Azole and thiazole derivatives and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), in which (i) R1 denotes C1-C6-alkyl or hydrogen; and R2 denotes hydrogen or a -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C(O)O-R7 or -Z-C(O)-R7 group; and R3 denotes an undefined pair or C1-C6-alkyl; or (ii) R1 and R3 together with a nitrogen atom with which they are bonded form a 5-6-member heterocycloalkyl ring; and R2 denotes an undefined pair or a -R7 , -Z-Y-R7 group; or (iii) R1 and R2 together with a nitrogen atom with which they are bonded form a 6-member heterocycloalkyl ring, where said ring is substituted with a -Y-R7 group, and R3 denotes an undefined pair or C1-C6-alkyl; R4 and R5 are independently selected from a group consisting of phenyl, C3-C6-cycloalkyl; R6 denotes -OH, C1-C6-alkyl, C1-C6-alkoxy or a hydrogen atom; A denotes an oxygen or sulphur atom; X denotes a C1-C6-alkylene group; R7 denotes C1-C6-alkyl, phenyl, phenyl(C1-C6-alkyl)-, dihydrobenzofuran or pyridine, where any phenyl in group R7 can be optionally substituted with one or two groups independently selected from halogen, aminoacyl, C1-C6-alkoxycarbonyl, aminosulphonyl, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl, -COOH; and any pyridine in group R7 can be optionaly substituted with C1-C6-alkyl; R8 denotes C1-C6-alkyl or a hydrogen atom; Z denotes a C1-C10-alkylene or C2-C10-alkenylene group; Y denotes a bond or an oxygen atom; R9 and R10 independently denote a hydrogen atom, C1-C6-alkyl group, isoxazole or 8-hydroxy-1H-quinolin-2-one-(C1-C6-hydroxyalkyl); and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition having activity with respect to M3 muscarinic receptor; use of the compounds of formula (I) to produce a medicinal agent for treating and a method of treating diseases or conditions in which M3 muscarinic receptor activity is involved.

EFFECT: compounds of given formula have activity with respect to M3 muscarinic receptor.

26 cl, 8 dwg, 91 ex

 

The technical field to which the invention relates.

The present invention relates to oxazolines and thiazole derivatives, pharmaceutical compositions, methods for their preparation and use for the treatment of diseases involving enhanced activation of the M3 receptor.

Background of invention

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

There are five subtypes of muscarinic cholinergic receptors (mAChR), denoted M1-M5, and each of them is the product of a separate gene, and each of them has unique pharmacological properties. mAChR widely distributed in the bodies of vertebrates, and these receptors can mediate both inhibitory and stimulating effects. For example, in the smooth muscle of the respiratory tract, the urinary bladder and gastrointestinal tract M3 mAChR mediate contractile responses (review Caulfield, 1993, Pharmac. Ther., 58, 319-379).

It was shown that in the lungs important muscarinic M1, M2 and M3 receptors, which are located in the trachea, bronchi, submucosal glands and parasympathicus is their ganglia (review presented in Fryer and Jacoby, 1998, Am J Resp Crit Care Med., 158 (5 part 3), S154-160). M3 receptors in the smooth muscle of the respiratory tract mediates the reduction, but because of the narrowing of the bronchi. Stimulation of M3 receptors located in the submucosal glands, leads to secretion of mucus.

Enhanced signaling through muscarinic acetylcholine receptors was noted in a number of different pathophysiological conditions, including asthma and COPD. When COPD vagal tone may be increased (Gross et al., 1989, Chest, 96:984-987) and/or may provoke to a high degree obstruction of light by geometric considerations when exposed on the surface of the swollen or impregnated with mucus walls of the respiratory tract (Gross et al., 1984, Am Rev Respir Dis 129:856-870). In addition, inflammatory conditions can lead to the loss of inhibitory activity of M2 receptor, which leads to an increase in the number of acetylcholine released by stimulation of the vagus nerve (Fryer et al., 1999, Life Sci., 64, (6-7) 449-455). Reinforced in the activation of M3 receptors leads to increased airway obstruction. Thus, the identification of possible antagonists of muscarinic receptors can be used for therapeutic treatment of painful conditions involving increased activity of the M3 receptor. In fact, modern treatment strategies currently supports the time the regular use of bronchodilators-M3 antagonists as first-line therapy in patients with COPD (Pauwels et al., 2001, Am Rev Respir Crit Care Med, 163:1256-1276).

It was also shown that incontinence of urine due to increased sacramenti bladder is mediated by increased stimulation of the M3 mAChR receptors. Thus, antagonists of M3 mAChR can be used as therapeutic agents in the treatment of such mAChR-mediated diseases.

Despite the considerable body of evidence in support of therapy against muscarinic receptors for the treatment of painful conditions of the respiratory tract, relatively little antimuskarinovoe act occurs compounds are used in the clinic for pulmonary indications. Thus, there remains a need for new compounds that can cause a blockade of muscarinic M3 receptors, in particular in connection with the long period of action, which allows the application of the scheme a single dose of the drug. Because muscarinic receptors are widely distributed in the organism, winning is the ability to delivery anticholinergic drugs directly into the respiratory tract, because it allows you to enter a smaller dose of medication. Development and application of topically active drugs with a long validity period and medicine, held on the receptor or the lungs, could reduce the undesirable side effects that can be observed when the system has established the Institute of the same drug.

Tiotropy (Spiriva™) is currently presented on the market an antagonist of muscarinic receptors long-term actions for the treatment of chronic nonspecific lung diseases, which is administered by inhalation.

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

In Chem. Pharm. Bull., 27(12) 3149-3152 (1979) and J. Pharm. Sci., 69(5) 534-537 (1980) described foreline derivatives with atropine-like activity. In The Med. Chem. Res., 10 (9), 615-633 (2001) as antagonists of muscarinic receptors described isoxazoles and Δ2-isoxazolines.

In WO 97/30994 as antagonists of muscarinic receptors described oxadiazole and thiadiazole.

In EP 0323864 as antagonists of muscarinic receptors described oxadiazole related to mono - or bicyclic ring.

Well known is the class of agonists β2 adrenergic receptor. Many famous β2-agonists, in particular β2-agonists long-term effects, such as salmeterol and formoterol, play a role in the treatment of asthma and COPD. These compounds, as a rule, also administered by inhalation. Connections that are currently under evaluation as taken once daily β2-agonists described in Expert Opin. Investig. Drugs 14 (7), 775-783 (205). Well-known pharmacophores with β2-agonistic action is the snippet:

Also known in the art are pharmaceutical compositions containing the agonist muscarinic receptors and β2-agonist, for use in the treatment of respiratory disorders. For example, in US 2005/0025718 described β2-agonist in combination with Tiotropium, oxitropium, ipratropium and other muscarinic antagonists; WO 02/060532 described ... the combination of exotropia in β2-agonists. Other combinations M3 antagonist/β2-agonists described in WO 04/105759 and WO 03/087097.

Also known in the art are compounds acting and the antagonist of muscarinic receptors, and as a β2-agonist. Such bifunctional molecules provide bronchodilatation two different modes of action, with the pharmacokinetics of a single molecule. Compared with two separate compounds such molecule may be easier included in the composition for therapeutic applications and may be easier included in the third active ingredient, for example, with the steroid. Such molecules are described, for example, in WO 04/074246, WO 04/089892, WO 05/111004, WO 06/023457 and WO 06/023460, each of which uses different linker radical for covalent binding of M3 antagonist with β2-agonist, indicating that the structure is interrogo radical is not critical for the conservation activity. This is not unexpected, since the molecule does not require simultaneous interaction with M3 - and β2-receptors.

A brief description of the invention

The present invention relates to the compound of formula (I):

in which

(i) R1represents a C1-C6is alkyl or hydrogen; and R2represents hydrogen or a group-R7, -Z-Y-R7, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9-C(O)O-R7or-Z-C(O)-R7; and R3is an uncertain couple or C1-C6-alkyl; or

(ii) R1and R3form together with the nitrogen atom to which they are attached, geteroseksualnoe ring; and R2is an uncertain couple or a group-R7, -Z-Y-R7, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9-C(O)O-R7or-Z-C(O)-R7; or

(iii) R1and R2form together with the nitrogen atom to which they are attached, geteroseksualnoe ring, and the said ring is substituted by a group-Y-R7, -Z-Y-R7, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9-C(O)O-R7or-Z-C(O)-R7; and R3is an uncertain couple or C1-C6-alkyl;

R4and R5independently selected from the group consisting of aryl fused with a heterocycle which the alkyl aryl, heteroaryl, C1-C6-alkyl, cycloalkyl;

R6represents-OH, C1-C6-alkyl, C1-C6-alkoxy, hydroxy-C1-C6-alkyl, nitrile, group CONR82or a hydrogen atom;

A represents an oxygen atom or sulfur;

X represents alkylenes, alkenylamine or alkynylamino group;

R7represents a C1-C6is an alkyl, aryl condensed with cycloalkyl aryl condensed with heterocyclization aryl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, cycloalkyl or geterotsyklicescoe group;

R8represents a C1-C6-alkyl or a hydrogen atom;

Z represents a C1-C16-alkylenes, C2-C16-alkenylamine or C2-C16-alkynylamino group;

Y represents a bond or an oxygen atom;

R9and R10independently represent a hydrogen atom, a C1-C6is an alkyl, aryl condensed with heterocyclization aryl condensed with cycloalkyl aryl, heteroaryl group, the aryl(C1-C6-alkyl)- or heteroaryl(C1-C6-alkyl)-; or R9and R10form together with the nitrogen atom to which they are attached, containing 4 to 8 atoms gets aziklicescoe ring, optionally containing an additional nitrogen atom or oxygen;

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

In one subclass of compounds of the present invention:

R1represents a C1-C6is alkyl or hydrogen atom; R2represents a C1-C6-alkyl, a hydrogen atom or a group-Z-Y-R7and R3is an uncertain couple or C1-C6-alkyl, or

R1and R2together with the nitrogen atom to which they are attached, geteroseksualnoe ring, or R1and R3form together with the nitrogen atom to which they are attached, geteroseksualnoe ring;

R4and R5independently selected from the group consisting of aryl, heteroaryl, C1-C6-alkyl, cycloalkyl;

R6represents-OH, halogen, C1-C6-alkyl, hydroxy-C1-C6-alkyl or a hydrogen atom;

A represents an oxygen atom or sulfur;

X represents alkylenes, alkenylamine or alkynylamino group;

Z represents alkylenes, alkenylamine or alkynylamino group;

Y represents a bond or an oxygen atom;

R7represents aryl, heteroaryl, heteroseksualci.

Note that the carbon atom is, attached to R4, R5and R6may be asymmetric center, so the compounds of the present invention can be in the form of the individual enantiomers or mixtures of enantiomers.

A preferred class of compounds of the present invention consist of Quaternary ammonium salts of formula (I), represented by the formula (I), the nitrogen atom is a Quaternary nitrogen atom carrying a positive charge.

Compounds of the present invention can be applied in the treatment or prevention of diseases involving the activation of muscarinic receptors, for example the compounds according to the present invention is applicable to treatment in a wide range of indications, including, without limitation:

disorders of the respiratory tract, such as chronic nonspecific lung disease, chronic bronchitis, all types (including associate with them shortness of breath), bronchial asthma (allergic and non-allergic; "bronchitis infants"), a syndrome of respiratory disorders adult/acute respiratory distress syndrome (ARDS), chronic obstruction of the respiratory tract, bronchial hyperactivity, pulmonary fibrosis, emphysema, allergic rhinitis, exacerbation of hyperresponsiveness of the Airways due to other drug therapy, in particular other is th drug therapy by inhalation, pneumoconiosis (for example, aluminas, antraks, asbestosis, helicos, Philos, sideros, silicosis, tabacos and bissines);

disorders of the gastrointestinal tract, such as irritable bowel syndrome, spastic colitis, stomach ulcers and duodenal ulcers, spasms or increased peristalsis of the gastrointestinal tract, diverticulitis, pain accompanying spasms of smooth muscles of the gastrointestinal tract;

accompanying urination disorders disorders of the urinary tract, including neurogenic increased urination, neurogenic bladder, nocturnal enuresis, psychosomatic bladder associated with bladder spasms or chronic cystitis, urinary incontinence, urgent urge to urinate or frequent urination;

the sickness; and

disorders of the cardiovascular system, such as induced vagus nerve, sinus bradycardia.

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

Another aspect of the present invention relates to pharmaceutical compositions containing the compound of the present invention and a pharmaceutically acceptable carrier or excipient.

Another aspect of the present invention refers to the use of compounds of the present invention for the manufacture of a medicinal product for the treatment or prevention of a disease or condition that involved the activity of the muscarinic M3 receptor.

Description definitions

Unless otherwise specified in the context in which they are used, when used in this document the following terms have the following meanings:

The term "acyl" means-CO-alkyl group, where the alkyl groups defined in this document. Examples of acyl groups include-COCH3and -- COCH(CH3)2.

The term "acylamino" means-NR-acyl group in which the values of R and acyl is defined in this document. Examples of acylamino include-NHCOCH3and-N(CH3)COCH3.

The terms "alkoxy" and "alkyloxy" means-O-alkyl group in which the alkyl value described below. Examples of alkoxygroup vlachoutsicos (-OCH 3and ethoxy (-OC2H5).

The term "alkoxycarbonyl" means-COO-alkyl group in which the alkyl value defined below. Examples alkylcarboxylic groups include methoxycarbonyl and etoxycarbonyl.

The term "alkyl", used to refer to as a group or part of a group, refers to an unbranched or branched saturated hydrocarbon group containing in the composition of the chain from 1 to 12, preferably 1-6, carbon atoms. Examples of alkyl groups include methyl, ethyl, 1-propyl and 2-propyl.

The term "alkenyl"used to refer to as a group or part of a group, refers to an unbranched or branched hydrocarbon group containing in the composition of the chain from 2 to 12, preferably 2-6, carbon atoms and one carbon-carbon double bond. Examples alkenyl groups include ethynyl, 1-propenyl and 2-propenyl.

The term "alkylamino" means-NH-alkyl group, in which the meaning of alkyl is defined above. Examples of alkylamino include methylamino, ethylamino.

The term "alkylene" means the group-alkyl-in which the value of alkyl defined above. Examples alkilinity groups include-CH2-, -(CH2)2and-C(CH3)HCH2-.

The term "albaniles" means a group of alkenyl-in which the value of alkenyl defined above. Examples alkenylamine groups including the up-CH=CH-, -CH=CHCH2- and-CH2CH=CH-.

The term "akinyan" means the group-quinil-where-quinil - refers to an unbranched or branched hydrocarbon group containing in the structure a chain of 2 to 12, preferably 2-6, carbon atoms and one carbon-carbon triple bond. Examples alkenylamine groups include ethinyl and propargyl.

The term "alkylsulfonyl" means-SO-alkyl group, in which the meaning of alkyl is defined above. Examples alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl.

The term "alkylsulfonyl" means-SO2-alkyl group, in which the meaning of alkyl is defined above. Examples alkylsulfonyl groups include methylsulphonyl and ethylsulfonyl.

The term "alkylthio" means-S-alkyl group, in which the meaning of alkyl is defined above. Examples of alkylthio include methylthio, ethylthio.

The term "aminoacyl" refers to the group-CO-NRR, where R is described in this document. Examples aminoaniline groups include-CONH2and-CONHCH3.

The term "aminoalkyl" refers to the group alkyl-NH2in which the value of an alkyl described above. Examples aminoalkyl groups include-CH2NH2.

The term "aminosulfonyl" means the group-SO2-NRR, where R is described in this document. Examples aminosulfonyl groups include-SO 2NH2and-SO2NHCH3.

The term "aryl", used to refer to as a group or part of a group, denotes optionally substituted monocyclic or polycyclic aromatic carbocyclic fragment containing from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group may be substituted by one or more substituting groups.

The term "arylalkyl" refers to the group aryl-alkyl-, in which values of aryl and alkyl fragments described above. Preferred arylalkyl groups contain C1-4the alkyl fragment. Examples arylalkyl groups include benzyl, phenethyl and naphthalenethiol.

The term "arylalkyl" means aryl-alkyloxy - group, in which values aryl, alkyloxy fragments described above. Preferred arylalkylamine contain C1-4the alkyl fragment. Examples arylalkyl groups include benzyloxy.

The term "condensed with cycloalkyl aryl" means a monocyclic aryl ring, such as phenyl condensed with cycloalkyl group where the values of aryl and cycloalkyl defined in this document. Examples of condensed with cycloalkyl aryl groups include tetrahydronaphthyl and indanyl. Each aryl and cycloalkyl ring can bytesneeded one or more substituting groups. Condensed with cycloalkyl aryl group may be attached to the remainder of the compound via any acceptable carbon atom.

The term "condensed with heterocyclization aryl" means a monocyclic aryl ring, such as phenyl condensed with geteroseksualnoe group where the values of aryl and geterotsiklicheskie defined in this document. Examples of condensed with heterocyclization aryl groups include tetrahydropyranyl, indolinyl, benzodioxolyl, benzodioxolyl, dihydrobenzofuranyl and isoindolyl. Each aryl and geteroseksualnoe ring may be substituted by one or more substituting groups. Condensed with heterocyclization aryl group may be attached to the remainder of the compound via any acceptable carbon atom or nitrogen.

The term "aryloxy" means-O-aryl group in which the value of aryl described above. Examples of aryloxy include phenoxy.

The term "cyclic amine" means an optionally substituted 3-8-membered monocyclic cycloalkyl ring system in which 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 defined in this document). Examples of cyclic amines in luchot pyrrolidin, piperidine, morpholine, piperazine and N-methylpiperazine. The cyclic amino group may be substituted by one or more substituting groups.

The term "cycloalkyl" means optionally substituted saturated monocyclic or bicyclic ring system containing from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl rings include, cyclopropyl, cyclopentyl, cyclohexyl and cyclopentyl. Cycloalkyl group may be substituted by one or more substituting groups.

The term "cycloalkenyl" means cycloalkyl-alkyl - group in which the values cycloalkyl and alkyl fragments described above. Examples of monocyclic cycloalkenyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

The term "dendrimer" refers to the Central group with multiple functional areas attached to each functional area branches off group. Every part of the branch can be connected with other branches off the molecule, and this process can be repeated many times.

The term "dialkylamino" means-N(alkyl)2the group in which the meaning of alkyl is defined above. Examples of dialkylamino include the metilamino, diethylamino.

The terms "halo" or "halogen" means fluorine, chlorine, bromine or iodine. Preferred are fluorine or chlorine.

The term "halogenoalkane" means-O-alkyl group in which alkyl is substituted by one or more halogen atoms. Examples halogenating groups include triptoreline, deformedarse.

The term "halogenated" means an alkyl group that is substituted by one or more halogen atoms. Examples halogenating groups include trifluoromethyl.

The term "heteroaryl"used to refer to as a group or part of a group, denotes optionally unsubstituted aromatic monocyclic or polycyclic organic fragment, containing from 5 to 14 ring atoms, preferably 5 to 10 ring atoms in which one or more ring atoms is (are) an element (s)other than carbon, for example nitrogen, oxygen or sulfur. Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothiazoline, follow, imidazolidinyl, indolenine, indolizinyl, isoxazolyl, athinodorou, isothiazolinone, oxazolidinyl, oxadiazolidine, personilnya, pyridazinyl, pyrazolidine, pyridyloxy, pyrimidinyl, pyrrolidinyl, chinazolinei, hyalinella, those who retailnow, 1,3,4-thiadiazolyl, thiazolidine, thienyl and triazolyl group. Heteroaryl group may be substituted by one or more substituting groups. Heteroaryl group may be attached to the remainder of the molecule compounds of the present invention according to any acceptable carbon atom or nitrogen.

The term "heteroaromatic" means heteroaryl-alkyl - group in which the values of the heteroaryl and alkyl fragments described above. Preferred heteroallyl groups contain a fragment of a lower alkyl. Examples heteroarylboronic groups include pyridylmethyl.

The term "heteroaromatic" means heteroaryl-alkyloxy - group, in which values heteroaryl, alkyloxy fragments described above. Preferred heteroarylboronic contain a fragment of a lower alkyl. Examples of heteroaromatics include pyridylmethylene.

The term "heteroaromatic" means heteroaromatic - group, in which the value of heteroaryl described above. Examples of heterokaryosis include pyridyloxy.

The term "condensed with cycloalkyl heteroaryl" means a monocyclic heteroaryl group such as pyridyl or furanyl condensed with cycloalkyl group where the values of heteroaryl and cycloalkyl described above. Examples of the condensed what's with cycloalkyl heteroaryl groups include tetrahydropyranyl and tetrahydrofuranyl. Heteroaryl and cycloalkyl ring may be substituted by one or more substituting groups. Condensed with cycloalkyl heteroaryl group may be attached to the remainder of the compound via any acceptable carbon atom or nitrogen.

The term "condensed with heterocyclization heteroaryl" means a monocyclic heteroaryl group such as pyridyl or furanyl condensed with geteroseksualnoe group where the values of heteroaryl and geterotsiklicheskie described above. Examples of condensed with heterocyclization heteroaryl groups include dihydrodesoxymorphine, dihydropyrimidines, dihydropyrimidines and dioxopiperidin. Heteroaryl and geteroseksualnoe ring may be substituted by one or more substituting groups. Condensed with heterocyclization heteroaryl group may be attached to the remainder of the compound via any acceptable carbon atom or nitrogen.

The term "heteroseksualci" means: (i) optionally substituted cycloalkyl group containing from 4 to 8 ring atoms and one or more heteroatoms selected from O, S, or NR; (ii) cycloalkyl group containing from 4 to 8 ring atoms and CONR and CONRCO (examples of such groups include Succinimidyl and 2-oxopyrrolidin). Heteros kalkilya group may be substituted by one or more substituting groups. Heterocytolysine group can be attached to the remainder of the compound via any acceptable carbon atom or nitrogen.

The term "geterotsiklicheskikh" means heteroseksualci-alkyl - group in which the values geteroseksualbnogo and alkyl fragments described above.

Unless specified otherwise, it is used to denote, as a group, the term "lower alkyl" means an aliphatic hydrocarbon group, which may be unbranched or branched, containing within the chain of 1 to 4 carbon atoms, i.e. methyl, ethyl, propyl (propyl or isopropyl) or butyl (butyl, isobutyl or tert-butyl).

The term "sulfonyl" means-SO2-alkyl group, in which the meaning of alkyl is defined in this document. Examples sulfanilic groups include methanesulfonyl.

The term "sulfonylamino" means-NR-sulfonyloxy group, in which values of R and sulfonyl defined in this document. Examples of sulfonylamino include-NHSO2CH3. R means alkyl, aryl or heteroaryl described in this document.

The term "pharmaceutically acceptable salt" means physiologically or toxicologically acceptable salts include, when appropriate, pharmaceutically acceptable salt, adding a base, pharmaceutically acceptable salts of addition of acid and f is rmaceuticals acceptable salt of Quaternary ammonium. For example, (i) if the connection of the present invention contains one or more acidic groups, such as carboxylate, pharmaceutically acceptable salt, adding a base, which can be formed 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) if the connection of the present invention contains a basic group such as an amino group, pharmaceutically acceptable salts of addition of acid, which can be formed, include hydrochloride, hydrobromide, sulfates, phosphates, acetates, citrates, lactates, tartratami, mesylates, maleate, fumarate, succinate, and the like; (iii) if the connection contains a Quaternary ammonium group, suitable counterions can be, for example, chlorides, bromides, sulfates, methansulfonate, bansilalpet, toluensulfonate (tozilaty), phosphates, acetates, citrates, lactates, tartratami, mesylates, maleate, fumarate, succinate, and the like.

Note that as used in this document, references to the compounds of the present invention also include pharmaceutically acceptable salts.

The term "prodrug" refers to a compound that can be converted in vivo way (for example, by hydrolysis, recovery or oxidation) in the compound of the present invention. Suitable for formation of prodrugs of the group described in The Practice of Medicinal Chemistry, 2ndEd. pp 561-585 (2003) and F. J. Leinweber, Drug Metab. Res., 18, 379, (1987).

Note that as used in this document, references to the compounds of the present invention also include proletarienne forms.

