Derivatives of sulfonamides and pharmaceutical composition based on thereof

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

 

Reference to related applications

This application claims the priority of provisional patent application No. 60/191302 filed March 21, 2000, in accordance with article 35 of the code, United States Code 119(e).

Technical rationale

The present invention relates to compounds useful in treating diseases associated with the activity metalloprotease, in particular the activity of the zinc-metalloprotease. The invention also concerns pharmaceutical compositions comprising the compounds, and methods of treatment associated with metalloprotease diseases by applying the compounds or pharmaceutical compositions.

Background of the invention

A number of structurally related metalloprotease produces destruction of structural proteins. These metalloprotease often act on the extracellular matrix and thus are involved in tissue destruction and reconstruction. Such proteins are called metalloprotease or MPs - MP.

There are several different families MP, classified by homology sequences known from the prior art. These MP include metalloprotease matrix (MMPs (MMP); zinc-metalloprotease; many of membrane-bound metalloprotease; TNF-converting enzyme; angiotensin-converting enzymes (ACEs ACE); disintegrin, including ADAMs (see, Wolfsberg et al, 131 J. Cell Bio. 275-78 October, 1995) and enkephalinase. Examples of MP in luchot collagenase fibroblasts of human skin, gelatinase fibroblasts of human skin, collagenase, aggrecanases and gelatinase saliva of man and stromelysin person. It is believed that collagenase, stromelysin, aggrecanases and similar enzymes are an important link in the symptomatology of diseases.

The literature discusses the potential therapeutic indications for use of inhibitors. MP See, for example, U.S. patents 5506242 (Ciba Geigy Corp.) and 5403952 (Kerck & Co.); the following published patent applications PCT WO 96/06074 (British Bio Tech Ltd.); WO 96/00214 (Ciba Geigy), WO 95/35275 (British Bio Tech Ltd.), WO 95/35276 (British Bio Tech Ltd.), WO 95/33731 (Koffman-LaRoche), WO 95/33709 (Hoffman-LaRoche), WO 95/32944 (British Bio Tech Ltd), WO 95/26989 (Merck), WO 9529892 (DuPont Merck), WO 95/24921 (Inst. Opthamology), WO 95/23790 (SmithKiine Beecham), WO 95/22966 (Sanofi Winthrop), WO 95/19965 (Glycomed), WO 95 19956 (British Bio Tech Ltd), WO 95/19957 (British Bio Tech Ltd.), WO 95/19961 (British Bio Tech Ltd.), WO 95/13289 (Chiroscience Ltd.), WO 95/12603 (Syntex), WO 95/09633 (Florida State Univ.), WO 95/09620 (Florida State Univ.), WO 95/04033 (Celltech), WO 94/25434 (Celltech), WO 94/25435 (Celltech); WO 93/14112 (Merck), WO 94/0019 (Glaxo)/ WO 93/21942 (British Bio Tech Ltd.), WO 92/22523 (Res. Corp. Tech Inc.), WO 94/10990 (British Bio Tech Ltd.), WO 93/09090 (Yamanouchi); patents great Britain GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd.); published European patent application EP 95/684240 (Hoffman LaRoche), EP 574758 (Hoffman LaRoche) and EP 575844 (Hoffman LaRoche); published Japanese patent application JP 08053403 (Fujusowa Pharm. Co. Ltd.) and JP 7304770 (Kanebo Ltd.); and Bird et al., J. Med. Chem.. vol.37, pp.158-69 (1994).

Examples of potential therapeutic inhibitors MP include rheumato the command arthritis Mullins, D.., et al, Biochim. Biophys. Acta. (1983) 695: 117-214; osteoarthritis - Henderson, B., et al., Drugs of the Future (1990) 15:495-508; cancer - Yu, A. E. et al., Matrix Metalloproteinases Novel Targets for Directed Cancer Therapy, Drugs & Aging. Vol.11(3), p.229-244 (Sept. 1997), Chambers, A.F. and Matrisian, L.M., Review: Changing Views of the Role of Matrix Metalloproteinases in Metastasis, J. of the Nat’1 Cancer Inst., Vol.89(17), p.1260-1270 (Sept. 1997), Bramhall, S.R., The Matrix Metalloproteinases and Their Inhibitors in Pancreatic Cancer, Internat’1 J. of Pancreatology. Vol.4, p.1101-1109 (May 1998), Nemunaitis, J. et al., Combined Analysis of Studies of the Effects of the Matrix Metalloproteinase Inhibitor Marimastat on Serum Tumor Markers in Advanced Cancer: Selection of a Biologically Active and Tolerable Dose for Longer-term Studies, Clin. Cancer Res. Vol 4, p.1101-1109 (May 1998) and Rasmussen, H.S. and McCann, P.P, Matrix Metalloproteinase Inhibition as a Novel Anticancer Strategy: A Review with Special Focus on Batimastat and Marimastat, Pharmacol. Ther. Vol 75(1), p.69-75 (1997); the metastasis of tumor cells ibid, Broadhurst, .J., et al., European patent application 276436 (published 1987), Reich, R., et al. Cancer Res. Vol.48, p.3307-3312 (1988); multiple sclerosis Gijbels et al., J. Clin. Invest., vol.94, p.2177-2182 (1994) and various ulcers or state of ulceration of the tissue. For example, the state of ulceration can occur on the cornea as a result of burns from alkali or as the result of a virus infection, Pseudomonas aeruginosa, Acanthamoeba spp., herpes virus and cowpox. Other examples of conditions characterized by undesired activity of metalloprotease include periodontal disease, congenital bullous bullosa, fever, inflammation and scleritis (for example, DeCicco et al., published patent application PCT publication WO 95/2S92, published on 9 November 1995).

Because of the involvement of these metalloprotease in pathological processes in a number of diseases, attempts were made to obtain inhibitors for these enzymes. A number of these inhibitors described in the literature. Examples include U.S. patent No. 5183900, issued February 2, 1993 Galardy; U.S. patent No. 4996358, issued February 26, 1991 Handa et al.; U.S. patent No. 4771038, issued September 13, 1988 Wolanin et al.; U.S. patent No. 4743587, issued may 10, 1988 Dickens et al., European patent application No. 575844, published on 29 December 1993 Broadhurst et al.; international patent application number WO 93/09090, published may 13, 1993 Isomura et al.; World Patent Publication 92/17460, published 15 October 1992 Markwell et al. and European patent application No. 498665 published 12 August 1992 Beckett et al.

It would be useful to inhibit these metalloprotease in the treatment of diseases associated with unwanted activity metalloprotease. Although the obtained set of inhibitors MP, continues to be an enduring need for effective inhibitors of metalloprotease matrix, useful in the treatment of diseases associated with the activity metalloprotease.

Brief description of the invention

The invention provides compounds, which are potential inhibitors t and effective in the treatment of conditions characterized by excess activity of these enzymes. the particular the present invention relates to compounds having a structure corresponding to formula (I):

where (A) R1choose from HE-NHOH;

(B) R2selected from the group comprising hydrogen, alkyl, alkenyl, quinil, heteroalkyl, halogenated, cycloalkenyl, geterotsiklicheskikh, arylalkyl and heteroaromatic; or R2may be associated with And as described in (D);

(C) R3selected from the group including alkyl, alkenyl, quinil, heteroalkyl, halogenated, cycloalkyl, heteroseksualci, arylalkyl and heteroaromatic;

D) And means a substituted or unsubstituted monocyclic heteroseksualci with 3-8 atoms in the cycle, of which 1-3 are heteroatoms; or a is linked with R2where they together form a substituted or unsubstituted monocyclic heteroseksualci with 3-8 atoms in the cycle, of which 1-3 are heteroatoms;

(E) n = 0~4;

(F) E is selected from the group comprising covalent bond, C1-C4-alkyl, -C(=O)-, -C(=O)O-, C(=O)N(R4)-, -SO2or-C(=S)N(R4)-, where R4selected from the group comprising hydrogen, alkyl, alkenyl, quinil, heteroalkyl, halogenated, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl and heteroaromatic; or R4and X are connected with the formation of the loop, as indicated in (G) (2);

(G) (1) X is chosen from the group including odor is d, alkyl, alkenyl, quinil, heteroalkyl, halogenated, aryl, arylalkyl, heteroaryl, heteroaromatic, cycloalkyl and heteroseksualci; or (2) X and R4connected, form a substituted or unsubstituted monocyclic heteroseksualci with 3-8 atoms in the cycle, of which 1-3 are heteroatoms;

(N) G is chosen from the group comprising-S-, -O-, -N(R5)-, -C(R5)=C(R5’)-, -N=C(R5and-N=N-, where each of R and R5independently selected from the group comprising hydrogen, alkyl, alkenyl, quinil, heteroalkyl, aryl, heteroaryl, cycloalkyl and heteroseksualci;

(I) G’ is chosen from the group comprising-S-, -O-, -N(R6)-, -C (R6)C(R6’)-, -N=C(R6)- and-N=N-, where each R6and R6’independently selected from the group comprising hydrogen, alkyl, alkenyl, quinil, heteroalkyl, aryl, heteroaryl, cycloalkyl and heteroseksualci;

(J) M is chosen from-CH - and-N-; and

(K) Z mean (CR7R7’)a-L-R8where

(1) and is 0-4;

(2) each of R7and R7’independently selected from the group comprising hydrogen, alkyl, alkenyl, quinil, aryl, heteroalkyl, heteroaryl, cycloalkyl, heteroseksualci, halogen, halogenated, hydroxy and alkoxy;

(3) L is chosen from the group comprising covalent bond, -O-, -SOb-, -C(=O)-, C(=O)N(R9)-, -N(R9and-N(R9)C(=O)-, where b is 0-2 and R9choose from the group VK is causa hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heteroseksualci and halogenated; or R7and R9together with the atoms to which they are chemically attached, together form an optionally substituted heterocycle containing 5 to 8 atoms, of which 1-3 are heteroatoms;

and

(4) R8selected from the group comprising hydrogen, alkyl, alkenyl, quinil, halogen, heteroalkyl, halogenated, aryl, heteroaryl, cycloalkyl and heteroseksualci; or R8and R9together with the atoms to which they are chemically attached, join to form optionally substituted heterocycle containing 5 to 8 atoms, of which 1-3 are heteroatoms;

or an optical isomer, diastereoisomer or enantiomer for formula (I)or their pharmaceutically acceptable salts, or biogerontology amide, complex ether or imide.

The present invention also includes optical isomers, diastereomers and enantiomers of the above formula and their pharmaceutically acceptable salts, Bioversity amides, esters, and imides.

Compounds of the present invention are useful for the treatment of diseases or disorders characterized by undesirable activity metalloprotease. Therefore, the invention also provides pharmaceutical compositions containing these compounds. To the ome, the invention provides methods of treatment-related metalloproteases diseases.

Detailed description of the invention

1. Terms and definitions

Following is the list used here definitions and terms.

"Acyl" or "carbonyl" means a radical formed by removal of the hydroxy-group of the carboxylic acid (i.e., R-C(=O)-). Preferred acyl groups include (for example) acetyl, formyl and propionyl.

"Alkyl" means a saturated hydrocarbon chain with 1 to 15 carbon atoms, preferably 1-10, more preferably 1-4 carbon atoms. "Alkene" means a hydrocarbon chain having at least one (preferably only one) double carbon-carbon bond and containing 2-15 of atsmon carbon, preferably 2-10, more preferably 2-4 carbon atoms. "Alkyne" means a hydrocarbon chain having at least one (preferably only one) triple carbon-carbon bond and containing 2 to 15 carbon atoms, preferably 2-10, more preferably 2-4 carbon atoms. Alkyl, alkenone and askinosie chain (called collectively the "hydrocarbon chain") can be linear or branched and may be unsubstituted or substituted. Preferred branched alkyl, alkenone and askinosie chains have one or two branches, preferably one branch. Preferred is apami are alkyl. Each of the alkyl, alkenovich and alkenovich chains may be unsubstituted or substituted by 1-4 substituents, where the preferred substituted chains are mono-, di - or tizamidine. Each of the alkyl, alkenovich and alkenovich chains may be substituted by a radical selected from the group including halogen, hydroxy, aryloxy (for example, phenoxy), heteroaromatic, acyloxy (for example, acetoxy), carboxy, aryl (e.g. phenyl), heteroaryl, cycloalkyl, heteroseksualci, spirits, amino, amido, acylamino, keto, taketo, cyano, or any combination thereof. Preferred hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl and eksootilisel.

Also, when using this term here is "lower" alkyl, Allenova or alkyne group (for example, "lower alkyl") refers to the chain of 1-6, preferably 1-4 carbon atoms in the case of alkyl and 2-6, preferably 2-4 carbon atoms in the case of alkene and alkyne.

"Alkoxy" means an oxygen radical having a hydrocarbon Deputy, where the hydrocarbon chain means alkyl or alkenyl (for example, -O-alkyl or-O-alkenyl). Preferred alkoxygroup include (for example) methoxy, ethoxy, propoxy, allyloxy.

"Aryl" means an aromatic hydrocarbon cycle. Aryl cycles are monocyclics the Yu or condensed bicyclic system. Monocyclic aryl ring containing 6 carbon atoms in the cycle. Monocyclic aryl rings are also called phenyl rings. Bicyclic aryl rings contain 8-17 carbon atoms, preferably 9 to 12 carbon atoms in the cycle. Bicyclic aryl ring include cyclic system, where one cycle is aryl and the other loop means aryl, cycloalkyl or heteroseksualci. Preferred bicyclic aryl ring include 5-, 6 - or 7-membered cycles, a condensed 5-, 6 - or 7-membered cycles.

Aryl cycles can be unsubstituted or substituted by 1-4 substituents on the cycle. Aryl can be substituted by a radical selected from the group comprising halogen, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, halogenated, phenyl, aryloxy, alkoxy, heteroalkyl, carbamyl, halogenated, methylendioxy, heteroaromatic or any combination of them. Preferred kilkee cycles include naphthyl, tolyl, xylyl and phenyl. The most preferred cyclic aryl radical is phenyl.

"Aryloxy" means oxygen radical, aryl having a substituent (ie, -O-aryl). Preferred alloctype include (for example) phenoxy, naphthyloxy, methoxyphenoxy, methylenedioxyphenoxy.

"Cycloalkyl" means a saturated or unsaturated uglev the full cycle. Cycloalkyl rings are non-aromatic. Cycloalkyl rings are monocyclic or condensed, Spiro or bridged bicyclic systems. Monocyclic cycloalkyl rings contain of the order of 3-9 carbon atoms, preferably 3 to 7 carbon atoms in the cycle. Bicyclic cycloalkyl rings contain about 7 to 17 carbon atoms, preferably 7-12 carbon atoms in the cycle. Preferred bicyclic cycloalkyl ring include 4-, 5, 6 - or 7-membered cycles, a condensed 5-, 6 - or 7-membered cycles. Cycloalkyl rings can be unsubstituted or substituted by 1-4 substituents on the cycle.

Cycloalkyl may be substituted by a radical selected from the group comprising halogen, cyano, alkyl, heteroalkyl, halogenated, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaromatic or any combination of them. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl.

"Halogen" or "halogen" means fluorine, chlorine, bromine or iodine. The preferred Halogens are fluorine, chlorine and bromine; usually preferred chlorine and fluorine, especially fluorine.

"Halogenated" means a linear, branched or cyclic hydrocarbon, substituted by one or more galogenovye substituents. Preferred are1 -C12-halogenated; more preferred C1-C6-halogenated; even more preferred C1-C3-halogenoalkane. Preferred halogen substituents are fluorine and chlorine. The most preferred halogenation is trifluoromethyl.

"Heteroatom" means an atom of nitrogen, sulfur or oxygen. Groups with more than one heteroatom can contain different heteroatoms.

