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

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (U): or its pharmaceutically acceptable salt wherein X is chosen from -NR1, sulfur atom (S); Y1 and Y2 represent oxygen atom (O); Z represents O; m = 0 or 1; A is chosen from a direct bond, (C1-C6)-alkyl; R1 is chosen from hydrogen atom (H), alkyl; R3 and R6 are chosen independently from H, alkyl, halogenalkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocycloalkyl-alkyl, alkylaryl, heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl or heterocycloalkyl; R4 is chosen from H, alkyl; R5 represents a bicyclic or tricyclic group comprising two or three ring structure wherein each of that comprises from 3 to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl wherein each ring structure is joined with the next ring structure through a direct bond, through -O-, through -S-, through (C1-C6)-alkyl, through (C1-C6)-heteroalkyl, through (C1-C6)-alkynyl, through carboxy-(C1-C6)-alkyl, or it is condensed with the next ring structure wherein heteroalkyl represents heteroatom-substituted alkyl comprising one heteroatom chosen from N, O and S. Also, invention describes compounds of formulae (Ib), (Ic) and (Id) given in the invention description, pharmaceutical composition and using these compounds in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

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

17 cl, 3 tbl, 17 ex

 

The present invention relates to compounds suitable for inhibiting metalloproteinases and, in particular, pharmaceutically 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 (MMP)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 such enzymes as protease 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 given the many physiological painful 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 lgE receptor CD23 low affinity (a more complete list, see N. M. 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); tumor metastasis or invasion; when the disease is associated with some of strairway the destruction of the 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 cos the van to the provocations of 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 that were administered a loading dose 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 MMR, COPD (emphysema and bronchitis) was discussed in the work of 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].

MMP13, or collagenase 3, was originally cloned from a cDNA library of 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 MMP13 limited to carcinomas of the breast, because 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 MMP13 was detected in transformed epidermal keratinocytes [N. Johansson et al. (1997) Cell Growth Differ. 8(2): 243-250], flat the cell carcinomas [N. Johansson et al. (1997) Am. J. Pathol. 151(2): 499-508] and epidermal tumors [K. Airola et al. (1997) J. Invest. Dermatol. 109(2): 225-231]. These results suggest that MMP13 is 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 of the cancer of the breast 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 al. (1996) J. Clin. Invest. 97(3): 761-768; V. Knauper et at., (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. Rheumatol. 23: 590-595; P. G. Mitchell et al., (1996) J. Clin. Invest. 97(3): 761-768; O. 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 periodontitis is zrelyh, because it is localized in the epithelium chronically inflamed mucosal tissue of the gums [V. J. Ditto 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, then cloned and sequenced in 1989 [S. M. Wilhelm et al. (1989) J. Biol. Chem. 264(29): 17213-17221; misprints published in J. Bioi. Chem. (1990) 265(36): 22570]. A recently published review on MR [T.N. Vu & Z. Werb (1998) (In: Matrix Metalloproteases, 1998. Edited by W. C. Parks & R. P. Mecham. pp 115-148. Academic Press. ISBN 0-12-545090-7)] is an excellent source of detailed information and links on this protease. From this 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), which is subsequently cleaved formed with the eating enzyme-active enzyme. Protease required for this activation in vivo is not known. Balance active MMR in comparison with the inactive enzyme addition is regulated in vivo by interaction with the natural protein TMR-1 (tissue inhibitor of metalloprotease-1). TMR-1 associated with C-end plot 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.

There is an increasing mass of information about the role MMR in various physiological and pathological processes. Physiological roles include 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 with other popular the s [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, 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 is mainly expressed in neutrophils. Recent studies indicate that MMR is expressed in other cells, such as osteoarthritis chondrocytes [Shiopov et al., 1997, Arthritis Rheum, 40: 2065]. DFID is produced by neutrophils, can cause remodeling of tissues. Therefore, blocking MMR can have a positive effect in fibrotic diseases, such as the lung and in degenerative diseases such as emphysema. Also found positive regulation MMR in osteoarthritis, indicating that blocking MMR can also be useful in this disease.

MMR (stromelysin-1) is an enzyme 53 CD collection matrix metalloprotease. Activity MMR was demonstrated in fibroblasts, vydelennymi inflamed gums [Uitto V. J. et at., 1981, J Periodontal Res., 16: 417-424], and it was shown that the enzyme levels correlate with severity of disease of the gums [Overall C. M. et al., 1987, J Periodontal Res., 22: 81-88]. MMR is produced also basal keratinocytes at various chronic ulcers [Saarialho-Kere U, K. et al., 1994, J. Clin. Invest. 94: 79-88 [in Russian]]. mRNA and protein MMR were detected in basal keratinocytes near the edge of the wound, but away from him, which probably has sites proliferating epidermis. Thus, MMR can hinder the healing of the epidermis. Several researchers have demonstrated persistent increase MMR in synovial fluids of patients with rheumatoid arthritis and osteoarthritis compared to controls [Walakovits L.. et al., 1992, Arthritis Rheum., 35: 35-42, Zafarullah M. et al., 1993, J. Rheumatol. 20: 693-697]. These studies suggest that the inhibitor MMR 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. [199, 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), at least one functional group, which provides interaction hydrogen bond 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 binding zinc group is at and trimethylpentanediol group in position P1.

The above connection is phthalimidopropyl, which inhibits collagenase. It has ones succinyldicholine connecting the zinc group and cyclic kidney group 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 (PCT 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:

in Japan patent No. 5097814 (1993) described a method of obtaining compounds which are useful as intermediates for the production of antibiotics, including the compound having the formula

Morton et al. [1993, J Agric Food Chem 41(1): 148-152] describe the formation of compounds with fungicidal activity, including the compound having the formula

Dalgatov, D. et al [1967, Khim. Geterotsikl. Soedin. 5: 908-909] describe the synthesis of the following compounds is not offering the use of this connection:

Crooks, P. et al. [198, J. Heterocyclic Chem. 26(4): 1113-17] describe the synthesis of the following compounds that were tested for anticonvulsant activity in mice:

Gramain, J.C. et al. [1990, Recl. Trav. Chim. Pays-Bas 109: 325-331] describe the synthesis of the following compounds:

In Japan patent No. 63079879 (1988) described a method for the synthesis of intermediates on the way to an important amino acids. As starting substances used the following connections:

Wolfe, J. et al [1971, Synthesis 6: 310-311] describe the synthesis of the following compounds is not offering the use of this connection:

Moharram et al. [1983, Egypt J. Chem. 26: 301-11] describe the following connections:

In the patent Hungary No. 26403 (1983) described the synthesis and application as a food additive the following connections:

Now, the inventors have discovered a new class of compounds, which are inhibitors of metalloproteinases and are of particular interest in terms of 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 that such compounds are selnode is adequate inhibitors MMR and possess the necessary activity. 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 connection-inhibitor can demonstrate the value of the IC50in vitro in the range of 0.1-10000 nanomoles preferably in the range of 0.1-1000 nanomoles.

Connecting the metal group represents a functional group capable of binding metal ion in the active site of the enzyme. For example, inhibitors of MMP binding metal g is the SCP is a binding zinc group, chelating ion zinc(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 NR2, O, S;

m is 0 or 1;

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

R2 is selected from H, alkyl, halogenoalkane;

R3 and R6 are independently selected from H, halogen (preferably F), alkyl, halogenoalkane, alkoxyalkyl, heteroalkyl, cycloalkyl, aryl, alkyl-cycloalkyl, alkyl-geterotsiklicheskie, heteroalkyl-cycloalkyl, heteroalkyl-geterotsiklicheskie, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heteroseksualci-alkyl, heteroseksualci-heteroalkyl, alkylaryl, heteroalkyl-aryl, heteroaryl, alkylglycerol, heteroalkyl-heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl is-alkyl, heteroaryl-heteroalkyl, bisarya, aryl-heteroaryl, heteroaryl-aryl, bageterie, cycloalkyl or geterotsiklicheskie containing from 3 to 7 ring atoms, where alkyl, heteroalkyl, aryl, heteroaryl, cycloalkenyl or heterologously radicals can be substituted one or more than one group independently selected from hydroxy, alkyl, heteroalkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, halogen, halogenoalkane, hydroxyalkyl, alkoxy, alkoxyalkyl, halogenoalkane, halogenocarboxylic, carboxy, carboxyamide, alkylcarboxylic, amino, N-alkylamino, N,N-dialkylamino alkylamino, alkyl(N-alkyl)amino, alkyl(N,N-dialkyl)amino, amido, N-alkylamino, N,N-dialkylamide, alkylamino, alkyl(N-alkyl)amido, alkyl(N,N-dialkyl)amido, allylcarbamate, allylcarbamate, thiol, sulfone, sulfonamide, alkylsulfonate, arylsulfonate, sulfonamide, halogenoalkanes, alkylthio, aaltio, alkylsulfonyl, arylsulfonyl, aminosulfonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, alkylaminocarbonyl, allumination, cyano, alkylsilane, guanidino N-cyanoguanidine, tioguanine, amidino, N-aminosulfonyl, nitro, alkilinity, 2-nitroethene-1,1-diamine;

R4 is selected from H, alkyl, hydroxyalkyl, halogenoalkane, alkoxyalkyl, halogenoalkane, aminoalkyl, amidol the sludge, thioalkyl;

R5 is a bicyclic or tricyclic group containing two or three ring structures, each of which contains from 3 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, tialo, thioalkyl, hydroxy, alkylcarboxylic, halogenoalkane, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, halogenoalkane, alkoxy, alkylsulfonyl, alkylsulfonamides, halogenoalkanes, alkylamino, allylcarbamate, allylcarbamate, carbonyl, carboxy, where any alkyl radical within any substituent itself may possibly be substituted by one or more than one group independently selected from halogen, hydroxy, amino, N-alkylamino, N,N-dialkylamino, alkylsulfonyl, alkylcarboxylic, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, alkylaminocarbonyl, alkylcarboxylic, amido, N-alkylamino, N,N-dialkylamide, allylcarbamate, allylcarbamate, alkoxy, halogenoalkane, carbonyl, carboxy;

R5 is a bicyclic or tricyclic group, each ring structure is connected with the following ring structure via a direct link, via-On-via-S-through-NH-through (the 1-6)alkyl, through (C1-6)halogenoalkane through (C1-6)heteroalkyl through (C1-6)alkenyl through (C1-6)quinil through sulfon, through the carboxy(C1-6)alkyl or condensed with the following ring structure;

perhaps, R2 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;

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

any alkyl, Alchemilla or Alchemilla group mentioned above or below, can be remotemachine or branched; unless otherwise specified, 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 O, m is 0, And represents a direct bond, R3 PR is dstanley a N, R4 represents H and R6 represents H, then R5 does not represent n-methylbenzimidazole or 5-(benzo[1,3]dioxol-5-yl);

when X represents S, at least one of Y1and Y2represents O, m is 0, And represents a direct bond, R3 represents H or methyl, R6 represents H or methyl, then R5 does not represent cinoxacin-1,4-dioxide.

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

X represents NR1;

at least one of Y1and Y2represents Oh, particularly preferably and Y1and Y2represent About;

Z represents O;

m is 0;

And is a direct link;

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

most preferably R1 represents H;

R3 represents H, alkyl or halogenated, particularly preferably R3 represents H, (C1-6)alkyl or (C1-6)halogenoalkane;

R4 represents H, alkyl or halogenated, particularly preferably R4 represents H, (C1-6)alkyl or (C1-6)halogenoalkane, most preferably R4 represents H;

R5 is a bicyclic group, the soda is containing two possibly substituted ring structure, each of which contains 5 or 6 ring atoms and is independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl, particularly preferably R5 contains two aryl or heteroaryl and 5 - or 6-membered ring, more preferably R5 represents a possibly substituted biphenyl, such as para-biphenyl, or para-phenoxyphenyl;

R6 represents H, alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, heteroalkyl, heteroseksualci-alkyl, alkyl-heteroseksualci, heteroaryl-alkyl or heteroalkyl-aryl, particularly preferably R6 represents alkyl, aminoalkyl or heteroaryl-alkyl.

Specific compounds according to the invention include compounds of formula I, where

at least one of Y1and Y2represents About (and preferably Y1and Y2represent O); X represents NH and m is 0; or

at least one of Y1and Y2represents O, X represents NH; Z represents O; a represents a direct link, a, R3 and R4 are independently selected from H, alkyl or halogenoalkane; or

and Y1and Y2represent O; X represents NH; m is 0;

Z represents O, and R4 represents N.

The following aspect of the proposed invention the compounds of formula Ib

p>

where X is selected from NR1, O, S;

Y1and Y2independently selected from O, S;

Z is selected from NR2, O, S;

m is 0 or 1;

And selected from a direct link, (C1-6)alkyl, (C1-6)halogenoalkane or (C1-6)heteroalkyl containing a heteroatom selected from O, S;

Selected from a direct link, -O-, -S-, -NH-, amide, carbamate, carbonyl, (C1-6)alkyl, (C1-6)halogenoalkane, (C2-6)alkenyl, (C2-6)quinil or (C1-6)heteroalkyl containing a heteroatom selected from O, S;

R1 is selected from H, (C1-3)alkyl or (C1-3)halogenoalkane;

R2 is selected from H, (C1-3)alkyl or (C1-3)halogenoalkane;

R3 is selected from H, (C1-3)alkyl or (C1-3)halogenoalkane;

R4 is selected from H, (C1-3)alkyl or (C1-3)halogenoalkane;

R6 is selected from H, alkyl, heteroalkyl, (C3-7)cycloalkyl, (C3-7)geterotsiklicheskie, (C3-7)aryl, (C3-7)heteroaryl, alkyl-(C3-7)cycloalkyl, alkyl-(C3-7)geterotsiklicheskie, alkyl-(C3-7)aryl, alkyl-(C3-7)heteroaryl, heteroalkyl-(C3-7)cycloalkyl, heteroalkyl-(C3-7)geterotsiklicheskie, heteroalkyl-(C3-7)aryl, heteroalkyl-(C3-7)heteroaryl, (C3-7)cycloalkyl-alkyl, (C3-7)heteroseksualci-alkyl, (C3-7)aryl-alkyl, (C3-7)heteroaryl-alkyl, (C3-7)cycloalkyl-heteroalkyl, (C3-7)heteroseksualci-heteroalkyl, (C3-7)aryl-heteroalkyl, (C3-7)heteroaryl-heteroalkyl;

alkyl, heteroalkyl, aryl, heteroaryl, cycloalkenyl or heterologously radicals in the Ostrava R6 may be substituted by one or more than one group, independently selected from hydroxy, alkyl, halogeno, halogenoalkane, hydroxyalkyl, alkoxy, alkoxyalkyl, halogenoalkane, halogenocarboxylic, carboxy, carboxyamide, alkylcarboxylic, amino, N-alkylamino, N,N-dialkylamino, alkylamino, alkyl(N-alkyl)amino, alkyl(N,N-dialkyl)amino, amido, N-alkylamino, N,N-dialkylamide, alkylamino, alkyl(N-alkyl)amido, alkyl(N,N-dialkyl)amido, allylcarbamate, allylcarbamate, thiol, sulfone, sulfonamide alkylsulfonamides, arylsulfonamides, sulfonamide, halogenoalkanes, alkylthio, aaltio, alkylsulfonyl, arylsulfonyl, aminosulfonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, alkylaminocarbonyl, allumination, cyano, alkylsilane, guanidino, N-cyanoguanidine, tioguanine, amidino, N-aminosulfonyl, nitro, alkilinity, 2-nitro-ethen-1,1-diamine;

or G1 is a monocyclic group, a G2 is selected from monocyclic group and a bicyclic group, G1 represents a bicyclic group, and G2 represents a monocyclic group, such monocyclic group contains one ring structure, such as a bicyclic group contains two ring structures, or condensed with each other or connected together through V, as defined above, with each ring structure contains up to 7 ring atoms and not avisio selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl, where each ring structure may may independently substituted by one or more than one Deputy, independently selected from halogen, tialo, thioalkyl, hydroxy, alkylcarboxylic, halogenoalkane, amino, N-alkylamino, N,N-dialkylamino, cyano, nitro, alkyl, halogenoalkanes, alkylsulfonyl, alkylsulfonamides, halogenoalkanes, alkylamino, allylcarbamate, allylcarbamate, where any alkyl radical within any substituent may itself be substituted by one or more than one group independently selected from halogen, hydroxy, amino, N-alkylamino N,N-dialkylamino, alkylsulfonyl, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, alkylaminocarbonyl, alkylcarboxylic, amido, N-alkylamino, N,N-dialkylamide, allylcarbamate, allylcarbamate, alkoxy, halogenoalkane;

maybe R3 and R6 can be joined to form a ring containing up to 7 ring atoms.