The term "saturated" refers to compounds and/or groups that do not contain carbon-carbon double or carbon-carbon triple bonds.

The above cyclic groups, namely aryl, heteroaryl, cycloalkyl condensed with cycloalkyl aryl condensed with cycloalkyl heteroaryl, heteroseksualci condensed with heterocyclization aryl condensed with heterocyclization heteroaryl and cyclic amine can be substituted by one or more substituting groups. Suitable optional substituting groups include acyl (for example, -COCH3), alkoxy (e.g.,- OCH3), alkoxycarbonyl (for example, -COOCH3), 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, -CH 2Ph 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, -CHO, -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 (for example, -NHSO2CH3), heteroaromatic, cyclic amine (e.g. morpholine), aryloxy, heteroaromatic, arylalkylamine (e.g., benzyloxy), heteroarylboronic.

Alkylene and alkenylamine groups can be optionally substituted. Suitable optional substituting groups 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, -OCF3 or OCHF2), halogenated (e.g.,- CF3), alkyl (e.g.,- CH3or-CH2CH3), -OH, -CHO and-NO2.

Compounds of the present invention may exist in one or more geometric, optical, enantiomeric, diastereoisomeric and tautomeric forms, including, without limitation, CIS - and TRANS-forms; E - and Z-forms; R-, S -, and meso-forms, keto and enol forms. Unless otherwise specifically approved, a reference to a particular connection includes all such isomeric forms, including racemic and other mixtures. When appropriate, these isomers can be separated from the mixtures by use or modification of known methods (for example, chromatographic methods and techniques recrystallization). When appropriate, these isomers can be obtained by application or modification of known methods (e.g., asymmetric synthesis).

Group R1, R2and R3

There are three combinations of groups R1, R2and R3.

In combination (i) R1represents a C1-C6is alkyl or hydrogen; and R2represents hydrogen or a group-R7, -Z-Y-R7, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9-C(O)O-R7or-Z-C(O)-R7; and R3is an uncertain couple or C1-C6-alkyl, and in which case the nitrogen atom, to which it is attached is a Quaternary nitrogen atom and carries a positive charge.

In combination (ii) R1and R3form together with the nitrogen atom to which they are attached, geteroseksualnoe ring, and R2represents the uncertain pair (i.e. the substituent R2missing) or a group-R7, -Z-Y-R7, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9-C(O)O-R7or-Z-C(O)-R7. In this case, of course, if R2does not represent an uncertain couple, then the nitrogen atom to which it is attached is a Quaternary nitrogen atom and carries a positive charge. In particular, R1and R3form together with the nitrogen atom to which they are attached, containing from 3 to 7 ring atoms of the monocyclic ring in which the heteroatoms are nitrogen atoms. Examples of such rings include azetidinone, piperidinyl, piperazinilnom, N-substituted piperazinilnom, such as methylpiperidine, and pyrrolidinyl rings.

In combination (iii), R1and R2form together with the nitrogen atom to which they are attached, geteroseksualnoe ring, and the said ring is substituted by a group-Y-R7, -Z-Y-R7, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9-C(O)O-R7or-Z-C(O)-R7and R3represents " lannou pair (i.e. Deputy R3absent), or C1-C6-alkyl, in particular methyl. In particular, R1and R2form together with the nitrogen atom to which they are attached, containing from 3 to 7 ring atoms of the monocyclic ring in which the heteroatoms are nitrogen atoms. Examples of such rings include azetidinone, piperidinyl, piperazinilnom, N-substituted piperazinilnom, such as methylpiperidine, and pyrrolidinyl rings. Of course, if R3does not represent an uncertain couple, then the nitrogen atom to which it is attached is a Quaternary nitrogen atom and carries a positive charge.

If the substituent R2contains a group-R7or-Y-R7, -Z-Y-R7or a group-Z-NR9R10; or a group-Z-CO - NR9R10; or a group-Z-NR9-C(O)O-R7or a group-Z-CO2-R7; or R1, R2and the nitrogen atom to which they are attached, form a ring, then:

Z can represent, for example, -(CH2)1-8-and up to three carbon atoms in the chain, the latter optionally substituted by stands;

Y is a bond or-O-;

R7can be a

C1-C6-alkyl, such as methyl, ethyl, n - or isopropyl, n-, sec - or tert-butyl;

optionally substituted aryl, such as phenyl or naphthyl, recondensing with heterocyclization aryl, 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, pyridinyl, triazinyl, indolyl and indazoles;

optionally substituted aryl(C1-C6-alkyl)-, such as the Deputy, in which the aryl part is any one of the specifically mentioned above aryl groups, and -(C1-C6-alkyl)- represents-CH2- or-CH2CH2-;

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

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

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

optionally substituted heteroseksualci(Csub> 1-C8-alkyl)-, such as the Deputy, in which heterocytolysine part is azetidine, piperidinyl, piperazinil, N-substituted piperazinil, such as methylpiperazine, or pyrrolidinyl, and -(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 optionally substituted aryl condensed with heterocyclization aryl, heteroaryl or aryl(C1-C8-alkyl)-, which is just above when considering R7; or

R9and R10may form together with the nitrogen atom to which they are attached, a heterocyclic ring containing 4 to 8 ring atoms, preferably 4-6 ring atoms, and optionally containing an additional nitrogen atom or oxygen, such as azetidine, piperidinyl, piperazinil, N-substituted piperazinil, such as methylpiperazine, pyrrolidinyl, morpholinyl and thiomorpholine.

In one preferred embodiment of the invention in the group-NR1R2R3R1represents methyl or ethyl, R2is a certain or above-Z-NR9R10or-Z-Y-R7Y represents the ligature or-O-, and-Z - represents an unbranched or branched alkalinity radical linking nitrogen atom, and-NR9R10or YR7chain containing up to 16, for example, to 10, carbon atoms, and R3represents methyl, to the nitrogen atom was quaternity and carried a positive charge. In these cases, R7preferably is a cyclic lipophilic group, such as phenyl, benzyl, dihydrobenzofuran or phenylethyl, and the values of R9and R10defined and discussed above.

In another preferred embodiment, the group-NR1R2R3R2is a certain or above-Z-NR9R10or-Z-Y-R7, Y is a bond or-O-, and Z - represents an unbranched or branched alkalinity radical linking nitrogen atom, and-NR9R10or YR7chain containing up to 16, for example, to 10, carbon atoms, and R1and R3form together with the nitrogen atom to which they are attached, a heterocyclic ring containing 4 to 8 ring atoms, preferably 4-6 ring atoms, and optionally containing an additional nitrogen atom or oxygen, such as azetidinone, piperidinyl, piperazinilnom, N-substituted piperazinilnom, such as methylpiperidine, pyrrolidinyl, mo is molinillo and thiomorpholine ring, to the nitrogen atom was quaternity and carried a positive charge. In these cases, R7preferably is a cyclic lipophilic group, such as phenyl, benzyl, dihydrobenzofuran or phenylethyl; R9and R10defined above. In one subclass of compounds according to this embodiment, R1and R3form together with the nitrogen atom to which they are attached, piperidinyl or pyrrolidinyl ring.

Group R4, R5and R6

R4and R5can be independently selected from any of the aryl condensed with heterocyclization aryl condensed with cycloalkyl aryl, heteroaryl, C1-C6is an alkyl or cycloalkyl groups, which is exactly the above when considering R5. R6can be a-OH, a hydrogen atom, a C1-C6-alkyl, such as methyl or ethyl, C1-C6-alkoxy, such as methoxy or ethoxy, hydroxy-C1-C6-alkyl, such as hydroxymethyl, nitrile, or a group CONR82in which each R8independently represents a C1-C6-alkyl, such as methyl or ethyl, or hydrogen atom. In the present invention, it is preferable for the case when R6represents-OH. Preferred combinations of R4and R5/sup> in particular, if R6represents-OH include those combinations, when (i) each of R4and R5represents an optionally substituted monocyclic heteroaryl containing 5 or 6 ring atoms, such as pyridyl, oxazolyl, thiazolyl, furyl and, in particular, thienyl, such as 2-thienyl; (ii) each of R4and R5represents optionally substituted phenyl; (iii) one of R4and R5represents optionally substituted phenyl, and the other is cycloalkyl, such as cyclopropyl, cyclobutyl or, in particular, cyclopentyl or cyclohexyl; and (iv) one of R4and R5represents an optionally substituted monocyclic heteroaryl containing 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.

Ring atom of A

A can represent an oxygen atom or sulfur.

Deputy R8

Although R8can be a C1-C6-alkyl, such as methyl or ethyl, in the present invention, preferably, when R8represents a hydrogen atom.

The radical X

Although X may be alkilinity, alkenylamine or alkynylaryl radical, in the present image is hetenyi preferably, if it is alkylen, for example, ethylene or methylene.

A preferred subclass of compounds, which include the present invention consists of compounds of formula (IA)

in which A represents-O - or-S-; m is 1 or 2; the ring A represents an optionally substituted phenyl ring, or containing 5 or 6 ring atoms, monocyclic heterocyclic ring or condensed with heteroseksualnymi the phenyl ring, where geteroseksualnoe ring is a containing 5 or 6 ring atoms, monocyclic heterocyclic ring; R4represents phenyl, thienyl, cyclopentyl or cyclohexyl; R5represents 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 16; Y is a bond or-O-, and X-represents a pharmaceutically acceptable anion.

Another preferred subclass of compounds, which include the present invention consists of compounds of formula (IB)

in which A represents-O - or-S-; m is 1 or 2; ring B represents pyrrolidino or piperidino ring; the ring A represents an optionally substituted phenyl to which ICO, or containing 5 or 6 ring atoms, monocyclic heterocyclic ring or condensed with heteroseksualnymi the phenyl ring, where geteroseksualnoe ring is a containing 5 or 6 ring atoms, monocyclic heterocyclic ring; R4represents phenyl, thienyl, cyclopentyl or cyclohexyl; R5represents 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 16; Y is a bond or-O-, and X-represents a pharmaceutically acceptable anion.

Another preferred subclass of compounds, which include the present invention consists of compounds of formula (IC)

in which A represents-O - or-S-; m is 1 or 2; ring B represents pyrrolidino or piperidino ring; R4represents phenyl, thienyl, cyclopentyl or cyclohexyl; R5represents phenyl, thienyl, cyclopentyl or cyclohexyl; R9and R10independently represent a hydrogen atom, or optionally substituted C1-C6is alkyl or aryl, such as optionally substituted phenyl; 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 16; Y represents a tie is or-O-, and X-represents a pharmaceutically acceptable anion.

In compounds (IA) and (IB) of the present invention, preferably, when the ring A is (i) optionally substituted phenyl, where the optional substituents are selected from alkoxy, halogen, in particular fluorine or chlorine, C1-C3-alkyl, amino1-C3-acyl, amino1-C3-alkyl, or (ii) the condensed system with heteroseksualnymi the phenyl ring, where geteroseksualnoe ring is a containing 5 or 6 ring atoms, monocyclic heterocyclic ring, such as dihydrobenzofuranyl.

In each of the subclasses (IA), (IB) and (IC) s+t can be equal, for example, 1, 2, 3, 4, 5, 6 or 7 and can be increased by suitable combinations of s and t, where t is 0, 1, 2, 3, 4, 5 or 6 and s is 1, 2, 3, 4, 5, 6 or 7.

In compounds (IA) and (IB) of the present invention, it is preferable combination of t, Y and s, where t is 0, s is 3, and Y represents-O-. Additional preferred for the present invention is a combination, where Y represents a bond and s+t is 2, 3 or 4.

In the compounds (IC) of the present invention, it is preferable combination of t, Y and s, where Y is a bond and s+t is equal to 8, 9 or 10.

It should be understood that certain combinations of R4, R5and R6can cause clicks the application of optical enantiomers. In such cases, as a rule, both enantiomers of the present invention have affinity for the M3 receptor, although a single enantiomer, as a rule, is more preferable in terms of the activity in relation to the M3 receptor and/or selectivity of action against the M2 receptor. In several embodiments of the present invention are known absolute stereochemistry of the preferred enantiomer. For example, in one preferred embodiment, R4represents a phenyl group; R5represents tsiklogeksilnogo or cyclopentyloxy group; R6represents a hydroxyl group; and the carbon atom to which they are attached, has an absolute R-configuration, which is determined by the rules of Cahn-Ingold-Prelog.

Examples of compounds of the present invention include compounds described in this document are examples.

Preferred compounds of the present invention include:

salt [2-(hydroxydiphenylmethyl)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylphenethylamine;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(4-methylpent-3-enyl)ammonium;

with the and [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]dimethylamine;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(6-methylpyridin-2-ylmethyl)ammonium;

salt [2-(cyclopentylacetyl)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium;

salt of 1-[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]-1-(3-phenoxypropan)pyrrolidine;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(4-phenoxybutyl)ammonium;

salt (2-benzyloxyethyl)-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(4-phenylbutyl)ammonium;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[3-(4-pertenece)propyl]dimethylamine;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenylpropyl)ammonium;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(2-phenoxyethyl)ammonium;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-para-trilateral)ammonium;

salt [3-(4-chlorophenoxy)propyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[3-(3,4-dichlorophenoxy)propyl]dimethylamine;

salt [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(8-methylaminomethyl)ammonium;

salt [2-((R)-cyclohexylamin oxiranylmethyl)oxazol-5-ylmethyl]dimethyl-[2-(4-methylaminomethyl)ethyl]ammonium;

salt of {2-[2-(cyclohexylhydroxylamine)oxazol-5-yl]ethyl}dimethyl(3-phenoxypropan)ammonium;

salt of {2-[2-(hydroxydiphenylmethyl)oxazol-5-yl]ethyl}dimethyl(3-phenoxypropan)ammonium;

salt [2-(hydroxydiphenylmethyl)thiazole-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium;

salt (3-benzyloxyphenyl)-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio;

salt [2-(4-chlorobenzoyloxy)ethyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio.

As reported above under "Background of invention", are known compounds which are antagonists of M3 receptor and agonists β2-adrenergic receptors, and treatment of respiratory diseases such compounds with dual activity is a recognised form of treatment. Known strategy to obtain compounds with such dual mechanisms of action, is a simple covalent binding compound is an antagonist of M3 receptor with the compound is an agonist of β2-adrenergic receptors. Such covalent conjugates which agonist M3 receptor compounds (I), which is defined and discussed above, and agonists 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, modifica is consistent by replacing groups of R 2group-L-B, where L is a linker moiety and B is a fragment having agonistic activity against β2-adrenergic receptors. Structurally such conjugates with dual activity can be represented by formula (III):

in which R1, R3, R4, R5, R6and R8defined and discussed above in relation to compounds (I) of the present invention, L is a divalent linker radical, and B is a fragment having agonistic activity against β2-adrenergic receptors such as the β2-agonistic pharmacophor, referred to above under "Background of invention". Such compounds (III) form another aspect of the present invention. An example of such a compound is the compound described in the document of example 77.

The present invention also relates to pharmaceutical compositions containing as active ingredient a compound of the present invention. For the prevention and treatment of inflammatory lung diseases other compounds can be combined with the compounds of the present invention. Therefore, the present invention also relates to pharmaceutical compositions for the prevention and treatment of disorders of the stomach is considerable ways, such as chronic nonspecific lung disease, chronic bronchitis, bronchial asthma, chronic obstruction of the respiratory tract, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis, containing a therapeutically effective amount of the compounds of the present invention and one or more other therapeutic agents.

For the prevention and treatment of inflammatory lung diseases other compounds can be combined with the compounds of the present invention. Therefore, the present invention includes the combination (a combination of) the means of the present invention, described earlier in this document, with one or more anti-inflammatory bronchodilators, antihistaminic, protivozastojnye or antitussive means, and the means of the present invention, described earlier in this document, and these combined funds exist in the same or in different pharmaceutical compositions, administered separately or simultaneously. Preferred combinations should include two or three different pharmaceutical compositions. Suitable therapeutic agents for a combination therapy with compounds of the present invention include:

one or more bronchodilators, such as PDE3 inhibitors;

metalx is tiny, such as theophylline;

other inhibitors of muscarinic receptors;

corticosteroid, such as fluticasone propionate, ciclesonide, mometasone 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 of glucocorticoid receptor;

the agonist of β2-adrenergic receptors, for example, 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 for 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 0439762, 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;

modulator leukotrienes, such as montelukast, zafirlukast or pranlukast;

inhibitors of proteases, such as inhibit the market of metalloprotease matrix, for example inhibitors of MMP12 and TACE, such as marimastat, DPC-333, GW-3333;

inhibitors of elastase human neutrophils, such as sivelestat and 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), such as roflumilast, arofylline, cilomilast, ONO-6126 or IC-485;

inhibitors of phosphodiesterase-7;

antitussive agent, such as codeine or dextromorphan;

kinase inhibitors, especially inhibitors of P38 MAPK;

antagonists RH;

inhibitors of iNOS;

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

the antagonist of the dopamine receptor;

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

A2a agonists, such as described in EP 1052264 and EP 1241176;

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

functional modulators of chemokine receptors, e.g., 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 modulating action prostanoid receptors, such as PGD2(DP1 or CRTH2), or antagonist of the thromboxane A2for example, ramatroban;

compounds modulating the functions of Th1 or Th2, for example, agonists of PPAR;

Anta is honesty receptor interleukin 1, such as the sea of Galilee;

agonists of interleukin 10, such as inadequacy;

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

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

anti-infective funds (antibacterial or antiviral), and anti-allergic medicines, including without limitation antihistamines.

The mass fraction of the first and second active ingredients can vary and depend upon the effective dose of each ingredient. As a rule, use effective dose of each ingredient.

Any suitable route of administration may be used for providing a mammal, especially a human, an effective dose of a compound of the present invention. In therapeutic practice, 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, ophthalmic, nasal, buccal and pulmonary.

The size of a prophylactic or therapeutic dose of the compounds of the present invention, no doubt, vary depending on a number of FA is tori, including activity specifically used connections, age, body weight, diet, General health, and sex of the patient, time of administration, route of administration, rate of excretion, the use of other drugs and the severity of the disease under treatment. Usually, the range of daily doses for inhalation is 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 per kg and more preferably from 0.1 μg to 50 μg per kg, in single or fractional doses. On the other hand, in some cases it may be necessary to use dosages outside these limits. Compositions suitable for administration by inhalation, known and may contain carriers and/or diluents known for use in such compositions. The composition may contain from 0.01 to 99 wt.% active compounds. Preferably, a single dose contains the 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 relates to pharmaceutical compositions that contain the compound of the present invention and a pharmaceutically acceptable carrier. The term "composition", as in "pharmaceutical is Kai composition", is intended to encompass a product containing the active ingredient (the ingredients) and components of the media inert ingredient (ingredients) (pharmaceutically acceptable excipients), as well as any product that is the result, directly or indirectly, combination, complexation or aggregation of any two or more of the ingredients, or dissociation of one or more ingredients, or other types of reactions or interactions of one or more of the ingredients. Therefore, the pharmaceutical compositions of the present invention encompass any composition made by mixing the compounds of the present invention, additional active ingredient (ingredient and pharmaceutically acceptable excipients.

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

For delivery by inhalation, the active compound is preferably in the form of microparticles. They can be obtained by a number of methods, including spray drying, lyophilization and micronization.

As an example, the composition according to the present invention can be prepared in the form of suspension for delivery with the help of a nebulizer or aerosol form in a liquid propellant, for example, for use in the dosing inhaler under pressure (PMDI). Propellants suitable for use in PMDI, known in the art and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl2F2) and HFA-152 (C2H4F2and isobutane.

In the preferred embodiment of the present invention the composition of the present invention is a dry powder form for delivery of a dry powder inhaler (DPI). There are many types DPI.

Microparticles for delivery can be included in the composition with fillers that contribute to the delivery and release. For example, in a dry powder comprising microparticles can be included in the composition with the large carrier particles, which contribute to the flux of the DPI in the lungs. Particles suitable carrier known and include particles of lactose; they can have a median mass aerodynamic diameter of 90 microns.

An example of a composition based on and is Rosalia contains the following:

the compound of the present invention to 24 mg/cylinder;

lecithin, NF fluid. conc. 1.2 mg/cylinder;

Trichlorofluoromethane, NF - 4,025 g/cartridge;

DICHLORODIFLUOROMETHANE, NF - 12,15 g/container.

The active compounds can be entered dosed as described, depending on the type of inhalation system. In addition to the active compounds of the input form may optionally contain fillers such as, for example, propellants (e.g., frigen in the case of dosing aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, additional active compounds.

For the purposes of inhalation is available with a wide range of systems in which aerosols with optimal particle size can be obtained and entered using the technique of inhalation, suitable for the patient. In addition to the use of adapters (spacers, expanders), pear-shaped containers (e.g., Nebulator®, Volumatic®and automatic spraying devices (Autohaler®for dosing aerosols, in particular in the case of powder inhalers available is a number of technical solutions (for example, Diskhaler®, Rotadisk®, Turbohaler®or inhalers, for example, described in EP-A-505321). In addition, the compounds of the present invention can be delivered in a multi-chambered device, thereby allowing the delivery of a combination of agents.

The synthesis methods

Compounds of the present invention can be obtained in accordance with the methodologies presented on the following schemes and examples, using appropriate materials and additionally illustrated by the following specific examples. Moreover, using the techniques described in the herein disclosure, a specialist in the art can easily get more of the compounds according to the present invention claimed in this document. However, the compounds are illustrated by the examples should not be construed as the only type, which is regarded as the invention. In the examples below are illustrated the details of obtaining compounds of the present invention. Experts in the art should understand that in order to obtain these compounds can be used known variations of the conditions and processes of the subsequent techniques receipt.

Compounds of the present invention can be isolated in the form of their pharmaceutically acceptable salts, such as described earlier in this document. In order to avoid their unwanted participation in the reactions, resulting in the th to the formation of compounds, it may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediate products used for obtaining compounds of the present invention. Can be used traditionally used protective group, for example, described in T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry" John Wiley and Sons, 1999.

Compounds of the present invention can be obtained in accordance with the ways of synthesis are illustrated in schemes 1-4.

Scheme 1

Scheme 2

Scheme 3

The compounds of formula (I-b), in which values of Rc, Rdand Redefined for R1, R2and R3and do not represent a hydrogen atom, can be obtained from compounds of formula (I-a) by reacting with an alkylating agent of the formula (XXI):

in which W is a leaving group such as halogen, tosylate, mesilate. Interaction can be done in a number of solvents, preferably DMF, chloroform or acetonitrile, at temperatures from 0°C to the temperature of sublimation of the solvent. Similarly, compounds of formula (I-e), (I-g), (I-i), (I-k) and (I-n) can be obtained from compounds of formula (I-d), (I-f), (I-h), (I-j) and (I-m), respectively.

Should the be clear some compounds may contain a chiral center and therefore exist in enantiomeric forms, which can be separated using techniques of chiral preparative HPLC using conditions known to experts in the art and is illustrated below.

Compounds of General formula (I-a) can be obtained from compounds of General formula (II):

by interacting with the compound of General formula (XXII):

in which Raand Rbdefined for R4and R5in the General formula (I), and M represents a counterion of the metal such as Li or MgBr. The reaction can be carried out in an aprotic organic solvent such as THF or diethyl ether, at temperatures preferably from -78°C to the temperature of sublimation of the solvent.

Compounds of General formula (XXII) are well known in the art and are readily available or can be obtained by known methods.

Compounds of General formula (II) can be obtained from compounds of General formula (III):

by interacting with the amine of formula (XXIII):

in which Rcand Rddefined for R1and R2in the General formula (I). The reaction is carried out in a number of RA the creators, preferably in THF/DCM, in the temperature range, preferably from 0 to 100°C.

Compounds of General formula (XXIII) are well known in the art and can be obtained by known methods or are commercially available.

The compounds of formula (III) can be obtained from compounds of General formula (IV):

by interacting with brainwashin agent such as N-bromosuccinimide in the presence of the initiator free radical reactions, such as AIBN or benzoyl peroxide. The reaction can be carried out in suitable solvents, such as CCl4in the temperature range, preferably from ambient temperature to the temperature of sublimation of the solvent.

