To 1-[5-(trimethylsilyl)-2-thienyl]cycloheptanol (Example 13A) (9.4 g)dissolved in tetrahydrofuran (200 ml), was added sodium hydride (60% in oil, 2,52 g). The reaction mixture was stirred for 5 minutes and added logmean (8,05 g). The mixture was stirred at 65°C overnight under reflux and then was added an additional amount of sodium hydride (60% in oil, 1.0 g) and iodomethane (1 ml) and the reaction mixture was stirred at 65°C for another 24 hours under reflux. The reaction mixture was cooled and carefully added water (200 ml). The reaction mixture was extracted with isohexane (2×200 ml) and the organic layer was separated, dried (MgSO4) and was evaporated to obtain specified in the subtitle compound (10,66 g)containing a certain quantity of oil from the sodium hydride.

1H NMR (299,946 MHz, CDCl3) δ 7.08 (d, 1H), 6.98 (d, 1H), 3.05 (s, 3H), 2.17 (dd, 2H), 2.04 (dd, 2H), 1.82-1.40 (m, 8H), 0.30 (s, 9H).

C) Methyl-1-(2-t is enyl)cyclohexenecarboxylic

Potassium (1.42 g) and sodium (0.4 g) were heated together at 120°C in mineral oil in a nitrogen atmosphere for 30 minutes and then cooled to room temperature. The oil was removed and replaced with ether (100 ml) was added [5-(1-methoxycyclohexyl)-2-thienyl](trimethyl)silane (Example 13B) (5.0 g)and the reaction mixture was stirred in nitrogen atmosphere overnight at room temperature. The reaction mixture was cooled to -78°C and added with stirring solid carbon dioxide (~20 g). The reaction mixture was left to warm to room temperature and carefully added water (100 ml) under nitrogen atmosphere. When the metal has been neutralized, the reaction mixture was poured into a separating funnel. Formed of three layers, the middle of which was a salt intermediate. It was evaporated to dryness, and then was heated under reflux in methanol (125 ml) and concentrated hydrochloric acid (10 ml) overnight. The methanol was removed, was added water (50 ml) and product was extracted with ether (2×50 ml), dried and evaporated. The product was purified on silica, elwira mixture isohexane/2.5% ethyl acetate. The target fraction was evaporated to obtain specified in the subtitle compound (1.9 g).

1H NMR (299,946 MHz, CDCl3) δ 7.18 (dd, 1H), 6.96-6.90 (m, 2H), 3.66 (s, 3H), 2.54 (dd, 2H), 2.10 (dd, 2H), 1.69-1.49 (m, 8H).

g) (3R)-1-asabis the CLO[2.2.2]Oct-3-yl 1-(2-thienyl)cyclohexenecarboxylic

Methyl-1-(2-thienyl)cyclohexenecarboxylic (Example 13B) (0.27 g) and (R)-Hinkley-3-ol (in 0.288 g) was heated under reflux in toluene (100 ml)containing sodium hydride (~10 mg), in the office of Dean-stark within 24 hours. The reaction mixture was separated between water (50 ml) and ether (2×50 ml) and the ether layer was separated, dried (MgSO4) and was evaporated. The crude product was purified by column chromatography on silica, elwira a mixture of ethyl acetate/triethylamine (99/1) to obtain the specified title compound (0.24 g) as oil.

m/e 334 [M+H]+

d) (3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-({[1-(2-thienyl)cycloheptyl]carbonyl}oxy)-1-azoniabicyclo[2.2.2]octane bromide

To (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-(2-thienyl)cyclohexenecarboxylic (Example 13 g) (0.12 g) in acetonitrile (5 ml) was added 2-bromo-N-isoxazol-3-yl-ndimethylacetamide (Example 4A) (73,8 mg). The reaction mixture was stirred at room temperature overnight and the product was subjected to crystallization. The solid is recrystallized three times with ethyl acetate, filtered and dried to obtain specified in the title compound (103 mg).

m/e 458 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 11.79 (s, 1H), 8.90 (d, 1H), 7.44 (dd, 1H), 7.03 (dd, 1H), 6.99 (dd, 1H), 6.91 (s, 1H), 5.16-5.07 (m, 1H), 4.35 (s, 2H), 4.19-3.99 (m, 1H), 3.77-3.56 (m, 4H), 3.56-3.41 (m, 1H), 2.48-2.36 (m, 1H), 2.33-2.10(m, 2H), 2.09-1.65 (m, 6H), 1.63-1.46 (m, 8H).

Example 14: (3R)-1-(2-oxo-2-pyrrolidin-1-retil)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 1-(bromoacetyl)pyrrolidine.

m/e 439 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.38-7.30 (m, 4H), 7.24 (tt, 1H), 5.14-5.08 (m, 1H), 4.31-4.21 (m, 2H), 4.12-4.03 (m, 1H), 3.65 (d, 1H), 3.58 (t, 2H), 3.52-3.40 (m, 1H), 3.41-3.29 (m, 4H), 2.42-2.26 (m, 2H), 2.21-2.11 (m, 2H), 2.02-1.86 (m, 5H), 1.85-1.64 (m, 3H), 1.69-1.43 (m, 10H).

Example 15: (3R)-1-(2-morpholine-4-yl-2-oxoethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 1-(bromoacetyl)morpholine.

m/e 455 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.38-7.30 (m, 4H), 7.25 (tt, 1H), 5.15-5.08 (m, 1H), 4.39 (d, 1H), 4.35 (s, 1H), 4.09-4.01 (m, 1H), 3.65-3.50 (m, 8H), 3.46 (t, 2H), 3.37 (t, 2H), 2.42-2.26 (m, 2H), 2.22-2.10 (m, 2H), 2.02-1.87 (m, 3H), 1.74 (m, 1H), 1.65-1.47 (m, 10H).

Example 16: (3R)-1-[2-oxo-2-(pyrazin-2-ylamino)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained is through methods similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-bromo-N-pyrazin-2-ylacetamide.

m/e 463 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 11.37 (s, 1H), 9.28 (s, 1H), 8.50-8.46 (m, 2H), 7.39-7.30 (m, 4H), 7.27-7.21 (m, 1H), 5.16-5.08 (m, 1H), 4.33 (s, 2H), 4.17-4.07 (m, 1H), 3.69-3.56 (m, 4H), 3.48-3.38 (m, 1H), 2.44-2.26 (m, 3H), 2.25-2.04 (m, 2H), 2.03-1.87 (m, 3H), 1.85-1.71 (m, 1H), 1.68-1.45 (m, 8H).

Example 17: (3R)-1-[2-oxo-2-(pyridazin-3-ylamino)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-bromo-N-pyridazin-3-ylacetamide.

m/e 463 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 11.68 (s, 1H), 9.06 (dd, 1H), 8.25 (d, 1H), 7.79 (dd, 1H), 7.39-7.30 (m, 4H), 7.27-7.21 (m, 1H), 5.15-5.10 (m, 1H), 4.34 (s, 2H), 4.16-4.06 (m, 2H), 3.69-3.56 (m, 4H), 3.46-3.36 (m, 1H), 2.43-2.27 (m, 2H), 2.24-2.10 (m, 2H), 2.04-1.89 (m, 3H), 1.84-1.71 (m, 1H), 1.68-1.45 (m, 8H).

Example 18: (3R)-1-{2-oxo-2-[(2-phenoxyethyl)amino]ethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-bromo-N-(2-phenoxyethyl)ndimethylacetamide.

m/e 505 [M]+/p>

1H NMR (399,826 MHz, DMSO-D6) δ 8.82 (t, 1H), 7.38-7.21 (m, 7H), 6.98-6.91 (m, 3H), 5.12-5.07 (m, 1H), 4.12-3.97 (m, 4H), 3.64-3.46 (m, 4H), 3.37-3.27 (m, 3H), 3.18 (s, 1H), 3.16 (s, 1H), 2.42-2.25 (m, 2H), 2.19-2.10 (m, 2H), 2.00-1.82 (m, 3H), 1.79-1.67 (m, 1H), 1.65-1.44 (m, 8H).