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

X represents NR1;

at least one of Y1and Y2represents Oh, particularly preferably and Y1and Y2represent About;

Z represents O;

m is 0;

And represents a direct bond,(C1-6)alkyl or (C1-6)heteroalkyl, containing a heteroatom selected from O, S;

Represents a direct link, acetylene, CON (amide), (C1-C4)alkyloxy, -O-, -S - or-NH-;

R1 represents H or methyl;

R3 represents H, (C1-3)alkyl or (C1-3)halogenoalkane;

R4 represents H, (C1-3)alkyl or (C1-3)halogenoalkane.

Especially preferred compounds of formula Ib are those in which

X represents NR1, R1 represents H;

Y1and Y2each represents About;

Z represents O;

m is 0;

And is a direct link;

Selected from a direct link, acetylene, -O-, -NH-, -S - or-CH2O;

R3 represents H and

R4 represents N.

Further suggested that the compounds of formula Ic

where a is selected from a direct link, acetylene, -O-, -NH-, -S - or-CH2O;

each of G1, G2 and R6 is as defined for formula Ib.

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

Selected from a direct link, -O-, -S - or-CH2Oh, most preferably selected from a direct link, -O-CH2O;

G2 represents a monocyclic group containing aryl ring, most preferably G2 represents a phenyl;

G1 represents a monocyclic or bicyclic the forge group, containing at least one aryl ring, most preferably G1 is a monocyclic or bicyclic group containing at least one five - or six-membered aryl ring;

R6 is selected from H, (C1-6)alkyl, (C1-6)heteroalkyl, geterotsiklicheskie, heteroseksualci-(C1-6)alkyl, heteroaryl or heteroaryl-(C1-6)alkyl, preferred heteroaryl are pyridine, diazine (such as pyrimidine) or azoles such as imidazole), preferred heteroseksualnymi are morpholine, piperidine or piperazine, the preferred heteroalkyl are amino-(C1-6)alkali, preferred substituents on heteroaryl are halogen, the preferred substituents on amines have had in heteroalkyl and geterotsiklicheskikh are alkyl, alkylsulfonyl alkylaminocarbonyl or allyloxycarbonyl.

Further suggested that the compounds of formula Id

where a is selected from a direct link, O, or CH2About;

G1 represents a monocyclic or bicyclic group containing at least one five - or six-membered aryl ring;

R6 represents H, alkyl, hydroxyalkyl, aminoalkyl, alkilany alkyl ether-carbamino acid, alkyl-alkyl-urea, alkylsulfonyl-alkyl, N-alkyl-alkylsulfonate, heteroaryl-alkyl;

L is selected symptom, of alkyl, halogenoalkane, hydroxy, alkoxy, halogenoalkane, amino, alkylamino, amido, alkylamino, allylcarbamate, allylcarbamate, alkylsulfonyl, alkylsulfonamides, nitro, cyano, halogeno;

or L is a group

T-U-V-

where V is attached to G1 and this V is selected from CH2Oh , NCO, NCOO, NCON or NSO2;

U represents (C1-5)alkyl;

T is selected from hydroxy, alkoxy, cyano, amino, alkylamino, alkylsulfonyl, alkylsulfonamides, allylcarbamate, allylcarbamate, alkylamide, imidazolyl, triazolyl or pyrrolidone.

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

G1 is selected from phenyl, pyridyl, naphthyl or quinoline;

R6 is selected from H, (C1-6)alkyl, hydroxy-(C1-6)alkyl, amino-(C1-6)alkyl or heteroaryl-(C1-6)alkyl, most preferably R6 represents H, methyl, pyridinylmethyl, N-substituted amino-(C1-4)alkyl (preferred N-substituents are alkyl, alkylsulfonyl or alkilany ether of carbamino acid);

L is selected from H, (C1-5)alkyl, (C1-5)halogenoalkane, hydroxy, alkoxy, halogenoalkane, amino, (C1-5)alkylamino, amido, (C1-5)alkylamino, (C1-5)allylcarbamate, (C1-5)allylcarbamate, (C1-5)alkylsulfonyl, (C1-5)alkylsulfonamides, nitro, cyano, halogeno; or L is a group T-U-V, where V is the same as op is Adelino formula Ic, U represents an unbranched (C1-5)alkyl, and T is selected from hydroxy, alkoxy, cyano, amino, (C1-3)alkylamino, (C1-3)alkylsulfonyl, (C1-3)alkylsulfonamides, (C1-3)allylcarbamate, (C1-3)allylcarbamate, (C1-3)alkylamino, imidazolyl, triazolyl or pyrrolidone;

L is a meta - or para-Deputy, when G1 represents a 6-membered ring.

A suitable value for R6 in the compounds of formulae I, Ib, Ic or Id include the following:

A suitable value for R5 in the compounds of the formula I or of G1-B-G2 in the compounds of formula Ib, Ic or Id include the following:

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 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 3 rdEdition: author J March, p104-107), 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 substituted carbon atom. The presence of one or more than one asymmetric center (chiral centers) in connection according to the invention can lead to the formation 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 according to the invention represents an independent and specific embodiment of the invention.

Some compounds according to the invention have particular application as inhibitors MMR and/or MMR, the/or MMR, and/or MMR. Some compounds according to the invention have particular application as inhibitors of aggrecanases, i.e. inhibitors destruction of aggrecan.

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

Compounds according to the invention can be presented 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.

These compounds can also be represented in the form of an in vivo hydrolyzable esters. These esters are pharmaceutically acceptable esters, to the verge hydrolyzed in the human body, induce the parent compound. Such esters can be identified by introducing, for example, intravenous trained animal tested compounds and subsequent studies of body fluids that of the test animal. Suitable in vivo hydrolyzable esters for carboxy include methoxymethyl ether, and for hydroxy include formally and acetyloxy esters, especially acetyloxy ether.

In order to use the compound of the invention (including a compound of formula I, Ib, Ic, Id) or its pharmaceutically acceptable salt or in vivo hydrolyzable ester in therapeutic treatment (including prophylactic treatment) of mammals including humans, it is usually 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 of the invention (such as a compound of formula I, Ib, Ic, Id) or its pharmaceutically acceptable salt or in vivo hydrolyzable ester and a pharmaceutically acceptable carrier.

The pharmaceutical compositions according to this invention it is possible to introduce a standard way of an illness or condition that you want to treat, for example, by oral, local, parenteral, transbukkalno, intranasal is, vaginal or rectal administration, or by 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 may also 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 this invention is usually administered to people so that the accepted daily intake 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, if necessary, can be given in divided doses, with the exact number of the obtained compound and the route of administration is avisat by weight, age and sex of the patient treated, and the specific disease or condition, which are treated in accordance with principles known in the art.

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 the formula I (in particular the compound of formula Ib, Ic, Id) 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, which is a metalloproteinase. 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 MRS and/or aggrecanases, particularly in the treatment of a disease or condition mediated MMR or MMR, mainly in the treatment of a disease or condition mediated 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 effect is active amount of a compound of formula I, Ib, Ic or Id, or its pharmaceutically acceptable salt or in vivo hydrolyzable ester.

The inventors also disclose the use of compounds of formula I, Ib, Ic, Id, 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.

Obtaining the compounds according to the invention

In another aspect of the present invention, a method for obtaining compounds of formula I, Ib, Ic, Id, or its pharmaceutically acceptable salt or in vivo hydrolyzable ester, the AK is described below in (b)-(C) (X, Y1, Y2, Z, m, and R1-R6 are as defined above for the compounds of formula (I).

(a) Compound according to the invention can be converted into a salt, especially pharmaceutically acceptable salt, or Vice versa by known methods; salt, in particular pharmaceutically acceptable salt, compounds according to the invention can be converted into another salt, in particular in pharmaceutically acceptable salt by known methods.

(b) Compounds according to the invention, in which Z=O and R4=H, can be obtained by reacting the compounds of formula IIa with a compound of formula IIIa or appropriately protected form the compounds of formula IIIa (as shown in scheme 1), followed by the possible formation of its pharmaceutically acceptable salt or in vivo hydrolyzable ester:

Scheme 1

The aldehydes or ketones of the formula IIa and the compounds of formula IIIa in a suitable solvent is treated with a base, preferably in the temperature range from ambient temperature to a temperature of education phlegmy. Preferred combinations of the base-solvent include aliphatic amines such as trimethylamine, pyrrolidine or piperidine, in solvents, such as methanol, ethanol, tetrahydrofuran, acetonitrile or dimethylformamide, if necessary, with the addition of water for dilution of reagents (Phillips, A P. and Murphy, J. G., 1951, J. Org. Chem. 16); or hexamethyldisilazane lithium in tetrahydrofuran (Mio, S. et a/., 1991, Tetrahedron 47: 2121-2132); or octahedral of barium hydroxide in a mixture of isopropanol-water (Ajinomoto K. K., 1993, the Japan patent No. 05097814).

Preferably, upon receipt of the compounds according to the invention in this manner R3, R5 or R6 must not contain additional functional groups such as aldehyde, ketone, halogenated radicals or other radicals, is well known to specialists in this field of technology that have the potential to interfere with the reaction of the formation of ties or to compete with or inhibit it.

It should be clear that many relevant source materials are commercially available or available by any other means or can be synthesized by known methods or to find in the scientific literature.

To obtain the compounds of General formula IIIa (R6 is as described here above) the compounds of formula IIIa, in which R6 represents H, can be subjected to interaction with a suitable aldehyde or ketone followed by dehydration and subsequent reduction of the resulting double bond in ways that are well known to specialists in this field of technology.

(C) Compounds according to the invention, in which Z=O, R4=H and X=N or NR1, in particular their specific stereoisomers can policitical, as shown for two of the four possible stereoisomers of the following schemes 2 and 3.

Since the derivatives of propenoate formulas IV through diols VIa or VIb either through asymmetric epoxidation and subsequent regioselective gap with water or asymmetric dihydroxypropane, depending on the chiral auxiliary substances when epoxydecane or dihydroxypropane can be obtained or shown stereoisomers diols of the formula VIa or VIb, or their enantiomers [for example, Ogino, Y. et at., 1991, Tetrahedron Lett. 32 (41): 5761-5764; Jacobsen, E. N. et al., 1994, Tetrahedron, 50 (15): 4323-4334; Song, C. E. et al., 1997, Tetrahedron Asymmetry, 8 (6): 841-844]. Treatment with organic base and thionyl chloride and subsequent oxidation catalyzed by ruthenium tetroxide, lead to cyclic sulfates VIIa and VIIb.

Cyclic sulfates of formula VIIa and VIIb in turn hydroxyacid (scheme 3) formulas VIIIa and VIIIb by treatment with sodium azide in dimethylformamide, followed by careful hydrolysis of the intermediate hemisulfate before water treatment (Gao, Sharpless, 1988, J. Am. Chem. Soc., 110: 7538; Kim, Sharpless, 1989, Tetrahedron Lett. 30: 655). Hidroxizina formulas VIIIa and VIIIb are subjected to hydrolysis and reduced to β-hydroxy-α-amino acids (not shown in scheme 3), preferably hydrolysis using LiOH in THF with PEFC is blowing the recovery of hydrogen sulfide, magnesium in methanol or organic phosphines according to the method of Staudinger (Stadinger). In turn, the result of processing the cyanate and acid in aqueous medium β-hydroxy-α-amino acids to give compounds of formula Ia.

(g) Compounds according to the invention, in which Z=O, a, R4 is not H, in particular their specific stereoisomers can also be obtained as depicted in schemes 2 and 3 for two of the four possible stereoisomers. These compounds can be obtained by the interaction of the epoxides of formula V according to scheme 2 with an alcohol of formula R4-OH with the formation of alcohols VIa. Subsequent transformation into azides using phosphatidate [Thompson, A. S. et al., 1993, J. Org. Chem. 58 (22): 5886-5888] results in the ether analogues of asidefrom VIIIa in figure 3, the transformation of which you can continue to the final products as described in method (b). The radical R4 in the alcohol R4-OH and the radicals R3, R5 and R6 can be properly protected. Protective groups can be removed after transformation into the hydantoins of the formula Ia, and this will be the last stage.

(d) Compounds according to the invention, in which Z represents S or NR2, a Y1and/or Y2represents O, in particular their specific stereoisomers can be obtained as depicted in schemes 2 and 3 for two of the four possible stereoisomers. These compounds can be manufactured is iravani by breaking epoxides of formula V (scheme 2) thiols R4-SH or amines R4-NH 2and subsequent transformations, similar to the transformations shown for alcohols VIIIa and VIIIb in scheme 3. When using amines R4-NH2you may want to protect the N intermediate aminoalcohols, especially when the radical R4 represents n-alkyl group.

