1,4-substituted piperazines or 4-alkylhydroperoxides, pharmaceutical composition and method of treatment

 

The present invention relates to 1,4-substituted piperizine or 4-alkylidenehydrazides General formula I

and its geometric isomers, enantiomers, diastereoisomers and pharmaceutically acceptable salt,

where G and G' - together form

,or

D - represents-CH= or =N-;

Y represents-L2-V(Z)t-L3- where t represents 0 or 1;

W represents-N(OM)C(O)N(R8R9.

Compounds have properties to inhibit leukotriene and antihistaminergic properties, and is applicable for the treatment of asthma, seasonal and chronic allergic rhinitis. Also described pharmaceutical composition based on compounds of the formula I and a method of treatment 4 N. and 18 C.p. f-crystals, 9 Il., 5 table.

The scope to which the invention relates.

The invention relates to 1,4-substituted the piperazines, 1,4-substituted piperidine and 1-substituted 4-alkylidenehydrazides.

The level of technology

Leukotrienes are affected, asthma, psoriasis and thrombosis. Leukotrienes are linear eicosanoids produced by the oxidation of arachidonic acid by using lipoxygenase. Arachidonic acid is oxidized with 5-lipoxygenase and as a result turns into leukotrienes And4In4With4D4or E4. 15-Lipoxygenase is responsible for conversion of arachidonic acid to various biologically active metabolites, including 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-NET). Both of these mediator associated with the pathogenesis of respiratory diseases and allergic diseases such as asthma, participating in bronchostenosis, mucus secretion and migration of eosinophils. It is known that a mixture with one or more of these leukotrienes is strong bronchospasm means. Thus, it was shown that leukotrienes play an important role in the pathology of asthma. Irrefutable evidence of the role of leukotrienes in asthma was obtained using several fundamental clinical trials, in which orally administered inhibitor of 5-lipoxygenase (5-LO) or antagonists of LTD4-receptor) had an absolute beneficial therapeutic effect on patients with asthma. These impacts include improved when Prime, some hydroxyacetone and gidrosiimidazolyatnye aromatic compounds can function as 5-LO inhibitors. For example, in international applications WO 92/09567 and WO 92/09566 contains a large number of compounds N-hydroxyacetone and hydroxamic acids as inhibitors of the enzyme lipoxygenase.

It was found that histamine is involved in inflammation in General. It is well known that antihistamines are most effective for control of allergies. In addition, I believe that histamine is associated with asthma. For example, it is known that histamine and containerisation (cLT) are key mediators for the tone of the respiratory tract. Clinical studies have shown that combined treatment with antagonist cLT-receptor and antihistamines entered asthma, weaken early asthmatic response (EAR) and late asthmatic response (LAR) to a much greater extent than either agent acting alone (A. Roquet, et al. Am. J. Respir Crit. Care Med., 155, 1856 (1997)). This indicates the involvement of histamine in asthmatic disease.

It is well known that some [bis(substituted and/or unsubstituted aryl)methyl - and methylene-]-1-piperidinyl compounds have antihistamine is 674) describe [[bis(aryl)methyl or methylene-]-1-piperidinyl]alkoxy-aryl and heteroaryl compounds used to treat allergic symptoms, including asthma and rhinitis. Teng et al. (U.S. patent 5 070 087) describe [bis(aryl) methyl or methylene-]-N-[(phenoxy, phenylthio)alkyl]piperidine for the quantification of histamine in Allergy.

Other studies have shown the use of [bis(aryl)methyl]piperazine-1-ilen compounds as Antiasthmatic and antiallergic agents, which inhibit the secretion of leukotrienes (for example, Japanese patent 97077754). In U.S. patent 4 525 358 shows the use of 2-[4-(diphenylmethyl)-1-piperazinil]-acetic acid and its amides as anti-allergic, spasmodic and antipruritic agents. Japanese patent 7138230 describes the use of derivatives of 4-aralkyl-1-piperazinil-unsaturated carboxylic acids as anti-allergic agents for the treatment of, for example, asthma and rhinitis. In the international application WO 97/23466 described receiving N-diarylpyrimidine used as analgesics.

However, nowhere in the prior art does not say, it is not intended and should not be considered a combination of 5-LO or 15-LO-inhibiting functional properties of residues hydrochemically with antihistaminergic properties [bis(substituted or unsubstituted aryl)methyl and m is its function as protiwaritmicescoy, and as an inhibitor of 5-LO/15-LO.

The invention

This invention covers a new connection with double action with as any abscopal lipoxygenase and protivogistaminnye properties. In a preferred embodiment of the invention each new connection according to the invention acts as an inhibitor of 5-LO and 15-LO and the antagonist of histamine receptor H1.

Compounds according to the invention is applicable for treating conditions involving histaminic or leukotriene component. These conditions preferably include asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory intestinal diseases, chronic obstruction lung, thrombosis and inflammation. Accordingly, the invention also includes pharmaceutical compositions containing the compounds according to the invention, and methods of treatment of asthma and rhinitis using the pharmaceutical compositions.

Compounds included in this description can also be used to study biological pathways, including leukotrienes and histamine, and, in particular, for further issledovania 1.

The Figure 2 shows the synthesis of compounds 12.

The Figure 3 presents the synthesis of compound 17.

The Figure 4 presents the synthesis of compounds 35 and 36.

The Figure 5 shows the synthesis of compound 37.

The Figure 6 shows the synthesis of compound 80.

The Figure 7 shows the synthesis of compound 32.

The Figure 8 shows the synthesis of compound 46.

The Figure 9 shows the synthesis of compound 27.

Detailed description of the invention

Connection

In one aspect, the invention encompasses the compounds of formula I, including geometric isomers, enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts:

where X and X' independently represent hydrogen, halogen, alkyl, alkenyl, quinil, alkoxy, trifluoromethyl or -(Y')m'-W;

G and G' together form

D represents-CH = or = N-;

R1and R2independently represent hydrogen or together represent -(CH2)n- where n is 0, 1, 2 or 3;

m & m' independently represent 0 or 1;

Y and Y' ó L1- or-L2-V(Z)t-L3where t represents 0 or 1;

L1denotes alkylene, albaniles or one of the above, the state Duma of the AET (a) alkylen, albaniles, akinyan or one of the above, where one or more methylene groups are replaced by-O-, -S-, -S(O)-, -S(O)2-, -N(Q')- or-N(R4), or (b) -L4-C(O)-N(Q')- or-L4(Q')-, or (C) a simple link;

L3means (a) alkylen, albaniles, akinyan or one of the above, where one or more methylene groups are replaced by-O-, -S-, -S(O)-, -S(O)2-, -N(Q") -, or-N(R5), or (b) simple connectivity;

L4means (a) alkylen, albaniles or akinyan or one of the above in which one or more methylene groups are replaced by-O-, -S-, -S(O)-, -S(O)2-, -N(Q") -, or-N(R5), or (b) simple connectivity;

V denotes (a) divalent arenas, divalent heteroaryl or divalent rich heterocycle, when t represents 0, or (b) trivalent arenas or trivalent heteroaryl, when t denotes 1;

Q Q' and Q ' independently represent hydrogen, AC(O)OR6or AC(O)NR6R7;

W and W' independently represent-N(OM)C(O)N(R8R9N(R8)C(O)N(OM)R9, -N(OM)C(O)R8, -C(O)NR8R9or-C(O)OR8provided that at least one of W and W' denotes N(OM)C(O)N(R8R9, -N(R8)C(O)N(OM)R9or-N(OM)C(O)R8;

Z represents-A"N(OM')C(O)N(R10R11p>10, a halogen, CH3, NR3R4, NR3C(O)R4, NO2CN, CF3, S(O)2NR3R4, S(O)2R3, SR3or S(O)R3;

And, As' and A" independently represent a simple bond, alkylene, albaniles, akinyan, youkilis, iloaiei or dieroller or one of the above in which one or more methylene groups are replaced by-O-, -NH-, -S-, -S(O)- or-S(O)2and/or one or more methylidene residues substituted at =N-;

M & M' independently denote hydrogen, a pharmaceutically acceptable cation or split in the process of metabolism group; and

R3, R4, R5, R6, R7, R8, R9, R10and R11independently represent hydrogen, alkyl, alkenyl, quinil, aryl, arylalkyl, alkylaryl, alkylaromatic or one of the above in which one or more methylene groups are replaced by-O-, -NH-, -S-, -S(O)- or-S(O)2and/or one or more methylidene residues substituted at =N-;

provided that in contrast to atoms of oxygen, associated with s in-S(O) -, and-S(O)2- when one or more methylene groups are replaced by-O-, -NH-, -S-, -S(O)- or-S(O)2and when one or more methylidene residues substituted at =N, this substitution does not occur On, W represents-C(O)NR8R9or-C(O)OR8,

and in addition, provided that the Vice-AC(O)OR6R6cannot denote hydrogen, And indicates when a simple link.

Preferred compounds according to this invention are the compounds of formula I':

and geometric isomers, enantiomers, diastereoisomers and pharmaceutically acceptable salts, where each of the variables has the above notation, except that: X and X' independently represent hydrogen, halogen, alkyl, alkenyl, quinil, alkoxy or trifluoromethyl; and

W represents-N(ON)C(O)N(R8R9N(R8)C(O)N(OM)R9or-N(OM)C(O)R8.

In another preferred embodiment of the invention the compounds of this invention represented by formula I:

and their geometrical isomers, enantiomers, diastereoisomers and pharmaceutically acceptable salts, where each of the variables has the above value.

In other preferred embodiments of the invention the compounds of formula I are represented by formulas II and III:

and geometries is shown above the value.

Preferred variants of compounds of formula II and formula III and their geometrical isomers, enantiomers, diastereoisomers and pharmaceutically acceptable salts are those in which each of the variables has the above value, except where:

1. X represents-Cl, X' denotes hydrogen, m is 1, and W represents-N(OH)C(O)NH2;

2. X is-Cl, X' denotes hydrogen, m represents 1, Y represents-L1- where L' refers to akinyan, isoalkane or realconverter;

3. X represents-Cl, X' denotes hydrogen, m represents 1, Y represents-L2-V(Z)t-L3-, t denotes 0, V denotes 1,4-phenylene or 1,3-phenylene, L2indicates isoalkane and L3denotes alkylene, albaniles or akinyan;

4. X represents-Cl, X' denotes hydrogen, m represents 1, Y represents-L2-V(Z)t-L3-t denotes 0, V denotes a 2,5-furillen, L2denotes alkylene and L3denotes alkylene, albaniles or akinyan; or

5. X represents-Cl, X' denotes hydrogen, m represents 1, Y represents-L2-V(Z)t-L3-, t denotes 1, L2indicates isoalkane, V denotes a trivalent heteroaryl, Z represents-A'C(O)NR10R11or-A&#ub>t-L3-, t denotes 0, V denotes 1,4-phenylene or 1,3-phenylene, L2indicates isoalkane and L3denotes alkylene, albaniles or akinyan.

