MXPA98007565A - New derivatives of imidazolidine, its preparation, its use, and pharmaceutical preparations that contain them - Google Patents

Abstract

The present invention relates to novel indazolidine derivatives of formula I, in which B, E, W, Z, R, R0, R2, R3, e and h have the meanings indicated in the claims. The compounds of formula I are valuable active drug substances, which are suitable, for example, for the therapy and prophylaxis of inflammatory conditions, for example rheumatoid arthritis, or of allergic conditions. The compounds of formula I are inhibitors of the adhesion and migration of leukocytes and / or antagonists of the adhesion receptor VLA-4 belonging to the group of integrins. They are generally suitable for the therapy or prophylaxis of diseases that are caused by, or are related to, an unwanted degree of adhesion of leukocytes and / or migration of leukocytes, or diseases in which cell-cell or cell interactions are involved. -Matrix that are based on interactions of VLA-4 receptors with their ligands. The invention also relates to processes for preparing the compounds of formula I, to their use in the therapy and prophylaxis of the aforementioned morbid conditions, and to pharmaceutical preparations containing compounds of formula

Description

New imidazolidine derivatives, their preparation, their use, and pharmaceutical preparations containing them The present invention relates to new imidazolidine derivatives of formula I, in which B, E, W, Z, R, R °, R2, R3, e and h have the meanings indicated below. The compounds of formula I are valuable active drug substances, which are suitable, for example, for the therapy and prophylaxis of inflammatory conditions, for example rheumatoid arthritis, or of allergic conditions. The compounds of formula I are inhibitors of the adhesion and migration of leukocytes and / or antagonists of the adhesion receptor VLA-4 belonging to the group of integrins. They are generally suitable for the therapy or prophylaxis of diseases that are caused by, or are related to, an undesired degree of adhesion of leukocytes and / or migration of leukocytes, or diseases in which cell-cell or cell-cell interactions are involved. cell-matrix that are based on interactions of VLA-4 receptors with their ligands. The invention also relates to processes for preparing the compounds of formula I, their use in the therapy and prophylaxis of the aforementioned disease states, and to pharmaceutical preparations containing compounds of formula I. Integrins are a group of adhesion receptors that perform an essential role in cell-cell and cell-extracellular matrix binding processes. They have an α-heterodimer structure, and show a wide cellular distribution and a considerable degree of evolutionary conservation. The integrins include, for example, the fibrinogen receptor on the thrombocytes, which interacts mainly with the RGD sequence of the fibrindgen, or the vitronectin receptor on the osteoclasts, which interacts mainly with the RGD sequence. of vitronectin or osteopontin. The integrins are divided into three major groups: the ß2 subfamily, with its representatives LFA-1, Mac-1 and pl50 / 95, which are responsible mainly for cell-cell interactions of the immune system, and the subfamilies ßl and ß3, whose representatives fundamentally induce cell adhesion to components of the extracellular matrix (Ruoslahti, Annu, Rev. Biochem, 1988, 57, 375). The integrins of the subfamily ßl, also called VLA proteins (from the English 5"very late (activation) antigen" = very late activation antigen), comprise at least six receptors, which interact specifically with fibronectin, collagen and / or laminin as ligands. Within the VLA family, the integrin VLA-4 (a4ßl) is atypical in that it is fundamentally limited to lymphoid and myeloid cells, and in these it is responsible for cell-cell interactions with numerous other cells. VLA-4 mediates, for example, the interaction of T and B lymphocytes with heparin binding fragment II of human plasmafibonectin (FN). The binding of VLA-4 with heparin-binding fragment II of plasmafibronectin is based above all on an interaction with a sequence of LDVP. Unlike the fibrinogen receptor or the vitronectin receptor, VLA-4 is not a typical RGD binding integrin (Kilger and Holzmann, J. Mol.Meth., 1995, 73, 347). o The leukocytes that circulate in the blood normally have only a low affinity towards the vascular endothelial cells, which line the blood vessels. The cytokines, which are released by inflamed tissues, produce the activation of endothelial cells and, therefore, s the expression of numerous cell surface antigens. These comprise, for example, the adhesion molecule ELAM-1 (endothelial cell adhesion molecule-1, also called E-selectin) which binds, among others, neutrophils, the ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (leukocyte function-associated antigen 1) on 5 leukocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds different leukocytes, among other lymphocytes (Osborn et al., Cell 1989, 59 1203). VCAM-1 is, like ICAM-1, a member of the immunoglobulin gene superfamily. VCAM-1 (known first as INCAM-110) or has been identified as an adhesion molecule that is induced on endothelial cells by inflammation cytokines such as TNF and IL-1 and lipopolysaccharides (LPS). Elices et al. (Cell 1990, 60, 577) have shown that VLA-4 and VCAM-1 form a receptor-ligand pair that induces the adhesion of lymphocytes to activated endothelium. The binding of VCAM-1 to VLA-4 is not effected in this case by an interaction of VLA-4 with an RGD sequence, which is not contained in VCAM-1 (Bergelson et al., Current Biology 1995, 5, 615 ). However, VLA-4 also appears on 0 other leukocytes and, through the adhesion mechanism VCAM-l / VLA-4, also induces the adhesion of leukocytes other than lymphocytes. The VLA-4 thus represents a unique example of an ßl integrin receptor which, through the ligands VCAM-1 or fibronectin, plays an essential role both in cell-cell interactions and in cell-extracellular matrix interactions. Adhesion molecules induced by cytokines play an important role in the recruitment of leukocytes in extravascular tissue regions. The leukocytes are recruited in the inflamed tissue regions through 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 (the s ligand and receptor concepts can also be used in reverse). Blood leukocytes must first adhere to endothelial cells, before they can migrate to the synovium. Since VCAM-1 binds to cells that are carriers of integrin VLA-4 (c.4ßl), such as eosinophils, T and B lymphocytes, monocytes and also neutrophils, it relapses into it and into the VCAM mechanism -l / VLA-4 the function of recruiting such cells from the bloodstream in the areas of infection and foci of inflammation (Elices et al., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutz et al., J. Exp. Med. 1996, 183, 2175). The adhesion mechanism VCAM-l / VLA-4 has been related to a series of physiological and pathological processes. VCAM-1 is expressed, in addition to the endothelium induced by cytokines, by the following cells, among others: myoblas-cough, lymphoid dendritic cells and tissue macrophages, rheumatoid synovium, neural cells stimulated by cytokines, parietal epithelial cells of the capsule of Bowman, the renal tubular epithelium, inflamed tissues in the rejection of heart and kidney transplants, and intestinal tissue in "graft versus host" disease. VCAM-1 is also expressed in those tissue areas of the arterial endothelium that correspond to early arteriosclerotic plaques in a rabbit model. VCAM-1 is also expressed in follicular dendritic cells of human lymph nodes, and is found in stromal cells of the bone marrow, for example in the mouse. This latter finding indicates a role of VCAM-1 in the development of B cells. VLA-4 is also found, for example, in addition to cells of hematopoietic origin, in melanoma cell lines, and the VCAM adhesion mechanism -l / VLA-4 has been related to the metastasis of such tumors (Rice et al., Science 1989, 246, 1303). The main form in which VCAM-1 occurs in vivo in endothelial cells, which is the dominant form in vivo, is called VCAM-7D, and contains seven immunoglobulin domains. Domains 4, 5 and 6 resemble in their amino acid sequences domains 1, 2 and 3. In another form that is composed of six domains, here called VCAM-6D, the fourth domain is separated by splicing ("spli- cing ") alternative. Also VCAM-6D can fix cells that express VLA-4. In the articles by Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley, Chichester 1995, page 79; Kuijpers, Springer Semin. Immunopathol. 1995, 16, 379, there are, for example, additional data on VLA-4, VCAM-1, integrins and adhesion proteins. By virtue of the role played by the VCAM-1 / VLA-4 mechanism in cell adhesion processes, which are important, for example, in infections, inflammations or atherosclerosis, an attempt has been made to combat diseases, in particular inflammations, for example by intervening in these adhesion processes (Osborn et al., Cell 1989, 59, 1203). One method for this is the use of monoclonal antibodies that are directed against VLA-4. These monoclonal antibodies (mAK) which, as antagonists of VLA-4, block the interaction between VCAM-1 and VLA-4, are known. Thus, mAK anti-VLA-4 HP2 / 1 and HPl / 3 inhibit, for example, the adhesion of Ramos cells (cells similar to B cells) that express VLA-4, to endothelial cells of the human umbilical cord and to cells COS transfected with VCAM-1. Likewise, mAK anti-VCAM-1 4B9 inhibits the adhesion of Ramos cells, Jurkat cells (cells similar to T cells) and HL60 cells (granulocyte-like cells), to COS cells transfected with genetic constructions that cause them to express themselves VCAM-6D and VCAM-7D. In vitro data with antibodies that are directed against the 4 subunit of VLA-4 show that the adhesion of lymphocytes to synovial endothelial cells is blocked, an adhesion involved in rheumatoid arthritis (van Dinther-Janssen et al., J. Immunol. 1991, 147, 4207). In vivo experiments have shown that experimental autoimmune encephalomyelitis can be inhibited by mAK anti-c-4. The migration of leukocytes to an inflammatory focus is also blocked by means of a monoclonal antibody against the c-4 chain of VLA-4. The intervention by antibodies in the VLA-4 dependent adhesion mechanism has also been tested in an asthma model, in order to investigate the role of VLA-4 in the recruitment of leukocytes in inflamed lung tissue (USSN 07 / 821,768; EP-A-626,861). The administration of anti-VLA-4 antibodies inhibited the reaction of late phases and the over-reaction of the respiratory tract in allergic sheep. The cell adhesion mechanism dependent on VLA-4 has also been investigated in a model of inflammatory bowel disease (IBD) in primates. In this model, which corresponds to ulcerative colitis in humans, the administration of anti-VLA-4 antibodies produced a significant reduction in acute inflammation. In addition, it has been demonstrated that cell adhesion dependent on VLA-4 plays a role in the following clinical conditions, including chronic inflammatory processes: rheumatoid arthritis (Cronstein and Weismann, Arthritis Rheum, 1993, 36, 147, Elices et al. , J. Clin, Invest, 1994, 93, 405), diabetes mellitus (Yang et al., Proc. Nati, Acad. Sci. USA 1993, 90, 10494), systemic lupus erythematosus (Takeuchi et al., J. Clin. Invest 1993, 92, 3008), delayed-type allergies (type IV allergies) (Elices et al., Clin. Exp. Rheumatol., 1993, 11, page 77), 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), transplants (Isobe et al., Transplantation Proceedings 1994, 26, 867-868), various malignancies, for example melanoma (Renkonen et al., Am. J. Pathol. 1992, 140, 763), lymphoma (Freedman et al., Blood 1992, 79, 206) I after (Albelda et al., J. Cell Biol. 1991, 114, 1059).

Accordingly, a blockade of VLA-4 by suitable antagonists offers effective therapeutic possibilities to treat in particular, for example, various inflammatory conditions, including asthma and IBD. The special relevance of VLA-4 antagonists for the treatment of rheumatoid arthritis is revealed in this case, as stated above, of the fact that blood leukocytes must first adhere to endothelial cells, before they can migrate to the synovia, and that in this adhesion plays a role the recipient of VLA-4. On the induction of VCAM-1 in endothelial cells by inflammatory agents (Osborn, Cell 1990, 62, 3, Stoolman, Cell 1989, 56, 907), and on the recruitment of different leukocytes in areas of infection and foci of inflammation, has already discussed previously. The T cells adhere essentially to the activated endothelium, in this case, through the adhesion mechanisms LFA-l / lCAM-1 and VLA-4 / VCAM-1 (Springer, Cell 1994, 76, 301). In rheumatoid arthritis the binding capacity of VLA-4 towards VCAM-1 is increased in the majority of synovial T cells (Postigo et al., J. Clin. Invest. 1992, 89, 1445). An enhanced adhesion of synovial T cells to fibronectin has also been observed (Laffon et al., J. Clin, Invest, 1991, 88, 546, Morales-Duck et al, J. Immunol., 1992, 149, 1424). VLA-4 is also highly regulated, both within the framework of its expression and from the point of view of its function on T lymphocytes of the rheumatoid synovium. The blocking of the binding of VLA-4 to its physiological ligands VCAM-1 and fibronectin makes it possible to eliminate or alleviate effectively the inflammatory processes of the joints. This is also confirmed by experiments with the HP2 / 1 antibody in Lewis rats with adjuvant arthritis, in which an effective prevention of the disease was observed.

(Barbadillo et al., Springer Semin, Immunopathol, 1995, 16, 427). The VLA-4 represents, therefore, a therapeutically important target molecule.

