Substituted derivatives of imidazolidine, method of preparation and pharmaceutical drug

 

(57) Abstract:

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the same or different; R1- N, (C1-C10)-alkyl, which optionally can be once3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C6)-alkoxy, and the remains of R8independently from each other can be Odie is 1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12A O-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which optionally can be singly or multiply substituted by fluorine, (C3-C126-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor. 3 N. and 20 C.p. f-crystals, 13 tables.

The present invention relates to substituted derivatives of imidazolidine formula I

in which B, E, W, Y, R, R2, R3, R301, e and h have the following values. The compounds of formula I are valuable active substances of medicines, which are suitable, for example, for the treatment and prevention of inflammatory diseases such as rheumatoid arthritis or allergic diseases. The compounds of formula I are inhibit is aptara VLA-4. They are suitable for universal therapy or prevention of diseases which are caused by unwanted scale of leukocyte adhesion and/or migration of leukocytes or associated with, or which play a role in the interaction cell-cell or cell-matrix based on the interactions of VLA-4 receptors with their ligands. Further, the invention relates to a method for producing compounds of the formula I, to their use, in particular as active ingredients of pharmaceuticals and to pharmaceutical preparations containing compounds of formula I.

Integrins are adhesion receptors that play a significant role in the binding process cell-cell and cell-extracellular matrix (ECM). They have a heterodimeric structure and show a wide cellular distribution and a high degree of evolutionary conservation. To integrins belong, for example, the fibrinogen receptor on platelets, which interacts primarily with the RGD sequence of fibrinogen or vitronectin receptor on osteoclasts, which interacts primarily with the RGD sequence of vitronectin or osteopontin. Integrins are divided into three large groups: 2-subfamily with representatives LF the STV 1 and 3, the representatives of which contribute mainly to the attachment of cells to components of the extracellular matrix (Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375). Integrins 1 subfamily, also known as VLA-proteins (very late(activation)antigen) include at least six receptors that specifically interact with fibronectin, collagen and/or laminin as ligands. Within VLA-family, the integrin VLA-4(41) is atypical in that it is limited mainly of lymphoid and myeloid cells, and at last he is responsible for intercellular interaction with a large number of other cells. VLA-4 is facilitated, for example, the interaction of T - and b-lymphocytes with the heparin II binding fragment of fibronectin human plasma (FN). The binding of VLA-4 with heparin II binding fragment of fibronectin plasma is primarily based on the interaction with LDVP-sequence. Unlike receptor fibrinogen or vitronectin VLA-4 is not typical GD-binding integrin (Kilger und Hoizmann, J. Mol. Meth. 1995, 73, 347).

Circulating blood leukocytes usually find only a small affinity for vascular endothelial cells that line blood vessels. Cytokines, wydase the VA surface antigens of the cells. The latter include, for example, adhesion molecule ELAM-1 (endothelial cell adhesion molecule-1; also referred to as E-selectin), which links including neutrophils, ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (leucocyte function-associated antigen 1) on leukocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds a variety of leukocytes, particularly lymphocytes (Osborn et al., Cell 1989, 59, 1203). ELAM-1=molecule (factor) adhesion of endothelial cells 1, ICAM-1=molecule (factor) intercellular adhesion 1, LFA-1=antigen associated with the function of leukocytes, 1, VCAM-1=molecule (factor) adhesion of vascular cells. VCAM-1, and ICAM-1 is a member of the superfamily of immunoglobulin genes. VCAM-1 (known at first as INCAM-110) was identified as an adhesion molecule that is induced on endothelial cells by inflammatory cytokines, such as TNF and IL-1, and lipopolysaccharide (LPS). Elices on et al. (Cell 1990, 60, 577) demonstrated that VLA-4 and VCAM-1 consists of a receptor-ligand, which promotes the attachment of lymphocytes to activated endothelium. When this binding VCAM-1 to VLA-4 is not due to the interaction of VLA-4 with RQD-posledovatelnostyu, the latter is not contained in VCAM-1 (Bergelson et al., Current Biology 1995, 5, 615). Ho VLA-4 also appears on other leukocytes and through the mechanism adhesively example 1 receptor-integrin, through ligands VCAM-1 or fibronectin plays an essential role in cell-cell interactions and interactions cell-extracellular matrix.

Cytokine-induced adhesion molecules play an important role in recruiting leukocytes into extravascular region of tissue. Leukocytes are recruited into the inflammatory area of tissue using adhesion molecules cells, which is expressed on the surface of endothelial cells and they serve as ligands for leukocyte surface proteins or protein complexes cells (receptors) (the concept of ligand and receptor can also be used Vice versa). Leukocytes from the blood must first be attached to endothelial cells before they can migrate into the synovial fluid. Since VCAM-1 binds to the cells that carry the integrin VLA-4 (41), such as eosinophils, T and b-lymphocytes, monocytes or neutrophils, he and VCAM-1/VLA-4-mechanism attached to the function of the recruitment of these cells from the bloodstream in the area of infection and inflammation (elices on et al., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutz et al., J. Exp.Med. 1996, 183, 2175).

The mechanism of adhesion VCAM-1/VLA-4 was associated with a number of physiological and pathological processes. VCAM-1, except indutsirovanie cells and tissue macrophages, rheumatoid synovia-stimulated cytokine nerve cells, parietal epithelial cells of Bowman's capsule, tubular epithelium of the kidney, inflammatory tissue for graft rejection heart and kidney and intestinal tissue for graft versus host. Found that VCAM-1 is expressed also in such areas and tissues of the arterial endothelium, which correspond to the early arteriosclerotic plaques rabbit model. Additionally VCAM-1 is expressed on follicular dendritic cells of lymph nodes of a person and is located on the stromal cells of the bone marrow, for example, in the mouse.

The recent discovery indicates the function of VCAM-1 in the development of b-cells. VLA-4, in addition to hematopoietic origin cells, are also, for example, in melanoma cell lines and the mechanism of adhesion VCAM-1/VLA-4 is associated with the metastasis of these tumors (Rice et al., Science 1989, 246, 1303).

The predominant form in which VCAM-1 occurs in vivo on endothelial cells and is the predominant form in vivo, denoted as VCAM-7D and is 7 domains of immunoglobulins. Domains 4, 5 and 6 are similar in their amino acid sequences for domains 1, 2 and 3. The fourth domain from another, sost is to also VLA-4-expressing cells.

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

On the basis of the role of VCAM-1/VLA-4-mechanism in the processes of cell adhesion, which have a value of, for example, infections, inflammation or atherosclerosis, attempts were made by intervening in these processes of adhesion to fight diseases, in particular, for example, inflammation (Osborn et al., Cell 1989, 59, 1203). One way to do this is the use of monoclonal antibodies which are directed against VLA-4. Such monoclonal antibodies (MACs) that block as VLA-4 antagonists of the interaction between VCAM-1 and VLA-4 are known. So, for example, anti-VL-4 mAK HP2/1 and HP1/3, inhibit the attachment of expressing VLA-4 Ramos cells (such as b-cells) to the endothelial cells of the umbilical cord and to transfitsirovannykh VCAM-1, COS-cells. Anti-VCAM-l mAK 4B9 also inhibit the adhesion of Ramos cells, Jurkat cells, like T cells and HL60 cells (such as granulocytes cells) to COS cells transfitsirovannykh genetic constructs that direct the expression of VCAM-6D and VCAM-7D. Data in vitro with antibodies which are directed against 4-subunit is playing a role in rheumatoid arthritis (van Dinther-Janssen et al., J. Immunol. 1991, 147, 4207).

In vivo studies showed that experimental autoimmune encephalomyelitis can be suppressed with anti-4 mAK. The leukocyte migration into the inflammatory focus will be blocked by monoclonal antibodies against the 4-chain of VLA-4. The influence of antibodies on dependent on VLA-4 the mechanism of adhesion was also investigated in models of asthma to determine the role of VLA-4 in the recruitment of leukocytes in inflammatory lung tissue (WO-A-93/13798). Receiving anti-VLA-4 antibodies inhibited the late phase reaction and over-reaction of the respiratory tract in sheep with allergies.

VLA-4-dependent mechanism of cell adhesion was also investigated on the model of primates with inflammatory bowel disease (IBD). In this model, which corresponds to ulcerative colitis in humans, intake of anti-VL-4-antibody gave a significant reduction in acute inflammation.

In addition, it was able to show that VLA-4-dependent adhesion of cells plays a role in the following clinical conditions, including chronic inflammatory processes such as rheumatoid arthritis (Cronstein und Weismann, Arthritis Rheum, 1993, 36, 147; elices on et al., J. Clin. Invest. 1994, 93, 405), diabetes (Yang et al., Proc. Natl. Acad. Sci. USA 1993, 90, 10494), systemic lupus erythematosus (Takeuchi et al., J. Clin. Invest. 1993, 92, 3008), Allergy delayed ti is. xp. Med.1992, 176, 1183), arteriosclerosis (O'Brien et al., J. Clin. Invest. 1993, 92, 945), transplantation (Isobe et al., Transplantation Proceedings 1994, 26, 867-868), various malignant diseases, such as melanoma (Renkonen et al., Am. J. Pathol. 1992, 140, 763), lymphoma (Freedman et al., Blood 1992, 79, 206) and others (Albelda et al., J. Cell Biol. 1991, 114, 1059).

In accordance with this VLA-4 blocking suitable antagonists provides an effective therapeutic opportunities for the treatment of, in particular, for example, various inflammatory conditions, including asthma and IBD. With particular relevance VLA-4 antagonists for the treatment of rheumatoid arthritis is detected, as already mentioned, from the fact that leukocytes from the blood must first be attached to endothelial cells before they can migrate into the synovia, and that attachment plays the role of VLA-4 receptor. That cause inflammation induce VCAM-1 on endothelial cells (Osborn, Cell 1990, 62, 3; Stoolman, Cell 1989, 56, 907) and the recruitment of various leukocytes in the area of infection and inflammation, have already referred to above. While T cells adhere to activated endothelium, mainly through the mechanisms of adhesion of LFA-1/ICAM-1 and VLA-4/ VCAM-1 (Springer, Cell 1994, 76, 301). Many of synovial T-cells the ability to bind VLA-4 to VCAM-1 s synovial T cells to fibronectin (Laffon et al., J. Clin. Invest. 1991, 88, 546; Morales-Ducret et al., J. Immunol. 1992, 149, 1424). Thus, VLA-4 has a high degree of regulation in the framework of its expression, and with respect to its action on T-lymphocytes of rheumatoid synovial membrane. Inhibition of binding of VLA-4 with its physiological ligands VCAM-1 and fibronectin enables effective prevention or mitigation of inflammatory processes in the joints. This is also confirmed by experiments with the antibody NR/1 on the Lewis rats with adjuvant arthritis who have watched the effective prevention of disease (Barbadillo et al., Springer Semin. Immunopathol. 1995, 16, 427). Thus, VLA-4 is an important therapeutic molecule-target.

The above VLA-4 antibodies and the use of antibodies as VLA-4 antagonists are described in patent applications WO-A-93/13798, WO-A-93/15764, WO-A-94/16094, WO-A-94/17828 and WO-A-95/19790. In the patent applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581, WO-A-96/06108 and WO-A-96/20216 described peptide compounds as VLA-4 antagonists. But the use of antibodies and peptide compounds as medicines has disadvantages, for example, lack of oral availability, easy redeployment or immunogenic activity during prolonged use, and sledovateljskie.

In WO-A-95/14008, WO-A-94/21607 (US-A-5658935), WO-A-93/18057, EP-A-449079 (US-A-5686421), EP-A-530505 (US-A-5389614), EP-A-566919 (US-A-5397796), EP-A-580008 (US-A-5424293) and EP-A-584694 (US-A-5554594) described substituted heterocycles with 5 cycles, which N-end molecules have amino, amidino or guanidinium and are inhibiting platelet aggregation steps. In EP-A-796855 described other heterocycles, which are inhibitors of bone resorption. In EP-A-842943, EP-A-842945 and EP-A-842944 (German patent applications 19647380.2, 19647381.0 and 19647382.9) described that the compounds from these groups and other compounds unexpectedly inhibit the adhesion of leukocytes and are VLA-4 antagonists. Further studies showed that the compounds of this application are also strong inhibitors of leukocyte adhesion and/or VLA-4 antagonists.

The present invention relates to compounds of formula I

where W denotes a bivalent residue of a range of R1-A-C(R13), R1-A-C(R13)=C,

where the cyclic systems

can contain one or two identical or different heteroatoms from the series N, O and S, can be saturated or singly or multiply unsaturated and can be substituted by 1, 2 or 3 identical and the e L denotes C(R13or N, and where m1 and m2 independently of one another denote one of the numbers 0, 1, 2, 3, 4, 5 and 6, but the sum m1 + m2 denotes one of the numbers 1, 2, 3, 4, 5 or 6;

Y represents a carbonyl group, thiocarbonyl group or a methylene group;

And denotes a direct bond, one of the divalent residues (C1-C6-alkylene, (C3-C7-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, phenylene-(C2-C6)-alkenyl or divalent residue of a 5-membered or 6-membered saturated or unsaturated heterocycle, which may contain one or two nitrogen atom or may be substituted once or twice (C1-C6)-alkyl or doubly bound oxygen or sulfur, and in the remainder of Familienhotel and phenylanaline the remainder R1associated with the group of phenylene;

In denotes the divalent residue of group (C1-C6-alkylene, (C2-C6-albaniles, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3-alkylen-phenyl and (C1-C3-alkylen-phenyl-(C1-C3)-alkyl, and (C1-C6)-alkalinity residue and (C2-C6)-alkenylamine the residue is not substituted or substituted by one or more identical or the sludge, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C6)-alkyl, substituted if necessary, heteroaryl, substituted, if necessary, in the heteroaryl residue heteroaryl-(C1-C6)-alkyl;

E. means tetrazolyl, (R8O)2P(O) R10OS(O)2, R9NHS(O)2, R6CO., R7CO., R10CO, HCO, R8O-CH2, R8CO-O-CH2, R8aO-CO-O-CH2or (R8O)2P(O)-O-CH2;

R denotes hydrogen, (C1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl or substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C8)-alkyl, all of the residues R are independent of each other and the residues R may be the same or different;

R1denotes hydrogen, (C1-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl substituted in the aryl residue, optionally, R21-((C6-C14)-aryl), substituted in the aryl residue, optionally, (R21-((C6-C14)-aryl))-(C1-C8)-alkyl, the remainder Het, Het-(C1-C8)-alkyl or one of the residues X-NH-C (=NH)-R20X1-NH-R20, R21O-R20-, R21N(R21)-R20, R21C(O)-, R21O-C(O)-, R22N(R21)-C(O)-, R22C (O)-N (R21)-, R21O-N=, O=, S=,

X denotes hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C10)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, substituted, optionally, (C6-C14-arylcarbamoyl, substituted, optionally, (C6-C14-aryloxyalkyl, (C6-C14) -aryl-(C1-C6-alkoxycarbonyl, kotori can also be substituted in the aryl residue, cyan, hydroxy, (C1-C6)-alkoxy, (C6-C14)-aryl-(C1-C6)-alkoxy which can also be substituted in the aryl residue amino;

X1has one of the values X or R1-NH-C (=N-R''), where R' and substituted, if necessary, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3denotes hydrogen, (C1-C10)-alkyl which can be substituted one or more times by fluorine, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, R11NH, CON(CH3R4, CONHR4, COOR21, COOR15, SOP-(CH3R15or CONHR15;

R4denotes hydrogen or (C1-C10)-alkyl, which is not substituted or substituted once or many times, equal or different statcall, hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C6-C14) -aryl-(C1-C8-alkoxycarbonyl, which can be substituted in the aryl residue, (C1-C8-alkoxycarbonyl, R6-CO, R7-CO, tetrazolyl, trifluoromethyl;

R5denotes a substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl or the residue is substituted, if necessary, monocyclic or bicyclic, 5-membered to 12-membered heterocyclic ring which may be aromatic, partially saturated or fully saturated and which may contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulfur;

R6denotes the residue of a natural or unnatural amino acids, aminokisloty, if necessary, N-(C1-C8)-alkilirovanny or N-((C6-C14) -aryl-(C1-C8)-alkilirovanny) esamination, which can also be substituted in the aryl residue, or a residue of the dipeptide, Tripeptide or tetrapeptide, as well as their esters and amides, where free functional groups can b the -CO can carry as Deputy residue R;

R7denotes the residue is linked via a nitrogen atom of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle, which may contain one, two, three or four identical or different additional ring heteroatoms from the series oxygen, nitrogen and sulfur and which has carbon atoms and on additional nitrogen atoms, the ring optionally can be substituted, where additional nitrogen atoms of the ring may bear as substituents the same or different residues from the series hydrogen, RhHCO, RhCO., RhO-CO, BUT CO-(C1-C4)-alkyl, and RhO-CO-(C1-C4)-alkyl, and Rhmeans (C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl or substituted in the remainder of the aryl, optionally, (C6-C14)-aryl-(C1-C8)-alkyl;

R8denotes hydrogen, (C1-C10)-alkyl, substituted, optionally, (C6-C14) -aryl or (C6-C14) -aryl-(C1-C8)-alkyl which can be substituted in the aryl residue, and residues R8independent from others who nd R8with the exception of hydrogen;

R9denotes hydrogen, aminocarbonyl, (C1-C10- alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, substituted, optionally, (C6-C14-allumination, (C1-C10)-alkyl, substituted, optionally, (C6-C14)-aryl or (C3-C8-cycloalkyl;

R10denotes hydroxy, (C1-C10)-alkoxy, (C6-C14)-aryl (C1-C8)-alkoxy which can be substituted in the aryl residue, substituted, optionally, (C6-C14)-aryloxy, (C1-C8)-alkylcarboxylic-(C1-C6)-alkoxy, substituted in the aryl residue, optionally, (C6-C14)-arylcarboxylic-(C1-C6)-alkoxy, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C6)-alkylcarboxylic-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, substituted in the aryl residue, optionally, (C6-C14) -aryloxyalkanoic-(C1-C6)-alkoxy, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C68R8N-CO-(C1-C6)-alkoxy, where the remains of R8independent of each other and can be identical or different;

R11denotes hydrogen, R12a, R12a-CO, H CO, R12a-O-CO, R12b-CO, R12b-CS, R12a-S(O)2or R12b-S(O)2;

R12ameans (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl, substituted, if necessary, in the heteroaryl residue heteroaryl-(C1-C8)-alkyl or the residue R15;

R12bdenotes amino, di-((C1-C10)-alkyl)-amino, or R12a-NH;

R13denotes hydrogen, (C1-C6)-alkyl, which optionally can be substituted one or more times by fluorine, substituted, optionally, (C6-C14) -aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C6)-alkyl, (>means R16-(C1-C6)-alkyl, or R16;

R16denotes a 6-membered - 24-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which may contain one, two, three or four identical or different heteroatoms from the series nitrogen, oxygen and sulfur and which may be substituted by one or more identical or different substituents from the series (C1-C4)-alkyl and oxo;

R20denotes a direct bond or a bivalent residue (C1-C6-alkylen;

R21denotes hydrogen, (C1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C8)-alkyl, the remainder of the Het - or Het-(C1-C8)-alkyl, where the alkyl residues can be substituted one or more times by fluorine, and the remainder R21when multiple occurrence independently of each other and can be identical or different;

R22means R21-, R21O-, R21N(R21)-, R21CLASS="ptx2">R30represents one of the residues R32(R)N-CO-N (R) -R31, R32(R)N-CS-N(R)-R31, R32(R) N-S (OH)n-N (R)-R31, R32-CO-N (R) -R31, R32-CS-N(R)-R31, R32-S(O)n-N(R)-R31, R32(R) N-CO-R31, R32(R) N-CS-R31, R32(R)N-S(O)n-R31, R32-CO-R31, R32-CS-R31, R32-S (O)n-R31or R12a-O-CO-N(R)-R31and R30cannot denote R32-CO-N (R)-R31if W denotes the R1-A-C(R13), And denotes a direct bond and R1and R13represent hydrogen;

R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula I;

R32denotes hydrogen, (C1-C8)-alkyl, which optionally may be substituted by 1 to 8 fluorine atoms, (C2-C8)-alkenyl, (C2-C8)-quinil, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C3-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, 6-C14) -aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl or substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C8)-alkyl;

R33denotes a direct bond or a bivalent residue (C1-C6-alkylen;

R34denotes a bivalent residue of a number (C1-C8- alkylene, (C3-C12-cycloalkyl, (C6-C12-bicycloalkyl, (C6-C12-tricyclohexyltin, substituted, optionally, (C6-C14)-aralen and replaced, if necessary, heteroaryl;

R35denotes a direct bond or a bivalent residue (C1-C8-alkylen;

R36denotes a direct bond, a group-CO - or a group-S(O)n-;

Het denotes the remainder of the monocyclic or polycyclic, 4-membered to 14-membered, aromatic or non-aromatic ring, which contains 1, 2, 3 or 4 identical or different heteroatoms from the series N, O and S as parts of the cycle and, if necessary, may be substituted by one or more identical or different substituents;

e and h independently of one another denote 0 or 1;

n Ref is whether different;

all their stereoisomeric forms and their mixtures in all ratios, and their physiologically tolerable salts.

If residues or substituents appear repeatedly in the compounds of the formula I, they can all be independently from each other, these values and may be the same or different. In compiled residues, for example, in arylalkyl free link through which bound the remainder comes from the right end of the name of the specified component, if the rest of arylalkyl, therefore, from the group of alkyl, which then as Deputy linked to the aryl group.

Alkyl residues can be straight or branched chain. This applies to that case, if they carry substituents or act as Vice-other residues, for example, in alkoxy residues, residues of alkoxycarbonyl or aryl-alkyl. Examples of suitable alkyl residues are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, isopropyl, isobutyl, isopentyl, isohexyl, 3-methylpentyl, neopentyl, neohexyl, 2,3,5-trimethylhexane, sec-butyl, tert-butyl, tert-pentyl. PR tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. If the alkyl residues substituted by fluorine atoms, they may, if not otherwise indicated, to contain, for example, 1, 2, 3, 4, 5, 6 or 7 fluorine atoms. For example, fluoro-substituted alkyl residue may have a methyl group as a group of trifloromethyl.

Alkylene residues (=alkadiene residues), i.e. bivalent formed from alkane residues, may also have a straight or branched chain. They can be linked via any position. Examples alkilinity residues are corresponding to the above-mentioned monovalent divalent residues residues, for example, methylene, ethylene (=1,2-ethylene or 1,1-ethylene), trimethylene (=1,3-propylene), tetramethylene (=1,4-butylene), pentamethylene, hexamethylene or substituted alkyl residues methylene or ethylene. Examples of the substituted methylene are methylene groups are replaced by methyl group, ethyl group, n-sawn group, isopropyl group, n-butilkoi group, isobutylene group, tert-butilkoi group, n-Pintilei group, isopentyl group or n-hexylene group. Substituted ethylene may be substituted on the same carbon atom and another carbon atom or the key) and alkyline residues may also be straight or branched chain. Examples alkenyl residues are vinyl, 1-propenyl, allyl, butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, alkenylamine residues - vinile, propylen, butylen, alkyl residues - ethinyl, 1-PROPYNYL, propargyl.

Cycloalkyl residues are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl and cyclododecyl, but which can also be substituted, for example, (C1-C4)-alkyl. Examples of substituted cycloalkyl residues are 4-methylcyclohexyl and 2,3-dimethylcyclobutyl. These clarifications to monovalent cycloalkyl balances refer, respectively, to cycloalkenyl residues (=cycloalkenyl residuals, i.e. divalent derived from cycloalkanes residues. Cycloalkene residues can be linked via any position.

Bicycloalkyl, critically residues and denoting R166-membered - 24-membered bicyclic and tricyclic receive the remains formally by removal of one hydrogen atom from bicyclo or tricycles. The underlying Bicycle and tricycles may contain as ring members only atoms ug is>6residue can also contain from 1 to 4 identical or different heteroatoms from the series nitrogen, oxygen and sulfur, therefore, we can talk about Aza-, oxa - and diabetically and tricyclodecane. If contains heteroatoms, preferably contains one or two heteroatoms, in particular nitrogen atoms or oxygen atoms. The heteroatoms can occupy any position in a bicyclic or tricyclic skeleton, they can be in the bridges or in the case of nitrogen atoms also on the head parts of the bridges. As bicycloalkanes and tricyclodecane and their heteroanalogues can be completely saturated or contain one or more double bonds. Preferably, they contain one or two double bonds, or are, in particular, a fully saturated. As bicycloalkanes and tricyclodecane and heteroanalogues and both saturated and unsaturated representatives may be unsubstituted or substituted at any suitable positions of one or more exography and/or one or more identical or different (C1-C4)-alkyl groups, e.g. methyl groups or isopropyl groups, preferably methyl groups. Free link bicyclic or tricycle atom head part of the bridge or through the atom in the bridge. Free link can be in any stereochemical position, for example, in the Exo-position or in the endo-position.

Examples of major components of bicyclic cyclic systems from which it is possible to form a bicyclic residue are norbornane (=bicyclo [2.2.1.]the heptane), bicyclo[2.2.2.]octane and bicyclo[3.2.1.]octane. Examples containing heteroatoms, unsaturated or substituted systems are 7-azabicyclo [2.2.1.]heptane, bicyclo [2.2.2.]Oct-5-ene and camphor (=1,7,7-trimethyl-2-oxobicyclo[2.2.1.]the heptane).

Examples of systems from which to form a tricyclic residue, are twisted (=tricyclo [4. 4. 0. 03,8] decane), adamantane (=tricyclo [3. 3.1.13,7] decane), noradsanta (=tricyclo [3.3.1.0.3,7]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.

