Derivants of bicyclo[2, 2, 1] hept-7-ylamine and their applications

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of the formula (I) that are characterized by the properties of M3 muscarine receptor antagonist that is applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases. In the formula (I) A is represented by the oxygen atom or the group -N(R12)-; (i) R1 is represented by C1-C6-alkyl or the hydrogen atom; and R2 is represented by the hydrogen atom or the group -R5, -Z-Y-R5, -Z-NR9R10, -Z-NR9CO-R5 or -Z-CO2H; and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; or (ii) R1 and R2 together with nitrogen to which they are bound form heterocycloalkyl ring; the mentioned ring is displaced by the group -Y-R5 or -Z-Y-R5, and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; R4 is represented by the formula group (a), (b), (c) or (d); Z is represented by C1-C16-alkylene group; Y is represented by the link or the oxygen atom; R5 is represented by C1-C6-alkyl, aryl, phenyl condensed with C3-C6cycloalkyl, phenyl condensed with heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, C3-C6cycloalkyl or heteroC3-C6cycloalkyl group; R6 is represented by C1-C6-alkyl or the hydrogen atom; n and m equal 0; R8a and R8b are independently chosen from the group consisting of aryl, phenyl condensed with heterocycloalkyl, heteroaryl, C1-C6-alkyl, C3-C6cycloalkyl; R8c is represented by -OH or C1-C6-alkyl; R9 and R10 are represented independently by the hydrogen atom, C1-C6-alkyl, aryl, phenyl condensed with heterocycloalkyl and other components mentioned in the invention formula.

EFFECT: new compounds applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases.

10 cl, 49 ex

 

The technical field

The present invention relates to a derivative of bicyclo[2.2.1]hept-7-ylamine, pharmaceutical compositions containing them, methods for their preparation and use for the treatment of diseases mediated by the muscarinic M3 receptor, for example, respiratory diseases.

Prior art

Anticholinergics prevent the passage or actions resulting from the passage of impulses through the parasympathetic nerves. This is a consequence of the ability of these compounds to inhibit the action of acetylcholine (Ach), blocking its binding to muscarinic cholinergic receptors.

There are five subtypes of muscarinic acetylcholine receptors (mAChR), called M1-M5, and each (of them) is the product of a separate gene, and each demonstrates the unique pharmacological properties. mAChR are widely distributed in the bodies of vertebrates, and these receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle, found in the respiratory tract, the urinary bladder and gastrointestinal tract, mAChR M3 mediate the contractile response (discussed in Caulfield, 1993, Pharmac. Ther., 58, 319-379).

In light muscarinic receptors M1, M2 and M3, as shown, have a (large) value and are located in the trachea, the bronchus, the x, submucosal (submucosa) glands and parasympathetic ganglia (nerve nodes) (see review Fryer and Jacoby, 1998, Am J Resp Crit Care Med., 158 (5 part 3) str-160). The M3 receptors on the smooth muscle of the respiratory tract mediates the reduction and, consequently, bronchospasm. Stimulation of M3 receptors localized in the submucosal glands, leads to secretion of mucus.

Increased signaling through muscarinic acetylcholine receptors was noted in a number of different pathophysiological conditions, including asthma and COPD. When COPD vagal tone may either increase (Gross et al. 1989, Chest; 96:984-987) and/or may cause a higher degree of obstruction, because of the distorted geometry when applying over swollen or filled with mucus walls of the respiratory tract (Gross et al. 1984, Am Rev Respir Dis; 129:856-870). In addition, the inflammatory condition can lead to loss of inhibitory activity of the M2 receptor, which leads to higher levels of the release of acetylcholine after stimulation of the vagus nerve (Fryer et al, 1999, Life Sci., 64, (6-7) 449-455). Received increased activation of M3 receptors leads to increased airway obstruction. Therefore, the identification of potent antagonists of muscarinic receptors may be useful for therapeutic treatment of disease States involving increased activity of the receptor M3. In the very fact, modern treatment strategies support the regular use of bronchodilatation M3 antagonist in the treatment of first choice for patients with COPD (Pauwels et al. 2001, Am Rev Respir Crit Care Med; 163:1256-1276).

Podergivani urine due to hypertonic [hyperreflection] the bladder, as shown, is also mediated through increased stimulation of mAChR M3. Therefore, antagonists of M3 mAChR may be useful as therapeutic agents for these mAChR-mediated diseases.

Despite the weight of evidence for the use of therapies directed against muscarinic receptors for the treatment of conditions associated with disease of the respiratory tract, the relatively small number protivokashlevyh compounds find application in clinic patients with evidence of pulmonary disease. Thus, there remains a need for new compounds that could cause blockage to the muscarinic M3 receptors, in particular, compounds of this type with a long duration of action, which makes it possible to implement the regimen of medicines once daily. Because muscarinic receptors are widely distributed throughout the body, the possibility of delivery of anticholinergics directly into the respiratory tract has an advantage because it allows you to enter Beletskii dose of the drug. Design and application of locally-acting drug with a long duration of action (prolonged action) and are able to stay on the receptor or in the lung could reduce the manifestation of undesirable side effects that can occur with systemic administration of the same drugs.

Tiotropy (Spiriva™) is a muscarinic antagonist long-acting currently supplied to the market for the treatment of chronic obstructive pulmonary disease, intended for administration by inhalation.

In addition, ipratropium is a muscarinic antagonist, available on the market, for the treatment of COPD.

There are reports and other modulators of muscarinic receptors. For example, U.S. patent 4353922 describes muscarinic modulators on the basis of cyclic systems [2.2.1]azabicycloalkanes. European patent 418716 and US 005610163 describe different cyclic-based systems [3.2.1]azabicycloalkanes. In international publication WO 06/017768 describe cyclic system [3.3.1]azabicycloalkanes. System [2.2.2]azabicycloalkanes (hioliday) have been previously described, for example, in US 2005/0209272 and international publication WO 06/048225. System [3.1.0]azabicyclo Aksana have been described, for example, in international publication WO 06/035282. System [3.2.1]usabillity have been described, for example, in international publication WO 06/035303.

Class agonists adrenergic receptor β2the well-known. Many well-known β2agonists, in particular, β2-long acting agonists, such as salmeterol and formoterol, play (specific) role in the treatment of asthma and COPD. In addition, these compounds are usually administered by inhalation. Compounds currently being evaluated as agonists β2daily steps (enter once a day), described in Expert Opin. Investig. Drugs 14 (7), 775-783 (2005). The well-known β2agonist, pharmacophor has part:

In this field of technology is also known pharmaceutical compositions, which contain both muscarinic antagonist and β2agonist used for the treatment of respiratory diseases. For example, in US 2005/0025718 described β2agonist in combination with Tiotropium, oxitropium, ipratropium and other muscarinic antagonists; in international publication WO 02/060532 described, the combination of ipratropium with β2agonists, and in international publication WO 02/060533 described the combination exotropia with β2-agonists. Other combinations antagonist of M3/β2agonist described in the international publician WO 04/105759 and WO 03/087097.

In this the field of technology also known connection, having activity as an antagonist of muscarinic receptor and β2-agonist, presented in the same molecule. Such bifunctional molecules provide bronchodilatation, acting in two separate ways for the manifestation of the pharmacokinetic characteristic of a single molecule. Such a molecule is much easier to enter in the composition of the medicinal product intended for therapeutic use, compared to the case with the introduction of two separate compounds, and it significantly easier to integrate in the composition containing the third active component, for example, a steroid. Such molecules are described, for example, in international publications WO 04/074246, WO 04/089892, WO 05/111004, WO 06/023457 and WO 06/023460, each of which use different radical-linker for covalent binding of the antagonist of M3 with β2-agonist, which indicates that the structure of the radical-linker is not decisive for the preservation of the manifestations of both activities. It is not a surprise, since it is not necessary that the molecule interacted with the M3 receptors and β2at the same time.

Summary of the invention

In accordance with the invention features a compound of formula (I):

where

A represents an oxygen atom or a group-N(R12-;

(i) R1represents a C1-C6-alkyl or a hydrogen atom and R2represents a hydrogen atom or a group-R5or a group-Z-Y-R5or a group-Z-NR9R10; or a group-Z-CO-NR9R10; or a group-Z-NR9-CO-R5; or a group-Z-CO2-R5; or a group-Z-CO2H; and R3represents a single couple or1-C6-alkyl, and in this case the nitrogen atom to which it is attached is a Quaternary nitrogen and carries a positive charge; or

(ii) R1and R3together with the nitrogen to which they are attached, form geteroseksualnoe ring, and R2represents a hydrogen atom; or a group-R5or a group-Z-Y-R5or a group-Z-NR9R10or a group-Z-CO-NR9R10or a group-Z-NR9-CO-R5or a group-Z-CO2-R5or a group-Z-CO2H; and in these cases the nitrogen atom to which it is attached is a Quaternary nitrogen and carries a positive charge; or

(iii) R1and R2together with the nitrogen to which they are attached, form geteroseksualnoe ring, such ring substituted by a group-Y-R5or a group-Z-Y-R5or a group-Z-NR9R10; or a group-Z-CO-NR9R10; or a group-Z-NR9-CO-R5; or a group-Z-CO2-R5 ; or a group-Z-CO2H; and R3represents a single couple or1-C6-alkyl, and in this case the nitrogen atom to which it is attached is a Quaternary nitrogen and carries a positive charge;

R4selected from one of the groups of formula (a), (b), (C) or (d):

Z represents a C1-C16-alkylenes,2-C16-alkenylamine or2-C16-alkynylamino group;

Y represents a bond or an oxygen atom;

R5represents a C1-C6is alkyl, aryl, aryl fused with cycloalkyl, aryl condensed with heterocyclization, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, cycloalkyl or geterotsyklicescoe group;

R6represents a C1-C6-alkyl or a hydrogen atom;

R7aand R7brepresent1-C6is an alkyl group or halogen;

n and m is independently 0, 1, 2 or 3;

R8aand R8bindependently selected from the group consisting of aryl, aryl fused with heterocyclization, heteroaryl,1-C6-alkyl, cycloalkyl;

R8crepresents-HE1-C6-alkyl, hydroxy-C1-C6-alkyl, nitrile, group CONR8d2or a hydrogen atom;

R8drepresents a C1-C6-alkyl or a hydrogen atom;

R9and R10represent independently a hydrogen atom, a C1-C6is alkyl, aryl, aryl fused with heterocyclization, aryl condensed with cycloalkyl, heteroaryl, aryl(C1-C6-alkyl)- or heteroaryl(C1-C6-alkyl)-group; or R9and R10together with the nitrogen atom to which they are attached, form a heterocyclic ring of 4-8 atoms, optionally containing an additional nitrogen atom or oxygen;

R12represent1-C6-alkyl or a hydrogen atom;

Ar1represents aryl, heteroaryl or cycloalkyl;

Ar2represents independently aryl, heteroaryl or cycloalkyl; and

Q represents an oxygen atom, -CH2-, -CH2CH2or communication;

or its pharmaceutically acceptable salt, MES, N-oxide or prodrug.

In one subgroup of compounds according to the present invention

A represents an oxygen atom or a group-N(R12)-;

R1represents a C1-C6-alkyl or a hydrogen atom and R2represents a C1-C6-alkyl, a hydrogen atom or a group-Z-Y-R5or a group-Z-NR9R10; or R1and R2together with the nitrogen to which they are connec the us, form geteroseksualnoe ring;

R3represents a single pair or a C1-C6-alkyl, and in this case the nitrogen atom to which it is attached is a Quaternary nitrogen and carries a positive charge; or R1and R3together with the nitrogen to which they are attached, form geteroseksualnoe ring and R2represents a C1-C6-alkyl, and in this case the nitrogen atom is quaternion and carries a positive charge;

R4selected from one of the groups of formula (a) and (b):

Z represents a C1-C8-alkylenes, C2-C8-alkenylamine or C2-C8-alkynylamino group;

Y represents a bond or an oxygen atom;

R5represents aryl, heteroaryl, aryl(C1-C8-alkyl)- or heteroaryl(C1-C8-alkyl)-group;

R6represents a C1-C6-alkyl or a hydrogen atom;

R7aand R7bare independently C1-C6is an alkyl group or halogen;

n and m is independently 0, 1, 2 or 3;

R8aand R8bindependently selected from the group consisting of aryl, heteroaryl, C1-C6-alkyl, cycloalkyl;

R8crepresents-OH, C1-C6-alkyl, hydroxy-C1-C6-alkyl or a is ω hydrogen;

R9and R10represent independently a hydrogen atom, a C1-C6is alkyl, aryl, heteroaryl, aryl(C1-C6-alkyl)- or heteroaryl(C1-C6-alkyl)-group; or R9and R10together with the nitrogen atom to which they are attached, form a heterocyclic ring of 4-8 atoms, optionally containing an additional nitrogen atom or oxygen; and

R12represents a C1-C6-alkyl or a hydrogen atom.

Compounds of the present invention are either SYN-or anti-forms;

Compounds of the present invention also exist in relation to group-AR4or in the Exo-or endo-orientation;

At present, it is preferable that the compounds of the present invention was mainly in anti-endo-configuration.

Compounds of the present invention may also exist as optical isomers, as substituted bicyclic structure may not have a plane of symmetry. The absolute configuration of a molecule can be determined in accordance with the rules Kanna-Ingold-Prelog, assigning the identifier (handle) R or S to each position. To avoid confusion, in the present description use nizes abusou numbering in the cyclic structure.

However, compounds of the present invention include the racemates, individual enantiomers and mixtures of enantiomers in any ratio, because all of the above forms have activity modulating muscarinic M3 receptor in varying degrees.

A preferred class of compounds of the present invention consist of Quaternary ammonium salts of formula (I), where the nitrogen shown in the formula (I)is a Quaternary nitrogen that carries a positive charge.

Compounds of the present invention can be used for the treatment or prevention of diseases, the pathology of which involves activation of muscarinic receptors, for example, the proposed connection is used to treat a number of symptoms, including, but not limited to, disorders of the respiratory tract such as chronic obstructive pulmonary disease, chronic bronchitis, all types (including shortness of breath associated with it), asthma (allergic and non-allergic; syndrome Striganova (wheezing) the child has a respiratory), acute respiratory distress syndrome in adults (ARDS), chronic obstruction of the respiratory tract, bronchial hyperactivity, pneumosclerosis, emphysema and allergic rhinitis, exacerbation of increased reactivity of the Airways due to treatment with other medicinal and means in particular, inhalation therapy, other drugs, pneumoconiosis (for example, aluminas, antraks, asbestosis, helicos, Philos, sideros, silicosis, tabacos, bissines);

disorders of the gastrointestinal tract, such as irritable bowel syndrome, gastro-duodenal ulcers, gastro-intestinal spasms or hyperkinesia, diverticulitis, pain accompanying spasms of smooth muscles of the gastrointestinal tract; disorders of the urinary tract, accompanying urination disorders, including the neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, podergivani incontinence associated with bladder spasms or chronic cystitis, strong need to urinate or pollakiuria; sickness (motion sickness); and

disorders of the cardiovascular system, such as vagal (vegasno) induced sinus bradycardia.

For the treatment of respiratory conditions introduction inhalation is often preferred, and in such cases it is often preferable to the introduction of compounds (I), which are salts of Quaternary ammonium. In many cases, the duration of the Quaternary ammonium salts of the present invention, administered by inhalation, may be more than 12 or more than 24 hours for a typical dose. For the treatment of disorders of the gastrointestinal tract and disorders of the cardiovascular system may be preferably the parenteral route, usually through the mouth.

Another aspect of the present invention is a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier or excipient.

Another aspect of the present invention is the use of compounds of the present invention for obtaining a medicinal product for the treatment or prevention of a disease or condition in the pathology of which involves the activity of the muscarinic M3 receptor.

Terminology

The following terms have the following meanings, unless the context in which they are used in the description, they are not defined otherwise.

“Acyl” means-CO-alkyl group, which alkyl group such as indicated in the description. Typical acyl groups include-PINES3and the PINES(CH3)2.

“Acylamino” means-NR-acyl group in which R and acyl are as defined in the description. Typical alluminare include-NHCOCH3and-N(CH3)COCH3.

“Alkoxy” and “alkyloxy” means-O-alkyl group in which alkyl such as defined below. Typical alkoxygroup include met the XI (-och 3and ethoxy (-OS2H5).

“Alkoxycarbonyl” means-COO-alkyl group in which alkyl such as defined below. Typical alkoxycarbonyl group include methoxycarbonyl and etoxycarbonyl.

“Alkyl” as a group or part of a group refers to a saturated hydrocarbon group with a straight or branched chain, containing in the chain from 1 to 12, preferably from 1 to 6 carbon atoms. Typical alkyl groups include methyl, ethyl, 1-propyl and 2-propyl.

“Alkenyl” as a group or part of a group refers to a hydrocarbon group with a straight or branched chain, containing in the chain from 2 to 12, preferably from 2 to 6 carbon atoms and one carbon-carbon double bond. Typical alkeneamine groups include ethynyl, 1-propenyl and 2-propenyl.

“Quinil” as a group or part of a group refers to a hydrocarbon group with a straight or branched chain, containing in the chain from 2 to 12, preferably from 2 to 6, carbon atoms and one carbon-carbon triple bond. Typical alkyline group include ethinyl, 1-PROPYNYL and 2-PROPYNYL.

“Alkylamino” means-NH-alkyl group, which alkyl such as defined above. Typical alkylamino include methylamino, ethylamino.

“Alkylene” means accelgroup, in which alkyl such as defined RAS is E. Typical alkylene groups include-CH2-, -(CH2)2- and- (CH3)HCH2-.

“Albaniles” means altergroup in which alkenyl such as defined above. Typical alkenylamine groups include-CH=CH-, -CH=SNSN2-

and CH2CH=CH-.

“Akinyan” means Altenilpe in which quinil such as defined previously. Typical alkenylamine groups include-SS-, -SSN2- and-CH2SS-.

“Alkylsulfonyl” means-SO-alkyl group in which alkyl such as defined above. Typical alkylsulfonyl group include methylsulfonyl and ethylsulfonyl.

“Alkylsulfonyl” means-SO2is an alkyl group in which alkyl such as defined above. Typical alkylsulfonyl groups include methylsulphonyl and ethylsulfonyl.

“Alkylthio” means-S-alkyl group, which alkyl such as defined above. Typical ancilliary include methylthio, ethylthio.

“Aminoacyl” means-CO-NRR group, in which R is the same as stated in the description. Typical aminoaniline groups include-CONH2and-CONHCH3.

“Aminoalkyl” means alkyl-NH2the group in which the alkyl such as described previously. Typical aminoalkyl groups include-CH2NH2.

