New five-membered heterocycles, receipt, use and containing pharmaceuticals

 

(57) Abstract:

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain selected from the group consisting of (C1-C6)-alkyl residues, (6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13 means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, and pharmaceutical drug that has sposobnoy I

in which b, E, W, Y, Z, R, R2, R2a, R2b, R3, g and h have the following values.

The compounds of formula I are valuable active substances of medicinal products, 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 inhibitors of the adhesion and migration of leukocytes and/or antagonists of the adhesion receptor VLA-4, which belongs to the group of integrins. They are generally suitable for therapy or prevention of diseases which are caused by undesirable level of leukocyte adhesion and/or migration of leukocytes or associated with, or which play a role in the interaction cell-cell or cell-matrix, which is based on the interaction of VLA-4 receptors with their ligands. This invention relates further to a method for producing compounds of the formula I, their use in the treatment and prevention of these pathological conditions and to pharmaceutical preparations containing compounds of formula I.

Integrins are a group of adhesion receptors that play a significant role in the binding process cell-cell and a high degree of evolutionary conservatism. To integrins include, for example, the fibrinogen receptor on platelets, which primarily interacts with the RGD sequence of fibrinogen or vitronectin receptor on osteoclasts, which primarily interacts with the RGD sequence of vitronectin or osteopontin. Integrins are divided into three large groups, subfamily 2 with representatives of LFA-1, Mac-1 and P150/95, which, in particular, are responsible for cell-cell interaction in the immune system, and subfamily 1 and 3, the representatives of which mainly contribute to the attachment of cells to components of the extracellular matrix (Ruoslahti, Annu.Rev.Biochem., 1988, 57, 375). Integrins subfamily 1, 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. In VLA-family, the integrin VLA-4(41) is unusual, because its presence is limited mainly of lymphoid and myeloid cells, and these cells it is responsible for cell-cell interaction with many other cells. VLA-4 is facilitated, for example, the interaction of T - and b-lymphocytes with the heparin-II binding fragment of fibronectin is this on the interaction with sequence LDVP. In contrast to the fibrinogen receptor or the vitronectin receptor VLA-4 is not typical RGD-binding integrin (Kilger und Holzman, J. Mol.Meth. 1996, 73, 347).

Circulating blood leukocytes usually find only a small affinity in relation to vascular endothelial cells that line the blood vessels. Cytokines, which are secreted inflamed tissue, causing activation of endothelial cells and thereby the expression of many cell surface antigens. They include, for example, adhesion molecule ELAM-1 (adhesion molecule on endothelial cells 1, also called E-selectin), which, among other things, binds neutrophils, ICAM-1 (intercellular adhesion molecule 1), which interacts with LFA-1 (antigen 1, associated with the function of leukocytes) white blood cells, and VCAM-1 adhesion molecule vascular cell 1), which binds a variety of leukocytes, among other lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1 is as ICAM-1, a member of the superfamily of immunoglobulin genes. Identified VCAM-1 (first known as INCAM-110) as an adhesion molecule, which is induced on endothelial cells by inflammatory cytokines, such as TNF and IL-1, and lipopolysacharide lymphocytes to activated endothelium. The binding of VCAM-1 to VLA-4 is not by the interaction of VLA-4 with RGD-sequence, because the sequence is not contained in VCAM-1 (Bergelson et al., Current Biology, 1995, 5, 615). But VLA-4 is also evident on other leukocytes and through the mechanism of adhesion VCAM-1/VLA-4 also promotes the attachment of other white blood cells other than lymphocytes. VLA-4 is thereby the only example of receptor integrin 1, through which the ligands VCAM-1 or fibronectin plays an important role in cell-cell interactions and interactions of cells with extracellular matrix.

Induced cytokine adhesion molecules play an important role in the release of leukocytes in unemasculated region of tissue. Leukocytes appear in the field of inflammatory tissue cell adhesion molecules that are expressed on the surface of endothelial cells and serve as ligands for proteins or protein complexes (receptors) on the cell surface of leukocytes (concepts ligand and receptor can also be applied vice versa). Leukocytes from the blood must first be attached to endothelial cells before they can move in sinovi. Since VCAM-1 binds to the cells that carry the integrin VLA-4 (41), Taku output of such cells from the bloodstream in the area of infection and inflammation (Eiices 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 is expressed, also induced by cytokines, endothelial, and the following cells: cultured myoblasts, lymphoid dendritic cells and tissue macrophages, rheumatoid synovial cells stimulated by cytokines, nerve cells, parietal epithelial cells of Bowman's capsule, renal tubular epithelium, inflammatory tissue in the rejection of the transplanted heart or kidney and tissue of the intestine in graft-versus-host. Found that VCAM-1 is expressed also in such areas arterial epithelium, which previously corresponded to arteriosclerotic plaques. In addition, 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, such as a mouse. The recent discovery indicates the function of VCAM-1 in the development of b-cells. VLA-4, in addition to cells of hematopoietic origin found 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 an a dominant form in vivo, referred to as VCAM-7D and carries seven domains of immunoglobulins. Domains 4, 5 and 6 are similar in their amino acid sequences with domains 1, 2 and 3. The fourth domain from another, consisting of six domains, forms, here denoted as VCAM-6D, removed by alternative splicing. VCAM-6D can also bind expressing VLA-4 cells.

Additional data on VLA-4, VCAM-1, integrins and adhesion proteins are, for example, articles Kilger und Holzman, 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.

Based on the role of the mechanism VCAM-1/VLA-4 in the processes of cell adhesion, which have a value of, for example, infections, inflammation or atherosclerosis, an attempt was made to control these diseases by intervening in these adhesion processes, including, for example, inflammatory diseases (Osborn et al., Cell, 1989, 59, 1203).

One way to do this is by using monoclonal antibodies which are directed against VLA-4. Such monoclonal antibodies (MACs), which as antagonists of VLA-4 blocking the interaction between VCAM-1 and VLA-4 are known. For example, monoclonal antibodies against VCAM-1 and VLA-4 mAK HP2/1 and HP1/3 inhibit price person and to transfitsirovannykh VCAM-1 OS cells. Also mAK 4B9 inhibits adhesion of Ramos cells, Jurkat cells (cells like T-cells) and HL60 cells (cells such as granulocytes) with COS cells, transfitsirovannykh genetic structures, which lead to the expression of VCAM-6D and VCAM-7D. Data in vitro with antibodies directed against 4-subunit of VLA-4, show that the attachment of lymphocytes to synovial endothelial cells is inhibited, and this adhesion plays a role in rheumatoid arthritis (van Dinther-Janssen et al., J. Immunol., 1991, 147, 4207).

In vivo studies showed that experimental autoimmune encephalomyelitis is inhibited by monoclonal antibodies against the 4. The movement of leukocytes into the inflammatory focus is also inhibited by a monoclonal antibody against 4-chain of VLA-4. The influence of antibodies to VLA-4-dependent mechanism of adhesion was also studied on the model of asthma to investigate the role of VLA-4 at the conclusion of leukocytes in inflamed lung tissue (USSN 07/821, 768; EP-A-626861). Antibodies against VLA-4 inhibit the late phase reaction and increased reaction of the Airways in allergic sheep.

VLA-4-dependent mechanism of cell adhesion was also studied on the model of inflammatory intestinal disease (BD) in primates. In this model, the corresponding ulcerative colitis in a human which, were able to show that VLA-4-dependent cell adhesion plays a role in the following clinical conditions, including the following chronic inflammation: rheumatoid arthritis (Cronstein und Weissman, 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), slow allergies (Allergy type IV) (elices on et al., Clin.Exp.Rheumatol., 1993, II, S77), multiple sclerosis (Yednock et al., Nature, 1992, 356, 63), malaria (Ockenhouse et al., J. Exp.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 other (Albelda et al., J. Cell Biol., 1991, 114, 1059).

VLA-4 is a suitable blocking antagonists provides an effective therapeutic opportunities, in particular for the treatment of, for example, inflammatory conditions, including asthma and IBD. Of particular relevance VLA-4 antagonists for the treatment of rheumatoid arthritis is found, as already stated, from the fact that leukocytes from the blood must first attach to endothelial cells before they can enter the synovial liquid is delroute VCAM-1 on endothelial cells (Osborn, Cell, 1990, 62, 3; Stoolman, Cell, 1989, 56, 907) and the conclusion of various leukocytes in the area of infection and inflammation. This E-cells are attached to activated endothelium via LFA-1/ICAM-1 and VLA-4/VCAM-1-mechanisms of adhesion (Springer, Cell, 1994, 76, 301). Many of synovial T-cells the ability to bind VLA-4 to VCAM-1 in rheumatoid arthritis increases (Postigo et al, J. Clin.Invest., 1992, 89, 1445). Additionally watched reinforced attachment synovial T cells to fibronectin (Laffon et al., J. Clin.Invest., 1991, 88, 546; Morales-Ducret et al., J. Immun. 1992, 149, 1424). VLA-4 is also highly regulated in the framework of its expression, and its function in T-lymphocytes and synovial membrane. Inhibition of binding of VLA-4 with its physiological ligand VCAM-1 and fibronectin can effectively suppress and relieve inflammation 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 the disease (Barbadillo et al., Springer Semin. Iimnunopathol., 1995, 16, 427). VLA-4 is also an important therapeutic molecule-target.

The above VLA-4 antibodies and the use of antibodies as antagonists of VLA-4 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/agoniston VLA-4. However, the use of antibodies and peptide compounds as medicines has disadvantages, such as insufficient oral applicability, easy degradability or immunogenic effect in long term use. So sushestvuet the need for antagonists of VLA-4 with a favorable profile of properties for use in therapy and prevention.

In WO-A-94/21607 and WO-A-95/14008 described 5-membered heterocyclic compounds in EP-A-449 079, EP-A-530 505 (USA-5 389 614), WO-A-93/18057, EP-A-566 919 (US-A-5 397 796), EP-A-580008 (US-A-5 424 293) and EP-A-584 694 (US-A-5 554 594) described derivatives as detected by inhibiting platelet aggregation effect. In EP-A-842 943 (German patent application 19647380.2) described that these compounds unexpectedly inhibit the adhesion of leukocytes and are antagonists of VLA-4. Further studies show that the compounds of this invention are powerful inhibitors of leukocyte adhesion and antagonists of VLA-4.

This invention relates to compounds of formula I

in which W denotes R1-A-C(R13or R1-A-CH=C;

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

Z group, includes (C1-C6-alkylene, (C3-C7-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6-alkylether, 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 single or twofold substituted (C1-C6)-alkyl or bound to a double bond with oxygen or sulfur;

In denotes the divalent residue (C1-C6)-alkylene, which may be unsubstituted or substituted (C1-C8) -alkyl, (C2-C8-alkenyl, (C2-C8-quinil, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, possibly substituted (C6-C14)-aryl, possibly substituted in the aryl residue, an aryl, possibly substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl, possibly substituted by heteroaryl or possibly substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl;

E and Ea, independently of one another, denote tetrazolyl, (RdO)2P(O), HOS(O)2, R9NHS(O)2or R10C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, possibly substituted (C6-C14) -aryl, possibly substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, possibly substituted heteroaryl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl, N -, (C1-C8)-alkyl-CO, (C3-C12-cycloalkyl-CO, (C3-C12-cycloalkyl- (C1-C8) -alkyl-CO, (C6-C12-bicycloalkyl-CO, (C6-C12-bicycloalkyl- (C1-C8) -alkyl-CO, (C6-C12-tricyclohexyl-CO, (C6-C12-tricyclohexyl-(C1-C8)-alkyl-CO, possibly substituted (C6-C14)-aryl-CO, possibly substituted in the aryl residue (C6-C14) -aryl- (C1-C8) -alkyl-CO, possibly substituted heteroaryl-WITH possibly substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-CO, (C1-C8)-alkyl-S(O)n, (C3-C12-cycloalkyl-s(O)n, (C3-C12-cycloalkyl-(C1-C8)-Ala-alkyl-S(O)n, (C6-C12-tricyclohexyl-S(O)n, (C6-C12-tricyclohexyl- (C1-C8) -alkyl-S(O)npossibly substituted (C6-C14)-aryl-S(O)npossibly substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl-S(O)npossibly substituted heteroaryl-S(OH)nor maybe substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl-S(O)nand n is 1 or 2;

R, RaRb, Rcand Rd, independently of one another, denote hydrogen, (C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C8)-alkyl, possibly substituted (C6-C14)-aryl or possibly substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

R1denotes X-NH-C(=NH)-(CH2)por X1-NH-(CH2)pand p is 0, 1, 2 or 3;