"Heteroalkyl" means a saturated or unsaturated chain containing carbon and at least one heteroatom, where two heteroatoms may not be related. Heteroalkyl chain containing 2 to 15 atoms (carbon and heteroatoms), members of the chain, preferably 2-10, more preferably 2-5.

For example, alkoxy (i.e.- O-alkyl or-O-heteroalkyl) radicals are heteroalkyl. Heteroalkyl chain can be linear or branched. Preferred branched heteroalkyl has one or two branches, preferably one branch. Preferred heteroalkyl is saturated. Unsaturated heteroalkyl has one or more double carbon-carbon bonds and/or one or more triple carbon-carbon bonds. Preferred unsaturated heteroalkyl have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chain can be n is substituted or is substituted by 1-4 substituents. Preferred substituted heteroalkyl are mono-, di - or tizamidine. Heteroalkyl may be substituted by a radical selected from the group comprising lower alkyl, halogenated, halogen, hydroxy, aryloxy, heteroaromatic, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heteroseksualci, spirits, amino, acylamino, amido, keto, taketo, cyano, or any combination thereof.

"Heteroaryl" means an aromatic cycle, containing carbon atoms and about 1 to 6 heteroatoms in the loop. Heteroaryl cycles are monocyclic or condensed bicyclic systems. Monocyclic heteroaryl cycles contain of the order of 5 to 9 atoms (carbon and heteroatoms) - members of the cycle, preferably 5 or 6 atoms of the members of the cycle. Bicyclic heteroaryl cycles 8-17 contain atoms of the members of the cycle, preferably 8-12 atoms members of the cycle. Bicyclic heteroaryl cycles include cyclic system, where one cycle is heteroaryl, and another cycle is aryl, heteroaryl, cycloalkyl or heteroseksualci. Preferred bicyclic system with heteroaryl cycles contain 5-, 6 - or 7-membered cycles, a condensed 5-, 6 - or 7-membered cycles. Heteroaryl cycles may be unsubstituted or substituted by 1-4 substituents on the cycle. Heteroaryl can be C is substituted radical, selected from the group comprising halogen, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, halogenated, phenyl, alkoxy, aryloxy, heteroaromatic or any combination of them. Preferred heteroaryl cycles include, but without limitation specified, the following:

"Heteroaromatic" means oxygen radical having a heteroaryl substituent (ie, -O-heteroaryl).

Preferred heterokaryosis include (for example) pyridyloxy, furanose, (thiophene)hydroxy, (oxisol)hydroxy, (thiazole)hydroxy, (isoxazol)hydroxy, pyrimidinone, pyrazinone, benzothiazolinone.

"Heteroseksualci" means a saturated or unsaturated cycle containing carbon atoms and about 1 to 4 (preferably, 1 to 3) heteroatoms in the loop. Heterocytolysine rings are non-aromatic. Heterocytolysine rings are monocyclic or condensed, connected in bridge connection or spirobicyclic systems. Monocyclic generalclassifiable contain from about 3 to about 9 atoms (carbon and heteroatoms) - members of the cycle, preferably 5-7 atoms of the members of the cycle. Bicyclic heterocytolysine rings contain 7-17 atoms members of the cycle, preferably 7-12 atoms members of the cycle. Bicyclic heterocytolysine rings contain from about 7 to about 17 atoms of the members of the cycle, preferably 7-12 atoms members of the cycle. Bicyclic heterocytolysine ring may be condensed, Spiro or bridged bicyclic systems. Preferred bicyclic heterocytolysine rings include 5-, 6 - or 7-membered cycles, a condensed 5-, 6 - or 7-membered cycles. Heterocytolysine rings can be unsubstituted or substituted by 1-4 substituents on the cycle. Heteroseksualci may be substituted by a radical selected from the group comprising halogen, cyano, hydroxy, carboxy, keto, taketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, halogenated, phenyl, alkoxy, aryloxy or any combination of them. Preferred substituents on heteroseksualci include halogen and halogenated. Preferred heterocytolysine rings include, but without limitation specified, the following:

As used here, the term "metalloprotease mammals" means the protease described in the section "Background of the invention this application. Compounds of the present invention mainly active against metalloprotease mammals, including any metal-containing (preferably zinc) enzyme found in animals, mostly mammals, capable of appropriate test conditions to catalyze the breakdown of collagen, gelatin or a proteoglycan. Suitable test conditions can be found, for example, in U.S. patent 4743587, which refer to the method Cawston'a, et al., Anal. Biochem. (1979) 99:340-345; synthetic substrate described in Weingarten, H., et al., Biochem. Biophv. Res. Comin. (1984) 139:1184-1187. See also Knight, C.G. et al., "A Novel Coumarin-Labelled Peptide for Sensitive Continuous Assays of the Matrix Metalloproteases", FEBS Letters. Vol.296, pp.263-266 (1992). Of course, you can use any standard method of analysis of the destruction of these structural proteins. The compounds being considered mainly active against enzymes-metalloprotease representing a zinc-containing proteases, which are similar in structure to, for example, human stromelysin or collagenase skin fibroblasts. The ability of the presented compounds to inhibit the activity meta is apoteosi, of course, it can be studied by the above analysis. The selected enzymes metalloprotease can be used to confirm the inhibitory activity of the compounds according to the invention, or can be used crude extracts contain a number of enzymes that can destroy the fabric.

"Spirits" means alkyl or heteroalkyl biradially Deputy alkyl or heteroalkyl where specified biradially Deputy joined in genialnom position and forms a cycle, and this cycle contains 4-8 atoms members cycle (carbon or a heteroatom), preferably 5 or 6 atoms of the members of the loop.

Although alkyl, heteroalkyl, cycloalkyl and heterocytolysine group may be substituted by hydroxy-, amino-, and aminopropane, as indicated above, the invention does not address the following structure:

1. Enols (IT is connected to the carbon bearing the double bond).

2. The amino group attached to the carbon bearing the double bond (except amides-homologues vinylamides).

3. More than one hydroxy-, amino - or aminogroups attached to the same carbon atom (except when two nitrogen atom attached to the same carbon atom and all three atoms are members forming heterocyclizations ring).

4. Hydroxy-, amino-, or aminogroups, prisoedinneny the I to the carbon which also has connected therewith heteroatom.

5. Hydroxy-, amino - or aminogroups attached to the carbon, which also has connected therewith a halogen.

"Pharmaceutically acceptable salt" means a cationic salt formed any acidic group (for example, hydroxamic or carboxylic acid), or an anionic salt formed any basic (e.g., amino) group. Many such salts are known in the art and are described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987, incorporated herein by reference. Preferred cationic salts include alkali metal salts (such as sodium and potassium), salts of alkaline earth metals (such as magnesium and calcium) and organic salts. Preferred anionic salts include halides (such as chloride salts, sulfonates, carboxylates, phosphates, and the like.

These salts are well known to experts, and the expert is able to get a number of salts on the basis of known in the field of information. In addition, it is clear that the specialist may prefer one salt to another for reasons of solubility, stability, ease of formulation, and the like. The definition and the optimal choice of salt relate to the field of competence of the specialist in medical practice.

"Biohydrology amide" means amide inhibitor meta is apoteosi, containing hydroxamic acid (i.e., R1in the formula (I) means-NHOH), which does not interfere with inhibitory activity of compounds or which can easily be converted in vivo in the body of an animal, preferably a mammal, more preferably human, with active inhibitor metalloprotease. Examples of these amide derivatives are alkoxyamine, where the hydroxyl hydrogen hydroxamic acids in the formula (I) substituted alkyl radical, and allocine, where the hydroxyl hydrogen is replaced by the acyl radical (i.e., R-C(=O)-).

"Biohydrology hydroxyamide" means imide inhibitor metalloprotease containing hydroxamic acid, which does not interfere with the inhibitory activity of these compounds against metalloprotease, or which is readily converted in vivo in the body of an animal, preferably a mammal, more preferably human, with active inhibitor metalloprotease. Examples of these imenik derivatives are derived, where the hydrogen of the amino hydroxamic acids in the formula (I) is replaced by the acyl radical (i.e. R-C(=O)-).

"Biohydrology ester" means an ester inhibitor metalloprotease containing carboxylic acid (i.e., R’ in the formula (I) means-HE), which does not interfere actively inhibiting the t of these compounds against metalloprotease, or which is easily converted into the body of the animal with the formation of the active inhibitor metalloprotease. Such esters include lower alkalemia esters, lower aryloxyalkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonylmethyl, pivaloyloxymethyl and pivaloyloxymethyl esters), lactonase esters (such as palidrome and totalidade esters), lower alkoxyalkanols esters (such as methoxycarbonylmethylene, ethoxycarbonylmethylene and isopropoxycarbonyloxymethyl esters), alkoxyalkyl esters, kalinovye esters and alchilcicloalchilsulfai esters (such as acetamidomethyl esters).

"MES" means a complex obtained by combining the solute (e.g., inhibitor metalloprotease) and solvent (e.g. water). See, J. Honig et al.. The Van Nostrand Chemist''s Dictionary, p.650 (1953).

Pharmaceutically acceptable solvents used in this invention include solvents that do not affect biological activity of the inhibitor metalloprotease (for example, water, ethanol, acetic acid, N,N-dimethylformamide and other known or easily select a specialist solvents).

The term "optical isomer", "stereoisomer and diastereoisomer" are commonly understood in the field of values (see, for example, Hawley's Condensed Chemical Dictionary, 11th Ed.). Illustrative examples of specific protected forms and other derivatives of the present invention not considered as limiting. Other useful protective groups form salts and the like is within the skill of a specialist.

II. Connection

Considering the invention includes compounds of formula (I):

where R1, R2, R3, n, a, E, X, G, G’, M and Z agree to the above values. The following is a description of a particularly preferred group values not considered as limiting the scope of invention.

R1choose from HE-NHOH, preferably HE.

R2selected from the group comprising hydrogen, alkyl, alkenyl, quinil, heteroalkyl, halogenated, cycloalkenyl, geterotsiklicheskikh, arylalkyl and heteroaromatic; preferably hydrogen or alkyl, more preferably hydrogen.

R3selected from the group including alkyl, alkenyl, alkynyl, heteroalkyl, halogenated, cycloalkyl, heteroseksualci, arylalkyl and heteroaromatic;

preferably, the alkyl, heteroalkyl, geterotsiklicheskikh, arylalkyl or heteroaromatic.

n = 0~4, preferably 0 or 1, more preferably 0.

A represents a substituted or unsubstituted monocyclic hetero cloacal with 3-8 atoms in the cycle, of which 1-3 are heteroatoms. Preferably contains 5 to 8 atoms in the cycle, more preferably, 6 or 8 atoms in the cycle. And means preferably substituted or unsubstituted piperidine, tetrahydropyran, tetrahydrothiopyran or perhydroanthracene; more preferably, piperidine, tetrahydropyran or tetrahydrothiopyran. An alternative, and R2may together form a substituted or unsubstituted monocyclic heteroseksualci with 3-8, preferably, 5 to 8, more preferably 6 or 8) atoms in the cycle and 1 to 3 heteroatoms. Of these cycles are preferred those in which not combined with R2forming a loop.

E is chosen from the group comprising covalent bond, C1-C4-alkyl, -C(=O)-, -C(=O)O-, C(=O)N(R4)-, -SO2or-C(=S)N(R4)-. In a preferred embodiment, E is chosen from the group comprising a bond, C1-C3-alkyl, -C(=O)- C (=O)O-, -C(=O)N(R4)- or-SO2-, more preferably, E means With1-C2-alkyl, -C(=O)-, -C(=O)O - or-S(=O)N(R4)-.

R4selected from the group comprising hydrogen, alkyl, alkenyl, quinil, heteroalkyl, halogenated, cycloalkyl, heteroseksualci, aryl, arylalkyl, heteroaryl and heteroaromatic; preferably hydrogen or lower alkyl.

X is chosen from the group comprising hydrogen, alkyl, alkenyl, quinil, heteroalkyl, Galaga is alkyl, aryl, arylalkyl, heteroaryl, heteroaromatic, cycloalkyl and heteroseksualci. X preferably denotes hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroaromatic, cycloalkyl or heteroseksualci; most preferably, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl or heteroaromatic. Alternative and preferably, X and R4join to form a substituted or unsubstituted monocyclic heteroseksualci with 3-8 atoms in the cycle, of which 1-3 are heteroatoms. When X and R4form a loop, preferably a 5-7 membered cycles with 1 or 2 heteroatoms.

G is chosen from the group comprising-S-, -O-, -N(R5)-, -C(R5)=C(R51)-, -N=C(R5)- and-N=N-; in a preferred embodiment, the G means-S - or-C(R5)=C(R51)-. Each of R5and R5’independently selected from the group comprising: hydrogen, alkyl, alkenyl, quinil, heteroalkyl, aryl, heteroaryl, cycloalkyl and heteroseksualci, preferably, at least one of R5and R5’means hydrogen, more preferably, both signify hydrogen.

G’ is chosen from the group comprising-S-, -O-, -N(R6)-, -C(R6)=C(R6’)-, -N=C(R6)- and-N=N-; in a preferred embodiment, the G’ is-S - or-C(R6)=C(R6’)-. Each of R6and R6’independently selected from the group, including the setup portion of the hydrogen, alkyl, alkenyl, quinil, heteroalkyl, aryl, heteroaryl, cycloalkyl and heteroseksualci; preferably, at least one of R6and R6’means hydrogen, more preferably, both signify hydrogen.

M is chosen from-CH - and-N-; preferably M means-SN-.

Z means (CR7R7’)a-L-R8where a is 0~4, preferably 0 or 1. Each of R7and R7’independently selected from the group comprising hydrogen, alkyl, alkenyl, quinil, aryl, heteroalkyl, heteroaryl, cycloalkyl, heteroseksualci, halogen, halogenated, hydroxy and alkoxy; preferably each of R7means hydrogen and each of R7’independently means hydrogen or lower alkyl.

L is chosen from the group comprising covalent bond, -O-, -SOb-, -C(=O)-, -C(=O)N(R9)-, -N(R9)- and-N(R9)C(=O)-; preferably L is-O-, -S-, -SO2-, -C(=O)N(R9)-, -N(R9)- and-N(R9)C(=O)-; more preferably, L is-O-or-S-. b is 0-2. R9selected from the group comprising hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heteroseksualci and halogenated; R9preferably means hydrogen, lower alkyl or aryl. Alternative, R7and R9together with the atoms to which they are attached, join to form a optionally substituted GE is erotic, containing 5-8, preferably 5 or 6) atoms, of which 1-3 (preferably 1 or 2) are heteroatoms.

R8selected from the group comprising hydrogen, alkyl, alkenyl, quinil, halogen, heteroalkyl, halogenated, aryl, heteroaryl, cycloalkyl and heteroseksualci; preferably R8means halogen, lower alkyl, lower heteroalkyl or aryl. Alternative, R8and R together with the atoms to which they are attached, join to form optionally substituted heterocycle containing 5-8, preferably 5 or 6) atoms, of which 1-3 (preferably 1 or 2) are heteroatoms.

III. Getting connections

Compounds according to the invention can be obtained using various methods. The raw materials used for producing compounds according to the invention are known, can be obtained by known methods or are produced industrially. Particularly preferred syntheses described in the following General reaction schemes (group R, is used to illustrate reaction schemes, not necessarily correlate with the corresponding R groups used to describe different variants of compounds of formula (I). That is, for example, R1in the formula (I) does not mean the same groups that R1in this section). Specific examples of the preparation of compounds according to the present image the structure below in section VII.

Scheme 1

According to scheme 1 ketone S1a is industrially produced material. By interacting with psfonts S1b specified ketone can be converted into unsaturated ester S1c with a very good yield. Hydrogenolysis of this material under standard conditions gives the complex aminoether S1d. At this stage can be introduced substituents R1and R2by applying the reductive amination and subsequent sulfonylamine, or Vice versa, sulfonylamine with subsequent alkylation sulfonamidnuyu group.