The compounds of formula (IV) can be obtained from compounds of General formula (V):

by reacting with acid, such as hydrochloric acid, sulfuric acid, methanesulfonate or triftormetilfullerenov acid, in a number of solvents such as THF, DCM, water and, preferably, 1,4-dioxane, in a temperature range, preferably from ambient temperature to the temperature of sublimation of the solvent.

Alternatively, the compounds of formula (IV) can be obtained from compounds of General formula (V) catalyzed by palladium cyclization using PAL is Diavolo catalyst, such as bis(dibenzylideneacetone)palladium, in the presence of ligand, such as triphenylphosphine, and a base, such as tert-piperonyl sodium in a solvent such as THF, at a temperature of from room temperature to the temperature of sublimation of the solvent.

Alternatively, the compounds of formula (IV) can be obtained from compounds of formula (XVI):

in accordance with the method described in J. Chem. Soc. 1948, 1960. Compounds of General formula (XVI) are known in the art and can be obtained by known methods, such as described in Tetrahedron 2002, 58(14), 2813.

Alternatively, the compounds of formula (IV) can be obtained from compounds of formula (XVII):

in accordance with the method described in J. Org. Chem., 1938, 2, 319. Compounds of General formula (XVII) are well known in the art and can be obtained by known methods, such as described in GB 2214180.

Compounds of General formula (V) can be obtained from compounds of General formula (VI):

by interacting with propargylamine in the presence of a suitable agent of combination reaction, such as DCC/HOBt, or other known methods of combinations. Alternatively, the compounds of formula (VI) can be converted, for example, chlorine is a hydride, and in a well-known conditions, the formation of amide, optionally in the presence of a suitable dinucleophiles base and a suitable solvent. Compounds of General formula (VI) are readily available or can be obtained by known methods.

Alternatively, compounds of General formula (I-a) can be obtained from compounds of General formula (VII):

in accordance with the methods described above to obtain compounds of the formula (II) from compounds of formula (III).

Compounds of General formula (VII) can be obtained from compounds of formula (VIII):

in accordance with the methods similar to those described for preparing compounds of the formula (III) from compounds of formula (IV)as described above.

Compounds of General formula (VIII) can be obtained from compounds of formula (IV) using the methods described above to obtain compounds of the formula (I-a) from compounds of formula (II).

Alternatively, the compounds of formula (VIII) can be obtained from compounds of formula (XIX):

using the methods described above to obtain compounds of the formula (IV) from compounds of formula (XVII). Compounds of General formula (XIX) can be obtained by known methods, such as described in GB 2214180.

As viola is rnative the compounds of formula (VIII) can be obtained from compounds of formula (XX):

using the methods described above to obtain compounds of the formula (IV) from compounds of formula (V).

Compounds of General formula (XX) can be obtained from compounds of formula (XVIII) using the methods described above to obtain compounds of the formula (V) from compounds of formula (VI).

Alternatively, the compounds of formula (I-b) can be obtained directly from compounds of formula (VII) by quaternization described above and suitably substituted tertiary amine.

Alternatively, the compounds of formula (I-a)in which-NRcRdrepresents a secondary amine (i.e. one of Rcor Rdrepresents a hydrogen atom)can be obtained from compounds of formula (I-a)in which-NRcRdrepresents a group-NH2by reductive alkylation appropriately substituted aldehyde. The interaction is carried out in the presence of a reducing agent, such as cyanoborohydride or sodium borohydride, preferably triacetoxyborohydride sodium, in a number of organic solvents, preferably dichloromethane.

The compounds of formula (I-d) and (I-e) can be obtained from compounds of formula (I-c) by the methods described above alkylation or reductive alkylation and in accordance with the standard and ways, well-known specialists in this field of technology.

The compounds of formula (I-c) can be obtained from compounds of General formula (IX):

by interaction with a reducing agent, such as sociallyengaged, diisobutylaluminium or borane, in some aprotic solvents such as diethyl ether or THF, or preferably by hydrogenation in the presence of a catalyst, such as Raney Nickel, in a suitable solvent, such as EtOAc or EtOH, at a temperature range from room temperature to the temperature of sublimation of the solvent.

Compounds of General formula (IX) can be obtained from compounds of General formula (VIII) by communicating with a source of cyanide ion, such as cyanhydrin acetone or inorganic cyanide, preferably sodium cyanide, in the presence of dinucleophiles base, such as tetramethylguanidine, in some solvent, preferably in ethanol, in a temperature range preferably from ambient temperature to the temperature of sublimation of the solvent.

The compounds of formula (I-f) can be obtained from compounds of formula (I-a) through interaction with a reducing agent, such as triethylsilane, in the presence of acid, such as triperoxonane acid, in a solvent such as DCM, at t is mperature from room temperature to the temperature of sublimation of the solvent.

The compounds of formula (I-h) can be obtained from compounds of formula (I-a) by reacting with an alkylating agent of the formula (XXIV):

in which the value of Rfdefined for R6in the General formula (I), and Y represents a leaving group such as halogen, tosylate. mesilate. The reaction is carried out in the presence of a base such as sodium hydride, in a solvent such as THF, at a temperature from 0°C to the temperature of sublimation of the solvent.

Compounds of General formula (I-m) can be obtained from compounds of formula (I-l) using the methods described above to obtain compounds of the formula (I-d) from compounds of formula (I-c).

Compounds of General formula (I-l) can be obtained from compounds of formula (XIV) using the methods described above to obtain compounds of the formula (I-c) from compounds of formula (IX).

Compounds of General formula (XIV) can be obtained from compounds of formula (XIII) using the methods described above to obtain compounds of the formula (IX) compounds of the formula (VII).

Alternatively, the compounds of formula (I-k) can be obtained directly from compounds of formula (XIII) by quaternization described above and suitably substituted tertiary amine.

Compounds of General formula (I-j) can be obtained from compounds of formula (XIII) with COI is whether the methods described above to obtain compounds of the formula (I-a) from compounds of formula (VII).

Compounds of General formula (XIII) can be obtained from compounds of formula (XII) using the methods described above to obtain compounds of the formula (III) from compounds of formula (IV).

Compounds of General formula (XII) can be obtained from compounds of General formula (XI):

by interaction with a reducing agent such as Raney Nickel, in a solvent such as ethanol at a temperature from room temperature to the temperature of sublimation of the solvent in accordance with the method described in J. Org. Chem. 2006, 71(8), 3026.

Compounds of General formula (XI) can be obtained from compounds of General formula (X):

by interaction with 1-(methylthio)acetone in the presence of anhydride triftormetilfullerenov acid, in a solvent such as DCM, at a temperature from 0°C to the temperature of sublimation of the solvent in accordance with the method described in J. Org. Chem. 2006, 71(8), 3026.

Compounds of General formula (X) are well known in the art and can be obtained by known methods or are commercially available.

Scheme 4

The compounds of formula (XXIX) can be obtained from compounds of formula (XXVI) with COI is whether the sequence of reactions, similar to those used to obtain the compounds of formula (I-b) from compounds of formula (VIII) in the above scheme 1.

The compounds of formula (XXVI)in which Raand Rbare the same, can be obtained from compounds of formula (XXV), in which R is a suitable alkyl group (such as ethyl or methyl), by treatment with a suitable ORGANOMETALLIC compound such as a Grignard reagent, in a suitable solvent, such as THF or diethyl ether. The compounds of formula (XXVI)in which Raand Rbare different, can be obtained from compounds of formula (XXV) by conversion to an intermediate amide, preferably amide Weinrebe, and for stepwise introduction of Raand Rbwith the help of their respective ORGANOMETALLIC compounds.

The compounds of formula (XXV) is well known from the literature, for example, Helv. Chim. Acta 1946, 29, 1957.

Further non-limiting examples illustrate the present invention.

General details of the experiments:

All reactions were carried out in nitrogen atmosphere, unless otherwise specified.

NMR spectra were obtained on a spectrometer Varian Unity Inova 400 with the registration of inverse-detected triple resonance in the sample (5 mm), operating at 400 MHz or on a spectrometer Bruker Avance DRX 400 with the registration of inverse-detected train the th resonance in the sample (5 mm), operating at 400 MHz or on a spectrometer Bruker Avance DPX 300 with the standard registration double resonance in the sample (5 mm), operating at 300 MHz. Shifts are presented in ppm relative to tetramethylsilane.

If the products were purified by the method of column chromatography, the term "flash chromatography on silica ' refers to silica gel chromatography with a particle size of from 0.035 to 0,070 mm (220-440 mesh) (e.g., silica gel 60 manufactured Fluka) and accelerated elution under the influence of the nitrogen pressure up to 10 pounds/inch2. If you used thin layer chromatography (TLC), it refers to TLC on silica gel using plates (usually 3×6 cm) of silica gel on aluminum foil with a fluorescent indicator (254 nm) (e.g., Fluka 60778). All solvents and commercial reagents were used as delivered.

All contain basically the center (centers) of the compound, which was purified by HPLC method, was obtained as TFA-salt, unless otherwise specified.

Conditions for preparative HPLC:

C18-reverse-phase column (column 100×22.5 mm Genesis with a particle size of 7 μm). UV detection at 230 nm.

LC/MS system

Used system for liquid chromatography/mass spectrometry (LC/MS):

Instructional method LC/MS No. 1

Waters Platform LCT with a C18-reverse-phase column (100×3.0 mm Higgins Clipeus with razmara the particles 5 microns), elution A: water + 0.1% of formic acid; B: acetonitrile + 0.1% of formic acid. Gradient:

Gradient timeFlow ml/min%%
0,001,0955
1,001,0955
15,001,0595
20,001,0595
22,001,0955
25,001,0955

Discovery - MS, ELS, UV (selection of 100 μl for hosting MS and built-in UV-detector at 254 nm)

The method of ionization when conducting MS - elektrorazpredelenie (positive ion)

Instructional method LC/MS No. 2

Waters Platform LC with a C18-reverse-phase column (30×4.6 mm Phenomenex Luna with the size of h is STIC 3 μm), elution A: water + 0.1% of formic acid; B: acetonitrile + 0.1% of formic acid. Gradient:

Gradient timeFlow ml/min%%
0,002,0955
0,502,0955
4,502,0595
5,502,0595
6,002,0955

Discovery - MS, ELS, UV (selection of 100 μl for hosting MS and built-in UV-detector)

The method of ionization when conducting MS - elektrorazpredelenie (positive and negative ion)

Instructional method LC/MS No. 3

Waters Micromass ZQ with a C18-reverse-phase column (30×4.6 mm Phenomenex Luna with a particle size of 3 μm), elution A: water + 0.1% of formic acid; B: acetonitrile + 0.1% of formic acid. Gradient:

Gradient timeFlow ml/min%%
0,002,0955
0,502,0955
4,502,0595
5,502,0595
6,002,0955

Discovery - MS, ELS, UV (selection of 100 μl for hosting MS and built-in UV-detector)

The method of ionization when conducting MS - elektrorazpredelenie (positive and negative ion)

Instructional method LC/MS No. 4

Waters ZMD with a C18-reverse-phase column (30×4.6 mm Phenomenex Luna with a particle size of 3 μm), elution solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid). Gradient:

Gradient timeOn the OK ml/min %%
0,002,0955
0,502,0955
4,502,0595
5,502,0595
6,002,0955

Discovery - MS, ELS, UV (a selection of 200 μl for hosting MS and built-in diode matrix detector Waters 996)

The method of ionization when conducting MS - elektrorazpredelenie (positive and negative ion)

Instructional method LC/MS No. 5

Waters Micromass ZQ with a C18-reverse-phase column (100×3.0 mm Higgins Clipeus with particle size 5 μm), elution A: water + 0.1% of formic acid; B: acetonitrile + 0.1% of formic acid. Gradient:

Gradient timeFlow ml/min%%
0,001,0955
1,001,0955
15,001,0595
20,001,0595
22,001,0955
25,001,0955

Discovery - MS, ELS, UV (selection of 100 μl for hosting MS and built-in UV-detector at 254 nm)

The method of ionization when conducting MS - elektrorazpredelenie (positive ion)

Instructional method LC/MS No. 6

Waters Micromass ZQ with a C18-reverse-phase column (100×3.0 mm Higgins Clipeus with particle size 5 μm), elution A: water + 0.1% of formic acid; B: acetonitrile + 0.1% of formic acid. Gradient:

Gradient timeFlow ml/min%%
0,001,0955
1,001,0955
15,001,0595
20,001,0595
22,001,0955
25,001,0955

Discovery - MS, ELS, UV (selection of 100 μl for hosting MS and built-in UV-detector at 254 nm)

The method of ionization when conducting MS - elektrorazpredelenie (positive ion)

Abbreviations used in the experimental section:

DCM=dichloromethane

DIPEA=diisopropylethylamine

DMAP=dimethylaminopyridine

DMF=dimethylformamide

EtOAc=ethyl acetate

EtOH=ethanol

IMS=industrial denatured spirit

MeOH=methanol

RT=room temperature (K.T.)

Rt=retention time

TFA=triperoxonane acid

THF=tetrahydrofuran

Sat=saturated (us.)

The intermediate p is the FL

The intermediate product 1

2-Oxo-2-phenyl-N-prop-2-enolacetate (V): Ra=Ph

To a solution of phenylglyoxylic acid (6.0 g, 40 mmol) and 3 drops of DMF in anhydrous DCM (50 ml) was added oxalicacid (6,1 g, 48 mmol). The reaction mixture was stirred at room temperature for 3 hours, and then solvent was removed. The residue was absorbed anhydrous DCM (50 ml) and cooled the solution to 0°C. Gently for 10 minutes was added a mixture of propargylamine (2.2 g, 40 mmol) and triethylamine (of 4.05 g, 40 mmol), and then leaving the mixture to warm to room temperature. Continued stirring for 2.5 hours, and then added water (10 ml). The mixture was washed with 1M HCl (2×20 ml), us. the sodium bicarbonate (aq.) (2×20 ml)and then brine. Then the organic phase was dried (Na2SO4) and solvent was removed. The residue was led from cyclohexane to obtain the product as a light brown solid.

Output: 5.75 g, 76%.

LC/MS (Method 3): Rt 2,47 min, m/z 188 [MH+].

The intermediate product 2

(5-Methoxazole-2-yl)phenylmethanone (IV): Ra=Ph

To a solution of 2-oxo-2-phenyl-N-prop-2-isolated (intermediate 1) (2.4 g, 12,83 mmol) in 1,4-dioxane (20 ml) was added dropwise methanesulfonyl acid (10 g, 104 mmol). The resulting solution was heated at 90°C for the of 66 hours. The reaction mixture was cooled and solvent was removed. The dark residue was distributed between DCM and water. DCM fraction washed with 1M HCl (2×), us. the sodium bicarbonate (2×)and then brine. The solution was dried (Na2SO4) and solvent was removed to obtain the crude product. Conducted clearing by the method of column chromatography, elwira cyclohexane/ethyl acetate (4/1). Received the product in the form of not-quite-white solid.

Yield: 1.0 g (41%).

LC/MS (Method 3): Rt 2,94 min, m/z 188 [MH+].

The intermediate product 3

(5-Bromatological-2-yl)phenylmethanone (III): Ra=Ph

A mixture of (5-methoxazole-2-yl)phenylmethanone (intermediate 2) (0.8 g, 4,28 mmol), N-bromosuccinimide (0.9 g, of 5.06 mmol) and 2,2'-azobis(2-methylpropionitrile) (56 mg, 0.34 mmol) in carbon tetrachloride (8 ml) was heated under reflux for 1.5 hours, the Reaction mixture was cooled to ambient temperature and filtered. The filtrate was diluted with DCM (20 ml) and washed with water, us. the sodium bicarbonate and saline. Dried (Na2SO4) and solvent was removed. Conducted clearing by the method of column chromatography, elwira cyclohexane/ethyl acetate (4/1). Received the product as a yellow solid.

Yield: 0.9 g (79%).

LC/MS (Method 3): Rt 3,26 min, m/z 266, 268 [MH+].

Intermediate the product 4

(5-Dimethylaminomethylene-2-yl)phenylmethanone (II): Ra=Ph, Rc, Rd=CH3

(5-Bromatological-2-yl)phenylmethanone (intermediate 3) (0.18 g, of 0.68 mmol) was dissolved in a 2M solution of dimethylamine in THF (3 ml, 6 mmol). The mixture was stirred at ambient temperature for 1 h, almost immediately formed precipitate. Solvent was removed and divided the remainder between DCM and saturated sodium bicarbonate (aq., 5 ml). The aqueous phase was extracted with DCM, the combined organic phase was dried (Na2SO4) and solvent was removed to obtain the product as an orange oil, which crystallized on standing.

Yield: 0.16 g (99%).

LC/MS (Method 2): Rt 1,22 min, m/z 231 [MH+].

In a similar way by the interaction of the intermediate product 3 with methylamine also obtained intermediate product 5

(5-Methylaminomethyl-2-yl)phenylmethanone (II): Ra=Ph, Rc=CH3, Rd=H

Output: 2,37 g (83%)

LC/MS (Method 3): Rt 0,26 and 1.44 min, m/z 217 [MH+].

The intermediate product 6

Cyclohexyl(5-methoxazole-2-yl)phenylmethanol (VIII): Ra=Ph, Rb=cyclohexyl

A solution of (5-methoxazole-2-yl)phenylmethanone (intermediate 2) (3.0 g, 16 mmol) in 32 ml betw the underwater THF at 0°C under nitrogen atmosphere for 10 minutes was treated dropwise 2M solution of cyclohexylaniline in diethyl ether (10 ml, 20 mmol). The obtained dark-yellow solution was stirred at 0°C for approximately 30 min, during which the formed precipitate, and then at room temperature for 1.5 hours. The reaction mixture was again cooled to 0°C and carefully treated us. solution of ammonium chloride (aq.) (10 ml). The mixture was stirred at room temperature for 10 min, and then was diluted with water (10 ml). The phases were separated and the organic phase is washed with salt solution. The combined aqueous phase was extracted with DCM (3×20 ml), the combined organic phase was dried (MgSO4) and concentrated in vacuo to obtain the crude product, which was triturated with ether (10 ml), was filtered and dried.

Output: 3,65 g (84%).

LC/MS (Method 3): Rt of 3.78 min, m/z 272 [MH+].

In a similar way by the interaction of the intermediate product 2 cyclopentylamine received intermediate product 7

Cyclopentyl(5-methoxazole-2-yl)phenylmethanol (VIII): Ra=Ph, Rb=cyclopentyl

Output: 3,82 g (70%)

LC/MS (Method 2): Rt 3,68 min, m/z 258 [MH+].

In a similar way by the interaction of the intermediate product 2 phenylmagnesium received intermediate product 8.

(5-Methoxazole-2-yl)diphenylethanol (VIII): Ra, Rb =Ph

Output: of 2.06 g (73%)

LC/MS (Method 3): Rt of 3.78 min, m/z 272 [MH+].

The intermediate product 9

(5-Bromatological-2-yl)cyclohexanemethanol (VII): Ra=Ph, Rb=cyclohexyl

A solution of cyclohexyl(5-methoxazole-2-yl)phenylmethanol (intermediate 6) (3.0 g, 11.1 mmol) in 1,2-dichloroethane (22 ml) was treated with N-bromosuccinimide (2.16 g, 12.2 mmol), and then 2,2'-azobis(2-methylpropionitrile) (0.18 g, 2.1 mmol). The mixture was heated up to 80°C for 2.5 h and then left to cool to room temperature. Added us. a solution of sodium bicarbonate and separated phases. The organic layer was washed with salt solution and was extracted with the combined aqueous layers DCM. The combined organic phase was dried (MgSO4) and concentrated in vacuo to obtain the crude product as a brown oil. Conducted clearing by the method of column chromatography, elwira 33-100% DCM/cyclohexane, and then 25% EtOAc/DCM.

Yield: 1.85 g (48%).

LC/MS (Method 3): Rt 4,27 min, m/z 350, 352 [MH+].

In a similar way from the intermediate product 7 was obtained intermediate product 10

(5-Bromatological-2-yl)cyclopentanemethanol (VII): Ra=Ph, Rb=cyclopentyl

Output: 10.7 g (83%)

LC/MS (Method 3): Rt 3,90 min, m/z 336, 338 [MH+].

A similar way of temporarily is on product 8 was obtained intermediate product 11

(5-Bromatological-2-yl)diphenylethanol (VII): Ra, Rb=Ph

Yield: 1.63 g (63%)

LC/MS (Method 4): Rt 3,53 min, m/z 326, 328 [MH+-N2O].

The intermediate product 12

[2-(Cyclohexylhydroxylamine)oxazol-5-yl]acetonitrile (IX): Ra=Ph, Rb=cyclohexyl

To a solution of ±-(5-bromatological-2-yl)cyclohexanemethanol (intermediate 9) (of 1.05 g, 3.0 mmol) in IMS (15 ml) was added sodium cyanide (169 mg, of 3.45 mmol). The mixture was heated at 70°C for 1 hour, then concentrated in vacuo and distributed between ethyl acetate (30 ml) and water (30 ml). The aqueous phase was extracted with ethyl acetate (2×30 ml), the combined organic phases were dried over sodium sulfate, filtered and evaporated to obtain orange oil. Using as eluent a mixture of 40% ethyl acetate/60% cyclohexane, conducted clearing method column flash chromatography on silica gel, and then recrystallization from DCM using hexane to obtain specified in the title compound as a white crystalline solid.

Yield: 700 mg (79%).

LC/MS (Method 3): Rt 3,66 min, m/z 279 [MH+-N2O].

In a similar way from the intermediate product 11 was obtained Intermediate product 13

[2-(Hydroxydiphenylmethyl)oxazol--yl]acetonitrile (IX): R a, Rb=Ph

Yield: 0.11 g (54%)

LC/MS (Method 3): Rt 2,96 min, m/z 291 [MH+].

The intermediate product 14

2-(1,1-Diphenylether)-5-methyl-4-methylsulfonylamino (XI): Ra, Rb=Ph, Rg=CH3

To a colorless solution of 1-methylthio-2-propanone (0,98 ml, 9.7 mmol) in 13 ml of anhydrous DCM at 0°C under nitrogen atmosphere was added dropwise a solution of anhydride triftormetilfullerenov acid (1,62 ml, 9.7 mmol) in 10 ml of anhydrous DCM. The obtained yellow solution was stirred at 0°C for 1 h, and then quickly was added dropwise a solution of 2,2-diphenylpropylamine (1 g, 4.8 mmol) in 10 ml of anhydrous DCM. The reaction mixture was stirred at 0°C for 2 h, then for 5 days at a temperature of from 0°C to room temperature, and it became dark red. The reaction mixture was cooled to 0°C and carefully treated us. the sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted DCM (×2). The combined organic phase was washed with water, us. a sodium bicarbonate solution and brine, dried (Na2SO4) and was evaporated to obtain a dark viscous oil (1,67 g). The crude product was purified by the method of chromatography on silica gel, elwira 5% diethyl ether/cyclohexane (Rf=0,25), obtaining specified in the title compounds as a pale yellow oil, which Chris who was allsouls when defending.

Output: 0,79 g (53%).

LC/MS (Method 2): Rt 4,37 min, m/z 310 [MH+].

The intermediate product 15

2-(1,1-Diphenylether)-5-methoxazole (XII): Ra, Rb=Ph, Rg=CH3

A suspension of 2-(1,1-diphenylether)-5-methyl-4-methylsulfonylamino (intermediate 14) (0,70 g, 2.3 mmol) in 15 ml of IMS was heated to dissolve. Added Raney Nickel 2800 (~3 g), which caused a rapid evolution of gas. The reaction mixture was stirred while heating under reflux in a nitrogen atmosphere. After 1.25 hours according to the method LC/MS showed the presence of a mixture of starting material/product (1/1), and after 1 h, no changes were observed. Was added 3 g of Raney Nickel 2800 and stirred the reaction mixture at reflux for 1 h TLC method was shown that all starting material had reacted. The catalyst was filtered through high-efficiency filter and evaporated volatiles to obtain a colorless viscous oil (or 0.57 g). The oil was purified according to the method of chromatography on silica gel, elwira 15% EtOAc/cyclohexane (Rf=0,36), obtaining specified in the title compounds as colorless oils.

