Inhibitors of metalloproteinases, their using and pharmaceutical compositions based on thereof

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I): wherein X represents -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO2N(R6), -N(R7)SO2; m = 1 or 2; A is chosen from a direct bond, (C1-C6)-alkyl; R1 represents hydrogen atom (H); each R2 and R3 is chosen independently from H, alkyl, aryl, alkylaryl, arylalkyl; each R4 is chosen independently from H, (C1-C3)-alkyl; R6 is chosen from H, alkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, arylalkyl, heteroaryl-alkyl; R2 and R6 can join to form a ring comprising up to 7 ring atoms, or R3 and R6 can join to form a ring comprising up to 7 ring atoms, or R4 and R6 can join to form a ring comprising up to 7 ring atoms; R5 represents monocyclic, bicyclic or tricyclic group comprising one or two ring structures wherein each of that comprises up to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl and possibly substituted; when R5 represents bicyclic group then each ring structure is bound with the next ring structure through a direct bond, through -O-, through (C1-C6)-alkyl or condensed with this next ring structure; R7 is chosen from (C1-C6)-alkyl. Also, invention describes compound of the formula (II) given in the description, pharmaceutical compositions and using compound of the formula (I) or the formula (II) in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes and representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of inhibitors and pharmaceutical compositions.

20 cl, 3 tbl, 6 ex

 

The present invention relates to compounds useful for the inhibition of metalloproteinases, in particular, to pharmaceutical compositions containing these compounds and to their use.

The compounds of this invention are inhibitors of one or more than one enzyme, which is a metalloproteinase. Metalloproteinases are a superfamily of proteases (enzymes), which in recent years has increased dramatically. Structural and functional reasons, these enzymes are divided into families and subfamilies, as described in N..Hooper (1994) FEBS Letters 354: 1-6. Examples of metalloproteinases are matrix metalloproteinases (MMPs), such as collagenase (MMR, MR, MMR), gelatinase (MMR, MMR), stromelysin (MMRS, MMR, MMR), matrilysin (MMR), metalloelastase (MMR), enamelin (MMR), MT-MMP (MMR, MR, MMR, MMR); radiolysis or adamisin or family MDC, which includes secretase and sheddase, such as TNF-converting enzyme (ADAM10 and TACE); family astatine, which includes enzymes such as proteinase processing of procollagen (PCP), and other metalloproteinases such as aggrecanases, the family of endothelin-converting enzyme and family of the angiotensin converting enzyme.

It is believed that metalloproteinases are important the ri many painful physiological processes, are involved in remodeling of tissues, such as embryonic development, bone formation and uterine remodeling during menstruation. This is based on the ability of metalloproteinases cleave a number of matrix substrates, such as collagen, proteoglycan and fibronectin. It is also believed that metalloproteinases play an important role in processing, or secretion of biologically important cellular mediators, such as tumor necrosis factor (TNF), and post-translational proteolytic processing, or shedding, biologically important membrane proteins, such as IgE receptor CD23 low affinity (a more complete list, see N..Hooper et al., (1997) Biochem. J. 321: 265-279).

Metalloproteinases are associated with many diseases or conditions. The inhibition activity of one or more than one metalloproteinases can be of great benefit in these diseases or conditions, such as when various inflammatory and allergic diseases such as inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis); metastases or invasion of the tumor; disease associated with uncontrolled what Arushanyan extracellular matrix, such as osteoarthritis; for diseases associated with bone resorption, such as osteoporosis and Paget's disease); diseases associated with aberrant angiogenesis; with increased remodeling of collagen associated with diabetes, periodontal disease (such as gingivitis, corneal ulceration, ulceration of the skin, post-operative conditions (such as intestinal anastomosis) and the healing of skin wounds; in diseases associated with demyelination of the Central and peripheral nervous systems such as multiple sclerosis); Alzheimer's disease; the remodeling of the extracellular matrix, which is observed in cardiovascular diseases such as restenosis and atherosclerosis; asthma; rhinitis and chronic obstructive lung disease (COPD).

MMR, also known as macrophage elastase or metalloelastase, was originally cloned in mouse researchers Shapiro et al. [1992, Journal of Biological Chemistry 267:4664] and in man the same group of researchers in 1995. MR predominantly expressed in activated macrophages, and it has been shown that it is secreted from alveolar macrophages of smokers [Shapiro et al., 1993, Journal of Biological Chemistry 268:23824], and in foam cells in atherosclerotic lesions [Matsumoto et al., 1998, Am J Pathol 153:109]. Murine model of COPD based on provocat and mice to cigarette smoke for six months, two cigarettes a day, six days a week. After this treatment in wild-type mice developed pulmonary emphysema. When this model was tested mice knocked out for MMR, they did not develop significant emphysema, which clearly indicates that MMR is a key enzyme in the pathogenesis of COPD. The role of MMP, such as MMP 12, COPD (emphysema and bronchitis) was discussed in Anderson and Shinagawa, 1999, Current Opinion in Anti-inflammatory and Immunomodulatory Investigational Drugs 1(1):29-38. Recently it was found that Smoking increases the infiltration of macrophages and the expression of MMR macrophage origin plaques Kangavari carotid artery [Matetzky S., Fishbein MC, et al., Circulation 102(18). 36-39 Suppl. S, Oct 31, 2000].

MMR, or collagenase 3, was originally cloned from a cDNA library derived from tumors of the breast [J. M. P. Freije et al. (1994) Journal of Biological Chemistry 269 (24): 16766-16773]. PCR RNA analysis RNA from different tissues showed that the expression of MMR limited to carcinomas of the breast, as it was not detected in fibroadenoma of the breast, in the normal or resting mammary gland, placenta, liver, ovary, uterus, prostate or parotid gland or cell lines breast cancer (T47-D, MCF-7 and ZR75-1). After this observation MMR was detected in transformed epidermal keratinocytes [N. Johansson et al. (1997) Cell Growth Differ. 8(2):243-250], flat is gunning carcinomas [N. Johansson et al. (1997) Am. J. Pathol. 151(2):499-508] and epidermal tumors [.Airola et al. (1997) J. Invest. Dermatol. 109(2):225-231]. These results suggest that MMR secreted transformed epithelial cells and may be involved in the destruction of the extracellular matrix and interaction cell-matrix associated with metastasis, in particular, as was found in invasive lesions cancer, breast cancer and malignant epithelial growth in the carcinogenesis of the skin.

Recently published data suggests that MMR plays a role in updating other connective tissues. For example, it has been hypothesized, consistent with the substrate specificity MMR and preferred the destruction of collagen type II [R. G. Mitchell et at. (1996) J. Clin. Invest. 97(3):761-768; V.Knauper et al., (1996) The Biochemical Journal 271:1544-1550], that MMR plays a specific role in the process of primary ossification and skeletal remodeling [M. Stahle-Backdahl et al. (1997) Lab. Invest. 76(5):717-728; N. Johansson et al. (1997) Dev. Dyn. 208(3):387-397]in destructive joint diseases such as rheumatoid arthritis and osteoarthritis [D. Wernicke et al. (1996) J. Pheumatol. 23:590-595; P.G.Mitchell et al., (1996) J.Clin. Invest. 97(3):761-768; .Lindy et al., (1997) Arthritis Rheum 40(8):1391-1399], and in aseptic loosening of substitutes hip [S.Imai et al. (1998) J. Bone Joint Surg. Br. 80(4):701-710]. MMP13 is also involved in chronic adult periodontitis, as is it is localized in the epithelium chronically inflamed mucosal tissue of the gums [V.J.Uitto et al. (1998) Am.J.Pathol. 152(6):1489-1499], and remodeling of the collagen matrix in chronic wounds [M Vaalamo et al. (1997) J.Invest. Dermatol. 109(1):96-101].

MMR (gelatinase; collagenase type IV 92 kDa; gelatinase 92 kDa) is a secretory protein that was first purified, and then cloned and sequenced in 1989 [S..Wilhelm et at. (1989) J.Biol. Chem. 264(29):17213-17221; misprints published in J.Biol. Chem. (1990) 265(36):22570]. A recently published review on MR [..Vu & Z. Werb (1998) (In: Matrix Metalloproteases, 1998. Edited by W.C.Parks & R.P.Mecnam. pp 115-148. Academic Press. ISBN 0-12-545090-7] is an excellent source of detailed information and links on this protease. From the above review of the so-CALLED. Vu & Z. Werb (1998) derives the following.

Expression MMR normal limited to a few cell types, including trophoblasts, osteoclasts, neutrophils and macrophages. However, its expression can be induced in these cells and in cells of other types of multiple mediators, including effects on these cells growth factors or cytokines. They are those mediators that are usually involved in the initiation of inflammatory responses. Like other secreted MMP, MMR is released in the form of inactive proferment (Pro-), who later split with the formation of enzymatically active enzyme. Protease required for this activation in vivo is unknown. Balance active is MR in comparison with the inactive enzyme addition is regulated in vivo by interaction with the natural protein TIMP-1 (tissue inhibitor of metalloprotease-1). TIMP-1 binds to the C-terminal site MMR, which leads to inhibition of the catalytic domain MMR. The combination of balance induced expression Lomr, cleavage of Pro - up to active MMR and the presence of TIMP-1 determines the number of catalytically active MMR present in website localization. Proteoliticeski active MMR attacks substrates, which include gelatin, elastin and natural collagens type IV and type V; it has no activity against native collagen type I, proteoglycans or laminin.

Increasing the mass of information about the role MMR in various physiological and pathological processes. Physiological roles include the invasion of embryonic trophoblasts through the epithelium of the uterus in the early stages of embryonic implantation, some part in the growth and development of bones and migration of inflammatory cells from the vasculature into the tissue.

Release MMR measured using enzyme-linked immunosorbent assay, was significantly higher in liquids and AM in supernatant from untreated asthmatics compared to other populations [Am.J.Resp. Cell & Mol. Biol., Nov 1997, 17(5):583-591]. Increased expression of MMR observed also in other pathological conditions, and these observations suggest that MMR involved in such a painful process, as COPD, arthritis is t, metastasis of tumors, Alzheimer's disease, multiple sclerosis and perforation of plaques in atherosclerosis, leading to acute coronary condition, such as myocardial infarction.

MMR (collagenase-2, neutrophil collagenase) is an enzyme 53 CD collection matrix metalloprotease, which are mainly expressed in neutrophils. Recent studies indicate that MMP-8 is expressed in other cells, such as osteoarthritis chondrocytes [Shlopov et al., 1997, Arthritis Rheum, 40:2065]. DFID is produced by neutrophils, can cause remodeling of tissues. Therefore, blocking of MMP-8 can have a positive effect in fibrotic diseases, such as the lung, and in degenerative diseases such as emphysema. Also found positive regulation of MMP-8 in osteoarthritis, indicating that blocking MMR can also be useful in this disease.

MMR (stromelysin-1) is an enzyme 53 CD collection matrix metalloprotease. The activity of MMP-3 was demonstrated in fibroblasts isolated from inflamed gums [Uitto V.J. et al., 1981, J.Periodontal Res., 16:417-424], and it was shown that the enzyme levels correlate with severity of disease of the gums [Overall S.M. et al., 1987, J.Periodontal Res., 22:81-88]. MMP-3 is produced also basal keratinocytes at the discrepancies between the different chronic ulcers [Saarialho-Kere U.. et al., 1994, J. Clin. invest. 94:79-88 [in Russian]]. the mRNA and protein of MMP-3 were detected in basal keratinocytes near the edge of the wound, but distal from him, where, probably, there are sites proliferating epidermis. Thus, MMP-3 can inhibit healing of the epidermis. Several researchers have demonstrated persistent increase MMR in synovial fluids of patients with rheumatoid and osteoarthritis compared to controls [Walakovits L.A. et al., 1992, Arthritis Rheum., 35:35-42, Zafarullah M. et al., 1993, J. Rheumatol. 20:693-697]. These studies suggest that the inhibitor of MMP-3 to treat diseases that involve the destruction of the extracellular matrix, leading to inflammation due to infiltration of lymphocytes or loss of structural integrity necessary for the functioning of the body.

There are many inhibitors of metalloproteinases (see, for example, the review of MMP inhibitors Beckett R. P. and Whittaker, M., 1998, Exp. Opin. Ther. Patents, 8(3):259-282). Different classes of compounds may have different degrees of efficiency and selectivity in relation to the inhibition of various metalloproteinases.

Whittaker M. et al. [1999, Chemical Reviews 99(9):2735-2776] consider a number of known compounds are inhibitors of MMP. They argue that effective inhibitor of MMP necessary binding zinc group (crystal) (functional group capable helatirovat ion zinc(II) in the active site), Myung is our least one functional group, which provides the interaction of hydrogen bonds with the main chain of the enzyme, and one or more than one side chain that is effective van der Waals interactions with the subsites of the enzyme. In the known inhibitors of MMP binding zinc groups include carbonisation group, hydroxymandelate groups, sulfhydryl or mercaptopropyl etc. for Example, Whittaker M. et al. discuss the following inhibitors of MMP.