Example 19: (3R)-1-[2-(3-forfinal)-2-oxoethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-bromo-1-(3-forfinal)Etalon.

m/e 464 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.85-7.77 (m, 2H), 7.71-7.59 (m, 2H), 7.40-7.32 (m, 4H), 7.29-7.23 (m, 1H), 5.20-5.14 (m, 3H), 4.16-4.06 (m, 1H), 3.69-3.54 (m, 4H), 3.50-3.37 (m, 1H), 3.30 (d, 1H), 2.44-2.29 (m, 2H), 2.27-2.11 (m, 2H), 2.06-1.92 (m, 3H), 1.89-1.74 (m, 1H), 1.68-1.45 (m, 8H).

Example 20: (3R)-1-{2-[(5-methylisoxazol-3-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-bromo-N-(5-methylisoxazol-3-yl)ndimethylacetamide.

m/e 466 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 11.55 (s, 1H), 7.40-7.28 (m, 4H), 7.28-7.20 (m, 1H), 6.61 (s, 1H), 5.15-5.07 (m, 1H), 4.32 (d, 1H), 4.27 (d, 1H), 4.15-4.06 (m, 1H), 3.67-3.53 (m, 4H), 3.44-3.38 (m, 1H), 3.30-3.28 (m, 1H), 2.41 (s, 3H), 2.39-2.27 (m, 2H), 2.23-2.11 (m, 2H), 2.03-1.87 (m, 3), 1.82-1.71 (m, 1H), 1.70-1.43 (m, 8H).

Example 21: (3R)-1-{2-[(6-chloropyridin-3-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-bromo-N-(6-chloropyridin-3-yl)ndimethylacetamide.

m/e 497 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 11.88 (s, 1H), 8.31 (d, 1H), 8.01 (d, 1H), 7.39-7.30 (m, 4H), 7.28-7.21 (m, 1H), 5.15-5.08 (m, 1H), 4.40-4.31 (m, 2H), 4.15-4.07 (m, 1H), 3.69-3.55 (m, 4H), 3.47-3.30 (m, 2H), 2.42-2.27 (m, 2H), 2.23-2.11 (m, 2H), 2.03-1.86 (m, 3H), 1.82-1.71 (m, 1H), 1.69-1.43 (m, 8H).

Example 22: (3R)-1-{2-[(3-forfinal)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-bromo-N-(3-forfinal)ndimethylacetamide.

m/e 479 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 10.86 (s, 1H), 7.59 (d, 1H), 7.42 (dd, 1H), 7.38-7.28 (m, 5H), 7.26-7.20 (m, 1H), 7.03-6.95 (m, 1H), 5.17-5.09 (m, 1H), 4.35-4.23 (m, 2H), 4.16-4.07 (m, 1H), 3.71-3.57 (m, 4H), 3.49-3.36 (m, 1H), 2.42-2.27 (m, 2H), 2.24-2.10 (m, 2H), 2.03-1.85 (m, 3H), 1.84-1.70 (m, 1H), 1.69-1.43 (m, N).

Example 23: (3R)-1-[2-(2-naphthyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-(2-bromacil)naphthalene.

m/e 482 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.40-7.31 (m, 4H), 7.29-7.22 (m, 2H), 6.93 (s, 1H), 6.88 (d, 1H), 6.84 (dd, 1H), 5.12-5.06 (m, 1H), 3.97-3.87 (m, 1H), 3.76 (s, 3H), 3.60-3.36 (m, 6N), 3.26 (d, 1H), 3.14-3.02 (m, 1H), 3.02-2.85 (m, 2H), 2.44-2.27 (m, 2H), 2.23-2.11 (m, 2H), 2.03-1.83 (m, 3H), 1.78-1.65 (m, 1H), 1.66-1.43 (m, 8H).

Example 24: (3R)-1-[2-(3-methoxyphenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 1-(2-bromacil)-3-methoxybenzoyl.

m/e 462 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.40-7.31 (m, 4H), 7.29-7.22 (m, 2H), 6.93 (s, 1H), 6.88 (d, 1H), 6.84 (dd, 1H), 5.12-5.06 (m, 1H), 3.97-3.87 (m, 1H), 3.76 (s, 3H), 3.60-3.40 (m, 5H), 3.26 (d, 1H), 3.14-3.02 (m, 1H), 3.02-2.85 (m, 2H), 2.44-2.27 (m, 2H), 2.23-2.11 (m, 2H), 2.03-1.83 (m, 3H), 1.78-1.65 (m, 1H), 1.66-1.43 (m, N).

Example 25: (3R)-1-[2-(5-methyl-2-thienyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-azabicyclo[2.2.2]octane (Example 1) and 2-(2-bromacil)-5-methylthiophene.

m/e 452 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.38-7.31 (m, 4H), 7.28-7.22 (m, 1H), 6.76 (d, 1H), 6.67 (dd, 1H), 5.10-5.02 (m, 1H), 3.91-3.82 (m, 1H), 3.52-3.34 (m, 5H), 3.23 (d, 1H), 3.19-2.98 (m, 3H), 2.40 (s, 3H), 2.38-2.27 (m, 2H), 2.22-2.13 (m, 2H), 2.03-1.82 (m, 3H), 1.74-1.41 (m, 10H).

Example 26: (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and (2-bromacil)benzene.

m/e 432 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.39-7.22 (m, 10H), 5.12-5.06 (m, 1H), 3.94-3.86 (m, 1H), 3.55-3.46 (m, 1H), 3.42 (t, 4H), 3.24 (d, 1H), 3.11-3.01 (m, 1H), 3.01-2.88 (m, 2H), 2.43-2.27 (m, 2H), 2.23-2.13 (m, 2H), 2.05-1.82 (m, 3H), 1.77-1.65 (m, 1H), 1.65-1.42 (m, N).

Example 27: (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-{2-[3-(trifluoromethyl)phenyl]ethyl}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 1-(2-bromacil)-3-(trifluoromethyl)benzene.

m/e 500 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.75 (s, 1H), 7.68-7.57 (m, 3H), 7.40-7.31 (m, 4H), 7.28-7.22 (m, 1H), 5.13-5.08 (m, 1H), 3.95-3.86 (m, 1H), 3.56-3.39 (m, 5H), 3.26 (d, 1H), 3.18-3.00 (m, 3H), 2.44-2.28 (m, 2H), 2.22-2.13 (m, 2H), 2.05-1.82 (m, 3H), 1.79-1.67 (m, 1H), 1.66-1.43 (m, N).

Example 28: (R)-1-[2-(1,3-benzodioxol-5-yl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 5-(2-bromacil)-1,3-benzodioxol.

m/e 476 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.39-7.31 (m, 4H), 7.27-7.22 (m, 1H), 6.92 (d, 1H), 6.88 (d, 1H), 6.76 (dd, 1H), 5.99 (s, 2H), 5.12-5.05 (m, 1H), 3.90-3.83 (m, 1H), 3.50-3.42 (m, 1H), 3.41-3.32 (m, 4H), 3.21 (d, 1H), 3.08-2.99 (m, 1H), 2.93-2.79 (m, 2H), 2.43-2.27 (m, 2H), 2.21-2.13 (m, 2H), 2.03-1.80 (m, 3H), 1.75-1.65 (m, 1H), 1.64-1.44 (m, N).

Example 29: (3R)-1-[2-(4-cyanophenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 4-(2-bromacil)benzonitrile.

m/e 457 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.85 (dd, 2H), 7.54 (d, 2H), 7.39-7.31 (m, 4H), 7.25 (td, 1H), 5.12-5.07 (m, 1H), 3.92-3.85 (m, 1H), 3.52-3.37 (m, 5H), 3.23 (d, 1H), 3.14-3.00 (m, 3H), 2.42-2.27 (m, 2H), 2.21-2.13 (m, 2H), 2.03-1.85 (m, 3H), 1.76-1.65 (m, 1H), 1.65-1.46 (m, N).

