Derivatives of 2-phenoxy and 2-phenylsulphonamide with ccr3 antagonistic activity for treating asthma and other inflammatory or immunological diseases

FIELD: chemistry.

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

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

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

13 cl, 1 tbl, 3 ex

 

The technical field

This invention relates to a derivative of benzosulfimide, which is suitable as an active ingredient of pharmaceutical preparations. Derivatives benzosulfimide of this invention have an antagonistic activity against CCR3 (the receptor of the chemokine 3 SS type) and can be used for the prevention and treatment of diseases associated with the activity of CCR3, in particular for the treatment of asthma, atopic dermatitis, allergic rhinitis and other inflammatory/immunological diseases.

Prior art

Chemokines are chemotactic cytokines, the main function of which is the migration of cells of inflammation, which Express the relevant chemokine receptors on their surface, inflammation, and activation of cells of inflammation. There are two classes of chemokines, C-X-C (alpha.) and (i), depending divided on whether the first two cysteines of one amino acid (C-X-C) or are adjacent (C-C).

Eotaxin, one of the C-C family of chemokines, is an 8.4 kDa (74 amino acids) polypeptide and binds specifically to the receptor CCR3 with high affinity. In vitro and in vivo eotaxin causes chemotaxis of cells inflammation, expressing CCR3 [J. Elsner, Hochstetter R., Kimming D. and A. Kapp: Human eotaxin represents a potent activator of the respiratory burst of human eosinophils. Eur. J. Imunol., 26: 1919-1925, 1996].

The receptor of the chemokine CCR3 is a conjugate with G protein seventh transmembrane domain receptor (GPCR)that is associated with known ligands, in addition to eotaxin, including eotaxin-2 (CCL24), RANTES (CCL5), MCP-3 (CCL7) and MCP-4 (CCL13). CCR3 is expressed in cells of inflammation relevant to the pathology of chronic asthma. These cells inflammation include eosinophils [Sabroe I., Conroy D.M., N.P. Gerard, Li Y., Collins P.D., Post, T.W., Jose P.J., Williams T.J., Gerard C.J., Ponath P.D. J. Immunol.161: 6139-6147, 1998], basophils [Uguccioni M., Mackay C.R., Ochensberger B., Loetscher, P., Rhis, S., LaRosa G.J., Rao P., Ponath P.D., Baggiolini M., Dahinden CA J. Clin. Invest.100: 1137-1143, 1997], Th2 cells [Sallusto F., Mackay C.R., Lanzavecchia A. Science.277: 2005-2007, 1997], alveolar macrophages [I.W. Park, Koziel H., Hatch, W., Li X., Du B., J.E. Groopman Am. J. Respir. Cell Mol. Biol.20: 864-71, 1999] and Metacity [Oliviera S.H. and the Lukacs N.W. Inflamm. res.50: 168-174, 2001]. It was also described that BEAS-2B cell line epithelium stimulated TNF-α and IFN-γ, expresses CCR3 [Stellato C., Brummet M.E., Plitt J.R., Shahabuddin s, Baroody F.M., Liu M., Ponath P.D. Beck and L.A. J. Immunol.,166: 1457-1461, 2001].

In animal models of mouse c embossed eotaxin showed reduced eosinophilia after verification of immunity to the antigen [M.E. Rothenberg, MacLean J.A., E. Pearlman, A.D. Luster and Leder P. J. Exp. Med.,185: 785-790, 1997]. In mice with double-embossed IL5/eotaxin not observed eosinophilia or AHR in response to antigenic stimulation [Foster P.S., Mould A.W., Yang M., Mackenzie J., Mattes J., Hogan SP, Mahalingam, S., Mckenzie, A.N.J., Rothenberg M.E., Young, I.G., K.I. Mattaaei and D.C. Webb Immunol. Rev.,179: 173-181, 2001]. Clinically, the expression of mRNA and protein eotaxin and CCR3 observed in the lung tissues in atopic asthma, and it is associated with AHR, low FEV1and lung eosinophilia [Ying S., Robin D.S., Q. Meng, J. Rottman, R. Kennedy, D.J. Ringler, Mackay C.R., Daugherty B.L., M.S. Springer, Durham S.R., Williams TJ. and Kay A.B.: Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma. Association with airway hyperresponsiveness and predominant colocalization of eotaxin mRNA to bronchial epithelial and endothelial cells. Eur. J. Immunol., 27, 3507-3516, 1997; Lamkhioued Renzi P.M., AbiYounes S., GarciaZepada E.A., Allakhverdi z, Ghaffar A., Rothenberg M.D., A.D. Luster and Hamid Q.: Increased expressions of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation. J. Immunol., 159: 4593-4601, 1997; Jahnz-Royk K., Plusa T. and Mierzejewska J.: Eotaxin in serum of patients with asthma or chronic obstructive pulmonary disease: relationship with eosinophil cationic protein and lung function. Mediators of Inflammation, 9: 175-179, 2000]. In addition, allergic rhinitis, expressing CCR3 Th2 lymphocytes colocalized with eosinophils in nasal polyps in close proximity to expressing eotaxin cells [Gerber B.O., Zanni M.P., Uguccioni, M., Loetscher, M., Mackay C.R., W.J. Pichler, Yawalkar N., Baggiolini M. and Moser Century: Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils. CURRENT BIOLOGY 7: 836-843, 1997]. Moreover, viral infection (RSV, influenza virus), which are known to be risk factors for asthma provide an increased expression of eotaxin in the lung tissues, which correlates with tissue eosinophilia [Matsukura, S., Kokubo F., Kubo H., Tomita T., Tokunaga H., Kadokura, M., Yamamoto T., Kuroiwa Y., Ohno T, Suzaki, H. and Adachi, M.: Expression of RANTES by normal airway epithelial cells after influenza A virus infection. Am. J. Respir. Cell and Mol. Biol.,18:255-264, 1998; Saito T., Deskin R.W., Casola, A., H. Haeberle, Olszewska Century, Ernest P.B., R. Alam, Ogra P.L. and R. Garofalo: Selective regulation of chemokine production in human epithelial cells. J. Infec. Dis., 175: 497-504, 1997]. Thus, binding to CCR3 and related chemokines, including eotaxin, is considered an important mediator in inflammatory and immunoregulatory diseases and disorders, including asthma, rhinitis and allergic diseases as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis. It is also believed that the binding of CCR3 and related chemokine is an important factor in viral infections, including HIV [(Marone G, de Paulis A, Florio G, Petraroli A, Rossi F, Triggiani M.: Int Arch Allergy Immunl 2001 Jun; 125(2)/89-95), (Li Y et al.,: Blood 2001 Lun 1; 97(11):3484-90) and (Marone G, Florio G, Pertaroli A, Triggiani M, de Paulis A: Trends Immunol 2001 May; 22(5):229-32)], granuloma of the lung (Ruth JH, Luakcs NW, Warmington KS, Polak TJ, Burdick M, Kunkel SL, Strieter RM, Chensue SW: J Immunol 1998 Oct 15; 161 (8):4276-82) and Alzheimer's disease (Xia MQ, Qin SX, Wu LJ, Mackay CR, and Hyman BT: Am J Pathol 1998 Jul; 153 (1):31-37).

Therefore, CCR3 is an important target, and antagonism to the CCR3 is probably effective in the treatment of such inflammatory and immunoregulatory disorders and diseases.

In applications WO 2000/76514 and WO 2000/76513 described cyclopentenone modulators of chemokine receptors, including CCR3 activity, represented by the General formula:

where

X”, x, y, R1', R2', R3', R4', R5', R6', R7'and R8'such as defined in these applications.

In other applications also describes modulators of CCR3. However, none of the presented links and other references not described simple derivatives benzosulfimide, which has antagonistic activity towards CCR3.

Desirable further development of compounds with efficient antagonistic activity against CCR3, which can be used for the prevention and treatment of diseases associated with the activity of CCR3.

Brief description of the invention

As a result of extensive research chemical modification of derivative benzosulfimide the authors of this invention have found that compounds having the structure presented in this invention have unexpectedly excellent antagonistic activity against CCR3. This invention based on this discovery.

Thus, the invention presents the derivatives of benzosulfimide having the formula (I), their tautomeric and stereoisomeric form, and salts.

where

X represents O or S;

R1represents hydrogen, halogen, hydroxy, nitro, cyano, C1-6alkoxycarbonyl, amino, C1-6alkylamino, di(C1-6 alkyl)amino, C1-6alkanoyl, phenyl, C1-6alkyl, optionally substituted with one, two or three halogen, or C1-6alkoxy, optionally substituted with one, two or three Halogens;

R2represents hydrogen, halogen, hydroxy, nitro, cyano, C1-6alkoxycarbonyl, amino1-6alkylamino, di(C1-6alkyl)amino, C1-6alkanoyl, phenyl, C1-6alkyl, optionally substituted with one, two or three halogen, or C1-6alkoxy, optionally substituted with one, two or three Halogens;

R3represents hydrogen, halogen, hydroxy, nitro, cyano, amino, carboxy, tetrazolyl,1-6alkoxy, C1-6alkoxycarbonyl,1-6alkanoyl,1-6alkanolamine,1-6alkyl, optionally substituted by one, two or three halogen or hydroxy;

R4is

or

where

R40is1-6alkyl, substituted pyrrolidinium or piperidinium where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography, 7-oxabicyclo[4.1.0]hept-3-yl, optionally having 1 or 2 substituent selected from the group comprising amino, (C1-6alkyl)amino and di(C1-6alkyl)amino, or a 5-8-membered ring on Ishenim heterocyclic ring, containing 1 or 2 heteroatoms selected from the group comprising N and O and optionally having 1 to 3 substituents selected from the group comprising hydroxy, amino, oxo and C1-6alkyl;

R41represents hydrogen, C1-6alkyl, optionally substituted amino, C1-6alkylamino, di(C1-6alkyl)amino or 2.5-dioxopiperidin-1-yl, or5-8cycloalkyl, optionally substituted hydroxy,

or

R40and R41together with the adjacent N atom may form a 5-8-membered saturated heterocyclic ring, optionally interrupted About;

R42is1-6alkylene, optionally substituted by hydroxy or carboxy, or5-8cycloalkyl, substituted by at least one hydroxy and, further, optional 1 or 2 substituents selected from the group comprising hydroxy, amino, oxo and C1-6alkyl,

or

R41and R42together with the adjacent N atom may form a 5-8-membered saturated heterocyclic ring optionally interrupted by NH or O, where the specified 5-8-membered saturated heterocyclic ring substituted by one or two exography,

provided that when R41is hydrogen, C1-6the alkyl, optionally substituted amino, C1-6alkylamino or di(C1-6alkyl)amino, R42is replacement With 1-6alkylene or carboxyterminal1-6alkylene;

R43represents hydrogen, C1-6alkyl, optionally substituted by hydroxy or carboxy;

R44represents hydrogen or C1-6alkyl, optionally substituted by hydroxy or carboxy,

provided that when R41and R42together with the adjacent N atom form a 5-8-membered saturated heterocyclic ring, R44is replacement With1-6the alkyl or carboxyterminal1-6by alkyl;

R45, R47, R49and R50independently represent hydrogen or C1-6alkyl;

R46and R48independently represent1-6alkylene, optionally substituted by hydroxy or carboxy;

n is an integer from 1 to 3;

m is an integer from 0 to 3;

R51represents hydrogen, C1-6alkyl or 3-8-membered saturated ring, optionally interrupted by NH or O;

R52represents hydrogen, C1-6alkoxycarbonyl or1-6alkyl, substituted carboxy, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, N-(C1-6alkylsulfonyl)amino, N-(C1-6alkanoyl)amino, C1-6alkoxycarbonyl, tetrazolyl, triazolyl, indolinyl, isoindolyl, indolium, isoindolyl, pyrrolidinyl, optionally substituted with one or two exography, or Pipa is Iginla, optionally substituted by one or two exography,

provided that when R51and R52simultaneously are hydrogen, R3is tetrazolyl or1-6alkanoyl, or when R51is hydrogen or C1-6the alkyl, R52different from hydrogen;

R61and R62independently represent hydrogen or C1-6alkyl, optionally substituted hydroxy, carboxy, phenyl or by one, two or three Halogens;

R71represents hydrogen or C1-6alkyl, optionally substituted amino, hydroxy, carboxy, pyrrolidinium or piperidinium where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

R72represents hydrogen, carboxy, C1-6alkanoyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, N-(C1-6alkyl)aminocarbonyl,1-6alkyl, optionally substituted by hydroxy, carboxy or by one, two or three halogen, C1-6alkoxy, optionally substituted with one, two or three halogen, pyrrolidinyl or piperidinyl where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

Z1represents- (CH2]p-where p is an integer 1 or 2;

R81represents hydrogen, C1-6alkoxycarbonyl or1-6 alkyl, substituted pyrrolidinium or piperidinium where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

R82represents hydrogen, hydroxy, carboxy or1-6alkyl, substituted hydroxy, amino or carboxy,

R83represents hydrogen, hydroxy, carboxy or1-6alkyl, substituted hydroxy, amino or carboxy,

provided that when R81is hydrogen, R82or R83other than hydrogen;

Z2represents- (CH2]q-where q is an integer from 0 to 3;

R91represents hydrogen or C1-6alkyl, optionally substituted by phenyl;

R111represents hydrogen, carboxy, C1-6alkoxycarbonyl,1-6alkanoyl, N-(C1-6alkyl)aminocarbonyl,1-6alkoxy, optionally substituted with one, two or three halogen, or C1-6alkyl, optionally substituted hydroxy, one, two or three halogen, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, N-(C1-6alkylsulfonyl)amino, N-(C1-6alkanoyl)amino, C1-6alkoxycarbonyl, tetrazolyl, triazolyl, indolinyl, isoindolyl, indolium, isoindolyl, pyrrolidinium or piperidinium where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

to LCA And is a 3-8-membered saturated heterocyclic ring, in which the nitrogen atom NAis the only heteroatom;

the ring is a 3-8-membered saturated heterocyclic ring in which the nitrogen atom NInis the only heteroatom;

ring and D ring together form a 7 to 15-membered diazabicyclo ring; and

ring E represents a 5-8-membered saturated heterocyclic ring in which the nitrogen atom NEis the only heteroatom.