The above compound has entered the stage of clinical development. It has mercaptoethanol binding zinc group, trimethylpentanediol group in position P1 and Latini-tert-butylpyridinium the main chain.

The above connection has mercaptoethanol connecting the zinc group and kidney group in position P1.

The above compound developed for the treatment of arthritis. It has ones succinyldicholine connecting the zinc group and trimethylpentanediol group in position P1.

The above connection is phthalimidopropyl, which inhibits collagenase. It has ones succinyldicholine connecting the zinc group and the cyclic aminogroup in position P1.

Whittaker M. et al. also discuss other MMP inhibitors with P1 cyclic aminogroup and various connecting the zinc group (succinyldicholine, carbonisation, thiol group, group-based phosphorus).

The above compounds are represented good inhibitors MMR and MMR (international application WO 9858925, WO 9858915). They have the pyrimidine-2,3,4-TRINOVA binding zinc group.

The following compounds are not known as MMP inhibitors: Lora-Tamayo, M. et al. (1968, 'an. Quim 64(6): 591-606) describe the synthesis of the following compounds as potential anticancer agents:

In the patents of the Czech Republic No. 151744 (19731119) and 152617 (1974022) described the synthesis and anticonvulsant activity of the following compounds:

R=4-NO2, 4-OMe, 2-NO2.

In U.S. patent No. 3529019 (19700915) described the following compounds used as intermediates:

In the international application WO 00/09103 described compounds useful for treating disorders, including the following (connection 81 and 83, table a, p.47):

Now, the inventors have discovered a new class of compounds that act as inhibitors of metalloproteinases and are of particular interests to the EU in the inhibition of MMP, such as MMR. These compounds are inhibitors of metalloproteinases with connecting metal group, in which there is no known inhibitors of metalloproteinases. In particular, the inventors have discovered compounds that are effective inhibitors MMR and possess desirable activity profiles.

The compounds of this invention have a favorable efficiency, selectivity and/or pharmacokinetic properties.

Compounds according to this invention, representing inhibitors of metalloproteinases contain binding metal group and one or more than one functional group or side chain, differ in that the connecting metal group has the formula (k)

where X is selected from NR1, O, S;

Y1and Y2independently selected from O, S;

R1 is selected from H, alkyl, halogenoalkane;

any alkyl groups mentioned above, can be remotemachine or branched; any alkyl group mentioned above, preferably represents (C1-7)alkyl, and most preferably (C1-6) alkyl.

The connection that represents the metalloproteinase inhibitor is a compound that inhibits the activity of an enzyme, representing the metalloproteinases (e.g. MMP). As a non-limiting example, the soybean is inania-inhibitor can show IC 50in vitro in the range of 0.1-10000 nanomoles, preferably 0.1 to 1000 nanomoles.

Connecting the metal group represents a functional group capable of binding metal ion in the active site of the enzyme. For example, connecting the metal group will constitute a binding zinc group, MMP inhibitors, binding of the zinc ion(II) in the active site. Connecting the metal group of the formula (k) based on the five-membered ring structure, and preferably is hydantoinyl group, most preferably a 5-substituted 1-N,3-N-imidazolidin-2,4-dione.

Thus, in the first aspect of the proposed invention the compounds of formula I

where X is selected from NR1, O, S;

Y1and Y2independently selected from O, S;

Z is selected from the SO2N(R6), N(R7)SO2N(R7)SO2N(R6);

m is 1 or 2;

And selected from a direct link, (C1-6)alkyl, (C1-6)halogenoalkane or (C1-6)heteroalkyl containing heterogroup selected from N, O, S, SO, SO2or containing two heterogroup selected from N, O, S, SO, SO2and separated by at least two carbon atoms; R1 is selected from H, (C1-3)alkyl, halogenoalkane; R2 and R3, each independently, selected from H, halogen (preferably fluorine), alkyl, heteroalkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, alkylaryl, alkylglycerol, heteroalkyl is aryl, heterooligomeric, arylalkyl, analgeticalkie, heteroallyl, heterotrimetallic, arylaryl, arylheteroacetic, heteroallyl, heteroarylboronic, cycloalkenyl, geterotsiklicheskikh;

each R4 is independently selected from H, halogen (preferably fluorine), (C1-3)alkyl or halogenoalkane;

R6 is selected from H, alkyl, heteroalkyl, geterotsiklicheskie, aryl, heteroaryl, alkylaryl, alkylglycerol, heteroalkyl, heterooligomeric, arylalkyl, analgeticalkie, heteroallyl, heterotrimetallic, arylaryl, arylheteroacetic, heteroallyl, heteroarylboronic;

each of the radicals R2, R3 and R6 independently can be substituted by one or more (preferably one group selected from alkyl, heteroalkyl, aryl, heteroaryl, halogen, halogenoalkane, hydroxy, alkoxy, halogenoalkane, thiol, alkylthiol, arylthiol, alkylsulfonyl, halogenoalkanes, arylsulfonyl, aminosulfonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, allumination, amino, N-alkylamino, N,N-dialkylamino, amido, N-alkylamino, N,N-dialkylamino, cyano, sulfonamide, alkylsulfonate, arylsulfonate, amidino, N-aminosulfonates, guanidino, N-cyanoguanidine, thioguanine, 2-nitro-ethen-1,1-diamine, carboxy, alkylcarboxylic, nitro;

R2 and R3 may join the education ring, containing up to 7 ring atoms, or R2 and R4 may be joined to form a ring containing up to 7 ring atoms, or R2 and R6 may be joined to form a ring containing up to 7 ring atoms, or R3 and R4 may be joined to form a ring containing up to 7 ring atoms, or R3 and R6 can be joined to form a ring containing up to 7 ring atoms, or R4 and R6 may be joined to form a ring containing up to 7 ring atoms;

R5 represents a monocyclic, bicyclic or tricyclic group containing one, two or three ring structures, each of which contains up to 7 ring atoms independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl, with each ring structure may independently substituted by one or more than one Deputy, independently selected from halogen, hydroxy, alkyl, alkoxy, halogenoalkane, amino, N-alkylamino, N,N-dialkylamino, alkylsulfonyl, alkylcarboxylic, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, halogenoalkanes, alkylaminocarbonyl, carboxylate, alkylcarboxylic aminocarboxyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, where any alkyl radical within any substituent itself may b shall be substituted one or more than one group, selected from halogen, hydroxy, alkoxy, halogenoalkane, amino, N-alkylamino, N,N-dialkylamino, N-alkylsulfonamides, N-alkylcarboxylic, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, N-alkylaminocarbonyl, carboxylate, alkylcarboxylic, aminocarboxyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl;

when R5 is a bicyclic or tricyclic group, each ring structure is connected with the following ring structure via a direct link, via-O -, (C1-6)alkyl, (C1-6)halogenoalkane through (C1-6)heteroalkyl through (C1-6)alkenyl through (C1-6)quinil through sulfon or condensed with this next ring structure;

R7 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C2-6)heteroalkyl, (C2-6) cyclogeranyl;

any heteroalkyl group, mentioned above, represents a substituted heteroatom alkyl containing one or more than one heterogroup, independently selected from N, O, S, SO, SO2(and heterogroup is a heteroatom or group of atoms);

any heterocytolysine or heteroaryl group, mentioned above, contains one or more than one heterogroup, independently selected from N, O, S, SO, SO2;

any alkyl, Alchemilla or Alchemilla group, mentioned above, can be remotemachine or branched; if not specified in the e, any alkyl group mentioned above, preferably represents (C1-7)alkyl, and most preferably (C1-6)alkyl;

provided that

when X represents NR1, R1 represents H, Y1represents O, Y2represents O, Z represents the SO2N(R6), R6 represents H, R2 represents H, m is 1, R3 represents H, R4 represents N and a represents a direct bond, then R5 is not phenyl, para-nitrophenyl, para-ethoxyphenyl or meta were;

when X represents S or NR1, and R1 represents H, Y1represents O, Y2represents O, Z represents the SO2N(R6), R6 represents alkyl, R2 represents H, m is 1, one of R3 and R4 represents N and the other represents alkyl, R3 and R6, or R4 and R6 are connected with the formation of 5-membered ring and a is a direct bond, then R5 is not phenyl.

Preferred compounds of formula I are those, who are subject to one or more of the following:

X represents NR1;

Z represents SO2N(R6), especially when the S atom of the group Z is attached to the group a in the compound of formula I;

at least one of Y1and Y2represents Oh, particularly preferably and Y1 and Y2represents About;

m is 1;

R1 represents H, (C1-3)alkyl, (C1-3)halogenoalkane, especially preferably R1 represents H;

R2 represents H, alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, alkylsilanes, arylalkyl, alkylaryl, heteroalkyl, geterotsiklicheskikh, alkylchlorosilanes, heteroallyl, heteroalkyl, particularly preferably R2 represents alkyl, aminoalkyl or heteroaromatic;

R3 and/or R4 represent H;

R3 and/or R4 represent methyl;

R3 and R4 form a 5 - or 6-membered ring (preferably a 5-membered ring, or R3 and R6 form a 5 - or 6-membered ring (preferably a 5-membered ring), or R4 and R6 form a 5 - or 6-membered ring (preferably a 5-membered ring); especially preferably R3 and R6 form a 5 - or 6-membered ring, most preferably a 5-membered ring;

R2 and R3 form a 5-membered ring, or R2 and R6 form a 5-membered ring;

R5 contains a possibly substituted aryl or heteroaryl and 5-or 6-membered rings in the amount of one, two or three;

R5 is a bicyclic or tricyclic group containing two or three possibly substituted ring structure;

R3 and R6 form a 5 - or 6-membered ring (preferably a 5-membered ring), or R4 and R6 form a 5 - or 6-membered ring (predpochtite is the super 5-membered ring), and R5 is a bicyclic or tricyclic group containing two or three possibly substituted ring structure.

Especially preferred compounds of formula I are those where R5 is a bicyclic or tricyclic group containing two or three possibly substituted ring structure.

For example, particular compounds of the formula I are those where Y1represents O, Y2represents O, X represents NR1, R1 represents H, R2 represents H, m is 1, R3 represents H, R4 represents N, Z represents the SO2N(R6), R6 represents H, (C1-4)alkyl, methylbenzyl or methylpyridyl, And represents a direct bond and R5 is a bicyclic or tricyclic group containing two or three possibly substituted ring structure. Some such compounds are described in examples 1 and 2.

Other specific compounds of formula I are those where Y1represents O, Y2represents O, X represents NR1, R1 represents H, R2 represents H, methyl or benzyl, m is 1, R3 represents H or methyl, R4 represents N, Z represents the SO2N(R6), R6 represents H, a represents a direct bond and R5 is a bicyclic or articlecheck group, containing two or three possibly substituted ring structure. Some of these compounds are described in example 3.

Further, according to the proposed invention the compounds of formula II

where each of G1 and G2 represents a monocyclic ring structure, each of which contains up to 7 ring atoms independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl, with each ring structure may independently substituted with one or two substituents, independently selected from halogen, hydroxy, halogenoalkane, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkylsulfonyl, halogenoalkanes, allylcarbamate, alkylamide, where any alkyl radical within any substituent may itself be substituted by one or more than one group selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, halogenoalkane;

Z represents SO2N(R6);

Selected from a direct link, O, (C1-6)alkyl, (C1-6)heteroalkyl;

R2 is selected from H, (C1-6)alkyl, halogenoalkane, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, aminoalkyl, thioalkyl or R2 represents a group of formula III

C and D independently researched the Simo selected from a direct link, H, (C1-6)alkyl, (C1-6)halogenoalkane or (C1-6)heteroalkyl containing one or two heteroatoms selected from N, O or S, so, when there are two heteroatoms, they are separated by at least two carbon atoms;

G3 represents a monocyclic ring structure containing up to 7 ring atoms independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl, possibly substituted by one or two substituents, independently selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkylsulfonyl, halogenoalkanes or alkyl substituted by one or more than one group selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, halogenoalkane;

R2 may be substituted, halogen, halogenoalkanes, hydroxy, alkoxy, halogenoalkane, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfonyl, aminosulfonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, amido, N-alkylamino, N,N-dialkylamino, cyano, sulfonamide, alkylsulfonate, amidino, N-aminosulfonates, guanidino, N-cyanoguanidine, thioguanine, 2-nitroguanidine, 2-nitroethene-1,1-diamino, carboxy, alkylcarboxylic;

R3 and R4 are independently selected from H or (C1-3)alkyl;

R6 is selected is C N, (C1-3)alkylamino or R6 represents (C1-3) alkyl, possibly substituted aryl, heteroaryl, heterocyclization;

R2 and R3 may join to form a ring containing up to 7 ring atoms, or R2 and R4 may be joined to form a ring containing up to 7 ring atoms, or R2 and R6 may be joined to form a ring containing up to 7 ring atoms; or R3 and R4 may be joined to form a ring containing up to 7 ring atoms; or R3 and R6 can be joined to form a ring containing up to 7 ring atoms; or R4 and R6 may be joined to form a ring containing up to 7 ring atoms;

any heteroalkyl group, mentioned above, represents a substituted heteroatom alkyl containing one or more than one heterogroup, independently selected from N, O, S, SO, SO2(and heterogroup is a heteroatom or group of atoms); any heterocytolysine or heteroaryl group, mentioned above, contains one or more than one heterogroup, independently selected from N, O, S,SO, SO2;

any alkyl, Alchemilla or Alchemilla group, mentioned above, can be remotemachine or branched; unless otherwise specified, any alkyl group mentioned above, preferably Ave is dstanley a (C1-7)alkyl, and most preferably (C1-6)alkyl.