X denotes hydrogen, (C3-C6)-alkyl, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C18-alkoxycarbonyl-(C1-C6-alkoxycarbonyl, possibly substituted (C6-C14-arylcarbamoyl, possibly substituted (C6-C14)-ar which may be substituted, (RdO)2P(O), cyano, hydroxy, (C1-C6)-alkoxy, (C6-C14)-aryl-(C1-C6)-alkoxy, in which the aryl residue may be substituted, or amino;

X1has one of the values X or denotes R’-NH-C(=N-R') with R’ and R’, independently of one another, have X-values;

R2, R2aand R2b, independently of one another, denote hydrogen, (C1-C8)-alkyl, possibly substituted (C6-C14)-aryl, possibly substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl or (C3-C8-cycloalkyl-(C1-C8)-alkyl;

R3means R11NH, (C9-C12-cycloalkyl, (C9-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C8)-alkyl, CO-N(Ra)-R4-Eaor CO-R5-R6-R7;

and R3cannot denote the 1-substituted, if W denotes the R1-A-C(R13), R1-A stands for 4-amidino-phenyl, R13denotes m E denotes hydroxycarbonyl, g is 0 and h is 1, and both in relation to the asymmetric carbon atom in dioxoimidazolidin the ring, and the carbon atom that bears the remains of R2and R3there are R-form and S-form with a molar ratio of 1:1;

R4denotes a bivalent residue (C1-C4)-alkylene, which is substituted by one residue from the group comprising R11NH, (C9-C12-cycloalkyl, (C9-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl and (C6-C12-tricyclohexyl-(C1-C8)-alkyl and which may optionally be substituted by one or two identical or different residues (C1-C4)-alkyl;

R5denotes a bivalent residue of a natural or unnatural amino acids, aminokisloty or esamination, and free functional groups can be protected customary in peptide chemistry, protective groups or they may be present in the form of ester or amide, or, in the case of amino acids or esamination, the nitrogen atom N-terminal amino group bears the remainder Rb;

R6regardless of the whether Het;

R8means (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl or (C6-C12-tricyclohexyl-(C1-C8)-alkyl;

R9denotes hydrogen, aminocarbonyl, (C1-C18-alkylaminocarbonyl, (C3-C8-cycloalkylcarbonyl, possibly substituted (C6-C14-allumination, (C1-C18)-alkyl, possibly substituted (C6-C14)-aryl, the aryl residue may substituted (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C12-cycloalkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl or (C6-C12)-tricyclo-alkyl- (C1-C8)-alkyl;

R10denotes hydroxy, (C1-C8)-alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy, in which the aryl residue may be substituted, possibly substituted (C6-C14)-aryloxy, (C1-C8)-alkylborane - or di-((C1-C8)-alkyl)amino, R8NH or Het;

R11means R12NH-CO, R12-NH-CS, R14aO-CO, R14bCO., R14cS(O) R14dS(O)2, R14eNH-S(O) or R14fNH-S(O)2;

R12indicates a possibly substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl which can be substituted in the aryl residue, a possibly substituted heteroaryl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-quinil or the remainder R15;

R13denotes hydrogen, (C1-C6)-alkyl, possibly substituted (C6-C14)-aryl, possibly substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C3-C8-cycloalkyl or (C3-C8-cycloalkyl-(C1-C8)-alkyl;

R14aindicates a possibly substituted heteroaryl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl, or R15;

R14band R14d, independently of one another, denote a possibly substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, perhaps C is15;

R14cand R14e, independently of one another, denote (C1-C18)-alkyl, possibly substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl which can be substituted in the aryl residue, a possibly substituted heteroaryl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl or the residue R15;

R14findicates a possibly substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, possibly substituted heteroaryl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl, (C9-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl or (C6-C12-tricyclohexyl-(C1-C8)-alkyl;

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

R16denotes the remainder of the 3-membered to 12-membered monocycle or the remainder of the 6-membered to 24-membered Bicycle or tricycle, and these cycles are saturated or partially unsaturated and may contain one, two, three it also substituted by one or more identical or different substituents from the group includes (C1-C4)-alkyl and oxo;

Het denotes the residue is linked via a ring nitrogen atom a 5-membered to 10-membered monocyclic or polycyclic heterocycle, which may be aromatic or partially unsaturated or saturated and may contain one, two, three or four identical or different additional heteroatoms in the ring group comprising oxygen, nitrogen and sulfur, and which may be optionally substituted on carbon atoms and more atoms in the ring, and on a secondary nitrogen atoms in the ring may be the same or different residues Rc, RcCO or RcO-as deputies;

g and h, independently of one another, 0 or 1;

in all their stereoisomeric forms and their mixtures in all respects, as well as their physiologically acceptable salts.

Alkyl residues may be linear or branched. This also applies to cases when they include Deputy or include as substituents other residues, for example, in alkoxylate, alkoxycarbonyl residues or arylalkyl residues. Accordingly, the same is true for divalent alkilinity residues. P is exil, heptyl, octyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, isopropyl, isobutyl, isopentyl, isohexyl, 3-methylpentyl, 2,3,5-trimethylhexane, sec-butyl, tert-butyl, tert-pentyl, neo-pentyl. Preferred alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. Both loose connection in the remainder of alkylene can come from the same carbon atom or from different carbon atoms. Examples of residues of alkylene are methylene, ethylene (=1,2-ethylene), tri-, Tetra-, Penta - and hexamethylene, 1-mutilation and 2-mutilation (=1,2-propylene), 1,1-dimethylethylene, 2,2-dimethyl-1,3-propylene, substituted alkyl residue methylene, for example methylene, substituted methyl group (=METROTILE or 1,1-ethylene or ethylidene), methylene which is substituted by an ethyl group, isopropyl group, isobutylene group or tert-butilkoi group, or methylene, which is substituted by two alkyl residues, such as dimethylmethylene (=2,2-propylene or 2-propylidene).

Alkeneamine residues and alkenylamine residues, as well as alkyline residues can also be linear or branched. Examples alkenyl residues are vinyl, 1-propene the flax. Examples etkinlik residues are ethinyl, 1-PROPYNYL, 2-PROPYNYL (=propargyl) or 6-hexenyl.

Examples cycloalkyl residues are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl and cyclododecyl, which can also be substituted, for example, (C1-C4)-alkyl. As examples of substituted cycloalkyl residues can be called 4-methylcyclohexyl and 2,3-dimethylcyclobutyl. The same applies to cycloalkenyl balances.

If R16denotes the residue of a saturated monocycle containing no heteroatoms in the ring, talking about cycloalkene the remainder if the remainder R16contains one or more heteroatoms in the ring, it is a heterocyclic residue. 3-membered to 12-membered cycles can contain 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms in the ring. Bicycloalkyl residues, critically residues and residue as R166-membered to 24-membered bicyclo and tricycles formally obtained by subtracting one hydrogen atom from bicyclo or tricycles. Form the basis of Bicycle and tricycles can ring to contain either only the carbon atoms, we can go the train from one to four identical or different heteroatoms from the group including nitrogen, oxygen and sulfur, we can talk also about Aza-, oxa - and tibetica and tricyclodecane. If contains heteroatoms, preferably one or two heteroatoms, in particular nitrogen atoms or oxygen. This also applies to the 3-membered to 12-membered monocyclic systems. The heteroatoms can occupy any position in a bicyclic or tricyclic structure, they can be bridges or, in the case of nitrogen atoms, also in 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, preferably, are fully saturated. As bicycloalkanes and tricyclodecane and heteroanalogues as saturated and unsaturated representatives may be unsubstituted or in any suitable positions substituted by one or more identical or different substituents, for example one or two exography and/or, in particular, one or more, for example one, two, three or four identical or different (C1-C4)-alkyl groups such as methyl groups or isopropylate can be in any position of the molecule, the residue may be linked via an atom is the head of the bridge or through the atom in the bridge. Free communication can also be in any stereochemical position, for example in the Exo-position or endo-position. The same refers to monocyclic rings.

Examples of the basic structure of bicyclic systems, which can be obtained bicycloalkyl balance or bicyclic residue as R16are norbornane (=bicyclo [2.2.1] heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]-octane, examples containing heteroatoms, unsaturated or substituted ring 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]heptane).

Examples of systems that can be obtained critically balance or tricyclic residue as R16are Twisted (=tricyclo[4.4.0.03,8]decane), adamantane (=tricyclo [3.3.1.13,7]decane), noradsanta (=tricyclo- [3.3.1.03,7] nonan), tricyclo(2.2.1.02,6] heptane, tricyclo[5.3.2.04,9] dodecan, tricyclo[5.4.0.02,9]undecane or tricyclo[5.5.1.03,11]-tridecan.

Preferably bicycloalkyl residues, critically residues and bicyclic or trice is also systems, in which the rings have two or more common atoms. Next, are preferred as R16bicyclic or tricyclic residue with 6 to 18 atoms in the ring, especially preferably from 7 to 12 atoms in the ring. In particular, in addition, preferred are 2-norbornylene the rest, as the remains with a free connection in the Exo-position, and remains with a free connection in the endo-position, 2-bicyclo[3.2.1]octillery the remainder, 1-adamantly the residue, 2-adamantly balance, noradrenaline residue, for example 3-noradrenaline balance, and homoalanine balance. Of them preferred 1 - and 2-adamantly the rest.

(C6-C14)-aryl groups are, for example, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, antrel or fluorenyl; (C6-C12)-aryl groups are, for example, phenyl, naphthyl or biphenylyl; (C6-C10)-aryl groups are, for example, phenyl or naphthyl. Preferred aryl residues are, in particular, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 1-naphthyl, 2-naphthyl and especially phenyl. Aryl residues, in particular phenyl residues can be substituted once or several times, preferably once, twice or SUB>-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, methylenedioxy, Ethylenedioxy, cyano-, hydroxycarbonyl, aminocarbonyl, (C1-C4-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (RdO)2P(O) (RdO)2P(O)-O-, tetrazolyl. The same applies, for example, to such balances, as arylalkyl or arylcarbamoyl. Arylalkyl residues, in particular, are benzyl, 1 - and 2-naphthylmethyl, 2-, 3 - and 4-biphenylyl and 9-fluorenylmethyl, then 1-phenylethyl and 2-phenylethyl, and they can all be replaced.

Substituted arylalkylamine residues are, for example, substituted by one or more (C1-C8)-alkyl residues, in particular (C1-C4)-alkyl residues, aryl part of benzil and naphthylmethyl, for example, 2-, 3 - and 4-methylbenzyl, 4-isobutylphenyl, 4-tert-butylbenzyl, 4-octyl-benzyl, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-methyl-1-naphthylmethyl, 1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthylmethyl, substituted by one or more (C1-C8)-alkoxy residues, in particular (C1-C4)-alkoxy residues, aryl part of benzil and naphthylmethyl, for example the 4-nitrobenzyl, halogenmethyl, for example 2-, 3 - and 4-Chlorobenzyl and 2-, 3 - and 4-tormentil, 3,4-dichlorobenzyl, pentafluorobenzyl, cryptomelane, for example, 3 - and 4-trifloromethyl or 3,5-bis(trifluoromethyl)benzyl. But substituted arylalkyl residues may also have different substituents. Substituted aryl residues containing named as examples of substituted arylalkyl residues, are both examples of substituted aryl residue.

In monosubstituted phenyl residues may be the substituent in position 2, position 3 or position 4, and the preferred position 3 and position 4. In double-substituted phenyl, the substituents can be in the 2,3 position of 2.4, position, 2,5, 2,6 position, position 3, 4, or position of 3.5. Preferably in double-substituted phenyl residues both Deputy are in position 3,4. If phenyl substituted three times, the substituents can be in position 2, 3 and 4, the position 2,3,5, position, 2,3,6, position, 2,4,5 -, 2,4,6 position or position 3,4,5.

The same applies to the substituted phenylenebis residues. Phenylenebis residues can, for example, be in the form of 1,4-phenylene or 1,3-phenylene.

Phenylene-(C1-C8)-alkyl represents, in particular, phenylanaline and phenylendiamine.

Examples of the heterocyclic core structures, which can be produced heteroaryl residues, 5-membered or 6-membered heterocycles, mono - or bicyclic 5-membered to 12-membered heterocycles containing one or more heteroatoms in the ring, a 3-membered to 12-membered monocyclic 6-membered - 24-membered bicyclic and tricyclic structures and 5-membered to 10-membered monocyclic or heterocycles, are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazol, thiazole, isothiazol, tetrazol, Piran, thiopyran, pyridine, pyrazin, pyrimidine, indole, isoindole, indazole, chroman, phthalazine, quinoline, isoquinoline, cinoxacin, cinnolin, azepin or benzeneamine, cyclopent-, cyclohexa or cycloheptanone derivatives of these heterocycles. The remains can be connected, depending on the circumstances, any provisions. Heterocycles can be, depending on the circumstances, in most unsaturated form or in partially saturated form (=partially unsaturated, for example in dihydrofuro or tetrahydrofurane, or fully saturated form (targetform). Heterocycles can be substituted, if there are no other instructions, neprimerne-(C1-C4)-alkyl, for example benzyl, and/or one or more carbon atoms (C1-C4)-alkyl, halogen, hydroxy, (C1-C4)-alkoxy, for example methoxy, phenyl-(C1-C4)-alkoxy, for example benzyloxy, actigraphy. Nitrogen-containing heterocycles can also be present as N-oxide.