“Aminosulfonyl” means-SO2-NRR group, in which R is as mentioned the description. Typical aminosulfonyl groups include-SO2NH2and-SO2NHCH3.

“Aryl” as a group or part of a group means optionally substituted monocyclic or polycyclic aromatic carbocyclic portion containing from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl. Aryl group may be substituted by one or more groups-substituents.

“Arylalkyl” means arylalkyl, in which the aryl and alkyl parts are such as previously described. Preferred arylalkyl groups contain From1-4is an alkyl part. Typical arylalkyl groups include benzyl, phenethyl and naphthalenethiol. They aryl part can be substituted by one or more groups-substituents.

“Arylalkyl” means arylalkylamine, in which aryl, alkyloxy parts such as previously described. Preferred arylalkylamine contain1-4alkyl part. Typical arylalkyl groups include benzyloxy. They aryl part can be substituted by one or more groups-substituents.

“Aryl condensed with cycloalkyl” means a monocyclic aryl ring, such as phenyl condensed with cycloalkyl group, and the aryl and cycloalkyl have such a value is, as stated in the description. Typical 'aryl condensed with cycloalkyl' groups include tetrahydronaphthyl and indanyl. Aryl and cycloalkyl ring may be each substituted by one or more groups-substituents. 'Aryl condensed with cycloalkyl' group can be attached to the remainder of the compound via any available carbon atom.

“Aryl condensed with heterocyclization” means a monocyclic aryl ring, such as phenyl condensed with geteroseksualnoe group, and the aryl and heteroseksualci have such values as specified in the description. Typical 'aryl condensed with heterocyclization' groups include tetrahydropyranyl, indolinyl, benzodioxolyl, benzodioxolyl, dihydrobenzofuranyl and isoindolyl. Aryl and heterocytolysine ring may be each substituted by one or more groups-substituents. 'Aryl condensed with heterocyclization' group can be attached to the remainder of the compound via any available carbon atom or nitrogen.

“Aryloxy” means-O-aryl group in which the aryl such as described above. Typical alloctype include phenoxy. They aryl part can be substituted by one or more groups-substituents.

“Cyclic amine” is a OS is a special case of “geterotsiklicheskie” or “heterocycle” refers to optionally substituted (3-8)-membered monocyclic cycloalkyl structure, where one of the ring carbon atoms is replaced by nitrogen and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as indicated in the description). Typical cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and N-methylpiperazine. The cyclic amino group may be substituted by one or more groups-substituents.

“Cycloalkyl” means optionally substituted saturated monocyclic or bicyclic structure containing from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms and more preferably from 3 to 6 carbon atoms. Typical monocyclic cycloalkyl patterns include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl group may be substituted by one or more groups-substituents.

“Cycloalkenyl” means cycloalkenyl in which cycloalkyl and alkyl parts are such as previously described. Typical monocyclic cycloalkenyl group include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. Their cycloalkyl part may be substituted by one or more groups-substituents.

“Dialkylamino” means-N(alkyl)2the group in which the alkyl such as defined above. Typical dialkylamino which include dimethylamino, diethylamino.

“Halo” or “halogen” means fluorine, chlorine, bromine or iodine. Preferred are fluorine or chlorine.

“Halogenoalkane” means-O-alkyl group in which alkyl is substituted by one or more halogen atoms. Typical halogenlampe include triptoreline, deformedarse.

“Halogenated” means an alkyl group that is substituted by one or more halogen atoms. Typical halogenoalkane groups include trifluoromethyl.

“Heteroaryl” as a group or part of a group means optionally substituted aromatic monocyclic or polycyclic organic portion containing from 5 to 14 atoms in the cyclic structure, preferably from 5 to 10 atoms in the cyclic structure in which one or more of the cyclic atoms is(are) other(them)than carbon, for example, nitrogen atom, oxygen or sulfur. Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothiazol, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, ethenolysis, isothiazolin, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, hintline, chinoline, tetrazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and thiazolidine group. Heteroaryl group may be substituted by one or more groups-what zamestitelyami. Heteroaryl group may be attached to the remainder of the compounds of the present invention through any available carbon atom or nitrogen.

“Heteroaromatic” means heteroallyl, in which the heteroaryl and alkyl part, such as described previously. Preferred heteroallyl groups include the lower alkyl part. Typical heteroallyl group include pyridylmethyl. Their heteroaryl portion may be substituted by one or more groups-substituents.

“Heteroaromatics” means heteroarylboronic, in which the heteroaryl and alkyloxy parts such as previously described. Preferred heteroarylboronic contain lower alkyl part. Typical heteroarylboronic include pyridylmethylene. Their heteroaryl portion may be substituted by one or more groups-substituents.

“Heteroaromatic” means heterokaryosis in which heteroaryl such as described previously. Typical heterokaryosis include pyridyloxy. Their heteroaryl portion may be substituted by one or more groups-substituents.

“Heteroaryl condensed with cycloalkyl” means a monocyclic heteroaryl group such as pyridyl or furanyl condensed with cycloalkyl group, and the th heteroaryl and cycloalkyl have such values, as described previously. Typical 'heteroaryl condensed with cycloalkyl' groups include tetrahydropyranyl and tetrahydrofuranyl. Heteroaryl and cycloalkyl ring may be each substituted by one or more groups-substituents. 'Heteroaryl condensed with cycloalkyl' group can be attached to the remainder of the compound via any available carbon atom or nitrogen.

“Heteroaryl condensed with heterocyclization” means a monocyclic heteroaryl group such as pyridyl or furanyl condensed with geteroseksualnoe group, and these heteroaryl and heteroseksualci are as previously described. Typical 'heteroaryl condensed with heterocyclization' groups include dihydrodesoxymorphine, dihydropyrimidines, dihydropyrimidines and dioxopiperidin. Heteroaryl and heterocytolysine ring may be each substituted by one or more groups-substituents. 'Heteroaryl condensed with heterocyclization' groups can be joined to the remainder of the compound via any available carbon atom or nitrogen.

“Heteroseksualci” or “heterocyclic” means: (i) optionally substituted cycloalkyl group containing from 4 to 8 members in the loop, which contains one or a few is to heteroatoms, selected from O, S, or NR; (ii) cycloalkyl group containing from 4 to 8 members in the loop, which contains CONR and CONRCO (examples of such groups include Succinimidyl and 2-oxopyrrolidin). Heterocytolysine group may be substituted by one or more groups-substituents. Heterocytolysine group can be attached to the remainder of the compound via any available carbon atom or nitrogen.

“Geterotsiklicheskikh” or “heteroseksualci” means geterotsiklicheskikh in which heterocytolysine and alkyl parts are such as previously described.

“Lower alkyl” as a group means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched, containing in the chain from 1 to 4 carbon atoms, i.e. methyl, ethyl, propyl (propyl or isopropyl) or butyl (butyl, isobutyl or tert-butyl).

“Sulfonyl” means-SO2is an alkyl group in which alkyl as mentioned in the description. Typical sulfonylurea groups include methanesulfonyl.

“Sulfonylamino” means-NR-sulfonyloxy group, in which R and sulfonyl such as indicated in the description. Typical sulfonylamino include

-NHSO2CH3. R means alkyl, aryl or heteroaryl specified in the description.

“Pharmaceutically acceptable salt” oznacza the t physiologically or toxicologically acceptable salt includes, when appropriate, pharmaceutically acceptable basic additive salts, pharmaceutically acceptable acid additive salts and pharmaceutically acceptable salts of Quaternary ammonium. For example, (i), in cases where the compound of the present invention contains one or more acidic groups, for example, carboxypropyl, pharmaceutically acceptable basic additive salts that can be obtained include salts of sodium, potassium, calcium, magnesium and ammonium, or salts with organic amines, such as diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g. lysine) and the like; (ii) in cases where the compound of the present invention contains a basic group such as amino group, pharmaceutically acceptable acid-additive salts that can be obtained include hydrochloride, hydrobromide, sulfates, phosphates, acetates, citrates, lactates, tartratami, mesylates, maleate, fumarate, succinate and the like; (iii) in cases where the compound contains the group of Quaternary ammonium acceptable counterions can represent, for example, chlorides, bromides, sulfates, methansulfonate, bansilalpet, toluensulfonate (tozilaty), phosphates, acetates, citrates, lactates, tartratami, mesylates, maleate, fumarate, succinate etc.

It should be borne in mind that when in the present description reference is connected to the I of the present invention, it is assumed that they also include pharmaceutically acceptable salts.

“Prodrug” refers to a compound that is capable of in vivo conversion metabolities means (e.g. by hydrolysis, recovery or oxidation) in the compound of the present invention. For example, the prodrug in the form of ester compounds of the present invention containing a hydroxy-group, can be transformed by hydrolysis in vivo to the parent (original) molecule. Suitable esters of compounds of the present invention containing a hydroxy-group, are for example acetates, citrates, lactates, tartratami, malonate, oxalates, salicylates, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoate, gentisate, isocyanate, di-p-toluoyltartaric, methansulfonate, econsultancy, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and hinata. As another example, the ester prodrug compounds of the present invention, containing carboxypropyl may develop as a result of hydrolysis in vivo to the parent molecule. Examples of ester prodrugs described F.J. Leinweber, Drug Metab. Res., 1987, 18, 379.

It should be borne in mind that when in the present description refer to the compounds of the present invention, it is assumed that they include and forms about is learning about your medicine.

The term “saturated” refers to compounds and/or groups that have no (no) carbon-carbon double bonds or carbon-carbon triple bonds.

“Optionally substituted” means optionally substituted by up to four substituents. Optional group substituents include acyl (for example, the PINES3), alkoxy (e.g.,- och3), alkoxycarbonyl (for example, SOON3), alkylamino (for example, -NHCH3), alkylsulfonyl (for example, -SOCH3), alkylsulfonyl (for example, -SO2CH3), alkylthio (for example, -SCH3), -NH2the aminoacyl (for example, -CON(CH3)2), aminoalkyl (for example, -CH2NH2), arylalkyl (for example, -CH2Ph or-CH2-CH2-Ph), cyano, dialkylamino (for example, -N(CH3)2), halogen, halogenoalkane (for example, -OCF3or OCHF2), halogenated (e.g.,- CF3), alkyl (e.g.,- CH3or-CH2CH3), -OH, -NO2, aryl (optionally substituted alkoxy, halogenoalkane, halogen, alkyl or halogenation), heteroaryl (optionally substituted alkoxy, halogenoalkane, halogen, alkyl or halogenation), heteroseksualci, aminoacyl (for example, -CONH2, -CONHCH3), aminosulfonyl (for example, -SO2NH2, -SO2NHCH3), acylamino (for example, -NHCOCH3), sulfonylamino (the example -NHSO2CH3), heteroaromatic, cyclic amine (e.g. morpholine), aryloxy, heteroaromatic, arylalkylamine (e.g., benzyloxy), heteroarylboronic.

Alkylene, alkenylamine or alkenylamine radicals can be optionally substituted. Optional group-substituents in the aforementioned radicals include alkoxy (e.g.,- och3), alkylamino (for example, -NHCH3), alkylsulfonyl (for example, -SOCH3), alkylsulfonyl (for example, -SO2CH3), alkylthio (for example, -SCH3), -NH2aminoalkyl (for example, -CH2NH2), arylalkyl (for example, -CH2Ph or-CH2-CH2-Ph), cyano, dialkylamino (for example, -N(CH3)2), halogen, halogenoalkane (for example, -OCF3or OCHF2), halogenated (e.g.,- CF3-), alkyl (e.g.,- CH3or-CH2CH3), HE-NO2.

Compounds of the present invention may exist in one or more geometric, optical, enantiomeric, diastereomeric and tautomeric forms, including, but not limited to, CIS - and TRANS-forms, E - and Z-forms; R-, S -, and meso-forms, keto and enol forms. Unless otherwise stated, a reference to a particular connection includes all of these isomeric forms, including racemic mixtures and other mixtures thereof. If necessary, these isomers can be allocated the s from their mixtures with known methods of separation or methods, adapted to them (e.g., chromatographic methods and recrystallization methods). If appropriate, these isomers can be obtained by known methods or methods that are adapted to them (e.g., asymmetric synthesis).

Group R1R2and R3

There are three combinations of groups R1, R2and R3.

In combination (i) R1represents a C1-C6-alkyl or a hydrogen atom; and R2represents a hydrogen atom or a group-R5or a group-Z-Y-R5or a group-Z-NR9R10or a group-Z-CO-NR9R10or a group-Z-NR9-CO-R5or a group-Z-CO2-R5or a group-Z-CO2H; and R3represents a single couple or1-C6alkyl, and in this case the nitrogen atom to which it is connec, is a Quaternary nitrogen and carries a positive charge.

In combination (ii) R1and R3together with the nitrogen to which they are attached, form geteroseksualnoe ring, and R2represents a hydrogen atom; or a group-R5or a group-Z-Y-R5or a group-Z-NR9R10or a group-Z-CO-NR9R10or a group-Z-NR9-CO-R5or a group-Z-CO2-R5or a group-Z-CO2H, and in these cases the nitrogen atom to which it is attached, presented yet a Quaternary nitrogen and carries a positive charge. In particular, R1and R3together with the nitrogen to which they are attached, may form a monocyclic ring containing from 3 to 7 ring atoms, which heteroatoms are nitrogen atoms. Examples of such rings include azetidine, piperidinyl, piperazinil, N-substituted piperazinil, such as methylpiperidine and pyrrolidinyl rings.

In combination (iii), R1and R2together with the nitrogen to which they are attached, form geteroseksualnoe ring, such ring substituted by a group-Y-R5or a group-Z-Y-R5or a group-Z-NR9R10or a group-Z-CO-NR9R10or a group-Z-NR9-CO-R5or a group-Z-CO2-R5or a group-Z-CO2H, and R3represents a single couple or1-C6-alkyl, and in this case the nitrogen atom to which it is attached is a Quaternary nitrogen and carries a positive charge. In particular, R1and R2together with the nitrogen to which they are attached, may form a monocyclic ring containing from 3 to 7 atoms in the ring, in which the heteroatoms are nitrogen atoms. Examples of such rings include azetidine, piperidinyl, piperazinil, N-substituted piperazinil, such as methylpiperidine and pyrrolidinyl rings.

In those cases, when the group-R55or a group-Z-NR9R10or a group-Z-CO-NR9R10or a group-Z-NR9-CO-R5or a group-Z-CO2-R5or a group-Z-CO2H is in R2or when the ring formed by R1, R2and the nitrogen to which they are attached:

Z can represent, for example, -(CH2)1-16-, the latter optionally substituted stands for up to three carbons in the chain;

Y is a bond or-O-;

R5can be a

With1-C6-alkyl, such as methyl, ethyl, n - or isopropyl, n-, sec - or tert-butyl;

optionally substituted aryl, such as phenyl or naphthyl, or aryl condensed with heterocyclization, such as 3,4-methylenedioxyphenyl, 3,4-atlanticcity or dihydrobenzofuranyl;

optionally substituted heteroaryl, such as pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazole, benzoxazole, thiazole, benzothiazole, hinely, thienyl, benzothiazyl, furyl, benzofuran, imidazolyl, benzimidazolyl, isothiazolin, benzisothiazole, pyrazolyl, isothiazolin, triazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, triazinyl, indolyl and indazoles;

optionally substituted aryl(C1-C6-alkyl)-, such as aryl(C1-C6-alkali)-, where aryl frequent represent any of the previously specifically mentioned aryl groups, and part(C 1-C6-alkyl)- represents-CH2- or-CH2CH2-;

optionally substituted aryl condensed with cycloalkyl, such as indanyl or 1,2,3,4-tetrahydronaphthalene;

optionally substituted heteroaryl(C1-C8-alkyl)-, as, for example, heteroaryl(C1-C8-alkali)-, in which the heteroaryl portion is any one of the previously specifically mentioned heteroaryl groups, and part(C1-C6-alkyl)- represents-CH2- or-CH2CH2-;

optionally substituted cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or

optionally substituted heteroseksualci(C1-C8-alkyl)-, as, for example, heteroseksualci(C1-C8-alkali)-in which heterocytolysine part is azetidine, piperidinyl, piperazinil, N-substituted piperazinil, such as methylpiperazine, or pyrrolidinyl and part -(C1-C6-alkyl)- represents-CH2- or-CH2CH2-.

R9and R10can be independently selected from hydrogen; C1-C6-alkyl, such as methyl, ethyl, or n - or isopropyl; or any of the groups specified in the discussion above R5, substituted aryl, aryl fused with heterocyclization, and the sludge, condensed with cycloalkyl, heteroaryl or aryl(C1-C8-alkyl)-; or

R9and R10together with the nitrogen atom to which they are attached, may form a heterocyclic ring of 4 to 8 ring atoms, preferably 4-6 ring atoms, optionally containing an additional nitrogen atom or oxygen, such as azetidine, piperidinyl, piperazinil, N-substituted piperazinil, such as methylpiperazine, pyrrolidinyl, morpholinyl and thiomorpholine.

Preferred (currently) are the compounds of the present invention, in which the group-NR1R2R3R1represents methyl or ethyl, R2represents a group-Z-Y-R5discussed above, in particular, in which R5is a lipophilic cyclic group, such as phenyl, benzyl or phenylethyl, Y is a bond or-O - and Z is a straight or branched alkalinity radical connecting the nitrogen and YR5chain containing up to 12, for example, up to 9, carbon atoms, and R3represents methyl, so that the nitrogen is quaternion and carries a positive charge.

Radical And

And represents the oxygen atom or the group-N(R12)-, where R12represents a C1-C6-alkyl (such as IU the sludge or ethyl) or R 12represents a hydrogen atom. Currently the preferred case, when a represents-O-.

The group R4

R4selected from one of the groups of formula (a), (b), (c) or (d):

In group (a) R6can be a1-C6-alkyl, such as methyl or ethyl, or hydrogen atom; Ar1can be an aryl group such as phenyl, heteroaryl group, such as thienyl, in particular, 2-thienyl, or cycloalkyl group, such as cyclohexyl, cyclopentyl, cyclopropyl or cyclobutyl; the substituents of the ring R7aand R7bcan represent, independently, With1-C6is an alkyl group such as methyl, ethyl, n - or isopropyl, n-, sec - or tert-butyl, or halogen, such as fluorine, chlorine or bromine; and m and n can be equal to independently 0, 1, 2, or 3.

