Five-membered heterocycles as inhibitors of leukocyte adhesion and vla-4 antagonists

 

(57) Abstract:

The invention relates to the field of medicine and relates to means for inhibiting the adhesion and/or migration of leukocytes or for inhibition of VLA-4 receptor, representing a compound of General formula (I): the Compounds may be used for the treatment and prevention of inflammatory diseases, rheumatoid arthritis, allergic diseases and other 9 C. and 24 C.p. f-crystals.

The object of the present invention is five-membered heterocycles of the formula (I)

as inhibitors of the adhesion and migration of leukocytes and/or antagonists belonging to the group of integrins of the adhesion receptor VLA-4. The invention relates to the use of compounds of formula (I) and pharmaceutical compositions which contain such compounds for the treatment or prevention of diseases caused by or associated with adhesion and/or migration of leukocytes in undesirable scale or in the case of which play a role in the interaction cell-cell or cell-matrix based on the interactions of VLA-4 receptors with their ligands, such as inflammation, rheumatoid arthritis or allergic diseases, in the same way as primenenii. Further, the invention relates to new compounds of the formula (I).

Integrins are a group of adhesion receptors that play a significant role in linking cell-cell or cell-extracellular matrix. They have-heterodimeric structure, widely distributed in cells and have a high degree of evolutionary conservation. To integrins include, for example, fibrinogenesis receptor for platelet, which interacts primarily with the RGD sequence of fibrinogen, or vitronektinove receptor osteoclasts, which interacts primarily with the RGD sequence of vitronectin or osteopontin. Integrins are divided into three large groups: 2-subfamily with representatives of LFA-1, Mac-1 and P150/95, which in particular is responsible for the interaction of cells of the immune system, and subfamily 1 and 3, the representatives of which mainly contribute to the connection of the cells with components of the extracellular matrix (Ruoslahti, Annu. Rev. Biochem., 57, 375 (1988)). Integrins 1 subfamily, also known as VLA-proteins (very activation antigen) include at least six receptors that specifically interact with fibronectin, collagen and/or laminin in ka is modname and myeloid cells and is responsible for the interaction of cells with other cells. VLA-4, for example, promotes the interaction of T - or b-lymphocytes with a fragment of the binding of the heparin-II human plasmafiltration (FN). The binding of VLA-4 binding fragment of heparin-II plasmafiltration is based primarily on the interaction with LDVP-sequence. Unlike fibrinogenesis or vitronektinove receptor, VLA-4 is not typical RGD-binding integrin (Kilger and Holzmann, J. Mol. Meth., 73, 347 (1995)).

Circulating blood leukocytes usually have only a slight affinity for vascular endothelial cells, which line the" blood vessels. Cytokines produced by inflamed tissue, induce the activation of endothelial cells and thereby the expression of multiple antigens on the cell surface. They include, for example, adhesion molecules ELAM-1 (adhesion molecule-1 on endothelial cells; also called E-selectin), which connects, in particular, neutrophils, ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (functionally associated with leukocyte antigen-1) cells, and VCAM-1 (adhesion molecule-1 vascular cell), which binds a variety of leukocytes, particularly lymphocytes (Osborn et al., Cell, 59, 1203 (1989)). VCAM-1, and ICAM-1, the adhesion molecule, which is induced in endothelial cells by produced by inflamed tissue cytokines as tumor necrosis factor (TNF) and IL-1 (interleukin-1), and lipopolysaccharides. Elices on and other (Cell, 60, 577 (1990)) have shown that VLA-4 and VCAM-1 consists of a receptor-ligand, which promotes adhesion of lymphocytes to activated endothelium. The binding of VCAM-1 to VLA-4 is not due to the interaction of VLA-4 with RGD sequence, which is not in VCAM-1 (Bergelson and other, Current Biology, 5, 615 (1995)). VLA-4, however, is also found in other cells, and due to the VCAM-1/VLA-4 adhesion mechanism is also the adhesion of other white blood cells than lymphocytes. VLA-4, thus, is an example of a 1-integranova receptor, which plays a significant role, through the ligands VCAM-1, respectively, fibronectin, as in the case of interactions of cells and the interactions of cell-extracellular matrix.

Induced by cytokines, adhesion molecules play an important role in recruiting leukocytes in extravascular tissues. Leukocytes in inflamed areas of tissue are replenished by cell adhesion molecules that are expressed on the surface of endothelial cells and serve as ligands for protein is also used interchangeably). Leukocytes from the blood must first "stick" to endothelial cells before they can migrate into the synovial membrane. Since VCAM-1 is associated with cells that contain the integrin VLA-4 (41), as eosinophils, T and b-lymphocytes, monocytes or neutrophils, he gives it and VCAM-1/VLA-4-the mechanism of the function of such cells from the bloodstream to type in the field of infectious and inflammation (elices on etc., Cell, 60, 577 (1990); Osborn, Cell, 62, 3 (1990), Issekutz, etc., J. Exp. Med., 183, 2175 (1996)).

VCAM-l/VLA-4-adhesive mechanism is associated with a number of physiological and pathological processes. VCAM-1, but induced cytokine endothelium, is expressed, in particular, the following cells: cultured myoblasts, lymphoid dendritic cells and tissue macrophages, cells in the rheumatoid synovial membrane, stimulated by cytokines, nerve cells, parentline epithelial cells of Bowman's capsule cells, renal tubular epithelium, the cells of the inflamed tissue in case of rejection of the transplant heart and kidneys and cells of the intestinal tissue in case of illness "graft versus host". VCAM-1 are also expressed in areas of the tissue of the arterial endothelium, which correspond to the early arteriosclerotic BLH lymph nodes located in the stromal cells of the bone marrow, for example, a mouse. Recent data indicate functioning of VCAM-1 in the development of b cells. VLA-4, except in cells of hematopoietic origin, is also, for example, in the line of melanoma cells and VCAM-1/VLA-4-adhesive mechanism is associated with the metastasis of these tumors (Rice and others, Scienece, 246, 1303 (1989)).

The main form in which VCAM-1 in vivo is located in endothelial cells and that represents the dominant form in vivo, is designated as VCAM-7D and it contains seven immunoglobulin domains. Domains 4, 5 and 6 in their amino acid sequences are similar to domains 1, 2 and 3. The fourth domain in the case of the other six domains form, denoted here as VCAM-6D, is removed by alternative splicing. Also VCAM-6D can bind expressing VLA-4 cells.

Other information about VLA-4, VCAM-1, integrins and adhesion proteins are, for example, articles Kilger and Holzmann, J. Mol. Meth., 73, 347 (1995); elices on, Cell Adhesion in Human Disease, Wiley, Chichester, 1995, S. 79; Kuijpers, Springer Semin. Immunopathol., 16, 379 (1995).

On the basis of the role of VCAM-1/VLA-4-mechanism in the case of the processes of cell adhesion, which have a value of, for example, infections, inflammation or atherosclerosis, an attempt was made through the intervention of these adhesive which this circuit is the use of monoclonal antibodies, which is directed against VLA-4. Such monoclonal antibodies (mAK), which as VLA-4 antagonists block the interaction between VCAM-1 and VLA-4 are known. So, for example, anti-VLA-4 mAK HP 2/1 and HP 1/3 inhibit adhesion expressing VLA-4 Ramos cells (such as b-cells cells) to human endothelial cells of the umbilical cord and to transfitsirovannykh with VCAM-1, COS-cells. Anti-VCAM-1 mAK 4B9 also inhibits the adhesion of Ramos cells, Jurkat cells (such as T-cell cell) and HL60 cells (such as granulocytes cells) to COS cells transfitsirovannykh using genetic constructs that cause the expression of VCAM-6D and VCAM-7D. Obtained in vitro data using antibodies directed against 4-subunit of VLA-4, show that the adhesion of lymphocytes to synovial endothelial cells is blocked, adhesion, which plays a role in rheumatoid arthritis (van Dinther-Janssen and others J. Immunol., 147, 4207 (1991)).

Tests in vivo show that experimental autoimmune encephalomyelitis can be suppressed with anti-4 mAK. The leukocyte migration into the inflammatory focus is also blocked with monoclonal antibodies against the 4-chain of VLA-4. Impact on VLA-4-dependent adhesion mechanism using antibodies was also the ü (USSN 07/821768; European patent application 626861). Introduction antibodies against VLA-4 inhibits the response in the late phase and increased reaction of the Airways in allergic sheep.

VLA-4-dependent mechanism of cell adhesion was also studied on the model of primates with inflammatory disease of the digestive tract (IBD). In this model, which corresponds to ulcerative colitis in humans, the antibodies against VLA-4 caused a marked decrease in acute inflammation.

In addition, it is shown that VLA-4-dependent adhesion of cells plays a role in the following clinical conditions, including chronic inflammation: rheumatoid arthritis (Cronstein and Weissmann, Arthritis Rheum., 36, 147 (1993); elices on etc., J. Clin. Invest., 93, 405 (1994)); diabetes (Yang and others, Proc. Natl. Acad. Sci. USA, 90, 10494 (1993)); systemic lupus erythematosus (Takeuchi and others, J. Clin. Invest., 92, 3008 (1993)); Allergy delayed type (type IV allergies) (elices on and others, Clin. Exp. Rheumatol., 11, 77 (1993)); multiple sclerosis (Yednock and others, Nature, 356, 53 (1992)); malaria (Ockenhouse, etc., J. Exp. Med., 176, 1183 (1992)); arteriosclerosis (Obrien and others, J. Clin. Invest., 92, 945 (1993)); transplantation (Isobe et al. Transplantation Proceeding, 26, 867-868 (1994)); various malignant diseases, such as melanoma (Renkonen et al., Am. J. Pathol., 140, 763 (1992)), lymphoma (Freedman et al., Blood, 79, 206 (1992) and others (Alb opens effective therapeutic opportunities to treat, for example, features a variety of inflammatory conditions, including asthma and IBD. Of particular importance VLA-4 antagonists for the treatment of rheumatoid arthritis in this case, as already mentioned, results from the fact that leukocytes from the blood must first "stick" to endothelial cells before they can migrate into the synovial membrane, and this adhesion plays the role of VLA-4 receptor. That by agents of inflammation in endothelial cells is induced VCAM-1 (Osborn, Cell, 62, 3 (1990)); Stoolman, Cell, 56, 907 (1989)), and for the recruitment of various leukocytes in the area of infection and inflammation mentioned above. T-cells thus connected with activated endothelium mainly through LFA-1/1CAM-1 - and VLA-4/VCAM-1-adhesive mechanisms (Springer, Cell, 76, 301 (1994)). In rheumatoid arthritis in most synovial T cells increased affinity VLA-4 with VCAM-1 (Postigo, etc., J. Clin. Invest., 89, 1445 (1992)). Additionally there is increased adhesion of synovial T cells with fibronectin (Laffon, etc., J. Clin. Invest., 88, 546 (1991); Morales-Ducret, etc., J. Immunol 149, 1424 (1992)). VLA-4, therefore, is highly regulated in their expression, and their effects on T-lymphocytes of rheumatoid synovial membrane. Blocking to reduce articular inflammatory processes. This is also confirmed by experiments using antibodies HP 2/1 in Lewis rats with adjuvant erythritol, in which case there is effective prevention of disease (Barbadillo, etc. Springer Semin Immunopathol., 16, 427 (1995)). Thus, VLA-4 is an important from the point of view of therapy molecule-target.

The above VLA-4 antibodies and antibodies as VLA-4 antagonists are described in international application No. 93/13798, 93/15764, 94/16094, 94/17828 and 95/19790. In international application No. 94/15958, 95/15973, 96/00581, 96/06108 and 96/20216 describes peptide compounds as antagonists of VLA-4. The use of antibodies and peptide compounds as medicines, however, associated with disadvantages, such as lack of ability to prepare oral dosage forms, easy destructible or immunogenic effect when applied over a longer period, and thus, there is a need for antagonists of VLA-4 with a favorable profile of properties for use in therapy and prophylaxis.

In international applications 94/21607 and 95/14008 describes substituted five-membered heterocycles, in European patent application 449079, European patent application 530505(saveproperty the patent application 580008 (application for U.S. patent 5424293) and European patent application 584694 (application for U.S. patent 5554594) describes derivatives as which have a suppressing platelet aggregation actions. However, there is no indication of the antagonism of these compounds to VLA-4.

Now unexpectedly found that these compounds also inhibit the adhesion of leukocytes and are antagonists of VLA-4.

The present invention thus relates to the use of compounds of formula (I):

where W stands for R1-A-C(R13or R1-A-CH=C;

Y represents carbonyl, thiocarbonyl or methylene group;

Z means N(R0), oxygen, sulfur or a methylene group;

A represents the bivalent residue selected from the series (WITH1-C6)-alkylene, (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, phenylene-(C2-C6-alkenyl, or the divalent residue of a five or six-membered saturated or unsaturated cycle which may contain 1 or 2 nitrogen atom and may be single or twofold substituted (C1-C6)-alkyl or double-bound oxygen or sulfur;

In the mean bivalent residue selected from the series (WITH1-C6)-alkylene, (C2-C6)-Alcanena, phenylene, Hairdryer who mcilravy residue may be unsubstituted or may be substituted by the residue selected from a number, (C1-C8)-alkyl, (C2-C8-alkenyl, (C2-C8)-quinil, (C3-C10)-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl in the aryl residue, optionally substituted (C6-C14)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl and heteroaryl residue optionally substituted heteroaryl-(C1-C6)-alkyl;

D means C(R2)(R3), N(R3) or CH=C(R3);

E. means tetrazolyl, (R8O)2P(O), HOS(O)2, R9NHS(O)2or R10CO;

R means hydrogen, (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or aryl residue, optionally substituted (C6-C14)-aryl-(C1-C8)-alkyl;

R0means hydrogen, (C1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, >the aryl in the aryl residue, optionally substituted (C6-C14)-aryl-(C1-C8)-alkyl, optionally substituted heteroaryl, heteroaryl residue optionally substituted heteroaryl-(C1-C8)-alkyl, Cho, (C1-C8)-alkyl-CO, (C3-C12-cycloalkylcarbonyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl-CO-, (C6-C12-bicycloalkyl-WITH, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-tricyclohexyl-WITH, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14)-aryl -, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted heteroaryl -, heteroaryl residue optionally substituted heteroaryl-(C1-C8)-alkyl-CO, (C1-C8)-alkyl-S(O)n, (C3-C12)-cycloalkyl-S(O)n, (C3-C12-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-bicycloalkyl-S(OH)n, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-tricyclohexyl-S(OH)n, (C6-UB>)-aryl-S(O)noptionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-S(O)noptionally substituted heteroaryl-S(O)nor optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-S(O)nand n is 1 or 2;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p is 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; and (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=N-R') with R' and R", independently of one another, have substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C2-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CONHR14, CSNHR14, COOR15, CON(CH3R15or CONHR15;

R4means hydrogen or (C1-C28)-alkyl, which optionally one or multiple can be substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)-aminocarbonyl, amino-(C2-C18-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C36-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, optionally substituted (C3-C8-cycloalkyl, halogen, the nitro-group, a trifluoromethyl or satok5;

R5means optionally substituted (C6-C14)-aryl, optionally substituted (C6-C14)-aryl-(C1-C8)-alkyl; mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny or may contain 1, 2 or 3 identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl and independently heterocyclic residues may be single - or multi-substituted by identical or different residues selected from the range (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids is B>-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2- as well as their esters and amides, and instead of free functional groups can be hydrogen or hydroxymethyl and/or with the free functional groups can be protected customary in the chemistry of peptides, protective groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-alkoxycarbonyl, and alkyl groups optionally can be substituted by amino and/or and aryl residues can be one or several times, preferably once, replaced by the same or different residues selected from the range (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and trifloromethyl; the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1 is or dipeptide, which in the aryl part can be substituted and/or in which the peptide bond can be restored to the-NH-CH2-;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted;

R9means hydrogen, aminocarbonyl, (C1-C18-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means hydrogen, (C1-C18)-alkyl, R12CO, optionally substituted (C6-C14)-aryl-S(O)2, (C1-C18)-alkyl-S(O)2if necessary someseni the>2means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)-amino group;

R13means hydrogen, (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R14means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues chosen from the series hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18)-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic in the aryl residue may be substituted; amino group, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(A)-(C1-C3)-alkyl, tetrazolyl-(C1-C3)-alkyl, halogen, nitro, trifloromethyl and R5;

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which can contain 1-4 identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the series consisting of (C1-C4)-alkyl and carbonyl group;

b, C, independently of one another, denote 0 or 1, but

d and f all at the same time may not mean zero;

e, g and h, independently of one another, mean 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio; and their physiologically acceptable salts Dania VLA-4 receptor, therefore, medicines for the treatment or prevention of diseases in which undesired scale is leukocyte adhesion and/or migration of leukocytes, or diseases in which play the role of VLA-4-dependent adhesion processes, such as inflammatory diseases, as well as to the use of compounds of formula (I) in the treatment and prevention of such diseases.

Alkyl residues may be linear or branched. This is important also when they contain substituents or as substituents of other residues, for example, in the CNS, alkoxycarbonyl or Uralkalij residues. The corresponding is valid for alkilinity residues. Examples of suitable (C1-C28)-alkyl residues are the following: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, hexadecyl, heptadecyl, Needell, eicosyl, docosyl, tricosal, pentasil, hexagonal, heptagonal, octagonal, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-were, 2,3,5-trimethylhexane, Deut.-butyl, tert.-butyl, tert.-pencil. Preferred alkyl residues are methyl, ethyl, propyl, isopropy the RA-, Penta - and hexamethylene or substituted alkyl residue methylene, for example methylene which is substituted by methyl group, ethyl group, isopropyl group, isobutylene group or tert.-butilkoi group.

Also alkanniny and alkenylamine residues, as well as alkyline residues may be linear or branched. Examples alkenyl residues are vinyl, propen-1-yl, propen-2-yl (=allyl), butenyl, 3-methylbutan-2-yl; examples alkenylamine residues are vinile or propylen; examples etkinlik residues are ethinyl, propyne-1-yl or propyne-2-yl (=propargyl).

Cycloalkenyl residues are particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl and cyclododecyl, which, however, can also be substituted, for example, using (C1-C4)-alkyl. As examples of substituted cycloalkyl residue should be called 4-methylcyclohexyl and 2,3-dimethylcyclohexyl. Similar applies to cycloalkenyl balances.

Denoted as R166-24-membered bicyclic and tricyclic residues are usually obtained by removing one hydrogen atom from bicyclic the scholars cycle may contain only carbon atoms, therefore, we can talk about bicycloalkanes or tricyclodecane; however, they can also contain 1-4 identical or different heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, therefore, it could also be about Aza-, oxa - and diabetico - and-tricyclodecane. If contains heteroatoms, preferably contains one or two heteroatoms, especially nitrogen atoms or oxygen. The heteroatoms can occupy any position in bi-, respectively tricyclic skeleton, they can be in the bridges or in the case of nitrogen atoms in the head parts of the bridges. As bicyclo - and tricyclodecane and their heteroanalogues can be fully saturated compounds or can contain one or more double bonds; preferably they contain one or two double bonds, or in particular, they are completely saturated. As bicyclo - and tricyclodecane and heteroanalogues, and both saturated and unsaturated their representatives may be unsubstituted or may be substituted at any suitable positions of one or more exography and/or one or more identical or different (C1-C4)-alkyl groups, for example methyl or izopet be located in any position of the molecule, therefore, the balance can be connected via the main bridge atom or atoms in the bridge. Free communication can also be in any terms of stereochemistry position, for example in the Exo - or endo-position.

Examples of bases bicyclic systems, which may be a bicyclic residue are norbornane (=bicyclo/2.2.1/heptane), bicyclo/2.2.2/octane and bicyclo/3.2.1/ octane. Examples containing heteroatoms systems, unsaturated or saturated systems are 7-azabicyclo/2.2.1/heptane, bicyclo/2.2.2/Oct-5-ene or 1,7,7-trimethyl-2-oxobicyclo/2. 2.1/heptane.

Examples of systems that can produce tricyclic residue, are twisted (=tricyclo/4.4.0.03,8) decane), adamantane (=tricyclo/3.3.1.13,7)Dean, noradsanta (=tricyclo/3.3.1.03,7-nonan), tricyclo/2.2.1.02,6/heptane, tricyclo/5.3.2.04,9/dodecan, tricyclo/5.4.0.02,9/undecane or tricyclo/5.5.1.03,11/tridecan.

Bicyclic or tricyclic residues preferably are made from bridging bizikov, respectively tricycles, therefore, from systems in which the cycles have in common two or more than two atoms. Further, also preferred bicyclic or tricyclic attackpattern bi - and tricyclic residues are 2-norbornylene residue, as such, with a free connection in the Exo-position, such as with a free connection in the endo-position, 2-bicyclo-/3.2.1/octillery the remainder, 1-adamantly the residue, 2-adamantly balance and noradrenaline residue, for example 3-noradrenaline balance. In addition, the preferred 1 - and 2-adamantly remains.

(C6-C14)-aryl groups are, for example, phenyl, naphthyl, biphenylyl, antrel or fluorenyl, preferably 1-naphthyl, 2-naphthyl and in particular phenyl. Aryl residues, in particular phenyl residues may be one or several times, preferably once, twice or three times, replaced by identical or different residues from the series consisting of (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxyl, in particular (C1-C3)-alkoxyl, halogen, nitro, amino, trifloromethyl, hydroxyl, methylenedioxy, Ethylenedioxy, ceanography, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, fenoxaprop, benzyl (R8O)2P(O) (R8O)2P(O)-O-, tetrazolyl. Relevant acts, for example, for such residues, as aralkyl or lmutil and 9-fertility, which can also be substituted. Substituted Uralkalij residues are, for example, substituted in the aryl part by one or more (C1-C8)-alkyl residues, in particular (C1-C4)-alkyl residues, benzyl and naphthylmethyl, for example, as 2-, 3 - and 4-methylbenzyl, 4-isobutylphenyl, 4-tert.-butylbenzyl, 4-octylbenzoic, 3,5-dimethylbenzyl, pentamethylbenzyl; 2-, 3-, 4-, 5-, 6-, 7- and 8-methyl-1-naphthylmethyl; 1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthylmethyl; substituted in the aryl part by one or more (C1-C8)-CNS residues, in particular (C1-C4)-CNS remains, benzyl or naphthylmethyl, for example 4-methoxybenzyl, 4-neopentecostal, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 2,3,4-trimethoxybenzyl, next, 2-, 3 - and 4-nitrobenzyl, halogenmethyl, for example 2-, 3 - and 4-Chlorobenzyl and 2-, 3 - and 4-tormentil, 3,4-dichlobenil, pentafluorobenzyl, cryptomelane, for example 3 - and 4-trifloromethyl or 3,5-bis (trifluoromethyl)benzyl. Substituted kalkilya remains, however, may also have different substituents. Examples of pyridyl are 2-pyridyl, 3-pyridyl and 4-pyridyl.