Compounds according to the invention include compounds shown in Table 1.

Especially preferred compounds are the compounds listed in Table 1

More preferred compounds N-{[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]methyl}amino-N-hydroxyamide, N-{[3-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]methyl}amino-N-hydroxyamide, amino-N-{[4-(2-{4-[bis(4-forfinal)-methyl]piperazinil}ethoxy)phenyl]ethyl}-N-hydroxyamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl] but-3-inyl}amino-N-N hydroxyamide-{[4-(3-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}propyl)phenyl]methyl}amino-N-hydroxyamide, N-{4-[3-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]but-3-inyl}amino-N-hydroxyamide, N-{[3-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]methyl}(methyl(hydroxyamino)) carboxamide, N-{4-[3-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]butyl}amino-N-hydroxyamide, amino-N-[4-(4-{2-[4-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-Liden)piperidyl]ethoxy}phenyl)but-3-inyl]-N-hydroxyamide, N-{3-[5-({4-[(4-forfinal)-methyl]piperazinil}methyl)(2-furyl)]but-3-inyl}-N-hydroxyamide, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]benzamide, methyl 2-[2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy]-5-[4-(amidohydrolase-carbylamine)buta-1-inyl]benzoate, 2-[2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy]-5-[4-(amidohydrolase-carbylamine)buta-1-inyl]benzoic acid, methyl 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(amidohydrolase-carbylamine)butyl]benzoate, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl] piperazinil}ethoxy)-5-[4-(amidohydrolase-carbylamine)butyl] benzoic acid, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl] piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)butyl]benzamide, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(amidohydrolase-carbylamine)butyl]benzoic acid, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(amidohydrolase-carbylamine)buta-1-inyl]benzoic acid, methyl 5-[4-(aminohydrocinnamic)buta-1-inyl]-2-(2-{4-[bis(4-forfinal) methyl]piperazinil}-ethoxy]benzoate, N-{4-[5-({4-[(1R)(4-chlorophenyl)-phenylmethyl] piperazinil}methyl)(2S,5S)oxolan-2-yl]but-3-inyl}amino-N-hydroxyamide, methyl (2E)-3-[2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)butyl]phenyl]prop-2-ENOAT, methyl (2E)-3-[2-(2-{4-[((aminohydrocinnamic)buta-1-inyl]-2-(2-{4-[bis(4-forfinal)methyl]piperazinil}-ethoxy) benzoic acid, N-{4-[4-(3-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}propoxy)phenyl]but-3-inyl)amino-N-hydroxyamide, amino-N-[4-(4-{2-[4-(8-chlorine(5,6,11-triggerevent[b]pyridine[3,2-f][7]annulen-11-yl) piperidyl]ethoxy}phenyl)but-3-inyl]-N-hydroxyamide, amino-N-[4-(4-{3-[3-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene)piperidyl]propoxy}phenyl)but-3-inyl]-N-hydroxyamide, (2ND)-3-[2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]phenyl]prop-2-ANOVA acid, N-{4-[3-((1E)-2-carbamoylmethyl)-4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}-ethoxy)phenyl]but-3-inyl}amino-N-hydroxyamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy)-3-forfinal]but-3-inyl}amino-N-hydroxyamide, 5-[4(amidohydrolase-carbylamine)buta-1-inyl]-2-(2-{4-[bis(4-forfinal)methyl]piperazinil}-ethoxy)benzamide, amino-N-{4-[4-(2-{4-[(bis(4-forfinal)methyl]piperidinyloxy)-3-forfinal]but-3-inyl}-N-hydroxyamide, 5-[4-(amidohydrolase-carbylamine)buta-1-inyl]-2-{2-[4-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene)piperidyl]ethoxy}benzamide, 2-(3-{4-[(1R)(4-chlorophenyl)-ylmethyl]piperazinil}propoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]benzamide, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil} ethoxy)-5-[5-(amidohydrolase-carbylamine)Penta-1-inyl]benzamide, 2-(2-{4-[(1-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-(trifluoromethyl) phenyl]but-3-inyl}amino-N-hydroxyamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-(trifluoromethyl)phenyl]but-3-inyl}amino-N-hydroxyamide, N-{4-[4-(2-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-cyanophenyl]but-3-inyl}amino-N-hydroxyamide, N-{4-[4-(4-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}butoxy)phenyl] but-3-inyl}amino-N-hydroxyamide, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[3-(aminohydrocinnamic) prop-1-inyl]benzamide, N-{4-[4-(4-{4-[(1R)(4-chlorophenyl)-phenylmethyl] piperazinil}butoxy)phenyl]butyl}amino-N-hydroxyamide, N-{4-[4-(2-{4-[(1S)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-(trifluoromethyl)phenyl]butyl}amino-N-hydroxyamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-(trifluoromethyl) phenyl]butyl}amino-N-hydroxyamide, amino-N-[4-(4-{4-(8-chlorine(5,6-dihydrobenzo,[f]pyridine[2,3-b][7]annulen-11-ilidene))piperidyl] butoxy}phenyl)but-3-inyl]-N-hydroxyamide, amino-N-[4-(4-{4-[4-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene)piperidyl]butoxy}phenyl)butyl]-N-hydroxyamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]but-3-inyl} ethoxy-N-hydroxycarboxylic, N-{4-[4-(4-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}butoxy)phenyl]butyl}amino-N-hydroxyamide, N-[2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)but-1-in the Nile]phenyl]acetamide", she N-{4-[4-(3-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}propoxy)phenyl]butyl) amino-N-hydroxyamide, amino-N-{4-[4-(4-{4-[bis(4-forfinal)-methyl]piperazinil}butoxy)phenyl]but-3-inyl}-N-hydroxyamide, N-{3-[4-(3-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}propoxy)phenyl] propyl}amino-N-hydroxyamide, amino-N-{4-[4-(3-{4-[bis(4-forfinal) methyl]piperazinil}propoxy)phenyl]but-3-inyl}-N-hydroxyamide, 2-(3-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}-propoxy)-5-[4-(aminohydrocinnamic)-butyl]benzamide, 5-{4-[(aminocarbonyl) (hydroxy)amino]butyl}-2-(2-{4-[bis(4-forfinal)methyl]-1-piperazinil}ethoxy)benzamide, N-{3-[4-(3-{4-[bis(4-tryptophanyl) methyl]-1-piperazinil}propoxy)phenyl]propyl}-N-hydroxyurea, N-{4-[4-(2-{4-[bis(4-forfinal)methyl]-1-piperazinil}ethoxy)-2-nitrophenyl]-3-butenyl}-N-hydroxyurea, -{4-[4-(2-{4-[bis(4-forfinal)methyl]-1-piperazinil}ethoxy)phenyl]butyl}-N-hydroxyurea, 5-{4-[(aminocarbonyl)(hydroxy)amino]-1-butenyl}-2-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}-ethoxy)benzamide, N-{4-[4-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}ethoxy)-2-nitrophenyl]-3-butenyl}-N-hydroxyurea, 5-{4-[(aminocarbonyl)(hydroxy)amino)-1-butenyl}-2-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}-ethoxy)benzamide, 5-{4-[(aminocarbonyl)(hydroxy)amino)-1-butenyl}-2-(2-{4-[(R)-(4-chlorphenyl)(phenyl)methyl]-1-piperazinil}-ethoxy) benzamide, N-{3-[4-(3-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}propyl) phenoxy]propyl}-N-hydroxyurea.

Most preferred are compounds N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]butyl}amino-N-hydroxyamide, amino-N-[4-(4-{2-[4-(8-chlorine(5,6-dihydrobenzo[f] pyridine[2,3-b][7]annulen-11-ilidene)piperidyl]ethoxy}phenyl)but-3-inyl]-N-hydroxyamide, amino-N-{4-[5-({4-[(bis(4-forfinal)-methyl] piperazinil}methyl)(2-furyl)]but-3-inyl}-N-hydroxyamide, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]benzamide, N-{4-[5-({4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}methyl)(2S,5S)oxolan-2-yl]but-3-inyl}amino-N-hydroxyamide, N-{4-[4-(3-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil} propoxy)phenyl]but-3-inyl)amino-N-hydroxyamide and amino-N-{4-[4-(4-{4-[bis(4-forfinal)-methyl] piperazinil}butoxy)phenyl]but-3-inyl}-N-hydroxine.

Definition

Below are definitions of the various chemical fragments (residues), which are part of the compounds according to the invention, and they remain unchanged throughout the description and in the claims, unless otherwise specified.

The term “alkyl” refers to monovalent fragment saturated linear cyclic branched C1-C6-alkane and konkretnej, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. An alkyl group can optionally have a Deputy, any suitable group, including, without limitation, R3or one or more fragments selected from the group consisting of halogen, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate or phosphonate, either unprotected, or protected, if necessary, as known to experts in the art or as described, for example, in Greene, et al., “Protective Groups in Organic Synthesis”, John Wiley and Sons, Third Edition, 1999.

The term “alkoxy” refers to alkyl slice-O ' -end with a free valency, for example CH3CH2-O-.

The term “alkoxy” represents alkoxy (as defined above), in which the alkyl fragment removed the hydrogen atom with the formation of bivalent radical, such as-CH2CH2-O - or-CH(CH3)-O-.

The term “illconcealed” refers to a bivalent fragment dialkylamide ether having one free valence in each of the alkyl fragments, and alkyl fragments are the same or different, for example - CH22CH(CH3)CH2CH2-.

The term “alkenyl” refers to a monovalent fragment C1-C5linear, branched, or in the case of5-6cyclic hydrocarbon with at least one double bond, optionally substituted as described above.

The term “albaniles” refers to Alchemilla fragment (see definition above), which removed the hydrogen atom with the formation of bivalent radical, such as-CH2SN=SNSN2-.

The term “quinil” refers to a monovalent fragment With2-C6linear or branched hydrocarbon with at least one triple bond (optionally substituted as described above), and specifically includes acetylenyl, PROPYNYL and WithCH2(alkyl), including-WithC-CH2(CH3).

The term “akinyan” refers to akinrinola fragment (see definition above), which removed a hydrogen atom, giving a divalent radical, for example, WithC-CH(CH3)-.

The term “aryl” refers to monovalent to phenyl (advantages the group, including, without limitation, one or more fragments selected from the group consisting of halogen, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as known to experts in the art, for example as described in Greene, et al., “Protective Groups in Organic Synthesis”, John Wiley and Sons, Third Edition, 1999, and, preferably, halogen (including, without limitation, fluorine), alkoxy (including methoxy), aryloxy (including phenoxy), W, cyano, or R3.

The term “Allen” or “divalent arene” refers to aryl fragment (as defined above), which removed the hydrogen atom with the formation of bivalent radical, such as-C6H4-.

The term “trivalent arene” refers to Allenova fragment (see definition above), which removed the hydrogen atom with the formation of trivalent radical, for example

The term “iliskileri” refers to divalent alkyl substituted aryl fragment in which one unbound valence refers to the alkyl part and one refers to aryl part, for example-CH2-CH2-C6the rum one unbound valence is alkyl part and one has the aryl part, for example-C6H4-CH2-CH2-.