In groups (b) and (d) R8aand R8bcan be independently selected from any of groups, aryl, aryl fused with heterocyclization, aryl condensed with cycloalkyl, heteroaryl,1-C6-alkyl or cycloalkyl specifically mentioned in the discussion above R5. R8ccan be a HE, a hydrogen atom, a C1-C6-alkyl, such as methyl or ethyl, hydroxy-C1-C6-alkyl, such as hydroxymethyl, neath the sludge or group CONR 8d2where each R8drepresents independently1-C6-alkyl, such as methyl or ethyl, or hydrogen atom. Currently the preferred case when R8cis a HE. Preferred combinations of R8aand R8bin particular, when R8cis a HE, include combinations where (i) each of R8aand R8brepresents an optionally substituted monocyclic heteroaryl with 5 or 6 ring atoms, such as pyridyl, oxazolyl, thiazolyl, furyl and, in particular, thienyl, such as 2-thienyl; (ii) optionally substituted phenyl; (iii) one of R8aand R8brepresents optionally substituted phenyl and the other is cycloalkyl, such as cyclopropyl, cyclobutyl or, in particular, cyclopentyl or cyclohexyl; and (iv) one of R8aand R8brepresents an optionally substituted monocyclic heteroaryl with 5 or 6 ring atoms, such as pyridyl, thienyl, oxazolyl, thiazolyl or furyl; and the other is cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In group (C) R8ccan be a HE, a hydrogen atom, a C1-C6-alkyl, such as methyl or ethyl, hydroxy-C1-C6- alkyl, such as hydroxymethyl, nitrile or a group CONR8d 2where each R8drepresents independently1-C6-alkyl, such as methyl or ethyl, or hydrogen atom. Currently the preferred case when R8cis a HE. Each Ar2represents aryl, heteroaryl or cycloalkyl ring and can represent, for example, any of the groups (rings), specifically mentioned in the discussion above R5, aryl, heteroaryl,1-C6-alkyl or cycloalkyl. Preferred rings Ar2include phenyl. Bridging the communication-Q between the two rings Ar2represents-O-, -CH2- or-CH2CH2-.

Option R4(a), (b), (c) and (d) (currently) preferably, R4represented a group (b) or (c).

A preferred subclass of compounds related to the present invention consists of compounds of formula (IA)

where ring a is an optionally substituted phenyl ring or a monocyclic heterocyclic ring of 5 or 6 ring atoms, or phenyl ring fused with heterocyclization in which geteroseksualnoe ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; R8arepresents phenyl, which Anil, cyclopentyl or cyclohexyl; R8brepresents phenyl; thienyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7, provided that s+t is not greater than 10; Y is a bond or-O-, and X-represents a pharmaceutically acceptable anion. In compounds (IA) (currently) preferably, when the ring a is (i) optionally substituted phenyl in which optional substituents selected from alkoxy, halogen, in particular fluorine or chlorine, C1-C6-alkyl, amino-C1-C3-acyl, amino-C1-C3-alkyl and aminosulfonyl, or (ii) a phenyl ring fused with heterocyclization where geteroseksualnoe ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms, such as dihydrobenzofuranyl.

Another preferred subclass of compounds related to the present invention consists of compounds of formula (IB)

where ring b is an optionally substituted phenyl ring or a monocyclic heterocyclic ring of 5 or 6 ring atoms, or aryl ring condensed with heterocyclization; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7, provided that s+t is not greater than 10; Y is a tie the or-O-, and X-represents a pharmaceutically acceptable anion. In the compounds (IB) (currently) preferably, when the ring represents (i) optionally substituted phenyl in which optional substituents selected from alkoxy, halogen, in particular fluorine or chlorine, C1-C6-alkyl, amino-C1-C3-acyl, amino-C1-C3-alkyl and aminosulfonyl, or (ii) a phenyl ring fused with heterocyclization where geteroseksualnoe ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms, such as dihydrobenzofuranyl.

In both subclasses (IA) and (IB) (amount) s+t can be equal, for example, 1, 2, 3, 4, 5, 6 or 7, or it may be the result of appropriate combinations of t and s, such as when t is equal to 0, 1, 2, 3, 4, 5 or 6 and s is 1, 2, 3, 4, 5, 6 or 7. In compounds (IA) and (IB), (currently) preferred a combination of t, Y and s is a combination, when t is 0, s is 3, and Y represents-O-. Another preferred combination is the combination, when Y is a bond and the sum of s+t is equal to 2, 3 or 4.

In both subclasses (IA) and (IB), as for the compounds of the present invention, in General, preferred compounds are mainly in the anti-endo-configuration.

Examples of compounds of the present invention include the compounds of examples, presented in the description. Preferred compounds of the present invention include:

anti-2-(biphenyl-2-ylcarbamate)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium salt,

anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenylpropyl)ammonium salt,

anti-(±)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenylpropyl)ammonium salt,

anti-(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium salt,

anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylphenethylamine salt,

anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(4-phenylbutyl)ammonium salt,

anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]trimethylammonium salt,

(2-benzyloxyethyl)-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylammonium salt,

anti-(1S,2R)-2-(2-hydroxy-2,2-diphenylacetate)bicyclo[2.2.1]-hept-7-yl]dimethyl-(3-phenoxypropan)ammonium salt,

anti-(1S,2R)-dimethyl-(3-phenoxypropan)-[2-(N-xanthene-9-carbonyloxy)bicyclo[2.2.1]hept-7-yl]ammonium salt,

anti-(1S,2R)-2-(9-hydroxy-N-xanthene-9-carbonyloxy)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium salt,

anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-iliceto the si)bicyclo[2.2.1]hept-7-yl]indan-2-ultimatemenu salt,

(benzylcarbamoyl)-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylammonium salt,

[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylammonium salt.

As mentioned above in the section “Prior art”, in connection with a double (dual) activity of M3 receptor antagonist and agonist β2-adrenergic receptors are known, and the treatment of respiratory diseases such compounds with dual activity is a recognized form of treatment. A well-known strategy of providing compounds such mechanisms dualistic activity is the formation of a simple covalent bond between the compound with the activity of M3 receptor antagonist and a compound with the activity of the agonist β2-adrenergic receptors. Such covalent conjugates of compound (I), agonist of the receptor M3, as defined and discussed above, and agonist β2-adrenergic receptors are also part of the present invention. For instance, such conjugates with dual activity include compounds of formula (I), as defined and discussed above, modified by replacing the group R2group-L-B, where L represents a moiety-linker and is a part with the activity of the agonist β2-adrenergic is eceptor. In a structural sense, such conjugates with dual activity can be represented by formula (III):

where R1, R2and R4such as defined and discussed above in relation to compounds (I) of the present invention, L is divalently radical-linker and is a part with the activity of the agonist β2-adrenergic receptors, as, for example, pharmacophor, β2agonist mentioned above in the section “Prior art”. Such compounds (III) are another aspect of the present invention. An example of such a compound is the compound of example No. 41 in the present description.

In addition, the present invention relates to pharmaceutical compositions containing, as active ingredient, a compound of the present invention. Other compounds can be combined with the compounds of the present invention for the prevention and treatment of inflammatory lung diseases. Thus, the present invention also relates to pharmaceutical compositions for the prevention and treatment of disorders of the respiratory tract such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic obstruction of the respiratory tract, pneumosclerosis, emphysema and allergic rhinitis, is holding a therapeutically effective amount of the compounds of the present invention and one or more other therapeutic agents.

Other compounds can be combined with the compounds of the present invention for the prevention and treatment of inflammatory lung diseases. Accordingly, the present invention includes a combination tool of the present invention, described above, with one or more anti-inflammatory agents, bronchodilators, antihistamines, protivostoyanie or antitussive funds, these funds according to the present invention described above, and these combined means are in the same composition or different compositions, administered separately or simultaneously. Preferred combinations usually have two or three different pharmaceutical compositions. Suitable therapeutic agents for a combination therapy, along with the compounds of the present invention, include:

one or more other bronchodilators, such as PDE3 inhibitors;

methylxanthines, such as theophylline;

other antagonists of muscarinic receptor;

corticosteroid, for example, fluticasone propionate, ciclesonide, mometazon furoate or budesonide, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679, WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920;

non-steroidal agonist receptor glucocorticoid;

agonist β2-adrenergic receptors, n is the sample, albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, piqueteros, GSK-159797, GSK-597901, GSK-159802, GSK-64244, GSK-678007, TA-2005, as well as connections EP 1440966, JP 05025045, WO 93/18007, WO 99/64035, US 2002/0055651, US 2005/0133417, US 2005/5159448, WO 00/075114, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/70490, WO 02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO 04/16578, WO 04/016601, WO 04/22547, WO 04/32921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618, WO 04/46083, WO 04/71388, WO 04/80964, EP 1460064, WO 04/087142, WO 04/89892, EP 01477167, US 2004/0242622, US 2004/0229904, WO 04/108675, WO 04/108676, WO 05/033121, WO 05/040103, WO 05/044787, WO 04/071388, WO 05/058299, WO 05/058867, WO 05/065650, WO 05/066140, WO 05/070908, WO 05/092840, WO 05/092841, WO 05/092860, WO 05/092887, WO 05/092861, WO 05/090288, WO 05/092087, WO 05/080324, WO 05/080313, US 20050182091, US 20050171147, WO 05/092870, WO 05/077361, DE 10258695, WO 05/111002, WO 05/111005, WO 05/110990, US 2005/0272769, WO 05/110359, WO 05/121065, US 2006/0019991, WO 06/016245, WO 06/014704, WO 06/031556, WO 06/032627, US 2006/0106075, US 2006/0106213, WO 06/051373, WO 06/056471;

a leukotriene modulator, e.g., montelukast, zafirlukast or pranlukast; protease inhibitors, such as inhibitors of matrix metalloprotease, for example, MMP12 and TACE inhibitors, such as marimastat, DPC-333, GW-3333;

inhibitors of human elastase of neutrophil, such as sivelestat, and the inhibitors described in WO 04/043942, WO 05/021509, WO 05/021512, WO 05/026123, WO 05/026124, WO 04/024700, WO 04/024701, WO 04/020410, WO 04/020412, WO 05/080372, WO 05/082863, WO 05/082864, WO 03/053930;

inhibitors of phosphodiesterase-4 (PDE4), for example, roflumilast, arofylline, cilomilast, ONO-6126 is whether IC-485;

inhibitors of phosphodiesterase-7;

antitussive agent, such as codeine or dextromorphan;

kinase inhibitors, in particular inhibitors of Martinez R;

antagonists RH;

inhibitors of INOS;

non-steroidal anti-inflammatory drug (NSAID)such as ibuprofen or Ketoprofen;

receptor antagonist dopamine;

inhibitors of TNF-α, for example, monoclonal antibodies against TNF, such as Remicade and CDP-870, and immunoglobulin molecules of the TNF receptor, such as Enbrel;

A2A agonists, such as agonists, described in EP 1052264 and EP 1241176;

the A2b antagonists such as antagonists described in WO 2002/42298;

modulators of the function of the receptor of the chemokine, for example, antagonists of CCR1, CCR2, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235, SB-656933, SB 265610, SB 225002, MCP-1(9-76), RS-504393, MLN-1202, INCB-3284;

compounds that modulate the action of prostanoid receptors, for example, PGD2(DP1 or CRTH2), or antagonist of the thromboxane A2for example, ramatroban;

compounds that modulate the function of Th1 or Th2, for example, agonists of PPAR;

antagonists of the receptor for interleukin 1, such as Kineret;

agonists of interleukin 10, such as Ilodecakin;

inhibitors of HMG-CoA reductase (statins); for example, rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin;

regulators mucus, such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI 1956, gefitinib;

antibacterial (antibiotic and antiviral and antiallergic drugs, including, but not limited to, antihistamines.

The mass ratio of the first and second active ingredients may vary and generally depends on the effective dose of each ingredient. Usually usually use effective dose of each ingredient.

Any suitable route of administration may be used for delivery to a mammal, particularly a human, an effective dose of the compounds of the present invention. For therapeutic use, the active compound may be administered in any convenient, appropriate or effective way. Suitable routes of administration known to experts in the art and include oral, intravenous, rectal, parenteral, local, ocular, nasal, (TRANS)buccal and lung.

The magnitude of prophylactic or therapeutic dose of the compounds of the present invention is usually, of course, varies depending on a number of factors, including the activity of the specific compound, pontegadea use, age, body weight, diet, General health, and sex of the patient, time of administration, route of administration, rate of excretion, the use of any other drugs and the severity of the disease, pantiederection. In General, the range of the daily dose in the case of the introduction of inhalation is usually in the range from about 0.1 μg to about 10 mg per kg of body weight of the person, preferably from 0.1 μg to about 0.5 mg / kg and more preferably from 0.1 μg to 50 μg per kg for a single dose or in small doses (which together constitute the daily dose), repeated at intervals of time. On the other hand, in some cases it may be necessary to use dosages outside the above values. Compositions suitable for administration by inhalation, known and may include carriers and/or diluents, which are known for use in such compositions. The composition may contain from 0.01 to 99 wt.% active compounds. Preferably, the standard dose includes an active compound in an amount of from 1 μg to 10 mg For oral administration suitable dosage range from 10 μg / kg to 100 mg / kg, preferably from 40 μg / kg up to 4 mg per kg

Another aspect of the present invention provides pharmaceutical compositions that contain the compound of the present invention and a pharmaceutically acceptable carrier. The term “composition”, as in pharmaceutical composition, as is implied covers product containing the active ingredient(s) and the inert ingredient(s) (pharmaceutically pickup is acceptable fillers), which is the media, as well as any product which is, directly or indirectly, the result of the combination, complexation or aggregation of any two or more ingredients, or the dissociation of one or more ingredients, or the result of other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition obtained by mixing the compounds of the present invention, additional active ingredient(s) and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprise as active ingredient a compound of the present invention or its pharmaceutically acceptable salt and can also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients (tools). The term “pharmaceutically acceptable salt” refers to salts derived from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids, and salts of Quaternary ammonium compounds with pharmaceutically acceptable counterions.

In the case of delivery by inhalation, the active compound is n edocfile in the form of microparticles. They can be obtained by various methods, including spray drying, freeze drying and turning into microscopic powder.

As an example, the composition of the present invention can be obtained in the form of suspension for the delivery of a spray or aerosol form in a liquid propellant, for example, for use under pressure, capable of normalized desopadec, the inhaler (PMDI). Propellants suitable for use in PMDI, well-known experts in this field and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl2F2) and HFA-152 (C2H4F2and isobutane.

In the preferred embodiment (implementation) of the invention composition according to the invention is in dry powder form, for delivery, which is used as a dry powder inhaler (DPI). There are various types DPI.

Microparticles for delivery through the introduction can be introduced into the composition (drug) together with fillers that contribute to their delivery and release. For example, in the preparation of a dry powder microparticles can be formulated together with the carrier (high level) particles of media that contribute to the traffic flow of the DPI in the lung. Suitable carrier particles are known and include particles of lactose; they may have an average aerodynamic diameter is the Tr is greater than 90 microns.

In the case of the drug on the basis of an aerosol, for example, he has the composition:

The connection according to the invention24 mg/tank
Lecithin, NF Liq. Conc.1.2 mg/tank
Trichlorofluoromethane, NF4,025 g/tank
DICHLORODIFLUOROMETHANE, NF12,15 g/tank

The active compounds can be dosed as described, depending on the system used an inhaler. In addition to the active compounds (drug) forms for administration can optionally contain fillers such as, for example, propellants (e.g., Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (diluents) (e.g. lactose in the case of dry powder inhalers) or, if appropriate, other active compounds.

Inhalation is available to a large number of systems with which can be generated and injected aerosols with optimal particle size, using the method of inhalation, which is suitable for the patient. In addition to the use of adaptors (spacers parts, dilating) the pear-shaped containers (e.g., Nebulator®, Volumatic®), and automatic devices emitting a drug aerosol (Autohaler®), for metered (calibrated) aerosols, in particular, in the case of powder inhalers, there are a number of technical solutions (for example, Diskhaler®, Rotadisk®, Turbohaler® or inhaler, for example, described in EP-A-0505321). In addition, the compounds of the present invention can be delivered using multiple devices, allowing delivery of the combined drugs.

Methods synthesis

Compounds of the present invention can be obtained according to the methods represented by the following schemes and examples, using appropriate substances, and further illustrated by the following specific examples. In addition, using the methods disclosed in the description in the disclosure of the invention, the person skilled in the art can easily obtain additional compounds claimed in the present invention. But we should not assume that the compounds illustrated in the examples, constitute the only class of compounds, which is offered in the form of the invention. In addition, the examples illustrate the details of obtaining compounds of the present invention. Specialists in the art it is obvious that to obtain these compounds can be is used known variations of the conditions and the modalities for the following preparative methods of obtaining.

Compounds of the present invention can be isolated in the form of their pharmaceutically acceptable salts, such as salts, described in the present description earlier.

It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediate products used to produce compounds of the present invention, to avoid their unwanted participation in the interaction leading to the formation of compounds. In this regard, can be used a conventional protective group, for example, the groups described by T.W. Greene and P.G.M. Wuts, “Protective groups in organic chemistry”, John Wiley and Sons, 1999.

Compounds of the present invention can be obtained according to the routes illustrated in scheme 1.

The compounds of formula (I-a) and (I-b), where Ra, Rband Rcand Rdare as defined for R1, R2, R3and R4in the compounds of formula (I)can be obtained from compounds of the formula (II-a) or (II-b):

by interacting with the compound of the formula (III-a):

Rc-X (III-a),

where X represents a removable group, such as halogen, tosylate, mesilate. The interaction can be implemented in a number of solvents, such as acetonitrile, chloroform, DMF or DMSO, neobythites is but in the presence of a tertiary amine base, such as DIPEA, at a temperature in the range from 0°C to the boiling point of the solvent, preferably from ambient temperature to boiling point of solvent.

The compounds of formula (II-a) and (II-b), where Ra, Rband Rdare as defined for R1, R2and R4in the compounds of formula (I)can be obtained from compounds of the formula (II-a) or (II-b), where Rbrepresents H, by reacting with the compound of the formula (III-b):

Rb-CHO (III-b)

in the presence of a suitable reducing agent such as borohydride metal, in particular, triacetoxyborohydride sodium. The interaction can be implemented in a number of solvents, such as 1,2-dichloroethane, chloroform, dichloromethane, alcohols, optionally in the presence of acid, such as acetic acid, at a temperature from 0°C to the boiling point of the solvent, preferably from 0°C. to ambient temperature. The compounds of formula (III-a) and (III-b) are well known in this field and are readily available or can be obtained by known methods.