The present invention also provides a method of treatment or prophylaxis associated with CCR3 disorders or diseases in a human or animal, including the introduction of the indicated patient a therapeutically effective amount of a derivative benzosulfimide formula (I), its tautomeric or stereoisomeric form, or its physiologically acceptable salt.

Also in this invention provided the use of a derived benzosulfimide formula (I), its tautomeric or stereoisomeric form, or its physiologically acceptable salt in obtaining medicines for the treatment or prevention associated with CCR3 disorders or diseases.

The compounds of this invention unexpectedly exhibit excellent antagonistic activity against CCR3. Therefore they are suitable to obtain drugs or therapeutic compositions that m is able to be used for the treatment associated with CCR3 diseases. More specifically, since the compounds of this invention are antagonists of CCR3, they are suitable for the treatment and prevention of the following diseases: asthma, rhinitis, allergic diseases, and autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis. Therefore, CCR3 is an important target, and antagonism against CCR3 may be effective in the treatment and prevention of such inflammatory and immunoregulatory disorders and diseases.

The compounds of this invention are also useful for the treatment and prevention of diseases such as viral infections, including HIV, pulmonary granuloma and Alzheimer's disease, as these diseases are also associated with CCR3.

In another embodiment, compounds of formula (I) are those, where

R4is

where

R40is1-6alkyl having Deputy selected from the group comprising 2-oxopyrrolidin-1-yl, 2,5-dioxopiperidin-1-yl, 2-oxopiperidin-1-yl, 2-oxopiperidin-3-yl, 4-oxopiperidin-1-yl, 2-oxopiperidin-6-yl, 2,5-dioxopiperidin-1-yl, 2,6-dioxopiperidin-1-yl and 2,6-dioxopiperidin-3-yl, piperidine-1-yl, -2-yl, -3-yl or-4-Il (where specified piperidine optionally substituted with one or two oxopropyl), hexahydroazepin the n-1-yl, -2-yl, -3-yl or-4-yl (where specified hexahydroazepin optionally substituted by one or two oxopropyl) and 7-oxabicyclo[4.1.0]hept-3-yl, optionally substituted amino;

R41represents hydrogen, cyclopentyl or1-6alkyl, optionally substituted amino, C1-6alkylamino, di(C1-6alkyl)amino or 2.5-dioxopiperidin-1-yl;

R42is1-4alkylene, substituted carboxy, or cyclohexyl substituted by one or two hydroxy,

or

R41and R42together with the adjacent N atom may form a 5-6-membered saturated heterocyclic ring,

provided that when R41is hydrogen, C1-6the alkyl, optionally substituted amino, C1-6alkylamino or di(C1-6alkyl)amino, R42is replacement With1-6alkylene or carboxyterminal1-6alkylene;

R43represents hydrogen or C1-6alkyl, optionally substituted by hydroxy;

R44is1-6alkyl, optionally substituted by hydroxy or carboxy,

provided that when R41and R42together with the adjacent N atom form a 5-6-membered saturated heterocyclic ring, R44is replacement With1-6the alkyl or carboxyterminal1-6by alkyl;

R45, R47, R49and R50 independently represent hydrogen, methyl or ethyl;

R46and R48independently represent1-6alkylene, optionally substituted by hydroxy or carboxy;

R51represents hydrogen, cyclopentyl, ethyl or methyl;

R52is methoxycarbonyl or1-6alkyl, substituted carboxy, amino, methoxycarbonyl, methanesulfonamido,

acetamido, indolium, tetrazolyl, 1,2,3-triazolium,

1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,

pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl,

2,5-dioxopiperidin-1-yl, 2-oxopiperidin-1-yl,

2-oxopiperidin-3-yl, 4-oxopiperidin-1-yl,

2-oxopiperidin-6-yl, 2,5-dioxopiperidin-1-yl,

2,6-dioxopiperidin-1-yl or 2,6-dioxopiperidin-3-yl;

R61and R62independently represent benzyl or phenethyl;

R72represents hydrogen, carboxy, C1-6alkanoyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, N-(C1-6alkyl)aminocarbonyl,1-6alkyl, optionally substituted by hydroxy, carboxy or by one, two or three halogen, C1-6alkoxy, optionally substituted with one, two or three halogen, pyrrolidinyl or piperidinyl where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

R81represents hydrogen, methoxycarbonyl or1-6alkyl, Zam is on 2-oxopyrrolidin-1-yl, 2,5-dioxopiperidin-1-yl, 2-oxopiperidin-1-yl, 2-oxopiperidin-3-yl, 4-oxopiperidin-1-yl, 2-oxopiperidin-6-yl, 2,5-dioxopiperidin-1-yl, 2,6-dioxopiperidin-1-yl or 2,6-dioxopiperidin-3-yl;

R82represents hydrogen, hydroxy or C1-6alkyl, substituted hydroxy,

R83represents hydrogen, hydroxy or carboxy,

provided that when R82or R83simultaneously are hydrogen, R81different from hydrogen, or when R81and R83simultaneously are hydrogen, R82different from hydrogen;

R91represents benzyl or phenethyl.

Other preferred compounds of formula (I) represented by formula (I-b)

where

R1represents fluorine, chlorine, bromine, iodine or nitro;

R2represents fluorine, chlorine, bromine, iodine or nitro;

R3represents acetyl, cyano or tetrazolyl;

R4is

or

where

R40is1-6alkyl, substituted pyrrolidinium or piperidinium where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography, 7-oxabicyclo[4.1.0]hept-3-yl, optionally having 1 or 2 substituent selected from the group including the cabbage soup amino, (C1-6alkyl)amino and di(C1-6alkyl)amino, or a 5-8-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from the group comprising N and O and optionally having 1 to 3 substituents selected from the group comprising hydroxy, amino, oxo and C1-6alkyl;

R41represents hydrogen, C1-6alkyl, optionally substituted amino, C1-6alkylamino, di(C1-6alkyl)amino or 2.5-dioxopiperidin-1-yl, or5-8cycloalkyl, optional someseni hydroxy,

or

R40and R41together with the adjacent N atom may form a 5-8-membered saturated heterocyclic ring, optionally interrupted About;

R42is1-6alkylene, optionally substituted by hydroxy or carboxy, or5-8cycloalkyl, substituted by at least one hydroxy and, further, optional 1 or 2 substituents selected from the group comprising hydroxy, amino, oxo and C1-6alkyl,

or

R41and R42together with the adjacent N atom may form a 5-8-membered saturated heterocyclic ring optionally interrupted by NH or O, where the specified 5-8-membered saturated heterocyclic ring substituted by one or two exography,

provided that when R41is hydrogen, C1-6the alkyl, optional samewe the major amino, With1-6alkylamino or

di(C1-6alkyl)amino, R42is replacement With1-6alkylene or carboxyterminal1-6alkylene;

R43represents hydrogen, C1-6alkyl, optionally substituted by hydroxy or carboxy;

R44represents hydrogen or C1-6alkyl, optionally substituted by hydroxy or carboxy,

provided that when R41and R42together with the adjacent N atom form a 5-8-membered saturated heterocyclic ring, substituted with one or two exography, R44is replacement With1-6the alkyl or carboxyterminal1-6by alkyl;

R45, R47, R49and R50independently represent hydrogen or C1-6alkyl;

R46and R48independently represent1-6alkylene, optionally substituted by hydroxy or carboxy;

n is an integer from 1 to 3;

m is an integer from 0 to 3;

R51represents hydrogen, C1-6alkyl or 3-8-membered saturated ring, optionally interrupted by NH or O;

R52represents hydrogen, C1-6alkoxycarbonyl or1-6alkyl, substituted amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, N-(C1_6alkylsulfonyl)amino, N-(C1-6alkanoyl)amino, C1_6alkoxycarbonyl, tetrazolyl, triazolyl, indole is'neil, isoindoline, indolium, isoindolyl, pyrrolidinium or piperidinium where specified pyrrolidinyl and piperidinyl, optionally substituted with one or two exography,

provided that when R51and R52simultaneously are hydrogen, R3is tetrazolyl or1-6alkanoyl, or when R51is hydrogen or C1-6the alkyl, R52different from hydrogen;

R61and R62independently represent hydrogen or C1-6alkyl, optionally substituted hydroxy, carboxy, phenyl or by one, two or three Halogens;

R71represents hydrogen or C1-6alkyl, optionally substituted amino, hydroxy, carboxy, pyrrolidinium or piperidinium where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

R72represents hydrogen, carboxy, C1-6alkanoyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, N-(C1-6alkyl)aminocarbonyl,1-6alkyl, optionally substituted by hydroxy, carboxy or by one, two or three halogen, C1-6alkoxy, optionally substituted with one, two or three halogen, pyrrolidinyl or piperidinyl where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

Z1represents- (CH2 p-where p is an integer 1 or 2;

R81represents hydrogen, C1-6alkoxycarbonyl or1-6alkyl, optionally substituted by pyrrolidinyl or piperidinyl where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

R82represents hydrogen, hydroxy, carboxy or1-6alkyl, substituted hydroxy, amino or carboxy,

R83represents hydrogen, hydroxy, carboxy or1-6alkyl, substituted hydroxy, amino or carboxy,

provided that when R81is hydrogen, R82or R83other than hydrogen;

Z2represents- (CH2]q-where q is an integer from 0 to 3;

R91represents hydrogen or C1-6alkyl, optionally substituted by phenyl;

R111represents hydrogen, carboxy, C1-6alkoxycarbonyl,1-6alkanoyl, N-(C1-6alkyl)aminocarbonyl,1-6alkoxy, optionally substituted with one, two or three halogen, or C1-6alkyl, optionally substituted hydroxy, one, two or three halogen, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, N-(C1-6alkylsulfonyl)amino, N-(C1-6alkanoyl)amino, C1-6alkoxycarbonyl, tetrazolyl, triazolyl, indolinyl, isoindolyl, indolium, isoindolyl, pyrrole is nil or piperidinium, where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

ring a is a 3-8-membered saturated heterocyclic ring in which the nitrogen atom NAis the only heteroatom;

the ring is a 3-8-membered saturated heterocyclic ring in which the nitrogen atom NInis the only heteroatom;

ring and D ring together form a 7 to 15-membered diazabicyclo ring; and

ring E represents a 5-8-membered saturated heterocyclic ring in which the nitrogen atom NEis the only heteroatom.

Other preferred compounds of formula (I-b) include compounds in which:

R1represents fluorine, chlorine or bromine;

R2represents fluorine, chlorine or bromine;

R3represents cyano;

R4is

where

R40is1-6alkyl having Deputy selected from the group comprising 2-oxopyrrolidin-1-yl, 2,5-dioxopiperidin-1-yl, 2-oxopiperidin-1-yl, 2-oxopiperidin-3-yl, 4-oxopiperidin-1-yl, 2-oxopiperidin-6-yl, 2,5-dioxopiperidin-1-yl, 2,6-dioxopiperidin-1-yl, 2,6-dioxopiperidin-3-yl, piperidine-1-yl, -2-and is, -3-yl or-4-yl (where specified piperidine optionally substituted with one or two oxopropyl), hexahydroazepin-1-yl, -2-yl, -3-yl or-4-yl (where specified hexahydroazepin optionally substituted by one or two oxopropyl) and 7-oxabicyclo[4.1.0]hept-3-yl, optionally substituted amino;

R41represents hydrogen, cyclopentyl or1-6alkyl, optionally substituted amino, C1-6alkylamino, di(C1-6alkyl)amino or 2.5-dioxopiperidin-1-yl;

R42is1-4alkylene, substituted carboxy, or cyclohexyl substituted by one or two hydroxy,

or

R41and R42together with the adjacent N atom may form a 5-6-membered saturated heterocyclic ring,

R43represents hydrogen or C1-6alkyl, optionally substituted by hydroxy;

R44is1-6alkyl, optionally substituted by hydroxy or carboxy,

provided that when R41and R42together with the adjacent N atom form a 5-6-membered saturated heterocyclic ring, R44is replacement With1-6the alkyl or carboxyterminal1-6by alkyl;

R45, R47, R49and R50independently represent hydrogen, methyl or ethyl;

R46and R48independently represent1-6alkylene, optionally substituted guide is hydroxy or carboxy;

R51represents hydrogen, cyclopentyl, ethyl or methyl;

R52is methoxycarbonyl or1-6alkyl, substituted carboxy, amino, methoxycarbonyl, methanesulfonamido, acetamido, indolium, tetrazolyl, 1,2,3-triazolium, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2,5-dioxopiperidin-1-yl, 2-oxopiperidin-1-yl, 2-oxopiperidin-3-yl, 4-oxopiperidin-1-yl, 2-oxopiperidin-6-yl, 2,5-dioxopiperidin-1-yl, 2,6-dioxopiperidin-1-sludge or 2,6-dioxopiperidin-3-yl;

R61and R62independently represent benzyl or phenethyl;

R72represents hydrogen, carboxy, C1-6alkanoyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, N-(C1-6alkyl)aminocarbonyl,1-6alkyl, optionally substituted by hydroxy, carboxy or by one, two or three halogen, C1-6alkoxy, optionally substituted with one, two or three halogen, pyrrolidinyl or piperidinyl where these pyrrolidinyl and piperidinyl optionally substituted by one or two exography;

R81represents hydrogen, methoxycarbonyl or1-6alkyl, substituted 2-oxopyrrolidin-1-yl, 2,5-dioxopiperidin-1-yl, 2-oxopiperidin-1-yl, 2-oxopiperidin-3-yl, 4-oxopiperidin-1-yl, 2-oxopiperidin-6-yl, 2,5-dioxopiperidin the Jn-1-yl, 2,6-dioxopiperidin-1-yl or 2,6-dioxopiperidin-3-yl;

R82represents hydrogen, hydroxy or C1-6alkyl, substituted hydroxy,

R83represents hydrogen, hydroxy or carboxy,

provided that when R82or R83simultaneously are hydrogen, R81different from hydrogen, or when R81and R83simultaneously are hydrogen, R82different from hydrogen;

R91represents benzyl or phenethyl.