Protective group BOC for sulfonamida S1e can be removed under standard conditions well known in the art, which leads to the formation of complex aminoether S1f. The methyl ester group of this compound can be hydrolyzed under standard conditions, which gives the amino acid S1g. At this stage of the substituent R3nitrogen atom of the piperazine may be entered under a variety of conditions. Thus, the reaction of reductive amination, acylation, arilirovaniya, carbamylcholine, sulfonylamine and education urea, all with good output lead to the target carboxylic acid S1i.

Alternatively, the substituent R3can be entered in standard conditions, at the stage of obtaining complex methyl ester S1f that when the result in connection with a complete set of functionalities S1i.

Scheme 2

Scheme 2 ketone S2a is industrially produced material. By interacting with the phosphonate S2b specified ketone can be converted into unsaturated ester S2c with a very good yield. May also be performed oxidation of the heteroatom X (X=S), which gives X=SO2. Hydrogenolysis of this material under standard conditions gives the complex aminoether S2d. At this stage can be introduced substituents R1and R2by applying the reductive amination and subsequent sulfonylamine, or, on the contrary, sulfonylamine with subsequent alkylation sulfonamidnuyu group. The sulfonamide S2f can then be converted to the desired carboxylic acid S2g using the standard conditions used for the hydrolysis of esters.

Scheme 3

In figure 3, the amino acid S3a is industrially produced material. Can be used with the standard terms for turning S3a into the corresponding methyl ester S3b. At this stage of the substituent R1can be entered in response sulfonylamine obtaining convenient intermediate S3c. If you can be entered more complex substituent R’ by applying a sequence of several stages of the synthesis. Deputy R2maybe it is b then put into a standard alkylation conditions, which leads to the intermediate connection S3d.

Protective BOC-group sulfonamida S3d can be removed under standard conditions well known in the art, which leads to the formation of complex aminoether S3. Konoma group of this compound can be hydrolyzed under standard conditions, which gives the amino acid S3f. At this stage of the substituent R3nitrogen atom of the piperazine may be entered under a variety of conditions. Thus, the reaction of reductive amination, acylation, arilirovaniya, carbamylcholine, sulfonylamine and education urea, all with good output result in the target complex ether carboxylic acid S3g. Standard hydrolysis of the ester functionality S3g leads to the target carboxylic acid S3h.

Methyl ester S3g is a common intermediate compound for the synthesis of hydroxamic acids S3h. Thus, the processing S3h the main solution of hydroxylamine in methanol leads to the corresponding hydroxamic acid in one stage. Alternatively, the carboxylic acid S3h can be converted to hydroxamic acid by two-stage transformation, including: 1) the combination of O-protected form of hydroxylamine and 2) removing the protective group. For a given transformation can be used protecting groups are well known in this field (e.g., be the ZIL, tert-butyl, tert-butyldimethylsilyl).

These stages may vary with the purpose of increasing the yield of the desired product. For professionals it is obvious that a reasonable choice of reagents, solvents and temperatures is an important component of any successful synthesis. Determination of optimal conditions, etc. is an everyday practice.

Thus, you can get a variety of connections using the instructions for the above schemes.

Obviously, a specialist in the field of organic synthesis can easily make a standard transformation of organic compounds without additional guidance; that is, the implementation of such transformations belongs to the sphere of competence of the specialist. These transformations include, but are not in the order limitations, reduction of carbonyl compounds to their corresponding alcohols, oxidation of the hydroxyl and the like, acylation, aromatic substitutions, both electrophilic and nucleophilic, etherification, esterification and saponification, and the like. Examples of these transformations are described in standard methods, such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol.2), and other sources known to specialists in this field of technology.

The specialist also knows that some interaction is best done when the others who potenziale reactive functionality on the molecule is masked or protected, that helps to avoid any undesirable side reactions and/or to increase the yield of the reaction. Often specialists use protective group to achieve higher outputs or to avoid unwanted interactions. Such reactions found in the literature and are also included in the competence of the specialist. Examples of many such transformations can be found, for example, in T. Greene, Protecting Groups in Organic Synthesis. Of course, used as starting material amino acids with reactive side chains preferably block, preventing unwanted side reactions.

Compounds according to the invention can have one or more chiral centers. The result can be selectively received one optical isomer, including diastereoisomer-and enantiomer prevailing over the other, for example, through the use of chiral starting materials, catalysts or solvents, or may be obtained both stereoisomer or both optical isomers, including diastereomers and enantiomers, at the same time (racemic mixture). Since the compounds according to the invention can exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as chiral salts, chiral chromatography and the like.

Cu is IU, it is obvious that one optical isomer, including diastereoisomer-and enantiomer, or stereoisomer may have superior properties. Therefore, when in the description or the attached points of the invention are mentioned only racemic mixture, it is clear that both optical isomers, including diastereomers and enantiomers, or stereoisomers, essentially free from each other, also referred to.

IV. Applications

Metalloprotease (MP), found in the body, causing, in particular, the destruction of the intercellular matrix, including intercellular proteins and glycoproteins. Inhibitors of metalloprotease useful in the treatment of diseases caused, at least in part, by the destruction of these proteins to glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of the body tissue. Thus, MP directly involved in the reconstruction of tissue.

It is noted that as a result of this exposure MP active in many diseases, including either:

(1) the destruction of tissues, including eye disease; degenerative diseases, such as arthritis, multiple sclerosis and the like; and the metastases or mobility of the tissues in the body, or (2) the reconstruction of tissues, including heart disease, fibrotic disease, scarring, benign hyperpl is the Zia and the like.

Compounds of the present invention prevent or treat disorders, diseases and/or unwanted conditions characterized by undesirable or excessive activity of MT. For example, the compounds can be used for inhibition of MP that:

1. destroy the structural proteins (i.e. proteins that support the stability of the fabric and structure);

2. prevent intracellular/intercellular signaling, including MP involved in positive regulation of cytokines, and/or processing of cytokines and/or inflammation, tissue destruction and other diseases [Mohler KM, et al, Nature 370 (1994) 218-220, Gearing AJH, et al, Nature 370 (1994) 555-557 McGeehan GM, et al. Nature 370 (1994) 558-561]; and

3. contribute to the processes that are undesirable in treated patients, for example the process of sperm maturation, fertilization and so on.

As used here, the term "associated with the MP violation" or "associated with the MP illness" means a condition associated with unwanted or increased activity of the MP in the biological manifestation of a disease or disorder; in the biological cascade leading to the violation; or symptom of the disease. This link MP includes:

1. Unwanted or increased activity of the MP as a "cause" of a disease or biological manifestations, where the activity of genetically improved due to infection, autoimmune R. the shares, injuries, biomechanical factors, lifestyle [e.g., obesity] or for some other reason;

2. MP as part of the visible manifestations of the disease or disorders. That is, the disease or disorder is measurable in terms of increased activity of the MP. From a clinical point of view, undesirable, or elevated levels of MP testify about the disease, however, MP is not necessarily a "criterion" of a disease or disorder; or

3. Unwanted or increased activity of the MP is part of the biochemical or cellular cascade that results in or is related to the disease or disorder. In this regard, the inhibition of the activity of the MP interrupts the cascade and thereby regulates the disease.

The term "treatment" (treatment), as used here, means that the introduction of the compounds of the present invention, at least facilitates disease associated with undesirable or increased activity of MP in a patient mammal, mostly human. Thus, the term "treatment" includes: prevention MP-mediated disease in a mammal, particularly when the mammal is predisposed to the disease, but the disease has not yet been identified; inhibition of MT-mediated diseases and/or mitigation MP-mediated disease or recovering MP-mediated Zabol the cation. Insofar as the methods of the present invention is aimed at the prevention of disease associated with undesirable activity of MP, it should be understood that teamin "warning" does not imply that the disease is completely suppressed. (See Webster's Ninth Collegiate Dictionary.). Rather, the term "preventing"as used here, means an opportunity for professionals to identify the population susceptible to MP-mediated disorders, so the introduction of the compounds of the present invention may be carried out before the onset of the disease. The term does not imply that the disease can be completely avoided. For example, osteoarthritis (OA) is the most common rheumatic disease with some changes in the joints, radiographically detectable in 80% of people over the age of 55 years. Fife, R. S., "A Short History of Osteoarthritis", Osteoarthritis: Diagnosis and Medical/Surgical Management, R.W.Moskowitz, D.S.Howell, V.M.Goldberg and H.J.Mankin Eds., p 11-14 (1992). The total risk factor that increases the incidence of OA is traumatic injury of the joint. Surgical removal of the meniscus after injury to the knee increases the risk of radiographically detectable OA, and this risk increases over time. Roos, H et al. "Knee Osteoarthritis After Menisectomy: Prevalence of Radiographic Changes After Twenty-one Years, Compared with Matched Controls." Arthritis Rheum., Vol.41, pp 687-693; Roos, H et al. "Osteoarthritis of the Knee After Injury to the Anterior Cruciate Ligament or eniscus: The Influence of Time and Age." Osteoarthritis Cartilege., Vol.3, pp 261-267 (1995). Thus, this group of patients was identified, and it is possible to enter the compounds of the present invention prior to the development of the disease. Consequently, the development of OA in these patients may be "warned".

Convenient that many MP are not distributed evenly throughout the body. Therefore, the distribution of MP, expressed in various tissues, is often specific to these tissues. For example, the distribution of metalloprotease involved in the destruction of the tissues of the joints, is not the same as the distribution of metalloprotease found in other tissues. Though not necessarily for the activity or efficacy of drugs, some diseases, disorders and unwanted conditions should preferably be treated with compounds that act on specific MP found in infected tissues or body parts. For example, found that the compound exhibiting a greater degree of activity and inhibition of MP found in the joints (e.g., chondrocytes), it will be more convenient for the treatment of diseases, disorders or unwanted conditions than other compounds, which are less specific.

In addition, some inhibitors are biologically more available to some tissues than others. The choice of inhibitor MP, which is more biologically available for certain fabrics and there is a very specific MP, found in this tissue, providing specific treatment of disease, disorders or unwanted conditions. For example, the compounds according to the invention vary in their ability to penetrate into the Central nervous system. Thus, it can be selected compounds for influence through MP found, in particular, outside of the Central nervous system.

Determination of the specificity of an inhibitor specific MP is a specialist in this field. The appropriate test conditions can be found in the literature. In particular, the known test stromelysin and collagenase. For example, U.S. patent No. 4743587 gives a reference to the method of Cawston, et al. Anal Biochem (1979) 99:340-345. See also, Knight, C.G. et al., "A Novel Coumarin-Labelled Peptide for Sensitive Continuous Assays of the Matrix Metalloproteases", FEES Letters. Vol.296, pp.263-266 (1992). The use of synthetic substrate in the tests described Weingarten, N., et al., Biochem Biophy Res comm (1984) 139: 1184-1187. Of course, you can use any standard method of analysis for the destruction of the structural proteins of metalloproteases. The ability of compounds according to the invention to inhibit the activity of metalloprotease undoubtedly can be investigated in the tests referred to in the literature, or modified methods. To confirm the inhibitory activity of the compounds according to the invention can be used selected enzymes metal the protease, either can be used crude extracts contain a number of enzymes that can destroy the fabric.

Compounds of the present invention is also useful for the prevention or treatment of acute diseases. These compounds enter any convenient for professionals in the field of medicine and pharmacology way. For professionals it is obvious that the preferred routes of administration are dependent on requiring treatment status and selected dosage forms. Preferred methods of systemic injections include oral or parenteral administration.

In addition, the specialist will appreciate the advantage of introducing inhibitor MP directly on/in the affected area in many diseases, disorders or undesirable conditions. For example, it may be convenient to enter inhibitors MP directly on/in this section of the diseases, disorders or unwanted conditions, how the plot that received surgical trauma (e.g., angioplasty), section scarring, burn (for example, local skin), or eye or periodontal indications.

Since the reconstruction of the bones involved MP, the compounds according to the invention is useful for preventing loosening of the prosthesis. In this area it is known that over time the prosthesis is loosened, it becomes painful for PAC the enta and can lead to additional damage to the bones, so you need to replace it. Requiring replacement prostheses include artificial limbs, as wspanialy joints (for example, wspanialy hip, knee and shoulder joints), dentures, including artificial teeth, dentures and bridges that strengthen the upper and/or lower jaw.

MP is also active in the reconstruction of the cardiovascular system (for example, in congestive heart failure). It is assumed that one of the reasons that plastic surgery on the blood vessels gives more than expected, slowing of heart rate (greater reclosing time) is that the activity of the MP is unwanted or elevated, that response can be recognized by the body as damage the basement membrane of the vessel. Thus, regulation of the activity of the MP with such indications as advanced cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, breach of reperfusion, ischemia, chronic obstructive lung disease, restenosis after plastic surgery on the blood vessels and aortic aneurysm, can increase long-term success of any treatment, or may serve as a treatment in itself.

When skin care MP involved in the reconstruction or renew the skin. As a result, the regulation of MP improves the treatment of skin conditions, including, but not okay restrictions, wrinkle removal, containment, prevention and elimination caused by UV damage to the skin. This treatment includes prophylactic treatment or treatment before physiological manifestations become apparent. For example, the mounting plate can be used as a treatment before irradiation to prevent caused by UV lesions and/or during or after exposure to prevent or minimize the destruction by ultraviolet light. In addition, the MP involved in skin disorders and diseases associated with abnormal tissue that occurs when abnormal update, which includes an active metalloprotease, such as congenital bullous bullosa, psoriasis, scleroderma, and atopic dermatitis. Compounds according to the invention are also useful for the treatment of the effects of "normal" skin damage including scarring or "contraction" of the fabric, for example, after burn. MP inhibitors are also useful in disrupting the skin surgery to prevent scarring and stimulate growth of healthy tissue, including such applications as in operation extremity replantation and refractory surgery (laser or cut).

In addition to this MP is linked to disorders including irregular reconstruction of other tissues, such as bone, for example, when otosclerosis and/or the OST is the porous, or tissue specific organs, as in the case of cirrhosis of the liver and pneumovirus. Similarly, when such diseases as multiple sclerosis, MP can be involved in irregular reconstruction of the blood-brain barrier and/or myelin layer of neural tissue. Thus, the method of regulating the activity of the MP can be used for the treatment, prevention and deterrence of the specified diseases.

It is also expected that the Marines involved in many infectious diseases, including cytomegalovirus [CMV-CMV]; retinitis; HIV and resulting syndrome, AIDS-AIDS.

MP may also be involved in extravascularly, where the tissue environment must be destroyed, which enables the formation of new blood vessels, as, for example, when angiofibroma and hemangioma.

Since MP destroy the extracellular matrix, it is assumed that the inhibitors for these enzymes can be used as agents of birth control, for example, to prevent ovulation, preventing the penetration of sperm inside the extracellular environment and through the extracellular environment of an egg, implantation of the fertilized ovum and to prevent sperm maturation.

In addition, it is assumed that MP is also useful to prevent or stop preterm birth and childbirth.

Since MP is also involved in the inflammatory response and in the processing of cytokines, the compounds are also useful as anti-inflammatory drugs for use in diseases where inflammatory process is predominant, including inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, asthma and related lung diseases, rheumatoid arthritis, gout and disease Reiter.

When the cause of the disease is autoimmune reaction, the immune response is often initiates the activity of the MP and cytokines. Regulation of MP in such autoimmune disorders is a useful method of treatment. So, MP inhibitors can be used to treat disorders, including lupus erythematosus, ankylosing spondylitis and autoimmune keratitis. Sometimes side effects autoimmune therapy lead to aggravation of other conditions mediated MP, here therapy MP inhibitors are also effective, for example, when the fibrosis caused by an autoimmune therapy.

In addition, treatment of the specified type are amenable to other fibrotic diseases, including pulmonary embolism, bronchitis, emphysema, cystic fibrosis, acute respiratory distress syndrome (in particular, the response to the acute stage).