Preferably, bicyclic or tricyclic formed from the remains of bridging bicyclo or tricycles, therefore, from systems in which the cycles have in common two or more than two atoms. Preferred further, if there are no other indications, also bicyclic or tricyclic residues 6-18 members of the cycles, especially/P>

In particular, especially preferred are bicyclic or tricyclic residues, which can indicate, for example, bicycloalkyl group or tricyclohexyl group, such as 2-norbornyl as a remainder with a free connection in the Exo-position, and the remainder with a free connection in the endo-position, 2-bicyclo[3.2.1.]octyl, substituted as 1-substituted, 2-substituted, homogametic and lordamantr, for example, 3-lordamantr. In addition, the preferred 1-substituted and 2-substituted.

The above explanation of monovalent residues bicycloalkyl and tricyclohexyl valid respectively for divalent bicycloalkanes residues and tricyclohexyltin residues (=bicycloalkyl and tricyclopentadiene residues).

(C6-C14)-aryl groups are, for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl, biphenylyl, for example, 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, antrel or fluorenyl, (C6-C10)-aryl groups are, for example, 1-naphthyl, 2-naphthyl and phenyl. Biphenylene residues, raftiline residues and especially phenyl residues are preferred aryl residues. Aryl residues, castrato, twice, three times or four, identical or different residues. Substituted aryl residues, in particular, phenyl residues, substituted, preferably, the remnants of the group (C1-C8)-alkyl, in particular (C1-C4)-alkyl, such as methyl; (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, such as methoxy; (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, which is substituted by one or more fluorine atoms, e.g. 1, 2, 3, 4 or 5 fluorine atoms, such as triptoreline; halogen; nitro; amino; trifluoromethyl; hydroxy; hydroxy-(C1-C4)-alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl; methylendioxy; Ethylenedioxy; formyl; acetyl; cyan; hydroxycarbonyl; aminocarbonyl; (C1-C4-alkoxycarbonyl; phenyl; phenoxy; benzyl; benzyloxy; tetrazolyl. Accordingly, it includes, for example, substituted aryl residues in groups, such as arylalkyl, arylcarbamoyl etc. Arylalkyl residues are, for example, 1 - and 2-naphthylmethyl, 2-, 3 - and 4-biphenylyl and 9-fluorenylmethyl and especially benzyl, which can all be substituted. Substituted arylalkyl residuals are from alkemi (C1-C8)-alkyl residues, in particular, (C1-C4)-alkyl residues, such as, for example, 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; benzyl residues and naphthylethylene residues, which in the aryl portion is substituted by one or more residues (C1-C8)-alkoxy, in particular residues (C1-C4)-alkoxy, such as, for example, 4-methoxybenzyl, 4-neopentecostal, 3,5-dimethoxybenzyl, 2,3,4-trimethoxybenzyl; 3,4-methylenedioxybenzyl; triphtalocyaninine residues; nitroaniline residues, for example, 2-, 3 - and 4-nitrobenzyl; halogenosilanes residues, for example, 2-, 3 - and 4-chloro and 2-, 3 - and 4-tormentil, 3,4-dichlorobenzyl, pentafluorobenzyl; triptoreline residues, for example, 3 - and 4-trifloromethyl or 3.5 bistrifluormethylbenzene. However, arylalkyl residues may contain also different from each other deputies. But in the compounds of formula I may be present in not more than two nitro groups in the molecule.

In monosubstituted phenyl residues Deputy may be in position 2, position 3 or position 4. Doubly substituted phenyl can triple substituted phenyl residues, the substituents may be located at positions 2, 3, 4, positions 2, 3, 5, positions 2, 4, 5, positions 2, 4, 6, positions 2, 3, 6, or positions 3, 4, 5.

The above explanation of monovalent aryl residues are, respectively, divalent Allenby residues, i.e., bivalent formed from aromatic compounds residues. Allenbyi residues can be attached through any situation. Example arenovich residues are phenylenebis residues that may be present, for example, 1,4-phenylene or 1,3-phenylene.

Familienhotel represents, in particular, phenylenedi (C6H4-CH2- or phenylenedi (for example, -C6H4-CH2-CH2), alkylester, in particular, methylindenyl (-CH2-C6H4-). Phenylanaline represents, in particular, phenylanaline or phenylendiamine.

Heteroaryl denotes the remainder of the monocyclic or polycyclic aromatic system with 5-14 ring members, which contains 1, 2, 3, 4 or 5 heteroatoms as ring members. Examples of heteroatoms are N, O and S. If there are several heteroatoms, they may be the same or different. Heteroaryl residues may be unsubstituted who or different residues from the group (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, which is substituted by one or more, e.g. 1, 2, 3, 4 or 5 fluorine atoms, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C1-C4)-alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, Ethylenedioxy, formyl, acetyl, cyan, hydroxycarbonyl, aminocarbonyl, (C1-C4-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl. Preferably, heteroaryl denotes a monocyclic or bicyclic aromatic residue, which contains 1, 2, 3 or 4, in particular 1, 2 or 3 identical or different heteroatoms from the series N, O and S, and which may be substituted by 1, 2, 3 or 4, especially 1 to 3 identical or different substituents from the series (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C1-C4)-alkyl, (C1-C4-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl. Particularly preferably, heteroaryl denotes a monocyclic or bicyclic aromatic residue with the Lee 3, especially 1 or 2, identical or different heteroatoms from the series N, O and S and may be substituted by 1 or 2 identical or different substituents from the series (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl, phenoxy, benzyloxy and benzyl.

Heterocycles, which denote monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring may be aromatic or partially saturated or fully saturated. They may be unsubstituted or substituted on one or more carbon atoms or one or more nitrogen atoms, equal or different substituents as indicated for the heteroaryl residue. In particular, the heterocyclic ring may be substituted one or more times, e.g. once, twice, three times or four, carbon atoms, equal or different residues from the series (C1-C8)-alkyl, for example, (C1-C4)-alkyl, (C1-C8)-alkoxy, for example, (C1-C4)-alkoxy, such as methoxy, phenyl-(C1-C4)-alkoxy, for example benzyloxy, hydroxy, oxo, halogen, nitro, amino or trifluoromethyl, and/or the nitrogen atoms of the ring in the heterocyclic ring, as debris gets what or ethyl, substituted, if necessary, phenyl or phenyl-(C1-C4)-alkyl, for example benzyl.

The group Het includes aromatic heterocycles and thereby also indicating heteroaryl group, if the latter relative to the number of ring members and the heteroatoms fall under the definition of Het. However, Het includes also non-aromatic heterocycles, which are completely saturated or contain one or more double bonds in the cyclic system. Het may be substituted on the nitrogen atoms and/or carbon atoms by one or more, e.g. 1, 2, 3 or 4 identical or different substituents, for example, (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl, heteroaryl, heteroaryl-(C1-C8)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy substituted, if necessary, phenoxy, benzyloxy, halogeno, nitro, amino, (C1-C8)-alkylamino, di-((C1-C8)-alkyl)-AMI-C4-alkoxycarbonyl and, in General, ether groups, acyl groups, oxo, thioxo, and alkyl residues can be substituted one or more times by fluorine.

Examples of basic substances (components) heterocycles, which may underlie the remainder of heteroaryl, residue Het, balance monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring divalent residue of a 5-membered or 6-membered heterocycle, denoted by R7heterocyclic residue or denoted R16heterocyclic residue are until they get into individual cases under the appropriate definition, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazol, thiazole, isothiazol, tetrazole, pyridine, pyrazin, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, cinoxacin, hinzelin, cinnolin-carbolin and benzenediamine, cyclopent-, cyclohexa or cyclohepta-bellerophone derivatives of these heterocycles.

Nitrogen heterocycles can also exist in the form of N-oxides or as Quaternary salts.

Residues, which can indicate heteroaryl or the remainder of the monocyclic or bicyclic 5-clenn the emer, 4 - or 5-phenyl-2-pyrrolyl, 2 - or 3-furyl, 2 - or 3-thienyl, 4-imidazolyl, methylimidazole, for example, 1-methyl-2-, -4 - or-5-imidazolyl, 1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3 - or 4-pyridyl-N-oxide, 2-pyrazinyl, 2-, 4 - or 5-pyrimidinyl, 2-, 3 - or 5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl, 5-methoxy-, 5-benzyloxy-, 5-chloro - 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-1,2-dihydro-3-ethanolic, 2-honokalani, 2-benzofuranyl, 2-benzothiazyl, 2-benzoxazolyl or 2-benzothiazolyl or in the form of remnants of partially saturated or fully saturated heterocyclic rings, for example, dihydropyridines, pyrrolidinyl, for example, 2 - or 3-(N-methylpyrrolidinyl), piperazinil, morpholinyl, thiomorpholine, tetrahydrothieno, benzodioxolyl.

Notes to, and heteroaryl residues are valid, respectively, for divalent heteroarylboronic residues, i.e. residues, derived from heteroaromatic compounds.

Denote R7heterocyclic residues may be substituted on the carbon atoms and/or on a secondary nitrogen atoms of the ring or substituted once or many times, the carbon may be substituted, for example, (C1-C8)-alkyl, in particular (C1-C4) - alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, oxo, cyan, hydroxycarbonyl, aminocarbonyl, (C1-C4-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolium, in particular (C1-C4)-alkyl, for example, stands, ethyl or tert-bootrom, (C1-C4)-alkoxy, for example methoxy, hydroxy, oxo, phenyl, phenoxy, benzyl, benzyloxy. Sulfur atoms may be oxidized to a sulfoxide or to the sulfone. Examples of the residue Het is 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinil, 4-substituted 1-piperazinil, 4-morpholinyl, 4-thiomorpholine, 1-oxo-4-thiomorpholine, 1,1-dioxo-4-thiomorpholine, peligrosas-1-yl, 2,6-dimethyl-1-piperidinyl, 3,3-dimethyl-4-morpholinyl, 4-isopropyl-2,2,6,6-tetramethyl-1-piperazinil, 4-acetyl-1-piperazinil, 4-etoxycarbonyl-1-piperazinil.

Halogen denotes fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.

The Deputy referred to In substituted Allenova residue or alkenylamine residue may contain, first, the loop if we are talking about the Deputy of the series (WITH3-C10)-cyclo is 4)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C6)-alkyl, substituted if necessary, heteroaryl and substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C6). Secondly, the substituents on substituted indicated In Allenova or alkenylamine the residue may be acyclic, if we are talking about the Deputy from the group (C1-C8)-alkyl, (C2-C8)-alkenyl and (C2-C8)-quinil. Acyclic substituents can 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 residues and etkinlik residues of the double bond or triple bond may be at any position and in the case of the double bond may be CIS - or TRANS-configuration. As explained above, these alkyl, alkeline and alkyline residues can be straight-chain or branched.

As examples of substituents that can carry denoted In (C1-C6)-alkalinity balance or (C2-C6)-alkynylaryl balance, it should be mentioned, in particular, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, Isobe is 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, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclooctylmethyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl, 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl or 2-(3-indolyl)ethyl.

Denote R6the balance of amino acids, aminokisloty or esamination or dipeptide, Tripeptide or tetrapeptide get, as usual in the chemistry of peptides, from the corresponding amino acids, aminokisloty or esamination or dipeptide, Tripeptide or tetrapeptide, and of the N-terminal amino group or aminogroup formally removing one hydrogen atom. Through the thus formed free link on the amino group or aminogroups this group connects then by the type of peptide amide bond with CO-group, R6CO.

Natural and unnatural amino acids can exist in all stereochemical forms, for example, in the D-form, L-form or in the form of a mixture of stereoisomers, particularly preferred amino acids. As take into account the amino acids should be called, for example, (compare Houben-Weyl, Methods der organischen Chemie, Band 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974):

Aad, Abu, Abu, ABz, 2ABz,Aca, Ach, Acp, Adpd, Ahb, Aib, Aib, Ala, l, Al, 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, hIle, 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, Tyr, Val, tert-butylglycol (Tbg), neopentylglycol (Npg), cyclohexylglycine (Chg), cyclohexylamine (Cha), 2-titillans (Thia), 2,2-diphenylsiloxane acid, 2-(p-tolyl)-2-phenyleneoxy acid, 2-(p-chlorophenyl)-aminouksusnoy acid.

If R6denotes the residue of a natural or unnatural amino acids, the residue may correspond to, for example, the formula-N(R)-CH(SC)-CO-AG, in which CO-AG denotes the acid group of the amino acid or its derivative, for example, ester group, amide group, or containing a residue of the peptide group, and SC denotes a side chain-amino acids, therefore, for example, one of the substituents contained in the-position of the above and sapropel in valine, benzyl residue to phenylalanine, the phenyl residue in phenylglycine, 4-aminobutyryl balance lysine or group hydroxycarbonylmethyl in aspartic acid. Such side chains, and thus amino acids can, in addition to their chemical structure, to combine, for example, also on the basis of their physico-chemical properties in one group, for example, lipophilic side chains may be different from the hydrophilic side chains, which contain polar groups. Examples of lipophilic side chains, which can be denoted in R6amino acids are alkyl residues, arylalkyl residues or aryl residues. It really is, respectively, of amino acids, which are part denoted R6residue of the dipeptide, Tripeptide or tetrapeptide.

Esamination represent natural or unnatural amino acids, in which a CH group is replaced by a nitrogen atom, for example, the amino acids of the Central element of the structure

As remnants of aminocyclo take into account especially the remains of heterocycles from the following group: pyrrolidin-2-carboxylic acid; piperidine-2-carboxylic acid; 1, 2,3,4-tetrahydroisoquinoline-3-kurbanbayeva acid; octahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid; 2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 2-azabicyclo[3.1.0]hexane-3-carboxylic acid; 2-azaspiro[4.4]nonan-3-carboxylic acid; 2-azaspiro[4.5]decane-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] decane-3-carboxylic acid; decahydrated[b]pyrrole-2-carboxylic acid; damageresistant [C]pyrrole-2-carboxylic acid; octahydrocyclopenta[C]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 can be optionally substituted (see the following formula):

Underlying the above balances heterocycles are known, for example, from patent US-A 4 344 949; US-A 4 374 847; US-A 4 350 704; EP-29 488; EP-A 31 741; EP-A 46 953;

EP-49 605; EP-49 658; UR-50 800; EP-51 020; ER-AND 52 870; EP-7 dipeptide and tetrapeptide can contain as elements the structure of a natural or unnatural amino acids, aminokisloty and esamination. Next, a natural or unnatural amino acids, aminokisloty, esamination, dipeptides, tripeptides and tetrapeptides can also exist in the form of derivatives of the group of carboxylic acids, such as esters or amides, such as, for example, methyl ether, ethyl ether, n-propyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, unsubstituted amide, methylamide, ethylamide, the formation of or-amino-(C2-C8-alkylamide.

Functional groups in the residues of amino acids, aminocyclo, esamination, dipeptides, tripeptides and tetrapeptides, as well as in other parts of the compounds of formula I can exist in a protected form. Suitable protective groups such as, for example, protective urethane group, a carboxyl protective group, and the protective groups of the side chains described Hubbuch, Kontatke (Merck) 1979, No. 3, s. 14-23, and Bullesbach, Kontakte (Merck) 1980, No. 1, s. 23-35. Especially it should be called: Aloc, Pyoc, Fmos, Tcboc, Z, BOC, Ddz, Rooted, Adoc, Msc, ISO, Z(NO2), Z (Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

Physiologically tolerated salts of the compounds of formula I are, in particular, pharmaceutically applicable or non-toxic salts. Of are, for example, salts of alkaline or alkaline-earth metals, such as salts of sodium, potassium salts, magnesium salts and calcium salts, or ammonium salts, such as, for example, salts with physiologically tolerable Quaternary ammonium ions and acid additive salts with ammonia and physiologically tolerable organic amines, such as, for example, triethylamine, ethanolamine, Tris(2-hydroxyethyl)-amine, ,,-Tris(hydroxymethyl) methylamine or with amino acids, particularly essential amino acids.

The compounds of formula I which contain basic groups, for example, an amino group, amidinopropane or guanidinium, form salts with inorganic acids such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid and with organic carboxylic acids or sulphonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or p-toluensulfonate. Compounds that contain both acidic groups and basic groups can also exist in the form of inner salts or betaines, which also includes the present invention.

Salt can be obtained from organicheskoi acid or base in a solvent or dispersant, or also aminoalkenes or cautionable from other salts.

The compounds of formula I can exist in stereoisomeric forms. If the compounds of formula I contain one or more centers of asymmetry, they are independently of each other can have the S-configuration or R-configuration. The invention includes all possible stereoisomers of the compounds of the formula I, for example, enantiomers and diastereoisomers, mixtures of two or more stereoisomeric forms, for example, mixtures of enantiomers and/or diastereomers, in all ratios. Thus, the enantiomers, enantiomeric pure form, as levogyrate, and programada antipodes, in the form of racemates and in the form of mixtures of both enantiomers in all ratios are the subject of the invention. The diastereomers in diastereomeric pure form and in the form of mixtures in all ratios are also the subject of the invention. When the existence of CIS/TRANS-isomerism as CIS-form and TRANS form and mixtures of these forms in all ratios are the subject of the invention. Getting the individual stereoisomers can be accomplished, if desired, by the application of stereochemical homogeneous starting substances in the synthesis, stereotypically synthesis or section is, what cromatografia on chiral phases. If necessary, before the separation of the stereoisomers can be used to form derivatives. Separation of a mixture of stereoisomers can be done at the stage of the compounds of the formula I or at the stage of initial substance or an intermediate product during the synthesis.

The compounds of formula I according to the invention can contain, in addition, the mobile hydrogen atoms, therefore, exist in different tautomeric forms. All tautomeric forms of the compounds of formula I are also the subject of the present invention. Further, the present invention includes derivatives of compounds of formula I, for example, a solvate such as a hydrate, and the addition products (adducts with alcohols, esters, prodrugs and other physiologically tolerated derivatives of compounds of formula I, as well as active metabolites of compounds of formula I. the Subject of the invention are, in particular, prodrugs of compounds of formula I, which under physiological conditions, are converted into compounds of formula I. Suitable prodrugs for the compounds of formula I, therefore, chemically modified derivatives of the compounds of formula I with an improved desired image properties, known since the 96) 115-130; Design of Prodrugs, H. Bundgaard, Ed., Elsevier, 1985; H. Bundgaard, Drugs of the Future 16 (1991) 443; Saulnier et al., Bioorg. Med. Chem. Lett. 4 (1994) 1985; Safadi et al., Pharmaceutical Res. 10 (1993) 1350. As prodrugs for compounds of formula I are especially taken into account the ether prodrugs formed by groups of carboxylic acids, amide prodrugs formed by groups of carboxylic acids, and alcohol prodrugs formed by groups of carboxylic acids and acyl-prodrugs and carbamate-prodrugs formed allereie nitrogen-containing groups such as amino groups, amidinopropane and guanidinium. In the acyl-prodrugs or carbamate-prodrugs under nitrogen atom the hydrogen atom is replaced by the acyl group or urethane group. As acyl groups and urethane groups to acyl-prodrugs and carbamate-prodrugs take into account, for example, the group Rp-CO and Rpa-O-CO -, in which Rpdenotes hydrogen, (C1-C18)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C14) -aryl, (C6-C14) -aryl-(C1-C8)-alkyl, heteroaryl or heteroaryl-(C1-C8)-alkyl, and Rpais specified for Rpvalues, except the water is to be placed, they may have independently from each other. Repeatedly occurring residues may have a value independent from each other and can be identical or different.

W denotes preferably, the bivalent residue of the group

where the cyclic systems

can contain one or two identical or different heteroatoms from the series N and O, may be saturated or unsaturated and may be substituted by 1 or 2 identical or different substituents R13and/or one or two oxygen atoms doubly linked, and where L denotes C(R13or N, and where m1 and m2 independently of one another denote 0, 1, 2, 3 and 4, the sum m1 + m2 indicates, however, the numbers 1, 2, 3 and 4, in particular, one of the numbers 1, 3 and 4. Particularly preferably, W represents a divalent residue R1-A-C(R13), where R13have the above values. But particularly preferably, W represents a divalent residue R1-A-C(R13), where R13have the above values, but different from hydrogen. Particular such group, W represents, for example, divalent residues of di-((C1-C4)-alkyl) methylene, ((C1-C4)-alkyl))2With<, dimiti the STATCOM

the number of such groups form a substituted, if necessary, as indicated, carbocyclic group of the formula (CH2)m3With <, in which the number of m3 is connected via end groups and an atom of serougleroda< a polymer chain refers to 2, 3, 4, 5 or 6. Special this group, W represents, for example, divalent residues of 1, 1-cyclopropylidene (=dimethylmethylene), 1,1-cyclopentadien (=tetramethylethylene) and 1,1-cyclohexylidene (=pentamethylenebis), i.e., residues

in which free communication indicated by strokes with a point at one end, and extending from the 5-membered rings and 6-membered ring residue, respectively, can carry doubly bound oxygen atom as a substituent. In total, the compounds of formula I, in which W has a different meaning than CH2form the group of the preferred compounds.

Y represents preferably a carbonyl group or thiocarbonyl group, particularly preferably a carbonyl group.

And means, preferably, a direct bond, one of the divalent residues (C1-C6-alkylene, in particular, (C1-C4-alkylene, (C5-C6-cycloalkyl, FeNi 5-membered or 6-membered saturated or unsaturated heterocycle, which may contain one or two nitrogen atom and may be substituted once or twice (C1-C6)-alkyl or doubly bound oxygen or sulfur. Particularly preferably, And denotes a direct bond or one of the divalent residues (C1-C4-alkylene, phenylene and phenylene-(C1-C2)-alkyl. If W denotes the residue R1-A-C(R13), there is a number of preferred residues R1-A - from residues (C1-C4)-alkyl, substituted if necessary, phenyl and substituted in the phenyl residue, if necessary, phenyl-(C1-C2)-alkyl, especially from residues (C1-C4)-alkyl and optionally substituted phenyl.

In a means, preferably a divalent residue of the methylene or the remainder of the ethylene (=1,2-ethylene), and the remainder of the methylene and the balance of ethylene is not substituted or substituted by one or more identical or different residues from the series (C1-C8)-alkyl, in particular (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C3-C10-cycloalkyl, in particular, (C3-C6-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, in particular (C3-C6-recloak the ri needed (C6-C10) -aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C6)-alkyl, in particular substituted in the aryl residue, optionally, (C6-C10) -aryl-(C1-C6)-alkyl, substituted if necessary, heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C6)-alkyl. Particularly preferably denotes a substituted therefore the remainder of the methylene or a residue of ethylene, especially substituted therefore the remainder of the analysis. If referred to In the remainder of alkylen or the remainder of albaniles one or more times substituted, it is substituted, preferably once, twice or three times, especially preferably once or twice, in particular, once. If referred to In the remainder of the methylene or ethylene substituted, it is substituted, preferably by one or two identical or different residues, in particular, the remainder of the series (C1-C8)-alkyl, in particular (C1-C6)-alkyl, i.e. alkyl straight or branched chain with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms and (C3-C6-cycloalkyl-(C1-C2)-alkyl.

E. means, preferably, tetrazolyl, R<, is particularly preferably tetrazolyl, R10CO., R8O-CH2, R8CO-O-CH2or (R8O)2P (O) -O-CH2but most preferably, R10CO., R8O-CH2or R8CO-O-CH2. Denote E the remainder R8-CH2represents, preferably, hydroxymethylene BUT the rest-CH2. Particularly preferably, E represents R10CO, HO-CH2or R8CO-O-CH2.

Residues R represent independently from each other preferably hydrogen or (C1-C8)-alkyl, especially hydrogen, methyl or ethyl.

R2means,preferably hydrogen or (C1-C8)-alkyl, in particular (C1-C6)-alkyl, particularly preferably hydrogen, methyl or ethyl.

R3means, preferably, hydrogen, (C1-C8)-alkyl, which optionally may be substituted by 1 to 8 fluorine atoms, substituted, optionally, (C6-C12)-aryl, substituted in the aryl residue, optionally, (C6-C12) -aryl-(C1-C6)-alkyl, substituted if necessary, heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C6)-alkyl, (C3-C8) > - C12-bicycloalkyl-(C1-C6)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, R11NN, COOR21, CON(CH3R4, CONHR4, SOP(CH3R15or CONHR15. R3means, particularly preferably hydrogen, (C1-C8)-alkyl which can be substituted by 1-6 fluorine atoms, substituted, optionally, (C6-C10) -aryl-(C1-C4)-alkyl, substituted, optionally heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C4)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C4)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C4)-alkyl, R11NH, COOR21, SOP(CH3R4, CONHR4, CON(CH3R15or CONHR15. But particularly preferably, R3denotes hydrogen, (C1-C8)-alkyl which can be substituted by 1-6 fluorine atoms, substituted, optionally, (C6-C10)-aryl, Samedan is necessary heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C4)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, R11NH, COOR21, SOP(CH3R4, CONHR4, CON(CH3R15or CONHR15. Particularly preferably, R3means, for example, (C1-C8)-alkyl, in particular (C1-C4)-alkyl, for example methyl, which may be substituted by 1-6 fluorine atoms, (C6-C10) -aryl, in particular phenyl, which may be unsubstituted or substituted, or CONHR4.