Preferred compounds of formula II are those, who are subject to one or more of the following:

Z represents SO2N(R6) and the S atom of the group Z is attached to the ring G2;

Represents a direct bond or O;

R2 is possibly substituted, or R2 is selected from H, (C1-6)alkyl, aryl-(C1-6)alkyl or heteroaryl-(C1-6)alkyl, possibly substituted, halogen, halogenoalkanes, hydroxy, alkoxy, halogenoalkane, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfonyl, aminosulfonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, amido, N-alkylamino, N N-dialkylamino, cyano, sulfonamide, alkylsulfonate, amidino, N-aminosulfonates, guanidino, N-cyanoguanidine, thioguanine, 2-nitroguanidine, 2-nitroethene-1,1-diamino, carboxy, alkylcarboxylic;

each of R3 and R4 represents H;

R6 represents H, benzyl or methyleneimine;

G1 and G2, each selected from aryl or heteroaryl;

R3 and R4 form a 5 - or 6-membered ring (preferably a 5-membered ring, or R3 and R6 form a 5 - or 6-membered ring (preferably a 5-membered ring), or R4 and R6 form a 5 - or 6-membered ring (preferably a 5-membered ring); especially preferably R3 and R6 form a 5 - or 6-membered ring, most preferably a 5-membered ring;

R2 and R3 form a 5-membered ring, or R2 and R6 form a 5-membered ring.

Especially preferred compounds of formula II are those where Z is a SO2N(R6) and the S atom of the group Z is attached to the ring G2.

For example, particular compounds of the invention include compounds of formula II, where

(a) represents a direct bond or O;

Z represents SO2N(R6) and R2 is selected from H, (C1-6)alkyl, aryl-(C1-6)alkyl or heteroaryl-(C1-6)alkyl, possibly substituted, halogen, halogenoalkanes, hydroxy, alkoxy, halogenoalkane, amino, aminoalkyl, N-alkylamino, N,N-dialkylamino, (N-alkylamino)alkyl, (N,N-dialkylamino)alkyl, alkylsulfonyl, aminosulfonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, amido, N-alkylamino, N,N-dialkylamino, cyano, sulfonamide, alkylsulfonate, amidino, N-aminosulfonates, guanidino, N-cyanoguanidine, thioguanine, 2-nitroguanidine, 2-nitroethene-1,1-diamino, carboxy, alkylcarboxylic; each of R3 and R4 represents H and R6 represents H, benzyl or methyleneimine, or

(b) Z represents the SO2N(R6), and R3 represents H, and R4 represents N (compounds of formula II'), where R2 is possibly substituted; preferably G1 and G2, each selected from aryl or heteroaryl

The appropriate values for the La R2 include the following:

Appropriate values for R5 include the following:

X'=bond, O, CH2, CHF, CF2;

R=F, Cl, Br, CF3, CF3O, CH3Oh, HE, CF3CH2,

It should be clear that the specific substituents and the number of substituents in the compounds according to the invention is chosen in such a way as to avoid steric undesirable combinations.

Each is illustrated with the example of the connection is a specific and independent aspect of the invention.

If the compounds according to the invention are optically active centers, the inventors disclose all individual optically active forms and their combinations as individual specific embodiment of the invention, as well as their corresponding racemates. The racemates can be separated into individual optically active form using known methods (see Advanced Organic Chemistry: 3rdEdition: author J March, p 104-107), including, for example, the formation of diastereoisomeric derivatives with suitable optically active auxiliary group, with subsequent separation, and then the removal of these subsidiary groups.

It should be clear that the compounds according to the invention can contain one or more than one asimmetricheskii replacing the n atom of carbon. The presence of one or more than one of these asymmetric centers (chiral centers) in the compound of the formula I capable of stereoisomers, and in each case it should be borne in mind that the invention extends to all such stereoisomers, including enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures.

In cases where there are tautomers of the compounds according to the invention, the inventors disclose all individual tautomeric forms and their combinations as individual specific embodiment of the invention.

As mentioned above, the compounds according to the invention are inhibitors of metalloproteinases, in particular they are inhibitors MMR. Each of the above indications for the compounds of formula I is an independent and specific embodiment of the invention.

Some compounds according to the invention are particularly applicable as inhibitors MMR and/or MMR, and/or MMR, and/or MMR.

Compounds according to the invention have a favorable selectivity profile. Although the inventors do not wish to be bound by theoretical considerations, they consider that the compounds according to the invention exhibit selective inhibition against any of the above indications than any inhibitory activity against MMR, as the e non-limiting example, they can be 100-1000-fold selectivity compared with inhibitory activity against MMR.

Compounds according to the invention can be provided in the form of pharmaceutically acceptable salts. These salts include the salts of joining acids, such as hydrochloride, hydrobromide, citrate and maleate and salts formed with phosphoric acid and sulfuric acid. In another aspect suitable salts are salts of bases, such as alkali metal salt, for example sodium or potassium salt, alkaline earth metal, e.g. calcium or magnesium, or salt of an organic amine, such as triethylamine.

They can also be provided in the form of in vivo hydrolyzable esters. These esters are pharmaceutically acceptable esters that are hydrolyzed in the body, giving the parental connection. Such esters can be identified by introducing, for example, intravenous trained animal tested compounds and subsequent studies of body fluids this epithemiou animal. Suitable in vivo hydrolyzable esters for carboxy include methoxymethyl and for hydroxy include formyl and acetyl, especially acetyl.

In order to use the connection according to the invention, representing a metalloproteinase inhibitor (compound of formula I or II), or its pharmaceutically acceptable salt or in vivo hydrolyzable ester for therapeutic treatment (including prophylactic cured the e) mammals, including people, usually it is prepared in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore, in another aspect of the present invention proposed a pharmaceutical composition which contains a compound according to the invention (compound of formula I or II) or its pharmaceutically acceptable salt or in vivo hydrolyzable ester and a pharmaceutically acceptable carrier.

The pharmaceutical compositions according to the invention it is possible to introduce a standard way of an illness or condition that you want to treat, for example oral, local, parenteral, transbukkalno, intranasal, vaginal or rectal route injection or inhalation. For these purposes the compounds of this invention can be prepared are known in the art methods in the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely ground powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) in the form of a sterile aqueous or oily solutions or suspensions or sterile emulsions.

In addition to the compound of the present invention the pharmaceutical composition according to this invention can also is to contain one or more than one pharmacological agent, useful in the treatment of one or more than one disease or condition described herein above, or it can be shared to enter (simultaneously or sequentially) with one or more than one such pharmacological agent.

The pharmaceutical compositions according to the invention will typically introduce people to the daily dose was, for example, from 0.5 to 75 mg/kg of body weight (and preferably from 0.5 to 30 mg/kg body weight). This daily dose can be given in divided doses as necessary, and the exact number of the obtained compound and route of administration depend on the weight, age and sex of the patient treated, and the specific disease or condition, which are treated in accordance with well-known in this field principles.

Typical standard dosage forms will contain about 1 to 500 mg of the compounds according to this invention.

Thus, in this aspect of the proposed compound of formula I or its pharmaceutically acceptable salt or in vivo hydrolyzable ester for use in a method of therapeutic treatment of the human or animal body or for use as a therapeutic agent. The inventors disclose the use in the treatment of a disease or condition mediated by one or more than one enzyme, representing metalloproteinases is. In particular, the inventors disclose the use in the treatment of a disease or condition mediated MMR and/or MMR, and/or MMR, and/or MMR, and/or MMR, especially used in the treatment of a disease or condition mediated MMR or MMR, mainly used in the treatment of a disease or condition mediated MMR.

In particular, the proposed compound of formula II or its pharmaceutically acceptable salt or in vivo hydrolyzable ester for use in a method of therapeutic treatment of the human or animal body or for use as a therapeutic agent (such as use in the treatment of a disease or condition mediated MMR and/or MMR, and/or MMR, and/or MMR, and/or MMR, especially MMR or MMR, mainly MMR).

The following aspect of the invention, a method of treatment mediated by metalloproteinases disease or condition in which warm-blooded animal is administered a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt or in vivo hydrolyzable ester. The inventors also disclose the use of compounds of formula I or its pharmaceutically acceptable salt or in vivo hydrolyzable precursor in the manufacture of medicaments for use in treating the disease or condition, operado who spent one or more than one enzyme, which is a metalloproteinase.

For example, a method of treatment mediated by metalloproteinases disease or condition in which warm-blooded animal is administered a therapeutically effective amount of the compounds of formula II (or its pharmaceutically acceptable salt or in vivo hydrolyzable ester). The proposed application of the compounds of formula II (or its pharmaceutically acceptable salt or in vivo hydrolyzable precursor in the manufacture of medicaments for use in the treatment of a disease or condition mediated by one or more than one enzyme, which is a metalloproteinase.

Disease or condition mediated by metalloproteinases include asthma, rhinitis, chronic obstructive pulmonary disease (COPD), arthritis (such as rheumatoid arthritis and osteoarthritis), atherosclerosis and restenosis, cancer, invasion and metastasis, diseases involving tissue destruction, loosening of the substitutes of the hip joint, periodontal disease, fibrotic disease, heart attack and heart disease, fibrosis of the liver and kidneys, endometriosis, diseases associated with the depletion of the extracellular matrix, heart failure, aortic aneurysms, CNS diseases such as Alzheimer's disease and multiple sclerosis (PC), hematological disorders the.

Obtaining the compounds according to the invention

In another aspect of the present invention, a method for obtaining compounds of formula I or II or its pharmaceutically acceptable salt or in vivo hydrolyzable ester, as described below in (a)-(C). It is clear that many relevant source materials are commercially available or available by any other means, or can be synthesized by known methods, or find in the scientific literature.

(a) the compounds of formula I in which Y1and Y2each represents O, Z represents the SO2N(R6), And represents a direct bond, X represents NR1, R1 represents H, R2 represents H, m is 1, R3 represents H, R4 represents H, a, R5 and R6 are as defined in formula I, can be obtained according to scheme 1.

When R6 represents H, derived N1-BOC-D-diaminopropionic acid of formula IV is subjected to interaction with a suitable sulphonylchloride formula V in a basic environment with the formation of sulfonamides of formula VI. Remove protection in an acidic environment, interaction with potassium cyanate to the corresponding urea and finally cyclization in acidic environment leading to the compounds of formula I.

When R6 represents alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, N2-alkyl-N1-BOC-D-diaminopropionic formula IV receive according Andruszkiewics, R.: Pol. J.Chem., 62, 257 (1988).

When R6 represents a possibly substituted benzyl, methylbenzyl, methylpyridyl, methylglutaryl, N2-substituted amino acid of formula IV receive according to Helv. Chim. Acta, 46, 327 (1963).

Scheme 1

The reaction of IV-VI is preferably carried out in a suitable solvent, possibly in the presence of a base, for 1-24 hours at a temperature of from ambient temperature to the temperature of reflux distilled. Preferably solvents, such as pyridine, dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane, is used with bases, such as triethylamine, N-methylmorpholine, pyridine or carbonates of alkali metals, when the ambient temperature within the reaction time 2-16 hours, or until the end of the reaction, which determine chromatographic or spectroscopic methods. Reaction sulphonylchloride formula V with various secondary amines previously described in the literature, and variations will be obvious to experts in the given field of technology. Many of the compounds of formula V are commercially available or their synthesis is described in the literature. Specific derivatives of the formula VI can be obtained by methods known to experts in this field of technology.

(b) the compounds of formula I in which Y1and Y2each represents O, Z represents SO 2N(R6), R6 represents H, a represents a direct bond, X represents NR1, R1 is H, m is 1, a, R2, R3, R4 and R5 are as defined in formula I, can be obtained according to scheme 1.

Compounds in which R2 represents H, R3 represents H and R4 represents alkyl or aryl, can be obtained from the appropriate BOC-N-protected-α-aminoaldehydes formula VII obtained according Fehrentz J.A., Castro Century: Synthesis, 676, (1983).

Compounds in which R2 represents alkyl or aryl, R3 represents H and R4 represents alkyl or aryl, can be obtained from the corresponding BOC-N-protected-α-aminoketone formula VII, as shown in diagram 2. BOC-N-protected-α-aminoketone receive according to Nahm, S., Weinreb, S. M.: Tetrahedron Lett., 22, 3815 (1981), perhaps when R6 does not represent H, according to Shuman, Robert T., U.S. patent 4448717 And 19840515.