In monosubstituted phenyl residues Deputy may be in position 2, 3 or 4, price, 1,3 or 1,4 relation to one another. Doubly substituted phenyl, therefore, may be substituted in position 2, 3, in position 2, 4, 2, 5, 2, 6, at position 3, 4 or in position 3, 5, relative to the binding site of. In the twice substituted phenyl residues, preferably both Deputy are in position 3 and in position 4 relative to the connection point. The corresponding is valid for filinovich residues, which may be, for example, 1,4-phenylene or 1,3-phenylene.

Phenylene-(C1-C6)-alkyl, represents in particular fineliner and phenylenedi. Phenylene-(C2-C6)-alkenyl is a particularly phenylanaline and phenylendiamine.

Mono - or bicyclic 5-to 12-membered heterocycles are, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazoles, phthalazine, hinely, ethanolic, honokalani, hintline, cinnoline or benzenediamine, cyclopent-, cyclohexa or cyclohepta-annulirovano derived these balances.

Unless nothing else, these heterocycles mo is1-C4)-alkyl, for example benzyl, and/or one or more carbon atoms, - (C1-C4)-alkyl, halogen, hydroxyl, (C1-C4-alkoxyl, such as benzyloxycarbonyl or exography, and can be aromatic or partially or completely saturated. Nitrogen-containing heterocycles can also be in the form of N-oxides.

Residues of aromatic heterocycles, therefore, heteroaryl residues, preferably contain the five-membered heterocycle or six-membered heterocycle with one, two, three or four, especially one or two, identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur, which can also be annylirovan, for example benzannulation, and which may be substituted by one or more, for example one, two, three or four identical or different substituents. As Vice use, for example, (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8-alkoxy, in particular (C1-C4-alkoxy, halogen, the nitro-group, amino, trifluoromethyl, hydroxyl, methylenedioxy, Ethylenedioxy, cyano, hydroxycarbonyl, aminomar is(O), (R8O)2P(O)-O - or tetrazolyl.

Examples of heterocyclic residues are 2 - or 3-pyrrolyl, phenylpyrrole, for example 4 - or 5-phenyl-2-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 4-imidazolyl, methylimidazole, for example 1-methyl-2-, -4 - or-5-imidazolyl; 1,3-thiazol-2-yl; -2-pyridyl, 3-pyridyl and 4-pyridyl; -2-, -3 - or-4-pyridyl-N-oxide; 2-pyrazinyl; -2-, -4 - or-5-pyrimidyl; -2-, -3 - or-5-indolyl; substituted 2-indolyl, for example 1-methyl-, 5-methyl, 5-methoxy-, 5-benzyloxy-, 5-hper - or 4,5-dimethyl-2-indolyl; 1-benzyl-2 - or-3-indolyl; 4,5,6,7-tetrahydro-2-indolyl; cyclohepta/b/-5-pyrrolyl; -2-, -3 - or-4-chinolin; -1-, -3 - or-4-ethanolic; 1-oxo-l,2-dihydro-3-ethanolic; 2-honokalani; 2-benzofuranyl; 2-benzothiazyl; 2-benzoxazolyl or benzothiazolyl. Partially gidrirovanie or fully gidrirovanie heterocycles are, for example, dihydropyridines, pyrrolidinyl, for example 2-, -3 - or-4-(N-methylpyrrolidinyl), piperazinil, morpholinyl, thiomorpholine, tetrahydrothieno, benzodioxolyl.

Halogen means fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

Natural or synthetic amino acids, if they are chiral, can be in the D - or L-form. Preferred are amino acids. For example, trace the bu ABz, 2ABz, Aca, Ach, Acp, Adpd, Ahb, Aib, Aib, Ala, Ala, A1A, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, nor, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, Lys, Lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tight, Val,

... tert.-butylglycol (Tbg), neopentylglycol (Npg), cyclohexylglycine (Chg), cyclohexylamine (Cha), 2-titillans (Thia), 2,2-diphenylsiloxane acid, 2-(n-tolyl)-2-Veniaminovna acid, 2-(n-chlorophenyl)aminouksusnoy acid.

Under amino acid side chains understand the side chain of a natural or synthetic amino acids. Esamination are natural or synthetic amino acids, in which the Central structural element

replaced by

As the rest of aminokisloty in particular use the remains of heterocycles from the following group: pyrrolidin-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroquinoline-3-carboxylic acid; octahedron-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta/b/pyrrole 2-azabicyclo/3.1.0)hexane-3-carboxylic acid; 2 azaspiro/4.4./nonan-3-carboxylic acid; 2-azaspiro/4.5/Dean-3-carboxylic acid; Spiro(bicyclo/2.2.1/heptane)-2,3-pyrrolidine-5-carboxylic acid; Spiro(bicyclo/2.2.2/octane)-2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo/4.3.0.16,9/Dean-3-carboxylic acid; decahydrated/b/pyrrole-2-carboxylic acid; damageresistant//pyrrole-2-carboxylic acid; octahydrocyclopenta// pyrrole-2-carboxylic acid; octahydrocyclopenta-1-carboxylic acid; and 2,3,3,4,6 and hexahydrotriazine/b/pyrrole-2-carboxylic acid; and 2,3,3,4,5,7 and-hexahedronal-2-carboxylic acid; tetrahydrocarbazol-4-carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine-3-carboxylic acid; hydroxypyrrolidine-2-carboxylic acid, all of which optionally can be substituted (see the following formula):

; ; ; ;

; ; ;

; ; ;

; ; ;

; ; ;

; ; ; ;

; ; ; ;

.

Form the basis of the above balances heterocycles are known, for example, from patent application U.S. No. 4344949, 4374847, 4350704; European patent applications№29488, 31741, 46953, 49605, 49658, 50800, 51020, 52870, 79022, 84164, 89637, 90341, 90362, 105102, 109020, 111873, 271865 and 344682.

Dipeptides as structural elements is e or synthetic amino acids, aminokisloty, esamination and dipeptides can also be in the form of esters and amides, such as, for example, in the form of a complex of methyl, ethyl, isopropyl, isobutyl, tert.-butyl, benzyl ether; unsubstituted amide, arylamide, semicarbazide or-amino-(C2-C8)-alkylamide.

Functional groups of amino acids, aminocyclo and dipeptides can be protected. Suitable protective group, such as for protective urethane group functions, protection for the carboxyl function group and the protective groups of the side chains are described in Hubbuch, Kontakte (Merck) 1979, No. 3, S. 14-23, and Bullesbach, Kontakte (Merck) 1980, No. 1, S. 23-35. In particular, we can mention: Aloc, Pyoc, Fmoc, Tcboc, Z, BOC, Ddz, Rooted, Adoc, Msc, OS, Z(NO2), Z(Hal)n, Bobz, Iboc, Adpoc, Mboc, Acm, tert-Butyl, OBzL, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

Physiologically acceptable salts of the compounds of formula (I) are in particular pharmaceutically applicable or non-toxic salt.

Such salts, for example, compounds of formula I which contain acidic groups, for example carboxyl formed with alkaline or alkaline earth metals, such as sodium, potassium, magnesium and calcium, as well as with physiologically acceptable organic amines, as is rat main groups, for example, an amino group, amidinopropane or guanidinium, form salts with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate or p-toluensulfonate.

Salts of compounds of formula (I) can be obtained in a regular, well-known specialist of ways, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation-exchange capacity of the other salts.

The compounds of formula (I) may be present in stereoisomeric forms. If the compounds of formula (I) contain one or more asymmetric centers, they are, independently from each other, can have the S-configuration or R-configuration. The invention includes all possible stereoisomers, such as enantiomers and diastereomers, and mixtures of two or more stereo-isomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. Enantiomers, therefore, in enantiomerically pure form, Komarov in any ratio are the subject of the invention. In the presence of CIS/TRANS-isomerism as CIS-form and TRANS form and mixtures of these forms also constitute the subject matter.

Proposed according to the invention the compounds of formula (I), in addition, may contain mobile hydrogen atoms, therefore, exist in different tautomeric forms. Also all of these tautomers are the subject of the present invention. The present invention further includes all of the solvate of the compounds of formula (I), for example hydrates or adducts with alcohols, and also derivatives of the compounds of formula (I), for example, esters, prodrugs and metabolites, which act as the compounds of formula (I).

The individual structural elements of the formula (I) preferably have the following meanings:

W means preferably R1-A-C(R13);

And means preferably methylene, ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexyl, phenylene, fineliner or phenylenedi;

Y represents preferably a carbonyl group;

Z means preferably N(R0);

In means preferably methylene, ethylene, trimethylene, tetramethylene, vinile, phenylene or substituted methylene or ethylene. Especially predpochtitelnei or may be substituted, in particular represents an unsubstituted or substituted methylene residue. Particularly preferably, both of these residue substituted. If you indicate In the divalent methylene residue or ethylene residue (=1,2-ethylene) substituted, preferably it is substituted by the residue from the series consisting of (C1-C8)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, (C3-C8)-cycloalkyl, in particular (C5-C6)-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, in particular (C5-C6-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl, optionally substituted in the aryl residue (C6-C10)-aryl-(C1-C4)-alkyl, optionally substituted heteroaryl or optionally substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl; and especially preferably, it is mixed (C1-C8)-alkyl, therefore, a linear or branched alkyl residue with 1 to 8 carbon atoms;

D means preferably(R2)(R3);

E. means preferably R10WITH;

R means will predpochtitelney preferably (C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl. R0especially preferably means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; particularly preferably optionally substituted in the aryl residue (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; moreover, preferably optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl. In particular, preferably, when R0means unsubstituted or singly or multiply substituted in the aryl residue biphenylyl, naphthylmethyl or benzyl;

R1means preferably X is-NH-C(=NH) -, X-NH(C=NX)-NH or X-NH-CH2;

X and X1means is preferably hydrogen, (C1-C6-allyloxycarbonyl or (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, hydroxyl; X1moreover, means R'-NH-C(=N-R') with R' and R", independently of one another, are specified for X preferred values;

R2means preferably hydrogen or (C1-C8)-alkyl;

R3means preferably (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CORH14, CSNHR14, COOR15, CON(CH3R15or CONHR15; particularly preferably optionally substituted (C6-C14)-aryl, R11NH, CON(CH3R14or CONR14;

R4and R14means preferably (C1-C8)-alkyl, which may optionally be substituted as indicated in the definition of R4accordingly, R14;

R13means are preferably hydrogen and, in particular, (C1-C6)-alkyl, (C3-C8-cycloalkyl or benzyl, and CCA is SUP>15means preferably R16-(C1-C3)-alkyl, or R16especially preferably, R16-(C1)-alkyl, or R16. Moreover, when R3means COOR15, R15preferably means Exo-2-norbornyl, endo-2-norbornyl or bicyclo/3.2.1/octyl, and when R3means CONHR15, R15means Exo-2-norbornyl, endo-2-norbornyl, 3-lordamantr and in particular 1-substituted, 2-substituted, 1-adamantylamine or 2-adamantylamine;

R16means preferably 7-12-membered bridged bicyclic or tricyclic residue, which is saturated or partially unsaturated and which can contain 1-4 identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents selected from the series (WITH1-C4)-alkyl and carbonyl group;

b, C and d, independently of one another, denote 1;

e, g and h, independently of one another, mean preferably the number 0, 1, 2, or 3.

Preferred for proposed according to the invention use compounds are those in which in formula (I) symbols of them is means a carbonyl, thiocarbonyl or methylene group;

Z means N(R0), oxygen, sulfur or a methylene group;

A represents the bivalent residue selected from the series (WITH1-C6)-alkylene, (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, phenylene-(C2-C6-alkenyl, or the divalent residue of a five or six-membered saturated or unsaturated cycle which may contain 1 or 2 nitrogen atom and may be single or twofold substituted (C1-C6)-alkyl or double-bound oxygen or sulfur;

In the mean bivalent residue selected from the series (WITH1-C6)-alkylene, (C2-C6)-Alcanena, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3)-alcelaphine;

D means C(R2)(R3), N(R3) or CH=C(R3);

E. means tetrazolyl, (R8O)2P(O), HOS(O)2, R9NHS(O)2or R10WITH;

R and R0, independently of one another, mean hydrogen, (C1-C8) alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl OST is or X1-NH-(CH2)pand p is 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; and (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; and (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=N-R') with R' and R", independently of one another, are specified for the X values;

R2means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally SUB>1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C2-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CONHR14, CSNHR14, COOR15, CON(CH3R15or CONHR15;

R4means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18-alkylaminocarbonyl, (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, optionally substituted (C3-Cbademosi substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, mono - or bicyclic five-dvenadtsatiletny a heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and which may contain one, two or three identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl and independently of the heterocycle can be single - or multi-substituted by identical or different residues chosen from the series consisting of (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2as well as their esters and amides, and instead SV is PPI can be protected customary in the chemistry of peptides, protective groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-alkoxycarbonyl, and alkyl groups may be substituted by amino and/or and aryl residues can be one or several times, preferably once, replaced by identical or different residues from the series consisting of (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and trifloromethyl; the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny)esamination or dipeptide, which in the aryl part can be substituted and/or in which the peptide bond can be restored to the-NH-CH2-;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl is B>-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means hydrogen, (C1-C18)-alkyl, R12CO, optionally substituted (C6-C14)-aryl-S(O)2, (C1-C18)-alkyl-S(O)2optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R9NHS(O)2;

R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; when necessary)-amino group;

R13means hydrogen, (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R14means hydrogen or (C1-C28)-alkyl which can be substituted one or more times, equal or different residues chosen from the series hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18)-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18)-alkylaminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, in which the aryl residue may be substituted; amino group, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(A)-(C1-C3

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which can contain 1-4 identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents from the series consisting of (C1-C4)-alkyl and carbonyl group;

b, C, independently of one another, denote 0 or 1, but

d and f all at the same time may not mean zero;

e, g and h, independently of one another, mean 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Especially preferred compounds of formula (I) are those in which simultaneously:

W means R1-A-CH=C, where a represents phenylenebis residue, or

W means R1-A-C(R13), in which a represents the bivalent residue selected from a number of methylene, ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexene, phenylene, finalemail;

< / the, the phenylene or substituted methylene or ethylene;

E. means R10WITH;

R means hydrogen, (C1-C6)-alkyl or benzyl;

R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1means X-NH-C(=NH) -, X-NH-C(=NX)-NH or X-NH-CH2;

X represents hydrogen, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C8)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, (C6-C14)-aryl-(C1-C6-alkoxycarbonyl or hydroxyl;

R2means hydrogen or (C1-C8)-alkyl;

R3means (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, pyridyl, R11NH, R4CO, COOR4, CONHR14, COOR15and CONHR15;

and e, g and h, independently of one another, denote the numbers 0, 1, 2 or 3;

all their stereo

Particularly preferred compounds of formula (1), where

W means R1-A-C(R13and R13means (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl,

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

One particularly preferred compounds of formula (I) are such compounds where

R3means optionally substituted (C6-C14)-aryl, COOR4, R11NH or CONHR14and other14means balance-amino acids-amino-(C2-C8)-alkylamide, (p1-C8)-Olkiluoto ether or (C6-C14)-aryl-(C1-C4)-Olkiluoto ether

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts. Referred to as-other14balance-amino acids are usually obtained by removing one hydrogen atom from the amino group of amino acids. In this series, particularly preferably, when R3means CONHR14and other14 1
-C8)-alilovic esters or (C6-C14)-aryl-(C1-C4)-alilovic ethers.

In addition, preferred compounds of formula (1) in this row are those where at the same time

W means R1-A-C(R13);

Y represents a carbonyl group;

Z N means(P0);

And means ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexyl, phenylene or phenylenedi;

In means unsubstituted or substituted methylene residue;

D means C(R2)(R3);

E. means R10CO;

R means hydrogen or (C1-C4)-alkyl, in particular hydrogen, methyl or ethyl;

R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1means H2N-C(=NH), H2-C(=NH)-NH or H2N-CH2;

R2means hydrogen;

R3means the residue CONHR14;

R10means hydroxyl or (C1-C8-alkoxy, preferably (C1-

R14means methyl, which is substituted by hydroxycarbonyl or a residue selected from the row (C1-C4)-alkyl, phenyl and benzyl, or methyl which is substituted by (C1-C8-alkoxycarbonyl, preferably (C1-C4-alkoxycarbonyl and residue selected from the series (WITH1-C4)-alkyl, phenyl and benzyl;

b, C and d mean 1;

e, f and g mean zero;

h denotes 1 or 2, preferably 1;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

If-other14means (C1-C8)-alkilany ether-amino acids, respectively, contains R14as alkoxycarbonyl residue, preferred is methyl, ethyl, isopropyl, isobutyl or tert.-butyl ester; if-other14means (C6-C14)-aryl-(C1-C4)-alkilany ether-amino acids, the preferred benzyl ester.

Other particularly preferred compounds of formula (I) are such compounds where at the same time

W means R1-A-CH=C, where a represents phenylene is Yes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexene, phenylene, finalemail;

In the mean bivalent residue selected from a number of methylene, ethylene, trimethylene, tetramethylene, vinylene, phenylene or substituted methylene or ethylene;

E. means R10WITH;

R means hydrogen or (C1-C6)-alkyl;

R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1means X-NH-C(=NH) -, X-NH-C(=NX)-NH or X-NH-CH2;

X represents hydrogen, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C8)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, (C6-C14)-aryl-(C1-C6-alkoxycarbonyl or hydroxyl;

R2means hydrogen or (C1-C8)-alkyl;

R3means CONHR15or CONHR14and R14in this case, means unsubstituted or substituted by one or more (C6-C14)-aryl residues (C1-C8)-alkylene which includes 7-12-membered bridged bicyclic or tricyclic residue, which is saturated or partially unsaturated and which may contain 1-4 identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents from the series consisting of (C1-C4)-alkyl and carbonyl group, and in particular, R15means adamantly balance or adamantylamine balances;

e, g and h, independently of one another, denote the numbers 0, 1, 2 or 3;

b, C and d mean 1;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Moreover, preferred compounds of formula (I) in this series are those in which simultaneously

W means R1-A-C(R13);

Y represents a carbonyl group;

Z means N(R0);

And means ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexyl, phenylene or phenylenedi;

In means unsubstituted or substituted methylene residue;

D means C(R2)(R3);

E. means R10WITH;

R means hydrogen or (C1-C4)-alkyl, in persons shall loukil, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1means H2N-C(=NH), H2N-C(=NH)-NH or H2N-CH2;

R2means hydrogen;

R3means CONHR15or CONHR14and R14in this case, means unsubstituted or substituted by one or more (C6-C10)-aryl residues (C1-C6)-alkyl residue;

R10means hydroxyl or (C1-C8-alkoxy, preferably (C1-C4-alkoxyl;

R13means (C1-C6)-alkyl, (C3-C7-cycloalkyl or benzyl, in particular methyl;

R15means adamantly balance or adamantylamine balances;

b, C and d mean 1;

e, f and g mean zero;

h denotes 1 or 2, preferably 1;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Further, a number of particularly preferred compounds of formula (1) form such compounds, where both

W means R

In means unsubstituted or substituted methylene residue or ethylene residue;

D means C(R2)(R3);

E. means R10WITH;

R means hydrogen or (C1-C4)-alkyl, in particular hydrogen, methyl or ethyl;

R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1means H2N-C(=NH), H2N-C(=NH)-NH or H2N-CH2;

R2means hydrogen;

R3means unsubstituted phenyl or nattily balance; phenyl residue or nattily residue, substituted by one, two or three identical or different residues selected from the range (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, halogen, trifloromethyl, nitro, methylenedioxy, Ethylenedioxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, cyanopropyl, phenyl, fenoxaprop, benzyl and Beaton, (C2-C4)-alkynylaryl balance or (C5-C6)-cycloalkenyl residue, and in particular, R3means unsubstituted or substituted phenyl residue or nattily residue

R10means hydroxyl or (C1-C8-alkoxy, in particular (C1-C4-alkoxyl; and preferably R10means the residue chosen from the series hydroxyl, metoxygroup, ethoxypropan, propoxylate and isopropoxy;

R13means (C1-C6)-alkyl, (C3-C7-cycloalkyl or benzyl, in particular methyl;

b, C and d mean 1;

e, f and g mean zero;

h denotes 1 or 2, preferably 1;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Finally, a number of particularly preferred compound of formula (1) form such compounds, where both

W means R1-A-C(R13);

Y represents a carbonyl group;

Z means N(R0);

And means ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexyl, phenylene, finaltotal;

In means unsubstituted or samisen the t R10CO;

R means hydrogen or (C1-C4)-alkyl, in particular hydrogen, methyl or ethyl;

R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1means N2N-C(=NH), H2N-C(=NH)-NH or H2N-CH2;

R2means hydrogen;

R3means R11NH;

R10means hydroxyl or (C1-C8-alkoxy, in particular (C1-C4-alkoxyl; and preferably R10means the residue chosen from the series hydroxyl, metoxygroup, ethoxypropan, propoxylate and isopropoxy;

R13means (C1-C6)-alkyl, (C3-C7-cycloalkyl or benzyl, in particular methyl;

b, C, d and e mean 1;

f and g mean zero;

h means zero;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Quite particularly preferred compounds of formula (I) are those where the lake which contains the remainder of the series, consisting of (C1-C8)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, (C3-C8)-cycloalkyl, in particular (C5-C6)-lalouche, (C3-C8-cycloalkyl-(C1-C4)-alkyl, in particular (C5-C6-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl, optionally substituted in the aryl part (C6-C10)-aryl-(C1-C4)-alkyl, optionally substituted heteroaryl and optionally substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl; in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts. Even more particularly preferred compounds of formula (I) are such that where denotes unsubstituted methylene residue or a methylene residue, which is substituted by (C1-C8)-alkyl residue, in particular (C1-C6)-alkyl residue; in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

In General, preferred compounds of formula (I), in which the centers of chirality, for example, have the same configuration.