The preferred compounds of this invention are the following:

3-(1-benzyloxypropionic[3,4-b]pyrrole-5-sulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile;

N-{4-[5-cyano-2-(3,5-dichlorophenoxy)benzazolyl]piperazine-2-ylmethyl}methanesulfonamide;

N-{4-[5-cyano-2-(3,5-dichlorophenoxy)benzazolyl]piperazine-2-ylmethyl}ndimethylacetamide;

N-{1-[5-cyano-2-(3,5-dichlorophenoxy)benzazolyl]piperazine-2-ylmethyl}methanesulfonamide;

N-{1-[5-cyano-2-(3,5-dichlorophenoxy)benzazolyl]piperazine-2-ylmethyl}ndimethylacetamide;

4-(3,5-dichlorophenoxy)-3-[(3R)-(2-hydroxyethylamino)pyrrolidin-1-sulfonyl]benzonitrile;

the dihydrochloride of 3-(2-AMINOETHYLPIPERAZINE-1-sulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile;

methyl ester 1-[5-cyano-2-(3,5-dichlorophenoxy)benzazolyl]-[1,4]diazepan-2-carboxylic acid;

4-(3,5-dichlorophenoxy)-3-[(3S)-(1H-indol-3-ylmethyl)piperazine-1-sulfonyl]benzonitrile;

4-(3,5-dichlorophenoxy)-3-[(2S)-(1H-indol-3-ylmethyl)piperazine-1-sulfonyl]benzonitrile;

4-(3,5-dichlorophenoxy)-3-[2-(2,5-dioxopiperidin-1-ylmethyl)piperazine-1-sulfonyl]benzonitrile;

N-{1-[5-cyano-2-(3,5-dichlorophenoxy)benzazolyl]-[1,4]diazepan-2-ylmethyl}methanesulfonamide;

1-[4-(3,5-dichlorophenoxy)-3-(piperazine-1-sulfonyl)phenyl]Etalon;

(R)-N-(1-azabicyclo[2.2.2]Oct-3-yl)-5-cyano-2-(3,5-dichlorophenoxy)benzosulfimide;

(S)-N-(1-azabicyclo[2.2.2]Oct-3-yl)-5-cyano-2-(3,5-dichlorophenoxy)benzosulfimide;

4-(3,5-dichlorophenoxy)-3-{4-[(2S)-(1-hydroxy-1-methylethyl)pyrrolidin-1-yl]piperidine-1-sulfonyl}benzonitrile;

4-(3,5-dichlorophenoxy)-3-(3-tetrazol-2-iletileri-1-sulfonyl)benzonitrile;

4-(3,5-dichlorophenoxy)-3-(3-[1,2,4]triazole-2-iletileri-1-sulfonyl)benzonitrile;

4-(3,5-dichlorophenoxy)-3-(2-[1,2,4]triazole-1-iletileri-1-sulfonyl)benzonitrile;

5-cyano-2-(3,5-dichlorophenoxy)-N-(2-dimethylaminoethyl)-N-[2-(2,5-dioxopiperidin-1-yl)ethyl]benzosulfimide;

4-(3,5-dichlorophenoxy)-3-[3-(2,5-dioxopiperidin-1-ylmethyl)piperazine-1-sulfonyl]benzonitrile;

4-(3,5-dichlorophenoxy)-3-[3-(2,5-dioxopiperidin-1-ylmethyl)-4-pyrrolidin-1-reparacin-1-sulfonyl]benzonitrile;

4-(3,5-dichlorophenoxy)-3-{4-[(2S)-hydroxyethylpyrrolidine-1-yl]piperidine-1-sulfonyl}benzonitrile;

4-(3,5-dichlorophenoxy)-3-{(2S)-[(2S)-hydroxyethylpyrrolidine-1-yl]piperidine-1-sulfonyl}benzonitrile and

4-(3,5-dichlorophenoxy)-3-(piperidine-4-sulfonyl)benzonitrile,

and Tau is Mernie and stereoisomeric forms and their physiologically acceptable salts.

Alkyl by itself and "ALK"and "alkyl" in alkylene, alkenyl, quinil, alkoxy, alkanoyl, alkylamino, alkylaminocarbonyl, alkylaminocarbonyl, alkylsulfonyl, alkoxycarbonyl, alkoxycarbonyl, alkanolamine represents a linear or branched alkyl radical having generally 1 to 6, preferably 1-4, and particularly preferably 1-3 carbon atoms, where the illustrative and preferred examples include methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy illustrative and is preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentox and n-hexose.

Alkylamino illustrative and preferably is acylaminoalkyl having one or two (independently selected) alkyl substituent, illustratively and preferably includes methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamine, n-hexylamine, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamine and N-n-hexyl-N-methylamino.

Cycloalkyl itself and in cyclooctylamino, and cycloalkylcarbonyl is cycloalkyl group containing usually 3-8, preferably 5-7 carbon atoms, illustratively and preferably including cyclo is ropel, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Heterocyclyl itself and the heterocycle is mono - or polycyclic, preferably mono - or bicyclic, non-aromatic heterocyclic radical having usually 4-10, preferably, 5 to 8 atoms in the ring, and up to 3, preferably up to 2 heteroatoms and/or heterogroup selected from the group comprising N, O, S, SO and SO2. Heterocyclyl radicals can be saturated or partially unsaturated. Preference is given to a 5-8-membered monocyclic saturated heterocyclyl radicals having up to two heteroatoms selected from the group comprising O, N and S.

The embodiment of the present invention

The compound of formula (I) of this invention can be obtained, but is not limited to this, a combination of various known methods. In some embodiments, one or more substituents, such as amino group, carboxyl group and hydroxyl group of compounds used as a starting or intermediate compounds, appropriately protect protecting group known to specialists in this field of technology. Examples of protective groups described in “Protective Groups in Organic Synthesis (3rdEdition)” by Green and Wuts.

Compounds represented by the General formula (I-i), (I-ii) and (I-iii), the present invention can be obtained, but not the Ogre is nicely this, using the methods [A], [B] and [C]below, respectively.

Method [A]

In method [A] the compound of the formula (I-i) (X, R1and R2such as defined above, R3'similar R3defined above, or a protected R3and R4'similar R4defined above, or a protected R4) can be obtained by the following methods in three or four stages.

On stage a-1 compound of the formula (2) (where X, R1, R2and R3'such as defined above) can be obtained by the coupling of compounds of formula (1) (where L is a leaving group, for example, halogen (fluorine, chlorine, bromine or iodine), sulfonates (such as mesilate, tosylate or triflate); and the like) with the compound of the formula (4) (where X, R1and R2such as defined above)in a solvent.

Examples of the solvent include, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; NITRILES, such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-organic; sulfoxidov, such as dimethyl sulfoxide, and others. Optional, can be used two or more mixed RA the creators of the above.

The reaction temperature is usually, but not limited to, from about -10°C to 200°C, preferably from about 10°to 80°C. the Reaction is usually carried out for from 30 minutes to 48 hours, preferably from 1 hour to 24 hours.

The reaction is mainly carried out in the presence of a base. Examples of the base include alkali metal hydride such as sodium hydride or potassium hydride; an alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium; alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.

On stage A-2 compound of formula (3) (where X, R1, R2and R3'such as defined above) can be obtained by reduction of compounds of formula (2) (where X, R1, R2and R3'such as defined above) with chloride of tin or iron powder in the presence of acid (e.g. hydrochloric acid) in a solvent such as ethyl acetate, water and others.

The compound of the formula (3) (where X, R1, R2and R3'such as defined above) can also be obtained by hydrolysis of compounds of formula (2) (where X, R1/sup> , R2and R3'such as defined above).

On stage a-3 compound of formula (6) (where X, R1, R2and R3'such as defined above, and L' is a leaving group, for example, halogen (chlorine, fluorine, bromine or iodine); and the like) can be obtained from compounds of formula (3) (where X, R1, R2and R3'such as defined above) in two stages.

First, the compound of formula (3) (where X, R1, R2and R3'such as defined above) is treated with acid (e.g. hydrochloric acid) and sodium nitrite in a solvent (for example, water, acetic acid) at a temperature of from about -20°C. to 0°C.

Then the reaction mixture was added to a solution of sulfur dioxide in acid, such as acetic acid and the like.

Examples of solvents include, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; NITRILES, such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-organic; water and others. Optional, can be used two or more mixed solvents of the above.

The reaction temperature is usually, but not limited to, from about -10°C to 200°C, prepact the tion from about 0°C. to 30°C. The reaction is usually carried out for from 30 minutes to 48 hours, preferably from 1 hour to 24 hours.

The reaction can be carried out in the presence of a catalyst, including, for example, salts of copper, such as copper chloride and others.

On stage a-4 compound of formula (I-i) (where X, R1, R2, R3'and R4'such as defined above) can be obtained by the coupling of compounds of formula (6) (where X, L', R1, R2and R3'such as defined above) with the compound of the formula (5) (where R4'the same as defined above) according to the method described for stage a-1 [A] to obtain a compound (2).

The compound (I-i) may be further processed for removal of the protective group R3'or R4'.

The compound of formula (6) can also be obtained by the method of stages a-1' and a-3', using the original compound (1') (where L and R3'such as defined above).

On stage a-1' compound formula (2') (where X, R1, R2and R3'such as defined above) can be obtained from compounds of formula (1') (where L and R3'such as defined above) instead of the compound of formula (1) according to the method described for stage a-1 to obtain the compounds of formula (2) using the compounds of formula (4) (where X, R1and R2such as defined above).

On stage a-3' compound of the formula (6) (where X, L', R1, R2and R3'the same is, as defined above) can be obtained using the compounds of formula (2') (where X, R1, R2and R3'such as defined above) and a sulfonic acid halide (for example, chlorosulfonic acid). The reaction can be carried out without solvent or in a solvent including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-organic; sulfoxidov, such as dimethyl sulfoxide, and others. Optional, can be used two or more mixed solvents of the above.

The reaction temperature is usually, but not limited to, from about -10°C to 200°C, preferably from about 0°C to 170°C. the Reaction is usually carried out for from 30 minutes to 48 hours, preferably from 1 hour to 24 hours.

The compounds of formula(1), (1'), (4) and (5) are commercially available or can be obtained by conventional methods.

Method [B]

The compound of the formula (I-ii) (R1and R2such as defined above, R3'similar R3defined above, or a protected R3and R4'similar R4defined above, or protect the seal R 4) can be obtained by the following method in three stages.

On stage In-1 compound of the formula (8) (where L and R3'such as defined above, and Y is a C1-6the alkyl can be obtained by the interaction of the compounds of formula (7) (where Y and R3'such as defined above, and W is hydrogen, amino and the like) according to the method described for stages a-3 or a-3' [A] to obtain the compounds of formula (6).

In stage-2 compound of formula (9) (where R3'and R4'such as defined above) can be obtained from compounds of formula (8) in two stages; (stage-2) interaction with the N-R4'and (stage b-2-b) removing protection from alkoxygroup.

In stage-2-and the interaction of the compounds of formula (8) (where Y, L and R3'such as defined above) with the compound of the formula (5) (where R4'the same as defined above) can be carried out according to the method described for stage And 4 way As to obtain the compounds of formula (I-i).

At the stage B-2-b subsequent withdrawal of protection from alkoxygroup with obtaining the compounds of formula (9) (where R3'and R4'such as defined above) can be carried out by reaction with a Lewis acid, such as, for example, BBr3in the solvent, including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; and others. Optional, can be used is two or more mixed solvents of the above.

The reaction temperature is usually, but not limited to, from about -30°C to 200°C, preferably from about -10°C. to 80°C. the Reaction is usually carried out for from 30 minutes to 48 hours, preferably from 1 hour to 24 hours.

At stage 3, a compound of the formula (I-ii) (where R1, R2, R3'and R4'such as defined above) can be obtained by the coupling of compounds of formula (9) (where R3'and R4'such as defined above) with the compound of the formula (10) (where R1and R2such as defined above, and L is a leaving group, such as boranova acid, halogen atom, e.g. fluorine, chlorine, bromine or iodine).

The reaction can be carried out in a solvent including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-organic; sulfoxidov, such as dimethyl sulfoxide, and others. Optional, can be used two or more mixed solvents of the above.

The reaction temperature is usually, but not limited to, from about -10°C to 200°C, prefer the Ino from about 10°C. to 100°C. The reaction is usually carried out for from 30 minutes to 48 hours, preferably from 1 hour to 24 hours.

The reaction can be carried out in the presence of a catalyst, including, for example, salts of copper, such as copper acetate(II), palladium salt such as palladium(II) acetate, and others. The reaction can mainly be carried out in the presence of a base. Examples of the base include alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium; alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; carbonates such as cesium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.

The compound (I-ii) can be subjected to further processing for modification of R3'and R4'for example the removal of protection.

Compounds of the formulas (7) and (10) are commercially available or can be obtained by conventional methods.

Way [C]

Way [C] especially preferred when R4formula (I) is a ring E, as defined above, in this case, R4”formula (I-iii) is the E ring with the substituent R111the same as defined for R4or secure option.

The compound of the formula (I-iii) (where X, R1, R2, R3'and R4”such as defined above) can be obtained by the following method in two stages.

At stage s-1, the compound of formula (12) (where X, R1, R2, R3'and R4”such as defined above) can be obtained by the coupling of compounds of formula (11) (where X, R1, R2and R3'such as defined above) with the compound of the formula (13) (R4”such as defined above, and L is a leaving group such as defined above) using a base such as alkali metal carbonates (e.g. sodium carbonate, potassium carbonate and the like), triethylamine, potassium hydroxide, and others.

The reaction can be carried out in a solvent including, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-organic; sulfoxidov, such as dimethyl sulfoxide, and others. Optional, can be used two or more mixed solvents of the above.

The reaction temperature is usually, but not exhaust anichini this, from about -10°C to 200°C, preferably from about 10°C. to 100°C. the Reaction is usually carried out for from 30 minutes to 48 hours, preferably from 1 hour to 24 hours.