The term “dildoultimate” refers to divalent dialkylamino arena in which one unbound valence features on each of sulfur, oxygen or nitrogen in the aromatic ring which may be substituted as described above for aryl groups. Non-limiting examples are furillen, peridinin, 1,2,4-thiadiazolyl, pyrimidine, tienlen, isothiazoline, imidazoline, tetrazole, personalen, pyrimidine, chinoline, ethanallen, benzothiazole, isobenzofuran, pyrazoline, indoline, phrenilin, carbazolyl, benzimidazolyl and isoxazolines.

The term “trivalent heteroaryl” refers to heteroarenes fragment (see definition above), which removed one hydrogen atom with the formation of trivalent radical, for example

The term halogen (halogen) refers to atoms of chlorine, fluorine, iodine or bromine.

When the methylene group in the alkyl, alkenylphenol or alchenilla (or the divalent radicals-analogues) radical is substituted by Oh, -NH-, -S-, -S(O)-or-S(O)2- it can be implemented in any suitable position in the fragment, or in the limit position, or in some the

Unbound (“open”) valence radicals presented in this description may be in any one (or more divalent radicals) of the atoms of the fragment. For example, monovalent3is an alkyl fragment includes both propyl and isopropyl. Another example, bivalent4-alkalinity fragment includes tetramethylene (-CH2(CH2)2CH2- ) and ethylethylene (-CH(CH2CH3)CH2-).

The term “organic” or “inorganic anion” refers to an organic or inorganic fragment, which carries a negative charge and can be used as a negative part of the salt.

The term “pharmaceutically acceptable cation” refers to organic or inorganic fragment, which carries a positive charge and which may be associated with a pharmaceutical agent, for example, as proteotion in salt. Pharmaceutically acceptable cations are known to experts in the art and include, but are not limited to, sodium, potassium and (Quaternary) ammonium.

The term “metabolic (metabolism) split group” refers to a fragment that can be chipped off in vivo from a molecule, which is an example (alkyl)C(O), including acetyl, propionyl, butyryl), alkyl, phosphate, sulfate and sulfonate, NH2C(O)- or(alkyl)C(O)-.

The term “inhibitor of 5-lipoxygenase” refers to a compound that inhibits the enzyme at 30 μm or below. The term “inhibitor of 15-lipoxygenase” refers to a compound that inhibits the enzyme at 30 μm or below.

Used in this description, the term “pharmaceutically acceptable salts or complexes” refers to salts or complexes that retain a specified biological activity of the above compounds and exhibit minimal undesired Toxicological effect or it does not show. Examples of such salts include, but are not limited to, salts of accession of inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc. and salts formed with organic acids such as fumaric acid, maleic acid, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamula acid, alginic acid, polyglutamine acid, naphthalenesulfonate acid and fields, well-known experts in the art, which specifically include the Quaternary ammonium salt of the formula-NR+Z-where R denotes hydrogen, alkyl or benzyl and Z represents a counterion, including chloride, bromide, iodide, -O-alkyl, toluensulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as fumarate, benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelot, baseload and diphenylacetate).

The term “pharmaceutically active derivative (derivative) refers to any compound, which after administration to the recipient is capable of becoming, directly or indirectly, as presented in this description for the connection.

Circuit synthesis

Schematic of the synthesis shown in Figures 1-9 and Examples 1-7 illustrate how to obtain the compounds according to the invention. Specialists in the art can easily modify and/or adapt these diagrams and descriptions for the synthesis of any of the compounds according to the invention.

Pharmaceutical compositions, methods of treatment and the introduction

Compounds according to the invention is applicable to the treatment of conditions in which supposedly exists histamine and/or leukotriene component. These SOS food allergies, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic pulmonary obstruction, thrombosis and inflammation. The compounds exhibit this biological activity, by acting as antagonists of histamine receptor H1, inhibiting lipoxygenase, such as 5-lipoxygenase, or showing a dual (double) activity, i.e. acting and as a receptor antagonist of histamine H1 and as a lipoxygenase inhibitor, such as 5-lipoxygenase. Subjects in need of treatment mediated by leukotrienes and/or histamine-state (preferably asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis media can be treated by introducing the patient an effective amount of one or more of the above compounds, or their pharmaceutically acceptable derivative or salt in a pharmaceutically acceptable carrier or diluent to reduce the formation of oxygen radicals. The active substance can be entered by any suitable means such as the REM, gel or solid form, in the form of a spray for insertion through the mouth or through the nose or in aerosol form.

In addition, the invention relates to the use of compounds of formula I to obtain a medical product for use in therapy. In particular, the invention relates to the use of compounds of formula I to obtain medical treatment for conditions in which presumably there histaminic and/or leukotriene component. The invention relates to the use of compounds of formula I to obtain medical drug suitable for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis.

The invention also relates to the use of compounds of the formula I as medicines. The invention relates to the use of compounds of formula I as a drug for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, the situation is, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis.

The active compound is administered in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects on the patient being treated. Preferably the dose of the active compound for all of the above conditions is about 0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg / day, more usually 0.5 to about 25 mg/kg body weight of recipient per day. The typical dose for local use is 0.01-3 wt.% in the corresponding media. The interval of effective doses pharmaceutically acceptable derivatives can be calculated based on the desired weight quantity of the original connection. If a derivative is itself active, effective dose is estimated as described above, using a weight derived, or others known to experts in the art by the way.

The methods according to the invention is administered to a mammal (preferably human) mediated by leukotrienes and/or histamine state is sufficient to to ease the condition. The compound is administered appropriately in the form of any suitable standard dosage forms, including, without limitation, a standard dosage form, containing 1-3000 mg, preferably 5-500 mg of the active ingredient of the generic (standard) pharmaceutical form. Usually is suitable dose for oral administration 1-500, preferably 10-250, more preferably 25-250 mg of the Active ingredient should be introduced in order to achieve the maximum concentration of active compound in the plasma of about 0.001 to 30 μm, preferably about 0.01-10 μm. This can be achieved, for example, intravenous injection of a solution or mixture of the active ingredient, optionally in saline or water, or by introducing a bolus of the active ingredient.

The concentration of the active compounds in medicinal drug depends on the rate of absorption, distribution, inaktivirovanie and selection of medicines, as well as other factors known to specialists in this field of technology. It should be noted that the magnitude of the doses also vary depending on the severity of the condition, which should be eased. In addition, it should be understood that for Katie with individual need and the professional assessment of who appoints or oversees the administration of drugs, it should also be understood that the present description, these concentrations are given only as examples, but not intended to limit the scope or practice of the use of the claimed composition. The active ingredient can be entered directly or can be divided into several smaller doses and enter at different intervals.

Preparations for oral administration include typically an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral administration the active compound can be combined with excipients and used in the form of tablets, lozenges and capsules. Pharmaceutically compatible binding and/or adjuvants can be included as part of the composition.

Tablets, pills, capsules, pills, etc. can contain any of the following ingredients, or compounds similar: a binder such as microcrystalline cellulose, resin tragakant or gelatin; expedient, such as starch or lactose; a dispersant such as alginic acid, Primogel (primogel) or starch; a lubricant such as magnesium stearate or Sterores; a substance that promotes ingestion (glidant), this is AK peppermint, methyl salicylate, or Supplement with orange. When the standard dosage form is a capsule, it may contain, in addition to the above substances, a liquid carrier such as fatty oil. In addition, dosage forms can contain various other materials, which may modify the physical form of the standard dose, for example a coating of sugar, shellac or intersolubility agents.

The active compound or its pharmaceutically acceptable salt or derivative can be entered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc., a Syrup may contain, in addition to the active compounds, sucrose as a sweetener and certain preservatives, dyes and corrigentov.

The active compound or its pharmaceutically acceptable derivative or salt can also be mixed with other active materials that do not weaken a given effect, or with substances that Supplement the specified effect, such as adrenergic agonists such as pseudoephedrine, antibiotics, antifungal agents, other anti-inflammatory or antiviral compounds.

Solutions or suspensions for parenteral, intradermal the sterile diluent (solvent), such as water for injection, saline solution, fatty oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. The right preparation can be enclosed in ampoules, disposable syringes or vials with multiple dose glass or plastic.

When intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

In one embodiment of the invention the active compounds are prepared with carriers that protect the compound against rapid removal from the body, the product of prolonged action, including implants and microencapsulation delivery system. You can use biorstwami, biocompatible polymers such as a copolymer of ethylene and vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyarteritis and polylactic Cologne to get for example, from Alza Corporation (CA) and Guilford Pharmaceuticals (Baltimore, Md). Liposomal suspensions can also be pharmaceutically acceptable carriers. They can be prepared by methods known to experts in the art, for example as described in U.S. patent 4 522 811. For example, liposomal formulations can be prepared by dissolving the corresponding (s) lipid (s) (such as stearoylethanolamine, stearoylethanolamine, arachidonylglycerol and cholesterol) in an inorganic solvent that is then evaporated, and it is a film of dried lipid on the surface of the container. An aqueous solution of active compound or its monophosphate, diphosphate and/or trifosfatnogo derivatives enter then into the container. Then the container mix (shake) the hand in order to separate the lipid from the side walls of the container and dispersing the lipid agents, thereby forming a liposomal suspension.

The following examples are given only for illustration and do not claim and shall not in any way be construed as limiting. Specialists in the art will understand that simple variations and modifications of the following examples, it is possible to do, without departing from the essence and scope of the invention. Examples

Example 1. P, is igure 1).

4-(2-Bromoethoxy)benzyl alcohol (compound 101).

To a solution of 4-hydroxybenzoato alcohol (2.0 g, 16,11 mmol) in DMF (10 ml) is added potassium carbonate (2.67 g, and 19.3 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then add the 1,2-dibromethane (3.03 g, 16,13 mmol). The reaction mixture was stirred at room temperature for 20 hours and then water is added and extracted with ethyl acetate. The organic layer was washed with water and brine, evaporated, receiving oil which is purified on a flash chromatography column (silica gel, 3:1 hexane/ethyl acetate) to give compound 101 (1.7 g, 45.7 per cent);1H NMR (CDCl3d of 3.64 (t, 2H), 4,29 (t, 2H), to 4.62 (s, 2H), 6,91 (d, 2H), 7,30 (d, 2H).

4-{2-[4-((1R)(4-chlorophenyl)phenylmethyl)piperazinil]ethoxy} benzyl alcohol (compound 103).