In particular, heteroaryl residue is derived 5-12-membered ring containing one or more aromatic rings heterocycle, which may contain one, two, three or four identical or different heteroatoms from the group comprising nitrogen, oxygen and sulfur. Preferably derivatives of 5-membered to 10-membered heterocycle, also 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle, particularly preferably 5-membered to 6-membered heterocycle. Preferably, it contains one, two or three heteroatoms, particularly preferably one or two heteroatoms. Examples of hetero-aryl residues are pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazoles, phthalazine, hinely, ethanolic, honokalani, hintline, cinnoline or benzeneamine, cyclo the key can be substituted once or many times, preferably one-, two - or three-fold, identical or different residues from the group comprising (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, methylenedioxy, Ethylenedioxy, cyano-, hydroxycarbonyl, aminocarbonyl, (C1-C4-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (RdO)2P(O) (RdO)2P(O)-O-, tetrazolyl.

Such heteroaryl residues are, for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, phenylpyrrole, for example 4 - or 5-phenyl-2-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, methylimidazole, for example 1-methyl-2-, 4 - or 5-imidazolyl, 1,3-thiazol-2-yl, 1-tetrazolyl, 5-tetrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxido-2-, 3 - or 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-indolyl, 3-indolyl, 5-indolyl, substituted 2-indolyl, such as, 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-chinolin, 3-chinolin or 4-chinolin, 1-ethanolic, 3-ethanolic or 4 Ishino oxazolyl or 2-benzothiazolyl.

The remnants of partially hydrogenated or fully hydrogenated heterocyclic compounds are, for example, dihydropyridines, tetrahydropyridine, pyrrolidinyl, for example 2-, 3 - or 4-(N-methylpyrrolidinyl), piperidinyl, piperazinil, morpholinyl, thiomorpholine, tetrahydrothieno, benzodioxan-2-yl.

Heterocyclic residues, labeled Het can be unsubstituted on the carbon atoms and/or nitrogen atoms in the ring or may be substituted one or more times, for example, twice, three times, four times or five, identical or different substituents. The carbon atoms can 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, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (RdO)2P(O) (RdO)2P(O)-O-, tetrazolium. Sulfur atoms may be oxidized to a sulfoxide or to the sulfone. Examples of the residue Het is 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-tetrazolyl, dihydropyridines-1-yl, tetrahydropyridine-1-yl, 1-pyrrolin the sludge, 1,1-dioxo-4-thiomorpholine, peligrosas-1-yl, 2,5-dimethyl-1-pyrrolyl, 2,6-dimethyl-1-piperidinyl, 3,3-dimethyl-4-morpholinyl, 4-isopropyl-2,2,6,6-tetramethyl-1-piperazinil.

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

Present as an R4bivalent residue of alkylene, which is substituted by a residue from the group comprising R11NH, (C9-C12-cycloalkyl, (C9-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C8)-alkyl, (C6-C12-tricyclohexyl and (C6-C12-tricyclohexyl- (C1-C8)-alkyl can be, for example, remnants of CH2-SN(OTHER11)- or-CH2-CH2-CH(OTHER11)-, CH(OTHER11), the group which is attached to the remainder of the Eain the group CO-N(Ra)-R4-Eaor a residue-CH2CH(OTHER11)-CH2-. Further, the bivalent residue of alkylene as R4may be a residue-CH(sa)- or it can be a residue-CH(Cy)-CH2-, CH2group which is attached to the remainder of the Eaand su denotes (C9-C12-cycloalkyl, (C9-C12-cycloalkyl-(C1-C86-C12-tricyclohexyl or (C6-C12-tricyclohexyl-(C1-C8)-alkyl. But all these are given as examples of the residuals instead of the specified one or two hydrogen atoms may contain alkyl residues such as methyl residues.

The bivalent residue of the amino acids, aminokisloty or esamination as R5or R6receive, as is customary in the chemistry of peptides from the corresponding amino acids, aminokisloty or esamination, by removal of their N-terminal amino group or aminogroup formally one atom of hydrogen and removal of C-terminal carboxyl group, hydroxy group. Then, after appearing free link on the amino group or aminogroups, this group is bound like peptide through an amide bond with the carbonyl group of a neighboring group, and is contained in R5N-terminal amino group or aminogroups connected with group CO-R5-R6-R7. Accordingly, formally emerged by removing the hydroxy-group of the carboxyl group, carbonyl group is connected through its free link like peptide through an amide bond with a nitrogen atom adjacent groups is that the group WITH the-R5-R6-R7connected with group, R5group and R5and R6connected to each other, connected with the substituent Rbthat can, for example, denote hydrogen or (C1-C4)-alkyl, for example methyl.

Natural and unnatural amino acids may be present in all stereochemical forms, for example in the D-form, L-form or in the form of a mixture of stereoisomers, for example in the form of a racemate. Preferred amino acids are amino acids and amino acids, especially preferred amino acids. As take into account amino acid derivatives which can be R5and R6as examples are called (cf. Houben-Weyl, Methods der organischen Chemie, Band 15/2, Georg Thieme Verlag, Stuttgart, 1974); Aad, Abu, Abu, 2ABz, Aca, Ach, Adpd, Ahb, Aib, Aib, Ala, Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (s)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, 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, Tie, Tly, Trp, Trta, Tyr, Val, tert-butylglycol (Tbg), neopentylglycol (Npg), cyclohexylglycine (Chg), cyclohexylamine (Cha), 2-titillans (Thia), 2,2-diphenylsiloxane acid, UP>6denote the residue of a natural or unnatural amino acids, which is the atom of carbon is connected with the hydrogen atom, is the divalent residue-N(Rb) -CH(SC) -CO-, where SC denotes the side chain-amino acids, as well as, for example, one of the substituents contained in the position above, unbranched in-position-amino acids. Examples of the side chains are alkyl residues such as methyl group in alanine or ISO-propyl group valine, benzyl residue to phenylalanine, the phenyl residue in phenylglycine, 4-aminobutyryl the lysine residue in or hydroxycarbonylmethyl group in aspartic acid. Such side chains and, thus, amino acids can be combined in the scope of the present invention, not only on the basis of their chemical structure, but also, for example, on the basis of their physico-chemical properties in one group, for example lipophilic side chains may be different from the hydrophilic side chains containing polar groups. Examples of lipophilic side chains, which may contain as R5and/or R6amino acids are alkyl residues, arylalkyl residues or aryl residues, for example (C1-C6)-Ala the e residues and possibly substituted (C6-C12)-aryl residues, and these residues are also above explanations.

Esamination represent natural or unnatural amino acids, in which SN-fragment is replaced by a nitrogen atom, for example in the Central amino acids fragment

replaced

As remnants of aminocyclo taken into account, in particular, residues of heterocyclic compounds from the following group: pyrrolidin-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroquinoline-3-carboxylic acid; octahedron-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta[b]-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)-1,3-pyrrolidin-5-carboxylic acid; 2-azatricyclo[4.3.0.16,9]-decane-3-carboxylic acid; decahydrated[b]pyrrole-2-carboxylic acid; damageresistant[C]-pyrrol-2-CT is 3,3 and 4,6 and hexahydrotriazine[b]pyrrole-2-carboxylic acid; 2,3,3 a,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, if necessary, replaced (see the following formula):

Which is the basis of these residues heterocycles are known for example from US-A-4344949; US-A-4374847; US-A-4350704; EP-A 29488; EP-A 31741; EP-A 46953; EP-A 49605; EP-A 49658; EP-A 50800; EP-A 51020; EP-A 52870; EP-A 79022; EP-A 84164; EP-A 89637; EP-A 90341; EP-A 90362; EP-A 105102; EP-A 109020; EP-A 111873; EP-A 271865 and EP-A 344682.

Acid group in a natural or unnatural amino acids, iminokislot and aseaninitiated may also exist in the form of esters or amides, such as (C1-C4)-Olkiluoto ether such as methyl ether, ethyl ether, isopropyl ether, isobutyl ether or tert-butyl ether, benzyl ether; unsubstituted amides, methylamide, ethylamide, semicarbazide or-amino-(C2-C8)-alkylamide.

Functional groups of amino acids, aminocyclo and esamination can be protected. Suitable protective groups such as, for example, urethane protective group, a carboxyl protective group, and C is t, are: Aloe, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Rooted, Adoc, Mcs, ISO, Z(NO2), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

The compounds of formula I can exist in stereoisomeric forms. If the compounds of formula I contain one or more asymmetric centers, they may independently have the S-configuration or R-configuration. This invention includes all possible stereoisomers, such as enantiomers and diastereomers, and mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. The subject of this invention are the enantiomers in enantiomerically pure form as levogyrate, and programada antipodes, in the form of racemates and in the form of mixtures of both enantiomers in all ratios. In the case of CIS/TRANS-isomerism as CIS-form and TRANS form and mixtures of these forms are the subject of this invention. Getting the individual stereoisomers may be performed, if desired, separating a mixture by conventional means, for example by chromatography or crystallization, by using a uniform stereochemical starting substances in the synthesis, or by stereospeakers synthesis. Re what about the reagent, and received diastereomeric compounds can be separated according to conventional methods, for example by crystallization or chromatography. Separation of a mixture of stereoisomers may occur at the stage of the compounds of the formula I or at the stage of an intermediate product during the synthesis.

With the existence of mobile hydrogen atoms, the invention also includes all tautomeric forms of the compounds of the formula I, for example, lactam/lactim-tautomers.

If the compounds of formula I contain one or more acidic or basic groups, the corresponding physiologically or toxicologically acceptable salts are also subject of this invention, in particular pharmaceutically acceptable salts. Thus, the compounds of formula I which contain one or more acidic groups such as carboxyl groups or sulfonylurea group may be, for example, in the form of salts of alkali metals, salts of alkaline-earth metals or of ammonium salts and used in accordance with this invention. Examples of such salts are salts of sodium, potassium salts, calcium salts, magnesium salts or ammonium salts, or salts with organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids.emer the amino group, amidinopropane or guanidinium may be in the form of their additive salts with inorganic or organic acids and used in accordance with this invention, for example as salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluensulfonate, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pavlinovoi acid, dietramszell acid, malonic acid, succinic acid, pipelinewall acid, fumaric acid, maleic acid, malic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compounds of formula I contain in the molecule at the same time acidic and basic groups, this invention include, along with the described forms salts, also inner salts or betaines.

Salts can be obtained from compounds of the formula I, an ordinary, well-known specialist of ways, for example, Association with organic or inorganic acid or base in a solvent or disperse the e salts of compounds of formula I, which because of low physiological tolerance unsuitable for use in pharmaceuticals but which can be used as, for example, intermediates for chemical reactions or for the preparation of physiologically acceptable salts.

The invention consists, further, all the solvate of the compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula I, for example, esters, prodrugs and active metabolites.

The individual structural elements of the formula I preferably have the following values.

W preferably represents R1-A-C(R13).

And preferably denotes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexyl, phenylene, fineliner or phenylenedi.

Y preferably denotes a carbonyl group.

Z preferably denotes N(R0).

In a preferably denotes a divalent residue of the methylene or a residue of ethylene (=1,2-ethylene), in particular the balance of methylene, each of the residues may be unsubstituted or substituted. Particularly preferably, both of these residue are substituted. If the n balance of the group, includes (C1-C8)-alkyl, (C2-C6)-alkenyl, (C2-C6)-quinil, (C3-C8-cycloalkyl, in particular (C5-C6-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, in particular (C5-C6-cycloalkyl-(C1-C4)-alkyl, possibly substituted (C6-C10)-aryl, possibly substituted in the aryl residue (C6-C10)-aryl-(C1-C4)-alkyl, possibly substituted heteroaryl and possibly substituted heteroaryl-(C1-C4)-alkyl. Especially preferably, it is substituted by a residue from the group comprising (C1-C8)-alkyl, in particular (C1-C6)-alkyl, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C4)-alkyl, phenyl, benzyl and phenylethyl, especially preferably, it is substituted (C1-C6)-alkyl residue, also alkyl residue with a linear or branched chain with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, osobennosti (C1-C6)-alkyl residue.

E and Eapreferably independently of one another, denote R10WITH.

R, Raand Rbdenote independently from each other hydrogen, (C1-C6)-ALK is (C1-C6)-alkyl, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C2)-alkyl, possibly substituted phenyl or possibly substituted in the phenyl residue, phenyl- (C1-C2) -alkyl.