Scheme 2

The compounds of formula VII is subjected to interaction with alkali metal cyanide and ammonium carbonate (reaction of Striker) to obtain the corresponding hydantoins of the formula VIIa. Diastereoisomer may be separated after any of the other three stages of the synthesis of carbamates of the formula VIIa and sulfonamidnuyu the compounds of formula II - chromatography on silica gel, after removing the protection premiato the tion of amino compounds by crystallization. The intermediate amino compounds maybe used for direct binding to sulphonylchloride formula V, as described in sulfonylurea (a) above, the primary environment with formation of compounds of formula I.

The reaction from VII to VIIa preferably carried out in a closed steel vessel in an aqueous alcohol solvent at 90-130°C for 3-16 hours, or until the end of the reaction, which determine chromatographic or spectroscopic methods. Processing 1-4-fold excess of cyanide salts, preferably 1-2 equivalents, and 2-6-fold excess of ammonium carbonate, preferably 4-6 equivalents, results hydantoins of the formula VIIa. Subsequent removal of the protection and sulfonylamine, as shown in figure 1, yield the compounds of formula I.

Aminoaldehyde or ketones of the formula VII and their protected derivatives are commercially available. There are other ways to get α-aminoaldehydes and ketones of the formula VII. Specific derivatives of formula VIIa can be obtained by methods known to experts in this field of technology.

(C) the compounds of formula I in which Y1and Y2each represents O, X represents NR1 (R1=H), Z=N(R7)SO2, m=1, R4=H, a, R2, R3, R5 and R7 are as defined in formula I, can be obtained by reacting the compounds of formula VIII, in which the R2, R3, R5, R7 and a are as described in formula I, with sulphonylchloride formula IX in polar aprotic solvents such as THF or DMF, in the presence of bases, such as carbonates, alkali metal or tertiary alkylamines followed, or polymeric amines.

Amines of formula VIII is widely known in the literature and are available from numerous commercial sources. Specific new variants of compounds of formula VIII can be obtained by methods known to experts in this field of technology. Sulphonylchloride formula IX can be obtained by oxidation with chlorine sulfides and disulfides of formula X, where R8 represents a group as hydrogen, isopropyl, benzyl or sulfide, so that the formula X comprises a symmetrical disulfide.

Sulfides of formula X can be obtained from cysteine or cystine (R2, R3=H) and their esters sequential treatment with an alkali metal cyanate and strong acids, such as potassium cyanate and hydrochloric acid. Alternative sulfides of formula X can be obtained, having twisted the ketones of formula XI to the conditions described in the conversion of VII to VIIa in (a) above.

Compounds according to the invention can be evaluated, for example, in the following analyses.

Analyses of selected enzyme

The family of matrix metalloprotein is, including, for instance. MMR, MMR

The catalytic domain of recombinant human MMR possible to Express and purify, as described in Parkar A.A. et al. (2000), Protein Expression and Purification, 20: 152. This purified enzyme can be used to monitor inhibitors of activity as follows: MR (final concentration 50 ng/ml) incubated for 30 minutes at RT (room temperature) in the analytical buffer (0.1 M Tris-HCl, pH to 7.3, containing 0.1 M NaCl, 20 mm CaCl2that 0,040 mm ZnCl and 0.05% (wt./about.) Brij 35), using a synthetic substrate Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa-NH2in the presence or in the absence of inhibitors. The activity is determined by measuring the fluorescence at λex 328 nm and λem 393 nm. The percentage inhibition is calculated as follows: % inhibition equal to [fluorescenceplus inhibitor- fluorescencebackground]divided by [the fluorescenceminus inhibitor- fluorescencebackground].

Recombinant human lomr possible to Express and purify, as described Knauper et al. [V.Knauper et al. (1996), The Biochemical Journal 271: 1544-1550 (1996)]. This purified enzyme can be used to monitor inhibitors of activity as follows: purified proMMP13 activate using 1 mm aminophenylarsonic acid (ARMA, amino phenyl mercuric acid), 20 hours at 21°; activated MMR (11,25 ng per assay) are incubated for 4-5 hours at 35&x000B0; With the analytical buffer (0.1 M Tris-HCl, pH 7.5, containing 0.1 M NaCl, 20 mm CaCl2, 0.02 mm ZnCl and 0.05% (wt./about.) Brij 35), using a synthetic substrate 7-(methoxycoumarin-4-yl)acetyl. Pro. Leu.Gly.Leu. N-3-(2,4-dinitrophenyl)-L-2,3-.Ala.Arg.NH2in the presence or in the absence of inhibitors. The activity is determined by measuring the fluorescence at λex 328 nm and λet 393 nm. The percentage inhibition is calculated as follows: % inhibition equal to [fluorescenceplus inhibitor- fluorescencebackground]divided by [the fluorescenceminus inhibitor- fluorescencebackground].

A similar Protocol can be used for other expressed and purified proMMP using conditions of substrates and buffers that are optimal for a particular DFID, for example, as described in .Graham Knight et al. (1992) FEBS Lett. 296 (3): 263-266.

Family agamaliev, including, for example, TNF-Mac

The ability of compounds to inhibit the enzyme proTNFα-Mac can be estimated using analysis of partially purified selected enzyme that is obtained from membranes TNR-1, as described ..Mohler et al. (1994) Nature 370: 218-220. The activity of this purified enzyme and its inhibition is determined by incubation of partially purified enzyme in the presence or in the absence of test compounds using the substrate 4',5'-dimethoxy-Ser.Pro.Leu.Ala.Gln.ala.val.arg.ser.ser.ser.arg.cys(4-(3-succinimido-1-yl)fluorescein)-NH 2in the analytical buffer (50 mm Tris-HCl, pH 7.4, containing 0.1% (wt./about.) Triton-X-100 and 2 mm CaCl2at 26°C for 18 hours. The amount of inhibition is determined as MMR, except that they use λex 490 nm and λem 530 nm. The substrate was synthesized as follows. The peptide portion of the substrate was assembled on the resin Fmoc-NH-Rink-MBHA-polystyrene, either manually or on an automatic peptide synthesizer by standard methods, including the use of Fmoc-amino acids and O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea of hexaflurophosphate (HBTU) as agent for combination with at least 4 - or 5-fold excess of Fmoc-amino acids and HBTU. Ser1and Pro2were connected by a double bond. Used the following strategy to protect the side chain: Ser1(But), Gln5(trityl), Arg8,12(Pmc or Pbf), Ser9,10,11(trityl), Cys13(trityl). After Assembly of the N-terminal Fmoc protective group was removed by treatment with Fmoc-peptidyl-resin in DMF). Thus obtained amino-peptidyl-resin was etilirovany by processing within 1.5-2 h at 70°1.5-2 equivalents of 4',5'-dimethoxyflavone-4(5)-carboxylic acid [Khanna & Ullman (1980) Anal. Biochem. 108: 156-161], which is pre-activated by diisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF)]. Then simultaneously removed protection from this dimethoxyphenethylamine and flake the Yali it from the resin by treatment triperoxonane acid, containing 5% water and triethylsilane. Dimethoxyphenylacetic were isolated by evaporation, by rubbing with diethyl ether and filtering.

This highlighted the peptide was subjected to interaction with 4-(N-maleimido)fluorescein in DMF containing diisopropylethylamine, the product was purified by HPLC with reversed phase and, finally, were isolated from aqueous acetic acid by lyophilization. Characteristics of the product were determined using MALDI-TOF MS (time-of-flight mass spectrometer with laser ionization by desorption from the matrix) and amino acid analysis.

Natural substrates

The active compounds according to the invention as inhibitors of the destruction of aggrecan can be analyzed using methods based on, for example, information Essages et al., (1998) Osteoarthritis and Cartilage 6: 214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601, and antibodies described therein. The effectiveness of compounds to act as inhibitors against collagenases can be determined as described .Cawston and A. Barrett (1979) Anal. Biochem. 99: 340-345.

Inhibition of metalloproteinase activity-based cells/tissues test the ability of the agent to inhibit membrane sheddase, such as TNF-convertase

The ability of compounds of this invention inhibit the cellular processing of the production of TNFα can be evaluated on the cells TNR-1 using ELISA (immuno is Ermentau solid-phase assay) for detection of released TNF, in fact, as described ..Mohler et al. (1994) Nature 370: 218-220. Similarly, processing, or shedding, other membrane molecules, such as molecules, described in N..Hooper et al., (1997) Biochem. J. 321: 265-279, can be tested using an appropriate cell line and the appropriate antibodies to detect chadderandom protein.

A test of the ability of the agent to inhibit cell invasion

The ability of compounds of this invention inhibit the migration of cells in the analysis on the invasion can be defined, as described in .Albini et al. (1987) Cancer Research 47: 3239-3245.

A test of the ability of the agent to inhibit the activity of TNF-sheddase whole blood

The ability of compounds of this invention inhibit the production of TNFα evaluate the analysis of whole human blood, where use LPS (lipopolysaccharide) stimulation of the release of TNFa. Heparinized (100 U/ml) human blood obtained from volunteers, diluted 1:5 medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160 μl) 20 μl of the test compounds (three repeats) in DMSO or in a suitable medium for 30 min at 37°C in humidified (5%CO2/95% air) incubator, and then add 20 μl of LPS (E. coli. 0111:B4; final concentration 10 μg/ml). Each analysis includes controls diluted blood, inkubiruemykh only with medium (6 holes/p is unset) or with a known inhibitor of TNFα as a standard. Then the tablets incubated for 6 hours at 37° (humidified incubator), centrifuged (2000 rpm for 10 min; 4° (C)collect plasma (50-100 µl) and stored in 96-well tablets at -70°to further analysis on the concentration of TNFα using ELISA.

A test of the ability of the agent to inhibit the destruction of cartilage in vitro

The ability of compounds of this invention inhibit the destruction aggrecanases or collagen component of cartilage can be evaluated essentially as described in ..Bottomley et al. (1997) Biochem. J. 323: 483-488.

Pharmacodynamic test

To evaluate properties of clearance and bioavailability of the compounds according to this invention is used ex vivo pharmacodynamic test, which uses the above analyses of the synthetic substrate or, alternatively, HPLC or mass spectrometry analysis. This test is a General test that can be used to estimate the rate of clearance of compounds in different species. Animals (such as rats, monkeys) intravenously or orally administered doses of soluble drug compounds (such as 20% wt./about. DMSO, 60% wt./about. PEG400) and in the subsequent moments of time (for example 5, 15, 30, 60, 120, 240, 480, 720, 1220 minutes) of a suitable vessel taking blood samples in 10 units of heparin. Plasma fractions get through zentrifugenbau is, and plasma proteins precipitated with acetonitrile (final concentration 80% wt./vol.). After 30 min at -20°With plasma proteins precipitated by centrifugation, and the supernatant fraction is evaporated to dryness using a speed vacuum pump Savant. Sediment pererastayut analytical buffer, and then analyze the content of a connection using the analysis of synthetic substrate. Briefly, to assess the connection build the curve of the concentration - response. Serial dilution of reconstituted plasma extracts appreciate on the activity and the number of connections present in the original plasma sample, calculated using the curve of the concentration-response taking into account the dilution factor total plasma.

Evaluation of in vivo

A test of the ability to act as an anti-TMF-agent

The ability of compounds of this invention act as inhibitors of TNFα ex vivo evaluated in rats. Briefly, groups of male Wistar rats Alderley Park (AP) (180-210 g) introducing the compound (6 rats) or a carrier for a drug (10 rats) suitable way, for example, orally (po), intraperitoneal (WB), subcutaneous (SC). After 90 minutes of rats killed, raising the concentration of CO2and take blood from the posterior Vena cava in 5 units of sodium heparin/ml of blood. Blood samples immediately placed on ice and centrifuged at 2000 on the rpm for 10 min at 4° With the collected plasma frozen at -20°for further analysis of the impact on the production of TNFα LPS-stimulated human blood. Plasma samples of rats thawed and 175 μl of each sample was added to the scheme of the serial format in 96-well plate. Then to each well was added 50 μl of heparinized human blood, mixed and incubated tablet for 30 min at 37° (humidified incubator). In wells add LPS (25 μl; final concentration 10 μg/ml) and incubation continued for the next 5.5 hours. Control wells incubated with 25 µl of only environment. Then the tablets centrifuged for 10 min at 2000 rpm, 200 μl of supernatant transferred into a 96-well plate and frozen at -20°for subsequent analysis on the concentration of TNF by ELISA.

Specialized computer program analyzes the data and calculates for each connection/dose:

Test for activity as an anti-arthritis agent

The activity of compounds as anti-arthritis agent tested for induced collagen arthritis (CIA, collagen-induced arthritis), as defined in D..Trentham et al. (1977) J.Exp. Med. 146: 857. In this model, acid-soluble native collagen type II causes polyarthritis in rats with the introduction of incomplete Freund's adjuvant. Such condition the conditions can be used to induce arthritis in mice and primates.

Test for activity as an anticancer agent

The activity of compounds as anti-cancer agent can be evaluated essentially as described in I.J.Fidler (1978) Methods in Cancer Research 15: 399-439, using, for example, the cell line B16 (described in .Hibner et al., Abstract 283 p75 10thNCI-EORTC Symposium, Amsterdam June 16-19 (1998).