Example 30: (3R)-1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-fenistil the heptyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-(2-bromacil)-1H-isoindole-1,3(2H)-dione.

m/e 501 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.95-7.85 (m, 4H), 7.38-7.31 (m, 4H), 7.28-7.22 (m, 1H), 5.08-5.02 (m, 1H), 4.01-3.91 (m, 3H), 3.56-3.37 (m, 5H), 3.30-3.27 (m, 1H), 3.23-3.13 (m, 1H), 2.45-2.27 (m, 2H), 2.26-2.12 (m, 2H), 2.01-1.81 (m, 3H), 1.75-1.41 (m, 10H).

Example 31: (3R)-1-{2-[(6-chloropyrazine-2-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-bromo-N-(6-chloropyrazine-2-yl)ndimethylacetamide.

m/e 497 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 11.69 (s, 1H), 9.24 (s, 1H), 8.61 (d, 1H), 7.38-7.31 (m, 4H), 7.27-7.22 (m, 1H), 5.15-5.09 (m, 1H), 4.37-4.27 (m, 2H), 4.16-4.07 (m, 1H), 3.69-3.57 (m, 4H), 3.42 (dd, 1H), 2.43-2.27 (m, 2H), 2.24-2.10 (m, 2H), 2.04-1.85 (m, 3H), 1.84-1.71 (m, 1H), 1.69-1.46 (m, N).

Example 32: (3R)-1-{[1-(4-chlorophenyl)cyclopropyl]methyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 1-[1-(methyl bromide)cyclopropyl]-4-chlorobenzene.

m/e 492 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.49 (dd, 2H), 7.42 (dd, 2H), 7.39-7.33 (m, 2H), 7.29-7.23 (m, 3H), 4.98-4.93 (m, 1H), 3.80 (d, 1H), 3.64 (ddd, 1H), 3.56 (d, 1H), 3.34-3.23 (m, 2H), 3.22-3.07 (m, 2H), 2.94-2.81 (m, 2H), 2.37-2.7 (m, 2H), 2.17 (s, 1H), 2.05 (s, 1H), 1.96-1.86 (m, 1H), 1.85-1.77 (m, 1H), 1.77-1.64 (m, 1H), 1.65-1.37 (m, 8H), 1.35-1.21 (m, 1H), 1.16-1.06 (m, 2H), 1.06-0.99 (m, 1H), 0.99-0.92 (m, 1H).

Example 33: (3R)-1-{2-[(5-methylpyridin-2-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 2-bromo-N-(5-methylpyrazine-2-yl)ndimethylacetamide.

m/e 477 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 11.28 (s, 1H), 9.15 (s, 1H), 8.36 (d, 1H), 7.38-7.31 (m, 4H), 7.27-7.22 (m, 1H), 5.16-5.08 (m, 1H), 4.31 (s, 2H), 4.16-4.08 (m, 1H), 3.69-3.55 (m, 4H), 3.46-3.27 (m, 2H), 2.48 (s, 3H), 2.42-2.29 (m, 2H), 2.23-2.11 (m, 2H), 2.03-1.87 (m, 3H), 1.83-1.72 (m, 1H), 1.70-1.45 (m, 8H).

Example 34: (3R)-1-(carboxymethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

a) (3R)-1-(2-tert-butoxy-2-oxoethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and tert-butylbromide.

m/e 442 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.38-7.30 (m, 4H), 7.25 (tt, 1H), 5.14-5.09 (m, 1H), 4.31 (d, 1H), 4.27 (d, 1H), 4.07-4.00 (m, 1H), 3.61-3.47 (m, 4H), 3.39-3.28 (m, 1H), 2.42-2.27 (m, 2H), 2.21-2.11 (m, 2H), 2.02-1.86 (m, 3H), 1.81-1.71 (m, 1H), 1.69-1.5 (m, 9H), 1.47 (s, 9H).

b) (3R)-1-(carboxymethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

(3R)-1-(2-tert-butoxy-2-oxoethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane (0,950 g) was dissolved in trichloroacetic acid (2 ml) and left to stand for 3.5 hours. The solution was evaporated to dryness and the residual oil was dissolved in acetonitrile (30 ml) and toluene (30 ml). The solution was evaporated to dryness and the procedure was repeated. The resulting oil was dissolved in acetonitrile (30 ml) was added diethyl ether (80 ml). The obtained crystals of (R)-1-(carboxymethyl)-3-(1-phenylcyclohexanecarboxylic)-1-azoniabicyclo[2.2.2]octane (0,600 g) was collected by filtration, washed with ether and dried.

m/e 342 [M+H-CO2]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.38-7.29 (m, 4H), 7.27-7.22 (m, 1H), 5.13-5.07 (m, 1H), 4.26-4.16 (m, 2H), 4.07-3.99 (m, 1H), 3.61-3.46 (m, 4H), 3.44-3.34 (m, 1H), 2.41-2.26 (m, 2H), 2.21-2.10 (m, 2H), 2.02-1.83 (m, 3H), 1.81-1.69 (m, 1H), 1.68-1.44 (m, N).

Example 35: (3R)-1-[2-(3-chlorophenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 1-(2-bromacil)-3-chlorobenzene.

m/e 466 [M]+

1H NMR (399,826 MHz, DMSO-D6

Example 36: (3R)-1-(2-amino-2-oxoethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.05 g) in acetonitrile (1 ml) was added 2-bromoacetamide (0,021 g). The reaction mixture was stirred at room temperature for 2 days and the acetonitrile was removed by a stream of nitrogen. The solid is washed with ethyl acetate and placed in a deep vacuum, and then mixed with an aqueous solution of ammonia (33%, 1 ml) for two days. Ammonia and water was removed by a stream of nitrogen and the last traces were removed under high vacuum to obtain specified in the header of the product (42 mg).

m/e 385 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.93 (s, 1H), 7.71 (s, 1H), 7.39-7.29 (m, 4H), 7.28-7.21 (m, 1H), 5.12-5.05 (m, 1H), 4.11-3.94 (m, 1H), 4.00 (s, 2H), 3.64 (d, 1H), 3.61-3.47 (m, 2H), 3.46-3.29 (m, 1H), 2.42-2.27 (m, 2H), 2.21-2.10 (m, 2H), 2.00-1.83 (m, 3H), 1.80-1.42 (m, 11N).

Example 37: (3R)-1-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabi is yclo[2.2.2]octane (Example 1) and 2-bromo-N-(3-phenylpropyl)ndimethylacetamide.

m/e 503 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 8.60 (t, 1H), 7.37-7.26 (m, 6N), 7.26-7.16 (m, 4H), 5.12-5.06 (m, 1H), 4.08-3.98 (m, 4H), 3.64-3.47 (m, 5H), 3.38-3.28 (m, 2H), 3.14 (d, 1H), 3.11 (d, 1H), 2.60 (t, 1H), 2.41-2.25 (m, 2H), 2.20-2.10 (m, 2H), 2.00-1.83 (m, 3H), 1.73 (quintet, 2H), 1.67-1.43 (m, 8H).

Example 38: (3R)-1-[2-(3-chloro-4-methoxyphenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) and 4-(2-bromacil)-2-chloro-1-methoxybenzo.

m/e 496 [M]+

1H NMR (399,826 MHz, DMSO-D6) δ 7.44 (d, 1H), 7.39-7.32 (m, 4H), 7.28-7.23 (m, 2H), 7.13 (d, 1H), 5.13-5.05 (m, 1H), 3.94-3.81 (m, 1H), 3.84 (s, 3H), 3.55-3.45 (m, 1H), 3.45-3.29 (m, 4H), 3.24 (d, 1H), 3.10-3.00 (m, 1H), 2.99-2.83 (m, 2H), 2.44-2.28 (m, 2H), 2.23-2.13 (m, 2H), 2.04-1.81 (m, 3H), 1.77-1.66 (m, 1H), 1.66-1.40 (m, N).