R0represents preferably hydrogen, (C1-C8)-alkyl, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C6)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C6)-alkyl, possibly substituted (C6-C12)-aryl, possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C6)-alkyl, possibly substituted heteroaryl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, (C1-C8)-alkyl-CO, (C3-C10-cycloalkyl-CO, (C3-C10-cycloalkyl-(C1-C6)-alkyl-CO, (C6-C12-bicycloalkyl-CO, (C6-C12-bicycloalkyl-(C1-C6)-alkyl-CO, (C6-C12-tricyclohexyl-CO, (C6-C12-tricyclohexyl-(C1-C6)-alkyl-CO, possibly substituted (C6-C12)-aryl-may sameenusman substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl-CO, (C1-C8)-alkyl-S(O)n, (C3-C10-cycloalkyl-S(O)n, (C3-C10-cycloalkyl-(C1-C6)-alkyl-S(O)n, (C6-C12-bicycloalkyl-S(OH)n, (C6-C12-bicycloalkyl-(C1-C6)-alkyl-S(O)n, (C6-C12-tricyclohexyl-S(O)n, (C6-C12-tricyclohexyl-(C1-C6)-alkyl-S(O)npossibly substituted (C6-C12)-aryl-S(O)npossibly substituted in the aryl residue (C6-C12)-aryl-(C1-C6)-alkyl-S(O)npossibly substituted heteroaryl-S(O)nor maybe substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl-S(O)nand n is 1 or 2. Particularly preferably, R0means (C1-C8)-alkyl, (C3-C10-cycloalkyl, (C3-C10-cycloalkyl-(C1-C6)-alkyl, (C6-C12-bicycloalkyl, (C6-C12-bicycloalkyl-(C1-C6)-alkyl, (C6-C12-tricyclohexyl, (C6-C12-tricyclohexyl-(C1-C6)-alkyl, possibly substituted (C6-C12)-aryl, possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C6)-alkyl, vomocil, even more preferably possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C4)-alkyl or possibly substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl, moreover, preferably, possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C4)-alkyl, especially unsubstituted or substituted one or more times (C6-C12)-aryl-(C1-C2)-alkyl.

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

X and X1denote preferably hydrogen, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C8)-alkylcarboxylic-(C1-C6-alkoxycarbonyl or (C6-C14)-aryl-(C1-C6-alkoxycarbonyl, hydroxy; X1in addition, denotes R’-NH-C(=N-R') with R’ and R’, independently of one another, have the preferred values of X.

R2, R2aand R2bmark, preferably independently of one another, hydrogen or (C1-C8)-alkyl, particularly preferably hydrogen.

R3preferably refers to R11NH, (C10-C12-cycloalkyl, (C10-C12)-qi is-C8)-alkyl, (C10-C12-tricyclohexyl, (C10-C12-tricyclohexyl-(C1-C8)-alkyl, CO-N(Ra)-R4-Eaor CO-R5-R6-Het, particularly preferably R11NH, (C7-C12-bicycloalkyl, (C7-C12-bicycloalkyl-(C1-C4)-alkyl, (C10-C12-tricyclohexyl or (C10-C12-tricyclohexyl-(C1-C4)-alkyl, CO-N(Ra)-R4-Eaor CO-R5-R6-Het, particularly preferably R11NH or CO-R5-R6-Het.

R4means preferably divalent residue (C1-C4)-alkylene, particularly preferably a residue (C1-C2)-alkylene, which is substituted by a residue from the group comprising R11NH, (C10-C12-cycloalkyl, (C10-C12-cycloalkyl-(C1-C6)-alkyl, (C7-C12-bicycloalkyl, (C7-C12-bicycloalkyl-(C1-C6)-alkyl, (C10-C12-tricyclohexyl and (C10-C12-tricyclohexyl-(C1-C6)-alkyl, which may optionally be substituted by one or two identical or different (C1-C4)-alkyl residues.

R5preferably denotes a divalent about is conventional in the chemistry of peptides, protective groups, or may exist in the form of esters or amides, and with the nitrogen atom N-terminal amino group contains a balance of Rb. Especially preferred amino acid as R5is an amino acid.

R6preferably refers to a simple link.

R10preferably represents hydroxy, (C1-C6)-alkoxy, (C6-C10)-aryl-(C1-C8)-alkoxy, in which the aryl residue may be substituted, possibly substituted (C6-C10)-aryloxy or (C1-C8)-alkylcarboxylic-(C1-C6)-alkoxy.

R11preferably refers to R12NH-CO, R14aO-CO, R14bCO., R14cS(O) or R14dS(O)2.

R12preferably denotes a possibly substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl which can be substituted in the aryl residue, a possibly substituted heteroaryl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C8)-alkyl or the residue R15.

R13preferably denotes hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl or benzyl, particularly preferably (C1-C6)-alkyl, (C3-C8-cycloalkyl or .

R14apreferably denotes a possibly substituted in the heteroaryl residue heteroaryl-(C1-C2)-alkyl or the residue R15especially preferably the residue R15.

R14band R14dpreferably denote, independently from each other, possibly substituted in the aryl residue (C6-C10)-aryl-(C1-C4)-alkyl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl or the residue R15.

R14cpreferably means (C1-C10)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyl, in which aryl residue may also be substituted, possibly substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl or the residue R15.

R14cpreferably means (C1-C10)-alkyl, possibly substituted (C6-C14)-aryl which can be substituted in the aryl residue, or a residue R15.

R14fpreferably denotes a possibly substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl, (C9-C12-cycloalkyl-(C1-C8)-alkyl, (C6-C12-bicycloalkyl, (C6-C1-C8)-alkyl.

R15preferably refers to R16-(C1-C3)-alkyl, or R16especially preferably, R16(C1) -alkyl, or R16.

R16preferably represents the residue of a 5-membered to 10-membered monocycle or the remainder of the 6-membered to 14-membered Bicycle or tricycle, and these cycles are saturated or partially unsaturated and may contain in the ring one, two, three or four identical or different heteroatoms from the group comprising nitrogen, oxygen and sulfur, and can also be substituted by one or more identical or different (C1-C4)-alkyl residues.

Het preferably denotes as a residue of a 5-membered to 10-membered monocyclic or polycyclic heterocycle connected through the nitrogen atom in the ring, and the heterocycle can be aromatic or partially unsaturated or saturated and may contain one or two identical or different additional heteroatoms in the ring from the group comprising oxygen, nitrogen and sulfur and may be optionally substituted on carbon atoms and nitrogen atoms in the ring, and additional nitrogen atoms in the ring as zamastil, Het represents a heterocycle which is saturated and does not contain an additional heteroatom in the ring or contains an additional heteroatom in the ring from the group comprising nitrogen, oxygen and sulfur. If the nitrogen atom in the ring in the group Het contains one residue R0O-CO, the remainder Rcpreferably has a different meaning than hydrogen.

If R3means R11NH, preferably g is 1 and N is 0. If R3means cycloalkenyl balance, bicycloalkyl balance or critically residue, preferably g is 0 or 1 and h is equal to 1, particularly preferably, g is 0 and h is 1. If R3means CO-N(Ra)-R4-Eaor CO-R5-R6-R7preferably g is 0 and h is 1. Of the compounds of formula I are preferred such compounds in which one or more residues are preferred values, and all combinations of the preferred meanings of the substituents are the subject of this invention. Especially preferred compounds of formula I are those in which simultaneously

W denotes R1-A-C(R13), where a denotes the divalent residue of the group, including cyclohexene, f is ptx2">In denotes the divalent residue of the methylene or a residue of ethylene (=1,2-ethylene), both residue is unsubstituted or substituted by a residue from the group comprising (C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, possibly substituted (C6-C10)-aryl, possibly substituted in the aryl residue (C6-C10)-aryl-(C1-C4)-alkyl, possibly substituted heteroaryl and possibly substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl;

E and Ea, independently of one another, denote R10CO;

R, Raand Rb, independently of one another, denote hydrogen, (C1-C6)-alkyl or benzyl;

Rcdenotes hydrogen, (C1-C6)-alkyl, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C2)-alkyl, possibly substituted phenyl or possibly substituted in the phenyl residue, phenyl-(C1-C2)-alkyl;

R0means (C1-C6)-alkyl, (C5-C10-cycloalkyl, (C5-C10-cycloalkyl-(C1-C4)-alkyl, (C7-C12-bicycloalkyl, (C7-C12-bicycloalkyl-(C1-C46-C12)-aryl, possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C4)-alkyl, possibly substituted heteroaryl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl, (C1-C6)-alkyl-CO, (C5-C10-cycloalkyl-CO, (C5-C10-cycloalkyl-(C1-C4)-alkyl-CO, (C7-C12-bicycloalkyl-CO, (C7-C12-bicycloalkyl-(C1-C4)-alkyl-CO, (C10-C12-tricyclohexyl-CO, (C10-C12-tricyclohexyl-(C1-C4)-alkyl-CO, possibly substituted (C6-C12)-aryl-CO, possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C4)-alkyl-CO, possibly substituted heteroaryl-WITH possibly substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl-CO, (C1-C6)-alkyl-S(O)n, (C5-C10-cycloalkyl-S(OH)n, (C5-C10-cycloalkyl-(C1-C4)-S(O)n, (C7-C12-bicycloalkyl-S(O)n, (C7-C12-bicycloalkyl-(C1-C4)-alkyl-S(O)n, (C10-C12-tricyclohexyl-S(O)n, (C10-C12-tricyclohexyl-(C1-C4)-alkyl-S(O)npossibly substituted (C6-alkyl-S(O)npossibly substituted heteroaryl-S(O)nor maybe substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl-S(O)nand n is 1 or 2,

R1denotes X-NH-C(=NH) -, X-NH-C(=NX)-NH or X-NH-CH2;

X denotes hydrogen, (C1-C6-alkylsulphonyl, (C1-C6-alkoxycarbonyl, (C1-C8)-alkoxycarbonyl-(C1-C6-alkoxycarbonyl, (C6-C14)-aryl-(C1-C6-alkoxycarbonyl or hydroxy;

R2, R2aand R2b, independently of one another, denote hydrogen or (C1-C8) -alkyl;

R3means R11NH, (C10-C12-cycloalkyl, (C10-C12-cycloalkyl-(C1-C4)-alkyl, (C7-C12-bicycloalkyl, (C7-C12-bicycloalkyl-(C1-C4)-alkyl, (C10-C12-tricyclohexyl, (C10-C12-tricyclohexyl-(C1-C4)-alkyl, CO-N(Ra)-R4-Eaor CO-R5-R6-Het;

R10denotes hydroxy, (C1-C6)-alkoxy, (C6-C10)-aryl-(C1-C8)-alkoxy, in which the aryl residue may be substituted, possibly substituted (C6-C1012NH-CO, R14aO-CO, R14bCO., R14cS(O) or R14dS(O)2;

R14aindicates a possibly substituted in the heteroaryl residue heteroaryl-(C1-C2)-alkyl or the residue R15;

R14band R14dindependently of one another denote a possibly substituted in the aryl residue (C6-C10)-aryl-(C1-C2)-alkyl, possibly substituted in the heteroaryl residue heteroaryl-(C1-C2)-alkyl or the residue R15;

R14cmeans (C1-C6)-alkyl, (C6-C10)-aryl-(C1-C2)-alkyl, which can also be substituted in the aryl residue, or a residue R15;

R15means R16-(C1-C4)-alkyl, or R16;

R16denotes the residue of a 5-membered to 10-membered monocycle or the remainder of the 6-membered to 14-membered Bicycle or tricycle, and these cycles are saturated and can also contain one or two identical or different heteroatoms in the loop from the group comprising nitrogen, oxygen and sulfur, and can also be substituted by one, two, three or four identical or different (C1-C4)-alkyl residues;

Het denotes a residue linked the definition or partially unsaturated or saturated and may contain one or two identical or different additional heteroatoms in the ring group, including oxygen, nitrogen and sulfur and may be substituted, with the nitrogen atoms in the ring may be present as substituents the same or different residues Rc, RcCO or RcO-CO and the carbon atoms may be present as substituents one or more identical or different substituents from the group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy, trifluoromethyl, phenyl and benzyl;

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

The most preferred compounds of formula I are those compounds in which W denotes R1-A-C(R13and R13means (C1-C6)-alkyl, possibly substituted in the aryl residue (C6-C14)-aryl- (C1-C8)-alkyl or (C3-C8-cycloalkyl;

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

In addition, preferred compounds of formula I are those compounds in which simultaneously

R3means R11NH, (C10-C12-cycloalkyl, (C10-C12-cycloalkyl-(C110-C12-tricyclohexyl, (C10-C12-tricyclohexyl-(C1-C4)-alkyl, CO-N(Ra)-R4-Eaor CO-R5-R6-Het;