In the patent applications WO-A-93/13798, WO-A-93/15764, WO-A-94/16094, WO-A-94/17828 and WO-A-95/19790 the antibodies against VLA are described. -4 mentioned above, and the use of antibodies as antagonists of VLA-4. Patent applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581, WO-A-96/06108 and WO-A-96/20216 describe peptide compounds as antagonists. of VLA-4. However, the use of antibodies and peptide compounds as drugs suffers from drawbacks, for example the lack of availability orally, the greater ease of degradation, or the immunogenic effect in the case of prolonged use. There is, therefore, a need for VLA-4 antagonists with a favorable profile of properties, for use in therapy and prophylaxis. In WO-A-95/14008, WO-A-94/21607, WO-A-93/18057, EP-A-449,079, EP-A-530,505 (US-A-5,389,614), EP- A-566,919 (US-A-5,397,796), EP-A-580,008 (US-A-5,424,293) and EP-A-584,694 (US-A-5,554,594) describe 5-membered ring heterocycles, substituted, which have at the N-terminal end of the molecule an amino, amidino or guanidino function, and which have thrombocyte aggregation inhibiting properties. In EP-A-796,855 (European patent application 97103712.2) other heterocycles which are inhibitors of osteorresorption are described. In EP-A-842 943, EP-A-842 945 and EP-A-842 944 (German patent applications 19647380.2, 19647381.0 and 19647382.9) it is described that certain compounds of this series and certain other compounds, surprisingly, also inhibit adhesion of leukocytes, and are antagonists of VLA-4. However, the selected compounds of formula I, which are distinguished by their antagonism to VLA-4 and / or their inhibitory effect on leukocyte adhesion and leukocyte migration, are not specifically disclosed in the said applications. the present invention.

The present invention therefore relates to compounds of formula I, wherein W represents RX-A-C (R13) or R1-CH = C; Z represents oxygen or sulfur; A represents a direct bond or alkylene Cj-Ca, -B means a divalent radical of the CX-C3 alkylene series, C2-C6 alkenylene, phenylene, phenylene-C1-C3 alkyl, alkylene (Cx-C3) - phenyl, the divalent C 1 -Cg alkylene radical being unsubstituted or substituted by a radical from the series of C 1 -C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C β alkynyl, C 3 -C 10 cycloalkyl, (C 3 -C 10) cycloalkyl-alkyl ( optionally substituted C6-C14 aryl (C6-C14) -alkyl (Cx-C6) optionally substituted on the aryl radical, optionally substituted heteroaryl and heteroaryl-alkyl (Ci-Cg), optionally substituted on the heteroaryl radical; E means tetrazolyl, (R80) 2P (0), HOS (0) 2, R9NHS (0) 2 or R10CO; R stands for hydrogen, C3-C12 cycloalkyl, (C3-C12) cycloalkyl (Cx-Cg) alkyl, C6 aryl C14 optionally substituted, aryl (C6-C14) -alkyl (Ci-Cg) optionally substituted on the aryl radical, optionally substituted heteroaryl or heteroaryl-alkyl (Cj-Cg) optionally its embedded in the heteroaryl radical; R ° represents hydrogen, C alquilo-C C alkyl, C 3 -C 12 cycloalkyl, (C 3 -C 12) cycloalkyl (C x -C 8) alkyl, C 3 -C 12 bicycloalkyl, (C 6 -C 12) bicycloalkyl (C 1 -C 8) ), C6-C12 tricycloalkyl, (C6-C12) tricycloalkyl (CX-C8) alkyl, optionally substituted C6-C14 aryl, (C6-C14) aryl (Cx-Cg) alkyl optionally substituted on the aryl radical, heteroaryl optionally substituted, heteroaryl-alkyl (Ci-Cg) optionally substituted on the heteroaryl radical, H-CO, alkyl (Cx-Cg) -CO, (C3-C12) cycloalkyl-CO, (C3-C12) cycloalkyl-alkyl (C ^ Cg) -CO, bicycloalkyl (C6-C12) -CO, bicycloalkyl (C6-C12) -alkyl (C ^ Cs) -0 -CO, tricycloalkyl (C6-C12) -CO, tricycloalkyl (C6-C12) - - alkyl (Cx-Cg) -CO, aryl (C6-C14) -CO optionally substituted, aryl (C6-C14) -alkyl (Cx-Cg) -CO optionally substituted on the aryl radical, heteroaryl -CO optionally substituted, heteroaryl- alkyl (Cj.-Cg) -CO optionally substituted on the heteroaryl radical, alkyl -S (O) n, cycloalkyl (C3-) C12) - -S (0) n, (C3-C12) cycloalkyl-alkyl (Ci-Cg) -S (O) n, bicycloalkyl (C6-C12) -S (O) n, bicycloalkyl (C6-C12) - alkyl (Cj.-Cg) -S (O) n, tricycloalkyl (C3-C12) -S (0) n, tricycloalkyl (C6-C12) - -alkyl (Ci-Cg) -S (O) n, aryl ( C6-C14) -S (O) n optionally substituted, aryl (C6-C14) -alkyl (Ci-Cg) -S (O) n optionally substituted on the aryl radical, heteroaryl -S (O) n optionally substituted, or heteroaryl-alkyl (Ci-Cg) -S (0) n optionally substituted on the heteroaryl radical, wherein n represents 1 or 2; R1 represents an optionally substituted radical of the series 5 of phenyl, furyl, thienyl, pyroyl, imidazolyl and pyridyl, each of these radicals also being benzo-condensed; R2 means hydrogen, Cx-Cg alkyl, C6-C aryl? optionally substituted, aryl (C6-C14) -alkyl (Cx-C8) optionally -or substituted on the aryl radical, or C3-C8 cycloalkyl; R3 means hydrogen, C ^ -Cal alkyl, C6-C aryl? optionally substituted, aryl (C6-C? 4) -alkyl (Cx-Cg) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (Cx-Cg) alkyl optionally substituted on the heteroaryl radical, C3-C8 cycloalkyl, (C3-C8) cycloalkyl-alkyl (Cj.-C8), C6-C12 bicycloalkyl, (C6-C12) bicycloalkyl (Cx-Cg), C6-C12 tricycloalkyl, tricycloalkyl (Cg-Cxj) -alkyl (Cx-) Cg), C2-C2 alkenyl, C2-C8 alkynyl, RX1NH, CON (CH3) R4, CONHR4, COOR15, CON (CH3) R15 or CONHR15; R4 means hydrogen or C? -C? 0 alkyl which may optionally be substituted once or several times with the same or different radicals, from the series of hydroxy, C? -C8 alkoxy, Rs, optionally substituted C3-C8 cycloalkyl, hydroxycarbonyl , aminocarbonyl, mono- or di- (CX-C18 alkyl) -aminocarbonyl, aryl (C6-C14) -alkoxy (C? -8) -carbonyl which may also be substituted on the aryl radical; (C 1 -C 8) alkoxycarbonyl, Het-CO, R 6 -CO, tetrazolyl and trifluoromethyl; R5 means optionally substituted C6-C14 aryl, aryl (C6-C14) -alkyl (C? -C8) optionally substituted on the aryl radical, or a possibly substituted 5 to 12 membered monocyclic or bicyclic ring, which may be aromatic, be partially or totally hydrogenated, and that may contain one, two or three heteroatoms the same or different from the series of nitrogen, oxygen and sulfur; R6 means the radical of a natural or non-natural amino acid, an imino acid, an aza-amino acid (optionally N-alkyl (C-C8) -substituted or N-aryl (C6-C14) -alkyl (C? -8) - substituted), which may also be substituted on the aryl radical, or the radical of a dipeptide, as well as its esters and amides, free functional groups may be protected by protective groups customary in peptide chemistry; R8 denotes hydrogen, C? -C? Alkyl, optionally substituted C3-C14 aryl, or aryl (C6-C? 4) -alkyl (C? -C8) which may also be substituted on the aryl radical; R9 means hydrogen, aminocarbonyl, alkyl (C? -C? G) -aminocarbonyl, (C3-C8) cycloalkyl-aminocarbonyl, optionally substituted aryl (C6-C14) -aminocarbonyl, C? -C? 8 alkyl, C6-aryl C 4 optionally substituted, or C 3 -C 8 cycloalkyl; R 10 denotes hydroxy, C 1 -C 18 alkoxy, aryl (C 6 -C 4) -alkoxy (C x -C 8), which may also be substituted on the aryl radical, optionally substituted C 6 -C 4 aryloxy, alkyl (C 1 -) C8) -carbonyloxy-alkoxy (C? -C6), aryl (C6-C? 4) -carbonyloxy-alkoxy (C? -C6), amino, or mono- or di- ((C? -C18) alkyl) - Not me; R11 represents hydrogen, R12a, R12a-CO, H-CO, R12aO-CO, R12b-CO, R12 -CS, R12a-S (0) 2 or R12 -S (0) 2; R12a means C6-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C2 cycloalkyl, (C3-C12) cycloalkyl (C6-8) alkyl, optionally substituted C6-C14 aryl, aryl (C6) -C14) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, or the radical R1S; R12b means amino, di- (alkyl (Cx-Cxg)) -amino, or R12-NH; R 13 is hydrogen, C 1 -C 6 alkyl, optionally substituted C 6 -C 14 aryl, (C 6 -C 4) aryl (C 1 -C 6) alkyl optionally substituted on the aryl radical, C 3 -C 8 cycloalkyl or (C 3 -C 8) cycloalkyl ) -alkyl (C? -C6); R1S represents R16-alkyl (C6C6) or represents R16; R16 represents a bicyclic or tricyclic radical of 6 to 24 members, which is saturated or partially unsaturated, and which may also contain one, two, three or four same or different heteroatoms, of the series of nitrogen, oxygen and sulfur, and which may also being substituted with one or more substituents, the same or different, of the C? -C4 alkyl and oxo series; Het represents the radical of a saturated 5- to 10-membered monocyclic or polycyclic heterocycle, linked through a nitrogen atom of the ring, which may contain one, two, three or four additional ring heteroatoms, the same or different, of the series of oxygen, nitrogen, and sulfur, and which may eventually be substituted on the carbon atoms and on the additional nitrogen atoms of the ring, and there may be radicals of the series of hydrogen, Rh, HCO, RhC0 and Rh0-C0, same or different, as substituents on additional nitrogen atoms of the ring, and Rh represents C?-C8 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C?-C8) alkyl, optionally substituted Cß-C14 ar aryl or aryl (C6-C14) -alkyl (C? -C8) optionally substituted on the aryl radical; e and h represent, independently of one another, 0 or 1; in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts. The alkyl radicals can be straight-chain or branched. This also applies if they are substituents or appear as substituents of other radicals, for example in alkoxy radicals, alkoxycarbonyl radicals or arylalkyl radicals. The analogous is valid for divalent alkylene radicals. Examples of suitable C 1 -C 18 alkyl radicals are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-pentadecyl, n-hexadecyl , n-heptadecyl, n-octadecyl, isopropyl, isobutyl, isopentyl, isohexyl, 3-methylpentyl, neopentyl, neohexyl, 2, 3, 5-trimethylhexyl, s-butyl, t-butyl, t-pentyl. Preferred alkyl radicals are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Examples of alkylene radicals are methylene, ethylene, tri-, tetra-, penta- and hexamethylene, or methylene or ethylene substituted with an alkyl radical, for example methylene which is substituted with a methyl group, an ethyl group, an isopropyl group , an isobutyl group, a t-butyl group, an n-pentyl group, an isopentyl group or an n-hexyl group, or for example ethylene which may be substituted on either one carbon atom or the other, or also on the other two carbon atoms. Also the alkenyl and alkenylene radicals, as well as the alkynyl radicals may be straight chain or branched. Examples of alkenyl radicals are vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl. Examples of alkenylene: vinylene or propenylene radicals are examples. Examples of alkynyl radicals are ethynyl, 1-propynyl or propargyl.