To a solution of compound 101 (205 mg, 0.89 mmol), [(1R)(4-chlorophenyl)phenylmethyl]-piperazine (102) (203 mg, 0.80 mmol) in methylene chloride (2.5 ml) is added triethylamine (122,0 mg of 1.21 mmol). The reaction mixture was stirred at 50°C for 20 hours. The solvent is evaporated and the residue purified on a flash chromatography column (silica gel, 3:1 hexane/ethyl acetate) to give compound 103 (330 mg, 94,1%);1H NMR (CDCl3d of 2.45 (m, 4H), 2,62 (m, 4H), of 2.81 (t, 2H), 4,08 (t, 2H), 4,22 (s, 1H), 4.5 carbonintensive (compound 104)

To a stirred solution of compound 103 (330 mg, from 0.76 mmol), phenoxycarbonylamino (251,6 mg of 0.92 mmol) and triphenylphosphine (225,2 mg, 0.86 mmol) in THF (8 ml) at 0°C. add diisopropylethylamine (RUB 171.1 mg, 0.86 mmol). After the addition the reaction mixture is heated to room temperature and stirred at room temperature for 2 hours. The solvent is evaporated and the residue purified on a flash chromatography column (silica gel, hexane/ethyl acetate 2:1) to give compound 104 (410 mg, 78,4%):1H NMR (CDCl3d 2,47 (m, 4H), to 2.65 (m, 4H), 2,84 (t, 2H), 4,12 (t, 2H), 4,23 (s, 2H), 4.95 points(s, 2H), 6,92 (d, 2H), 7,20 (m, 5H), 7,26 (m, 6N), 7,40 (m, 10H).

N-{[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy) phenyl]methyl}-amino-N-hydroxyamide (compound 1)

In a vessel with a screw cap was placed a solution of compound 104 (410 mg, 0.59 mmol) in methanol (15 ml) and cooled to -78°C in a bath of dry ice-acetone. In this vessel add liquid ammonia (2-3 ml) and close. Bath acetone-dry ice is then removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture is again cooled in acetone with dry ice and down the pressure. Capacity open and the solvent evaporated. Connection 1 is separated in a column flush chromatography is N), 3,98 (t, 2H), 4,20 (s, 1H), 4,57(s, 2H), 5,22 (ush.s, 2H), 6,77 (d, 2H), 7,25 (m, 6N), was 7.36 (m, 5H).

Example 2. Obtaining N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl] piperazinil}ethoxy)phenyl]but-3-inyl}amino-N-hydroxyamide (compound 12, Figure 2).

4-(2-Bromoethoxy)-1-iodobenzoyl (compound 105)

To a solution of 4-itfinal (10.0 g, 45,45 mmol) in DMF (50 ml) is added potassium carbonate (12,6 g, 91,17 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then add the 1,2-dibromethane (17,07 g, 90,91 mmol). The reaction mixture was stirred at room temperature for 16 hours and then quenched with water and extracted with methylene chloride. The organic layer was washed with water and brine, evaporated, receiving oil which is purified on a flash chromatography column (silica gel, hexane) to give compound 105 (2.7 g, 18.2 per cent):1H NMR (CDCl3d 3,63 (t, 2H), 4.26 deaths (t, 2H), 6,70 (d, 2H), 7,58 (d, 2H).

4-[4-(2-Bromoethoxy)phenyl]but-3-in-1-ol (compound 106)

To a mixture of compound 105 (2.7 g, compared to 8.26 mmol), 3-buten-1-ol (696,3 mg, 9,94 mmol), dichlorobis(triphenylphosphine)palladium (II) (1,15 g,1,64 mmol) and copper iodide (is 317.1 mg, 1,67 mmol) is added triethylamine (45 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent is evaporated and the residue purified on a column of flash chromatogra who 2H), is 3.82 (m, 2H), 4,30 (t, 2H), 6,83 (d, 2H), 7,37 (d, 2H).

4-{4-[2-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinil)ethoxy] phenyl}but-3-in-1-ol (compound 107)

To a solution of compound 106 (1.5 g, to 5.58 mmol), [(1R)(4-chlorophenyl)phenylmethyl]-piperazine (102) (1.6 g, 5,59 mmol) in DMF (15 ml), add triethylamine (871,2 mg, 8,63 mmol). The reaction mixture was stirred at 50°C for 20 hours, water is added and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with water and brine, dried with magnesium sulfate, filtered and evaporated, the resulting oil is purified by column flash chromatography (silica gel, hexane/ethyl acetate, 1:1) to give compound 107 (2.6 g, 98.1 per cent):1H NMR (CDCl3d to 2.42 (m, 4H), 2,61 (m, 4H), 2,68 (t, 2H), 2,82 (t, 2H), 3,80 (t, 2H), 4,10 (t, 2H), 4,21 (s, 1H), 6,80 (d, 2H), 7,26 (m, 5H), 7,35 (m, 6N).

N-{4-[4-(2-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinil)ethoxy) phenyl]but-3-inyl}phenoxycarbonylamino (compound 108)

To a stirred solution of compound 107 (1.5 g, and 3.16 mmol), phenoxycarbonylamino (1,05 g of 3.85 mmol) and triphenylphosphine (937,1 mg of 3.57 mmol) in THF (35 ml) at 0°C was added diisopropylethylamine (721,4 mg of 3.57 mmol). After addition, the reaction mixture is heated to room temperature and stirred at room temperature for 2 hours aluca connection 108 (1.4 g, 60,6%):1H NMR (CDCl3d is 2.44 (m, 4H), 2,62 (m, 4H), 2,82 (m, 2H), 2.91 in (t, 2H), 4,10 (m, 4H), 4,21 (s, 1H), 6,80 (d, 2H), 7,18 (m, 5H), 7,30 (m, 8H), 7,37 (m, 8H).

N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy)phenyl]but-3-inyl}amino-N-hydroxyamide (compound 12)

In a vessel with a screw cap was placed a solution of compound 108 (1.4 g, 1.92 mmol) in methanol (50 ml) and cooled to -78°C in the bath “acetone-dry ice”. In this reactor type liquid NH3(6 ml) and close. Then leave bath with dry ice in acetone and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture is again cooled in acetone with dry ice and down the pressure. The reactor was opened and the solvent evaporated. Connection 12 emit a flash chromatography column (silica gel, CH2Cl2/CH3HE is 19:1) (580 mg, 56,9%):1H NMR (CDCl3d of 2.45 (m, 4H), to 2.65 (m, 4H), of 2.72 (t, 2H), 2,84 (t, 2H), 3,80 (t, 2H), 4,10 (t, 2H), 4,22 (s, 1H), 5.25-inch (ush.S., 2N), to 6.80 (d, 2H), 7,25 (m, 5H), was 7.36 (m, 6N).

Example 3. Obtaining N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl] piperazinil}ethoxy)phenyl]butyl}amino-N-hydroxyamide (compound 17, Figure 3)

4-[4-(2-Bromoethoxy)phenyl]butane-1-ol (compound 109)

A solution of compound 106 (1.3 g, a 4.83 mmol) in methanol (15 ml) hydronaut 10% palladium on coal (130 mg) in quiescent who,31 g, 99,2%):1H NMR (CDCl3d of 1.65 (m, 4H), 2,60 (t, 2H), 3,66 (m, 4H), 4,28 (m, 2H), 6,83 (d, 2H), 7,10 (d, 2H).

4-{4-[2-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinil)ethoxy] phenyl}butane-1-ol (compound 110)

To a solution of compound 109 (1.3 g, 4.76 mmol), [(1R)(4-chlorophenyl)phenylmethyl]-piperazine (102) (1.39 g, a 4.86 mmol) in DMF (12 ml), add triethylamine (762,3 mg of 7.55 mmol). The reaction mixture was stirred at 50°C for 15 hours, water is added and the reaction mixture is extracted with methylene chloride. The organic layer was washed with water and brine, dried with magnesium sulfate, filtered and evaporated, receiving oil which is purified on a flash chromatography column (silica gel, hexane/ethyl acetate, 1:1) to give compound 110 (2,42 g, 104%):1H NMR (CDCl3d of 1.65 (m, 4H), of 2.45 (m, 4H), 2,62 (m, 6N), of 2.81 (t, 2H), 3,66 (t, 2H), 4,08 (t, 2H), 4,21 (s, 1H), for 6.81 (d, 2H), was 7.08 (d, 2H), 7,25 (m, 4H), of 7.36 (m, 5H), 8,02 (ush.S., 1H).

N-{4-[4-(2-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinil)ethoxy) phenyl]butane-1-ol}phenoxycarbonylamino (compound 111)

To a stirred solution of compound 110 (1.5 g, 3.14 mmol), phenoxycarbonylamino (1,05 g of 3.85 mmol) and triphenylphosphine (938,0 mg, 3.58 mmol) in THF (35 ml) at 0°C was added diisopropylcarbodiimide (724,0 mg, 3.58 mmol). After addition, the reaction mixture is heated up to the Ute flash chromatography on a column (silica gel, hexane/ethyl acetate, 2:1) to give compound 111 (1,58 g, 68.7 per cent).

N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy) phenyl]butyl}-amino-N-hydroxyamide (compound 17)

In the reactor (vessel) with a screw cap was placed a solution of compound 111 (1,58 g of 2.16 mmol) in methanol (50 ml) and cooled in acetone with dry ice. In this reactor type liquid ammonia (6 ml) and close. I put a bath of dry ice in acetone and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then again cooled with dry ice in acetone and remove the pressure. The reactor was opened and the solvent evaporated. The connection 17 is separated by flash chromatography on a column (silica gel, 19:1 CH2CL2/CH3HE) and further purified by recrystallization from a mixture of ethyl acetate-hexane (550 mg, 47,4%):1H NMR (CDCl3d to 1.60 (m, 4H), 2,44 (m, 4H), 2,52 (t, 2H), to 2.67 (m, 4H), and 2.83 (t, 2H), 3,48 (t, 2H), 4,08 (t, 2H), 4,21 (s, 1H), 6,78 (d, 2H),? 7.04 baby mortality (d, 2H), 7,25 (m, 4H), 7,35 (m, 5H).

Example 4. Obtain methyl-2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]benzoate (compound 36, Figure 4), 2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]benzamide (compound 35, Figures is islote (compound 37, Figure 5)

4-itfinal, methylacetate (compound 112).

To a solution of 5-iodosalicylic acid (5.0 g, 18,94 mmol) in methanol (100 ml) was added a few drops of sulfuric acid. The reaction is stirred at boiling for 24 hours. The solvent (methanol) and evaporated to a small volume, add water and extracted with methylene chloride. The organic layer is washed with 10% NaHCO2-solution, water and brine, dried with magnesium sulfate, filtered and evaporated, receiving the specified compound (3.5 g, 66,5%):1H NMR (CDCl3d of 3.96 (s, 3H), 6,78 (d, 1H), of 7.70 (DD, 1H), 8,12 (d, 1H).

Methyl 2-hydroxy-5-(4-hydroxyben-1-inyl)benzoate (compound 113)

To a mixture of compound 112 (2.0 g, 7.19 mmol), 3-buten-1-ol (655,2 mg, 9,35 mmol), dichlorobis(triphenylphosphine)palladium (II) (1.0 g, of 1.42 mmol) and copper iodide (276,3 mg, 1,45 mmol) is added triethylamine (40 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent is evaporated and the residue purified on a flash chromatography column (silica gel, hexane/ethyl acetate, 2:1) to give compound 113 (1.6 g, 101,3%):1H NMR (CDCl3d of 2.68 (t, 2H), 3,81 (m, 2H), 3.96 points (s, 3H), 6,92 (d, 1H), 7,50 (DD, 1H), to 7.93 (d, 1H).