R11means R15O-CO-or R15S(O)2;

R15means R16-(C1-C3) -alkyl, or R16;

R16denotes the residue of a 5-membered to 6-membered monocycle or the remainder of the 6-membered to 12-membered Bicycle or tricycle, and these cycles are saturated and can also contain one or two identical or different heteroatoms in the ring from the group comprising nitrogen and oxygen, and can also be substituted by one, two or three identical or different (C1-C4)-alkyl residues;

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

Particularly preferred compounds of formula I are those compounds in which simultaneously

W denotes R1-A-C(R13);

Y represents a carbonyl group;

Z represents N(R0);

And denotes a bivalent residue from the group comprising cyclohexene, phenylene and fineliner;

In denotes a shaft which 8)-alkyl, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C4)-alkyl, possibly substituted phenyl, possibly substituted in the phenyl residue, phenyl- (C1-C4)-alkyl, possibly substituted 5-membered or 6-membered heteroaryl or optionally substituted in the heteroaryl residue heteroaryl-(C1-C4)-alkyl;

E and Ea, independently of one another, denote R10CO;

R, Raand Rb, independently of one another, denote hydrogen or (C1-C4) -alkyl;

R0means (C1-C6)-alkyl, (C5-C6-cycloalkyl, (C5-C6-cycloalkyl-(C1-C2)-alkyl, possibly substituted (C6-C12)-aryl, possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C2)-alkyl, possibly substituted heteroaryl, possibly substituted in the heteroaryl residue heteroaryl- (C1-C2)-alkyl, (C1-C6)-alkyl-CO, (C5-C6-cycloalkyl-CO, (C5-C6-cycloalkyl-(C1-C2)-alkyl-CO, possibly substituted (C6-C12)-aryl-CO, possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C2)-alkyl-CO, (C1-C6)-alkyl-SSUB>npossibly substituted (C6-C12)-aryl-S(O)nor maybe substituted in the aryl residue (C6-C12)-aryl-(C1-C2)-alkyl-S(O)nand n is 1 or 2;

R1denotes H2N-C(=NH), H2N-C(=N-OH), CH3O-CO-NH-C(=NH), H2N-C(=NH)-NH or H2N-CH2;

R2, R2aand R2brepresent hydrogen;

R3means R11NH, (C10-C12-cycloalkyl, (C10-C12-cycloalkyl-(C1-C3)-alkyl, (C7-C12-bicycloalkyl, (C7-C12-bicycloalkyl-(C1-C3)-alkyl, (C10-C12-tricyclohexyl, (C10-C12-tricyclohexyl-(C1-C3)-alkyl, CO-N(Ra)-R4-Eaor CO-R5-R6-Het;

R10denotes hydroxy, (C1-C4)-alkoxy, phenoxy, benzyloxy or (C1-C4)-alkylcarboxylic-(C1-C4)-alkoxy;

R11means R15O-CO-or R15S(O)2;

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

R15means R16- (C1-C3) -alkyl, or R16;

R16denotes the residue of a 5-membered to 6-h is diversified and can also contain one or two identical or different heteroatoms in the ring group, including nitrogen and oxygen, and can also be substituted by one, two or three identical or different (C1-C4)-alkyl residues;

Het denotes the residue is linked via a nitrogen atom in the ring is 5-membered to 6-membered monocyclic heterocycle which is saturated and can contain possibly one additional heteroatom in the ring from the group comprising oxygen and sulfur and may be optionally substituted once or twice in an identical or different substituents from the group comprising (C1-C4)-alkyl, (C1-C4)-alkoxy, trifluoromethyl, phenyl and benzyl;

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

Even the most reverent are those compounds of formula I in which at the same time

W denotes R1-A-C(R13), where a denotes the divalent residue of phenylene;

Y represents a carbonyl group;

Z represents N(R0);

In denotes the divalent residue of the methylene which is unsubstituted or substituted by a residue from the group comprising (C1-C6)-alkyl, (C5-C6-cycloalkyl, (C5-CR, Raand Rb, independently of one another, denote hydrogen or (C1-C4)-alkyl;

R0means (C1-C6)-alkyl, possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C2)-alkyl, (C1-C6)-alkyl-S(O)nor maybe substituted in the aryl residue (C6-C12) -aryl-S(O)n;

R1denotes H2N-C(=NH), N2N-C(=N-OH), CH3O-CO-NH-C(=NH), H2N-C(=NH)-NH or H2N-CH2;

R2, R2aand R2brepresent hydrogen;

R3means R11NH or CO-R5-Het;

R5denotes a bivalent residue of a natural or unnatural amino acids are lipophilic side chain, and free functional groups can be protected customary in peptide chemistry, protective groups or may be in the form of esters or amides, and the nitrogen atom in the N-terminal amino group contains a balance of Rb;

R10denotes hydroxy, (C1-C4) -alkoxy, phenoxy, benzyloxy or (C1-C4)-alkoxycarbonyl-(C1-C4)-alkoxy;

R11means R15O-or R15S(O)2;

RLi R16;

R16denotes the residue of a 5-membered to 6-membered monocycle or a residue of a 7-membered to 12-membered Bicycle or tricycle, and these rings are saturated and can also contain one or two identical or different heteroatoms in the ring from the group comprising oxygen and nitrogen, and can also be substituted by one or two identical or different (C1-C4)-alkyl residues;

Het denotes the residue is linked via a nitrogen atom in the ring is 5-membered or 6-membered monocyclic heterocycle which is saturated and can contain possibly one additional heteroatom in the ring from the group comprising oxygen and sulfur, and which may be substituted by one or two identical or different (C1-C4)-alkyl residues;

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

Especially preferred are such compounds of formula I in which at the same time

W denotes R1-A-C(R13), where a denotes the divalent residue of phenylene;

Y represents a carbonyl group;

Z represents N(R0);

In denotes dei (C1-C6)-alkyl, (C5-C6-cycloalkyl-(C1-C4)-alkyl, phenyl, benzyl and phenylethyl;

In denotes R10CO;

R, Raand Rbindependently from each other represent hydrogen or methyl;

R0means (C1-C6)-alkyl or possibly substituted in the aryl residue (C6-C12)-aryl-(C1-C2)-alkyl;

R1denotes H2N-C(=NH), H2N-C(=N-OH), CH3O-CO-NH-C(=NH), H2N-C(=NH)-NH or H2N-CH2;

R2, R2aand R2brepresent hydrogen;

R3means R11NH or CO-R5-Het;

R5denotes a bivalent residue of a natural or unnatural amino acids are lipophilic side chain, and free functional groups can be protected customary in peptide chemistry, protective groups or may be in the form of esters or amides, and the nitrogen atom in the N-terminal amino group contains a balance of Rb;

R10denotes hydroxy, (C1-C4)-alkoxy, phenoxy, benzyloxy or (C1-C4)-alkoxycarbonyl-(C1-C4)-alkoxy;

R11means R15O-CO;

R13"ptx2">R16denotes cyclopentyl, cyclohexyl, 1-substituted, 2-substituted or lordamantr;

Het denotes the residue is linked via a nitrogen atom in the ring is 5-membered or 6-membered monocyclic heterocycle which is saturated and may optionally contain an oxygen atom as an additional heteroatom in the ring and which may be substituted by one or two identical or different (C1-C4)-alkyl residues;

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

In General, preferred compounds of formula I, which by chiral centers, for example on the chiral carbon atom containing residues R2and R3and/or center W 5-membered heterocycle in formula I, are homogeneous configuration.

The compounds of formula I can be obtained, for example, by condensation of fragments of the compounds of formula II

with the compound of the formula III,

in formulas II and III group W, Y, Z, b, E, R, R2, R2a, R2band R3and g and h have the above values or functional groups may be in protected form or in automatic carboxylic acid derivative, such as the acid chloride or active ester. In the compounds of the formula III, if the compounds of formula I should be obtained, in which R3in the formula I denotes CO-N(Ra)-R4-Eaor CO-R5-R6-R7may , for example, the remainder R3first, designate an existing in protected form hydroxycarbonyl group, and then, only after the condensation of formulas II and III in one or more successive stages, to turn in the desired group R3.

For the condensation of compounds of the formula II with compounds of the formula III is used primarily well known to the expert methods of binding 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 means take into account, for example, carbonyldiimidazole, carbodiimides, such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, O-((CYANOGEN(taxicar-bonyl)methylene)amino)-N,N,N’,N’-tetramethylethylenediamine (TOTU) or anhydride propylphosphonic acid (PPA). During condensation, as a rule, you need to available areagirls amino groups were protected by reversible protective groups. The same applies for not participating in the reaction, carbon what about the ether, for example, tert-butyl methyl ether, or benzyl ether. Protection of the amino groups is unnecessary, if the amino groups are in the form of precursors, such as nitro groups or cyano groups, and only after bonding are formed, for example, by hydrogenation. After binding of the present protective groups otscheplaut appropriate way. For example, NO2group (guanidinate), benzyloxycarbonyl and benzyl ether is removed by hydrogenation. Protective groups such as tert-Budilnik otscheplaut in an acidic environment, while 9-fluorenylmethoxycarbonyl the residue is removed with a secondary amine.

The compounds of formula II in which W denotes R1-A-C(R13), Y denotes a carbonyl group and Z represents NR0can be obtained, for example, primarily by the interaction of the compounds of formula IV

by the reaction of Bugerere to obtain the compounds of formula V

in which, as in formula IV, R1, R13and a have the above values (H. T. Bucherer, V. A. Lieb, J. Prakt. Chem., 141 (1934), 5).

The compounds of formula VI

in which R1, R13, A, b and G have the above values, can then be p which leads to the remainder of the molecule-B-G. The interaction of compounds of the formula VI with a second reagent of the formula R0-LG, in which R0has the above meanings and LG represents nucleophile replaced the deleted group, for example halogen, in particular chlorine or bromine, (C1-C4)-alkoxy, possibly substituted, phenoxy or heterocyclic delete the group, such as, for example, imidazolyl, leads to the corresponding compounds of formula II. These interactions can be those known to a person skilled ways. In some cases, in this case, as in all stages of the synthesis of compounds of formula I, a valid temporary blocking of functional groups, which can lead to adverse reactions or adverse reactions when using the strategy of protective groups suitable for problems of this synthesis, which is known to the specialist. For obtaining compounds of formulas V and VI in racemic form and in enantiomerically pure form, it is necessary to specifically refer to appropriate forms of execution described in WO-A-96/33976, which are part of the disclosure of this invention.

If W denotes the R1-A-CH=C, this structural element can be introduced, for example, those known sposobstvuyem group W.

The amino compounds of formula III can be obtained in a standard way or a similar way of starting compounds, which are commercially available or can be obtained as described in the literature or similar methods.

The compounds of formula I, in which 5-membered heterocycle is dioxa or thioxo-oxo-substituted imidazolidinone ring in which W denotes R1-A-C(R13) can also be obtained in the following way:

The response obtained according to the standard method-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 with a compound of formula VII

where R0, R1, R13and a are as defined above, with the isocyanate or isothiocyanates, for example of the formula VIII

where b, E, R, R2, R2a, R2b, R3, g and h have the above values and U denotes isocyanato or isothiocyanato receive a derivative of urea or a derivative of thiourea, for example of the formula IX

to which also belong to the above values radiologist in the compounds of formula Ia

where V denotes oxygen or sulfur, W denotes R1-A-C (R13and the remaining radicals have the above values. Cyclization of compounds of formula IX in the compounds of formula Ia can also be performed by treatment with bases in inert solvents, for example by treatment with sodium hydride in an aprotic solvent such as dimethylformamide.

During the cyclization of guanidinium can be blocked by protective groups, such as NO2. Amino groups can be present in protected form or, for example, be in the form of NO2group or ceanography, which may later be restored to the amino group or, in the case of ceanography can be transformed into formamidines.

The compounds of formula I, in which 5-membered heterocycle is dioxa or thioxo-oxo-substituted imidazolidinone ring in which W denotes R1-A-C(R13) can also be obtained by the coupling of compounds of formula VII with an isocyanate or isothiocyanato formula X

in which V and U have the above for formula VIII values and Q denotes alkoxygroup, for example (C1-C4)-alkoxygroup, such as methoxy, ethoxy4)-alkoxygroup, for example benzyloxy.

You get a connection formula XI

in which V, a, b, Q, R0, R1and R13have the above for formulas IX and X values

then under the action of acid or base as described above for the cyclization of compounds of formula IX, cyclist in the compound of formula XII

in which W denotes R1-A-C(R13and V, V, Q, and R0have the above for formula Ia and X values.