Output: 0,57 g (89%).

LC/MS (Method 2): Rt 3,96 min, m/z 264 [MH+].

The intermediate product 16

5-methyl bromide-2-(1,1-diphenylether)oxazol (XIII): Ra , Rb=Ph, Rg=CH3

Obtained from intermediate 15 according to method used to obtain the intermediate product 9.

Yield: 0.75 g (Quant.)

LC/MS (Method 2): Rt 4,06 min, m/z 342, 344 [MH+].

The intermediate product 17

Complex 8-methoxycarbonyl ether methanesulfonate acid

To a solution of 8-meloxicam-1-ol (217 mg, 1.35 mmol) in anhydrous DCM (1 ml) was added diisopropylethylamine (170 mg, 1,49 mmol). The solution was cooled in a bath with ice and added in nitrogen atmosphere methanesulfonanilide (170 mg, 1,49 mmol). The solution was left to warm overnight to ambient temperature. According to the method of TLC showed the presence of some amount of starting material. Additionally added methanesulfonamide (231 mg, a 2.01 mmol) and was stirred solution at ambient temperature over night. The reaction mixture was treated with water and separated phases. The organic layer was dried (MgSO4) and the solvent evaporated. The crude product was purified by the method of chromatography on silica gel, elwira diethyl ether/cyclohexane (1/1), and then diethyl ether/cyclohexane (2/1), to obtain specified in the connection header in the form of oil. 8-Meloxicam-1-ol may be obtained in accordance with the methods described in Synthesis 2004, 4, 595.

Output: 135 m is (42%).

LC/MS (Method 2): Rt 3,14 min, molecular ion observed.

The intermediate product 18

Complex of 8-(tert-butoxycarbonylmethylene)oktilovom ether methanesulfonate acid

Specified in the title compound was obtained in accordance with the method described for intermediate product 17, using sophisticated tert-butyl ester (8-hydroxyacyl)methylcarbamate acid instead of 8-meloxicam-1-ol. Complex tert-butyl ester (8-hydroxyacyl)methylcarbamate acid can be obtained in accordance with the methods described in US 2005277688 or US 2004254219.

Yield: 225 mg (71 %).

1H-NMR (CDCl3): δ 1,20-of 1.57 (m, N), a 1.75 (m, 2H), and 2.83 (s, 3H), 3,01 (s, 3H), 3,19 (t, 2H), 4,22 (t, 2H).

The intermediate product 19

2-(4-Bromomethylphenyl)ethanol

A solution of 4-(methyl bromide)phenylacetic acid (458 mg, 2.0 mmol) in 10 ml of toluene and 8 ml of THF under nitrogen atmosphere was treated with a 2M solution of borane-dimethylsulfide complex in THF (2 ml, 4.0 mmol) and stirred the reaction mixture at room temperature over night. Method LC/MS interaction was not observed. Addition was added 1.5 ml (3.0 mmol) of borane-dimethylsulfide complex and stirred the reaction mixture for 2 hours was Added EtOAc and water and separated phases. The organic layer was dried (MgSO4and the issue is ivali solvent to obtain specified in the connection header.

Output: 347 mg (81%).

1H-NMR (CDCl3): δ 2,89 (t, 2H), 3,49 (s, 1H), 3,86 (t, 2H), 4,49 (s, 2H), 7,21 (d, 2H), 7,35 (d, 2H).

The intermediate product 20

2-{4-[(Benzylmethylamine)methyl]phenyl}ethanol

A solution of 2-(4-bromomethylphenyl)ethanol (intermediate 19) (347 mg, 1.6 mmol) in 15 ml of acetonitrile was treated with potassium carbonate (557 mg, 4.0 mmol)and then N-methylbenzylamine (293 mg, 2.4 mmol). The reaction mixture was stirred at reflux for 6 h, when the method LC/MS was shown to be a complete transformation of the starting material. The reaction mixture was left to cool to room temperature and the solvent evaporated. The residue was distributed between EtOAc and water and separated phases. The organic layer was dried (MgSO4) and the solvent evaporated. The crude product was purified by the method of chromatography on silica gel, elwira from DCM to 1% MeOH/DCM, to obtain specified in the connection header in the form of oil.

Output: 258 mg (63%).

1H-NMR (CDCl3): δ 2,09 (users, 1H), 2,16 (s, 3H), of 2.81 (t, 2H), 3,48 (s, 2H), 3,50 (s, 2H), 3,79 (t, 2H), 7,15 (d, 2H), 7,20-7,25 (m, 1H), 7,26-7,37 (m, 6N).

The intermediate product 21

2-(4-Methylaminomethyl)ethanol

A solution of 2-{4-[(benzylmethylamine)methyl]phenyl}ethanol (intermediate 20) (258 mg, 1.0 mmol) in 10 ml of IMS was treated with 20% palladium hydroxide on the where (50 mg). The reaction mixture was stirred in an atmosphere of hydrogen for 3 h, when the method LC/MS was shown to be a complete transformation of the starting material. The reaction mixture was filtered through celite and the solvent evaporated. The crude product was applied to a SCX cartridge-2 using 10% MeOH/DCM, and impurities removed by washing the column MeOH/DCM. Was suirable 2M ammonia in methanol/DCM (1/1) and the solvent was removed to obtain specified in the connection header.

Yield: 91 mg (55%).

1H-NMR (MeOD): δ of 2.35 (s, 3H), and 2.79 (t, 2H), the 3.65 (s, 2H), and 3.72 (t, 2H), 7.18 in-7,25 (m, 4H).

The intermediate product 22

Complex tert-butyl ester [4-(2-hydroxyethyl)benzyl]methylcarbamate acid

A solution of 2-(4-methylaminomethyl)ethanol (intermediate 21) (91 mg, 0.55 mmol) in 3 ml of anhydrous DCM at 0°C was treated dropwise with a solution of di-tert-BUTYLCARBAMATE (144 mg, 0.66 mmol) in 2 ml of anhydrous DCM and the reaction mixture is left to warm to room temperature. After 2 h was added water and the mixture was stirred for 10 minutes two layers were Separated, the organic layer was dried (MgSO4) and the solvent evaporated to obtain specified in the connection header.

Yield: 146 mg (Quant.).

1H-NMR (CDCl3): δ 1,48 (s, N), 2,81 (users, 3H), of 2.86 (t, 2H), 3,86 (ushort, 2H), 4,40 (users, 2H), 7,14-7,22 (m, 4H).

The intermediate product 23

Complex 2-{4-[(tert-butoxycarbonylmethylene)methyl]phenyl}ethyl ester methanesulfonic acid

Specified in the title compound was obtained in accordance with the method described for intermediate product 17, using intermediate product 22 instead of 8-meloxicam-1-ol.

Yield: 106 mg (50%).

1H-NMR (CDCl3): δ 1,48 (s, N), 2,75-2,84 (users, 3H), 2,87 (s, 3H), 3.04 from (t, 2H), 4,36-of 4.44 (m, 4H), 7,15-7,22 (m,4H).

The intermediate product 24

4-(3-Bromopropane)benzosulfimide

A suspension of 4-hydroxybenzenesulfonate (4.1 g, 23 mmol), 1,3-dibromopropane (6,83 g, 34 mmol) and potassium carbonate (3,17 g, 23 mmol) in acetonitrile (35 ml) was heated at 55°C over night. The mixture was left to cool to ambient temperature and filtered. The filtrate was evaporated to obtain a residue, which was distributed between DCM and 0,1M NaOH (aq.). The organic layer was dried (MgSO4) and the solvent evaporated. Conducted clearing method column chromatography on silica gel, elwira cyclohexane, then diethyl ether, and then recrystallized from isopropanol.

Output: 483 mg (7%).

LC/MS (Method 2): Rt 3,01 min, molecular ion observed.

The intermediate product 25

Bromide (9-hydroxyaryl)methylamine

To a solution of 9-bromo-1-nonanol (10.2 g, of 45.7 mmol) in IS (50 ml) at 0°C was added a solution of methylamine (57 ml, 8M in EtOH, 456 mmol). After 30 minutes at 0°C the reaction mixture was left to warm to K.T. and was stirred for 26 hours, the Solvent is evaporated to obtain a white solid, which was triturated with diethyl ether to obtain specified in the title compound as a white solid.

Output: becomes 9.97 g, 86%.

LC/MS (Method 3): Rt 1,51 min, m/z 174 [MH+].

The intermediate product 26

9-{[2-(Cyclohexylhydroxylamine)oxazol-5-ylmethyl]methylamino}nonan-1-ol

To a solution of bromide (9-hydroxyaryl)methylamine (686 mg, of 2.86 mmol) and N,N-diisopropylethylamine (1.0 ml, 5.7 mmol) in anhydrous DCM was added (5-bromatological-2-yl)cyclohexanemethanol (1.0 g, of 2.86 mmol). After stirring the mixture at K.T. within 4 h were added by us. NaHCO3(aq.). The phases were separated and the aqueous layer was extracted DCM. The combined organic layers were dried (Na2SO4), filtered and concentrated to dryness to obtain a yellow oil. Conducted clearing method column chromatography on silica gel, using as eluent a gradient of 5-10% MeOH/DCM, and got mentioned in the title compound as a colourless oil.

Output: 0,80 g, 63%.

LC/MS (Method 2): Rt 2,42 min, m/z 443 [MH+].

The intermediate product 27

9-{[2-(Cyclohexylhydroxylamine)oxazol--ylmethyl]methylamino}nonanal

To a solution of oxalicacid (94 μl) in anhydrous DCM (3 ml) at -78°C under nitrogen atmosphere was added dropwise a solution of DMSO (0.17 ml, 2.3 mmol) in anhydrous DCM (3 ml). Then was added a solution of 9-{[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]methylamino}nonan-1-ol (0,49 g, 1.1 mmol) in anhydrous DCM (5 ml) and stirred the reaction mixture at -78°C for 15 minutes was Added triethylamine (of 0.62 ml, 4.4 mmol) and the reaction mixture is left to warm to K.T. After 1 h was added to us. NaHCO3(aq.), separated phase and the aqueous layer was extracted DCM. The combined organic layers were washed with saline, dried (Na2SO4), filtered and concentrated to dryness to obtain a yellow/brown viscous oil. The crude product is re-transferred in the same reaction conditions for conversion of starting material to obtain a yellow viscous oil and solids. The solids triturated with diethyl ether and concentrated supernatant to dryness to obtain a solid foam, which was used without further purification.

Output: 0,59,

LC/MS (Method 2): Rt to 2.74 min; m/z 441 [MH+].

Intermediate 28

5-[(R)-1-(tert-Butyldimethylsilyloxy)-2-(9-{[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]methylamino}nonylamine)ethyl]-8-hydroxy-1H-x is the nolin-2-he

A mixture of 9-{[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]methylamino}of nonanal (0,49 g, 1.1 mmol), 5-[(R)-2-amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-hydroxy-1H-quinoline-2-she (and 0.37 g, 1.1 mmol) and triacetoxyborohydride sodium (0.33 g, 1.6 mmol) in anhydrous DCE (10 ml) was stirred in nitrogen atmosphere at K.T. for 19 hours, the Solvents evaporated in vacuum and the residue was purified according to the method of column chromatography on silica gel, using as eluent a mixture of DCM/MeOH/acetic acid/water (120/15/3/2), to obtain the product as a slightly brownish resin. The residue was absorbed MeOH was passed through the cartridge SCX-2 and released using a 2M solution of ammonia in MeOH. By evaporation of the solvent in vacuum has been specified in the title compound in the form of a mixture of diastereoisomers in the form of a yellow-green resin.

Yield: 78 mg, 9%.

LC/MS (Method 2): Rt 2,64 min, m/z 760 [MH+].

Intermediate 29

Complex ethyl ester 5-methylthiazole-2-carboxylic acid

Received according to Helv. Chim. Acta., 1946 (29), 1957.

The intermediate product 30

(5-Methylthiazole-2-yl)diphenylethanol

In the ice-cold solution of intermediate 29 (0.24 g, to 1.402 mmol) in anhydrous THF (7 ml) under nitrogen atmosphere was added dropwise 3M solution phenylmagnesium in diethyl ether (0,934 ml, 2,80 mmol). With the ABC after complete addition, the reaction mixture was left to warm to K.T. and was stirred for 20 min then the solution was poured into 1M HCl and was extracted twice with diethyl ether. The combined organic layers were washed us. the sodium bicarbonate (aq.), water and saline, dried (MgSO4) and was evaporated. The residue was subjected to column chromatography (SiO2, 40 g), elwira 10% EtOAc in isohexane, to obtain the desired substance.

Output=0.27 g (67%).

LC/MS (Method 6): Rt3,20 min, m/z 282 [MH]+.

1H-NMR, 400 MHz, DMSO-d6: 7,4 (1H, m), and 7.3 (4H, m), 7.3 to 7.2 for (6N, m)and 7.1 (1H, s) and 2.4 (3H, d).

The intermediate product 31

Complex of 2-(4-methylbenzylamino)ethyl ester methanesulfonic acid

Was obtained analogously to the method described in J. Am. Chem. Soc. 2002, 124(28), 8206.

LC/MS (Method 4): Rt 2,44 min, molecular ion observed.

The intermediate product 32

Complex of 2-(4-chlorobenzoyloxy)ethyl ester methanesulfonic acid

Was obtained analogously to intermediate product 31.

LC/MS (Method 2): Rt 3,34 min, molecular ion observed.

The intermediate product 33

Complex of 2-(4-chlorobenzoyloxy)ethyl ester methanesulfonic acid

Was obtained analogously to intermediate product 31.

LC/MS (Method 4): Rt 3,59 min, molecular ion observed.

The intermediate product 34

1-Benzyloxy-3-methyl-3-phenoxybutyl

To a solution of (3-methylbut-3-relaxometer)benzene (4,22 g of 23.9 mmol) and phenol (2.25 g, of 23.9 mmol) in 20 ml of anhydrous DCM under nitrogen atmosphere was added BF3·Et2O (0,582 ml, 4,78 mmol). The solution was stirred at ambient temperature overnight, added an H2O and separated phases. The aqueous phase was extracted with DCM (×2), the organic layer was dried (MgSO4) and solvent was removed to obtain oil. The crude product was purified by the method of column chromatography on silica gel, elwira gradient from cyclohexane to 5% diethyl ether in cyclohexane.

Yield: 0.9 g (14%).

LC/MS (Method 4): Rt 4,47 min, molecular ion observed.

Intermediate 35

3-Methyl-3-phenoxybutyl-1-ol

In an inert atmosphere in the flask was added palladium hydroxide (II) coal (20 wt.%) (150 mg), and then cooled IMS (5 ml) and (3-benzyloxy-1,1-DIMETHYLPROPANE)benzene (0.73 g, 2.7 mmol). The flask was purged with hydrogen (×3) and the mixture was stirred at ambient temperature overnight with an attached balloon of hydrogen. The mixture was filtered through celite in an inert atmosphere and the filtrate was evaporated to obtain the crude product, which was purified according to the method of column chromatography, using as eluent a gradient from cyclohexane to 50% diethyl ether in a cyclo is hexane.

Yield: 71 mg, 14%.

LC/MS (Method 4): Rt 2,87 min, molecular ion observed.

The intermediate product 36

Complex 3-methyl-3-proximately ether methanesulfonate acid

Specified in the title compound was obtained in accordance with the method described for intermediate product 17.

Yield: 37 mg, 37%.

LC/MS (Method 2): Rt to 3.45 min, molecular ion observed.

Intermediate 37

[2-(Cyclopentylacetyl)oxazol-5-yl]acetonitrile (IX): Ra=Ph, Rb=cyclopentyl

Received in accordance with the method used to obtain the intermediate product 12.

Yield: 0.75 g (57 %).

LC/MS (Method 4): Rt 3,47 min, m/z 265 [MH+-N2O].

EXAMPLES

The following compounds were obtained using the synthesis pathway presented in figure 5.

Scheme 5

Example 1

(5-Dimethylaminomethylene-2-yl)diphenylethanol (I-a): Ra, Rb=Ph, Rc, Rd=CH3

To a cold (0°C) solution of (5-dimethylaminomethylene-2-yl)phenylmethanone (intermediate 4) (0.15 g, of 0.65 mmol) in anhydrous THF (1.5 ml) was added dropwise phenylmagnesium (0.75 ml 1M solution in THF, 0.75 mmol). The mixture was stirred cold for 1.5 h and then added dropwise more the tion was added phenylmagnesium (0.4 ml 1M solution in THF, 0.4 mmol). The mixture was stirred at 0°C for 0.5 h, and then treated with excess us. solution of ammonium chloride (aq.). The mixture was extracted with DCM (×2), the combined organic phase was washed with saline, dried (Na2SO4) and solvent was removed to obtain the crude product. Were purified by HPLC method, elwira within 18,5 min 5-70% acetonitrile/water containing 0.1% TFA.

Output: 0,19 g (69%, as TFA-salt)

LC/MS (Method 1): Rt 5,56 min, m/z 309 [MH+].

LC/MS (Method 3): Rt 1,72 min, m/z 309 [MH+].

1H-NMR (DMSO-d6): δ 2,74 (C, 6N), 4,48 (s, 2H), 7,25-7,37 (m, 10H), 7,40 (s, 1H), 10,23 (users, 1H).

A sample of this substance was converted into the free base by passing through the cartridge SCX-2 and elwira MeOH (×3)and then 2M ammonia/MeOH (×3), to give the desired compound as a white solid.

LC/MS (Method 1): Rt of 5.68 min, m/z 309 [MH+].

1H-NMR (DMSO-d6): δ 2,12 (C, 6N), 3,47 (s, 2H), 6,98 (s, 1H), 7,02 (s, 1H), 7,22-7,34 (m, 10H).

Example 2

Formate [2-(hydroxydiphenylmethyl)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium (1-b): Ra=Rb=Ph, Rc, Rd=CH3, Re=3-phenoxypropan

A solution of (5-dimethylaminomethylene-2-yl)diphenylmethane (example 1) (24 mg, 0,078 mmol) in acetonitrile (0.3 ml) and chloroform (0,5ml) was treated with 3-phenoxypropylamine (37 μl, 0,mol) and stirred the reaction mixture at room temperature over night, and then at 50°C for 42 hours Volatiles evaporated and the crude product is purified by the method of preparative HPLC, elwira for 30 min 25-75% acetonitrile/water containing 0.1% formic acid, to obtain the product as a colourless resin.

Yield: 24 mg, 63%.

LC/MS (Method 1): Rt 7,56 min, m/z 443 [MH+].

1H-NMR (MeOD): δ to 2.29 (m, 2H), 3,11 (C, 6N), of 3.45 (m, 2H), 3,98 (t, 2H), 4,79 (s, 2H), 6,85-of 6.90 (m, 2H), 6,93-6,98 (m, 1H), 7.24 to 7,38 (m, N), 7,56 (s, 1H), 8,51 (users, 1H).

The following compounds were obtained in a similar way using the synthesis pathway presented in figure 2:

ExampleNameStructure1H-NMRLC/MS
3(5-methylaminomethyl-2-yl)diphenylethanol (I-a): Ra, Rb=Ph, Rc=H, Rd=CH3(CDCl3): 2,31 (s, 3H), 3,06 (users, 2H), 3,68 (d, 2H), for 6.81 (s, 1H), 7,25 was 7.36 (m, 10H).(Method 3): Rt 1,44 min, m/z 217 [MH+]

Scheme 6

The following compounds were obtained using the synthesis pathway presented in figure 6.

Example 4

Cyclohexyl(5-dimethylaminomethylene-2-yl)phenylmethanol (I-a): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3

A solution of (5-bromatological-2-yl)cyclohexanemethanol (intermediate 9) (3.2 g, 9.2 mmol) in 40 ml THF was treated with 2M solution of dimethylamine in THF (40 ml, 80 mmol). After stirring for several minutes, the formed suspension. The reaction mixture was stirred at room temperature overnight and then the solid was filtered and discarded. The filtrate was concentrated under reduced pressure and distributed the residue between DCM and us. a solution of sodium bicarbonate. The organic layer was dried (Na2SO4) and was evaporated to obtain specified in the connection header in the form of solids.

Output: 2,74 g (95%).

LC/MS (Method 1): Rt to 6.57 min, m/z 315 [MH+].

1H-NMR (DMSO-d6): δ 0,92-of 1.29 (m, 6N), 1,42-of 1.74 (m, 4H), 2,10 (C, 6N), 2,22 (m, 1H), 3.45 points (s, 2H), 5,90 (s, 1H), 6,98 (s, 1H), 7.18 in-7,22 (m, 1H), 7,27-7,34 (m, 2H), 7,40-7,46 (m, 2H).

Two enantiomers of cyclohexyl(5-dimethylaminomethylene-2-yl)phenylmethanol (Example 4) (2,74 g) were divided according to the method of chiral preparative HPLC using a 250×20 mm column, Chiralpak®IA with immobilized to 5 microns silica gel Tris(3,5-dimethylphenylcarbamate) amylase. The column was suirable with a speed of 15 ml/min of 5% ethanol in heptane, buffered with 0.1% ditrame the om. The first was suirable enantiomer (Rt 8.5 min) (S)-cyclohexyl(5-dimethylaminomethylene-2-yl)phenylmethanol (I-a): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3(Example 5) as a white solid.

Example 5

Yield: 0.73 g (27%)

LC/MS (Method 1): Rt 6,50 min, m/z 315 [MH+].

1H-NMR (CDCl3): δ 1,12-of 1.39 (m, 7H), 1,62 to 1.76 (m, 3H), of 2.25 (s, 6N), 2,29 of-2.32 (m, 1H), 3,54 (DDAB, 2H), 3,70 (users, 1H), 6,84 (s, 1H), 7,24 (t, 1H), 7,33 (t, 2H), to 7.64 (d, 2H).

The second was suirable (Rt 10,3 min) enantiomer (R)-cyclohexyl(5-dimethylaminomethylene-2-yl)phenylmethanol (I-a): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3(Example 6) as a white solid.

Example 6

Yield: 1.04 g (38%)

LC/MS (Method 1): Rt 6,48 min, m/z 315 [MH+].

1H-NMR (CDCl3): δ 1,10-of 1.39 (m, 7H), 1,62 to 1.76 (m, 3H), of 2.25 (s, 6N), 2,29 to 2.35 (m, 1H), 3,54 (DDAB, 2H), 3,70 (users, 1H), 6,84 (s, 1H), 7,24 (t, 1H), 7,33 (t, 2H), to 7.64 (d, 2H).

Example 7

Bromide [2-((S)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-phenoxypropan

A solution of (S)-cyclohexyl(5-dimethylaminomethylene-2-yl)phenylmethanol (Example 5) (to 0.060 g, 0,19 mmol) and 3-phenoxypropylamine (0,215 g, 1 mmol) in acetonitrile (1,33 ml) and chlorof is RME (2 ml) was left to stand at K.T. within 5 days. Solvent was removed to obtain the crude product. Conducted clearing by the method of column chromatography, consistently elwira DCM and 2.5%, 5%, 10% and 20% methanol in DCM.

Yield: 50 mg (43%).

LC/MS (Method I): Rt 8,32 min, m/z 449 [M+].

1H-NMR (Dl3): δ 1.06 a-1,17 (m, 3H), 1,23-of 1.36 (m, 4H), 1,52-of 1.85 (m, 3H), of 2.28 to 2.35 (m, 3H), of 3.32 (s, 3H), of 3.33 (s, 3H), 3,63 (DD, 2H), Android 4.04 (t, 2H). 5,23 (DDAB, 2H), 6,85 (d, 2H), 6,98 (t, 1H), 7,20 (m, 1H), 7,26-7,30 (m, 4H), 7,55-7,58 (m, 3H).

Example 8

Bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Rr=3-phenoxypropan

A solution of (R)-cyclohexyl(5-dimethylaminomethylene-2-yl)phenylmethanol (Example 6) (98 mg, 0,31 mg) and 3-phenoxypropylamine (740 mg, 3,44 mmol) in chloroform (1.5 ml) and acetonitrile (1.5 ml) was heated at 50°C for 22 hours, the Reaction mixture was concentrated to dryness to obtain a colorless viscous oil, which was triturated with diethyl ether to obtain a white resin. The resin was purified by the method of column chromatography, elwira 2.5 to 25% MeOH/DCM, to obtain the product in the form of a turbid viscous oil. Was dried in vacuum at 45°C for 1-2 days to get a white solid.