Suitable methods of preparing compounds of the formula (II-a) or (II-b), where Rbrepresents H, include the interaction of (II-a) or (II-b), where Rbrepresents benzyl, with hydrogen in the presence of palladium on carbon or palladium hydroxide on carbon under Odesa solvents, such as methanol, ethanol, acetic acid, ethyl acetate and mixtures thereof. Alternatively, the interaction of (II-a) or (II-b), where Rbrepresents methyl or benzyl, 1-claritinclaritin in a suitable solvent, such as 1,2-dichloroethane, at the boiling temperature of the solvent, and then the subsequent interaction with methanol is the preferred method of preparing compounds of the formula (II-a) or (II-b), where Rbrepresents N.

The compounds of formula (II-a) and (II-b) exist in two enantiomeric forms, which can be separated by chiral preparative HPLC using conditions known to the specialists in the art and illustrated below. Alternatively, since the absolute configuration of the compounds (II-a) and (II-b) is dictated by the absolute configuration of the compounds (X) and (XV), respectively, and the compounds (X) and (XV) are known in the literature (see EP0074856A2), the specialist in the art it is obvious that the use of homochiral the original product can provide homochiral product specific stereochemistry.

The compounds of formula (II-a), where Rdrepresents a group of formula (a) and R6represents H, as defined above for formula (I)can be obtained from compounds of the formula (IV-a), where Raand Rbare as defined above, by the interaction between the ia with a compound of formula (V):

where R7a, R7bn and m are such as defined for formula (I), the interaction can be carried out in a number denuclearising organic solvents, such as DMF or toluene, at temperatures, preferably from 0°C. to boiling point of solvent.

The compounds of formula (V) are known in the art and are readily available or can be obtained by known methods.

The compounds of formula (II-a), where Rdrepresents a group of formula (b), defined above, can be obtained from compounds of the formula (IV-a) by reacting with the compound of the formula (VI):

where R8a, R8band R8csuch as defined for formula (I)and LG represents a removable group, for example, O-alkyl, halogen or 1-imidazolidinyl group. The interaction is carried out in the presence of a strong base, such as NaH, in a solvent such as toluene, THF or dichloromethane, in a temperature range, preferably from 0°C. to boiling point of solvent.

The compounds of formula (VI), where R8a, R8band R8csuch as defined for formula (I)and LG represents O-alkyl, halogen or 1-imidazolidinyl group can be obtained from compounds of formula (VII) by known methods.

Soedineniya (VII) are known in the art and readily available, or they can be obtained by known methods such as methods described in WO 01/04118.

The compounds of formula (II-a), where Rdrepresents a group of formula (C), defined above, can be obtained from compounds of the formula (IV-a) by reacting with the compound of the formula (VI-a):

where Ar2is as defined for formula (I)and LG represents a removable group, for example, O-alkyl, halogen or 1-imidazolidinyl group. The interaction is carried out in the presence of a strong base, such as NaH, in a solvent such as toluene, THF or dichloromethane, in a temperature range, preferably from 0°C. to boiling point of solvent.

The compounds of formula (VI-a), where R8dand R8csuch as defined for formula (I)and LG represents O-alkyl, halogen or 1-imidazolidinyl group can be obtained from compounds of formula (VII-a) by known methods.

The compounds of formula (VII-a) are known in the art and readily available, or they can be obtained by known methods.

The compounds of formula (II-a)in which Rdrepresents a group of formula (d), defined above, can be obtained from compounds of the formula (IV-a) by reacting with the compound of the formula (VI-b):

Interaction about the W ill result in the presence of a strong base, such as NaH, in a solvent such as toluene, THF, preferably DMSO, at temperatures preferably from 0°C. to boiling point of solvent.

The compounds of formula (VI-b) are known in the art and readily available, or they can be obtained by known methods.

The compounds of formula (IV-a) can be obtained from compounds of formula (VIII-a) by reacting with a suitable reducing agent, preferably a reducing agent with the three-dimensional structure, such as LiAlH(OtBu)3. The interaction is carried out in a polar organic solvent, preferably THF, at temperatures preferably from -78°C to the boiling point of the solvent.

The compounds of formula (VIII-a) can be obtained from compounds of formula (IX-a) by reacting with tin-containing reagent, preferably Bu3SnH, and a radical initiator, preferably AIBN. Interaction can be done in a number of solvents, preferably toluene, at temperatures preferably from ambient temperature to boiling point of solvent.

The compounds of formula (IX-a) can be obtained from compounds of formula (X) by reacting with an amine of formula (XI):

RaRbNH (XI).

The interaction is carried out in a number of solvents, preferably a mixture of THF/DHM, in the preferred temperature range is compulsory from 0 to 100°C.

The compounds of formula (X) are known in the art: J. Chem. Soc. Perkin Trans 1 (1975) 1767-1773; Synthesis (1997), 155-166.

The compounds of formula (XI) are known in the art, and they can be obtained by known methods or are commercially available.

The compounds of formula (I-b) can be obtained from compounds of the formula (II-b) in a manner analogous to the formation of compounds of formula (I-a) of the compounds of the above formula (II-a). The compounds of formula (II-b) can be obtained from compounds of formula (XII-b) by reacting with tin-containing reagent, preferably Bu3SnH, and a radical initiator, preferably AIBN. Interaction can be done in a number of solvents, preferably toluene, at temperatures preferably from ambient temperature to boiling point of solvent.

The compounds of formula (XII-b) can be obtained from compounds of the formula (IV-b) by reacting with brainwashin agent, preferably triphenylphosphine in tetrabromide carbon as a solvent.

The compounds of formula (IV-b) can be obtained from compounds of formula (XIII-b) by reacting with a suitable reducing agent, preferably sodium borohydride. The interaction is carried out in a polar organic solvent, preferably THF, at temperatures preferably from -78°C. to a temperature which tours the boiling point of the solvent.

The compounds of formula (XIII-b) can be obtained from compounds of formula (XIV-b) by methods similar to the methods used to obtain compounds of the formula (II-a) from compounds of formula (IV-a).

The compounds of formula (XIV-b) can be obtained from compounds of formula (XV):

by interacting with the amine of formula (XI). The interaction is carried out in a number of solvents, preferably a mixture of THF/DHM, in the temperature range preferably from 0 to 100°C.

The compounds of formula (XV) are described in UK patent 2075503.

Obtaining compounds of formula (I)in which a represents a group-NR-, in General terms, is presented in scheme 2.

The compounds of formula (XVI-a) can be obtained from compounds of formula (XVII-a) by methods similar to those used to obtain the compounds of formula (I-a) from compounds of formula (II-a).

The compounds of formula (XVII-a) can be obtained from compounds of formula (XVIII-a) processing ORGANOMETALLIC reagent of formula (XXI-a):

R-M (XXI-a),

where M is a type of metal, such as Li or Mg-halide, in particular, the Grignard reagent, in a suitable inert solvent such as THF or diethyl ether, at a temperature in the range from -78° to the boiling point of the solvent, preferably from 0° to tempera is URS the environment. The compounds of formula (XXI-a) are known in the art or can be obtained according to known methods.

The compounds of formula (XVIII-a) can be obtained from compounds of formula (XIX-a):

where X represents a removable group, especially the group of halogen, optionally in the presence of a suitable solvent, such as dichloromethane, in the absence or in the presence of a base, such as diisopropylethylamine. The compounds of formula (XIX-a) are commercially available, or easily get in line with the literature.

The compounds of formula (XIX-a) can be obtained from compounds of formula (XX-a) by the reduction of oxime with a suitable reducing agent, such as borhydride reagent, in particular, NaBH4/NiCl2, in a suitable solvent, such as methanol, at a suitable temperature such as 20°C.

The compounds of formula (XX-a) can be obtained from compounds of formula (VIII-a) by treatment with hydroxylamine or its salt in the presence of a suitable solvent, such as methanol, optionally in the presence of a base such as sodium acetate, at a temperature in the range from 0°C to the boiling point of the solvent, preferably at ambient temperature.

The following non-limiting examples illustrate the present invention.

About the s experimental details

All communication is carried out in nitrogen atmosphere, unless otherwise specified.

In cases where the products were subjected to purification using column chromatography, 'flash silica' refers to silica gel for chromatography, particle size of from 0.035 to 0,070 mm (220 to 440 mesh) (for example, silica gel Fluka 60)applied nitrogen pressure up to 10 p.s.i. (psi) accelerated elution column. In those cases, when used thin-layer chromatography (TLC), it refers to the use of plates intended for TLC-coated silica gel, typically 3×6 cm of silica gel on the plates of aluminum foil with a fluorescent indicator (254 nm) (e.g., Fluka 60778). All solvents and commercial reagents were used as the common.

All compounds containing the main(s) room(s), which was purified by HPLC, was received in the form of a salt of TN, unless agreed otherwise.

Conditions preparative HPLC

The HPLC system 1

Column reversed-phase C18 (column Genesis 100×22.5 mm VND, particle size 7 μm), elution gradient: water + 0.1% of TN; b: acetonitrile + 0.1% of TN a flow rate of 5 ml/min and a gradient of 1%/min increase in C. UV detection at 230 nm.

The HPLC system 2

Column filled with phase containing grafted phenylhexane group (column Luna 250×21,20 mm, particle size 5 μm), Grady is ntoe elution with a mixture of solvent A: water + 0.1% of TN; In: acetonitrile + 0.1% of TN a flow rate of 5 ml/min with UV detection at 254 nm.

System LC/MS

Used combined methods of analysis, system combining liquid chromatography and mass spectrometry (LC/MS).

Method LC-MS 1

The combination of a mass spectrometer Micromass Platform LCT with column reversed-phase C18 (Higgins Clipeus 100×3.0 mm, particle size 5 μm), elution with a mixture of solvent A: water + 0.1% of formic acid; b: acetonitrile + 0.1% of formic acid. Gradient:

The gradient-TimeFlow ml/min%%
0,001,0955
1,001,0955
15,001,0595
20,001,0595
22,001,0955
25,00/td> 1,0955
Detection - MS, ELS (scattering in the vapor phase), UV (100 μl are taken and sent to MS, with built-in UV detector)
MS ionization method - elektrorazpredelenie (in registration mode positive ion)

Method LC-MS 2

The combination of a mass spectrometer Micromass Platform LCT with column reversed-phase C18 (Phenomenex Luna 30×4.6 mm, particle size 3 μm), elution with a mixture of solvent A: water + 0.1% of formic acid; b: acetonitrile + 0.1% of formic acid. Gradient:

The gradient-TimeFlow ml/min%%
0,002,0955
0,502,0955
4,502,0595
5,502,0595
6,00 2,0955
Detection - MS, ELS, UV (100 μl are taken and sent to MS, with built-in UV detector)
MS ionization method - elektrorazpredelenie (in the registration mode, the positive and negative ions)

Method LC-MS 3

The combination of a mass spectrometer (Waters Micromass ZQ with column reversed-phase C18 (Phenomenex Luna 30×4.6 mm, particle size 3 μm), elution with a mixture of solvent A: water + 0.1% of formic acid; b: acetonitrile + 0.1% of formic acid. Gradient:

The gradient-TimeFlow ml/min%%
0,002,0955
0,502,0955
4,502,0595
5,502,0595
6,002,0 955
Detection - MS, ELS, UV (100 μl are taken and sent to MS, with built-in UV detector)
MS ionization method - elektrorazpredelenie (in the registration mode, the positive and negative ions)

Method LC-MS 4

The combination of a mass spectrometer (Waters Micromass ZQ with column reversed-phase C18 (Higgins Clipeus C18, 5 μm, 100×3.0 mm or equivalent), elution with a mixture of solvent A: water + 0.1% of formic acid; b: acetonitrile + 0.1% of formic acid. Gradient:

The gradient-TimeFlow ml/min%%
0,001,0955
1,001,0955
15,001,0595
20,001,0595
22,001,095 5
25,001,0955
Detection - MS, ELS, UV (100 μl are taken and sent to MS, with built-in UV detector)
MS ionization method - elektrorazpredelenie (in the registration mode, the positive and negative ions)

Abbreviations used in the experimental section:

DHM = dichloromethane; THF = tetrahydrofuran; MeOH = methanol; EtOH = ethanol; DMSO = dimethylsulfoxide; EtOAc = ethyl acetate; DIPEA = diisopropylethylamine; EDCl = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP = dimethylaminopyridine; RT = ambient temperature; HATU = O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate; TN = triperoxonane acid; Rt = retention time; feast upon. = rich.

EXAMPLE 1

7-dimethylaminomethyl[2.2.1]hept-2-silt ether (±)-anti-biphenyl-2-ylcarbamate acid (II-a): RaRb= CH3Rd= biphenyl-2-ylcarbonyl

A. (±)-anti-5-bromo-7-dimethylamino-bicyclo[2.2.1]heptane-2-he (IX-a): RaRb= CH3

To a cooled (-10°C.) solution of (±)-2,3-dibromobicyclo[3.2.0]heptane-6-she DHM (20 ml) is added dropwise a solution of dimethylamine (2 M, 8,23 ml, 16.5 mmol) in the THF. The reaction mixture provide the ability to slowly warm to ambient temperature over several hours. After 17 hours the reaction mixture was concentrated and the residue is dissolved in Et2O and filtered. The filtrate absorb on diatomaceous earth and chromatographic on a column of silica gel, elwira a mixture of 25% Et2O in pentane, getting 0.88 g (58%) indicated in the title product as an orange solid.1H-NMR (CDCl3, 400 MHz): δ 1,70 (1H, DDD, J=14,2 Hz and 4.4 Hz, 1.3 Hz), to 2.18 (6H, s), 2,2 (1H, m), 2,47 (1H, d, J=1.2 Hz), 2,60 (1H, d, J=4,8 Hz), 2,80 (3H, m), of 4.66 (1H, m).

b. (±)-anti-7-dimethylaminomethyl[2.2.1]heptane-2-it. (VIII-a): RaRb= CH3

Toluene, before interaction, is subjected to degassing by energetic ozonation (inert) gas, nitrogen for 30 minutes. To (±)-5-bromo-7-dimethylaminomethyl[2.2.1]heptane-2-ONU (200 mg, 0.75 mmol) and azoisobutyronitrile (12 mg, 0.07 mmol) under nitrogen atmosphere add degassed toluene (8 ml). To the solution add tributyltinhydride (221 μl, 0.82 mmol) and the solution stirred under nitrogen atmosphere at 80°C for 1 hour. Add a solution of tributyltinhydride (30 μl, 0.11 mmol) in toluene (300 ml) and a few flakes of azoisobutyronitrile and the reaction mixture is heated at 80°C for 1.5 hours. The reaction mixture is evaporated, the floor is th 0.5 g of a yellow liquid, which chromatographic on a column of silica gel, elwira pentane, then a mixture of 20% Et2O in pentane up to 100% Et2O, receiving a colorless oil, 214 mg (>100%, pollution remains of the tin). TLC: Rf 0.25 in (a blend of 50% Et2O in pentane);1H-NMR (CDCl3, 400 MHz): including signals for the remainder of tin. δ of 0.90 (3H, t, J=7.4 Hz), of 1.35 (6H, m)to 1.61 (2H, m)to 1.98 (2H, m), is 2.09 (2H, m)to 2.18 (6H, in), 2.25 (1H, s), 2,53 (1H, t, J=4.4 Hz), 2,58 (1H, d, J=4,8 Hz).

C. (±)-anti-7-dimethylamino-bicyclo[2.2.1]heptane-2-ol. (IV-a): RaRb= CH3

To a cooled (-10°C.) solution of (±)-7-dimethylaminomethyl[2.2.1]heptane-2-she (214 mg, ≤0.75 mmol) in THF (4 ml) is added tri-tert-butoxyaniline lithium (380 mg, 1,49 mol). The reaction mixture was stirred at 0°C for 1.5 hours and then add the other portion of the three-tert-butoxycarbonylamino lithium (190 mg, 0.75 mol) and the reaction mixture is stirred for another 1.5 hours. The reaction mixture was diluted with DHM and directly evaporated (concentrate) on diatomaceous earth and chromatographic on a column of silica gel, elwira a mixture of 5% MeOH in DHM and later in the gradient from 2.5% MeOH 20% MeOH in DHM, receiving 120 mg (100%) specified the title product as a white solid.1H-NMR spectroscopy indicates that the solid is a mixture of 93:7 specified in the header of the product and its (±)-2-EPI-isomer. Isomers are not separated. TLC: Rf 0,1 (75% Et2O in pentane);1H-NMR (d4-MeOH, 400 MHz): δ 0,96 (1H, DD, J=4.0 Hz, 13,2 Hz), 1,31 (1H, m), and 1.56 (1H, m), of 1.80 (1H, m)of 1.93 (1H, m), a 2.01 (1H, m), 2,17 (1H, m), 2,28 (8H, s), 4,14 (1H, m).

d. 7-dimethylaminomethyl[2.2.1]hept-2-silt ether (±)-anti-biphenyl-2-ylcarbamate acid

To a solution of (±)-7-dimethylamino-bicyclo[2.2.1]heptane-2-ol (120 mg, 0.75 mmol) in DMF (1.5 ml) and toluene (0.5 ml) add a quantity of powdered molecular sieves 3Å and 2-biphenylmethanol (189 mg, 0.97 mmol). The reaction mixture was stirred at 50°C for 15,5 hours and then diluted with EtOAc and washed twice with water, then with saturated salt solution, dried (Na2SO4), filtered and evaporated, getting 358 mg of colorless syrup. The resulting syrup is purified on a column of silica gel, elwira a mixture of 2-4% MeOH in DHM, receiving two fractions (143 mg) with different purity. Collected more pure fraction (91 mg) re chromatographic on a column of silica gel, elwira a mixture of 80% Et2O in pentane, receiving three factions, the most pure of them contains specified in the title compound, containing no (±)-2-EPI-isomer, 42 mg (16%). TLC: Rf Of 0.2 (100% Et2O in pentane); LC-MS (method 1): Rt 6,99 min, m/z 351 [MH]+;1H-NMR (CDCl3, 400 MHz): δ 1,11 (1H, DD, J=3,6 Hz to 13.6 Hz), 1,25 (1H, m)of 1.62 (2H, m)and 1.83 (1H, m), is 2.05 (2H, m), 2,13 (1H, t, J=4.4 Hz), 2,18 (6, C)of 2.56 (1H, m), of 4.95 (1H, m), 6,60 (1H, users), 7,13 (1H, dt, J=1.2 Hz, 7.4 Hz), 7,22 (1H, DD, J=1.6 Hz and 7.6 Hz), 7,33-7,44 (4H, m), 7,49 (2H, m), of 8.09 (1H, d, J=8.0 Hz).