Methyl 2-(2-bromoethoxy)-5-(4-hydroxyben-1-inyl)benzoate (compound 114)

To a solution of compound 113 (1.6 g, 7,27 mmol) in DMF (8 ml) EXT is m add 1,2-dibromethane (vs. 5.47 g, 29,09 mmol). The reaction mixture was stirred at room temperature for 16 hours and then add water and extracted with methylene chloride. The organic layer was washed with water and brine, evaporated, receiving oil which is purified on a flash chromatography column (silica gel, hexane/ethyl acetate 2:1) to give compound 114 (710 mg, 29,8%):1H NMR (CDCl3d 2,70 (t, 2H), 3,68 (t, 2H), 3,82 (t, 2H), 3,90 (s, 3H), 4,35 (t, 2H), 6.90 to (d, 1H), 7,50 (DD, 1H), 7,88 (d, 1H).

Methyl 2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy)-5-(4-hydroxyben-1-inyl)benzoate (compound 115)

To a solution of compound 114 (300,0 mg of 0.92 mmol), [(1R)(4-chlorophenyl)-phenylmethyl]piperazine (102) (262,4 mg of 0.92 mmol) in DMF (2 ml), add triethylamine (139,0 mg, 1.38 mmol). The reaction mixture was stirred at 50°C for 20 hours and extracted with methylene chloride. The organic layer was washed with water and brine, dried with magnesium sulfate, filtered and evaporated, receiving oil which is purified on a flash chromatography column (silica gel, ethyl acetate), get a connection 115 (510 mg, 102,4%):1H NMR (CDCl3d is 2.44 (m, 4H), 2,68 (m, 6N), 2,90 (m, 2H), 3,81 (t, 2H), of 3.84 (s, 3H), 4,08 (m, 2H), 4,21 (s, 1H), 6.90 to (d, 1H), 7,25 (m, 4H), 7,38 (m, 5H), 7,49 (DD, 1H), a 7.85 (d, 1H).

N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy)-3-(meloxicam is of 115 (320,0 mg, of 0.60 mmol) phenoxycarbonylamino (198,4 mg, 0.73 mmol) and triphenylphosphine (55.7 mg, 0.21 mmol) in THF (2 ml) at 0°C. add diisopropylethylamine (78,2 mg of 0.68 mmol). After the addition the reaction mixture is heated to room temperature and stirred at this temperature for 2 hours. The solvent is evaporated and the residue purified on a flash chromatography column (silica gel, hexane/ethyl acetate, 1:1) to give compound 116 (350 mg, 73,9%):1H NMR (CDCl3d to 2.42 (m, 4H), 2,65 (m, 6N), 2,90 (m, 2H), 3,82 (s, 3H), 4,15 (m, 4H), 4,21 (s, 1H), 6,85 (d, 1H), 7,25 (m, 8H), 7,40 (m, N), of 7.82 (s, 1H).

Methyl-2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]benzoate (compound 36) and 2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydroxylation-amino)but-1-inyl]benzamide (compound 35).

In the vessel (reactor) with screw cap was placed a solution of compound 116 (350 mg, 0.44 mmol) in methanol (20 ml) and cooled to -78°C. dry ice in acetone. In this reactor pour liquid ammonia (3 ml) and close. The cooling bath is then put aside and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was again cooled with dry ice in acetone and the pressure is removed. The reactor QCD is Cl2/CH3HE 9:1) as a white solid. The mixture of compounds 35 and 36 are additionally purified on a flash chromatography column (silica gel, CH2CL2/CH3HE 9:1), receiving additional connection 36 (31 mg) and compound 35 (containing about 5% of compound (36). The connection 35 is additionally separated from the connection 36 by recrystallization, using as solvent a mixture of ethyl acetate-hexane (35 mg).

The connection 36:1H NMR (CDCl3d of 2.45 (m, 4H), 2,70 (m, 6N), 2,90 (t, 2H), 3.75 to (t, 2H), 3,83 (s, 3H), 4,18 (t, 2H), 4,21 (s, 1H), 5,34 (ush.s, 2H), 6,85 (d, 1H), 7,25 (m, 4H), 7,37 (m, 5H), the 7.43 (DD, 1H), 7,80 (s, 1H). Compound 35:1H NMR (CDCl3d is 2.40 (m, 4H), of 2.54 (m, 4H), to 2.75 (t, 2H), 2,80 (t, 2H), 3,80 (t, 2H), 4,20 (m, 3H), 5,42 (ush.s, 2H), 5,80 (ush.s, 1H), 6.87 in (d, 1H), 7,25 (m, 4H), of 7.36 (m, 5H), was 7.45 (DD, 1H), 8,14 (d, 1H), 8,75 (ush.s, 1H).

2-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl)piperazinyl}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]benzoic acid (compound 37)

In a small round bottom flask was placed compound 36 (30 mg, 0.05 mmol). To this flask was added 1 M KOH/CH3HE (to 0.30 ml, 0.30 mmol). The reaction mixture was stirred at room temperature for 48 hours and then cooled in a bath of ice. Add 1M HCl/ether (of 0.30 ml, 0.30 mmol) and the mixture is purified on a flash chromatography column (forces is H NMR (CD3OD) d of 2.56 (m, 4H), to 2.66 (t, 2H), 2,96 (m, 4H), 3,10 (t, 2H), 3,68 (t, 2H), 4,32 (t, 2H), 4,34 (s, 1H), 6,98 (d, 2H), 7,20 (m, 1H), 7,30 (m, 4H), 7,44 (m, 6N).

Example 5. Obtaining amino N-{4-[4-(2-{4-(8-chlorine(5,6-dihydrobenzo[f] pyridine[2,3-b][7]-annulen-11-ilidene))piperidyl}ethoxy)phenyl]but-3-inyl}-N-hydroxyamide (compound 32, Figure 7)

4-(2-Bromoethoxy)-1-iodobenzoyl

To a stirred solution of 4-itfinal (25 g, 110 mmol) and K2CO3(31 g, 220 mmol) in DMF (250 ml) for 1 hour add 1,2-dibromoethane (5 ml, 55 mmol). The warm solution at 50°C with stirring under Ar overnight. To complete the reaction, add an additional 1.2-dibromoethane (20 ml, 220 mmol) and K2CO3(6 g, 43 mmol) and the mixture is heated in an atmosphere of Ar at 50°C for 12 hours. Water is added and the reaction mixture is extracted with methylene chloride, dried with Na2SO4, filtered and the solvent evaporated in vacuum. The crude mixture is purified by chromatography on silica gel, elwira 10% ethyl acetate in hexane, obtaining the desired compound as a white solid (5.5 g, 17 mmol).

4-[4-(2-Bromoethoxy)phenol]but-3-in-1-ol

To a mixture of 4-(2-bromoethoxy)-1-iodobenzoyl (5.5 g, 17 mmol), 3-buten-1-ol (1.9 ml, 25 mmol), CuJ (952 mg, 5 mmol) and dichlorobis(triphenylphosphine)palladium (II) (3.5 g, 5 mmol) in methylene chloride (100 ml) procure under argon. The solvent is evaporated in vacuum and add ethyl acetate to dissolve the reaction mixture was filtered through celite to remove the greater part of Pd. The crude product is purified by chromatography on silica gel, elwira a mixture of hexane/ethyl acetate (2:1). 4 g of the Title compound obtained as a light brown solid.

4-[4-(2-{4-(8-chloro-5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene)-piperidyl}ethoxy) but-3-in-1-ol

8-chloro-11-(4-piperidylidene)-5,6-dihydrobenzo[and]pyridine[2,3-d][7]annulen (2.5 g, of 7.75 mmol) and 4-[4-(2-bromoethoxy)phenol]but-3-in-1-ol (2.5 g, 9.2 mmol) is dissolved in methylene chloride. To this solution was added Et3N (2.6 ml, 18.5 mmol) and the reaction mixture is boiled under argon over night. Methylene chloride evaporated in vacuum. Unreacted educt regenerate after purification by chromatography, elwira 10% Meon in methylene chloride. The title compound obtained as a white solid (1.9 g, 3,76 mmol).

Phenyl-{N-{4-[4-(2-{4-(8-chlorine(5,6-dihydrobenzo[f] pyridine[2,3-b][7]annulen-11-ilidene)piperidyl}ethoxy)phenyl]but-3-inyl}phenoxycarbonylamino}formate

The solution 4-[4-(2-{4-(8-chloro-5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene)piperidyl}ethoxy)but-3-in-1-ol (1.9 g, 3,76 mmol), triphenylphosphine ( To the solution with stirring, added dropwise diisopropylethylamine (950 mg, 4.7 mmol). The reaction mixture is heated to room temperature and stirred for one hour. Upon completion of the reaction, the solvent is evaporated in vacuum. The product was then purified by chromatography on silica gel with 10% Meon in methylene chloride as eluent. Obtain 4.5 g of the title compounds (with a small amount of impurities).

Amino-N-{4-[4-(2-{4-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]-annulen-11-ilidene)piperidyl}ethoxy)phenyl]but-3-inyl}-N-hydroxyamide

Phenyl-{N-{4-[4-(2-{4-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene)piperidyl}ethoxy)phenyl]but-3-inyl}phenoxycarbonylamino}-formate

(4.5 g) is Dissolved in Meon, saturated NH3(100 ml). The system is closed by a rubber membrane and stirred at room temperature overnight. The solvent is evaporated in vacuum and the crude product is purified by chromatography on silica gel with 10% Meon, saturated NH3in methylene chloride as eluent, to obtain the title compound 32 (800 mg) (or the reaction can be carried out in ampoule under pressure).

Example 6. Obtaining N-{4-[4-(3-{4-[(1R)(4-chlorophenyl)-phenylmethyl] piperazinil}propoxy)phenyl]but-3-inyl)amino-N-hydroxyamide (compound 52)

4-(2-Bromoethoxy)-1-iodobenzoyl

To a solution of 4-itfinal (15 g, 70 mmol) and K2CO3 the R heated at 50°C under stirring overnight in an argon atmosphere. Add water (500 ml) and extracted with methylene chloride, dried with Na2SO4, filtered and the solvent evaporated in vacuum. Purify by chromatography on silica gel, elute with 10% ethyl acetate in hexane, obtaining the title compound as a white solid (10 g, 29 mmol).