Yield: 142 mg (86%).

LC/MS (Method I): Rt to 8.41 min, m/z 449 [MN+].

1H-NMR (CDCl3): δ of 1.06-1.16 (m, 3H), of 1.21 to 1.37 (m, 4H), 1,59-of 1.74 (m, 3H), 2,32 (m, 3H), of 3.32 (s, 3H), of 3.33 (s, 3H), 3,61 (DD, 2H), a 4.03 (t, 2H), 4,14 (user. s, 1H), 5,20 (DDAB, 2H), 6,85 (d, 2H), 6,98 (t, 1H), 7,19 (t, 1H), 7,26-7,30 (m, 4H), 7,55-7,58 (m, 3H).

Example 9

Toilet [2-((R) -cyclohexylhydroxylamine)oxazol-6-ylmethyl]dimethyl(3-phenoxypropan)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-phenoxypropan

Received in accordance with the method used in example 8, but using 3-phenoxypropionate instead of 3 phenoxypropylamine.

Yield: 80%.

LC/MS (Method 5): Rt7,72 min, m/z 449 [MN]+.

1H-NMR (DMSO-d6): δ 0,96-1,25 (m, 6N), and 1.54-1,71 (m, 4H), 2,18-of 2.27 (m, 3H), of 2.28 (s, 3H), 3,03 (s, 3H), 3.04 from (s, 3H), 3.33 and-3,39 (m, 2H), 3,99 (t, 2H), amounts to 4.76 (s, 2H), 6,10 (s, 1H), 6,92 (d, 2H), of 6.96 (t, 1H), 7,11 (d, 2H), 7,22 (m, 1H), 7,31 (dt, 4H), 7,45-7,49 (m, 4H), 7,54 (s, 1H).

Example 10

(Z)-3-carboxyamide[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan) ammonium (I-b); Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-phenoxypropan

A mixture of silver oxide(I) (59 mg, 0.25 mmol) and bromide [(R)-2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium (Example 8) (265 mg, 0,500 mmol) in water (10 ml) was stirred at K.T. within 5 hours To the reaction mixture was added maleic acid (58 mg, 0.50 mmol), who then Meon (10 ml). The suspension is vigorously stirred at K.T. for 1 h, then filtered through celite and liofilizirovanny obtaining specified in the title compound as a white solid.

Yield: 97%.

LC/MS (Method 5): Rt 7,92 min, m/z 449 [M+].

1H-NMR (Dl3): δ of 1.05 to 1.42 (m, 7H), 1,59-1,72 (m, 3H), 2,23 is 2.33 (m, 3H), 3,13 (C, 6N), 3,53 (m, 2H), 4.00 points (m, 2H), 4,89 (DDAB2N), of 6.20 (s, 2H), 6,83 (d, 2H), of 6.96 (t, 1H), 7,19 (t, 1H), 7,25-7,30 (m, 4H), 7,47 (s, 1H), 7,55 (d, 2H).

Example 11

Received in accordance with the method used in example 10, but using succinic acid instead of maleic acid:

3-Carboxypropyl [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-phenoxypropan

Yield: 97%

LC/MS (Method 5): Rt of 7.90 min, m/z 449 [M+].

1H-NMR (CDCl3): δ of 1.03 and 1.35 (m, 6N), 1,42-of 1.45 (m, 1H), 1,59-of 1.73 (m, 3H), 2,22 is 2.33 (m, 3H), 2,46 (s, 4H), 3,14 (s, 6H), 3,52 (m, 2H), 4.00 points (m, 2H), is 4.93 (DDAB2N), at 6.84 (d, 2H), 6,97 (t, 1H), 7,19 (t, 1H), 7,26-7,30 (m, 4H), of 7.48 (s, 1H), 7,55 (d, 2H).

Example 12

Received in accordance with the method used in example 10, but using (S)-malic acid instead of maleic acid.

(S)-3-carboxy-2-hydroxypropionate [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-pheno is sapropel)ammonium (I-b): R a=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-phenoxypropan

Yield: 89%

LC/MS (Method 5): Rt of 7.90 min, m/z 449 [M+].

1H-NMR (CDCl3): δ of 1.02 to 1.34 (m, 6H), to 1.38 to 1.47 (m, 1H), 1,58-1,72 (m, 3H), 2,17 to 2.35 (m, 3H), 2,60-a 2.71 (m, 2H), 3,09 (users, 6H), 3,44 (users, 2H), 3,98-4,10 (m, 3H), 4,85 (users, 2H), at 6.84 (d, 2H), of 6.96 (t, 1H), 7,18 (t, 1H), 7,25-7,29 (m, 4H), 7,47 (s, 1H), 7,54 (d, 2H).

Example 13

Cyclohexyl(5-{[methyl(3-phenoxypropan)amino]methyl}oxazol-2-yl)phenylmethanol (I-a): Ra=Ph, Rb=cyclohexyl, Rc=CH3, Rd=3-phenoxypropan

A mixture of (5-bromatological-2-yl)cyclohexanemethanol (intermediate 9) (102 mg, 0,286 mmol), N-methyl-3-phenoxypropylamine (57 mg, 0.34 mmol) and diisopropylethylamine (65 μl, of 0.37 mmol) in THF (2 ml) was stirred at K.T. in a period of 1.75 hours, the Reaction mixture was treated with us. a solution of sodium bicarbonate (aq.) and separated the organic phase. The aqueous layer was extracted with DCM. The combined organic layers were washed with saline, dried (Na2SO4), filtered and concentrated to dryness to obtain a pale brown oil. Conducted clearing method column chromatography on silica gel, using as eluent a gradient of 25-30% ethyl acetate/DCM, and got mentioned in the title compound as a colourless oil.

Yield: 60%.

LC/MS (Method 1): Rt 8,61 min, m/z 435 [M+ ].

1H-NMR (CDCl3): δ 1,09-of 1.39 (m, 7H), 1,61-of 1.74 (m, 3H), 1,96 (p, 2H), 2,27 is 2.33 (m, 4H), of 2.53 (t, 2H), to 3.67 (s, 3H), 3,99 (t, 2H), 6,83 (s, 1H), 6.89 in (d, 2H), 6,94 (t, 1H), 7,20-7,33 (m, 5H), 7,63 (d, 2H).

Example 14

Two enantiomers of cyclohexyl(5-{[methyl(3-phenoxypropan)amino]methyl}oxazol-2-yl)phenylmethanol (Example 13) were separated as in example 4, elwira 10% EtOH/heptane + 0.1% diethylamine. The first was suirable (Rt=8,3 min) enantiomer (S)-cyclohexyl(5-{[methyl(3-phenoxypropan)amino]methyl}oxazol-2-yl)phenylmethanol (I-a): Ra=Ph, Rb=cyclohexyl, Rc=CH3, Rd=3-phenoxypropan.

LC/MS (Method 1): Rt 8,44 min, m/z 435 [MH+].

1H-NMR (CDCl3): δ 1,09-of 1.39 (m, 7H), 1,61-of 1.74 (m, 3H), 1,96 (p, 2H), 2,27 is 2.33 (m, 4H), of 2.53 (t, 2H), to 3.67 (s, 3H), 3,99 (t, 2H), 6,83 (s, 1H), 6.89 in (d, 2H), 6,94 (t, 1H), 7,20-7,33 (m, 5H), 7,63 (d, 2H).

Example 15

The second (Rt 10,9 min) was suirable enantiomer (R)-cyclohexyl(5-{[methyl(3-phenoxypropan)amino]methyl}oxazol-2-yl)phenylmethanol (I-a): Ra,=Ph, Rb=cyclohexyl, Rc=CH3, Rd=3-phenoxypropan.

LC/MS (Method 1): Rt 8,51 min, m/z 435 [MH+].

1H-NMR (CDCl3): δ 1,09-of 1.39 (m, 7H), 1,61-of 1.74 (m, 3H), 1,96 (p, 2H), 2,27 is 2.33 (m, 4H), of 2.53 (t, 2H), to 3.67 (s, 3H), 3,99 (t, 2H), 6,83 (s, 1H), 6.89 in (d, 2H), 6,94 (t, 1H), 7,20-7,33 (m, 5H), 7,63 (d, 2H).

The following compounds of the examples were treated in a similar fashion using route of synthesis presented in figure 3.

(CDCl3): δ to 1.14 to 1.76 (9H,m), of 2.25 (6H, s), 2.95 and-of 3.07 (1H, m), 3.46 in-of 3.60 (2H, 2×d), and 3.72 (1H, users), at 6.84 (1H,s), 7,19-7,28 (1H,m), 7,28 and 7.36 (2H, m), to 7.59-the 7.65 (2H, m).
ExampleNameStructure1H-NMRLC/MS
16cyclohexyl(5-methylaminomethyl-2-yl)phenylmethanol (I-a): Ra=Ph, Rb=cyclohexyl, Rc=CH3, Rd=H(CDCl3): δ of 1.42 (m, 7H), 1,57-of 1.81 (m, 3H), 2,31 (m, 1H), 2,42 (s, 3H), 8,30 (d, 2H), 6,85 (s, 1H), 7,21-7,27 (m, 1H), 7,31-7,37 (m, 2H), 7,60-7,66 (m, 2H).(Method 3): Rt 2,13 and 2,20 min, m/z 301 [MH+]
17cyclopentyl(5-dimethylaminomethylene-2-yl)phenylmethanol (I-a): Ra=Ph, Rb=cyclopentyl, Rc=Rd=CH3(CDCl3): δ to 1.14 to 1.76 (9H, m), of 2.25 (6H, s), 2.95 and-of 3.07 (1H, m), 3.46 in-of 3.60 (2H, HD), and 3.72 (1H, users), at 6.84 (1H, s), 7,19-7,28 (1H,m), 7,28 and 7.36 (2H, m), to 7.59-the 7.65 (2H, m).(Method 2): Rt to 2.1 min, m/z 301 [MH+]
18cyclopentyl(5-dimethylaminomethylene-2-yl)phenylmethanol - eluruumis first enantiomer (I-a): Ra=Ph, Rb=cyclopentyl, Rc=Rd=CH3(Method 2): Rt to 2.1 min, m/z 301 [MH+]
19cyclopentyl(5-dimethylaminomethylene-2-yl)phenylmethanol - eluruumis second enantiomer (I-a): Ra=Ph, Rb=cyclopentyl, Rc=Rd=CH3(CDCl3): δ to 1.14 to 1.76 (9H, m), of 2.25 (6H, s), 2.95 and-of 3.07 (1H, m), 3.46 in-of 3.60 (2H, 2×d), and 3.72 (1H, users), at 6.84 (1H, s), 7,19-7,28 (1H, m), 7,28 and 7.36 (2H, m), to 7.59-the 7.65 (2H, m).(Method 2): Rt to 2.1 min, m/z 301 [MH+]
20cyclohexylphenol(5-piperidine-1-ylmethylamino-2-yl)methanol (I-a): Ra=Ph, Rb=cyclohexyl, Rc=Rd=piperidinyl(CDCl3): δ 1.04 million of 1.50 (10H,m), 1,50-of 1.85 (6H, m), 2,23 is 2.51 (5H, m), 3,61(2H, s)to 3.67 (1H, s), PC 6.82 (1H, s), 7,19-7,28 (1H, m), 7,28-7,37 (2H, m), 7,60-to 7.67 (2H, m).(Method 2): Rt 2.21 and 2,35 min, m/z 355 [MH+]
21cyclohexylphenol(5-piperidine-1-ylmethylamino-2-yl)methanol - eluruumis first enantiomer (I-a): Ra=Ph, Rb=cyclohexyl, Rc=Rd=piperidinyl (CDCl3): δ1,04-1,50 (10H, m), 1,50-of 1.85 (6H, m), 2,23 is 2.51 (5H, m), 3,54-3,70 (3H, 2×s), PC 6.82 (1H, s), 7,19-7,28 (1H, m), 7,28-7,37 (2H, m), 7,60-to 7.67 (2H, m).(Method 2): Rt 2.21 and 2,35 min, m/z 355 [MH+]
22cyclohexylphenol(5-piperidine-1-ylmethylamino-2-yl)methanol - eluruumis second enantiomer (I-a): Ra=Ph, Rb=cyclohexyl, Rc=Rd=piperidinyl(CDCl3): δ 1.04 million of 1.50 (10H, m), 1,50-of 1.85 (6H, m), 2,23 is 2.51 (5H, m), 3,54-3,70 (3H, 2×s), PC 6.82 (1H, s), 7,19-7,28 (1H, m), 7,28-7,37 (2H, m), 7,60-to 7.67 (2H, m).(Method 2): Rt 2.21 and 2,35 min, m/z 355 [MH+]
23cyclohexylphenol(5-pyrrolidin-1-ylmethylamino-2-yl)methanol (I-a): Ra=Ph, Rb=cyclohexyl, Rc=Rd=pyrrolidinyl(CDCl3): δ 1.04 million-of 1.44 (8H, m), 1,50 is 1.86 (6H, m), 2,23-is 2.37 (1H, m), 2,50-of 2.64 (4H, m), the 3.65 (1H, s), and 3.72 (2H, s), 6,85 (1H, s), 7,20-7,28 (1H, m), 7,28 and 7.36 (2H, m), to 7.59-7,66 (2H, m).(Method 2): Rt 1,84 and to 1.98 min, m/z 341 [MH+]
24cyclohexylphenol(5-pyrrolidin-1-ylmethylamino-2-yl)methanol - eluruumis first enantiomer (I-a): Ra=Ph, Rb=CEC shall hexil, Rc=Rd=pyrrolidinyl(CDCl3): δ 1.04 million-of 1.44 (8H, m), 1,50 is 1.86 (6H, m), 2,23-is 2.37 (1H, m), 2,50-of 2.64 (4H, m), of 3.69 (2H, s), 3,91 (1H, users), 6,85 (1H, s), 7,20-7,28 (1H, m), 7,28 and 7.36 (2H, m), to 7.59-7,66 (2H, m).(Method 2): Rt 1,84 and to 1.98 min, m/z 341 [MH+]
25cyclohexylphenol(5-pyrrolidin-1-ylmethylamino-2-yl)methanol - eluruumis second enantiomer (I-a): Ra=Ph, Rb=cyclohexyl, Rc=Rd=pyrrolidinyl(CDCl3): δ 1.04 million-of 1.44 (8H, m), 1,50 is 1.86 (6H, m), 2,23-is 2.37 (1H, m), 2,50-of 2.64 (4H, m), 3,67-of 3.77 (3H, 2×s), 6,85 (1H, s), 7,20-7,28 (1H, m), 7,28 and 7.36 (2H, m), to 7.59-7,66 (2H, m).(Method 2): Rt 1,84 and to 1.98 min, m/z 341 [MH+]
26[5-(4-phenoxypyridine-1-ylmethyl)oxazol-2-yl]diphenylethanol (I-a): Ra=Rb=Ph, Rc=Rd=4-phenoxypyridine(CDCl3): δ equal to 1.82 (m,2H), of 1.97 (m, 2H), 2,34 (m, 2H), 2,71 (m, 2H), the 3.65 (s, 2H), 4,17-to 4.33 (m, 2H), 6.87 in (d, 2H), 6,93 (t, 2H), 7.24 to 7,38 (m, 12H).(Method 1): Rt 7,89 min, m/z 441 [MH+]
27{5-[(benzylmethylamine)methyl]oxazol-2-yl}cyclopentylphenol the ol (I-a): R a=Ph, Rb=cyclopentyl, Rc=CH3, Rd=benzil(CDCl3): δ 1,36, (1H, m), 1,44-of 1.66 (7H, m), 2,24 (3H, s), to 3.02 (1H, m), 3,49 (2H, s)to 3.64 (2H, s), 3,69 (1H, s), at 6.84 (1H, s), 7.24 to to 7.35 (8H, m), the 7.65 (2H, m).(Method 4): Rt 2,63 min, m/z 377 [MH+]
28{5-[(benzylmethylamine)methyl]oxazol-2-yl}cyclopentanemethanol - eluruumis second enantiomer (I-a): Ra=Ph, Rb=cyclopentyl, Rc=CH3, Rd=benzil(DMSO-d6) δ 1,19, (1H,m)to 1.37 (2H,m)and 1.51 (3H, m), and 1.63 (2H, m), of 2.08 (3H, s)to 2.94 (1H, m)to 3.41 (2H, d, J=2.7 Hz), to 3.58 (2H, s), of 5.99 (1H, s), 7,02 (1H, s), 7,24, (4H, m), 7,31 (4H, m), 7,46 (2H, m).(Method 1): Rt 7,54 min, m/z 377 [MH+]
29{5-[(benzylmethylamine)methyl]oxazol-2-yl}cyclopentanemethanol - eluruumis first enantiomer (I-a): Ra=Ph, Rb=cyclopentyl, Rc=CH3, Rd=benzil(DMSO-d6) δ 1,19, (1H, m)to 1.38 (2H, m)and 1.51 (3H, m), and 1.63 (2H, m), of 2.08 (s, 3H), equal to 2.94 (1H, m)to 3.41 (2H, d, J=2,8 Hz), to 3.58 (2H, s), of 5.99 (1H, s), 7,02 (1H, s), 7.23 percent (4H, m), 7,32 (4H, m), 7,46 (2H, m).(Method 1): Rt 7,29 min, m/z 377 [MH+]
30[2-(1,1-diphenylether)oxazol-5-ylmethyl]dimethylamine (I-j): Ra=Rb=Ph, Rc=Rd=Rg=CH3(CDCl3): δ 2,17 (s, 3H), of 2.21 (s, 6H), 3,51 (s, 2H), 6,91 (s, 1H), 7,15 (m, 4H), 7,21-to 7.32 (m, 6H).(Method 1): Rt to 6.57 min, m/z 307 [MH+]
31bromide [2-((S)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylphenethylamine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-phenethyl(CDCl3): δ 1,01-to 1.38 (m, 7H), of 1.65 (m, 3H), 2,30 (m, 2H), 3,13 (t, 2H), 3,32 (s, 3H), of 3.33 (s, 3H), 3,66 (m, 2H), total of 5.21 (DD, 2H), 7,16-to 7.32 (m, 8H), 7,53 (m, 3H).(Method 1): Rt 8,05 min, m/z 419 [M+]
32bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylphenethylamine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-phenethyl(CDCl3): δ 1,02-to 1.38 (m, 8H), of 1.66 (m, 3H), 2,30 (users, 1H), 3,12 (users, 2H), 3,32 (users, 6H), 3,67(users, 2H), total of 5.21 (userid, 2H), 7,16-to 7.32 (m, 8H), 7,53 (m, 3H).(Method 1): Rt to 7.93 min, m/ 419 [M +]
33bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(4-methylpent-3-enyl)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=4-methylpent-3-enyl(MeOD): δ 1.04 million-of 1.40 (m, 6H), 1,52-of 1.81 (m, 10H)to 2.41 (m, 1H), 2.49 USD at 2.59 (m, 2H), 3,06 (s, 3H), of 3.07 (s, 3H), 3,17 (dt, 2H), 4.72 in (s, 2H), 4,99 (m, 1H), 7,22-7,28 (m, 1H), 7.29 trend was 7.36 (m, 2H), of 7.48-rate of 7.54 (m, 3H).(Method 1): Rt 8,12 min, m/z 397 [M+]
34bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]dimethylamine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-(2,3-dihydrobenzofuran-5-yl)ethyl(CDCl3): δ 1,07-of 1.36 (m, 8H), 1,59-1,72 (m, 3H), to 2.29 (m, 1H), 3.04 from (t, 2H), and 3.16 (t, 2H), 3,32 (s, 3H), of 3.33 (s, 3H), 3,61 (m, 2H), 4.53-in (t, 2H), total of 5.21 (DDAB, 2H), of 6.68 (d, 1H), of 6.96 (d, 1H), 7,15-7,28 (m, 4H), 7,54 (m, 3H)(Method 1): Rt 8,14 min, m/z 461 [M+]
35formate [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(6-methylpyridin-2-ylmethyl)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re =6-methylpyridin-2-ylmethyl(MeOD): δ of 1.05 to 1.24 (m, 3H), 1,28-of 1.40 (m, 3H), by 1.68 (m, 4H), 2,42 (m, 1H), 2,60 (s, 3H), 3,06 (s, 3H), of 3.07 (s, 3H), 4,48 (s, 2H), 7,25 (TT, 1H), 7.29 trend was 7.36 (m, 2H), 7,39 (DD, 2H) 7,50-7,56 (m, 2H), 7,60 (s, 1H), 7,81 (t, 1H), 8,53 (users, 1H).(Method 1): Rt EUR 7.57 min, m/z 420 [M+]
36bromide [2-(cyclopentylacetyl)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium (I-b): Ra=Ph, Rb=cyclopentyl, Rc, Rd=CH3, Re=3-phenoxypropan(CDCl3): δ 1,24-1,49 (4H, m)and 1.51-1.69 in (4H, m), 2,32 (2H, m)of 3.00 (1H, m)to 3.34 (6H, s)to 3.64 (2H, m), a 4.03 (2H, m), with 5.22 (2H, m), 6,85 (2H, d), to 6.88 (1H, t), 7,20 (1H, t), 7,25-to 7.32 (5H, m), 7,52-of 7.60 (3H, m).(Method 1): Rt 7,99 min, m/z 436 [M+]
37bromide [2-(cyclopentylacetyl)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium (I-b): Ra=Ph, Rb=cyclopentyl, Rc, Rd=CH3, Re=3-phenoxypropan(CDCl3): δ 1,20-1,80 (8H), and 2.14 (2H, m)of 3.00 (1H, m)to 3.35 (6H, s)to 3.64 (3H, m), Android 4.04 (2H, s), a total of 5.21 (2H, m), 6,85 (2H, d), 6,98 (1H, t), 7,17-to 7.32 (5H, m), 7,50 to 7.62 (3H, m).(Method 1): Rt of 7.96 min, m/z 436 [M +]
38bromide 1-[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]-1-(3-phenoxypropan)piperidine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=piperidinyl, Re=3-phenoxypropan(CDCl3): δ 1,01-to 1.38 (8H, m), 1.56 to 1,99 (8H, m), 2,35-of 2.38 (3H, m), 3,41 is 3.57 (4H, m), the 3.65 (1H, s), 3,78-a 4.03 (4H, m), 5,19 (1H, d), of 5.34 (1H, d), for 6.81 (2H, m), 6,97 (1H, t), 7,17-7,31 (5H, m), 7,50-of 7.60 (3H, m).(Method 1): Rt 8,77 min, m/z 489 [M+]
39bromide 1-[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]-1-(3-phenoxypropan)piperidine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=piperidinyl, Re=3-phenoxypropan(CDCl3): δ 1,01-to 1.38 (8H, m), 1.56 to 1,99 (8H, m), 2,35-of 2.38 (3H, m), 3,41 is 3.57 (4H, m), 3,71-4,10 (5H,), 5,19 (1H, d), of 5.34 (1H, d), for 6.81 (2H, m), 6,97 (1H, t), 7,17-7,31 (5H, m), 7,50-of 7.60 (3H, m).(Method 1): Rt 8,78 min, m/z 489 [M+]
40bromide 1-[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]-1-(3-phenoxypropan)pyrrolidine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=pyrrolidinyl, Re=3-phenoxypropan (CDCl3): δ 1,03-of 1.39 (8H, m), 1,53 and 1.80 (2H, m), 2.05 is-2,44 (7H, m), of 3.48 (2H, m), 3,62 (2H, m), 3,80 (1H, s), 3,99-4,18 (4H, m), 5,16 (1H, d), from 5.29 (1H, d), at 6.84 (2H, m), of 6.99 (1H, t), 7,19-7,34 (5H, m), 7,54-7,60 (3H, m).(Method 1): Rt is 8.75 min, m/z 475 [M+]
41bromide 1-[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]-1-(3-phenoxypropan)pyrrolidine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=pyrrolidinyl, Re=3-phenoxypropan(CDCl3): δ 1,03-of 1.39 (8H, m), 1,53 and 1.80 (2H, m), 2.05 is-2,44 (7H, m), of 3.48 (2H, m), 3,62 (2H, m), 3,80 (1H, s), 3,99-4,18 (4H, m), 5,16 (1H, d), from 5.29 (1H, d), at 6.84 (2H, m), of 6.99 (1H, t), 7,19-7,34 (5H, m), 7,54-7,60 (3H, m).(Method 1): Rt to 8.57 min, m/z 475 [M+]
42formate [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-(8-methoxyacetyl)dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=8-methoxyacetyl(CDCl3): δ 0,99-1,42 (14H, m), 1,44 of-1.83 (8H, m)to 2.29 (1H, m), 2,78-3,27 (8H, m), or 3.28-3.46 in (5H, m), of 4.95 (2H, m), 7,16-7,34 (3H, m), the 7.43 (1H, m), 7,55 (2H, d), 8,67 (1H, s).(Method 1): Rt 8,50 min, m/z 457 [M+]
43bromide [2-(R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(4-phenoxybutyl)ammonium (I-b): R a=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=4-phenoxybutyl(CDCl3): δ 1,05-1,88 (12H, m), 1,96-of 2.08 (2H, m), of 2.34 (1H, m), and 3.31 (6H, 2×s), 3,44-3,59 (2H, m), of 3.78 (1H, s)to 4.01 (2H, t), of 5.15 (1H, d), 5,32 (1H, d), 6.87 in (2H, d), 6,97 (1H, t), 7,20 and 7.36 (5H, m), 7,52-7,60 (3H, m).(Method 1): Rt cent to 8.85 min, m/z 463 [M+]
44bromide (2-benzyloxyethyl)-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-benzyloxyethyl(CDCl3): δ 1,04 of-1.83 (10H, m), 2,31 (1H, m), 3,30 (6H, s), and 3.72 (1H, s), 3,82-4,00 (4H, m), 4,56 (2H, s), 4,98-of 5.26 (2H, m), 7,20-7,41 (8H, m), 7,44 (1H, s), 7,56 (2H, d).(Method 5): Rt 7,52 min, m/z 499 [M+]
45bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(4-phenylbutyl)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=4-phenylbutyl(CDCl3): δ 1.04 million-1,85 (14H, m), 2,31 (1H, m), 2,70 (2H, t), 3,12-3,44 (8H, m), the 3.65 (1H, s), 5,10 (1H, d), 5,28 (1H, d), 7,11-7,37 (8H, m), 7,46 (3H, m).(Method 5): Rt 7,79 min m/z 447 [M +]
46bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[3-(4-pertenece)propyl]dimethylamine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-(4-pertenece)propyl(CDCl3): δ 1,01-of 1.41 (8H, m), 1.56 to of 1.80 (2H, m), 2,25-2,39 (3H, m)to 3.34 (6H, s), 3,59-3,70 (2H, m), 3,92-of 4.05 (3H, m), 5,19 (1H, d), and 5.30 (1H, d), 6.75 in-PC 6.82 (2H, m), 6,92-7,01 (2H, m), 7,17-7,33 (3H, m), 7,51-7,60 (3H, m).(Method 5): Rt 7,51 min, m/z 467 [M+]
47methanesulfonate [8-(tert-butoxycarbonylmethylene)octyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=Me, Re=8-(tert-butoxycarbonylmethylene)octyl(CDCl3): δ 1,02-1,81 (31H, m), is 2.30 (1H,m), 2,70 (3H, s), and 2.83 (3H, s), 2,97-3,32 (10H, m), 4,82-of 5.06 (2H, m), 7,17-7,37 (3H, m), 7,43-to 7.64 (3H, m).(Method 5): Rt 8,50 min, m/z 556 [M+]
48formate [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenylpropyl)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-phenylpropyl (CDCl3): δ 0,98 and 1.35 (6H, m), 1,46 and 1.80 (4H, m), 1,88 e 2.06 (2H, m), 2,28 (1H, s)to 2.55 (2H, users), of 2.97 (6H, s), 3,07-of 3.27 (2H, m), 4,47-5,04 (2H, users), 7,06-7,39 (9H, m), 7,46-to 7.61 (2H, m), 8,67 (1H, users).(Method 1): Rt 8,27 min, m/z 433 [M+]
49formate [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(2-phenoxyethyl)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-phenoxyethyl(CDCl3): δ 0,98 and 1.35 (6H, m), 1,50-to 1.77 (4H, m)to 2.29 (1H, m), 3,14 (6H, s), 3,86 (2H, users), 4,35 (2H, users), is 4.93 (2H, users), 6,87 (2H, d), of 6.96-7.03 is (1H, m), 7,13-7,19 (5H, m), 7,44 (1H,s), 7,54 (2H, d), 8,64 (1H, users).(Method 1): Rt 8,09 min, m/z 435 [M+]
50methanesulfonate (2-{4-[(tert-butoxycarbonylmethylene)methyl]phenyl}ethyl)-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-{4-[(tert-butoxycarbonylmethylene)methyl]phenyl}ethyl(CDCl3): δ 1,00-1,80 (19H, m)to 2.29 (1H, m), by 2.73 (3H, s), 2,80 (3H, s)to 3.09 (2H, t), 3,18 (6H,s), 3.43 points-to 3.58 (2H, m), 4,34 (1H, s), to 4.38 (2H, s), of 4.95 (1H, d), of 5.05 (1H, d), 7,16-7,29 (7H, is), 7,51-EUR 7.57 (3H, m).(Method 5): Rt 8,11 min, m/z 562 [M+]
51bromide [3-(4-carbamoylphenoxy)propyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-(4-carbamoylphenoxy)propyl(DMSO-d6) δ 0,90-1,30 (6H, m), 1,49 is 1.75 (4H, m), 2,17-2,31 (3H, m), 3.04 from (6H, s), 3,28-of 3.43 (2H, m)4,06 (2H, t), of 4.77 (2H, s)6,09 (1H, s), 6,93-6,99 (2H, m), 7,15-7,26 (2H, m), 7,27-to 7.35 (2H, m), 7,44 is 7.50 (2H, m,), 7,54 (1H, s), to 7.77-to $ 7.91 (3H, m).(Method 5): Rt 6,11 min, m/z 792 [M+]
52bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-(isoxazol-3-ylcarbonyl)dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=isoxazol-3-ylcarbamate(CDCl3): δ 0,99 of-1.83 (10H, m), up 3.22 (1H, m), 3,44 (6H, s), 4,28 (1H, s), 5,04 (2H, s), 5,16 at 5.27 (2H, m), 6,77 (1H, d), 7,17-7,22 (1H, m), 7,27-7,33 (2H, m), 7,50-7,58 (3H, m), 8,21 (1H, d), 11,40 (1H, s).(Method 1): Rt 6,93 min, m/z 439 [M+]
53bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[3-(4-methoxy is Boniface)propyl]dimethylamine (I-b): R a=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-(4-ethoxycarbonylphenyl)propyl(CDCl3): δ 1,02-of 1.40 (8H, m), 1.56 to of 1.80 (2H, m), 2.26 and-to 2.42 (3H, m)to 3.35 (6H, s), 3,60 is 3.76 (2H, m)to 3.89 (3H, s), 3,98 (1H,s), a 4.03-to 4.14 (2H, m), 5,20 (1H, d), and 5.30 (1H, d), 6.87 in (2H, d), 7,17-7,24 (1H, m), 7.24 to-7,33 (2H, m), 7,53-to 7.64 (3H, m), 7,98 (2H, d).(Method 1): Rt 8,02 min, m/z 507 [M+]
54bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl[3-(4-sulfamoylbenzoic)propyl}ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-(4-sulfamoylbenzoic)propyl(MeOD): δ 1,02-of 1.42 (6H, m)and 1.51-is 1.82 (4H, m), 2,27 is 2.46 (3H, m), of 3.12 (6H, m), 3,34-of 3.54 (2H, m), 4.04 the-4,17 (2H, m), 4,78 (2H, s), 6,98-7,07 (2H, m), 7,17-to 7.35 (3H, m), 7,47-,54 (3H, m), 7,78-7,88 (2H, m).(Method 1): Rt 7,05 min, m/z 528 [M+]
55bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-para-trilateral)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-para-tolylacetate(CDCl3): δ 1,00-1,39 (7H, m), 1,50-to 1.77 (3H, m), 2,22-2,37 6H, m), 3,30 (3H, s), of 3.32 (3H, s), of 3.57 (2H, m in), 3.75 (1H, s), 3,94-was 4.02 (2H, m)to 5.17 (1H, d), of 5.34 (1H, d), of 6.71 (2H, d), 7,05 (2H, d), 7,15-7,30 (3H, m), 7,51-EUR 7.57 (3H, m).(Method 5): Rt 7,88 min, m/z 463 [M+]
56bromide [3-(4-chlorophenoxy)propyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-(4-chlorophenoxy)propyl(CDCl3): δ 1,02-1,41 (7H, m), 1,57-to 1.79 (3H, m), 2,58-of 2.38 (3H, m)to 3.33 (6H, s), 3,61-3,70 (2H, m), 3,94-Android 4.04 (3H, m), is 5.18 (1H, d), and 5.30 (1H, d), 6.75 in-for 6.81 (2H, m), 7.18 in-to 7.32 (5H, m), 7,53-to 7.59 (3H, m).(Method 1): Rt 8,07 min, m/z 483 [M+]
57bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[3-(3,4-dichlorophenoxy)propyl]dimethylamine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-(3,4-dichlorophenoxy)propyl(CDCl3): δ 1,02-of 1.40 (8H, m), 1,52 and 1.80 (2H), 2.26 and-2,39 (3H, m)to 3.34 (6H, s), 3,60-to 3.73 (2H, m), 3,86 (1H, s), 3.95 to Android 4.04 (2H, m), 5,20 (1H, d), 5,33 (1H, d), 6,69 to 6.75 (1H, m), to 6.95 (1H, d), 7,19 and 7.36 (4H, m), 7,53-to 7.59 (3H, m).(Method 5): Rt to 8.62 min, m/z 517 [M+]