(e) Compounds according to the invention, in which X represents S, a Y1and/or Y2represents O, in particular their specific stereoisomers can be obtained as depicted in schemes 2 and 3 for two of the four possible stereoisomers. These compounds can be obtained by the interaction of cyclic sulfates of formula VIIa or VIIb or α-hydroxyamino formula VIa through their sulphonate ester with thiourea and acid (1997, Japan patent No. 09025273).

Derivatives of propenoate formula IV can be easily obtained, for example, aldehydes and fofanah or phosphonate derivatives of acetic acid by the reaction of Wittig (Wittig or Horner-Emmons (Horner-Emmons) (see, for example, van Heerden, P. S. et al., 1997, J. Chem. Soc., Perkin Trans. 1(8): 1141-1146).

(g) the Compounds according to the invention in which X=NR1 and R1=H, can be obtained by interaction of the corresponding substituted aldehyde or ketone of formula IId with ammonium carbonate and potassium cyanide in aqueous alcohols at 50-100°in a sealed vessel for 4-24 hours.

Paul is an increase of some aldehydes or ketones of the formula (IId) are described in the following sources:

Marte, A.-M. et al., Tetrahedron Lett, 1990, 31 (18): 2599-2602;

Kren, V., et al., 1993, J. Chem. Soc., Chem. Commun., 4: 341-343;

Schmittel, M. et al., 1990, Angew. Chem., 102 (10): 1174-1176;

Chakraborty, R. et al., 1992, Synth. Commun., 22 (11): 1523;

Harder, T. et al., 1994, Tetrahedron Lett., 35 (40): 7365-7368;

Ruder, S. M., 1992, Tetrahedron Lett, 33 (9): 2621-2624;

Maeda, H.ef al., 1997, Chem. Pharm. Bull., 45 (11): 1729-1733;

Montana, J. G. et al., 1994, J. Chem. Soc., Chem. Commun., 19: 2289-2290;

Davis, B. R. et al., 1992, Aust. J. Chem. 45 (5): 865-875.

Some of the aldehydes or ketones get through

Andolini reactions (m=1, Z=O):

Mahrwald, R.et al., 1998, J. Am. Chem. Soc., 120 (2): 413-414;

Auerbach, R. A. et al., 1988, Org. Synth., VI: 692;

Mukaiyama, T., 1977, Angew. Chem. (Int. Ed.) 16;

Shimizu, N. et al., 1983, Bull. Chem. Soc. Jpn., 56 (12): 853;

Maruoka, K. et al., 1986, J. Am. Chem. Soc., 108 (13): 3827.

Known examples of the preparation of compounds of formula IId are listed in table 1.

Table 1
Name (formyl first, even when not "IUPAC")CAS (Chemical Abstracts)
2-formyl-5-pyridin-3-yl-furan38588-49-7
2-formyl-5-pyridin-2-yl-furan55484-36-1
5-formyl-2-phenyl-oxazol92629-13-5
2-formyl-5-phenyl-furan13803-39-9
2-formyl-3-methyl-5-phenyl-furan160417-25-4
2-formyl-Z-etoxycarbonyl-furan50800-39
2-formyl-5-phenyl-3,4-oxadiazol 22816-01-9
2-formyl-5-phenyl-oxazol96829-89-9
2-formyl-4-chloro-5-phenyl-oxazol119344-57-9
2-formyl-4-chloro-2-pyridin-3-yl-thiazole131969-58-9
2-formyl-5-pyridin-3-yl-thiophene133531-43-8
2-formyl-5-pyridin-2-yl-thiophene132706-12-8
2-formyl-5-pyridin-4-yl-thiophene21346-36-1
5-formyl-2-phenyl-thiazole1011-40-1
5-formyl-4-chloro-2-phenyl-thiazole108263-77-0
5-formyl-4-methyl-2-phenyl-thiazole55327-23-6
2-formyl-5-phenyl-thiophene19163-21-4
2-formyl-3-methyl-5-phenyl-thiophene1604417-30-1
4-formyl-2-pyridin-2-yl-imidazol279251-08-0
2-formyl-1-methyl-5-pyridin-3-yl-pyrrol3614-77-5
4-formyl-2-pyridin-3-yl-imidazol279251-09-1
4-formyl-2-pyridin-4-yl-1,3,4-triazole42786-73-2
4-formyl-2-pyridin-4-yl-imidazol279251-10-4
4-formyl-5-methoxy-5-phenyl-thiazole73725-36-7
4-formyl-5-etoxycarbonyl-5-phenyl-thiazole88469-73-2
4-formyl-5-etoxycarbonyl-5-phenyl-oxazol189271-85-0
2-formyl-3-methyl-5-phenyl-1,3,4-triazole89060-36-6
4-formyl-1-methyl-2-phenyl-imidazol94938-02-0
5-formyl-1-methyl-2-phenyl-imidazol94938-03-1
4-formyl-1-butyl-2-phenyl-imidazol198066-02-3
4-formyl-1-propyl-2-phenyl-imidazol75378-63-1
5-formyl-1-butyl-2-phenyl-imidazol198065-92-8
2-formyl-1-methyl-4-phenyl-imidazol123511-51-3
4-formyl-2-phenyl-5-methyl-oxazol70170-23-9
2-formyl-5-phenyl-1,3,4-triazole26899-64-9
4-formyl-2-phenyl-5-chloro-imidazol60367-52-4
4-formyl-2-phenyl-imidazol68282-47-3
4-formyl-2-phenyl-5-methyl-imidazol68282-50-8
2-formyl-1-methyl-5-phenyl-1,3,4-triazole219600-03-0
2-formyl-4-phenyl-imidazol56248-10-3
2-formyl-1-methyl-4-phenyl-imidazol118469-06-0
2-formyl-5-phenyl-pyrazole52179-74-5
2-formyl-3-methyl-5-phenyl-pyrazole160417-28-7
2-formyl-3-etoxycarbonyl-5-phenyl-pyrazole63202-77-7
2-formyl-5-morpholine-1-yl-furan3680-96-4
2-formyl-5-piperidine-yl-furan 22868-60-6
2-formyl-5-cyclohexyl-furan14174-51-7
2-formyl-3-methyl-5-cyclohexyl-furan160417-27-6

(C) Compounds according to the invention can be synthesized also by the following scheme 4. Suitable target compounds include a group of compounds representing a substituted 5-(biphenyl-4-yl-hydroxy-methyl)-imidazolidin-2,4-dione, and the group of compounds representing substituted 5-[4-phenoxy-phenyl]-hydroxy-methyl-imidazolidin-2,4-dione, described in example 8.

The key reaction is andolina condensation (method), in which are formed the target compounds. Synthetic intermediate in this reaction are 5-hydantoins, derived from amino acids (method A), and the aldehydes obtained by the reaction of a combination of Suzuki (method B) accepted way. Way To also get the connection 1 and 2, which can be used for subsequent transformations, combinations Suzuki (method G) and amide combination (method D).

Andolina condensation gives diastereomer mixture. The racemates allocate chromatography or, in some cases, the crystallization. The enantiomers can be divided chiral chromatography.

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

Analyses of selected enzyme

The family of matrix metalloproteinases, including, for example, MMR, MMR

The catalytic domain of recombinant human MMR possible to Express and purify, as described Parkar A. A. et al. (2000), Protein Expression and Purification, 20: 152. This purified enzyme can be used to monitor activity inhibitors as follows.

MMR (final concentration 50 ng/ml) incubated for 30 minutes at RT (room temperature) in the analytical buffer (0.1 M Tris-HCI, pH of 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 lomr activate using 1 mm aminophenylarsonic acid (ARMA), for 20 hours at 21°With; the act is vorovannuyu MMR (11,25 ng per assay) are incubated for 4-5 hours at 35° With the analytical buffer (0.1 M Tris-HCI, pH 7.5, containing 0.1 M NaCI, 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 λem 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 lomr using conditions of substrates and buffers that are optimal for a particular DFID, for example, as described in C. Graham Knight etal. (1992) FEBS Lett. 296 (C): 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 by K. M. 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-fluorescein the Il-Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.ser.ser.ser.arg.(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 CaCl2) at 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 aminopeptide-resin was etilirovany by processing within 1.5-2 h at 70°1.5-2 equivalents of 4',5'-dimethoxy-fluorescein-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 dimethoxyphosphinyl-peptide and tsalala it from the malls by processing triperoxonane acid, containing 5% water and triethylsilane. Dimethoxyphosphinyl-peptide was isolated by evaporation, by rubbing with diethyl ether and filtered. This highlighted the peptide was subjected to interaction with 4-(N-maleimido)-fluorescein in DMF containing diisopropylethylamine, the product was purified using HPLC (high performance liquid chromatography) 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 E.S. Arner et al., (1998) Osteoarthritis and Cartilage 6: 214-228; (1999) Journal of Biological Chemistry, 274 (10). 6594-6601, and antibodies described therein. The ability of compounds to act as inhibitors against collagenases can be determined as described So 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 estimate the shape on the cells TNR-1, using ELISA (ELISA test) for detection of released TNF essentially as described by K. M. Mohler et al. (1994) Nature 370: 218-220. Similarly, processing, or shedding, other membrane molecules, such as molecules, described in N. M. 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 determined as described in A. 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 LPS (lipopolysaccharide) is used to stimulate the release of TNFα. 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). Ka is every analysis includes controls diluted blood, inkubiruemykh only with medium (6 wells/plate) or with a known inhibitor of TNFα as 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 assessed, in particular, as described in K. M. 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 dose 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 to take samples of blood and 10% heparin. Plasma fractions get by centrifugation, 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

Test the ability of compounds to act as an anti-TNF 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 per Hepar is on sodium/ml of blood. Blood samples immediately placed on ice and centrifuged at 2000 rpm for 10 min at 4°and the collected plasma was frozen at -20°for further analysis of its 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 the same 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/doses

Test the activity of compounds as anti-arthritis agent

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

Test the activity of compounds as anti-cancer 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 C. Hibner et al., Abstract 283 p75 10thNCl-EORTC Symposium, Amsterdam June 16-19 (1998).

Test the potency of the compound 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 illustrated by, but not limited to, the following examples.

Common analytical methods. 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-d4N3.31 mln-1). Mass spectra of lower resolution were obtained on the system Agilent 1100 LC-MS (liquid chromatography-mass spectrometry), equipped with an ionization chamber head (chemical ionization at atmospheric pressure).

Unless otherwise noted, used a commercially available source materials or intermediate compounds, etc is presented in tables 2 and 3.

EXAMPLE 1

5-(Biphenyl-4-yl-hydroxy-methyl)-5-methyl-imidazolidin-2,4-dione

4-Biphenylcarboxylic (182 mg, 1.0 mmol) and trimethylamine (45% in water, 160 μl, 1.0 mmol) was added to a warm solution of 5-methylimidazolidine-2,4-dione (114 mg, 1.0 mmol) in methanol (4.0 ml) and water (1.0 ml). This reaction mixture was heated to education phlegmy for 16 hours with nitrogen as the inert atmosphere.

The solution was cooled, evaporated and stirred in a mixture of 100:1 dichloromethane/methanol (15 ml). Filtration, washing the precipitate with the same mixture of solvents (10 ml) and dried by suction of air led to a 5-(biphenyl-4-yl-hydroxy-methyl)-5-methyl-imidazolidin-2,4-dione (190 mg) with the release of 64.1 per cent in the form of a 60/40 mixture of diastereoisomers according to1H NMR.

This mixture of isomers (180 mg) was dissolved in dioxane (8 ml) and water (4 ml). Preparative HPLC on a column of Chromasli C18 250/20 mm (KR-100-5-C18) with a gradient of acetonitrile/water (with 0.1% triperoxonane acid) is from 20/80 to 40/60 for 25 min resulted in two separate diastereomers with a total output of 43.5%.

Preliminary determination of the stereostructures of each isomer was performed by comparison of the1H NMR with two diastereomers of 5-[(4-chloro-phenyl)-hydroxy-methyl)]-imidazolidin-2,4-dione, both diastereomers patterns which have been detailed previously defined various PITS the experiments. Offset 1-NH proton and phenyl attached to imidazolidinedione, was particularly revealing in this diastereomer distribution.

(RR)-5-(Biphenyl-4-yl-hydroxy-(SS)-methyl)-5-methyl-imidazolidin-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 10.19 (1H, s); 8.11 (1H, s); 7.66 (2H, d, J=7.6 Hz); 7.59 (2H, d, J=8.20 Hz); 7.45 (2H, t, J=7.68 Hz); 7.37 (2H, d, J=8.27 Hz); 7.35 (1 H, t, J=7.62 Hz); 5.92 (1 H, bs); 4.67 (1 H, s); 1.44 (3H s).

13With NMR (400 MHz, DMSO-d6) δ: 176.79; 156.25; 139.74; 139.39; 139.14; 128.91; 128.20; 127.37; 126.51; 125.54; 75.32; 66.96; 21.11.

Head-MS: m/z 297,3 [MH+].

(SR)-5-(Biphenyl-4-yl-hydroxy-(RS)-methyl)-5-methyl-imidazolidin-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 10.48 (1H, s); 7.67 (2H, d, J=7.48 Hz); 7.64 (2H, d, J=8.29 Hz); 7.56 (1H, s); 7.48-7.45 (4H, m); 7.36 (1H, t, J=7.30 Hz); 5.75 (1H, d, J=4.73 Hz); 4.65 (1 H, d, J=3.57 Hz); 1.08 (3H, s).

13C NMR (400 MHz, DMSO-d6) δ: 177.89; 157.28; 139.88; 139.44; 139.27; 128.95; 128.47; 127.38; 126.54; 125.89; 74.68; 66.18; 20.22.

Head-MS: m/z 297,3 [MH+].

The compounds described in examples 2-4 were obtained using a method similar to the method described in example 1.

EXAMPLE 2

(RR)-5-(Biphenyl-4-yl-hydroxy-(SS)-methyl)-imidazolidin-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 10.33 (1H, s); 8.10 (1H, s); 7.66 (2H, d, J=8.20 Hz); 7.61 (2H, d, J=8.20 Hz); 7.45 (2H, dd, J=8.20/7.20 Hz); 7.39 (2H, d, J=8.24 Hz); 7.35 (1H, t, J=7.48 Hz); 5.89 (1H, bs); 4.97 (1H, d, J=2.5 Hz); 4.40 (1H, d, J=2.5 Hz).

Head-MS: m/z 283,1 [MH+].

(SR)-5-(Beef is Neil-4-yl-hydroxy-(RS)-methyl)-imidazolidin-2,4-dione

Head-MS: m/z 283,1 [MH+].

EXAMPLE 3

5-(Biphenyl-4-yl-hydroxy-methyl)-thiazolidine-2,4-dione

(RR)-5-(Biphenyl-4-yl-hydroxy-(SS)-methyl)-thiazolidine-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 11.81 (1H, s); 7.68 (2H, d, J=8.20 Hz); 7.64 (2H, d, J=8.20 Hz); 7.46 (2H, dd, J=8.30/7.50 Hz); 7.42 (2H, d, J=8.30 Hz); 7.36 (1H, t, J=7.50 Hz); 6.24 (1H, d, J=3.96 Hz); 5.36 (1H, t, J=3.95 Hz); 5.06 (1H, d, J=4.03 Hz).