Example 39: (3R)-1-{2-[(3-methylisoxazol-5-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

a) 2-bromo-N-(3-methylisoxazol-5-yl)ndimethylacetamide

3-Methylisoxazol-5-amine (2.9 g) and potassium carbonate (9.8 g) suspended in dichloromethane (100 ml) at room temperature was added dropwise 2-bromoacetamide (6 g). The mixture was left to mix overnight. Was added water (0.3 ml) together with an additional amount of potassium carbonate (3 g) and reactionuses was stirred for another 30 minutes. The reaction mixture was poured into water (100 ml) and was extracted with dichloromethane (2×50 ml). The combined organic extracts were dried over magnesium sulfate and then evaporated in vacuum. The crude product was purified by column chromatography on silica gel, elwira a mixture of ethyl acetate/isohexane (50:50), obtaining specified in the subtitle compound (4.8 g).

1H NMR (299,946 MHz, CDCl3) δ 11.97 (s, 1H), 6.16 (s, 1H), 4.09 (s, 2H), 2.19 (s, 3H).

To (3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azabicyclo[2.2.2]octane (Example 1) (0.1 g) in acetonitrile (2 ml) was added 2-bromo-N-(3-methylisoxazol-5-yl)ndimethylacetamide (Example 39A) (74 mg). The reaction mixture was stirred at room temperature overnight and the acetonitrile was removed under reduced pressure. The residue was purified by column chromatography on silica gel, elwira a mixture of methanol/dichloromethane (10:90), with specified title compound (75 mg).

m/e 466 [M]+

1H NMR (299,947 MHz, DMSO-D6) δ 7.41-7.29 (m, 4H), 7.29-7.20 (m, 1H), 6.16 (s, 1H), 5.16-5.07 (m, 1H), 4.29 (d, 1H), 4.23 (d, 1H), 4.13-4.04 (m, 1H), 3.68-3.52 (m, 4H), 3.45-3.34 (m, 2H), 2.42-2.27 (m, 2H), 2.24-2.10 (m, 4H), 2.04-1.43 (m, 14H).

Comparative Examples 1-9, referred to in Table 3

Comparative Example 1: (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-phenylcyclohexanecarboxylic

To methyl-1-phenylcyclohexanecarboxylic is (1.8 g) and (R)-Hinkley-3-Olu (1.1 g) in toluene (100 ml) was added sodium hydride (100 mg, 80% in oil). The mixture was heated to reflux distilled in the apparatus of the Dean-stark for 20 hours. The reaction mixture was left to cool to room temperature and added water (125 ml). The obtained organic layer was separated, dried (MgSO4) and evaporated to an oil, which was purified on silica gel, elwira with ethyl acetate containing 2% of triethylamine, to obtain the specified title compound as a solid (1.2 g).

m/e 300 [M+H]+

1H NMR (399,826 MHz, DMSO) δ 7.29-7.39 (m, 4H), 7.20-7.27 (m, 1H), 4.55-4.62 (m, 1H), 2.98 (add, 1H), 2.41-2.68 (m, 4H), 2.19-2.26 (m, 1H), 1.14-1.90 (m, 13H).

Comparative Example 2: (3R)-1-methyl-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane iodide

Specified in the title compound was obtained by a technique similar to the method of Example 2, using (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-vinylcyclopentane carboxylate (comparative Example 1) and jodean.

m/e 314 [M]+

1H NMR (399,826 MHz, DMSO) δ 7.31-7.42 (m, 4H), 7.23-7.30 (m, 1H), 4.95-5.01 (m, 1H), 3.80 (ddd, 1H), 3.14-3.43 (m, 5H), 2.94 (s, 3H), 2.56-2.64 (m, 2H), 2.09-2.15 (m, 1H), 1.78-2.02 (m, 4H), 1.63-1.75 (m, 5H), 1.49-1.59 (m, 1H).

Comparative Example 3: (3R)-1-[2-oxo-2-(pyrazin-2-ylamino)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, IP is by using (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-vinylcyclopentane carboxylate (comparative Example 1) and 2-bromo-N-pyrazin-2-ylacetamide.

m/e 435 [M]+

1H NMR (399,826 MHz, DMSO) δ 11.36 (s, 1H), 9.28 (s, 1H), 8.45-8.50 (m, 2H), 7.22-7.43 (m, 5H), 5.03-5.10 (m, 1H), 4.29-4.36 (m, 2H), 4.04-4.14 (m, 1H), 3.56-3.72 (m, 4H), 3.42-3.54 (m, 1H), 2.56-2.70 (m, 2H), 2.16-2.25 (m, 1H), 1.57-2.03 (m, 10H).

Comparative Example 4: (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-phenylcyclohexanecarboxylic

Specified in the title compound was obtained by a technique similar to the method of comparative Example 1, using methyl-1-phenylcyclohexanecarboxylic and (R)-Hinkley-3-ol.

m/e 314 [M+H]+

1H NMR (399,826 MHz, DMSO) δ 7.42-7.31 (m, 4H), 7.27-7.22 (m, 1H), 4.68-4.62 (m, 1H), 3.01 (ddd, 1H), 2.68-2.35 (m, 6H), 1.82-1.16 (m, 14H).

Comparative Example 5: (3R)-1-methyl-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane iodide

Specified in the title compound was obtained by a technique similar to the method of comparative Example 2, using (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-phenylcyclohexanecarboxylic (comparative Example 4) and itmean.

m/e 328 [M]+

1H NMR (399,826 MHz, DMSO) δ 7.33-7.44 (m, 4H), 7.24-7.30 (m, 1H), 5.00-5.07 (m, 1H), 3.82 (ddd, 1H), 3.11-3.43 (m, 5H), 2.94 (s, 3H), 2.32-2.45 (m, 2H), 2.11-2.17 (m, 1H), 1.22-1.97 (m, 12H).

Comparative Example 6: (3R)-1-[2-oxo-2-(pirati-2-ylamino)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by IU Tiki, similar to the method of Example 3, using (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-phenylcyclohexanecarboxylic (comparative Example 4) and 2-bromo-N-pyrazin-2-ylacetamide.

m/e 449 [M]+

1H NMR (399,826 MHz, DMSO) δ 11.37 (s, 1H), 9.27 (s, 1H), 8.44-8.51 (m, 2H), 7.33-7.46 (m, 4H), 7.22-7.30 (m, 1H), 5.07-5.17 (m, 1H), 4.34 (s, 2H), 4.08-4.17 (m, 1H), 3.56-3.72 (m, 4H), 3.44-3.56 (m, 1H), 2.34-2.45 (m, 2H,), 2.22 (s, 1H), 1.21-2.02 (m, 12H).

Comparative Example 7: (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-phenylcyclohexanecarboxylic

a) 1-Phenylcyclohexanol

Specified in the title compound was obtained by a technique similar to the method of Example 1A, using cyclooctane (5,04 g), to obtain the desired compound (8.5 g).

1H NMR (299,946 MHz, CDCl3) δ 7.56-7.47 (m, 2H), 7.39-7.31 (m, 2H), 7.29-7.20 (m, 1H), 2.13-1.82 (m, 4H), 1.83-1.65 (m, 4H), 1.64-1.46 (m, 7H).

b) 1-Methoxy-1-phenylcyclohexane

Specified in the title compound was obtained by a technique similar to the method of Example 1B, using 1-phenylcyclohexanol (comparative Example 7a) (8.5 g), to obtain the desired compound (12 g crude material).

1H NMR (299,946 MHz, CDCl3) δ 7.44-7.38 (m, 2H), 7.38-7.30 (m, 2H), 7.25-7.20 (m, 1H), 2.95 (s, 3H), 2.10 (dd, 2H), 1.96 (dd, 2H), 1.82-1.36 (m, 10H).

C) 1-Phenylcyclohexanone acid

Specified in the subtitle compound was obtained by the method of Example 1B, ispolzuya-methoxy-1-phenylcyclohexane (Example 2(b)) (8 g), to obtain the desired compound (1.6 g).