They are cycloalkyl radicals, in particular: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl, which may also be substituted, for example with C -C4 alkyl. Examples of substituted cycloalkyl radicals are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl. The analogous is valid for cycloalkylene radicals. The bicycloalkyl radicals, the tricycloalkyl radicals and the 6 to 24 member, bicyclic and tricyclic radicals, represented by R 16, are formally obtained by abstraction of a hydrogen atom of bicycles or tricyclenes. The bicycles and tricyclenes that serve as base can contain only carbon atoms as ring members, and thus are bicycloalkanes or tricycloalkanes, but also, in the case of the radicals represented by R1S, they can also contain one to four heteroatoms, equal or different, from the series of nitrogen, oxygen and sulfur, and can therefore be treated with aza-, oxa- and thiabicyclo- and tricycloalkanes. If heteroatoms are contained, they are preferably one or two heteroatoms, especially nitrogen atoms or oxygen atoms. The heteroatoms can be located in any position of the bicyclic or tricyclic skeleton, and can be found in the bridges or, in the case of the nitrogen atoms, also in the bridge heads. Both the bicycloalkanes and tricycloalkanes and their hetero-analogues may be completely saturated or contain one or more double bonds; they preferably contain one or two double bonds or, especially, they are completely saturated. Both the bicycloalkanes and tricycloalkanes as well as the hetero-analogues, and both their saturated and unsaturated representatives, can be unsubstituted or substituted in any suitable position by one or more oxo groups and / or one or more same C? -C4 alkyl groups or different, for example methyl groups or isopropyl groups, preferably methyl groups. The free bond of the bicyclic or tricyclic radical can be found in any position of the molecule, and the radical can also be linked through a bridgehead atom or an atom within a bridge. The free bond can also be found in any stereochemical position, for example in an exo position or in an endo position. Examples of basic bicyclic ring systems, from which a bicyclic radical, norbor-nano (= bicyclo [2.2.1] heptane), bicyclo [2.2.2] octane, and bicyclo [3.2.1] octane, can be derived. . Examples of ring systems containing heteroatoms, unsaturated or substituted are: 7-azabi-cyclo [2.2.1] eptane, bicyclo [2.2.2] oct-5-ene, and camphor (= 1,7,7-trimethyl- 2-oxobicyclo [2.2.1] heptane). Examples of systems from which a tricyclic radical can be derived: twistane (= tricyclo [4.4. O. O3,8] -decano), adamantane (= tricyclo- [3.3.1.13'7] decane), noradamantane ( = tricycle- [3.3.1. O3'7] nonane), the tricycle- [2.2.1. O2'6] heptane, the tricycle [5.3.2. O4'9] dodecane), the tricycle [5.4. O.O2'9] undecane or the tricycle [5.5.1. O3'11] tride-cano. The bicyclic or tricyclic radicals are preferably derived from bicycles or tricyclenes bridged, ie systems in which there are rings that share two or more than two atoms. Also preferred, unless otherwise indicated, are bicyclic radicals or tricyclic radicals with 6 to 18 members in the ring, particularly preferably those having 6 to 14 members in the ring, and most preferably those having 6 to 14 members in the ring. 7 to 12 members in the ring. In particular, the bicyclic and tricyclic radicals which are particularly preferred are the 2-norbornyl radical, both the one having the free bond in the exo position and the one having the free bond in the endo-position, the 2-bicyclo [3.2.1] octyl radical , the adamantyl radical, both the 1-adamantyl radical and the 2 -admantyl radical, the homoadamantyl radical and the noradamantyl radical, for example the 3-noradiminyl radical. Of these, the l-adamantyl radical and the 2-adamantyl radical are preferred. C6-C14 aryl groups are, for example, phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl, C6-C10 aryl groups, for example 1-naphthyl, 2-naphthyl and especially phenyl. The aryl radicals, in particular the phenyl radicals, can be substituted one or more times, preferably one, two or three times, with radicals which are the same or different from the C? -C8 alkyl group, especially C? -j alkyl, C? -C8, especially C?-C4 alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy (C?-C4) alkyl such as for example hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, alkoxy (Cj .-- C4) -carbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl. The analogous is valid, for example, for radicals such as arylalkyl or arylcarbonyl. Arylalkyl radicals, in particular benzyl and 1- and 2-naphthylmethyl, 2-, 3- and 4-biphenylylmethyl, and 9-fluorenylmethyl, which may also be substituted, are radicals. Substituted arylalkyl radicals are, for example, benzyl radicals and naphthylmethyl radicals substituted on the aryl part with one or more C?-C8 alkyl radicals, especially C.sub.1 -C.sub.1 alkyl radicals for example 2-, 3- and 4-methylbenzyl, -isobutylbenzyl, 4-t-butylbenzyl, 4 -octylbenzyl, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 1- and 8-methyl-1-naphthylmethyl, -, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphylmethyl, benzyl radicals and naphthylmethyl radicals substituted on the aryl part with one or more C? -C8 alkoxy radicals, especially radicals C.sub.1 -C.alkoxy, for example 4-methoxybenzyl, 4-neopentyloxybenzyl, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 2,3-trimethoxybenzyl, nitrobenzyl radicals, for example 2-, 3- and 4-methoxybenzyl. -nitrobenzyl, halobenzyl radicals, for example 2-, 3- and 4-chlorobenzyl and 2-, 3- and 4-fluo-robencil, 3,4-dichlorobenzyl, pentafluorobenzyl, trifluoromethylbenzyl radicals, for example 3- and 4- trifluoromethylbenzyl or 3, 5 bis (trifluoromethyl) benzyl. However, the substituted arylalkyl radicals may also have different substituents. In monosubstituted phenyl radicals, the substituent may be in the 2-position, the 3-position or the 4-position, with the 3-position and the 4-position being preferred. If the phenyl is doubly substituted, the substituents may be in the 1-position, 2-, 1,2- or 1,4-, one with respect to another. Therefore, the double-substituted phenyl can be substituted in the 2,3-position, the 2,4-position, the 2,5-position, the 2,6-position, the 3,4-position or the 3,5-position, referred to the of link. In two-substituted phenyl radicals, the two substituents arranged in the 3-position and the 4-position, based on the binding site, are preferred. In triply substituted phenyl radicals, the substituents can be, for example, in the 2,3,4 position, the 2,3,5 position, the 2,3,6 position, the 2,4,5 position, the 2 position. , 4,6 or position 3,4,5. The analogous is valid for phenylene radicals, which may occur, for example, as 1, 4-phenylene or as 1,3-phenylene.

Phenylene-C 1 -C 3 alkyl is, in particular, phenylenemethyl (-C 6 H 4 -CH 2 -) and phenylethylene, (C 1 -C 3) alkylene-phenyl, especially methylenephenyl (-CH 2 -C 6 H 4 -). Phenylene-alkenyl (C2-C6) is, in particular, phenylene-tennyl and phenyl-propenyl. Heteroaryl represents a monocyclic or polycyclic aromatic radical with 5 to 14 members in the ring, containing 1, 2, 3, 4 or 5 heteroatoms as ring members. Examples of heteroatoms are: N, O and S. If several heteroatoms are present, these can be the same or different. The heteroaryl radicals can also be substituted one or more times, preferably one, two or three times, with radicals which are the same or different from the C -C.sub.8 alkyl group, especially C? -C4 alkyl, C? -C8 alkoxy , especially C 1 -C 4 alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy (C 1 -C 4) alkyl such as for example hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl , aminocarbonyl, (C 1 -C 4) alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl. Heteroaryl preferably represents a monocyclic or bicyclic aromatic radical containing 1, 2, 3 or 4, especially 1, 2 or 3 heteroatoms, the same or different, of the series of N, O and S, and which may be substituted by 1, 2, 3 or 4, in particular 1, 2 or 3 substituents, the same or different, from the series of C C-C6 alkyl, C?-C6 alkoxy, fluoro, chloro, nitro, amino, trifluoromethyl, hydroxy, hydroxy-alkyl (C? -C4), (C? -C4) alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl. Heteroaryl is particularly preferably a monocyclic or bicyclic aromatic radical with 5 to 10 members in the ring, in particular a 5-membered or 6-membered monocyclic aromatic radical containing 1, 2 or 3, in particular 1 or 2 heteroatoms, which are the same or different, from the series of N, 0 and S, and which may be substituted with 1 or 2 substituents, the same or different, from the series of C 1 -C 4 alkyl, C 1 -C alkoxy, phenyl, phenoxy, benzyloxy and benzyl The heterocycles which constitute monocyclic or bicyclic heterocyclic rings of 5 to 12 members can be aromatic or partially or totally saturated. They may be unsubstituted or they may be substituted on one or more carbon atoms or on one or more nitrogen atoms with the same or different substituents, as indicated for the heteroaryl radical. In particular, the heterocyclic ring can be substituted at carbon atoms, once or several times, with the same or different radicals from the C? -C8 alkyl group, for example C? -C4 alkyl, C? -C8 alkoxy, for example C 1 -C 4 alkoxy such as methoxy, phenyl-C 1 -C 4 alkoxy, for example benzyloxy, hydroxy, oxo, halogen, nitro, amino, or trifluoromethyl, and / or the ring nitrogen atoms of the rings heterocyclics may be substituted, as in the heteroaryl radicals, with C?-C8 alkyl / for example C?-C4 alkyl such as methyl or ethyl, with optionally substituted phenyl or phenylalkyl (C?-C4), for example benzyl. Examples of heterocycles which may serve as a base are the heteroaryl radical or the 5 or 12-membered monocyclic or bicyclic heterocyclic ring radical: pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, pyridine, pyrazine. , pyrimidine, indole, isoindol, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, ß-carboline, or benzocondensate derivatives, cyclopentacondensates, cyclohexacondensates or cycloheptacondensates, of these heterocycles. The heterocycles with nitrogen can also be present as N-oxides. They are radicals which can be represented by heteroaryl or by the radical of a 5- or 12-membered monocyclic or bicyclic heterocyclic ring, for example: 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 4-imidazolyl, methylimidazolyl, for example l-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxide-2-, -3- or -4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyridyl. -pyrimidinyl, 2-, 3- or 5-indolyl, 2-substituted indolyl, for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyl-xi-, 5-chloro- or 4,5 -dimethyl-2-indolyl, l-benzyl-2- or -3-indolyl, 4, 5, 6, 7-tetrahydro-2-indolyl, cyclohepta [b] -5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-l, 2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofu-ranyl, 2-benzothienyl, 2-benzoxazolyl or 2-benzothiazolyl or well, as partially hydrogenated or fully hydrogenated heterocyclic ring radicals, also, for example, dihydropyridinyl, pyrrolidinyl, for example 2-or 3- (N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, benzodioxolanyl. The heterocyclic radicals represented by the radical Het can be unsubstituted at the carbon atoms and / or nitrogen atoms of the ring, or they can be substituted once or several times, for example one, two, three, four or five times , with the same or different substituents. The carbon atoms may be substituted, for example with C?-C8 alkyl, especially C?-C 4 alkyl, C?-C8 alkoxy, especially C?-C 4 alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, oxo, cyano, hydroxycarbonyl, aminocarbonyl, (C? -C4) alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl, especially with C-, -0-C4 alkyl / for example methyl, ethyl or t-butyl, alkoxy C C4, for example methoxy, hydroxy, oxo, phenyl, phenoxy, benzyl, benzyloxy. The sulfur atoms may be oxidized to the sulfoxide or the sulfone. Exemplary radical of Het are: 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl in position 5 4, 1-piperazinyl substituted, 4-morpholinyl, 4-thiomorpholinyl, l-oxo-4-thiomorpholinyl, 1, l-dioxo -4-thiomorpholinyl, perhydroazepin-1-yl, 2,6-dimethyl-1-piperidinyl, 3,3-dimethyl-4-morpholinyl, 4-isopropyl-2,6,6,6-tetramethyl-1-piperazinyl, 4-acetyl-l-piperazinyl, 4-ethoxycarbonyl-l-0-piperazinyl. The heteroatomatic radicals represented by R 1 furyl, thienyl, pyrrolyl, imidazole and pyridyl can be attached through any of the carbon atoms, that is, the 2-furyl, 3-furyl, 2-thienyl, 3- radicals can be present. thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl, The phenyl radical and the heteroaromatic radicals represented by R 1 may also be benzoalylated, that is, Rx can also represent either naphthyl, benzo [b] furyl (= benzofuryl), benzo [c] furyl, benzo [b] thienyl (= benzothienyl), benzo [c] thienyl, indolyl, benzimidazolyl, quinolyl and isoquinolyl, in particular naphthyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, quinolyl and isoquinolyl. The benzocondensate radicals represented by R.sub.1 are preferably linked through a carbon atom of the heterocyclic ring, and can in turn be bound through any of these carbon atoms. Examples of such benzocondensate radicals represented by R 1: 1-naphthyl, 2-naphthyl, 2-benzofuryl, 3-benzofuryl, 2-benzothienyl, 3-benzothienyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 2-benzimidazolyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl. The radicals represented by R 1 can be unsubstituted, or they can be substituted at any position with one or more, for example one, two, three or four identical or different substituents. In this case, the above explanations are valid, for example regarding the positions of substituents on phenyl radicals and heterocyclic radicals, and analogously for the radicals represented by R 1. Thus, as substituents on the carbon atoms, for example, C? -C8 alkyl, especially CX-C alkyl, are suitable?, Ct-C8 alkoxy, especially C?-C4 alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy (C?-C4) alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, cyano , formyl, acetyl, hydroxycarbonyl, aminocarbonyl, (C 1 -C 4) alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, and tetrazolyl, these substituents being able to be placed on carbon atoms of the heterocyclic ring and / or on carbon atoms of a condensed benzene ring. The nitrogen atoms in pyrrolyl radicals, imidazolyl radicals and their benzocondensate analogues can be unsubstituted or, in particular, substituted, for example, with C 1 -C 8 alkyl, for example C 1 -C alkyl such as methyl or ethyl, phenyl optionally substituted or phenyl-Cx-C4 alkyl, for example benzyl, or for example with (C? -C4) -CO alkyl. On the one hand, the substituent on a substituted alkylene radical represented by B may contain a ring, if it is a substituent of the series of C3-C6 cycloalkyl, (C3-C6) cycloalkyl-alkyl (C? C6), optionally substituted C6-C ?4 aryl, aryl (C6-C ?4) -alkyl (C?-C6) optionally substituted on the aryl radical, optionally substituted heteroaryl and heteroaryl (C-C6) alkyl optionally substituted on the heteroaryl radical, and on the other hand it can be acyclic, if it is a substituent of the series of C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl. The acyclic substituents may contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms or, in the case of the saturated alkyl radical, may contain. also 1 carbon atom. In the case of the alkenyl and alkynyl radicals the double bond or the triple bond can be in any position and, in the case of the double bond, it can have the cis configuration or the trans configuration. As explained above, these alkyl radicals, alkenyl radicals and alkynyl radicals may be straight chain or branched. As examples of substituents which can be carried by the C? -C6 alkylene radical represented by B, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, isopentyl, isohexyl, s-butyl, t-butyl, t-pentyl, neopentyl, neohexyl, 3-methylpentyl, 2-ethylbutyl, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3- methyl-2-butenyl, ethynyl, 1-propynyl, 2-propynyl, 6-hexynyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-biphenylylmethyl, cyclopropyl, cyclopropylmethyl, cyclopethyl, cyclohexyl , cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclo-octylpropyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyridylmethyl, 2- (4-pyridyl) ethyl, 2-furylmethyl, 2-thienylmethyl, 3-thienylmethyl or 2- (3-indolyl) ethyl. Halogen represents fluoro, chloro, bromo or iodo, especially fluoro or chloro. The radical of an amino acid, imino acid or aza-amino acid, or of a dipeptide, is obtained in the usual way in peptide chemistry from the corresponding amino acid, imino acid or aza-amino acid, or dipeptide, formally removing an atom of hydrogen of the N-terminal amino group or of the imino group. Through this resulting free bond in the amino group or in the imino group this group can be linked by an amide linkage, such as a peptide, to the group CO of the R6-CO group. The natural and non-natural amino acids can be present in all their stereochemical forms, for example in the D form, in the L form or in the form of a mixture of stereoisomers, for example in the form of a racemate. Preferred amino acids are α-amino acids and β-amino acids, and -amino acids are especially preferred. They will be mentioned as amino acids that come into consideration, for example (see Houben-Weyl, Methoden der organischen Chemie, volumes 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974): Aad, Abu,? Abu, ABz, 2ABz , eAca, Ach, Acp, Adpd, Ahb, Aib, ßAib, Ala, ßAla,? Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) 2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dte, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hile, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, lie, Ise, Iva, Kyn, Lant, Len, Leu, Lsg, Lys, Lys, Lys , Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pee, Pen, Phe, Phg, Pie, Pro,? Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, ßThi, Thr, Thy, Thx, Tia, Tie, Tiy, Trp, Trta, Tyr, Val, t-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexyl-alanine (Cha ), 2-thienylalanine (Thia), 2, 2-diphenylamidoacetic acid, 2- (p-tolyl) -2-phenylaminoacetic acid, 2- (p-chlorophenyl) aminoacetic acid. If Rd represents the radical of a natural or unnatural a-amino acid, which is not branched at the carbon atom a, ie carrying a hydrogen atom on the carbon atom OI, the divalent radical -N ( Rb) -CH (SC) -CO-L, in which CO-L represents the acid group of the amino acid or a derivative thereof, for example an ester group or an amide group, Rb represents for example hydrogen and SC represents the side chain of the α-amino acid, ie, for example, one of the substituents that are contained in the α-position of the α-amino acids without branching at the α-position, mentioned above. Examples of side chains are: alkyl radicals, for example the methyl group in alanine, or the isopropyl group in valine, the benzyl radical in phenylalanine, the phenyl radical in phenylglycine, the 4-aminobutyl radical in lysine , or the hydroxycarbonylmethyl group in aspartic acid. Such side chains, and with them the amino acids, can be grouped, in the sense of the present invention, apart from their chemical structure, for example also on the basis of their physico-chemical properties; for example, the lipophilic side chains of the hydrophilic side chains, which contain polar groups, can be distinguished. Examples of lipophilic side chains which may be contained in amino acids represented by R6 are alkyl radicals, arylalkyl radicals or aryl radicals. The aza-amino acids are natural or non-natural amino acids, in which a CH unit has been replaced by a nitrogen atom, for example in a-amino acids the central structure As radicals of imino acids, radicals of heterocycles of the following group are especially suitable: pyrrolidin-2-carboxylic acid; piperidin-2-carboxylic acid; 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindol-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta [b] pyrrole-2-carboxylic acid; 2-azabi-cyclo [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] nonane-3-carboxylic acid, • 2-azaspiro [4.5] decane-3-carboxylic acid; Spiro- (bicyclo [2.2.1] heptane) -2,3-pyrrolidine-5-carboxylic acid; Spiro acid (bicyclo [2.2.2] octane) -2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo [4.3.0.16'9] decane-3-carboxylic acid; decahydrocyclohepta [b] pyrrole-2-carboxylic acid; decahydrocyclocyclo [c] pyrrole-2-carboxylic acid; octahydro-cyclopenta [c] pyrrole-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2, 3, 3a, 4, 6a-hexahydrocyclopent [b] pyrrole-2-carboxylic acid; 2, 3, 3a, 5, 7a-hexahydroindol-2-carboxylic acid; tetrahydrothiazole-4-carboxylic acid; isoxazolidin-3-carboxylic acid; pyrazolidin-3-carboxylic acid; hydroxypyrrolidin-2-carboxylic acid, all of which may optionally be substituted (see the following formulas): ; .