R4means, preferably, (C1-C8)-alkyl, which is not substituted or is substituted as specified in the definition of R4. Particularly preferably, R4means (C1-C8)-alkyl, especially (C1-C6)-alkyl, which is not substituted or substituted by one or two identical or different substituents from the series hydroxy, (C1-C8)-alkoxy, R5substituted, if necessary, (C3-C8-cycloalkyl, hydroxycarbonyl, aminocarbonyl, (C6-C10)-aryl-(C1-C4-alkoxycarbonyl, which can be substituted in the aryl residue, (C1-C6deputies referred to in R4the alkyl group is connected to position 1 of the group of alkyl, therefore, with the carbon atom of the alkyl group linked to the nitrogen atom in the group CONHR4or in group CON(CH3R4and if the substituent in position 1 represents one of the residues, such as hydroxycarbonyl, aminocarbonyl, (C6-C10)-aryl-(C1-C4-alkoxycarbonyl, which can also be substituted in the aryl residue, R6-CO, R7-CO, (C1-C6-alkoxycarbonyl or tetrazolyl. But in this particularly preferred case, the balance-other4or a residue-N(CH3R4denotes a residue of amino acid or N-methyl--amino acids or their derivative, and formally, the amino acid residue obtained by removing one hydrogen atom from the amino group of amino acids (if the Deputy is in position 1 group, R6-CO, the remainder-other4or a residue-N(CH3R4denotes, respectively, the residue of the dipeptide, Tripeptide, tetrapeptide or Pentapeptide). It is particularly preferred amino acids are amino acids with lipophilic side chain, for example, phenylglycine, phenylalanine, valine, leucine, isoleucine and their homologues and derivatives ATIC R6-CO or R7CO.

R5means, preferably substituted, if necessary, (C6-C12)-aryl, particularly substituted, if necessary, (C6-C10)-aryl, particularly substituted, if necessary, phenyl.

R8means, preferably, hydrogen, (C1-C8)-alkyl, substituted, optionally, (C6-C12) -aryl or (C6-C12)-aryl-(C1-C8)-alkyl, in which aryl residue may be substituted, particularly preferably hydrogen, (C1-C6)-alkyl, substituted, optionally, (C6-C10)-aryl or (C6-C10)-aryl-(C1-C6)-alkyl, in which aryl residue may be substituted, particularly preferably hydrogen, (C1-C6)-alkyl or substituted phenyl residue, if necessary, phenyl-(C1-C4)-alkyl. R8ais mostly one of the preferred values of R8with the exception of hydrogen.

R10means, preferably, hydroxy, (C1-C8)-alkoxy, (C6-C12)-aryl-(C1-C8)-alkoxy which can be substituted in the aryl residue, substituted, optionally, (C6-C126-C12)-aryl-(C1-C6)-alkylcarboxylic-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, substituted in the aryl residue, optionally, (C6-C12) -aryl-(C1-C6)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C8)-alkyl)-amino, aminocarbonyl-(C1-C6)-alkoxy, (mono - or di-((C1-C8)-alkyl)-amino)-carbonyl-(C1-C6)-alkoxy, (mono - or di-((C6-C12) -aryl-(C1-C6)-alkyl)) -amino) -carbonyl-(C1-C6)-alkoxy or (N-((C1-C8)-alkyl) -N-((C6-C12) -aryl-(C1-C6)-alkyl) -amino) -carbonyl-(C1-C6)-alkoxy, both in the aryl residue, optionally, can be substituted. Particularly preferably, R10denotes hydroxy, (C1-C8)-alkoxy, (C6-C10)-aryl-(C1-C6)-alkoxy, in which the aryl residue may be substituted, replaced, if necessary, (C6-C10)-aryloxy, (C1-C6) - alkylcarboxylic-(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-(-alkyl) -amino) -carbonyl-(C1-C6)-alkoxy.

R11means, preferably hydrogen, R12a, R12a, -CO, R12a-O-CO, R12b-CO, R12b-CS or R12a-S(O)2especially preferably hydrogen, R12a, R12a-CO, R12a-O-CO, R12b-CO or R12a-S(O)2but particularly preferably, R12a, R12a-CO, R12a-O-CO-or R12a-S(O)2.

R12ameans, preferably, (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C5-C10-cycloalkyl, (C5-C10-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl, substituted in the heteroaryl. the remainder, if necessary, heteroaryl-(C1-C8)-alkyl or the residue R15.

R13means, preferably hydrogen or (C1-C6)-alkyl, preferably alkyl residue, which means R13is a methyl residue. Particularly preferably, R13means (C1-C6)-alkyl, even more preferably, (C13)-alkyl, or R16especially R16-C1-alkyl, or R16.

R20means, preferably a direct link or a divalent residue (C1-C4-alkylene, particularly preferably a direct bond or a bivalent residue (C1-C2-alkylene, in particular a direct bond or the residue is methylene, or a residue of ethylene (1,2-ethylene), even more preferably a direct bond or the residue of the methylene.

R21means, preferably, hydrogen, (C1-C8)-alkyl, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, substituted, optionally, (C6-C10)-aryl, substituted in the aryl residue, optionally, (C6-C10)-aryl-(C1-C6)-alkyl, the remainder of the Het - or Het-(C1-C6)-alkyl, and alkyl residues can be substituted one or more times by fluorine and the remains of R21when multiple occurrence independently of each other and can be identical or different. R21refers particularly preferably hydrogen, (C1-C6)-alkyl, (C3-C6-cycloalkyl, (C3-C6-cycloalkyl-(C1-C4)-alkyl, substituted, optionally, (C6- What SUB>)-alkyl, and alkyl residues can be substituted one or more times by fluorine. R21means, particularly preferably hydrogen, (C1-C6)-alkyl, (C3-C6-cycloalkyl, (C3-C6-cycloalkyl-(C1-C2)-alkyl, substituted, optionally, (C6-C10)-aryl or substituted in the aryl residue, optionally, (C6-C10)-aryl-(C1-C2)-alkyl, and alkyl residues can be substituted one or more times by fluorine, and again the remains of R21when multiple occurrence independently of each other and can be identical or different.

R30means, preferably one of the residues R32(R)N-CO-N(R)-R31, R32(R)N-CS-N(R)31, R32(R) N-S (OH)n-N (R)-R31, R32-CO-N(R)-R31, R32-S(O)n-N(R)-R31, R32(R)N-CO-R31, R32(R) N-S (O)n-R31, R32-CO - R31, R32-S(O)n-R31or R12a-O-CO-N(R)-R31where n denotes 1 or 2. Particularly preferably, R30represents one of the residues R32(R)N-CO-N(R)-R31, R32(R)N-CS-N(R)-R31, R32-CO-N (R)-R31or R32(R)N-CO-R31. But particularly preferably, R30the convoy is in particular, R32NH-CO-NH-R31.

R32means, preferably, hydrogen, (C1-C8)-alkyl, which, if necessary, may be substituted by 1 to 8 fluorine atoms, (C2-C8)-alkenyl, (C2-C8)-quinil, (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, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl, substituted, optionally heteroaryl or substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C8)-alkyl. Particularly preferably, R32denotes hydrogen, (C1-C6)-alkyl, which optionally may be substituted by 1-6 fluorine atoms, (C2-C6)-alkenyl, (C2-C6)-quinil, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C6)-alkyl, substituted, optionally, (C6-C10)-aryl, substituted in the aryl residue, which if substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C6)-alkyl. But particularly preferably, R32denotes hydrogen, (C1-C6)-alkyl, which optionally may be substituted by 1-6 fluorine atoms, (C2-C6)-alkenyl, (C2-C6)-quinil, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C4)-alkyl, substituted, optionally, (C6-C10)-aryl, substituted in the aryl residue, optionally, (C6-C10)-aryl-(C1-C4)-alkyl, substituted if necessary, heteroaryl or substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C4)-alkyl. Particularly preferred denoted R32the remainder represents substituted, if necessary, (C6-C10)-aryl, in particular, unsubstituted phenyl or phenyl which can be substituted on aromatic compounds by one or more identical or different of the above substituents. If the remainder R32associated with the sulfur atom, it is preferably a different value than hydrogen.

R33means, preferably a direct link or a divalent residue (C1-C4-alkylen, especially predpochyol connection.

R34means, preferably, the divalent residue of a number (C1-C8-alkylene, (C5-C10-cycloalkyl, (C6-C12-bicycloalkyl, substituted, if necessary, (C6-C14)-aralen and replaced, if necessary, heteroaryl, particularly preferably, the divalent residue of a number (C1-C6-alkylene, (C5-C6-cycloalkyl, substituted, optionally, (C6-C10)-aralen and replaced, if necessary, heteroaryl, but more preferably, the divalent residue of a number (C1-C6- alkylene, substituted, optionally, (C6-C10)-aralen and replaced, if necessary, heteroaryl, in addition, preferably, the divalent residue of a number (C1-C4-alkylen and replaced,if necessary, (C6-C10)-Allen.

R35means, preferably a direct link or a divalent (C1-C4-the rest of alkylene, particularly preferably a direct bond or a bivalent residue (C1-C2-alkylene, in particular, a direct link or is methylene or ethylene (1,2-ethylene), but particularly preferably, (C1-C2-alkylene (methylene or ethylene).

what about, the divalent residue of R33-R34-R35-R36- in which one or more residues R33, R34, R35and R36have the preferred values. Particularly preferably, R31denotes a bivalent residue of a number (C1-C8-alkylene, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C6)-alkyl, substituted, optionally, (C6-C10)-aralen substituted in Allenova residue, optionally, (C6-C10)-aralen-(C1-C6)-alkyl, substituted if necessary, heteroaryl substituted in heteroarenes residue, if necessary, heteroaryl-(C1-C6)-alkyl, (C1-C8-alkylene-substituted, optionally, (C6-C10)-aralen-substituted in Allenova residue, optionally, (C6-C10)-aralen-(C1-C6)-alkyl -, substituted, if necessary, heteroaryl-substituted in heteroarenes residue, if necessary, heteroaryl-(C1-C6)-alkyl-substituted, optionally, (C6-C10)-aralen-S(O)nsubstituted in Allenova residue, optionally, (C6-C10) -aralen-(C1-C6)- ade, if necessary, heteroaryl-(C1-C6)-alkyl-S(O)nwhere n denotes 1 or 2, WITH group and S(O)n-group linked to the nitrogen atom in the ring of imidazolidine in formula I, and in the case of residues cycloalkenyl, areenalla and heteroallyl alkyl group linked to the nitrogen atom in the ring of imidazolidine in formula I. But particularly preferably, R31denotes a bivalent residue of a number (C1-C6-alkylene, substituted, optionally, (C6-C10)-Allen and substituted in the aryl residue, optionally, (C6-C10)-aralen-(C1-C4)-alkyl, and the remainder of areenalla alkyl group linked to a nitrogen atom in the ring of imidazolidine in formula I. in Addition, R31means, preferably, the divalent residue of a number (C1-C6-alkylene and substituted in the aryl residue, optionally, (C6-C10)-aralen-(C1-C4)-alkyl, in particular (C6-C10)-aralen-(C1-C2)-alkyl, and the remainder of areenalla alkyl group linked to the nitrogen atom in the ring of imidazolidine in formula I. Particularly preferably, R31denotes a bivalent residue phenylenedi (C6H4

If R3denotes hydrogen or one of the residues (C1-C10)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C8) - alkyl, substituted if necessary heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, COOR21, SOP(CH3R4, CONHR4, COOR15, CON(CH3R15or CONHR15i.e. means, preferably 0, and h denotes preferably 1. If R3means R11NH, e represents, preferably, 1 and h denotes preferably 0. The compounds of formula I in which e represents 0 and h denotes 1, form a preferred group of compounds. In these preferred compounds, the group-NR-[C(R)(R)]eC (R2) (R3)-[C(R)(R)]hIn the formula I on the s of the formula I are those compounds in which one or more residues have preferred values or specific of the preferred values, and all combinations of preferred values of the residues are the subject of the present invention.

Especially preferred group of compounds is formed by compounds of formula I, where

W denotes a bivalent residue from the group R1-A-C(R13), R1-A-C(R13)=C,

moreover, the cyclic system

can contain one or two identical or different heteroatoms from the series N, O and S, can be saturated or singly or multiply unsaturated and can be substituted by 1, 2 or 3 identical or different substituents R13and/or one or two doubly bound oxygen atoms and/or sulfur atoms, and L represents C(R13or N and m1 and m2 independently of one another denote numbers 0, 1, 2, 3, 4, 5 or 6, but the sum m1 + m2 denotes the number 1, 2, 3, 4, 5 or 6;

Y represents a carbonyl group, thiocarbonyl group, a methylene group;

And denotes a direct bond, one of the divalent residues (C1-C6-alkylene, (C3-C7-cycloalkyl, phenylene, a hair dryer is certain saturated or unsaturated heterocycle, which may contain one or two nitrogen atom and may be substituted once or twice (C1-C6)-alkyl or doubly bound oxygen or sulfur, and in the remainder of Familienhotel and phenylanaline the remainder R1associated with the group of phenylene;

In denotes the divalent residue of a number (C1-C6-alkylene, (C2-C6-albaniles, phenylene, phenylene-(C1-C3)-alkyl, (C1-C3-alkylester and (C1-C3-alkylether-(C1-C3)-alkyl, and the remainder (C1-C6) -alkylene and the remainder (C2-C6)-Alcanena not substituted or substituted by one or more identical or different residues from the series (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C6)-alkyl, substituted if necessary, heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C6)-alkyl;

E denotes tetrazolyl, (R8O)1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl or substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C8)-alkyl, all of the residues R are independent of each other and the residues R may be the same or different;

R1denotes hydrogen, (C1-C10)-alkyl, which, if necessary, may be substituted one or more times by fluorine, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl substituted in the aryl residue, if necessary, R21-((C6-C14)-aryl), substituted in the aryl residue, optionally, (R21-((C6-C14) -aryl))-(C1-C8)-alkyl, the remainder of the Het-, Het-(C1-C8)-alkyl or one of the residues X-NH-C (=NH)-R20-, X1-NH-R20-, R21O-R20-, R21N(R21)-R20-, R21C(O)-, R21O-C(O)-, R22N (R21)-C (O)-, R22C(O)-N(R21)-, R21O-N=, O=, and S=;

X1indicates one of the values X or denotes R'-NH-C(=N-R''), moreover, R' and R" independently from each other are X-values;

R2denotes hydrogen, (C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl or (C3-C8-cycloalkyl;

R3denotes hydrogen, (C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl, substituted in the heteroaryl residue, if necessary, GE is>)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, R11NH, SOP(CH3R4, CONHR4, COOR21, COOR15, CON (CH3R15or CONHR15;

R4denotes hydrogen or (C1-C10)-alkyl, which is not substituted or substituted once or many times, equal or different residues from the series hydroxy, (C1-C8)-alkoxy, R5substituted, if necessary, (C3-C8-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono - or di((C1-C10)-alkyl)-aminocarbonyl, (C6-C14)-aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted, (C1-C8-alkoxycarbonyl, R6-CO, R7-CO, tetrazolyl, trifluoromethyl;

R5denotes a substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl or the residue is substituted, if necessary, monocyclic or bicyclical and fully saturated and which may contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulfur;

R6denotes the residue of a natural or unnatural amino acids, aminokisloty, if necessary, N-(C1-C8)-alkilirovanny or N-((C6-C14) -aryl-(C1-C8)-alkilirovanny) esamination, in which the aryl residue may be substituted, or a residue of the dipeptide, Tripeptide or tetrapeptide, as well as their esters or amides, with the free functional groups can be protected customary in the chemistry of peptides, protective groups and the nitrogen atoms in the amide linkages in the group R6-CO can carry the remainder R as a substituent;

R7denotes the residue is linked via a nitrogen atom of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle, which may contain one, two, three or four identical or different additional heteroatoms of the ring from the series oxygen, nitrogen and sulfur and which is optionally may be substituted on carbon atoms and on additional nitrogen atoms of the ring, and the additional nitrogen atoms of the ring may bear as substituents the same or different residues from the series hydrogen, Rh, HCO, THE (C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14) -aryl or substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl;

R8denotes hydrogen, (C1-C10)-alkyl, substituted, optionally, (C6-C14) -aryl or (C6-C14) -aryl-(C1-C8)-alkyl, in which aryl residue may be substituted, and the remains of R8do not depend on each other;

R9denotes hydrogen, aminocarbonyl, (C1-C10-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, substituted, optionally, (C6-C14-allumination, (C1-C10)-alkyl, substituted, optionally, (C6-C14) -aryl or (C3-C8-cycloalkyl;

R10denotes hydroxy, (C1-C10)-alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can be substituted in the aryl residue, substituted, optionally, (C6-C14)-aryloxy, (C1-C8)-alkylcarboxylic-(C1-C6)-alkoxy, substituted in the mono - or di-((C1-C10)-alkyl)-amino;

R11denotes hydrogen, R12a, R12a-CO, H CO, R12a-O-CO, R12b-CO, R12b-CS, R12a-S(O)2or R12b-S(O)2;

R12ameans (C1-C10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C8)-alkyl or the residue R15;

R12bdenotes amino, di-((C1-C10)-alkyl)-amino, or R12a-NH;

R13denotes hydrogen, (C1-C6)-alkyl, which optionally can be substituted one or more times by fluorine, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C6) - alkyl, (C3-C8-cycloalkyl or (C3-C8-cycloalkyl-(C1-C6)-alkyl;

R1-C4)-alkyl and oxo;

R20denotes a direct bond or a bivalent residue (C1-C6)-alkylene;

R21denotes hydrogen, (C1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C8)-alkyl, the remainder of the Het - or Het-(C1-C8)-alkyl, and alkyl residues can be substituted one or more times by fluorine, and the remainder R21when multiple occurrence independently of each other and can be identical or different;

R22means R21-, R21O-, R21N(R21)-, R21C(O)-, R21O-C(O)-, R21N(R21)-C(O)-, R21N(R21)-C(=N(R21)) or R21C (O) -N (R21) -;

R30represents one of the residues R32/SUP>-CS-N (R)-R31, R32-S(O)n-N(R) -R31, R32(R)N-CO-R31, R32(R) N-CS-R31, R32(R)N-S(O)n-R31, R32-CO-R31, R32-CS-R31or R32-S(O)n-R31and R30cannot denote R32-CO-N(R)-R31if W denotes the R1-A-C(R13), And denotes a direct bond and R1and R13represent hydrogen;

R31denotes the divalent residue of R33-R34-R35-R36-, and R36linked to the nitrogen atom in the ring of imidazolidine in formula I;

R32denotes hydrogen, (C1-C8)-alkyl which can be substituted, if necessary, 1 to 8 fluorine atoms, (C2-C8)-alkenyl, (C2-C8)-quinil, (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, substituted, optionally, (C6-C14) -aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl, substituted if necessary

R33denotes a direct bond or a bivalent residue (C1-C6-alkylen;

R34denotes a bivalent residue of a number (C1-C8-alkylene, (C3-C12-cycloalkyl, (C6-C12-bicycloalkyl, (C6-C12-tricyclohexyltin, substituted, optionally, (C6-C14)-aralen and replaced, if necessary, heteroaryl;

R35denotes a direct bond or a bivalent residue (C1-C8-alkylen;

R36bonache direct link, group-CO - or a group-S(O)n-;

Het denotes the remainder of the monocyclic or polycyclic, 4-membered to 14-membered, aromatic or non-aromatic ring which contains 1, 2, 3 or 4 identical or different heteroatoms from the series N, O and S as ring members and optionally may be substituted by one or more identical or different substituents;

e and h represent independently from each other 0 or 1;

n denotes 1 or 2, and n if they appear multiple times, independent of each other and can be identical or different;

all stereoisomeric forms and their mixtures in all soo the deposits form the compounds of formula I, where

W denotes a bivalent residue of a range of R1-A-C (R13), R1-A-C-(R13)=C,

where the cyclic systems

can contain one or two identical or different heteroatoms from the series N and O, may be saturated or unsaturated and just may be substituted by 1 or 2 identical or different substituents R13and/or may be substituted by one or two doubly bound oxygen atoms, and where L denotes C(R13or N, and where m1 and m2 independently of one another denote 0, 1, 1, 3, 4 and 5, the sum m1 + m2 indicates, however, the numbers 1, 2, 3, 4 and 5;

Y represents a carbonyl group or thiocarbonyl group;

And denotes a direct bond, one of the divalent residues (C1-C6-alkylene, (C3-C7-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, phenylene-(C2-C6)-alkenyl or divalent residue of a 5-membered or 6-membered saturated or unsaturated heterocycle, which may contain one or two nitrogen atom and may be substituted once or twice (C1-C6)-alkyl or doubly bound oxygen or sulfur, and in the residues of phenylanaline and phenylenevinylene, the remaining methylene and the balance of ethylene is not substituted or substituted by one or more identical or different residues from the group (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C6)-alkyl, substituted if necessary, heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C6)-alkyl;

E denotes tetrazolyl, R10CO., R8O-CH2, R8CO-O-CH2or (R8O)2P(O) -O-CH2;

R denotes hydrogen, (C1-C8)-alkyl, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, substituted, optionally, (C6-C10)-aryl, substituted in the aryl residue, optionally, (C6-C10)-aryl-(C1-C6)-alkyl, substituted if necessary, heteroaryl or substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C6)-alkyl, and all residues R the independence of the C1-C10)-alkyl which can be substituted, if necessary, one or more times by fluorine, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl substituted in the aryl residue, optionally, R21-((C6-C14) -aryl), substituted in the aryl residue, optionally, (R21-((C6-C14) -aryl))-(C1-C8)-alkyl, the remainder of the Het-, Het-(C1-C8)-alkyl or one of the residues X-NH-C (=NH) -R20-, X1-NH-R20-, R21O-R20-, R22C(O)-N(R21)-, R22N(R21)-C(O)-, R21O-N=, O=, and S=;

X denotes hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C10)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, substituted, optionally, (C6-C14-arylcarbamoyl, substituted, optionally, (C6-C14-aryloxyalkyl, (C6-C14) -aryl-(C1-C6- alkoxycarbonyl, in which the aryl residue may be substituted, hydroxy, (C1-C6)-alkoxy, (C6-C14) -aryl-(C1-C6)-alkoxy, in which the aryl residue may be substituted, or amino;

X' and the ptx2">R2denotes hydrogen, (C1-C8)-alkyl, substituted, optionally, (C6-C10)-aryl or substituted in the aryl residue, optionally, (C6-C10)-aryl-(C1-C8)-alkyl;

R3denotes hydrogen, (C1-C8)-alkyl which can be substituted, if necessary, 1 to 8 fluorine atoms, substituted, optionally, (C6-C14) -aryl, substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl, substituted in the aryl residue, optionally, heteroaryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, R11NH, COOR21, CON(CH3R4, CONHR4, COOR15, SOP(CH3R15or CONHR15;

R4denotes hydrogen or (C1-C8)-alkyl, which is unsubstituted or substituted one or more times odbcdirect, (C3-C8-cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono - or di((C1-C10)-alkyl)-aminocarbonyl, (C6-C14) -aryl-(C1-C8-alkoxycarbonyl, in which the aryl residue may be substituted, (C1-C8-alkoxycarbonyl, R6-CO, R7-CO, tetrazolyl, trifluoromethyl;

R5denotes a substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl or the residue is substituted, if necessary, monocyclic or bicyclic, 5-membered to 12-membered heterocyclic ring which may be aromatic, partially saturated or fully saturated and which may contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulfur;

R6denotes the residue of a natural or unnatural amino acids, aminokisloty, if necessary, N-(C1-C8)-alkilirovanny or N-((C6-C14)-aryl-(C1-C8)-alkilirovanny) esamination, which can also be substituted in the aryl residue, or a residue of the dipeptide, Tripeptide or tetrapeptide, as well as their esters and amides, where the nitrogen in the amide linkages in the group R6-CO can carry the remainder R as a substituent;

R7denotes the residue is linked via a nitrogen atom of a 5-membered to 10-membered saturated monocyclic or polycyclic heterocycle, which may contain one, two, three or four identical or different additional heteroatoms of the ring from the series oxygen, nitrogen and sulfur and which has carbon atoms and on additional nitrogen atoms, the ring optionally can be substituted, where additional nitrogen atoms of the ring may bear as substituents the same or different residues from the group hydrogen, RhHCO, RhCO., RhO-CO, BUT CO-(C1-C4)-alkyl, and RhO-CO-(C1-C4)-alkyl, and Rhmeans (C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C8)-alkyl, substituted, optionally, (C6-C14)-aryl or substituted in the aryl residue, optionally, (C6-C14) -aryl-(C1-C8)-alkyl;

R8denotes hydrogen, (C1-C6)-alkyl, substituted, optionally, (C6-C10) -aryl or (C6-C10)-aryl-(C1-C6)-alkyl, in which the residue of the aryl may also be UB>-C8)-alkoxy, in which the aryl residue may be substituted, replaced, if necessary, (C6-C12)-aryloxy, (C1-C8)-alkylcarboxylic-(C1-C6)-alkoxy, substituted in the aryl residue, optionally, (C6-C12)-aryl-(C1-C6)-alkylcarboxylic-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, substituted in the aryl residue, optionally, (C6-C12) -aryl-(C1-C6)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C8)-alkyl)-amino, aminocarbonyl-(C1-C6)-alkoxy, (mono - or di-((C1-C8)-alkyl)-amino)-carbonyl-(C1-C6)-alkoxy or (mono - or di-((C6-C12)-aryl-(C1-C6)-alkyl)) -amino) -carbonyl-(C1-C6)-alkoxy or (N-((C1-C8)-alkyl) -N-((C6-C12)-aryl-(C1-C6)-alkyl) -amino) -carbonyl-(C1-C6)-alkoxy, both in the aryl residue may be optionally substituted;

R11denotes hydrogen, R12a, R12a-CO, R12a-O-CO, R12b-CS or R12a-S(O)2;

R12ameans (C1-C10)-alkyl is cloaker-(C-C8)-alkyl, substituted, optionally, (C6-C14)-aryl, substituted in the aryl residue, optionally, (C6-C14)-aryl-(C1-C8)-alkyl, substituted if necessary, heteroaryl, substituted in the heteroaryl residue, if necessary, heteroaryl-(C1-C8)-alkyl or the residue R15;

R12bdenotes amino, di-((C1-C10)-alkyl)-amino, or R12a-NH;

R13denotes hydrogen or (C1-C6)-alkyl;

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

R16denotes a 6-membered to 14-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which may contain one, two, three or four identical or different heteroatoms from the series nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the series (C1-C4)-alkyl and oxo;