1H NMR (299,946 MHz, CDCl3) δ 7.40 (d, 2H), 7.32 (t, 2H), 7.23 (t, 1H), 2.38 (dd, 2H), 2.18 (dd, 2H), 1.72-1.34 (m, 10H).

g) Methyl-1-phenylcyclohexanecarboxylic

1-Phenylcyclohexanecarboxylic acid (Example 2(C)) (1.6 g) was heated under reflux in methanol (150 ml) and concentrated hydrochloric acid (10 ml) for 48 hours. The solvent is evaporated and the residue was dissolved in ether (100 ml) which was washed with water (100 ml), saturated sodium bicarbonate (50 ml) and water (100 ml), dried (MgSO4) and was evaporated to obtain specified in the subtitle compound (1.6 g) in the form of oil.

1H NMR (299,946 MHz, CDCl3) δ 7.43-7.18 (m, 5H), 3.62 (s, 3H), 2.44-2.31 (m, 2H), 2.24-2.07 (m, 2H), 1.71-1.39 (m, 10H).

Comparative Example 7: (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-phenylcyclohexanecarboxylic

Specified in the title compound was obtained by a technique similar to the method of comparative Example 1, using methyl-1-phenylcyclohexanecarboxylic (comparative Example 7(g)and (R)-Hinkley-3-ol.

m/e 342 [M+H]+

1H NMR (399,826 MHz, DMSO) δ 7.17-7.39 (m, 5H), 4.71-4.77 (m, 1H), 3.12 (ddd, 1H), 2.14-2.86 (m, 10H), 1.06-1.93 (m, 14N).

Comparative Example 8: (3R)-1-methyl-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane iodide

Specified in the header connect the Addendum was received by technique, similar to the method of comparative Example 2, using (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-phenylcyclohexanecarboxylic (comparative Example 7) and itmean.

m/e 356 [M]+

Comparative Example 9: (3R)-1-[2-oxo-2-(pyrazin-2-ylamino)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide

Specified in the title compound was obtained by a technique similar to the method of Example 3, using (3R)-1-azabicyclo[2.2.2]Oct-3-yl 1-phenylcyclohexanecarboxylic (comparative Example 7) and 2-bromo-N-pyrazin-2-ylacetamide.

m/e 477 [M]+

Pharmacological analysis

Analysis of the activity of the M3-receptor

Affinity (pIC50connections to M3the receptor was determined using competitive binding [3H]N-methylscopolamine (NMS) with the cellular membranes of Cho-K1 (ovaries of Chinese hamsters), expressing the human muscarinic acetylcholine receptors M3(M3-ACh), in the format analysis scintillation proximity (SPA).

Granules SPA pre-coated membranes and then incubated in 2 mg of beads per well with serial dilutions of the compounds according to the invention, 0.2 nm [3H]NMS, half-Kd (experimentally determined the dissociation constant) and analytical buffer (20 mm HEPES pH 7.4 containing 5 mm MgCl2). Analysis of Prov is conducted in the final volume of 200 μl, in the presence of 1% (vol./about.) dimethyl sulfoxide (DMSO). Total binding of [3H]NMS was determined in the absence of competitive compounds and nonspecific binding of [3H]NMS was determined in the presence of 1 μm atropine. The plates were incubated for 16 hours at room temperature and then read on a Wallac Microbeta™using normirovanie3H Protocol. Determined the value pIC50defined as the negative logarithm of the concentration of the compound required for 50%reduction of specific binding of [3H]NMS. Table 1 shows numerical values pIC50for some typical Examples.

Table 1
Compound of Example No.pIC50
110,2
28,5
310,3
410,2
108,5
16the 10.1

Table 2 shows the values of IC50for compounds of Examples.

Table 2
Example No.M3 binding IC50Example No.M3 binding IC50Example No.M3 binding IC50
1+++15++29++
2++16+++30+
3+++17+++31+++
4+++18+++32++
5+19+++33+++
6+20+++34 +
7+21+++35+++
8+22+++36+++
9+23+++37++
10++24+++38+++
11+++25+++39+++
12+++26+++
13+++27+++
14++28++
M3 binding: IC50<2 nm "+++"; IC502-10 nm "++"; IC50>10 nm "+"; NT - not investigated.

One feature of the compounds of the present invention is that they contain cycloheptene ring (C7 ring). As shown in Table 3, the inclusion of cycloheptene ring in the compounds of the present invention gives the compounds significantly higher values pIC50M3-activities than other identical compounds containing cyclopentene (C5), tsiklogeksilnogo (C6) or cyclooctene (C8) rings.

Table 3
Data M3 pIC50for typical Examples according to the invention (C7) and comparative Examples containing cyclopentyl (C5), tsiklogeksilnogo (C6) and cyclooctene (C8) ring
pIC50cycloheptyl (C7) connectionpIC50comparative compounds containing cyclopentene (C5), tsiklogeksilnogo (C6) or cyclooctene (C8) ring instead cycloheptyl (C7)
C7C5C6 C8
10,2 (Note 1)8,7 (EUR. Approx. 1)8,9 (EUR. Prim)9,1 (EUR. Prim)
8,5 (note 2)7,4 (EUR. 2)7,3 (EUR. Note5)7,4 (EUR. Prim)
10,1 (Prim)9,5 (EUR. Approx. 3)9,7 (EUR. Prim)9,5 (EUR. Prim)

Measurement of binding of plasma proteins

The degree of binding plasma proteins was determined by equilibrium dialysis connection between human plasma and aqueous buffer at 37°C and determine the concentration of the compound in plasma and buffer using HPLC-MS/MS.

Way

Dialysis cells (cutoff molecular weight 5000) was prepared by washing with water, followed by keeping in the buffer for dialysis for at least 1 hour. Buffer for dialysis was an isotonic buffered solution with a pH of 7.4. The original solutions of the compound in dimethyl sulfoxide was prepared with a concentration of 0.5 mmol. Frozen joint human plasma was obtained from volunteers.

The original solutions of the compounds in DMSO were added to the plasma in relation to 10 μl of DMSO to each ml of plasma That gave 1% DMSO in solution plasma with the presence of each compound at a concentration of 5 μm.

Then was prepared by dialysis of the cell and one half of the cell was filled with 750 μl of buffer for dialysis and the other half of the cells - 750 μl of a solution of the compound in plasma. The prepared cell was closed and placed in a cell of a thermostat at 37°C. Then, these cells were rotated for at least 4 hours to trim.

After equilibration 500 ál of sample buffer was collected and added into vials for HPLC with 100 µl of plasma sample in a 6-fold diluted plasma) and 100 µl plasma samples were collected and added into HPLC vials with 500 ál of buffer for dialysis (sample 6-fold diluted plasma).

Then the samples were analyzed using HPLC-MS/MS. Four-point calibration curve was obtained by dilutions of initial solutions 6-fold diluted plasma concentrations of 0.013 mmol, 0.05 mmol, 0.25 and 1.25 µmol µmol that were introduced in this order, followed by the sample buffer and the sample was then plasma.

Calculation

The concentration in the samples was determined using version 4.1 of the software MassLynx (created Waters/Micromass), which automatically calculated the calibration curve and the concentration in the cells. Binding to plasma proteins was determined from the calibration curve as a percentage of the connection associated in human plasma (% binding), using the following equation:

For Example, the 16 measured value of binding of the proteins of human plasma using the method described above, was 94% linking.