Stage C-2 compound of formula (I-iii) (where X, R1, R2, R3'and R4”such as defined above) can be obtained by treating compounds of formula (12) (where X, R1, R2, R3'and R4”such as defined above) in a suitable oxidation conditions, such as hydrogen peroxide, periodate sodium m-chloroperbenzoic acid (m-CPBA), potassium permanganate and other, in the presence or in the absence of a catalyst, such as catalytic trichloride ruthenium, in a solvent, including, for example, water, halogenated hydrocarbons such as methylene chloride, carbon tetrachloride, chlorobenzene, dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; NITRILES such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-organic; and others. Optional, can be used two or more mixed solvents of the above.

The reaction temperature is usually, but not limited to, from about -10°C to 200°C, preferably from about 10 the C to 50°C. The reaction is usually carried out for from 30 minutes to 48 hours, preferably from 1 hour to 20 hours.

The compound (I-iii) may be subjected to further processing to remove the protection with R3'or R4'.

Compounds of the formulas (11) and (13) are commercially available or can be obtained by conventional methods.

If the compounds of formula (I) or their salts are tautomeric isomers and/or stereoisomers (for example, geometric isomers and conformational isomers), each separated isomers and mixtures are also included in the scope of this invention.

If the compounds of formula (I) or their salts have an asymmetric carbon atom in the structure, their optically active compounds and racemic mixtures are also included in the scope of this invention.

Typical salts of the compounds of formula (I) include salts obtained by the interaction of the compounds of the present invention with a mineral or organic acids or organic or inorganic bases. Such salts are known as acid-additive and basically additive, respectively.

Acid forming acid additive salts include inorganic acids such as, but not limited to, sulfuric acid, phosphoric acid, hydrochloric acid, Hydrobromic acid, uudistoodetena acid and the like, and organic acids, such as, but is limited to, p-toluensulfonate acid, methanesulfonate acid, oxalic acid, p-bromophenylacetate acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.

Basically additive salts include salts derived from inorganic bases, such as, but not limited to, ammonium hydroxide, a hydroxide of an alkali metal, hydroxides of alkaline earth metal carbonates, bicarbonates and the like, and organic bases, such as, but not limited to, ethanolamine, triethylamine, Tris(hydroxymethyl)aminomethane and the like. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like.

The compound of this invention or its salt, depending on the substituents, may be modified to obtain a complex of the lower alilovic esters or other known esters; and/or hydrate or other solvate. Such ester, hydrate and solvate included in the scope of this invention.

The compound of this invention can be introduced in the form of oral forms, such as, but not limited to, conventional tablets and pills with intersolubility shell, capsules, pills, powders, granules, elixirs, tinctures, races the thieves, suspensions, syrups, solid and liquid aerosols and emulsions. They can also be introduced in the form of parenteral forms such as, but not limited to, intravenous, intraperitoneal, subcutaneous, intramuscular and other similar forms, well-known specialist in the field of pharmaceutics. The compounds of this invention can be introduced in the form of intranasal form via topical use of suitable intranasal carriers or by percutaneous, with the use of delivery systems through the skin, a well-known specialist in this field.

The dosage of the compounds of the present invention selects a specialist in this field, taking into account various factors such as, but not limited to, age, weight, sex and health status of the patient, the severity treat the condition, the route of administration, the levels of metabolic and excretory functions of the patient, the applied dosage forms, certain of the applied compound or salt.

The compounds of this invention preferably before the introduction is mixed with one or more pharmaceutically acceptable excipients. Excipients are inert substances, such as, but not limited to, carriers, diluents, flavoring agents, sweeteners, lubricants, soljubilizatory, suspendresume agents, binding agents, dezintegriruetsja agents for the of Ableton and the encapsulating material.

Another option of the present invention is a pharmaceutical composition comprising a compound of this invention and one or more pharmaceutically acceptable excipients that are compatible with other ingredients of the composition and do not have negative effects on the patient. The pharmaceutical compositions of the present invention is produced by combining a therapeutically effective amount of the compounds of this invention with one or more pharmaceutically acceptable excipients. Upon receipt of the compositions of the present invention the active ingredient may be mixed with a diluent, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. The filler may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a carrier, or may be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% wt. active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and powders in a sterile package.

For oral administration the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable carrier such as, but not about rancevas them lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methylcellulose and the like; optionally may be combined with dezinfeciruyuhimi agents such as, but not limited to, corn starch, starch, methylcellulose, agar, bentonite, xanthan gum, alginic acid and the like; and, optionally, with a binder agents such as, but not limited to, gelatin, gum Arabic, natural sugars, beta-lactose, corn sweeteners, natural and synthetic resins, gum Arabic, tragakant, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like; and, optionally, with lubricants, such as, but not limited to, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc and the like.

Carriers for powders can be a finely ground solids in a mixture with finely ground active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired, to obtain tablets. The powders and tablets preferably contain from about 1 to about 99% wt. the active ingredient, which is a new composition of this image is to be placed. Suitable solid carriers include carboxymethyl cellulose magnesium, waxes with low melting point and coconut oil.

Sterile liquid compositions include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of sterile water and sterile organic solvent.

The active ingredient may be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be obtained by dispersing finely ground active ingredient in aqueous starch or carboxymethylcellulose sodium, or in a suitable oil.

The composition can be in the form of a single dosage form, which is a physically discrete unit containing one dose suitable for administration to a human or other mammal. The unit dosage form can be a capsule or tablet, or the number of capsules or tablets. A "unit dose" is a predetermined amount of the active compounds of the present invention calculated to produce the desired therapeutic effect, in combination with one or more excipients. The amount of active ingredient in a unit dose which can vary from about 0.1 to about 1000 milligrams or more, depending on the specific treatment.

A typical oral dose of the present invention used to obtain the specified action, be from about 0.01 mg/kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, more preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. When administered parenterally, is the preferred proven doses for administration are from about 0.001 to 100 mg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The compounds of this invention can be typed in a single daily dose, or the total daily dose may be entered in divided doses of two, three or more times a day. If the introduction occurs with the use of percutaneous forms, it is, of course, is continuous.

EXAMPLES

Below is a detailed description of the present invention using examples, which should not be construed as limiting the scope of the invention.

In the following examples, all data, unless otherwise stated, refer to mass percent.

1H NMR spectrum recorded using any of the spectrometer Bruker DRX-300 (300 MHz for1N) in CDCl3. Chemical shifts are presented in ppm (ppm) with tetramethylsilane was (TMS) as internal standard at zero ppm Constant interaction(J) are given in Hertz, and abbreviations s, d, t, sq, m and user. means singlet, doublet, triplet, Quartet, multiplet, and broad, respectively. Data mass spectroscopy recorded on a FINNIGAN MAT 95. TLC is performed on pre-coated silica gel plate (Merck silica gel 60 F-245). Silica gel (WAKO-gel C-2000 (75-150 μm)) is used for all separations column chromatography. Z in the table means the decomposition.

All chemicals are reactive degree of purity and purchased from Sigma-Aldrich, Wako pure chemical industries, Ltd., Tokyo kasei kogyo Co., Ltd., Nacalai tesque, Inc., Watanabe Chemical Ind. Ltd., Maybridge plc, Lancaster Synthesis Ltd., Merck KgaA, Kanto Chemical Co., Ltd.

The effect of the compounds of this invention were tested using the following assays and pharmacological tests.

[Determination of IC50 values for compounds in the analysis of receptor binding]

(1) Cells

Use human CCR3-transformed cells C. Cloned CCR3 cDNA construct with rdnc vector and transferout the cell line K. Human SK-transformed cells C incubated in RPMI-1640 (cat. No. 22400-089, Life Technologies) supplemented with 10% FSC (cat. No. a-1115-L, Hyclone), 55 μm 2-mercaptoethanol (cat. No. 21985-023, Life Technologies), 1 mm sodium pyruvate (cat. No. 11360-070, Life Technologies), 100 units/ml penicillin G and 100 μg/ml streptomycin (cat. No. 15140-122, Life Technologies) and 0.4 mg/ml Geneticin (cat. No. 10131-035, Life Technologies) (hereinafter designated as "culture medium"). Before the scarlet studies on receptor binding, the cells were pre-treated with 5 mm sodium butyrate culture medium (cat. No. 193-01522, Wako) (2×105cells/ml) for 20-24 hours to increase expression of CCR3.

(2) Analysis of receptor binding

Pre-treated with butyrate cells, suspended in binding buffer (25 mm HEPES pH of 7.6, 1 mm CaCl2, 5 mm MgCl2, 0,5% BSA, 0,1% NaN3) at a density of cells 2×106cells/ml, add 60 ál/well in 96-well round-bottom polypropylene tablet (cat. No. 3365, Costar). Compounds diluted binding buffer (concentration 4 times higher than the final concentration), add 30 ál/well polypropylene plate. [125I]-labeled human eotaxin (cat. No. IM290, Amersham Pharmacia Biotech)diluted binding buffer at a concentration of 0.2 nm (final concentration, 0.1 nm)add 30 ál/well polypropylene plate. Mixture for binding assays in the total number of 120 µl/well (60 μl/well of cell suspension, 30 ál/well of a solution of the compound and 30 ál/well of [125I]-labeled eotaxin) incubated in polypropylene tablet for 1 hour at room temperature after incubation 100 μl/well of the reaction mixture is transferred to a filter tablet (cat. No. MAFB-N0B, Millipore) and washed with wash buffer (25 mm HEPES pH of 7.6, 1 mm CaCl2, 5 mm MgCl2, 0,5% BSA, 0,1% NaN3, 0.5m NaCl) twice. 96-well filter tablet pre is sustained fashion is treated with 100 μl/well 0.5% polyethylenimine (cat. No. p-3143, Sigma) for 2-4 hours at room temperature and washed twice with wash buffer before use. Nonspecific binding is determined by parallel incubation in the presence of 500 nm is not labeled eotaxin (cat. No. 23209, Genzyme Techne). The radioactivity remaining on the filter is measured by liquid scintillation counter (TopCount™, Packard) after addition of 45 μl/well of scintillant (Microscint20, cat. No. 6013621, Packard). The percentage of inhibition for each concentration of the compound calculated and IC50 values determined on the basis of the inhibition curve.

[Determination of IC50 values of compounds in the analysis of the mobilization of calcium]

(1) Cells

Use human CCR3-transformed cells C. Human R3-transformed cells C incubated in RPMI-1640 with the addition of 10% FSC, 55 μm 2-mercaptoethanol (cat. No. 21985-023, Life Technologies), 1 mm sodium pyruvate, 100 units/ml penicillin G and 100 μg/ml streptomycin, and 0.4 mg/ml Geneticin. Prior to analyzing the mobilization of calcium, the cells were pre-treated with 5 mm sodium butyrate culture medium (2×105cells/ml) for 20-24 hours to increase expression of CCR3.

(2) analysis of the mobilization of calcium

Pre-treated with butyrate cell load Fluo-3AM (cat. No. F-1242, Molecular Probes) in loading buffer (solution Hank, the cat. No. 05906 Nissui, 20 mm HEPES pH 7, 0,12% BSA, 1 mm probenecid, cat. No. p-8761, Sigma, 1 mm Fluo-3AM, 0,01% pluronic F-127, cat. No. p-6866, Molecular Probes) at a density of cells 1×107cells/ml the cells are Then washed with buffer for analysis calcium (solution Hank, the cat. No. 05906 Nissui, 20 mm HEPES pH of 7.6, with 0.1% BSA, 1 mm probenecid, cat. No. P-8761, Sigma). Cell suspension (3,3×106cells/ml) add 60 μl/well in 96-well black plate with clear bottom (cat. No. 3904, Costar). The compounds, dissolved (concentration 5 times the final concentration) buffer for analysis of calcium is added in the amount of 20 μl/well in the tablet for 10 minutes before analysis. Human recombinant eotaxin, diluted with buffer for analysis of calcium at a concentration of 50 nm (final concentration; 10 nm), add in polypropylene tablet (cat. No. 3365, Costar). Mobilization of calcium in the cytoplasm was measured using FDSS-6000 or SS-3000 (Hamamatsu Photonics) within 60 seconds after stimulation 10 nm eotaxin. Calculate the percentage of inhibition for each concentration of the compound and the IC50 values determined on the basis of the inhibition curve.

[Determination of IC50 values of compounds in the analysis of chemotaxis]

(1) Cells

Use human CCR3-transformed cells L1.2. Human CCR3-expressing L1.2 stable transformant set by electroporation according to the methods described in J. Exp. Med. 183:2437-2448, 1996. People the human SK-transformed L1.2 cells incubated in RPMI-1640 with the addition of 10% FSC, 100 units/ml penicillin G and 100 μg/ml streptomycin, and 0.4 mg/ml Geneticin. One day before the beginning of the analysis of chemotaxis of cells pre-treated with 5 mm sodium butyrate culture medium (5×105cells/ml) for 20-24 hours to increase expression of CCR3.

(2) Analysis of chemotaxis

Pre-treated with butyrate cells suspended in buffer for chemotaxis (solution Hank, the cat. No. 05906 Nissui, 20 mm HEPES pH of 7.6, 0.1% human serum albumin, cat no A-1887, Sigma) at a density of cells of 1.1×107cells/ml of a Mixture of 90 ál of cell suspension and 10 μl of a solution of the compound dissolved with buffer to chemotaxis (concentration 10 times greater than the end), pre-incubated for 10 minutes at 37°C. the Mixture of cells and connections added to the upper chamber of a 24-cell camera for chemotaxis (Transwell™, cat. No. 3421, Costar, pore size 5 μm). 0.5 ml of a 10 nm solution of human recombinant eotaxin (cat. No. 23209, Ganzyme Techne), diluted with buffer for chemotaxis, add in the lower chamber of the tablet for chemotaxis. Then spend chemotaxis in CO2incubator at 37°C for 4 hours. After incubation for 4 hours, migrated cells counted using a FACScan (Becton Dickinson). Calculate the percentage of inhibition for each concentration of the compound and the IC50 values of Radelet, on the basis of the inhibition curve.