When MP is involved in unwanted destruction of the fabric is by exogenous agents, they can be treated with inhibitors MP. For example, inhibitors MP effective as antidotes by the bite of a rattlesnake, remedy for boils, for the treatment of allergic inflammatory diseases, septicemia and shock. In addition, they are useful as antiparasitic means (e.g., malaria) and antibacterial agents. For example, it is believed that they are useful in the treatment or prevention of viral infections, including infection, leading to herpes, "cold" (for example, rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS.

Inhibitors MP are also useful in the treatment of Alzheimer's disease, side amyotrophies sclerosis (ALS ALS), muscular dystrophy, complications, arising out of or resulting from diabetes, in particular, including the loss of viability of the tissue, coagulation, homologous disease (graft versus host), leukemia, cachexia, anorexia, proteinuria and possibly to regulate hair growth.

In some diseases, conditions or disorders inhibitors MP seen as the preferred methods of treatment. Such diseases, conditions or disorders include arthritis (including osteoarthritis and rheumatoid arthritis), cancer (in particular, to prevent or delay the growth of tumors or Metastasio), eye diseases (the particular corneal ulcers, poor wound healing of the cornea, macular degeneration and Parigi) and gum disease (especially periodontal disease and gingivitis).

Preferred, but not considered in order restrictions, compounds for the treatment of arthritis (including osteoarthritis and rheumatoid arthritis) are those compounds that are selective against metalloprotease matrix and disintegrin-metalloprotease.

Preferred, but not considered in order restrictions, compounds for the treatment of cancer (in particular, prevention or delay of tumor growth and metastasis) are those compounds that mainly inhibit gelatinase or collagenase type IV.

Preferred, but not considered in order restrictions, compounds for the treatment of eye diseases (in particular, corneal ulcers, weak corneal healing, macular degeneration and pterygia) are those compounds that inhibit a wide range of metalloprotease. Preferably these compounds to enter local, more preferably, in the form of drops or gel.

Preferred, but not considered in order restrictions, the compounds for treating diseases of the gums (especially periodontal disease and gingivitis) are those compounds that preferentially inhibit collagened.

V. Composition

The composition of the invention include:

(a) a safe and effective amount of the compounds according to the invention and

(b) a pharmaceutically acceptable carrier.

As discussed above, there are many diseases mediated by excessive or unwanted activity metalloprotease. These diseases include metastatic tumors, osteoarthritis, rheumatoid arthritis, inflammatory skin diseases, ulcers, particularly the cornea, the reaction to the infection, periodontitis, and the like. Thus, the compounds according to the invention are useful for treatment of conditions associated with such undesirable activity.

Therefore, the compounds according to the invention can be prepared as pharmaceutical compositions for the treatment or prevention of these conditions. Use standard technology for preparation of pharmaceutical compositions, such as described in Remington''s Pharmaceutical Sciences. Mack Publishing Company, Easton, Pa., latest edition.

"Safe and effective amount" of the compounds of formula (I) means the amount, which is effective for the inhibition of metalloprotease on the site (sites) activity in the body of an animal, preferably a mammal, more preferably human, and do not have undesirable side effects (such as toxicity, sosbud the susceptibility or allergic reaction), commensurate with a reasonable benefit ratio/risk when used according to the method of the present invention. The exact "safe and effective amount"will obviously vary according to such factors as specific requiring treatment condition, the physical condition of the patient, duration of treatment, the nature of concurrent therapy (if any), the specific dosage form used by the media, the solubility therein of compounds of formula (I) and desirable for the composition scheme of administration of the medicine.

In addition to the compounds of the composition according to the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used here, means one or more compatible solid or liquid fillers, diluents or encapsulating substances that are suitable for administration to an animal, preferably a mammal, more preferably human. The term "compatible", as used here, means that the components of the composition is able to be mixed with the compound according to the invention and with each other so that there is no interaction, can substantially reduce the pharmaceutical efficacy of the composition under conditions of normal use. Pharmaceutically acceptable carriers should the s, of course, to have a sufficiently high purity and sufficiently low toxicity to be suitable for introduction to the needy in the treatment of an animal, preferably a mammal, more preferably human.

Some examples of substances which can serve as pharmaceutically acceptable carriers or their components, are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and methyl cellulose; powdered tragakant; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, Kungaeva oil, olive oil, corn oil and oil cocoa; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents, such as nutriceuticals; dyes; corrigentov; tabletiruemye agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline and phosphate buffer solutions.

The choice of pharmaceutically acceptable carrier used in combination with the connection according to the invention, mainly the allocated offered by way of introduction connections.

If the connection according to the invention is intended for administration by injection, the preferred pharmaceutically acceptable carrier is sterile physiological solution containing compatible with blood suspendisse agent, the pH is increased to approximately 7,4.

In particular, pharmaceutically acceptable carriers for systemic injections include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, etiloleat, pyrrolidone, ethanol and Kungaeva oil. Preferably pharmaceutically acceptable carrier in a composition for parenteral administration is at least about 90 mass % of the whole composition.

The compositions of the present invention is preferably presented in a standard dosage form. As used here, the term "standard formulation" means a composition according to the invention, containing a number of compounds of formula (I)suitable for administration to an animal, preferably a mammal, more preferably human, one dose, in accordance with us is oasa medical practice. These compositions preferably contain from about 5 mg (milligrams) up to 1000 mg, more preferably from 10 mg to 500 mg, more preferably, from about 10 mg to 300 mg, of the compounds of formula (I).

The compositions of the present invention can be presented in any of a number of existing forms, suitable (for example) for oral, rectal, local, nasal, ophthalmic, or parenteral administration. Depending on the desired specific method of administration can be used a variety of pharmaceutically acceptable carriers that are well known in this field. These carriers include solid or liquid fillers, diluents, girotropnye compounds, surface-active agents, and encapsulating substances. Can be enabled with optional pharmaceutically active materials, essentially no effect on the inhibitory activity of the compounds of formula (I). The number of media used in combination with the compound of the formula (I)is sufficient to ensure convenient for practical use, the amount of material with the aim of introducing the compounds of formula (I) in a single dose. The techniques and compositions for making dosage forms in accordance with the methods according to this invention, is described in the following literature included here in the quality of the ve links: Modern Pharmaceutics. Chapters 9 and 10 (Banker &Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

Can be used in a variety of oral dosage forms, including such solid forms as tablets, capsules, granules, and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5% and preferably from 25% to 50%, of compounds of formula (I). Tablets can be compressed, powdered tablets, coated intersolubility layer, covered with sugar, covered with a film or a composite compressed, contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, corrigentov providing flowability agents, and agents, giving the ability to melt in your mouth. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions recovered from nishiuchi granules and effervescent preparations recovered from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspendresume tools, diluents, sweeteners, agents, giving the ability to melt in your mouth, dyes and corrigentov.

Pharmaceutically acceptable carriers suitable for receiving a standard dosage forms that are intended for peror the form of further introduction, well known in this field. Tablets typically comprise conventional pharmaceutically acceptable auxiliary means, as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrating agents such as starch, alginic acid and crosscarmellose; lubricants such as magnesium stearate, stearic acid and talc. To improve the characteristics of flowability of the powder mixture can be used a means to slip, such as silicon dioxide. Coloring agents such as dyes, FD&C can be added to improve appearance. Sweeteners and corrigentov, such as aspartame, saccharin, menthol, peppermint and fruit flavours are useful tools for chewable tablets. Capsules typically include one or more of the above solid diluents. The choice of component carriers is determined by secondary considerations such as taste, price and shelf life, which are not critical, and can be easily installed by a specialist in this field.

Oral compositions can also include liquid solutions, emulsions, suspensions and the like. Pharmaceutically acceptable carriers that are suitable to obtain the compositions shown, well known in this field. Typical media components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, liquid sucrose, sorbitol and water. For suspensions normal suspendresume agents include methylcellulose, sodium carboxymethyl cellulose, Avicel" RC-591, tragakant and sodium alginate; wetting characteristic tools include lecithin and Polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as the above sweeteners, corrigentov and dyes.

These compositions can also be coated in conventional manner, typically by coating providing a dependence on pH or from time to time, so that the connection according to the invention is released in the gastrointestinal tract in place of the required local application, or at various times to extend the desired action. These dosage forms usually include, but are not in the order of limits, coverage of one or more compounds comprising a phthalate of acetylcellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose, ethylcellulose, Eudragit, wax and shellac.

The compositions of the present invention can optionally include other active drug is ngredient.

Other compositions useful for systemic delivery of the compounds according to the invention include sublingual, transbukkalno and nasal dosage forms. These compositions typically include one or more soluble compounds, fillers, such as sucrose, sorbitol and mannitol; binders, such as juice acacia, microcrystalline cellulose and hypromellose. May also be included the above mentioned means for sliding, lubricants, sweeteners, colorants, antioxidants and corrigentov.

The compositions of this invention can also be injected to the patient topically, for example, by direct application or spreading of the composition on epidermal or epithelial tissue of the patient, or by transdermal injection through a "patch". These compositions include, for example, lotions, creams, solutions, gels and solids. These local compositions preferably comprise a safe and effective amount, usually at least about 0.1% and preferably from about 1% to 5%, of compounds of formula (I). Suitable carrier materials for the local introduction of predominantly remain in place on the skin as a continuous film and is resistant to destruction under the action of perspiration or immersion in water. Typically, the carrier is organic Avenue is the genus and capable of dispersing or dissolving the compound of formula (I). The media may include pharmaceutically acceptable softeners, emulsifiers, thickeners, solvents and the like.

VI. Methods introduction

In the present invention are also methods of treating or preventing disorders associated with excessive or unwanted activity metalloprotease in the body of man or other mammal, through the introduction of safe and effective amount of the compounds of formula (I) specified patient. As used here, the term "disease associated with excess or unwanted activity metalloprotease" means any breach, characterized by disruption of the protein matrix. The methods of the invention are useful for the treatment or prevention of the above violations.

The compositions of this invention can be injected locally or systemically. Systemic application includes any method of introducing the compounds of formula (I) in the body tissue, for example, intra-articular (in particular, for the treatment of rheumatoid arthritis), intracapsular, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal or oral administration. The compounds of formula (I) according to the present invention are preferably administered orally.

Specific input dose of the inhibitor, as well as the duration of treatment and on the definition, whether the treatment of local or systemic, are interdependent factors. The dose and regimen of medicines also depend on such factors as the specific compound of formula (I), therapeutic indications, the ability of the compounds of formula (I) to achieve a minimum ingibiruyah concentrations at the site of location of inhibiting metalloprotease, personal characteristics of the patient (such as weight), compliance with the treatment regimen and the presence and severity of side effects.

Typically, for an adult (weighing approximately 70 kilograms) is administered from about 5 mg to 3000 mg, more preferably, from about 5 mg to 1000 mg, more preferably, from about 10 mg to 100 mg of the compounds of formula (I) per day for systemic administration. It is clear that these dose limits are given only for the purpose of example and that daily administration can be refined by taking into account the above factors.

The preferred method of administration for treatment of rheumatoid arthritis is oral administration or parenteral via intra-articular injection. As is known and practiced in the field, all the compositions for parenteral administration must be sterile. For mammals, especially humans (based on estimated average body weight of 70 kg) is preferred individual doses, priblizitel is but from 10 mg to 1000 mg

The preferred method of system introduction is oral. Preferred individual dose from about 10 mg to 1000 mg, more preferably, from about 10 mg to 300 mg

Local injection can be used for systemic delivery of the compounds of formula (I) or local treatment of the patient. The number entered locally the compounds of formula (I) depend on such factors as skin sensitivity, type and location of the treated tissue is entered, the composition and carrier (if any), the specific input connection of the formula (I), as well as the specific violation, requiring treatment, and the extent to which the desired system (as distinguished from local) effects.

The inhibitors according to the invention can be directed to specific areas where accumulated metalloprotease, through the use of targeted ligands. For example, in order to concentrate inhibitors in tumors containing metalloprotease, inhibitor kongugiruut with the antibody or its fragment, which takes an immune response to tumor marker, as usually assumed in obtaining immunotoxins in General. The targeting ligands may also be ligands suitable for the present on tumor receptor. For introduction into the target tissue can be used any directed ligands that specifically cooperation is midastouch with the marker. Methods of coupling compounds according to the invention with directional ligands are well known and similar to the methods described below for coupling with a carrier. The conjugates are prepared and injected as described above.

For localized States preferably local introduction. For example, for treatment of ulcerated cornea can be used for direct application on the affected eye composition in the form of eye drops or spray. For the treatment of corneal compounds according to the invention can also be prepared in the form of gels, straw or ointments or can be incorporated into collagen or hydrophilic polymer container. The materials can also be introduced in the form of contact lenses or reservoir, or in the form of subconjunctival composition. For the treatment of inflammatory skin diseases, the compound is applied topically or locally in the form of a gel, paste, cream or ointment. For the treatment of diseases of the oral cavity, the connection may be applied locally in the form of a gel, paste, rinse mouth or dental implant. Thus, the method of treatment reflects the nature of the state, and in this area are available suitable compositions for any selected method.

Of course, in all the above cases, the compounds according to the invention can be introduced separately or as mixtures, and compositions can optionally include an extension medicinal cf is DSTV or fillers, appropriate indication.

Some compounds according to the invention also inhibit bacterial metalloprotease. Some bacterial metalloprotease can be less dependent on the stereochemistry of the inhibitor, whereas found significant differences between the diastereomers in their ability to inactivate the protease mammals. Thus, this activity can be used to establish differences between the enzymes of the mammalian and bacterial enzymes.

VII. Examples - Getting connections

In this description, the following notation is used:

Meon: methanol

EtOAc: ethyl acetate

Ph: phenyl

DMF: N,N-dimethylformamide (DMF)

DME: dimethoxyethane (DME)

conc.: concentrated (conc.)

DCC: 1,3-dicyclohexylcarbodiimide

Et3N: triethylamine

Et2A: diethyl ether

b: tert-butyloxycarbonyl

ASAS: acetate

dil.: diluted (razb.)

wrt: with regard to

NOT: 1-hydroxybenzotriazole

Group R used to illustrate examples of the compounds does not correlate with the corresponding R groups used to describe the various components of the formula (I). That is, for example, R1and R2used to describe the formula (I) in the section "Brief description of the invention" and in section II of the "Detailed description", do not mean the same groups who, what R1and R2in this section VII.

EXAMPLES 1-16

The following table 1 shows the structures of the compounds obtained according to the methods described in examples 1-16. In these examples And in the formula (I) means piperidinyl cycle.

Table 1

ExampleEXR1R2
1-C(=O)-Me-C6H4-4-OMe
2-C(=O)--CH2Ph-C6H4-4-OMe
3-C(-O)--Et-C6H4-4-OMe
4-C(=O)--Me-C6H4-4-VG
5-C(=O)O--CH2CH2OMe-Me-C6H4-4-OMe
6-C(=O)O--CH2CH2OMe-Et-C6H4-4-OMe
7-C(=O)O-CH 2CH2OMe-CH2CH2CH2CH2-C6H4-4-OMe
8-C(=O)O--CH2CH2OMe-CH2CH2OMe-C6H4-4-OMe
9-C(=O)O--CH2CH2OMe-CH2Ph-C6H4-4-OMe
10-C(=O)O--CH2CH2OMe-CH2CH2Ph-C6H4-4-OMe
11-C(=O)O--CH2CH2OMe-CH2-2-pyridyl-C6H4-4-OMe
12-C(=O)O--CH2CH2OMe-CH2-3-pyridyl-C6H4-4-OMe
13-C(=O)O--CME3-C6H4-4-OMe
14-C(=O)O--CME3-Me-C6H4-4-F
15-SO2--CH2Ph-Me-C6H4-4-OMe
16-CH2--CH2RHMe -C6H4-4-OMe

Example 1

[(4’-Methoxybiphenyl-4-sulfonyl)methylamino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid

a) tert-Butyl ether 4-(benzyloxycarbonylamino)piperidine-1-carboxylic acid.