EXAMPLE 2

7-dimethylaminomethyl[2.2.1]hept-2-silt ether (±)-anti-biphenyl-2-ylcarbamate acid (II-a): RaRb= CH3Rd= biphenyl-2-ylcarbonyl (first eluting enantiomer)

Specified in the title compound emit after preparative chiral HPLC of example 1 (Chiralpac IA, 250×20 mm VND; a mixture of 12% tert-butyl methyl ether/heptane/0.25% diethylamine; 14 ml/min; Rt of 20.6 minutes). LC-MS (method 1): Rt 7,03, m/z 351,2 [MH]+; NMR, as for example 1.

EXAMPLE 3

7-dimethylaminomethyl[2.2.1]hept-2-silt ether anti-biphenyl-2-ylcarbamate acid (II-a): RaRb= CH3Rd= biphenyl-2-ylcarbonyl (second eluting enantiomer)

Specified in the title compound emit after preparative chiral HPLC of example 1 (Chiralpac IA, 250×20 mm VND; a mixture of 12% tert-butyl methyl ether/heptane/0.25% diethylamine; 14 ml/min; Rt 24 minutes). LC-MS (method 1): Rt 7,07, m/z 351,2 [MH]+; NMR, as for example 1.

EXAMPLE 4

(±)-anti-[2-(biphenyl-2-ylcarbamate)bicyclo[2.2.1]hept-7-yl]ammonium iodide (I-a): RaRbRc= CH3R d= biphenyl-2-ylcarbonyl

A solution of 7-dimethylaminomethyl[2.2.1]hept-2-silt ether (±)-biphenyl-2-ylcarbamate acid methyliodide (2.5 ml) was stirred at 40°C for 21 hours. The reaction mixture is evaporated and the resulting solid chromatographic on a column of silica gel, elwira a mixture of 10% Meon in DHM, receiving 61 mg (41%) indicated in the title compound in the form of a solid of light yellow color. LC-MS (method 3): Rt 2.2 min, m/z 365 [M]+; LC-MS (method 1): Rt 7,16 minutes, m/z 365 [M]+;1H-NMR (CDCl3, 400 MHz): δ 1,13 (1H, DD, J=3.2 Hz, to 13.6 Hz), 1,60 (1H, m), is 1.81 (1H, m)to 1.99 (2H, m)to 2.06 (1H, s)to 2.41 (1H, m), 2,78 (1H, s), 3,11 (1H, t, J=3.8 Hz), 3,52 (9H, s)4,00 (1H, s), 5,02 (1H, m), 6,63 (1H, C)7,13 (1H, dt, J=0.8 Hz, 7.2 Hz), 7,22 (1H, DD, J=1.6 Hz, 8.0 Hz), 7,31-7,51 (6H, m), 7,95 (1H, d, J=6,4 Hz).

EXAMPLE 5

7-dimethylaminomethyl[2.2.1]hept-2-silt ether (±)-SYN-biphenyl-2-ylcarbamate acid (II-b): RaRb= CH3Rd= biphenyl-2-ylcarbonyl

A.(±)-7-dimethylamino-5-hydroxybenzyl[2.2.1]heptane-2-it. (XIV-b): RaRb= CH3

A solution of dimethylamine (2.0 M, 24 ml, 48 mmol) in THF are added to a solution of 2-Brambilla[3.2.0]heptane-3-ol (4,00 g of 19.5 mmol) in acetone (40 ml) at 0°C and the mixture provide an opportunity to warm to ambient temperature during the AI 1 hour and stirred at ambient temperature over night. The orange solution is filtered and the filtrate evaporated to dryness. Cleaning perform column chromatography on silica gel using a mixture of 5% Meon in DHM, receiving a 3.01 g (91%) of product as a yellowish brown powder. LC-MS (method 2): Rt 0,37 minutes, m/z 170,09 [MH]+.

b. 7-dimethylamino-5-oxobicyclo[2.2.1]hept-2-silt ether (±)-SYN-biphenyl-2-ylcarbamate acid (XIII-b): RaRb= CH3Rd= biphenyl-2-ylcarbonyl

2-biphenylmethanol (90 μl, 0.52 mmol) are added to a solution of 7-dimethylamino-5-hydroxybenzyl[2.2.1]hept-2-she (90 mg, of 0.53 mmol) in toluene (1 ml) and the mixture is heated at 70°C over night. The solvent is removed in vacuo and the residue purified column chromatography using 100% DHM, and then a mixture of 1% Meon in DHM, receiving the product as a white powder, 144 mg (75%). LC-MS (method 1): Rt 6,50 minutes, m/z 365,15 [MH]+.

c. 7-dimethylamino-5-hydroxybenzyl[2.2.1]hept-2-silt ether (±)-SYN-biphenyl-2-ylcarbamate acid (IV-b): RaRb= CH3Rd= biphenyl-2-ylcarbonyl

Sodium borohydride (25 mg, of 0.68 mmol) are added to a solution of 7-dimethylamino-5-oxobicyclo[2.2.1]hept-2-silt ether-biphenyl-2-ylcarbamate acid (200 mg, 0.55 mmol) in anhydrous Meon at 0°C and the mixture provide the opportunity for agresja to ambient temperature for 1 hour. The solvent is removed in vacuo and the residue purified column chromatography using 100% DHM, and then a mixture of 2% Meon in DHM getting 194 mg (97%) of product as a white powder. LC-MS (method 1): Rt of 6.31 min, m/z 367,16 [MH]+.

d. 5-bromo-7-dimethylaminomethyl[2.2.1]hept-2-silt ether (±)-SYN-biphenyl-2-yl-carbamino acid (XII-b): RaRb= CH3Rd= biphenyl-2-ylcarbonyl

A suspension of 7-dimethylamino-5-hydroxybenzyl[2.2.1]hept-2-silt ether-biphenyl-2-ylcarbamate acid (180 mg, 0.49 mmol), applied to the polymer of triphenylphosphine (2,18 mmol/g to 0.90 g, a 1.96 mmol), tetrabromomethane (1.56 g, 4,71 mmol) and imidazole (130 mg, at 1.91 mmol) in acetonitrile (4 ml) was gently stirred at 50°C over night. The solvent is removed in vacuo and the residue purified using HPLC (system 2: the flow rate of 18 ml/min, a gradient of the increase in 0.25%/min). The obtained Sol TN transformed into free base loading in the cartridge SCX-2, followed by elution with a mixture of NH3/MeOH, receiving 45 mg (21%) specified in the connection header. LC-MS (method 3): Rt 2.25 min, m/z 429,19/431,14 [MH]+.

E. 7-dimethylaminomethyl[2.2.1]hept-2-silt ether (±)-SYN-biphenyl-2-ylcarbamate acid

The solution tributyltinhydride (40 μl, 0.15 mmol) in anhydrous toluene (200 MK is) are added to a solution of 5-bromo-7-dimethylaminomethyl[2.2.1]hept-2-silt ether-biphenyl-2-ylcarbamate acid (45 mg, 0.10 mmol) and 2,2'-azobis(2-methylpropionitrile) (10 mg, 0.06 mmol) in anhydrous toluene (0.8 ml) at 50°C and stirring at 80°C for 40 minutes. The solvent is removed in vacuo and the residue purified using HPLC (system 2: the flow rate of 18 ml/min, a gradient of the increase in 4%/min. and UV detection at 210 nm). The obtained Sol TN make a free base, passing through the cartridge SCX-2, to obtain 28 mg (76%) specified in the connection header. LC-MS (method 1): Rt 7,18, m/z 351,19 [MH]+; (CDCl3) δ 1,09 (1H, m)of 1.36 (2H, m)of 1.66 (2H, m), 2,13 (1H, t, J=4.3 Hz), 2,24 (7H, s), of 2.34 (1H, m), of 2.54 (1H, t, J=4.0 Hz), 5,26 (1H, m), to 6.58 (1H, s), 7,11 (1H, TD, J=7,5, 1.2 Hz), 7,21 (1H, DD, J=7,5, 1,6 Hz), 7,34 (1H, m), 7,38 (2H, m), 7,41 (1H, m), 7,49 (2H, m), 8,11 (1H, d, J=8,2 Hz).

EXAMPLE 6

7-dimethylaminomethyl[2.2.1]hept-2-silt ether SYN-biphenyl-2-ylcarbamate acid (II-b): RaRb= CH3Rd= biphenyl-2-ylcarbonyl (first eluting enantiomer)

Specified in the title compound emit after preparative chiral HPLC of example 5 under the conditions described for example 2 (Rt 19 minutes). LC-MS (method 1): Rt 7,16 min, m/z 351 [MH]+; NMR, as for example 5.

EXAMPLE 7

7-dimethylaminomethyl[2.2.1]hept-2-silt ether SYN-biphenyl-2-ylcarbamate acid (II-b): RaRb= CH3Rd= biphenyl-2-icarbon is l (second eluting enantiomer)

Specified in the title compound emit after preparative chiral HPLC of example 5 under the conditions described for example 2 (Rt 20.4 minutes). LC-MS (method 1): Rt 7,14 min, m/z 351 [MH]+; NMR, as for example 5.

EXAMPLE 8

(±)-SYN-[2-(biphenyl-2-ylcarbamate)bicyclo[2.2.1]hept-7-yl]ammonium iodide (I-b): RaRbRc= CH3Rd= biphenyl-2-ylcarbonyl

Specified in the header of the get connection using the conditions described for an example 4. LC-MS (method 1): Rt 7,02, m/z 365 [M]+; (CDCl3) δ USD 1.43 (1H, m), 1,50 (1H, DD, J=15,1, and 3.8 Hz), of 1.78 (1H, m), a 1.88 (1H, m), 2,04 (1H, m), of 2.51 (1H, m), 2,73 (1H, t, J=4.0 Hz), 2,96 (1H, t, J=3,9 Hz), 3,54 (9H, s), or 4.31 (1H, s)5,33 (1H, m), of 6.65 (1H, C), 7,17 (1H, m), 7,25 (1H, m), 7,37 (3H, m), the 7.43 (1H, m)to 7.50 (2H, m), to 7.99 (1H, d, usher.).

The following examples receive in a manner analogous to the method described for example 1.

EXAMPLE 13

Anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium bromide (II-a): RaRc= IU, Rb= 3-phenylpropyl, Rd= 2.2-dateopen-2-RECETOX

A. Anti-(1S,2R)-7-(benzylmethylamine)bicyclo[2.2.1]heptane-2-ol

Specified in the title compound floor is given from (1S,2R,3R)-2,3-dibromobicyclo[3.2.0]heptane-6-it N-methylbenzylamine, using methods similar to the methods of example 1. LC-MS (method 2): Rt 0,76 minutes, m/z 232 [MH]+.

b. (1S,2R)-7-(benzylmethylamine)bicyclo[2.2.1]hept-2-silt ether anti-hydroxylation-2-luxusni acid

To a cooled (0°C.) solution of anti-(1S,2R)-7-(benzylmethylamine)bicyclo[2.2.1]heptane-2-ol (1 g, 4.3 mmol) is added dropwise sodium hydride (432 mg, 60% suspension in mineral oil, to 10.8 mmol). Mixtures provide an opportunity to warm up to ambient temperature for 10 minutes, then re-cooled to 0°C. are added in several Portions of ethyl ether hydroxylation-2-luxusni acid (1.39 g, 5.2 mmol) and the mixture is then heated at 80°C for 2 hours. After allowing the mixture to cool to ambient temperature, the reaction mixture was quenched with dropwise adding an aqueous ammonium chloride (feast upon. 50 ml), then extracted with ethyl acetate (3×100 ml). The combined organic layers dried over sodium sulfate, filtered and evaporated to a yellow oil. Purification with flash column silica gel, using as eluent a mixture of 5-10% ethyl acetate in hexane, then another flash column, using as eluent a mixture of 0-5% ethyl acetate in DHM, give 1.12 g (57%) indicated in the title compound as a yellow oil: LC-MS (method 2): Rt 2,44 minutes, m/z 454 [MH]+.

C. (1S,2R)-7-methylaminomethyl[2.2.1]hept-2-silt ether anti-hydroxylation-2-luxusni acid

To a solution of (1S,2R)-7-(benzylmethylamine)bicyclo[2.2.1]hept-2-silt ether anti-hydroxylation-2-luxusni acid (400 mg, 0.88 mmol) in 1,2-dichloroethane (5 ml) was added 1-chloroethylphosphonic (or 0.57 ml, 5.3 mmol) and the mixture is heated at 80°C for 8 hours. The solvent and excess 1-chloroethylphosphonic removed under reduced pressure, obtaining a yellow/brown oil. The oil obtained is again dissolved in methanol (5 ml) and stirred at ambient temperature for 1 hour, then evaporated, receiving a yellow foam. The residue is suspended in water (10 ml) and alkalinized using sodium hydroxide (0.1 N.), then extracted with ethyl acetate (4×20 ml). The combined organic layers dried over sodium sulfate, filtered and evaporated to dryness, obtaining a brown solid. Clean flash-chromatography on silica gel, using as eluent a mixture of 5-10% methanol in DHM, give 180 mg (56%) indicated in the title compound as a yellow solid: LC-MS (method 2): Rt 2,20 minutes, m/z 364 [MH]+.

d. (1S,2R)-7-[methyl-(3-phenylpropyl)amino]bicyclo[2.2.1]hept-2-silt ether anti-hydroxylation-2-luxusni acid

To a solution of (1S,2R)-7-methylaminomethyl[2.2.1]hept-2-silt ether anti-Hydra is xidation-2-luxusni acid (150 mg, 0.41 mmol) in 1,2-dichloroethane (10 ml) is added 3-phenylpropanal (55 μl, 0.41 mmol). The mixture was stirred at ambient temperature for 10 minutes, then add triacetoxyborohydride sodium (174 mg, 0.82 mmol) and the mixture was stirred at ambient temperature for 2 hours. Add aqueous sodium bicarbonate (feast upon. 10 ml) and the mixture is separated through a phase separation cartridge, washing the aqueous phase DHM. The combined organic layers evaporated, receiving a yellow oil. Clean flash-chromatography on silica gel, using as eluent a mixture of 0-10% ethyl acetate in DHM, give 150 mg (76%) indicated in the title compound: LC-MS (method 2): Rt to 2.65 min, m/z 482 [MH]+.

e. Anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenylpropyl)ammonium bromide

A solution of (1S,2R)-7-[methyl-(3-phenylpropyl)amino]bicyclo[2.2.1]hept-2-silt ether anti-hydroxylation-2-luxusni acid (150 mg, mol) in 30% wt./wt. a solution of bromide in acetonitrile (5 ml) is heated in a sealed tube for 3 days at 60°C. the Solvent is removed and the residue purified on a flash chromatography on silica gel, using as eluent a mixture of 5-10% methanol in DHM, receiving 100 mg (65%) indicated in the title compound as a white solid: LC-MS (method 1): Rt 8,43 mi is by Uta, m/z 496 [M]+;1H-NMR (DMSO, 400 MHz) δ 1,01 (1H, DD, J=13,4 Hz, 3.1 Hz), of 1.35 (1H, m), 1.69 in (2H, m), of 1.95 (1H, m), 2,04 (2H, m), 2,19 (1H, m), 2,61 (3H, m), with 2.93 (1H, ushort, J=3.5 Hz), of 3.07 (3H, s), 3,06 (3H, s), 3,39 (2H, m), of 3.53 (1H, s), 5,0 (1H, m), 7,01 (2H, m), 7,10 (2H, m), 7,22 (1H, m), 7,27 (2H, m), 7,32 (2H, m), 7,39 (1H, s), 7,51 (2H, m).

EXAMPLES 14 and 15

TRANS-1-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]-1-methyl-4-phenylpiperidine bromide and CIS-1-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]-1-methyl-4-phenylpiperidine bromide (II-a): NRaRb= piperidinyl, Rc= Me, Rd= 2.2-dateopen-2-RECETOX

A. (1S,2R)-7-(4-phenylpiperazin-1-yl)bicyclo[2.2.1]hept-2-silt ether anti-hydroxylation-2-luxusni acid

Specified in the title compound is obtained from (1S,2R,3R)-2,3-dibromobicyclo[3.2.0]heptane-6-she 4-phenylpiperidine, using methods similar to the methods of examples 1 and 13. LC-MS (method 2): Rt 2,60 minutes, m/z 494 [MH]+.

b. TRANS-1-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]-1-methyl-4-phenylpiperidine bromide and CIS-1-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]-1-methyl-4-phenylpiperidine bromide

Listed in the connection header is obtained from (1S,2R)-7-(4-phenylpiperazin-1-yl)bicyclo[2.2.1]hept-2-silt ether anti-hidroxidice the EN-2-luxusni acid, using a method similar to example 13, and then separated using column chromatography on silica gel, using as eluent a mixture of 5-15% methanol in DHM:

TRANS-1-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]-1-methyl-4-phenylpiperidine chloride: LC-MS (method 1): Rt 8,06 minutes, m/z 508 [M]+; (CDCl3) δ of 1.27 (1H, m), of 1.57 (1H, m), 1.77 in (1H, m)to 1.86 (1H, m)to 2.06 (3H, m), 2,20 (2H, d, J=15.3 Hz), is 2.40 (1H, m), 2,86 (1H, ushort, J=3,7 Hz), 3,03 (1H, ushort, J=3,7 Hz), 3,42 (1H, m), 3,61 (3H, s), the 3.65 (1H, d, J=13,6 Hz), 3,69 (1H, s), 3,82 (1H, d, J=13,6 Hz), 4,50 (2H, m), of 4.66 (1H, s), 5,16 (1H, m), 7,00 (2H, m), 7,17 (2H, m), 7.23 percent (2H, m), 7,26 (1H, m), 7,33 (4H, m).

CIS-1-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]-1-methyl-4-phenylpiperidine chloride: LC-MS (method 1): Rt 8,10 minutes, m/z 508 [M]+; (CDCl3) δ of 1.16 (1H, DD, J=13,8, 3.0 Hz), of 1.52 (1H, m), 1,72 (2H, m), of 2.08 (5H, m), 2,59 (1H, m), 2,86 (1H, ushort, J=4.0 Hz), to 3.09 (1H, m), 3,20 (1H, users), to 3.36 (3H, s), 3,82 (2H, d, J=12,2 Hz)to 3.99 (2H, t, J=12,2 Hz), 4,63 (1H, s), free 5.01 (1H, s), 5,32 (1H, m), of 6.96 (2H, m), 7,16 (2H, m), from 7.24 (5H, m), 7,31 (2H, m).

The following examples receive in a manner analogous to the method described for examples 13-14.