[Test selectivity]

Test the selectivity is carried out in the framework of the analysis of the mobilization of calcium and analysis of receptor binding using CCR1, CCR2, CCR4, CCR5, CCR7, CCR8, CXCR1 and PAR-1 receptor activation peptidases) stable transformants. Testing methods are the same as for CCR3. The only difference is the use of a variety of stable transformants in these tests selectivity.

[Determination of IC50 values of compounds in the analysis of chemotaxis using human eosinophils]

Human eosinophils purified from peripheral blood. Twenty-five ml of heparinized blood gently rasclaat in 15 ml of Mono-Poly Resolving Medium (No. 16-980-49DN, ICN Biomedicals Co. Ltd, Japan) in 50 ml test tube (No. 2335-050, Iwaki, Japan) and then centrifuged at 400g for 20 min at room temperature. After centrifugation, the red blood cells are removed by hypotonic lysis. Sediment polymorphically leukocytes incubated with anti-human CD16 Microbeads (No. 130-045-701, Milteynyi Biotec GmbH, Germany) for 30 min at 4°C. After washing the cells, magnetically-labeled neutrophils is reduced by treating the cell suspension on BS columns (No. 130-041-304, Milteynyi Biotec GmbH, Germany)attached to a VarioMACS (No. 130-090-282, Milteynyi Biotec GmbH, Germany).

Analysis of chemotaxis using the obtained eosinophils Prov is car Ried out according to the same Protocol, which is used for CCR3 stable transformants, L1.2 cells.

[Model of chronic asthma in primates: report]

Materials and methods: The animals used in the study represent a wild adult male monkeys, cynomolgus (Macaca fascicularis), weight of from 4.0 to 9.0 kg (Charles River BRF, Inc.). All study animals have natural respiratory sensitivity to inhaled extractAscaris suum. Animals are contained separately in rooms with environment control in cells with open grate and give twice a day food and waterad libitum. Each animal was fasted for approximately 12 hours before the day of the start of the study. For each study animal anaesthetize hydrochloride ketamine (7 mg/kg, V.M. Ketaset, Fort Dodge, IA;) and xylazine (1.2 mg/kg, V.M., Bayer Corp., Elkart, IN), incubated endotracheal tube with cuff (5.0 mm inner diameter, Mallinckrodt Critical Care, Glen Falls, NY) and seated in a specially designed supporting chair. To maintain anesthesia, if necessary, apply ketamine (5 mg/kg, VM).

The study Protocol: The reaction of the respiratory tract (AR) on inhaled methacrolein followed bronchoalveolar lavage (BAL) to assess the cellular composition of the respiratory tract (ACC) define 3 days before (day 0) and 3 days after (day 10) three alternating inhalati the (days 3, 5, 7) extract ofAscaris suum. Animals allow to rest for 6 to 8 weeks between studies for the reaction of the Airways and inflammation returned to the original (before-antigen) levels. Studies using drugs combine with studies using control substances in order to ensure that any changes in the sensitivity of antigen does not occur within the time.

Test compounds, dissolved in a mixture of ethanol:PEG:water (10:50:40./vol.), enter under light anesthesia.

The system of delivery of aerosol and inhalation type antigenic stimulus: Aerosol inhalation type antigenic stimulus injected with periodic breathing at a positive pressure with the use of a respirator Bird Mark 7A and microasperities (model 8158). Each inhalation consists of 30 breaths (maximum inspiratory pressure=20 cm H2About). Extract ofAscaris suum(Greeg Laboratories, Lenoir, NC) diluted PBS to a final threshold concentration, predefined for each animal, and is administered in aerosol form (particle size <2 μm). Metafolin (Sigma Chemical Co, St. Louis, Missouri) was dissolved in PBS with a concentration of 100 mg/ml and serial dilutions 30, 10, 3, 1, 0.3 and 0.1 mg/ml consistently prepared for spraying.

Measure the resistance of the respiratory system (Rrs) : Animal is attached to a Harvard Ventilator (Harvard Apparatus, S. Natick, MA) through the endotracheal tube and ventilated with a speed of 30 to 35 breaths per minute. The air flow is measured by Fleish (Hans Rudolph) pneumotachograph, and thoracic pressure is measured by transducer pressure alidina (as the difference between the pressure in the peripheral end of the endotracheal tube and room pressure). Pneumotachograph and validin connected to pre-amplifier and then to MI2the breath analyzer (Malvern, PA). Using primary signals of flow and pressure, the analyzer calculates the resistance of the Airways and the coefficient of compliance (as well as many other respiration parameters).

Definition of response to dose methacholine: To evaluate the response of the Airways to inhaled metacholine build curves depending on the cumulative dose by introducing higher concentrations of methacholine up until Rrs not going from 100 to 200%. Before the first dose of metacholine a dose of media as a control. Changes Rrs measured continuously for 10 minutes after entering the aerosol. Enter aerosol share a 5-10 minute breaks or up until Rrs not going back to the original levels.

The determination of the values of PC100: Resistance obtained for PBS, accept for zero. The percentage of increase in resistance above n the La for each dose of methacholine injected into the computer, and the program uses an algorithm to determine the exact concentration of methacholine, which causes an increase in resistance by 100% compared to baseline levels (RS100). Differences (day 10-day 0) values RS100calculated as the logarithm (base 10) to normalize the data and calculations for large variations in absolute values for RS100for different animals.

Bronchoalveolar lavage: After determining the response to dose methacholine each monkey was placed in position on the back, and fiber-optic bronchoscope (Olympus Optical, model 3C-10, Lake Success, NY) performed under the keel and include in the fifth-seventh generation bronchi. Only 15 ml of physiological solution with bicarbonate buffer (pH 7.4) pour in and gently sucked off through the channel in the bronchoscope. Collected samples immediately centrifuged at 2000 rpm for 10 minutes at 4°C. the precipitate after centrifugation, re-suspended in not containing Ca++ and Mg++ balanced saline solution, Hank. In order to avoid possible effects of treatments BAL cellular composition of the lung, BAL conduct alternately on the right and left lung. The total number of white cells per milliliter of BAL fluid was determined by Coulter counter (Coulter Corp., Miami, FL). The composition of BAL cells was determined by counting at least 200 cells from labeled PR the preparations of cytospin Wright.

Blood samples: Blood samples collected before and after 30 minutes, 1 hour and 2 hours after the first dose of the test compounds (the morning of the 2nd day) immediately prior to each subsequent dose after 30 minutes, 1 hour and 2 hours after the final dose (evening of the 9th day). Blood taken from the femoral vein in EDTA, centrifuged at 1500 rpm for 15 minutes at 4°C and the plasma stored at -70°C prior to the study tested compounds.

Statistical analysis: All data is evaluated statistically with the use of checks by student's criterion, where p value <0.05 is considered statistically significant.

The results of the analysis of receptor binding (RBA), analysis of the mobilization of Ca2+(Ca2+shown in the examples and the tables of the examples presented below. Data correspond to the compounds obtained by solid-phase synthesis, and thus, the purity levels range from 40 to 90%. For practical reasons, the compounds are grouped in three classes of activity as follows:

IC50=And 100nm<500 nm<

The compounds of this invention also show a more than 100-fold selectivity with respect to CCR1, CCR5, CCR7, CCR8 and CXCR1 in the analysis of receptor binding.

The compounds of this invention show a dose-dependent inhibitory effect on the evoked eotaxin the m chemotaxis of human eosinophils and strong activity in assays in vivo.

Methods of obtaining the source connections

[Original connection]

5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl

(1) To a mixture of 4-chloro-3-nitrobenzonitrile (24,0 g, 131 mmol) and 3,5-dichlorphenol (32,0 g, 197 mmol) in dry THF (150 ml) was added in several portions NaH (6,84 g, 171 mmol) and the mixture refluxed for 1 hour. After cooling to room temperature the solvent is evaporated and 100 ml of ice water and 20 ml of 4 n aq. NaOH added to the residue. The precipitate is collected by filtration, washed with 0.5 n aq. NaOH and water, dried in vacuum to obtain 5-cyano-2-(3,5-dichlorophenoxy)nitrobenzene (40,0 g, 98.4 per cent) in the form of a slightly yellow solid.

(2) a Mixture of 5-cyano-2-(3,5-dichlorophenoxy)nitrobenzene (4,08 g, 13,20 mmol) and chloride dihydrate tin(II) (17,87 g, 79,20 mmol) in EtOAc (200 ml) is heated at the boil under reflux for 2 hours. After cooling to room temperature the reaction mixture was poured into saturated aqueous NaHCO3. The mixture is extracted with EtOAc. The extract is washed with saturated salt solution and dried over MgSO4. The solvent is evaporated in vacuo to obtain 5-cyano-2-(3,5-dichlorophenoxy)aniline (3,53 g, 95,8%).

(3) 5-cyano-2-(3,5-dichlorophenoxy)aniline (3,53 g, 12,65 mmol) dissolved in a mixture of conc. aq. HCl (6,33 ml) and HOAc (2,53 ml). The solution is cooled to a temperature of 0°C and added dropwise on billaut sodium nitrite (0.96 g, a 13.9 mmol) in water (1,27 ml) under stirring. After 30 minutes the reaction mixture was added dropwise suspended in a mixture of CuCl (0,63 g, 6,32 mmol) in a saturated solution of SO2in HOAc (25,3 ml) at 5°C. the Reaction mixture is stirred for 30 minutes at a temperature of 10°C and poured into water. The resulting mixture was extracted with EtOAc. The extract was washed with saturated aqueous NaHCO3saturated salt solution and dried over MgSO4. The solvent is evaporated in vacuo to obtain 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylacetate in the form of a brown powder (4,45 g, 97%): HPLC-MS (ESI): calculated for C13H6Cl3NO3S [M+H]+362, found: 362.

Example 1-1

N-(R)-(+)-(1-azabicyclo[2.2.2]Oct-3-yl)-5-cyano-2-(3,5-dichlorophenoxy)benzosulfimide

To a suspension of (R)-(+)-3-aminoquinuclidine 2HCl (2,87 g, 14.4 mmol) in dry CH2Cl2(25 ml) was added Et3N (5,88 ml, 42.0 mmol). The mixture is stirred for 2 hours at room temperature followed by the addition dropwise of a solution of 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylacetate (90%, 4.83 g, 12 mmol) in dry CH2Cl2(10 ml). After stirring for 5 hours at room temperature add CH2Cl2(160 ml), the mixture is washed with water, saturated aqueous Na2CO3saturated salt solution and dried n the l MgSO 4. The solvent is evaporated and the product recrystallized from a mixture of EtOAc and hexane to obtain N-(R)-(+)-(1-azabicyclo[2.2.2]Oct-3-yl)-5-cyano-2-(3,5-dichlorophenoxy)benzosulfimide (4,30 g, 79,2%) as a white solid.

1H NMR (300 MHz, CDCl3): 1,46-to 1.59 (2H, m), 1,68-1,72 (1H, m), 1,86-of 1.88 (2H, m), 2,69-2,99(6H, m), 3,20 of 3.28 (1H, m), 3.46 in-3,51 (1H, m), 7,00 (1H, d, J=8,67 Hz),? 7.04 baby mortality (2H, s), 7,32 (1H, t, J=1.7 Hz), 7,79 (1H, DD, J=8,64, 2,07 Hz), 8,31 (1H, d, J=2,07 Hz); HPLC-MS (ESI): Calculated for C20H19With12N3O3S [M+H]+452, found: 452.

Molecular weight: 452,36

Melting point: 215-220°C (decomposition)

The level of activity of CCR3:

The level of activity IC50: And

Example 1-2

5-cyano-2-(3,5-dichlorophenoxy)-N-(2-dimethylaminoethyl)-N-[2-(2,5-dioxopiperidin-1-yl)ethyl]benzosulfimide

(1) 5-cyano-2-(3,5-dichlorophenoxy)-N-(2-dimethylaminoethyl)benzosulfimide

To a solution of N1N1-dimethylated-1, 2-diamine (74,0 mg, 0.84 mmol) and Et3N in dry CH2Cl2(3 ml) added dropwise a solution of 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylacetate (90%, 282 mg, 0.7 mmol) in dry CH2Cl2(6 ml). The resulting solution was stirred at room temperature for 1 hour. Add CH2Cl2(60 ml), the mixture is washed with water, saturated salt solution and dried over MgSO4. The solvent is evaporated and the headed the remainder of the purified column chromatography (CH 2Cl2/CH3OH=10:1) to give 5-cyano-2-(3,5-dichlorophenoxy)-N-(2-dimethylaminoethyl)benzosulfimide (220 mg, 75,9%): HPLC-MS (ESI): calculated for C19H21Cl2N3O4S [M+H]+414, found: 414.

(2) 1-(2-bromacil)pyrrolidin-2,5-dione

To a mixture of dihydrofuran-2,5-dione (396 mg, 4.00 mmol) and 1,2-dibromethane (1.50 g, 8,00 mmol) in CH3CN (20 ml) add K2CO3(829 mg, 6,00 mmol) at room temperature. The mixture is stirred at the boiling point under reflux overnight and the solvent is evaporated. The mixture is diluted with EtOAc (150 ml), washed with water, saturated aqueous Na2CO3saturated salt solution and dried over MgSO4. The solvent is evaporated to obtain 1-(2-bromacil)pyrrolidin-2,5-dione, which is used in the next stage without further purification (580 mg, 70,4%).

(3) 5-cyano-2-(3,5-dichlorophenoxy)-N-(2-dimethylaminoethyl)-N-[2-(2,5-dioxopiperidin-1-yl)ethyl]benzosulfimide

To a solution of 5-cyano-2-(3,5-dichlorophenoxy)-N-(2-dimethylaminoethyl)benzosulfimide (41,4 mg, 0.1 mmol) in dry DMF (2 ml) was added 1-(2-bromacil)pyrrolidin-2,5-dione (30.9 mg, 0.15 mmol) and NaH (60%, 6,00 mg, 0.15 mmol). The mixture is stirred for 8 hours at 90°C. After cooling to room temperature the solvent is evaporated. A mixture of razbam Aut EtOAc (60 ml), washed with saturated salt solution and dried over MgSO4. The solvent is evaporated, the residue is purified preparative TLC (CH2Cl2/CH3OH=20/1) to give 5-cyano-2-(3,5-dichlorophenoxy)-N-(2-dimethylaminoethyl)-N-[2-(2,5-dioxopiperidin-1-yl)ethyl]benzosulfimide (44 mg, 81.6 per cent)and the free base is converted into the HCl salt using 4 N. HCl in dioxane.