Test activity as protivoallergennogo agent

The potency of the compound as protivoallergennogo agent can be evaluated essentially as described in Hautamaki et al. (1997) Science 277: 2002.

The invention is further illustrated by, but not limited to, the following examples.

General methods of analysis. Spectra1H-NMR were recorded on instruments or VarianUnityInova 400 MHz or Varian Mercury-VX 300 MHz. As internal standards used the Central peak of the solvent chloroform-d (δH7,27 million-1), dimethylsulfoxide-d6H2,50 million-1) or methanol-d4H3.31 mln-1). Mass spectra of lower resolution were obtained on the system Agilent 1100 LC-MS (liquid chromatography-mass spectroscopy), equipped with a camera ionization of head (head, chemical ionization at atmospheric pressure).

EXAMPLE 1

N-{[(4S)-2,5-Dioxoimidazolidin]methyl}-4-(4-pertenece)benzosulfimide

and

N-{[(4S)-2,5-dioxoimidazolidin]methyl}[1,1'-biphenyl]-4-sulfonamide

To a stirred solution of N-alpha-BOC-(S)-diaminopropionic acid (100 mg, 0.5 mmol) in 2.5 ml of water containing 0.04 g (0.55 mmol) of sodium carbonate solution was added sulphonylchloride (0.5 mmol) in 2.5 ml of dioxane. This solution was stirred over night at room temperature, was distributed between ethyl acetate (10 ml) and about 20% citric acid (10 ml), the aqueous phase three times were extracted with ethyl acetate, the organic extract was washed with brine, dried, evaporated, and the residue was treated with 4 N. HCl in dioxane. This mixture was stirred for 20 min, evaporated and dried under vacuum for 4 h at 40°C. Then the residue was strike 3 ml of an aqueous solution of sodium carbonate (0.08 g, 0.85 mmol) was added 0.9 g (1.1 mmol) of potassium cyanate, the mixture was stirred for 4 h at 100°C. After this period, was added 1 ml of concentrated HCl was stirred for 1 h at the same temperature, and then left to stand at room temperature overnight. The crystals were filtered off, washed with distilled water and dried under vacuum (if necessary, recrystallized from ethanol).

N-{[(4S)-2,5-Dioxoimidazolidin]methyl}-4-(4-pertenece)benzosulfimide

MC: m/z=380,1.

N-{[(4S)-2,5-Dioxoimidazolidin]methyl}[1,1'-biphenyl]-4-sulfonamide

MC: m/z=346,1.

1H NMR (DMSO): 3.00 m (1,5 H), 3.10 m (0,6 H), (CH2), 4.10 m (1H, CH),7.5 m (3H), 7.70 d (2H), 7.4 s (4H).

EXAMPLE 2

Were obtained the compounds of formula I, where Y1represents O, Y2represents O, X represents NR1, R1 represents H, R2 represents H, m is 1, R3 represents H, R4 represents N, Z represents the SO2N(R6), R6 represents H, (C1-4)alkyl, methylbenzyl or methylpyridyl, And represents a direct bond and R5 varies.

The syntheses were performed in parallel on a 20-hole tablet, conducting operations manually.

Amino acid (20 μm) was dissolved in 5 ml of water containing 6,36 mg (60 μm) of sodium carbonate. In each of the wells with the pipette was added to 0.5 ml of this solution was then added to 0.5 ml of a dioxane solution containing 20 μm of the corresponding sulphonylchloride. The reaction mixture was shaken for 18 h at room temperature, was diluted with 2 ml of methanol and was treated with 20 mg of cation-exchange resins Lewatite S100 (acid form) in each well for 5 minutes Then all of the reaction mixture was filtered, evaporated in vacuo and the residue was treated with 1 ml of 4 N. HCl in dioxane for 30 min, evaporated in vacuo and added to 0.5 ml of 0.5 M solution of potassium cyanate and was heated to 100°C for 3 hours Then after cooling to room temperature, each well was added 10 mg Lewatite S100 (acid form), and then added 2 ml of methanol was evaporated in vacuum is processed triperoxonane acid at 80° C for 2 h After evaporation the residue was purified flash chromatography on silica using a gradient of ethyl acetate-methanol (up to 10% of the Meon). Monitoring the purity and molecular weight was performed using HPLC-MS. The outputs of 0.5 to 1 mg per well.

(2,5-Dioxoimidazolidin-4-ylmethyl)amide 5-(2-methylthiazole-5-yl)thiophene-2-sulfonic acid

LC-MS (head) M++H+=373,4 (m/z).

3-(4-Chlorophenoxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)benzosulfimide

LC-MS (head) M++H+=396,8 (m/z).

4-(4-Chlorophenoxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)benzosulfimide

LC-MS (head) M++H+=396,8 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(4-methoxyphenoxy)benzosulfimide

LC-MS (head) M++H+=392,6 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-3-(4-methoxyphenoxy)benzosulfimide

LC-MS (head) M++N+=392,6 (m/z).

(2,5-Dioxoimidazolidin-4-ylmethyl)amide 5-(5-trifluoromethyl-N-pyrazole-3-yl)thiophene-2-sulfonic acid.

LC-MS (head) M++N+=410,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-tolylacetylene

W is-MS (head) M ++H+=376,4 (m/z).

3-(3,4-Dichlorophenoxy)-N-(dioxoimidazolidin-4-ylmethyl)benzosulfimide

LC-MS (head) M++H+=430,6 (m/z).

4-(3,4-Dichlorophenoxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)benzosulfimide

LC-MS (head) M++H+=430,6 (m/z).

(2,5-Dioxoimidazolidin-4-ylmethyl)amide 4'-forbiten-4-sulfonic acid

LC-MS (head) M++H+=364,4 (m/z).

(2,5-Dioxoimidazolidin-4-ylmethyl)amide 5-pyridin-2-althofen-2-sulfonic acid

LC-MS (head) M++H+=353,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(2-methoxyphenoxy)benzosulfimide

LC-MS (head) M++H+=392,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-3-(2-triptoreline)benzosulfimide

LC-MS (head) M++H+=430,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-3-(4-triptoreline)benzosulfimide

LC-MS (head) M++H+=430,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(4-triptoreline)benzosulfimide

LC-MS (head) M++H+=430,4 (m/z).

4'-Triptorelin-4-sulfonic acid (2,5-who dioxoimidazolidin-4-ylmethyl)amide

LC-MS (head) M++H+=414,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-o-tolylacetylene

LC-MS (head) M++H+=376,4 (m/z).

4-(3,5-Dichlorophenoxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)benzosulfimide

LC-MS (head) M++N+=that amount to 431,3 (m/z).

4-(2-Chlorophenoxy)-N-(dioxoimidazolidin-4-ylmethyl)benzosulfimide

LC-MS (head) M++H+=396,8 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-p-tolylacetylene

LC-MS (head) M++H+=376,4 (m/z).

4-(4-Cianfrocca)-N-(2,5-dioxoimidazolidin-4-ylmethyl)benzosulfimide

LC-MS (head) M++H+=387,4 (m/z).

4-(4-Cianfrocca)-N-(2,5-dioxo-imidazolidin-4-ylmethyl)-N-methylbenzenesulfonamide

LC-MS (head) M++N+=401,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-methyl-4-(4-triptoreline)benzosulfimide

LC-MS (head) M++H+=444,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-ethyl-4-(4-triptoreline)benzosulfimide

LC-MS (head) M++H+=458,4 (m/z).

N-(2,5-D is Oxymetazoline-4-ylmethyl)-N-isopropyl-4-(4-triptoreline)benzosulfimide

LC-MS (head) M++H+=472,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-isobutyl-4-(4-triptoreline)benzosulfimide

LC-MS (head) M++H+=486,5 (m/z).

N-Benzyl-N-(2,5-dioxoimidazolidin-4-ylmethyl)-4-(4-triptoreline)benzosulfimide

LC-MS (head) M++H+=520,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-pyridin-3-ylmethyl-4-(4-triptoreline)benzene

LC-MS (head) M++H+=521,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(4-pertenece)-N-methylbenzenesulfonamide

LC-MS (head) M++H+=394,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-ethyl-4-(4-pertenece)benzosulfimide

LC-MS (head) M++H+=408,4 (m/z).

N-Benzyl-N-(2,5-dioxoimidazolidin-4-ylmethyl)-4-(4-pertenece)benzosulfimide

LC-MS (head) M++H+=equal to USD 470.5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(4-pertenece)-N-pyridin-3-ylmethylphosphonate

LC-MS (head) M++H+=471,5 (m/z).

4-(4-Chlorophenoxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)-N-methylbenzenesulfonamide

LC-MS (head) M++H+=410,5 (m/z).

4-(4-Chlorophenoxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)-N-ethylbenzylamine

LC-MS (head) M++H+=424,88 (m/z).

4-(4-Chlorophenoxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)-N-isopropylbenzenesulfonyl

LC-MS (head) M++H+=424,88 (m/z).

N-Benzyl-4-(4-chlorophenoxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)benzosulfimide

LC-MS (head) M++H+=486,9 (m/z).

4-(4-Chlorophenoxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)-N-pyridin-3-ylmethylphosphonate

LC-MS (head) M++N+=487,9 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-methyl-4-p-tolylacetylene

LC-MS (head) M++H+=RUR 390.4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-ethyl-4-p-tolylacetylene

LC-MS (head) M++H+=404,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-isopropyl-4-p-tolylacetylene

LC-MS (head) M++H+=418,5 (m/z).

N-Benzyl-N-(2,5-dioxoimidazolidin-4-ylmethyl)-4-p-tolylacetylene

LC-MS (head) M++H+=466,5 (m/z).

N-(2,5-D is Oxymetazoline-4-ylmethyl)-N-pyridin-3-ylmethyl-4-p-tolylacetylene

LC-MS (head) M++H+=467,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(4-methoxyphenoxy)-N-methylbenzenesulfonamide

LC-MS (head) M++H+=is 406.5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-ethyl-4-(4-methoxyphenoxy)benzosulfimide

LC-MS (head) M++H+=420,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-isopropyl-4-(4-methoxyphenoxy)benzosulfimide

LC-MS (head) M++H+=433,5 (m/z).

N-Benzyl-N-(2,5-dioxoimidazolidin-4-ylmethyl)-4-(4-methoxyphenoxy)benzosulfimide

LC-MS (head) M++H+=482,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(4-methoxyphenoxy)-N-pyridin-3-ylmethylphosphonate

LC-MS (head) M++H+=483,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(pyridine-4-yloxy) benzosulfimide

LC-MS (head) M++H+=363,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-methyl-4-(pyridine-4-yloxy)benzosulfimide

LC-MS (head) M++H+=377,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-ethyl-4-(pyridine-4-yloxy)benzosulfimide

LC-MS (head) M++H+=363,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(pyridine-4-yloxy)benzosulfimide

LC-MS (head) M++H+=363,5 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(pyridine-2-yloxy)benzosulfimide

LC-MS (head) M++H+=376,4 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-ethyl-4-(pyridine-2-yloxy)benzosulfimide

LC-MS (head) M++H+=391,4 (m/z).

4-(5-Chloropyridin-2-yloxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)benzosulfimide

LC-MS (head) M++H+=397,8 (m/z).

4-(5-Chloropyridin-2-yloxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)-N-methylbenzenesulfonamide

LC-MS (head) M++H+=410,8 (m/z).

4-(5-Chloropyridin-2-yloxy)-N-(2,5-dioxoimidazolidin-4-ylmethyl)-N-ethylbenzylamine

LC-MS (head) M++H+=425,8 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-N-ethyl-4-(5-ftorpirimidinu-2-yloxy)benzosulfimide

LC-MS (head) M++H+=409,8 (m/z).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(5-ftorpirimidinu-2-yloxy)-N-methylbenzenesulfonamide

LC-MS (head) M++H+=396,4 (m/).

N-(2,5-Dioxoimidazolidin-4-ylmethyl)-4-(5-ftorpirimidinu-2-yloxy)benzosulfimide

LC-MS (head) M++H+=382,4 (m/z).

EXAMPLE 3

Compounds were obtained according to scheme 2 as shown above in the description.

(a) obtaining a starting compounds (aldehydes or ketones)

Aldehydes were obtained according to the method described Fehrentz JA and Castro, Synthesis, 676 (1983). Ketones were obtained according to the method described Nahm, S., Weinreb, S. M.: Tetrahedron Lett, 22, 3815 (1981).

(b) Obtaining an intermediate hydantoins

The aldehyde or ketone (5 mmol) was dissolved in 50% aqueous ethanol (10 ml) was added 0.55 g (10 mmol) of sodium cyanide and 2.7 g (25 mmol) of ammonium carbonate, the mixture was heated in a sealed tube to 80°C for 6 hours Then it was cooled, the pH was brought to 4 and it was evaporated in vacuum. The residue was distributed between water (10 ml) and ethyl acetate and the aqueous phase 3 times was extragonadal with ethyl acetate, then was evaporated and the diastereomers were separated by chromatography on silica (gradient of TWO (tert-butyl methyl ether)-methanol 0-10% Meon). Got the following hydantoins.

tert-Butyl ether R-1-(2,5-dioxoimidazolidin-4-S-yl)ethylcarbamate acid

LC-MS (head): M++H+=244,4, M+-56 (isobutylene) RUR 188.6, M+-VOS=144,4 (main peak).