Of the compounds of formula XII then get the connection formula Ia by hydrolysis of the group CO-Q to COOH carboxylic acid and subsequent linkage with the compound of the formula III, as described above for binding of the compounds of formulas II and III. Also here during the cyclization functional groups can be present in protected form or in the form of precursors.

The next method of obtaining compounds of the formula Ia is, for example, the interaction of compounds of formula XIII

in which W denotes R1-A-C(R13and the remaining radicals have the above values,

with phosgene, thiophosgene or appropriate equivalents (similar to S. Goldschmidt, M. Wick, Liebigs'an is complete with the following reagents:

1. O-methylisoleucine (S. Weiss und H. Krommer, Chemiker Zeitung, 98 (19740, 617-618).

2. S-methylisothiazoline (R. F. Bopne, 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-pyrazolyl-formamidine (F. L. Scott, D. G. O Donovan und J. Reiily, J. Amer.Chem.Soc., 75 (1953), 4053-4054).

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

7. N-alkoxycarbonyl-, n, N’-dialkoxybenzene-, N-alkylsulphonyl - and N,N’-dialkylamino-S-methylisothiazoline (H. Wollweber, H. Kolling, E. Niemers, A. Widdig, P. Andrews, H.-P. Schutz und H. Thomas, Arzneim.Forsch./Drug Res., 34 (1984), 531-542).

Amidine can be obtained from the appropriate cyanocobalamine attach alcohols (e.g. methanol or ethanol) in acid anhydrous environment (for example, dioxane, methanol or ethanol) and subsequent aminolysis, for example by treatment with ammonia in alcohols, such as isopropanol, methanol or ethanol (G. Wagner, P. Richner und Ch.Garbe, Pharmazie, 29 (1974), 12-55). The following method of obtaining amidino is joining H2S to the cyano followed by methylation of the resulting thioamide and POS is the group with the formation of N-hydroxyamides, then, if desired, can be converted in amidine, for example by hydrogenation.

For obtaining compounds of formula (I need to reference the full description of WO-A-96/33976 and the following works, which describe compounds with inhibiting platelet aggregation action: WO-A-94/21607, WO-A-95/14008, EP-A-449079, EP-A-530505 (US-A-5389614), WO-A-93/18057, EP-A-566919 (US-A-5397796), EP-A-580008 (US-A-5 424293) and EP-A-584694 (US-A-5554594).

The compounds of formula I are valuable pharmaceutical active substances which are suitable, for example, for the treatment and prevention of inflammatory diseases, allergic diseases or asthma. The compounds of formula I and their physiologically acceptable salts in accordance with this invention be applied to animals, preferably mammals, and in particular to humans as pharmaceuticals for therapy or prophylaxis. They can be applied individually, in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which as active component contains an effective amount of at least one of the compounds of formula I and/or physiologically acceptable salts, along with the usual f is Auda also the compounds of formula I and/or their physiologically acceptable salts for use as pharmaceuticals, the use of compounds of the formula I and/or their physiologically acceptable salts to obtain drugs for therapy and prevention of the above and further diseases, for example for the treatment and prevention of inflammatory diseases, as well as the use of compounds of the formula I and/or their physiologically acceptable salts in the treatment and prevention of these diseases. Next, the subject of this invention are pharmaceutical preparations which contain an effective dose of at least one of the compounds of formula I and/or physiologically acceptable salts, along with the usual pharmaceutically acceptable carriers and/or additives.

Drugs can be administered orally, for example in the form of pills, tablets, coated film tablets, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions or suspensions. But the application can also be rectally, for example in the form of suppositories, or parenterally, for example in the form of injection or infusion solutions, microcapsules or rods, or transdermally, for example in the form of ointments, solutions or tinctures, or in any other way, for example in the form of nasal sprays or aerosol mixtures.

The cooking is poison with the compound or compounds of the formula I and/or their physiologically acceptable salts are used inert inorganic or organic carriers. For the preparation of pills, tablets, coated tablets and hard gelatin capsules can be used, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. as carriers for the preparation of solutions, for example injection solutions, or emulsions or syrups are suitable, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oil, etc. as carriers for seeds, transplants or sticks are suitable, for example, copolymerizate of glycolic acid and lactic acid. Pharmaceutical preparations usually contain ~0.5 to 90 wt.% compounds of the formula I and/or their physiologically acceptable salts.

Pharmaceuticals, along with active substances and media may contain additional substances, such as fillers, spray agents, binding agents, softeners, wetting, stabilizers, emulsifiers, preservatives, sweeteners, dyes, improves the taste and odor agents, thickeners, diluents, buffer wakie salts for modifying the osmotic pressure, covering substances or antioxidants. They can also contain two or more compounds of the formula I and/or their physiologically acceptable salts. Further, they may contain, along with at least one compound of the formula I and/or its physiologically acceptable salt and one or more other therapeutically or prophylactically active substances, for example substances inhibiting inflammation effect. Pharmaceutical preparations usually contain 0.2 to 500 mg, preferably 1-100 mg of the active substance of the formula I and/or its physiologically acceptable salt.

The compounds of formula I have the ability to inhibit interaction between cell-cell and 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 test, which measure the binding of cells that detect receptor VLA-4, such as leukocytes, with ligands of this receptor, such as VCAM-1, which can be obtained for this purpose, preferably by genetic engineering. Details of this test are described below. In particular, the compounds of formula I can inhibit the adhesion and migration of leukocytes in the case of attachment of leukocytes to the endo is ome use as anti-inflammatory drugs, the compounds of formula I and their physiologically acceptable salts are generally suitable for therapy and prophylaxis of diseases which are caused by the interaction between VLA-4 receptor and its ligands, or which can be influenced by inhibition of this interaction, and, in particular, they are suitable for therapy and prophylaxis of diseases which are at least partially due to undesirable levels of leukocyte adhesion and/or migration of leukocytes or associated with, or for the prevention, mitigation or cure of which should be reduced adhesion and/or migration of leukocytes.

The compounds of formula I can be used in inflammatory phenomena of different reasons as inhibitors of inflammation. They are used, for example, for the treatment or prevention of rheumatoid arthritis, inflammatory intestinal disease (ulcerative colitis), systemic lupus erythematosus, or for therapy or prophylaxis of inflammatory diseases of the Central nervous system such as multiple sclerosis, for the treatment or prophylaxis of asthma or allergies, such as delayed-type allergies (Allergy type IV). Further, they are suitable for therapy or prevention of cardiovascular dis is ransplantation bodies, to suppress tumor growth or metastasis of tumors in various malignant diseases, for the treatment of malaria, and other diseases in which the inhibition of the integrin VLA-4 and/or impact on the activity of leukocytes leads, apparently, to prevent, alleviate or cure.

Dose when using compounds of formula I can vary within wide limits and, as usual, must in each case be adjusted to the individual data. It depends on the connection or the type and severity of the subject to treatment of the disease or whether the treatment of acute or chronic pathological condition, or is prevention. In General, by oral administration, the daily dose is about 0.01 to 100 mg/kg, preferably 0.1 to 10 mg/kg, in particular from 0.3 to 2 mg/kg (per kg body weight) for adults weight ~75 kg to achieve effective results. When administered intravenously is daily dose in General ~0.01 to 50 mg/kg, preferably 0.01 to 10 mg/kg of body weight. The daily dose may be divided, in particular with the introduction of large quantities for several, for example 2, 3 or 4 separate input dose. If necessary, depending on the individual on what dmeta of the present invention are also the compounds of formula I for the inhibition of the adhesion and/or migration of leukocytes or for inhibition of VLA-4 receptor and the use of compounds of formula I for the preparation of drugs for this, as well as pharmaceuticals for therapy or prophylaxis of diseases, in which leukocyte adhesion and/or migration of leukocytes is undesirable size, or diseases in which play the role of VLA-4-dependent adhesion processes, as well as the use of compounds of the formula I and/or their physiologically acceptable salts for the treatment and prevention of such diseases.

The compounds of formula I and their salts may also be used for diagnostic purposes, for example in in vitro diagnoses, and as an aid in biochemical studies, which seek to obtain the blocking of VLA-4 or impact on the interaction of cell-cell or cell-matrix. In addition, they can be used as intermediates for other compounds, in particular of other pharmaceutical active substances, which can be obtained from compounds of the formula I, for example, the change or the introduction of residues or functional groups.

Examples

Compounds identified by mass spectra (MS) and/or NMR spectra. Compounds that were purified by chromatography using eluent which contained, for example, acetic acid or triperoxonane acid, and then su is received partially or completely in the form of salt used acid, for example, in the form of a salt of acetic acid or salt triperoxonane acid.

Abbreviations:

DMF N,N-dimethylformamide

THF tetrahydrofuran

DCC N,N’-dicyclohexylcarbodiimide

HOBt 1-hydroxybenzotriazole

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

Example 1

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

1a) (R,S)-4-(4-Tianfeng)-4-methyl-2,5-dioxoimidazolidin

20 g (138 mmol) of p-acetylbenzoate, 115,6 g of ammonium carbonate (1,21 mol) and 11.6 g of potassium cyanide (178 mmol) was dissolved in 600 ml of a mixture of 50% ethanol and 50% water. The mixture was stirred for 5 hours at 55°C and kept overnight at room temperature. The solution was brought to pH 6.3 6N hydrochloric acid and then stirred for 2 hours at room temperature. The precipitate was aspirated, washed with water and dried over phosphorus pentoxide in a high vacuum. Output: 22,33 g (75%).

1b) Methyl ester ((R,S)-4-(4-tianfeng)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid

1,068 g of sodium (46,47 mmol) was dissolved under nitrogen atmosphere in 110 ml of absolute is) and the mixture is boiled for 2 hours under reflux. Added to 7.75 g (of 46.68 mmol) of potassium iodide and dropwise within 1 hour solution was added to a 4.53 ml methyl ester Chloroacetic acid (from 51.3 mmol) in 5 ml of methanol. The mixture was heated for 6 hours to boiling, kept over night at room temperature and concentrated. Oily residue was chromatographically through silica gel with a mixture of methylene chloride/ethyl acetate (9:1). Output: 8,81 g (66%).

1C) Methyl ester ((R,S)-4-(4-tianfeng)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid

To a solution of 4.5 g (15.7 mmol) of the methyl ester ((R,S)-4-(4-tianfeng)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid in 25 ml of absolute DMF) in an argon atmosphere at 0°With the added 754 mg (17,27 mmol) of sodium hydride was left to mix for 15 minutes at room temperature, was added 2,05 ml (17,27 mmol) benzylbromide and left to mix for 4 hours at room temperature. The solvent was removed in vacuo and the residue was chromatographically on silica gel with a mixture of heptane/acetaldehyde. After concentrating the product fractions were received 9.81 g (76%) of target compound.

1d) Hydrochloride methyl ester ((R,S)-4-(4-amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic KIS the DIN-1-yl)-acetic acid in 80 ml of absolute ethanol was cooled to 0°C. Dry gaseous hydrogen chloride was introduced into the suspension while keeping the temperature below 10°C, while the IR spectrum did not show bands nitrile. The ethanol solution was concentrated by half and mixed with 1 l of diethyl ether. The suspension was concentrated in vacuo and the residue was dried in high vacuum. Thus obtained intermediate product was dissolved in 60 ml of absolute isopropanol and 50°With mixed from 13.7 ml of 1.9 n solution of ammonia in isopropanol. After 5 hours of stirring at 50°C, the reaction mixture was cooled and poured into 1 l of diethyl ether. The precipitate was sucked out, the filtrate was concentrated, both of residue were combined and purified by chromatography on silica gel with a mixture of dichloromethane/methanol/acetic acid/water(9:1:0,1:0,1). Received 2,94 g (64%) of target compound.

1E) Hydrochloride ((R,S)-4-(4-amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid

2,82 g (7.2 mmol) of methyl ester hydrochloride ((R,S)-4-(4-amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid was heated in 60 ml of concentrated hydrochloric acid for 5 hours under reflux. The solution was concentrated in vacuo, the residue was diluted with water and Carbonyl-aminopropionic acid

10 g (42 mmol) of (S)-3-amino-2-benzyloxycarbonylamino acid in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of concentrated H2SO4was shaken for 3 days at 20 ATM N2-pressure in the autoclave. Excess isobutylene was released under pressure and the remaining solution was added 150 ml of diethyl ether and 150 ml of a saturated solution of Panso3. The phases were separated and the aqueous phase was extracted with 2×100 ml of diethyl ether. The combined organic phases are washed 2×100 ml of water and dried over Na2SO4. After removal of solvents in vacuo received 9,58 g (78%) of target compound as pale yellow oil.