Head-MS: m/z 183,1 [MH+- thiazolidin-2,4-dione].

(SR)-5-(Biphenyl-4-yl-hydroxy-(RS)-methyl)-thiazolidine-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 12.04 (1H, s); 7.67 (2H, d, J=8.30 Hz); 7.65 (2H, d, J=8.30 Hz); 7.51 (2H, d, J=8.20 Hz); 7.46 (2H, dd, J=8.20/7.40 Hz); 7.36 (1H, t, J=7.40 Hz); 6.22 (1H, d, J=5.20 Hz); 5.42 (1H, dd, J=5.20/2.60 Hz); 5.02 (1H, d, J=2.60 Hz).

Head-MS: m/z 183,1 [MN+- thiazolidin-2,4-dione].

EXAMPLE 4

5-(Biphenyl-4-yl-hydroxy-methyl)-1-methyl-imidazolidin-2,4-dione

(RR)-5-(Biphenyl-4-yl-hydroxy-(SS)-methyl)-1-methyl-imidazolidin-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 10.53 (1H, s); 7.67 (2H, d, J=7.20 Hz); 7.63 (2H, d, J=8.43 Hz); 7.46 (2H, dd, J=7.71/7.20 Hz); 7.38 (2H, d, J=8.63 Hz); 7.35 (1H, t, J=7.63 Hz); 6.01 (1H, d, J=4.16 Hz); 5.13 (1H, dd, J=4.18/2.60 Hz); 4.33 (1H, d, J=2.58 Hz); 2.97 (3H, s).

13With NMR (400 MHz, DMSO-d6) δ: 176.63; 156.83; 139.78; 138.97; 138.95; 128.89; 127.35; 127.13; 126.53; 125.91; 71.28; 28.63.

Head-MS: m/z 297,1 [MH+].

(SR)-5-(Biphenyl-4-yl-hydroxy-(RS)-methyl)-1-methyl-imidazolidin-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 10.73 (1H, s); 7.70 (4H, m); 7.54 (2H, d, J=8.22 Hz); 7.46 (2H, dd, J=8.20/7.10 Hz); 7.36 (1H, t, J=7.11 Hz); 5.96 (1H, d, J=6.06 Hz); 5.11 (1H, dd, J=6.06/2.14 Hz); 4.38 (1H, d, J=2.14 Hz); 2.33 (3H, s).

Head-MS: m/z 297,1 [MH+].

EXAMPLE 5

5-[Hydroxy-(3-phenoxy-phenyl)-methyl]-imidazolidin-2,4-dione

This compound was obtained as described in example 1, but instead of getting using HPLC, flash chromatography (SiO, dichloromethane/methanol: gradient to 100/4) received 60 mg of the compound indicated in the title, in the form of a white solid with a yield of 20.1% (mixture of diastereomers).1H NMR confirmed that the ratio of the diastereomers in the mixture was 1:1.

1H NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, bs); 10.37 (1H, bs); 8.04 (1H, s); 7.56 (1H, s); 7.40-7.29 (6N, m); 7.16-7.09 (4H, m); 6.96 (2H, d, J=8.71 Hz); 6.89 (2H, m); 5.89 (1H, d, J=3.91 Hz); 5.78 (1H, d, J=5.68 Hz); 4.93-4.90 (2H, m); 4.34 (1H, dd); 4.25 (1H, dd).

13With NMR (400 MHz, DMSO-d6) δ: 174.04; 173.05; 158.09; 157.40; 156.89; 156.83; 156.31; 155.63; 144.01; 141.69; 129.96; 129.94; 129.55; 129.15; 123.20; 123.06; 122.26; 121.28; 118.44; 118.06; 118.02; 117.80; 117.46; 116.76; 71.98; 70.28:64.01.

Head-MS: m/z 281,1 [MN+-H2O].

EXAMPLE 6

5-[Hydroxy-(4-phenoxy-phenyl)-methyl]-imidazolidin-2,4-dione

This compound was obtained as described in example 1, but instead of getting using HPLC, flash chromatography (SiO, dichloromethane/methanol: gradient to 100/3) received 40 mg of the compound indicated in the title VI is e white solid with a yield of 13.4% (mixture of diastereomers). 1H NMR confirmed that the ratio of the diastereomers in the mixture was 1:1.

1H NMR (400 MHz, DMSO-d6) δ: 10.49 (1H, bs); 10.36 (1H, bs); 8.04 (1H, s); 7.55 (1H, s); 7.41-7.35 (6N, m); 7.31 (2H, d, J=8.60 Hz); 7.13 (2H, ddd, J=7.44/3.52/1.14 Hz); 7.01-6.92 (8H, m); 5.84 (1H, d, J=3.76 Hz); 5.74 (1H, d, J=5.55 Hz); 4.91 (2H, m); 4.34 (1H, dd, J=3.03/1.05 Hz); 4.22 (1H, dd, 2.68/1.52 Hz).

Head-MS: m/z 281,1 [MN+-H2O].

EXAMPLE 7

The following compounds were obtained by the methods described in the examples above.

5-[(4'-Fluoro-biphenyl-4-yl)-hydroxy-methyl]-imidazolidin-2,4-dione

Head-MS: m/z 283 [MH+-H2O].

5-[(4'-Fluoro-biphenyl-4-yl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione

Head-MS: m/z 314,9 [MH+].

5-[(4'-Fluoro-biphenyl-4-yl)-hydroxy-methyl]-5-isobutyl-imidazolidin-2,4-dione

Head-MS: m/z 357,1 [MH+].

5-[(4'-Chloro-biphenyl-4-yl)-hydroxy-methyl]-imidazolidin-2,4-dione

Head-MS: m/z to 298.9 [MH+-H2O].

5-[(4'-Chloro-biphenyl-4-yl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione

Head-MS: m/z 331 [MH+].

5-[(4'-Chloro-biphenyl-4-yl)-hydroxy-methyl]-5-isobutyl-imidazolidin-2,4-dione

Head-MS: m/z 373,1 [MN+].

5-[(Biphenyl-4-yl)-hydroxy-methyl]-5-hydroxymethyl-imidazolidin-2,Dion

Head-MS: m/z 313,0 [MN+].

EXAMPLE 8

Compounds synthesized by the method In scheme 4 (see above).

a) Obtaining an intermediate hydantoins (method a in scheme 4)

According to the diagram below 5 hydantoins 5 was obtained in two stages of the common amino acids 3 with selection of intermediate compounds 4.

Figure 5 (method A)

Table 2 shows the list of intermediate hydantoins, which were synthesized. A common way to obtain was as follows. A suspension of 3 amino acids (25 mmol) and potassium cyanate (5,1 g, 63 mmol) in water (75 ml) was heated at 80°C for about 1 hour. The clear solution was cooled to 0°and acidified to approximately pH 1 with concentrated hydrochloric acid (aq.). The obtained white precipitate 4 was heated under reflux for 0.5-1 hour, and then cooled on ice. In some cases, complete conversion was achieved after 1 hour of heating. In these cases, the crude substance was processed again according to the same Protocol. White solid was filtered, washed with water, dried and analysed by1H NMR and LC-MS.

Table 2
Intermediate hydantoins
NameOutput (%)Head-MS m/z: [MH+]
5-(4-Chloro-benzyl)-imidazolidin-2,4-dione87224,9
Benzyl ester [3-(2,5-dioxo-imidazolidin-4-yl)-propyl]-carbamino acid50292,0
5-Isobutyl-imidazolidin-2,4-dione85157,0
5-Benzylsulfamide-imidazolidin-2,4-dione87237,0
5-Methylsulfonylmethyl-imidazolidin-2,4-dione45161,0
5-Cyclohexylmethyl-imidazolidin-2,4-dione63197,1
5-sec-Butyl-imidazolidin-2,4-dione52157,0
5-Phenethyl-imidazolidin-2,4-dione94205,1
5-Butyl-imidazolidin-2,4-dione82157,0
5-Isopropyl-imidazolidin-2,4-dione49
5-(N-Indol-3-ylmethyl)-imidazolidin-2,4-dione94230,0
5-(2-Hydroxy-ethyl)-imidazolidin-2,4-dione36

b) Receiving the intermediate aldehydes (method B in scheme 4)

Substituted benzaldehyde was obtained by Suzuki reaction mix between different com is archacki available phenylpropene and 4-formylphenylboronic acid according to the following scheme 6.

Scheme 6 (method B)

4-Pyridin-2-yl-benzaldehyde

This compound was prepared as follows. A mixture of 4-formylphenylboronic acid (195 mg, 1.3 mmol), 2-bromopyridine (102,7 mg of 0.65 mmol) and powdered To2CO3(1.07 g, 7.8 mmol) in dioxane (12 ml) and water (2 ml) was subjected to deoxygenating (vacuum and argon). Added palladium diacetate (30 mg, 0.2 mol.%) and the mixture was stirred for 2 hours at 80°C in argon atmosphere.

The suspension was cooled to room temperature. Filtration and evaporation gave the crude product. Preparative HPLC (column Chromasil C18, acetonitrile, water and triperoxonane acid) resulted in the receipt of the connection specified in the header, a 4-pyridine-2-yl-benzaldehyde (72 mg, yield 60%).

1H NMR (400 MHz, DMSO-d6) δ: 10.07 (1H, s); 8.73 (1H, d, J=4.20 Hz); 8.31 (2H, d, J=8.20); 8.11 (1H, d, J=8.01); 8.03 (2H, d, J=8.20); 7.97 (1H, m).

Head-MS: m/z 184,2 [MH+].

Other substituted benzaldehyde (listed in table 3) were obtained in the same way.

Table 3
Substituted benzaldehyde
NameOutput (%)Head-MS m/z
4'-Formyl-biphenyl-4-carbonitrile65208,0
4'-Formyl-biphenyl-3-carbonitril208,0
4'-Methoxy-biphenyl-4-carbaldehyde50213,1
3-Methoxy-biphenyl-4-carbaldehyde62213,1
Biphenyl-4,4'-dicarbollide211,0
4'-Formyl-biphenyl-3-silt ether acetic acid239,1
4'-Formyl-biphenyl-4-silt ether acetic acid239,1
N-(4'-Formyl-biphenyl-3-yl)-ndimethylacetamide75240,1
4'-Hydroxymethyl-biphenyl-4-carbaldehyde55213,1
3'-Fluoro-biphenyl-4-carbaldehyde70201,1
4-Pyridin-W-yl-benzaldehyde67184,2
3',4'-Debtor-biphenyl-4-carbaldehyde72219,1
4-Pyridin-4-yl-benzaldehyde67184,2
N-[4-(4-Formyl-phenyl)-pyridine-2-yl]-ndimethylacetamide30241,0
4-Benzo,3]dioxol-5-yl-benzaldehyde 20226,1

in) Andolina condensation of intermediate hydantoins and aldehydes (method b In figure 4)

A General method is illustrated by example of synthesis of 5-{[4-(4-fluoro-phenoxy)-phenyl]-methyl-methyl}-5-propyl-imidazolidin-2,4-dione below.

5-{[4-(4-Fluoro-phenoxy)-phenyl]-methyl-methyl}-5-propyl-imidazolidin-2,4-dione

Commercially available 4-(4-fluoro-phenoxy)-benzaldehyde (201,5 mg, 1.0 mmol), 5-propyl-as (438 mg, is 3.08 mmol) and 45%aqueous trimethylamine (0,240 ml, 1.5 mmol) was boiled under reflux in ethanol (12 ml) and water (3 ml) for 20 hours.

Evaporation and preparative HPLC (C18 column, acetonitrile, water and triperoxonane acid) resulted in the receipt of the connection specified in the header, 5-{[4-(4-fluoro-phenoxy)-phenyl]-methyl-methyl}-5-propyl-imidazolidin-2,4-dione (11 mg, 0.03 mmol), exit 3% in the form of a white solid substance in the form of pure racemate.

1H NMR (300 MHz, DMSO-d6) δ: 10.71 (1H, s); 7.99 (1H, s); 7.70 (2H, dd, J=4.38, 5.37 Hz); 7.75 (2H, d, J=8.44 Hz); 7.35 (2H, d, J=8.03 Hz); 7.27 (2H, dd, J=4.59, 8.60 Hz); 5.89 (1H, d, J=4.42 Hz); 4.66 (1H, d, J=4.34 Hz); 1.96 (1H, dd, J=12.89, 4.36 Hz); 1.71 (1H, dd, J=12.95, 4.77 Hz); 1.32 (1H, m); 1.10 (1H, m); 0.89 (3H, t, J=7.49 Hz).

Head-MS: m/z 343,1 [MH+-OH].

The following compounds were obtained in the same way.

5-[4-Phenoxy-phenyl]-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 10.12 (1H, bs); 8.06 (1H, s); 7.38 (2H, dd, J=3.94, 7.60 Hz); 7.28 (2H, d, J=at 8.62 Hz); 7.13 (1H, t, J=7.43 Hz); 6.96 (2H, d, J=8.75 Hz); 6.91 (2H, d, J=8.61 Hz); 5.89 (1H, d, J=4.33 Hz); 4.62 (1H, d, J=4.48 Hz); 1.41 (3H, s).

Head-MS: m/z 313,0 [MH+].

Benzyl ether of 4-[hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-piperidine-1-carboxylic acid

Was obtained from commercially available starting materials.

Head-MS: m/z 362,1 [MH+].

5-[(4'-Fluoro-biphenyl-4-yl)-hydroxy-methyl]-imidazolidin-2,4-dione

Was obtained from commercially available starting materials.

1H NMR (400 MHz, DMSO-d6) δ: 10.32 (1H, s); 8.09 (1H, s); 7.71 (2H, dd, J=4.47, 5.60 Hz); 7.60 (2H, d, J=8.27 Hz); 7.38 (2H, d, J=8.33 Hz); 7.28 (2H, dd, J=5.05, 8.68 Hz); 5.88 (1H, d, J=3.90 Hz); 4.97 (1H, t, J=3.29 Hz); 4.39 (1H, d, J=2.64 Hz).

Head-MS: m/z 301,2 [MH+].

5-Ethyl-5-[(4'-fluoro-biphenyl-4-yl)-hydroxy-methyl]-imidazolidin-2,4-dione

Received Alderney the condensation of 4'-fluoro-biphenyl-4-carbaldehyde and 5-ethyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, s); 7.96 (1H, s); 7.69 (2H, dd, J=8.77/5.53 Hz); 7.57 (2H, d, J=8.20 Hz); 7.35 (2H, d, J=8.20 Hz); 7.26 (2H, t, J=8.87 Hz); 5.87 (1H, d, J=4.39 Hz); 4.66 (1H, d, 4.39 Hz); 1.98 (1H, m); 1.75 (1H, m); 0.78 (3H, t, J=7.34 Hz).