1H NMR (300 MHz, CDCl3): δ was 2.76 (4H,s), 2,85 (6H, s), of 3.56 (4H, users), 3,74-of 3.80 (2H, m), of 3.94 (2H, users), 7,01 (1H, d, J=8,64 Hz), to 7.09 (2H, s), 7,33 (1H, s), 7,81 (1H, d, J=8,64 Hz), 8,21 (1H, s); HPLC-MS (ESI): Calculated for C23H24Cl2N4O5S.HCl [M+H]+539, found: 539.

Molecular weight: 575,90

Melting point:

The level of activity of CCR3:

The level of activity IC50: And

Example 1-3

4-(3,5-dichlorophenoxy)-3-[(3S)-(1H-indol-3-ylmethyl)piperazine-1-sulfonyl]benzonitrile

(1) ethyl ester [(2S)-benzyloxycarbonylamino-3-(1H-indol-3-yl)propionamido]acetic acid

To a mixture of (2S)-benzyloxycarbonylamino-3-(1H-indol-3-yl)propionic acid (4,16 g, 12.3 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.83 g, of 14.8 mmol), 1-hydroxybenzotriazole (1,99 g of 14.8 mmol) and Et3N (5,14 ml, 36,9 mmol) in dry THF (20 ml) was added in several portions of ethyl ester hydrochloride aminouksusnoy acid (1,72 g, 12.3 mmol). The reaction mixture per mesilat for 3 days at room temperature. The organic solvent is evaporated in vacuum and the residue diluted with EtOAc. The organic layer is washed with 0.5 N. HCl, saturated aqueous NaHCO3saturated salt solution and dried over MgSO4. The organic layer is concentrated to obtain ethyl ester [(2S)-benzyloxycarbonylamino-3-(1H-indol-3-yl)propionamido]acetic acid (5.10 g, 97,9%) as a yellow sticky oil: HPLC-MS (ESI): calculated for C23H25N3O5[M+H]+424, found: 424.

(2) ethyl ester of [(2S)-amino-3-(1H-indol-3-yl)propionamido]acetic acid

To a suspension of 10% Pd/C (0.50 g) in dry Meon (70 ml) add a solution of ethyl ester [(2S)-benzyloxycarbonylamino-3-(1H-indol-3-yl)propionamido]acetic acid (5.10 g, 17.6 mmol) in dry Meon (30 ml). The reaction mixture is stirred under 1 ATM of H2in hydrogenator for 1 day at room temperature. After removal of all particles through the layer of cellica the filtrate was concentrated in vacuo to obtain ethyl ester [(2S)-amino-3-(1H-indol-3-yl)propionamido]acetic acid (2,36 g of 91.6%) in the form of oil: HPLC-MS (ESI): calculated for C15H19N3O3[M+H]+290, found: 290.

(3) (3S)-(1H-indol-3-ylmethyl)piperazine-2,5-dione

A solution of ethyl ester [(2S)-amino-3-(1H-indol-3-yl)propionamido]acetic acid (3.25 g, 11.2 mm is l) and Et 3N in dry Meon heated at the boil under reflux overnight. The obtained white precipitate collected and dried to obtain (3S)-(1H-indol-3-ylmethyl)piperazine-2,5-dione (1.80 g, 65,9%): HPLC-MS (ESI): calculated for C13H13N3O2[M+H]+244, found: 244.

(4) 3-(piperazine-(2S)-ylmethyl)-1H-indole

To a suspension of lithium aluminum hydride (0,19 g, 5.08 mmol) in dry THF (10 ml) added dropwise a solution of (3S)-(1H-indol-3-ylmethyl)piperazine-2,5-dione (0,30 g of 1.23 mmol) in THF (10 ml). The reaction mixture is stirred at a temperature of 75°C. overnight, cooled to room temperature, to the mixture successively added to 0.19 ml of water, to 0.19 ml 4 N. aqueous NaOH and of 0.58 ml of water at 0°C. the Obtained white precipitate is filtered over a layer of celite and the filtrate was concentrated in vacuo to obtain 3-(piperazine-(2S)-ylmethyl)-1H-indole (0.26 g, quantitative) as a yellow oil: HPLC-MS (ESI): calculated for C13H17N3[M+H]+216, found: 216.

(5) 4-(3,5-dichlorophenoxy)-3-[(3S)-(1H-indol-3-ylmethyl)piperazine-1-sulfonyl]benzonitrile

To a solution of 3-(piperazine-(2S)-ylmethyl)-1H-indole (33,0 mg, 0.15 mmol) and diisopropylethylamine (of 0.08 ml, 0.46 mmol) in dry THF (2 ml) was added in several portions of 5-cyano-2-(3,5-dichlorophenoxy)benzosulphochloride (50.0 mg, 0.14 mmol). The reaction mixture p is remediat for 2 hours at room temperature. The solvent is evaporated in vacuum. The residue is purified preparative TLC (CH2Cl2/Meon=10/1) twice to obtain 4-(3,5-dichlorophenoxy)-3-[(3S)-(1H-indol-3-ylmethyl)piperazine-1-sulfonyl]benzonitrile (6,20 mg, 7,5%) as a white solid.

1H NMR (300 MHz, CDCl3): δ 2,56-3,07 (7H, m), 3,71 of 3.75 (1H, d, J=10,9 Hz), 3,83-3,86 (1H, d, J=11,1 Hz), 6,98 (2H, d, J=1.7 Hz),? 7.04 baby mortality-7,05 (1H, d, J=2.3 Hz), 7,10-to 7.15 (1H, t, J=7.0 Hz), 7,20-of 7.25 (1H, t, J=7.0 Hz), 7,28-7,29 (1H, t, J=1.9 Hz), 7,37-7,40 (1H, d, J=7.9 Hz), 7,55-7,58 (1H, d, J=7.5 Hz), 7,75 for 7.78 (1H, DD, J=2,1, to 8.7 Hz), of 8.09 (1H, usher.), 8,28-8,29 (1H, d, J=2.1 Hz); HPLC-MS (ESI): Calculated for C26H22C12N4About3S [M+H]+541, found: 541.

Molecular weight: 541,46

Melting point: 128-129°C

The level of activity of CCR3:

The level of activity IC50: And

Example 1-4

The hydrochloride of 4-(3,5-dichlorophenoxy)-3-{[2-(1H-1,2,4-triazole-1-ylmethyl)-1-piperazinil]sulfonyl}benzonitrile

(1) Methyl ether 1,4-dibenzylpiperazine-2-carboxylic acid

To the preheated solution (50°C) methyl ester of 2,3-dibromopropionate acid in toluene (40 ml) and Et3N (5,80 ml of 41.6 mmol) added dropwise N,N'-dibenzylidene-1,2-diamine (4,90 ml of 20.8 mmol). The obtained white suspension is heated at the boil under reflux to obtain a clear solution and the solution is stirred at the boil under reflux the night. After cooling to room temperature the reaction mixture is extracted with 2 N. HCl (500 ml) and the extract is neutralized 4 N. NaOH. The aqueous layer was extracted with EtOAc three times. The organic layer was washed with saturated salt solution, dried over MgSO4and concentrated to obtain methyl ether 1,4-dibenzylpiperazine-2-carboxylic acid (5.73 g, 84,8%) as a colorless oil: HPLC-MS (ESI): calculated for C20H24N2O2[M+H]+325, found: 325.

(2) (1,4-dibenzylpiperazine-2-yl)methanol

To a suspension of lithium aluminum hydride (1.54 g, to 40.6 mmol) added in several portions methyl ether 1,4-dibenzylpiperazine-2-carboxylic acid (3.00 g, a 9.25 mmol) at room temperature. The reaction mixture is stirred at the boil under reflux for 3 hours. After cooling to a temperature of 0°C. to the mixture successively added 1.5 ml of water, 1.5 ml 4 N. aqueous NaOH and 4.5 ml of water. The mixture is stirred for 1 hour and the white precipitate is filtered over a layer of celite. The filtrate was concentrated in vacuo to obtain (1,4-dibenzylpiperazine-2-yl)methanol (2,74 g, quantitative) as a yellow oil: HPLC-MS (ESI): calculated for C19H24N2O [M+H]+297, found: 297.

(3) 1,4-dibenzyl-2-chloromethylpyridine

To a solution of thionyl chloride (1,63 ml of 22.4 mmol) in CCl4 (30 ml) added dropwise a solution of (1,4-dibenzylpiperazine-2-yl)methanol (2,74 g, a 9.25 mmol) in CCl4within 10 minutes. The resulting suspension is stirred for 2 hours at a temperature of 77°C. After cooling to room temperature, add 20 ml of ice water and the aqueous layer was separated from the organic solvent. Bring the pH of the aqueous layer from 4 to 12 N. aqueous NaOH and extracted with CHCl3three times. The combined organic layer is dried over MgSO4and concentrate with getting brownish oil, which was purified column chromatography with silica gel (CH2Cl2/Meon=30/1) to give the 1,4-dibenzyl-2-chloromethylpyridine untreated (is 3.08 g, 95%, purity about 90% according to HPLC analysis). The connection used in the next stage without further purification: HPLC-MS (ESI): calculated for C19H23ClN2[M+H]+315, found: 315.

(4) 1,4-dibenzyl-2-(1H-1,2,4-triazole-1-ylmethyl)piperazine

To a solution of 1,2,4-triazole (48,3 mg, 0.70 mmol) in DMF (2 ml) is added NaH (18.3 mg, from 0.76 mmol). After 10 minutes stirring to the mixture 1,4-dibenzyl-2-chloromethylpyridine (200 mg, 0.64 mmol) and KI (156 mg, 0.70 mmol). The mixture is stirred at a temperature of 60°C during the night. The mixture is diluted with EtOAc and washed with water and saturated salt solution. The organic layer is dried over MgSO4, filtered and conc is t in vacuum. The resulting residue is purified column chromatography with NH-silica gel (Hex/AcOEt=1/4) to give the 1,4-dibenzyl-2-(1H-1,2,4-triazole-1-ylmethyl)piperazine (220,0 mg, 99,7%): HPLC-MS (ESI): calculated for C21H25N5[M+H]+348, found: 348.

(5) the Dihydrochloride of 2-(1H-1,2,4-triazole-1-ylmethyl)piperazine

To a solution of 1,4-dibenzyl-2-(1H-1,2,4-triazole-1-ylmethyl)piperazine (206 mg, 0.59 mmol) in Meon (3.0 ml) add a few drops of 4 N. HCl in 1,4-dioxane and 20% wet Pd(OH)2(100 mg). The mixture is stirred overnight in an atmosphere of H2from the container. The catalyst was filtered through a layer of celite and the filtrate was concentrated in vacuo to obtain the dihydrochloride of 2-(1H-1,2,4-triazole-1-ylmethyl)piperazine (122,9 mg, 86,3 %): HPLC-MS (ESI): calculated for C7H13N5[M+H]+168, found: 168.

(6) tert-butyl-3-(1H-1,2,4-triazole-1-ylmethyl)-1-piperidinecarboxylate

To a suspension of the dihydrochloride of 2-(1H-1,2,4-triazole-1-ylmethyl)piperazine (104 mg, 0,39 mmol) and Et3N (157,7 mg, 1.56 mmol) in CH2Cl2(3 ml) is added [{[(tert-butoxycarbonyl)oxy]amino}(cyano)methyl]benzene (106,5 mg, 0.43 mmol). The mixture is stirred for 2 hours at room temperature. The solvent is evaporated in vacuo and the residue purified column chromatography with silica gel (Meon/CHCl3=1/10) to obtain tert-butyl-3-(1H-1,2,4-t is eazol-1-ylmethyl)-1-piperidinecarboxylate (50.9 mg, 48,9%): HPLC-MS (ESI): calculated for C11H20N6O2[M+H]+268, found: 268.

(7) tert-butyl 4-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-3-(1H-1,2,4-triazole-1-ylmethyl)-1-piperidinecarboxylate

To a solution of tert-butyl 3-(1H-1,2,4-triazole-1-ylmethyl)-1-piperidinecarboxylate (29.5 mg, 0.11 mmol) and diisopropylethylamine (28.5 mg, 0.22 mmol) in THF (2 ml) is added 5-cyano-2-(3,5-dichlorophenoxy)benzosulphochloride (40,0 mg, 0.11 mmol). The mixture is stirred at a temperature of 50°C during the night. The solvent is removed, the residue diluted with CHCl3, washed with saturated aqueous NaHCO3and a saturated solution of salt. The organic layer is dried over MgSO4. The solvent is evaporated in vacuo and the resulting residue purified preparative TLC (Meon/CHCl3=1/10) to obtain tert-butyl 4-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-3-(1H-1,2,4-triazole-1-ylmethyl)-1-piperidinecarboxylate (42,5 mg, 64,9%): HPLC-MS (ESI): calculated for C25H26Cl2N6O5S [M+H]+593, found: 593.

(8) of the Hydrochloride of 4-(3,5-dichlorophenoxy)-3-{[2-(1H-1,2,4-triazole-1-ylmethyl)-1-piperazinil]sulfonyl}benzonitrile

To a solution of tert-butyl 4-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-3-(1H-1,2,4-triazole-1-ylmethyl)-1-piperidinecarboxylate (37 mg, 0.06 mmol) in CH2Cl2(1 ml) is added 4 N. HCl is 1,4-dioxane (1 ml). The mixture is stirred for 2 hours at room temperature. The solvent is evaporated in vacuo, the residue triturated with Et2O and the white solid collected by filtration to obtain hydrochloride of 4-(3,5-dichlorophenoxy)-3-{[2-(1H-1,2,4-triazole-1-ylmethyl)-1-piperazinil]sulfonyl}benzonitrile (28.5 mg, 86,3%).