The compounds of formula (I) can be obtained, for example, by fragment condensation of compounds of formula (II):

with the compound of the formula (III):

moreover, W, Y, Z, b, D, E, R, and b, d, e, f, g and h have the above significance and G means hydroxycarbonyl, (C1-C6-alkoxycarbonyl, the remainder of activated derivatives of the carboxylic acid as the acid anhydrides or activated esters, or isocyanatopropyl.

For the condensation of compounds of the formula (II) with compounds of the formula (III) preferably use themselves known methods of a combination of peptide chemistry (see, for example, Houben-Weil, Methods of organic chemistry, volume 15/1 and 15/2, ed. Georg Thieme, Stuttgart, 1974). For this purpose, as a rule, you need to existing, not reactive amino groups during condensation were protected then remove the protective groups. The same applies for not participating in the reaction of carboxyl groups, which are preferably in the form (C1-C6)-Olkiluoto, benzyl or tert.-butyl ether complex. Protection of the amino groups is unnecessary, when the generated amino groups are in the form of nitro - or cyano groups and are formed only after reacts is one way. For example, nitro (protection of guanidinium), benzyloxycarbonyl groups and complex benzyl esters can be removed by hydrogenation. The protective group is tert.-butyl type otscheplaut in acidic conditions, while the 9-fertilitycaretm the residue is removed by secondary amines. The compounds of formula (I), for example, you can also get the fact that the compounds are synthesized by conventional methods gradually on the solid phase, as explained below in the examples.

The compounds of formula (II) in which W stands for R1-A-C(R13), Y represents a carbonyl group and Z denotes NR0can be obtained, for example, the fact that first, the compounds of formula (IV):

by the reaction of Bucherer converted into the compounds of formula (V):

in which also, as in the formula (IV), R1, R13and a have the above-mentioned value N.T. Bucherer, V. A. Lieb, J. Prakt. hem., 141, 5 (1934)).

The compounds of formula (VI):

in which R1, R13, A, b and G have the abovementioned meaning, then you can get the fact that the compounds of formula (V), for example, first introduced in the interaction with the alkylating agent which introduces the rest-B-G in the molecule. The interaction of compounds of formula (VI replaced the deleted group, for example halogen, in particular chlorine or bromine, (C1-C4-alkoxyl possibly substituted fenoxaprop or heterocyclic delete the group, as, for example, imidazolyl, leads to the corresponding compounds of the formula (II). These transformations can be performed similarly well-known specialist methods. However, depending on the specific case, as it is carried out in all stages of the synthesis of compounds of formula (I), functional groups, which can lead to adverse reactions or adverse reactions, you can temporarily block by adapted to the problem of synthesis strategy, the protective groups that are known to the specialist.

If W stands for R1-A-CH=C, then this structural element can be entered, for example, that by analogy with known methods aldehyde condensed with a five-membered heterocycle, which contains a methylene group in the corresponding group W position.

The compounds of formula (I), in which the five-membered heterocycle is dioxa or trioxolane imidazolidinone ring in which W stands for R1-A-C(R13) can also be obtained as follows.

By reaction-amino acids or N-substituted-aminocapronic, the compounds of formula (VII):

where R0, R1, R13and a have the above meaning, with an isocyanate or isothiocyanates, for example, of the formula (VIII):

where b, D, E and R and b, c, d, e, f, g and h have values above and U represents isocyanato or isothiocyanato receive a derivative of urea or thiourea, for example, of the formula (IX):

which have a value above definitions and in which V denotes oxygen or sulfur, which by heating with acid saponification of the ester function cyclist to compounds of formula (Ia):

in which V denotes oxygen or sulfur, W implies R1-A-C-(R13), and other symbols have the above meanings. The cyclization of compounds of formula (IX) to compounds of formula (1A) can also be performed by treatment with bases in an inert solvent, for example, by treatment with sodium hydride in an aprotic solvent such as dimethylformamide.

During the cyclization of guanidinium can be blocked with protective groups, such as the nitro-group. Amino groups can be present in protected form or in the form of nitro - or ceanography, which is genogroup.

The compounds of formula (I), in which the five-membered heterocycle is dioxa or trioxolane imidazolidinone ring in which W stands for R1-A-C(R13and with means 1, you can also get the fact that the compound of formula (VII) enter into interaction with the isocyanate or isothiocyanato formula (X):

in which B, U and b are specified in the case of the formula (VIII) value and Q means alkoxygroup, for example (C1-C4)-alkoxygroup as a methoxy group, ethoxypropan or tert.-butoxypropan, (C6-C14)-alloctype, such as fenoxaprop, or (C6-C14)-aryl-(C1-C4)-alkoxygroup, such as benzyloxy. While getting the connection formula (XI):

in which a, b, V, Q, R0, R1, R13and b have the above in the case of formulas (IX) and (X) values, which is then under the influence of acid or base as described above for the cyclization of compounds of formula (IX), cyclist to the compounds of formula (XII):

in which, Q, V, W, R0and b have the above in the case of formulas (Ia) and (X) values. Then, from the compounds of formula (XII) by hydrolysis of the group CO-Q to the carboxylic acid COOH and the last is (III), get the compound of formula (Ia). Also in this case, during the cyclization functional groups can be present in protected form or in the form of precursors, such as guanidinium block with nitro or amino groups are in protected form or in the form of nitro - or ceanography, which you can later restore to the amino group or, in the case of ceanography also it can be turned into formamidines.

Another method of preparing compounds of formula (Ia) is, for example, the introduction in the interaction of the compounds of formula (XIII):

in which W stands for R1-A-C(R13and other definitions have the above significance, with phosgene, thiophosgene or appropriate equivalents (similar to S. Goldschmidt M. Wick, Liebigs Ann. Chem., 575, 217-231 (1952)); C. Tropp, Chem. Ber., 61, 1431-1439 (1928)).

The transfer of an amino group in guanidinium can be performed using the following reagents:

1. O-methylisoleucine (S. Weiss and H. Kroramer, Chemiker Zeitung, 98, 617-618 (1974));

2. S-methylisothiazoline (R. F. Borne, M. L. Forrester, I. W. Waters, J. Med. Chem., 20, 771-776 (1977));

3. Nitro-S-methylisothiazoline (L. S. Hafner, and R. E. Evans, J. Org. Chem., 24, 57 (1959));

4. Formamidinesulfinic (K. Kim, Y.-T. Lin and H. S. Mosher, , 5, 4053-4054 (1953));

6. N,N'-di-tert.-butoxycarbonyl-S-methylisothiazoline (R. J. Bergeron and J. S. McManis, J. Org. Chem. 52, 1700-1703 (1987));

7. N-alkoxycarbonyl-, N,N'-dialkoxybenzene-, N-alkylaryl and N,N'-dialkylamino-S-methylisothiazoline (H. Wollweber, H. Kolling, E. Niemers, A. Widdig, P. Andrews, H.-P. Schulz, and H. Thomas, Azzneim. Forsch./Drug Res., 34, 531-542 (1984)).

Amidine can be obtained from the relevant cyanocobalamine by the addition of alcohols (such as methanol or ethanol) in acid anhydrous environment (such as dioxane, methanol or ethanol) and subsequent aminolysis, for example, by treatment with ammonia in alcohols, such as isopropanol, methanol or ethanol (G. Wagner, P. Richter and Ch. Garbe, Pharmazia, 29, 12-55 (1974)). Another way to get amidino is the joining of hydrogen sulfide to the cyano followed by methylation of the resulting thioamide and then the introduction of the interaction with ammonia (GDR patent No. 235866).

In obtaining compounds of formula (I) further reference should be made entirely on the following publications: international application 94/21607 and 95/14008; European patent application No. 449079, 530505 (application for U.S. patent 5389614); international application 93/18057; European patent application No. 566919 (application for U.S. patent 5397796), 580008 (application for U.S. patent 54 is raised antagonists of the adhesion receptor VLA-4. They have the ability to inhibit interaction between cell-cell and cell-matrix, which play the role of the interaction between VLA-4 with its ligands. The effectiveness of compounds of the formula (I) can be proved, for example, in the experiment, which determine the binding of cells that have a VLA-4 receptor, such as leukocytes, with ligands of this receptor, for example with VCAM-l, which for this purpose preferably also can be obtained using genetic engineering. Detailed description of such experience is given below in the description. In particular, the compounds of formula (I) can inhibit the adhesion and migration of leukocytes, such as adhesion of leukocytes with endothelial cells, which, as explained above, is regulated VCAM-l/VLA-4-adhesive mechanism.

The compounds of formula (I) and their physiologically acceptable salts are therefore suitable for the treatment and prophylaxis of diseases which are based on the interaction between VLA-4 receptor and its ligands, or which can be influenced by inhibition of this interaction, and in particular they are suitable for treatment and prophylaxis of diseases which are at least partly resulting from leukocyte adhesion and/or migration of leukocytes in undesirable scale illegalto. Thus, they can be used, for example, in inflammatory events that occur for a variety of reasons as to reduce the intensity of inflammation funds. The compounds of formula (I) according to the present invention find application, for example, for the treatment or prevention of rheumatoid arthritis, inflammatory diseases of the digestive tract (ulcerative colitis), systemic lupus erythematosus, or for the treatment or prevention of inflammatory diseases of the Central nervous system, such as multiple sclerosis, for the treatment or prophylaxis of asthma or allergies, such as Allergy delayed type (type IV allergies), then, for the treatment or prevention of cardiovascular diseases, arteriosclerosis, restenosis, for the treatment or prevention of diabetes, to prevent damage to transplants of organs, to suppress tumor growth or metastasis of tumors in various malignant tumors, to treat malaria, and other diseases in which for the purpose of preventing, abating or treatment is necessary blocking integrin VLA-4 and/or influence on the activity of leukocytes. The compounds of formula (I) and their salts, hereinafter, can be used to diag the research, when seeking to block VLA-4 or impact on the interaction of cell-cell or cell-matrix.

The compounds of formula (I) and their physiologically acceptable salts according to the invention it is possible to enter an animal, preferably a mammal, and especially a man as a drug for treatment or prevention. You can enter them individually, as mixtures with one another or in the form of pharmaceutical compositions, which you can enter the intestinal or parenteral and which as active constituent parts contain an effective dose of at least one of the compounds of formula (I) and/or its physiologically acceptable salts along with conventional, pharmaceutically acceptable carriers and/or additives. The object of the present invention is also the use of pharmaceutical compositions that contain one or more compounds of the formula (I) and/or their physiologically acceptable salts, for the above according to the invention using compounds of formula (I). Pharmaceutical compositions typically contain about 0.5 to 90 wt.% therapeutically effective compounds of formula (I) and/or their physiologically acceptable salts.

Medicines can is solid and soft gelatin capsules, solutions, syrups, emulsions or suspensions. The introduction, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection or infusion, microcapsules or rods, or subcutaneously, for example, in the form of ointments or tinctures, or in any other way, for example in the form of a spray for insertion through the nose or aerosol mixtures.

Used according to the invention pharmaceutical drugs get itself known, along with the compound or compounds of formula (I) and/or their physiologically acceptable salts are used inert inorganic and/or organic carriers. For more pills, tablets, coated tablets and hard gelatin capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils. As carriers to obtain solutions, such as solutions for injection, or of emulsions or syrups are suitable, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, g is emer, copolymers of glycolic acid with lactic acid.

Along with active substances and carriers, the pharmaceutical preparations can contain additives, such as fillers, parafora, binder, which imparts lubricity (tablets) agents, wetting, stabilizers, emulsifiers, preservatives, sweetening agents, colouring agents, which impart taste or flavoring agents, thickeners, diluents, buffer substances, further, solvents or agents dissolved or means to achieve the effect, and also salts for modifying the osmotic pressure, means for coating or antioxidants. They can also contain two or more compounds of the formula (I) and/or their physiologically acceptable salts. Further along at least one compound of formula (I) and/or its physiologically acceptable salts, they can contain one or more other therapeutically or prophylactically active substances, for example substances with overwhelming inflammation effect.

The dose can be changed within wide limits and in each case fitted to individual data. In General, with the introduction of oral daily dose of approximately 0.01 to 100 mg/kg, before nom the introduction of the daily dose is in General about 0.01 to 50 mg/kg, preferably 0.01 to 10 mg/kg of body weight. The daily dose, particularly with the introduction of large quantities, can be divided into several, for example 2, 3 or 4 individual doses. If necessary, depending on individual behaviour, it may be necessary deviation from the specified daily dose up or down. The pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1-100 mg of the active substance of the formula (I) and/or its physiologically acceptable salts on the dose.

Certain compounds of formula (I) have not been disclosed in the prior art. The object of the present invention is also, in itself, these new connections (per se).

The present invention thus relates, firstly, is also in itself (per se) to compounds of formula (Ib):

where W stands for R1-A-CH or R1-A-CH=C;

Y represents carbonyl, thiocarbonyl or methylene group;

A represents the bivalent residue of the series consisting of (C1-C6)-alkylene, (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, phenylene-(C2-C6-alkenyl; or a bivalent residue of a five or testicleswhat substituted (C1-C6)-alkyl or double-bound oxygen or sulfur;

In the mean bivalent residue selected from the series (WITH1-C6)-alkylene, (C2-C6)-Alcanena, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3)-alcelaphine;

D means C(R2)(R3);

E. means tetrazolyl, (R8O)2P(O), HOS(O)2, R9NHS(O)2or R10CO;

R means hydrogen, (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R0means (C7-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand R denotes the number 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(Timothy substituted (C6-C14-aryloxyalkyl; and (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; and (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=NR), where R' and R", independently of one another, are specified for the X values;

R2means hydrogen or phenyl;

R3means hydrogen, COOR4, CON(CH3R4or CONHR4;

R4means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18-oxycarbonyl, which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, optionally substituted (C3-C8-cycloalkyl, halogen, the nitro-group, a trifluoromethyl or a residue R5;

R5means optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and which may contain one, two or three identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl and independently heterocyclic residues may be single - or multi-substituted by identical or different residues selected from the range (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids, aminokisloty, is profiled) esamination or dipeptide, which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2- as well as their esters or amides, and instead of free functional groups may optionally be hydrogen or hydroxymethyl and/or with the free functional groups can be protected customary in the chemistry of peptides, protective groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C18)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-allyloxycarbonyl, and alkyl groups optionally can be substituted by amino and/or and aryl residues can be one or several times, preferably once, replaced by the same or different residues selected from the range (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and trifloromethyl; the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((the m residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2-;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted;

R9means hydrogen, aminocarbonyl, (C1-C18-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

b, C and d, independently from each other, can mean zero or 1, but not all at the same time can mean zero;

n means the number 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms or mixtures thereof in any ratio, and their physiologically acceptable salts.

All the above shows is related to compounds of formula (Ib). Also the above preferred meanings apply here respectively.

The above explanations with respect to obtaining the compounds of formula (I) and their use exactly also apply to compounds of formula (Ib). These connections, of course, are also inhibitors of leukocyte adhesion and/or antagonists of VLA-4 receptor and is suitable for the treatment and prevention of diseases that arise due to leukocyte adhesion and/or migration of leukocytes in undesirable scale or associated with or in the case of which play a role in the interaction cell-cell or cell-matrix based on the variable action VLA-4 receptors with their ligands, such as inflammatory processes. The object of the present invention, then, are the compounds of formula (Ib), used as a medicine as well as pharmaceutical preparations that contain one or more compounds of formula (Ib) and/or their physiologically acceptable salts, together with pharmaceutically acceptable carriers and/or additives, and the above explanations apply to these pharmaceutical drugs.

Certain compounds of formula (I) unclear disclosed in the prior art and predstavlyaetsia these are also in itself new connections per se. Thus, the present invention secondly relates also per se, by itself, to compounds of formula (IC):

where W stands for R1-A-C(R13);

Y represents carbonyl, thiocarbonyl or methylene group;

And means phenylenebis balances;

In the mean bivalent residue selected from the series (WITH1-C6)-alkylene, (C2-C6)-Alcanena, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3)-alcelaphine;

D means C(R2)(RC), N(R3) or CH=C(R3);

E. means tetrazolyl, (R8O)2P(O), HOS(O)2, R9NHS(O)2or R10CO;

R means hydrogen, (C1-C8) -alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R0means optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p is 0, 1, 2 6
-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; and (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; and (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=N-R') with R' and R", independently of one another, are specified for the X values;

R2means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (the UB>-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CONHR14, CSNHR14, COOR15, CON(CH3R15or CONHR15;

R4means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)-aminocarbonyl, amino-(C2-C18-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18-alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, optionally substituted (C3-C8-cycloalkyl, halogen, the nitro-group, a trifluoromethyl or a residue R5;

R5means optionally substituted (C6-C14)-aryl, Ilichevsky 5-12-membered heterocycle, which can be aromatic, partially gidrirovanny or fully gidrirovanny and which may contain one, two or three identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl and independently heterocyclic residues may be substituted one or more times, equal or different residues selected from the range (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2- as well as their esters and amides, and instead of free functional groups may optionally be hydrogen or hydroxymethyl and/or with the free functional groups can be protected customary in the chemistry of p is SUB>)-aryl-(C1-C8)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-alkoxycarbonyl, and alkyl groups optionally can be substituted by amino and/or and aryl residues can be one or several times, preferably once, replaced by the same or different residues selected from the range (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and trifloromethyl; the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2-;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted;

R96-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means hydrogen, (C1-C18)-alkyl, R12CO, optionally substituted (C6-C14)-aryl-S(O)2, (C1-C18)-alkyl-S(O)2optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R9NHS(O)2;

R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C18-alkoxy, which is also in the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype or mono - or on the value substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R14means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues chosen from the series hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl) aminocarbonyl, amino-(C2-C18)-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18)alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, which can also be substituted in the aryl residue; amino, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(A)-(C1-C3)-alkyl, tetrazolyl-(C1-C3)-alkyl, halogen, nitro, trifloromethyl and R5;

1-C4)-alkyl and carbonyl group;

b, C, d and f, independently of one another, denote zero or 1, but not all at the same time can mean zero;

e, g and h, independently of one another, mean 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

All of the above explanations for the formula (I), for example, in relation to alkyl residues, aryl residues, etc. accordingly also relates to compounds of formula (IC). Also the above preferred meanings apply here respectively. Especially preferred compounds of formula (IC), in addition, independently from each other, b means 1, p is 1, d is 1, f is zero and g mean zero, e and h are particularly preferably, independently of one another, denote zero or 1. Also especially preferably, when Y in the compounds formulary (I) and their use exactly also apply to compounds of formula (IC). These connections, of course, are also inhibitors of leukocyte adhesion and/or antagonists of VLA-4 receptor and is suitable for the treatment and prevention of diseases that arise due to leukocyte adhesion and/or migration of leukocytes in undesirable scale or associated with or in the case of which play a role in the interaction cell-cell or cell-matrix based on the interactions of VLA-4 receptors with their ligands, such as inflammatory processes. The object of the present invention, then, are the compounds of formula (IC), used as a medicine as well as pharmaceutical preparations that contain one or more compounds of formula (IC) and/or their physiologically acceptable salts, together with pharmaceutically acceptable carriers and/or additives, and also the above explanations refer to these pharmaceutical drugs.

Further, in the prior art it is not clear yet disclosed the compounds of formula (I) in which b is 1 and means substituted alkalinity balance. The object of the present invention, therefore, in itself (per se) are also compounds of formula (Id):

where W stands for R1-A-C(R13or R1-A-CH=2">

A represents the bivalent residue selected from the series (WITH1-C6)-alkylene, (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, phenylene-(C2-C6-alkenyl; or a bivalent residue of a five - or six-membered saturated or unsaturated cycle which may contain 1 or 2 nitrogen atom and may be single or twofold substituted (C1-C6)-alkyl or double-bound oxygen or sulfur;

In the mean bivalent (C1-C6)-alkalinity residue, which is substituted by a residue selected from the series (WITH1-C8)-alkyl, (C2-C8-alkenyl, (C2-C8)-quinil, (C3-C10)-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl and optionally substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl;

D means C(R2)(R3), N(R3) or CH=C(R3);

E. means tetrazolyl, (R8O)23-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R0means hydrogen, (C1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, optionally substituted heteroaryl, optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl, formyl, (C1-C8)-alkyl-CO, (C3-C12-cycloalkyl-WITH, (C3-C12-cycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-bicycloalkyl-WITH, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-tricyclohexyl-WITH, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-CO, optionally substituted (C6-Clcil WITH, optionally substituted heteroaryl -, optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-CO, (C1-C8)-alkyl-S(O)n, (C3-C12-cycloalkyl-S(OH)n, (C3-C12-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-bicycloalkyl-S(OH)n, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-tricyclohexyl-S(OH)n, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-S(O)noptionally substituted (C6-C14)-aryl-S(O)noptionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-S(O)noptionally substituted heteroaryl-S(OH)nor optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-S(O)nand n is 1 or 2;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p is 0, 1, 2 or 3;

X means hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6)-alkoxide>C14-aryloxyalkyl; and (C6-C14)-aryl- (C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; and (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=N-R') with R' and R", independently of one another, are specified for the X values;

R2means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C2-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CONHR1
-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18)alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18-alkylaminocarbonyl, (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, optionally substituted (C3-C8-cycloalkyl, halogen, the nitro-group, a trifluoromethyl or a residue R5;

R5means optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovannoe, selected from the series nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl residue and independently heterocyclic residue can be single - or multi-substituted by identical or different residues selected from the range (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, which in the aryl part can be substituted and/or in which the peptide bond can be restored to the-NH-CH2- as well as their esters and amides, and instead of free functional groups may optionally be hydrogen or hydroxymethyl and/or with the free functional groups can be protected customary in the chemistry of peptides, protective groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18)-SUB>1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-allyloxycarbonyl, and alkyl groups may optionally be protected amino group and/or and aryl residues can be one or several times, preferably once, replaced by the same or different residues selected from the range (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and trifloromethyl; the residue of a natural or synthetic amino acids, aminokisloty, if necessary - (C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2-;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted;

R9means hydrogen, aminocarbonyl, (C1-C18-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C1i (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means hydrogen, (C1-C18)-alkyl, R12CO, optionally substituted (C6-C14)-aryl-S(O)2optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R9NHS(O)2;

R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl) amino;

R13means hydrogen, (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(28
)-alkyl, which optionally may be single - or multi-substituted by identical or different residues chosen from the series hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18) alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18)-alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, in which the aryl residue may be substituted; amino group, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(A)-(C1-C3)-alkyl, tetrazolyl-(C1-C3)-alkyl, halogen, nitro, trifloromethyl and R5;

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic to iliat 1-4 identical or different heteroatoms, selected from the series nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents from the series consisting of (C1-C4)-alkyl and carbonyl group;

c, d, and f, independently of one another, denote zero or 1, but not all at the same time can mean zero;

e, g and h, independently of one another, mean 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

All of the above explanations for the formula (I), for example, in relation to alkyl residues, aryl residues, etc. respectively, also apply to compounds of formula (Id). Also the above preferred meanings apply here respectively. In addition, the compounds of formula (Id) are particularly preferably, independently of one another, with means 1, d is 1, f is 0 and g is 0, e and h are particularly preferably, independently of one another, denote 0 or 1. In respect of group b, in addition, for compounds of formula (Id) is set to the following.