The heterocycles which are the basis for the mentioned radicals are known, for example, from US Pat. No. 4,344,949; US-A 4,374,847; US-A 4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682. The dipeptides can contain natural or non-natural amino acids, imino acids and aza-amino acids as building blocks. In addition, natural or unnatural amino acids, imino acids, aza-amino acids and dipeptides can also be present in the form of derivatives of the carboxylic acid group, for example as esters or amides such as, for example, methyl esters, ethyl esters, n-esters propyl esters, isopropyl esters, isobutyl esters, t-butyl esters, benzyl esters, unsubstituted amides, methylamides, ethylamides, semicarbazides or? -amino-C2-C8 alkyl-amides. The functional groups of the amino acid radicals, imino acids, aza-amino acids and dipeptides, as well as other parts of the molecule of formula I can be presented in protected form. In the Hubbuch article in Kontakte (Merck) 1979, number 3, pages 14 to 23, and in that of Bülles-bach, Kontakte (Merck) 1980, number 1, pages 23 to 35, suitable protective groups are described such as, for example, urethane protective groups, carboxyl protecting groups and side chain protecting groups. Special mention will be made of: Aloe, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (N02), Z (Hal, Bobz, Iboc, Adpoc, Mboc, Acm, t-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pie, Trt The physiologically tolerable salts of the compounds of formula I are in particular pharmaceally usable salts or non-toxic salts In the case of compounds of formula I containing acid groups, for example carboxylic acid groups, such salts are, for example, alkali metal salts or alkaline earth metal salts, as well as salts with ammonia and physiologically tolerable organic amines.Therefore, such compounds of formula I can be presented, for example, as salts of sodium, potassium salts, calcium salts, magnesium salts, or as salts by addition of acid with amines such as for example triethylamine, ethanolamine, tris- (2-hydroxy-ethyl) -amine or amino acids, especially basic amino acids. compounds of formula I containing basic groups for example an amino group or a guanidino group, form salts with inorganic acids such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic acids or sulfonic acids, such as for example acetic acid, citric acid , benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. If the compounds of formula I simultaneously contain acidic and basic groups in the molecule, it belongs to the invention, in addition to the salt forms outlined above, also internal salts 0 or betaines. Salts can be obtained from the compounds of formula I according to customary methods known to the person skilled in the art, for example by bringing them together with an organic or inorganic acid or base in a solvent or dispersing agent, also by anion exchange or cation exchange, starting from other salts The present invention also encompasses all salts of the compounds of formula I which, because of their lower physiological tolerance, are not directly suitable for use in medicaments, but can be used, for example, as intermediates for chemical reactions or to prepare physiologically tolerable salts. The compounds of formula I can be present in stereoisomeric forms. If the compounds of formula I contain one or more centers of asymmetry, these may have, independently of one another, the S-configuration or the R-configuration. All possible stereoisomers, for example enantiomers and diastereomers, and mixtures thereof, belong to the invention. two or more stereoisomeric forms, for example or mixtures of enantiomers and / or diastereomers, in all proportions. Enantiomers in an enantiomerically pure form, both levorotatory and dextrorotatory antipodes, are thus subject to the invention in the form of racemates and in the form of mixtures of both enantiomers in all proportions. In case of presenting a cis / trans isomerism, both the cis form and the trans form, and mixtures of these forms, are the object of the invention. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by use in the synthesis of stereochemically homogeneous starting materials, or by stereoselective synthesis. If necessary, a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out in the stage of the compounds of formula I, or in the stage of a starting substance or of an intermediate product in the course of the synthesis. The compounds of formula I according to the invention can containIn addition, mobile hydrogen atoms, that is to say, present themselves in different tautomeric forms. Also these tautomers are object of the present invention. The present invention also encompasses all solvates of compounds of formula I, for example hydrates or adducts with alcohols, as well as derivatives of the compounds of formula or I, for example esters, prodrugs and active metabolites. Independently of each other, the individual structural elements in formula I preferably have the following meanings: W preferably represents R1-A-C (R13). 5 Z preferably represents oxygen. A preferably represents a direct bond or methylene, most preferably a direct bond. B preferably represents a divalent radical of the series of methylene, ethylene, trimethylene, tetramethylene, vinylene, phenylene or a substituted Cx-C4 alkylene radical. Particularly preferably, B represents a divalent methylene radical or ethylene (= 1,2-ethylene) radical, in particular a methylene radical, each of these radicals being unsubstituted or substituted. Particularly preferably, B represents a substituted methylene radical or ethylene radical, especially a substituted methylene radical. If a divalent alkylene radical, especially a methylene radical or ethylene radical (= 1,2-ethylene), represented by B is substituted, it is preferably substituted with a radical of the C?-C8 alkyl, C2- alkenyl group. -C8 / C2-C8 alkynyl, C3-C7 cycloalkyl, especially C3-C6 cycloalkyl, (C3-C7) cycloalkyl (Cx-C4) alkyl, especially (C3-C6) cycloalkyl-(C? -C4) alkyl, aryl C6-C10 optionally substituted, aryl (C6-C? 0) -alkyl (C? -C4) optionally substituted on the aryl radical, optionally substituted heteroaryl or heteroaryl (C? -C4) alkyl optionally substituted on the heteroaryl radical . Particularly preferably, a substituted alkylene radical represented by B is substituted by C? -C8 alkyl, that is, a straight or branched chain alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms carbon. E preferably represents tetrazolyl or R10C0, particularly preferably R10CO. R preferably represents hydrogen, C 1 -C 8 alkyl or benzyl, particularly preferably hydrogen or C 1 -C 8 alkyl, very particularly preferably hydrogen or C 1 -C alkyl, especially hydrogen, methyl or ethyl. R ° preferably represents C? -C8 alkyl, C3-C12 cycloalkyl, (C3-C12) cycloalkyl (C? -8) alkyl, C6-C? Bicycloalkyl, (C6-C? 2) bicycloalkyl-alkyl (C ? -C8), C6-C12 tricycloalkyl, (C6-C12) tricycloalkyl (C? -C8) alkyl, optionally substituted C6-C? 4 aryl, aryl (C6-C? 4) -alkyl (C? -C8) ) optionally substituted on the aryl radical, optionally substituted heteroaryl, or heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, particularly preferably C? -C8 alkyl, C3-C? 2 cycloalkyl, cycloalkyl (C3-? -C12) -alkyl (C? -C4), optionally substituted C6-C14 aryl, aryl (C6-C? 4) -alkyl (C? -C4) optionally substituted on the aryl radical, optionally substituted heteroaryl, or heteroaryl-alkyl (C? -C4) optionally substituted on the heteroaryl radical, very particularly preferably optionally substituted C6-C14 aryl, aryl (C6-C1) -alkyl (Cj .-- C4) optionally substituted on the aryl radical, heteroaryl optionally substituted or heteroaryl (C? -C4) alkyl optionally substituted on the heteroaryl radical, most preferably aryl (C6-C14) -alkyl (C? -C4) optionally substituted at the aryl radical, or heteroaryl-alkyl ( C? -C) optionally substituted on the heteroaryl radical. It is especially preferred that R ° represents aryl (C3-C14) -alkyl (C? -C4) optionally substituted on the aryl radical, especially biphenylylmethyl, naphthylmethyl or benzyl unsubstituted or substituted once or several times on the aryl radical.

R1 preferably represents a radical of the series of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, which is not benzocondensed. Especially preferably, R 1 represents a phenyl radical, a 2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a 3-thienyl radical, a 3-pyrrolyl radical, a 4-imidazolyl radical, a 3-pyridyl radical or a 4-pyridyl radical, most preferably a phenyl radical, a 2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a 3-thienyl radical, a 4-imidazolyl radical or a 4-pyridyl radical, most preferably a phenyl radical or a 4-pyridyl radical. Preferably, a radical represented by R1 is unsubstituted or substituted with one, two or three radicals, especially with one or two radicals, the same or different, from those previously indicated as substituents which are suitable for carbon atoms and Nitrogen atoms in R1. Particularly preferably, a radical represented by R1 is unsubstituted. Preferred substituents on carbon atoms are the radical R1: C?-C4 alkyl, C?-C4 alkoxy, halogen, amino, trifluoromethyl, hydroxy, hydroxy (C x C 4) alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, especially as substituents on carbon atoms of a heteroaryl radical represented by R1. Especially preferred substituents on carbon atoms of R1, in particular on carbon atoms, of a phenyl radical respresented by R1: C?-C4 alkyl, C?-C 4 alkoxy, halogen, trifluoromethyl, hydroxy, hydroxy-alkyl (C ? -C4), methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy. R 2 preferably represents hydrogen or C 1 -C 8 alkyl, particularly preferably hydrogen or C 1 -C 4 alkyl.