Head-MS: m/z 329,1 [MH+].

5-[(4'-Fluoro-biphenyl-4-yl)-hydroxy-methyl]-5-propyl-imidazolidin-2,4-dione

Received aldol the second condensation of 4'-fluoro-biphenyl-4-carbaldehyde and 5-propyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.16 (1H, s); 7.98 (1H, s); 7.69 (2H, dd, J=8.68/5.44 Hz); 7.56 (2H, d, J=8.20 Hz); 7.34 (2H, d, J=8.20 Hz); 7.26 (2H, t, J=8.77 Hz); 5.87 (1H, d, J=4.39 Hz); 4.64 (1H, d, 4.39 Hz); 1.94 (1H, m); 1.70 (1H, m); 1.31 (1H, m); 1.10 (1H, m); 0.88 (3H, t, J=7.34 Hz).

Head-MS: m/z 343,1 [MN+].

5-[Hydroxy-(4'-methoxy-biphenyl-4-yl)-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 4'-methoxy-biphenyl-4-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.16 (1H, s); 8.08 (1H, s); 7.59 (2H, d, J=8.77 Hz); 7.52 (2H, d, J=8.20 Hz); 7.31 (2H, d, J=8.20 Hz); 6.99 (2H, d, J=8.58 Hz); 5.87 (1H, d, J=4.39 Hz); 4.63 (1H, d, 4.39 Hz); 3.77 (ZN, t); 1.42 (3H s).

Head-MS: m/z 327,1 [MN+].

5-[Hydroxy-(3'-methoxy-biphenyl-4-yl)-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of Z-methoxy-biphenyl-4-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, s); 8.08 (1H, s); 7.59 (2H, d, J=8.01 Hz); 7.35 (3H, m); 7.21 (1H, d, J=7.63 Hz); 7.17 (1H, s); 6.91 (1H, dd, J=8.11/2.19 Hz); 5.91 (1H, d, J=4.39 Hz); 4.65 (1H, d, 4.39 Hz); 3.81 (3H, t); 1.43 (3H, s).

Head-MS: m/z 327,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carbonitrile

Received Alderney the condensation of 4'-formyl-biphenyl-4-carbonitrile and 5-methyl-imidazolidin-2,4-dione.

p> 1H NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, s); 8.11 (1H, s); 7.89 (4H, m); 7.69 (2H, d, J=8.20 Hz); 7.40 (2H, d, J=8.20 Hz); 5.97 (1H, d, J=4.39 Hz); 4.67 (1H, d, J=4.39 Hz); 3.81 (ZN, t); 1.43 (ZN, s).

Head-MS: m/z 322,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-3-carbonitril

Received Alderney the condensation of 4'-formyl-biphenyl-3-carbonitrile and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, s); 8.14 (1H, s); 8.11 (1H, s); 8.02 (1H, d, J=8.01 Hz); 7.80 (1H, d, J=7.63 Hz); 7.69 (2H, d, J=8.20 Hz); 7.64 (1H, t, J=7.82 Hz); 7.38 (2H, d, J=8.20 Hz); 5.96 (1H, d, J=4.20 Hz); 4.67 (1H, d, 3.81 Hz); 1.42 (3H, s).

Head-MS: m/z 322,1 [MH+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carbaldehyde

Received Alderney condensation biphenyl-4,4'-dicarbollide and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.19 (1H, s); 10.03 (1H, s); 8.12 (1H, s); 7.97 (2H, d, J=8.40 Hz); 7.91 (2H, d, J=8.40); 7.71 (2H, d, J=8.20 Hz); 7.40 (2H, d, J=8.40 Hz); 5.97 (1H, d, J=4.39 Hz); 4.67 (1H, d, 4.39 Hz); 3.81 (MN, t); 1.43 (3H, s).

Head-MS: m/z 325,1 [MH+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-3-silt ether acetic acid

Received Alderney the condensation of 4'-formyl-biphenyl-3-silt ester of acetic acid and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) ´ : 10.18 (1H, s); 8.16 (1H, s); 8.11 (1H, s); 7.92 (1H, dd, J=7.72/1.24 Hz); 7.66 (2H, d, J=8.40); 7.60 (1H, t, J=7.73 Hz); 7.38 (2H, d, J=8.40 Hz); 5.94 (1H, d, J=4.39 Hz); 4.67 (1H, d, 4.39 Hz); 2.63 (3H, s); 1.42 (3H, s).

Head-MS: m/z 321,1 [MN+-H2O].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-silt ether acetic acid

Received Alderney the condensation of 4'-formyl-biphenyl-4-silt ester of acetic acid and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.19 (1H, s); 8.11 (1H, s); 8.01 (2H, d, J=8.39 Hz); 7.82 (2H, d, J=8.20); 7.68 (2H, d, J=8.20 Hz); 7.39 (2H, d, J=8.20 Hz); 5.96 (1H, d, J=4.39 Hz); 4.67 (1H, d, 4.39 Hz); 2.59 (3H, t); 1.43 (3H, s).

Head-MS: m/z 321,1 [MH+-N2O].

N-{4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-3-yl}-ndimethylacetamide

Received Alderney the condensation of N-(4'-formyl-biphenyl-3-yl)-ndimethylacetamide and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, s); 9.98 (1H, s); 8.08 (1H, s); 7.87 (1H, s); 7.50 (3H, m); 7.32 (4H, m); 5.91 (1H, d, J=4.56 Hz); 4.64 (1H, d, 4.28 Hz); 2.05 (3H, s); 1.42 (3H, s).

Head-MS: m/z 354,1 [MH+].

5-[Hydroxy-(4-hydroxymethyl-biphenyl-4-yl)-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 4'-hydroxymethyl-biphenyl-4-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, s); 8.09 (1H, s); 7.61 (2H, d, J=8.20 is C); 7.57 (2H, d, J=8.20); 7.38 (2H, d, J=8.20 Hz); 7.34 (2H, d, J=8.20 Hz); 5.90 (1H, d, J=4.39 Hz); 5.19 (1H, t, 5.72 Hz); 4.65 (1H, d, 4.39 Hz); 4.52 (2H, d, J=5.72 Hz); 1.43 (3H, s).

Head-MS: m/z 327,1 [MN+].

5-[(4-Benzyloxy-phenyl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 4-benzyloxy-benzaldehyde and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.10 (1H, s); 8.01 (1H, s); 7.46-7.27 (5H, m); 7.18 (2H, d, J=8.58 Hz); 6.89 (2H, d, J=8.58 Hz); 5.75 (1H, d, J=4.39 Hz); 5.04 (2H, s); 4.55 (1H, d, J=4.39 Hz); 1.43 (3H, s).

Head-MS: m/z 309,1 [MH+-H2O].

5-[Hydroxy-(4-pyridin-3-yl-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 4-pyridin-3-yl-benzaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 298,1 [MH+].

5-[(3'-Fluoro-biphenyl-4-yl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 3'-fluoro-biphenyl-4-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, s); 8.10 (1H, s); 7.63 (2H, d, J=8.20 Hz); 7.49 (3H, m); 7.36 (2H, d, J=8.20 Hz); 7.17 (1H, m); 5.93 (1H, d, J=4.20 Hz); 4.66 (1H, d, 3.81 Hz); 1.42 (3H, s).

Head-MS: m/z 315 [MN+].

5-[Hydroxy-(4-phenylethynyl-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione

The original aldehyde was synthesized according Thorand S. et al. (J. Org. Chem. 1998, 63(23), 8551-8553).

1H NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, s); 8.08 (1H, s); 7.53 (2H, m); 7.45 (2H, d, J=8.40 Hz); 7.41 (3H, m); 7.30 (2H, d, J=8.20 Hz); 5.99 (1H, d, J=4.58 Hz); 4.64 (1H, d, 4.39 Hz); 1.41 (3H, s).

Head-MS: m/z 321,1 [MH+].

5-[Hydroxy-(4-pyridin-4-yl-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 4-pyridin-4-yl-benzaldehyde and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.19 (1H, s); 8.61 (2H, m); 8.12 (1H, s); 7.74 (2H, d, J=8.39); 7.70 (2H, m); 7.41 (2H, d, J=8.20 Hz); 5.99 (1H, s); 4.67 (1H, s); 1.42 (3H, s).

Head-MS: m/z 298,1 [MN+].

N-{4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-yl}-ndimethylacetamide

Received Alderney the condensation of N-(4'-formyl-biphenyl-4-yl)-ndimethylacetamide and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 354,1 [MH+].

N-(5-{4-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-phenyl}-pyridine-2-yl)-ndimethylacetamide

Received Alderney the condensation of N-[4-(4-formyl-phenyl)-pyridine-2-yl]-ndimethylacetamide and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 355,1 [MH+].

5-[(3',4'-Debtor-biphenyl-4-yl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 3',4'-debtor-biphenyl-4-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ 10.16 (1H, s); 8.10 (1H, s); 7.75 (1H, m); 7.61 (2H, d, J=8.27 Hz); 7.50 (2H, m); 7.35 (2H, d, J=8.27); 5.93 (1H, d, J=3.99 Hz); 4.66 (1H, d, J=3.98 Hz); 1.41 (3H, s).

Head-MS: m/z 333 [MH+].

5-[Hydroxy-(4-[1,2,3]thiadiazole-5-yl-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 4-[1,2,3]thiadiazole-5-yl-benzaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 305 [MH+].

5-{[5-(2-Chloro-4-trifluoromethyl-phenyl)-furan-2-yl]-hydroxy-methyl}-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 5-(3-chloro-4-trifluoromethyl-phenyl)-furan-2-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 389 [MN+].

5-{[5-(4-Chloro-phenylsulfanyl)-thiophene-2-yl]-hydroxy-methyl}-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 5-(4-chloro-phenylsulfanyl)-thiophene-2-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 350,9 [MN+-H2O].

5-{[4-(4-tert-Butyl-thiazol-2-yl)-phenyl]-hydroxy-methyl}-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 4-(4-tert-butyl-thiazol-2-yl)-benzaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 360 [MH+].

5-{[4-(2-Chloro-6-fluoro-benzyloxy)-3-methoxy-phenyl]-hydroxy-methyl}-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 4-(2-chloro-6-the top-benzyloxy)-3-methoxy-benzaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 391 [MH+-H2O].

5-{[2-(4-Chloro-phenylsulfanyl)-phenyl]-hydroxy-methyl}-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 2-(4-chloro-phenylsulfanyl)-benzaldehyde and 5-methyl-imidazolidin-2,4-dione.

5-{[1-(4-Chloro-phenyl)-1H-pyrrol-2-yl]-hydroxy-methyl}-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 1-(4-chloro-phenyl)-1H-pyrrole-2-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 302,1 [MN+-H2O].

5-[Hydroxy-(2-pyridin-2-yl-thiophene-2-yl)-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 5-pyridin-2-yl-thiophene-2-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 304 [MH+].

5-[Hydroxy-(5-thiophene-2-yl-2H-pyrazole-3-yl)-methyl]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 5-thiophene-2-yl-2H-pyrazole-3-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 293,1 [MH+].

5-{Hydroxy-[5-(4-trifluoromethyl-phenyl-2H-pyrazole-3-yl)]-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 5-(4-trifluoromethyl-phenyl-2H-pyrazole-3-carbaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 355 [MH+ ].

5-(Biphenyl-4-yl-hydroxy-methyl)-5-(4-chloro-benzyl)-imidazolidin-2,4-dione

Received Alderney condensation biphenyl-4-carbaldehyde and 5-(4-chloro-benzyl)-imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 9.89 (1H, s); 8.29 (1H, s); 7.65 (2H, d, J=7.73 Hz); 7.59 (2H, d, J=8.20 Hz); 7.43 (2H, m); 7.39 (2H, d, J=8.20 Hz); 7.32 (3H, m); 7.20 (2H, d, J=8.39 Hz); 6.13 (1H, d, J=4.01 Hz); 4.85 (1H, d, J=4.01 Hz); 3.28 (1H, d, J=13.35 Hz); 3.04 (1H, d, J=13.35).

Head-MS: m/z 407,2 [MH+].

5-Benzylsulfamide-5-(biphenyl-4-yl-hydroxy-methyl)-imidazolidin-2,4-dione

Received Alderney condensation biphenyl-4-carbaldehyde and 5-benzylsulfamide-imidazolidin-2,4-dione.

Head-MS: m/z 419,2 [MH+].

5-(Biphenyl-4-yl-hydroxy-methyl)-5-methylsulfonylmethyl-imidazolidin-2,4-dione

Received Alderney condensation biphenyl-4-carbaldehyde and 5-methylsulfonylmethyl-imidazolidin-2,4-dione.

Head-MS: m/z 343,1 [MH+].

5-(Biphenyl-4-yl-hydroxy-methyl)-5-cyclohexylmethyl-imidazolidin-2,4-dione

Received Alderney condensation biphenyl-4-carbaldehyde and 5-cyclohexylmethyl-imidazolidin-2,4-dione.

Head-MS: m/z 379,3 [MH+].

5-(Biphenyl-4-yl-hydroxy-methyl)-5-phenylethyl-imidazolidin-2,4-dione

Received Alderney condensation biphenyl-4-carbaldehyde and 5-phenylethyl-imidazolidin-2,4-dione.

Head-MS: m/z 387,3 [MH+].

5-(Biphenyl-4-yl-hydroxy-methyl)-5-(2-hydroxy-ethyl)-imidazolidin-2,4-dione

Received Alderney condensation biphenyl-4-carbaldehyde and 5-(2-hydroxy-ethyl)-imidazolidin-2,4-dione.

Head-MS: m/z 309,3 [MH+-H2O].

5-[Hydroxy-(4'-methoxy-biphenyl-4-yl)-methyl]-imidazolidin-2,4-dione

Received Alderney the condensation of 4'-methoxy-biphenyl-4-carbaldehyde and imidazolidin-2,4-dione.

1H NMR (400 MHz, DMSO-d6) δ: 10.30 (1H, s); 8.06 (1H, s); 7.60 (2H, d, J=8.77 Hz); 7.54 (2H, d, J=8.39 Hz); 7.33 (2H, d, J=8.20 Hz); 7.00 (2H, d, J=8.77 Hz); 5.83 (1H, d, J=3.81 Hz); 4.94 (1H, t, J=3.34 Hz); 4.33 (1H, d, J=2.67 Hz); 3.77 (3H, s).

Head-MS: m/z 295 [MH+-N2O].

5-(Biphenyl-4-yl-hydroxy-methyl)-5-pyridin-4-ylmethyl-imidazolidin-2,4-dione

Received Alderney condensation biphenyl-4-carbaldehyde and 5-pyridin-4-ylmethyl-imidazolidin-2,4-dione.