Metholodology bronchostenosis in vivo

Guinea pigs line Dunkin-Hartley (300-600 g) was placed in accordance with established standards of breeding. Animals were given a certain dose of the compounds or means of delivery or by inhalation in conscious Guinea pigs or by intratracheal instillation (0.5 ml/kg) with recoverable gas anesthesia (5% halothane). The animal was allowed to recover from anesthesia before measuring bronchostenosis. Up to 48 hours after a dose of Guinea pigs was finally anestesiologi pentobarbitone sodium (60 mg/kg), the trachea was Coulibaly for artificial ventilation and jugular vein were Coulibaly for intravenous methacholine. Guinea pigs were ventolinbuy using the respiratory pump constant volume (fan Harvard Rodent model 683) at a rate of 60 breaths/min and tidal volume of 5 ml/kg during surgical training. Lung function (pulmonary resistance and compliance) were determined in shot and ventilated Guinea pigs, using the system of pulmonary measurements Flexivent (SCIREQ, Montreal, Canada)connected to the tracheal cannula. Alive is the shaft was ventolinbuy (good as utility power scheme ventilation) with a frequency of 60 breaths/min respiratory volume of 5 ml/kg Used positive pressure at the end of exhalation 2-3 cm H2O. breathing Resistance was determined using the apparatus for "snapshot" Flexivent (duration 1 second, 1 Hz frequency). Pulmonary resistance and compliance were determined before and after intravenous methacholine (3, 10 and 30 µg/kg). Expected maximum increase in resistance after metacholine provocation and determined the effect of the compounds on metabolizirovannom changes in pulmonary functions.

The percentage inhibition of bronchostenosis was calculated for each dose of methacholine as follows:

[Change of resistance in the group treated with carrier - Change of resistance in the group treated with connection] × 100 / [Change of resistance in the group treated with carrier]

Suppression procurementservices salivation using intranasal introduced compounds.

Guinea pigs (450-550 g) were supplied by Harlan UK or David Hall, Staffs UK, and they have acclimatized to the equipment, intended for use, for at least three days before using. Guinea pigs were randomly divided into treatment group and weighed. Each animal was easily anestesiologi (4% halothane) and intranasally administered the compound or vehicle (0.5 ml/kg) for up to 24 hours before provoking pilocarpin the and. In the analyzed time Guinea pigs was finally anestesiologi with urethane (25%solution in H2O, 1.5 g/kg). After it has reached a sufficient anesthesia (lack of reflex toes to pinch), each animal was placed in the mouth absorbent towel for 5 minutes to drain residual saliva, this cloth was removed and replaced with a new pre-weighed tissue for 5 minutes to establish the value of the original production of saliva. At the end of this 5-minute period the tissue was removed and weighed. A new pre-weighed tissue was placed in his mouth, and then each animal was subcutaneously injected under the skin on the scruff of the neck pilocarpine (0.6 mg/kg 2 ml/kg). The cloth was removed, weighed and replaced with a new pre-weighed tissue every 5 minutes up to 15 minutes.

The production of saliva was calculated by subtracting the mass weighted napkins from the mass tissues, weighed after each 5-minute period, and the quantities are summed to obtain the accumulation of saliva for 15 minutes. Each 5-minute period could be analyzed in addition to a 15-minute period of data recording. The original production of saliva was assumed constant and was multiplied by three to obtain the values for the original production of saliva in 15 minutes.

Suppression of saliva obtained by connecting, can be calculated using the following equation: (1-(test-initial value) / (media-original value))*100.

1. The compound of formula (I)

where R1and R2together with the carbon atom to which they are both directly attached form a 7-membered cycloalkyl ring which may be substituted by one or more substituents, independently selected from halogen, hydroxyl and C1-4of alkyl;
R3represents phenyl or 5-6-membered heteroaryl ring;
R4represents a group of formula (II)

where Y represents-CH2CH2-and the substitution of the ring in the group (II) can occur in clauses 3 or 4;
R5represents a group of formula (IV)

where w is 0 or 1;
R6represents a C1-4alkylen, possibly substituted by one or more substituents, independently selected from halogen, hydroxyl, C1-6alkoxy, NH2, NH(C1-6alkyl) and N(C1-6alkyl)2;
if w is equal to 0, then 0; if w = 1, u is 0 or 1;
Q represents OH, -CONR8- or-C(O)O-;
R7is a cyclic group WM1or1-4alkyl group, where C1-4the alkyl group may be substituted by one or is more substituents, independently selected from a cyclic group WM2and-ASUS2; and R7may additionally represent hydrogen;
each WM1and WM2independently represents an aryl, heteroaryl or 3-8-membered aliphatic carbocyclic ring, each of which can be substituted by one or more substituents, independently selected from halogen, cyano, OR26, phenyl and C1-6of alkyl, where the phenyl or C1-6the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl;
R8represents hydrogen; and
R26represents hydrogen or C1-6alkyl, where C1-6the alkyl can be substituted by one or more substituents, independently selected from halogen and hydroxyl;
and where the heteroaryl group may be monocyclic or bicyclic and contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur;
and X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

2. The compound according to claim 1, where R1and R2together with the carbon atom to which they are both directly attached form a 7-membered cycloalkyl ring, and R3represents phenyl.

3. The compound according to claim 1, where R4present which allows a group of formula (IIa)

4. The compound according to claim 1, where R5represents-C1-4alkylen-Q-R7;
where Q represents OH, -CONH -, or-C(O)O-;
R7represents hydrogen, WM1or1-4alkyl group, where C1-4the alkyl group may be substituted by one or more substituents, independently selected from phenyl, phenoxy, where phenyl and phenoxy can possibly be substituted by one or more substituents, independently selected from halogen, hydroxyl, cyano, C1-4alkoxy and OCF3;
WM1represents phenyl or 5-6-membered heteroaryl ring, each of which can be substituted by one or more substituents, independently selected from halogen, C1-4alkoxy, phenyl, and C1-4of alkyl, where phenyl and C1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl.

5. The compound according to claim 1, where R5represents a
-C1-4alkylen-About-WM1;
where Q represents a-CONH-; and WM1is a 5-6-membered heteroaryl, possibly substituted by one or more substituents, independently selected from halogen, C1-4alkoxy, phenyl and C1-4of alkyl, where phenyl and C1-4the alkyl may be substituted by one or more substituents, not avisio selected from halogen and hydroxyl.

6. The compound according to claim 1, where R1and R2together with the carbon atom to which they are both directly attached form a 7-membered cycloalkyl ring, R3represents phenyl, and R5represents-C1-4alkylen-Q-WM1;
where Q represents a-CONH-; and WM1is a 5-6-membered heteroaryl, possibly substituted by one or more substituents, independently selected from halogen, C1-4alkoxy, phenyl and C1-4of alkyl, where phenyl and C1-4the alkyl may be substituted by one or more substituents, independently selected from halogen and hydroxyl.

7. The compound according to claim 1, selected from
(3R)-1-methyl-3-{[(1-phenylcyclohexyl)carbonyl] oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-(3-phenoxypropan)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-(4-terbisil)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-benzyl-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-[3-(triptoreline)benzyl]-1-azoniabicyclo [2.2.2]octane X,
(3R)-1-(3,4-diferensial)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-3-{[(1-phenylcyclohexyl)carbonyl]on the si}-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1-azoniabicyclo[2.2.2]octane,
(3R)-1-(3-methoxybenzyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2,2 .2]octane X,
(3R)-1-(2-phenoxyethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(benzyloxy)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(isoxazol-3-ylamino)-2-oxoethyl]-3-({[1-(2-thienyl)cycloheptyl]carbonyl} oxy)-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-oxo-2-(pyrazin-2-ylamino)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-oxo-2-(pyridazin-3-ylamino)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-{2-oxo-2-[(2-phenoxyethyl)amino]ethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-{2-[(5-methylisoxazol-3-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-{2-[(6-chloropyridin-3-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-{2-[(3-forfinal)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(2-naphthyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(3-methoxyphenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(5-methyl-2-thienyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-3-{[(1-phenylcyclohexyl)ka is bonyl]oxy}-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]octane X,
(3R)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-{2-[3-(trifluoromethyl)phenyl]ethyl}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(1,3-benzodioxol-5-yl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(4-cyanophenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-{2-[(6-chloropyrazine-2-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-{[1-(4-chlorophenyl)cyclopropyl]methyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-{2-[(5-methylpyridin-2-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-(carboxymethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(3-chlorophenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-(2-amino-2-oxoethyl)-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X,
(3R)-1-[2-(3-chloro-4-methoxyphenyl)ethyl]-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X, and
(3R)-1-{2-[(3-methylisoxazol-5-yl)amino]-2-oxoethyl}-3-{[(1-phenylcyclohexyl)carbonyl]oxy}-1-azoniabicyclo[2.2.2]octane X;
where X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.