To a solution of 4-BOC-piperidone (30 g) and phosphonate (50 g) in dichloromethane (100 ml), cooled to 0°add dropwise diazabicyclo (32,16 g). The resulting mixture was stirred at room temperature for 5 days. The solvent is removed under reduced pressure and the mixture is dissolved in EtOAc. The organic extracts washed with water, then with saturated salt solution, then dried (Na2SO4). The crude product obtained after evaporation of the solvent, purified by chromatography on silica gel using a mixture of 3/2 hexane/EtOAc, giving the desired product as a white solid.

b) tert-Butyl ether 4-(aminoethoxymethyl) piperidine-1-carboxylic acid

Tert-butyl methyl ether

4-(benzyloxycarbonylamino)piperidine-1-carboxylic acid (49,1 g) dissolved in methanol (100 ml) and add 10% palladium on coal (2.36 in). The flask was filled with hydrogen and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered through a plug of celite and the solvent of pariva the t under reduced pressure, receiving the desired product, which is used in subsequent reactions without purification.

c) tert-Butyl ether 4-[(4’-methoxybiphenyl-4-sulfonylamino)methoxycarbonylmethyl]piperidine-1-carboxylic acid

To a solution of tert-butyl ester 4-(aminoethoxymethyl)piperidine-1-carboxylic acid (5,42 g) in dichloromethane (80 ml), add triethylamine (3,05 g), then 4’-methoxybiphenyl-4-sulphonylchloride (to 6.19 g). The reaction mixture was stirred at room temperature overnight, washed successively 1 N. hydrochloric acid, water, 5% aqueous sodium bicarbonate and saturated salt solution, then dried (Na2SO4). The crude product obtained after evaporation of the solvent, purified by chromatography on silica gel using a mixture of 3/2 hexane/EtOAc, giving the desired product as a colourless solid.

d) salt of the methyl ester (4’-methoxybiphenyl-4-sulfonylamino)piperidine-4-luxusni acid with TFU

The salt solution tert-butyl ester 4-[(4’-methoxybiphenyl-4-sulfonylamino)methoxycarbonylmethyl] piperidine-1-carboxylic acid with TFU (triperoxonane acid) (6.7 g) in dichloromethane (60 ml) is added triperoxonane acid (60 ml) and the reaction mixture was stirred at room temperature for 3 hours. The solvents are removed under reduced pressure and the crude product solidified when XP is on, use in the next stage without additional purification.

e) Methyl ether (4’-methoxybiphenyl-4-sulfonylamino)-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid

To a suspension of the salt of the methyl ester (4’-methoxybiphenyl-4-sulfonylamino)piperidine-4-luxusni acid with TFU (5,02 g) in dichloromethane (30 ml) was added triethylamine (2.5 ml) followed by the addition of morpholinylcarbonyl (1.4 g)and the reaction mixture stirred at room temperature for 4 hours. The solvents are removed under reduced pressure and the residue diluted with ethyl acetate and washed successively 1 N. hydrochloric acid, water, saturated salt solution and then dried (Na2SO4). The crude product obtained after evaporation of the solvent, purified by crystallization from methanol, obtaining the desired product as a colourless solid.

f) Methyl ether [(4’-methoxybiphenyl-4-sulfonyl)methylamino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid

To a solution of methyl ester (4’-methoxybiphenyl-4-sulfonylamino)-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid (1.04 g) in dimethylformamide (8 ml) is added anhydrous cesium carbonate (0.75 g) followed by the addition under the conditions of 0.85 ml)and the reaction mixture stirred at room temperature overnight. The solvents are removed under reduced pressure, the NII and the residue diluted with methylene chloride and washed successively with water, saturated salt solution, and then dried (PA2SO4). The crude product obtained after evaporation of the solvent, is purified using RP-HPLC - RP-HPLC, giving the desired product as a colourless solid.

g) [(4’-Methoxybiphenyl-4-sulfonyl)methylamino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid

To a solution of methyl ester [(4’-methoxybiphenyl-4-sulfonyl)methylamino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid (323 mg) in tetrahydrofuran (10 ml) is added 50% sodium hydroxide (3 ml) and the reaction mixture was stirred at room temperature for 2 hours. The solvents are removed under reduced pressure and the residue diluted with ethyl acetate and washed successively with water, saturated salt solution, and then dried (Na2S04). The crude product obtained after evaporation of the solvent, purified using OF SASH, giving the desired product as a colourless solid.

Example 2

[Benzyl-(4’-methoxybiphenyl-4-sulfonyl)amino]-[1-(morpholine-4-carbonyl) piperidine-4-yl]acetic acid

a) Methyl ether [benzyl-(4’-methoxybiphenyl-4-sulfonyl) amino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid

To a solution of methyl ester (4’-methoxybiphenyl-4-sulfonylamino)-[1-(morpholine-4-carbonyl)piperidine-4-yl]-acetic acid (493 mg) in dimethylformamide (6 ml) is added anhydrous cesium carbonate (300 mg) followed by the addition of benzylbromide (353 mg), and the reaction mixture was stirred at room temperature for 3 days. The solvents are removed under reduced pressure and the residue diluted with ethyl acetate and washed successively with water, saturated salt solution, and then dried (Na2SO4). The crude product obtained after evaporation of the solvent, is purified using RP-HPLC, giving the desired product as a colourless solid.

b) [Beneil-(4’-methoxybiphenyl-4-sulfonyl)amino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid

To a solution of methyl ester [benzyl-(4’-methoxybiphenyl-4-sulfonyl)amino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid (196 mg) in tetrahydrofuran (10 ml) is added 50% sodium hydroxide (4 ml) and the reaction mixture was stirred at room temperature overnight. The solvents are removed under reduced pressure and the residue diluted with ethyl acetate and sequentially washed with water, saturated salt solution, and then dried (Na2SO4). The crude product obtained after evaporation of the solvent, is purified using RP-HPLC, giving the desired product as a colourless solid.

Example 3

The product of example 3 is obtained from the product of example 1E, following the procedure described in example 1, and using ethyliodide on stage 1f.

Example 4

The product of example 4 is obtained from product PR is a measure 1b, following the procedure described in example 1, and using bromodiphenylmethane on stage 1C.

Example 5

The product of example 5 is obtained from the product of example 1d, following the procedure described in example 1, and using methoxyethylmercury on stage 1E.

Example 6

The product of example 6 is obtained from the product of example 1d, following the procedure described in example 1, and using methoxyethylmercury on stage 1E and ethyliodide on stage 1f.

Example 7

The product of example 7 is obtained from the product of example 1d, following the procedure described in example 1, and using methoxyethylmercury on stage 1E and N.-butylated on stage 1f.

Example 8

The product of example 8 is obtained from the product of example 1d, following the procedure described in example 1, and using methoxyethylmercury on 1st stage and 2-methoxyethylamine - stage 1f.

Example 9

The product of example 9 is obtained from the product of example 1d, following the procedure described in example 1, and using methoxyethylmercury on stage 1E and benzylbromide on stage 1f.

Example 10

The product of example 10 is obtained from the product of example 1d, following the procedure described in example 1, and using methoxyethylmercury on stage 1E and fenilatilamin on stage 1f.

Example 11

The product of example 11 is obtained from the product of example 1d, following the procedure described in example 1, and using methoxyethylmercury n the 1st stage and 2-picolylamine on stage 1f.

Example 12

The product of example 12 is obtained from the product of example 1d, following the procedure described in example 1, and using methoxyethylmercury on stage 1E and 3-picolylamine on stage 1f.

Example 13

The product of example 13 is obtained from the product of example 1C, following the procedure described in example 12, and using 4-(2-chloroethyl)morpholine in stage 1f.

Example 14

The product of example 14 is obtained from the product of example 1b, following stages 1C, 1f and 1g, described in example 1, and using forgivenessinventory on stage 1C.

Example 15

The product of example 15 is obtained from the product of example 1d, following the procedure described in example 1, and using benzolsulfonate on stage 1E.

Example 16

[(4’-Methoxybiphenyl-4-sulfonyl)methylamino]-(1-finetipped-4-yl)acetic acid

a) Methyl ether (4’-Methoxybiphenyl-4-sulfonylamino)-(1-finetipped-4-yl)acetic acid

To mix the salt solution of the methyl ester (4’-methoxybiphenyl-4-sulfonylamino)piperidine-4-luxusni acid with TFU (1d) (5,02 g, to 9.15 mmol) in methanol (30 ml) add phenylacetaldehyde (1.80 g, 15.0 mmol) and pyridine (1 ml). Then added dropwise complex, borane-pyridine (~8 M NR3, 2 ml) and the solution stirred at room temperature. Four hours later add another 0.5 ml of the complex NR3the pyridine and the reaction mixture is left to mix the night. The solvent is removed under reduced pressure and the resulting white solid product absorb with ethyl acetate, washed with 1N. hydrochloric acid and water. Adding 1N. sodium hydroxide to ethyl acetate leads to the formation of a white precipitate, which is filtered, washed with diethyl ether and dried in vacuum, obtaining the desired product.

b) [(4’-Methoxybiphenyl-4-sulfonyl)methylamino]-(1-finetipped-4-yl)acetic acid

To a solution of methyl ester (4’-methoxybiphenyl-4-sulfonylamino)-(1-finetipped-4-yl)acetic acid (522 mg, 1.0 mmol) in N,N-dimethylformamide (5 ml) is added cesium carbonate (326 mg, 1.0 mmol) and methyliodide (142 mg, 1.0 mmol). The mixture is stirred for four hours, then diluted with water and extracted with dichloromethane. The organic extracts are combined, washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining the desired product as a white solid.

C) Methyl ester [(4’-methoxybiphenyl-4-sulfonyl) methylamino]-(1-finetipped-4-yl)acetic acid

To a stirred solution of [(4’-methoxybiphenyl-4-sulfonyl) methylamino]-(1-finetipped-4-yl)acetic acid (125 mg, 0.23 mmol) in tetrahydrofuran (4 ml) is added aqueous sodium hydroxide (50% wt./mass., 200 μl), methanol (0.5 ml). Slightly turbid mixture was stirred then for the night. The reaction mixture was acidified with 1N. hydrochloric acid and extracted with dichloromethane. The organic phase is washed with saturated salt solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified using preparative RP-HPLC, giving the desired product as a white glassy solid.

EXAMPLES 17-22

The following table 2 shows the structures of the compounds obtained according to the methods described in examples 17-22. B this formula, a and R2formula (I) are heteroseksualci containing A’, which means heteroatom in the loop.

Table 2
ExampleAnd’EXR1
17-O---Me
18-N-C(=O)--Me
19-N-C(=O)--CH2Ph
20-N-C(=O)--CH2CH2OMe-CH2Ph
21-N-Is(=O)O- -CH2CH2OMe-CH2CH2OMe
22-N-CH2--Ph-CH2Ph

Example 17

4-[(4’-Methoxybiphenyl-4-sulfonyl)methylamino]tetrahydropyran-4-carboxylic acid

The product of example 17 receive according to the method similar to that shown below in example 18.

Example 18

4-[(4’-Methoxybiphenyl-4-sulfonyl)methylamino]-1-(morpholine-4-carbonyl)piperidine-4-carboxylic acid

a) 1-tert-Butyl ether, 4-methyl ester 4-aminopiperidin-1,4-dicarboxylic acid

To a suspension of mono-tert-butyl ester 4-aminopiperidin-1,4-dicarboxylic acid (13,9 g) in methanol (150 ml) and tetrahydrofuran (100 ml), cooled to 0°C, is added dropwise within 4 hours 2 M trimethylsilyldiazomethane in hexane (57 ml) followed by addition of 4-nitrophenylacetonitrile (2.0 g). The solvents are evaporated in vacuum and the crude product used in the next stage without additional purification.

b) 1-tert-Butyl ether, 4-methyl ester 4(4’-methoxybiphenyl-4-sulfonylamino) piperidine-1,4-dicarboxylic acid

To a solution of 1-tert-butyl ether, 4-methyl ester 4-aminopiperidin-1,4-dicarboxylic acid (155 mg) in dichloromethane (10 ml), add triethylamine (125 l), and then adding p-methoxydibenzoylmethane (187 is g). The reaction mixture was stirred over night at room temperature, washed with water and saturated salt solution, then dried (MgSO4). The crude product obtained after evaporation of the solvent, purified by chromatography on silica gel using a mixture of 4/1 hexane/EtOAc, giving the desired product as a colourless solid.

c) TFU salt of methyl ester of 4-(4’-methoxybiphenyl-4-sulfonylamino)piperidine-4-carboxylic acid

1-tert-Butyl ether, 4-methyl ester 4(4’-methoxybiphenyl-4-sulfonylamino)piperidine-1,4-dicarboxylic acid (3.12 g, to 6.19 mmol) dissolved in CH2Cl2(15 ml) in a flask 100 ml of the solution add anisole (1.35 ml, 12.4 mmol), followed by the addition triperoxonane acid (15 ml), dropwise, via syringe, and the mixture was stirred at 22°C for 8 hours. The yellow reaction mixture is concentrated to approximately CA. 4-5 ml before adding it dropwise to a mixed solution of diethyl ether/hexane (25 ml/475 ml). The precipitate is collected by filtration and washed with a mixture of 10:90 diethyl ether/hexane, receiving by a spectroscope clean TFU salt.

d) Methyl ester of 4-(4’-methoxybiphenyl-4-sulfonylamino)-1-(morpholine-4-carbonyl)piperidine-4-carboxylic acid

TFU salt of methyl ester of 4-(4’-methoxybiphenyl-4-sulfonylamino)piperidine-4-carboxylic acid (313 mg, of 0.60 mmol) var who're asked to CH 2CL2(25 ml) in a round bottom flask of 200 ml. Add morpholinylcarbonyl (85 l to 0.72 mmol) and triethylamine (211 l, of 1.52 mmol)and the mixture stirred at room temperature for 17 hours. The reaction mixture was diluted with more methylene chloride (50 ml) and extracted with water (3×75 ml). The extracts are washed with saturated salt solution, dried over gS4, filtered and concentrated in vacuo before the formation of the solid residue. Chromatography on silica gel using the eluent ethyl acetate/hexane gives the desired compound in the form of a colorless solid.

e) Methyl ester of 4-[(4’-methoxybiphenyl-4-sulfonyl) methylamino]-1-(morpholine-4-carbonyl)piperidine-4-carboxylic acid

Methyl ester of 4-(4’-methoxybiphenyl-4-sulfonylamino)-1-(morpholine-4-carbonyl)piperidine-4-carboxylic acid (65 mg, 0.13 mmol) dissolved in DMF (2 ml) in a conical reaction vial 10 ml of the solution add cesium carbonate (82 mg, 0.25 mmol), followed by the addition of iodomethane (40 l, 1.2 mmol) via syringe, and the mixture is stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (75 ml) and extracted four times with water (75 ml). The extracts are washed with saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo, resulting in the balance of the required connection in the ideal solid.

f) 4-[(4’-Methoxybiphenyl-4-sulfonyl)methylamino]-1-(morpholin-4-carbonyl)piperidine-4-carboxylic acid

Methyl ester of 4-[(4’-methoxybiphenyl-4-sulfonyl) methylamino]-1-(morpholine-4-carbonyl)piperidine-4-carboxylic acid (215 mg, 0.49 mmol) dissolved in THF (5 ml) in a round bottom flask of 50 ml Add a solution of the monohydrate of lithium hydroxide (210 mg, 5.0 mmol) in 5 ml of water and the mixture is heated on an oil bath to 70°With stirring for 4 hours. After extracting most of the THF under reduced pressure remains the aqueous layer was twice washed with diethyl ether. The aqueous layer was diluted with water (50 ml) and ethyl acetate (100 ml) and placed in an Erlenmeyer flask. Under stirring is added dropwise 6 N. Hcl, followed by addition of 1 N. Hcl to achieve in aqueous layer pH 2-3. The layers are separated and the aqueous layer was extracted with additional ethyl acetate. The extracts are washed with saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo to obtain a solid residue.