1g) Tert-butyl ether (S)-2-benzyloxycarbonylamino-3-tert-butoxycarbonylamino acid

To a solution of 10 g (34 mmol) of tert-butyl methyl ether (S)-3-amino-2-benzyloxycarbonylamino acid in 600 ml of a mixture of THF/water (2:1) at 0°With the added 8,9 g (of 40.8 mmol) di-tert-BUTYLCARBAMATE and then portions 1 N. NaOH so that the pH of the solution was between 9 and 10 (flow 1 N. NaOH 32 ml). After 3 hours stirring at room temperature was added 1 l of water and was extracted 3 times with diethyl ether. After drying over sodium sulfate, filtering Received 13,19 g (98%) of target compound.

1h) Hydrochloride tert-butyl ether (S)-2-amino-3-tert-butoxycarbonylamino acid

of 13.1 g of tert-butyl methyl ether (S)-2-benzyloxycarbonylamino-3-tert-butoxycarbonylamino acid was first made in a mixture of methanol/Hcl over 10% Pd/C. After 1.5 hours, filtered and the filtrate was concentrated in vacuum. Received 9,77 g (99%) target compound as a colorless solid.

1i) Tert-butyl ether (S)-2-(1-adamantanecarbonyl)-3-tert-butoxycarbonylamino acid

A solution of 10.9 g (of 65.4 mmol) 1-(hydroxymethyl) adamantane and 10.6 g (of 65.4 mmol) carbonyldiimidazole in 60 ml THF was stirred for 1.5 hours at 50°C. was Added 9.7 g (to 32.7 mmol) of the hydrochloride tert-butyl ether (S)-2-amino-3-tert-butoxycarbonylamino acid in 25 ml of THF and 5.6 ml (to 32.7 mmol) diisopropylethylamine, was stirred for 4 hours at 60°C and kept overnight at room temperature. The solvent was removed in vacuo and the residue was chromatographically on silica gel with a mixture of heptane/ethyl acetate (7:3). Received 8.7 g (59%) of target compound as a colourless oil.

1j) Tert-butyl ether (S)-2-(1-adamantanecarbonyl)-3-aminopropionic Ki is taxicab-delamination acid in 180 ml of a mixture of triperoxonane acid/dichloromethane (1:1) after 1 minute was poured into 1.5 liters of ice solution Panso3the mixture was extracted three times with dichloromethane and then the combined dichloromethane phases were dried over sodium sulfate. After filtration and removal of solvent in vacuo received 6,35 g (94%) of target compound as a colorless solid.

1k) (S)-3-(((R,S)-4-(4-Amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-(1-adamantanecarbonyl)-propionic acid

417 mg (1 mmol) of hydrochloride ((R,S)-4-(4-amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid and 163 mg (1 mmol) of HOOBt suspended in 5 ml of DMF and, at 0°With connected with 220 mg (1.1 mmol) DCC.

Was stirred for 1 hour at 0°C and for 1 hour at room temperature and then added 353 mg (1 mmol) tert-butyl ether (S)-2-(1-adamantanecarbonyl-amino)-3-aminopropionic acid and 11.7 μl (0.9 mmol) of N-ethylmorpholine, was stirred for 2 hours at room temperature and kept overnight at room temperature. After filtration, the filtrate was concentrated in vacuo and the residue was chromatographically on silica gel with a mixture of dichloromethane/methanol/acetic acid/water(9:1:0,1:0,1). After concentration of the product fractions, the residue RA is oruxexoy acid was removed in vacuo, the residue was distributed between diethyl ether and water, the aqueous phase was concentrated and the residue was purified by chromatography on silica gel with a mixture of dichloromethane/methanol/acetic acid/water (9:1:0,1:0,1) followed the prep administrative VGH on RP-18. After concentration of the product fractions and lyophilization got to 26.3 mg (4%) of target compound FAB-MS: 659,4 (M+N)+.

Example 2

(S)-3-((S)-4-(4-Aminohydrocinnamic)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-(1-adamantanecarbonyl)-propionic acid

2A) 2-naphthylmethyl ester ((S)-4-(4-tianfeng)-3-(2-naphthylmethyl)-4-methyl-2, 5-dioxoimidazolidin-1-yl)-acetic acid

To a solution of 13,66 g (50 mmol) ((S)-4-(4-tianfeng)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid in 100 ml of absolute DMF under ice cooling was added 5,28 g (110 mmol) of sodium hydride. After 1 hour stirring at room temperature was added over 1 hour of 24.3 g (110 mmol) of 2-bromoethylamine. The reaction mixture was stirred for 20 hours at room temperature and then poured in a mixture of acetic acid/water. After separation of the phases the aqueous phase was extracted with ethyl acetate. The combined organic phase datak was chromatographically on silica gel with a mixture of heptane/ethyl acetate (2:1). Received 8,51 g (56%) of target compound.

2b) 2-naphthylmethyl ester ((S)-4-(4-aminohydrocinnamic)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid

To a solution 6,64 g (12 mmol) 2-naphthylmethyl ester ((S)-4-(4-tianfeng)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid in 120 ml of absolute ethanol was added to 1.67 g (24 mmol) of hydroxylammonium and 5,04 ml (36 mmol) of triethylamine and heated the mixture under reflux for 2.5 hours. The solvent was removed in vacuum and the residue was distributed between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and dried over magnesium sulfate. After filtration the solvent was removed in vacuum and received between 6.08 g (86%) of target compound.

2C) ((S)-4-(4-Aminohydrocinnamic)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid

2 g (3.4 mmol) of 2-naphthylmethyl ester ((S)-4-(4-aminohydrocinnamic)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid in 200 ml of absolute methanol was first made within 4 hours over a mixture of palladium hydroxide/barium sulfate. The catalyst otfit in high vacuum. Was obtained 0.56 g (37%) of target compound.

2d) Tert-butyl ether (S)-3-((S)-4-(4-aminohydrocinnamic)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl) -acetylamino)-2-(1-adamantanecarbonyl)-propionic acid

To a solution of 223 mg (0.5 mmol) ((S)-4-(4-aminohydrocinnamic)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid and 176 mg (0.5 mmol) of tert-butyl methyl ether (S)-2-(1-adamantanecarbonyl)-3-aminopropionic acid (see Example 1) in 10 ml of absolute DMF was added 164 mg (0.5 mmol) TOTU (O-(cyan-(etoxycarbonyl)methylamino)-1,1,3,3-tetramethyluronium-tetrafluoroborate) and 165 mg (1,26 mmol) diisopropylethylamine. After 2 hours stirring at room temperature and standing overnight the reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate and water. The phases were separated, the aqueous phase was extracted with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium bicarbonate and water. After drying over sodium sulfate, filtering and concentrating the filtrate in vacuo, the residue was placed in ethyl acetate and the solution was sequentially washed with a solution of KHSO4/K2SO4N.

2E) (S)-3-((S)-4-(4-Aminohydrocinnamic)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-(1-adamantanecarbonyl)-propionic acid

220 mg (0.28 mmol) of tert-butyl methyl ether (S)-3-((S)-4-(4-aminohydrocinnamic)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-(1-adamantanecarbonyl)-propionic acid was dissolved in 20 ml of 90% triperoxonane acid. After 1 hour at room temperature triperoxonane acid was removed in vacuo and the residue was stirred with diethyl ether. The product was aspirated, washed with diethyl ether and dried in high vacuum. Received 110 mg (54%) of target compound (in the form of a salt triperoxonane acid). ES(+)-MS: 725,4 (M+H)+.

Example 3

(S)-3-(((R,S)-4-(4-Amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-benzylaminocarbonyl acid

3A) Dihydrochloride (S)-3-(((R,S)-4-(4-amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-aminopropionic acid

A solution of 4.4 g (6.7 mmol) of (S)-3-(((R,S)-4-(4-amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-benzyloxy ensil-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetic acid and tert-butyl methyl ether (S)-3-amino-2-benzyloxycarbonylamino acid analogously to Example 1 and the subsequent cleavage of the tert-butyl ether (as in Example 1) in 100 ml of methanol was first made over a mixture of palladium hydroxide/barium sulphate for 1 hour at room temperature. The catalyst was filtered, the solvent was removed in vacuum and the residue in 40 ml of 6N hydrochloric acid was stirred for 30 minutes at 40°C. the Solution was concentrated in vacuum, diluted with water and liofilizirovanny. Received 2,39 g (77%) of target compound.

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

To a solution of 570 mg (1.2 mmol) of the dihydrochloride of (S)-3-(((R,S)-4-(4-amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl) -acetylamino) -2-aminopropionic acid in 20 ml of absolute DMF was added 0.4 ml of diisopropylethylamine (2.4 mmol) and 0.15 ml (1.2 mmol) benzenesulfonate. After 4 hours stirring at room temperature the solvent was removed in vacuum and the crude product was purified by chromatography on silica gel with dichloromethane, a mixture of dichloromethane/methanol (8:2) and then with methanol. After concentration of the product fractions, the residue was dissolved in water and liofilizirovanny. Received 70 mg (10%) of target compound. FAB-MS: 600,3 (M+N)+.

Example 4

(S)-(((R,S)-4-(4-(Amino-imino-methyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-2-Ben-siemikolienova Ki the cyanate benzylisothiocyanate. ES(+)-MS: 616,3 (M+N)+.

Example 5

((R,S)-4-(4-(Amino-imino-methyl)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-diimidazole-1-yl)-acetyl-L-(N-methylaspartate)-L-valinotti

5A) L Valimotie

To a solution 3,01 g (12 mmol) of N-benzyloxycarbonyl-L-valine and 1.04 g (12 mmol) of the research in 30 ml of absolute DMF was added 3,93 g (12 mmol) of TOTU (see Example 2) and 2,04 ml diisopropylethylamine. After 2 hours stirring at room temperature the solvent was removed in vacuo, the residue was placed in ethyl acetate and the solution successively washed with 3 aqueous solution of KHSO4/K2SO4, 3 x a saturated solution Panso3and 3 x water. After drying over sodium sulfate, filtration and removal of solvent in vacuo received 3.88 g N-benzyloxycarbonyl-L-valimotie in the form of the crude product, which for removal of benzyloxycarbonyl group was first made in methanol for 3 hours over 10% Pd/C. Got 2,11 g (95%) of target compound.

5b) of L-(N-methylaspartate(OtBu))-L-valinotti

This compound was obtained by combination of L-Z-N-(CH3)-Asp(OtBu)-HE L-valintatalo and subsequent gidrodinamicheskim the removal of the Z-group (benzyloxycarbonyloxy group), as opian-(4-(Amino-imino-methyl)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-diimidazole-1-yl)-acetyl-L-(N-methylaspartate)-L-valinotti

This compound was obtained by combination hydrochloride ((R,S)-4-(4-(amino-imino-methyl)-phenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-diimidazole-1-yl)-acetic acid (obtained analogously to Example 1 using 2-bromoethylamine instead of benzylbromide) and L-(N-methylaspartate(OtBu))-L-valimotie and subsequent cleavage of the tert-butyl ester 90% triperoxonane acid analogously to Example 2. ES(+)-MS: 728,4 (M+N)+.

Similarly to the compound of Example 1 can be obtained other carbamates, for example, (S)-3-(((S)-4-(4-aminoiminomethyl)-phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-((R,S)-2-(2-methylpropyl)-acetylamino)-2-(cyclohexyloxycarbonyloxy)-propionic acid of the formula

and instead of used in Example 1, stage b) ester Chloroacetic acid can be used ether of 2-bromo-4-methylpentanoic acid.

Study of biological activity

As a test method to determine the effectiveness of compounds of the formula I on the interaction between VCAM-1 and VLA-4 apply a test that is specific for this interaction. Cellular binding partners, i.e., VLA-4 integrins, are used in their natural form as the surface of the mole is uneven binding using the obtained genetic engineering recombinant soluble fused proteins, consisting of unaryoperation domains of human VCAM-1, and constant region of human immunoglobulin IgG1 subclass.

Test ways

The test for measuring the adhesion of U937 cells (ATSC CRL 1593) on hVCAM-1

1. Obtaining human VCAM-1(1-3)-IgG and human CD4-IgG

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 IgGI immunoglobulin (hinge region, a CH2 region and a CH3), obtained from Dr. Brian Seed, Massachusetts General Hospital, Boston, USA (cf. Damie find Aruffo, Proc.Natl. Acad.Sci.USA, 1991, 88, 6403-6407). Soluble protein hVCAM-1(1-3)-IgG contains three aminobenzoic extracellular immunoglobulin-like domain of human VCAM-1 (Damie und Aruffo, Proc.Natl.Acad.Sci.USA, 1991, 88, 6403). CD4-IgG (Zettlmeissl et al., DNA and Cell Biology, 1990, 9, 347) served as a fused protein for negative controls. Recombinant proteins expressibility in the form of soluble proteins after DNA transfection according to DEAE-dextranomer method in COS-cells (ATSC CRL 1651) in accordance with standard procedures (Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc., 1994).