Using the synthesis pathway presented in figure 3, also the were given:

Example 58

Bromide 1-[2-(hydroxydiphenylmethyl)oxazol-5-ylmethyl]-1-methyl-4-phenoxypyridine (I-b): Ra=Rb=Ph, Rc, Rd=piperidinyl, Re=CH3

To a solution of [5-(4-phenoxypyridine-1-ylmethyl)oxazol-2-yl]diphenylethanol (Example 26) (35 mg, 0.08 mmol) in 0.5 ml of acetonitrile was added 1.5 ml (~5 mmol) of 40 wt.% solution of bromide in acetonitrile. The reaction mixture was heated in a sealed vessel at 40°C for 18 h, during which the formed precipitate. The solvent evaporated and triturated the residue with diethyl ether. The solid is recrystallized from acetonitrile to obtain specified in the title compounds as a mixture of CIS/TRANS isomers (8/1) as a white solid.

Yield: 6 mg (14%).

LC/MS (Method 1): Rt to 7.93 min, m/z 455 [M+].

1H-NMR (CDCl3): δ 2,11-is 2.37 (m, 4H), 3.15 in (s, 3H, side-isomer), 3,30 (s, 3H), to 3.58 (user. s, 4H), 3,67 (user. s, 4H, side-isomer), 4,67 (user. s, 1H), 4,71 (user. s, 1H, side-isomer), 5,04 (user. s, 2H), 5,23 (user. s, 2H, side-isomer), 6.87 in (d, 2H), 6,91 (d, 2H, side-isomer), 7,02 (t, 1H), 7,26-7,38 (m, 12H), 7,58 (users, 1H), 7,63 (users, 1H, side-isomer).

Example 59

In accordance with the method used in example 58, but using the compound of example 28 instead of the compound of example 26 was received

Bromide benzyl[2-(cyclopentyl hydroxyphenylethyl)oxazol-5-ylmethyl]dimethylammonio (I-b): R a=Ph, Rb=cyclopentyl, Rc, Rd=CH3, Re=benzil

Yield: 11 mg (17%)

LC/MS (Method 1): Rt 6,70 min, m/z 391 [M+].

1H-NMR (DMSO-d6) δ 1,22 (1H, m)to 1.38 (2H, m), of 1.52 (3H, m), by 1.68 (2H, m), is 2.88 (3H, s), of 2.92 (3H, s) of 2.97 (1H, m), 4,55 (2H, s), 4,70 (2H, s), 6,18 (1H, s), 7,25 (1H, m), 7,34, (2H, m), of 7.48-7,58 (7H, m).

Example 60

In accordance with the method used in example 58, but using the compound of example 29 instead of the compound of example 26 was received

Bromide benzyl[2-(cyclopentylacetyl)oxazol-5-ylmethyl]dimethylammonio (I-b): Ra=Ph, Rb=cyclopentyl, Rc=Rd=CH3, Re=benzil

Yield: 27 mg (58%)

LC/MS (Method 1): Rt 7,30 min, m/z 391 [M+].

1H-NMR (DMSO-d6) δ of 1.23 (1H, m)to 1.37 (2H, m), of 1.52 (3H, m)to 1.67 (2H, m), is 2.88 (3H, s), of 2.92 (3H, s), of 2.97 (1H, m), 4,55 (2H, s), 4,70 (2H, s), 6,18 (1H, s), 7,25 (1H, m), 7,34, (2H, m), of 7.48-7,58 (7H, m).

Example 61

Cleaners containing hydrochloride salt methansulfonate [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(8-methylaminomethyl)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc=Rd=CH3, Re=8-methylaminomethyl

Methanesulfonate [8-(tert-butoxycarbonylmethylene)octyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylamine (Example 47) (60 mg, 0.09 mmol) was dissolved in 6 ml of 1M HCl in dioxane. The solution was stirred while the temperature is round the environment during the night. The solvent was removed and the crude product is purified according to the method of column chromatography on silica gel, elwira gradient from DCM to 20% MeOH/DCM, to obtain specified in the connection header in the form of solids.

Yield: 21 mg (42%).

LC/MS (Method 1): Rt 5,50 min, m/z 456 [M+].

1H-NMR (CDCl3): δ 1,01-2,19 (22H, m), 2,33 (1H,m)of 2.64 (3H, s), 2,69 (3H, s), of 2.21 (2H, m), and 3.16 (6H, s), 3,35-3,50 (2H, m), 4,78-5,08 (2H, m), 7,16 and 7.36 (3H, m), 7,46-of 7.60 (3H, m), 9,31 (2H, s).

Example 62

In accordance with the method used in example 61, but using the compound of example 50 instead of the compound of example 47, received hydrochloride methansulfonate [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl[2-(4-methylaminomethyl)ethyl]ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-(4-methylaminomethyl)ethyl.

Yield: 51%.

LC/MS (Method 5): Rt with 4.64 min, m/z 462 [M+].

1H-NMR (MeOD): δ 1,01-of 1.41 (6H, m), 1,50-of 1.81 (4H, m), 2,39 (1H, m), 2,69 (3H, s), a 2.71 (3H, s), is 3.08-3.27 to (8H, m), 3,39 is 3.57 (2H, m), 4,19 (2H, s), 7,20-to 7.35 (3H, m), 7,39-to 7.59 (7H, m).

Scheme 7

The following compounds of the examples were obtained using the synthesis pathway presented in figure 7.

Example 63

[5-(2-amino-ethyl)oxazol-2-yl]cyclohexanedimethanol (I-c): Ra=Ph, Rb=cyclohexyl

To a solution of [2-(cyclohexyl proximinality)oxazol-5-yl]acetonitrile (intermediate 12) (600 mg, 2.0 mmol) in THF (20 ml), heated at 55°C was added dropwise a solution of borane-dimethylsulfide complex (2 ml, 2M solution in THF, 4 mmol). The mixture was heated under reflux for 90 minutes and then left to cool to room temperature. The mixture is then cooled in a bath with ice and extinguished by adding dropwise methanol (5 ml), and then hydrochloric acid (1N., 2 ml). This mixture was stirred for 30 minutes and then neutralized us. aqueous solution of sodium bicarbonate. The mixture was distributed between water (80 ml) and ethyl acetate (80 ml), the aqueous phase was extracted with ethyl acetate (2×50 ml), the combined organic phases were dried over sodium sulfate, filtered and evaporated to obtain oil. The residue was purified by SCX cartridge, washed with ethanol, and then was suirable 4h. ammonia in methanol to obtain specified in the title compounds as colorless oils.

Yield: 400 mg (67%).

LC/MS (Method 2): Rt 2,18 min, m/z 283 [MH+-N2O].

1H-NMR (CDCl3): δ 1,10-1,38 (7 H, m), and 1.54-1.77 in (3H, m), 2,28 (1H, m), 2,80 (2H, t), 2,98 (2H, t)to 3.67 (1H, user. C)6,72 (1H, s), 7,24 (1H, m), 7,34 (2H, m), a 7.62 (2H, m).

Example 64

Cyclohexyl-[5-(2-dimethylaminoethyl)oxazol-2-yl]phenylmethanol (I-d): Ra=Ph, Rb=cyclohexyl, Rc=Rd=CH3

To a solution of [5-(2-amino-ethyl)oxazol-2-yl]cyclohexanedimethanol (Example 63) (250 is g, 0.83 mmol) in 1,2-dichloroethane (5 ml) was added formaldehyde (0.3 ml of 37% solution in water, 4.0 mmol) and triacetoxyborohydride sodium (352 mg, 1.7 mmol). This mixture was stirred at room temperature for 6 hours, then was added DCM (10 ml) and us. aqueous sodium bicarbonate (10 ml) and thoroughly mixed. The organic phase was separated on the cartridge and evaporated to obtain oil. Conducted clearing method column flash chromatography on silica gel, using as eluent a mixture of 10% methanol/90% DCM, obtaining specified in the title compound as a white solid.

Yield: 200 mg (73%).

LC/MS (Method 2): Rt 2,20 min, m/z 329 [MH+].

The NMR spectrum corresponds to the compound of example 66.

Example 65

Bromide {2-[2-(cyclohexylhydroxylamine)oxazol-5-yl]ethyl)dimethyl(3-phenoxypropan)ammonium (I-e): Ra=Ph, Rb=cyclohexyl, Rc=Rd=CH3, Re=3-phenoxypropan

To a solution of cyclohexyl[5-(2-dimethylaminoethyl)oxazol-2-yl]phenylmethanol (Example 64) (10.5 mg, 0.03 mmol) in a mixture of acetonitrile (0.5 ml) and chloroform (0.75 ml) was added 3-phenoxypropylamine (50 μl, 0.32 mmol). This mixture was heated at 50°C for 6 hours, and then solvent was removed in vacuum. Conducted clearing method column flash chromatography on silica gel, using as eluent gradie the t 2-10% methanol in DCM, obtaining specified in the title compound as a white solid.

Yield: 8.6 mg (53%).

LC/MS (Method 1): Rt 8,66 min, m/z 463 [M+].

1H-NMR (MeOD): δ of 1.06 and 1.35 (6H, m)of 1.66 (4H, m), 2,24 (2H, m), is 2.37 (2H, m), 3,17 (6H, s), 3,29 (1H, m)and 3.59 (2H, m), 3,66 (2H, m)4,06 (2H, t), 6,91-6,97 (3H, m), of 6.99 (1H, s), 7,20-7,33 (5H, m), 7,50 (2H, m).

Example 66

[5-(2-amino-ethyl)oxazol-2-yl]cyclohexanedimethanol (I-d): Ra=Ph, Rb=cyclohexyl, Rc=Rd=CH3(eluruumis first enantiomer)

Specified in the title compound was isolated according to the method of chiral preparative HPLC of compound of example 64 (column Chiralpax IA, 250×20 mm; 5% ethanol/95% heptane/0.1% diethylamine; 15 ml/min; Rt 12 min).

LC/MS (Method 1): Rt 6,74 min, m/z 329 [MH+].

1H-NMR (CDCl3): δ 1,10-1,37 (7H, m), 1,61 to 1.76 (3H, m), and 2.26 (6H, s), to 2.57 (2H, t), of 2.81 (2H, t), 3,66 (1H, s), 6,69 (1H, s), 7,24 (1H, m), 7,34 (2H, t), 7,63 (2H, d).

Example 67

[5-(2-amino-ethyl)oxazol-2-yl]cyclohexanedimethanol (I-d): Ra=Ph, Rb=cyclohexyl, Rc=Rd=CH3(eluruumis second enantiomer)

Specified in the title compound was isolated according to the method of chiral preparative HPLC of compound of example 64 using the conditions described in example 66; (Rt 13,5 min).

LC/MS (Method 1): Rt 6,76 min, m/z 329 [MH+].

The NMR spectrum corresponds to the compound of example 66.

Example 68

Bromide {2-[2-(cyclohexylhydroxylamine)oxazol-5-yl]ethyl}dimethyl(3-phenoxypropan)ammonium (I-e): Ra=Ph, Rb=cyclohexyl, Rc=Rd=CH3, Re=3-phenoxypropan - enantiomer 1

Specified in the title compound was obtained from the compound of example 66, using the method of example 65.

LC/MS (Method 1): Rt 8,54 min, m/z 463 [M+].

1H-NMR (DMSO-d6) δ 0,95 of 1.28 (6H, m), 1,48 is 1.70 (4H, m), 2,12-of 2.28 (3H, m), 3,11 (6H, s), 3,20 (2H, t), 3,51 (2H, m), 3,61 (2H, m), a 4.03 (2H, t), of 5.89 (1H, s), 6,92-6,98 (3H, m), 7,00 (1H, s), 7,20-7,24 (1H, m), 7,28-7,34 (4H, m), 7,43-7,47 (2H, m).

Example 69

Bromide {2-[2-(cyclohexylhydroxylamine)oxazol-5-yl]ethyl}dimethyl(3-phenoxypropan)ammonium (I-e): Ra=Ph, Rb=cyclohexyl, Rc=Rd=CH3, Re=3-phenoxypropan - enantiomer 2

Specified in the title compound was obtained from the compound of example 67 using the method of example 65.

LC/MS (Method 1): Rt to 8.62 min, m/z 463 [M+].

The NMR spectrum corresponds to the compound of example 68.

Example 70

[5-(2-amino-ethyl)oxazol-2-yl]diphenylethanol (I-c): Ra=Rb=Ph

To a solution of [2-(hydroxydiphenylmethyl)oxazol-5-yl]acetonitrile (intermediate 13) (0.36 g, 1.2 mmol) in IMS (7 ml) was added Raney Nickel (catalytic amount) and the stirred suspension in the atmosphere of hydrogen (balloon) at K.T. those who tell the night. The reaction mixture was filtered through celite, washed with IMS and the filtrate was concentrated in vacuum to obtain a brown oil, which was used without further purification.

LC/MS (Method 2): Rt of 1.85 min, m/z 295 [M+].

1H-NMR (CDCl3): δ 2,66-by 2.73 (m, 2H), 2,81-of 2.86 (m, 2H), only 6.64 (s, 1H), 7,25-7,37 (m, 10H).

The following compounds of the examples were treated in a similar fashion using route of synthesis presented in figure 7.

ExampleNameStructure1H-NMRLC/MS
71[5-(2-dimethylaminoethyl)oxazol-2-yl]diphenylethanol (I-d): Ra=Rb=Ph, Rc=Rd=CH3(CDCl3): δ of 2.23 (s, 6H), to 2.55 (t, 2H), 2,80 (t, 2H), 4,50 (users, 1H), 6,76 (s, 1H), 7,27-7,37 (m, 10H).(Method 5): Rt to 5.03 min, m/z 323 [MH+]
72bromide {2-[2-(hydroxydiphenylmethyl)oxazol-5-yl]ethyl}dimethyl(3-phenoxypropan)ammonium (I-e): Ra=Rb=Ph, Rc=Rd=CH3, Re=3-phenoxypropan (DMSO-d6) δ 2,17 (m, 2H), 3,12 (s, 6H), 3,24 (t, 2H), 3,52 (m, 2H), to 3.64 (m, 2H), Android 4.04 (t, 2H), to 6.95 (m, 3H), of 6.99 (s, 1H),? 7.04 baby mortality (s, 1H), 7.24 to 7,34 (m, 12H)(Method 1): Rt 7,43 min, m/z 457 [M+]

The following compounds of the examples were treated in a similar fashion using route of synthesis presented in figure 8.