1H-NMR (CDCl3million-1): 1.23 (d (3H), 1.45 s (9, N), 4.36 m (1,1 H), 5.30 (bs 1,1 N), 10,1 bs (1,31-1).

R-1-(4-Methyl-2,5-dioxoimidazolidin-4-8-yl)ethylcarbamate acid

LC-MS (head): [M++N+]=258,3, M+-56 (-isobutylene) 202,3, M+-VOS=158,3 (main peak).

1H-NMR (CDCl3million-1): 1.22 d (3H), 1.44 s (9,2 H), 1.58 s (3,1 M), 3.95 m (0,9 H),5.5 bs (1,5H),7,9 bs (0,8H).

tert-Butyl ether R-1-(4-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylcarbamate acid

LC-MS (head): M++H+=258,3, M+-56 (-isobutylene) 202,3, M+-VOS=158,3 (main peak).

1H-NMR (CDCl3million-1): 1.29 (d (3H), 1.54 s (9,1 M), 1.50 s (2,95 M), 4.25 m (1,1, N), 5.5 (bs 1,81-1), 7,9 ds (0.6 N).

tert-Butyl ether R-1-{2.5-dioxo-4-phenylimidazole-4-S-yl)ethylcarbamate acid

LC-MS (head): M++H+=320,3, M+-56 (-isobutylene) 264,3, M+-BOC=230,3 (main peak).

1H-NMR (CDCl3million-1): 1.31 (d (3 H), 1.35 s (9,2 H), 4.65 m (0,9 M), 6.10 (d (0,94 N), 7,25 m (3,2 M), 7.60 (d (2,05 M).

tert-Butyl(2S)-2-[(4R)-2,5-dioxoimidazolidin-4-yl]pyrrolidin-1-carboxylate

LC-MS: M++H+=170,0 (M+-BOC).

1H-NMR (CDCl3million-1): 1.26 s (9 H), 1.7-1.9 m (3,37 M), 2.1-2.2 m (0,84 M), 3.35-3.44 m (1,82 H), 4.1 bs(H 1,1).

tert-Butyl(2S)-2-[(4S)-2,5-dioxoimidazolidin-4-yl]pyrrolidin-1-carboxylate

LC-MS: M++H+=170,0 (M+-VOS).

1H-NMR (CDCl3million -1): 1.27 s (9 H), 1.65-2.0 m (wide) (4,47 M), 3.55 m (1,15 H), 3.62 m (0,55 M), 4.4 m (0,87 N).

tert-Butyl(2R)-2-[(4S)-2,5-dioxoimidazolidin-4-yl]pyrrolidin-1-carboxylate

LC-MS: M++H+=170,0 (M+-VOS).

1H-NMR (CDCl3million-1): 1.47 s (9 H), 1.7-2.2 m (wide) (4,30 H), 3.6 m (1,12 H), 3.8 m (0,78 M), 3.6 m (1,1, N).

tert-Butyl(2R)-2-[(4R)-2,5-dioxoimidazolidin-4-yl]pyrrolidin-1-carboxylate

LC-MS: M++H+=170,0 (M+-BOC).

1H-NMR (CDCl3million-1): 1.47 s (9 H), 1.7-2.2 m (wide) (4,30 H), 3.6 m (1,12 H), 3.8 m (0,78 M), 3.6 m (1,1, N).

tert-Butyl(2R)-2-[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]pyrrolidin-1-carboxylate

LC-MS: M++N+=183,1 (M+-VOS).

1H-NMR (CDCl3million-1): 1.4 s (9 H), 1.50 s (3,2 M), 1.65-2.1 m (wide) (4,20 M), 3.4 m (1,1, N), 3.5 (bs 0,78 M), 4.4 m (0,94 N).

Remove protection with BOC-protected hydantoins was performed using 40% triperoxonane acid in dichloromethane (DHM), and the end connection triptorelin 5-(1-amino-ethyl)-5-alkylimidazole-2,4-dione was besieged diethyl ether after evaporation to dryness.

Triptorelin R-5-(S-1-amino-ethyl)imidazolin-2,4-dione

LC-MS (head): M++H+=144,2 (m/z).

Triptorelin R-5-(1-amino-ethyl)-5-S-methylimidazolidine-2,4-dione

LC-MS (head): M++H+=158,2 (m/z).

Triptorelin R-5-(1-amino-ethyl)-5-R-methylimidazolidine-2,4-dione

LC-MS (head): M++H+=158,2 (m/z).

Triptorelin R5-(1-amino-ethyl)-5-S-phenylimidazoline-2,4-dione

LC-MS (head): M++H+=to 220.3 (m/z).

Triptorelin (5R)-5-[(2S)-pyrrolidin-2-yl]imidazolidin-2,4-dione

LC-MS (head): M++H+=169,1 (m/z).

(5R)-5-[(2R)-pyrrolidin-2-yl]imidazolidin-2,4-dione

LC-MS (head): M++H+=169,1 (m/z).

(5R)-5-[(2S)-pyrrolidin-2-yl]imidazolidin-2,4-dione

LC-MS (head): M++H+=169,1 (m/z).

(5S)-5-[(2S)-pyrrolidin-2-yl]imidazolidin-2,4-dione

LC-MS (head): M++H+=169,1 (m/z).

(5S)-5-methyl-5-[(2R)-pyrrolidin-2-yl]imidazolidin-2,4-dione

LC-MS (head): M++N+=183,21 (m/z).

(C) Receiving hydantoins of the formula I

The synthesis was performed in parallel on a 20-hole tablets, producing operations manually.

To each well was brought about 7.5 µmol corresponding sulphonylchloride in 0.5 ml DHM, and then about 15-20 µmol of triptoreline 5-(1-amino-ethyl)-5-alkylimidazole-2,4-dione in 0.5 ml DHM (for complete dissolution, if necessary, was added a small amount of DMF) was added 10 mg diethylaminoethylamine resin. This mixture was shaken overnight, filtered through 200 mg of silica gel (washed with 3-5 ml of ethyl acetate and the monitoring of the purification was performed using LC-MS). The solutions were evaporated to dryness to obtain all expected compounds with a sufficient degree of purity.

4-R-(4-Chlorphenoxy-N-(1-(2,5-dioxoimidazolidin-4-S-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=411,1 (m/z).

4-R-(5-Chloropyridin-2-hydroxy)-N-(1-(2,5-dioxoimidazolidin-4-S-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=412,1 (m/z).

R-N-(1-(2,5-Dioxoimidazolidin-S-4-yl)ethyl)-4-(pyridine-2-yloxy)benzosulfimide

LC-MS (head): M++2 H+=378,9 (m/z).

R-N-(1-(2,5-Dioxoimidazolidin-S-4-yl)ethyl)-4-(pyridine-4-yloxy)benzosulfimide

LC-MS (head): M++2 H+=378,9 (m/z).

4-R-(4-Cianfrocca-N-(1-(2,5-dioxoimidazolidin-4-S-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=is 401.5 (m/z).

4-R-(4-Pertenece-N-(1-(2,5-dioxoimidazolidin-4-S-yl)ethyl)benzosulfimide

LC-MS (head): M++N+=394,3 (m/z).

4-R-(4-Triptoreline-N-(1-(2,5-dioxoimidazolidin-4-S-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=444,4 (m/z).

4-R-(4-Methylphenoxy-N-(1-(2,5-dioxoimidazolidin-4-S-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=389,43 (m/z).

4-R-(4-Methoxyphenoxy-N-(1-(2,5-dioxoimidazolidin-4-S-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=to 406.4 (m/z).

4-R-(4-Phenoxy-N-(1-(2,5-dioxime azolin-4-S-yl)ethyl)benzosulfimide

LC-MS (head): M++2 H+=376,2 (m/z).

R-N-(1-(4-Methyl-2,5-dioxoimidazolidin-4-S-yl)ethyl-4-phenoxybenzenesulfonyl

LC-MS (head): M++H+=RUR 390.4 (m/z).

4-(4-Chlorphenoxy-N-(1-(4-S-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=423,4 (m/z).

4-(5-Chloropyridin-2-hydroxy)-N-(1-(4-S-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=424,4 (m/z).

N-(1-(4-S-Methyl-2,5-dioxoimidazolidin-4-R-yl)ethyl-4-(pyridine-2-yloxy)benzosulfimide

LC-MS (head): M++2 H+=392,4 (m/z).

N-(1-(4-S-Methyl-2,5-dioxoimidazolidin-4-R-yl)ethyl)-4-(pyridine-2-yloxy)benzosulfimide

LC-MS (head): M++2 H+=392,4 (m/z).

4-(4-Cianfrocca-N-(1-(4-S-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++2 N+=415,4 (m/z).

R-N-(1-(4-Methyl-2,5-dioxoimidazolidin-4-R-yl)ethyl-4-phenoxybenzenesulfonyl

LC-MS (head): M++H+=RUR 390.4 (m/z).

4-(4-Chlorphenoxy-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=423,4 (m/z).

4-(5-Chloropyridin-2-hydroxy)-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=424,4 (m/z).

N-(1-(4-R-Methyl-2,5-dioxoimidazolidin-4-R-yl)ethyl)-4-(pyridine-2-yloxy)benzosulfimide

LC-MS (head): M++2 H+=392,4 (m/z).

N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-yl)ethyl)-4-(pyridine-2-yloxy)benzosulfimide

LC-MS (head): M++2 H+=392,4 (m/z).

4-(4-Cianfrocca-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=415,4 (m/z).

4-(4-Pertenece-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-S-yl)ethylbenzophenone

LC-MS (head): M++H+=407,4 (m/z).

4-(4-Triptoreline-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-S-yl)ethylbenzophenone

LC-MS (head): M++H+=458,4 (m/z).

4-(4-Methylphenoxy-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-S-yl)ethylbenzophenone

LC-MS (head): M++H+=404,5 (m/z).

4-(4-Methoxyphenoxy-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-S-yl)ethylbenzophenone

LC-MS (head):M ++N+=420,5 (m/z).

4-(4-Phenoxy-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-S-yl)ethylbenzophenone

LC-MS (head): M++H+=390,5 (m/z).

4-(4-Pertenece-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=407,4 (m/z).

4-(4-Triptoreline-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=458,4 (m/z).

4-(4-Methylphenoxy-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=404,5 (m/z).

4-(4-Methoxyphenoxy-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=420,5 (m/z).

4-(4-Phenoxy-N-(1-(4-R-methyl-2,5-dioxoimidazolidin-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=390,5 (m/z).

4-(4-Chlorphenoxy-N-(1-((2,5-dioxo-4-S-phenylimidazole-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=486,8 (m/z).

4-(5-Chloropyridin-2-yloxy)-N-(1-((2,5-dioxo-4-S-phenylimidazole-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=487,8 (m/z).

N-(1--(2,5-Dioxo-4-phenylimidazole-4-R-yl)ethyl-4-(pyridine-2-yloxy)benzosulfimide

LC-MS (head): M++2 H+=454,6 (m/z).

N-(1-S-(2,5-Dioxo-4-phenylimidazole-4-R-yl)ethyl-4-(pyridine-4-yloxy)benzosulfimide

LC-MS (head): M++2 H+=454,6 (m/z).

4-(4-Cianfrocca-N-(1-((2,5-dioxo-4-S-phenylimidazole-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=477,6 (m/z).

4-(4-Pertenece-N-(1-((2,5-dioxo-4-S-phenylimidazole-4-R-yl)ethyl)benzosulfimide

LC-MS (head): M++N+=equal to USD 470.5 (m/z).

4-(4-Triptoreline-N-(1-((2,5-dioxo-4-S-phenylimidazole-4-R-Il)ethylbenzophenone

LC-MS (head): M++H+=519,1 (m/z).

4-(4-Methylphenoxy)-N-(1-((2,5-dioxo-4-S-phenylimidazole-4-R-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=466,4 (m/z).

4-(4-Methoxyphenoxy-N-(1-((2,5-dioxo-4-S-phenylimidazole-4-R-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=482,4 (m/z).

4-(4-Phenoxy)-N-(1-((2,5-dioxo-4-S-phenylimidazole-4-R-yl)ethyl)benzosulfimide

LC-MS (head): M++H+=452,5 (m/z).

5-(1-{[4-(4-Chlorophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione

LC-MS (head): M++H+=450,5 (m/z).

5-(1-{[4-(4-Methoxyphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione

LC-MS (head): M++H+=446,2 (m/z).

5-(1-{[4-(4-Methylphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione

LC-MS (head): M++H+=430,1 (m/z).

5-(1-{[4-(4-Pertenece)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione

LC-MS (head): M++H+=of 434.1 (m/z).

(1-{[4-(4-Cianfrocca)phenyl]sulfonyl}pyrrolidin-2-yl)-5-methylimidazolidine-2,4-dione

LC-MS (head): M++H+=441,1 (m/z).

5-(1-{[4-(4-Chlorophenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidin-2,4-dione

LC-MS (head): M++H+=436,1 (m/z).