R20denotes a direct bond or (C1-C4-alkylen;

R21denotes hydrogen, (C1-C8)-alkyl, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, for>-C10)-aryl-(C1-C6)-alkyl, the remainder of the Het - or Het-(C1-C6)-alkyl, and alkyl residues can be substituted one or more times by fluorine, and the remainder R21in case of repeated occurrence may be the same or different;

R22represents one of the residues R21-, -R21N(R21)-, R21C(O)-, R21O-C(O)- or R21N(R21)-C(=N(R21))-;

R30represents one of the residues R32(R)N-CO-N(R)-R31, R32(R)N-CS-N(R)-R31, R32(R)N-S(OH)n-N (R)-R31, R32-CO-N(R)-R31, R32-S(O)n-N(R)-R31, R32(R)-N-CO-R31, R32(R)N-S (O)n-R31, R32-CO-R31, R32-S(O)n-R31or R12a-O-CO-N (R)-R31and R30cannot denote R32-CO-N(R)-R31if W denotes the R1-A-C (R13), A denotes a direct bond and R1and R13represent hydrogen;

R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula I;

R32denotes hydrogen, (C1-C8)-alkyl, which may optionally be substituted by 1-8 atoms, f is B>-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 in the aryl residue, optionally substituted (C6-C14)-aryl-(C1-C8)-alkyl, optionally substituted heteroaryl or heteroaryl residue optionally substituted heteroaryl-(C1-C8)-alkyl;

R33denotes a direct bond or a bivalent residue (C1-C6-alkylen;

R34denotes a bivalent residue of a number (C1-C8-alkylene, (C5-C10-cycloalkyl, (C6-C12-bicycloalkyl optionally substituted C6-C14)-arisen or, if necessary, replaced heteroaryl;

R35denotes a direct bond or a bivalent residue (C1-C8-alkylen;

R36denotes a direct bond or a group-CO - or a group - S(O)n;

Het denotes the remainder of the monocyclic or polycyclic, 5-membered to 12-membered, aromatic or nonaromatic to the, if necessary, can be substituted by one or more identical or different substituents;

e and h represent independently from each other 0 or 1;

n denotes 1 or 2, and n, if present repeatedly, do not depend on each other and can be identical or different;

in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

Even more preferred compounds of formula I are those compounds where

W denotes a bivalent residue of a range of R1-A-C(R13and

where the cyclic systems

can contain one or two identical or different heteroatoms from the series N and O, may be saturated or unsaturated and just may be substituted by 1 or 2 identical or different substituents R13and/or one or two oxygen atoms doubly linked, and where L denotes C(R13or N, and where m1 and m2 independently of one another denote one of the numbers 0, 1, 2, 3 and 4, however, the sum m1 + m2 denotes one of the numbers 1, 2, 3, and 4;

Y represents a carbonyl group or thiocarbonyl group;

And denotes a direct Svilen-(C1-C4)-alkyl or divalent residue of a 5-membered or 6-membered saturated or unsaturated heterocycle, which may contain one or two nitrogen atom and may be substituted once or twice (C1-C6)-alkyl or doubly bound oxygen or sulfur, and in the remainder of Familienhotel and phenylanaline the remainder R1associated with the group of phenylene;

In denotes a bivalent residue of the methylene or the remainder ethylene, and the remainder of the methylene or the balance of ethylene is not substituted or is substituted by two identical or different residues from the series (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C3-C6-cycloalkyl, (C3-C6-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C10)-aryl in the aryl residue, optionally substituted (C6-C10)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl, heteroaryl residue optionally substituted heteroaryl-(C1-C6)-alkyl;

E denotes R10CO, HO-CH2or R8CO-O-CH2;

R denotes hydrogen or (C1-C8)-alkyl, and all traces of R independent etc is B>-C10)-alkyl, which optionally can be substituted one or more times by fluorine, aryl residue, optionally substituted by R21-((C6-C10)-aryl), aryl residue, optionally substituted by R21-((C6-C10)-aryl) -(C1-C6)-alkyl, the remainder Het, Het-(C1-C6)-alkyl or one of the residues X-NH-C (=NH)-R20-, X1-NH-R20-, R22N(R21)-C(O)-, O= and S=;

X denotes hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C8)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C10-arylcarbamoyl, optionally substituted (C6-C10-aryloxyalkyl, (C6-C14) -aryl-(C1-C6-alkoxycarbonyl, which can also be substituted in the aryl residue, hydroxy, (C1-C6)-alkoxy or amino;

X1has one of the values X or denotes R'-NH-C(=N-R), where R' and R" independently from each other are X-values;

R2denotes hydrogen or (C1-C8)-alkyl;

R3denotes hydrogen, (C1-C8)-alkyl, which, when the mu is Mr. residue, optionally substituted (C6-C10)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl or heteroaryl residue optionally substituted heteroaryl-(C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C6)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C6)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, R11NH, COOR21, SOP(CH3R4, CONHR4, SOP(CH3R15or CONHR15;

R4means (C1-C8)-alkyl, which is unsubstituted or substituted once or twice, the same or different residues from the series hydroxy, (C1-C8)-alkoxy, R5optionally substituted (C3-C8-cycloalkyl, hydroxycarbonyl, aminocarbonyl, (C6-C10) -aryl-(C1-C4-alkoxycarbonyl, in which the aryl residue may be substituted, (C1-C6-alkoxycarbonyl, R6-CO, R7-CO, tetrazolyl, trifluoromethyl;

R5indicates if necessary)-aryl-(C1-C8)-alkyl or the residue, optionally substituted monocyclic or bicyclic, 5-membered to 12-membered heterocyclic ring which may be aromatic, partially saturated or fully saturated and may contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulfur;

R6denotes the residue of a natural or unnatural amino acids, aminokisloty, if necessary, N-(C1-C8)-alkilirovanny or N-((C6-C12) -aryl-(C1-C8)-alkilirovanny esamination, which can also be substituted in the aryl residue, or a residue of a dipeptide or Tripeptide, as well as their esters and amides, where free functional groups can be protected customary in the chemistry of peptides, protective groups, and where the nitrogen atoms in the amide linkages in the group R6-CO can carry the remainder R as a substituent;

R7denotes the residue is linked via a nitrogen atom of a 5-membered to 7-membered, saturated monocyclic or bicyclic heterocycle, which may contain one, two, three or four identical or different additional heteroatoms of the ring from the series oxygen, nitrogen and sulfur and which moliterni ring nitrogen atoms can carry as substituents the same or different residues from the series hydrogen, Rh, HCO, RhCO., RhO-CO, HO-CO-(C1-C4)-alkyl, and RhO-CO-(C1-C4)-alkyl, and Rhmeans (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C10)-aryl or aryl residue, optionally substituted (C6-C10) -aryl-(C1-C4)-alkyl;

R8denotes hydrogen, (C1-C6)-alkyl or phenyl residue optionally substituted phenyl-(C1-C4)-alkyl;

R10denotes hydroxy, (C1-C8)-alkoxy, (C6-C10) -aryl-(C1-C6)-alkoxy which can be substituted in the aryl residue, optionally substituted (C6-C10)-aryloxy, (C1-C6)-alkylcarboxylic-(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl -(C1-C6)-alkoxy, amino, mono - or di-((C1-C6)-alkyl)-amino, aminocarbonyl-(C1-C6)-alkoxy or (mono - or di-((C1-C6)-alkyl) -amino) -carbonyl-(C1-C6)-alkoxy;

R11denotes hydrogen, R12a, R12a-CO, R12a-O-CO, R12b-CO or R2-C8)-quinil, (C5-C10-cycloalkyl, (C5-C10-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl in the aryl residue, optionally substituted (C6-C14) -aryl-(C1-C8)-alkyl, optionally substituted heteroaryl, heteroaryl residue optionally substituted heteroaryl-(C1-C8)-alkyl or the residue R15;

R12bdenotes amino, di-((C1-C10)-alkyl)-amino, or R12a-NH;

R13denotes hydrogen or (C1-C6)-alkyl;

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

R16denotes a 6-membered to 14-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which may contain one, two, three or four identical or different heteroatoms from the series nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the series (C1-C4)-alkyl and oxo;

R20denotes a direct bond or (C1-C2-alkylen;

R21denotes hydrogen, (C1-C6)-Alty, substituted (C6-C10)-aryl in the aryl residue, optionally substituted (C6-C10) -aryl-(C1-C4)-alkyl, the remainder of the Het - or Het-(C1-C4)-alkyl, and alkyl residues can be substituted one or more times by fluorine, and the remainder R21when multiple presence may be the same or different;

R22represents one of the residues R21-, R21N(R21)- or R21N(R21)-C(=N(R21))-;

R30represents one of the residues R32(R) N-CO-N (R)-R31, R32(R)N-CS-N(R)-R31, R32-CO-N (R) -R31or R32(R) N-CO-R31and R30cannot denote R32-CO-N(R)-R31if W denotes the Rl-A-C(R13), And denotes a direct bond and R1and R13represent hydrogen;

R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula I;

R32denotes hydrogen, (C1-C6)-alkyl, which optionally may be substituted by 1-6 fluorine atoms, (C2-C6)-alkenyl, (C2-C6)-quinil, (C5-C6-cycloalkyl, (C5- 6-C10)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl or heteroaryl residue optionally substituted heteroaryl-(C1-C6)-alkyl;

R33denotes a direct bond or a bivalent residue (C1-C4-alkylen;

R34denotes a bivalent residue of a number (C1-C6-alkylene, (C5-C6-cycloalkyl optionally substituted C6-C10)-arisen or, if necessary, replaced heteroaryl;

R35denotes a direct bond or a bivalent residue (C1-C4-alkylen;

R36denotes a direct bond, a group-CO - or a group - S(O)n;

Het denotes the remainder of the monocyclic or polycyclic, 5-membered to 12-membered, aromatic or non-aromatic ring which contains 1 or 2 identical or different heteroatoms from the series N and O as ring members and optionally may be substituted by one or more identical or different substituents;

e and h represent independently from each other 0 or 1;

n denotes 1 or 2;

all their stereoselectively compounds of formula I are compounds such where

W denotes a bivalent residue R1-A-C(R13);

Y represents a carbonyl group;

And denotes a direct bond, one of the divalent residues (C1-C6-alkylene, phenylene, phenylene-(C1-C2)-alkyl or divalent residue of a 5-membered or 6-membered saturated or unsaturated heterocycle, which may contain one or two nitrogen atom and may be substituted once or twice (C1-C6)-alkyl, or oxygen, or sulfur double bond, and in the remainder of Familienhotel and phenylanaline the remainder R1associated with the group of phenylene;

In denotes a bivalent residue of the methylene or the remainder ethylene, and the remainder of the methylene or the balance of ethylene is not substituted or substituted by a residue of a number (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, (C3-C6-cycloalkyl, (C3-C6-cycloalkyl-(C1-C6)-alkyl, optionally substituted (C6-C10)-aryl in the aryl residue, optionally substituted (C6-C10)-aryl-(C1-C6)-alkyl, optionally substituted heteroaryl, heteroaryl residue optionally substituted LASS="ptx2">R denotes hydrogen or (C1-C8)-alkyl, all of the residues R are independent of each other and the residues R may be the same or different;

R1denotes hydrogen, (C1-C10)-alkyl, which optionally can be substituted one or more times by fluorine, aryl residue, optionally substituted by R((C6-C10) -aryl), aryl residue, optionally substituted (R21-((C6-C10)-aryl))-(C1-C6)-alkyl, the remainder of the Het-, Het-(C1-C4)-alkyl or one of the residues X-NH-C(=NH) -R20-, X1-NH-R20and O=;

X denotes hydrogen, (C1-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C6)-alkylcarboxylic-(C1-C6-alkoxycarbonyl, optionally substituted (C6-C10-arylcarbamoyl, optionally substituted (C6-C10-aryloxyalkyl, (C6-C14) -aryl-(C1-C6-alkoxycarbonyl, which can also be substituted in the aryl residue, hydroxy, (C1-C6)-alkoxy or amino;

X1has one of the values X or denotes R'-NH-C(=N-R), where R' R'' independently of each means hydrogen, (C1-C8)-alkyl, which optionally may be substituted by 1 to 6 fluorine atoms, optionally substituted (C6-C10)-aryl in the aryl residue, optionally substituted (C6-C10)-aryl-(C1-C4)-alkyl, optionally substituted heteroaryl or heteroaryl residue optionally substituted heteroaryl-(C1-C4)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C4)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C4)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil, R11NH, COOR21, CON(CH3R4, CONHR4, CON(CH3R15or CONHR15;

R4means (C1-C6)-alkyl, which is unsubstituted or substituted once or twice with the same or different residues from the series hydroxy, (C1-C8)-alkoxy, R5optionally substituted (C3-C8-cycloalkyl, hydroxycarbonyl, aminocarbonyl, (C6-C10) -aryl-(C1-C4-alkoxycarbonyl, in which the aryl residue is m;

R5denotes optionally substituted (C6-C10)-aryl in the aryl residue, optionally substituted (C6-C10)-aryl-(C1-C4)-alkyl or the residue, optionally substituted monocyclic or bicyclic, 5-membered to 12-membered heterocyclic ring which may be aromatic, partially saturated or fully saturated and may contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulfur;

R6denotes the residue of a natural or unnatural amino acid or a residue of a dipeptide or Tripeptide, as well as their esters and amides, where free functional groups can be protected customary in the chemistry of peptides, protective groups, and where the nitrogen atoms in the amide linkages in the group R6-CO can carry the remainder R as a substituent;

R7denotes the residue is linked via a nitrogen atom of a 5-membered to 7-membered saturated monocyclic heterocycle which may contain one or two identical or different additional heteroatoms of the ring from the series oxygen, nitrogen and sulfur and which may be optionally substituted on carbon atoms or will complete the same or different residues from the series hydrogen, RhHCO, RhCO., RhO-CO, HO-CO-(C1-C4)-alkyl, and RhO-CO-(C1-C4)-alkyl, and Rhmeans (C1-C4)-alkyl, optionally substituted (C6-C10)-aryl or aryl residue, optionally substituted (C6-C10)-aryl-(C1-C4)-alkyl;

R8denotes hydrogen, (C1-C6)-alkyl or phenyl residue optionally substituted phenyl-(C1-C4)-alkyl;

R10denotes hydroxy, (C1-C8)-alkoxy, (C6-C10)-aryl-(C1-C6)-alkoxy which can be substituted in the aryl residue, optionally substituted (C6-C10)-aryloxy, (C1-C6)-alkylcarboxylic-(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C6)-alkyl)-amino, aminocarbonyl-(C1-C6)-alkoxy or (mono - or di-((C1-C6)-alkyl) -amino) -carbonyl-(C1-C6)-alkoxy;

R11denotes hydrogen, R12a, R12a-CO, R12a-O -, R12b-CO or R12a-S(O)2;

R12ameans (C1-C8)-alkyl, (C2-C8C4)-alkyl, optionally substituted (C6-C10)-aryl in the aryl residue, optionally substituted (C6-C10) -aryl-(C1-C4)-alkyl, optionally substituted heteroaryl, heteroaryl residue optionally substituted heteroaryl-(C1-C4)-alkyl or the residue R15;

R12bdenotes amino, di-((C1-C8)-alkyl)-amino, or R12a-NH;

R13denotes hydrogen or (C1-C6)-alkyl;

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

R16denotes a 6-membered to 12-membered bicyclic or tricyclic residue, which is saturated or partially unsaturated and which may contain one, two, three or four identical or different heteroatoms from the series nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the series (C1-C4)-alkyl and oxo;

R20denotes a direct bond or methylene;

R21denotes hydrogen, (C1-C6)-alkyl, optionally substituted (C6-C10)-aryl in the aryl residue, optionally substituted (C is the action can be once to four times substituted by fluorine, and the remains of R21when multiple presence may be the same or different;

R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31;

R31denotes a bivalent residue of a number (C1-C6-alkylene, optionally substituted (C6-C10)-aralen in Allenova residue, optionally substituted (C6-C10) -aralen-(C1-C4)-alkyl, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C4)-alkyl, optionally substituted, heteroaryl or heteroarenes residue, optionally substituted, heteroaryl-(C1-C4)-alkyl, and the remainder of allinall, leaving cycloalkenyl and balance heteroaromatic alkyl group linked to the nitrogen atom in the ring of imidazolidine in formula I;

R32denotes hydrogen, (C1-C6)-alkyl, which optionally may be substituted by 1-6 fluorine atoms, (C2-C6)-alkenyl, (C2-C6)-quinil, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C4)-alkyl, optionally substituted (C6-C10)-aryl in the aryl residue, the initial heteroaryl or heteroaryl residue, optionally substituted heteroaryl-(C1-C4)-alkyl;

Het denotes the remainder of the monocyclic or polycyclic, 5-membered to 10-membered, aromatic or non-aromatic ring which contains 1 or 2 identical or different heteroatoms from the series N and O as ring members and optionally may be substituted by one or more identical or different substituents;

e and h represent independently from each other 0 or 1;

in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

A number of especially preferred compounds includes compounds of formula I, where In denotes unsubstituted methylene or methylene which is substituted by (C1-C8)-alkyl residue, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts. Most preferred in this series are the compounds of formula I, where In denotes the methylene that is substituted (C1-C8)-alkyl residue, in all their stereoisomeric forms and their mixtures in all ratios, and their physiological acceptable salt.

Another series of especially preferred is UP>(R) N-CO-N (R) -R31and R32(R) N-CS-N (R)-R31and R31denotes a bivalent residue of a number (C1-C6-alkylen and Allenova residue, optionally substituted (C6-C10) -aralen-(C1-C4)-alkyl, and in the case of arrenaline balance alkyl group linked to the nitrogen atom in the ring of imidazolidine in the formula I, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts. In addition, in this series preferred are the compounds of formula I, where R30denotes the residue R32NH-CO-NH-R31where R32indicates, if necessary, replaced.phenyl and R31denotes a bivalent residue of 1,4-phenylenedi (i.e., the remainder -(1,4-C6H4)-CH2- ) in which the methyl group linked to the nitrogen atom in the ring of imidazolidine in the formula I, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

Another series of especially preferred compounds includes compounds of formula I, where R13denotes hydrogen or methyl, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts. Even BolognaFiere group R13also does not denote hydrogen, i.e. compounds in which W represents CH2in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, and most preferably, if in these compounds R13denotes methyl, i.e. are compounds in which W denotes a bivalent residue R1-A-C(CH3and R1A has a value other than hydrogen.

Another series of especially preferred compounds includes compounds of formula I, where R13and R1A - both are not hydrogen, R30denotes the residue R32-NH-CO-NH-(1,4-C6H4)-CH2where the group -(1,4-C6H4means a is connected through position 1 and 4 the rest of phenylene and R32denotes optionally substituted phenyl, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

Another series of especially preferred compounds includes compounds of formula I, where R13and R1A - both are not hydrogen, R30denotes the residue R32-NH-CO-NH-(1,4-C6H4) -CH2, R32means, when the necessity is Orme, substituted (C1-C6)-alkyl or (C3-C6-cycloalkyl-(C1-C2)-alkyl, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

Another series of especially preferred compounds includes compounds of formula I, where R13and R1A - both are not hydrogen, R30denotes the residue R32-NH-CO-NH-(1,4-C6H4) -CH2, R32denotes optionally substituted phenyl, A represents the bivalent residue of the methylene which is unsubstituted or, in a preferred form, substituted (C1-C6)-alkyl or (C3-C6-cycloalkyl-(C1-C2)-alkyl, and the remainder is-N(R)-[C(R) (R)]e-C(R2) (R3)-[C(R) (R)]hIn the formula I denotes a residue-NH-CH(R3)-CH2-E, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

Another series of especially preferred compounds includes compounds of formula I, where W represents one of the divalent residues of 1,1-cyclopropylidene, 1,1-cyclopentadien and 1,1-cyclohexylidene more explained above, and derived 5-Inoi communication, R30denotes the residue R32-NH-CO-NH-(1,4-C6H4) -CH2and R32denotes optionally substituted phenyl, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

Another series of especially preferred compounds includes compounds of formula I, where W represents one of the divalent residues of 1,1-cyclopropylidene, 1,1-cyclopentadien and 1,1-cyclohexylidene, R30denotes the residue R32-NH-CO-NH-(1, 4-C6H4)-CH2, R32denotes optionally substituted phenyl and represents the bivalent residue of the methylene which is unsubstituted or, in a preferred form, substituted (C1-C6)-alkyl or (C3-C6-cycloalkyl-(C1-C2) - alkyl, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

Another series of especially preferred compounds includes compounds of formula I, where W represents one of the divalent residues of 1,1-cyclopropylidene, 1,1-cyclopentadien and 1,1-cyclohexylidene, R30denotes the residue R32-NH-CO-NH-(1,4-C6H4)-CH2, R32about the or in the preferred form, substituted (C1-C6)-alkyl or (C3-C6-cycloalkyl-(C1-C2)-alkyl, and the remainder-N-(R) -[C (R) (R)]e-C (R2) (R3) -[C (R) (R)]hIn the formula I denotes a residue-NH-CH(R3) -CH2-E, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

Another series of especially preferred compounds includes compounds of formula I, where in residue-N-(R)-[C (R) (R)]e-C(R2) (R3)-[C(R) (R)]h-E, which through amide linkage associated with the group-IN-WITH-chain carbon atoms between the group N(R) and the first connected with this chain group, which is an acid group such as carboxylic acid group, sulfonic acid group, phosphonic acid group, or a group tetrazolyl or its derivative such as ester or amide that contains two or more than two carbon atoms, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

This first acid group (or its derivative), which is based on the group N(R), associated with this chain of carbon atoms, can be a group or can be a group, R3if the latter do are the compounds of formula I, where in the residue-N-(R) -[C (R) (R)]e-C (R2) (R3) -[C (R) (R)]h-E chain of carbon atoms between the group N(R) and the first connected with this chain group, which is an acid group or its derivative, contains exactly two atoms of carbon, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts. Such especially preferred compounds of formula I can be, for example, compounds where e denotes 1, i.e. compounds containing the group-N(R) (R)(R)-C(R2) (R3)-[C(R) (R)]h-E, and in the case of such compounds h may designate 1 or 0 and in the case of these compounds is preferred if R3means R11NH and at the same time h represents 0, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts. Such most preferred compounds of formula I can be, for example, compounds where e denotes 0, h denotes 1 and R3doesn't mean acid group or its derivative, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, i.e. compounds which contain the residue of N-(R)-C (R2) (R3apreferably denotes hydrogen, (C1-C8)-alkyl, which optionally may be substituted by 1 to 6 fluorine atoms, optionally substituted C6-C14)-aryl in the aryl residue, optionally substituted (C6-C14) -aryl-(C1-C8)-alkyl, optionally substituted heteroaryl in the heteroaryl residue optionally substituted heteroaryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, (C2-C8)-alkenyl or (C2-C8)-quinil. In these compounds R3Aespecially preferably represents hydrogen, (C1-C6)-alkyl, which optionally may be substituted by 1 to 6 fluorine atoms, optionally substituted (C6-C10)-aryl in the aryl residue, optionally substituted (C6-C10)-aryl-(C1-C4)-alkyl, optionally substituted heteroaryl, heteroaryl residue, and when n is UB>-cycloalkyl-(C1-C4)-alkyl, (C10-C12-tricyclohexyl or (C10-C12-tricyclohexyl-(C1-C4)-alkyl. In addition, preferred compounds of this series is, if the group-N(R)- residue-N (R) -[C (R) (R)]e-C (R2) (R3) -[C (R) (R)]h-E refers to a group-NH-.

Another series of especially preferred compounds includes compounds of formula I, where in residue-N(R)-[C (R) (R)]e-C(R2) (R3) -[C(R) (R)]h-E, the chain of carbon atoms between the group N(R) and the first connected with this chain group, which is an acid group or its derivative, contains only one carbon atom, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, however, in these compounds the first acid group or its derivative, which is based on the group N(R), associated with a chain of carbon atoms, must fulfill the following conditions: a) the first acid group or its derivative is an amide group, but in the alkyl substituents on the amide nitrogen atom does not contain the related alkyl Deputy group of the carboxylic acid (or its derivative, such as the ether group is erva acid group or its derivative is an ester group. Compounds of this series can be, for example, the compounds of formula I, where e is zero, and R3means COOR21, COOR15, CONHR15or CON(CH3R15preferably, CONHR15and h is 0 or 1, preferably 1. Compounds of this series can be, for example, compounds of formula I, where e is 0, h is 0 or 1, preferably 1, and R3indicates SOP(CH3R4or CONHR4where, however, representing the remainder (1-C10)-alkyl, R4may not be substituted by a carboxylic acid group or its derivative, for example, complex ether or Amida, i.e., for example, compounds in which R4denotes hydrogen or, in particular, (C1-C10)-alkyl, which is unsubstituted or substituted by one or more identical or different residues from the series hydroxy, (C1-C8)-alkoxy, R5optionally substituted (C3-C8-cycloalkyl, tetrazolyl, trifluoromethyl. In compounds of this series E represents, preferably, an acid group or its derivative.