1H NMR (500 MHz, DMSO-d6): 2,30-3,37 (1H, m), 3,71 (1H, t, J=12.9 Hz), 4,01 (2H, d, J=14,2 Hz), 4,56 (1H, DD, J=14,2, a 5.4 Hz), 4,60-4,63 (1H, m), 4,82 (1H, DD, J=13,9, 9.5 Hz), 7,21 (1H, d, J=8.5 Hz), 7,40 (2H, d, J=1,6 Hz), to 7.59 (1H, t, J=3,5, and 1.6 Hz), 7,68 (1H, s), with 8.05 (1H, d, J=2.2 Hz), 8,07 (1H, s), 8,59 (1H, s), of 9.51 (1H, users), 9,58 (1H, users); HPLC-MS (ESI): Calculated for C25H26Cl2N6O5S [M+H]+494, found: 494.

Molecular weight: 529,84

Melting point: 177°C (decomposition)

The level of activity of CCR3:

The level of activity IC50: And

Connection examples (1-5)-(1-47), shown in the table, get on the methods of examples (1-1)to(1-4) or the corresponding reactions.

Example 2-1

4-(3,5-dichlorophenoxy)-3-(Piperi the Jn-4-sulfonyl)benzonitrile

(1) To a solution of 3-amino-4-(3,5-dichlorophenoxy)benzonitrile (4,19 g, 15 mmol) in aq. HCl (conc. HCl (10 ml)+water (25 ml) added dropwise a solution of NaNO2(1,14 g, 16.5 mmol) in water (6 ml) under stirring at a temperature below 4°C. After the addition the pH of the solution was adjusted to 4 by adding sodium acetate. After stirring at 0°C for 20 minutes the mixture was added to a hot solution (80°C) O-utilityservice potassium (to 4.81 g, 30 mmol) in water (45 ml) with stirring. The mixture is stirred at a temperature of 80°C for 0.5 hour. After cooling to room temperature, the solution is extracted with EtOAc, dried over MgSO4. The solvent is evaporated to obtain a complex of O-ethyl ester S-[5-cyano-2-(3,5-dichlorophenoxy)phenyl]ether complex dithiocarbonic acid, which is used in the next stage without further purification (5.50 g, 66,8% (purity 70%)).

(2) a complex Mixture of O-ethyl ester S-[5-cyano-2-(3,5-dichlorophenoxy)phenyl]ether complex dithiocarbonic acid (5.50 g, 66,8% (purity 70%)), CON (3,37 g, 60.1 mmol) in ethanol (20 ml) is refluxed for 1 hour. After cooling to room temperature the solvent is evaporated. To the residue add 30 ml of ice water. the pH of the mixture was adjusted to 4 by adding acetic acid. The mixture is extracted with EtOAc. The extract is washed with the ode, saturated salt solution, dried over MgSO4. The solvent is evaporated to obtain 4-(3,5-dichlorophenoxy)-3-mercaptobenzoxazole, which is used in the next stage without further purification (3,20 g, 75,5% (purity 70%)).

(3) To a suspension hydrobromide 4-bromopyridine (2,94 g, 12 mmol) in CH2Cl2(30 ml) add NEt3(3.04 from g to 4.2 ml, 30 mmol) under stirring. After 10 minutes add bi-tert-BUTYLCARBAMATE (3,14 g, 14.4 mmol). The mixture is stirred at room temperature for 3 hours and diluted with CH2Cl2(60 ml). The mixture is washed with 0.2 n aq. HCl, 5% aq. NaHCO3saturated salt solution, dried over MgSO4. The solvent is evaporated to obtain tert-butyl ester 4-bromopyridin-1-carboxylic acid as colorless liquid, which is used in the next stage without further purification (2,60 g, 69.5 per cent (purity 70%)).

(4) a Mixture of 4-(3,5-dichlorophenoxy)-3-mercaptobenzotriazole ester (338 mg, 0.8 mmol (purity 70%)), tert-butyl ester 4-bromopyridin-1-carboxylic acid (362 mg, 0.96 mmol, (purity 70%)) and K2CO3(552 mg, 4 mmol) in dry DMF (8 ml) is stirred at a temperature of 95°C during the night. The solvent is evaporated and the residue diluted with EtOAc (100 ml). The mixture was washed with saturated salt solution and the organic layer is dried over MgSO4 . The solvent is evaporated to obtain tert-butyl ester 4-[5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl]piperidine-1-carboxylic acid, which is used in the next stage without further purification (360 mg, 56.3 per cent, (purity 60%)).

(5) To a solution of tert-butyl ester 4-[5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl]piperidine-1-carboxylic acid (320 mg, 0.4 mmol (60 purity)in a mixture of CCl4(6 ml) and CH3CN (6 ml) add a solution NaIO4(599 mg, 2,80 mmol) and RuCl3at 41.5 mg, 0.2 mmol) in water (12 ml). The mixture is stirred at room temperature for 4 hours and the solvent is evaporated. The residue was diluted with EtOAc (100 ml). The mixture is washed with water, saturated salt solution and dried over MgSO4. The solvent is evaporated and the crude product purified preparative TLC (EtOAc/hexane=1:1) to give tert-butyl ester 4-[5-cyano-2-(3,5-dichlorophenoxy)benzazolyl]piperidine-1-carboxylic acid (50.0 mg, 24,4%): HPLC-MS (ESI): calculated for C23H24Cl2N2O5S [M+H]+511, found: 511.

(6) To a solution of tert-butyl ester 4-[5-cyano-2-(3,5-dichlorophenoxy)benzazolyl]piperidine-1-carboxylic acid (30 mg, 0.06 mmol) in CH2Cl2(1 ml) is added 4 N. HCl (in dioxane, 0.6 ml) and the mixture is stirred at room temperature for 1.5 hours. Receiving the hydrated white precipitate is collected by filtration and dried in vacuum to obtain hydrochloride of 4-(3,5-dichlorophenoxy)-3-(piperidine-4-sulfonyl)benzonitrile (23 mg, 87,6%).

1H NMR (300 MHz, DMSO-d6): 1,72-to 1.77 (2H, DDM, J=a 13.4 Hz, J=3,78 Hz), 2,03-of 2.09 (2H, DDM, J=a 13.4 Hz, J=3,78 Hz)to 3.09 (2H, users), 3,18 (2H, users), 4,94 (1H, square, J=3,78 Hz), 7,54 (1H, d, J=9,03 Hz), of 7.96 (2H, s), 8,07 (1H, s), 8,76 (1H, s), 8,46 (1H, s), 8,83 (1H, users), 9,14 (1H, users); HPLC-MS (ESI): Calculated for C18HI7Cl3N2O3S [M+H]+411, found: 411.

Molecular weight: 447,77

Melting point: 220-226°C (decomposition)

The level of activity of CCR3:

The level of activity IC50:

Example 3-1

N-(1-azabicyclo[2.2.2]Oct-3-yl)-2-(3,5-dichlorobenzenesulfonyl)-5-nitrobenzenesulfonamide

(1) To a suspension of the dihydrochloride of 1-azabicyclo[2.2.2]Oct-3-ylamine (of 44.9 mg, 0,205 mmol) in THF portions add NaH (60%, 41.0 mg, of 1.03 mmol) and the mixture is stirred for 30 minutes. Then stir the mixture was added dropwise to a solution of 2-chloro-5-nitrobenzenesulfonamide (52,2 mg, 0,205 mmol) in THF at 0°C. the resulting mixture was stirred at 0°C for 2 hours.

(2) After removing the ice bath to the mixture is added NaH (60%, 9,90 mg, 0,246 mmol) followed by addition of 3,5-dichlorobenzamide (to 44.0 mg, 0,246 mmol). The mixture is stirred at room temperature for 2 hours and concentrated in vacuo. The residue was diluted with EtOAc and washed with water, 1 N. NaOH and saturated salt solution. The organic layer is dried over MgSO4and conc is t in vacuum to obtain the crude product. Then the crude compound purified preparative TLC to obtain N-(1-azabicyclo[2.2.2]Oct-3-yl)-2-(3,5-dichlorobenzenesulfonyl)-5-nitrobenzenesulfonamide (41.3 mg, 41,3%) as a white powder:

1H NMR (300 MHz, CDCl3): δ 1,48-to 1.59 (1H, m), 1,61-of 1.73 (1H, m), a 1.75 of-1.83 (2H, m), 2,54-2,61 (1H, m), 2,64-2,82 (2H, m), 2,85-2,90 (2H, t, J=7.5 Hz), 3,19-of 3.27 (1H, DD, J=9,4, 14.1 Hz), 3,42-of 3.46 (1H, m), 7,13-7,16 (1H, d, J=8,9 Hz), 7,39-7,40 (2H, d, J=1.9 Hz), 7,52-7,53 (1H, t, J=1.9 Hz), 8,18 is 8.22 (1H, DD, J=2,6, a 8.9 Hz), 8,87-8,88 (1H, d, J=2.5 Hz); HPLC-MS (ESI): Calculated for C19H19Cl2N3O4S2[M+H]+488, found: 488.

Molecular weight: 488,41

Melting point: 256°C

1. Derived benzosulfimide having the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt:

where X is O or S;
R1represents hydrogen or halogen;
R2represents hydrogen or halogen;
R3represents nitro or cyano;
R4is
,
where R71represents hydrogen;
R72is hydrogen; and
Z1represents- (CH2]p-where p is the number 2.

2. Derived benzosulfimide formula (I), its tautomeric or stereoisomeric form, or its physiologically acceptable salts according to claim 1, where R4is:

where R72represents hydrogen.

3. Derived benzosulfimide according to claim 1, having the formula (I-b), its tautomeric or stereoisomeric form, or a physiologically acceptable salt:

where R1represents fluorine, chlorine, bromine or iodine;
R2represents fluorine, chlorine, bromine or iodine;
R3represents cyano;
R4is

where R71represents hydrogen;
R72represents hydrogen;
Z1represents- (CH2]p-where p is the number 2.

4. Derived benzosulfimide according to claim 3, its tautomeric or stereoisomeric form, or a physiologically acceptable salt,
where R1represents fluorine, chlorine or bromine;
R2represents fluorine, chlorine or bromine;
R3represents cyano;
R4is

where R72represents hydrogen.

5. Derived benzosulfimide, its tautomeric or stereoisomeric form, or a physiologically acceptable salt according to any one of claims 1 to 4, where the specified derived benzosulfimide selected from a group including:
(R)-N-(1-azabicyclo[2.2.2]Oct-3-yl)-5-cyano-2-(3,5-dichlorophenoxy)benzosulfimide;
(S)-N-(1-azabicyclo[2.2.2]Oct-3-yl)-5-cyano-2-(3,5-dichlorophenoxy)benzosulfimide;
N-(1-azabicyclo[2.2.2]Oct-3-yl)-2-(3,5-diclofe ylsulphonyl)-5-nitrobenzenesulfonamide.

6. Drug exhibiting antagonistic activity against CCR3 containing derived benzosulfimide formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt according to claim 1 as an active ingredient.

7. The drug according to claim 6, containing one or more pharmaceutically acceptable excipients.

8. The application of the derived benzosulfimide, its tautomerism or stereoisomeric form, or a physiologically acceptable salt according to claims 1 to 5 to obtain drugs for treatment or prevention of disorders or diseases associated with the activity of CCR3.

9. The use of claim 8, where the specified disorder or disease selected from the group comprising asthma, rhinitis, allergic diseases and autoimmune diseases.

10. The use of claim 8, where the specified disorder or disease selected from the group including HIV, pulmonary granuloma and Alzheimer's disease.

11. The use of claim 8, where the specified derived benzosulfimide, its tautomeric or stereoisomeric form, or a physiologically acceptable salt is mixed with one or more pharmaceutically acceptable excipients.

12. The drug according to claim 7, where excipient is an inert substance, such as the media, will dilute the ü, flavoring agent, a sweetener, lubricant, solubilizer, suspendisse agent, a binder agent, disintegrity agent for tablets and the encapsulating material.

13. The application of claim 11, where excipient is an inert substance, such as a carrier, a diluent, flavoring agent, a sweetener, lubricant, solubilizer, suspendisse agent, a binder agent, disintegrity agent for tablets and the encapsulating material.



 

Same patents:

FIELD: pharmacology.

SUBSTANCE: present invention relates to antagonists of serotonin 5-HT5 receptors with general formula 1 and their pharmaceutically acceptable salts and/or hydrates, particularly to substituted 3-sulphonyl-[1,2,3]triazolo[1,5-a]quinazolines and 3-sulphonyl-thieno[2,3-e][1,2,3]triazolo [1,5-a]pyrimidines, as active compounds for pharmaceutical compositions and medicinal agents, and methods of producing said compounds. In general formula 1 , Ar is a phenyl which is unsubstituted or substituted with halogen or at least one lower alkyl; R1 is a hydrogen atom or optionally substituted amine group, or optionally substituted 5-6 member azaheterocyclyl, bonded by a nitrogen atom to a carbon atom of a triazolopyrimidine ring with 1-2 heteroatoms selected from nitrogen, oxygen or sulphur, and optionally annulated with a benzene ring; where the substitutes are selected from hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C8cycloalkyl, alkoxy group, acyl, saturated or unsaturated optionally annulated 5-7 member heterocyclyl, where heteroatoms are selected from nitrogen, oxygen or sulphur, optionally substituted phenyl; R2 and R3 together with carbon atoms to which they are bonded form an optionally substituted benzene or thiophene ring, where substitutes are selected from C1-C5alkyl or halogen atom.

EFFECT: invention also relates to pharmaceutical compositions and medicinal agents, a method of treating or preventing development of CNS diseases mediated by action of serotonin 5-HT5 receptors, for example Alzheimer's disease.