4-[4-(2-Bromopropane)phenyl]but-3-in-1-ol

To a solution of 4-(2-bromopropane)-1-iodobenzoyl (10 g, 29 mmol), 3-buten-1-ol (2.6 ml, 37 mmol), CuJ (980 mg, 5.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (3.6 g, 5.2 mmol) in methylene chloride (40 ml) was added Et3N (6,0 ml, 44 mmol) dropwise. The reaction mixture was stirred over night at room temperature in argon atmosphere. The solvent is evaporated in vacuum and add ethyl acetate to dissolve the compounds, filtered through celite to remove the greater part of Pd. The crude product is purified by chromatography on silica gel, elute with a mixture of hexane/ethyl acetate (2:1). Obtain 2.6 g of the title compound as a light brown solid connections.

4-{4-[3-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinil)propoxy] phenyl}but-3-in-1-ol

[(1R)(4-chlorophenyl)phenylmethyl]piperazine (1.6 g, 5.6 mmol) and 4-[4-(2-bromopropane)phenyl]but-3-in-1-ol (2.0 g,? 7.04 baby mortality mmol) dissolved in methylene chloride (10 ml). Added dropwise Et3N (1 ml,? 7.04 baby mortality is the graphy on silica gel, elute with ethyl acetate. Obtain 2.0 g of the title compound as a white substance.

N-{4-[4-(3-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinil)propoxy)phenyl]but-3-inyl}phenoxycarbonylamino

The solution 4-{4-[3-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinil) propoxy]phenyl}-but-3-in-1-ol (1.6 g, 5.6 mmol), triphenylphosphine (1.3 g, 5.1 mmol) and N,O-bis(phenoxycarbonyl)hydroxylamine (1.4 g, 5.1 mmol) in THF (20 ml) cooled to 0°C in the bath with ice. To the solution with stirring, added dropwise diisopropylethylamine (1 g, 5.1 mmol). Then the reaction mixture was left to warm to room temperature and stirred for one hour. Upon completion of the reaction, the solvent is evaporated in vacuum. The substance is additionally not clean.

N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}propoxy)phenyl]but-3-inyl}amino-N-hydroxyamide (compound 52)

N-{4-[4-(3-(4-((1R)(4-chlorophenyl)phenylmethyl)piperazinil) propoxy)phenyl]but-3-inyl}phenoxycarbonylamino dissolved in Meon and added to 20 ml of liquid (dry ice/acetone) NH3in vitro to work under pressure. The tube is closed, leave to warm to room temperature. Stirred overnight, slowly relieve the pressure, remove the cap (tube), opening systems the m NH3in methylene chloride as eluent gives the title compound 52 (1,05 g).

Example 7. Obtaining amino-N-{4-[4-(4-{4-[bis(4-forfinal)-methyl] piperazinil}butoxy)phenyl]but-3-inyl}-N-hydroxyamide (compound 80, Figure 6)

1-(4-Bromobutoxy)-4-iodobenzoyl (117)

To a solution of 4-itfinal (100 g of 0.5 mol) and K2CO3(70 g of 0.5 mol) in DMF (400 ml) with stirring 1,4-dibromethane (100 ml, from 0.84 mol) for 1 hour. The solution is stirred over night at room temperature under argon. Type H2O (1000 ml) and extracted with CH2CL2. Then the organic layer was washed with 1000 ml of brine, dried with MgSO4, evaporated, getting a white solid (100 g);1H NMR (CD3Cl) d 2,15-to 1.87 (m, 6N), 3,50-3,20 (m, 4H), of 3.94 (t, 2H), 6,85 (d, 2H), 7,55 (d, 2H).

4-[4-(4-Bromobutoxy)phenol]but-3-in-1-ol (118)

A solution of compound 117 (100 g of 0.3 mol), 3-buten-1-ol (45 ml, 0.6 mol), CuJ (800 mg, 4.2 mmol) and dichlorobis(triphenylphosphine) palladium(II) (2.9 g, 4.2 mmol) in methylene chloride (400 ml) cooled at 0°C (bath with ice). At low temperature there are added dropwise Et3N (84 ml, 0.6 mol). The mixture is then heated to room temperature and stirred under argon overnight. Methylene chloride evaporated in vacuum. The obtained semi-liquid compound races the OAc in hexane, then 50% EtOAc:50% hexane. Obtain 75 g of a light brown solid:1H NMR (CDCl3d of 2.10 and 1.80 (m, 4H), to 2.66 (t, 2H), 3,25 (t, 1H), 3,50 (t, 2H), 3,80 (t, 2H), 3,94 (t, 2H), 6,85 (d, 2H), 7,55 (d, 2H).

Connection (119). 4-Bis(4-forfinal)methylpiperazin (58 g, 0.2 mol) and 118 (74 g, and 0.25 mol) dissolved in CH2CL2(500 ml). To this solution add NEt3(43 ml) at 0.31 mol). The mixture is stirred for 48 hours at room temperature under argon. After evaporation of the solvent in vacuum, the obtained semi-solid substance dissolved in a minimum amount of CH2CL2pass through a large layer of silica gel and elute with 50% EtOAc:50% hexane, then EtOAc, selecting the desired connection. The evaporation of the solution get the foam off-white color (70 g) of 90% purity;1H NMR (CDCl3d of 1.78 and 1.75 (m, 6N), 2,72 at 2.45 (m, N), of 3.78 (t, 2H), 3,94 (t, 2H), 4,23 (s, 1H), 6,76 (d, 2H), 6,97 (t, 4H), 7,37-7,25 (m, 6N).

Compound 80: a Solution of 119 (70 g of 0.14 mol) of triphenylphosphine (45 g, to 0.17 mol) and N,O-bis(phenoxycarbonyl)hydroxylamine (46 g of 0.17 mol) in THF (500 ml) cooled to 0°C with ice. To the solution was added with stirring dropwise diisopropylethylamine (34 ml of 0.17 mol). I put a bath with ice, the reaction mixture is heated to room temperature, it is stirred for one hour. The end of the reaction the ACOM. The mixture is stirred overnight in a round bottom flask, closed with a rubber membrane. The reaction mixture is treated, extragere acid/base, and passed through a high layer of silica gel (45 g), elwira 10% Meon in methylene chloride. The product is recrystallized from 500 ml of boiling EtOAc and cooled at room temperature over night, get 20 grams of pure compounds;1H NMR (CDCl3d of 1.78 and 1.75 (m, 6N), 2.57 m at 2.45 (m, 10H), of 2.72 (t, 2H), of 3.78 (t, 2H), 3,94(t, 2H), 4,23 (s, 1H), 5,34 (ush.s, 2H), 6,76 (d, 2H), 6,97 (t, 4H), 7,37-7,25 (m, 6N).

Table 2 shows NMR data for preferred connections.

Example 8. The Protocol Cho-K1 HIR-link

This test is usually conducted to determine the ability of compounds to behave as a ligand that binds to the histamine receptor H1. Since in this test using cloned receptors H1 person, he can give a good approximation to what to expect when the compound is administered to a person.

Details of the test methods are given below. Cells Cho-K1 expressing cloned human H1 receptor grown to monolayer in dies for tissue cultures. Cells are harvested using D-PBS buffer (JRH Biosciences), stored at 4°C, centrif the th buffer (20 nm Tris, 250 mm sucrose, pH 7.4 at 4°C). Aliquots of the preparation of membranes stored at -70°C.

On the day of analysis, the preparation of the membrane is thawed and centrifuged (rotor TLA 100.3, 4°C, 15 min, 23 000 rpm). The precipitate again first suspended in Tris/sucrose buffer, and then further diluted, if necessary, analytical buffer A (50 mm Na/KPO4, 2 mm MgCl2and 0.5% (wt/vol) BSA, pH 7.5).

To analyze the binding of the drug to the membrane, the test connection and3N-pyrilamine (2 nm at the end) in the buffer And end with 1 wt.% DMSO incubated in 96-well-plate from polypropylene for 3 hours at 37°C. Nonspecific binding determined in the presence of 10 μm of pyrilamine. To migrate from a 96-well plate pre-treated with 0.1% vol. PEI filter-tablet gF/B use 96-well harvester (Packard). The tablet is considered “on Packard Topcounter after adding scintillation fluid Microscint 20 (Packard). From these data calculate the Kifor each connection associated with the receptors of histamine H1. The results are given below in Table 3.

Example 9. Inhibition of LTB4 production in whole human blood

In this test examines the ability of compounds to inhibit the production of leukotriene4in ceedees activating enzyme 5-lipoxygenase, this test allows to predict the ability of compounds to inhibit the human enzyme 5-lipoxygenase.

The analysis is performed as follows. The blood of normal human volunteers taken in heparinized tubes. 1 ml of Heparinized blood is transferred by pipette into a polypropylene test tube of 1.5 ml of this sample type or different concentrations of the test compound (5 μl) dissolved in DMSO, or 5 ál of DMSO as a control medium. These samples are incubated in a water bath at 37°C for 15 minutes. 5 μl of Calcium-ionophore And 23187 (final concentration 50 μm) then add in each sample, the sample is shaken out and put back in the water bath for 30 minutes. Then the samples are centrifuged at 2500 rpm for 10 minutes at 4°C. 50 μl of the Supernatant is transferred into pre-chilled Eppendorf tubes containing 950 μl of buffer for enzyme immunoassay (EIA). Manufactured by industry EIA kit (Cayman Chemical Co., Ann Arbor, MI, USA) used for the subsequent measurement of the production of LTB4in the samples. Levels of LTB4produced in the sample carrier, then compare with the levels when adding the test compounds. Based on this count inhib the IC50for inhibition of the production of LTB4for each of the test compounds. The results are given in Table 3.

Example 10. Antihistaminergic activity in vivo

Male Hartley Guinea pigs weighing 350-400 grams obtained from Charles River Labs. Inhibition histamines activity determined by the method of Konzett and Rossler (Konzett and Roessler) (Naonyn-Schmiedebergs Arch. Exp. Path. Pharmacol. 195, 71-74 (1940)). Sleeping Guinea pigs subjected to artificial ventilation. Determine endotracheal pressure. Bronchostenosis induced sequential intravenous injections of histamine. Compound is administered orally in the form of 1% Metallostroy suspension in multiple (group) time points before the introduction of histamine.

The results (table 4) show the percent inhibition vitaminization bronchostenosis selected compounds at several time points after oral administration. Considered a significant 50% inhibition or more.

From table 4 it is seen that the compounds according to this invention have high activity in regard to their ability to inhibit vitaminization bronchostenosis. the ability of prolonged action. For example, the connection 27 at the dose of 2 mg/kg still inhibits vitaminization bronchostenosis 91% 6 hours after oral administration.

These experiments also indicate that the compound is bioavailable when administered orally.

Example 11. 5-Lipoxygenase inhibiting activity in vivo

Male Hartley Guinea pigs weighing 350-400 g, obtained from Charles River Labs. Compounds prepared in the amount of [1-2 mg/ml] in 1% methylcellulose for oral dosing. Animals are divided into groups of 5 pigs (5). Each test includes a control group, which we give in the form of the dose carrier. Each group of animals given either dose of media or connection orally through a feeding tube. Animals give to relax one, two, three or six hours after a dose. Through appropriate intervals of animals subjected to anesthesia with Urethane, 1.5 g/kg, WB. Blood take “heparinized” syringe via cardiac puncture.