Scheme 8

Example 73

(2-Benzhydrylamine-5-ylmethyl]dimethylamine (I-f): Ra=Rb=Ph, Rc, Rd=CH3

To a solution of (5-dimethylaminomethylene-2-yl)diphenylmethane (Example 1) (100 mg, 0,325 mmol) in DCM (0.7 ml) was added triethylsilane (720 μl, 4,51 mmol)and then TFA (0.7 ml), and heated under reflux for 6 hours the Reaction mixture was concentrated, passed through the cartridge SCX-2 and released 2M solution of ammonia in methanol. After evaporation of the volatiles the residue was purified on silica gel, using as eluent a gradient of 1-5% MeOH/DCM, to obtain specified in the title compounds as colorless oils.

Yield: 74 mg (78%).

LC/MS (Method 5): Rt to 5.03 min, m/z 293 [MH+].

1H-NMR (CDCl3): δ 2,24 (s, 6H), 3,50 (s, 2H), 5,59 (s, 1H), 6,91 (s, 1H), 7,22-7,33 (m, 10H).

Example 74

Bromide (2-benzhydrylamine-5-ylmethyl)dimethyl(3-phenoxypropan)ammonium (I-g): Ra=Rb=Ph, Rc, Rd=Me, Re=3-phenoxy the filing

Specified in the title compound was obtained from the compound of example 73 in accordance with the method used to obtain the compounds of example 8.

Yield: 87%.

LC/MS (Method 1): Rt 8,05 min, m/z 427 [M+].

1H-NMR (CDCl3): δ 2,32 (m, 2H), 3,39 (s, 6H)and 3.59 (m, 2H), 3,93 (m, 2H), and 5.30 (S, 2H), 5,62 (s, 1H), 6,79 (d, 2H), 6,97 (t, 1H), 7,20-to 7.32 (m, 12H), to 7.61 (s, 1H).

Example 75

[2-(Methoxycarbonylmethyl)oxazol-5-ylmethyl]dimethylamine (I-h): Ra=Rb=Ph, Rc=Rd=Rf=Me

To a solution of (5-dimethylaminomethylene-2-yl)diphenylmethane (Example 1) (100 mg, 0.32 mmol) in 3 ml of DMF under nitrogen atmosphere was added sodium hydride (60% dispersion in oil, 16 mg, 0.40 mmol) and stirred the reaction mixture for 5 minutes was Added logmean (40 μl, of 0.65 mmol) and stirred the reaction mixture at room temperature for 18 hours was Added water and EtOAc and separated phases. The organic layer was dried (Na2SO4) and the solvent evaporated. The crude product was purified using a 10 g Isolute NH2cartridge, elwira 5-10% EtOAc/cyclohexane, to obtain specified in the connection header.

Yield: 56 mg (53%).

LC/MS (Method 4): Rt 2,22 min, m/z 323 [MH+].

1H-NMR (CDCl3): δ of 2.21 (s, 6H), of 3.27 (s, 3H), 3,55 (s, 2H), 6,99 (s, 1H), 7.23 percent-7,37 (m, 6H), 7,43-7,52 (m, 4H).

Example 76

Bromide [2-(methoxycarbonylmethyl)oxazol-5-ILM is Teal]dimethyl(3-phenoxypropan)ammonium (I-l): R a=Rb=Ph, Rc, Rd=Me, Re=3-phenoxypropan, Rf=Me

Specified in the title compound was obtained from the compound of example 75 in accordance with the method used to obtain the compounds of example 8.

Yield: 40 mg (45%).

LC/MS (Method 5): Rt 7,46 min, m/z 457 [M+].

1H-NMR (MeOD): δ of 2.27 (m, 2H), to 3.09 (s, 6H), 3,23 (s, 3H), 3,42 (m, 2H), 3,98 (t, 2H), 4,78 (s, 2H), to 6.88 (DD, 2H), of 6.96 (m, 1H), 7,25-7,34 (m, 8H), 7,47 (m, 4H), a 7.62 (s, 1H).

Example 77

5-[(R)-2-(9-{[2-(Cyclohexylhydroxylamine)oxazol-5-ylmethyl]methylamino}nonylamine)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-he

A solution of 5-[(R)-1-(tert-butyldimethylsilyloxy)-2-(9-{[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]methylamino}nonylamine)ethyl]-8-hydroxy-1H-quinoline-2-she (75 mg, 0.10 mmol) in anhydrous THF (1 ml) under nitrogen atmosphere was treated with trihydrochloride of triethylamine (48 μl, 0.30 mmol). After stirring at K.T. during the night the reaction mixture was neutralized by adding us. NaHCO3(aq.) and was extracted with DCM. The combined organic phases are washed with saline, dried (Na2SO4), filtered and concentrated to dryness to obtain a green-brown resin. The resin was purified by the method of preparative HPLC (system 1, 25% B + 1,7% B/min). Fraction of the product was concentrated, the residue was absorbed MeOH/DCM, passed through the cartridge SCX-2 and released the use of 2M solution of ammonia in MeOH. The solvent is evaporated in vacuum to obtain specified in the title compound as a yellow resin.

Yield: 21 mg, 33%.

LC/MS (Method 2): Rt 2,22 min, m/z 645 [MH+].

Example 78

(5-Dimethylaminomethylene-2-yl)diphenylethanol (XXVIII): Ra=Ph, Rb=Ph, Rc=Me, Rd=Me

To a mixture of AIBN (of 5.84 mg, being 0.036 mmol), N-bromosuccinimide (0,070 g, 0,391 mmol) and intermediate 30 (0.1 g, 0,355 mmol) was added DCE (3 ml). The suspension was placed in a preheated oil bath at 90°C. After 40 min the reaction was completed, judging by the results of LC/MS analysis. The solution was poured into a mixture of diethyl ether and us. of sodium bicarbonate and the layers were separated. The organic phase is washed with water and brine, dried (MgSO4) and was evaporated. The residue was dissolved in THF (2 ml), cooled to -10°C in nitrogen atmosphere and was treated with 2M solution of diethylamine in THF (0,178 ml, 0,355 mmol). After heating up to K.T. the solvent evaporated and the residue was subjected to column chromatography (SiO2, 8 g), elwira 50% EtOAc in isohexane, to give the desired substance.

Yield: 0.06 g (51%).

LC/MS (Method 6): Rt 2,84 min, m/z 325 [MH+].

1H-NMR, 400 MHz, DMSO-d6: 7,5 (1H, s), and 7.4 (4H, m), and 7.3 to 7.2 (7H, m), 3,6 (2H, s) and 2.1 (6H, s).

Example 79

Bromide [2-(hydroxydiphenylmethyl)thiazole-5-ylmethyl]dimethyl-3-(fenoxaprop is)ammonium (XXIX): R a=Ph, Rb=Ph, Rc=Me, Rd=Me, Re=3 phenoxy-1-propyl

To a solution of intermediate 3 (by 0.055 g, 0,170 mmol) in CHCl3(1 ml) and MeCN (1 ml) was added phenoxypropylamine (0,438 g 2,034 mmol). The solution was heated at 55°C for 20 h, while according to the method of TLC (10% MeOH in DCM) was not determined almost complete reaction. The solvents are evaporated and the residue was subjected to column chromatography (SiO2, 8 g), elwira 5-15% MeOH in DCM, to give the desired substance in the form of a white solid.

Output: 0,061 g (66,7%).

LC/MS (Method 1): Rt 2,39 min, m/z 459 [M-Br]+.

1H-NMR, 400 MHz, DMSO-d6: 8,0 (1H, s), and 7.5 (1H, s), and 7.4 (4H, m), and 7.3 to 7.2 (8H, m), 6,9 (3H, m), 4,9 (2H, s), 4,0 (2H, s), 3,4 (2H, m), 6,1 (6H, s), 2.2 (2H, m).

Example 80

Bromide (3-benzyloxyphenyl)-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-benzyloxyphenyl

Specified in the title compound was obtained in accordance with the method used to obtain the compounds of example 8.

LC/MS (Method 5): Rt 7,26 min, m/z 463 [M+].

1H-NMR (DMSO-d6) δ 0,90-of 1.29 (m, 6H), 1,50-of 1.74 (m, 4H), 2,04 (m, 2H), and 2.26 (m, 1H), 2,98 (s, 3H), 2,99 (s, 3H), of 3.27 (m, 2H), 3.45 points (t, 2H), 4,46 (s, 2H), 4.72 in (s, 2H), between 6.08 (s, 1H), 7,24 (t, 1H), 7,28-7,39 (m, 7H), 7,46 (d, 2H), 7,52 (s, 1H).

Example 81

Methanesulfonate [2-(4-chlorobenz is lexi)ethyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio (I-b): R a=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-(4-chlorobenzoyloxy)ethyl

Specified in the title compound was obtained in accordance with the method used to obtain the compounds of example 8.

LC/MS (Method 1): Rt 8,73 min, m/z 483 [M+].

1H-NMR (CDCl3): δ 1,02-1,49 (7H, m), 1.56 to to 1.79 (3H, m), 2.21 are of 2.34 (1H, m)to 2.67 (3H, s), 3,14 (6H, s)to 3.64 (2H, user. C), 3,88 (2H, user. C)of 4.49 (2H, s), 4,79-4,99 (3H, m), 7,16 and 7.36 (7H, m), the 7.43 (1H, s), 7,51-7,58 (2H, m).

Example 82

Bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(2-oxo-2-phenylethyl)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-oxo-2-phenylethyl

Specified in the title compound was obtained in accordance with the method used to obtain the compounds of example 8.

LC/MS (Method 2): Rt 2,53 and 2,60 min, m/z 433 [M+].

1H-NMR (CDCl3): δ 1,02-1,87 (10H, m), 2,17 of-2.32 (1H, m)and 3.59 (3H, s), of 3.60 (3H, s)to 3.89 (1H, user. C), 5,28 (1H, d), vs. 5.47 (1H, m), USD 5.76 (2H, s), 7,17-7,33 (3H, m), 7,42 (1H, s), 7,45-rate of 7.54 (4H, m), to 7.61-to 7.67 (1H, m), 8,05-8,11 (2H, m).

Example 83

Bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(2-penetrometer)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-penetrometer

Specified in the title compound was obtained in accordance with the method used for the floor of the possible connections of example 8.

LC/MS (Method 1): Rt 8,51 min, m/z 463 [M+].

1H-NMR (CDCl3): δ 1,07-of 1.40 (m, 7H), 1,60-1,80 (m, 3H), 2,32 (m, 1H), 2,87 (t, 2H), 3,12 (s, 6H), 3.72 points-a 3.87 (m, 6H), 4,17 (s, 1H), 4,91 (DD, 2H), 7,16 (m, 3H), 7,20-7,28 (m, 3H), 7,29-7,37 (m, 3H), EUR 7.57 (d, 2H).

Example 84

Bromide [3-(4-carboxyphenoxy)propyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-(4-carboxyphenoxy)propyl

To a solution of bromide [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[3-(4-ethoxycarbonylphenyl)propyl]dimethylamine (Example 53) (41 mg, 0,069 mmol) in H2O (3 ml) and MeOH (3 ml) was added 1M NaOH (0,209 ml). The solution was stirred at ambient temperature for 2 days, and then was added 1M HCl (2 ml). The solution liofilizirovanny and purified the crude product by the method of column chromatography, elwira 20% MeOH in DCM to obtain specified in the title compound, which presumably was the bromide.

Yield: 40 mg (100%).

LC/MS (Method 1): Rt 7,35 min, m/z 493 [M+].

1H-NMR (CD3OD): δ 1,02-of 1.39 (6H, m), 1,53-to 1.79 (4H, m), 2,22 of 1.46 (3H, m), of 3.12 (6H, s), 3,39-to 3.52 (2H, m), 4,05-4,16 (2H, m), of 4.77 (2H, s), 6,93-7,01 (2H, m), 7,16-to 7.35 (3H, m), of 7.48-7,56 (4H, m), 7,95-8,02 (2H, m).

Example 85

Methanesulfonate [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl[2-(4-methylbenzylamino)ethyl]ammo the Oia (I-b): R a=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-(4-methylbenzylamino)ethyl

Specified in the title compound was obtained in accordance with the method used to obtain the compounds of example 8.

LC/MS (Method 1): Rt 8,67 min, m/z 463 [M+].

1H-NMR (CDCl3): δ 1,03-2,07 (10H, m), 2,22 is 2.43 (4H, m), 2,69 (3H, s), 3,14 (6H, s)to 3.64 (2H, user. C), 3,86 (2H, user. C)4,48 (2H, s), 4,60 (1H, user. C), 4,82-5,02 (2H, m),? 7.04 baby mortality-7,37 (7H, m), 7,42 (1H, s), 7,55 (2H, d).

Example 86

Methanesulfonate [2-((R)-cyclohexylhydroxylamine]oxazol-5-ylmethyl]-[2-(3,4-dichloraniline)ethyl]dimethylamine (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-(3,4-dichloraniline)ethyl

Specified in the title compound was obtained in accordance with the method used to obtain the compounds of example 8.

LC/MS (Method 1): Rt is 9.09 min, m/z 517 [M+].

1H-NMR (CDCl3): δ 1,03-1,39 (7H, m), 1,58 and 1.80 (3H, m), 2,23 to 2.35 (1H, m), 2,71 (3H, s), 3,17 (6H, s), 3,71-of 3.77 (2H, m), 3,89-3,98 (2H, m), 4,42 (1H, s), of 4.49 (2H, s), 4,87-5,04 (2H, m), 7,11-7,33 (4H, m), of 7.36-7,49 (3H, m), 7,53-to 7.59 (2H, m).

Example 87

Toluene-4-sulfonate (2-benzyloxyethyl)-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=2-benzyloxyethyl

Specified in the title compound was obtained in the fit is shown by the way that used to obtain the compounds of example 8, using 2-(benzyloxyethyl)-para-toluensulfonate.

LC/MS (Method 2): Rt 2,60 min, m/z 449 [M+].

1H-NMR (CDCl3): δ of 1.02 to 1.76 (10H, m), 2,22-is 2.37 (4H, m), 3,19 (6H, s), of 3.69 (2H, user. C), 3,86 (2H, user. C), 4,25 (1H, user. C)4,48 (2H, s), 4,89 is 5.07 (2H, m), 7,05-to 7.15 (2H, m), 7,16-the 7.43 (9H, m), 7,55 (2H, d), 7,73 (2H, d).

Example 88

[5-(2-amino-ethyl)oxazol-2-yl]cyclopentanemethanol (I-c): Ra=Ph, Rb=cyclopentyl

Received in accordance with the method used to obtain the compound of example 70.

LC/MS (Method 2): Rt 2,03 min, m/z 287 [MH+].

1H-NMR (CDCl3): δ 1,28-1,71 (m, 11H), 2,78 (t, 2H), 2,97 (m, 3H), 6,72 (s, 1H), 7,22-7,28 (m, 1H), 7,30 and 7.36 (m, 2H), to 7.59-to 7.64 (m, 2H).

Example 89

Cyclopentyl[5-(2-dimethylaminoethyl)oxazol-2-yl]phenylmethanol (I-c): Ra=Ph, Rb=cyclopentyl, Rc=Rd=CH3

Received in accordance with the method used to obtain the compound of example 64.

LC/MS (Method 2): Rt 2,05 min, m/z 315 [MH+].

1H-NMR (CDCl3): δ 1,29 is 1.70 (m, 8H), and 2.26 (s, 6H), 2.57 m (m, 2H), 2,80 (t, 2H), 2,97 (m, 1H), 3,68 (users, 1H), 6,69 (s, 1H), 7,21-7,27 (m, 1H), 7,33 (t, 2H), a 7.62 (d, 2H).

Example 90

Methanesulfonate [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-methyl-3-phenoxybutyl)ammonium (I-b): Ra=Ph, Rb=cyclohexyl, Rc, Rd=CH3, Re=3-methyl-3-phenoxybutyl

Specified in the title compound was obtained in accordance with the method used to obtain the compounds of example 8.

Yield: 5 mg (6%).

LC/MS (Method 4): Rt 2,85 min, m/z 477 [M+].

1H-NMR (CDCl3): δ 0.70 to a 2.00 (16H, m), 2,02 and 2.13 (2H, m), 2,16-of 2.30 (1H, m), 2,62 (3H, s), of 3.07 (6H, s), 3,44-3,55 (2H, m), 4,77-4,91 (2H, m), 6,83 (2H, d), 6,97-7,27 (5H, m), 7,43-7,52 (4H, m).

BIOLOGICAL EXAMPLES

Effects of inhibition of the compounds of the present invention muscarinic M3 receptor and (in the case of compound of example 77) β2-adrenergic receptors was determined by the following methods of analysis of binding.

Methods of analysis of binding of radiolabelled ligand with muscarinic receptor

To assess the affinity of antagonists of muscarinic M2 and M3 receptors have conducted studies of the binding of radiolabelled ligand with [3H]-N-methylscopolamine ([3H]-NMS) and commercially available cell membranes expressing muscarinic receptors person (M2 and M3). Membranes in Tris-buffer were incubated in 96-well-microplate with [3H]-NMS and an antagonist of M3 receptor in various concentrations for 3 hours. Then the membrane with bound radiolabelled ligand was collected by filtration and left to dry over night. Then add scin ilational fluid and counted associated radiolabelled ligand using a scintillation counter Canberra Packard Topcount.

The half-life antagonists on each of the muscarinic receptor was measured using alternative radiolabelled ligand [3H]-QNB and modification of the above method of analysis of affinity. Antagonists were incubated for 3 hours at a concentration of 10 times their value of Ki is defined with [3H]-QNB ligand membranes expressing the muscarinic receptors of the man. At the end of incubation was added [3H]-QNB to concentrations greater than the Kd value of the studied receptor 25 times, and continued incubation for various periods of time from 15 to 180 minutes. Then the membrane with bound radiolabelled ligand was collected by filtration and left to dry over night. Then were added to scintillation fluid and counted associated radiolabelled ligand using a scintillation counter Canberra Packard Topcount.

Determine the rate of binding of [3H]-QNB with muscarinic receptors linked to the speed at which dissociation occurs antagonist and the receptor, i.e. with a half-life of antagonists to the receptors.

Method of analysis of the receptor binding were tested with the following connections:

+ +++ NT
Connection example the Ki binding to muscarinic M3 receptor
1++
2+++
3NT
4+++
5+
6+++
7++
8+++
9+++
10NT
11+++
12+++
13++
14+
15++
16NT
17NT
18NT
19NT
20 NT
21NT
22NT
23NT
24NT
25NT
26+
27NT
28+
29+
30+
31+
32+++
33+++
34+++
35++
36+++
37+++
38++
39+
40+++
41
42++
43+++
44+++
45+++
46+++
47++
48+++
49+++
50+
51++
52++
53++
54++
55+++
56+++
57+++
58++
59++
60+
61+++
62
63NT
64NT
65+++
66++
67+++
68++
69+++
70NT
71++
72+++
73+
74+
75NT
76+
77+
78NT
79+++
80+++
81+++
82NT
83
84NT
85NT
86NT
87NT
88NT
89NT
90NT

Compounds with a Ki value of binding to muscarinic M3 receptor is less than 1 nm was defined as "+++", with a value of Ki from 1 to 10 nm was defined as "++" and with a Ki value greater than 10 nm are designated "+". All tested compounds had Ki values of less than 5 microns. The connection labeled "NT", in this method of analysis was not tested.

Methods of analysis of binding of radiolabelled ligand with β-adrenergic receptors

To assess the affinity of antagonists to β2-adrenergic receptors have conducted studies of the binding of radiolabelled ligand with [125I]-itsinitial and commercially available cell membranes expressing β2-adrenergic receptors of human rights. Membrane and SPA areas were incubated in Tris-buffer with [125I]-itsinitial and various concentrations of antagonist β2-adrenergic receptors in those who tell 3 hours at room temperature. The analysis was carried out in 96-well microplate, the readings from which to read using counter Wallac Microbeta. In this method of analysis it was shown that the compound of example 77 has a Ki value less than 100 nm.

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

Cell line CHO expressing the M3 receptor human, were sown, and incubated overnight in a coated collagen 96-well microplate (black wall, clear bottom) with a density of 50000 cells/75 μl of medium with 3% serum. The next day, prepare a solution sensitive to calcium dye (Molecular Devices, Cat #R8041) in HBSS buffer with the addition of 5 mm probenecid (pH of 7.4). Equal volume of dye solution (75 μl) was added to cells and incubated for 45 minutes, after which was added 50 μl of antagonists of muscarinic receptors or solvent. After another 15 minutes to read the values for 15 seconds on FLEXstation™ (excitation at 488 nm, emission at 525 nm) to determine background fluorescence. Then added agonist muscarinic receptors carbachol in concentrations equal to EC80and he measured fluorescence for another 60 seconds. The value of the signal was calculated by subtracting from the maximum values of response average background fluorescence in the control wells in the absence of the antagonist. To build distorting the IC 50expected maximum response in the presence of antagonist, expressed as a percentage.

Evaluation capacity and duration of action on isolated Guinea-pig trachea

The experiments were performed 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) in an atmosphere of 95% O2/5% CO2. Added indomethacin to a final concentration of 3 μm.

The trachea was removed from adult male Guinea pigs line Dunkin Hartley and cut the surrounding tissue prior to a longitudinal cut along the line, the opposite muscle. Cut individual pieces 2-3 cartilaginous rings in width, hung using cotton thread to include the water jacket baths for bodies with a capacity of 10 ml and was connected to a torque Converter, making sure the fabric is located between two platinum electrodes. Responses were recorded with the help connected with a personal computer recording system MP100W/Acknowledge. Tissue was balanced within 1 hour, and then subjected to a stimulation electric field with a frequency of 80 Hz and a pulse duration of 0.1 MS, a unipolar pulse, called every 2 minutes. For each piece of fabric built curve according to the voltage response is, and then worked on each piece of fabric submaximal voltage in accordance with his own sensitivity to voltage. Tissue was rinsed with Krebs solution and left to stabilize for stimulation before adding the test compound. Concentration curves were obtained by cumulative addition of the test compounds with semi-logarithmic increment the number. As soon as the response to adding reached a plateau, and spent the next add. For each concentration of each of the added compounds were calculated the percentage inhibition of EFS-induced contractions were building dose curves using the software Graphpad Prism and counted for each connection is EC50.

Research time of the development of response and duration of action carried out by adding the compound in the previously determined concentration EC50it collapsed under the action of EFS tissues and allowed the value of the answer to reach a plateau. Determined the time required to reach 50% of the response value, which represents the time development of the reaction. Then the tissue was washed from the connection by rinsing baths for bodies of fresh Krebs solution and measured the time required to return the reduction in response to the impact of EFS to the level of 50% of the ve who icine response in the presence of compounds. This time is called the duration.

Induced by methacholine narrowing of the bronchi in vivo

Male Guinea pigs (Dunkin Hartley) weighing 500-600 g were reared in groups of 5 and individually identified. The animals were allowed to adapt to their surrounding environment for at least 5 days. During this time and the time of the study, the animals were allowed access to water and food ad libitum.

Guinea pigs were given anesthesia entered by inhalation anesthetic halothane (5%). Intranasal were administered the test compound or solvent (0,25-0,50 ml/kg). Animals were placed on a heating Mat and gave them to recover from anesthesia before being returned to their cages. At 72 h after dose Guinea pigs were given a lethal dose of urethane anesthesia (250 μg/ml, 2 ml/kg). At the time of surgical anesthesia in the jugular vein was injected filled with heparinized phosphate buffer saline (hPBS) (10 U/ml) intravenous Portex catheter for intravenous methacholine. Was isolated trachea, inserted hard Portex catheter and inserted through the mouth into the esophagus Portex catheter with a flexible tube for infant feeding.