R 3 preferably represents C 1 -C 8 alkyl, optionally substituted C 6 -C 14 aryl, (C 6 -C 14) aryl-C 1 -C 4 alkyl optionally substituted on the aryl radical, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-alkyl (C? -C4), C6-C12 bicycloalkyl, (C6-C12) bicycloalkyl (C? -C4) alkyl, C6-C12 tricycloalkyl, (C6-C? 2) tricycloalkyl (C? -C4), alkenyl C2-C8, C2-C8 alkynyl, optionally substituted heteroaryl, heteroaryl-C (-C4) alkyl optionally substituted on the heteroaryl radical, R NH, CON (CH3) R4, CONHR4, C0N (CH3) R1S or CONHR, especially preferably optionally substituted C6-C14 aryl, especially optionally substituted C3-C? 0 aryl, optionally substituted 5- or 6-membered heteroaryl, with one or two heteroatoms, the same or different, of the nitrogen series, oxygen and sulfur, especially pyridyl, RX1NH, CON (CH3) R4, CONHR4, C0N (CH3) R15 or CONHR15, very particularly preferably optionally substituted C6-C10 aryl, R1XNH, CON (CH3) R4, CONHR4, CON ( CH3) Rls or CONHR15.

R 4 preferably represents C 1 -C 8 alkyl, which may optionally be substituted as indicated above in the definition of R 4, particularly preferably C 1 -C 8 alkyl, especially C 1 -C 6 alkyl, which is substituted with one or two of the substituents indicated in the above definition of R4. It is very particularly preferred that one of the substituents is attached at the 1-position of the alkyl group, ie at that carbon atom of the alkyl group to which the nitrogen atom of the CONHR4 group or the C0N (CH3) group is also attached. R4, and that this substituent is in position 1 of one of the hydroxycarbonyl, aminocarbonyl, mono- or di- (alkyl- (C? -C18)) -aminocarbonyl, aryl (C6-C14) -alkoxy (C) radicals ? -C8) -carbonyl, which may also be substituted on the aryl radical, Het-CO, R6-CO, (C? -C8) alkoxycarbonyl or tetrazolyl. Therefore, in this very especially preferred case, the radical -NHR4 or the radical -N (CH3) R4 represent the radical of an α-amino acid or of an N-methyl-α-amino acid or a derivative thereof, formally obtaining this radical by abstraction of a hydrogen atom of the amino group of the amino acid. Especially preferred a-amino acids in this case are those having a lipophilic side chain, for example phenylglycine-0-na, phenylalanine, valine, leucine, isoleucine and homologs thereof, as well as derivatives of these amino acids such as esters, amides or derivatives in which the carboxylic acid group has been transformed into the radical Het- CO. R11 preferably represents hydrogen, R1a, R1 -CO, 5 HCO, R12a-0-CO, R12b-CO, R12b-CS or R12a-S (0) 2 / most preferably hydrogen, R1Za, R12a-C0, R12a- 0-C0, R12b-CO, R12b-CS or R12a-S (0) 2, very especially preferably R12a, R12a-CO, R12a-0-CO, R12b-CO, R1 -CS or R12a-S (0 ) 2, and most preferably R1Za, R12a-CO, R12a-0-CO, R12b-CO or R12a-S (0) 2. 0 R 12a preferably represents C 1 -C 10 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 7 cycloalkyl- (C 1 -C 8) alkyl, C 6 -C 14 aryl optionally substituted, aryl (C6-C? 4) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl-alkyl (C? -8) alkyl optionally substituted on the heteroaryl radical, or radical R15. R12b preferably represents R12a-NH. R 13 preferably represents hydrogen, C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl or benzyl, particularly preferably hydrogen or C 1 -C 6 alkyl, very particularly preferably hydrogen or C 1 -C 4 alkyl, especially C 1 alkyl --C, the methyl radical being a preferred alkyl radical represented by R13. r R 15 represents preferably R 16 -alkyl (C-C 3) or represents Rld, particularly preferably represents R 1 -alkyl (C x) or represents R 16. Most preferably, if R3 represents COOR15, R15 represents the radical exo-2-norbornyl, the endo-2-norbornyl radical or the bicyclo [3.2.1] octyl radical, and if R3 represents CNOHR15, then R15 represents the radical exo. -2-norbornyl, the endo-2-5 -norbornyl radical, the 3-noradiminyl radical and in particular the 1-adamantyl radical, the 2-adamantyl radical, the 1-adamantylmethyl radical or the 2-adamantylmethyl radical. R16 preferably represents a bridged bicyclic or tricyclic radical, from 6 to 14 members, especially from 7 to 12 members, which is saturated or partially unsaturated, and which may also contain from one to four, in particular one, two or three, in special one or two, the same or different heteroatoms, of the series of nitrogen, oxygen and sulfur, and which may also be substituted with one or more substitutes, the same or different, of the C? -C and oxo alkyl series . Het preferably represents the radical of a saturated 5- to 10-membered monocyclic or polycyclic heterocycle, linked through a ring nitrogen atom, which may contain one or two additional heteroatoms in the ring, 0 same or different, of the series of oxygen, nitrogen and sulfur, and which may eventually be substituted on the carbon atoms and on the nitrogen atoms of the ring, and may exist as substituents on additional nitrogen atoms of the ring, the same or different radicals of the series of hydrogen, Rh, HCO, RhCO or RhO-CO. Especially preferably Het represents one such heterocyclic group, which contains no additional ring heteroatom, or contains an additional heteroatom in the ring, of the series of nitrogen, oxygen and sulfur, and very particularly preferably Het represents the radical of a saturated monocyclic heterocycle, of 5, 6 or 7 members, linked through a nitrogen atom, which does not contain any additional heteroatom in the ring, or contains an additional heteroatom in the ring, of the series of nitrogen, oxygen and sulfur, the radical Het may also be unsubstituted in these cases, or be replaced by carbon atoms and / or additional nitrogen atoms of the ring.