5-(1-{[4-(4-Pertenece)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidin-2,4-dione

LC-MS (head): M++H+=420,1 (m/z).

5-(1-{[4-(4-Methylphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidin-2,4-dione

LC-MS (head): M++H+=416,1 (m/z).

5-(1-{[4-(4-Methoxyphenoxy)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidin-2,4-dione

LC-MS (head): M++H+=432,1 (m/z).

5-(1-{[4(4-Cianfrocca)phenyl]sulfonyl}pyrrolidin-2-yl)imidazolidin-2,4-dione

LC-MS (head): M++H+=427,1 (m/z).

EXAMPLE 4

[(4R)-2,5-Dioxoimidazolidin]methanesulfonamide, [(4S)-2,5-dioxoimidazolidin]methanesulfonanilide or [(R)-2,5-dioxoimidazolidin]methanesulfonanilide were subjected to interaction with the corresponding primary or secondary amine to obtain the compounds listed below. All used amines are commercially available.

Sulphonylchloride (to 0.060 mmol), amine (to 0.060 mmol), triethylamine (0,0084 ml, to 0.060 mmol) in anhydrous tetrahydrofuran (0,70 ml) was stirred at room temperature overnight. Added politicalmilitary (0.025 g, being 0.030 mmol) and the mixture was shaken over night. The white suspension was filtered and the solids were washed with tetrahydrofuran (2×1 ml). The filtrate was evaporated and the white solid is suspended in water (5 ml), collected on a filter, washed with water (2×1 ml)was aspirated water and dried in vacuum at 45°during the night with obtaining the compounds specified in the header.

The initial substance was prepared as follows.

5-Methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione

The steel vessel was loaded ethanol and water (315 ml/135 ml). Added to 31.7 g (0,175 mol) of benzyltoluene, 22.9 g (0.351 mol) of potassium cyanide and 84.5 g (0,879 mol) of ammonium carbonate. The closed reaction vessel was kept in mA what lanai bath (bath temperature 90° (C) under vigorous stirring for 3 hours

The reaction vessel was cooled with ice water (0.5 h), yellowish suspension was evaporated to dryness, the solid residue was distributed between 400 ml of water and 700 ml of ethyl acetate and separated. The aqueous phase was extracted with ethyl acetate (300 ml). The combined organic phases were washed with saturated brine (150 ml), dried (Na2SO4), filtered and evaporated to dryness. If the product is not crystallized, the oil was added 300 ml of dichloromethane. Evaporation resulted in the receipt of the product in the form of a slightly yellowish powder that 43.8 g (90%).

LC-MS (head): m/z 251,1 (MN+).

1H NMR (DMSO-d6) δ: 10.74 (1 H, s); 8.00 (1 H, s); 7.35-7.20 (5 H, m); 3.76 (2 H, s); 2.72, 2.62 (1 H each, ABq, J=14,0 Hz); 1.29, (3H, s).

13With NMR (DMSO-d6) δ: 177.30, 156.38, 138.11, 128.74, 128.24, 126.77, 62.93, at 37.96, 36.39, 23.15.

(5S)-5-Methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione

The connection specified in the header of the received chiral separation of racemic substances, using a column of 250 mm ×50 mm in the system preparative HPLC with a dynamic axial compression (Dynamic Axial Compression Preparative HPLC). Used stationary phase CHIRALPAK AD, as eluent : methanol, flow rate was equal to 89 ml/min, temperature equal to the ambient temperature, ultraviolet radiation (UV) 220 nm, the concentration of the sample 150 mg/ml, injection volume 20 ml retention Time for the connection specified in the header, amounted to 6 minutes

Analysis of chiral purity was performed using column CHIRALPAK AD 250 mm ×4.6 mm from Daicel, flow rate 0.5 ml/min, eluent - ethanol, UV 220 nm temperature environment.

Retention time for the connection specified in the header, was 9,27 minutes

It is established that the purity was more than 99% EE (enantiomeric excess, the enantiomeric excess).

LC-MS (head): m/z 251,1 (MH+).

[α]D=-30,3° (C=0.01 g/ml, Meon, T=20°).

1H NMR (DMSO-d6) δ: 10.74 (1 H, s); 8.00 (1 H, s); 7.35-7.20 (5 H, m); 3.76 (2 H, s); 2.72, 2.62 (1 H each, Abq, J=14,0 Hz); 1.29 (3H, s).

13C NMR (DMSO-d6) δ: 177.30, 156.28, 138.11, 128.74, 128.24, 126.77, 62.93, at 37.96, 36.39, 23.15.

(5R)-5-Methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione

The connection specified in the header, was obtained by chiral separation of racemic substances using column 250 mm ×50 mm preparative HPLC with a dynamic axial compression. Used stationary phase CHIRALPAK AD, eluent : methanol, flow rate 89 ml/min, ambient temperature, UV=220 nm, the concentration of the sample 50 mg/ml, injection volume 20 ml retention Time for the connection specified in the header was 10 minutes

Analysis of chiral purity was performed using column CHIRALPAK AD 250 mm × 4.6 mm from Daicel, flow rate 0.5 ml/min, eluent - ethanol, UV 220 nm, temperature is round the environment.

Retention time for the connection specified in the header, was 17,81 minutes

Installed chiral purity was more than 99% EE.

LC-MS (head): m/z 251,0 (MH+).

[α]D=+30,3° (C=0.01 g/ml, Meon, T=20°).

1H NMR (DMSO-d6) δ: 10.74 (1 H, s); 8.00 (1 H, s); 7.35-7.20 (5 H, m); 3.76 (2 H, s); 2.72, 2.62 (1 H each, ABq, J=14,0 Hz); 1.29 (3H, s).

13With NMR (DMSO-d6) δ: 177.31, 156.30, 138.11, 128.74, 128.25, 126.77, 62.94, 37.97, 36.40, 23.16.

[(4S)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonanilide

(5S)-5-Methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione (42.6 g; to 0.17 mol) was dissolved in a mixture of Asón (450 ml) and N2O (50 ml). This mixture was immersed in a bath of ice/water. Cl2(gas) was barbotirovany through this solution, the gas flow is regulated in such a way as to maintain the temperature below +15°C. After 25 min the solution became yellow-green in color, was selected sample for LC-MS and HPLC analysis. The analysis showed that starting material had been consumed. Yellow clear solution was stirred for 30 min, it was formed of an opaque solution/suspension. The solvent was removed on a rotary evaporator using a water bath with the temperature to be maintained at +37°C. a Yellowish solid is suspended in toluene (400 ml) and in the same rotary evaporator solvent was removed. The operation was repeated once again. The ZAT the crude product is suspended in isohexane (400 ml) and heated to +40° With stirring, the suspension was left to cool to room temperature, after which the insoluble product was removed by filtration, washed with isohexane (6×100 ml) and dried under reduced pressure at +50°With during the night. This gave the product as a slightly yellow powder. Received 36.9 g (95%) of the connection specified in the header.

Purity by HPLC 99%, NMR confirmed the purity.

[α]D=by 12,4° (C=0.01 g/ml, THF, T=20°).

1H NMR (THF-d8) δ: 9.91 (1 H, bs); 7.57 (1 H, s); 4.53, 4.44 (1 H each, ABq, J=14.6 Hz); 1.52(s, 3 H, CH3).

13With NMR (THF-d8) δ: 174.96, 155.86, 70.96, 61.04, at 23.66.

[(4R)-4-Methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonanilide

Following the procedure described for [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonanilide, starting from (5R)-5-methyl-5-{[(phenylmethyl)thio]methyl}imidazolidine-2,4-dione (10.0 g, 40 mmol), received 8,78 g (yield 96%) of the connection specified in the header.

Purity by NMR over 98%.

[α]D=+12,8° (C=0.01 g/ml, THF, T=20°).

1H NMR (THF-d8) δ: 9.91 (1 H, brs); 7.57 (1 H, s); 4.53, 4.44 (1 H each, ABq, J=14.6 Hz); 1.52(s, 3H, CH3).

13With NMR (THF-d8) δ: 174.96, 155.84, 70.97, 61.04, at 23.66.

In the following table 1 shows the group "Amin" for each of the compounds of the above structure.

Table 1

< / br>
N.M. 336

m/z 367 (M+1)
< / br>
M.M. 373,43

m/z 374 (M+1)
< / br>
Mm 320

m/z 321 (M+1)
< / br>
M.M. 331,78

m/z 332 (M+1)
< / br>
M.M. 357,39

m/z 358 (M+1)
< / br>
M.M. 331,44

m/z 332 (M+1)
< / br>
M.M. 336,37

m/z 337 (M+1)

In the following table 2 shows the group "Amin" for each of the compounds of the above structure.

Table 2

< / br>
N.M. 336

m/z 367 (M+1)
< / br>
M.M. 373,43

m/z 374 (M+1)
< / br>
Mm 320

m/z 321 (M+1)
< / br>
M.M. 331,78

m/z 332 (M+1)
< / br>
M.M. 357,39

m/z 358 (M+1)
< / br>
M.M. 331,44

m/z 332 (M+1)
< / br>
M.M. 336,37

m/z 337 (M+1)
< / br>
M.M. 403,46

m/z 404 (+1)
< / br>
M.M. 389,43

m/z 390 (M+1)

In the following table 3 shows the group "Amin" for each of the compounds of the above structure.

Table 3

As theAnalysis(1)
MW 375,41

m/z 410 (MH+)
m/z 374 (MH+)

MW 373,43
m/z 388 (MH+)

MW 387,42

N-[4-(4-Chlorophenoxy)phenyl]-C-((4S)-4-methyl-2,5-dioxoimidazolidin-4-yl)methanesulfonamide

LC-MS (head): m/z 410 (MH+).

1H NMR (DMSO-d6) δ: 10.75 (1 H, s); 9.89 (1 H, s); 8.04 (1 H, s); 7.45-7.39 (2 H, m); 7.25-7.19 (2 H, m); 7.06-6.97 (4 H, m); 3.54 (1 H (ABq, J=14.1 Hz); 1.31 (3H, s).

N-(4-Benzoylphenyl)-S-((4S)-methyl-2,5-dioxoimidazolidin-4-yl)methanesulfonamide

LC-MS (head): m/z 374 (MH+).

1H NMR (DMSO-d6) δ: 10.74 (1 H, s); 9.82 (1 H, s); 8.01 (1 H, s); 7.33-7.05 (M, m); 3.49, 3.36 (1 H each, ABq, J=16.2 Hz); 1.28 (3H, s).

N-(4-Benzoylphenyl)-S-((4S)-4-methyl-2,5-dioxoimidazolidin-4-yl)methanesulfonamide

LC-MS (head): m/z 388 (MH+).

1H NMR (DMSO-d6) δ: 10.81 (1 H, s); 10.58 (1 H, s); 8.08 (1 H, s); 7.76-7.62 (5 H, m); 7.60-7.52 (2 H, m); 7.33-7.27 (2 H, m); 3.68, 3.52 (1 H each, ABq, J=14,7 Hz);1.33(3H, s)./p>

EXAMPLE 5

The compound of this example was obtained from commercially available M-BOC-4-piperidone the methods described in example 3.

m/z 437 (MH+), M.M. 435,89

m/z 432 (MH+), M.M. 431,47

m/z 416 (MH+), M.M. 415.47

m/z 420 (MH+), M.M. 419.43

m/z 427 (MH+), M.M. 426,45

EXAMPLE 6

The manufacture of pharmaceutical compositions and medicaments containing the metalloproteinase inhibitor

The following examples illustrate typical pharmaceutical dosage forms containing the compound of formula (I) or (II) designed for the treatment mediated by metalloproteinases diseases.

(a)

Tabletmg tablet
The compound of formula (I)/(II)100
Lactose (European Pharmacopoeia)179
Croscarmelose sodium saltto 12.0
Polyvinylpyrrolidone6
Magnesium stearate3,0

(b)

Capsulemg/capsule
The compound of formula (I)/(II)10
Lactose (the Euro is Yeysk Pharmacopeia) 389
Croscarmelose sodium salt100
Magnesium stearate1,0

These drugs can be obtained by conventional methods well known in the pharmaceutical art. Tablets can be coated in the usual way.

A method of manufacturing

The compound of formula (I)/(II) is placed in a vessel, add these excipients, are thoroughly mixed to homogeneity (controlling visually). Then (a) the resulting mixture is pressed into tablets or (b) this mixture is filled capsules suitable for oral administration.