Purification by preparative HPLC gives the desired compound in the form of a colorless solid.

Example 19

The product of example 19 is obtained from the product of example 18d, following the procedure described in example 18, and using benzylbromide (1.5 EQ.) instead under the conditions at the stage 18E.

Example 20

The product of example 20 floor is up from the product of example 18C, following the procedure described in example 18, and using as a replacement methoxyethylmercury on stage 18d and benzylbromide on stage 18E.

Example 21

The product of example 21 is obtained from the product of example 18C, following the procedure described in example 18, and using as a replacement methoxyethylmercury on stage 18d and methoxyethylamine on stage 18E.

Example 22

The product of example 22 is obtained from the product of example 18C, following the procedure described in example 18, and using as a replacement benzylbromide on stage 18d and benzylbromide - stage 18E.

EXAMPLES 23-33

The following table 3 shows the structures of the compounds obtained according to the methods described in the examples 23-33.

Table 3
ExampleEXR1R2
23-C(=O)-Me-C6H4-4-OMe
24-C(=O)--CH2Ph-C6H4-4-OMe
25-C(=O)--Et-C6 H4-4-OMe
26-C(=O)--Me-C6H4-4-Br
27-C(=O)O--CH2CH2OMeMe-C6H4-4-OMe
28-C(=O)O--CH2CH2OMe-Et-C6H4-4-OMe
29-C(=O)O--CH2CH2OMe-CH2CH2Ph-C6H4-4-OMe
30-C(=O)O--CME3-Me-C6H4-4-OMe
31-C(=O)O--Cme3-Me-C6H4-4-F
32-SO2--CH2Ph-Me-C6H4-4-OMe
33-CH2--CH2RH-Me-C6H4-4-OMe

Example 23

N-Hydroxy-2-[(4’-methoxybiphenyl-4-sulfonyl)methylamino]-2-[1-(morpholine-4-carbonyl)piperidine-4-yl]ndimethylacetamide

Methyl ester [(4’-methoxybiphenyl-4-sulfonyl)methylamino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid (311 mg) is treated with methanol concrete is hydroxylamine (1,76 M, 3 ml) and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed sequentially 1H. hydrochloric acid, water, saturated salt solution and then dried (Na2SO4). The crude product obtained after evaporation of the solvent, purified using OF SASH, giving the desired product as a colourless solid.

Examples 24-33

The products of examples 24-33 obtained from the corresponding methyl ester by following the procedure described in example 23.

EXAMPLES 34-38

The following table 4 shows the structures of the compounds obtained according to the methods described in examples 34-38. The presented compounds of formula (I), where R1means-HE, n is 0, R2means H and a means depicted below the X-containing loop.

td align="center"> -C2H4-4-OMe
Table 4
ExampleXR1R2
34OMe-C6H4-4-OMe
35O-CH2Ph-C6H4-4-OMe
36O-CH2CH2OMe
37O-CH2-3-pyridyl-C2H4-4-OMe
38O-C6H4-4-OMe

Example 34

[(4’-Methoxybiphenyl-4-sulfonyl)methylamino]

(tetrahydropyran-4-yl)acetic acid

a) Methyl ester of benzyloxycarbonylamino (tetrahydropyran-4-ilidene)acetic acid

In a round bottom flask of 50 ml and receive a solution in acetonitrile (10 ml) trimethylboron ether N-(benzyloxycarbonyl)phosphonoglycine (1000 mg, to 3.02 mmol), to which is added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 ml, to 3.02 mmol). The mixture is left to mix for 10 minutes, then add tetrahydro-4H-Piran-4-one (299 mg, 2,95 mmol)and the reaction mixture stirred for 2 days. Then the solution was diluted with EtOAc (75 ml) and subsequently washed with 1 N. a solution of N2SO4. Then the solution is dried by washing with a saturated solution of salt and stirring with MqSO4. After filtration and concentration of the filtrate by evaporation on a rotary evaporator resulting dark reddish-brown oil was diluted with ethyl acetate and hexane (1:1) and filtered through a plug of silica gel to remove excess complex phosphorylating ether, using as eluent a mixture of 1:1 is tracecut/hexane. The solvent is removed in vacuum, obtaining the desired connection.

b) Methyl ester amino(tetrahydropyran-4-yl)acetic acid

Methyl ether benzyloxycarbonylamino(tetrahydropyran-4-ilidene)acetic acid (361 mg, 1.18 mmol) is added to the flask of the apparatus Parra for hydrogenation containing anhydrous methanol (6 ml)and the solution Tegaserod with argon for 10 minutes. Then the flask was added the catalyst is 5% palladium/charcoal. The solvent is then placed under a protective layer of hydrogen at a pressure of 3 ATM and shaken overnight. Thereafter, the catalyst was removed by filtration through celite. The removal of organic solvent under reduced pressure, followed by drying in vacuum to give an oily residue, NMR and mass spectrometric analyses which show that the required ester. The crude product is used without further purification.

c) Methyl ether (4’-methoxybiphenyl-4-sulfonylamino) (tetrahydropyran-4-yl)acetic acid

In a 100 ml round bottom flask and dissolved in a nitrogen atmosphere crude methyl ester amino(tetrahydropyran-4-yl)acetic acid (288 mg, 1,17 mmol) in anhydrous CH2Cl2(8 ml). After adding triethylamine (330 l of 2.35 mmol), add p-methoxydibenzoylmethane (499 mg, of 1.76 mmol) and the solution stirred overnight at room temperature. The reaction mixture is raybaut water and saturated salt solution and dried over MgSO 4. The crude material obtained after removal of solvent, and purified flash chromatography (solvent 40:60 ethyl acetate:hexane), giving the desired product as a white solid.

d) Methyl ester [(4’-methoxybiphenyl-4-sulfonyl) methylamino](tetrahydropyran-4-yl)acetic acid

Methyl ether (4’-methoxybiphenyl-4-sulfonylamino) (tetrahydropyran-4-yl)acetic acid (231 mg, 0.55 mmol) dissolved in DMF (4 ml) in a conical reaction vial 10 ml of the solution add cesium carbonate (359 mg, 1.12 mmol), followed by the addition under the conditions (343 l, 5.51 mmol) via syringe, and the mixture was stirred at 67°C for 16 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and extracted four times with water (75 ml). Washed with saturated salt solution and dried over MgSO4, filtered and concentrated in vacuo, resulting in the balance of the desired compound as a crude solid.

e) [(4’-Methoxybiphenyl-4-sulfonyl)methylamino] (tetrahydropyran-4-yl) acetic acid

Methyl ester [(4’-methoxybiphenyl-4-sulfonyl) methylamino](tetrahydropyran-4-yl)acetic acid (215 mg, 0.49 mmol) dissolved in THF (5 ml) in a round bottom flask of 50 ml Add a solution of the monohydrate of lithium hydroxide (210 mg, 5.0 mmol) in 5 ml of water and the mixture is stirred on an oil bath at 70°C for 4 hours. After removal the Oia mostly THF by evaporation on a rotary evaporator, the aqueous layer was twice washed with diethyl ether. The aqueous layer was diluted with water (50 ml) and ethyl acetate (100 ml) and placed in an Erlenmeyer flask. Under stirring is added dropwise 6 N. Hcl, followed by addition of 1 N. Hcl to achieve in aqueous layer pH 2-3. The layers are separated and the aqueous layer was extracted with additional ethyl acetate. Washed with saturated salt solution and dried over MgS4, filtered and concentrated in vacuo to obtain a solid residue. Purification by preparative HPLC gives the desired compound in the form of a colorless solid.

Example 35

The product of example 35 is obtained from the product of example 34, following the procedure described in example 34 and using as a replacement benzylbromide on stage 34d.

Example 36

The product of example 36 is obtained from the product of example 34C, following the procedure described in example 34 and using as a replacement, methoxyethylamine on stage 34d.

Example 37

The product of example 37 is obtained from the product of example 34C, following the procedure described in example 34 and using as a replacement 3-picolylamine on stage 34d.

Example 38

The product of example 38 is obtained from the product of example 34C, following the procedure described in example 34 and using as a replacement morpholinylcarbonyl on stage 34d.

Additional examples of making connections

Additional example 1

2-Methoxyethylamine ether (4-{carboxy-[4’-methoxy-biphenyl-4-sulfonyl)-(2-methoxyethyl)amino]methyl}piperidine-1-carboxylic acid (compound according to example 8).

a) Methyl ester of benzyloxycarbonylamino-(1-tert-butoxycarbonyl-piperidine-4-ilidene)-acetic acid. To a solution of 4-BOC-piperidine (6 g, 30 mmol) and trimethylboron ether N-(benzyloxycarbonyl)-α-phosphonoglycine (10 g, 30 mmol) in dichloromethane (25 ml) was added dropwise diazabicyclo (6,9 g, 42 mmol). The resulting mixture

was stirred at room temperature for 2 days and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and the organic phase is washed with water, 1 N. a solution of hydrochloric acid, saturated sodium bicarbonate solution and saturated saline and then dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the solvent, was purified by chromatography on silica gel using 3/2 hexane/EtOAc to obtain 11.2 g (yield 93,2%) of the desired product as a yellowish solid.1H NMR (Dl3) δ for 1.49 (m, N), 2,04-2,22 (m, 2H), 2,41-2,49 (m, 2H), 2,90 (s, 2H), 3,52 (s, 2H), 3,79 (s, 3H), of 5.17 (s, 2H), 7.37-7.42 (m, 5H). MS m/z 305 [M+H-(tert-Visa2)]+.

b) Methyl ether (1-tert-butoxycarbonyl-piperidine-4-yl)-(4’-methoxy-biphenyl-4-sulfonylamino)-acetic acid. Methyl ether of benzyloxycarbonylamino-(1-tert-butoxycarbonyl-piperidine-4-ilidene)-acetic acid (11,05 g and 27.3 mmol) was dissolved in methanol (100 m is) and added 10% palladium on coal (0.75 g). The flask was purged with hydrogen and created pressure to 45 psi, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered through a layer of celite and the solvent evaporated under reduced pressure to get crude product, which was used in the next stage without additional purification.

The crude product (5,44 g, 20 mmol) was dissolved in dichloromethane (80 ml) and to the mixture was added triethylamine (3,05 g and 21.8 mmol) followed by addition of 4'-methoxy-biphenyl-4-sulphonylchloride (5,94 g, 21 mmol). The reaction mixture was stirred over night at room temperature, then washed 1 N. a solution of hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and saturated saline, then was dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the solvent, was purified by chromatography on silica gel using 3/2 hexane/EtOAc to obtain by 8.22 g (combined yield 58%) of the desired product as a colourless solid.1H NMR (CDCl3) δ to 1.24 to 1.34 (m, 2H), 1,43-to 1.59 (m, 10H), 1,65 is 1.86 (m, 2H), 2,52-a 2.71 (m, 2H), 3.45 points (s, 3H), 3,74-3,88 (m, 1H), 3,94 (s, 3H), 4,11-4,24 (m, 2H), 5,19 (d, J 10.1 Hz, 1H), 7,01 (d, J=8,8 Hz, 2H), 7,58 (d, J=8,8 Hz, 2H), 7,69 (d, J=8.6 Hz, 2H), 7,86 (d, J=8.6 Hz, 2H). MS m/z 419 [M+H-(tert-Visa2)]+.

C) Methyl ether (4’-methoxy-beef the Nile-4-sulfonylamino)-[1-(2-methoxy-etoxycarbonyl)-piperidine-4-yl]-acetic acid. To a solution of methyl ester (1-tert-butoxycarbonyl-piperidine-4-yl)-(4’-methoxy-biphenyl-4-sulfonylamino)-acetic acid (6,1 g, 11.7 mmol) in dichloromethane (15 ml) at room temperature was added triperoxonane acid (TFUC) (8 ml) and the reaction mixture was stirred for 4 hours. The solvents are evaporated in vacuum and the resulting oil triturated with diethyl ether. The precipitate was collected, washed with diethyl ether and dried in vacuum to obtain 6.2 g of the crude salt TFUCK.

Salt TFUK suspended in dichloromethane (30 ml) was added triethylamine (3.9 ml, 28 mmol) followed by the addition of methoxyacetanilide (1.78 g, 12.9 mmol). The reaction mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and the solution washed successively 1 N. a solution of hydrochloric acid, water, saturated saline and then dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the solvent, was purified by crystallization from methanol with the receipt of 5.24 g (combined yield 86%) of the desired product as a colourless solid.1H NMR (Dl3) δ 1,22-to 1.87 (m, 5H), 2,73 (users, 2H), 3,41 (s, 3H), 3,47 (s, 3H), 3,62 (t, J=4,8 Hz, 2H), 3,81-3,86 (m, 1H), with 3.89 (s, 3H), 4,18-4,32 (m, 4H), 5,20 (d, J=10.1 Hz), 7,03 (d, J=8,8 Hz, 2H) 7,58 (d, J=8,8 Hz, 2H), 7,69 (d, J=8,4 Hz, 2H), 7,86 (d, J=8,4 Hz, 2H). MS m/z 521 [M+H]+.

d) Methyl ester [(4’-Methoxy-biphenyl-4-sulfonyl)-(2-methoxyethyl)-amino]-[1-(2-methoxyethoxymethyl)-piperidine-4-yl]-acetic acid. To a solution of methyl ester (4’-methoxy-biphenyl-4-sulfonylamino)-[1-(2-methoxy-etoxycarbonyl)-piperidine-4-yl]-acetic acid (1.04 g, 2 mmol) in dimethylformamide (8 ml) was added anhydrous cesium carbonate (0.75 g, 2.3 mmol) followed by addition of 2-methoxyethylamine (282 μl, 3 mmol), the reaction mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. The residue was diluted with methylene chloride and washed successively with water, saturated saline and then dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the solvent, was purified by chromatography on silica gel using 3/2 hexane/EtOAc to obtain 1.27 g (yield 91%) of the desired product as a colourless solid.

1H NMR (Dl3) δ 1,22-of 1.30 (m, 2H), 1,46 is 1.60 (m, 2H), 2,04-of 2.08 (m, 1H), 2,79-to 2.99 (m, 2H), 3.33 and (s, 3H), 3,39 (s, 3H), 3,41 (s, 3H), 3,51-to 3.64 (m, 6N), 3,90 (s, 3H), 4,19-to 4.28 (m, 5H),? 7.04 baby mortality (d, J=8,8 Hz, 2H), 7,58 (d, J=8,9 Hz, 2H), 7,68 (d, J=8,4 Hz, 2H), 7,87 (d, J=8,2 Hz, 2H). MS m/z 579 [M+H]+.

e) [(4’-Methoxy-biphenyl-4-sulfonyl)-(2-methoxyethyl)-amino]-[1-(2-methoxyethoxymethyl)-piperidine-4-yl]-acetic acid. It races the thief methyl ester [(4’-methoxy-biphenyl-sulfonyl)-(2-methoxyethyl)-amino]-[1-(2-methoxyethoxymethyl)-piperidine-4-yl]-acetic acid (323 mg, 0,558 mmol) in tetrahydrofuran (10 ml) was added a solution of lithium hydroxide (67 mg, 2.8 mmol) in a mixture of methanol-water (0.7 ml, 5:2 V/V) and the reaction mixture was stirred at room temperature for 12 hours. The solvents were removed under reduced pressure and the residue was dissolved in water and washed with diethyl ether. Then the aqueous layer was acidified using 1 N. a solution of hydrochloric acid and was extracted several times with ethyl acetate. The combined organic extracts were washed with saturated saline and then dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the solvent, was purified using RP-HPLC to obtain 256 mg (yield 81%) of the desired product as a colourless solid.1H NMR (Dl3) δ 1,17-of 1.29 (m, 2H), 1,65-1,71 (m, 1H), 1,86-2,07 (m, 2H), 2,85 (users, 2H), 3.33 and (s, 3H), 3,39 (s, 3H), 3,49-3,71 (m, 6N), the 3.89 (s, MN), 4,12-to 4.23 (m, 5H), 7,03 (d, J=9.0 Hz, 2H), 7,58 (d, J=8,8 Hz, 2H), to 7.68 (d, J=8.6 Hz, 2H), 7,89 (d, J=8.6 Hz, 2H);13With NMR (Dl3) δ 29,6, 36,6, 43,5, 43,8, 44,0, 46,2, 55,8, 59,1, 59,3, 71,3, 72,6, 114,9, 127,2, 128,5, 128,8, 131,8, 137,2, 145,8, 155,7, 160,6, 171,9; MS m/z 565 [M+H]+. Anal. (C27H36N2O9S·0,5H2O) C, H, N.