Head-MS: m/z 374,2 [MH+].

5-(Hydroxy-{3-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-phenyl}-methyl)-5-methyl-imidazolidin-2,4-dione

Received Alderney the condensation of 4-[4-(5-trifluoromethyl-pyridine-2-yl)-piperazine-1-yl]-benzaldehyde and 5-methyl-imidazolidin-2,4-dione.

Head-MS: m/z 450,2 [MH+].

5-[(4-{2-[4-(3-Chloro-5-trifluoromethyl-pyridine-2-yl)-p is perazin-1-yl]-ethoxy}-phenyl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione

Was obtained from commercially available starting materials.

Head-MS: m/z consists 528.3 [MH+].

EXAMPLE 9

The compound was synthesized according to method D (combination Suzuki) in figure 4 (shown in the above description) of commercially available arylboronic acid and 5-[hydroxy-(4-iodine-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione or 5-[hydroxy-(4-iodine-phenyl)-methyl]-imidazolidin-2,4-dione, described below.

5-[Hydroxy-(4-iodine-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione

4-Iodine-benzaldehyde (9,280 g, 40.0 mmol), 5-methyl-as (4,564 g, 40.0 mmol) and 45%aqueous trimethylamine (6,40 ml, 40.0 mmol) was boiled under reflux in ethanol (60 ml) and water (40 ml) for 20 hours under nitrogen atmosphere. White precipitate appeared. After cooling at room temperature for about 15 minutes this precipitate was collected by filtration, washed successively with ethanol (50%, 50 ml), water (50 ml) and diethyl ether (50 ml). Drying by suction of air led to the connection specified in the header, 5-[hydroxy-(4-iodine-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione (7,968 g, 23,0 mmol) with a yield of 57.5% in the form of a white solid substance in the form of pure racemate.

1H NMR (300 MHz, DMSO-d6) δ: 10.19 (1H, s); 8.08 (1H, s); 7.64 (2H, d, J=8.55 Hz); 7.07 (2H, d, J=8.43 Hz); 5.98 (1H, d, J=4.49 Hz); 4.57 (1H, d, J=4,32 Hz); 1.40 (3H, s).

Head-MS: m/z 346,9 [MN ].

5-[Hydroxy-(4-iodine-phenyl)-methyl]-imidazolidin-2,4-dione

Received the same Protocol that was used to obtain 5-[hydroxy-(4-iodine-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione, described above.

1H NMR (300 MHz, DMSO-d6) δ: 10.32 (1H, s); 8.06 (1H, s); 7.66 (2H, d, J=8.14 Hz); 7.10 (2H, d, J=8.27 Hz); 5.91 (1H, d, J=3.90 Hz); 4.87 (1H, t, J=2.70 Hz); 4.34 (1H, d, J=2.48 Hz).

Head-MS: m/z 333,1 [MH+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid

The stirred mixture of 4-carboxy-phenyl-Bronevoy acid (214 mg, 1.3 mmol), 5-[hydroxy-(4-iodine-phenyl)-methyl]-imidazolidin-2,4-dione (347 mg, 1.0 mmol) and sodium hydrogen carbonate (318 mg, 3.8 mmol) in acetone (5.0 ml) and water (5.0 ml) was subjected to deoxygenating 3 shifts vacuum/nitrogen. Added palladium diacetate (20 mg) and deoksigenirovanii repeated, and then the mixture was stirred at 50°C for 90 minutes under nitrogen atmosphere.

Solid matter was allowed to settle. The supernatant was distributed between water (20 ml), ethyl acetate (15 ml) and diethyl ether (15 ml). The aqueous phase was acidified using 1 M HCl (aq., 10 ml), then was extracted twice with ethyl acetate (15 ml) and diethyl ether (15 ml). Evaporation of the organic phase gave 340 mg of the crude product, which was suspended in dioxane (6 ml) and water (6 ml) together with triperoxonane acid (100 microlitres) is filtered. Preparative HPLC (column, acetonitrile/water/triperoxonane acid) resulted in the receipt of the connection specified in the header, 4'-[hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid (114 mg, 0.33 mmol) as a white solid with a yield of 33.5%.

1H NMR (400 MHz, DMSO-d6) δ: 10.20 (1H, s); 8.13 (1H, s); 8.00 (2H, d, J=8.33 Hz); 7.79 (2H, d, J=8.49 Hz); 7.67 (2H, d, J=8.39); 7.40 (2H, d, J=8.48); 5.97 (1H, bs); 4.68 (1H, s); 1.44 (3H, s).

Head-MS: m/z 341 [MH+].

The following compounds were obtained according to the same Protocol that was used to obtain 4'-[hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid described above.

5-[Hydroxy-(4'-methylsulfanyl-biphenyl-4-yl)-methyl]-5-methyl-imidazolidin-2,4-dione

1H NMR (300 MHz, DMSO-d6) δ: 10.18 (1H, s); 8.10 (1H, s); 7.62 (2H, d, J=8.61 Hz); 7.57 (2H, d, J=8.42 Hz); 7.35 (2H, d, J=5.73); 7.32 (2H, d, J=6.30); 5.91 (1H, d, J=4.32 Hz); 4.65 (1H, d, J=4.31 Hz); 2.50 (3H, s); 1.43 (3H s).

Head-MS: m/z 343,0 [MN+].

5-[Hydroxy-(4-naphthalene-2-yl-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione

Head-MS: m/z 347,1 [MH+].

5-(Hydroxy[1,1';4,1"]terphenyl-4"-yl-methyl)-5-methyl-imidazolidin-2,4-dione

Head-MS: m/z 373,1 [MN+].

5-[(3'-Benzyloxy-biphenyl-4-yl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione

Head-MS: m/z 403,1 [MN+].

5-[(4-Benzo[1,3]dioxol-5-yl-phenyl)-hydroxy-methyl]-imidazolidin-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 10.31 (1H, s); 8.04 (1H, s); 7.53 (2H, d, J=8.39 Hz); 7.33 (2H, d, J=8.20 Hz); 7.24 (1H, s); 7.14 (1H, d, J=8.11); 6.97 (1H, d, J=8.01 Hz); 6.03 (2H, d, J=6.87 Hz); 5.84 (1H, d, J=3.62 Hz); 4.92 (1H, s); 4.35 (1H, s).

Head-MS: m/z 309 [MH+-H2O].

5-[Hydroxy-(3'-nitro-biphenyl-4-yl)-methyl]-5-methyl-imidazolidin-2,4-dione

1H NMR (400 MHz, DMSO-d6) δ: 10.18 (1H, s); 8.41 (1H, t, J=8.41 Hz); 8.20 (1H, m); 8.15 (1H, m); 8.12 (1H, s); 7.73 (3H, m); 7.41 (2H, d, J=8.20); 5.97 (1H, d, J=4.39 Hz); 4.68 (1H, d, J=4.58 Hz); 1.43 (3H, s).

Head-MS: m/z 342,1 [MH+].

EXAMPLE 10

The compound was synthesized according to method D (amide combination) in figure 4 (shown in the above description). Compounds were obtained by the General method described below. All used in combination amines commercially available.

To a 0.3 M solution of 4'-[hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid 1-methyl-2-pyrrolidinone (50 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.3 EQ., 45 μl of 0.5 M in 1-methyl-2-pyrrolidinone), 1-hydroxybenzotriazole (1.7 equiv., 51 ál of 0.5 M in 1-methyl-2-pyrrolidinone), N,N-diisopropylethylamine (1 EQ., 20 ál of 1 M in 1-methyl-2-pyrrolidinone) and the corresponding s is n (2 EQ., 100 μl of 0.3 M in 1-methyl-2-pyrrolidinone). This reaction mixture was stirred over night at room temperature. Purification was performed by preparative HPLC-C18.

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid (2-hydroxy-ethyl)-methyl-amide

Head-MS m/z: 398,1 [MH+].

5-{Hydroxy-[4'-(morpholine-4-carbonyl)-biphenyl-4-yl]-methyl}-5-methyl-imidazolidin-2,4-dione

Head-MS m/z: 410,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid methyl-(1-methyl-pyrrolidin-3-yl)-amide

Head-MS m/z: 437,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid (2-morpholine-4-yl-ethyl)-amide

Head-MS m/z: 453,1 [MH+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid (2-methoxy-ethyl)-amide

Head-MS m/z: 398,1 [MN+].

5-{Hydroxy-[4'-(pyrrolidin-1-carbonyl)-biphenyl-4-yl]-methyl}-5-methyl-imidazolidin-2,4-dione

Head-MS m/z: 394,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid (2-cyano-ethyl)-methyl-amide

Head-MS m/z: 407,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid methyl-phenethyl-amide

Head-MS m/z: 458,1 [MH+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid (4-cyano-cyclohexyl)-methyl-amide

Head-MS m/z: 461,1 [MH+].

5-{Hydroxy-[4'-(4-hydroxymethyl-piperidine-1-carbonyl)-biphenyl-4-yl]-methyl}-5-methyl-imidazolidin-2,4-dione

Head-MS m/z: 438,1 [MH+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

Head-MS m/z: 465,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid cyclopentolate

Head-MS m/z: 408,1 [MH+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid (1-phenyl-ethyl)-amide

Head-MS m/z: 444,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid (pyridin-4-ylmethyl)-amide

Head-MS m/z: 431,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-IU is Il]-biphenyl-4-carboxylic acid benzylamine

Head-MS m/z: 430,1 [MH+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid cyclopropylamino

Head-MS m/z: 380,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid 4-methoxy-benzylamine

Head-MS m/z: 460,1 [MN+].

4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-4-carboxylic acid (3-imidazol-1-yl-propyl)-amide

Head-MS m/z: 448,1 [MH+].

N-{4-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-phenyl}-benzamide

5-[Hydroxy-(4-nitro-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione was synthesized according to the method according to the Protocol described in example 1 (head-MS m/z: 268,8 [MN+]). The corresponding amine 5-[(4-amino-phenyl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione was obtained catalyzed by Pd(0) by hydrogenation in ethanol (head-MS m/z: 218,0 [MN+] (-H2O)). At the end of 5-[(4-amino-phenyl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione was subjected to combination with benzoic acid according to the above Protocol (method D) to give the compounds specified in the header.

Head-MS m/z: 240,0 [MH+].

EXAMPLE 11

The enantiomers were isolated ways the Ohm, described below for the separation of 4'-(hydroxy-(4-methyl-2,5-dioxoimidazolidin-4-yl)-methyl) - biphenyl-4-carbonitrile.

4'-(Hydroxy-(4-methyl-2,5-dioxoimidazolidin-4-yl)-methyl) - biphenyl-4-carbonitrile

Chromatographic separation

0.10 g diastereomers pure 4'-(hydroxy-(4-methyl-2,5-dioxoimidazolidin-4-yl)-methyl) - biphenyl-4-carbonitrile was dissolved in 76 ml of a mixture of absolute ethanol/isohexane (75:25) and filtered through 0.45 µm nylon filter. The volume of 5.0 ml was re-injected on a chiral column (Chiralpak AD-H, internal diameter 2 cm × length 25 cm)connected to a UV detector (254 nm) and a collector fractions. Separation was carried out with a mixture of absolute ethanol/isohexane (75:25) at a flow rate of 8.0 ml/min and the pure enantiomers were suirable after about 15 minutes and 21 minutes, respectively. The fractions containing the same enantiomer, were combined, concentrated and evaluated optical purity by chiral chromatography (see below).

Enantiomer A ("early" faction)

Output 0,047 g of a white solid.

Chiral chromatography (Chiralpak AD-H (inner diameter of 0.45 cm × length 25 cm) at a flow rate of a mixture of absolute ethanol/isohexane (75:25) of 0.43 ml/min)

The retention time of 11.4 minutes.

Optical purity of 99.9% EE (enantiomer B is not present).

1H NMR (CD3OD) δ: 1.60 (s, H), 4.84 (m, obscured by singlet water, 1H), 7.50 (d, 2H, J=8 Hz), 7.62 (d, 2H, J=8 Hz) and 7.79 (m, 4H) million-1.

Enantiomer B ("late" faction)

Output 0,040 g of a white solid.

Chiral chromatography (Chiralpak AD-H (inner diameter of 0.45 cm × length 25 cm) at a flow rate of a mixture of absolute ethanol/isohexane (75:25) of 0.43 ml/min)

The retention time of 18.0 minutes.

Optical purity 99,0% AI (present 0,50% enantiomer A).

1H NMR (CD3OD) δ: 1.60 (s, 3H), 4.84 (m, obscured by singlet water, 1H), 7.50 (d, 2H, J=8 Hz), 7.62 (d, 2H, J=8 Hz) and 7.79 (m, 4H) million-1.

N-(4'-(Hydroxy-(4-methyl-2,5-dioxoimidazolidin-4-yl)-methyl)-biphenyl-3-yl)ndimethylacetamide

Chromatographic separation

0,040 g diastereomers pure N-4'-(hydroxy-(4-methyl-2,5-dioxoimidazolidin-4-yl)-methyl) - biphenyl-3-yl)ndimethylacetamide was dissolved in 224 ml of a mixture of absolute ethanol/isohexane (71:29) and was divided as described above, a mixture of absolute ethanol/isohexane (50:50) as eluent at a flow rate of 6.0 ml/min

Enantiomer A ("early" faction)

Output 0,019 g of a white solid.

Chiral chromatography (Chiralpak AD-H (inner diameter of 0.45 cm × length 25 cm) at a flow rate of a mixture of absolute ethanol/isohexane (50:50) of 0.43 ml/min).

The retention time of 10.4 minutes.

Optical purity of 99.9% EE (enantiomer B is not present).

1H NMR (CD3OD) 4 : 1.60 (s, 3H), 2.14 (s, 3H), 4.82 (m, obscured by singlet water, 1H), 7.33 (m, 1H), 7.36 (t, 1H, J=8 Hz), 7.44 (d, 2H, J=8 Hz), 7.50 (m, 1H), 7.54 (d, 2H, J=8 Hz) and 7.82 (m, 1H) million-1.

Enantiomer B ("late" faction)

Output 0,018 g of a white solid.

Chiral chromatography (Chiralpak AD-H (inner diameter of 0.45 cm × length 25 cm) at a flow rate of a mixture of absolute ethanol/isohexane (50:50) of 0.43 ml/min)

The retention time of 14.8 minutes.

Optical purity 99.6% of AI (there is 0.20% of the enantiomer A).

1H NMR (CD3OD) δ: 1.60 (s, 3H), 2.14 (s, 3H), 4.82 (m, obscured by singlet water, 1H), 7.33 (m, 1H), 7.36 (t, 1H, J=8 Hz), 7.44 (d, 2H, J=8 Hz), 7.50 (m, 1H), 7.54 (d, 2H, J=8 Hz) and 7.82 (m, 1H) million-1.