1. The compound of formula I or its pharmaceutically acceptable salt

X is NR1;

Y1and Y2represent About;

Z is selected from the SO2N(R6), N(R7)SO2;

m is 1 or 2;

And selected from a direct link, (C1-6)alkyl;

R1 represents H;

R2 and R3, each independently, selected from H, alkyl, aryl, alkylaryl, arylalkyl;

each R4 is independently selected from H, (C1-3)alkyl;

R6 is selected from H, alkyl, aryl, heteroaryl, alkylaryl, alkylglycerol, arylalkyl, heteroallyl;

R2 and R6 may be joined to form a ring containing up to 7 kalawy the atoms, or R3 and R6 can be joined to form a ring containing up to 7 ring atoms, or R4 and R6 may be joined to form a ring containing up to 7 ring atoms;

R5 represents a monocyclic, bicyclic, containing one or two ring structures, each of which contains up to 7 ring atoms independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl, with each ring structure may independently substituted by one or more than one Deputy, independently selected from halogen, hydroxy, alkyl, alkoxy, halogenoalkane, cyano, where any alkyl radical within any substituent itself may possibly be substituted by one or more than one group selected from halogen;

when R5 is a bicyclic group, each ring structure is connected with the following ring structure via a direct link, via-O -, (C1-6)alkyl or condensed with this next ring structure;

R7 is selected from (C1-6)alkyl;

provided that

when X represents NR1, R1 represents H, Y1represents O, Y2represents O, Z represents the SO2N(R6), R6 represents H, R2 represents H, m is 1, R3 represents H, R4 made the focus of a H and a represents a direct bond, then R5 is not phenyl, para-nitrophenyl, para-ethoxyphenyl or Mat-were;

when X represents NR1, R1 represents H, Y1 represents O, Y2 represents O, Z represents the SO2N(R6), R6 represents alkyl, R2 represents H, m is 1, one of R3 and R4 represents N and the other represents alkyl, R3 and R6, or R4 and R6 are connected with the formation of 5-membered ring and a is a direct bond, then R5 is not phenyl.

2. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, where X represents NR1, R1 represents H, at least one of Y1 and Y2 represents O, Z represents the SO2N(R6)m is 1.

3. The compound according to claim 1 or 2, or its pharmaceutically acceptable salt, where R2 represents H, alkyl, arylalkyl, alkylaryl.

4. The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, where each of R3 and R4 is independently selected from H, methyl.

5. The compound of formula I according to any one of claims 1 to 4, or its pharmaceutically acceptable salt, where R3 and R6 form a 5 - or 6-membered ring, or R4 and R6 form a 5 - or 6-membered ring, or R2 and R3 form a 5-membered ring, or R2 and R6 form a 5-membered ring.

6. The compound of formula I according to any one of claims 1 to 5, or its pharmaceutically acceptable salt wherein R5 contains enabled the substituted aryl or heteroaryl and 5 - or 6-membered ring in the number one or two.

7. The compound of formula I according to any one of claims 1 to 6, or its pharmaceutically acceptable salt, where R5 is a bicyclic group containing two possibly substituted ring structure.

8. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, where Y1represents O, Y2represents O, X represents NR1, R1 represents H, R2 represents H, m is 1, R3 represents H, R4 represents N, Z represents the SO2N(R6), R6 represents H, (C1-4)alkyl, methylbenzyl or methylpyridyl, And represents a direct bond and R5 is a bicyclic group containing two possibly substituted ring structure.

9. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt, where Y1represents O, Y2represents O, X represents NR1, R1 represents H, R2 represents H, methyl or benzyl, m is 1, R3 represents H or methyl, R4 represents N, Z represents the SO2N(R6), R6 represents H, a represents a direct bond and R5 is a bicyclic group containing two possibly substituted ring structure.

10. The compound of formula II or its pharmaceutically acceptable salt

where

it is gdy of G1 and G2 represents a monocyclic ring structure, each of which contains up to 7 ring atoms independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl, with each ring structure may independently substituted with one or two substituents, independently selected from halogen, hydroxy, halogenoalkane, cyano, alkyl, alkoxy, where any alkyl radical within any substituent may be possibly substituted by one or more than one group selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkoxy, halogenoalkane;

Z represents SO2N(R6);

Selected from a direct link, O, (C1-6)alkyl;

R2 is selected from H, (C1-6)alkyl or R2 represents a group of formula III

C and D are independently selected from a direct link, H, (C1-6)alkyl;

G3 represents a monocyclic ring structure containing up to 7 ring atoms independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl;

R3 and R4 are independently selected from H or (C1-3)alkyl;

R6 is selected from H or R6 represents (C1-3)alkyl, possibly substituted aryl, heteroaryl;

R2 and R6 may be joined to form a ring containing up to 7 ring atoms, or R3 and R6 can be connected with the formation of the ring, containing up to 7 ring atoms, or R4 and R6 may be joined to form a ring containing up to 7 ring atoms.

11. The compound of formula II according to claim 10 or its pharmaceutically acceptable salt, where Z represents the SO2N(R6), and the S atom of the group Z is attached to the ring G2.

12. The compound of formula II according to claim 10 or 11, or its pharmaceutically acceptable salt, where a represents a direct bond or O.

13. The compound of formula II according to any one of p-12 or its pharmaceutically acceptable salt, where R2 is possibly substituted, or R2 is selected from H, (C1-6)alkyl, aryl-(C1-6)alkyl or heteroaryl-(C1-6)alkyl.

14. The compound of formula II according to any one of PP-13 or its pharmaceutically acceptable salt, where each of R3 and R4 represents N.

15. The compound of formula II according to any one of p-14 or its pharmaceutically acceptable salt, where R6 represents H, benzyl or methyleneimine.

16. The compound of formula II according to any one of p-15 or its pharmaceutically acceptable salt, where G1 and G2, each selected from aryl or heteroaryl.

17. The compound of formula II according to any one of p-16 or its pharmaceutically acceptable salt, where R3 and R6 form a 5 - or 6-membered ring, or R4 and R6 form a 5 - or 6-membered ring, or R2 and R6 form a 5-membered ring.

18. Pharmaceutical composition useful in the inhibition of metalloproteinases, the content is based on the compound of the formula I according to claim 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

19. Pharmaceutical composition useful in the inhibition of metalloproteinases containing the compound of formula II according to claim 10 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

20. The use of the compounds of formula I or formula II or pharmaceutically acceptable salts in the manufacture of medicaments for use in the treatment of a disease or condition mediated by one or more than one enzyme, which is a metalloproteinase.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C1-C4)-alkyl, -O-(C1-C4)-alkyl, -N-[(C1-C4)-alkyl]2, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 13 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: chemistry of polymers, chemical technology.

SUBSTANCE: invention relates to sulfoxides or sulfones grafted on polymers, polymeric compositions, a method for grafting and method for stabilization of polymers. Invention describes polymers comprising a grafted compound of the formula (I): [R1-SOm]n-R-SOp-R2 (I) wherein total symbols have values given in cl. 1 of the invention claim and represents a composition comprising thereof, a method for grafting compound of the formula (I) on polymers and a method for stabilization of polymers. Polymers comprising grafted sulfoxides or sulfones possess high stability against oxidative, thermal, dynamic destruction caused by the light effect and/or destruction caused by ozone effect.

EFFECT: improved preparing method, improved and valuable properties of polymers.

14 cl, 14 tbl, 24 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chromane of the formula (I): and its salts. Method involves direct reaction of 5-(4-fluorophenyl)pyridine-3-carbaldehyde of the formula (II): with 2-aminomethylchromane or its salts under reductive conditions resulting to formation of compound of the formula (I). Synthesized compound of the formula (I) is converted to one of its salts by treatment with acid. Method provides simplifying process based on decreasing amount of by-side products formed.

EFFECT: improved method of synthesis.

8 cl, 2 dwg, 4 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C1-C4)-alkyl, -O-(C1-C4)-alkyl, -N-[(C1-C4)-alkyl]2, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 13 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted indoles or its pharmaceutically acceptable salts of the formula (I): , wherein R1 means hydrogen (H) atom, halogen atom, -CN, nitro-group, -SO2R4, -OH, -OR4, -SO2NR5R6, -CONR5R6, -COOH, -COOCH3, -NR5R6, phenyl, naphthyl or (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atom, -OR8 and -NR5R6 wherein x = 2; R2 means (C1-C7)-alkyl; R3 means phenyl, naphthyl or heteroaryl and each of them is possibly substituted with one or more substitutes chosen independently from H, halogen atom, -CN, -OH, -SO2R4, -OR4, -SO2NR5R6, -CONR5R6, phenyl, naphthyl, (C1-C6)-alkyl wherein the latter group is possibly substituted with one or more substitutes chosen independently from halogen atoms, -OR8 and -NR5R6, -S(O)xR7 wherein x = 2; R4 means (C1-C6)-alkyl; R5 and R6 mean independently H, (C1-C6)-alkyl, or R5 and R6 in common with nitrogen atom to which they are bound can form 6-membered saturated heterocyclic ring comprising one atom chosen from -NR16; R7 means (C1-C6)-alkyl; R8 means H, (C1-C6)-alkyl; R16 means H, -COY-(C1-C4)-alkyl wherein Y means oxygen atom (O) and wherein alkyl group in the substitute group can be direct, branched or cyclic, and wherein heteroaryl means 5-6-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or means 6,6-condensed bicyclic aromatic ring system comprising one nitrogen atom. Compounds of the formula (I) can be used in production of a medicinal agent used in treatment of asthma and chronic obstructive disease.

EFFECT: valuable medicinal properties of compounds.

7 cl, 2 tbl, 59 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I): wherein X means -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO, -SO2; m = 1; A represents a direct bond; R1 means hydrogen atom (H); R2 and R3 are chosen independently from H, (C1-C6)-alkyl, heterocycloalkyl, phenyl, heteroaryl, phenylalkyl, phenylheteroalkyl, heteroarylalkyl, heterocycloalkylalkyl; R4 represents H; R5 represents monocyclic, bicyclic or tricyclic group. Also, invention describes a pharmaceutical composition and using compounds in preparing a medicinal agent for using in treatment of diseases or states mediated by one ore more enzymes representing metalloproteinase. Compounds of the formula (I) are useful as inhibitors of metalloproteinases being especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

14 cl, 16 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel condensed cyclopropylpyrrolidines of the formula: wherein x means 0 or 1 and y means 0 or 1 under condition that x means 1 when y means 0, and x means 0 when y means 1; and wherein n means 0 or 1; X means hydrogen atom (H) of group -CN; R1, R2, R3 and R4 are similar or different and chosen independently from H, (C1-C10)-alkyl, (C2-C12)-alkenyl, saturated (C3-C10)-cycloalkyl, saturated (C3-C10)-cycloalkyl-(C1-C10)-alkyl, saturated (C3-C10)-bicycloalkyl, saturated (C3-C10)-tricycloalkyl, hydroxyl-(C1-C10)-alkyl-saturated (C3-C10)-cycloalkyl, (C1-C10)-alkylthio-(C1-C10)-alkyl, (C6-C10)-aryl-(C1-C10)-alkylthio-(C1-C10)-alkyl, (C6-C10)-aryl-(C1-C10)-alkyl, 5- or 6-membered heteroaryl comprising one nitrogen atom (N) or one oxygen atom (O), 5- or 6-membered heteroaryl comprising one atom N condensed with (C6-C10)-aryl ring, 5- or 6-membered heteroaryl comprising one atom N or one atom O, (C1-C10)-alkyl, cycloheteroalkyl that represents (C5-C8)-saturated ring comprising one heteroatom, such as N or O; if necessary, all compounds comprise 1, 2, 3, 4 or 5 groups of substitutes at corresponding carbon atom chosen from halogen atom, (C1-C10)-alkyl, (C2-C12)-alkenyl, hydroxy-group, hydroxy-(C1-C10)-alkyl or cyano-group; R1 and R4 can form in common, if necessary, the group -(CR5R6)m- wherein m means 2-6, and R5 and R6 are similar or different and chosen independently from hydroxy-group, H or (C1-C10)-alkyl including all their stereoisomers; and their pharmaceutically acceptable salt, or prodrug esters and all their stereoisomers. These compound inhibit activity of dipeptidyl peptidase IV that allows their using in pharmaceutical compositions used in treatment of diabetes mellitus of type-2.

EFFECT: valuable medicinal properties of compounds.

20 cl, 6 tbl, 113 ex

FIELD: organic chemistry, chemical technology, medicine, ophthalmology.

SUBSTANCE: invention relates to a new method for synthesis of 5-bromo-6-[(2-imidazolin-2-yl)amino]quinoxaline L-tartrate (brimonidine L-tartrate) of the formula (I): that is a highly effective medicinal agent used in glaucoma treatment. Method involves condensation of N,N-dimethyldichloromethylene immonium chloride of the formula: (CH3)2N+=CCl2Cl- with 5-bromo-6-aminoquinoxaline in organic solvent medium followed by treatment with ethylenediamine of formed N,N-dimethyl-N1-(5-bromoquinoxalin-6-yl)-α-chloroformamidine of the formula: RN=C(Cl)N(CH3)2 wherein R means 5-bromoquinoxalin-6-yl. Synthesized intermediate compound is extracted from reaction and mass and subjected for cyclization to 5-bromo-6-[(2-imidazolin-2-yl)amino]quinoxaline that is converted to L-tartrate by interaction with L-tartaric acid in acetone medium. Invention provides simplifying the technological process that is carried out under mild conditions and without isolation of intermediate substances that allows preparing the end preparation with the high yield about 40% as measure for 5-bromo-6-aminoquinoxaline.

EFFECT: improved method of synthesis.

1 cl, 2 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

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