Aliquots of blood (5 ml) is placed in a different way labeled Eppendorf tubes. Each sample load 5 ál of [15 mm] arachidonic acid and placed for 5 minutes in a water bath with a temperature of 37°C. After 5 minutes, the blood stimulated with 5 ál of [5 mm] A (calcium-ionophore), and left the Ute at 14 000 rpm for 2 minutes. The plasma is diluted with EIA buffer and carry out EIA according to the manufacturer's instructions (Cayman Chemical Co., Ann Arbor, MI, USA).

The results (table 5) show inhibition in percent 5-lipoxygenase selected compounds at various time points after oral administration of doses. Inhibition of 50% or more is considered significant.

From table 5 it is seen that the compounds according to this invention have high activity in regard to their ability to inhibit the enzyme 5-lipoxygenase. In addition, some of these compounds, administered at a single dose, have a 5-lipoxygenase inhibitory activity of prolonged action. For example, the connection 87 with the dose of 2 mg/kg still inhibits 5-lipoxygenase activity by 94% after 6 hours after oral dose.

Example 12. Inhibition of 15-lipoxygenase

Using this test examines the ability of compounds to inhibit the production of 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-NET) due to the action of 15-lipoxygenase on arachidonic acid. 15-Lipoxygenase purified from rabbit peritoneal polymorphonuclear leukocytes. The enzyme responsible for the conversion of Arah is rainbow acid (15-NET), which is then reduced in 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-NET).

Below described method. Arachidonic acid is incubated together with 15-NET for 5 minutes at 37°C in the presence or absence of various concentrations of the test compounds (10-8-10-5M). Production of 15-NET in each sample is then determined by radioimmunoassay. Levels 15-NET produced in the control sample with the carrier, then compare with levels in samples with added test compound. On this basis determine the inhibition of the production of 15-NET for each of the test compounds. IC50(nm) is equal to 1300, 170, 46, 61 and 110 for compounds 1, 32, 35, 52 and 80, respectively.

Example 13. Antihistaminergic and 5-lipoxygenase inhibiting activity in vivo

UCB 62045: Pharmacology of a new protivovospalitelnoe agent with a double feature with the activity of antagonist receptor histamine-1 and the activity of the inhibitor of 5-lipoxygenase

I believe that as histamine and leukotrienes are key mediators of asthma and other inflammatory or allergic pathophysiological disorders. The available data suggest that the combination of antagonists lake is experimental, and clinical cases of asthma or rhinitis. Was synthesized compound found in Table 3 at number 80, which resists the action of histamine receptor-1 (H1) (26 nm in cells SNO, transfected with the human receptor H1), and also inhibits 5-lipoxygenase (5-LO; IC50193 nm and 88 nm against human recombinant 5-LO inhibition induced by using A education LTB4in whole human blood, respectively). Orally administered compound (2 mg/kg in 1% methylcellulose), depending on the dose inhibited as induced by histamine bronchostenosis (0, 98, and 97% after 1, 3 and 6 h after dose) and ex vivo stimulated with A education LTB4in Guinea pigs (66, 73, and 88% after 1, 3 and 6 h after dose). In addition, the compound (2 mg/kg) also reduces the content of histamine and leukotrienes components allergic bronchostenosis (ovalbumin, 0.1 mg/ml centuries) in the model under anesthesia suffering from allergic Guinea pigs (37, 86, and 91% after 1, 3 and 6 h after dose) These results show that the claimed compounds may be clinically useful for the treatment of respiratory diseases due to protyvovospalytel.

Claims

1. 1,4-Substituted piperazines or 4-alkylhydroperoxides formula I

and its geometric isomers, enantiomers, diastereoisomers and pharmaceutically acceptable salt,

where X and X' independently represent hydrogen, halogen, or -(Y')m'-W';

G and G' together form

or

D represents-CH= or =N-;

R1and R2is isimo 0 or 1;

Y represents-L1- or-L2-V(Z)t-L3where t = 0 or 1;

Y' denotes the-L1-;

L1denotes alkylene, albaniles or one of the above, where one or more methylene groups are replaced by-O-;

L2means (a) alkylen, akinyan or one of the above, where one or more methylene groups are replaced by-O-, or (b) -L4-C(O)-N(Q')-, or-L4(Q')-;

L3means (a) alkylen and akinyan or one of the above, where one or more methylene groups are replaced by-O-;

L4denotes alkylene which one or more methylene groups are replaced by-N(R5)-;

V denotes (a) divalent arenas, divalent heteroaryl or divalent rich heterocycle, when t = 0, or (b) trivalent arenas or trivalent heteroaryl, when t = 1;

Q represents hydrogen, AC(O)OR6or AC(O)NR6R7;

W represents-N(OM)C(O)N(R8R9, -N(R8)C(O)N(OM)R9, -N(OM)C(O)R8or-C(O)OR8;

W' refers to-N(OM)C(O)N(R8R9or-C(O)OR8provided that at least one of W and Wrepresents N(OM)C(O)N(R8R9;

Z represents-A'C(O)NR10R11, -A'C(O)OR10the halogen is inlen;

M & M' independently denote hydrogen, a pharmaceutically acceptable cation or split in the process of metabolism group;

R3-R11independently represent hydrogen, alkyl, arylalkyl or one of the above in which one or more methylene groups are replaced by-O-,

provided that in contrast to atoms of oxygen, associated with s in-S(O) -, and-S(O)2- when one or more methylene groups are replaced by-O-, -NH-, -S-, -S(O)- or-S(O)2and when one or more methylidene residues substituted at =N, this substitution does not occur in two heteroatoms covalently associated with each other; and, in addition, provided that when m = 0, W represents-C(O)OR8; and, in addition, provided that the Vice-AC(O)OR6R6cannot denote hydrogen, And indicates when a simple link.

2. Connection on p. 1 having the formula II

in which the value of the substituents defined in paragraph 1,

and its geometric isomers, enantiomers, diastereoisomers and pharmaceutically acceptable salts.

3. Connection on p. 1, having the formula III

in which the value of the substituents defined in paragraph 1,

and its geometric isomers, is that X represents-CL; X' denotes hydrogen; m = 1, and W represents-N(OH)C(O)NH2.

5. Connection on p. 2 or 3, characterized in that X represents-CL; X' denotes hydrogen; m = 1; Y represents-L'-, L'- means akinyan, illcox or illconcealed.

6. Connection on p. 2 or 3, characterized in that X represents-CL; X' denotes hydrogen; m = 1; Y represents-L2-V(Z)t-L3-, t = 0, V denotes 1,4-phenylene or 1,3-phenylene, L2indicates illcox and L3denotes alkylene or akinyan.

7. Connection on p. 2 or 3, characterized in that X represents-CL; X' denotes hydrogen; m = 1; Y represents-L2-V(Z)t-L3-, t = 0, V denotes a 2,5-furillen, L2denotes alkylene and L3denotes alkylene or akinyan.

8. The compound according to any one of p. 2 or 3, characterized in that X represents-CL; X' denotes hydrogen; m = 1; Y represents-L2-V(Z)t-L3-, t = 1, L2indicates illcox, V denotes heteroaryl (heteroaryl); Z represents A'C(O)NR10R11or A'C(O)OR10and W represents-N(OH)C(O)NH2.

9. The compound according to any one of p. 2 or 3, characterized in that X and X' denote F; m = 1; Y represents-L2-V(Z)t-L3-, t = 0, V denotes a 1,4-FeNi is on p. 1, wherein X and X' independently denote hydrogen, halogen or -(Y')m'-W'; G and G' together formor

D represents-CH= or =N-; R1and R2independently represent hydrogen or together represent -(CH2)2-; m m' independently represent 0 or 1; Y represents-L1- or-L2-V(Z)t-L3where t = 0 or 1; Y' denotes the-L1-; L1denotes alkylene, akinyan or one of the above in which one or more methylene groups are replaced by-O-; L2means (a) alkylen, akinyan or one of the above in which one or more methylene groups are replaced by-O - or (b) -L4-C(O)-N(Q')-; L3means (a) alkylen, akinyan or one of the above in which one or more methylene groups are replaced by-O-; L4denotes alkylene; V denotes (a) divalent arenas, divalent heteroaryl or divalent rich heterocycle, when t = 0, or (b) trivalent arenas or trivalent heteroaryl, when t = 1; Q represents hydrogen; Q' means-AC(O)OR6or-AC(O)NR6R7; W represents-N(OM)C(O)N(R -C(O)OR8provided that at least one of W and W' is a N(OM)C(O)N(R8R9; Z denotes-A'C(O)NR10R11, -A'C(O)OR10, halogen, NR3C(O)R4, NO2CN or CF3; And A' independently represent a simple bond, alkylene or albaniles; M M' independently denote hydrogen, a pharmaceutically acceptable cation or a metabolically degradable group; R3-R11if present, independently represent hydrogen or alkyl, in which one or more methylene groups are replaced by-O-, provided that in contrast to the oxygen atoms associated with the sulfur atoms in the-S(O) -, and-S(O)2- when one or more methylene groups are replaced by-O - or-NH - and when one or more methylidene groups substituted on =N-, when such a substitution is not formed of two covalently linked to each other heteroatoms, provided that when m = 0, W represents-C(O)OR8and another provided that the Vice-AC(O)OR6R6cannot denote hydrogen, And indicates when a simple link.

11. Connection on p. 10, characterized in that X and X' independently represent-H or halogen; G and G' together form

or

Y bosnali more methylene groups may be replaced by-O-; V(Z)tdenotes phenylene, optionally substituted groups-A'C(O)NR10R11, -A'C(O)OR10, halogen, NR3C(O)R4, NO2CN or CF3or furillen or oxalanilide; L3denotes alkylene C1-C6in which one or more methylene groups may be replaced by-O-, or C2-C6-akinyan; W represents-N(OM)C(O)N(R8R9, -N(R8)C(O)N(OM)R9or-N(OM)C(O)R8; And' denotes methylene, vinile or a simple bond; R3-R11if present, independently represent hydrogen or C1-C6, -alkyl in which one or more methylene groups may be replaced by-O-.

12. Connection on p. 11, characterized in that X represents fluorine or chlorine; X' denotes hydrogen or fluorine; Y represents-L2-V(Z)t-L3where t = 0 or 1; L2represents C1-C6-alkylene in which one methylene group may be replaced by-O-; V(Z)tdenotes phenylene, optionally containing a Deputy-A'C(O)NR10R11, -A'C(O)OR10, halogen, NR3C(O)R4, NO2CN or CF3or furillen or oxalanilide; L3represents C1-C6-alkylene in which one methylene group can be Zli simple communication; R3-R11if present, independently represent hydrogen or C1-C6,-alkyl, in which one methylene group may be replaced by-O-;

13. Connection on p. 1, characterized in that X and X' independently represent hydrogen or halogen; W represents-N(OM)C(O)N(R8R9, -N(R8)C(O)N(OM)R9or-N(OM)C(O)R8.