The following analogs were obtained in accordance with the methodology described in Additional example 1.

Additional example 2

[(4’-Methoxy-biphenyl-4-sulfonyl)-methylamino]-[1-(2-methoxyethoxymethyl is)-piperidine-4-yl]-acetic acid (compound according to example 5). 1H NMR(Dl3) δ 1,15-1,35 (m, 2H), 1,75 (t, J=18,1 Hz, 2H), 1,98-to 2.18 (m, 1H), 2,88 (users, 2H), 2,93 (s, 3H), 3,40 (s, 3H), 3,61-to 3.64 (m, 2H), a 3.87 (s, 3H), 4,11-4,27 (m, 5H), S (d, J=9.0 Hz, 2H), 7,66 (d, J=9,0 Hz, 2H), 7,78 (d, J=8,8 Hz, 2H), 7,88 (d, J=8.6 Hz, 2H);13With NMR (CD3D) δ 30,5, 31,1, 36,5, 44,9, 45,0, 56,2, 57,1, 59,5, 65,0, 66,1, 72,3, 114,6, 128,2, 129,6, 129,8, 133,2, 138,3, 146,9, 157,4, 162,1, 172,3; MS m/z 521 [M+H]+. Anal. (C25H32N2O8S·0,5H2O) C, H, N.

Additional example 3

[(4’-Methoxy-biphenyl-4-sulfonyl)-(pyridine-3-ylmethyl)-amino]-[1-(2 methoxyethoxymethyl)-piperidine-4-yl]-acetic acid (compound in example 12). Output 64,3%;1H NMR (Dl3) δ 0,82-0,98 (m, 1H), 1,02-1,25 (m, 2H), 1.70 to 1.55V (m, 2H), 1,78-of 1.97 (m, 1H), 2,84 is 2.51 (users, 1H), 2,68-2,83 (users, 1H), 3,30-of 3.42 (m, 4H), 3,56-3,68 (m, 2H), 3,92-3,98 (m, MN), 3,95-4,10 (m, 2H), 4,15-of 4.25 (m 2N), or 4.31-4,39 (m, 1H), with 4.64-4.72 in (m, 1H), 7,07 (d, J=8,8 Hz, 2H), 7,41-7,50 (users, 1H), 7,66 (d, J=8,8 Hz, 2H), 7,73 (d, J=8,8 Hz, 2H), 7,82 (d, J=8,8 Hz, 2H), 8,01-to 8.12 (m, 1H);13With NMR (CD3OD) δ 30,5, 31,2, 37,6, 44,9, 47,8, 56,2, 59,5, 66,1, 66,4, 72,3, 115,8, 115,9, 127,7, 128,2, 129,6, 129,8, 133,1, 139,4, 140,3, 147,1, 148,9, 150,5, 157,3, 162,2; MS m/z 598 [M+H]+. Anal. (C30H35N3O8S·0,8EtOAc·0.1HCl) C, H, N.

Additional example 4

(R)-(1-tert-Butoxycarbonyl-piperidine-4-yl)-(4’-methoxy-biphenyl-4-sulfonylamino)-acetic acid (compound A, R-enantiomer).

a) Methyl ester of (R)-amino-(1-tert-butoxycarbonyl-piperidine-4-yl)-acetic acid. To a solution of methyl ester ()-[(N-fluoren-9 ylmethoxycarbonyl)]-(1-tert-butoxycarbonyl-piperidine-4-yl)-acetic acid (402,9 mg, 0,838 mmol) in methanol at room temperature was added trimethylsilyldiazomethane (3.4 mmol) and the solution was stirred until the yellow color is not bleached. The solvent was removed in vacuum to obtain a white solid. Then the crude ester was consumed in ethanol, was added a catalytic amount of 10% Pd/C and the mixture was placed in a hydrogenation installation Parr (Parr) at night at a pressure of 40-45 psi. After 24 hours the reaction mixture was filtered through a layer of Celite and concentrated to obtain the crude aminoether in the form of a white solid.

b) Methyl ester of (R)-(1-tert-Butoxycarbonyl-piperidine-4-yl)-(4’-methoxy-biphenyl-4-sulfonylamino)-acetic acid. To a solution of methyl ester of methyl (R)-amino-(1-tert-butoxycarbonyl-piperidine-4-yl)-acetic acid (10 ml) was added a solution of sodium bicarbonate (214 mg, 2.55 mmol) in water (10 ml). The mixture was cooled to 0°and to the solution was added 4'-methoxy-biphenyl-4-sulphonylchloride (270 mg, 0,955 mmol) in tetrahydrofuran (10 ml), then the reaction mixture was allowed to warm to room temperature over night. The mixture was concentrated under vacuum and the resulting suspension was distributed between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×25 ml) and the combined organic phases are washed with 1 N. a solution of hydrochloric acid, water, saturated with the left solution and dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the solvent, was purified by chromatography on silica gel (60:40 hexane:ethyl acetate) to obtain 180 mg (41%yield from the three stages) of the desired product as a white solid. Cm. data of NMR for compound b in Additional synthesis example 1 above.

C) (R)-(1-tert-Butoxycarbonyl-piperidine-4-yl)-(4’-methoxybiphenyl-4-sulfonylamino)-acetic acid. To a solution of methyl ester of methyl (R)-(1-tert-butoxycarbonyl-piperidine-4-yl)-(4’-methoxy-biphenyl-1-4-sulfonylamino)-acetic acid (180 mg, 0,347 mmol) in tetrahydrofuran (15 ml) was added a hydrate of lithium hydroxide and the solution was stirred and heated to 50°With during the night. After cooling, the solvents were removed in vacuo and the resulting suspension was diluted with ethyl acetate and acidified to pH 4. The aqueous layer was extracted with ethyl acetate (2×25 ml) and the combined organic layers were washed with saturated soleum solution and dried. The solvents are evaporated in vacuum to obtain 80 mg (yield 46%) of the desired product as a white solid: aD-46,9.1H NMR (Dl3) δ 1,14-of 1.46 (m, 2H), 1,47 (s, N), of 1.62 (t, J=15.6 Hz, 2H), 1.93 and (m, 1H), 2,75 (m, 2H), 3,79 (d, J=5,9 Hz, 1H), 3,90 (s, 3H), 4.09 to (userd, J=13,6 Hz, 2H), 7,05 (d, J=8,8 Hz, 2H), of 7.75 (d, J=8,8 Hz, 2H), the 7.65 (d, J=8,4 Hz, 2H), 7,88 (d, 8.6 Hz, 2H);13With NMR (CD3D) δ 29,1, 30,3, 40,6, 56,2, 61,8, 81,5, 115,9, 128,1, 129,2, 129,8, 133,2, 140,3, 146,6, 56,8, 162,1, 174,9. Anal. (C25H31N3O7S·0,5H2O) C, H, N.

(S)-(1-tert-Butoxycarbonyl-piperidine-4-yl)-(4’-methoxy-biphenyl-4-sulfonylamino)-acetic acid (compound A, S-enantiomer). αD+46.9.

Additional example 5

[1-(2-Methoxyethoxymethyl)-piperidine-4-yl]-(4’-methylsulfanyl-biphenyl-4-sulfonylamino)-acetic acid (compound B). 92,3%;1H NMR (Dl3) δ 1,19-1,50 (m, 2H), 1,57-of 1.73 (m, 2H), 1,87-2,12 (m, 1H), 2,54 (s, 3H), 2,72-2,90 (users, 2H), 3,35 is 3.40 (m, 3H), 3,56-3,68(m, 2H), 3,76-a-3.84 (m, 1H), 4,10-4.26 deaths (m, 4H), 7,38 (d, J=8,4 Hz, 2H), 7,65 (d, J=8.6 Hz, 2H), 7,79 (d, J=8.6 Hz, 2H), 7,92 (d, J=8.6 Hz, 2H);13With NMR (CD3OD) δ 15,7, 28,9, 30,2, 40,5, 45,2, 45,2, 59,5, 61,8, 66,1, 72,3, 128,1, 128,4, 129,3, 129,8, 137,4, 140,9, 141,5, 146,3, 157,3, 174,5; MS m/z 523 [M+H]+. Anal. (C24H30N2O7S2) C, H, N.

Note: the compounds a and B in additional examples 4 and 5 are not exactly the compounds of the present invention, but is very close to him. They meet the following structural formula:

in which X represents the group of tert-butyl (compound a) and 2-methoxyethyl (-CH2CH2Och3) (compound B), a Z - groups-och3(compound a) and-S3(compound B). As you can see, the difference is only in the radical R3when the nitrogen atom in sulfonamidnuyu group, which compounds a and B is hydrogen.

the data of elemental analysis are shown in table 5.

Elemental analysis

Table 5
Connection exampleMol. formulaCalculatedFound
8 (comprimer 1)With27H36N2About9S·0,5H2OWith, 56,53; N 6,50; N 4,88With, 56,25; N 6,60; N 4,76
5 (comprimer 2)C25H32N2O8S·0,5H2OWith, 56,70; N 6,28; N of 5.29With, 56,55; N 6, 16; N to 5.21
12 (comprimer 3)C30H35N3O8S·0,8EtOAc·HClWith, 59,98; N 6,37; N 6,21With, 60,14; N 6,30; N of 5.82
Connection And (comprimer 4)With25H31N3O7S·0,5H2OWith, 58,46; N 6,48; N the 5.45With, 58,29; N. Of 6.65; N 5,38 αD- 46,9°
Connection And (comprimer 4)With25H31N3O7S·0,5H2OWith, 58,46; N 6,48; N the 5.45With, 58,65; N 6, 71; N 5,14 αD- 42,0°
Compound B (comprimer 5)C24H30N2O7S2With, 55,16; N 5,79; N are 5.36With, 54,91; N 5,77; N 5,22

VIII. Examples of Biological activity of compounds according to the invention

The SAR studies in vitro. Connect the Oia were tested for inhibition of collagenase -1, -2 and -3 (MMP-1, -8 and -13, respectively), gelatinase a and b (MMP-2 and -9, respectively), stromelysin (MMP-3) and matrilysin (MMP-7), as described in the literature. All indicators of binding were obtained at pH 7.4 and presented in Table 6.

The examined compounds were obtained and tested as racemic mixtures. To connect And received both enantiomers ((R)- and (S)-antipodes). Both isomers showed a relatively small difference that differ by 1 order in the inhibition of MMP-3 and MMP-13, which were the main targets.

4993,0
Table 6.

Inhibition in vitro of the enzyme MMP IC50(nm)
Conn No.DFID (IC50nm)
 MMP-1MMP-2MMP-3MMP-7MMP-8MMP-9MMP-13
518460,969,639523,613,92,4
1611326,81131,0473124,433,014,0
18280,8187,0-100243,016,51,4
216641,0 219,055411,714,61,6
812210,645,526502,49,11,0
1233091,086,136443,218,73,0
933500,865,132712,811,31,8
20-123382116,06373,0-242074453,05231,04729,0
21101673665,0 -216557519,03466,03990,0
18-162203773,07421,0>100002982,0-16290,06533,0
22-26817210,04663,0-11074115,0-15713,0700,0
19-238203981,06072,0-172764632,0>10000,0-13203,0
34>10000161,05364,0>1000082,1830,5307,5
36-1848582,1>1000041,5764,0350,0
37>10000159,08836,0>10000to 83.51022,0874,0
38>1000080,59455,0>1000090,91546,0253,0
732361,093,251715,918,91,4
1014971,550,225103,67,0a-0.7
1146251,440,044593,559,81,9
35>10000132,06002,0>1000052,63433,0322,0
And14200,5of 56.425901,2of 5.40,7
(R)-A1370<0,433,736601,56,60,4
(S)-A34907,234585103,071,56,9
B10800,440,61020 1,87,31,0

Selected compounds were also tested for solubility in buffer with pH 7 and plasma protein binding data are presented in Table 7. Most of these compounds have good solubility and meets or exceeds the minimum set value 1 mg/ml is Determined that the plasma protein binding is high enough (>90%) for all compounds with substituted piperidinyl ring that contrasts sharply with the relatively low binding proteins (62%)observed for the unsubstituted analog. Interestingly, N-substituted sulfonamides showed relatively low protein binding in comparison with the unsubstituted NH-sulfonamide, which gives two inhibitor (compound in examples 12 and 8) with an acceptable level of binding proteins (93.2% and 90.7 percent, respectively).

Table 7.

Solubility and binding to plasma proteins selected inhibitors
Connection example No.Solubility (mg/ml)Protein binding (%)
516,3896,8
20,32 
811,0990,7
120,363,2
9the 7.4399,0
And (comprimer 4)1,3599,6
B (comprimer 5)3,50of 98.2

IX. Examples of Compositions and methods of use

Compounds according to the invention is useful for obtaining compositions for treatment of diseases associated with undesirable activity of MT. The following examples of compositions and methods do not limit the invention, but provide guidance to professionals on obtaining and using the compounds, compositions and methods according to the invention. In each case, the following compound of example may be replaced by other compounds according to the invention, giving similar results. For the practitioner it is obvious that the examples give General guidance and may be modified depending on requiring treatment condition and the patient.

In this section the following notation is used:

EDTA: ethylenediaminetetraacetic acid (etc)

SDA: synthetically denatured alcohol

USP: USP

Example

According to the present invention are compositions in

a tablet designed for oral administration,

including:

Component Quantity

Connection example 31 15 mg

Lactose 120 mg

Corn starch 70 mg

Talc 4 mg

M the wrath Stuart 1 mg

A patient weighing 60 kg (132 lb)suffering from rheumatoid arthritis, treated by the method according to the invention. In particular, within 2 years of treatment specified patient: oral three pills a day.

After treatment, the patient was examined, found attenuation of the inflammatory process with improved mobility, not accompanied by pain.

The example In

According to the present invention receive a capsule for oral administration, including:

Component Amount (% wt./mass.)

Connection example 2 15%

The glycol 85%

Patient weight 90 kg (198 pounds), suffering from osteoarthritis, treated by the method according to the invention. In particular, during the 5 years specified patient took a daily capsule containing 70 mg of the compound in example 3.

At the end of the treatment period the patient was examined by x-ray, arthroscopy and/or MRI detected no further progression of erosion/fibrillation of the articular cartilage.

The example

According to the present invention are based composition of saline solution for local use, including:

Component Amount (% wt./mass.)

Connection example 10 5%

Polyvinyl alcohol 15%

Saline 80%

The patient with deep erosion of the cornea buries one drop in each eye twice a day. For ellenie faster without apparent complications.

Example D

According to the present invention receive a topical composition for topical application, including:

Component Amount (% wt./mass.)

Connection example 21 0,20

Benzylaniline 0,02

Thimerosal 0,002

d-Sorbitol 5,00

Glycine 0,35

Aromatic compounds 0,075

Purified water q.s.

Total = 100,00

The patient with chemical burns cause the composition at

each ligation (b.i.d.). Scars are significantly reduced.