The referent group (C1-C6)-alkalinity residue in the compounds of formula (Id) is preferably (=1,2-ethylene), even more particularly preferably a methylene residue. The substituent in the group, first, may include the loop when it comes to the substituents selected from the series (WITH3-C10)-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl, optionally substituted of heteroaryl and optionally substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, and, secondly, can be acyclic, when it comes to the Deputy, selected from a number (1-C8)-alkyl, (C2-C8-alkenyl and (C2-C8)-quinil. Each of these acyclic substituents may contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms and in the case of saturated alkyl residue of 1 carbon atom. If alkenyl and etkinlik remnants of a double or triple bond may be at any position and in the case of the double bond is CIS - or TRANS-configuration. As explained above, these alkyl, alkeline and alkyline residues may be linear or branched.

As examples to call methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, isopentyl, isohexyl, Deut.-butyl, tert.-butyl, tert.-pencil, neopentyl, neohexyl, 3-methylpentyl, 2-ethylbutyl, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 6-hexenyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-biphenylyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclooctylmethyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyridylmethyl, 2-(4-pyridyl)-ethyl, 2-furylmethyl, 2-thienylmethyl, 3-thienylmethyl or 2-(3-indolyl)ethyl.

Preferred compounds of formula (Id) are those in which simultaneously

W means R1-A-C(R13);

Y represents a carbonyl;

Z means N (R0);

A represents the bivalent residue selected from the series (WITH3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, or the divalent residue of a five or six-membered saturated or unsaturated cycle which may contain 1 or 2 nitrogen atom and may be single or twofold substituted (C1-C6)-alkyl or double-bound oxygen is m, selected from a number (1-C8)-alkyl, (C2-C8-alkenyl, (C2-C8)-quinil, (C3-C10)-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl and optionally substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl;

D means C(R2)(R3);

E. means tetrazolyl or R10WITH;

R means hydrogen or (C1-C8)-alkyl;

R0means hydrogen, (C1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, optionally substituted heteroaryl, when neo>-alkyl-CO, (C3-C12-cycloalkyl-WITH, (C3-C12-cycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-bicycloalkyl-WITH, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-tricyclohexyl-WITH, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14)-aryl -, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted heteroaryl -, optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-CO, (C1-C8)-alkyl-S(O)n, (C3-C12-cycloalkyl-S(O)n, (C3-C12-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-bicycloalkyl-S(OH)n, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-tricyclohexyl-S(OH)n, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-S(O)noptionally substituted (C6-C14)-aryl-S(O)noptionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-S(O)noptionally substituted heteros who Kil-S(OH)nand n is 1 or 2;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p is 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; and (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; cyano, hydroxyl, (C1-C6-alkoxyl; and (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=N-R') with R' and R", independently of one another, are specified for the X values;

R2means hydrogen or (C1-C8)-alkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1- the 2-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, CON(CH3R14, CONHR14, CON(CH3R15or CONHR15;

R5means if possible, substituted (C6-C14)-aryl, where possible, substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and which may contain one, two or three identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur; or denotes a residue R6CO-, and aryl residue and independently heterocyclic residue can be single - or multi-substituted by identical or different residues selected from the range (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means the residue of a natural or synthetic amino acids, aminokisloty, possibly N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be zames the MIA peptides, protective groups;

R10means hydroxyl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means R12CO, optionally substituted (C6-C14)-aryl-S(O)2or (C1-C18)-alkyl-S(O)2;

R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxyl; (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted, or optionally substituted (C6-C14)-alloctype;

R13means hydrogen or (C1-C4)-alkyl;

R14means (C1-C10)-alkyl, which optionally may be single - or multi-substituted by identical or different residues from the series consisting of hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl) aminocarbonyl, (C6-UB>1-C8)-alkoxyl, (C1-C8)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, tetrazolyl-(C1-C3)-alkyl, trifloromethyl and R5;

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which can contain 1-4 identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents selected from the series (WITH1-C4)-alkyl and carbonyl group;

C and d is 1 and f is zero;

e and h, independently of one another, denote zero or 1, and g means zero;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Especially preferred compounds of formula (Id) are those in which the residue, which is substituted by the group, is a (C1-C8)-alkyl residue, in all their stereoisomeric forms and mixtures thereof in any ratio, and their f the crystals (I) and their use just as well apply to compounds of formula (Id). These connections, of course, are also inhibitors of leukocyte adhesion and/or antagonists of VLA-4 receptor and is suitable for the treatment and prevention of diseases that arise due to leukocyte adhesion and/or migration of leukocytes in undesirable scale or associated with or in the case of which play a role in the interaction cell-cell or cell-matrix based on the variable action VLA-4 receptors with their ligands, such as inflammatory processes. The object of the present invention, then, are the compounds of formula (Id), used as medicines as well as medications that contain one or more compounds of formula (Id) and/or their physiologically acceptable salts, together with pharmaceutically acceptable carriers and/or additives, and the above explanations also apply to these pharmaceutical drugs.

In the prior art undisclosed compounds of formula (I) in which R0means acyl residue, sulfanilyl balance or sulfanilyl balance. The object of the present invention, thus, further, are also (per se) is itself the compounds of formula (Ie):

where W stands for R1-A-C(R0
), oxygen, sulfur or a methylene group;

A represents the bivalent residue selected from the series consisting of (C1-C6)-alkylene, (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, phenylene-(C2-C6-alkenyl, or the divalent residue of a five or six-membered saturated or unsaturated cycle which may contain 1 or 2 nitrogen atom and may be single or twofold substituted (C1-C6)-alkyl or double-bound oxygen or sulfur;

In the mean bivalent residue selected from the series (WITH1-C6)-alkylene, (C2-C6)-Alcanena, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3)-alcelaphine;

D means C(R2)(R3), N(R3) or CH=C(R3);

E. means tetrazolyl, (R8O)2P(O), HOS(O)2or R10WITH;

R means hydrogen, (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R0means formyl, (C1-C IS, (C6-C12-bicycloalkyl-WITH, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-tricyclohexyl-WITH, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14)-aryl -, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted heteroaryl -, optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-CO, (C1-C8)-alkyl-S(O)n, (C3-C12-cycloalkyl-S(OH)n, (C3-C12-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-bicycloalkyl-S(O)n, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-tricyclohexyl-S(OH)n, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-S(O)nif necessary (C6-C14)-aryl-S(O)noptionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-S(O)noptionally substituted heteroaryl-S(OH)nor optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-S(SUB>)pand p is 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, possibly substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; and (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; and (C6-C14)-aryl-(C1-C14-alkoxy, in which the aryl residue may be substituted, or an amino group;

X1has one of these for X values or means R'-NH-C(=NP), and R' and R", independently of one another, are specified for the X values;

R2means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)- is>
-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C2-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CONHR14, CSNHR14, COOR15, CON(CH3R15or CONHR15;

R4means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18-alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, optionally substituted (C3-C8-cycloalkyl, halogen or>-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8) -alkyl; mono - or bicyclic 5-12 membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and may contain one, two or three identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur; the remainder R6or the remainder R6-CO-, and aryl residue and independently heterocyclic residue can be single - or multi-substituted by identical or different residues selected from the range (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2- as well as their esters and amides, and instead Svobodnoye group can be protected customary in the chemistry of peptides, protective groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-alkoxycarbonyl, and alkyl groups optionally substituted by amino and/or and aryl residues can be one or several times, preferably once, replaced by the same or different residues selected from the range (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and trifloromethyl; the residue of a natural or synthetic amino acids, aminokisloty, possibly N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2-;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-ALSIP, in which aryl about enaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means hydrogen, (C1-C18)-alkyl, R12CO, optionally substituted (C6-C14)-aryl-S(O)2, (C1-C18)-alkyl-S(O)2optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R9NHS(O)2;

R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6

R13means hydrogen, (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R14means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues chosen from the series hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C1-C3)-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18)-alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, in which the aryl residue may be substituted; amino group, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(A)-(C1< a CLASS="ptx2">

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which can contain 1-4 identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents chosen from the series consisting of (C1-C4)-alkyl and carbonyl group;

b, C, d and f, independently of one another, denote zero or 1, but not all at the same time can mean zero;

e, g and h, independently of one another, mean 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

All the above explanations of the formula (I), for example, in relation to alkyl residues, aryl residues, etc. are respectively for compounds of formula (Ie). Also the above preferred meanings apply here respectively.

The above explanations for obtaining compounds of formula (I) and their use just as well apply to the connection of the VLA-4 receptor and is suitable for the treatment and prevention of diseases, which arise due to leukocyte adhesion and/or migration of leukocytes in undesirable scale or associated with or in the case of which play a role in the interaction cell-cell or cell-matrix based on the variable action VLA-4 receptors with their ligands, such as inflammatory processes. The object of the present invention, then, are the compounds of formula (Ia) used as a medicine as well as pharmaceutical preparations that contain one or more compounds of the formula (S) and/or their physiologically acceptable salts, together with pharmaceutically acceptable carriers and/or additives, and also the above explanations apply again for these pharmaceuticals.

EXAMPLES

Products identified by mass spectra (MS) and/or NMR spectra. Compounds that purify by chromatography using a solvent which contains, for example, acetic acid or triperoxonane acid, and then subjected to drying by freezing, depending on the implementation of the freeze-drying contain partially derived from the solvent acid is, therefore, obtained partially or completely in formebolone further abbreviations have the following meanings:

DMF - N,N-dimethylformamide

THF - tetrahydrofuran

DCC - N,N'-dicyclohexylcarbodiimide

HOBt is 1-hydroxybenzotriazole

HOOBt - 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazin

OBut- tert.-butoxypropan

EXAMPLE 1

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

1A). (R, S)-4-(4-Cyanophenyl)-4-methyl-2,5-dioxoimidazolidin

20 g (138 mmol) of p-Acetylbenzoate, 115,6 g (1,21 mol) of ammonium carbonate and 11.6 g (178 mmol) of potassium cyanide dissolved in a mixture of 50% ethanol and 50% water. The mixture is stirred for 5 hours at 55C and incubated over night at room temperature. In the solution set pH 6.3 using 6 N. hydrochloric acid and then stirred for two hours at room temperature. The precipitate is filtered under vacuum, washed with water and dried in high vacuum over phosphorus pentoxide. The output is 22,39 g (75%).

Mass spectrum (fast atom bombardment): 216,1 (M+N)+.

1B). Methyl ester ((R, S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxo-imidazolidin-1-yl) acetic acid

1,068 g (46,67 mmol) of Sodium in the atmosphere of nitrogen dissolved in 110 is of atomidine and the mixture is refluxed for two hours. Type of 7.75 g (of 46.68 mmol) of potassium iodide and within hours was added dropwise a solution 4,53 ml methyl ester Chloroacetic acid (51,3 mmapi) in 5 ml of methanol. Boil for 6 hours, incubated over night at room temperature and concentrate. Oily residue chromatographic on silica gel using mixtures of dichloromethane with ethyl acetate in the ratio of 9:1. The output is 8,81 g (66%).

Mass spectrum (fast atom bombardment): 288 (M+H)+.

1B). Hydrochloride methyl ester ((R, S)-4-(4-toksienosti)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid

A suspension of 4 g (13,92 mmol) methyl ester ((R, S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid in 60 ml of absolute ethanol is cooled to 0C. The suspension is passed drained gaseous hydrogen chloride, and the temperature all the time support below 10C up until the IR spectrum no longer be detected related to the nitrile band. The ethanol solution is mixed with 200 ml of diethyl ether and incubated over night at a temperature of 4C. The precipitate is filtered under vacuum and dried in high vacuum. The output is of 3.96 g (77%).

Mass spectrum (bombarded by fast atoms is imidazolidin-1-yl) acetic acid

of 3.96 g (of 10.7 mmol) of methyl ester Hydrochloride ((R, S)-4-(4-(ethoxybenzoyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid are suspended in 40 ml of isopropanol and mixed with 11.9 ml of a 2 n solution of ammonia in isopropanol. The reaction mixture is stirred for two hours at 50C. The mixture is cooled and then mixed with 200 ml of diethyl ether. The precipitate is filtered under vacuum and dried in high vacuum. The output is of 3.27 g (89%).

Mass spectrum (fast atom bombardment): 305 (M+N)+.

1D). Hydrochloride ((R, S)-4-(4-aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid

of 3.27 g (9.6 mmol) of methyl ester Hydrochloride ((R,S)-4-(4-(aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid are dissolved in 50 ml of concentrated hydrochloric acid. The solution is boiled for 6 hours and then concentrated. The output is 2,73 g (87%).

Mass spectrum (fast atom bombardment): 291,2 (M+N)+.

1E). Hydrochloride, di-tert.-butyl ester ((R, S)-4-(4-(aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

To a solution of 1 g (a 3.06 mmol) of hydrochloride ((R, S)-4-(4-(aminoiminomethyl)Fe and 413 mg of HOBt in 10 ml of dimethylformamide at a temperature of 0C add 673 mg DCC (a 3.06 mmol). Is stirred for one hour at 0C and for four hours at room temperature. The mixture is then up to the end of the week leave to stand in the refrigerator, the precipitate is filtered off under vacuum and the filtrate concentrated. For purification, the substance chromatographic on silica gel using mixtures of dichloromethane with methanol, glacial acetic acid and water at a ratio of 8.5:1.5 to:0,15:0,15. The output is 920 mg of the product as oil (contains acetic acid).

Mass spectrum (fast atom bombardment): 651,3 (M+N)+.

1G). ((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

920 mg of the Hydrochloride di-tert.-butyl ester ((R, S)-4-(4- (aminoiminomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine dissolved in a mixture of the 5.4 ml triperoxonane acid, 0.6 ml of water and 0.6 ml of dimercaptan. Incubated for one hour at room temperature and concentrated in vacuo water-jet pump. For purification, the substance chromatographic on Sephadex LH20 using a mixture of glacial acetic acid, n-butanol and water. Fractions with pure substance concentrate. The residue is dissolved in water and subjected to drying by freezing. Vygon)+.

EXAMPLE 2

((R, S)-4-(4-(Aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-di-Oxymetazoline-1-yl)-acetyl-L-aspartyl-L-phenylglycine

2A). Methyl ester ((R, S)-4-(4-cyanophenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl) acetic acid

3 g (10.4 mmol) of Methyl ester ((R, S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid are dissolved in 15 ml of anhydrous dimethylformamide in an argon atmosphere. In a countercurrent of argon add 275,5 mg dispersion of sodium hydride in mineral oil (to 11.4 mmol). The reaction mixture is stirred for 15 minutes at room temperature, then mixed with 721 µmol (11,4 mmol) under the conditions. Stirred for 4 hours at room temperature and then left to stand overnight at room temperature. The solution concentrate. For purification, the substance chromatographic on silica gel using mixtures of dichloromethane with ethyl acetate in the ratio of 9.5:0.5 to. Fractions with pure substance concentrate. The output is 2.14 g of oil (68%).

Mass spectrum (fast atom bombardment): 302,2 (M+N)+.

2B). Hydrochloride methyl ester ((R, S)-4-(4-(ethoxybenzoyl)-phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl) acetic acid

Rast ml of absolute ethanol cooled to a temperature of 0C. The solution is passed drained gaseous hydrogen chloride, and the temperature all the time support below 10C, up until the IR spectrum will not be detected related to the nitrile band. The ethanol solution was concentrated to a volume of 20 ml and mixed with 200 ml of diethyl ether. The suspension is concentrated and the residue dried in high vacuum. The output is of 2.27 g (76%).

Mass spectrum (fast atom bombardment): 348,1 (M+H)+.

2B). Hydrochloride methyl ester ((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl) acetic acid

of 2.26 g (6.4 mmol) of methyl ester Hydrochloride ((R, S)-4-(4- (ethoxybenzoyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl) acetic acid are suspended in 25 ml of isopropanol and mixed with 7.2 ml of a 2 n solution of ammonia in isopropanol. The reaction mixture is stirred for 2.5 hours at a temperature of 50 ° C, then cooled and mixed with 200 ml of diethyl ether. The precipitate is filtered under vacuum and dried in high vacuum. The output is 1.03 g (45%).

Mass spectrum (fast atom bombardment): 319,4 (M+N)+.

2G). Hydrochloride ((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl) acetic who Oxymetazoline-1-yl) acetic acid dissolved in 20 ml of concentrated hydrochloric acid. The solution is boiled for 6 hours and then concentrated. The output is 770 mg (81%).

Mass spectrum (fast atom bombardment): 305 (M+N)+.

2D). Hydrochloride, di-tert.-butyl ester ((R, S)-4-(4-aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl) acetyl-L-aspartyl-L-phenylglycine

To a solution of 340 mg (1 mmol) of hydrochloride ((R, S)-4-(4-(aminoiminomethyl)phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl) acetic acid, 415 mg (1 mmol) of H-Asp (Obut)-Phg-Obut-hydrochloride and 135 mg of HOBt in 7 ml of dimethylformamide at 0C add 220 g (1 mmol) DCC. Type of 0.13 ml of N-ethylmorpholine, until pH 5.0, and stirred for one hour at a temperature of 0C and for two hours at room temperature. Then the mixture was kept until the end of the week in the refrigerator, the precipitate is filtered off under vacuum and the filtrate concentrated. For purification, the substance chromatographic on Sephadex LH20 using a mixture of glacial acetic acid, n-butanol and water. Fractions with pure substance is concentrated and the residue is dissolved in water and subjected to drying by freezing. The output is 377 mg (57%).

Mass spectrum (fast atom bombardment): 665,2 (M+N)+.

2E). ((R, S)-4-(4-(Aminomonosaccharide di-tert.-butyl ester ((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)acetyl)-L-aspartyl-L-phenylglycine dissolved in a mixture of 3.6 ml triperoxonane acid, 0.4 ml of water and 0.4 ml of dimercaptan. Incubated for one hour at room temperature and then concentrate in a water-jet vacuum pump. For purification, the substance chromatographic on Sephadex LH2 using a mixture of glacial acetic acid, n-butanol and water. Fractions with pure substance is concentrated and the residue is dissolved in water and subjected to drying by freezing. The output is 210 mg (72%) of a white solid.

(C=1, methanol).

Mass spectrum (fast atom bombardment): 553,2 (M+N)+.

Connection examples 3-17 receive is similar to the technique of example 2.

EXAMPLE 3

((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3-ethyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 567,2 (M+N)+.

EXAMPLE 4

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 629,0 (M+N)+.

USE Spartel-L-phenylglycine

Mass spectrum (fast atom bombardment): 685,4 (M+N)+.

EXAMPLE 6

((R, S)-4-(4-(Aminoiminomethyl)-phenyl-3-(2,3,4,5,6-pentafluorobenzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 719,3 (M+N)+.

EXAMPLE 7

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-(4-nitrobenzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 674,3 (M+N)+.

EXAMPLE 8

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-(3,5-dimethylbenzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 657,3 (M+N)+.

EXAMPLE 9

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-((2-naphthyl)methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) acetate-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): of 679.2 (M+N)+.

EXAMPLE 10

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-((2-(phenylsulfonyl)-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 783,2 (M+N)+.

EXAMPLE 11

Mass spectrum (fast atom bombardment): 705,2 (M+N)+.

EXAMPLE 12

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-(4-methylbenzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 643,3 (M+N)+.

EXAMPLE 13

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-((1-naphthyl)-methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 679,3 (M+N)+.

EXAMPLE 14

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-((4-biphenylyl)methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 705,3 (M+N)+.

EXAMPLE 15

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-(4-trifloromethyl) -4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 697,3 (M+N)+.

EXAMPLE 16

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-(3,5-bis (trifluoromethyl) benzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 765,2 (M+N)+.

EXAMPLE 17

Mass spectrum (fast atom bombardment): 699,3 (M+N)+.

EXAMPLE 18

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-((4-biphenylyl)-methyl) 4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-N-methylaspartate-L-phenylglycine

18a). Benzyl ester ((S)-3-benzyloxycarbonyl-5-oxo-1,3-oxazolidin-4-yl) acetic acid

3.57 g (10 mmol) -Benzyl ester of L-N-benzyloxycarbonyl-aspartic acid are dissolved in 300 ml of toluene. Add 4.5 g (50 mmol) of trioxane, 5.7 ml (0.03 mmol) of p-toluenesulfonic acid, and 3 a molecular sieves. The mixture is refluxed for 30 minutes and then concentrated in vacuo. For purification, the substance chromatographic on silica gel using a mixture of toluene with ethyl acetate in the ratio 3:2. The output is equal to 2.94 g (80%).