14. Connection on p. 1, characterized in that the L4denotes alkylene; Z denotes-A'C(O)NR10R11or-A'C(O)OR10.

15. Connection on p. 1, characterized in that X and X' independently represent-H or halogen; L4denotes alkylene; W represents-N(OM)C(O)N(R8R9, -N(R8)C(O)N(O)R9or-N(OM)C(O)R8; Z denotes-A'C(O)NR10R11or-A'C(O)OR10.

16. Connection on p. 1, characterized in that when M or M' refers to the metabolic tsepliaeva group, this group is chosen from organic or inorganic anion, a pharmaceutically acceptable cation, acyl, alkyl, phosphate, sulfate and sulfonate, NH2C(O)- or (alkyl)OC(O)-.

17. Connection on p. 16, wherein acyl represents an (alkyl)C(O)-, including acetyl, propionyl, butyryl.

18. Connection on p. 1, selected from the group comprising N-{[4-(2-{4-[(1�l]piperazinil}ethoxy)phenyl]methyl}amino-N-hydroxyamide, amino-N-{[4-(2-{4-[bis(4-forfinal)-methyl]piperazinil}ethoxy)phenyl]ethyl}-N-hydroxyamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]but-3-inyl}amino-N-hydroxyamide, N-{[4-(3-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}propyl)phenyl]methyl}amino-N-hydroxyamide, N-{4-[3-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]but-3-inyl}amino-N-hydroxyamide, N-{[3-(2-{4-1(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]methyl}(methyl(hydroxyamino))carboxamide, N-{4-[3-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]butyl}amino-N-hydroxyamide, amino-N-[4-(4-{2-[4-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-Liden)piperidyl]ethoxy}phenyl)but-3-inyl]-N-hydroxyamide, N-{3-[5-({4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}methyl)(2-furyl)]-1-methylprop-2-inyl}amino-N-hydroxyamide, amino-N-{4-[5-({4-[(bis(4-forfinal)-methyl]piperazinil}methyl)(2-furyl)]but-3-inyl}-N-hydroxyamide, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]benzamide, methyl 2-[2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy]-5-[4-(amidohydrolase-carbylamine)buta-1-inyl]benzoate, 2-[2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy]-5-[4-(amidohydrolase-carbylamine)buta-1-inyl]benzoic acid, methyl 2-(2-{4-[(1R)(4-chlorophenyl)-fenile the Nile}ethoxy)-5-[4-(aminohydrocinnamic)butyl]benzoic acid, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)butyl]benzamide, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinyl}ethoxy)-5-[4-(amidohydrolase-carbylamine)butyl]benzoic acid, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(amidohydrolase-carbylamine)buta-1-inyl]benzoic acid, methyl 5-[4-(aminohydrocinnamic)buta-1-inyl]-2-(2-{4-[bis(4-forfinal)methyl]piperazinil}-ethoxy]benzoate, N-{4-[5-({4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}methyl) (2S, 5S)oxolan-2-yl]but-3-inyl}amino-N-hydroxyamide, methyl(2E)-3-[2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)butyl]phenyl]prop-2-ENOAT, methyl(2E)-3-[2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]phenyl]prop-2-ENOAT, 5-[4-(amidohydrolase-carbylamine)buta-1-inyl]-2-(2-{4-[bis(4-forfinal)methyl]piperazinil}-ethoxy)benzoic acid, N-{4-[4-(3-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}propoxy)phenyl]but-3-inyl)amino-N-hydroxyamide, amino-N-[4-(4-{2-[4-(8-chlorine(5,6,11-triggerevent[b]pyridine[3,2-f][7]annulen-11-yl) piperidyl]ethoxy}phenyl)but-3-inyl]-N-hydroxyamide, amino-N-[4-(4-{3-[3-(8-chlorine(5.6 dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene)piperidyl]propoxy}phenyl)but-3-inyl]-N-hydroxyl the op-2-ANOVA acid, N-{4-[3-((1E)-2-carbamoylmethyl)-4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}-ethoxy)phenyl]but-3-inyl}amino-N-hydroxyamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}ethoxy)-3-forfinal]but-3-inyl}amino-N-hydroxyamide, 5-[4(amidohydrolase-carbylamine)buta-1-inyl]-2-(2-{4-[bis(4-forfinal)methyl]piperazinil}-ethoxy)benzamide, amino-N-{4-[4-(2-{4-[(bis(4-forfinal)methyl]piperazinil}ethoxy)-3-forfinal]but-3-inyl}-N-hydroxyamide, 5-[4-(amidohydrolase-carbylamine)buta-1-inyl]-2-{2-14-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene)piperidyl]ethoxy}benzamide, 2-(3-{4-[(1R)(4-chlorophenyl)-ylmethyl]piperazinil}propoxy)-5-[4-(amidohydrolase-carbylamine)buta-1-inyl]benzamide, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[5-(amidohydrolase-carbylamine)Penta-1-inyl]benzamide, 2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminohydrocinnamic)buta-1-inyl]benzamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-(trifluoromethyl)phenyl]but-3-inyl}amino-N-hydroxyamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-(trifluoromethyl)phenyl]but-3-inyl}amino-N-hydroxyamide, N-{4-[4-(2-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-cyanophenyl]but-3-inyl}amino-N-hydroxyamide, N-{4-[4-(4-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}Butoh is carbylamine)prop-1-inyl]benzamid, N-{4-[4-(4-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}butoxy)phenyl]butyl}amino-N-hydroxyamide, N-{4-[4-(2-{4-[(1S)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-(trifluoromethyl)phenyl]butyl}amino-N-hydroxyamine, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-3-(trifluoromethyl)phenyl]butyl}amino-N-hydroxyamide, amino-N-[4-(4-{4-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene))piperidyl]butoxy}phenyl)but-3-inyl]-hydroxyamide, amino-N-[4-(4-{4-[4-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b][7]annulen-11-ilidene)piperidyl]butoxy}phenyl)butyl]-N-hydroxyamide, N-{4-[4-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]but-3-inyl}ethoxy-N-hydroxycarboxylic, N-{4-[4-(4-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinyl}butoxy)phenyl]butyl}amino-N-hydroxyamide, N-[2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(aminoglutaric-carbylamine)buta-1-inyl]phenyl]acetamide", she N-[2-(2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)-5-[4-(amidohydrolase-carbylamine)buta-1-inyl]phenyl]acetamide", she N-{4-[4-(3-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}propoxy)phenyl]butyl)amino-N-hydroxyamide, amino-N-{4-[4-(4-{4-[bis(4-forfinal)-methyl]piperazinil}butoxy)phenyl]but-3-inyl}-N-hydroxyamide, N-{3-[4-(3-{4-[(1R)(4-chlorophenyl)phenylmethyl]piperazinil}propoxy)phenyl]propyl}amino-N-hidroxi the Il)phenylmethyl]piperazinil}-propoxy)-5-[4-(amidohydrolase-carbylamine)-butyl]benzamide, 5-{4-[(aminocarbonyl)(hydroxy)amino]butyl}-2-(2-{4-[bis(4-forfinal)methyl]-1-piperazinil}ethoxy)benzamide, N-{3-[4-(3-{4-[bis(4-tryptophanyl)methyl]-1-piperazinil}propoxy)phenyl]prolyl}-N-hydroxyurea, N-{4-[4-(2-{4-[bis-(4-forfinal)methyl]-1-piperazinil}ethoxy)-2-nitrophenyl]-3-butenyl}-N-hydroxyurea, -{4-[4-(2-{4-[bis-(4-forfinal)methyl]-1-piperazinil}ethoxy)phenyl]butyl}-N-hydroxyurea, 5-{4-[(aminocarbonyl)(hydroxy)amino]-1-butenyl}-2-(2{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}ethoxy)benzamide, N-{4-[4-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}ethoxy)benzamide, 5-{4-[(aminocarbonyl)(hydroxy)amino)-1-butenyl}-2-(2-{4-[(R-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}-ethoxy)benzamide, 5-{4-[(aminocarbonyl)(hydroxy)amino)-1-butenyl}-2-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}-ethoxy)benzamide, 5-{4-[(aminocarbonyl)(hydroxy)amino]-1-butenyl}-2-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}-ethoxy)benzamide, N-{3-[4-(3-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinil}propyl)phenoxy]propyl}-N-hydroxyurea.

19. Connection on p. 1, selected from the group comprising N-{4-[4-2-{4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}ethoxy)phenyl]butyl}amino-N-hydroxyamide, amino-N-[4-(4-{2-[4-(8-chlorine(5,6-dihydrobenzo[f]pyridine[2,3-b] [7]annulen-11-ilidene)piperidyl]ethoxy}phenyl)but-3-inyl]-N4-chlorophenyl)-phenylmethyl]piperazinyl}ethoxy)-5-[4-(amidohydrolase-carbylamine)buta-1-inyl]benzamid, N-{4-[5-({4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}methyl)(2S,5S)oxolan-2-yl]but-3-inyl}amino-N-hydroxyamide, N-(4-[4-(3-4-[(1R)(4-chlorophenyl)-phenylmethyl]piperazinil}propoxy)phenyl]but-3-inyl)amino-N-hydroxyamide and amino-N-{4-[4-(4-{4-[bis(4-forfinal)-methyl]piperazinil}butoxy)phenyl]but-3-inyl}-N-hydroxyamine.

20. Pharmaceutical composition having the property of inhibiting leukotriene and antihistaminergic property containing a pharmaceutically acceptable carrier and a compound according to any one of paragraphs.1-19.

21. The method of simultaneous inhibition as leukotriene-and gistaminopodobnyh biological processes, which consists in the introduction of effective leukotrien and vitaminmineral number of compounds according to any one of paragraphs.1-19 to a subject in need of such inhibition.

22. A method for the treatment of asthma, seasonal and chronic allergic rhinitis, which consists in the introduction of a therapeutically effective amount of a compound according to any one of paragraphs.1-19 to a subject in need of such treatment.



 

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The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

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< / BR>
where Z denotes a group of General formula II

< / BR>
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The invention relates to new derivatives cycloalkane-pyridine of General formula (I), where a is aryl with 6-10 carbon atoms, unsubstituted or monosubstituted with halogen, D-aryl with 6-10 carbon atoms, unsubstituted or substituted by phenyl, nitro, halogen, trifluoromethyl or triptoreline, or a residue of the formula presented in the claims, E-cycloalkyl with 3-8 carbon atoms, a linear or branched alkyl with 1-8 carbon atoms or phenyl, unsubstituted or substituted with halogen or trifluoromethyl, R1and R2together form a linear or branched alkylenes chain with 1-7 carbon atoms, which is substituted by a carbonyl group and/or a residue of the formula shown in the formula of the invention, mixtures of their isomers, or individual isomers, their salts and N-oxides, with the exception of 5(6N)-quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl

The invention relates to a piperidine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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