8. Pharmaceutics is the first composition for use in the treatment of chronic obstructive pulmonary disease, containing the compound of formula (I)as defined according to any one of claims 1 to 7, together with a pharmaceutically acceptable auxiliary substance, diluent or carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: pharmacology.

SUBSTANCE: invention refers to the compound of formula(I) or to is salt where R1 is -H or C1-6 alkyl; R2 is bridged aza-ring chosen out of group including formula and where ring hydrogen atom in bridged aza-ring may be substituted by one or several groups of R22; m, n and p have respective values 1 or 2; r has the value 0 or 1; R21 is C1-6 alkyl, -C1-6 alkyl-O-phenyl or -C1-6 alkyl-phenyl; R22 is C1-6 alkyl-cycloalkyl or -C1-6 alkyl-phenyl; R2 is thienyl, phenyl, pyridyl, pyranzinyl, thiazolyl or pyrazolyl, each of which can be substituted by one or several R31; R31 is the halogen, -OH, -CN, -CF3, C1-6 alkyl or -O-C1-6 alkyl; ring A is the group consisting of thiophene, thiazole, isothiazole, thidiazole, oxazole, isooxazole, cyclohexan, norboran, benzothiophene and 5,6-dihydro-4H-cyclopentathiophene, each of which can be substituted by the group chosen out of the group consisting out of one or several RA1; where RA1 is a halogen, -CN, -NH2, C1-6 alkyl, -O-C1-6 alkyl, CONH2, - HN-C1-6 alkyl, -HN-C1-6 alkyl-O-C1-6 alkyl-phenyl, -HN-C1-6 alkyl-phenyl or -HN-C1-6 alkyl-OH where C1-6 alkyl can be substituted with one or several halogen atoms; V is -NH- or -O-; W is -(CH2)q-; q has the value 0.1 or 2; X is the counteranion and is an ordinary bond; on condition when in case ring A is cyclohexane, R3 is phenyl which can be replaced with one or several R31. The invention also refers to pharmaceutical composition that has antagonistic effect on muscarine receptor M3, on the basis of said compound.

EFFECT: production of new compound and pharmaceutical composition on its basis, which can be applied in the medicine as an active substance for preventive and/or therapeutic drug for treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like.

14 cl, 60 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 1-azabicyclo[2.2.2]oct-3(R)yl ether of 2-hydroxy-2,2-dithien-2-ylacetic acid and 3-phenoxypropyl bromide, where the reaction takes place in a solvent or mixtures of solvents, having boiling point ranging from 50 to 210°C and selected from a group comprising ketones and cyclic ethers, preferably in acetone, dioxane and tetrahydrofuran.

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (R)- quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate or salt thereof, involving: 1) converting a compound which is 4-amino-3-methoxypiperidine-1-carboxylate to a salt; 2) converting the ethyl 4-amino-3-methoxypiperidine-1-carboxylate salt into ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate 3) treating ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with hydroxide or hydride of an alkali metal to obtain 3-methoxy-N,N-diphenylpiperidine-4-amine 4) obtainijng a chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine by bringing 3-methoxy-N,N-diphenylpiperidine-4-amine into contact with a chiral splitting agent and extracting the obtained chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine; optional recrystalisation of product 4; converting product 4 or 5 to a base to obtain product 4 or 5 in form of a free base; 7) bringing product 6 into contact with ethyl 6-bromohexanoate to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 8) esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate using (R)-quinuclidin-3-ol with a Lewis acid to obtain (R)- quinuclidin-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 9) removing protection from the 4-amine group of product 8 to obtain (R- quinuclidin-3-yl 6- [(3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate; 10) acylation of product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)- quinuclidin-3-yl 6-((38,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate; 11) optional conversion of product 10 into a salt.

EFFECT: method increases output of the end product and reduces content of impurities.

7 cl, 3 ex, 6 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I where X1-X4 each independently represent CR1, B represents -C(O)-O- or -C(O)-NH-CH2-, Y represents S or NH, R1 represents H, C1-C4alkoxy, unsubstituted or substituted by once or several times with F, or Het, and Het stands for heterocyclic group, fully saturated, partly saturated or fully unsaturated, containing in cycle 5-10 atoms, of which at least one atom represents N, O or S, unsubstituted or substituted once or several times with C1-C8alkyl, or to its pharmaceutically acceptable salt.

EFFECT: obtaining pharmaceutical composition for selective activation/stimulation of nicotine receptors α7 on the basis of said compound, as well as to their application for treatment of patient, suffering from psychotic disease, neurodegenerative disease, including cholinergic system dysfunction and/or condition of memory failure and/or failure of cognitive abilities.

52 cl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacy and represents an immunostimulating extract of one or more bacterial species specified in Moraxella catarrhalis, Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus sanguinis, wherein while preparing said extract one or more bacterial strains are lysed at pH more than 12, and the extract is processed in order to remove nucleic acids; and wherein the extract dies not cause the onset of a prion disease if introduced into a patient wherein the extract contains less than 100 mcg/ml of nucleic acid, wherein the extract contains chemically modified saccharide, including chemically modified lipopolysaccharide, and wherein at least one amino acid which is specified in aspartic acid, glutamic acid, serine, histidine, alanine, arginine, tyrosine, methionine, phenylalanine and lysine, is racemised at least by 10%.

EFFECT: invention does not cause a risk or eliminates a risk of the prion disease when introduced into the patient that provides maximum safety and efficacy.

48 cl, 12 ex, 10 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to phthisiology, and may be used for treating patients with pulmonary tuberculosis. That is ensured by conducting the tuberculosis therapy in compliance with the standard schedules and additionally prescribing the probiotic biologically active additive SimBiovital 9.0 g in a single dose every second day with food for two months, and also the Hepel 1 tablet once a day sublingually daily for four months.

EFFECT: method provides higher clinical effectiveness in pulmonary tuberculosis as indicated by infiltration resolution, cavity closure and abacillation with reduced rate of developing adverse hepatotoxic reactions and disbiotic intestinal disorders.

3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of neuroleptic haloperidol as means able to prevent development of abnormalities in lung tissue, caused by introduction of cytostatics. Reduction in development of inflammatory response due to reduction of development of connective tissue (pneumofibrosis) in lungs at the background of bleomicin introduction is shown.

EFFECT: invention can be applied for pharmacological correction of abnormalities in lung tissue developing with administration of anti-tumour medications.

1 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 6-substituted isoquinoline and isoquinolone derivatives of formula (I) where R1 denotes OH; R2 denotes H; R3 denotes H; R4 denotes H, (C1-C6)alkyl; R5 denotes H, halogen; R6 denotes H, (C1-C8)alkyl, (C1-C6)alkyleneR', (C1-C6)alkylene-C(O)NH-(C1-C6)alkyl, (C1-C6)alkylene-C(O)O-(C1-C6)alkyl, C(O) (C1-C6)alkyl, C(O)R1 or C(O)-(C1-C6)alkyleneR'; R7 denotes H, halogen, (C1-C6)alkyl; R8 denotes H; n equals 1, 2, 3 or 4; m equals 1, 2, 3, 4 or 5; and L denotes O or O-(C1-C6)alkylene; where R' denotes (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl; where in residues R4, R6 and R7 alkyl or alkylene can optionally be substituted once or several times with OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONHCH3 or CON(CH3)2; where in residues R4, R6 and R7 alkyl or alkylene can optionally be substituted once or several times with halogen; where in residue R6(C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted once or several times with suitable groups independently selected from halogen; where, if m equals 3, R6 does not denote H; and where, if m equals 3 and R6 denotes a residue selected from (C1-C8)alkyl, (C1-C6)alkylene-R'; alkyl, alkylene in said residue is substituted with once or several times, preferably once to three times, with OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONHCH3 or CON(CH3)2; or stereoisomeric forms thereof and/or tautomeric forms thereof and/or pharmaceutically acceptable salts thereof. The invention also relates to use of compounds of formula I to prepare a medicinal agent which inhibits Rho-kinase, as well as to the medicinal agent itself.