EXAMPLE 40

Anti-(1S,2R) 2-(2-hydroxy-2,2-diphenylethane)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropylamine bromide

A. 2-{anti-(1S,2R)-7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-yloxy}-1,1-diphenylethanol

A solution of anti-(1S,2R)-7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]heptane-2-ol (177 mg, 0.64 mmol) in 5 ml of DMSO is stirred in nitrogen atmosphere at ambient temperature. Add a dispersion of sodium hydride (45 mg, 60% dispersion in oil) and the reaction mixture is heated to 70°C for 60 minutes before cooling to 50°C. the anion added 1,1-diphenylethylene (256 mg, 1,31 mmol) and continue heating for 60 minutes. The reaction mixture was cooled to ambient temperature, quenched by addition of water, extracted into EtOAc and the combined organic extracts washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The reaction mixture is purified by chromatography on silica gel, using as eluent a gradient of 0-15% Et2O-cyclohexane, receiving the product as a clear oil (22 mg). LC-MS (method 3): Rt 2,62 minutes, m/z 472 [MH]+.

b. Anti-(1S,2R) 2-(2-hydroxy-2,2-diphenylethane)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium bromide

Specified in the title compound is obtained from 2-{anti-(1S,2R)-7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-yloxy}-1,1-diphenylethanol, using methods similar to the methods described in the example 13. LC-MS (method 1): Rt 8,69 minutes, m/z 486 [M]+; (CDCl3) δ 1,07 (1H, DD, J=13.3-inch, 3,4 Hz)to 1.60 (2H, m), 1,89 (1H, m), is 2.09 (1H, m), is 2.30 (1H, m), is 2.37 (2H, m)to 2.66 (1H, ushort, J=4.0 Hz), with 2.93 (1H, ushort, J=4.0 Hz), up 3.22 (1H, s), 3,37 (3H, s)to 3.38 (3H, s)to 3.09 (2H, C)of 3.97 (2H, m), 4,07 (1H, s), 4,14 (2H, t, J=5.5 Hz), 4,17 (1H, m)6,86 (2H, m), of 6.96 (1H, m), 7,26 (3H, m), 7,31 (5H, m), 7,40 (4H, m).

EXAMPLE 41

(1S,2R,4S,7S)-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}methylamino)bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

A. (9 panoniansee)-tert-butyldimethylsilyl

Tert-butyldimethylsilyloxy (28,16 g, 186,8 mmol) is added by portions to a solution of 9-brannan-1-ol (27.8 g, of 124.6 mmol) and imidazole (25.4 g, 373 mmol) in dry DJM (400 ml) at -10°C. in a nitrogen atmosphere. The reaction mixture allow to warm to ambient temperature over night. Solids are removed by filtration and the filtrate washed with 10% citric acid (aq.), then a saturated solution of salt, dried (MgSO4), filtered and concentrated to dryness, obtaining mentioned in the title compound as a yellow oil.

Output: 41,4 g, 98%.

TLC: Rf 0,91 (a mixture of 50% diethyl ether/cyclohexane).

b. [9-(tert-butyldimethylsilyloxy)nonyl]methylamine

A solution of methylamine (120 ml, 2 M) is added to a solution of (9 panoniansee)-tert-b is telemedicine (41,4 g, 123 mmol) in IMS (200 ml) at -10°C. and then the mixture provide an opportunity to warm to ambient temperature over night. After evaporation of the solvent the residue is triturated in diethyl ether and the solids removed by filtration, getting mentioned in the title compound in the form of HBr salt. The filtrate was concentrated in vacuo, suspended in K2CO3(aq.) and extracted DHM. The combined organic layers are dried (MgSO4), filtered and concentrated, obtaining mentioned in the title compound in the form of oil.

Output: 24,1 g, 68% (11.1 g HBr salt, 24%).

LC-MS (method 2): Rt 2,80 minutes, m/z 288 [MH]+.

C. (1S,4S,7S)-5-bromo-7-{[9-(tert-butyldimethylsilyloxy)nonyl]methylamino}bicyclo[2.2.1]heptane-2-he

To a solution of (1S)-2,3-dibromobicyclo[3.2.0]heptane-6-she (2.15 g, 8,02 mmol) in acetone (20 ml) is added [9-(tert-butyldimethylsilyloxy)nonyl]methylamine (5,77 g, 12.3 mmol) and the reaction mixture stirred at ambient temperature for 3 days. After evaporation of the solvent the residue is absorbed in a mixture of diethyl ether/ethyl acetate and washed with a mixture .NaHCO3(aq.)/a saturated solution of salt. The aqueous layer was extracted with diethyl ether. The combined organic layers are dried (Na2SO4), filtered and concentrated to dryness, obtaining a dark brown oil, which cleaned the Ute column chromatography on silica gel, using as eluent a gradient of 5-15% diethyl ether/pentane. After evaporation of volatile components specified in the title compound obtained as light yellow/brown oil.

Output: 1,67 g, 44%.

LC-MS (method 3): Rt of 4.83 min, m/z 474+476 [MH+].

d. (1S,4S,7S)-7-{[9-(tert-butyldimethylsilyloxy)nonyl]methylamino}bicyclo[2.2.1]heptane-2-he

To a solution of (1S,4S,7S)-5-bromo-7-{[9-(tert-butyldimethylsilyloxy)nonyl]methylamino}bicyclo[2.2.1]heptane-2-it (1.97 g, 4.2 mmol) and AIBN (70 mg, 0.42 mmol) in dry degassed toluene (40 ml) under nitrogen atmosphere add tri-n-butylaldehyde (1.25 ml and 4.65 mmol) and heated at 80°C in a pre-heated sand bath. After 2 hours at 80°C. the reaction mixture was concentrated in vacuo and purified column chromatography on silica gel, using as eluent a gradient of between 1 and 40% diethyl ether/pentane. After evaporation of volatile components get mentioned in the title compound as light yellow/brown oil.

Output: 2,41 g, quantitative (contains the remains of butyanova).

LC-MS (method 3): Rt 3,10 minutes, m/z 396 [MH+]

that is, (1S,2R,4S,7S)-7-{[9-(tert-butyldimethylsilyloxy)nonyl]methylamino}bicyclo[2.2.1]heptane-2-ol

To a solution of (1S,4S,7S)-7-{[9-(tert-butyldimethylsilyloxy)nonyl]methylamino}bicyclo[2.2.1]heptane-2-she (4.11 g, 1.4 mmol max) in dry THF (41 ml) at -5°C. in a nitrogen atmosphere add three-tert-butoxyaniline lithium (3,44 g, 13.5 mmol). After 1.5 hours at -5°C. add another three-tert-butoxyaniline lithium (2.64 g, 10.4 mmol). After 1 hour at -5°C. the reaction extinguish feast upon. solution (aq.) ammonium chloride and distributed between ethyl acetate and water. Solids are removed by filtration and washed with ethyl acetate. The phases are separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers washed feast upon. NaHCO3(aq.), saturated salt solution, dried (Na2SO4), filtered and concentrated to dryness, getting muddy yellow oil. The crude product is purified column chromatography on silica gel, using as eluent a gradient of 7.5-10% Meon/DHM. After evaporation of volatile components receive yellowish-brown viscous oil.

Output: a 2.36 g, 57%.

LC-MS (method 2): Rt 2,95 minutes, m/z 398 [MH+].

f. (1S,2R,4S,7S)-7-{[9-(tert-butyldimethylsilyloxy)nonyl]methylamino}bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

Sodium hydride (254 mg, 60% suspension in mineral oil, 6,35 mmol) are added to a solution of (1S,2R,4S,7S)-7-{[9-(tert-butyldimethylsilyloxy)nonyl]methylamino}bicyclo[2.2.1]heptane-2-ol (1.01 g, 2.54 mmol) in dry toluene (20 ml) at 0°C under nitrogen atmosphere. As soon as you fall off the gas, added in several portions of ethyl ether hydroxylation-2-luxusni acid (817 mg, totaling 3.04 mmol), and the last is how to stop the gas, the reaction mixture is heated at 80°C in a pre-heated sand bath. After 2.5 hours, the reaction mixture was poured into a mixture of saturated ammonium chloride (aq.) and simple ether. The layers separated, the aqueous layer was extracted with simple ether and the combined organic layers washed with saturated salt solution, dried (Na2SO4), filtered and concentrated to dryness, obtaining a light brown viscous oil. The crude product is purified column chromatography on silica gel, using as eluent a gradient 1-40% ethyl acetate in DHM, getting the product in the form of (very) light brown viscous oil.

Output: 0,76 g, 48%.

LC-MS (method 3): Rt 3,44 minutes, m/z 620 [MH+].

g. (1S,2R,4S,7S)-7-[(9-hydroxyaryl)methylamino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

A solution of (1S,2R,4S,7S)-7-{[9-(tert-butyldimethylsilyloxy)nonyl]methylamino}bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid (0.51 g, 0.82 mmol) in THF (7 ml) is treated with 1 M HCl (3.5 ml) and stirred at ambient temperature for 45 minutes. The reaction mixture is neutralized feast upon. NaHCO3(aq.) and extracted with ethyl acetate. The combined organic layers are dried (Na2SO4), filtered and concentrated to dryness, obtaining a light brown oil which is used without additional is Oh cleanup.

Output: 273 mg, 66%.

LC-MS (method 3): Rt 2,39 minutes, m/z 506 [MH+].

h. (1S,2R,4S,7S)-7-[methyl-(9-octanoyl)amino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

Periodinane Dess-Martin (450 mg, 1.06 mmol) are added to a solution of (1S,2R,4S,7S)-7-[(9-hydroxyaryl)methylamino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid (370 mg, 0,732 mmol) in dry DHM (3 ml) at 0°C and the reaction mixture provides the opportunity to warm up to ambient temperature. After 1 hour at a temperature of acrawsa environment, the reaction mixture is treated with a feast upon. NaHCO3(aq.) and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried (Na2SO4), filtered and concentrated to dryness. The residue is triturated in a simple ether and the solids removed by filtration. The filtrate is concentrated, obtaining an orange-brown viscous oil, and used directly without further purification.

Output: 458 mg, 0.73 mmol Max.

i. (1S,2R,4S,7S)-7-({9-[(R)-2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}methylamino)bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

A mixture of (1S,2R,4S,7S)-7-[methyl-(9-octanoyl)amino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni key is lots (max 0.73 mmol), 5-[(R)-2-amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-hydroxy-1H-quinoline-2-she (245 mg, 0.73 mmol), triacetoxyborohydride sodium (186 mg, 0.88 mmol) and acetic acid (2 drops) in dry 1,2-dichloroethane was stirred at ambient temperature over night. The reaction mixture was partitioned between DHM and feast upon. NaHCO3(aq). The organic layer is dried (Na2SO4), filtered and concentrated in vacuo, getting a dark green/brown resin, which solidifies upon standing and which purified preparative HPLC (system 2, 2,35% + 1%/min). The fractions containing pure product, concentrate, neutralize feast upon. NaHCO3(aq.) and extracted DHM. After concentration in vacuo get a greenish-brown oil.

Yield: 72 mg, 12%.

LC-MS (method 3): Rt of 2.51 min, m/z 822 [MH+].

j. (1S,2R,4S,7S)-7-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}methylamino)bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

A solution of (1S,2R,4S,7S)-7-({9-[(R)-2-(tert-butultimately-silyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}methylamino)bicyclo[2.2.1]-hept-2-silt ether hydroxy-dateopen-2-luxusni acid (72 mg, 0,087 mmol) and trihydrochloride of triethylamine (60 μl, of 0.37 mmol) is stirred in a mixture of THF/DHM (1:1, 2 ml) at ambient temperature among the s during the night. The reaction mixture is neutralized feast upon. NaHCO3(aq.) and extracted DHM. The organic layer is concentrated to dryness, obtaining a green/brown oil, which was purified preparative HPLC (system 1, 15% + 1%/min for 20 minutes, then 6%/min for 10 minutes). The fractions containing pure product, concentrate, neutralize feast upon. NaHCO3(aq.) and extracted with THF. After concentration in vacuo get a light brown oil.

Yield: 50 mg, 81%.

LC-MS (method 3): Rt 2,04 minutes, m/z 708 [MH+].

EXAMPLE 42

(Benzylcarbamoyl)-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylammonium bromide

A. Anti-(1S,2R)-7-[(benzylcarbamoyl)methylamino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

Get a solution of (1S,2R)-7-methylaminomethyl[2.2.1]hept-2-silt ether anti-hydroxylation-2-luxusni acid (50 mg, 0.14 mmol) in acetonitrile (3 ml). Add DIPEA (49 μl, 0.28 mmol) and N-benzyl-2-bromoacetamide (48 mg, 0.21 mmol) and the mixture was stirred at 50°C for 2 hours. The solvent is evaporated and purified column flash chromatography on silica gel, using as eluent a gradient of 0-10% etelaat in DHM, getting mentioned in the title compound as a pale yellow oil (60 mg, 84%): LC-MS (method 2): Rt for 2.83 min, m/z 511 [MH+].

b. (Benzylcarbamoyl)-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylammonium bromide

Specified in the title compound is obtained from anti-(1S,2R)-7-[(benzylcarbamoyl)methylamino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid, using a method similar to the method described in example 13: LC-MS (method 4): Rt 7,53 minutes, m/z 525 [M+]; (CDCl3) δ 1,12 (1H, DD), 1,45-of 1.52 (1H, m), and 1.63 (1H, m), 1,72 and 1.80 (1H, m), 1,88-of 1.97 (1H, m), 2,28 (1H, m), is 2.74 (1H, ushort), 3,06 (1H, ushort), to 3.34 (3H, s)to 3.36 (3H, s), 4,17 (1H, s)to 4.41 (2H, d), and 4.68 (2H, DD), 4,79 (1H, s), ceiling of 5.60 (1H, m), 6,98 (2H, m), to 7.15 (2H, m), 7,19-of 7.23 (1H, m), 7,25-7,31 (4H, m), of 7.36 (2H, d), of 9.55 (1H, t).

The following example receives a manner analogous to the method described for example 42.

EXAMPLE 44

Anti-(1S,2R) [2-(2-cyclohexyl-2-hydroxy-2-phenylacetate)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium bromide

A. Anti-(1S,2R) 7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-silt ether oxopentanoic acid

A solution of anti-(1S,2R) 7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]heptane-2-ol (of 0.77 g, 2.8 mmol) in anhydrous THF (10 ml) was stirred at ambient temperature in an atmosphere of nitrogen with sodium hydride (145 mg, 60% dispersion in oil) in 3 hours. Add oxopentanenitrile (611 mg, 3,mol) and the reaction mixture provide the ability to stand for 60 hours. The reaction is quenched by adding feast upon. NH4Cl, extracted into EtOAc and the combined organic extracts washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The reaction mixture is purified by chromatography on silica gel, using as eluent a gradient of 0-5% Et2O-cyclohexane, receiving the product as a yellow oil (600 mg). (CDCl3) δ 1,20-1,30 (2H, m), 1,63-1,71 (2H, m), 1,78-of 1.88 (1H, m), 1,88 is 1.96 (2H, m), 2,14 was 2.25 (5H, m), 2,35-is 2.37 (1H, m), 2,50-of 2.58 (2H, m), 2,66-2,70 (1H, m), 3,97-a 4.03 (2H, m), 5,20-of 5.26 (1H, m), 6,85-to 6.95 (3H, m), 7,24-7,30 (2H, m), of 7.48-rate of 7.54 (2H, m), 7,63-of 7.69 (2H, m), 7,95-of 8.00 (2H, m).

A. Anti-(1S,2R) 7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-silt ether cyclohexylhydroxylamine acid

To a stirred solution of anti-(1S,2R) 7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-silt ether oxopentanoic acid (200 mg, 0.49 mmol) in anhydrous THF (5 ml) under nitrogen atmosphere add cyclohexylaniline (0.5 ml, 0.98 mmol). The reaction mixture is heated at 50°C for 18 hours. The cooled mixture was quenched by adding feast upon. NH4Cl, extracted into EtOAc and the combined organic extracts dried over MgSO4and concentrated in vacuo. The reaction mixture is purified by chromatography on silica gel, using as eluent a gradient of 5-10% Et2O-cyclohexane, receiving the product as a clear oil (123 mg). LC-M the (method 1): Rt 2.86 min, m/z 492 [MH+].

C. Anti-(1S,2R) [2-(2-cyclohexyl-2-hydroxy-2-phenylacetate)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium bromide

Specified in the title compound is obtained from anti-(1S,2R) 7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-silt ether cyclohexylhydroxylamine acid, using the techniques described in General terms in example 13. LC-MS (method 1): Rt 2,75 minutes, m/z 506 [M+].

EXAMPLE 45

Anti-(1S,2R) 7-[methyl-(3-phenoxypropylamine]bicyclo[2.2.1]hept-2-silt ester 2-hydroxy-3,3-dimethyl-2-phenylalkanoic acid

Specified in the title compound is obtained from anti-(1S,2R) 7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-silt ether oxopentanoic acid, using the techniques described in General terms in example 44. (CDCl3) δ 0,97-of 1.05 (9H, s), 1,07 of 1.28 (2H, m), 1,68-to 1.79 (2H, m), 1,81 is 1.96 (3H, m), 2,1-2,24 (5H, m), 2,31 (1H, s), 2,49-2,61 (3H, m), 3,80 (1H, s), 3,97-a 4.03 (2H, m), 5,02-5,11 (1H, m), 6,86-to 6.95 (3H, m), 7.23 percent-7,34 (5H, m), 7,69-7,74 (2H, m).

LC-MS (method 4): Rt 8,29 minutes, m/z 466 [MH+].

EXAMPLE 46

Anti-(1S,2R) [2-(2-tert-butyl-2-hydroxy-2-phenylacetate)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium bromide

Specified in the title compound is obtained from anti-(1S,2R) 7-[methyl-(3-phenoxypropylamine]bicyclo[2.2.1]hept-2-silt ester 2-hydroxy-3,3-dimethyl-2-phenylal the Noah acid, using the techniques described in example 13. LC-MS (method 2): Rt 2,82 minutes, m/z 480 [M+].