Generally preferred are the compounds of formula I which have one or more centers of chirality, for example, with appropriate substitution of the bearing residues R

The compounds of formula I can be obtained, for example, fragmented by condensing the compounds of formula II:

with the compound of the formula III

in formulas II and III group W, Y, b, E, R, R2, R3, R30and e and h have values above or these groups may also contain functional groups in protected form or in the form of precursors and G denotes hydroxycarbonyl, (C1-C6-alkoxycarbonyl or activated derivatives of carboxylic acids, such as floridawhere acid or active esters. If you want to obtain the compounds of formula I, in which, for example, R3in the formula I denotes a carboxylic acid derivative or contains such a group, the compounds of formulas which do contain such a group, and only then after condensation of the compounds of formula II and formula III in one or more stages may be synthesized desired final group R3. Precursors of functional groups are groups that use conventional, well-known specialists of synthesis methods, can be converted into the desired functional groups, for example, a nitrogroup through recovery, for example by catalytic hydrogenation to convert the amino group, and it can be called a precursor to the amino group or the other group, obtained by further transformations. The cyano, through which recovery can be converted to the aminomethyl group or by hydrolysis of amide acid group or carboxylic acid group, can be called a predecessor for these groups. Alcohol group, which can oxidize in the aldehyde group or ketone group can be called a predecessor for these groups. However, a precursor to the group may be the group from which in the course of the next several reaction stages synthesize larger part of the target molecule. Examples of protective groups, which before the I-condensing compounds of the formula II with compounds of formula III are used, preferably, well known in themselves methods reactions combination of peptide chemistry (see, for example, Houben-Weyl, Methods der Organischen Chemie, Band 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). As the condensing medium or linking reagents can be used, for example, carbonyldiimidazole, carbodiimides, such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, O-((CYANOGEN(etoxycarbonyl)methylene)amino)-N,N,N',N'-tetramethylethylenediamine (TOTU) or anhydride propylphosphonic acid (PPA).

The condensation can be carried out with well-known specialists standard conditions. During condensation, as a rule, it is necessary to protect the existing, not reacting the amino group with reversible protective groups. The same applies to not participating in the reaction of carboxyl groups, which during the condensation are preferably in the form (C1-C6)-Olkiluoto ether, benzyl ether or tert-butyl methyl ether. Protection of the amino groups is not necessary, if the amino groups are in the form of precursors, such as nitro or ceanography, and only after condensation formed, for example, by hydrogenation. After condensation of the existing protective group is relevant to the e and benzyl groups in benzyl esters can be separated by hydrogenation. Protective groups such as tert-butyl separate the acid, while the 9-fluorenylmethoxycarbonyl the residue is separated by means of secondary amines. Obtaining compounds of formula I may also, for example, be carried out in such a way that using a conventional connection methods synthesize Paladino on the solid phase, and the individual structural elements of the molecule can be introduced in a different sequence.

The compounds of formula II, where W denotes the R1-A-C(R13and Y represents a carbonyl group, can be obtained, for example, so that at the beginning of the compounds of formula IV

in the reaction of Bucherer, for example, with ammonium carbonate and potassium cyanide, is converted into the compounds of formula V

(N.T. Bucherer, V. A. Lieb, J. Prakt. Chem. 141(1934), 5), and in formulas IV and V groups of R1, R13and a have the above values.

Then the compounds of formula VI

where R1, R13, A, b and G have the above values, can be obtained by the interaction of the compounds of formula V first, for example, with an alkylating reagent that introduces the rest-To-G in the molecule. Interaction of the compounds of the formula VI with a second reagent of the formula R301-C4)-alkoxy, optionally substituted, phenoxy or heterocyclic leaving group, such as, for example, imidazolyl, leads to the corresponding compounds of formula II.

In General, depending on the value of the remainder R30and other residues may also be preferred to introduce into the molecule is not the final remainder R30using the reagent R30-LG, and after joining the predecessor group, R30to the ring of imidazolidine to synthesize the remainder R30on the ring of imidazolidine. This may occur, for example, at the stage of the compounds of formula VI, or its derived compounds of the formula II or stage another intermediate product synthesis. As an example of such method steps are presented below for the compounds in which R30denotes a carbamide group, R32(R)N-CO-N (R)-R31. The compounds of formula II in which R30means R32(R)N-CO-N(R)-R31you can get this way, for example, so that the compound of formula VI is first using a reagent of the formula PG-N(R)-R31-LG, where LG is CLASS="ptx2">and PG denotes a protective amino group, for example, tert-butoxycarbonyl or benzyloxycarbonyl, and the other radicals have the above values. After removal of the protective group PG is produced by interaction emerged amino HNR-for example, with isocyanate of formula R32-N=C=O, the compounds of formula II, where R30means R32NH-CO-N (R) -R31. Interaction, for example, carbamoylation formula R32(R)N-CO-CL get the compounds of formula II in which R30means R32(R)N-CO-N(R)-R31. Accordingly, isothioscyanates and thiocarbamoylation you can get similar thiourea derivatives, by reacting the amino group with a reactive derivative of carboxylic acid derivatives thiocarbonic acid, derivatives of sulfonic kilty derived sulfinol acid and derivatives sulfhemoglobin you can get (thio)acylamine, sulfonylamine, sulfanilamide and sulfonamides. As the compounds of formula VII can be obtained, and to use compounds in which in formula VII group PG-N(R) is replaced by a group which is a precursor for the amino group and subsequent reaction stage is transferred to the amino group. Possible example is ormula NC-R31-LG to turn into one of the compounds corresponding to the compounds of formula VII, then the nitro-group or cyano, for example by catalytic hydrogenation to transfer to the amino group, and then the amino group to convert to the desired target group, for example, by using an isocyanate of formula R32-N=C-O derivative of urea, in which R30means R32NH-CO-NH-R31or with other compounds. Using this method, it is possible to synthesize numerous other compounds of formula I, if this be conducting the reaction always are standard reactions known to specialists.

In General, the individual stages of the compounds of formula I can be carried out in accordance or similarly known to specialists in methods. However, depending on specific cases, as mentioned above, can be useful in all stages of the synthesis of compounds of formula I temporarily block functional groups, which can lead to adverse reactions or unwanted reactions using coherent with the problems of synthesis strategies for the application of protective groups, which is known to specialists.

Description and first introduced into the molecule precursors and then at the stage of intermediate product synthesize the final functional group, you can apply, as mentioned above, accordingly, also for other parts of the molecule of formula I, for example, for a group R1or for a group of R3.

The compounds of formula II, where W denotes

and Y denotes carbonyloxy group, can be obtained, for example, the conversion of compounds of formula VIII

where R1, A, L, m1 and m2 have the above values in the reaction of Bucherer similar to that described above to obtain compounds of the formula V into compounds of the formula IX

and turning them with a reagent which introduces the remainder of the molecule-B-G, as described above, when obtaining the compounds of formula VI, a compound of the formula X

moreover, in the compounds of formulas IX and X of the group R1A , b, G, L, and ml and m2 have the above values. Then the compounds of formula X can be in accordance with the above described transformations of compounds of formula VI to convert using a reagent of formula R30-LG or reagent of the formula PG-N(R)-R31-LG.

If W denotes the R1-A-C (R13)=C, or the residue

you can enter this structural element, for example, by condensation of similar known methods appropriate ALD is the group of methylene in position, which corresponds to a group W.

The amino compounds of formula III are commercially available or can be synthesized according to or analogously to the well-known standard methods of the parent compounds, which are commercially available or which can be obtained according to or analogously described in the literature procedures.

The compounds of formula I, where W denotes the R1-A-C(R13) can also be obtained as follows:

By reaction obtained using standard methods-amino acids or N-substituted-amino acids, or preferably their esters, for example methyl ester, ethyl ester, tert-butyl methyl ether, or benzyl ether, for example, compounds of formula XI

where R1, R13, R30and a have the above meanings, with an isocyanate or isothiocyanates, for example, of the formula XII

where V, E, R, R2, R3, e and h have the above values and U denotes isocyanato or isothiocyanato receive a derivative of urea or thiourea derivatives, for example, of the formula XIII

where the symbols have the above meanings and Z represents oxygen or sulfur. The compounds of formula XIII can be cyklinowanie petenia. The cyclization of compounds of formula XIII in the compounds of formula Ia can be produced by processing bases in an inert solvent, for example by treatment with sodium hydride in an aprotic solvent, e.g. dimethylformamide. During the cyclization functional groups can be placed again in a protected form.

The compounds of formula I, where W is denoted by R1-A-C(R13), can be obtained also by the interaction of the compounds of formula XI with an isocyanate or isothiocyanato formula XIV

where V and U have the above for formula XII values and Q denotes an alkoxy group, for example, the group (C1-C4)-alkoxy, such as methoxy, ethoxy or tert-butoxy, group (C6-C14)-aryloxy, for example, phenoxy, or group (C6-C14) -aryl-(C1-C4)-alkoxy, for example benzyloxy. You get a connection formula XV

where Z denotes oxygen or sulfur, and a, b, Q, R1, R13and R30have the above for formula XI and XIV values, which are then under the influence of acid or base as described above for the cyclization of compounds of formula XIII, cyclist in the compound of formula XVI

where the but then, for example, using a hydrolysis group CO-Q in the group of the carboxylic acid COOH and subsequent reactions combination with the compound of the formula III, as described above for the combination of compounds of formula II and formula III to obtain a compound of formula Ia. In this way the synthesis of functional groups can also again be in protected form or in the form of precursors.

Another method of preparing compounds of the formula Ia is, for example, in the interaction of compounds of formula XVII

where W denotes the R1-A-C(R13and other symbols have the above values with phosgene or thiophosgene, or corresponding equivalents (similar to S. Goldschmidt, M. Wick, Liebigs Ann. Chem. 575 (1952), 217-231 and S. Tropp, Chem. Ber. 61 (1928), 1431-1439).

The compounds of formula Ia where Z denotes oxygen, can be obtained primarily by linking compounds of the formula XVIII

where R1, R13and a have the above values and PG denotes a protective amino group, such as, for example, benzyloxycarbonyl group, with a compound of formula XIX

where has the above values and Q' indicates a protected hydroxyl group, carboxylic acid, for example, an alkoxy group, t is Q' have the above values. Then, in the compound of formula XX can be selectively separate the protective group PG from the amino group, e.g. by hydrogenation in the case of a group of benzyloxycarbonyl and by introducing the group to produce ring closure with the formation of compounds of formula XXI

where R1, R13And, and Q' have the above values. For the introduction of a carbonyl group can be used, for example, phosgene or the equivalent of phosgene (see above transformation of compounds of formula (XVII). As an intermediate product in the transformation of compounds of formula XX to a compound of formula XXI may occur isocyanate or it can be obtained purposefully. The transformation of compounds of formula XX to a compound of formula XXI can occur in one or several stages.

The cyclization can be carried out, for example, after the introduction of the carbonyl group, as in the above-described cyclization, separately in the presence of a base such as sodium hydride. The compounds of formula XX, where PG denotes the group of benzyloxycarbonyl, you can also directly be converted into the compounds of formula XXI no use for the introduction of a carbonyl group such element synthesis as phosgene. If soemone directly to obtain the compounds of formula XXI.

Then, in the compounds of formula XXI can, as indicated for compounds of formula VI, to the NH group to enter the rest R30or the remainder PG-NR-R31- and after separation of the protective group CO-Q' for the carboxylic acid group COOH described for compounds of formulas VII and II to synthesize the desired compound of formula Ia (where Z denotes oxygen). In this way the synthesis of functional groups can be present in protected form or in the form of precursors.

Contained in the residue R1group guanidino can be obtained from amino groups, which, in turn, can be obtained from nitro or ceanography with recovery, for example, using the following reagents:

1. O-methylisoleucine (S. Weiss und N. Chammah, Chemiker-Zeitung 98 (1974), 617-618).

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

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

4. Formamidinesulfinic acid (K. Kim, Y.-T. Lin and H. S. Mosher, Tetrah. Lett. 29 (1988), 3183-3186).

5. Nitrate 3,5-dimethyl-1-personinformation (F. L. Scott, D. G.'Donovan und J. Reilly, J. Amer. Chem. Soc. 75 (1953), 4053-4054).

6. N, N' -di-tert-butyloxycarbonyl-S-methyl-estimacion (R. J. Bergeron and J. S. McManis, J. Org.Chem.52 (1987) ethyl-estimacion (H. Wollweber, H. Kolling, E. Niemers, A. Widdig, P. Andrews, H-P. Schuiz und H. Thomas, Arzneim. Forsch./Drug Res. 34 (1984), 531-542).

Amidine can be obtained from corresponding compounds of CYANOGEN by joining alcohols, such as methanol or ethanol, in the acidic anhydrous medium, for example, dioxane, methanol or ethanol, and subsequent aminolysis, for example, treatment with ammonia in alcohols, such as isopropanol, methanol or ethanol (G. Wagner, P. Richter und Ch. Garbe, Phannazie 29 (1974), 12-55). Another method to obtain amidino is the joining of hydrogen sulfide to the cyano with subsequent methylation occurred thioamide and subsequent interaction with ammonia (DDR-Patent No. 235 866). In addition, you can attach the hydroxylamine to the cyano, and there N-hydroxyamides, which, if desired, also can be translated in amidine, for example, by hydrogenation.

In obtaining compounds of formula I are referred to in full in WO-A-95/14008, EP-A-796 855 and their corresponding applications, as well as in WO-A-96/33976. In particular, in obtaining compounds of formulas V and VI in racemic and enantiomerically-pure form reference is made to the corresponding embodiments of the in WO-A-96/33976, which are part of the present disclosure.

Therefore, the object of the present invention are also the compounds of formula I and/or their physiologically acceptable salts and derivatives for use as drugs, the use of compounds of the formula I and/or their physiologically acceptable salts and derivatives for the manufacture of pharmaceuticals for therapy and prophylaxis of the above and in the following diseases, for example, for the treatment and prevention of inflammatory diseases, and t is the phenomenon of these diseases. In addition, the subject of the present invention are pharmaceutical preparations which contain an effective dose of at least one of the compounds of formula I and/or physiologically acceptable salts and derivatives and conventional pharmaceutically flawless media, i.e., the normal pharmaceutically perfect carriers and/or additives.

Drugs can be applied systemically or locally. They can be taken, for example, orally in the form of pills, tablets, film tablets, coated tablets, granules, hard or soft gelatin capsules, powders, solutions, syrups, emulsions, suspensions or other dosage forms. However, they can be administered vaginally or rectally, for example in the form of suppositories, or parenterally, or implanting, for example, in the form of solutions for injection or infusion solutions, microcapsules or rods, or topically or through the skin, for example, in the form of ointments, solutions or tinctures, or in other ways, for example, in the form of sprays for the nose or aerosol mixtures. Solutions you can enter parenterally, for example intravenously, intramuscularly, subcutaneously, intra-articular, nutrizionale or other means.

Manufacture of pharmaceutical preparations the mi formula I and/or their physiologically acceptable salts and derivatives, can be used pharmaceutically inert inorganic and/or organic carriers. For the manufacture of 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, glycols, natural or hardened oils, etc. as carriers for the manufacture of solutions, such as solutions for injection, or of emulsions or syrups are suitable, for example, water, alcohols, glycerin, diatomic alcohols, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. as carriers for microcapsules, implants or rods are suitable, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations contain normally about 0.5 to 90 wt.% compounds of the formula I and/or their physiologically acceptable salts and derivatives.

Pharmaceuticals, along with active substances and media may also contain auxiliary substances or additives, such as, for example, napolnitelyami, coloring, giving a flavor or fragrance, condensing, diluting means, buffer substances, solvents and contributing to the dissolution of the tools, the means to achieve a cumulative effect, salts for modifying the osmotic pressure, coating materials or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically acceptable salts and derivatives.

In addition, along with at least one compound of the formula I and/or physiologically acceptable salts and derivatives, they may contain one or more therapeutically or prophylactically active substances, for example, substances inhibiting inflammation effect. The pharmaceutical preparations contain in the normal case 0.2 to 500 mg, preferably 1-100 mg of the active substance of the formula I and/or physiologically acceptable salts and derivatives on a single dose.

If the compounds of formula I, or containing pharmaceutical composition is administered in the form of aerosols, such as nasal aerosols or by inhalation, this can be accomplished, for example, with the use of the spray, spray, pump spray, inhalator device, the dosing inhaler or insole can be produced by well-known specialists of ways. For their manufacture can be used, for example, solutions or dispersions of the compounds of formula I in water, mixtures of alcohols with water or a suitable salt solutions with conventional additives, for example benzyl alcohol or other suitable preservatives, tools, improves absorption, to increase the biological availability, contributing to the dissolved substances, dispersants and others, and, if necessary, conventional pore-formers, for example, perchloroethane and/or fluorocarbons.

The compounds of formula I are, for example, the ability to inhibit interaction between the cells and the processes of interaction of cell-matrix, which play the role of the interaction between VLA-4 and its ligands. The effectiveness of compounds of the formula I can be demonstrated, for example, in the experiment, which measured the binding of cells that contain receptor VLA-4, for example, leukocytes, with ligands of this receptor, for example, VCAM-1, which can be fabricated, preferably, also with the help of genetic engineering. Details of this test are shown below. The compounds of formula I have, in particular, the ability of inhibition of adhesion and migration of leukocytes, for example, adhesion of leukocytes is soedineniya formula I and their physiologically acceptable salts and derivatives are suitable not only as inhibitors of inflammation, but also in General for therapy and prophylaxis of diseases which are based on the interaction between the receptor VLA-4 and its ligands, or which can be influenced by inhibition of this interaction, and in particular, they are suitable for the treatment and prevention of diseases. at least partly caused undesirable amount of leukocyte adhesion and/or migration of leukocytes or related to it, and to prevent, mitigate, and which treatment should be reduced adhesion and/or migration of leukocytes.

Therefore, the object of the present invention are also the compounds of formula I and their physiologically acceptable salts and derivatives for the inhibition of the adhesion and/or migration of leukocytes or for inhibition of receptor VLA-4 and the use of compounds of the formula I to get this drugs, i.e. drugs for therapy or prevention of diseases in which leukocyte adhesion and/or migration of leukocytes have undesirable sizes, or for therapy or prevention of diseases in which play a role dependent on VLA-4 adhesion processes, and also the use of compounds of the formula I and/or their physiologically acceptable salts and derivatives in tera is reavley, caused by a variety of reasons, as inhibitors of inflammation to prevent, reduce, or suppress undesirable or harmful effects of inflammation. They are used for example for the treatment or prevention of arthritis, rheumatoid arthritis, polyarthritis, inflammatory bowel disease (ulcerative colitis), systemic lupus erythematosus, for the treatment or prevention of inflammatory diseases of the Central nervous system, like multiple sclerosis, or for therapy or prophylaxis of asthma or allergies, such as Allergy delayed type (type IV allergies). In addition, they are suitable for therapy or prevention of cardiovascular diseases, arteriosclerosis, restenosis, diabetes, damage to transplants of organs, immunological diseases, autoimmune diseases, tumor growth or metastasis of tumors at various zlokacestvennosti, malaria, and other diseases in which to prevent, mitigate or cure, it seems appropriate blocking of the integrin VLA-4 and/or influence on the activity of leukocytes.

Dose when using compounds of formula I can vary within wide limits and is, as usual, agreed to the t type and severity of the subject to treatment, from the connection you use, or whether the treatment of acute or chronic state of the disease or prevention, or whether, along with the compounds of formula I, other active ingredients. Usually, when oral administration the daily dose is from about 0.01 to 100 µg/kg, preferably 0.1 to 10 µg/kg, in particular from 0.3 to 2 µg/kg (in each case per 1 kg body weight) for adults to achieve effective impact. With intravenous administration the daily dose is usually about 0.01 to 50 MC/kg, preferably 0.01 to 10 µg/kg body weight. Daily dose, particularly when large doses, can be divided into several, for example 2, 3 or 4 servings per day. Depending on the individual reactions may be necessary under certain conditions to deviate upwards or downwards from the specified daily dose.

Along with the application as biologically active substances in medicinal products in medicine and veterinary medicine, it is possible to use the compounds of formula I and their salts and suitable for their respective uses derivatives for diagnostic purposes, for example, carried out in vitro diagnoses of samples of cells or tissue, and as an aid or as a research tool is aimogasta at the level of cell-cell or cell-matrix. In addition, the compounds of formula I and their salts can serve as intermediates for other compounds, in particular, other biologically active substances of medicines that can be obtained from compounds of the formula I, for example, the modification or the introduction of radicals or functional groups, for example, by esterification, reduction, oxidation or other transformations of functional groups.

Examples

Products are identified by using mass spectra (MS) or NMR spectra. The main compound that was purified by chromatography using the mobile phase, which contains, for example, acetic acid or triperoxonane acid, and then dried by freezing, or who have been treated with acid, for example, triperoxonane acid, and processing of, for example, was dried by freezing, partially contained also used acid, i.e., there were partially or completely in the form of salts of acid used, for example, in the form of a salt of acetic acid or salt triperoxonane acid.

Legend:

MTBE methyl tert-butyl ether

DMF N,N-dimethylformamide

THF tetrahydrofuran

DMAP 4-CLASS="ptx2">N,N,N',N'-tetramethyluronium-tetrafluoroborate

NOT 1-hydroxybenzotriazole

DIPEA N,N-diisopropylethylamine

TFA triperoxonane acid

DCM dichloromethane

Me methyl CH3-

PWG n-propyl CH3-CH2-CH2-

nBu n-butyl CH3-CH2-CH2-CH2-

tBu tert-butyl (CH3)3WITH-

Et ethyl CH3-CH2-

iPr isopropyl (CH3)2CH-

the iBu is isobutyl (CH3)2SNSN2

Ph phenyl C6H5-

Fmoc 9-fluorenylmethoxycarbonyl

The compounds in the examples were obtained partly by using conventional methods, which are described below and in the form of diagrams. Radicals in formula schemes, which have the same designations as the corresponding radicals in the formula I are indicated for formula I values. The values of the other radicals are given depending on the circumstances. Values radicals to a specific substance of example, as well as for the parent compounds, which are used in the individual steps of the synthesis of specific substances of example, follow from the structure of matter.

A General method according to the scheme 1

For p the>-A-alkilany ether-amino acids with tert-butyl everettingerson acid in urea and cyclically its sodium hydride (stages a and b) or alkilirovanie substituted in position 4 groups of R13or R1A-as with tert-butyl methyl ether bromocarbons acid (stage C). The intermediate product of the formula VIa or in situ or after pre-allocation and, if necessary, after chromatographic purification alkilirovanie 4-nitrobenzylamine in the derived 3-(4-nitrobenzyl)-as (stage D). The nitrogroup restored catalytic hydrogenation of the amino group (stage E), which is then by means of isocyanate of the formula R32-N=C=O was converted into urea (stage F). After translation tert-butyl ester group in the carboxylic acid group with triperoxonane acid (stage G) connected intermediate product of the formula II with aminoguanidinium formula III, in which an existing group of carboxylic acids were protected as esters (stage N). Finally, through the Department of protective ester groups received the compound of formula I (stage J). Alk in the diagram, 1 denotes methyl or ethyl. A separate stage was carried out as follows

General specilaty was dissolved in dimethylformamide (about 2 ml per 1 mmol of ester) and was diluted 1 equivalent of tert-butyl methyl ether isocyanatobenzene acid (obtained analogously to J. S. Nowick et al., J. Org.Chem. 1996, 61, 3929). The mixture was stirred for 12 h at room temperature. The solution obtained urea in dimethylformamide without further purification and processing used in further reactions.

For cyclization of urea in the as the urea solution was cooled to 0°C and mixed with 1.2 equivalents (relative to urea) of sodium hydride. The mixture was stirred for 15 minutes at a temperature of 0°C and then for 2 h at room temperature. After this was added 1.1 equivalent (relative to urea) 4-nitrobenzylamine and the mixture was stirred 3 h at room temperature. In case of incomplete conversion was added 0.1 equivalent of sodium hydride and stirred for another 3 h at room temperature. The reaction mixture was suppressed by the addition of water and the solvent was removed on a rotary evaporator. The oily residue was dissolved in ethyl acetate and the solution washed with water. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuum. The residue was purified by thin-layer chromatography (hexane/methyl tert-butyl ether). Fraction of the product together.

A common method of obtaining derivatives of 3-(4-nitrobenzyl) as; stage a, b, D (method 2)

Stage and performed like poroduct formula VIa chromatography on silica gel using a mixture of heptane/methyl tert-butyl ether. Fractions of product were combined and the solvent was removed in vacuum. The residue was dissolved in dimethylformamide (2.5 ml per 1 mmol of compound of formula VIa), was added 1 equivalent of 4-nitrobenzylamine and 1.2 equivalents of cesium carbonate and stirred the mixture for about 5 h at room temperature and then left overnight at room temperature. After filtration the solvent was removed in vacuo and the residue was chromatographically using a mixture of heptane/methyl tert-butyl ether through silica gel. Fraction of the product was concentrated and used in stage E.

A common method of obtaining derivatives of 3-(4-nitrobenzyl)-as; stage C, D (method 1)

The as (16 mmol) was dissolved in dimethylformamide (about 7.5 ml per 1 mmol of as) and was added 1.2 equivalents of sodium hydride. The mixture was stirred 4 h at room temperature. After adding 1.7 equivalent tert-butyl ether bromocarbons acid was continued stirring at room temperature over night. The solvent was removed in a rotary evaporator. The residue was purified by thin-layer chromatography (heptane/methyl tert-butyl ether). Received alkilirovanny as the formula VIa. Alkilirovanny as the formula VIa dissolved in dimethylfuran room temperature. After addition of 1.1 equivalents of 4-nitrobenzylamine was stirred for 2-3 h at room temperature. The reaction mixture was suppressed by the addition of water and the solvent was removed in a rotary evaporator. The oily residue was dissolved in ethyl acetate and the solution washed with water. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuum. The residue was purified by thin-layer chromatography (heptane/methyl tert-butyl ether). Fraction of the product, which contained derivatives of 3-(4-nitrobenzyl)-as United.

A common method of obtaining derivatives of 3-(4-nitrobenzyl)-as; stage C, D (method 2)

Stage performed as described above in stages C, D (method 1). In method 2 in phase With the intermediate product of the formula VIa transformed using a 4-nitrobenzylamine and cesium carbonate (the same as the above method for stages a, b, D (method 2) and the crude product was purified by chromatography, as described for stages C, D (method 1).