5-(Biphenyl-4-yl-hydroxy-methyl)-imidazolidin-2,4-dione

Chromatographic separation

Separation was carried out on the system Gilson HPLC (column: CHIRALPAK AD, 2,0×25 cm Solvent: isohexane/EtOH=25/75. The flow rate of 6.0 ml/min UV 254 nm. The injected volume of 3.0 ml). 24 mg of racemic substance was dissolved in 24 ml of a mixture of isohexane/EtOH 25/75. Two enantiomers with Rt 17,72 min and 20,47 min was collected and the solvent was removed by evaporation. Analyzed for enantiomeric purity using the following system Gilson HPLC (column: CHIRALPAK AD, 0,46,0×25 cm Solvent: isohexane/EtOH 25/75. A flow rate of 0.5 ml/min UV 254 nm). Faster enantiomer: 9 mg, Rt=10,12 min, EE=99,9%. Slower enantiomer: 7 mg, Rt=11,78 min, I=99,2%.

EXAMPLE 12

The following compounds were obtained in a manner analogous to the method described in example 1.

5-[(N-Fluoren-2-yl)-hydroxy-methyl]-imidazolidin-2,4-dione

Head-MS m/z: 277 [MH+-N2O].

(3-{4-[(4'-Fluoro-biphenyl-4-yl)-hydroxy-methyl]-2,5-dioxo-imidazolidin-4-yl}-propyl)-carbamino acid benzyl ester

1H NMR (400 MHz, DMSO-d6) δ: 10.20 (1H, s); 8.53 (1H, d, J=4.01 Hz); 8.01 (1H, s); 7.69 (2H, m); 7.56 (2H, d, J=8.39); 7.30 (D, m); 5.90 (1H, d, J=4.20 Hz); 4.99 (2H, s); 4.64 (1H, d, J=4.20 Hz); 2.98 (2H, m); 1.97 (1H, m,); 1.72 (1H, m); 1.42 (1H, m); 1.22(1H, m).

Head-MS m/z: 492,2 [MH+].

5-(3-Amino-propyl)-5-[(4'-fluoro-biphenyl-4-yl)-hydroxy-methyl]-imidazolidin-2,4-dione

Received from the above-described (3-{4-[(4'-fluoro-biphenyl-4-yl)-hydroxy-methyl]-2,5-dioxo-imidazolidin-4-yl}-propyl)-carbamino acid benzyl ester in a standard way, well-known specialists in this field of technology.

Head-MS m/z: 358,1 [MN+].

5-[Hydroxy-(4'-methoxy-biphenyl-4-yl)-methyl]-5-methylsulfonylmethyl-imidazolidin-2,4-dione

Was obtained from 4'-methoxy-biphenyl-4-carbaldehyde (table 3, method B) and 5-methylsulfonylmethyl-imidazolidin-2,4-dione (table 2, method A) according to the method In example 1.

1H NMR (400 MHz, DMSO-d6) δ: 10.25 (1H, s); 8.16 (1H, s); 759 (2H, d, J=8.77 Hz); 7.53 (2H, d, J=8.20); 7.31 (2H, d, J=8.20 Hz); 6.99 (2H, d, J=8.77 Hz); 5.98 (1H, d, J=4.20 Hz); 4.71 (1H, d, J=4.01 Hz); 3.77 (3H, s); 3.16 (1H, d, J=14.3 Hz); 2.92 (2H, d, J=14.31 Hz); 2.11 (3H, s).

Head-MS m/z: 373,1 [MH+].

5-[Hydroxy-(4'-methoxy-biphenyl-4-yl)-methyl]-5-pyridine-2-ylmethyl-imidazolidin-2,4-dione

Was obtained from 4'-methoxy-biphenyl-4-carbaldehyde (table 3, method B) and commercially available 5-pyridin-2-ylmethyl-imidazolidin-2,4-dione according to the method In example 1.

1H NMR (400 MHz, DMSO-d6) δ: 10.00 (1H, s); 8.53 (1H, d, J=4.01 Hz); 8.13 (1H, s); 7.91 (1H, s); 7.58 (2H, m); 7.53 (2H, m); 7.38 (4H, m); 7.00 (2H, m); 6.11 (1H, s);4.81 (1H, s); 3.48 (2H, m).

Head-MS m/z: 404,3 [MH+].

5-[Hydroxy-(4-pyrazin-2-yl-phenyl)-methyl]-5-methyl-imidazolidin-2,4-dione

Was obtained from commercially available 4-pyrazin-2-yl-benzaldehyde and 5-methyl-as according to the method In example 1.

Head-MS m/z: 299 [MH+].

5-{3-[4-(5-Chloro-pyridine-2-yloxy)-phenyl]-1-hydroxy-propyl}-5-methyl-imidazolidin-2,4-dione

3-[4-(5-Chloro-pyridine-2-yloxy)-phenyl]-propan-1-ol

3-(4-Hydroxyphenyl)-propanol (768,5 mg of 5.05 mmol), 2,5-dichloropyridine (934,8 mg, 6,32 mmol), cesium carbonate (2,48 g, 7,60 mmol), mixed in N-methyl-pyrrolidone (10 ml)was stirred and heated (100°C) for 20 hours. The flask was cooled and the content was distributed between ethyl acetate (100 ml), di-tert-butyl ether (100 ml) and water (300 ml The organic phase is washed with water (3×30 ml). Evaporation gave specified in the title crude compound (1,502 g, 5,70 mmol) as a yellow oil with a yield of 113%. Pure according to TLC analysis.

Head-MS m/z: 264 [MH+].

3-[4-(5-Chloro-pyridine-2-yloxy)-phenyl]-Propionaldehyde

3-[4-(5-Chloro-pyridine-2-yloxy)-phenyl]-propan-1-ol (267 mg, 1.0 mmol) and pyridineboronic (302 mg, 1.4 mmol) was stirred in dichloromethane (20 ml, dried by molecular sieves) for 2 hours. Flash chromatography (SiO2, dichloromethane/methanol: gradient to 100/5) resulted specified in the title compound (169 mg, of 0.65 mmol) in the form of an oil with a yield of 65%.

Head-MS m/z: 262 [MH+].

5-{3-[4-(5-Chloro-pyridine-2-yloxy)-phenyl]-1-hydroxy-propyl}-5-methyl-imidazolidin-2.4-dione

3-[4-(5-Chloro-pyridine-2-yloxy)-phenyl]-Propionaldehyde and commercially available 5-methyl-as used for the synthesis is specified in the header of the compounds according to the method In example 1.

Head-MS m/z: 376,0 [MN+].

5-{[4-(5-Chloro-pyridine-2-yl-oxy)-phenyl]-hydroxy-methyl}-5-methyl-imidazolidin-2,4-dione

4-(5-Chloro-pyridine-2-yloxy)-benzaldehyde

4-Hydroxy-benzaldehyde (620,9 mg, 5.08 mmol), cesium carbonate (2.6 g, 7,98 mmol) and 2,5-dichloropyridine (947 mg, 6,40 mmol), mixed in N-methyl-pyrrolidone (10 ml)was stirred and heated (75° (C) for 16 hours. LC-MS analysis of n is revealed the formation of the product in a minor amount. Further reaction at elevated temperature (150° (C) for an additional six hours has led to an increase in product education. The flask was cooled and the content was distributed between ethyl acetate (100 ml), ether (100 ml) and water (200 ml). The organic phase is washed with water (3×30 ml). Evaporation and flash chromatography (SiO2, dichloromethane/methanol: gradient to 100/4) led to 4-(5-chloro-pyridine-2-yloxy)-benzaldehyde (181 mg, 0.77 mmol) with a yield of 15.2%.

1H NMR (400 MHz, DMSO-d6) δ: 9.98 (1H, s); 8.27 (1H, d); 8.04 (1H, dd); 7.97 (2H, d); 7.35 (2H, d); 7.23 (1H, d).

Head-MS m/z: 234 [MH+].

5-{[4-(5-Chloro-pyridine-2-yloxy)-phenyl]-hydroxy-methyl}-5-methyl-imidazolidin-2.4-dione

4-(5-Chloro-pyridine-2-yloxy)-benzaldehyde and commercially available 5-methyl-as used for the synthesis of compounds specified in the header, according to the method In example 1.

Head-MS m/z: 348 [MN+].

EXAMPLE 13

5-[(3'-Amino-biphenyl-4-yl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione

Was obtained from 5-[hydroxy-(3'-nitro-biphenyl-4-yl)-methyl]-5-methyl-imidazolidin-2,4-dione, described in example 8, the standard method of synthesis, are well known to experts in the art (catalyzed by Pd(0) by hydrogenation in ethanol).

Head-MS m/z: 312,1 [MH+].

EXAMPLE 14

Sleduyusheye received according to the Protocol, used for the synthesis of N-{4'-[hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-3-yl}-methanesulfonamide described below.

N-{4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-3-yl}-methanesulfonamide

Methanesulfonanilide (10 MCP, 0,165 mmol) was added dropwise to a solution of 5-[(3'-amino-biphenyl-4-yl)-hydroxy-methyl]-5-methyl-imidazolidin-2,4-dione (41 mg, 0,132 mmol) in pyridine (1 ml). The resulting mixture was stirred for 6 hours at ambient temperature. Was added water (15 ml) and the aqueous mixture was extracted with EtOAc (3×10 ml). The combined EtOAc extracts were dried (MgSO4) and concentrated under reduced pressure to get crude product. Preparative HPLC on a column of Chromasil C18 with acetonitrile/water (with 0.1% triperoxonane acid) received 40 mg (yield 80%) of the compound indicated in the title, N-{4'-[hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-3-yl}-methanesulfonamide.

1H NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, s); 9.79 (1H, s); 8.10 (1H, s); 7.57 (2H, d, J=8.39 Hz); 7.40 (5H, m); 7.19 (1H, m); 7.25 (2H, d, J=8.39 Hz); 7.20 (1H, m); 5.92 (1H, m); 4.65 (1H, s); 3.01 (3H, s); 1.42 (3H, s).

Head-MS m/z: 390,1 [MN+].

N-{4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-3-yl}-propionate

1H NMR (400 MHz, DMSO-d6) δ: 10.17 (1H, s); 9.90 (1H, s); 8.9 (1H, s); 7.90 (1H, s); 7.51 (3H, m); 7.32 (4H, m); 5.92 (1H, d, J=4.39 Hz); 4.65 (1H, d, J=4.39 Hz); 2.32 (1H, q, J=7.44 Hz); 1.42 (3H, s); 1.08 (3H, t, J=7.53 Hz).

Head-MS m/z: 368,1 [MN+].

N-{4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-3-yl}-isobutyramide

1H NMR (400 MHz, DMSO-d6) δ: 10.15 (1H, s); 9.87 (1H, s); 8.09 (1H, s); 7.92 (1H, s); 7.52 (3H, m); 7.33 (4H, m); 5.92 (1H, d, J=4.39 Hz); 4.65 (1H, d, J=4.39 Hz); 2.59 (1H, m); 1.42 (3H, s); 1.10 (6N, d, J=6.87 Hz).

Head-MS m/z: 382,1 [MN+].

N-{4'-[Hydroxy-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-methyl]-biphenyl-3-yl}-2,2-dimethylpropanamide

1H NMR (400 MHz, DMSO-d6) δ: 10.15 (1H, s); 9.23 (1H, s); 8.09 (1H, s); 7.93 (1H, s); 7.58 (3H, m); 7.33 (4H, m); 5.91 (1H, d, J=4.39 Hz); 4.65 (1H, d, J=4.39 Hz); 1.42 (3H, s); 1.22 (9H, s).

Head-MS m/z: 396,2 [MN+].

EXAMPLE 15

5-[(4'-Chlorobiphenyl-4-yl)methoxymethyl]-5-methyl-imidazolidin-2,4-dione

4-Chloro-4'-(2-nitropropyl)biphenyl -

4-(4-Chlorophenyl)benzaldehyde (0.66 g, 3.0 mmol), nitroethane (2 ml), ammonium carbonate (3.5 g) and glacial acetic acid (17 ml) was stirred in nitrogen atmosphere at 82°C for 20 hours. Volatiles evaporated and the yellow residue was dissolved in ether and washed once with water. The aqueous phase was separated and washed once with ether. The combined organic phases are washed with water, brine, dried over anhydrous sodium sulfate, fil is listed and concentrated with dykedom silica (3 g) by rotary evaporation. The dry residue was applied on a column with silica. Elution with a mixture of ethyl acetate/n-heptane (1:20) to (1:8) gave 0.50 g (yield 61%) of the compound indicated in the title, in the form of yellow crystals. So pl. 113,8-114,3°With (not adjusted).

FT-IR (ATR (Fourier transform infrared spectrum of frustrated total internal reflection (ATR)) ν 1647 (w), 1504 (str), 1484 (str), 1320 (ν str), 812 (str) cm-1.

1H NMR (300 MHz, CDCl3) δ: 2.50 (d, 3H, J=1 Hz); 7.44 (d, 2H, J=9 Hz); 7.52 (d, 2H, J=9 Hz); 7.55 (d, 2H, J=9 Hz); 7.65 (d, 2H, J=9 Hz) and 8.12 (br s, 1H) million-1.

13C NMR (100 MHz, CDCl3) δ: 14.2, 127.2, 128.2, 129.1, 130.5, 131.5, 132.9, 134.1,138.1, 141.3 and 147.6 million-1.

4-Chloro-4'-(1-methoxy-2-nitropropyl)biphenyl -

A mixture of 4-chloro-4'-(2-nitropropyl)biphenyl (0.39 g, 1.3 mmol), sodium methylate (4.0 mmol; freshly prepared from 0,091 g of sodium and dry methanol) and anhydrous 1,2-dimethoxyethane (3.0 ml) was stirred in nitrogen atmosphere at 22°C for three hours, acidified 10%acetic acid in methanol (4 ml), concentrated to dryness by rotary evaporation, and then was dissolved in ethyl acetate and water. The aqueous phase was separated and washed once with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated with silica (3 g) by rotary evaporation. The dry residue was applied on a column of silica. Elution CME is using dichloromethane/n-heptane (1:3) to (1:1) resulted in the receipt of 0.40 g (yield 95%) compound specified in the header, in the form of a white solid.

FT-IR (ATR) v 1552 (ν str), 1485 (str), 1092 (str), 814 (str) cm-1.

1H NMR (400 MHz, CDCl3) δ: 1.30 (d, 1,33H, J=7 Hz); 1.56 (d, 1,7H, J=7 Hz); 3.22 (s, 1,2H), 3.32 (s, 1,8H), 4.56 (d, 1,2H, J=10 Hz); 4.63 (me, 1,8 M), 4.76 (me, 1,2H), 4.88 (d, 1,8H, J=5 Hz) and 7.38-7.62 (m's, 8H) million-1.