EXAMPLE 47

[Anti-(1R,2R)-2-(2-hydroxy-2,2-diphenylethylamine)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium bromide

A. (1R,7S)-N7N-methyl-N7-(3-phenoxypropan)bicyclo[2.2.1]heptane-2,7-diamine

Get a solution of (1S,7S)-7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]heptane-2-it (1.35 g, 4.9 mmol) in methanol (90 ml). Add sodium acetate (648 mg, 7.9 mmol)and then hydroxylamine hydrochloride (566 mg, 8.2 mmol). The mixture is stirred at room temperature for 18 hours. Add the uranyl chloride Nickel(II) (2,11 g, 8.9 mmol), and then added in several portions sodium borohydride (1.68 g, to 44.5 mmol). The mixture is stirred at room temperature for a further 18 hours. The solvent is removed under reduced Dulaney and the residue distributed between ethyl acetate and aqueous sodium hydroxide. The organic phase is dried over sodium sulfate, filtered and evaporated to a resin. The last load in the SCX cartridge, washed with methanol and then elute with 4 M ammonia in methanol. The substance is further purified column chromatography on silica gel, using as eluent a gradient of 0-10% methanol in DHM, getting mentioned in the title compound as a brown oil (526 mg, 39%). LC-MS (method 2): Rt 0,34 minutes, m/z 275 [MH+].

b. N-{(1R,7S)-7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-yl}-2-oxo-2-phenylacetamide

Get a solution of (1R,7S)-N7N-methyl-N7-(3-phenoxypropan)bicyclo[2.2.1]heptane-2,7-diamine (200 mg, 0.73 mmol) in DHM (3 ml) with diisopropylethylamine (0.25 ml, of 1.46 mmol). Added dropwise a solution of oxopentanenitrile (184 mg, of 1.09 mmol) in DHM (1 ml). The mixture is stirred at room temperature for 3 hours. The solvent is evaporated and the residue purified by chromatography on silica gel, using as eluent a gradient of 0-20% ethyl acetate in DHM, getting mentioned in the title compound as a colourless oil (150 mg, 51%). LC-MS (method 2): Rt 2,28 minutes, m/z 407 [MH+].

C. 2-hydroxy-N-{anti-(1R,2R)-7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-yl}-2,2-diphenylacetamide

Receive a chilled (0°C.) solution of N-{(1R,7S)-7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-yl}-2-oxo-2-phenylacetamide (100 mg, 0.25 mmol) in THF (5 ml). Add a solution of formanilide (of 0.26 ml, 2 M in THF, 0.52 mmol) and the solution stirred for 1 hour at 0°C, then the solution provide the ability to warm to room temperature for another 1 hour. The reaction is quenched by addition of aqueous ammonium chloride (feast upon. 10 ml). The mixture is extracted with ethyl acetate, then the combined organic extracts are dried with natalitetom sodium, filtered and evaporated. Purification by chromatography on silica gel using a gradient of 0-5% methanol in DHM gives specified in the title compound as a colourless oil (20 mg, 17%). LC-MS (method 2): Rt 2,55 minutes, m/z 485 [MH+].

d. [Anti-(1R,2R)-2-(2-hydroxy-2,2-diphenylethylamine)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium bromide

Specified in the title compound is obtained from 2-hydroxy-N-{anti-(1R,2R)-7-[methyl-(3-phenoxypropan)amino]bicyclo[2.2.1]hept-2-yl}-2,2-diphenylacetamide, using a method similar to the method of example 13: LC-MS (method 1): Rt 7,88 minutes, m/z 499 [M+]; (CD3OD) δ of 1.27 (1H, m), of 1.66 and 1.75 (1H, m), of 1.85 (2H, t), is 2.05 (1H, m), 2,22-of 2.38 (3H, m), 2,73 (1H, m)3,00 (1H, s), 3,20 (6H, s), 3,60-3,68 (3H, m), 4,11 (3H, m), 6,92-of 6.96 (3H, m), 7,25-7,34 (8H, m), 7,40-7,45 (4H, m).

EXAMPLE 48

Anti-(1S,2R)-7-[(3-dimethylaminopropyl)methylamino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

Specified in the title compound is obtained from (1S,2R)-7-methylaminomethyl[2.2.1]hept-2-silt ether anti-hydroxylation-2-luxusni acid and chloride (3-methanesulfonylaminoethyl)dimethylammonio, using a method similar to the method of example 42: LC-MS (method 1): Rt 5,02 minutes, m/z 449 [MH+]; (CD3OD) δ 1,07-of 1.18 (2H, m)of 1.50 (2H, m), 1.77 in (3H, m), 2,10 (1H, m), 2,17 (3H, s), 2,32 (1H, s), 2,42 (2H, t), of 2.54 (1H, s), 2,61 (6H, s), and 2.79 (2H, m), of 4.57 (1H, users), 5,02 (1H, m), 6,98 (2H, m), 7,14 (2H, m), 7,38 (2, m).

EXAMPLE 49

(3-dimethylaminopropyl)-[anti-(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylammonium bromide

A. Anti-(1S,2R)-7-{[2-(1,3-dioxo-1,3-dihydroindol-2-yl)ethyl]methylamino}bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

Specified in the title compound is obtained from (1S,2R)-7-methylaminomethyl[2.2.1]hept-7-silt ether anti-hydroxylation-2-luxusni acid and N-(2-bromacil)phthalimide, using a method similar to the method of example 42. LC-MS (method 2): Rt 2,70 minutes, m/z 537 [MH+].

b. Anti-(1S,2R)-7-[(2-amino-ethyl)methylamino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

Get solution of anti-(1S,2R)-7-{[2-(1,3-dioxo-1,3-dihydroindol-2-yl)ethyl]methylamino}bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid (80 mg, 0.15 mmol) in ethanol (3 ml). Added hydrazine monohydrate (72 μl, 1,49 mmol) and the mixture is heated at 80°C for 1 hour, then the mixture allow to cool to room temperature. The obtained white precipitate is filtered off and the filtrate is washed with ethanol. The filtrate is evaporated, receiving untreated specified in the title compound: LC-MS (method 3): Rt 2,03 minutes, m/z 407 [MH+].

C. Anti-(1S,2R)-7-[(2-benzoylamino)IU is ylamino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid

The crude anti-(1S,2R)-7-[(2-amino-ethyl)methylamino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid (0.15 mmol) dissolved in DHM (5 ml). Add diisopropylethylamine (31 μl, 0.23 mmol)and then benzoyl chloride (17 μl, 0.15 mmol). The mixture is stirred at room temperature for 30 minutes. Add water (5 ml) and the organic layer is separated by using a phase separation cartridge and evaporated. Purification by chromatography on silica gel, using as eluent a gradient of 0-20% ethyl acetate in DHM gives specified in the title compound as a colourless oil (30 mg, 39%). LC-MS (method 3): Rt 2,47 minutes, m/z 511 [MH+].

d. (2-benzoylamino)-anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylammonium bromide

Specified in the title compound is obtained from anti-(1S,2R)-7-[(2-benzoylamino)methylamino]bicyclo[2.2.1]hept-2-silt ether hydroxylation-2-luxusni acid, using a method similar to the method of example 13: LC-MS (method 1): Rt 7,25 minutes, m/z 525 [M+]; (CD3OD) δ of 1.18 (1H, DD), 1,47-of 1.55 (1H, m), 1,74-1,90 (2H, m), 1,99-of 2.09 (1H, m), 2,31 (1H, m), 2,80 (1H, m), of 3.12 (1H, m), with 3.27 (3H, s), with 3.27 (3H, s), 3,64 at 3.69 (3H, m)to 3.89 (2H, t), 5,09 (1H, m), 7,00 (2H, m,), 7,14 (2H, m), 7,40 (2H, m), 7,45 is 7.50 (2H, m), 7,54-7,58 (1H, m), a 7.85-7,88 (2H, m).

BIOLOGICAL EXAMPLES

Inhibiting action of the compounds according to the present invention in relation to the ICC is irinovka receptor M3, and (in the case of example 41) adrenergic receptor β 2determined using the following assays binding.

Analyses linking radioligand with muscarinic receptor

To assess the affinity of muscarinic antagonists in relation to muscarinic receptors M2 and M3 use research associate radioligand with the use of [3H]-N-methylscopolamine ([3H]-NMS) and commercially available cell membranes expressing human muscarinic receptors (M2 and M3). Membranes in Tris-buffer and incubated in 96-well tablets with [3H]-NMS and an antagonist of M3 at various concentrations for 3 hours. Then the membrane and the associated radioligand collected by filtration and allowed to dry over night. Then add scintillation fluid and the associated radioligand read using a scintillation counter Canberra Packard Topcount.

The half-life antagonists on each of the muscarinic receptor is measured using alternative radioligand [3H]-QNB and adaptation (modification) the above analysis of affinity. Antagonists incubated for 3 hours at a concentration 10 times higher than their Ki, a specific ligand [3H]-QNB membranes expressing human muscarinic receptors. At the end of this time [3H]-QNB add up to a concentration of 25 times its Kd for the receptor, podlasek the study, and continue incubation for various periods of time from 15 minutes to 180 minutes. Then the membrane and the associated radioligand collected by filtration and allowed to dry over night. Then add scintillation fluid and read the linked radioligand using scintillation counter Canberra Packard Topcount.

The rate at which reveals the binding of [3H]-QNB with muscarinic receptors correlated to the speed at which the antagonist dissociates from the receptor and is taken as the half-life of antagonists to the receptors.

The results:

ExampleThe efficiency of binding
1+++
2+++
3++
4++
5+++
6++
7++
8++
9+
10 +
11+++
12+++
13+++
14+
15+
16++
17+++
18++
19+++
20+++
21+++
22+++
23+
24+++
25+++
26+++
27++
28+
29+
30+
31 +
32+
33+++
34++
35++
36+++
37+++
38+++
39+
40+
41+++
42+++
43+++
44NT
45+
46NT
47NT
48NT
49NT

In the above table the binding efficacy M3 (Ki values) are specified as follows: <1 nm '+++'; 1-10 nm '++'; >10 nm '+'. All compound displayed the t values Ki < 5000 nm. NT = not tested.

Analysis of the binding of radioligand with β-adrenergic receptor

To assess the affinity of antagonists against β-adrenergic receptor use research associate radioligand with the use of [125I]-itsinitial and commercially available cell membranes expressing human β2-adrenergic receptor. Membrane and SPA-beads incubated with [125I]-itsinitial and antagonist β2at various concentrations for 3 hours at ambient temperature in Tris-buffer. The analysis is carried out in a 96-well tablets that read, using the counter Wallac Microbeta. In this analysis example 41 shows the value of Ki <100 nm.

Analysis of the inhibition of the activation of the receptor M3 by mobilizing calcium

In the alternative analysis of binding of M3 receptor cells SNO expressing the human receptor M3, seeded and incubated overnight in 96-well tablets adsorbed collagen (black wall, clear bottom) with density 50000/75 ál environment in 3% serum. Next day I get sensitive to calcium dye (Molecular Devices, Cat # R8041) in HBSS buffer with the addition of 5 mm probenecid (pH 7.4). To cells add an equal volume of dye solution (75 μl) and incubated for 45 the minutes, followed by adding 50 μl of muscarinic antagonists or filler. After another 15 minutes the tablet read on FLEXstationTM(excitation 488 nm, emission 525 nm) for 15 seconds to determine the baseline fluorescence. Then add the muscarinic agonist, Carbachol, at a concentration of EU80and measure fluorescence for another 60 seconds. The signal is calculated by subtracting the maximum response of the mean baseline fluorescence in the control wells in the absence of the antagonist. Then calculate the percentage of maximum response in the presence of the antagonist to get curves IC50.

Inhibiting action of the compounds according to the present invention the muscarinic receptor M3 can be estimated in the following ex-viva and in vivo assays.

To evaluate the efficacy and duration of action in the isolated trachea of the Guinea pig

Experiments carried out at 37°C in a modified Krebs solution-Henseleit (114 mm NaCl, 15 mm NaHCO3, 1 mm MgSO4, 1.3 mm CaCl2that 4.7 mm KCl, 11.5 mm glucose, and 1.2 mm KH2PO4, pH 7.4)saturated with a gas mixture of 95% O2/5% CO2. Indomethacin added to a final concentration of 3 μm.

Trachea extract in Guinea pigs Dunkin Hartley, adult males, and is separated from the fused fabric before open lengthwise, in the direction opposite to the muscle. Separate strips across the width 2-3 cartilaginous rings are cut and hung, use the cotton thread, a 10-ml baths bodies with the water jacket and attached to a torque sensor to provide the location of the tissue between the two platinum electrodes. The answers are recorded by a data acquisition system MP100W/Ackowledge that is connected to your computer (PC). Tissue balance within one hour of resting tone in 1g and then subjected to electric field stimulation (EFS) at a frequency of 80 Hz with a pulse duration of 0.1 MS (milliseconds), monopolar pulse that runs every 2 minutes. For each tissue build up a curve according to the “stress response” and then make a submaximal voltage to each piece of fabric in accordance with his own reaction to stress. Fabric washed with Krebs solution and left to stabilize stimulated before adding the test compounds. Curves concentration-response receive by cumulative addition of the test compounds in a semi-log (half-log increments. As soon as the answer to every add will reach a plateau, make the following addition. The percentage inhibition of EFS-induced contraction is calculated for each concentration of each added connection and using the software Graphpad Prism, build curves dose-response and (according to him) calculate EC50for each of the first connection.

Studies aimed at defining the start time and duration of the test compounds is carried out by adding a pre-defined concentration EC50connect to EFS shortened tissues and achievements (their) response to a plateau. The time required to reach 50% of this response, defined as the start time. Then the tissues were washed off the connection by washing bath tissue fresh Krebs solution and measure the time required to return up to 50% status (reply) compression in response to EFS in the presence of compounds. This period is defined as the duration of action. As an example, in this assay, the compound of example 20 had EC500.8 nm, and the duration of 540 minutes.

Metacholine-induced bronchostenosis in vivo

Guinea pigs (Dunkin Hartley), male, weighing 500-600 g, placed in cages groups of 5 individuals, identify individually. Animals provide an opportunity to acclimate to the environment for at least 5 days. During this time and time studying the animals have free access to water and food.

Guinea pigs subjected to anesthesia by inhalation anesthetic, Halothane (5%). The test compound or filler (0,25-0,50 ml/kg) injected II andstc the nasal. Animals are placed on the heated soft pad and give a chance to recover before returning to their cells, where they contain.

24 hours after dosing Guinea pigs finally subjected to anesthesia with urethane (250 μg/ml, 2 ml/kg). On surgical (third) stage of anesthesia jugular vein are kemuliaan using portex I.V cannula filled with heparinised, phosphate buffered physiological solution (hPBS) (10 u/ml), for centuries the introduction of methacholine. The trachea naked and subjected to kemuliaan hard portex cannula and the esophagus is subjected catheterization transoral using flexible infant tube (for enteral feeding).

Then spontaneously breathing animal attached to the pulmonary measurement system (EMMS, Hants, UK), consisting of flow pneumotachograph and pressure sensor. The tracheal cannula attached to pneumotachograph and esophageal cannula attached to the pressure sensor.

Esophageal cannula positioned so that the base resistance (breathing) ranged from 0.1 to 0.2 cm H2O/ml/sec 2-minute basic reading registrat centuries before the introduction of metacholine (up to 30 μg/kg, 0.5 ml/kg). 2-minute registration-induced contractions (of bronchi) start I.V injection.

Software that uses DL the analysis bronchospastic action of the tested compounds, allows you to calculate the maximum resistance (breathing) and the drag area under the curve (AUC) during each 2-minute registration period. Figure 1 presents the results obtained in this assay for compounds of example 20 (0.1, 0.3 and 1 mg/kg; intranasal), introduced for 4 hours prior to Mch (10 µg/kg I.V)-induced bronchospasm, and connections compare, Tiotropium.

1. The compound of formula (I):

where a represents an oxygen atom or a group-N(R12)-;
(i) R1represents a C1-C6-alkyl or a hydrogen atom; and R2represents a hydrogen atom or a group-R5, -Z-Y-R5, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9CO-R5or-Z-CO2H; and
R3absent or represents a C1-C6-alkyl, and in this case the nitrogen atom to which it is attached is a Quaternary nitrogen and carries a positive charge; or
(ii) R1and R2together with the nitrogen to which they are attached, form geteroseksualnoe ring, such ring substituted by a group-Y-R5or-Z-Y-R5and
R3absent or represents a C1-C6-alkyl, and in this case the nitrogen atom to which it is attached is a Quaternary nitrogen and carries a positive charge;
R4PR is dstanley a group of formula (a), (b), (C) or (d);

Z represents a C1-C16-alkylenes group;
Y represents a bond or an oxygen atom;
R5represents a C1-C6is alkyl, aryl, phenyl condensed with C3-C6cycloalkyl, phenyl condensed with heterocyclization, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, C3-C6cycloalkyl or hetero3-C6cycloalkyl group;
R6represents a C1-C6-alkyl or a hydrogen atom;
n and m are 0;
R8aR8bindependently selected from the group consisting of aryl, phenyl condensed with heterocyclization, heteroaryl, C1-C6-alkyl, C3-C6cycloalkyl;
R8cis a HE or1-C6-alkyl;
R9and R10represent independently a hydrogen atom, a C1-C6is alkyl, aryl, phenyl condensed with heterocyclization, phenyl condensed with C3-C6cycloalkyl, heteroaryl, phenyl(C1-C6-alkyl)- or heteroaryl (C1-C6-alkyl)-group;
R12represent1-C6-alkyl or a hydrogen atom;
Ar1represents phenyl;
Ar2are independently phenyl; and
Q is the battle of the oxygen atom;
when the compound contains the group of Quaternary ammonium acceptable counterions are selected from chloride, bromide, iodide, sulfate, methanesulfonate, bansilalpet, toluensulfonate (tosilata), phosphate, acetate, citrate, lactate, tartrate, nelfinavir, maleate, fumarata and succinate;
each heterocytolysine group is a
(i) optionally substituted cycloalkyl group containing from 5 to 6 members in the loop, which contains one heteroatom selected from O or NR;
(ii) cycloalkyl group containing from 5 to 6 members in the loop, which contains CONR and CONRCO; and where R represents a C1-C6alkyl;
aryl represents monocyclic or bicyclic aromatic carbocyclic portion containing from 6 to 10 carbon atoms;
heteroaryl represents an aromatic monocyclic or bicyclic organic portion containing from 5 to 10 atoms in the cyclic structure in which one, two or three atoms in the cycle selected from a nitrogen atom, oxygen or sulfur, and unless otherwise specified cyclic group optionally substituted with up to four substituents selected from-HE or phenyl; and unless otherwise specified
alkylene radicals optionally substituted C1-C6alkylamino, -NH2aminos1-C6the alkyl, phenyl, dis1-C6alkylamino is, C1-C6the alkyl, or
HE,
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where
And represents the oxygen atom or the group-N(R12)-;
R1represents a C1-C6is alkyl or hydrogen atom, and
R2represents a C1-C6-alkyl, a hydrogen atom or a group-Z-Y-R5or a group-Z-NR9R10; or R1and R2together with the nitrogen to which they are attached, form geteroseksualnoe ring, and the specified ring substituted by a group-Y-R5or-Z-Y-R5;
R3absent or represents a C1-C6-alkyl, and in this case the nitrogen atom to which it is attached is a Quaternary nitrogen and carries a positive charge;
R4represents a group of formula (a) or (b):

Z represents a C1-C8alkylenes group;
Y represents a bond or an oxygen atom;
R5represents phenyl, phenyl condensed with C3-C6cycloalkyl, phenyl condensed with heterocyclization, heteroaryl, phenyl (C1-C8-alkyl)-, heteroaryl (C1-C8-alkyl) - or hetero3-C6cycloalkyl-group;
R6represents a C1-C6-alkyl or a hydrogen atom;
n and m are 0;
R8aand R 8bindependently selected from the group consisting of phenyl, heteroaryl,1-C6-alkyl, C3-C6cycloalkyl;
R8cis a HE or1-C6-alkyl;
R9and R10represent independently a hydrogen atom, a C1-C6is alkyl, aryl, heteroaryl, aryl(C1-C6-alkyl) - or heteroaryl(C1-C6-alkyl)-group; and R12represents a C1-C6-alkyl or a hydrogen atom.