A common way catalytic reduction of nitro compounds; stage E

The derived 3-(4-nitrobenzyl)-as was dissolved in methanol (about 10 ml per 1 mmol of the derivative as) and was first made with palladium/charcoal in atmospheres which was alocale derived 3-(4-aminobenzyl) -as.

A common way to obtain urea; stage F

The derived 3-(4-aminobenzyl)-as was dissolved in tetrahydrofuran (4 ml per 1 mmol of the derivative as) and was mixed with 1 equivalent of isocyanate of the formula R32-N=C=O. the Mixture until complete conversion was heated under reflux. The solvent was removed in vacuum. The residue was purified by thin-layer chromatography (hexane/methyl tert-butyl ether). After concentrating the product fractions were obtained the corresponding urea.

A common way of translating tert-butyl ether carboxylic acids; stage G

For removal of the tert-butyl ester group obtained in stage F urea was stirred triperoxonane acid (about 10 ml per 1 mmol) for 1 h at room temperature. After removal triperoxonane acid in a rotary evaporator, the residue was dried by freezing. Received carboxylic acid of the formula IIA.

A common way to connect carboxylic acids with amino compounds; stage N (method 1)

Carboxylic acid of the formula IIA was dissolved in dimethylformamide (5 ml per 1 mmol of carboxylic acid) and mixed with 1 equivalent to be connected to the amino compounds of the formula III, in kamidana, in the form of ethers, and mixed with 1 equivalent of 1-hydroxybenzotriazole. The mixture was cooled to 0°C, was mixed with 1 equivalent of N,N'-dicyclohexylcarbodiimide (DCC) and stirred 1 h at 0°C. Then stirred 4 h at room temperature. The mixture was filtered and the solvent was removed in vacuum. Purification of the residue by thin-layer chromatography led to the product of the merger.

A common way to connect carboxylic acids with amino compounds; phase H (method 2)

Carboxylic acid of the formula IIA and 1 equivalent subject to the accession of the amino compounds of formula III was dissolved in dimethylformamide (5 ml per 1 mmol of carboxylic acid). The solution was sequentially added 1 equivalent of O-((CYANOGEN (etoxycarbonyl) methylene) amino-N,N,N'N' -tetramethyluronium-tetrafluoroborate (TOTU) and 1 equivalent of N,N-diisopropylethylamine (DIPEA) (if aminosidine formula III used as hydrochloride, was added 2 equivalents of N,N-diisopropylethylamine). The mixture was stirred at room temperature. After the reaction the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and an ethyl acetate phase is then washed twice with a saturated solution of sodium bicarbonate, the solution is ABC was dried over sodium sulfate. After filtration the solvent was removed in vacuum and the residue was purified by chromatography through silica gel. In cases where the compound of formula III contain one or more protected groups of the carboxylic acid in the form of tert-butyl methyl ether, methyl ester or ethyl ester, or first purified ether chromatography through silica gel, or first tsalala ester group (see stage (J) and then purified final product (carboxylic acid).

A common way of splitting protective tert-butyl ester groups; stage J (method 1)

For cleavage of the protective tert-butyl ester groups of the product of the merger of stage N was dissolved in triperoxonane acid (about 10 ml per 1 mmol) and stirred 1 h at room temperature. The solvent was removed in a rotary evaporator. The rest, partly after adding a mixture of acetic acid/water was dried by freezing or purified by chromatography and then liofilizirovanny. Getting the appropriate acid of formula I.

A common way of splitting protective methyl ester groups and ethyl ester groups; stage J (method 2)

For cleavage of the protective methyl and ethyl ester groups of the product of the merger of stage N restore. The mixture was left overnight at room temperature and then brought to pH 1 of 1 N. hydrochloric acid. Added ethyl acetate, the phases were separated, the organic phase is washed with water and the solvent was removed in vacuum. The residue after addition of acetic acid and water, dried by freezing.

A General method according to the scheme 2

To obtain an intermediate product of the formula VIa N-benzyloxycarbonyl--amino acid was coupled with tert-butyl ether amino acids (stage K) and the product of the merger after the separation of the group of benzyloxycarbonyl (=group Z) cyclically catalytic hydrogenation (stage L) and the introduction of one group in the resulting free amino group in the compound of the formula VIa (stage M). Similar to the way according to the scheme 1 it alkilirovanie 4-nitrobenzylamine in the derived 3-(4-nitrobenzyl)-as was converted into compound of formula IIA and a compound of formula IIA by connecting with aminoguanidinium formula III, in which the carboxylic acid group was protected in the form of esters, and separating the protective groups were transferred to the compound of formula I (stage D-J). Some stages were performed as follows.

A common method of obtaining derivatives of 3-(4-nitrobenzyl)-M ether amino acids, as described for the method according to the scheme 1, stage H (method 2). For stage L, the product compound was first made over palladium/charcoal as described for scheme 1, stage Ie, Then at stage M first, similar to J. S. Nowick et al., J.Org. Chem. 1996, 61, 3929

group H2N using phosgene in toluene was transferred into the isocyanate. The resulting isocyanate was dissolved in dimethylformamide (2.5 ml per 1 mmol of isocyanate). To the solution at 0°C was added 1.2 equivalents of sodium hydride and the mixture was stirred 1.5 h at room temperature. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and washed twice with water. The phases were separated, the ethyl acetate phase was dried over sodium sulfate and after filtration the solvent was removed in vacuum. Received the compound of formula VIa, which is at the stage D either directly or after preliminary chromatographic purification using described for scheme 1, stage C, D (method 2) method were converted using 4-nitrobenzylamine.

Subsequent phases E, F and G, performed on stage N with the use of TOTU, linking with aminoguanidinium formula III, and, if the product of the merger of stage N contained protective ester group, and stage J performed similarly to the method according to the scheme 1, the stud is e see above) by introducing N-Boc-protected side chain of aminoalkyl (stage N) and subsequent selective separation of N-Boc-group (stage R) has been derived aminoalkylsilanes, then similarly to the method according to the scheme 1 was converted to compound of formula IIb (stage F, G). Then the compound of formula IIb by combining with aminoguanidinium formula III, in which the carboxylic acid group was protected in the form of esters, and by removal of protective groups were transferred to the compound of formula I (stage H, J). Some stages were performed as follows

A common method of obtaining derivatives of 3-(aminoalkyl)as; stage N, R

At stage N is derived as formula VIa was dissolved in dimethylformamide (3 ml per 1 mmol of the derivative as), the solution was mixed with N-Boc-aminoalkylation and 1.05 equivalents of cesium carbonate and the mixture was heated for 8-16 h to 60°C. the Solvent was removed in vacuo and the residue was chromatographically using a mixture of heptane/methyl tert-butyl ether through silica gel. Fraction of the product together. After removal of the solvent in vacuo at stage R. the residue was dissolved in a mixture of triperoxonane acid and dichloromethane (1:1) (about 8.5 ml per 1 mmol) and after 4 minutes and poured into ice-cold sodium bicarbonate solution (70 ml, 1 mmol). The aqueous phase was twice extracted with dichloromethane. The combined organic phases sushi is Kil)as.

Subsequent phases F, G and H (using TOTU) and, if the product of the merger of stage N contained protective ester group, stage J performed similarly to the method according to the scheme 1, stage F, G, H (method 2) and J.

Racemic-amino acids, which in the above-described methods at stage N was used as the amino compounds of formula III were obtained by the method according to the scheme 5 described below. Enantiomerically pure or highly saturated esters of 3-substituted 3-aminopropionic acid were purchased or obtained analogously S. G. Davis et al., Tetrahedron Asymmetry 1991, 2(3), 183-186. When this was done the following.

A common way to obtain tert-butyl ester of 3-substituted 3-aminopropionic acid

The corresponding 3-substituted acrylic acid (0.1 mol) with 1.1 equivalent of oxalicacid was dissolved in 100 ml of dichloromethane. The mixture was stirred 4 h at room temperature. The solvent was removed in a rotary evaporator. The residue was dissolved in 100 ml of tert-butanol and 2 hours and stirred at room temperature. After the reaction, the solvent was removed in a rotary evaporator. The residue was dissolved in diethyl ether and washed with water, sodium bicarbonate solution and again with water. The organic phase was dried on which the notes with the release of more than 80%.

For introduction of the amino group was added dropwise to a solution of (R)-(+)-N-benzyl-N-(1-phenyl-ethyl) -amine (60 mmol) in 100 ml of tetrahydrofuran at -70°C for 1 h 0.95 equivalent of n-utility (in n-hexane). The mixture was stirred 1 h at this temperature, then added dropwise a solution of tert-butyl methyl ether 3-substituted acrylic acid (0.9 equivalent) in 75 ml of tetrahydrofuran for 1 h the Mixture was stirred 2 h at -70°C. After removal of the cooling was added dropwise 115 ml of 5% citric acid solution. The solution was stirred 1 h, diluted with acetic ether and washed with water. The organic phase is washed with sodium bicarbonate solution and water and dried over magnesium sulfate. The solvent was removed in vacuum. The residue was purified by thin-layer chromatography (heptane/ethyl acetate, 9:1). Got tert-butyl ether 3-substituted 3-(N-benzyl-N-(1-phenyl-ethyl)-amino)-propionic acid with a yield of about 50% in the form of a yellow oil. For the Department group of the benzyl and phenylethyl substance (about 30 mmol) was dissolved in a mixture of ethyl acetate and acetic acid (4:1) was added 1.5 g of palladium hydroxide. In an atmosphere of hydrogen was first made 8 h at room temperature. The catalyst was filtered and the filtrate koncentriruiutsia, volatile oil at the exit of more than 50%.

Similar to the transformations described above in solution can be performed in reaction to produce compounds of formula I in the solid phase, i.e. with the application associated with the resin structure. You can perform single or multiple stages of solid-phase synthesis. In particular, you can perform instead of attaching compounds of formulas IIA, IIb to the amino compounds of formula III in solution, are also associated with the resin, the amino compounds of formula III. Methods for obtaining compounds of formula I with the use of reactions in the solid phase are described below and summarised in schemes 4 and 5.

Specifying quantities protocols for solid-phase synthesis always refer to the appropriate loading of the resin, which is determined photometrically in the UV range after removal of the protective Fmoc group (see, for example, The Combinatorial Chemistry Catalog, Novabiochem).

D) General method according to the scheme 4

Obtaining compounds of formula I which contain a unit aspartic acid using solid-phase synthesis

For communication with the polymer carrier used orthogonal protected block aspartic acid. Fmoc-Asp(OH)-O-allyl in the presence of connective Rea is Thira (stage Q). Then the free-end subjected in the presence of a coupling reagent interaction with tert-butyl ether amino acids (stage R). After separation of the protective Fmoc group was performed turning on the N-end by connecting with gigantochloa acid, which was obtained above (stage S). After separation of the protective groups and the separation of the resin obtained compound of formula I (stage T). The radicals in the formula in figure 4, which have the same designations as the corresponding radicals in the formula I are indicated for the formula I values. R41together with a group of SN, which is linked to the radical R41and along with the associated with the group CH group COOtBu, corresponds to the group R4according to the definition of the compounds of the formula I, which denotes alkyl, which is substituted specified for R4substituents. Some stages were performed as follows

Obtaining Fmoc-Asp(OH)-O-allyl

40 g (88.7 mmol) Fmoc-Asp(OtBu)-O-allyl mixed with 25 ml triperoxonane acid and stirred for 30 min at room temperature. The solvent was removed in a rotary evaporator. The residue was dried in vacuum. Got Fmoc-Asp(OH)-O-allyl in the form of a yellow oil with a yield to 33.9 g (97%).

ES(+)-MS: 395,2 (M+Nerdom medium; stage Q

40 g of polystyrene Wang resin (1.1 mmol/g; Bachem) pre for 5 min was allowed to swell with 20 ml of dimethylformamide at room temperature. After adding the solution to 26.0 g (1.5 equivalent) of Fmoc-Asp(OH)-O-allyl, 34.3 g (1.5 equivalent) 1 benzothiazolinone-triprolidine-hexafluorophosphate (Rubor) and 1.5 equivalent of N,N-diisopropylethylamine in 120 ml of dimethylformamide and the mixture was shaken for 10 h at 40°C (as a coupling reagent with the same result, you can use TOTU/HOBT). After the reaction solution was aspirated and the resin washed with dimethylformamide (5×20 ml). After adding a solution of acetic anhydride (10 ml) and N,N-diisopropylethylamine (DIPEA) (1.5 equivalent) in 40 ml of dimethylformamide, the mixture was again shaken for 30 min at room temperature. The solution was aspirated and the resin is successively washed three times each time with 40 ml of dimethylformamide, methanol and dichloromethane. Then the resin was dried in vacuum. The definition of a boot according to the method of Fmoc showed a loading of 0.6 mmol/g

To separate the protective group of the allyl ether in an atmosphere of argon was previously allowed to swell for 5 min at room temperature in dimethylformamide. After cobaltocene argon for 6 h at 40°C. After the reaction solution was aspirated and the resin was successively washed three times each time with dimethylformamide, methanol, toluene and dichloromethane and then dried.

A common way of connecting with amino compounds on the polymer carrier; stage R

Obtained at the stage of Q resin with a free carboxyl group was previously allowed to swell for 5 min in dimethylformamide at room temperature. After adding a solution of 1-hydroxybenzotriazole (1.2 equivalents), O-((CYANOGEN (etoxycarbonyl) methylene) amino-N,N, N', N' -tetramethyluronium tetrafluoroborate (1.2 equivalent) and N,N-diisopropylethylamine (1.2 equivalent) in dimethylformamide and the mixture was shaken for 30 min at room temperature. Aminosidine (tert-butyl ether amino acids) (1.2 equivalent) was added in the form of a solution in dimethylformamide. The suspension until complete conversion was shaken at room temperature (control using high-performance liquid chromatography). After the reaction solution was aspirated and the resin is successively washed three times each time with dimethylformamide, methanol, toluene and dichloromethane and then dried.

A common way of separating the protective Fmoc group on the floor of the Hai R resin was added 5 ml of 20% solution of piperidine in dimethylformamide and the mixture was shaken for 20 min at room temperature. The resin was pumped out and repeated the process again. Then the resin several times thoroughly washed with dimethylformamide and dichloromethane.

To attach to the resin solution was added with 2 equivalents NOWT, TOTU, DIPEA and gigantochloa acid (each) in dimethylformamide (10 ml/g resin) and the mixture was shaken for 12 h at room temperature. The resin was filtered and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml dichloromethane.

A common way of separating from the resin; stage T

To the obtained at stage S the resin was added a mixture of triperoxonane acid and dichloromethane (1:1). The suspension was shaken 1 h the Resin was filtered and the solution concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane and ethyl acetate).

(E) a General method according to the scheme 5

Obtaining compounds of formula I which contain a unit-amino acids using solid-phase synthesis.

Used Matematicheskie-amino acids were obtained from the corresponding aldehydes by the interaction with malonic acid and ammonium acetate.

After protection of the amino group with the introduction of the Fmoc group the acid was converted with the help of separating the protective Fmoc group and then in the presence of a coupling reagent was combined with gigantochloa acid, which was obtained in the manner described above (stage V). After separation of the resin obtained compound of formula I (phase W).

According to scheme 5, option b after separation of the protective Fmoc group on the polymer carrier in the presence of a coupling reagent spent the connection block as that instead of R32-NH-CO-NH contained in the compound of formula IIA in scheme 2, contains a group of Fmoc-NH (Y stage). This unit as was obtained by the method according to the scheme 1 in the solution, and obtained after the hydrogenation in stage E group aminobenzyl translated into the group of N-Fmoc-aminobenzyl. In obtained in stage Y product connection on the polymer carrier is separated then the protective Fmoc group. Then, the resulting free amino group in the benzyl substituents on N-3 as transformed using isocyanates, isothioscyanates or carboxylic acids in the urea, thiourea or amides, or with a reactive derivative of carbonic acid and alcohols were transformed into affery carbamino acid or urea (stage Z). After separation of the resin was finally received the compound of formula I (phase W). Some stages were performed as follows.

A common way to obtain matematicheskikh-aminoacetate ammonium and 4.0 mmol of the corresponding aldehyde of formula R3-CHO suspended in 10 ml of ethanol. The mixture was stirred 6 h at 90°C. the Precipitate was aspirated and washed twice with 5 ml of ethanol.

A common way of introducing protective groups in Fmoc-amino acid 4.0 mmol of amino acid and 0.66 g (8.0 mmol) of sodium bicarbonate diluted in 7 ml of water. Added by pipette to a solution of 1.5 g (4.0 mmol) of N-(9-fluorenylmethoxycarbonyloxy)-succinimide in 15 ml of dioxane and the mixture was stirred 6 h at room temperature. Then the mixture was filtered and the precipitate washed with 5 ml of ethyl acetate. The residue was dissolved in 20 ml of 1 N. hydrochloric acid and was extracted twice with 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated.

A common way to connect N-Fm--amino acid with a polymer carrier; stage U

Protected Fmoc-amino acids suspended from trailhead-polystyrene resin and 0.5 ml of DIPEA in 6 ml of dichloromethane. The mixture was shaken for 6 h at room temperature. To the mixture was added 1 ml of methanol and shaken for another 30 min at room temperature. The resin was aspirated carefully and several times washed with dimethylformamide and dichloromethane. The identity and purity of the compounds was checked by high performance liquid chromatography and mass spectrometer is a way of separating the protective Fmoc group on the polymer carrier and connection with gigantocellular acids; stage V

To 100 mg of the obtained obtained at the stage U resin was added 5 ml of 20% solution of piperidine in dimethylformamide and shook the mixture for 20 min at room temperature. The resin was pumped out and repeated the process again. Then the resin several times thoroughly washed with dimethylformamide and dichloromethane. Then 100 mg of the resin, which was loaded-amino acid solution was added to 12.2 mg (0.09 mmol) of NOVR, 29,5 mg (0.09 mmol) of the LTTE, 16 μl (0.09 mmol) DIPEA and 0.09 mmol gigantochloa acid in 5 ml of dimethylformamide and the mixture was shaken for 12 h at room temperature. The resin was filtered and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml dichloromethane.

A common way of separating from the polymer carrier; stage W

For the separation of suspended resin in 3 ml triperoxonane acid/dichloromethane and shaken for 1 h the Resin was filtered and washed with 1 ml dichloromethane. The combined solutions were concentrated in a rotary evaporator. The residue was dissolved in dichloromethane and was chromatographically using dichloromethane and ethyl acetate over silica gel.

Option

A common way of separating the protective Fmoc group on polimernoi on stage U resin was added 5 ml of 20% solution of piperidine in dimethylformamide and shook the mixture for 20 min at room temperature. The resin was pumped out and repeated the process again. Then the resin several times thoroughly washed with dimethylformamide and dichloromethane. To the resulting resin solution was added with 2 equivalents NOWT, TOTU, DIPEA and N-Fmoc-aminobenzyl-gigantochloa acid (each) in dimethylformamide (10 ml/g resin) and the mixture was shaken for 12 h at room temperature. The resin was filtered and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml dichloromethane.

A common way of separating the protective Fmoc group on the polymer carrier and derivatization of the amino group; Z stage

To 100 mg of the loaded N-Fmoc-aminobenzyl-gigantochloa acid resin was added 5 ml of 20% solution of piperidine in dimethylformamide and shook the mixture for 20 min at room temperature. The resin was pumped out and repeated the process again. Then the resin several times thoroughly washed with dimethylformamide and dichloromethane. Then, the resulting free amino group was derivateservlet on the pitch.

To obtain amides derived free amino group was coupled with carboxylic acids. For this to 100 mg loaded aminobenzylidene resin solution was added or 0.027 mmol of NEWT, or 0.027 mmol TOTU, or 0.027 mmol DIPEA round. The resin was filtered and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml dichloromethane.

To obtain thioureas derived free amino group was converted with the help of isothioscyanates. For this to 100 mg loaded aminobenzylidene resin solution was added or 0.027 mmol of isothiocyanate and a catalytic amount of 1 mg of 4-dimethylaminopyridine in 5 ml of dimethylformamide and shook the mixture for 8 h at room temperature. The resin was filtered and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml dichloromethane.

To obtain ureas obtained free group made use of isocyanates. For this to 100 mg loaded aminobenzylidene resin solution was added or 0.027 mmol of isocyanate and a catalytic amount of 1 mg of 4-dimethylaminopyridine in 5 ml of dimethylformamide and shook the mixture for 8 h at room temperature. The resin was filtered and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml dichloromethane.

To obtain N,N-disubstituted ureas derived free amino group is first transformed using di-(N-succinyl added a tenfold excess of di-(N-Succinimidyl)-carbonate and DIPEA and shook the mixture for 5 hours at a temperature of 40°C. The solution was aspirated. To the resin was added a ten-fold excess of amine in dimethylformamide. The mixture was shaken for 8 h at room temperature. The resin was filtered and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml dichloromethane.

To obtain the corresponding carbamates alcohol was subjected to reaction with di-(N-Succinimidyl)-carbonate, and then the intermediate product was subjected to reaction obtained with a free amino group. This was dissolved in alcohols (0,027 mmol) with a corresponding equivalent amount of di-(N-Succinimidyl)-carbonate and DIPEA for 5 h at 40°C. the Solution was added to 100 mg loaded aminobenzylidene resin and the mixture was shaken for 8 h at room temperature. The resin was filtered and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml dichloromethane.

Separation from the polymer carrier (phase W) in version b was performed as in option A.

F) a General method of preparing compounds of the formula I which contain a block of a peptide using solid phase synthesis

The compounds of formula I which contain a block of a peptide can be obtained so that the VNA is obojdennoju the amino group is connected with the next N-Fmoc-amino acid and the protective Fmoc group otscheplaut. Such accession the following amino acid units, repeat until you get the desired peptide block. Finally, using the coupling reagent attached gigantocellular acid, the product is separated from the resin and separating may present protective groups. Separate stages perform the following way.

A common way of joining N-Fmoc-amino acid to the polymeric carrier

Protected group of N-Fmoc-amino acid (1.5 equivalent), together with Fritillaria-polystyrene resin (1.2 mmol/g) and DIPEA (2 equivalents) is suspended in dichloromethane (5 ml/g of carrier). The mixture is shaken for 6 h at room temperature. The mixture was added 1 ml of methanol and shaken for 30 min at room temperature. The resin is sucked off and thoroughly washed several times with dimethylformamide and dichloromethane. The identity and purity of the compounds is checked by high-performance liquid chromatography and mass spectrometry.

A common way of separating the protective Fmoc group on the polymer carrier

To 100 mg of the loaded N-Fmoc-amino acid resin add 5 ml of 20% solution of piperidine in dimethylformamide and the mixture is shaken for 20 min at room temperature. The resin is sucked off and Prim.

A common way connection-amino acids on the polymer carrier with N-Fmoc-amino acids

To 100 mg uploaded-amino acid resin add a solution of 12.2 mg (0.09 mmol) NOWT, 29,5 mg (0.09 mmol) of TOTU, 16 μl (0.09 mmol) DIPEA and 0.09 mmol of N-Fmoc-amino acid in 5 ml of dimethylformamide and the mixture is shaken for 12 h at room temperature. The resin is filtered and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml dichloromethane.

For the introduction of the following amino acids in the peptide unit, respectively, repeat the two previous steps (separation of the protective Fmoc group and attach the following N-Fmoc-amino acids).

A common way of separating the protective Fmoc group on the polymer carrier and the peptide compounds of the block polymer carrier with gigantocellular acids

The protective Fmoc group synthesized on the resin peptide unit is separated as stated above, then to 100 mg of the loaded peptide block of resin add a solution of 12.2 mg (0.09 mmol) NOWT, 29,5 mg (0.09 mmol) of TOTU, 16 μl (0.09 mmol) DIPEA and 0.09 mmol gigantochloa acid in 5 ml of dimethylformamide and the mixture is shaken for 12 h at room temperature. The resin is filtered off and washed TRIG is the overall way of separating from the resin

To separate the compounds from the resin to the resin add the mixture triperoxonane acid and dichloromethane (1:9). The suspension is shaken for 1 h, the Resin is filtered off. The remaining solution was concentrated in vacuo and the residue purified by chromatography on silica gel.

(G) a General method of obtaining unsubstituted amides of carboxylic acids in the solid phase

To convert compounds of the formula I which contain a carboxylic acid group-COOH, the compounds with unsubstituted amide group, carboxylic acid-CONH2the group of carboxylic acids were added using the coupling reagent for amide resin Rinca. Joining the amino group in the resin was performed similarly to the method of attaching carboxylic acids to the Wang resin (see method according to the scheme 4). Then banding triperoxonane acid resulted in the receipt of unsubstituted amides.

WITH HE + amide resin Rink-amide resin Rinca-CO-NH2

In a separate case 0.5 g of carboxylic acid of formula I is subjected to reaction with 0.35 mg TOTU, 0.15 ml of DIPEA and 2 g of amide resin Rinca in 10 ml of dimethylformamide. The suspension was shaken for 1 h at room temperature. The resin was pumped out and thoroughly washed dimethylformamide removal of the solvent the residue was purified.