Then was given spontaneously breathing animal to the system measurements of respiration (EMMS, Hants, UK), consisting of pneumotachometer flow type and barometric sensor. Su is allendy in the trachea, the catheter was connected to pneumotachometer, and inserted into the esophagus catheter to the barometric sensor. Inserted into the esophagus catheter configured on the background resistance from 0.1 to 0.2 cm H2O/ml/sec Before intravenous injection of methacholine (up to 30 μg/kg, 0.5 ml/kg) was detected background resistance for 2 minutes. After intravenous injection was detected induced reduction within 2 minutes. Using the software calculated the maximum resistance and the area under the curve resistance (AUC) for every 2 minutes during the registration period, which was used for the analysis bronchospastic effects of the test compounds. The results obtained in this method of analysis for the compound of example 32 (0.1, 0.3 and 1 mg/kg intranasal), administered 4 hours prior to methacholine induced (10 mg/kg intravenously) contraction of the bronchi, and acting as a connection for comparing Tiotropium, represented in the drawing.

Inhibition of pilocarpine-induced salivation intranasal input connections

Guinea pigs (450-550 g) was acquired in Harlan UK or David Hall, Staffs UK and gave them to get used to the living conditions for at least three days before using. Guinea pigs were divided randomly into groups and weighed. Each animal was given a light General anesthesia (4% halothane) and his entrana the material was administered the test compound or solvent (0.5 ml/kg) 24 hours before injection of pilocarpine. At the time of the test Guinea pigs were given a lethal dose of urethane anesthesia (25% solution in H2O, 1.5 g/kg). Once developed to a sufficient level of anesthesia (lack of reflex in response to pinch toe), each animal in the mouth for 5 minutes was placed absorbent pad for drying of residual saliva, this strip was removed and replaced with 5 minutes a new pre-weighed gasket to determine the background level of production of saliva. Upon completion of this 5-minute period of time, the gasket was removed and weighed. Before each animal in the back of the neck was subcutaneously injected pilocarpine (0.6 mg/kg @ 2 ml/kg), it is in the oral cavity put a new pre-weighed gasket. The gasket was removed, weighed and replaced with a new pre-weighed gasket every 5 minutes for 15 minutes.

The production of saliva was calculated by subtracting the previously obtained values for the mass of the strip from the mass of the strip obtained every 5 minutes to measure, and put these values together to obtain the value of the accumulation of saliva for 15 minutes. In addition to a 15-minute measurement period can be analyzed every 5-minute period. It was assumed that the background production of saliva is a constant, and to obtain background cont the functions of saliva for 15 minutes for the past 5 minutes is multiplied by three.

Inhibition of salivary flow under the action of the compounds can be calculated using the following equation:

(1-(test - background)/(solvent - background))·100.

1. The compound of formula (I)

in which
(i) R1represents a C1-C6is alkyl or hydrogen; and R2represents hydrogen or a group-R7, -Z-Y-R7, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9-C(O)O-R7or-Z-C(O)-R7; and R3is an uncertain couple or C1-C6-alkyl; or
(ii) R1and R3form together with the nitrogen atom to which they are attached, 5-6-membered geteroseksualnoe ring; and R2is an uncertain couple or a group-R7, -Z-Y-R7; or
(iii) R1and R2form together with the nitrogen atom to which they are attached, a 6-membered geteroseksualnoe ring, and the said ring is substituted by a group-Y-R7and R3is an uncertain couple or C1-C6-alkyl;
R4and R5independently selected from the group consisting of phenyl, C3-C6-cycloalkyl;
R6is a HE, C1-C6-alkyl, C1-C6-alkoxy or hydrogen atom;
A represents an atom of oxygen or sulfur;
X represents a C1-C6-lkilebu group;
R7represents a C1-C6-alkyl, phenyl, phenyl(C1-C6-alkyl)-, dihydrobenzofuran or pyridine, where any phenyl group, R7may be optionally substituted by one or two groups independently selected from halogen, aminoacyl, C1-C6-alkoxycarbonyl, aminosulfonyl, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl, -COOH; and any pyridine group, R7may be optionally substituted C1-C6-alkyl;
R8represents a C1-C6-alkyl or a hydrogen atom;
Z represents a C1-C10-alkylenes or3-C10-alkenylamine group;
Y represents a bond or an oxygen atom;
R9and R10independently represent a hydrogen atom, a C1-C6is an alkyl group, an isoxazol or 8-hydroxy-1H-quinoline-2-he-(C1-C6-hydroxyalkyl);
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R1represents methyl or ethyl, or hydrogen atom; R2represents hydrogen or a group-R7, -Z-Y-R7, -Z,-NR9R10, -Z,-CO-NR9R10, -Z,-NR9-C(O)O-R7or-Z-C(O)-R7; and R3is an uncertain couple or C1-C6-alkyl, and in this case the nitrogen atom, to which is it attached, is a Quaternary nitrogen atom and carries a positive charge.

3. The compound according to claim 2, in which R3represents methyl, therefore the nitrogen atom to which it is attached is a Quaternary nitrogen atom and carries a positive charge.

4. The compound according to claim 1, in which R1and R3form together with the nitrogen atom to which they are attached, 5-6-membered monocyclic geteroseksualnoe ring and R2is an uncertain couple or a group-R7, -Z-Y-R7.

5. The compound according to claim 1, in which the group-NR1R2R3R1represents methyl or ethyl, R2represents-Z-NR9R10or-Z-Y-R7, Y is a bond or-O-, and Z-represents an unbranched or branched alkalinity radical linking nitrogen atom, and-NR9R10or YR7chain containing up to 10 carbon atoms, and R3represents methyl.

6. The compound according to claim 1, in which R7represents phenyl or phenylethyl, and may be substituted by one or more groups, as defined in claim 1.

7. The compound according to claim 1, in which (i) each R4and R5represents phenyl; or (ii) one of R4and R5represents phenyl and the other is cyclopentyl or cyclohexyl.

8. The compound according to claim 1, to which m R 6is a HE.

9. The compound according to claim 1, in which R8represents hydrogen.

10. The compound according to claim 1, in which X represents-CH2- or-CH2CH2-.

11. The compound according to claim 1, which has the formula (IA)

in which a represents a-O - or-S-; m is 1 or 2; the ring a represents an optionally substituted phenyl ring; R4represents phenyl, cyclopentyl or cyclohexyl; R5represents phenyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5 or 6, and t is 0, 1, 2, 3, 4, 5 or 6, provided that s+t is not greater than 10; Y is a bond or-O-, and X - represents a pharmaceutically acceptable anion.

12. The compound according to claim 1, selected from the group consisting of salts [2-(hydroxydiphenylmethyl)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylphenethylamine;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(4-methylpent-3-enyl)ammonium;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[2-(2,3-dihydro-benzofuran-5-yl)ethyl]dimethylamine;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(6-methylpred is n-2-ylmethyl)ammonium;
salts [2-(cyclopentylacetyl)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium;
salts of 1-[2-(cyclohexylhydroxylamine)oxazol-5-ylmethyl]-1-(3-phenoxypropan)pyrrolidine;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(4-phenoxybutyl)ammonium;
salts (2-benzyloxyethyl)-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(4-phenylbutyl)ammonium;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[3-(4-pertenece)propyl]dimethylamine;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenylpropyl)ammonium;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(2-phenoxyethyl)ammonium;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-para-trilateral)ammonium;
salt [3-(4-chlorophenoxy)propyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[3-(3,4-dichlorophenoxy)propyl]dimethylamine;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(8-methylaminomethyl)ammonium;
salts [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl-[2-(4-methylaminomethyl)ethyl]ammonium;
salts {2-[2-(cyclohexylamino sevenler)oxazol-5-yl]ethyl}dimethyl(3-phenoxypropan)ammonium;
salts {2-[2-(hydroxydiphenylmethyl)oxazol-5-yl]ethyl}dimethyl(3-phenoxypropan)ammonium;
salts [2-(hydroxydiphenylmethyl)thiazole-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium;
salt (3-benzyloxyphenyl)-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio;
salts [2-(4-chlorobenzoyloxy)ethyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio.

13. The compound according to claim 1, which represents a salt of [2-(R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(3-phenoxypropan)ammonium.

14. The compound according to claim 1, which represents a salt of [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]-[3-(3,4-dichlorophenoxy)propyl]dimethylamine.

15. The compound according to claim 1, which represents a salt of [2-(4-chlorobenzoyloxy)ethyl]-[2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethylammonio.

16. The compound according to claim 1, which represents a salt of [2-((R)-cyclohexylhydroxylamine)oxazol-5-ylmethyl]dimethyl(2-penetrometer)ammonium.

17. The compound according to claim 1, which represents a salt of [2-((R)-cyclohexylhydroxylamine]oxazol-5-ylmethyl]-[2-(3,4-dichloraniline)ethyl]dimethylamine.

18. The compound according to claim 1 having activity against muscarinic M3 receptor, for use in therapy.

19. Pharmaceutical composition having activity against muscarinic M3 receptor, the content is Asa compound according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier or excipient.

20. The pharmaceutical composition according to claim 19 in a form suitable for inhalation.

21. The use of compounds according to any one of claims 1 to 17 for obtaining a medicinal product for use for the treatment or prevention of a disease or condition that involved the activity of the muscarinic M3 receptor.

22. The method of treatment of a disease or condition that involved the activity of the muscarinic M3 receptor, comprising an introduction to the needy in this subject an effective amount of a compound according to any one of claims 1 to 17.

23. Use item 21, where the disease or condition constitutes a violation of the respiratory tract.

24. Use item 21, where the disease or condition is a chronic obstruction of the respiratory tract.

25. The method of treatment according to article 22, where the disease or condition constitutes a violation of the respiratory tract.

26. The method of treatment according to article 22, where the disease or condition is a chronic obstruction of the respiratory tract.



 

Same patents:

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, where R1 denotes H; R6, R7, R8, R9, R10 independently denote H, F, Cl, Br, CF3, OCH3, OCF3, OCHF2, SCH3, SCF3, phenyl, (C1-C6)-alkyl, O-(C1-C6)-alkyl or NR3R4, where the alkyl and phenyl can be substituted with R2 once or many times, and where any two residues from R6, R7, R8, R9, R10 in neighbouring positions of the phenyl ring can form a -CH=CH-CH-CH- residue together; m equal 0, 1, 2 or 3; X denotes -(CH2)2-; R2 denotes F, Cl, Br, CN, OCH3, OCF3, CH3, CF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl, where the alkyl can be substituted once or many times with OH, F, Cl, Br or CN; R3, R4 independently denote H or (C1-C6)-alkyl; or physiologically acceptable salts thereof, provided that the compound 3-(2-o- tolylamino-benzoxazol-6-yl)-propionic acid is excluded. The invention also relates to use of compounds of formula (I) to prepare a medicinal agent which activates GPR40 receptors and use of said compounds to prepare a medicinal agent for lowering blood sugar level, for treating diabetes and for increasing insulin secretion.

EFFECT: compounds of formula I which activate GPR40 receptors are obtained.

6 cl, 2 tbl, 146 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), where A1, A2, A3, A4, A5 ad A6 are independently selected from a group comprising CR3 and N; provided that the biggest one of A1, A2, A , A4, A5 and A6 denotes N; B1, B2 and B3 are independently selected from a group comprising CR2 and N; each R3 independently denotes H or C1-C6 alkyl; and R1, R2, R4, R5, W and n are as given in the description, or salts thereof which are suitable for use in agriculture. The invention also relates to compositions containing compounds of formula (1), and insect-pest control methods which involve contact between the pest or habitat thereof with a biologically effective amount of the compound or composition according to the present invention, as well as to methods of protecting seeds and animals from insects-pests.

EFFECT: high effectiveness of the obtained compounds in insect-pest control.

29 cl, 12 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula I: or salt thereof, where: y equals 0; R1 and R2 are taken together to form a 3-tetrahydrofuran ring; R9 is hydrogen; R10 is 5-oxazolyl; R11 is a methoxy-, ethoxy- or isopropoxy group; each V1 is independently selected from halogen, NO2, CN, OR12, OC(O)R13, OC(O)R12, OC(O)OR13, OC(O)OR12, OC(O)N(R13)2, OP(O)(OR13)2, SR13, SR12, S(O)R13, S(O)R12, SO2R13, SO2R12, SO2N(R13)2, SO2NR12R13, SO3R13, C(O)R12, C(O)OR12, C(O)R13, C(O)OR13, NC(O)C(O)R13, NC(O)C(O)R12, NC(O)C(O)OR13, NC(O)C(O)N(R13)2, C(O)N(R13)2, C(O)N(OR13)R13, C(O)N(OR13)R12, C(NOR13)R13, C(NOR13)R12, N(R13)2, NR13C(O)R12, NR13C(O)R13, NR13C(O)OR13, NR13C(O)OR12, NR13C(O)N(R13)2, NR13C(O)NR12R13, NR13SO2R13, NR13SO2R12, NR13SO2N(R13)2, NR13SO2NR12R13, N(OR13)R13, N(OR13)R12, P(O)(OR13)N(R13)2 and P(O)(OR13)2; where each R12 is a monocyclic or bicyclic ring system consisting of 5-6 members in each ring, where said ring system optionally contains up to 4 heteroatoms selected from N, O or S, and where CH2 lying next to said N, O or S can be substituted with C(O); and each R12 optionally contains up to 3 substitutes selected from R11; where each R13 is independently selected from H, (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl; and where each R13 optionally contains a substitute which is R14; where R14 is a monocyclic or bicyclic ring system consisting of 5-6 members in each ring, where said ring system optionally contains up to 4 heteroatoms selected from N, O or S, and where CH2 lying next to said N, O or S can be substituted with C(O); and each R14 optionally contains up to 2 substitutes independently selected from H, (C1-C4)-straight or branched alkyl or (C2-C4)-straight or branched alkenyl, 1,2-methylenedioxy-, 1,2-ethylenedioxy group or (CH2)n-Z; where Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S(C1-C4)alkyl, SO(C1-C4)alkyl, SO2(C1-C4)alkyl, NH2, NH(C1-C4)-alkyl, M((C1-C4)alkyl)2, COOH, C(O)O(C1-C4)alkyl or O(C1-C4)-alkyl; and where any carbon atom in any R13 is optionally substituted with O, S, SO, SO2, NH or N(C1-C4)alkyl; where said method includes a step for reacting a compound of formula II with a compound of formula III in a polar or nonpolar aprotic, virtually anhydrous solvent or mixture thereof, and optionally in an acceptable base selected from an organic base, inorganic base or a combination of an organic base and an inorganic base; and while heating the reaction mixture to temperature ranging from approximately 30°C to approximately 180°C for approximately 1 to 48 hours in a virtually inert atmosphere: where: LG is -OR16; where R16 is -(C1-C6)-straight or branched alkyl; -(C2-C6)-straight or branched alkenyl or alkynyl; or a monocyclic ring system consisting of 5-6 members in each ring, where said ring system optionally contains up to 3 heteroatoms selected from N, O or S, and each R16 optionally contains up to 5 substitutes independently selected from (C1-C4)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl or (CH2)n-Z; n equals 0, 1, 2, 3 or 4; V1, y, Z, R1, R2, R9, R10 and R11 are as indicated above; and provided that R16 is not a halogen-substituted (C2-C3)-straight alkyl.

EFFECT: improved method.

19 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where: X is a nitrogen or carbon atom; Ar is phenyl or a heteroaromatic ring selected from pyrazolyl, furanyl, thiophenyl and isoxazolyl; R1 is hydrogen, halogen, CN or (C1-C4)alkyl; R2 is halogen or (C1-C3)alkoxy optionally fluorinated with 1-3 fluorine atoms; R3 and R5 independently denote hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkenyl or hydroxymethyl; R4 is hydrogen, halogen, optionally fluorinated (C1-C4)alkoxy or aryl(C1-C4)alkoxy; R6 is hydrogen, optionally fluorinated (C1-C4)alkyl; each R7 independenlty denotes hydrogen, halogen, optionally fluorinated (C1-C4)alkyl or (C1-C4)alkoxy optionally fluorinated with 1-3 fluorine atoms; or pharmaceutically acceptable acid addition salts thereof. The invention also relates to use of compounds of formula (I) in a pharmaceutical composition and when preparing a medicinal agent meant for treatment, the aim of which is to change the secondary signal activity level after activation of glucocorticoid receptors.

EFFECT: compounds of formula I for changing the secondary signal activity level after activation of glucocorticoid receptors.

7 cl, 5 dwg, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of general formula I and pharmaceutically acceptable salts thereof, where R1 is selected from a group comprising aryl and alkyl, optionally substituted hydroxy; R2 is selected from a group comprising hydrogen and alkyl; R3 is selected from a group comprising hydrogen and -X-A, where X is selected from a group comprising -C(O)- and -S(O)2-; and A is selected from a group comprising hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted cycloalkyl, where the optionally substituted groups are substituted with 1-2 substitutes selected from a group comprising alkyl, substituted alkyl, alkoxy, substituted amine which is a -NRR group, substituted aryloxy, heteroaryl, heterocycle, halogen, hydroxy and -S(O)2-R9, where R9 is an alkyl; or R1 and R3 together with a carbon atom bonded to R1 and a nitrogen atom bonded to R3 form a heterocyclic or substituted heterocyclic group; R4 is selected from a group comprising hydrogen, linear alkyl, -alkylene-aminoacyl-, -alkylene-hydroxy-, -[alkylene]p-nitrogen-containing heterocycle, -[alkylene]p-nitrogen-containing substituted heterocycle, -[alkylene]p-nitrogen-containing heteroaryl, -[alkylene]p-nitrogen-containing substituted heteroaryl and -[alkylene]p-NR10R11, where p equals 0 or 1, the alkylene contains 1-5 carbon atoms and can have 1 or 2 substitutes selected from a group comprising amine, hydroxy and halogen, aminoacyl relates to a group -C(O)NRR, where each R is independently selected from a group comprising hydrogen and alkyl, R10 and R11 are independently selected from a group comprising hydrogen, alkyl, substituted alkyl, -S(O)2-alkyl, substituted aryl, substituted heteroaryl, cycloalkyl, or when R10 is hydrogen, R11 is hydroxy, alkoxy or substituted alkoxy; or when R1 and R3 together with carbon and nitrogen atoms respectively bonded to them do not form a heterocyclic or a substituted heterocyclic group, R3 and R4 together with a nitrogen atom to which they are bonded form a spiro-condensed heterocyclic group; R5 is selected from a group comprising L-A1, where L is selected from a group comprising C1-C5alkylene, where the alkylene is defined above; and A1 is selected from a group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle; and one of R6 or R7 is selected from a group comprising aryl and heteroaryl, each of which can optionally be substituted with -(R8)m, where m equals a whole number from 1 to 2, and the other of R6 or R7 is selected from a group comprising hydrogen, halogen and alkyl; or R6 as well as R7 denotes hydrogen; R8 is selected from a group comprising cyano, alkyl, -CF3, alkoxy, halogen, where alkyl, aryl, aryloxy, cycloalkyl, heterocycle, heteraryl and substituted alkyl, aryl, aryloxy, cycloalkyl, heterocycle and heteroaryl are described in claim 1. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula I, a method of inhibiting KSP and use of the composition to prepare a medicinal agent.

EFFECT: novel imidazole derivatives are useful as kinesin spindle protein inhibitors for treating cancer.

25 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to drugs and concerns a combination for tumour cell growth inhibition containing a cytotoxic compound selected from camptothecin compounds; metabolic antagonists; periwinkle alkaloids; taxanes; platinum compounds; topoisomerase 2 inhibitors; and a combination of two or more said types, or a signal transfer inhibitor selected from antibodies a target of which is EGFR receptor; tyrosine kinase EGFR inhibitors; from antibodies a target of which is a VEGF/VEGF receptor system; PDGFR inhibitors; Raf inhibitors and PKB transfer inhibitors in an effective amount and a compound of formula (IV).

, where R1, R2, R11, T, U and g have the values specified in formula.

EFFECT: what is offered is a pharmaceutical composition, a method for tumour cell growth inhibition, a method of treating a malignant growth in a patient and application of the combination for preparing a drug; the new effective combinations for tumour cell growth inhibition are presented.

77 cl, 20 dwg, 7 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxazole derivatives of general formula I. The disclosed compounds have affinity to the µ-opioid receptor. In general formula I

, n equals 0, 1 or 2, R1 denotes a phenyl residue bonded through a C1-C3alkyl chain, R2 denotes phenyl or thienyl, each of which is unsubstituted or mono-substituted with F or Cl, R3 and R4 independently denote a saturated, branched or straight C1-C6alkyl, phenyl or a phenyl residue bonded through a C1-C3akyl chain, or R3 and R4 together form an unsubstituted five-, six- or seven-member saturated ring which can optionally contain an extra heteroatom selected from a group comprising O or NR9, where R9 denotes phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which is unsubstituted or mono-substituted with a substitute selected from a group comprising F, Cl, Br, I and O-C1-C6alkyl, where the ring can be optionally condensed with a phenyl ring, R5 and R6 independently denote a saturated, branched or straight C1-C6alkyl, R7 and R8 independently denote a saturated, branched or straight unsubstituted C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, or R7 and R8 together form an unsubstituted or mono- or disubstituted five-, six- or seven-member saturated ring, where the substitutes are selected from a group comprising C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, where the ring can optionally contain an extra heteroatom selected from a group comprising S, O and NR10, where R10 denotes a phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which can be unsubstituted or mono-substituted with O-C1-C6alkyl. The invention also relates to methods of producing the disclosed compounds, a medicinal agent containing at least one substituted oxazole derivative of formula I, use of the compounds to prepare a medicinal agent.

EFFECT: improved properties.

13 cl, 1 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I) or to their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity, and to a based pharmaceutical composition. (I) where P represents phenyl optionally substituted by 1 or 2 substitutes independently selected from halogen, C1-4alkyl, cyano, trifluoromethyl, C1-4alkoxy and trifluormethylthio, and R2 has the values specified in the patent claim.

EFFECT: preparation of new compounds of general formula (I) or their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity.

16 cl, 340 ex

FIELD: medicine.

SUBSTANCE: there is described application of 1-hetaryl-2-nitro-2-(3-phenyl-1,2,4-oxadiazole-5-yl)ethanes of general formula I a-m 1a, e, and R1=NO2, R2=H; 1b, f, to R1=NO2, R2=Me; 1c, g, l R1=CO2Et, R2=H; 1d, h, m R1 =CO2Et, R2 =Me; 1a-d R2 =piperidino; 1e-h R3 =1-pyrrolidinyl, 1j-m R3=morpholino as psychotropic substances.

EFFECT: substances are low-toxic and have an evident psychotropic effect on rats.

4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds which are methyl-3-azabicyclo[3.3.0]octane-7-carboxylate, N-methyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, N-propyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, or pharmaceutically acceptable salts thereof. The invention also relates to compounds selected from a group, a pharmaceutical composition, methods of treating or preventing central nervous system disorders, as well as use of compounds in any of claims 1-4.

EFFECT: obtaining novel biologically active compounds having activity on neural nicotinic acetylcholine receptor.

11 cl, 14 ex, 7 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of hetaryl derivatives of 2-nitro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-ethanes of general formula where, I a,d,i R1=NO2, R2=H; I b,e,k R1=NO2, R2=Me; I v,g,l R1=CO2Et, R2=H; I e,z,m R1=CO2Et, R2=Me; I a-r R3=piperidinyl; I d-z R3=1-pyrrolidinyl, I i-m R3=morpholinyl, based on a nucleophilic substitution reaction of terminal chlorine in 2-nitro-1-chloro-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethanes of formula IV with 2,5 times excess piperdine, pyrrolidine or morpholine, while heating and stirring in dried ethanol and holding at temperature 25°C for 2 days.

EFFECT: efficient method of producing hetaryl derivatives.

1 cl, 2 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the 2,9-disubstituted imidazo[1,2-a]benzimidazole family, specifically to water-soluble salts of 9-aminoethyl-substituted 2-(4-fluorophenyl)imidazo[1,2-a]benzimidazole of general formula I:

,

where NR2 = pyrrolidine-, piperidine-, morpholine-; Y=HBr, H2SO4, (CH2COOH)2 and [CH(OH)COOH]2; n=1, 2.

EFFECT: novel compounds have analgesic action.

2 cl, 2 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

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