Example F

According to the present invention are compositions for aerosol inhalation, including:

Component Amount (% wt./about.)

Connection example 18 5,0

Alcohol 33,0

Ascorbic acid 0,1

Menthol 0,1

Nachrichten 0,2

Propellant (F12, F114) q.s.

Total = 100,00

During inhalation asthmatic spray into the mouth of 0.01 ml of the composition from the dispenser with pump. Asthma symptoms are reduced.

Example F

According to the present invention receive the ophthalmic composition for topical application, including:

Component Amount (% wt./about.)

Connection example 30 0,10

Benzylaniline 0,01

Add 0,05

Hydroxyethylcellulose (NATROSOL M) 0,50

Metabisulphite sodium 0,10

Sodium chloride (0.9 per cent) q.s.

Total = 100,00

Patient weight 90 kg (198 pounds) with ulcerations of the cornea treated SPO is obom according to the invention. In particular, within 2 months injected into the affected eye of a specified patient twice a day with saline solution containing 10 mg of the compound from example 16.

Example G

Get the composition for parenteral administration containing:

Component Quantity

Connection example 27 (100 mg/ml media

Media:

Buffer solution of sodium citrate, containing, in percentage by weight of carrier):

lecithin 0,48%

carboxymethycellulose 0,53

povidone 0,50

methylparaben 0,11

propylparaben 0,011

The above ingredients are mixed, obtaining a suspension. Approximately 2.0 ml of the suspension is administered by injection to a patient with premetastatic tumor. The injection impose on the site of the tumor. Introduction this dose was repeated twice a day for approximately 30 days.

After 30 days the symptoms of the disease are dulled and gradually reduce the dose to maintain the patient's condition.

Example N

Get the song for mouthwash:

Component (wt. -%/about.)

Connection example 3 3,00

Alcohol SDA 40 8,00

Add 0,05

Odorant 0,08

Emulsifier 0,08

Sodium fluoride 0.05 to

Glycerin 10,00

Sweetener 0,02

Benzoic acid 0,05

Sodium hydroxide 0,20

Dye 0,04

Water to 100%

Patients with gum disease uses 1 ml rinse three times a day for warned is I further oral degeneration.

Example I

Get the song for pellet:

Component (wt. -%/about.)

Connection example 20 0,01

Sorbitol 17,50

Mannitol 17,50

Starch 13,60

Sweetener 1,20

Odorant 11,70

Dye 0,10

Corn syrup to 100%

The patient applies the pellet to prevent loosening of the implant in the upper jaw.

Example J

Composition for chewing gum

Component % wt./about.

Connection example 6 0,03

The sorbitol crystals 38,44

The basis for Paloja gum 20,00

Sorbitol (70% aqueous solution) 22,00

Mannitol 10,00

Glycerin 7,56

Odorant 1,00

The patient is chewing gum for preventing loosening of dentures.

Example

Component (wt. -%/about.)

Connection example 33 4,0

USP Water 50,656

Methylparaben 0,05

Propylparaben 0,01

Xanthan gum 0,12

Guar gum 0,09

Calcium carbonate 12,38

Protivovospalitel 1,27

Sucrose 15,0

Sorbitol 11,0

Glycerin 5,0

Benzyl alcohol 0,2

Citric acid and 0.15

The refrigerant 0,00888

Odorant 0,0645

Dye 0,0014

Get the original song by mixing 80 kg of glycerol and just benzyl alcohol and heated to 65°With, then slowly adding and mixing together of methylparaben, propyl paraben, water, xanthan gum, guar gum. Mix these ingredients approx the sory for 12 minutes in a continuous mixer of Silverson (Silverson). Then slowly add the remaining ingredients in the following order: the remaining glycerin, sorbitol, protivovospalitel, calcium carbonate, citric acid and sucrose. Separately combine perfumes and dyes, and then slowly add to other ingredients. Stirred for about 40 minutes. The patient takes the composition to prevent sudden exacerbation of colitis.

Example L

The patient suffering from obesity, prone to osteoarthritis, takes the capsule described in example V, to prevent signs and symptoms of osteoarthritis. Namely, the capsule is made by the patient on a daily basis.

The patient was examined by x-ray, arthroscopy and/or MRI detected no significant progression of erosion/fibrillation of the articular cartilage.

Example M

Patient weight 90 kg (198 pounds), have a sports injury, receives the capsule described in example V, to prevent signs and symptoms of osteoarthritis. Namely, the capsule is made by the patient on a daily basis.

The patient is examined by x-ray, arthroscopy and/or MRI detected no significant progression of erosion/fibrillation of the articular cartilage.

All the recommendations mentioned here for details.

Although described specific ways of performing this invention, for the person skilled in the art it is obvious, csomagot to be made various changes and modifications, not contradict the essence of the invention and are not beyond the scope of the present invention. It is implied that all such modifications are covered by the attached points and are included in the scope of the present invention.

1. The connection, which is derived sulfonamida, having a structure according to formula (I)

characterized in that

(A) R1choose from HE-NHOH;

(B) R2represents hydrogen;

(C) R3selected from the group including alkyl, alkoxyalkyl, and arylalkyl, pyridylethyl and morpholinylmethyl;

(D) A means piperidyl or tetrahydrofuranyl;

(E) n is 0;

(F) E is selected from the group comprising covalent bond, C1-C4-alkylene, -C(=O)-, -C(=O)O - and-SO2-;

(G) X is chosen from the group comprising hydrogen, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl;

(H) each of G and G’ represents a group-C(R5)=C(R5′-, where each R5and R5′means hydrogen;

(I) M stands for the group-CH-;

(J) Z means a group -(CR7R7’)a-L-R, where a is 0;

(K) each of R7and R7′represents hydrogen;

(L) L is a covalent bond;

(M) R8 are selected from the group including halogen and alkoxy;

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein R1is a HE.

3. The compound according to claim 1, wherein R1represents-NHOH.

4. Connection to items 1, 2 or 3, characterized in that a represents piperidyl.

5. Connection to items 1, 2 or 3, characterized in that a represents tetrahydrofuranyl.

6. The compound according to any one of items 1 to 5, characterized in that E is chosen from the group comprising covalent bond and C1-C4-alkylen.

7. The compound according to any one of items 1 to 5, characterized in that E is chosen from the group comprising-C(=O)-, -C(=O)O - and-SO2-.

8. The compound according to claim 1, characterized in that X is chosen from the group comprising hydrogen, alkyl, aryl, arylalkyl and alkoxyalkyl.

9. The compound according to claim 1, characterized in that X is chosen from the group including morpholinyl and tetrahydropyranyl.

10. The compound according to claim 1, selected from the group comprising the following compounds:

[(4’-methoxybiphenyl-4-sulfonyl)methylamino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid;

[benzyl-(4’-methoxybiphenyl-4-sulfonyl)amino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid;

[ethyl-(4’-methoxybiphenyl-4-sulfonyl)amino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid;

[(4’-bromodiphenyl-4-sulfonyl)methylamino]-[1-(morpholine-4-carbonyl)piperidine-4-yl]acetic acid;

2-methoxyethylamine ether 4-{carboxy[(4’-methoxybiphenyl-4-sulfonyl)methylamino]methyl}piperidine-1-carboxylic acid;

2-methoxyethylamine ether 4-{carboxy-[ethyl-(4’-methoxybiphenyl-4-sulfonyl)amino]methyl}piperidine-1-carboxylic acid;

2-methoxyethylamine ether 4-{[butyl-(4’-methoxybiphenyl-4-sulfonyl)amino]carboxymethyl} piperidine-1-carboxylic acid;

2-methoxyethylamine ether 4-{carboxy[(4’-methoxybiphenyl-4-sulfonyl)-(2-methoxyethyl)amino]methyl}piperidine-1-carboxylic acid;

2-methoxyethylamine ether 4-{[benzyl-(4’-methoxybiphenyl-4-sulfonyl)amino]carboxymethyl} piperidine-1-carboxylic acid;

2-methoxyethylamine ether 4-{carboxy[(4’-methoxybiphenyl-4-sulfonyl)phenethylamine]methyl}piperidine-1-carboxylic acid;

[N-(2-pyridylmethyl)-N-(4’-methoxybiphenyl-4-sulfonyl)]-amino-2-[N-(2-methoxyethoxymethyl)piperidine-4-yl]acetic acid;

[N-(3-pyridylmethyl)-N-(4’-methoxybiphenyl-4-sulfonyl)]-amino-2-[N-(2-methoxyethoxymethyl)piperidine-4-yl]acetic acid;

tert-butyl ether 4-{carboxy[(4’-methoxybiphenyl-4-sulfonyl)-(2-morpholine-4-retil)amino]methyl}piperidine-1-carboxylic acid;

tert-butyl ether 4-{carboxy[(4’-forgivenes-4-sulfonyl)methylamino]ethyl}piperidine-1-carboxylic acid;

[(4’-methoxybiphenyl-4-sulfonyl)methylamino]-[(1-phenyl-methanesulfonyl)piperidine-4-yl]acetic acid;

[(4’-methoxybiphenyl-4-sulfonyl)methylamino]-[(1-phenethyl)-piperidine-4-yl]acetic acid;

4-[(4’-methoxybiphenyl-4-sulfonyl)methylamino]tetrahydropyran-4-carboxylic acid;

4-[(4’-methoxybiphenyl-4-sulfonyl)methylamino]-1-(morpholine-4-carbonyl)piperidine-4-carboxylic acid;

4-[benzyl-(4’-methoxybiphenyl-4-sulfonyl)amino]-1-(morpholine-4-carbonyl)piperidine-4-carboxylic acid;

mono-2-methoxyethoxy ester 4-[benzyl-(4’-methoxybiphenyl-4-sulfonyl)amino]-piperidine-1,4-dicarboxylic acid;

mono-2-methoxyethoxy ester 4-[(4’-methoxybiphenyl-4-sulfonyl)-(2-methoxyethyl)amino]-piperidine-1,4-dicarboxylic acid;

1-benzyl-4-[benzyl-(4’-methoxybiphenyl-4-sulfonyl)amino]-piperidine-4-carboxylic acid;

N-hydroxy-2-[(4’-methoxybiphenyl-4-sulfonyl)methylamino]-2-[1-(morpholine-4-carbonyl)piperidine-4-yl]ndimethylacetamide;

2-[benzyl(4’-methoxybiphenyl-4-sulfonyl)amino]-N-hydroxy-2-[1-(morpholine-4-carbonyl)piperidine-4-yl]ndimethylacetamide;

2-[ethyl(4’-methoxybiphenyl-4-sulfonyl)amino]-N-hydroxy-2-[1-(morpholine-4-carbonyl)piperidine-4-yl]ndimethylacetamide;

2-[(4’-bromodiphenyl-4-sulfonyl)methylamino]-N-hydroxy-2-[1-(morpholine-4-carbonyl)piperidine-4-yl]ndimethylacetamide;

2-met is ketelbey ether 4-{hydroxycarbamoyl-[(4’-methoxybiphenyl-4-sulfonyl)-methylamino]methyl}piperidine-1-carboxylic acid;

2-methoxyethylamine ether 4-{[ethyl-(4’-methoxybiphenyl-4-Sul hanil)amino]hydroxycarbonylmethyl}piperidine-1-carboxylic acid;

2-methoxyethylamine ether 4-{hydroxycarbamoyl-[(4’-methoxybiphenyl-4-sulfonyl)phenethylamine]methyl}piperidine-1-carboxylic acid;

tert-butyl ether 4-{hydroxycarbamoyl-[(4’-methoxybiphenyl-4-sulfonyl)-methylamino]methyl}piperidine-1-carboxylic acid;

tert-butyl ether 4-{[(4’-forgivenes-4-sulfonyl)-methylamino]hydroxycarbonylmethyl}piperidine-1-carboxylic acid;

[(4’-methoxybiphenyl-4-sulfonyl)methylamino]-2-[(1-phenylmethanesulfonyl)piperidine-4-yl]acetylhydrolase acid;

[(4’-methoxybiphenyl-4-sulfonyl)methylamino]-2-[(1-phenethyl)piperidine-4-yl]acetylhydrolase acid;

2-[(4’-methoxybiphenyl-4-sulfonyl)methylamino]-2-(tetrahydropyran-4-yl)acetylhydrolase acid;

2-[(4’-methoxybiphenyl-4-sulfonyl)benzoylamino]-2-(tetrahydropyran-4-yl)acetylhydrolase acid;

2-[(4’-methoxybiphenyl-4-sulfonyl)-2-methoxyethylamine]-2-(tetrahydropyran-4-yl)acetylhydrolase acid;

2-[N-(3-pyridylmethyl)-N-(4’-methoxybiphenyl-4-sulfonyl)]amino-2-(tetrahydropyran-4-yl)acetylhydrolase acid; and

[(4’-methoxybiphenyl-4-sulfonyl)-2-(morpholine-4-yl)ethylamino]-2-(tetrahydropyran-4-yl)acetylide samova acid.

11. The compound according to any one of the preceding paragraphs applicable for the manufacture of a medicinal product for the treatment of diseases associated with unwanted activity metalloprotease in the body of a mammal.

12. Connection claim 11, wherein the disease is a arthritis and selected from the group including osteoarthritis and rheumatoid arthritis.

13. Connection claim 11, wherein the disease is a cancer and the treatment prevents or stops tumor growth or metastasis.

14. Connection claim 11, wherein the disease is a disease of the cardiovascular system and selected from the group including dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, damage during reperfusion, ischemia, chronic obstructive lung disease, restenosis after plastic surgery on the blood vessels and aneurysms of the aorta.

15. Pharmaceutical composition having inhibitory metalloprotease activity, comprising (a) a safe and effective amount of a compound according to any one of the preceding paragraphs and (b) a pharmaceutically acceptable carrier.



 

Same patents:

The invention relates to new chemical compounds of the heterocyclic series, with pronounced anticalcium activity, which may find application in medical practice in the treatment and prevention of cardiovascular diseases and represent derivatives of 2-N-1-benzopyran-2-it General formula I

where R and R1have the meanings indicated in the claims

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to the field of chemistry of heterocyclic compounds and relates, in particular, a new chemical compound 2-isopropyl-4-[(furyl-2)metalinox] methylene-1,3-dioxolane exhibiting the properties of activator germination of wheat seeds and increases the resistance of seedlings to water stress

The invention relates to new compounds of the class of cetomacrogol and semisolids, potential intermediates in obtaining new macrolide and asamenew antibiotics, as well as the way they are received and intermediate compounds for their production

The invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds
The invention relates to the field of chemistry and can be used in industry as vulcanizing agents and vulcanization accelerators

The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to organic chemistry and can find application in medicine

The invention relates to organic chemistry and can find application in medicine

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">

where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of sulfonamides of General formula I, where R1- [(A1)CH2]c[(A2)CH2]b[(A3)CH2]andC-, each of a, b and C is 1; each of the A1AND2and a3independently selected from H, (C1-C5)alkyl and phenyl or substituted phenyl; R2and R3independently (C1-C6)alkyl, or R2and R3together form a 3-7-membered cycloalkyl, tetrahydropyran-4-ilen ring or bicyclical formula

< / BR>
where the asterisk denotes a carbon atom common to R2and R3; Q - (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl, where each (C6-C10, WITH6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl,

(C6-C10)aryl(C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl possibly substituted on any of the ring carbon atoms capable of forming additional links, one or more than one substituents on the ring, independently selected from fluorine, chlorine, bromine, (C1-C6)alkyl, (C1-C6)alkoxy, PERFLUORO (C1-C3)alkyl, PERFLUORO(C1-C3)alkoxy and (C6-C10)aryloxy; and Y is hydrogen or (C1-C6)alkyl

The invention relates to a new method of producing compounds of the formula I

< / BR>
where a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, - inhibitors of 5-lipoxygenase, are useful for the treatment or relief of inflammatory diseases, Allergy and cardiovascular diseases

The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione
Up!