Example 1

((RS)-2-((RS)-4-phenyl-3-(4-(3-phenylurea)-benzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetyl)-L-aspartyl-L-phenylglycine

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 1), J (method 1). At stage N (initial amount of 0.3 mmol) was used as the amino compounds of the formula III H-Asp(OtBu)-Phg-OtBu (hydrochloride; S=aspartyl, hg=phenylglycyl). Yield: 52 mg

ES(+)-MS: 777,9 (M+N)+

Example 2

((RS)-2-((RS)-4-phenyl-3-(4-(3-(2-were)-ureido)-benzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetyl)-L-aspartyl-L-phenylglycine

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 1), J (method 1). At stage N (initial amount 0,184 mmol) was used as the amino compounds of the formula III H-Asp(OtBu)-Phg-OtBu (hydrochloride). Yield: 59 mg

ES(+)-MS: 791,9 (M+H)+

Example 3

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

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 1), J (method a new ether (S)-3-amino-3-(3, 4-methylenedioxyphenyl)-propionic acid. Yield: 92 mg

ES(+)-MS: 734,9 (M+N)+

Example 4

(R)-3-((RS)-2-((RS)-4-phenyl-3-(4-(3-(2-were)-ureido)-benzyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropionate acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 1), J (method 1). At stage N (initial amount 0,184 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Yield: 109 mg

ES(+)-MS: 628,4 (M+H)+

Example 5

(S)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino-3-(3,4-methylenedioxyphenyl)-propionic acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 1), J (method 1). At stage N (the initial number of 2.6 mmol) was used as the amino compounds of formula III tert-butyl ether (S)-3-amino-3-(3,4-methylenedioxyphenyl)-propionic acid. Output: 284 mg.

ES(+)-MS: 658,7 (M+H)+

Example 6

(R)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino is D (method 1), E, F, G, H (method 1), J (method 1). At stage N (the initial number of 2.6 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Output: 451 mg

ES(+)-MS: 552,6 (W+H)+

The compound of example 6 was also obtained by the method according to the scheme 1, stage a, b, D (method 2), E, F, G, H (method 1), J (method 1).

The compound of example 6 was also obtained by the method according to the scheme 2.

Example 7

(S)-3-((S)-2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-(3,4-methylenedioxyphenyl)-propionic acid

The compound was obtained by the method according to the scheme 1, stage a, b, D (method 1), E, F, G, H (method 1), J (method 1). At stage N (initial amount of 2.3 mmol) was used as the amino compounds of formula III tert-butyl ether (S)-3-amino-3-(3,4-methylenedioxyphenyl)-propionic acid. Output: 453 mg

ES(+)-MS: 672,7 (M+N)+

Example 8

(R)-3-((S)-2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropionate acid

The compound was obtained by the method according to the scheme 1, stage a, b, D (method 1), E, F, G, H (method 1), Hotelowy ether (R)-3-amino-3-methylpropionic acid. Yield: 420 mg

ES(+)-MS: 566,7 (M+N)+

Example 9

(R)-3-(2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-3-methylpropionate acid

The compound was obtained by the method according to the scheme 1, stage C,

D (method 1), E, F, G, H (method 1), J (method 1). At stage N (initial amount 1.5 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Yield: 440 mg

ES(+)-MS: 510,6 (M+H)+

Example 10

2-((S)-2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl-2,5 dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-acetic acid

The compound was obtained by the method according to the scheme 1, stage a, b, D (method 1), E, F, G, H (method 1), J (method 1). At stage N (initial amount of 0.21 mmol) was used as the amino compounds of formula III methyl ester of glycine. Yield: 26 mg

ES(+)-MS: 538,4 (M+N)+

Example 11

(S)-3-)2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido) benzyl-2,5-dioxoimidazolidin-1-yl)-acetylamino-3-phenylpropionate acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 2). On a hundred is about 3-phenylpropionic acid. Output: 534 mg

ES(+)-MS: 572,4 (M+N)+

The compound of example 11 was received also by the way according to the scheme 1, stage C, D (method 2), E, F, G, H (method 2), J (method 2).

Example 12

(R)-3-((S)-2-(4,4-dimethyl-3-(2-(3-(2-were)-ureido)-ethyl) -2,5-dioxoimidazolidin-1-yl) -2-(2-methylpropyl) -acetylamino)-3-methylpropionate acid

The compound was obtained by the method according to the scheme 3 (stage J method 1). The compound of formula VIa received by way according to the scheme 1, stage A, C. At stage N (initial amount to 0.19 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Yield: 58 mg

ES(+)-MS: 504,4 (M+H)+

Example 13

(R)-3-((S)-2-(4,4-dimethyl-3-(3-(3-(2-were)-ureido)-propyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropionate acid

The compound was obtained by the method according to the scheme 3 (stage J method 1). The compound of formula VIa received by way according to the scheme 1, stage A, C. At stage N (initial amount of 0.25 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Yield: 54 mg

ES(+)-MS: 518,4 (M+H)+

The compound was obtained by the method according to the scheme 1 (stages C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount 1.94 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Output: 414 mg.

ES(+)-MS: 514,3 (M+N)+

Example 15

3-(2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-propionic acid

The compound was obtained by the method according to the scheme 1 (stages C, D (method 1), E, F, G, H (method 2), J (method 2). At stage N (initial amount of 0.47 mmol) was used as the amino compounds of formula III methyl ester 3-aminopropionic acid. Yield: 136 mg

ES(+)-MS: 496,2 (M+H)+

Example 16

3-((S)-2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-propionic acid

The compound was obtained by the method according to the scheme 1 (stage a, b, D (method 1), E, F, G, H (method 1), J (method 2). At stage N (initial amount of 0.21 mmol) was used as the amino compounds of formula III methyl ester 3-aminopropionic acid. Yield: 23 mg

ES(+)-MS: 552,3 (M+H)+

<-methylpropyl)-acetylamino)-3-phenylpropionate acid

The compound was obtained by the method according to the scheme 1 (stage a, b, D (method 1), E, F, G, H (method 2), J (method 2). At stage N (initial amount 0,208 mmol) was used as the amino compounds of formula III ethyl ester of (S)-3-amino-3-phenylpropionic acid. Yield: 66 mg

ES(+)-MS: 628,4 (M+N)+

Example 18

3-(2-(4,4-dimethyl-3-(4-(3-(2-forfinal)-ureido-benzyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-propionic acid

The compound was obtained by the method according to the scheme 1 (stages C, D (method 1), E, F, G, H (method 2), J (method 2). At stage N (initial amount 1.94 mmol) was used as the amino compounds of formula III hydrochloride ethyl ester 3-aminopropionic acid. Output: 368 mg.

ES(+)-MS: 500,2 (M+N)+

Example 19

(S)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-phenylpropionate acid

The compound was obtained by the method according to the scheme 1 (stage a, b, D (method 1), E, F, G, H (method 2), J (method 2). At stage N (initial amount of 4.1 mmol) was used as the amino compounds of formula III ethyl ester of (S)-3-amino-3-phenylpropionic acid. Output: 1,

ES(+)-MS: 6 is ethyl-N-methyl-L-aspartyl-(2-adamantylamine)

The compound was obtained by the method according to the scheme 1 (stage C,

D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount of 1.26 mmol) was used as the amino compounds of formula III hydrochloride tert-butyl ester 2-adamantylamine N-methyl-L-aspartic acid. Output: 617 mg

ES(+)-MS: 659,4 (M+H)+

Example 21

(2-(3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-acetyl)-L-aspartyl-(2-adamantylamine)

The compound was obtained by the method according to the scheme 1 (stages C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount 0,882 mmol) was used as the amino compounds of formula III tert-butyl ester 2-adamantylamine L-aspartic acid. Yield: 470 mg

ES(+)-MS: 645,4 (M+H)+

Example 22

(2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl) -

2,5-dioxoimidazolidin-1-yl) -acetyl) -N-methyl-L-aspartyl-(2-adamantylamine)

The compound was obtained by the method according to the scheme 1 (stages C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount 0,942 mmol) was used as the amino compounds of formula III hydrochloride tert-butyl ester 2-adaman is SS="ptx2">(2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl-2,5-dioxoimidazolidin-1-yl)-acetyl)-N-methyl-L-aspartyl-(2-adamantylamine)

The compound was obtained by the method according to the scheme 1 (stages C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount of 1.41 mmol) was used as the amino compounds of formula III hydrochloride tert-butyl ester 2-adamantylamine N-methyl-L-aspartic acid. Output: 599 mg

ES(+)-MS: 673,4 (M+H)+

Example 24

(2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl-2,5-dioxoimidazolidin-1-yl)-acetyl)-L-aspartyl-(2-adamantylamine)

The compound was obtained by the method according to the scheme 1 stage,

D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount 0,974 mmol) was used as the amino compounds of formula III hydrochloride tert-butyl ester 2-adamantylamine-L-aspartic acid. Yield: 410 mg

ES(+)-MS: 659,4 (M+H)+

Example 25

((S)-(2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl-acetyl)-L-aspartyl-(2-adamantylamine)

The compound was obtained by the method according to the scheme 1, stage a, b, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (source is Yes L-aspartic acid. Output: 576 mg.

ES(+)-MS: 715,5 (M+N)+

Example 26

(R) -3-(2-(-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-methylpropionate acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount 1.5 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Yield: 7 mg

ES(+)-MS: 482,3 (M+N)+

Example 27

((S)-(2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl-acetyl)-L-aspartic acid

The compound was obtained by the method according to the scheme 1 phase a, b, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount of 4.2 mmol) was used as the amino compounds of formula III hydrochloride di-tert-butyl ester of L-aspartic acid. Output: 692 mg

ES(+)-MS: 596,4 (M+N)+

Example 28

(2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl) -acetyl) -N-methyl-L-aspartic acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, the uly III hydrochloride di-tert-butyl ether N-methyl-L-aspartic acid. Output: 628 mg

ES(+)-MS: 554,3 (M+H)+

Example 29

(S)-3-(2-(3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-phenylpropionate acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount 1.5 mmol) was used as the amino compounds of formula III ethyl ester of (S)-3-amino-3-phenylpropionic acid. Yield: 59 mg

ES(+)-MS: TO 544.3 (M+H)+

Example 30

(R)-3-(2-(3-(4-(3-(2-chlorophenyl)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-methylpropionate acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount of 1.44 mmol) was used as the amino compounds of formula III tert-butyl ether (R) -3-amino-3-methylpropionic acid. Output: 448 mg

ES(+)-MS: 502,3 (M+N)+

Examples 31-46

Compounds were obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2). At stage N (initial amount 0.23 mmol) was used as the amino compounds of formula III in the case of examples 31-38 tert-butyl ether (R)-3-amino-3-methylpr and in the case of examples 31-38 according to method 1 (with triperoxonane acid), in the case of examples 39-46 - method 2 (lithium hydroxide). Output: 30-87 mg of the Obtained compound of the formula Ib are shown in table 1.

Example 47

((S)-(2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl-acetyl)-L-aspartyl-L-phenylglycine

The compound was obtained by the method according to the scheme 1, stage a, b, D (method 1), E, F, G, H (method 1), J (method 1). At stage N (initial amount 1.04 mmol) was used as the amino compounds of the formula III H-Asp(OtBu)-Phg-OtBu (hydrochloride). Yield: 350 mg

ES(+)-MS: 729,4 (M+N)+

Examples 48-69

Compounds were obtained by the method according to scheme 4 by reaction of compounds gigantocellular acids of the formula IIA with H-Asp-Phg-OtBu, which over the free group COOH - block Asp was connected with polystyrene Wang resin. As the ester of the amino acids of the formula H2N-CH(R41)-COOtBu in figure 4 was used tert-butyl ester L-phenylglycine. The compounds of formula IC are shown in table 2.

Examples 70-87

Compounds were obtained by the method according to scheme 5, option a, by reaction accession gigantocellular acids of the formula IIA with 3-amino-3-(3,4-atlanticcity)-praly Id are shown in table 3.

Example 88

Sodium salt of (R)-3-((S)-(2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropionic acid

In a solution of 1 g (is 1.81 mmol) of (R)-3-((S)-(2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropionic acid in 20 ml of tetrahydrofuran and 50 ml of water was added 1 equivalent of 1 N sodium lye. After 30 min at room temperature the greater part of the tetrahydrofuran was removed in vacuo and the residue was dried by freezing. After chromatography on Sephadex LH20 (solvent: water) received 930 mg indicated in the title salt.

ES(+)-MS: IS 552.5 (M+H)+, 574,4 (sodium salt)

Example 89

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

The compound was obtained by the method according to the scheme 2 (stage J method 1). At stage N (initial amount of 5.2 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Yield: 1.86 g

ES(+)-MS: 510,4 (M+N)+

Example 90

(R) -3-((S)-(2-(4,4-dieta

The compound was obtained by the method according to the scheme 2 (stage J method 1). At stage N (initial amount to 11.9 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Output: 4,3,

ES(+)-MS: 524,3 (M+N)+

Example 91

3-(2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-acetylamino-3,3-dimethyl-propionic acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 2). At stage N (initial amount of 0.9 mmol) was used as the amino compounds of formula III methyl ester 3-amino-3,3-dimethylpropionic acid. Yield: 53 mg

ES(+)-MS: 524,4 (M+N)+

Example 92

(R)-3-((S)-(2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethyl-acetylamino)-3-methylpropionate acid

The compound was obtained by the method according to the scheme 2 (stage J method 1). At stage N (initial amount of 1.29 mmol) was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid. Output: 493 mg

ES(+)-MS: 550,5 (M+N)+

Pre-methylenedioxyphenyl)-propionic acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (the initial number of 4 mmol) was used as the amino compounds of formula III tert-butyl ether (S)-3-amino-(3,4-methylenedioxyphenyl)-propionic acid. Output: 1,08,

ES(+)-MS: 616,2 (M+N)+

Example 94

(S)-2-benzyloxycarbonylamino-3-((4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-acetylamino)-propionic acid

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount 1,89 mmol) was used as the amino compounds of formula III tert-butyl ether (S)-3-amino-2-benzyloxycarbonylamino acid. Yield: 410 mg

ES(+)-MS: 645,2 (M+N)+

Examples 95-116

Esters of examples 95, 96, 98-102 and 104-116 were obtained from the corresponding carboxylic acids (compounds of formula I, where E denotes the R10CO and R10=hydroxy) via esterification group COOH - using the following General method: to a solution of carboxylic acid in absolute dichloromethane (DCM) (7-10 ml per 1 mmol of carboxylic acid) was added to 6 the NTA N,N'-dicyclohexylcarbodiimide and left the reactive mixture to stand over night at room temperature. After filtration the solvent was removed in vacuum and the residue was purified by chromatography. Esters of examples 97 and 103 received immediately upon receipt of carboxylic acids of examples 19 and 11 (as intermediate products after stage N). The obtained esters of formula I are given in table 4.

Example 117

Isopropyl ether (2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-acetyl)-L-aspartyl-(2-adamantylamine)

The compound was obtained from (2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-acetyl)-L-aspartyl-(2-adamantylamine) and isopropanol as described for examples 95, 96, 98-102 and 104-116. Original number: 0,371 mmol original aspartyl connection. Yield: 210 mg

ES(+)-MS: 715,4 (M+N)+

Example 118

Isopropyl ether (S)-2-benzyloxycarbonylamino-3-((4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-L-aspartyl-(2-adamantylamine)-propionic acid

The compound was obtained from (S)-2-benzyloxycarbonylamino-3-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-acetylamino)-propionic acid and the lots. Exit 233 mg.

ES(+)-MS: 687,3 (M+H)+

Examples 119-124

The synthesis was performed as described N. M. Nielsen, H. Bundgaard, Journal Of Pharmaceutical Sciences, 1988, 77(4), 285-response interaction (R)-3-(2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-methylpropionic acid with the corresponding chloracetamide (examples 119, 120, 122) or climaterealists (example 121) or (1-chloroethyl)-ethylcarbonate (example 123) or Bromeliaceae (example 124). The reaction was carried out at 80°C. the Purification of substances produced preparative high performance liquid chromatography on Sephadex LH20 (solvent: acetonitrile/water). Original number: 1,374 mmol source propionic acid. The compounds of formula If are given in table 5.

Examples 125-129

Examples 125, 127, 128 and 129 were obtained by the method according to the scheme 1, stage a, b, D (method 1), E, F, G, H (method 2). At stage N was used as the amino compounds of formula III (R)-3-amino-3-methylpropanol (examples 125 and 129) or (S)-3-amino-3-phenylpropanol (example 128) or (S)-3-amino-3-(4-methoxyphenyl)-propanol (example 127). Example 126 obtained by the process according to scheme 1, stage C, D (method 1), E, F, G, H (method 2). At stage N was used as aminos 6.

Used 3-aminopropanol to obtain the compounds of examples 125-129 was prepared as follows.

(S)-3-amino-3-phenylpropanol

To a suspension of 3.5 g (of 15.2 mmol) of the hydrochloride of the ethyl ester of (S)-3-amino-3-phenylpropionic acid in 150 ml of tetrahydrofuran under ice cooling was added in portions 1.45 g (38,1 mmol) socialwise-hydride and stirred 1 h Then cooled with ice was carefully added dropwise 5 ml of water. The precipitate was filtered and the filtrate was concentrated in vacuum. The residue was dissolved in dichloromethane and the solution was extracted with water. The organic phase was dried over sodium sulfate. After filtration and removal of solvent in vacuo was obtained 1.84 g (S)-3-amino-3-phenylpropanol.

(R)-3-amino-3-methyl-propanol and (S)-3-amino-3-(4-methoxyphenyl)-propanol

To a solution of trichloride aluminum in absolute diethyl ether (about 3 ml per 1 mmol of trichloride aluminum) was added in portions of 1 equivalent socialwise-hydride and the mixture was heated for 30 min under reflux. Was slowly added dropwise 0.4 equivalent tert-butyl ether (R)-3-amino-3-methylpropionic acid or tert-butyl methyl ether (S)-3-amino-3-(4-methoxyphenyl)-propionic acid and the reaction is m water (0,072 ml per 1 mmol socialwise-hydride) and a solution of potassium hydroxide in water (1 mmol socialwise-hydride 1,688 potassium hydroxide in 2.8 ml of water). The mixture was left to stand overnight at room temperature, decantation of the ether phase and stirred several times the residue with diethyl ether and dichloromethane. The combined organic phases were dried over sodium sulfate. After filtration and removal of solvent in vacuo received appropriate amerosport.

Example 130

(R)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropanol

56,5 mg (R)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropanol together from 10.8 mg of potassium bromide was dissolved in a mixture of 3 ml of ethyl acetate, 1 ml of toluene and 1 ml of water. After adding a catalytic amount of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl (=4-acetamido-TEMPO) was added dropwise at 0°With a mixture of 0.5 ml of sodium hypochlorite solution (13%), 0.5 ml of saturated solution of sodium bicarbonate and 1 ml of water. The mixture was stirred 25 min at 0°C. After complete conversion, the mixture was mixed with ethyl acetate, the organic phase is washed with a sodium sulphate solution and dried over sodium sulfate. After filtration the solvent was removed in a rotary evaporator and the residue was purified in the measures 131

(R)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropionamide

The connection was obtained from 0.5 g of (R)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropionic acid and amide resin Rinca using the above General method of obtaining unsubstituted amides of carboxylic acids in the solid phase. Output: 349 mg

ES(+)-MS: OF 551.3 (M+H)+

Example 132

(S)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-phenylpropionamide

The compound was obtained analogously to example 131 (S)-3-((S) - 2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl-2,5 dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-phenylpropionic acid.

ES(+)-MS: 613,3 (M+H)+

Example 133

((S)-2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetyl)-L-aspartyl-L-poured-L-Proline

The compound was obtained analogously to the above General method of preparing compounds of the formula I which contain a peptide unit, solid-phase synthesis. For donkey Department of protective Fmoc group in the second stage of accession used 3.1 g Fmoc-Val-OH and after repeated separation of the protective Fmoc group in the third stage of the accession used 3.4 g Fmoc-Asp(OtBu)-HE. Received 11 g loaded with Fmoc-Asp(OtBu) - Val-Pro resin. 4 g of this resin after separation of the protective Fmoc group was connected with 2.7 g (S)-2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetic acid, 1.8 g TOTU, 0.75 g NOWT and 0.72 g of DIPEA in 25 ml of dimethylformamide. After washing, the resin was separated the compound from the resin using triperoxonane acid/dichloromethane (and simultaneously separated protective tert-butyl ester group).

The separated solution was concentrated and the residue was led with the use of diethyl ether. Output: 750 mg

Example 134

2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl-2,5-dioxoimidazolidin-1-yl)-acetyl-L-aspartyl-(2-adamantylamine)

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount of 1.41 mmol) was used as the amino compounds of formula III tert-butyl ester 2-adamantylamine L-aspartic acid. Output: 504 mg

ES(+)-MS: 673,4 (M+H)+

Examples 135-158

Urea examples 135-158 was obtained by the method according to scheme 5, option C. As described above, the corresponding 3-(4-Fmoc-amino)-benzyl)-gigantomania acid of soedineniya to the resin, then tsalala the protective Fmoc group and derivateservlet the amino group by its interaction with the appropriate isocyanate or 6-di-(N-Succinimidyl)-carbonate and the appropriate amine. The compounds of formula Ih are shown in table 7.

Examples 159-166

Thiourea examples 159-166 was obtained by the method according to scheme 5, option C. As described above, the corresponding 3-(4-(Fmoc-amino)-benzyl)-gigantomania acid was coupled with 3-amino-3-(3,4-methylenedioxyphenyl)-propionic acid, which over the free COOH group was attached to the resin, then remove the protective Fmoc group and derivateservlet the amino group by its interaction with the corresponding isothiocyanates. The compounds of formula Ik is given in table 8.

Examples 167-182

Connection examples 167-182 was obtained by the method according to scheme 5, option C. As described above, the corresponding 3-(4-N-Fmoc-amino)-benzyl)-gigantomania acid was coupled with 3-amino-3-(3,4-methylenedioxyphenyl)-propionic acid, which over the free COOH group was attached to the resin, then tsalala the protective Fmoc group and translated amino group, as described above, carbamate or amide. Obtained�-3-(4-(3-(2-were) ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-2,3-diphenylpropionic acid

The compound was obtained by the method according to the scheme 1, stage a, b, D (method 1), E, F, G, H (method 2). At stage N (initial amount 0.33 mmol) was used as the amino compounds of formula III methyl ester (2RS,3R)-3-amino-2,3-diphenylpropionic acid. At stage J spent the removal of the protective ester group is similar to method 2 with 5 equivalents of 1 N. aqueous solution of lithium hydroxide in methanol for 3 h and acidification of the solution triperoxonane acid to pH 3. The suction is obtained solids and drying in vacuo resulted in the receipt specified in the connection header.

Yield: 81 mg

ES(+)-MS: 704,2 (M+H)+

Examples 184-188

Compounds were obtained by the method according to the scheme 1, stage a, b, D (method 1), E, F, G, H (method 2). At stage N (initial amount of 0.5 mmol) in the case of examples 184, 185, 186 and 188 as the amino compounds of formula III used the appropriate tert-butyl ether (S)-3-amino-3-arylpropionic acid, in the case of example 187 - ethyl ester of (S)-3-amino-3-pentafluoropropionic acid. In the case of examples 184, 185, 186 and 188 stage J was performed according to method 2 using triperoxonane acid, in the case of example 187 similar to method 2 using hydroxide is)-2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-arylpropionate acid of the formula shown In table 10.

Example 189

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

The compound was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount of 0.5 mmol) was used as the amino compounds of formula III tert-butyl ether (S)-3-amino-3-(2,4-acid) propionic acid. Yield: 320 mg

ES(+)-MS: 750,5 (M+H)+

Examples 190-194

Compounds were obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2). At stage N (initial amount of 0.25 mmol) was used corresponding ethyl ester of (RS)-3-amino-3-arylpropionic acid. Separation of the ether protective group at the stage J was similar to method 2 using lithium hydroxide as described in example 183. Obtained (RS)-3-((RS)-(2-((RS)-4-methyl-4-phenyl-3-(4-(3-(2-were)-ureido)-bemail-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-aryl-propionic acids of formula IP are shown in table 11.

Example 195

(RS)-2-butylsulfonyl-3-((RS)-2-((RS)-4-methyl-4-phenyl-3-(4-(3-(2-were)-ureido)-benzene was obtained by the method according to the scheme 1, stage C, D (method 1), E, F, G, H (method 2), J (method 1). At stage N (initial amount of 0.25 mmol) was used as the amino compounds of formula III ethyl ester of (RS)-3-amino-3-(n-butylsulfonyl)-propionic acid. The Department of protective groups of ester at stage J was similar to method 2 using lithium hydroxide as described in example 183. Output: 259 mg (contained triptorelin lithium).

ES(+)-MS: 749,4 (M+H)+

Example 196

(RS)-3-((S)-2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-phenylpropionate acid

The compound was obtained analogously to the method according to scheme 5, by rakli connection associated with the resin (RS)-3-amino-3-phenyl-propionic acid with the corresponding obtained by the method according to the scheme 1 gigantochloa acid of the formula IIA (original number when connecting 0.05 mmol of compounds of formula IIA). Output: 4.2V mg.

ES(+)-MS: 628,1 (M+H)+

Examples 197-218

Compounds were obtained analogously to the method according to scheme 5, by reaction of the corresponding connection is associated with the resin 3-substituted (RS)-3-amino-propionic acid with the corresponding obtained by the method Enya formula IIA). The obtained 3-substituted (RS)-3-((RS)-2-((RS)-4-methyl-4-phenyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-propionic acid of formula Iq are shown in table 12.

Example 219

Tert-butyl ether (RS)-2-((RS)-4-methyl-4-phenyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-L-aspartyl-L-phenylglycine

The compound was obtained analogously to the method according to scheme 4 by solid-phase synthesis. Tert-butyl ether, aspartyl-phenylglycine, which was associated with horticulture-polystyrene resin, was combined with the corresponding obtained by the method according to the scheme 1 gigantochloa acid of the formula IIA (original number when connecting: 0.55 mmol of compounds of formula IIA). Separation from the resin produced using a 10% solution triperoxonane acid in dichloromethane for 20 minutes Yield: 4,7 mg

ES(+)-MS: 846,9 (M+N)+

Example 220

(R)-3-(2-(4,4-pentamethylene-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-methylpropionate acid

The compound was obtained by the method according to the scheme 1, stage C,D (method 1), E,-3-amino-3-methylpropionic acid.