EFFECT: novel compounds which can be useful when treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation are obtained and described.

34 cl, 75 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzothiazolone derivatives of formula (I) or to their pharmaceutically acceptable salts showing β2-adrenoreceptor agonist activity, to a method for producing and using them for preparing a drug. wherein Ra and Rb independently represent hydrogen; R1 represents: α- or β-branched C3-12alkyl (optionally substituted by hydroxy, OC(O)(C1-6alkyl)), CH2(C3-12cycloalkyl) wherein cycloalkyl is optionally condensed with a benzene ring, C3-12cycloalkyl (optionally substituted by halogen, C1-6alkyl) or R28; R6 represents a phenyl or 5- or 6-phenyl heteroaromatic ring (each of which is optionally substituted by halogen, trifluoromethyl, hydroxy, C1-6alkyl, -C(O)NHR13, -SO2NHR14, C1-6alkoxy, optionally substituted by halogen), C1-6halogenoalkyl, benzodioxolyl, benzothiazolyl substituted by oxo and hydroxy group; R2, R3 and R4 independently represent hydrogen or C1-6alkyl; R29 represents hydrogen; R4 represents hydrogen, hydroxy or C1-6alkyl. The values R13, R14 and R28 are those as specified in the patent claim.

EFFECT: producing the pharmaceutically acceptable salts showing β2-adrenoreceptor agonist activity.

10 cl, 1 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (1): R1 means haloalkyl containing 1-6 fluorine atoms; R2 means C1-C6alkyl or halogen; R3 means -L-NR4R5, -X-NR-C(O)R8 or -X-NR-C(O)NR4R5 wherein L means -X-C(O), -(CR2)j, -O(CR2)1-4 or and X means (CR2)j or [C(R)(CR2OR)]; R4 and R5 independently mean H, C1-C6alkyl, halogen-substituted C1-C6alkyl, hydroxy group-substituted C1-C6alkyl, or (CR2)k-R6; R8 independently means (CR2)k-R6 or C1-C6alkyl, or halogen-substituted C1-C6alkyl; R7 means H; alternatively, R4 and R5 together with N atom in each NR4 R5 form a 4-7-member heterocyclic ring containing 1 -2 heteroatoms independently specified in N and O substituted by 0-3 groups R11; R11 means R8, (CR2)k-OR7, CO2R7, (CR2)k-C(O)-(CR2)k-R8, (CR2)kC(O)NR7R7 or (CR2)kS(O)1-2R8; each R means H or C1-C6alkyl; each k is equal to 0-6; and j and m are independently equal to 0-4; provided R1 does not mean trifluoromethoxygroup, provided R3 means C(O)NH2, C(O)NR12R13; wherein R12 and R13 together form piperazinyl; the values of the radical R6 are presented in the patent claim. The invention also refers to the pharmaceutical composition containing said compounds.

EFFECT: producing new 5-(4-(halogenalkoxy)phenyl)pyrimidin-2-amine derivatives showing c-kit, PDGFRα, PDGFRβ kinase inhibitory activity, optionally in the form of isomers or pharmaceutically acceptable salts.

12 cl, 77 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there are disclosed method and composition for intensifying mucus excretion and treating pulmonary disorders, such as cystic fibrosis. They use together with osmotically active substance a synthetic pulmonary surfactant containing one or more pharmaceutically acceptable phospholipids mixed with SP-B polypeptide or its fragment, or polypeptide containing at least 10 amino acid residues and no more than about 60 amino acid residues, said polypeptide containing a sequence having variable areas of hydrophobic and hydrophilic amino acid residues presented by formula (ZaUb)cZd, wherein surfactant activity of mixed phospholipids and polypeptide higher than that of one phospholipid, has osmolarity varying between 220-1200 mOsm/kg, the concentration of free anions varying between 20-200 mmole/l and the pH value varying between 6.8 and 8.0, and the surfactant provides the pulmonary delivery of a daily dose varying between approximately 20 and 200 mg of total phospholipid equivalent.

EFFECT: invention provides intensified mucus excretion and improved quality of life in the patients suffering cystic fibrosis, bronchitis, bronchiectasis, ciliary diskinesia, COPD, or sinusitis.

15 cl, 2 dwg, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: there are disclosed method and composition for intensifying mucus excretion and treating pulmonary disorders, such as cystic fibrosis. They use together with osmotically active substance a synthetic pulmonary surfactant containing one or more pharmaceutically acceptable phospholipids mixed with SP-B polypeptide or its fragment, or polypeptide containing at least 10 amino acid residues and no more than about 60 amino acid residues, said polypeptide containing a sequence having variable areas of hydrophobic and hydrophilic amino acid residues presented by formula (ZaUb)cZd, wherein surfactant activity of mixed phospholipids and polypeptide higher than that of one phospholipid, has osmolarity varying between 220-1200 mOsm/kg, the concentration of free anions varying between 20-200 mmole/l and the pH value varying between 6.8 and 8.0, and the surfactant provides the pulmonary delivery of a daily dose varying between approximately 20 and 200 mg of total phospholipid equivalent.

EFFECT: invention provides intensified mucus excretion and improved quality of life in the patients suffering cystic fibrosis, bronchitis, bronchiectasis, ciliary diskinesia, COPD, or sinusitis.

15 cl, 2 dwg, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: there are disclosed method and composition for intensifying mucus excretion and treating pulmonary disorders, such as cystic fibrosis. They use together with osmotically active substance a synthetic pulmonary surfactant containing one or more pharmaceutically acceptable phospholipids mixed with SP-B polypeptide or its fragment, or polypeptide containing at least 10 amino acid residues and no more than about 60 amino acid residues, said polypeptide containing a sequence having variable areas of hydrophobic and hydrophilic amino acid residues presented by formula (ZaUb)cZd, wherein surfactant activity of mixed phospholipids and polypeptide higher than that of one phospholipid, has osmolarity varying between 220-1200 mOsm/kg, the concentration of free anions varying between 20-200 mmole/l and the pH value varying between 6.8 and 8.0, and the surfactant provides the pulmonary delivery of a daily dose varying between approximately 20 and 200 mg of total phospholipid equivalent.

EFFECT: invention provides intensified mucus excretion and improved quality of life in the patients suffering cystic fibrosis, bronchitis, bronchiectasis, ciliary diskinesia, COPD, or sinusitis.

15 cl, 2 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I), salts and solvates thereof as ligands for G-protein conjugated receptors, , as well as a library consisting of elements which are compounds of formula (I). In general formula (I) , y equals 1 or 2; z equals 0; X denotes -CO-(Y)k-(R1)n, or SO2-(Y)k-(R1)n; k equals 0; each R1 is independently selected from hydrogen or alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylamino, alkylaminoalkyl, alkylaminodialkyl, having an alkylaminotrialkyl charge or having an alkylcarboxylate charge from 1-20 carbon atoms; or each R1 is independently selected from fluorine, chlorine, bromine, iodine, hydroxy, oxyalkyl, amino, aminoalkyl, aminodialkyl, having the charge of aminotrialkyl or a carboxylate radical; n is an integer from 1 to m, where m is the maximum number of allowable substitutes; R1 contains a carbon atom next to the carbonyl group of carbonamide or the sulphonyl group of sulphanilamide, which is di-substituted or identical or different groups selected from: alkyl, haloalkyl, alkoxy, haloakoxy, alkenyl, alkynyl and aklylamino radical; and the carbon atom next to the carbonyl group of carbonamide or the sulphonyl group of sulphanilamide in R1 forms essentially tetrahedral valence-bond angles.

EFFECT: obtaining a compound, salt or solvates thereof for use as ligands for G-protein conjugated receptors.

4 cl, 4 ex

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