Mass spectrum (fast atom bombardment): 370,2 (M+N)+.

18b). -Benzyl ester of L-N-benzyloxycarbonyl-N-methyl-aspartic acid

886 mg (2.4 mmol) of Benzyl ester ((S)-3-benzyloxycarbonyl-5-oxo-1,3-oxazolidin-4-yl) acetic acid are dissolved in 25 ml of a mixture in the ratio of 1:1 dichloromethane and triethylsilane. Type molecular sieve 3 and then portions add 2 ml of epirate of boron TRIFLUORIDE. Re and the organic phase is then shaken with an aqueous solution of sodium bicarbonate. The organic phase is concentrated and the residue dried in vacuum. The output is 820 mg (92%).

Mass spectrum (fast atom bombardment): 394,3 (M+N)+.

18V). Tert.-Butyl ester of L-N-benzyloxycarbonyl-N-methyl-aspartyl-( - complex benzyl ester) -L-phenylglycine

197 mg (0.5 mmol) -Benzyl ester of L-N-benzyloxycarbonyl-N-methyl-aspartic acid, 122 mg (0.5 mmol) of H-Phg-Obut-hydrochloride, 164 mg (0.5 mmol) of TOTU (O-((cyano-ethoxycarbonylmethylene)amino)-N,N,N',N'-tetramethylethylenediamine) and 225 μl (1.5 mmol) of diisopropylethylamine at a temperature of 0C dissolved in 3 ml of anhydrous dimethylformamide. Stirred for 10 minutes at 0C and 1.5 hours at room temperature and then the reaction solution concentrate. The residue is distributed between ethyl acetate and 1000 ml of a solution of KHSO4/K2SO4(50 kg KHSO4and 100 g of K2SO4in 1000 ml of water). The organic phase is washed three times with sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. For purification, the substance chromatographic on silica gel using a mixture of toluene with ethyl acetate in the ratio of 10:1. The output is 214 mg (76%).

Mass spectrum (bombing of the-L-phenylglycine

2,98 g (5,32 mmol) tert.-Butyl ester of L-N-benzyloxycarbonyl-N-methyl-aspartyl (complex-benzyl ester)-L-phenylglycine dissolved in 300 ml of methanol and autobrite with the addition of 2 N. methanolic solution of hydrogen chloride at a pH value of 6.5 hydronaut in the presence of palladium-on-active charcoal grill. The catalyst is filtered under vacuum through kieselguhr and the filtrate concentrated. The residue is triturated with diethyl ether, filtered under vacuum and dried.

The output is 1,623 g (82%).

Mass spectrum (fast atom bombardment): 337,3 (M+N)+.

D). tert.-Butyl ester ((R, S)-4-(4-aminoiminomethyl)-phenyl) -3-((4-biphenylyl)-methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-N-methyl-aspartyl-L-phenylglycine

To a solution of 123 mg (0.25 mmol) of hydrochloride ((R, S)-4-(4-aminoiminomethyl)-phenyl)-3-((4-biphenyl)-methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid, 84 mg (0.25 mmol) of N-(N-methyl-s)-Phg-Obut-hydrochloride and to 33.8 mg (0.25 mmol) of HOBt in 5 ml of dimethylformamide at a temperature of 0C add 55 mg (0.25 mmol) DCC. Is stirred for one hour at 0 C and for 4 hours at room temperature. Then the reaction mixture is left to stand overnight at room temperature, sediment Hotfile

Mass spectrum (fast atom bombardment): 775,2 (M+N)+.

18E). ((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-((4-biphenylyl)-methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-N-methylaspartate-L-phenylglycine

270 mg of tert.-Butyl ester ((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3-(biphenyl-4-yl)-methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-N-methylaspartate-L-phenylglycine dissolved in a mixture of 2.7 ml triperoxonane acid and 0.3 ml of water. Incubated for one hour at room temperature and concentrated in vacuo water-jet pump. For purification, the substance chromatographic on Sephadex LH20 using a mixture of glacial acetic acid, n-butanol and water. Fractions with pure substance is concentrated and the residue is dissolved in water and subjected to drying by freezing. Output: 30 mg solids white (15%).

Mass spectrum (fast atom bombardment): 719,0 (M+N)+.

EXAMPLE 19

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-N-methylaspartate-L-phenylglycine

The compound of example 19 receive similarly to the method of example 18. Mass spectrum (fast atom bombardment): 643,2 (M+N)+.

Compounds of examples 20-25 get analysemethoden-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 705,2 (M+H)+.

EXAMPLE 21

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-valine

Mass spectrum (fast atom bombardment): 595,2 (M+N)+.

EXAMPLE 22

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-leucine

Mass spectrum (fast atom bombardment): 609,3 (M+N)+.

EXAMPLE 23

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-serine

Mass spectrum (fast atom bombardment): 583,2 (M+H)+.

EXAMPLE 24

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylalanine

Mass spectrum (fast atom bombardment): 643,3 (M+N)+.

EXAMPLE 25

Methyl ester ((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 643,2 (M+N)+.

EXAMPLE 26

Mass spectrum (fast atom bombardment): 629,5 (M+N)+.

EXAMPLE 27

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-(1-substituted-amide)

Mass spectrum (fast atom bombardment): 629,3 (M+N)+.

EXAMPLE 28

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-((1-adamantylamine)amide

Mass spectrum (fast atom bombardment): 643,4 (M+N)+.

The compounds of examples 29 and 30 are diastereomers. One of the compounds of examples 29 and 30 in the center of chirality at the carbon atom in position 4 of the imidazoline cycle has the (S)-configuration, and the other (R)-configuration. Compounds derived from the compound of example 4 by separation using preparative high performance liquid chromatography (HPLC) (eluting agent: a mixture of acetonitrile with water and ammonium acetate in the ratio of 18:83:0,1).

EXAMPLE 29: Diastereoisomer I

((S or R)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 628,3 (M+N)

Mass spectrum (fast atom bombardment): 628,3 (M+N)+.

EXAMPLE 31

Hydrochloride (R, S)-3-((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-phenylpropionic acid

Mass spectrum (fast atom bombardment): 452 (M+N)+.

EXAMPLE 32

Hydrochloride (R, S)-3-((R, S)-4-(4-(aminoiminomethyl)-phenyl-3-ethyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-phenylpropionic acid

Mass spectrum (fast atom bombardment): 466 (M+N)+.

EXAMPLE 33

Hydrochloride (R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-phenylpropionic acid

Mass spectrum (fast atom bombardment): consists 528.3 (M+N)+.

EXAMPLE 34

Hydrochloride 3-(((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino) propionic acid

Mass spectrum (fast atom bombardment): 452,3 (M+N)+.

EXAMPLE 35

((S)-4-(3-aminopropyl)-3-ethyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Connection get Ana is collected using triperoxonane acid.

Mass spectrum (fast atom bombardment): 492,6 (M+N)+.

EXAMPLE 36

((S)-4-(3-Guanidinopropionic)-3-ethyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-D-phenylglycine

36A). Ethyl ester ((S)-4-(3-benzyloxycarbonylamino)-2,5-dioxoimidazolidin-1-yl) acetic acid

52 g (185,7 mmol H-Orn(Z)-och3and 24,15 ml (185,7 mmol) ethylmorpholine dissolved in 500 ml DMF and cooled to a temperature of 0C. Then under stirring was added dropwise 23,77 ml (185,7 mmol) of ethyl ether isocyanatoacetate acid and incubated overnight with increasing temperature to room. To handle the DMF is removed under vacuum and the residue is treated with 500 ml of ethyl acetate. An ethyl acetate solution is washed repeatedly with water, an ethyl acetate phase is cooled overnight at 0C and usageprice the product is filtered. Then again recrystallized from ethyl acetate. The output is a 55.4 g (79%).

Mass spectrum (chemical ionization): 378 (M+N)+.

36B). Ethyl ester ((S)-4-(3-benzyloxycarbonylamino)-3-ethyl-2,5-dioxoimidazolidin-1-yl) acetic acid

6,74 g (17.8 mmol) of Ethyl ester of ((S)-4-(3-benzyl-oxcarbazepine)-2,5-dioxoimidazolidin-1-yl) criminal code of mesilat from 2.18 g (20 mmol) of ethylbromide and incubated over night at room temperature. Upon completion of the reaction the solvent is removed in vacuum and the crude product is separated by chromatography on silica gel using mixtures of dichloromethane with methanol, ethyl acetate and water at a ratio of 99:1:0,1:0,1). The output is 5.4 g (75%).

Mass spectrum (electron spray): 406 (M+N)+.

36V). ((S)-4-(3-benzyloxycarbonylamino)-3-ethyl-2,5-dioxoimidazolidin-1-yl) acetic acid

2,025 g (5 mmol) of Ethyl ester of ((S)-4-(3-benzyloxycarbonylamino)-3-ethyl-2,5-dioxoimidazolidin-1-yl) acetic acid are dissolved in 15 ml of ethanol and mixed with 50 ml of 0.1 n solution of lithium hydroxide. Stirred for four days at room temperature. After the reaction is mixed with 200 ml of water and citric acid set pH 3. The aqueous phase is extracted with ethyl acetate, the organic phase is washed repeatedly with water and concentrated. The remainder chromatographic on silica gel using mixtures of dichloromethane with methanol in the ratio of 8:3. The output is 810 mg (40%).

Mass spectrum (electron spray): 378,3 (M+N)+.

G). Di-tert.-butyl ester ((S)-4-(3-benzyloxycarbonylamino)-3-ethyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-D-phenylglycine

8 the MFA mixed with 87 mg (2.36 mmol) DCC and 290 mg (2,15 mmol) HOBt and stirred for 30 minutes. Then add 928 mg (2,15 mmol) of H-Asp(Obut)-D-Phg-OButand 280 μl (2,15 mmol) N-ethylmorpholine. Left to react overnight. Upon completion of the reaction the solvent is removed in vacuum, the residue is treated with dichloromethane and osadovskaya dicyclohexylphosphino filtered under vacuum. The solution is concentrated and the residue chromatographic on silica gel using mixtures of dichloromethane with methanol, acetic acid and water at a ratio of 97:3:0,1:0,1. Yield 1.5 g (94%).

Mass spectrum (electron spray): 738,4 (M+N)+.

D). Di-tert.-butyl ester ((S)-4-(3-aminopropyl)-3-ethyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-D-phenylglycine

1.5 g (2.03 mmol) of Di-tert.-butyl ether (S)-4-(3-benzyloxycarbonylamino)-3-ethyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-D-phenylglycine dissolved in 70 ml of methanol, mixed with 0.5 g of 10% palladium-on-coal as a catalyst and hydronaut. Upon completion of the reaction the catalyst is filtered off under vacuum, the filtrate is concentrated and the residue dried in vacuum. Output: 1.2 (92%).

Mass spectrum: 604,3 (M+N)+.

E). Di-tert.-butyl ester ((S)-4-(3-guanidinopropionic)-3-ethyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-D-feel)-acetyl-L-aspartyl-D-phenylglycine dissolved in 17 ml of DMF. To the solution add 0,228 g (1.56 mmol) of 1H-pyrazole-1-carboxamide-hydrochloride and 0.8 ml (4,68 mmol) diisopropylethylamine and left to react overnight. Upon completion of the reaction the solvent is removed in vacuo and the residue purified by chromatography on silica gel using mixtures of dichloromethane with methanol, acetic acid and water at a ratio of 95:5;0,5:0,5. Yield 0.68 g (68%).

Mass spectrum (electron spray): 646,4 (M+N)+.

G). ((S)-4-(3-Guanidinopropionic)-3-ethyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-D-phenylglycine

of 0.68 g (1.05 mmol) of Di-tert.-butyl ester ((S)-4-(3-guanidinopropionic)-3-ethyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-D-phenylglycine dissolved in 10 ml of a mixture of triperoxonane acid and water in the ratio 95:5. After 30 minutes the reaction solution was concentrated in vacuo and the residue is treated with 100 ml of water. Then use tar Amberlite IRA 93/45 converted into acetic acid and salt by chromatography on Sephadex G25 clear when using 1 M acetic acid. The output is 0,181 g (32%).

Mass spectrum (fast atom bombardment): 534,3 (M+N)+.

EXAMPLE 37

((S)-4-(3-Aminopropyl)-3-benzyl-2,5-dioxoimidazolidin-1-yl)-the LASS="ptx2">

Mass spectrum (fast atom bombardment): 553,6 (M+N)+.

Compounds of examples 38-40 receive similarly to the method of example 36.

EXAMPLE 38

((S)-4-(3-Guanidinopropionic)-3-benzyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Mass spectrum (fast atom bombardment): 596,4 (M+H)+.

EXAMPLE 39

((S)-4-(3-Guanidinopropionic)-3-benzyl-2,5-dioxoimidazolidin-1-yl)-acetyl-D-aspartyl-L-phenylglycine-L-tyrosine hydrochloride

Mass spectrum (fast atom bombardment): 792.4 M. (M+H)+.

EXAMPLE 40

((S)-4-(3-Guanidinopropionic)-3-benzyl-2,5-dioxoimidazolidin-1-yl)-acetyl-D-glutamyl-L-phenylglycine-L-tyrosine hydrochloride

Mass spectrum (fast atom bombardment): 806,4 (M+N)+.

EXAMPLE 41

((S)-4-(4-(Aminoiminomethyl)-phenyl)-3-((2-naphthyl)-methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

The connection is obtained by dividing ((R, S)-4-(4-aminoiminomethyl)-phenyl)-3-((2-naphthyl)-methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine (see, for example, 9) using the average effective liquid chromatography (idcast,3 (M+N)+.

EXAMPLE 42

(R, S)-4-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-(4-methoxybenzyl)-propionic acid

(+)-Mass spectrum (electron spray): 572,3 (M+N)+.

EXAMPLE 43

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-phenyl-propionic acid

(+)-Mass spectrum (electron spray): consists 528.3 (M+N)+.

EXAMPLE 44

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-((naphthas-1-yl) methyl)-propionic acid

(+)-Mass spectrum (electron spray): 592,4 (M+N)+.

EXAMPLE 45

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-(4-tert.-butylbenzyl)-propionic acid

(+)-Mass spectrum (electron spray): 598,4 (M+N)+.

EXAMPLE 46

(S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-benzyloxycarbonylamino acid

46a). tert.-Butyl ether (S)-3-amino-2-benzile the acid in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of concentrated sulfuric acid under nitrogen pressure of 20 ATM for three days and shaken in an autoclave. Excess isobutylene otdovat and to the remaining solution was added 150 ml of diethyl ether and 150 ml of saturated solution of sodium bicarbonate. The phases are separated and the aqueous phase is extracted with twice 100 ml of diethyl ether. The combined organic phases are washed with twice 100 ml of water and dried over sodium sulfate. After removal of solvent in vacuo get 9,58 g (78%) of product in the form of oil is pale yellow in color.

46B). tert.-Butyl ether (S)-3-(((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-benzyloxy-beniaminoneone acid

208 mg (0.5 mmol) of Hydrochloride ((R, S)-4-(4-aminoiminomethyl)phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid (obtained similarly to the method of example 2A) when using benzylbromide instead of under the conditions and subsequent reactions; see examples 2B).-2G).) and 81.5 mg (0.5 mmol) of HOOBt suspended in 5 ml of DMF and, at 0 ° C is mixed with 110 mg (0.55 mmol) DCC. Stirred for 1 hour at 0 C and for 1 hour at room temperature and then add 147 mg (0.5 mmol) of tert.-butyl ether (S)-3-am is to stand over night at room temperature. The solvent is removed in vacuo and the residue chromatographic on silica gel using mixtures of dichloromethane with methanol, glacial acetic acid and water at a ratio of 9:1:0,1:0,1. After concentration and freeze-drying receive 225 mg (69%) tert-butyl ether (S)-3-(((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylamino acid as colorless solid.

V). (S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-benzyloxycarbonylamino acid

220 mg (0.33 mmol) of tert.-Butyl ether (S)-3-(((R, S)-4- (4-(aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-benzyloxycarbonylamino acid in 5 ml of 90% triperoxonane acid was incubated for one hour at room temperature. After concentration in vacuo the residue chromatographic on silica gel using mixtures of dichloromethane with methanol, glacial acetic acid and water in the ratio 8:2:0,2:0,2.

After concentration of the product fractions and freeze-drying obtain 155 mg (78%) of (S)-3-(((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin the C-spectrum (fast atom bombardment): 601,3 (M+N)+.

EXAMPLE 47

(R)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl-3-((2-naphthyl) methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-benzyloxycarbonylamino acid

The synthesis is carried out analogously to the procedure of example 46 using (R)-3-amino-2-benzyloxycarbonylamino-tert.-butyl complex ester instead of (S)-isomer and 2-bromoethylamine instead of benzylbromide.

(+)-Mass spectrum (electron spray): 651,3 (M+N)+.

EXAMPLE 48

(S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-N-methylamino)-2-benzyloxycarbonylamino acid

The synthesis is carried out analogously to the procedure of example 46 using tert.-butyl ether (S)-2-benzyloxycarbonylamino-3-(N-methylamino) propionic acid (obtained from tert.-butyl ether (S)-3-amino-2-benzyloxycarbonylamino acid similar to S. S. Miller, T. S. Scanlan, J. Am. hem., Soc., 119, 2301 (1997)).

(+)-Mass spectrum (electron spray): 615,3 (M+N)+.

EXAMPLE 49

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl)-acetyl-L-aspartic acid

(+) the Teal)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetyl)-L-aspartyl-L-phenylglycine

50A). (S)-4-(4-Cyanophenyl)-4-methyl-2,5-dioxoimidazolidin (connection 50.1)

6 g (of 22.2 mmol) of (S)-4-(4-Bromophenyl)-4-methyl-2,5-dioxoimidazolidin and 9 g (100,2 mmol) of copper cyanide-(1) in 57 ml of DMF is refluxed for 5 hours. After cooling to room temperature the reaction mixture is mixed with water and ethyl acetate and cooled with 2 N. hydrochloric acid to establish a pH-value of 2. After filtration the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and after filtration the filtrate was concentrated in vacuo. The crude product chromatographic on silica gel using mixtures of dichloromethane with methanol in the ratio 95:5. After concentration containing the product fractions get to 2.74 g (57%) of compounds 50.1.

50B). tert.-Butyl ether (R, S)-2-((S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoic acid (compound 50.2)

To a solution of 1 g (with 4.64 mmol) of the compound 50.1 in 15 ml of absolute DMF in an atmosphere of argon added 128 mg (5,35 mmol) of sodium hydride, stirred for two hours at room temperature, add to 1.23 g (4,9 eshivot 4 hours at room temperature. After adding the following 40 mg of sodium hydride, the mixture was incubated for three days at room temperature, the solvent is removed in vacuo and the residue distributed between ethyl acetate and water.

Using a saturated solution of KHSO4/K2SO4set the pH value is 4, the phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered from the drying agent and filtrat concentrated in vacuo. The residue is filtered through silica gel using a mixture of heptane to ethyl acetate in the ratio 2:1, then 1:2. After concentration containing the product fractions get 666 mg (37%) of compound 50.2.

50V). tert.-Butyl ether (R, S)-2-((S)-4-(4-cyanophenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoic acid (compound 50.3)

To a solution of 990 mg (2.56 mmol) of the compound 50.2 in absolute DMF in an argon atmosphere and at a temperature of 0C added 74 mg (of 3.07 mmol) of sodium hydride, stirred for 1 hour at room temperature, add 334 μl (2,81 mmol) benzylbromide and stirred for 1.5 hours at room temperature. The solvent is removed in vacuo, the residue partitioned between water and utilize sodium sulfate, the drying agent is filtered off and the filtrate was concentrated in vacuo. Obtain 1.22 g (100%) connection 50.3.

50g). tert.-Butyl ether (R, S)-2-((S)-4-(4-(aminohydrocinnamic)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoic acid (compound 50.4)

To a solution of 1.21 g (2.54 mmol) of the compound 50.3 in 30 ml ethanol add 353 mg (between 6.08 mmol) hydroxylaminopurine and 1.05 ml (7.62 mmol) of triethylamine and the mixture is boiled for two hours under reflux. The solvent is removed in vacuum, the residue is treated with a mixture of water with ethyl acetate and after phase separation the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, the drying agent is filtered off and the solvent is removed in vacuum. Gain of 1.16 g (90%) of compound 50.4.

50D). Hydrochloride (R, S)-2-((S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoic acid (compound 50.5)

A solution of 850 mg (1,67 mmol) of the compound 50.4 in 50 ml of acetic acid hydronaut in the presence of Raney Nickel. After two hours the catalyst is filtered off, the filtrate was concentrated in vacuo, the residue is dissolved in 10% acetic acid, the solution is subjected to drying by freezing and OST is the temperature triperoxonane acid is removed in vacuo, the residue is concentrated twice with toluene, mixed with 0.5 n hydrochloric acid and subjected to drying by freezing. Get 700 mg (87%) of compound 50.5.

50 ppm). ((R, S)-2-((S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetyl)-L-aspartyl-L-phenylglycine (connection 50.6)

To a solution of 200 mg (0,422 mmol) of the compound 50.5 and 175 mg (0,422 mmol) of H-Asp (Obut)-Phg-Obut-hydrochloride in 20 ml of absolute DMF added 138 mg (0,422 mmol) of TOTU (O-[cyan (etoxycarbonyl) methylamino]-1,1,3,3-tetramethylethylenediamine) and 216 μl (1,26 mmol) diisopropylethylamine. After stirring for two hours at room temperature the reaction mixture was concentrated in vacuo, the residue is treated with ethyl acetate and the organic phase is washed twice with a saturated solution of sodium bicarbonate and water. After drying over sodium sulfate, filtering and concentrating the filtrate in vacuo obtain 320 mg of crude product, which chromatographic on silica gel using mixtures of dichloromethane with methanol, glacial acetic acid and water at a ratio of 9:1:0,1:0,1. After concentration containing the product fractions, the residue is dissolved in 5 ml of 90% triperoxonane acid, incubated for the remainder concentrated twice with toluene and finally, the residue is dissolved in 20% acetic acid and subjected to drying by freezing. Get 132 mg (46%) of compound 50.6.