Example 221

(R)-3-((S)-2-((S)-4-(4-(amino-imino-methyl)-phenyl)-4-methyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methylpropionate acid

The connection can be obtained by the method according to the scheme 1, stage a, b, D (method 1), E, F, G, H (method 2), J (method 1). At stage N was used as the amino compounds of formula III tert-butyl ether (R)-3-amino-3-methylpropionic acid.

Study of biological activity

A) Test the adhesion of U937 cells/VCAM-1

As a method of testing the validity of the compounds of formula I on the interaction between VCAM-1 and VLA-4 use the following test, which is specific for this interaction. Cellular binding partners, i.e., the integrins VLA-4, used in their natural form as surface molecules on human U937 cells (ATSC CRL 1593), which belong to the group of cells. As specific binding partners use are obtained using genetic engineering soluble recombinant fused protein consisting of unaryoperation domain of human VCAM-1, and constant region of human immunoglobulin subclass lgGI.

Used a genetic construct for the expression of the extracellular domains of human VCAM-1, associated with the genetic sequence of the heavy chain of human immunoglobulin lgG (Hinge, CH2 and CH3 regions) (from Dr. Brian Seed, Massachusetts Genegal Hospital, Boston, USA; see also Damle und Ruffo, Proc. Natl. Sci. USA 1991, 88, 6403-6407). Soluble fused protein hVCAM-1 (1-3) - lgG contained three aminoterminal similar extracellular immunoglobulin-like domain of human VCAM-1 (Damle und Ruffo, Proc. Natl. Sci. USA 1991, 88, 6403 -6407). CD4-lgG (Zettlmeissl et al., DNA and Cell Biology 1990, 9, 347) served as a fused protein for negative control. Recombinant proteins expressed as soluble proteins by standard procedures after due DEAE/dextran transfection DNA in COS cells (Ausubel et al. “Current protocols in molecular biology”, John Wiley & Sons, Inc., 1994).

2. Experience on the measurement of the adhesion of U937 cells to hVCAM-1 (1-3) - lgG

2.1 96-well plates for microteriofauna (Nunc Maxicorb) were incubated for 1 h at room temperature with 100 μl per well of a solution of goat antibodies to human lgG (10 μg/ml in 50 mmol Tris, pH of 9.5). After removal or antibody-based test solution once washed with PBS.

2.2 150 μl per well of blocking buffer (1% BSA in PBS) were incubated on.

2.3 100 µl per well of excess cell cultures transfected COS cells were incubated on the plates for 1.5 h at room temperature. COS cells were transliterowany a plasmid, which encodes the three N-terminal immunoglobulin-like domain of VCAM-1, associated with the Fc part of human IgG1(hVCAM-1 (1-3) - lgG). Content hVCAM-1 (1-3) - lgG was about 0.5-1 µg/ml After removal of excess culture once washed by PBS.

2.4 the Plates were incubated for 20 min at room temperature with 100 μl per well of blocking buffer receptor Fc (1 mg/ml-globulin, 100 mmol NaCl, 100 mmol MgCl2, 100 µmol MnCl2, 100 µmol CaCl21 mg/ml BSA in 50 mmol HEPES, pH 7.5). After removing the blocking buffer receptor Fc once washed with PBS.

2.5 Took 20 μl of binding buffer (100 mmol NaCl, 100 mmol MgCl2, 100 µmol MnCl2, 100 µmol CaCl21 mg/ml BSA in 50 mmol HEPES, pH 7.5) was added under test substance in 10 μl of binding buffer and incubated for 20 min In the quality control samples were used antibodies against VCAM-1 (IWT, No. VVA) and against VLA-4 (Iminunotech, No. 0764).

2.6 U937 Cells were incubated for 20 min in blocking buffer Fc receptor and then added by pipette at the end of the if in stop buffer (100 mmol NaCl, 100 mmol MgCl2, 100 µmol MnCl2, 100 µmol CaCl21 mg/ml BSA in 25 mm Tris, pH 7.5) and were removed. The process was repeated.

2.8 Then the plates were incubated with 50 μl per well of staining solution (16.7 ug/ml of the coloring matter 33258 company Hoechst, 4% formaldehyde and 0.5% Triton-X-100 in PBS) for 15 minutes

2.9 Plates were taken out and at an angle of 45° slowly immersed in stop buffer (100 mmol NaCl, 100 mmol MgCl2, 100 µmol MnCl2, 100 µmol CaCl21 mg/ml BSA in 25 mm Tris, pH 7.5). The process was repeated. Then the plates from those liquid (stop buffer) measured in the flow cytometer (Millipore) (sensitivity: 5, filter: wavelength excitation: 360 nm, the wavelength of emission: 460 nm).

The intensity of the emitted colored cells U937 light is a measure of the number remaining on the plate stuck to hVCAM-1 (1-3) - lgG U937 cells, and thus an indicator of the ability of the introduced test substance to inhibit this adhesion. The degree of inhibition of adhesion at various concentrations of the test substance was calculated concentration IC50which leads to the inhibition of adhesion by 50%.

3. Results

The test results obtained for the

On the model of leukocyte adhesion examine the effect on adhesion of the compounds of formula I in venules of the rat. Adhesion of leukocytes to the endothelium of postcapillary venules seen as an important step in inflammatory reactions (J. M. Harlan, Blood 1985, 65, 513-525). When the recruitment of leukocytes from the blood into the inflamed area is well coordinated dynamic sequence of events, in which the active role of chemotactic cytokines and cell adhesion molecules. It was found that the interaction of VCAM-1/VLA-4 plays a crucial role in adhesion and emigration of leukocytes and increased vascular permeability for macromolecules, which are induced razlichnimi mediator substances and cytokines (D. Seifge, Int. J Microcirc. 1995, 15, 301-308). In this model, by local or systemic injection of endotoxin, for example, zymosan, bacterial toxins, such as lipopolysaccharides (LPS) or adjuvant-blockers cause General inflammation, respectively, rheumatoid arthritis, leading to leukocyte adhesion and migration into the affected area authorities. Caused by endotoxin increased adhesion measured on the endothelium of venules.

To measure the adhesion of leukocytes used the chamber in which was neziroglu under light sedation with halothane gas of imosan or bacterial endotoxin. Control animals received the same volume of 0.9% sodium chloride solution. Then animals were injected with the test substance subcutaneously or orally as single dose or in multiple doses. For measurements the rats were given General anesthesia by intramuscular injection of 1.25 g/kg urethane. Rats were allowed to breathe spontaneously through the tracheal tube. Body temperature was maintained constant 37°With the help of an adjustable heating blankets. On thermostatization window (37°C) the microscope table by laparotomy was carefully freed the mesentery of the small intestine and at 37°coated With liquid paraffin. With three blunt needles and plastic mass held in a fixed position ileocecal region of the mesentery. After a 30-minute equilibrane, during which the fabric could stabilize, we measured the adhesion of leukocytes in postcapillary venules with a diameter of 20-30 μm and a length of about 100 μm by counting in 2-3 segments venules with an interval of 10 min for 1 h Leukocyte believed linked with endothelium if it remained stationary for more than 30 seconds After the experiment has measured the system the number of leukocytes and the content of fibrinogen in the blood. Inhibition of leukocyte adhesion to p the animal compared with those of control animals.

(C) a delayed-type Hypersensitivity in the mouse

On the model of delayed-type hypersensitivity (DTH) examine antiallergic, respectively, inhibiting inflammation action of the compounds of formula I. DTH is an inflammatory reaction of the skin that is triggered by sensibilizirovannoy antigenic substances. To measure in vivo the appropriate inflammatory response and recruitment of leukocytes into inflamed areas experiencing substance on the mouse on the next model DTH (see also T. C. Issekutz, J. Immunol., 1991, 147, 4178-4184).

Groups of mice BALB/C female (body weight about 20 g) were sensitized on the shaved skin area epicuran with 150 μl of 3% solution of oxazolone, which strongly induces an inflammatory response DTH. 6 days later the reaction was caused at the right ear of the animals by giving 20 µl of 1% solution of oxazolone. Subjects substances were administered subcutaneously or orally respectively for 44 h to call the reaction, for 20 hours before calling reactions and 4 h after the challenge response. Directly before calling reactions and 24 h after challenge response using a micrometer firm Mitutoyo Engineering measured on the right ear modified swelling thickness of the ear. Differences processed test substance group of animals, on the one hand, and not processed in the control group, on the other hand. Specifies the percentage inhibition of ear swelling.

D) anti-asthma effect on Guinea pig

The influence of lung function and anti-asthma effect of the compounds of formula I can be measured on the model in the Guinea pig, which is based on the method described by G. Moacevic, Arch. Toxicol. 1975, 34, 1. For this conduct technical training for research as described Moacevic details. Use white Guinea pigs male with a body weight of 300-500 Animals, placed in plethysmograph (FMI) and measure three initial values of parameters of the respiration rate and amplitude of respiration. On this model, asthmatic breathing is characterized by a decrease in the amplitude of breathing (i.e., a decrease in respiration based on the reduction of the bronchi) and increased frequency of breathing (i.e., reflex reaction). This is the condition of patients with asthma is known as shortness of breath.

White Guinea pigs sensibiliser least 22 days before the start of the test with 1 ml on each animal 0,1% solution of ovalbumin for two consecutive days. Experimental asthma attack caused by inhalation of a 0.3% solution of ovalbumin in techina. Immediately after this was introduced for 1 min with 0.3% solution of ovalbumin. In the subsequent rest phase for 30 min the animals were breathing normal air. This method povtorot twice. If asthma attacks become dangerous to life, animals give oxygen.

1. The compounds of formula I

where W denotes the R1-A-C(R13or

where the ring system

may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4;

Y represents a carbonyl group;

A denotes a direct bond or a bivalent residue of phenylene;

In denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl;

E denotes R10CO., HCO, or R8O-CH2;

R denotes hydrogen or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C

R1denotes hydrogen, (C1-C10)-alkyl, which may optionally be substituted one or more times by fluorine, or the remainder of the X-NH-C(=NH)-R20;

X denotes hydrogen;

R2denotes hydrogen or (C1-C8)-alkyl;

R3denotes hydrogen, (C1-C10)-alkyl, which may optionally be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15;

R4means (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6- ;

R5denotes optionally substituted (C6-C14)-aryl;

R6denotes the residue of a natural or unnatural amino acids;

R8denotes hydrogen or (C1-C10)-alkyl, and R8 is, (C1-C10)-alkoxy, (C1-C8)-alkylcarboxylic-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C6)-alkoxy, and the remains of R8independently from each other may be the same or different;

R11means R12a-O-C or R12a-S(O)2;

R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15;

R13denotes hydrogen or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine;

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

R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue;

R20denotes a direct bond or (C1-C6-alkylen;

R21denotes hydrogen or (C1-C8)-alkyl;

R30represents one of the residues R32(R)N-CO-N(R)-R31be used R32-CO-N(R)-R31if W denotes the R1-A-C(R13), And denotes a direct bond and R1andR13represent hydrogen;

R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula I;

R32means (C1-C8)-alkyl, which may optionally be substituted one or more times by fluorine, (C3-C12-cycloalkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl;

R33denotes a direct bond;

R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen;

R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene;

R36denotes a direct bond;

e and h represent independently from each other 0 or 1,

in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

2. olava system

may be substituted by 1 or 2 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4;

Y represents a carbonyl group;

A denotes a direct bond or a bivalent residue of phenylene;

In denotes the divalent residue of the methylene or ethylene, and the remainder of the methylene or a residue of ethylene unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl;

E denotes R10CO or R8O-CH2;

R denotes hydrogen or (C1-C8)-alkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl or, if necessary, substituted (C6-C10)-aryl, and all residues R are independent of each other, may be the same or different;

R1denotes hydrogen, (C1-C10)-alkyl, which may optionally be substituted one or more times by fluorine, or the remainder of the X-NH-C(=NH)-R20;

X denotes hydrogen;

R2denotes a hydrogen ulitimate can be from once to eight times substituted by fluorine, optionally substituted C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15;

R4means (C1-C8)-alkyl, which is unsubstituted or substituted once or twice with the same or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl , (C1-C8-alkoxycarbonyl, R5, R6- ;

R5denotes optionally substituted (C6-C14)-aryl;

R6denotes the residue of a natural or unnatural amino acids;

R8denotes hydrogen or (C1-C6)-alkyl, and R8independently from each other may be the same or different;

R10denotes hydroxy, (C1-C8)-alkoxy, (C1-C8)-alkylcarboxylic-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C8)-alkyl)-amino, or R8R8N-CO-(C1-C6)-alkoxy, and the remains of R8independently from each other may be the same or different;

10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15;

R13denotes hydrogen or (C1-C6)-alkyl;

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

R16denotes a 6-membered to 14-membered bicyclic or tricyclic residue;

R20denotes a direct bond or (C1-C4-alkylen;

R21denotes hydrogen or (C1-C8)-alkyl;

R30represents one of the residues R32(R)N-CO-N(R)-R31, R32(R)N-CS-N(R)-R31, R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13denote hydrogen,

R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula I;

R32means (C1-C8)-alkyl, which may optionally be odnokratno 14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl;

R33denotes a direct bond;

R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen;

R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene;

R36denotes a direct bond;

e and h represent independently from each other 0 or 1,

in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

3. The compounds of formula I under item 1 or 2,

where W denotes the R1-A-C(R13or

where the ring system

may be substituted by 1 or 2 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4;

Y represents a carbonyl group;

A denotes a direct bond or a bivalent residue of phenylene;

In denotes a bivalent residue merilee or different residues from the series (WITH1-C8)-alkyl and (C3-C6-cycloalkyl-(C1-C6)-alkyl,

E denotes R10CO or BUT-CH2;

R denotes hydrogen or (C1-C8)-alkyl, all of the residues R are independent of each other, may be the same or different;

R1denotes hydrogen, (C1-C10)-alkyl, which may optionally be substituted one or more times by fluorine, or X-NH-C(=NH)-R20;

X denotes hydrogen;

R2denotes hydrogen or (C1-C8)-alkyl;

R3denotes hydrogen, (C1-C8)-alkyl, which optionally can be from once to six times substituted by fluorine, optionally substituted (C6-C12)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15;

R4means (C1-C8)-alkyl, which is unsubstituted or substituted once or twice with the same or different residues from the series hydroxycarbonyl, aminocarbonyl, (C1-C6-alkoxycarbonyl, R5, R6- ;

R5denotes optionally substituted (C6-C12<>denotes hydrogen or (C1-C6)-alkyl;

R10denotes hydroxy, (C1-C8)-alkoxy, (C1-C6)-alkylcarboxylic-(C1-C6) -alkoxy, (C1-C6)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C6)-alkyl)-amino, or R8R8N-CO-(C1-C6)-alkoxy,

R11means R12a-O-C or R12a-S(O)2;

R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15;

R13denotes hydrogen or (C1-C6)-alkyl;

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

R16denotes a 6-membered to 14-membered bicyclic or tricyclic residue;

R20denotes a direct bond or (C1-C2-alkylen;

R21denotes hydrogen or (C1-C6)-alkyl;

R30represents one of the residues R32(R)N-CO-N(R)-R31, R32(R)N-CS-N(R)-R31or R32-CO-N(R)-R31and R30can't OGU communication and R1andR13represent hydrogen;

R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula I;

R32means (C1-C6)-alkyl, which optionally can be from once to six times substituted by fluorine, (C5-C6-cycloalkyl, optionally substituted (C6-C10)-aryl, optionally substituted in the aryl residue (C6-C10)-aryl-(C1-C6)-alkyl or optionally substituted heteroaryl;

R33denotes a direct bond;

R34denotes a bivalent residue of a number (C1-C6-alkylene, optionally substituted (C6-C10)-Allen;

R35denotes a direct bond or a bivalent residue (C1-C4)-alkylene;

R36denotes a direct bond;

e and h represent independently from each other 0 or 1,

in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

4. The compounds of formula I according to one of paragraphs.1-3,

where W denotes the R1-A-C(R13);

is nelena;

In denotes the divalent residue of the methylene or ethylene, and the remainder of the methylene or a residue of ethylene unsubstituted or substituted by a residue from the row (C1-C8)-alkyl and (C3-C6-cycloalkyl-(C1-C6)-alkyl,

E denotes R10CO or BUT-CH2;

R denotes hydrogen or (C1-C8)-alkyl, all of the residues R are independently from each other may be the same or different;

R1denotes hydrogen, (C1-C10)-alkyl, which may optionally be substituted one or more times by fluorine, or X-NH-C(=NH)-R20;

X denotes hydrogen;

R2denotes hydrogen or (C1-C6)-alkyl;

R3denotes hydrogen, (C1-C8)-alkyl, which optionally can be from once to six times substituted by fluorine, optionally substituted (C6-C10)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15;

R4means (C1-C6)-alkyl, which is unsubstituted or substituted once or twice with the same or different residues from the series hydroxyl optionally substituted (C6-C10)-aryl;

R6denotes the residue of a natural or unnatural amino acids;

R8denotes hydrogen or (C1-C6)-alkyl;

R10denotes hydroxy, (C1-C8)-alkoxy, (C1-C6)-alkylcarboxylic-(C1-C6) -alkoxy, (C1-C6)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C6)-alkyl)-amino;

R11means R12a-O-C or R12a-S(O)2;

R12ameans (C1-C8)-alkyl, optionally substituted (C6-C10)-aryl, optionally substituted in the aryl (C6-C10)-aryl-(C1-C4)-alkyl, or R15;

R13denotes hydrogen or (C1-C6)-alkyl;

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

R16denotes a 6-12 membered bicyclic, or tricyclic residue;

R20denotes a direct bond or methylene;

R21denotes hydrogen or (C1-C6)-alkyl;

R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31;

R31The SUB>10)-arisen, and in the case of arrenaline balance alkyl group linked to the nitrogen atom in the ring of imidazolidine in formula I;

R32means (C1-C6)-alkyl, which optionally can be from once to six times substituted by fluorine, (C5-C6-cycloalkyl, optionally substituted (C6-C10)-aryl, optionally substituted in the aryl residue (C6-C10)-aryl-(C1-C4)-alkyl or optionally substituted heteroaryl;

e and h represent independently from each other 0 or 1,

in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

5. The compounds of formula I according to one of paragraphs. 1-4, where W is other than CH2the value, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

6. The compounds of formula I according to one of paragraphs. 1-5, where In denotes unsubstituted methylene or methylene substituted (C1-C6)-alkyl or (C3-C6-cycloalkyl-(C1-C2)-alkyl, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

7. THE R32(R)N-CS-N(R)-R31in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

8. The compounds of formula I according to one of paragraphs. 1-7, where R30denotes the residue R32NH-CO-NH-R31and where R31denotes a bivalent residue (1,4-phenylene)-CH2- in which a methylene group connected to the nitrogen atom in the ring of imidazolidine, and R32represents unsubstituted or substituted phenyl, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts.

9. The compounds of formula I according to one of paragraphs. 1-8, where W is other than CH2the value denotes unsubstituted methylene or methylene substituted (C1-C6)-alkyl or (C3-C6-cycloalkyl-(C1-C2)-alkyl, R30denotes the residue R32NH-CO-NH-R31, R31denotes a bivalent residue (1,4-phenylene)-CH2- in which a methylene group connected to the nitrogen atom in the ring of imidazolidine, and R32represents unsubstituted or substituted phenyl, and the group-NR-[C(R)(R)]e-C(R2)(R3)-[C(R)(R)]h-E in the formula I denotes the group-NH-CH(R3)-CH2-E, in all their stereoisomeric forms and mixtures of the one I made of PP. 1-9, characterized in that conduct fragmented condensation of the compounds of formula II

with the compound of the formula III

in formulas II and III group W, Y, b, E, R, R2, R3, R30also e and h are specified in the PP. 1-9 values, or may contain functional groups in protected form or in the form of a precursor, and G denotes hydroxycarbonyl, (C1-C6-alkoxycarbonyl or activated derivatives of carboxylic acids.

11. The compounds of formula I according to one of paragraphs. 1-9 and/or their physiologically acceptable salts are suitable as a drug that inhibits adhesion and/or migration of leucocytes and/or VLA-4 receptors.

12. The compound of formula I under item 1, which represents the (R)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-methyl-propionic acid of the formula

and its physiologically acceptable salt.

13. The compound of formula I under item 1, which represents the (S)-3-((S)-2-(4,4-dimethyl-3-(4-(3-(2-were)-ureido)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetylamino)-3-phenyl-propionic acid of the formula

and b (R)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)-acetyl-amino)-3-methyl-propionic acid of the formula

15. The compound of formula I under item 1, which represents the (R)-3-((S)-2-(4,4-dimethyl-3-(4-(3-phenylurea)-benzyl)-2,5-dioxoimidazolidin-1-yl)-2-cyclopropylmethyl-acetylamino)-3-methyl-propionic acid of the formula

and its physiologically acceptable salt.

16. Connection on p. 1 corresponding to the formula

where R3denotes methyl;

R57denotes hydrogen;

R58represents isobutyl.

17. Connection on p. 1 corresponding to the formula

18. Pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor, characterized in that it contains one or more compounds of the formula I according to any one of paragraphs 1-9 or 12-17 and/or their physiologically acceptable salts and pharmaceutically acceptable carrier.

19. The compounds of formula I according to any one of paragraphs. 1-9, 12-17 and/or their physiologically acceptable salts are suitable as reducing inflammation of the substance.

20. The compounds of formula I according to any one of paragraphs. 1-9, 12-17 and/or their physiologically acceptable salts are suitable in the treatment or prevention of arthritis, rheumatoid arthritis, polyarthritis, inflammatory prannoy nervous system.

21. The compounds of formula I according to any one of paragraphs. 1-9, 12-17 and/or their physiologically acceptable salts are suitable in the treatment or prophylaxis of asthma or allergies.

22. The compounds of formula I according to any one of paragraphs. 1-9, 12-17 and/or their physiologically acceptable salts are suitable in the treatment or prevention of cardiovascular diseases, arteriosclerosis, restenosis, diabetes, damage to transplants of organs, immunological diseases, autoimmune diseases, tumor growth or metastasis of tumors or malaria.

23. The compounds of formula 1 according to any one of paragraphs. 1-9, 12-17 and/or their physiologically acceptable salts are suitable as inhibitors of the adhesion and/or migration of leukocytes or for inhibition of receptor VLA-4.



 

Same patents:

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

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

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, 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

The invention relates to a simple, effective method of obtaining the N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2), which includes the first stage of implementation of the alkaline hydrolysis of N2-(1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-TRIFLUOROACETYL-L-lysyl-L-Proline (1) in a mixed solution consisting of water and a hydrophilic organic solvent using an inorganic base n number of molar equivalents (n3) per mole of the above compound (1), the second stage of neutralization of the hydrolysis product with the use of inorganic acid in an amount of (n-1) to n molar equivalents (n3) and remove inorganic salts, obtained at deposition from a solvent system suitable for reducing the solubility of the inorganic salt, and the third stage is crystallization of the compound (2) present in the mixture after removal of inorganic salts from the solvent at its isoelectric point and thereby removing the compound (2) in the form of crystals, salts containing salt of organic acid - derived triperoxonane acid remains dissolved in the mother

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to a group of new compounds - heterocyclic derivatives of glycyl-beta-alanine General formula I

< / BR>
or pharmaceutically acceptable salt of this compound, where

< / BR>
is a 5-8-membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the group comprising N and S, and1selected from the group comprising SN, SN2, N, NH, O and S, provided that

< / BR>
is not pyrrolidinium when V represents NH;

A represents a group of the formula

< / BR>
where Y1selected from the group comprising N-R2and R2means hydrogen; R2means hydrogen, R7when not with R2and R8mean hydrogen, alkyl, substituted alkoxy group, or R2together with R7form a 4 to 12-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted by one or more substituents selected from the group comprising hydroxy, C1-C10< / BR>
where R2together with R7form a 5-8-membered ring containing two nitrogen atom a heterocycle, R5means hydrogen, R8means alkyl, optionally substituted by alkoxygroup; or A signifies a group

< / BR>
where R2together with R7form a 5-8-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted hydroxy-group; R8- alkyl, substituted alkoxygroup; V means-N(R6)-; R6is hydrogen; Y and Z denote hydrogen, t = 0, n and R = 1, 2; R means X-R3where X is-O-; R3is hydrogen, alkyl; R1selected from the group including aryl, alkyl, optionally substituted one or more times by halogen, alkyl, HE; monocyclic heterocycle; haloalkyl; R11means hydrogen, or a pharmaceutically acceptable salt of the compounds; pharmaceutical compositions having properties antagonistV3-integrin, as well as to a method of treating diseases mediatedV3-integrin in a mammal

The invention relates to substituted derivatives of benzo (b) thiepin-1,1-dioxides and their additive salts with acids of the formula I, in which R1is methyl, ethyl, propyl, butyl; R2- H, HE; R3a balance of amino acids, the remainder of diaminoanisole, and the balance of amino acids, the remainder of diaminoanisole in case you need one - or multi-substituted aminoadenine group; R4is methyl, ethyl, propyl, butyl; R5is methyl, ethyl, propyl, butyl; Z is a covalent bond

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 3-dibenzoylethylene-7-nitro-2-honokalani form (1) with analgesic activity

The invention relates to the use of derivatives tetrahydropyridine(or 4-hydroxypiperidine)butylation General formula (I) and their physiologically acceptable salts, when receiving therapeutic agents useful in therapy and veterinary medicine for the treatment of acute pain, neuropathic pain and nociceptive pain, alone or in combination with other analgesics, and in this case there is a synergy

The invention relates to medicine and can be used to treat a variety of rhinitis: allergic, polynosic, year-round
The invention relates to medicine, specifically to medicines, analgesic action

The invention relates to medicine, infectious diseases and can be used for the treatment of brucellosis

The invention relates to medicine, infectious diseases and can be used for the treatment of brucellosis

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

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

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, 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
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