If R 3 represents one of the radicals C 1 -C 8 alkyl, optionally substituted C 6 -C 4 aryl, aryl (C 3 -C 14) -alkyl (C 1 -C 8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C-C8) alkyl optionally substituted on the heteroaryl radical, C3-C8 cycloalkyl, (C3-C8) cycloalkyl-(C? -8) alkyl, C6-C? bicycloalkyl, (C6-C12) bicycloalkyl-alkyl (C? -C8), C6-C2 tricycloalkyl, (C6-C? 2) tricycloalkyl (C? -C8), C2-C8 alkenyl, C2-C8 alkynyl, CON (CH3) R4, CONHR4, COOR15, C0N (CH3) R15 or CONHR15, e preferably represents 0 and h preferably represents 1. If R3 represents R13NH, e represents preferably 1 and h represents preferably 0. Preferred compounds of formula I are those compounds in which one or more of the radicals have preferred meanings, all preferred combinations of substituents being the object of the present invention. Especially preferred compounds of formula I are those in which, simultaneously: W represents R1-A-C (R13); Z represents oxygen or sulfur; A represents a direct bond, or methylene; B represents a methylene or ethylene divalent radical, both radicals being unsubstituted or substituted by a radical from the series of C?-C8 alkyl, Cj-Cg alkenyl, C2-C8 alkynyl, C3-C ?cycloalkyl, cycloalkyl (C3) -C10) -alkyl (C? -C6), optionally substituted C6-C14 aryl, (C6-C14) aryl- (C? -C6) alkyl optionally substituted on the aryl radical, optionally substituted heteroaryl and heteroaryl-alkyl (Cx) - C6) optionally substituted on the heteroaryl radical; E means tetrazolyl or R10CO; R means hydrogen or C? -C8 alkyl; R ° represents hydrogen, C? -C8 alkyl, C3-C? C cycloalkyl, (C3-C12) cycloalkyl (C? -C8) alkyl, C6-Clcy bicycloalkyl, (C6-C? 2) bicycloalkyl (C) ? -C8), C6-C12 tricycloalkyl, tricycloalkyl-alkyl (C? -C8), optionally substituted C6-C14 aryl, aryl (C6-C14) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, H-CO, alkyl (C? -8) -CO, cycloal-s quil (C3-C12) -CO, cycloalkyl (C3-) C? 2) -alkyl (Cx-C8) -CO, bicycloalkyl (C6-C12) -CO, bicycloalkyl (C6-C12) -alkyl (C? -8) -CO, tricycloalkyl (C6-C12) -CO, tricycloalkyl (C6-C12) - -alkyl (C? -C8) -CO, aryl (C6-C14) -CO optionally substituted, aryl (C6-C? 4) -alkyl (Cx-C8) -CO optionally substituted at 0 aryl radical, optionally substituted heteroaryl -CO, heteroaryl (C? -C8) -CO alkyl optionally substituted on the heteroaryl radical, (C? -C8) -S (0) n alkyl, (C3-) cycloalkyl -C? 2) -S (0) n, (C3-C? 2) cycloalkyl-alkyl (C? -C8) -S (0) n, bicycloalkyl (C6-C12) -S (O) -., Bicycloalkyl (C6-C? 2) -alkyl (C? -C3) -S (O) n, 5 (C6-C12) tricycloalkyl-S (0) n, (C6-C12) tricycloalkyl-alkyl- (C? - C8) -S (0) n, aryl (C6-C? 4) -S (0) n optionally substituted, aryl (C6-C14) -alkyl (C? -C8) -S (O) n optionally substituted on the optionally substituted aryl radical, heteroaryl-S (O) n, or heteroaryl-C 1 -C 8 alkyl-S (0) n optionally substituted on the heteroaryl radical, wherein n represents 1 or 2; R1 represents an optionally substituted radical of the phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl series, each of these radicals also being benzocondensed; R 2 represents hydrogen or C 1 -C 8 alkyl; R 3 is hydrogen, C 1 -C 8 alkyl, optionally substituted C 6 -C 14 aryl, (C 6 -C 14) aryl-C 1 -C 8 alkyl optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl-alkyl (C 1 -C 8) ) optionally substituted or on the heteroaryl radical, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C? -8) alkyl, C6-C? bicycloalkyl, (C6-C? 2) bicycloalkyl (C) ? -C8), C6-C? 2 tricycloalkyl, (C6-C12) tricycloalkyl (C? -C8), C2-C8 alkenyl, C2-C8 alkynyl, R1: LNH, CON (CH3) R4, CONHR4, COOR15, CON (CH3) R15 or CONHR15; R 4 means C 1 -C 8 alkyl which may optionally be substituted one or more times with radicals, the same or different, from the series of hydroxy, C 1 -C 8 alkoxy, Rs, optionally substituted C 3 -C 8 cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono - or di- (C 1 -C 18 alkyl) -aminocarbonyl, (C 6 -C 14) aryl-C 1 -C 8 alkoxycarbonyl which may also be substituted on the aryl radical, C 1 -C 8 alkoxy carbonyl, Het-CO, R6-CO, tetrazolyl and trifluoromethyl: R5 means optionally substituted C6-C14 aryl, aryl (C6-C1) -alkyl (C? -C8) optionally substituted on the aryl radical, or a monocyclic heterocyclic ring or bicyclic 0 to 12-membered optionally substituted, which may be aromatic, be partially or totally hydrogenated, and which may contain one, two or three heteroatoms the same or different from the series of nitrogen, oxygen and sulfur; R6 means the radical of a natural or non-natural amino acid, an imino acid, an aza-amino acid (optionally N-alkyl (C? -8) -substituted or N-aryl (C? -C14) -alkyl (C? -8) - substituted), which may also be substituted on the aryl radical, or the radical of a dipeptide, as well as its esters and amides, where free or functional groups may be protected by protective groups customary in peptide chemistry; R10 means hydroxy, C?-C18 alkoxy, aryl (C6-C ?4) -alkoxy (C?-C8) which may also be substituted on the aryl radical, optionally substituted C 6 -C 4 aryloxy, alkyl (C ?-) C8) -5-carbonyloxy-alkoxy (C? -C6), aryl (C6-C? 4) -carbonyloxy-alkoxy (C? -C6), amino or mono- or di- (alkyl (C? -C? 8 ) ) -Not me; R11 represents hydrogen, R12a, R12a-CO, R12a-0-CO, R12b-CO, R12b-CS or R12a-S (0) 2; R12a means C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C12 cycloalkyl / (C3-C ?2) cycloalkyl (C?-C8) alkyl, optionally substituted C6-C1 aryl, aryl ( C6-C? 4) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C-C8) alkyl optionally substituted on the heteroaryl radical, or the radical R15; s R1b means amino, di- (alkyl (C? -C? 8)) -amino, or R12a-NH; R 13 is hydrogen or C 1 -C 6 alkyl; R1S represents R16-alkyl (C? -C6) or represents R16; R16 represents a bicyclic or tricyclic radical of 6 to 14 members, which is saturated or partially unsaturated, and which may also contain one, two, three or four same or different heteroatoms, of the series of nitrogen, oxygen and sulfur, and which may also being substituted with one or more substituents, the same or different, of the C? -C4 alkyl and oxo series; Het represents the radical of a 5- to 10-membered monocyclic or polycyclic heterocycle, saturated, linked through a ring nitrogen atom, which may contain one, two, three or four additional ring heteroatoms, the same or different, of the series of oxygen, nitrogen, and sulfur, and which may eventually be substituted on the carbon atoms and on the additional nitrogen atoms of the ring, and may exist as substitutes on additional nitrogen atoms of the ring, the same or different radicals of the series of hydrogen, Rh, HCO, RnC0 or RhO-CO, and Rn represents C?-C3 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl-(C?-C8) alkyl, C6-C ar aryl; 4 optionally substituted or aryl (C6-C14) -alkyl (Cx-Cg) optionally substituted on the aryl radical; e and h represent, independently of one another, 0 or 1; in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts. Especially preferred compounds of formula I are those in which, simultaneously: W represents Rx-A-C (R13); Z represents oxygen; A represents a direct bond, or methylene; B represents a methylene or ethylene divalent radical, both radicals being unsubstituted or substituted by a radical from the series of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl ) -alkyl (C? -C6), optionally substituted C3-C14 aryl, (C3-C1) -alkyl (C? -C6) optionally substituted on the aryl radical, optionally substituted heteroaryl and heteroaryl-alkyl (Cx-) C6) optionally substituted on the heteroaryl radical; E means R10CO; R is hydrogen or C 1 -C 4 alkyl; R ° represents C?-C3 alkyl, C3-C12 cycloalkyl, (C3-C12) cycloalkyl (C?-C8) alkyl, C6-C12 bicycloalkyl, (C6-C ?2) bicycloalkyl (C?-C8) alkyl , tricycloalkyl Cg-C? 2, tricycloalkyl (C6-C12) -alkyl (C? -8), aryl C6-C14 optionally substituted, aryl (C6-C? 4) -alkyl (C? -8) optionally substituted on the aryl radical, optionally substituted heteroaryl, or heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical; R 1 represents an optionally substituted radical of the series p of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl; R2 means hydrogen or CX-C4 alkyl; R3 means C?-C4 alkyl, optionally substituted C 6 -C 14 aryl, (C 6 -C 14) aryl-C 1 -C 4 alkyl optionally substituted at 0 the aryl radical, optionally substituted heteroaryl, heteroaryl (C 1 -C 4) alkyl optionally substituted on the heteroaryl radical, C3-C8 cycloalkyl, (C3-C8) cycloalkyl-(C? -C4) alkyl, C6-C? bicycloalkyl, (C6-C12) bicycloalkyl (C? -C4) , tricycloalkyl CC? 2, tricycloalkyl (C-Cia) -5-alkyl (C? -C4), R1XNH, CON (CH3) R4, CONHR4, COOR15, CON (CH3) R15 OR CONHR15; R4 means C?-C8 alkyl which may optionally be substituted once or several times with the same or different radicals, from the series of hydroxy, C?-C8 alkoxy, R5, or optionally substituted C3-C8 cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di- (C 1 -C 8 alkyl) -aminocarbonyl, aryl (C 6 -C 4) -alkoxy (C 1 -C 8) -carbonyl which may also be substituted on the aryl radical, alkoxy (C 1 -) C8) -carbonyl, Het-CO, Rd-CO, tetrazolyl and trifluoromethyl; R5 means optionally substituted Ce-Cxy aryl, aryl (C6-C? 4) -alkyl (C? -C8) optionally substituted on the aryl radical, or a monocyclic or bicyclic 5 to 12 membered monocyclic or bicyclic ring, optionally substituted, which can be aromatic, be partially or totally hydrogenated, and which can contain one, two or three heteroatoms the same or different from the series of nitrogen, oxygen and sulfur; R6 means the radical of a natural or non-natural amino acid, an imino acid or an aza-amino acid (optionally N-alkyl (C? -8) -substituted or N-aryl (C6-C14) -alkyl (C? -8) - -substituted), which may also be substituted on the aryl radical, as well as their esters and amides, free functional groups may be protected by protective groups customary in peptide chemistry; R 10 is hydroxy, C 1 -C 8 -alkoxy, aryl (C 6 -C 14) -alkoxy (C 1 -C 8), which may also be substituted on the aryl radical, optionally substituted C 6 -C 14 aryloxy, (C 1 -C 8) alkyl carbonyloxy-alkoxy (C? -C6), aryl (C6-C? 4) -carbonyloxy-alkoxy (C? -C6), amino or mono- or di- ((C? -C8) alkyl) -amino; R11 represents R12a, R12a-C0, R12a-0-C0, R12b-C0, or R12a-S (0) 2; R 12a means C 1 -C 0 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 2 cycloalkyl, (C 3 -C 2) cycloalkyl- (C 1 -C 8) alkyl, C 6 -C 4 aryl optionally substituted, aryl (C6-C14) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, or the radical R1S; R12b means amino, di- (alkyl (C? -C? 0)) -amino, or R12a-NH; R13 is hydrogen or C? -C alkyl; R15 represents R16-alkyl (C? -C3) or represents R16; R16 represents a bicyclic or tricyclic radical of 7 to 12 members, which is saturated or partially unsaturated, and which may also contain one or two identical or different heteroatoms, of the series of nitrogen, oxygen and sulfur, and which may also be substituted with one or more substituents, the same or different, of the C de-C4 alkyl and oxo series, -Het represents the radical of a saturated 5- to 10-membered monocyclic or polycyclic heterocycle linked through a ring nitrogen atom , which may contain one or two additional ring heteroatoms, the same or different, of the oxygen, nitrogen, and sulfur series, and which may optionally be substituted on the carbon atoms and additional nitrogen atoms of the ring, and may exist as substituents on additional ring nitrogen atoms, the same or different, from the series of hydrogen, Rh, HCO, RhCO and RhO-CO, and Rh represents C alquilo-C6 alkyl, C-cycloalkyl 3-C8, (C3-C8) cycloalkyl-(C? -C4) alkyl, optionally substituted C6-C? 4 aryl or (C6-C14) aryl-C3-C4 alkyl optionally substituted on the aryl radical, • e and h represent, independently of one another, 0 or 1; in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts. Especially preferred compounds of formula I are those in which, simultaneously: W represents Rx-A-C (R13); Z represents oxygen; A represents a direct bond, or methylene; B represents an unsubstituted methylene radical or a methylene radical which is substituted with a radical from the series of C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, (C3-C7) cycloalkyl-alkyl (C? -C4), optionally substituted C6-C? 0 aryl, aryl (C6-C10) -alkyl (C? -C4) optionally substituted on the aryl radical, optionally substituted heteroaryl, and heteroaryl-alkyl (C? -C4) optionally substituted on the heteroaryl radical; E means R10CO; R means hydrogen or C-C4 alkyl; R ° means aryl (C3-C14) -alkyl (C? -C4) optionally substituted on the aryl radical or heteroaryl (C? -C4) alkyl optionally substituted on the heteroaryl radical; R1 represents an optionally substituted radical of the series of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl; R 2 means hydrogen or C 1 -C 4 alkyl; R 3 represents a phenyl radical or naphthyl radical, unsubstituted, or a phenyl radical or naphthyl radical substituted with one, two or three radicals, the same or different, from the series of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, methylenedioxy, ethylenedioxy, hydroxycarbonyl, (C 1 -C 4) alkoxycarbonyl, aminocarbonyl, cyano, phenyl, phenoxy, benzyl and benzyloxy, or R 3 represents pyridyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl , C2-C4 alkynyl, C5-C6 cycloalkyl? R1XNH, C0N (CH3) R4, CONHR4, CON (CH3) R15 or CONHR15; R4 means C?-C8 alkyl which may be optionally substituted with one or two radicals, the same or different, from the series of hydroxy, C?-C8 alkoxy, Rs, optionally substituted C 3 -C 8 cycloalkyl, hydroxycarbonyl, aminocarbonyl, aryl (Cg) -C? 0) -alkoxy (C? -C4) -carbonyl which may also be substituted on the aryl radical, (C? -C6) alkoxycarbonyl, Het-CO, R6-CO, tetrazolyl and trifluoromethyl; Rs means C6-C? Or optionally substituted aryl, aryl (C6-C10) -alkyl (C?-C4) optionally substituted on the aryl radical, or a 5- or 10-membered monocyclic or bicyclic heterocyclic ring optionally substituted, which it may be aromatic, partially or totally hydrogenated, and may contain one, two or three heteroatoms, the same or different, from the series of nitrogen, oxygen and sulfur; R 10 denotes hydroxy, C 1 -C 8 alkoxy, aryl (C 6 -C 0) -alkoxy (C x C 4), which may also be substituted on the aryl radical, optionally substituted C 6 -C 10 aryloxy, alkyl (C 8 -C 8) -carbonyloxy-alkoxy (C? -C4), aryl (C6-C10) -carbonyloxy-alkoxy (Cx-C4), amino or mono- or di- ((C? -C8) alkyl) -amino; R11 represents R12a, R12a-CO, R12a-0-C0, R12b-CO, or R12a-S (0) 2; R 12a means C 1 -C 0 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, (C 3 -C 12) cycloalkyl- (C 1 -C 8) alkyl, optionally substituted C 6 -C 4 aryl, aryl (C6-C14) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, or the radical R1S; R 12b means amino, di- (C 1 -C 10 alkyl) amino, or R 12a-NH; R 13 is hydrogen or C 1 -C 4 alkyl; R15 represents R16-alkyl (C? -C3) or represents R16; R16 represents a bicyclic or tricyclic radical of 7 to 12 members, which is saturated, and which may also contain one or two heteroatoms which are the same or different from the series of nitrogen, oxygen and sulfur, and which may also be substituted by one or more substituents , the same or different, from the C? -C4 alkyl and oxo series; Het represents the radical of a 5- to 7-membered, saturated monocyclic heterocycle, attached through a ring nitrogen atom, which may contain one or two additional ring heteroatoms, the same or different, of the oxygen, nitrogen series , and sulfur, and which may optionally be substituted on the carbon atoms and on the additional nitrogen atoms of the ring, and there may exist as substituents on additional nitrogen atoms of the ring radicals, the same or different, of the hydrogen series, Rh, HCO, RhCO or RhO-CO, and Rh represents C? -C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C? -C4) alkyl, C3-C? Optionally substituted aryl or aryl (C6-) CXo) -alkyl (Cx-C4) optionally substituted on the aryl radical; e and h represent, independently of one another, 0 or 1; in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts. Especially preferred compounds of formula I are, on the one hand, those in which B represents unsubstituted methylene or methylene which is substituted with a C 1 -C 8 alkyl radical, in all its stereoisomeric forms and mixtures thereof in all proportions, and its physiologically tolerable salts. Particularly preferred compounds of formula I are those in which B represents methylene which is substituted with a C? -C8 alkyl radical, in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts. Especially preferred compounds of formula I, on the other hand, are those in which R.sub.1 represents a radical of the series of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, which is unsubstituted or substituted by one, two or three substituents , the same or different, from the series of C C-C 4 alkyl, C?-C 4 alkoxy, halogen, amino, trifluoromethyl, hydroxy, hydroxy-alkyl (C x -C 4), methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts. Particularly preferred compounds of formula I are those in which R.sup.1 represents a radical from the series of phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 4-imidazolyl and pyridyl and 4-pyridyl, the phenyl radical being unsubstituted or substituted by one or two radicals, the same or different, from the series of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, trifluoromethyl, hydroxy, hydroxy-alkyl (C ? -C4), methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, and the heteroaromatic radicals being unsubstituted or substituted with one or two substituents, the same or different, from the series of C? -C4 alkyl, C? C4, halogen, amino, trifluoromethyl, hydroxy, hydroxy-alkyl (C? -C4), methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiological salts tolerable Particularly preferred compounds of formula I are those in which R 1 represents an unsubstituted radical, of the series of phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 4- imidazolyl, 3-pyridyl and 4-pyridyl, in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.

Especially preferred compounds of formula I are those in which R.sup.1 represents an unsubstituted radical, of the series of phenyl, 2-furyl, 3 -furyl, 2-thienyl, 3-thienyl, 4-imidazolyl and pyridyl, in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts. In general, compounds of formula I are preferred than in the centers of chirality, for example in the case of a corresponding substitution at the chiral carbon atom bearing the radicals R 2 and R 3, and / or at the center W of the imidazoline ring of Formula I, have a uniform configuration. The compounds of formula I can be prepared, for example, by condensation of fragments of a compound of formula II with a compound of formula III, (lll) where, in formulas II and III, the groups W, Z, B, E, R, R °, R2 and R3, as well as e and h, are defined as indicated above, or may also be contained in these groups , functional groups in protected form or in the form of precursors, and wherein G represents hydroxycarbonyl, (C 1 -C 6) alkoxycarbonyl or activated carboxylic acid derivatives such as acid chlorides or active esters. However, if compounds of formula I are to be prepared in which, for example, R3 represents in formula I a carboxylic acid derivative, or contains a similar group, in compounds of formula III the radical R3 may also represent firstly, for example, a hydroxycarbonyl group present in protected form, or contain a similar group, and only after the condensation of the compounds of formulas II and III the desired definitive group R3 is constructed, in one or more additional steps. For the condensation of the compounds of formula II with those of formula III, the methods of coupling the peptide chemistry itself are well known to the person skilled in the art (see for example Houben-Weyl, Methoden der Organischen Chemie, volumes 15/1 and 2/15, Georg Thieme Verlag, Stuttgart, 1974). Suitable condensing agents are, for example, carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide or diisopro-picarbodiimide, 0- ((cyano (ethoxycarbonyl) methylene) -N, N, N ', N' -tetramethyluronium tetrafluoroborate. (TOTU) or propylphosphonic acid anhydride (PPA). As a general rule it is necessary that in the condensation the amino groups present, and that do not react, are protected by reversible protective groups. The same is true for carboxyl groups which do not participate in the reaction, which can be found during condensation preferably as esters of C.sub.1 -C.sub.6 alkyl, for example t-butyl esters, or as benzylic esters. A protective group of amino groups is not necessary if the amino groups are still in the form of precursors, for example as nitro groups, and are only formed, for example by hydrogenation, after coupling. After copulation, the protective groups present are cleaved off in a suitable manner. For example, the groups N02 (protection of guanidino in amino acids), benzyloxycarbonyl groups and benzyl groups in benzylic esters are removed by hydrogenation. The protective groups of the t-butyl type are cleaved acidically, while the 9-fluorenylmethyloxycarbonyl radical is removed by secondary amines. The preparation of the compounds of formula I can also be carried out, for example, by step-by-step construction of the compounds, according to customary methods, on a solid phase, whereby the individual components of the molecule can be introduced in a different sequence. The compounds of formula II in which W represents R1-A-C (R13) and Z represents oxygen can be prepared, for example, by first reacting compounds of formula IV in a Bucherer reaction to provide compounds of formula V wherein, as in formula IV, R1, R13 and A are defined as indicated above (H.T. Bucherer, V.A.