2. The test for measuring the adhesion of U937 cells to hVCAM-1(1-3)-IgG

2.1 9 is avechicago IgG (10 μg/ml in 50 mm Tris, pH of 9.5) for 1 hour at room temperature. After removal of the antibody solution, the residue was washed once with PBS (SFR).

2.2 150 µl/well blocking buffer (1% BSA in SFR) incubated for 0.5 hour at room temperature on tablets. After removing the blocking buffer once washed SFR.

2.3 100 µl/well of the cell culture supernatant of transfected COS cells were incubated for 1.5 hours at room temperature on tablets. 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)-IgG). Content hVCAM-1(1-3)-IgG was ~0.5-1 microgram/ml After removal of the culture supernatant were washed once SFR.

2.4 the plates were incubated with 100 µl/well Fc-receptor-blocking buffer (1 mg/ml-globulin, 100 mm NaCl, 100 mm MgCl2, 100 mm CaCl21 mg/ml BSA in 50 mm HEPES, pH 7.5) for 20 minutes at room temperature. After removal of the Fc-receptor-blocking buffer, washed once SFR.

2.5 20 μl of buffer for binding (100 mm NaCl, 100 mm MgCl2, 100 mm MnCl2, 100 mm CaCl21 mg/ml BSA in 50 mm HEPES, pH 7.5) was provided, the test substance was added to 10 µl of the. BA6) and against VLA-4 (Immunotech, Nr. 0764).

2.6 U937 cells were incubated for 20 minutes in a mixture of Fc-receptor-blocking buffer and then added to the pilot in a concentration of 1×106per ml in the amount of 100 μl per well (final volume of 125 μl per well).

2.7 the Tablets slowly immersed at an angle of 45° in stop buffer (100 mm NaCl, 100 mm MgCl2, 100 mm MnCl2, 100 mm CaCl2in 25 mm Tris, pH 7.5) and was rejected. The process was repeated.

2.8 Then 50 μl per well of dye solution (16.7 ug/ml of dye hahsta 33258, 4% formaldehyde and 0.5% Triton X-100 in SFR) were incubated 15 minutes on tablets.

2.9 Tablets tilted, slowly immersed at an angle of 45° in stop buffer (100 mm NaCl, 100 mm MgCl2, 100 mm MnCl2, 100 mm CaCl2in 25 mm Tris, pH 7.5). The process was repeated. Then measured with the liquid in the flow cytometer (Millipore) (sensitivity: 5, filter: length excitation wavelength: 360 nm, the length of the emitted wavelength: 460 nm).

The intensity of the emitted colored U937 cells light is a measure of the amount of remaining tablets anchoring hVCAM-1(1-3)-IgG U937 cells and, therefore, a measure of the ability of the added test substance to inhibit the adhesion. Of inhibition of adhesion at various concentrations ">Got the following test results:

1. Compounds of General formula I

in which W denotes R1-A-C(R13);

Y represents a carbonyl group;

Z represents N(Rabout);

And denotes phenylene;

E denotes R10CO;

In means (C1-C6-alkylene, which may be unsubstituted or

substituted (C1-C6)-alkyl;

R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl;

Rrepresents H or (C1-C6)-alkyl;

R1denotes X-NH-C(=NH)-(CH2)p;

p = 0;

X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or in the case

having substituted in the aryl residue phenoxycarbonyl or

benzyloxycarbonyl;

R2, R2a, R2brepresent hydrogen;

R3means R11NH -, or-R5-R6-R7;

R4denotes a divalent (C1-C4)-alkalinity balance;

R5denotes a bivalent residue of the nature of the worth of(C1-C6)-alkyl residues, (C6-C12)-aryl-(C1-C4)-alkyl

residues, if necessary, replaced byin the aryl residue, and

if necessary, replaced by(C6-C12)-aryl residues;

R6represents a simple bond;

R7denotes Het;

R10denotes hydroxyl or (C1-C6)-alkoxygroup;

R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O),

R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary

replaced byin the aryl residue;

R13means (C1-C6)-alkyl;

R14aindicates if necessary substituted heteroaryl,

heteroaryl-(C1-C6)-alkyl, if necessary substituted in

heteroaryl residue, or R15;

R15means R16or R16-(C1-C6)-alkyl;

R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic or tricyclic ring;

Het means a 5-7 membered monocycline additional heteroatom from the group consisting of

N, O or S;

g and h denote 0 or 1,

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

2. The compounds of formula I under item 1, in which

W denotes R1-A-C(R13);

Y represents a carbonyl group;

Z represents N(R°);

E denotes R10CO;

In denotes the divalent residue of the methylene or ethylene, and

both residue is unsubstituted or substituted (C1-C6)-

by alkyl;

R0indicates if necessary substituted in the aryl

the residue (C6-C12)-aryl-(C1-C4)-alkyl;

Rrepresents H or (C1-C6)-alkyl;

R1denotes X-NH-C(=NH);

X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or

benzyloxycarbonyl;

R2, R2a, R2brepresent hydrogen;

R3means R11NH -, or-R5-R6-Het;

R10denotes hydroxyl or (C1-C6)UP>14adenotes heteroaryl-(C1-C2)-alkyl, if necessary

substituted in the heteroaryl residue, or R15;

R15means R16or R16-(C1-C4)-alkyl;

R16mean residue 5-10-membered monocyclic or

6-14-membered bicyclic or tricyclic ring;

Het denotes a 5-membered monocyclic residue of a heterocycle,

linked through the nitrogen atom in the ring, containing in the case

the need for additional heteroatom from the group consisting of

N, O or S,

in all their stereoisomeric forms and their mixtures in all

ratios, and their physiologically acceptable salts.

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

in which R3means R11NH -, or-R5-R6-Het;

R11means R15O-C(O),

R15 means R16or R16-(C1-C3)-alkyl;

R16mean residue 5-6 membered monocyclic or 6-12-

membered bicyclic or tricyclic residue

in all their stereoisomeric forms and mixtures VPO one or more paragraphs.1-3,

in which W denotes R1-A-C(R13);

Y represents a carbonyl group;

Z represents N(Rabout);

And denotes phenylene;

E denotes R10CO;

In denotes methylene, which may be unsubstituted or

substituted (C1-C6)-alkyl;

R0indicates if necessary substituted in the aryl

the residue (C6-C12)-aryl-(C1-C2)-alkyl;

Rrepresents H or (C1-C4)-alkyl;

R1denotes H2N-C(=NH) or CH3O-CO-NH-C(=NH);

R2, R2a, R2brepresent hydrogen;

R3means R11NH -, or-R5-R6-Het;

R10denotes hydroxyl or (C1-C4)-alkoxygroup;

R11means R15-O-C(O),

R13means (C1-C6)-alkyl;

R15means R16or R16-(C1-C3)-alkyl;

R16mean residue 5-6-membered monocyclic or 6-12 membered

bicyclic or tricyclic residue;

Het means a 5-6-membered monocyclic residue is additional heteroatom from the group consisting of

O or S;

in all their stereoisomeric forms and their mixtures in all

ratios, and their physiologically acceptable salts.

5. The compounds of formula I on PP.1-4, in which

W denotes R1-A-C(R13), where a denotes a phenylene;

Y represents a carbonyl group;

Z represents N(R°);

E denotes R10CO;

In denotes a divalent methylene, which can be

unsubstituted or substituted (C1-C6)-alkyl;

R0indicates if necessary substituted in the aryl

the residue (C6-C12)-aryl-(C1-C2)-alkyl;

Rrepresents H or (C1-C4)-alkyl;

R1denotes H2N-C(=NH) or CH3O-CO-NH-C(=NH);

R2, R2a, R2brepresent hydrogen;

R3means R11NH -, or-R5-Het;

R5denotes a bivalent residue of a natural or unnatural

-amino acids with lipophilic side chain, and free

functional groups can be protected customary in chemistry

the protective peptides will grouppanel R15-O-C(O);

R13means (C1-C6)-alkyl;

R15means R16or R16-(C1-C3)-alkyl;

R16denotes the residue 5-6 membered monocyclic or a 7-12 membered bicyclic or tricyclic ring;

Het means a 5-6-membered monocyclic residue of a heterocycle,

linked through the nitrogen atom in the ring, containing in the case

the need for additional heteroatom in the ring from the group

consisting of O and S,

in all their stereoisomeric forms and their mixtures in all

ratios, and their physiologically acceptable salts.

6. The compounds of formula I on PP.1-5, in which

W denotes R1-A-C(R13), where a denotes a bivalent

phenylenebis balance;

Y represents a carbonyl group;

Z represents N(R°);

E denotes R10CO;

In denotes a divalent methylene, which can be

unsubstituted or substituted (C1-C6)-alkyl;

R0indicates if necessary substituted in the aryl

the residue (C6-C12)-aryl-(C1-C3O-CO-NH-C(=NH);

R2, R2a, R2brepresent hydrogen;

R3means R11NH -, or-R5-Het;

R5denotes a bivalent residue of a natural or unnatural

-amino acids with lipophilic side chain, and free

functional groups can be protected customary in chemistry

peptides, protective groups;

R10denotes hydroxyl or (C1-C4)-alkoxygroup;

R11means R15-O-C(O),

R13means (C1-C6)-alkyl;

R15means R16or R16-CH2;

R16denotes cyclopentyl, cyclohexyl, 1-substituted, 2-substituted

or lordamantr;

Het means a 5-6-membered monocyclic residue of a heterocycle,

linked through the nitrogen atom in the ring, containing in the case

necessary oxygen as a further heteroatom in

ring;

in all their stereoisomeric forms and their mixtures in all

ratios, and their physiologically acceptable salts.

7. The compounds of formula I according to one or more paragraphs.1-6 and/Ilir CLASS="ptx2">8. The compounds of formula I according to one or more paragraphs.1-6 and/or their physiologically acceptable salts, useful as anti-inflammatory drugs.

9. The compounds of formula I according to one or more paragraphs.1-6 and/or their physiologically acceptable salts are suitable for use in the treatment or prevention of rheumatoid arthritis, inflammatory intestinal diseases, systemic lupus erythematosus or inflammatory diseases of the Central nervous system.

10. The compounds of formula I according to one or more paragraphs.1-6 and/or their physiologically acceptable salts are suitable for use in the treatment or prophylaxis of asthma or allergies.

11. The compounds of formula I according to one or more paragraphs.1-6 and/or their physiologically acceptable salts are suitable for

use in therapy or prevention of cardiovascular diseases, arteriosclerosis, restenosis or diabetes, to suppress damage to transplants of organs, to suppress tumor growth or metastasis of tumors or for the treatment of malaria.

12. The compounds of formula I according to one or more paragraphs.1-6 and/or their physiologically acceptable salts are suitable for use as inhibitors of the adhesion and/or migration lallu to inhibit adhesion, characterized in that it contains one or more compounds of the formula I according to one or more paragraphs.1-6 and/or their physiologically acceptable salts, together with pharmaceutically acceptable carriers and/or additives.



 

Same patents:

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 continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- 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-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-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 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 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, when neobloc 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, 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

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 the compounds and their pharmaceutically acceptable salts and methods for treating HIV infections and related viruses and/or treatment of acquired immunodeficiency syndrome (AIDS)

The invention relates to containing proven pharmaceutical mixture, which has a content of propene above 85%, preferably above 90% and contains up to 1% nonionic surface active agent having products HLB (hydrophilic-lipophilic balance)9, and the usual disintegrity agent and a lubricating agent and, if appropriate, cellulose and/or hydroxyethylcellulose

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 continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- 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-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-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 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 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, when neobloc 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, 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

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

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

The invention relates to the field of medicine and relates to a drug for treatment of pain, particularly migraine syndrome Bing-Horton, headaches vasomotor character, muscle pain, pain in inflammatory processes or chamber containing a combination of epinastine in various forms and esteroidales anti-inflammatory drug

The invention relates to medicine, specifically to non-steroidal anti-inflammatory drug Ketoprofen

The invention relates to new compounds of General formula

which have the properties of receptor antagonists neirokinina-1(NK-1)

The invention relates to organic chemistry, in particular to derive phenylalaninol formula (I)

where X denotes a group of formula X-1, and Y denotes a group of formula Y-1

in which R15denotes halogen, nitro, (ness.)alkyl, PERFLUORO(ness.)alkyl; R16denotes hydrogen, halogen, nitro, (ness.)alkyl; R22and R23independently represent hydrogen, (ness.)alkyl, halogen or PERFLUORO(ness.)alkyl and at least one of the radicals R22and R23does not denote hydrogen, R24denotes hydrogen; or Y represents the group Y-3, which is a 3-7-membered ring of the formula

where R25denotes a group of formula R26-(CH2)e-; R26means (ness.)alkoxy, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.) alkylsulfonyl; Q represents a group -(CH2)f-; e represents an integer from 0 to 4; and f denotes an integer from 1 to 3

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