(+)-Mass spectrum (electron spray): 685,4 (M+N)+.

G). Synthesis of tert.-butyl ester of D,L-2-bromo-4-methylpentanoic acid (compound 50.7)

To a solution of 2.5 g (12.8 mmol) of D,L-2-bromo-4-methylpentanoic acid in 80 ml of chloroform and 80 ml of tert.-butyl acetate add a 1.96 ml of concentrated sulfuric acid and 0,515 ml of 20% oleum and the mixture is stirred for three hours at room temperature. By adding a 10% aqueous solution of sodium bicarbonate set the pH value to 4. The aqueous phase is separated and extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate. After filtration and concentration of the filtrate in vacuo get 2,62 g (82%) of compound 50.7.

EXAMPLES 51 and 52

The compounds of examples 51 and 52 are diastereomers. They are obtained by separation of a mixture of diastereoisomers of the compounds 50.6 from example 50 using preparative HPLC (phase RP-18; eluting agent: a/b=60:40, where a means the mixture of water/0.1% of triperoxonane acid; means a mixture of 80% acetonitrile (20% water)/0,1% triperoxonane acid) is t (R)-configuration, other (S)-configuration.

EXAMPLE 51

((R or S)-2-((S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetyl)-L-aspartyl-L-phenylglycine

(+)-Mass spectrum (electron spray): 685,4 (M+N)+.

EXAMPLE 52

((S or R)-2-((S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetyl)-L-aspartyl-L-phenylglycine

(+)-Mass spectrum (electron spray): 685,4 (M+N)+.

EXAMPLE 53

(R, S)-3-((R, S)-2-((S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-(2,4-acid) propionic acid

The compound obtained by the reaction of a combination of the hydrochloride of (R, S) -2-((S)-4-(4-(aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoic acid (compound 50.5) hydrochloride and tert.-butyl ether (R, S)-3-amino-3-(2,4-acid) propionic acid and subsequent cleavage complex tert.-butyl ether as described in example 50.

(+) -Mass spectrum (electron spray): 644,4 (M+N)+.

Substituted in position 3-amino acids and esters of amino acids, which are used in PI 3-amino acids and esters of amino acids.

Substituted in position racemic 3-amino receive according to W. M. Radionow, E. A. Postovskaya, J. Am. Chem. Soc., 51, 841 (1929) (see also Houben-Weil, Methods of organic chemistry, volume X1/2, ed. Georg Thieme, Stuttgart, 1958, S. 497). According to known literature methods, of these acids get a methylene or ethyl esters. tert.-Butyl esters substituted in position 3-amino acids derived from these acids by the fact that they are first transferred to benzyloxycarbonylamino, then according to the General method of synthesis of tert get.-butyl ester: to a 1 mmol-benzyloxycarbonylamino acid in 13 ml of absolute dichloromethane added 1.5 mmol of oxalicacid. After stirring for four hours at room temperature, the reaction mixture was concentrated and to the residue is added to 6.5 ml of tert.-butanol. Stirred for 1 hour at room temperature and the reaction mixture was concentrated in vacuo. The residue is treated with ethyl acetate and extracted twice with a saturated solution of sodium bicarbonate and water. The organic phase is dried over sodium sulfate and after filtration the solvent is removed in vacuum. To obtain hydrochloride tert.-butyl esters of amino acids benzyloxycarbonyloxy the I-to-corner.

Enantiomerically pure substituted in position 3 esters of amino acids receive according to S. G. Davis, O. Ichihara, Tetrahedron Asymmetry, 2, 183 (1991); S. G. Davis, N. M. Garrido, O. Ichihara, I. A. S. Walters, J. Chem. Soc., Chem. Commun., 1153 (1993); S. G. Davis, I. A. S. Walters. J. Chem. Soc., Perkin Trans., I, 1129(1994).

EXAMPLE 54

(R, S)-3-((R, S)-2-((S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino) -3-(3,4-methylenedioxyphenyl)-propionic acid

The connection is produced by the interaction of compounds 50.5 hydrochloride tert.-butyl ether (R, S)-3-amino-3-(3,4-methylenedioxyphenyl) propionic acid and subsequent cleavage of the tert.-butyl ether as described in example 50.

(+) -Mass spectrum (electron spray): 628,4 (M+N)+.

Analogously to example 54 provide examples 55-60.

EXAMPLE 55

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-(1-naphthyl)-propionic acid

(+) -Mass spectrum (electron spray): 578,3 (M+N)+.

EXAMPLE 56

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-butyric acid

(+)-Mass spectrum (electron spray clomidsaleyr-1-yl)-acetylamino)-3-(3,4-acid) propionic acid

Mass spectrum (fast atom bombardment): 588,3 (M+N)+.

EXAMPLE 58

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-(3,4-atlanticcity)-propionic acid

(+)-Mass spectrum (electron spray): 586,2 (M+N)+.

EXAMPLE 59

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-(3,5-acid) propionic acid

(+) -Mass spectrum (electron spray): 588,2 (M+N)+.

EXAMPLE 60

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-(3-methoxyphenyl)-propionic acid

(+) -Mass spectrum (electron spray): 558/2 (M+N)+.

EXAMPLE 61

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-(3-methoxyphenyl)-propionic acid

(+) -Mass spectrum (electron spray): 558,2 (M+N)+.

EXAMPLE 62

((R, S)-2-((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-methylacyl)-L-aspartyl-L-phenylglycine

t)-Phg-Obut. HCl ethyl ester split with 6 N. hydrochloric acid.

(+)-Mass spectrum (electron spray): 643,3 (M+N)+.

EXAMPLE 63

((S)-4-(4-(aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-di-Oxymetazoline-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Connection receive according to the method of example 50 so that the connection 50.1 enter into interaction with ethyl ether 2-bromoxynil acid and before the reaction of a combination of peptide H-Asp(Obut)-Phg-OBut. HCl ethyl ester split with 6 N. hydrochloric acid.

(+) -Mass spectrum (electron spray): 629,3 (M+N)+.

EXAMPLE 64

(3-((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-propionyl)-L-aspartyl-L-phenylglycine

Connection receive according to the method of example 50 the fact that racemic compound 50.1 enter into interaction with ethyl ether of 3-bromo-propionic acid and before the reaction of a combination of peptide H-Asp(Obut)-Phg-OBut. HCl ethyl ester split with 6 N. hydrochloric acid.

(+) -Mass spectrum (electron spray): 643,3 (M+N)+.Tyl-L-aspartyl-L-N-methylphenothiazine

Connection receive according to the method of example 63 and using racemic compound 50.1 and instead of H-Asp(OBut)-Phg-Obut. HCl is combined with H-Asp(OBut)-(N-methyl-Phg)-OBut. HCl.

(+) -Mass spectrum (electron spray): 643,3 (M+N)+.

EXAMPLE 66

(R, S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl(N-methylamino)-3-phenyl-propionic acid

(+) -Mass spectrum (electron spray): USD 542.3 (M+N)+.

EXAMPLE 67

(S)-3-(((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-(4-triftoratsetilatsetonom)-propionic acid

To a solution of 300 mg (0,644 mmol) dihydrochloride (S)-3-(((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-aminopropionic acid (obtained from tert.-butyl ether (S)-3-(((R, S)-4(4-(aminoiminomethyl)phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-2-benzyloxycarbonylamino acid by gidrodinamicheskogo off benzyloxycarbonyl groups and cleavage of the tert.-butyl ether using 6 N. hydrochloric acid) is added to 0.22 ml (1,29 mmol) given within 4 hours at room temperature. The solvent is removed in vacuo and the residue chromatographic on silica gel using mixtures of dichloromethane with methanol, acetic acid and water at a ratio of 9:1:0,1:0,1 and methanol. Containing the product fractions are concentrated and chromatographic on Sephadex LH20 using a 40% acetic acid. After concentration containing the product fractions and freeze-drying obtain 145 mg (37%) of the target product.

(+) -Mass spectrum (electron spray): 669,3 (M+N)+.

EXAMPLE 68

((R, S)-4-(4-Aminomethylphenol)-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

(+) -Mass spectrum (electron spray): 616,3 (M+N)+.

EXAMPLE 69

(R, S)-4-(4-Guanidiniocarbonyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

69A). Methyl ester ((R, S)-4-(4-aminomethylphenol)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid

of 7.55 g (20 mmol) of the Methyl ester ((R, S)-4-(4-cyanophenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid (obtained from racemic compounds 50.1 by interacting with methyl ether 2-bromoxynil acid and the interaction of the reaction product with enallage-on-coal hydronaut for 7 hours under hydrogen pressure of 3 ATM. The catalyst is filtered off and the residue chromatographic on silica gel using mixtures of dichloromethane with methanol in the ratio 8:2. After concentration containing the product fractions get 7,6 (100%) methyl ester ((R, S)-4-(4-aminomethylphenol)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid.

B). ((R, S)-4-(4-Aminomethylphenol)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid

3.7 g (9.7 mmol) of the Methyl ester ((R, S)-4-(4-aminomethylphenol)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid in 80 ml of concentrated hydrochloric acid is refluxed for 6 hours. The solution was concentrated in vacuo, the residue is treated with water, filtered and the filtrate is subjected to drying by freezing. Get 2,79 g (78%) ((R, S)-4-(4-aminomethylphenol)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid.

V). ((R, S)-4-(4-Guanidiniocarbonyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid

807 ml (2 mmol) of ((R, S)-4-(4-aminomethylphenol)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid in 20 ml of absolute DMF is mixed with of 1.02 ml (6 mmol) of diisopropylethylamine and then with 220 mg (2 mmol) 1-H-pyrazole-1-carboxamide-hydrochloride. Reacciona the temperature. Again add 0.2 ml (0.4 mmol) of diisopropylethylamine and 44 mg (0.4 mmol) 1-H-pyrazole-1-carboxamide-hydrochloride and stirred for another 6 hours at 50C. The reaction mixture was concentrated in vacuo, the residue triturated twice with diethyl ether, the diethyl ether is removed by decantation and the residue chromatographic on Sephadex LH20 using a mixture of water with butanol and acetic acid in the ratio of 43:4,3:3,5. Receive 682 mg (83%) ((R, S)-4-(3-guanidiniocarbonyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid.

G). ((R, S)-4-(4-Guanidiniocarbonyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

The connection is obtained by combination of ((R, S)-4-(4-guanidiniocarbonyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid with H-Asp(OBut)-Phg-(OBut). HC1 and subsequent cleavage of the tert.-butyl ether, according to the method of example 2.

(+) -Mass spectrum (electron spray): 658,3 (M+N)+.

EXAMPLE 70

((R, S)-4-(4-AMINOPHENYL)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)- acetyl-L-aspartyl-L-phenylglycine

70A). ((R, S)-4-(4-AMINOPHENYL)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid

A solution of 6, is of overmedication according to the synthesis of ((R, S)-4-(4-cyanophenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid from 4-cyanophenylacetic, see example 1; for the introduction of 3-benzyl group (see example 50) in 150 ml of methanol hydronaut for 4 hours in the presence of 10% palladium-on-charcoal grill. The catalyst is filtered off, the filtrate was concentrated in vacuo and the residue triturated with diethyl ether and then filtered under vacuum. Get 3,82 g (60%) ((R, S)-4-(4-AMINOPHENYL)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid.

B). ((R, S)-4-(4-AMINOPHENYL)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

The compound obtained by the reaction of a combination of ((R, S)-4-(4-AMINOPHENYL)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid with H-Asp(OBut)-Phg-(OBut). HCl and subsequent cleavage of the tert.-butyl ether according to example 2, and the residue after removal of triperoxonane acid triturated with diethyl ether, filtered under vacuum and dried in high vacuum.

(+) -Mass spectrum (electron spray): to 602.3 (M+N)+.

EXAMPLE 71

((R, S)-4-(4-Guanidinium)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetyl-L-aspartyl-L-phenylglycine

Soy 70) after converting the amino group in guanidinium using 1-H-pyrazole-1-carboxamide-hydrochloride (described in example 69) and the subsequent combination with H-Asp(OBut)-Phg-(OBut). HCl and cleavage of the tert.-butyl ether according to example 2, and the residue after removal of triperoxonane acid only triturated with diethyl ether, filtered under vacuum and dried in high vacuum.

(+) -Mass spectrum (electron spray): 644,3 (M+N)+.

EXAMPLE 72

((R, S)-4-(4-Aminobenzyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-phenylglycine

Connection get that ((R, S)-4-(4-aminobenzyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid, which is obtained according to example 70 (R, S)-4-(4-nitrobenzyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid (in turn derived from 4-nitrobenzylidene according to the synthesis of ((R, S)-4-(4-cyanophenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid from 4-cyanophenylacetic, see example 1; for the introduction of 3-benzyl group, see example 50), is introduced into the reaction mix with H-Asp(OBut)-Phg-(OBut). HCl according to example 2 and, after cleavage of the tert.-butyl ether using 90% triperoxonane acid residue chromatographic on Sephadex LH20, elwira with a mixture of water with butanol and acetic acid in the ratio of 43:4,3:3,5.

energizin

The connection is obtained from ((R, S)-4-(4-aminobenzyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetic acid (see example 72) by converting the amino group in guanidinium using 1-H-pyrazole-1-carboxamide-hydrochloride (described in example 69), the following combinations with H-Asp(OBut)-Phg-(OBut). HCl and cleavage of the tert.-butyl ether according to example 2, and the residue after removal of triperoxonane acid chromatographic on Sephadex LH20 using a mixture of water with butanol and acetic acid in the ratio of 43:4,3:3,5.

(+) -Mass spectrum (electron spray): 658,3 (M+N)+.

Compounds of examples 74 and 75 can also be obtained by the method of example 67 the fact that, for example, the dihydrochloride of (S)-3-(((R, S)-4-(4-aminoiminomethyl)phenyl-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) acetylamino)-2-aminopropionic acid (see example 67) being in engagement with the relevant carbonylchloride. To get you can also proceed from the hydrochloride tert.-butyl ether (S)-2-amino-3-tert.-butoxycarbonylamino acid. Similarly, can be obtained according to example 67 other benzylcarbamoyl with any substituents benzyl cycle in urethane group.

EXAMPLE 74

EXAMPLE 75

(S)-3-((R, S)-2-((S)-4-(4-Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-2- (2,2-dimethylpropanediamine)-propionic acid

Connection examples 77-79 obtained by solid-phase synthesis according to the General method given in example 76.

EXAMPLE 76

Solid-phase synthesis (General method)

General information

Syntheses on the polymer carrier is carried out according to the sequence of synthesis, which is represented in the diagram. The remains of R51-R55in the diagram indicate residues, which in the formula (I) are in the corresponding position in the molecule, or they may contain functional groups in protected form or in the form of precursors. R51equal to the remaining R14and R15and available in the remains of functional groups can be present in protected form or in the form of precursors. R52together with the CH group to which this balance relates, corresponds to the group (R52corresponds, therefore, one of the substituents denoted as methylene group). R53corresponds to R13; R54corresponds to the group is enikov, in particular, for example, in the present case, amidinopropane is in the form of a precursor of ceanography. R54acorresponds to the group R1-A. R55corresponds to the group R0.

Synthesis of intermediate products on a larger scale is carried out in special reactors inserted Frits in the bottom of the reactor, the synthesis of compounds of formula (I) is carried out in syringes or reaction blocks (Act 496, MultiSynTech). The synthesis of the resin is carried out by use used for analysis beads (FT-IR with ATR device and MS-NMR) and removal of an analytical sample from the resin (HPLC, MS, NMR).

Obtaining structural element aspartic acid Fmoc-Asp (HE) Ollil

40 g (88.7 mmol) FmocAsp (OBut) Ollila mixed with 25 ml triperoxonane acid and stirred for 30 minutes at room temperature. The solvent is removed in a rotary evaporator. The residue is dried in vacuum. Get FmocAsp (HE) Ollil in the form of a yellow oil (33,9 g, 97%).

(+) -Mass spectrum (electron spray): 395,2 (M+N)+.

Linking polymer carrier (stage a in the diagram)

40 g Wang-polystyrene resin (1.1 mmol/g; Bachem) previously subjected to swelling in t is Asp (HE) Ollila, 34.3 g (1.5 equivalent) 1 benzothiazolinone-triprolidine-hexaphosphate (Rubor) and 9.3 ml (1.5 equivalents) of diisopropylethylamine in 120 ml of DMF, the mixture shaken for 10 hours at a temperature of 40C. Upon completion of the reaction the solution is filtered under vacuum and the resin is washed with DMF (5 times 20 ml). After adding a solution of acetanhydride (10 ml) and diisopropylethylamine (9.3 ml, 1.5 equivalents) in 40 ml of DMF, the mixture was again shaken for 30 minutes at room temperature. The solution is filtered under vacuum and washed the resin sequentially, each time three times with 40 ml of DMF, methanol and dichloromethane. The resin is then dried in vacuum. Definition download Fmoc-method specifies the loading of 0.6 mmol/g

Cleavage of allyl groups from the polymer carrier (stage b)

Resin in an argon atmosphere for 5 minutes and at room temperature is subjected to swelling in DMF. After addition of tetrakis (triphenylphosphine)palladium and N-methylpyrrolidine (10 equivalents) and the mixture is shaken in an atmosphere of argon for 6 hours at a temperature of 40C. Upon completion of the reaction the solution is filtered under vacuum and the resin washed consecutively, each time three times with DMF, methanol, tol is Diya (C)

The loaded resin with a free carboxyl function is subjected to swell in DMF for 5 minutes at room temperature. After adding a solution of HOBt (1.2 equivalent), TOTU (1.2 equivalent) and diisopropylethylamine (1.2 equivalent) in dimethylformamide, the mixture shaken for 30 minutes at room temperature. Add 1.2 equivalent of amino compounds in the form of a solution in dimethylformamide. The suspension is shaken at room temperature until complete conversion (monitoring by HPLC). Upon completion of the reaction the solution is filtered under vacuum and the resin washed consecutively, each time three times with DMF, methanol, toluene and dichloromethane and then dried.

The removal of Fmoc-protective group (stage D)

For removal of Fmoc protecting group, the resin is subjected to swell for 5 minutes in DMF at room temperature. After adding a solution of DMF/piperidine (in the ratio 1:1) and shaken for 20 minutes at room temperature. The solution is filtered under vacuum and the process is repeated. Selected for analysis of the sample shows the complete transformation according to a study by HPLC and mass spectrometry. After complete conversion of the resin three times promisewe (stage E)

From halogencarbonic acid (5 equivalents) by introducing them into interaction within 30 minutes diisopropylcarbodiimide (2.4 equivalents) (DIC) in dichloromethane get symmetrical anhydrides. After this time, add 2 equivalent diisopropylethylamine. The mixture was added to the resin and shaken for 12 hours at room temperature after the reaction the solution is filtered under vacuum and the resin sequentially, each time three times, washed with DMF, toluene and dichloromethane and then immediately again enter into interaction.

Instead of using acids and diisopropylcarbodiimide the reaction mix can also be carried out with halogenide acids. The resin for 5 minutes, subjected to swelling in dichloromethane at room temperature. Galodamadruga-halogencarbonic acid (1.5 equivalents) is added in the form of a solution in dichloromethane. After adding a catalytic amount of 4-dimethylaminopyridine and Diisopropylamine (1 equivalent) and the mixture shaken for 8 hours at room temperature. Upon completion of the reaction the solution is filtered under vacuum and the resin sequentially, each time three times, washed with DMF, toluene and dichloromethane and C and (stage F)

4-Cyanobenzylidene (2 equivalent) in dimethylformamide activate at room temperature using databaseconnect (DBU) (2 equivalent). The activated solution after 15 minutes add subjected to swell in DMF for 5 minutes the resin. Upon completion of the reaction the solution is filtered under vacuum and the resin sequentially, each time three times, washed with DMF, methanol, toluene and dichloromethane and then dried.

N-Alkylation as on the polymer carrier (stage G)

The resin is subjected to swell for 5 minutes in dimethylformamide at room temperature. After the addition of cesium carbonate (3 equivalents) is shaken for 30 minutes at room temperature. After adding the alkylating agent (bromide or iodide) is shaken for 6 hours at 50C. Upon completion of the reaction the solution is filtered under vacuum and the resin sequentially, each time three times, washed with DMF, a mixture of methanol with water and DMF in a ratio of 1,5:1,5:7, dimethylformamide, toluene and dichloromethane and then dried.

Instead of using cesium carbonate alkylation can also be carried out with the help of phosphazenes. This resin was subjected to the N",N"-hexamethylphosphoramide (phosphazene base R 1-tert.-butyl) (3 equivalent), shaken for 30 minutes at room temperature. After adding the alkylating agent (bromide or iodide) is shaken for four hours at room temperature. Upon completion of the reaction the solution is filtered under vacuum and the resin sequentially, each time three times, washed with DMF, toluene and dichloromethane and then dried.

Getting amidinopropane from ceanography on the polymer carrier (stage N)

Within 12 hours at room temperature the resin is shaken with a saturated solution of hydrogen sulfide in a mixture of pyridine with triethylamine in the ratio 2:1. The solution is filtered under vacuum and the resin sequentially, each time three times, washed with methanol, DMF, toluene and dichloromethane. After adding 20% aqueous solution under the conditions in a mixture of acetone toluene in the ratio of 4:1 shake following 12 hours at room temperature. The solution is filtered under vacuum and the resin sequentially, each time three times, washed with a mixture of acetone toluene in the ratio of 4:1, DMF, methanol and mixtures of methanol with toluene in the ratio of 4:1. After addition of ammonium acetate (10 equivalents) in a mixture of methanol with toluene and acetic acid in the ratio of 80:16:4 mixture shaken for three hours at ambient temperature, raybaut with DMF, methanol, toluene and dichloromethane and then dried.