Lieb, J. Prakt. Chem. 141 (1934), 5). The compounds of formula VI, wherein R1, R13, A, B and G are defined as indicated above, can be obtained by first reacting, for example, the compounds of formula V with an alkylating reagent, which introduces the radical into the molecule - BG. The reaction of compounds of formula VI with a second reagent of formula R ° -LG, in which R ° has the meanings given above and LG constitutes a nucleophilically substitutable leaving group, for example halogen, especially chlorine or bromine, alkoxy C? -C 4, optionally substituted phenoxy, or a heterocyclic leaving group such as for example imidazolyl, leads to the corresponding compounds of formula II. These reactions can be carried out analogously to known methods, common to the technician. According to the particular case, it can be applied here, as in all the steps of the synthesis of the compounds of formula I, to temporarily block, by means of a protective group strategy adapted to the synthesis problem, functional groups that could lead to secondary reactions or unwanted reactions. , which is known to the technician. With regard to the preparation of the compounds of formulas V and VI in racemic form and enantiomerically pure form, reference is made here especially to the corresponding embodiments in WO-A 96/33976, which are a component part of the invention. present disclosure. If W represents R1-A-CH = C, this structural element can be introduced, for example, by condensing in a manner analogous to known methods an aldehyde with a dioxo-imidazolidine or thioxo-oxo-imidazolidine, which it contains, in the position corresponding to the group W, an unsubstituted methylene group. The amino compounds of formula III can be constructed according to standard procedures that are well known or analogous to these, from starting compounds that are commercially available or can be obtained according to or analogously to methodologies of the literature. The compounds of formula I in which W represents R1-A-C (R13), can also be obtained as follows: By reaction of α-amino acids or α-amino acids N-substituted, which can be obtained by standard procedures, or preferably their esters, for example the methyl, ethyl, t-butyl or benzyl esters, for example a compound of formula VII, wherein R °, R1, R13 and A are defined as indicated above, with a socianate or isothiocyanate, eg of formula VIII wherein B, E, R, R2, R3, e and h are defined as indicated above, and U represents isocyanate or isothiocyanate, urea derivatives or thiourea derivatives, of formula IX, are obtained, in which the above definitions are valid, and that by heating with acid, and with saponification of the ester functions, compounds of formula for which the meanings indicated above are valid. The cyclization of the compounds of formula IX to provide the compounds of formula I can also be carried out by treatment with bases in inert solvents, for example by treatment with sodium hydride in an aprotic solvent such as dimethylformamide. In turn, functional groups can be presented in protected form during cyclization. The compounds of formula I in which W represents R1-A-C (R13) can also be obtained by reacting a compound of formula VII with an isocyanate or isothiocyanate of formula X wherein B and U are defined as indicated above for formula VIII, and Q signifies an alkoxy group, for example a C 1 -C 4 alkoxy group such as methoxy, ethoxy or t-butoxy, a C 6 aryloxy group C14, for example phenoxy, or an aryl (C6-C? 4) -alkoxy group (C? -C4), for example benzyloxy. In this case, a compound of formula XI is obtained wherein Z, A, B, Q, R °, R1 and R13 are defined as indicated above for formulas IX and X, which compound is then cyclized, under the influence of an acid or a base, as described above for the cyclization of compounds of formula IX, to provide a compound of formula XII, wherein W represents R1-AC (R13) and Z, B, Q and R ° are defined as indicated above for formulas la and X. From the compound of formula XII, by hydrolysis of the group CO-Q to the carboxylic acid COOH and subsequent coupling with a compound of formula III, a compound of formula la is obtained. Here too, functional groups can be presented in protected form or in the form of precursors, during the cyclization. Another method for preparing compounds of formula la is, for example, the reaction of compounds of formula XIII, 0 in which W represents R1-AC (R13) and for the rest the above definitions are valid, with phosgene or thiophosgene, or corresponding equivalents (analogously to S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575 (1952), 217-231 and C. Tropp, Chem. Ber 61 (1928), 1431-1439). s With regard to the preparation of compounds of formula I, reference is also made in all its contents to WO-A-95/14008, EP-A-796,855 (European patent application 97103712.2) and their corresponding applications, as well as to WO-A-96/33976. The compounds of formula I are valuable medicinal substances, which are suitable, for example, for the therapy and prophylaxis of inflammatory affections, allergic conditions or asthma. The compounds of formula I and their physiologically tolerable salts can be administered according to the invention to animals, preferably mammals, and in particular to humans, as medicaments for therapy or prophylaxis. They can be administered alone as such, mixed with one another, or in the form of pharmaceutical preparations which allow application by enteral or parenteral route and which contain, as an active ingredient, together with excipient substances and / or usual pharmaceutically innocuous additives, a effective dose of at least one compound of formula I and / or its physiologically tolerable salts. The present invention therefore also relates to the compounds of formula I and / or their physiologically tolerable salts, for use as medicaments, the use of compounds of formula I and / or their physiologically tolerable salts, for preparing medicaments for therapy and prophylaxis of the diseases explained before or in the following, for example for the therapy and prophylaxis of inflammatory conditions, as well as the use of compounds of formula I and / or their physiologically tolerable salts in the therapy and prophylaxis of these diseases. The present invention also provides pharmaceutical preparations containing, together with usual excipient substances and / or pharmaceutically acceptable additives, an effective dose of at least one compound of formula I and / or its physiologically tolerable salts. The medicaments can be administered orally, for example in the form of pills, tablets, coated tablets, dragees, granules, hard and soft gelatine capsules, solutions, syrups, emulsions or suspensions. The administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection or solutions for infusion, microcapsules or rods, or percutaneously, for example in the form of ointments, solutions or dyes, or otherwise, for example in the form of nasal sprays or aerosol mixtures. The preparation of the pharmaceutical preparations according to the invention is carried out in a manner known per se, and in combination with the compound or compounds of formula I and / or their physiologically tolerable salts, pharmaceutically inert, inorganic or organic excipient substances are used. To prepare pills, tablets, dragees and hard gelatine capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. can be used. The excipients for soft gelatine capsules and suppositories are, for example, fats, waxes, semi-solid polyols and liquids., natural or hardened oils, etc. Suitable excipients for preparing solutions, for example solutions for injection, or for emulsions or syrups, are suitable, for example, water, alcohols, glycerin, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable excipients for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain approximately 0.5 to 90% by weight of compounds of formula I and / or their physiologically tolerable salts. In addition to active substances and excipient substances, the pharmaceutical preparations may also contain additive substances such as, for example, fillers, disintegrating agents, binders, lubricants, humectants, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavors or flavorings, thickeners, diluents, buffering substances, and also solvents or inducers of the solution or agents to achieve a deposition effect, as well as salts for modifying the osmotic pressure, coating agents or antioxidants. They may also contain two or more compounds of formula I and / or their physiologically tolerable salts. They may also contain, together with at least one compound of formula I and / or its pharmaceutically tolerable salts, one or more other therapeutically or prophylactically active substances, for example substances with an inhibitory effect on inflammation. The pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1 to 100 mg of active substance of formula I and / or their physiologically tolerable salts. --- The compounds of formula I have the ability to inhibit cell-cell and cell-matrix interaction processes, in which mutual actions intervene between VLA-4 and its ligands. The efficacy of the compounds of formula I can be verified, for example, in a determination in which the binding of cells having the VLA-4 receptor, for example leukocytes, to ligands of this receptor, for example VCAM-1, is measured. that for this they can also be prepared, advantageously, by means of genetic engineering. The details of such a determination are described more fully below. In particular, the compounds of formula I have the ability to inhibit leukocyte adhesion and migration, ie the adhesion of leukocytes to endothelial cells which is regulated - as explained above - through the VCAM adhesion mechanism - l / VLA-4. Therefore, in addition to inflammation inhibiting substances, the compounds of formula I and their physiologically tolerable salts are generally suitable for the therapy and prophylaxis of diseases which are based on the interaction between the VLA-4 receptor and its ligands, or diseases which can be influenced by an inhibition of this interaction, and in particular are suitable for the therapy and prophylaxis of diseases that are at least in part caused by an unwanted degree of leukocyte adhesion and / or leukocyte migration, or are Related to this, or for the prevention, relief or cure of the adhesion and / or migration of leukocytes. The compounds of formula I can be used as inhibitors of inflammation in inflammatory manifestations of the most diverse origin. They find application, for example, for the therapy and prophylaxis of rheumatoid arthritis, of inflammatory bowel disease (ulcerative colitis), of systemic lupus erythematosus, or for the therapy and prophylaxis of inflammatory diseases of the central nervous system such as, for example, multiple sclerosis, for the therapy or prophylaxis of asthma or allergies, for example allergies of the delayed type (allergies of type IV). Other suitable for the therapy and prophylaxis of cardiovascular diseases, arteriosclerosis, restenosis, for the therapy or prophylaxis of diabetes, to prevent the deterioration of transplanted organs, to prevent tumor growth or tumor metastasis in different malignancies, for the therapy of malaria and other diseases in which it seems applicable for its prevention, relief or cure, a blockade of the integrin VLA-4 and / or an intervention about the activity of leukocytes. In the use of the compounds of formula I, the dose can vary within wide limits and, as usual, it must be adapted in each particular case to the individual data. The dose depends, for example, on the compound used or on the type and severity of the disease to be treated, whether it is a morbid acute or chronic condition or whether it is a prophylaxis. In the case of oral administration, in order to achieve effective results, a daily dose of approximately 0.01 to 100 mg / kg, preferably 0.1 to 10, is generally indicated in an adult of about 75 kg. mg / kg, especially 0.3 to 2 mg / kg (in each case per kilogram of body weight). In the case of intravenous administration, the daily dose as a rule amounts to approximately 0.01 to 50 mg / kg, preferably 0.01 to 10 mg / kg of body weight. The daily dose can be divided, in particular in the case of the administration of larger amounts, into several, for example 2, 3 or 4, partial administrations. Eventually it may be necessary, according to the individual behavior, to deviate from the indicated daily dose, upwards or downwards. The present invention also relates to compounds of formula I for inhibiting the adhesion and / or migration of leukocytes, or for inhibiting the VLA-4 receptor, and the use of the compounds of formula I for preparing medicaments therefor, ie , medicaments for the therapy and prophylaxis of diseases in which the adhesion of leukocytes and / or the migration of leukocytes presents an undesired degree, or of diseases in which processes of 5 adhesion dependent on the VLA-4, as well as the use of the compounds of formula I and / or their physiologically tolerable salts in the therapy and prophylaxis of such diseases. The compounds of formula I and their salts can also be used for diagnostic purposes, for example in in vitro diagnostics, and as auxiliary agents in biochemical investigations in which a blockade of VLA-4 or an influence on cell-cell or cell interactions is intended. cell-matrix. They can also serve as intermediate products for preparing other compounds, in particular other active drug substances, which can be obtained from the compounds of formula I, for example, by modification or introduction of radicals or functional groups.

Examples o The compounds were identified by mass spectra (MS) and / or NMR spectra. Compounds that had been purified by chromatography using an eluent containing for example acetic acid or trifluoroacetic acid, and then lyophilized, still partially contained, depending on the execution of the lyophilization process, the acid from the eluent, and they were therefore, partially or entirely, in the form of a salt of the acid used, for example in the form of the acetic acid salt or the trifluoroacetic acid salt. 0 Meanings of abbreviations: DMF N, N-Dimethylformamide THF Tetrahydrofuran DCC N, N'-Dicyclohexylcarbodiimide s HOBt 1-Hydroxybenzotriazole TOTU O- (cyano (ethoxycarbonyl) methyleneamine) -1,1,3,3-tetramethyluronium Tetrafluoroborate Example 1 ((R, S) -2- ((S) -4-phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolium-din-l-yl) -2- (2-methyl- propyl) -acetyl) -L-aspartyl-L-phenylglycine la) t-Butyl acid (R, S) -2-bromo-4-methylpentanoic ester (1.1) To a solution of 2.5 g (12.8 mmol) of (R, S) -2-bromo-4-methylpentanoic acid in 80 ml of chloroform and 80 ml of t-butyl acetate was added 1.96 ml. of concentrated sulfuric acid and 0.515 ml of oleum (20%), and the mixture was stirred for 3 hours at room temperature. A pH value 4 was then adjusted by the addition of 10% NaHCO 3 solution. The aqueous phase was separated and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate. After filtering and concentrating the filtrate in vacuo, 2.62 g (82%) of 1.1 was obtained. lb) t-Butyl acid ester (R, S) -2- ((S) -4- (4-bromo-phenyl) -4-methyl-2, 5-dioxo-imidazolidin-1-yl) -4 -methylpentanoi-co (1.2) To a solution of 2.08 g (7.72 mmol) of (S) -4- (4-bromo-phenyl) -4-methyl-2, 5-dioxo-imidazolidine in 20 ml of absolute DMF were added, under argon and at 0 ° C, 213 mg (8.87 mmol) of sodium hydride, was left stirring for 1 hour at room temperature, 1.94 g (7.72 mmol) of 1.1 was added, stirred for 5 hours at room temperature environment, and the mixture was allowed to stand at room temperature overnight. The solvent was removed in vacuo, the residue was taken up in ethyl acetate, and the solution was washed with water in ethyl acetate. The organic phase was dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel with heptane / ethyl acetate (2: 1). After concentrating the fractions with product, 2.45 g (72%) of 1.2 were obtained. lc) T-butyl acid ester (R, S) -2 - ((S) -4- (4-bromo-phenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1- í1) -4 - methylpentanoic (1.3) To a solution of 1.92 g (4.37 mmol) of 1.2 in 10 ml of absolute DMF were added, under argon and at 0 ° C, 126 mg (5.24 mmol) of sodium hydride, stirred at room temperature during 1 hour, 570 μl (4.8 mmol) of benzyl bromide was added, and it was stirred again at room temperature for 1 hour. The solvent was removed in vacuo, the residue was distributed between water and ethyl acetate and, after separating the phases, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated in vacuo. 2.17 g (94%) of 1.3 were obtained.