3. The compound according to claim 1 or 2, where R1represents methyl or ethyl, or hydrogen atom, and R2represents methyl or ethyl, a hydrogen atom or a group-Z-Y-R5or a group-Z-NR9R10.

4. The compound according to claim 3, where R3represents methyl, so that the nitrogen atom to which it is attached is a Quaternary nitrogen and carries a positive charge.

5. The compound according to claim 1 or 2, where R1and R2together with the nitrogen atom to which they are attached, form a monocyclic heterocyclic ring comprising 3-7 ring atoms, in which the heteroatom is nitrogen.

6. The compound according to claim 4, where R1and R2together with the nitrogen atom to which they are attached, form azetidinone, piperidinyl, piperazinilnom, N-methylpiperidine or pyrrolidinyl ring.

7. The compound according to claim 5 or 6, where tomasita, attached to R1and R2is a Quaternary nitrogen and carries a positive charge.

8. The compound according to any one of the preceding paragraphs, where in any group, R5, -Y-R5, -Z-Y-R5, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9-CO-R5or-Z-CO2H:
Z represents - (CH2)1-16-alkylene, optionally substituted stands for up to three carbon atoms in the chain;
Y is a bond or-O-;
R5represents methyl, ethyl, n - or isopropyl, n-, sec - or tert-butyl; or
phenyl, 3,4-methylenedioxyphenyl, 3,4-atlanticcity, dihydrobenzofuranyl, naphthyl; or
pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazole, benzoxazole, thiazole, benzthiazole, hinely, thienyl, Bastiani, furyl, bankfull, imidazolyl, benzimidazolyl, isothiazolin, benzisothiazole, pyrazolyl, isothiazolin, triazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, triazinyl, indolyl or indazole; or
arils1-C6alkyl, where the aryl part is a phenyl, 3,4-methylenedioxyphenyl, 3,4-atlanticcity, dihydrobenzo-furanyl or naphthyl, and -(C1-C6-alkyl)- represents-CH2- or-CH2CH2-; or
heteroallyl, where heteroaryl is pyridyl, n is roll, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazole, benzoxazole, thiazole, benzthiazole, hinely, thienyl, Bastiani, furyl, bankfull, imidazolyl, benzimidazolyl, isothiazolin, benzisothiazole, pyrazolyl, isothiazolin, triazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, triazinyl, indolyl or indazoles, and part (C1-C6-alkyl) - represents-CH2- or-CH2CH2-; or
indanyl or 1,2,3,4-tetrahydronaphthalene; or
heteroseksualci(C1-C6-alkyl)-, where heterocytolysine part is azetidine, piperidinyl, piperazinil, N-substituted piperazinil, such as methylpiperazine, or tetrahydropyranyl, and part(C1-C6-alkyl)- represents-CH2- or-CH2CH2-; or
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and
R9and R10represent independently
hydrogen; methyl, ethyl or n - or isopropyl;
phenyl, 3,4-methylenedioxyphenyl, 3,4-atlanticcity, dihydrobenzofuranyl, naphthyl;
pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazole, benzoxazole, thiazole, benzthiazole, hinely, thienyl, Bastiani, furyl, bankfull, imidazolyl, benzimidazolyl, isothiazolin, benzisothiazole, pyrazolyl, isothiazolin, triazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl is, pyridazinyl, triazinyl, indolyl or indazole; or
arils1-C6alkyl, where the aryl part is a phenyl, 3,4-methylenedioxyphenyl, 3,4-atlanticcity, dihydrobenzo-furanyl, or naphthyl, and -(C1-C6-alkyl)- represents-CH2- or-CH2CH2-.

9. The compound according to claim 1 or 2, where in the group-NR1R2R3, R1represents methyl or ethyl, R2represents a group-Z-Y-R5and R3represents methyl, so that the nitrogen to which it is attached, is quaternion and carries a positive charge.

10. The connection according to claim 9, where R5represents phenyl or phenyl (C1-C6-alkyl)-, Y is a bond or-O-, and-Z is a straight or branched alkalinity radical connecting the nitrogen and YR5- chain containing up to 12, or up to 9, carbon atoms.

11. The compound according to any one of the preceding paragraphs, where a represents an oxygen atom.

12. The compound according to claims 1-11, where a represents a group-N(R12)-, where R12represents methyl or ethyl, or hydrogen atom.

13. The compound according to any one of the preceding paragraphs, where R4represents a group (a), R6represents methyl or ethyl, or hydrogen atom; Ar1represents phenyl;and
m and n are equal to 0.

14. The compound according to claims 1-12, where R4represents a group (b), and R8aand R8bcan be independently selected from methyl, ethyl, n - or isopropyl, n-, sec - and tert-butyl; phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylendiamine, dihydrobenzofuranyl, naphthyl; pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazole, benzoxazole, thiazolyl, benzothiazolyl, chinoline, teinila, bastianini, furil, benzpyrene, imidazolyl, benzimidazolyl, isothiazoline, benzisothiazole, pyrazolyl, isothiazoline, triazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, triazinyl, indolyl or indazole; indanyl and 1,2,3,4-tetrahydronaphthalene; cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R8cis a HE, methyl or ethyl.

15. The compound according to claims 1 or 3 to 12, where R4is a group (d) and R8aand R8bcan be independently selected from methyl, ethyl, n - or isopropyl, n-, sec - and tert-butyl; phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylendiamine, dihydrobenzofuranyl, naphthyl; pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazole, benzoxazole, thiazolyl, benzothiazolyl, chinoline, teinila, bastianini, furil, benzpyrene, imidazolyl, benzimidazolyl, isothiazoline, benzisothiazole, pyrazolyl isothiazoline, triazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, triazinyl, indolyl or indazole; indanyl and 1,2,3,4-tetrahydronaphthalene; cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R8cis a HE, methyl or ethyl.

16. The connection 14 or 15, where R8cis a HE.

17. The compound according to any one of p and 15, where (i) each of R8aand R8brepresents optionally substituted pyridyl, oxazolyl, thiazolyl, furyl, thienyl or phenyl; or (ii) one of R8aand R8brepresents optionally substituted phenyl and the other is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or (iii) one of R8aand R8brepresents optionally substituted pyridyl, thienyl, oxazolyl, thiazolyl or furyl and the other is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

18. Connection p and 15, where each of R8aand R8bis a 2-thienyl or phenyl; or one of R8aand R8brepresents phenyl and the other is a 2-thienyl.

19. The compound according to claims 1 or 3 to 12, where R4is a group (C), and R8cis a HE, methyl or ethyl;
each Ar2represents phenyl; and bridging the communication-Q-between the two rings Ar2represents --.

20. The connection according to claim 19, where R8cis a HE.

21. The compound according to claim 1, having the formula (IA)

where ring a is an optionally substituted phenyl ring or monocyclic heterocyclic structure comprising 5 or 6 atoms in the cycle, or phenyl condensed with heterocyclization where heterocytolysine structure represents a monocyclic heterocyclic structure comprising 5 or 6 atoms in the cycle; R8arepresents phenyl, thienyl, cyclopentyl or cyclohexyl; R8brepresents phenyl; thienyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7, provided that the sum s+t is not greater than 10; Y is a bond or-O-, and X-represents a pharmaceutically acceptable anion selected from chloride, bromide, iodide, sulfate, methanesulfonate, bansilalpet, toluensulfonate, phosphate, acetate, citrate, lactate, tartrate, nelfinavir, maleate, fumarata and succinate.

22. The compound according to claim 1, having formula (IB)

where ring b is an optionally substituted phenyl ring or monocyclic heterocyclic structure comprising 5 or 6 atoms in the cycle, or phenyl condensed with heterocyclization where heterocytolysine structure to depict is to place a monocyclic heterocyclic structure comprising 5 or 6 atoms in the cycle; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7, provided that the sum s+t is not greater than 10; Y is a bond or-O-, and X-represents a pharmaceutically acceptable anion selected from chloride, bromide, sulfate, methanesulfonate, bansilalpet, toluensulfonate, phosphate, acetate, citrate, lactate, tartrate, nelfinavir, maleate, fumarata and succinate.

23. The compound according to any one of the preceding paragraphs, which is predominantly anti-endo-configuration.

24. The compound according to claim 1, selected from the group consisting of:
anti-[2-(biphenyl-2-ylcarbamate)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium salts,
anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenylpropyl)ammonium salts,
anti-[(±)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenylpropyl)ammonium salts,
anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium salts,
anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylphenethylamine salts,
anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethyl-(4-phenylbutyl)ammonium salts,
anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]trimethylammonium salts,
(2-benzyloxyethyl)-anti-[(1S,2R)-2-(2-what hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]dimethylammonium salts,
anti-[(1S,2R)-2-(2-hydroxy-2,2-diphenylacetate)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium salts,
anti-[(1S,2R)dimethyl-(3-phenoxypropan)-[2-(N-xanthene-9-carbonyloxy)bicyclo[2.2.1]hept-7-yl]ammonium salts,
anti-[(1S,2R)2-(9-hydroxy-N-xanthene-9-carbonyloxy)bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium salts and
anti-[(1S,2R)-2-(2-hydroxy-2,2-dateopen-2-RECETOX)bicyclo[2.2.1]hept-7-yl]indan-2-ultimatemenu salts.

25. The compound according to claim 1, which is an anti-[(1S,2R)2-(9-hydroxy-N-xanthene-9-carbonyloxy)-bicyclo[2.2.1]hept-7-yl]dimethyl-(3-phenoxypropan)ammonium bromide.

26. The compound according to claim 1, having the properties of an antagonist of muscarinic receptor M3, to obtain the drug.

27. Pharmaceutical composition having properties antagonist of muscarinic M3 receptor containing the compound according to any one of claims 1 to 25 in an effective amount and a pharmaceutically acceptable carrier or excipient.

28. The pharmaceutical composition according to item 27 in a form suitable for administration by inhalation.

29. The use of compounds according to any one of claims 1 to 25 for obtaining a drug suitable for the treatment or prevention of a disease or condition in (pathology) which involved the activity of the muscarinic M3 receptor.

30. The method of treatment of a disease or condition in which otologie which involved the activity of the muscarinic receptor M3, includes introduction to the subject in need of such treatment, an effective amount of a compound according to any one of claims 1 to 25.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having structure

, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.

EFFECT: novel compounds which are active towards PPAR are obtained and described.

41 cl, 622 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

where there are R3/R3', R4/R4' and R5/R5' where at least one of either R4/R4' or R5/R5' always represents a fluorine atom, and the other radical values are disclosed in the description.

EFFECT: making the compounds which are γ-secretase inhibitors, and can be effective in treating Alzheimer's disease or advanced cancers, including but not limited to carcinoma of uterine cervix and breast carcinoma and malignant tumours of hematopoietic system.

15 cl, 3 tbl, 18 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to novel cyclohexane derivatives of formula (I) or their pharmaceutically acceptable salts having inhibitory effect on Na+-glucose cotranspoter (SGLT2), as well as to pharmaceutical compositions based on the said compounds and their use in preventing or treating diabetes, diabetic complications caused by hyperglycaemia or obesity. , where A is -O-; n is an equal to 0 or 1; R6 and R7 each independently represents a hydrogen atom or a C1-C6alkyl group, m is an integer selected from 1-3; Q is selected from Q1 - Q5, given in formula 2.

EFFECT: obtaining novel cyclohexane derivatives or their pharmaceutically acceptable salts and preparation of a pharmaceutical composition based on the said compounds.

15 cl, 19 dwg, 11 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.

124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new method for synthesis of derivative of thieno[3,2-c]pyridine of the formula (1): (ticlopidine and clopidogrel). Method involves interaction of compound of the formula (2e): with compound of the formula (3): or its salt wherein R represents hydrogen atom or methoxycarbonyl; each among X' and Y' represents independently chlorine, bromine atom, methanesulfonyl or p-toluenesulfonyl, and to novel intermediate compounds and methods for their synthesis. Ticlopidine and clopidogrel possess the high inhibitory activity with respect to blood platelets aggregation and antithrombosis activity.

EFFECT: simplified process of synthesis, valuable medicinal properties of compounds.

15 cl, 32 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of aniline of the general formula (I): and their pharmaceutically acceptable salts and isomeric forms possessing properties of phosphodiesterase-4 inhibitors. Compounds can be used, fore example, for enhancing cognitive ability. In compounds of the general formula (I) R1 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more halogen atoms; R2 means linear or branched (C1-C4)-alkyl that can be unsubstituted or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkoxy or their combinations, (C3-C10)-cycloalkyl, (C4-C16)-cycloalkylalkyl wherein alkyl fragment comprises from 1 to 4 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and alkyl fragment that can be linear or branched and comprises from 1 to 5 carbon atoms and wherein radical arylalkyl can be unsubstituted or substituted in aryl fragment with one or more substitutes of the following order: halogen atom, alkoxy group comprising from 1 to 4 carbon atoms or their combinations, and in alkyl fragment one group -CH2CH2- is optionally replaced for group -CH=CH-, and one group -CH2- is optionally replaced for -O- for -NH-, partially unsaturated carbocyclic group comprising from 5 to 9 carbon atoms that can comprise condensed benzene ring, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including one atom chosen from oxygen (O), or heterocyclylalkyl group wherein heterocyclic fragment can be saturated, partially saturated or unsaturated and comprises from 5 to 6 carbon atoms in cycle including 1-2 atoms chosen from nitrogen (N) or sulfur (S) atoms, and alkyl fragment that can be linear or branched comprises from 1 to 5 carbon atoms; R3 means partially unsaturated carbocyclylalkyl group wherein carbocyclic fragment comprises from 5 to 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms, (C7-C11)-arylalkyl wherein aryl fragment comprises 6 carbon atoms, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein arylalkyl radical can be linear or substituted in aryl fragment with one or more substitutes of the following group: trifluoromethyl, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations, heterocyclylalkyl group wherein heterocyclic fragment can be aromatic, partially or completely saturated and comprises from 5 to 10 atoms in cycle including 1-2 atoms chosen from N, O or S, and linear or branched alkyl fragment comprises from 1 to 5 carbon atoms and wherein heterocyclylalkyl group can be linear or substituted in heterocyclic fragment with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy or their combinations; R4 means (C6-C12)-aryl that can be linear or substituted with one or more substitutes of the following order: halogen atom, (C1-C4)-alkyl, (C2-C4)-alkenyl, hydroxy, (C1-C4)-alkoxy, (C2-C4)-alkoxyalkoxy, nitro, trifluoromethyl, -OCF3, amino group, aminoalkyl, aminoalkoxy, hydroxy-(C1-C4)-alkyl, hydroxamic acid, tetrazol-5-yl, 2-(heterocyclyl)-tetrazol-5-yl, carboxy, alkoxycarbonyl, cyano, acyl, alkylsulfonyl, phenoxy, trialkyloxy, R5-L or their combinations, or heteroaryl comprising from 5 to 10 atoms in cycle including 1-2 atoms chosen from N wherein heteroaryl can be linear or substituted with one or more substitutes of the following order: (C1-C4)-alkyl, (C1-C4)-alkoxy, carboxy, alkoxycarbonyl or their combinations; R5 means hydrogen atom, (C1-C8)-alkyl, (C3-C10)-cycloalkyl, C6-aryl, heterocyclic group that can be saturated, partially saturated or unsaturated and comprises from 5 to 10 atoms in cycle from which at least atom means N or O, and wherein heterocyclic group can be linear or substituted with one or more (C1-C4)-alkyls, or group heterocyclylalkyl, and others. Also, invention relates to intermediates compounds and to a method for enhancing the cognitive ability.

EFFECT: valuable biological and biochemical property of compounds.

49 cl, 8 sch, 26 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to derivatives of aminodicarboxylic acids of the general formula (I) and a medicinal agent able to stimulate activity of soluble guanylate cyclase being independently of the presence of the heme group comprising in it and able to cause relaxation of vessels and comprising at least one compound of the general formula (I). Agent is designated for treatment of cardiovascular diseases and for treatment of the central nervous system diseases characterizing by disorder of the system NO/cGMP, and shows high bioavailability and effectiveness.

EFFECT: improved and valuable medicinal properties of agent.

7 cl, 232 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

The invention relates to compounds of General formula (I)

in which R1means a hydrogen atom, a radical, CH3or the radical (CH2HE; R2means the radical (CH2HE; X-Y represents a relationshiporZ indicates cycle selected among the cycles of the following formulas:

; R3means alkyl chain with 4 to 8 carbon atoms, substituted by one or more hydroxyl groups and, in addition, possibly substituted by one or more lower alkyl groups and/or substituted by one or more halogen atoms and/or substituted by one or more groups of CF3and/or in which one or a few simple links of the chain may be substituted with one or more double bonds, and R3is a cycle in the para - or meta-position relative to the link X-Y, as well as optical and geometrical isomers of the above compounds of formula (I)

The invention relates to new derivatives of balkanov General formula (A)

< / BR>
where Ar is phenyl which may be unsubstituted or substituted one, two or three substituents independently chosen among Cl, Br, F, -OMe, NO2, CF3C1-4lower alkyl, -NMe2, -NEt2, -SCH3, -NHCOCH3; 2-thienyl, 2-furyl; 3-pyridyl; 4-pyridyl or 3-indolyl; R-OCH2R1where R1choose from a number of-CH= CME2The CME=CH2-The CCH; provided that when Ar is a phenyl,4-alkylphenyl, 4-methoxyphenyl or 3,4-acid, R can be any except 3-methyl-2-butenyloxy

-diketones and ketoesters" target="_blank">

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining-dicarbonyl derivatives of adamantane General formula

< / BR>
where R=CH3:R1=CH3OC2H5; R=C6H5: R1=OC2H5C6H5, CF2H

R=CF3:R1=C6H5n-C6H4C1

< / BR>
< / BR>
which are the products for the synthesis of biologically active substances

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

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