13C NMR (100 MHz, CDCl3) δ: 13.0, 16.3, 57.0, 57.7, 83.5, 84.8, 86.9, 87.5, 127.3, 127.5, 128.3, 129.0, 129.1, 132.7, 133.7, 133.9, 135.1, 135.9, 138.7, 138.8, 140.4, 140.9 million-1(diastereomer signals).

1-(4'-Chlorobiphenyl-4-yl)-1-methoxypropan-2-he

A mixture of 4-chloro-4'-(1-methoxy-2-nitropropyl)biphenyl (0,123 g, 0.40 mmol), dry dichloromethane (2.8 ml) and powdered molecular sieves CÅ (0,040 g) in an argon atmosphere was cooled in an ice bath. Perruthenate of tetrapropylammonium (0,170 g, 0.48 mmol) was added in portions to a cold stirred mixture. After complete addition, the ice bath was removed and the mixture was stirred at 22°C for 4.0 hours. Added diethyl ether (30 ml) and the resulting dark suspension was filtered through celite. Transparent filtrate was concentrated with silica (4 g) by rotary evaporation. The dry residue was applied on a column with silica. Elution with a mixture of dichloromethane/n-heptane (1:2) up (2:1) resulted in 0,052 g (yield 47%) of the compound indicated in the title, in the form of a white solid.

FT-IR (ATR) ν 1716 (ν str), 1485 (str), 1093 cm-1(ν str).

1H NMR (300 MHz, CDCl3) δ: 2.16 (s, 3H); 3.42 (s, 3H); 4.69 (s, 1H), 7.40 (d, 2H, J=9 Hz); 7.46 (d, 2H, J=8 Hz), 7.51 (d, 2H, J=9 Hz) and 7.56 (d, 2H, J=8 Hz) million-1.

13C NMR (100 MHz, CDCl3) δ: 25.1, 57.3, 89.1, 127.2, 127.4, 128.2, 128.8, 133.5, 135.1, 138.8, 140.1 and 206.4 million-1.

5-[(4'-Chlorobiphenyl-4-yl)methoxymethyl]-5-methyl-imidazolidin-2,4-dione

1-(4'-Chlorobiphenyl-4-yl)-1-methoxypropan-2-he (0,051 g 0,19 mmol), ammonium carbonate (0,089 g of 0.93 mmol), potassium cyanide (0.025 g, of 0.37 mmol; be CAREFUL!) and 50%ethanol in water (1.4 ml) was stirred in a sealed vessel (4,5 ml) at 87°C (oil bath temperature) for 19 hours. The solvent is evaporated, add water to a final volume of about 20 ml, the pH was brought to 3 glacial acetic acid and the crude product was dissolved in ethyl acetate (50 ml). The organic phase was washed once with brine, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to obtain 0,065 g (yield 100%) of the compound indicated in the title, in the form of a white solid.

1H NMR (400 MHz, DMSO-d6) δ: 1.06 (s, 2H); 1.43 (s, 1H); 3.07 (s, 2H), 3.17 (s, 1H), 4.33 (s, 0,7H); 4.34 (s, 0.3 H), 7.30-7.75 (m, s, 8,7H), 8.24 (brs, 0,3H), 10.26 (br s, 0,3H) and 10.56 (br s, 0,7H) million-1.

13C NMR (100 MHz, DMSO-d6) δ: 20.2, 21.1, 56.6, 57.0, 65.5, 66.2, 84.2, 84.9, 125.8, 126.1, 128.20, 128.22, 128.74, 128.76, 128.79, 128.9, 132.2, 135.3, 135.4, 138.2, 138.3, 138.3, 138.4, 156.1, 156.9, 175.9 and 177.1 million-1(diastereomer signals).

P the EMER 16

5-[Hydroxy-(4-quinoline-3-yl-phenyl)-methyl]-imidazolidin-2,4-dione

This compound was synthesized according to J. Org. Chem. 2001, 66, 1500-1502, from commercially available 3-bromo-quinoline and 5-[hydroxy-(4-iodine-phenyl)-methyl]-imidazolidin-2,4-dione, described above.

Head-MS m/z: 348,2 [MN+].

EXAMPLE 17

The manufacture of pharmaceutical compositions and medicaments containing the inhibitor of metalloproteinases.

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

(a)

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

(b)

Capsulemg/capsule
The compound of formula (I)10
Lactose (European Pharmacopoeia)389
Croscarmelose sodium saltMagnesium stearate1,0

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

A method of manufacturing

The compound of formula (I) 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

where X is selected from NR1, S;

Y1and Y2represent About;

Z represents O;

m is 0 or 1;

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

R1 is selected from H, alkyl;

R3 and R6 are independently selected from H, alkyl, halogenoalkane, heteroalkyl, cycloalkyl, aryl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heteroseksualci-alkyl, alkylaryl, heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl or geterotsiklicheskie containing from 3 to 7 ring atoms, where alkyl, heteroalkyl, aryl, heteroaryl, cycloalkenyl or heterologously rediculious to be possibly substituted by one or more than one group, independently selected from hydroxy, alkyl, cycloalkyl, aryl, heteroaryl, halogen, alkoxy, carboxy, amino, alkylthio where heteroalkyl represents replaced by a heteroatom alkyl containing one heteroatom selected from N and S;

R4 is selected from H, alkyl;

R5 is a bicyclic or tricyclic group containing two or three ring structures, each of which contains from 3 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, thioalkyl, hydroxy, halogenoalkane, amino, cyano, nitro, alkyl, halogenoalkane, alkoxy, alkylsulfonamides, alkylamino, allylcarbamate, allylcarbamate, carbonyl, carboxy, where any alkyl radical within any substituent itself may possibly be substituted by one or more than one group independently selected from halogen, hydroxy, cyano, alkoxy;

R5 is a bicyclic or tricyclic group, each ring structure is connected with the following ring structure via a direct link, via-O-, thru-S -, (C1-6)alkyl, (C1-6)heteroalkyl through (C1-6)quinil, through the carboxy(C1-6)alkyl or condensed with mark is the fact that the ring structure, where heteroalkyl represents a substituted heteroatom alkyl containing one heteroatom selected from N, O and S;

provided that

when X represents NR1, R1 represents H, Y1represents O, Y2represents O, Z represents O, m is 0, And represents a direct bond, R3 represents H, R4 represents H and R6 represents H, then R5 is not h-methylbenzimidazole or 5-(benzo[1,3]dioxol-5-yl);

when X represents S, at least one of Y1and Y2represents O, m is 0, And represents a direct bond, R3 represents H or methyl, R6 represents H or methyl, then R5 is not cinoxacin-1,4-dioxide.

2. The compound of formula I according to claim 1, or its pharmaceutically acceptable salt, where X represents NR1, R1 represents H or (C1-3)alkyl, at least one of Y1and Y2represents O, Z represents O, m is 0, and a is a direct link.

3. The compound according to claim 1 or 2, or its pharmaceutically acceptable salt, where R3 represents H, alkyl or halogenated, R4 represents H, alkyl.

4. The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, where R5 is a bicyclic group containing two possibilities is substituted 5 - or 6-membered ring, independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl.

5. The compound according to any one of claims 1 to 4, or its pharmaceutically acceptable salt, where R6 represents H, alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, arylalkyl, alkylaryl, heteroalkyl, heteroseksualci-alkyl, heteroaryl-alkyl.

6. The compound of formula Ib or its pharmaceutically acceptable salt

where X is selected from NR1, S;

Y1and Y2represent About;

Z represents O;

m is 0 or 1;

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

Selected from a direct link, -O-, -S-, amide, carbonyl, (C1-6)alkyl, (C2-6)quinil or (C1-6)heteroalkyl containing a heteroatom selected from O, S;

R1 is selected from H, (C1-3)alkyl;

R3 is selected from H;

R4 is selected from H;

R6 is selected from H, alkyl, heteroalkyl, (C3-7)cycloalkyl, (C3-7)geterotsiklicheskie, (C3-7)aryl, (C3-7)heteroaryl, alkyl-(C3-7)aryl, (C3-7)cycloalkyl-alkyl, (C3-7)heteroseksualci-alkyl, (C3-7)aryl-alkyl, (C3-7)heteroaryl-alkyl, (C3-7)cycloalkyl-heteroalkyl, (C3-7)aryl-heteroalkyl, (C3-7)heteroaryl-heteroalkyl;

alkyl, heteroalkyl, aryl, heteroaryl, cycloalkenyl or heterologously radicals in the composition of R6 may be substituted by one or more than one of the GRU who sing, independently selected from hydroxy, alkyl, halogen, alkoxy, carboxy, amino, alkylthio where heteroalkyl is a substitution of a heteroatom alkyl containing one heteroatom selected from N and S;

or G1represents a monocyclic group, a G2selected from a monocyclic group and a bicyclic group, or G1represents a bicyclic group, a G2represents a monocyclic group, and the monocyclic group contains one ring structure, and a bicyclic group contains two ring structures or condensed with each other or connected together through V, as defined above, with each ring structure contains up to 7 ring atoms independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl, where each ring structure may independently substituted by one or more than one Deputy, independently selected from halogen, thioalkyl, hydroxy, halogenoalkane, amino, cyano, nitro, alkyl, alkylsulfonamides, alkylamino, allylcarbamate, allylcarbamate and any alkyl radical within any substituent may itself be substituted by one or more than one group independently selected from halogen, hydroxy, cyano, alkoxy.

7. The compound of formula Ib according to claim 6 or it is pharmaceutically acceptable salt, where X represents NR1; at least one of Y1and Y2represents O; Z represents O; m is 0; a represents a direct bond, (C1-6)alkyl; represents a direct bond, acetylene, CON (amide), (C1-C4)alkyloxy, -O-, -S-; R1 represents H or methyl; R3 represents H; R4 represents N.

8. The compound of formula Ib according to claim 6 or its pharmaceutically acceptable salt, where X represents NR1, R1 represents H; Y1and Y2each represents O; Z represents O; m is 0; a is a direct link; selected from a direct link, acetylene, -O-, -S - or-CH2O; R3 represents H and R4 represents N.

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

where a is selected from a direct link, acetylene, -O-, -S - or-CH2About;

R6 is selected from H, alkyl, heteroalkyl, (C3-7)cycloalkyl, (C3-7)geterotsiklicheskie, (C3-7)aryl, (C3-7)heteroaryl, alkyl-(C3-7)aryl, (C3-7)cycloalkyl-alkyl, (C3-7)heteroseksualci-alkyl, (C3-7)aryl-alkyl, (C3-7)heteroaryl-alkyl, (C3-7)cycloalkyl-heteroalkyl, (C3-7)aryl-heteroalkyl, (C3-7)heteroaryl-heteroalkyl;

alkyl, heteroalkyl, aryl, heteroaryl, cycloalkenyl or heterologously radicals in the composition of R6 may be substituted by one the or more than one group, independently selected from hydroxy, alkyl, halogeno, amino, alkylthio where heteroalkyl represents replaced by a heteroatom alkyl containing one heteroatom selected from N and S;

or G1represents a monocyclic group, and G2selected from a monocyclic group and a bicyclic group, or G1represents a bicyclic group, a G2represents a monocyclic group, where the monocyclic group contains one ring structure, and a bicyclic group contains two ring structures, or condensed with each other or connected together through V, as defined above, with each ring structure contains up to 7 ring atoms independently selected from cycloalkyl, aryl, geterotsiklicheskie or heteroaryl, where each ring structure may independently substituted by one or more than one Deputy, independently selected from halogen, thioalkyl, hydroxy, halogenoalkane, amino, cyano, nitro, alkyl, alkylsulfonamides, alkylamino, allylcarbamate, allylcarbamate, and any alkyl radical within any substituent may itself be substituted by one or more than one group independently selected from halogen, hydroxy, cyano, alkoxy.

10. The compound of the formula Ic according to claim 9 or its pharmaceutically PR is acceptable salt, where a is selected from a direct link, -O-, -S - or-CH2About; G2represents a monocyclic group containing aryl ring; G1represents a monocyclic or bicyclic group containing at least one aryl ring; R6 is selected from H, (C1-6)alkyl, (C1-6)heteroalkyl, geterotsiklicheskie, heteroseksualci-(C1-6)alkyl, heteroaryl or heteroaryl-(C1-6)alkyl; alkyl, heteroalkyl, aryl, heteroaryl, cycloalkenyl or heterologously radicals in the composition of R6 may be substituted by one or more than one group.

11. The compound of formula Id or its pharmaceutically acceptable salt

where a is selected from a direct link, O, or CH2About;

G1represents a monocyclic or bicyclic group containing at least one five - or six-membered aryl ring;

R6 represents H, alkyl, hydroxyalkyl, aminoalkyl, alkilany alkyl ether-carbamino acid, heteroaryl-alkyl;

L is selected from H, alkyl, halogenoalkane, hydroxy, alkoxy, amino, alkylamino, allylcarbamate, allylcarbamate, alkylsulfonamides, nitro, cyano, halogeno;

or L is a group

T-U-V-,

where V is attached to the G1, a V is a NCO;

U made is employed, a (C1-5)alkyl;

T is selected from hydroxy, alkoxy, cyano, imidazolyl or pyrrolidone.

12. The compound of formula Id according to claim 11 or its pharmaceutically acceptable salt, where G1selected from phenyl, pyridyl, naphthyl or quinoline.

13. The compound of formula Id according to claim 11 or 12, or its pharmaceutically acceptable salt, where R6 is selected from H, (C1-6)alkyl, hydroxy-(C1-6)alkyl, amino-(C1-6)alkyl or heteroaryl-(C1-6)alkyl.

14. The compound of formula Id according to any one of § § 11-13 or its pharmaceutically acceptable salt, where L is selected from H, (1-5)alkyl, (C1-5)halogenoalkane, hydroxy, alkoxy, amino, (C1-5)alkylamino, (C1-5)allylcarbamate, (C1-5)allylcarbamate, (C1-5)alkylsulfonamides, nitro, cyano, halogeno or

L represents a group T-U-V-, where U is an unbranched (C1-5)alkyl, and T is selected from hydroxy, alkoxy, cyano, imidazolyl or pyrrolidone.

15. The compound of formula Id according to any one of § § 11-14, or its pharmaceutically acceptable salt, where L is a meta - or para-Deputy, and G1represents a 6-membered ring.

16. Pharmaceutical composition suitable for inhibiting metalloproteinases, which contains a compound of the formula I according to claim 1, or a compound of formula Ib according to claim 6, or a compound of the formula Ic according to claim 9, or a compound of formula Id according to item 11, or its pharmaceutically acceptable salt and pharmaceutically acceptable novtel is.

17. The use of compounds of formulas I or Ib, or Ic, or Id, or its 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, 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

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 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

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 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

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