Cleavage from the resin (stage J)

For removal of compounds from the resin to the resin add the mixture triperoxonane acid and dichloromethane in the ratio of 1:1. The suspension is shaken for 1 hour, and then the resin is filtered off. The remaining solution was concentrated in vacuo, the residue is purified by chromatography on silica gel (eluting agent: dichloromethane and ethyl acetate).

EXAMPLE 77

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-((2-naphthyl) methyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-valine

(+) -Mass spectrum (electron spray): 645,7 (M+N)+.

EXAMPLE 78

Methyl ester ((R, S)-4-(4-(aminoiminomethyl)-phenyl)-3-((2-naphthyl)-methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-serine

(+) -Mass spectrum (electron spray): 647,7 (M+N)+.

EXAMPLE 79

((R, S)-4-(4-(Aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-L-isoleucine

(+) -Mass spectrum (electron spray): 609,7 (M+N)+.

Study of biological activity

The quality is which is specific for this interaction. Cellular components of the binding, that is, VLA-4 integrins, in their natural form are in the quality of surface molecules in U937-human cells (ATSC CRL 1593), which belong to the group of cells. As a specific binding components used are obtained using genetic engineering soluble recombinant fused protein consisting of extracytoplasmic domains of VCAM-1, and constant region of human immunoglobulin subclass IgGI.

Test method

Analysis to measure adhesion of U937 cells (ATSC CRL 1593 with hVCAM-1 (1-3)-IgG

1. Getting V-1 (1-3)-IgG person and CD4-IgG man

Use genetic construct for the expression of the extracellular domains of VCAM-1 person associated with a genetic sequence more heavy chain immunoglobulin human IgGI (Hinge, a CH2 region and a CH3, Dr. Brian Seed, Chief of the Massachusetts General Hospital, Boston, USA). Soluble protein hVCAM-1(1-3)-IgG contains three aminobenzoic extracellular immunoglobulin-like domain of VCAM-1 person (Damle and Aruffo, Proc. Natl. Acad. Sci. USA, 88, 6403 (1991)). CD4-IgG (Zettlmeissl, etc., DNA and Cell Biology, 9, 347 (1990)) is used as a fused protein for negative control. Recombinant proteins Express under a hundred the tion, in COS-cells (ATSC CRL 1651) (Ausubel and others, Current protocols in molecular biology, John Wiley and Sons, Inc. 1994).

2. Analysis to determine the adhesion of U937 cells with hVCAM-1 (1-3)-IgG

2.1. The microtiter plate with 96 holes (Nunc Maxisorb) with 100 μl per well of a solution of antibody to goat IgG against human (10 μg/ml in 50 mm TRIS, pH 9.5) is incubated for 1 hour at room temperature. After removal of the antibody solution is washed once with SFR (phosphate buffered saline).

2.2. 150 μl per well of Blocking buffer (1% bovine serum albumin in SFR) on plates incubated for 0.5 hour at room temperature. After removing the blocking buffer, washed once with SFR.

2.3. 100 μl per well of the supernatant liquid cell culture transfected COS-cells on plates incubated for 1.5 hours at room temperature. COS cells transferout using the plasmid, which encodes N-terminal, similar to the immunoglobulin domains of VCAM-1, associated with the Fc-part of IgG1man (hVCAM-1(1-3)-IgG). Content hVCAM-1(1-3)-IgG is approximately 0.5-1 µg/ml After removal of the supernatant of the culture was washed once with SFR.

2.4. Plates with 100 µl per well lock the
1 mg/ml bovine svarochnogo albumin in 50 mm HEPES, pH 7.5) and incubated for 20 minutes at room temperature. After removal of the blocking Fc receptor buffer, washed once with SFR.

2.5. Made of 20 μl of binding buffer (100 mmol NaCl, 100 µmol MDS2, 100 µmol MnCl2, 100 µmol CaCl21 mg/ml bovine serum albumin in 50 mm HEPES, pH 7.5) add subjects matter in 10 μl of binding buffer and incubated for 20 minutes. As a control are antibodies against VCAM-1 (BBT, No. VVA) and against VLA-4 (Immunotech, No. 0764).

2.6. U937 cells incubated for 20 minutes in blocking Fc receptor buffer and then in a concentration of 1106ml and 100 μl make a pipette to each well (final volume of 125 μl/well).

2.7. Plate slowly immersed at an angle of 45 in termination buffer (stop buffer (100 mmol NaCl, 100 mmol MgCl2, 100 µmol MnCl2, 100 µmol CaCl2in 25 ml of TRIS, pH 7.5) and take out. The process is repeated.

2.8. Then the plates with 50 µl per well of staining solution (16.7 ug/ml of dye 33258 company HOECHST, 4% formaldehyde and 0.5% TRITON-X-100 in SFR) incubated for 15 minutes.

2.9. Plates are removed, slowly immersed at an angle of 45 with stop buffer (100 is ATEM fluid conducting measurements in the flow cytometer (firm Millipor) (sensitivity 5; filter: wavelength excitation 360 nm, the wavelength of emission 460 nm).

The intensity of the emitted colored U937 cells light is a measure of the number of remaining on the plate, stuck with VCAM-1(1-3)-IgG U937 cells and, thus, a measure of the ability of the added test substance to inhibit the adhesion. Of inhibition of adhesion at various concentrations of test substances calculate the concentration IR50which leads to the suppression of adhesion by 50%.

Given the following test results:

1. Means for inhibiting the adhesion and/or migration of leukocytes or for inhibition of VLA-4 receptor, which are compounds of formula (I)

where W stands for R1-A-C(R13or R1-A-CH=C;

Y represents carbonyl, thiocarbonyl or methylene group;

Z means N(R0), oxygen, sulfur or a methylene group;

A represents the bivalent residue selected from (C1-C6)-alkylene, (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6-alkylen-phenyl, phenylene-(C2-C6-alkenyl or divalent residue of a five or six-membered saturated or Genaside
)-alkyl or double-bound oxygen or sulfur;

In the mean bivalent residue selected from (C1-C6)-alkylene, (C1-C6)-Alcanena, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3-alkylen-phenyl, and divalent (C1-C6)-alkalinity residue may be unsubstituted or substituted by a residue selected from (C1-C8)-alkyl, (C2-C8-alkenyl, (C2-C8)-quinil, (C3-C10)-cycloalkyl, (C3-C10-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl and optionally substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl;

D means C(R2)(R3), N(R3) or CH=C(R3);

E. means tetrazolyl, (R8O)2P(O), OS(O)2, R9NHS(O)2or R10CO;

R means hydrogen, (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)aryl or optionally substituted UB>1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, optionally substituted(C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, optionally substituted heteroaryl, optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl, Cho, (C1-C8)-alkyl-CO, (C3-C12-cycloalkyl-CO, (C3-C12-cycloalkyl-(C1-C8)-alkyl-CO-, (C6-C12-bicycloalkyl-CO, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-tricyclohexyl-CO, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14)-aryl -, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted heteroaryl -, optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-CO, l-(C1-C8)-alkyl-S(O)n, (C6-C12-bicycloalkyl-S(O)n, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-tricyclohexyl-S(O)n, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-S(O)noptionally substituted C6-C14)-aryl-S(O)noptionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-S(O)noptionally substituted heteroaryl-S(OH)nor optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-S(O)nand n = 1 or 2;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p = 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl, (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hidrootkit can also be substituted, or amino group;

X1has one of these for X values or means R'-NH-C(=N-R') with R' and R" independently from each other are specified for the X values;

R2means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C2-C8)-alkenyl-carbonyl, (C2-C8-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, SOP(CH3R14, CONHR14, CSNHR14, COOR15, SOP(CH3R15or CONHR15;

R4means hydrogen or (C1-C28)-alkyl, which optionally one or multiple can be substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - and what SUB>3-alkylphenyl-(C1-C3)-alkyl-aminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18-alkylaminocarbonyl; (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, possibly substituted (C3-C8-cycloalkyl, halogen, the nitro-group, a trifluoromethyl or a residue R5;

R5means optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny or may contain 1, 2 or 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl and independently heterocyclic residues may be single - or multi-substituted by identical or different residues selected from (C1-C18< 6 means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or-N((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2- as well as their esters and amides, and instead of free functional groups can be hydrogen or hydroxymethyl and/or free functional groups can be protected customary in the chemistry of peptides, protective groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-alkoxycarbonyl, and alkyl groups optionally can be substituted amino group and/or aryl residues can be one or several times, preferably once, replaced by identical or different residues, the choice is methyl; the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, which in the aryl part can be substituted and/or in which the peptide bond can be restored to the-NH-CH2;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted;

R9means hydrogen, aminocarbonyl, (C1-C18-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14-aryloxy, amino or mono - or di-((C1-C18)-alkyl)-amino group;

14)-aryl-S(O)2, (C1-C18)-alkyl-S(O)2optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R9NHS(O)2;

R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted C6-C14-aryloxy, amino or mono - or di-((C1-C18)-alkyl)-amino group;

R13means hydrogen, (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R14means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18)-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylimidazole, (C1-C18-alkylsulphonyl-amino-(C2-C18)-alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, in which the aryl residue may be substituted; amino group, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(A)-(C1-C3)-alkyl, tetrazolyl-(C1-C3)-alkyl, halogen, nitro, trifloromethyl and R5;

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which can contain 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents selected from (C1-C4)-alkyl and carbonyl group;

b, C, d and f independently of one another denote 0 or 1, but not all at the same time can mean 0;

e, g and h independently d is the train of their physiologically acceptable salts.

2. Means under item 1, wherein in the formula (I) W implies R1-A-C(R13or R1-A-CH=C; Y represents carbonyl, thiocarbonyl or methylene group; Z means N(R0), oxygen, sulfur or a methylene group; a represents a divalent residue selected from (C1-C6)-alkylene, (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, phenylene-(C2-C6-alkenyl, or the divalent residue of a five or six-membered saturated or unsaturated cycle which may contain 1 or 2 nitrogen atom and may be single or twofold substituted (C1-C6)-alkyl or doubly bound oxygen or sulfur; means a divalent residue selected from (C1-C6)-alkylene, (C2-C6)-Alcanena, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3-alkylen-phenyl; D is C(R2)(R3), N(R3) or CH=C(R3); E. means tetrazolyl, (R8O)2P(O), HOS(O)2, R9NHS(O)2or R10CO; R and R0independently of one another denote hydrogen, (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl, or when n is o, X is-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p = 0, 1, 2 or 3; X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14)-aryl-carbonyl, optionally substituted (C6-C14-aryloxyalkyl, (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue may be substituted; or amino group; X1has one of these for X values or means R'-NH-C(=N-R') with R' and R" independently from each other are specified for the X values; R2means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl; R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, when necessary shall alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C2-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CONHR14, CSNHR14, COOR15, SOP(CH3R15or CONHR15; R4means hydrogen or (C1-C28)-alkyl, which optionally one or multiple can be substituted by identical or different residues R4'; R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)-aminocarbonyl, amino-(C2-C18-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkyl-aminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3) alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18-alkylaminocarbonyl; (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, possibly substituted (C3-C8-cycloalkyl, halogen, the nitro-group, a trifluoromethyl or a residue R5; R5means what
-C14)-aryl-(C1-C8)-alkyl; mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and which may contain 1, 2 or 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl and independently of the heterocycle can be single - or multi-substituted by identical or different residues selected from (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, amino or trifloromethyl; R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to NH-CH2- as well as their esters and amides, and instead of free functional groups can be hydrogen or hydroxymethyl and/or free functional groups can be protected in normal chemistry >-C8) alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-alkoxycarbonyl, and alkyl groups may be substituted amino group and/or aryl residues can be one or several times, preferably once, replaced by the same or different residues selected from (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and trifloromethyl; the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, which in the aryl part can be substituted and/or in which the peptide bond can be restored to the-NH-CH2-; R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted; R9means hydrogen, aminocarbonyl, (C1-C18-alkylaminocarbonyl, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl; R10means hydroxyl, (C1-C18-alkoxyl; (C6-C14)-aryl-(C1-C8- alkoxy, in which the aryl residue may be substituted; optionally substituted C6-C14-aryloxy, amino or mono - or di((C1-C18)-alkyl)-amino group; R11means hydrogen, (C1-C18)-alkyl, R12CO, optionally substituted (C6-C14)-aryl-S(O)2, (C1-C18)-alkyl-S(O)2optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R9NS(O)2; R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18)-alcocer; (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14-aryloxy, amino or mono - or di-((C1-C19)-alkyl)-amino group; R13means hydrogen, (C1-C6)-alkyl, optionally substituted SUP> means hydrogen or (C1-C28)-alkyl, which if necessary can be singly or multiply substituted by identical or different residues selected from hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18)-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18)-alkylaminocarbonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, in which the aryl residue may be substituted; amino group, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted(C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(A)-(C1-C3)-alkyl, tetrazolyl-(C1-C3)-alkyl, halogen, nitro, trifloromethyl and R5; R15means R16-(C1-C6)-alkyl, or R16; R16means 6-24-membered bicyclic erati 1-4 identical or different heteroatoms, selected from nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents selected from (C1-C4)-alkyl and carbonyl group; b, c, d and f independently of one another denote 0 or 1, but not all at the same time can mean 0; e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, as well as stereoisomeric forms and mixtures thereof in any ratio, and physiologically acceptable salts.

3. The means of the formula (I) under item 1, wherein in the formula (I) R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, preferably unsubstituted or mono - or multiply substituted in the aryl residue biphenylyl, naphthylmethyl or benzyl, as well as stereoisomeric forms and mixtures thereof in any ratio, and physiologically acceptable salts.

4. The means of the formula (I) under item 1 and/or 3, characterized in that in formula (I) simultaneously W implies R1-A-CH=C, where a represents phenylenebis residue, or W means1-A-C(Rthe, pentamethylene, cyclohexene, phenylene, finalemail; means a divalent residue selected from methylene, ethylene, trimethylene, tetramethylene, vinylene, phenylene or substituted methylene or ethylene; E. means R10CO; R is hydrogen, (C1-C6)-alkyl or benzyl; R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8) -alkyl; R1means X-NH-C(=NH) -, X-NH-C(=NX)-NH or X-NH-CH2; X represents hydrogen, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C8)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, (C6-C14)-aryl-(C1-C6-alkoxycarbonyl or hydroxyl; R2means hydrogen or (C1-C8)-alkyl; R3means (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, pyridyl, R11NH, R4CO, COOR4, CONHR14, CSNHR14, COOR15and CONHR15. (e, g, and h are independent is logically acceptable salt.

5. The means of the formula (I) according to any one of paragraphs.1-4, characterized in that in formula (I) W implies R1-A-C(R13and R13means (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl, as well as stereoisomeric forms and mixtures thereof in any ratio, and physiologically acceptable salts.

6. The means of the formula (I) according to any one of paragraphs.1-5, characterized in that in formula (I) R3means optionally substituted (C6-C14)-aryl, COOR4, R11NH or CONHR14and other14means the rest of its amino acid-amino-(C2-C8)-alkylamide, it (C1-C8)-Olkiluoto ether or (C6-C14)-aryl-(C1-C4)-Olkiluoto ester, preferably the residue of such amino acids like valine, lysine, phenylglycine, phenylalanine, or tryptophan, or (C1-C8)-alilovic esters, or (C6-C14)-aryl-(C1-C4)-alilovic esters, as well as stereoisomeric forms and mixtures thereof in any ratio, and physiologically acceptable salts.

7. The means of the formula (I) according to any one of paragraphs.1, 3-6, characterized in that in formula (I) simultaneously W means12)(R3); E. means R10CO; R is hydrogen or C1-C4)-alkyl, in particular hydrogen, methyl or ethyl; R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; R1means H2N-C(=NH), H2N-C(=NH)-NH or H2N-CH2; R2means hydrogen; R3means the residue CONHR14; R10means hydroxyl or (C1-C8-alkoxy, preferably (C1-C4-alkoxyl; R13means (C1-C6)-alkyl, (C3-C7-cycloalkyl or benzyl, in particular methyl; R14means methyl, which is substituted by hydroxycarbonyl and the remainder selected from (C1-C4)-alkyl, phenyl and benzyl; or methyl, which is substituted by (C1-C8-alkoxycarbonyl, preferably (C1-C4-alkoxycarbonyl and the remainder selected from (C1-C4)-alkyl, phenyl and benzyl; b, c, and d = 1; e, f, and g = 0; h = 1 or 2, preferably 1, and testo formula (I) according to any one of paragraphs.1, 3 and 4, characterized in that in formula (I) simultaneously W means 1-A-CH=C, where a represents phenylenebis balance or W implies R1-A-C(R13), where a represents the bivalent residue selected from methylene, ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexene, phenylene, finalemail; means a divalent residue selected from methylene, ethylene, trimethylene, tetramethylene, vinylene, phenylene or substituted methylene or ethylene; E. means R10CO; R is hydrogen or C1-C6)-alkyl; R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; R1means X-NH-C(=NH) -, X-NH-C(=NX)-NH or X-NH-CH2; X represents hydrogen, (C1-C6-alkylsulphonyl, (C1-C6)-alkoxy-carbonyl, (C1-C8)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, (C6-C14)-aryl-(C1-C6-alkoxycarbonyl or hydroxyl; R2means hydrogen or (C1-C8)-alkyl; R3means CONHR15or CONHR14and R14in this case, means unsubstituted or; R15means R16-(C1-C6)-alkyl, or R16and R16means 7-12-membered bridged bicyclic or tricyclic residue, which is saturated or partially unsaturated and which may contain 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents selected from (C1-C4)-alkyl and carbonyl group, and in particular, R15means adamantly balance or adamantylamine residue; e, g, h, independently of one another denote 0, 1, 2 or 3; b, C, d = 1, as well as stereoisomeric forms and mixtures thereof in any ratio, and physiologically acceptable salts.

9. The means of the formula (I) according to any one of paragraphs.1, 3-5 and 8, characterized in that in formula (I) simultaneously W means1-A-C(R13); Y represents a carbonyl group; Z means N(R0); And means ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexyl, phenylene or phenylenedi; means unsubstituted or substituted methylene residue; D is C(R2)(R3); E. means R10CO; R is hydrogen or C1-C4)-alkyl, in particular hydrogen, methyl or e is C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; R1means H2N-C(=NH), H2N-C(=NH)-NH or H2N-CH2; R2means hydrogen; R3means CONHR15or CONHR14and R14in this case, refers to unsubstituted or substituted by one or more (C6-C10)-aryl residues (C1-C6)-alkyl residue; R10means hydroxyl or (C1-C8-alkoxy, preferably (C1-C4-alkoxyl; R13means (C1-C6)-alkyl, (C3-C7-cycloalkyl or benzyl, in particular methyl; R15means adamantly balance or adamantylamine residue; b, C, d = 1; e, f, g = 0; h = 1 or 2, preferably 1, as well as stereoisomeric forms and mixtures thereof in any ratio, and physiologically acceptable salts.

10. The means of the formula (I) according to any one of paragraphs.1, 3, 4 and 5, characterized in that in formula (I) simultaneously W means 1-A-C(R13); Y represents a carbonyl group; Z means N(R0); And means ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexyl, phenylene, finaltotal; means unsubstituted or substituted methylene number 1-C4)-alkyl, in particular hydrogen, methyl or ethyl; R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; R1means H2N-C(=NH), H2N-C(=NH) -NH or H2N-CH2; R2means hydrogen; R3means unsubstituted phenyl or nattily balance; phenyl residue or nattily residue, substituted by one, two or three identical or different residues selected from (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, halogen, trifloromethyl, nitro, methylenedioxy, Ethylenedioxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, cyanopropyl, phenyl, fenoxaprop, benzyl and benzyloxy; peredelnyj residue, (C1-C4)-alkyl residue, (C2-C4)-alkanniny residue, (C2-C4)-alkynylaryl balance or (C5-C6)-cycloalkenyl residue, and in particular, R3means unsubstituted or substituted phenyl or nattily residue; R10means hydroxyl or (C1-C8)- the group ethoxypropan, propoxylate and isopropoxy; R13means (C1-C6)-alkyl, (C3-C7-cycloalkyl or benzyl, in particular methyl; b, C and d = 1; e, f, and g = 0; h = 1 or 2, preferably 1, as well as stereoisomeric forms and mixtures thereof in any ratio, and physiologically acceptable salts.

11. The means of the formula (I) according to any one of paragraphs.1, 3, 4 and 5, characterized in that in formula (I) simultaneously W means1-A-C(R13);

Y represents a carbonyl group;

Z means N(R0);

And means ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexyl, phenylene, finaltotal;

In means unsubstituted or substituted methylene residue or ethylene residue; D is C(R2)(R3); E. means R10CO; R is hydrogen or C1-C4)-alkyl, in particular hydrogen, methyl or ethyl; R0means (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; R1means H2N-C(=NH), H2N-C(=NH)-NH or H2N-CH2; R2means hydrogen; R3means R10
mean residue selected from hydroxyl, metoxygroup, ethoxypropan, propoxy - and isopropoxy; R13means (C1-C6)-alkyl, (C3-C7-cycloalkyl or benzyl, in particular methyl; b, C, d and e = 1; f and g = 0; h = 0, as well as stereoisomeric forms and mixtures thereof in any ratio, and physiologically acceptable salts.

12. The means of the formula (I) according to any one of paragraphs.1, 3-11, characterized in that the means group substituted methylene residue or substituted ethylene residue as substituents contains a residue selected from (C1-C8)-alkyl, (C2-C6-alkenyl, (C2-C6)-quinil, (C3-C8)-cycloalkyl, in particular (C5-C6)-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, in particular (C5-C6-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl, optionally substituted in the aryl residue (C6-C10)-aryl-(C1-C4)-alkyl, optionally substituted heteroaryl and optionally substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl, as well as stereoisomeric forms and their Messiah. .1, 3-12, characterized In that means unsubstituted methylene residue or a methylene residue, substituted (C1-C8)-alkyl residue, as well as stereoisomeric forms and mixtures thereof in any ratio, and physiologically acceptable salts.

14. The means of the formula (I) according to any one of paragraphs.1-13 and/or its physiologically acceptable salts, characterized in that suitable for receiving drugs to reduce the intensity of inflammation.