20 cl, 6 dwg, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazolpyrimidine derivatives of formula (I) where p is 0 or 1; R1 and R2 can independently represent H, halogen, lower alkyl, lower alkoxy, possibly substituted with one or more halogens or CF3; R3 is lower alkyl, hydroxy-lower alkyl or NRaRb; Ra and Rb are independently selected from a group consisting of H; cycloalkyl containing 3-6 carbon atoms; phenyl; lower alkyl possibly substituted with one or more hydroxy, fluorine, C3-6cycloalkyl, phenyl, pyridyl or NRcRd, where Rc and Rd are independently selected from H or lower alkyl; or where Ra and Rb together with the nitrogen atoms to which they are bonded can form a 5- or 6-member hetero-ring, possibly additionally containing 1 or 2 heteroatoms selected from O or N, and possibly substituted with lower alkyl or hydroxy-lower alkyl; R4 is H, Cl, lower alkoxy, cycloalkyl, containing 3-6 carbon atoms, or straight lower alkyl which is possibly substituted with one or more F; R5 is H; halogen or lower alkyl; as well as to their pharmaceutically acceptable salts.

EFFECT: invention also relates to pharmaceutical compositions based on these compounds and their use in preparing medicine for treating or preventing acute and/or chronic neurological disorders in which activation of mGluR2 is involved.

19 cl, 179 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to new 2-alkylamino-3-arylsulphonylcycloalkano[e]pyrazolo[1,5-a]pyrimidines of general formula 1 and 2-alkylamino-3-arylsulphonylcycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2 with properties of serotonin 5-NT6 receptor antagonists, to pharmaceutical compositions containing specified compounds as a principle, medical products and method of treatment and the prevention of CNS diseases. In general formulae 1 and 2, R1 represents hydrogen atom or C1-C3 alkyl; R2 represent C1-C3 alkyl; R3 represent hydrogen atom, one or two optionally substituted identical halogen atoms, C1-C3 alkyl or hydroxyl optionally substituted with C1-C3alkyl; n represents an integer 1, 2 or 3. The invention also relates to the method for making the compounds of general formula 1 or 2 by interaction of 3-amino-4-arylsulphonyl-2H-pyrazoles of general formula 3 with relevant β-dicarbonyl compounds of general formula 4 or their derivatives of general formula 5. 3, 4, 5, where: R1, R2, R3 and n have said values.

EFFECT: new 2-alkylamino-3-arylsulphonyl-cycloalkano[e or c1]pyrazolo[1,5]pyrimidines - serotonin 5-NT6 receptor antagonists, methods of making and applying thereof.

12 cl, 1 dwg, 4 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention is related to 4-((2)-4'-hydroxybutene-2'-yl)-2-R-6-phenyl-1,2,4-triazolo[5,1-c][1,2,4]triazine-7-ons of common formula (1) ,

where R=H, CH3,SCH3 have antiviral action against herpesvirus of simple type 1 (HSV-1).

EFFECT: new derivatives have useful biological properties.

1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: invention is related to antagonists of serotonin 5-HT6 receptors of common formula 1 and their pharmaceutically acceptable salts and/or hydrates, pharmaceutical compositions, dosage forms and methods of production. Invention also includes new compounds of formula 1.1. In formulae 1 and 1.1 , Ar represents aryl, selected from unnecessarily substituted phenyl or unnecessarily substituted 5-6-member heteroaryl, which contains atom of nitrogen or atom of sulfur and heteroatom; R1 represents atom of hydrogen, unnecessarily substituted C1-C5 alkyl; Ar represents aryl, selected from unnecessarily substituted phenyl or unnecessarily substituted 5-6-member heteroaryl, which contains atom of nitrogen or atom of sulfur as heteroatom; R1 represents atom of hydrogen, which is unnecessarily substituted C1-C5 alkyl; R21,R22, R31, R32 independently from each other represent atom of hydrogen or substituent of aminogroup, selected from unnecessarily substituted C1-C4 alkyl, unnecessarily substituted phenyl, or R31 and R32 together with atom of nitrogen, to which they are bound, create unnecessarily substituted saturated 6-member heterocycle, possibly containing atom of nitrogen in cycle; or R1 together with atom of nitrogen, to which it is bound, and R21 and R22 together with atom of nitrogen, to which they are bound, create substituted pyrimidine cycle. In formula 1.1 R4, R5 and R6 independently from each other represent atom of hydrogen, unnecessarily substituted C1-C3 alkyl or phenyl.

EFFECT: compounds of invention may find application for treatment and prevention of development of conditions and disorders of central nervous system.

13 cl, 11 dwg, 4 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: there are described new p38 kinase inhibitors that are compounds of general formula (I) (radical values are presented in the patent claim), their pharmaceutically acceptable salts and solvates, a pharmaceutical composition containing thereof, and method for treating inflammatory diseases.

EFFECT: new compounds have effective biological activity.

24 cl, 311 ex

FIELD: medicine.

SUBSTANCE: there are described new isoindole derivatives of general formula (1), wherein A1, A2 and A4 stands for CH, and A3 means N or C-OH; n is equal to 2; R1 represents O; R2-stands for H; and a pharmaceutical composition containing thereof.

EFFECT: new compounds are inhibitors of chaperone protein Hsp90 activity and can be used in chemotherapy of cancerous diseases.

6 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new 2-alkylsufanyl-3-arylsufonyl-cycloalkano[e]pyrazolol[1,5-a]pyrimidines of general formula 1 or 2-alkylsufanyl-3-arylsufonyl-cycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2, which are antagonist of 5-HT6 receptors. In compounds of formula 1

and 2 ,

R1 is a hydrogen atom or C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is a hydrogen atom, one or two optionally identical halogen atoms, C1-C3 alkyl or hydroxyl, optionally substituted with C1-C3 alkyl; n is an integer equal to 1, 2 or 3.

EFFECT: compounds can be used in preventing and treating diseases of the central nervous system, anxiolytics and as compounds with nootropic effect and suitable for enhancing memory.

12 cl, 1 dwg, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a cyclic bioisostere of purine system derivatives, with general structural formula given below , where R = , Li, Na or K, R1 = -H, -NH2, -Br, -Cl, -OH, -COOH; A = -N- for B=-N=, Z = -CH-; A = -CH= for B = -N=, Z = -CH-; A = -CH= for B = -N=, Z = -N=; A = -CH= for B = -CH=, Z - -CH=; A = -CH= for B = -CH=, Z = -N=, except compounds in which A = -CH= for B = -CH=, Z = -CH=, R= Li, Na or K and R1= -NH2 in the 5th position of the benzo[d]-3H-pyridazine-1,4-dione nucleus, and its pharmacologically acceptable salts, with normalising effect on intracellular processes.

EFFECT: obtaining compounds which can be used for normalising intracellular processes in therapy of disorders, caused by intracellular acidosis and/or oxygen deficiency and/or excess formation of free radicals and/or excess formation of free radical forms of oxygen and/or high thrombocyte aggregation and/or erythrocytes and/or adverse effects and/or nitrergic cell mechanism disorder.

17 cl, 14 tbl, 15 dwg

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Novel insecticides // 2379301

FIELD: chemistry.

SUBSTANCE: compounds with formula I are described, where each of E and Z is oxygen; A is C1-C6alkylene or a 3-member monocyclic ring system, which can be monosubstituted; Y is C1-C6alkylene; p equals 0; q equals 0 or 1; B represents a 3- or 4-member ring system which is completely or partially saturated and can contain a heteroatom selected from oxygen, possibly substituted; each R1 independently represents halogen, nitro group, C1-C6alkyl; or each R1 independently represents an amino group; n equals 1, 2; each of R2 and R3 represents hydrogen; D represents a group and agronomically acceptable salts of said compounds. Also described is a method of producing formula I compounds, intermediate compounds, a pesticide composition containing a formula I compound, as well as an insect control method and a method of protecting plant propagation material.

EFFECT: novel anthranylamide derivatives have good insecticidal activity.

16 cl, 8 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: novel isoquinoline derivatives are described by general formula I, where q equals zero; p equals zero or one; Ra is -COOH or WR8; under the condition that, if Ra is -COOH, then p equals zero, and if Ra is -WR8, then p equals one; W is selected from an oxygen atom and -NR9-, where R9 is selected from a group consisting of a hydrogen atom, acyl and alkyl; and R8 is selected from a group consisting of a hydrogen atom and alkyl; R1 is selected from a group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl substituted with alkyl, and -XR6, where X is an oxygen atom, -S(O)n- or -NR7, where n equals zero, one or two, R6 is selected from a group consisting of alkyl, aryl, aryl substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamide, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, and R7 is a hydrogen atom or aryl; R2 and R3 are independently selected from a group consisting of a hydrogen atom, amino, amino substituted with alkoxy-substituted phenylsulfonyl, alkyl, alkyl substituted with up to three times by a halogen atom, aryl, halogen atom -NR6C(O)NR6R6, and -XR6, where X is an oxygen atom or -S(O)n-, where n equals zero, one or two, each of the substitutes R6 is independently selected from a group consisting of hydrogen, alkyl, alkyl substituted with aryl, aryl , aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with up to three times by a halogen, alkoxy, alkoxy substituted with up to three times by a halogen, aryloxy substituted with a halogen, nitro, alkylsulfonamide, arylsulfonamide and alkyl-substituted arylsulfonamide, cycloalkyl, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, under the condition that if X is -SO2-, R6 cannot be a hydrogen atom; or R2 and R3 together with carbon atoms to which they are bonded, are bonded with formation of an aryl group; R4 and R5 are independently selected from a hydrogen atom or aryl; R is selected from a group which includes a hydrogen atom, deuterium and methyl; R' is selected from a group consisting of a hydrogen atom, deuterium, alkyl or alkyl substituted with one group selected from hydroxyl, amino, carboxyl, aryl, aryl substituted with one hydroxyl and heteroaryl, containing up to five carbon atoms, two of which can be nitrogen; on the other hand, R and R' and the carbon atom to which they are bonded can be bonded with formation of cycloalkyl; R" is formed from a hydrogen atom and alkyl, or R" together with R' and the nitrogen atom to which they are bonded can be bonded with formation of a heterocyclic group containing up to six carbon atoms, one of which is nitrogen; R'" is selected from a group consisting of hydroxyl, alkoxy, alkoxy substituted with aryl, acyloxy, aryl, -S(O)n-R10, where R10 is hydrogen, and n is zero; or its pharmaceutically acceptable salts, esters or amides; under the condition that restrictive conditions given in paragraph 1 of the formula of invention are met. The invention also relates to specific produced and described compounds, a pharmaceutical composition based on compounds with general formula I, a method of treating, preventing and pretreatment using said pharmaceutical composition, a method of inhibiting activity of hydrolase enzyme, based on taking an effective amount of a formula I compound, a composition for preventing and pretreatment, based on formula I compound and erythropoietin.

EFFECT: new isoquinoline derivatives have useful biological properties.

53 cl, 4 tbl, 253 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted derivatives of N-(3-benzoylaminophenyl)-4-pyridyl-2-pyrimidine amine of general formula (I), with inhibitory activity towards protein kinase, method of producing said derivatives and pharmaceutical compositions based on the derivatives. In the compound of formula 1 R1 is hydrogen and R2 is NR5R6, or R1 is NR5R6 and R2 is hydrogen; R3 is trifluoromethyl; R4 is lower alkyl; and R5 and R6 are independently hydrogen, lower alkyl, di(lower alkyl)amino-lower alkyl, N-lower alkylpiperidinyl, N-lower alkylpyrrolidinyl, or lower alkyl, or NR5R6 together represent pyrrolidino, piperidino, morpholino, N-lower alkylpiperazino, 1N-imidazolyl, 1H-2-lower alkylimidazolyl, 1H-4-lower alkylimidazolyl or 1H-2,4-di-lower alkylimidazolyl, or a pharmaceutically acceptable salt of such a compound.

EFFECT: compounds can be used in treating diseases related to inhibition of protein kinase activity, such as neoplastic diseases or leukaemia.

13 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) , where R1 is hydrogen, C1-C7 alkyl; R2 is C1-C7 alkyl, aryl, C1-C7 haloalkyl or C3-C8 cycloalkyl; R3, R4 each independently represents hydrogen, halogen, C1-C7 alkoxy, C1-C7 alkylsuphonyl; R5 is hydrogen, halogen, C1-C7 alkyl, C1-C7 haloalkoxy, or aryloxy, or is -NR7R8, where R7 and R8 represent C1-C7 alkyls, or R7 and R8 together with the nitrogen atom to which they are bonded can form a 4-7-member heterocycloalkyl group, which can be substituted with one or more substitutes selected from a group consisting of halogen, C1-C7 alkyl, C1-C7 alkoxy, hydroxyl, phenyl and di(C1-C7)alkylamino; R6 is hydrogen or together with R5 can form a 5- or 6-member heterocycloalkyl group which can be substituted with one or more halogens; and their pharmaceutically acceptable salts of acid compound, except the range of compounds given in paragraph 1 of the formula of invention. The invention also relates to medicine based on said compounds, with activity of allosteric enhancer of GABA-B receptors and use of compounds of the formula to prepare medicines used in treating central nervous system disorders, including anxiety and depression.

EFFECT: novel compounds are obtained and described, which can be used for preparing medicines used in treating central nervous system disorders, including anxiety and depression.

14 cl, 58 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds of formula I , or its pharmaceutically acceptable salt of this, in which: R1 means C1-6-aliphatic group, besides, R1 may be substituted with substituents in number of up to 2 groups, independently selected from -OR or -C1-3 halogenalkyl; each R independently means hydrogen or C1-4-aliphatic group; R2 means R, fluorine or chlorine; m means 0, 1 or 2; and R3 means hydrogen, C1-3-aliphatic group, fluorine or chlorine, to composition for inhibition of activity of protein kinase ERK1 or ERK2, on the basis of these compounds, to method for inhibition of activity of protein kinase ERK1 or ERK2, and also to use of compounds of formula I or composition on their basis, for treatment or reduction of disease severity.

EFFECT: new compounds are produced and described, which may be used as inhibitors of protein kinases.

11 cl, 7 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: chemistry.

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

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

23 cl, 41 ex

Up!