15. The means of the formula (I) according to any one of paragraphs.1-13 and/or its physiologically acceptable salts, characterized in that suitable to obtain drugs for treatment or prevention of rheumatoid arthritis, inflammatory diseases of the digestive tract, systemic lupus erythematosus or inflammatory diseases of the Central nervous system.

16. The means of the formula (I) according to any one of paragraphs.1-13 and/or its physiologically acceptable salts, characterized in that suitable to obtain drugs for the treatment or prophylaxis of asthma or allergies.

17. The means of the formula (I) according to any one of paragraphs.1-13 and/or its physiologically acceptable salts, characterized in that suitable to obtain drugs for the treatment or prevention the Oia transplants of organs, to suppress tumor growth or metastasis of tumors or to treat malaria.

18. The means of the formula (I) according to any one of paragraphs.1-13 and/or its physiologically acceptable salts, characterized in that suitable for inhibiting the adhesion and/or migration of leukocytes or for inhibition of VLA-4 receptor.

19. The means of the formula (I) according to any one of paragraphs.1-13 and/or its physiologically acceptable salts, characterized in that suitable for the treatment or prevention of diseases in which takes place in an undesirable scale leukocyte adhesion and/or migration of leukocytes, or diseases in which play the role of VLA-4-dependent adhesion processes for the treatment or prevention of rheumatoid arthritis, inflammatory diseases of the digestive tract, systemic lupus erythematosus, inflammatory diseases of the Central nervous system, asthma, allergies, cardiovascular diseases, arteriosclerosis, restenosis, diabetes, prevent damage to transplants of organs, to suppress tumor growth or metastasis of tumors, for the treatment of malaria or reduce the intensity of inflammation funds.

20. 5-Membered heterocycles of the formula (Ib)

where W stands for R1-C6)-alkylene, (C3-C7)cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, phenylene-(C2-C6-alkenyl; or a bivalent residue of a five - or six-membered saturated or unsaturated cycle which may contain 1 or 2 nitrogen atom and may be single or twofold substituted (C1-C6)-alkyl or double-bound oxygen or sulfur;

In the mean bivalent residue selected from (C1-C6)-alkylene, (C2-C6)-Alcanena, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3)-alcelaphine;

D means C(R2)(R3);

E. means tetrazolyl, (R8O)2P(O), HOS(O)2, R9NS(O)2or R10CO;

R means hydrogen, (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R0means (C7-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the arilje>or X1-NH-(CH2)pand p = 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; (C6-C14)-aryl-(C1-C6)-alkoxy, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=NR), where R' and R" independently from each other are specified for the X values;

R2means hydrogen or phenyl;

R3means hydrogen, COOR4, SOP(CH3R4or CONHR4;

R4means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues R4';

R4'oznachaet the 2-C18-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkyl-aminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18-alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, optionally substituted (C3-C8-cycloalkyl, halogen, the nitro-group, a trifluoromethyl or a residue R5;

R5means optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and which may contain one, two or three identical or different heteroatoms selected from nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl and independent of the heterocyclic residue may be single or multiply alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids, aminokisloty, possibly N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2and their esters or amides, and instead of free functional groups may optionally be hydrogen or hydroxymethyl and/or free functional groups can be protected customary in the chemistry of peptides, protective groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-allyloxycarbonyl, and alkyl groups optionally can be substituted amino group and/or aryl residues can be one or many of the8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and trifloromethyl; the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2-; R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted;

R9means hydrogen, aminocarbonyl, (C1-C18-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted C6-C14)-arith friend can mean 0 or 1, however, not all at the same time can mean 0;

h= 0, 1, 2, 3, 4, 5 or 6

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

21. 5-Membered heterocycles of the formula (Ib) p. 20 and/or their physiologically acceptable salts are used as medicines.

22. Pharmaceutical drug-based active agents and conventional additives, characterized in that the active substance it contains one or more compounds of formula (Ib) p. 20 and/or their physiologically acceptable salts in an effective amount, as well as pharmaceutically acceptable carriers and/or additives target.

23. 5-Membered heterocycles of the formula (IC)

where W stands for R1-A-C (R13);

Y represents carbonyl, thiocarbonyl or methylene group;

And means phenylenebis balances;

In the mean bivalent residue selected from (C1-C6)-alkylene, (C2-C6)-Alcanena, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3-alkylene-phenylene;

D means C(R2)(R3), N(R3) or CH=C(R3);

E. means tetrazol the -C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R0means optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p = 0, 1, 2 or 3;

X means hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; and (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxy, (C6-C14)-aryl-(C1-C6-paxil, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=N-R') with R' and R" independently of tradimenti substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C2-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CONHR14, CSNHR14, COOR15, CON(CH3R15or CONHR15;

R4means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)-aminocarbonyl, amino-(C2-C18-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3)-and the -C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, optionally substituted (C3-C8-cycloalkyl, halogen, the nitro-group, a trifluoromethyl or a residue R5;

R5means optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and which may contain one, two or three identical or different heteroatoms selected from nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl and independent of the heterocyclic residue may be substituted one or more times, equal or different residues selected from (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or 4)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2- as well as their esters and amides, and instead of free functional groups may optionally be hydrogen or hydroxymethyl and/or free functional groups can be protected customary in the chemistry of peptides groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl, or (C6-C14)-aryl-(C1-C18-alkoxycarbonyl, and alkyl groups optionally can be substituted by amino and/or and aryl residues can be one or several times, preferably once, replaced by the same or different residues selected from (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and trifloromethyl; the residue of a natural or synthetic amino acids, aminokisloty when neobhodimosti or dipeptide, which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2-;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted;

R9means hydrogen, aminocarbonyl, (C1-C18-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means hydrogen, (C1-C18)-alkyl, R12CO, optionally substituted (C6-C14)-aryl-S(O)2, (C1-C18)-alkyl-S(O)2if necessary someseni the 12 means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, which is also in the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype or mono - or di-((C1-C18)-alkyl)amino;

R13means (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R14means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18)alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18)alcosan in the aryl residue; amino group, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(A)-(C1-C3)-alkyl, tetrazolyl-(C1-C3)-alkyl, halogen, nitro, trifloromethyl and R5;

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which may also contain 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents selected from (C1-C4)-alkyl and carbonyl group;

b, C, d and f independently of one another denote 0 or 1, but not all at the same time can mean 0;

e, g and h, independently of one another denote 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

24. 5-Membered Gederite.

25. Pharmaceutical drug-based active agents and conventional additives, characterized in that the active substance it contains one or more compounds of formula (IC) on p. 23 and/or their physiologically acceptable salts and pharmaceutically acceptable carriers and/or additives target.

26. 5-Membered heterocycles of the formula (Id)

where W stands for R1-A-C(R13or R1-A-CH=C;

Y represents carbonyl, thiocarbonyl or methylene group;

Z means N(R0);

A represents the bivalent residue selected from (C1-

WITH6)-alkylene, (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, phenylene-(C2-C6-alkenyl; or a bivalent residue of a five - or six-membered saturated or unsaturated cycle which may contain 1 or 2 nitrogen atom and may be single or twofold substituted (C1-C6)-alkyl or double-bound oxygen or sulfur;

In the mean bivalent (C1-C6)-alkalinity residue, which is substituted by a residue selected from (C1-C8)-alkyl, (C2-C8-alkenyl, (C2-C86-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl and optionally substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl;

D means C(R2)(R3), N(R3) or CH=C(R3);

E. means tetrazolyl, (R8O)2P(O), HOS(O)2, R9NHS(O)2or R10WITH;

R means hydrogen, (C1-C8)-alkyl, (C3-C8-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R0means hydrogen, (C1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl optionally is-alkyl, SNO, (C1-C8)-alkyl-CO, (C3-C12-cycloalkyl-WITH, (C3-C12-cycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-bicycloalkyl-CO, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-tricyclohexyl-WITH, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14) -aryl -, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted heteroaryl -, optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-CO, (C1-C8)-alkyl-S(O)n, (C3-C12-cycloalkyl-S(OH)n, (C3-C12-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-bicycloalkyl-S(OH)n, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-tricyclohexyl-S(OH)n, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-S(O)noptionally substituted (C6-C14)-aryl-S(O)noptionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-S(O)nwhen neibhour-(C1-C8)-alkyl-S(O)nand n = 1 or 2;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p = 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=N-R') with R' and R" independently from each other are specified for the X values;

R2means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8)-the CEC is SUB>-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C2-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CONHR14, CSNHR14, COOR15, CON(CH3R15or CONHR15;

R4means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl) aminocarbonyl, amino-(C2-C18-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl-(C1-C3-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18-alkylaminocarbonyl; (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C5;

R5means optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and which may contain one, two or three identical or different heteroatoms selected from nitrogen, oxygen and sulfur; the remainder R6or the remainder R6CO-, and aryl residue and independently heterocyclic residue can be single - or multi-substituted by identical or different residues selected from (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means R7R8N, R7O or R7S or amino acid side chain residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny seminarista or dipeptide, which in the aryl part can be substituted and/or catoon functional groups may optionally be hydrogen or hydroxymethyl and/or free functional groups can be protected customary in the chemistry of peptides, protective groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C1-C18-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-allyloxycarbonyl, and alkyl groups may optionally be protected amino group and/or aryl residues can be one or several times, preferably once, replaced by the same or different residues selected from (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino and three-formatia; the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2-;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, which is18-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted ((C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means hydrogen, (C1-C18)-alkyl, R12CO, optionally substituted (C6-C14)-aryl-S(O)2, (C1-C18)-alkyl-S(O)2optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R9NHS(O)2;

R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; when necessary the l)-amino group;

R13means hydrogen, (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R14means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18)-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C1-C3-alkylphenyl- (C1-C3)-alkylaminocarbonyl, (C1-C18)-alkylcarboxylic-(C2-C18)-alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, in which the aryl residue may be substituted; amino group, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(A)-(C1="ptx2">

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which can contain 1-4 identical or different heteroatoms selected from the series nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents selected from (C1-C4)-alkyl and carbonyl group;

C, d and f independently of one another denote 0 or 1, but not all at the same time can mean 0;

e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

27. 5-Membered heterocycles of the formula (I) p. 26, where both W implies R1-A-C(R13);

Y represents a carbonyl;

Z means N(R0);

A represents the bivalent residue selected from (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, or the divalent residue of a five or six-membered saturated or unsaturated cliam or double-bound oxygen or sulfur;

In the mean divalent methylene or ethylene residue, which is substituted by a residue selected from (C1-C8)-alkyl, (C2-C8-alkenyl, (C2-C8)-quinil, (C3-C10)-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl and optionally substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl;

D means C(R2)(R3);

E. means tetrazolyl or R10WITH;

R means hydrogen or (C1-C8)-alkyl;

R0means hydrogen, (C1-C8)-alkyl, (C3-C12-cikalkis, (C3-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-ayrilmam the rest of heteroaryl-(C1-C8)-alkyl, CHD, (C1-C8)-alkyl-CO, (C3-C12-cycloalkyl-WITH, (C3-C12-cycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-bicycloalkyl-WITH, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-tricyclohexyl-CO, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14)-aryl -, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted heteroaryl -, optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-CO; (C1-C8)-alkyl-S(O)n, (C3-C12-cycloalkyl-S(OH)n, (C3-C12-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-bicycloalkyl-S(OH)n, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-S(O)n, (C6-C12-tricyclohexyl-S(O)n, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-S(O)noptionally substituted (C6-C14)-aryl-S(O)noptionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-S(O)n1-C8)-alkyl-S(O)nand n = 1 or 2;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p = 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; and (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; cyano, hydroxyl, (C1-C6-alkoxyl; and (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue may be substituted; or an amino group;

X1has one of these for X values or means R'-NH-C(=N-R') with R' and R" independently from each other are specified for the X values;

R2means hydrogen or (C1-C8)-alkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(2
-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, CON(CH3R14, CONHR14, CON(CH3R15or CONHR15;

R5means optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; mono - or mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and which may contain one, two or three identical or different heteroatoms selected from nitrogen, oxygen and sulfur; or denotes a residue R6CO-, and aryl residue and independently heterocyclic residue can be single - or multi-substituted by identical or different residues selected from (C1-C8)-alkyl, (C1-C8)-alkoxyl, halogen, nitro, amino or trifloromethyl;

R6means the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, which aryl residue that is diseny conventional in the chemistry of peptides, protective groups;

R10means hydroxyl, (C1-C18-alkoxy, (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means R12CO, optionally substituted (C6-C14)-aryl-S(O)nor (C1-C18)-alkyl-S(O)2;

R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18)alkoxy; (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; or optionally substituted (C6-C14)-alloctype;

R13means hydrogen or (C1-C14)-alkyl;

R14means (C1-C10)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, (C6-C148)-alkoxyl, (C1-C8)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, tetrazolyl-(C1-C3)-alkyl, trifloromethyl and R5;

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which can contain 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents selected from (C1-C4)-alkyl and carbonyl group,

c and d = 1 and f = 0;

e and h independently of one another denote 0 or 1, and g = zero; in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

28. 5-Membered heterocycles of the formula (Id) on p. 26 and/or p. 27, where the residue, which is substituted by the group, is a (C1-C8)-alkyl residue, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

29. 5-Membered heterocycles of the formula (Id) according to Liu the ptx2">

30. Pharmaceutical drug-based active agents and conventional additives, characterized in that the active substance it contains one or more compounds of formula (Id) according to any one of paragraphs.26-28 and/or their physiologically acceptable salts in an effective amount and a pharmaceutically acceptable carriers and/or additives target.

31. 5-Membered heterocycles of the formula (S)

where W stands for R1-A-C(R13or R1-A-CH=C;

Y represents carbonyl, thiocarbonyl or methylene group,

Z means N(R0), oxygen, sulfur or a methylene group;

A represents the bivalent residue selected from (C1-C6)-alkylene, (C3-C7)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-alcelaphinae, phenylene-(C2-C6-alkenyl, or the divalent residue of a five or six-membered saturated or unsaturated cycle which may contain 1 or 2 atom of isota and can be single or twofold substituted (C1-C6)-alkyl or double-bound oxygen or sulfur;

In the mean bivalent residue selected from (C1-C6)-alkylene, (C2-C6)-Alcanena, Fe>(R3), N(R3) or CH=C(R3);

E. means tetrazolyl, (R8O)2P(O), HOS (O)2, R9NHS(O)2or R10WITH;

R means hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, optionally substituted (C6-C14)-aryl or optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R0means CHO, (C1-C8)-alkyl-CO, (C3-C12-cycloalkyl-WITH, (C3-C12-cycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-bicycloalkyl-WITH, (C6-C12-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-C12-tricyclohexyl-WITH, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14)-aryl -, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted heteroaryl -, optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-CO, (C1-C8)-alkyl-S(O)n, (C3-C12-cycloalkyl-S(O)n, (C3-C12-cycloalkyl-(C1-C8)-alkyl-S(O)n, (C6 , (C6-C12-tricyclohexyl-S(OH)n, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-S(O)noptionally substituted (C6-C14)-aryl-S(O)noptionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-S(O)noptionally substituted heteroaryl-S(OH)nor optionally substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-S(O)nand n = 1 or 2;

R1means X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p = 0, 1, 2 or 3;

X represents hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C14-arylcarbamoyl, optionally substituted (C6-C14-aryloxyalkyl; and (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, in which the aryl residue may be substituted; (R8O)2P(O), cyano, hydroxyl, (C1-C6-alkoxyl; and (C6-C14)-aryl-(C1-C6-alkoxy, in which the aryl residue also R"), and R' and R" independently from each other are specified for the X values;

R2means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3means hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C2-C8-alkenylboronic, (C2-C8-alkenylboronic, pyridyl, R11NH, R4CO, COOR4, CON(CH3R14, CONHR14, CSNHR14, COOR15, CON(CH3R15or CONHR15;

R4means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues R4';

R4'means hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)-aminocarbonyl, amino-(C2-C18-alkylaminocarbonyl, is ylamino-(C1-C3-alkylphenyl-(C1-C18-alkylaminocarbonyl, (C2-C18)-alkylcarboxylic-(C2-C18-alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted; an amino group, mercaptopropyl, (C1-C18-alkoxy, (C1-C18-alkoxycarbonyl, optionally substituted (C3-C8-cycloalkyl, halogen, the nitro-group, a trifluoromethyl or a residue R5;

R5means optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; mono - or bicyclic 5-to 12-membered heterocycle, which may be aromatic, partially gidrirovanny or fully gidrirovanny and may contain one, two or three identical or different heteroatoms selected from nitrogen, oxygen and sulfur; the remainder R6or the remainder R6-CO-, and aryl residue and independently heterocyclic residue can be single - or multi-substituted by identical or different residues selected from (C1-C18)-alkyl, (C1-C18)-alkoxyl, halogen, nitro, nokiatool side chain, the residue of a natural or synthetic amino acids, aminokisloty, optionally N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2- as well as their esters and amides, and instead of free functional groups may optionally be hydrogen or hydroxymethyl and/or free functional groups can be protected customary in the chemistry of peptides, protective groups;

R7means hydrogen, (C1-C18)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18-alkylsulphonyl, (C1-C18-alkoxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C8-alkylsulphonyl or (C6-C14)-aryl-(C1-C18-alkoxycarbonyl, and alkyl groups optionally substituted by amino group and/or aryl residues can be one or several times, preferably once, replaced by the same or different residues selected from (C1-C8)-alkyl, (C1-C8)-alkoxyl, acid, if necessary, N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination or dipeptide, in which the aryl residue may also be substituted and/or in which the peptide bond can be restored to the-NH-CH2-;

R8means hydrogen, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted;

R9means hydrogen, aminocarbonyl, (C1-C18-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, optionally substituted (C6-C14-allumination, (C1-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10means hydroxyl, (C1-C18-alkoxyl; and (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl)amino;

R11means hydrogen, (C1-C182optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, or R9NHS(O)2;

R12means hydrogen, (C1-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, optionally substituted (C6-C14)-aryl, (C1-C18-alkoxyl; (C6-C14)-aryl-(C1-C8-alkoxy, in which the aryl residue may be substituted; optionally substituted (C6-C14)-alloctype, amino or mono - or di-((C1-C18)-alkyl) amino;

R13means hydrogen, (C1-C6)-alkyl optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R14means hydrogen or (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from hydroxyl, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C18)-alkyl)aminocarbonyl, amino-(C2-C18)-alkylaminocarbonyl, amino-(C1-C3-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C11-C18)-alkylcarboxylic-(C2-C18)-alkylaminocarbonyl; and (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl, in which the aryl residue may be substituted; amino group, mercaptopropyl, (C1-C18)-alkoxyl, (C1-C18)-alkoxycarbonyl, optionally substituted (C3-C8)-cycloalkyl, HOS(O)2-(C1-C3)-alkyl, R9NHS(O)2-(C1-C3)-alkyl, (R8O)2P(O)-(C1-C3)-alkyl, tetrazolyl-(C1-C3)-alkyl, halogen, nitro, trifloromethyl and R5;

R15means R16-(C1-C6)-alkyl, or R16;

R16means 6-24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which can contain 1-4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, and which may also be substituted by one or more identical or different substituents selected from (C1-C4)-alkyl and carbonyl group;

b, C, d and f independently of one another denote 0 or 1, but not all at the same time can mean 0;

e, g and h independently from the deposits, and their physiologically acceptable salts.

32. 5-Membered heterocycles of the formula (Ie) on p. 31 and/or their physiologically acceptable salts are used as medicines.

33. Pharmaceutical drug-based active agents and conventional additives, characterized in that the active substance it contains one or more compounds of formula (Ie) on p. 31 and/or their physiologically acceptable salts in an effective amount and a pharmaceutically acceptable carriers and/or additives target.

 

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The invention relates to new phenylimidazoline formula 1 by the method of their preparation and to pharmaceutical compositions based on

The invention relates to new derivatives of imidazolidine formula (I), where W denotes the R1-A-C(R13), Z denotes oxygen, And represents a simple bond or alkylene, denotes a bivalent residue of group (C1-C6-alkylene, phenylene, and divalent alkalinity residue may be substituted or unsubstituted, E denotes R10CO, R denotes hydrogen or (C1-C8)-alkyl, R0denotes hydrogen, (C1-C8)-alkyl, if necessary substituted (C6-C14)-aryl, substituted heteroaryl, R1indicates, if necessary, replaced the rest of the series phenyl, thienyl or pyridyl, R2denotes hydrogen or alkyl, R3denotes hydrogen, alkyl, substituted aryl, substituted heteroaryl, R11NH, CONHR4, CONHR15, R4denotes hydrogen, alkyl, which can be repeatedly replaced, R5denotes a substituted aryl, R10represents hydroxy or alkoxy, R11denotes hydrogen, R12a-CO, R12a-O-CO, R12b-CO, R12adenotes alkyl, alkenyl, cycloalkyl, substituted aryl, R12bmeans R12a-NH, R13denotes hydrogen or alkyl, R15means R16-alkyl, or R16

The invention relates to a derivative of sulfoaluminate and sulphoniumhydroxide acid of formula I, its pharmaceutically acceptable salts, where W is-HE-or-NHOH; X denotes (a) a heterocyclic radical selected from the group comprising imidazolines, dihydrobenzofuranyl and so on, b) -NR1SO2R2where R1denotes a hydrogen atom, R2denotes an unsubstituted phenylalkyl and so on; Y represents carbon or sulfur, with the proviso that when Y represents carbon, n is equal to 2; Z represents phenyl, optionally substituted with halogen, unsubstituted alkoxy, phenyloxy, optionally substituted with halogen, phenylacetonitrile, 4-methylpiperazine, 4-phenylpiperidine, pyridyloxy, -NR'1COR'2, -SO2R'2where R'1denotes a hydrogen atom, R'2denotes phenyl, optionally substituted by hydroxy or phenyl, pyridinyl, substituted-CF3; m denotes an integer from 1 to 4, n represents an integer of 1 or 2

The invention relates to compounds of the formula I, in all stereoisomeric forms and mixtures in any ratio, where NV denotes maleic acid, to a method for producing compounds of formula I, which lies in the fact that compounds of the formula II exercise anionic exchange with maleic acid and/or maleate
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