Id) Acid (R, S) -2- ((S) -4-phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -4-methylpentanoic acid (1.4) A solution of 1 g (1.88 millimoles) of 1.3 in 100 ml of ethanol was hydrogenated over 40 mg of 10% Pd / C. After 2 hours the catalyst was filtered off, the filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with 10% NaHC03 solution and water, and dried over sodium sulfate. After filtering and removing the solvent in vacuo, 10 ml of 90% trifluoroacetic acid was added to the residue. After 15 minutes at room temperature, trifluoroacetic acid was removed in vacuo and the residue was concentrated twice with toluene. 740 mg (100%) of 1. were obtained. le) ((R, S) -2- ((S) -4-Phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazo-lidin-1-yl) -2- (2-methyl- propyl) -acetyl) -L-aspartyl-L-phenylglycine (1.5) To a solution of 200 mg (0.507 millimoles) of 1.4 and 210 mg (0.507 millimoles) of H-Asp hydrochloride (O ^ u) -Phg-OfcBu in 10 ml of absolute DMF was added 166 mg (0.507 millimoles) of TOTU and 172 μl (1.014 mmol) of diisopropyl-ethylamine. After stirring for 2 hours at room temperature, the reaction mixture was concentrated in vacuo, the residue was taken up in ethyl acetate and washed twice with saturated NaHCO 3 solution and with water, the organic phase. After drying over sodium sulfate, filtering and concentrating the filtrate in vacuo, 393 mg of crude product was obtained, which was chromatographed on silica with heptane / ethyl acetate (3: 1). After concentrating the fractions with product, the residue was dissolved in 5 ml of 90% trifluoroacetic acid, after 15 minutes at room temperature, trifluoroacetic acid was removed in vacuo, and the residue was dissolved in 20% acetic acid and lyophilized. 219 mg (67%) of 1.5 were obtained. ES (+) - MS: 643.3 (M + H) + Example 2 Acid (S) -3 - ((R, S) -2 - ((S) -4-phenyl-3-benzyl-4 -methyl -2,5-dioxo-imidazolidin-1-yl) -2 - (2-methyl-propyl) -acetylamino) -2-benzyl-oxycarbonylamino-propionic The compound was prepared by reaction of (R, S) -2- ((S) -4-phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -4-methyl -pentanoic acid (1.4) and (S) -3-amino-2-benzyloxycarbonylamino-propionic acid t-butyl ester, analogously to the preparation of 1.4, chromatographed on silica gel with dichloromethane / methanol / acetic acid / water ( 9: 1: 0.1: 0.1) the residue after cleavage of the t-butyl ester and elimination of trifluoroacetic acid in vacuo. ES (+) - MS: 615.4 (M + H) + The (S) -3-amino-2-benzyloxycarbonylamino-propionic acid t-butyl ester was prepared as follows: in an autoclave, 10 g (42 mmol) of sodium hydroxide were stirred for 3 days at a pressure of N2 of 20 atmospheres. (S) -3-amino-2-benzyloxycarbonylaminopropionic acid in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of concentrated H2SO4. Excess isobutylene was removed by disintegrating, and 150 ml of diethyl ether and 150 ml of saturated NaHCO3 solution were added to the remaining solution. The phases were separated and the aqueous phase was extracted 2 times, each with 100 ml of diethyl ether. The combined organic phases were washed twice, each with 100 ml of water, and dried over Na 2 SO 4. After removing the solvent in vacuo, 9.58 g (78%) of t-butyl ester of (S) -3-amino-2-benzyloxycarbonylamino-propionic acid in the form of a pale yellow oil were obtained.

EXAMPLE 3 Acid (R, S) -3- ((R, S) -2- ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl-propyl) -acetylamino) -3-- (3, -methylenedioxy-phenyl) -propionic The compound was prepared by reaction of 1.4 with (R, S) -3-amino-3- (3,4-methylenedioxy-phenyl) -propionic acid t-butyl ester hydrochloride, and subsequent cleavage of t-butyl ester as described in Example 1.

ES (+) - MS: 586.3 (M + H) + The (R, S) -3-amino-3- (3,4-methylenedioxy-phenyl) -propionic acid t-butyl ester hydrochloride was prepared analogously to W.M. Radionow, E.A. Postovskaya, J. Am. Chem. Soc. 1929, 51, 841 (see also Houben-Weyl, Methoden der organischen Chemie, volume XI / 2, Georg Thieme Verlag, Stuttgart, 1958, page 497), preparing first the ß - corresponding amino acid. This was converted into the benzyloxycarbonylamino derivative, from which the t-butyl ester was obtained according to the following synthesis method: to 1 millimole of 3-benzyloxycarbonylaminocarboxylic acid in 13 ml of absolute dichloromethane was added 1.5 millimole of oxalyl chloride. After stirring for 4 hours at room temperature, the reaction mixture was concentrated and 6.5 ml of t-butanol were added to the residue. It was stirred for 1 hour at room temperature, and the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and extracted twice with saturated NaHCO 3 solution and with water. The organic phase was dried over sodium sulfate, and after filtration the solvent was removed in vacuo. Then, to prepare the t-butyl ester hydrochloride of the β-amino acid, the benzyloxycarbonyl group was removed by hydrogenation over 10% Pd / C in methanol / HCl.

Example 4 (S) -3- ((R, S) -2- ((R, S) -4-phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) acid -2-isopropyl-acetylamino) -2- (1-adamantylmethyloxycarbonylamino) -propionic The compound was prepared by reaction of (R, S) -2- ((R, S) -3-benzyl-4-phenyl-4-methyl-2, 5-dioxo-imidazolium-din-1-yl) - 2-isopropyl-acetic acid (prepared analogously to the method of Example 1 from (R, S) -4-methyl-2, 5-dioxo-imidazolidine and t-butyl ester of (S) -3- amino-2- (1-adamantylmethyloxycarbonylamino) -propionic acid and subsequent cleavage of the t-butyl ester as described in Example 1. The crude product was purified by means of preparative HPLC on RP-18. MS: 659.4 (M + H) + The (S) -3-amino-2- (1-adamantylmethyloxycarbonylamino) -propionic acid t-butyl ester was prepared as follows: To a solution of 10 g (34 g. millimoles) of (S) -3-amino-2-benzyloxycarbonylamino) -propionic acid t-butyl ester (see Example 2) in 600 ml of THF / water (2: 1) were added at 0 ° C. 8.9 g (40.8 mmol) of di-t-butyl dicarbonate, and then, in portions, 1 N NaOH, so that the pH of the solution The concentration was maintained between 9 and 10 (NaOH consumption l N: 32 ml). After stirring for 3 hours at room temperature, 1 1 of water was added and extracted 3 times with diethyl ether. After drying the organic phase over sodium sulfate, filtering and removing the solvent in vacuo, the residue was chromatographed on silica gel with dichloromethane / methanol (20: 1). 13.19 g (98%) of t-butyl ester of 5 (S) -2-benzyloxycarbonylamino-3-t-butoxycarbonylaminopropionic acid were obtained. Hydrogenated in methanol / HCl, on 10% Pd / C, 13.1 g of (S) -2-benzyloxycarbonylamino-3-t-butoxycarbonylamino-propionic acid t-butyl ester. After 1.5 hours it was filtered and the filtrate was concentrated in vacuo. 9.11 g (99%) of (S) -2-amino-3-t-butoxycarbonylamino-propionic acid t-butyl ester hydrochloride was obtained as a colorless solid. A solution of 10.9 g 5 (65.4 millimoles) of 1- (hydroxymethyl) -adamantane and 10.6 g was stirred for 1.5 hours at 50 ° C. (65.4 millimoles) of carbonyldiimidazole in 60 ml of THF. 9.7 g (32.7 mmol) of (S) -2-amino-3-t-butoxycarbonylamino-propionic acid t-butyl ester hydrochloride in 25 ml of THF and 5.6 ml (32 ml) were added. , 7 mmol) of diiso- or propyl-ethylamine, was stirred for 4 hours at 60 ° C, and allowed to stand overnight at room temperature. The solvent was removed in vacuo, and the residue was chromatographed on silica gel, with heptane / ethyl acetate (7: 3). 8.7 g (59%) of (S) -2-5- (l-adamantylmethyloxycarbonylamino) -3-t-butoxycarbonylamino-propionic acid t-butyl ester was obtained as a colorless oil.

A solution of 8.7 g (19.22 millimoles) of (S) -2- (1-adamantylmethyloxycarbonylamino) -3-t-butoxycarbonylamino-propionic acid t-butyl ester in 180 ml of trifluoroacetic acid / dichloromethane (1 1) was poured into ice-cold NaHC03 solution after 1 minute, the mixture was extracted three times with dichloromethane, then the combined dichloromethane phases were dried over sodium sulfate. After filtering and removing the solvent in vacuo, 6.35 g (94%) of (S) -3-amino-2- (1-adamantylmethoxycarbonylamino) -3-aminopropionic acid t-butyl ester were obtained in the form of colorless solid.

Example 5 ((R, S) -4- (-Pyridyl) -3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -acetyl) -L-aspartyl-L-phenylglycine 5a) (R, S) -4- (4-Pyridyl) -4-methyl-2, 5-dioxo-imidazolidine (5.1) In 400 ml of 50% ethanol, 36.34 g (300 millimoles) of 4-acetylpyridine and 259.2 g (2.944 moles) of ammonium carbonate were suspended. Thereto were added 25.5 g (392 millimoles) of potassium cyanide. It was stirred for 5 hours at 50-60 ° C, the mixture was allowed to cool to room temperature, the pH value was adjusted to 6.3 by the addition of 6 N HCl, and it was allowed to stand overnight at room temperature. A pH value of 6.3 was again adjusted and the solvent was removed in vacuo. The residue was suspended several times with dichloromethane. The insoluble portions were filtered off in each case, and the combined filtrates were concentrated in vacuo. The residue was chromatographed on silica gel, with dichloromethane / methanol. After concentrating the fractions with product, 37.53 g (65%) of 5.1 were obtained. 5b) ((R, S) -4- (4-Pyridyl) -3-benzyl-4-methyl-2, 5-dioxo-imidazo-lidin-1-yl) -acetyl-L-aspartyl-L-phenylglycine ( 5.2) To a solution of 50 mg (0.133 millimoles) of (R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) hydrochloride - acetic acid (prepared by cleavage of ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -acetic acid t-butyl ester with trifluoroacetic acid and subsequent transformation into the hydrochloride, having prepared the t-butyl ester of ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin- -1-yl) -acetic by alkylation of 5.1, first with t-butyl bromoacetic acid ester, and then with benzyl bromide analogously to Example 1) and 55 mg (0.133 mmoles) of H-Asp (OfcBu) - Phg- (OfcBu) x HCl in 10 ml of absolute DMF were added 43.6 mg of TOTU and 68 μl of diisopropyl-ethylamine. After 3 days at room temperature, the solvent was removed in vacuo, the residue was taken up in ethyl acetate, the solution was washed with saturated NaHCO 3 solution, water and KHS 04 / K 2 SO 4, and dried over sodium sulfate. After filtration, the solvent was removed in vacuo, and 10 ml of 90% trifluoroacetic acid was added to the residue. After one hour at room temperature, trifluoroacetic acid was removed in vacuo, the residue was partitioned between diethyl ether and water, the aqueous phase was lyophilized, and the residue was purified by duplicate chromatography on silica gel. 19.5 mg (25%) of 5.2 were obtained. ES (+) - MS: 588.3 (M + H) + Example 6 ((R, S) -2 - ((R, S) -4- (4-Pyridyl) -3-benzyl-4-methyl- 2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl-propyl) -acetyl) -L-aspartyl-L-phenylglycine 6a) T-Butyl acid ester (R, S) -2- ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1- il) -2- (2-methyl-propyl) -acetic (6.1) To a solution of 4.1 g (21.44 mmol) of (R, S) -4- (4-pyridyl) -4-methyl-2, 5-dioxo-imidazolidine (see Example 5) in 30 ml of Absolute DMF was added, by cooling with ice, 1.03 g (23.58 millimoles) of sodium hydride. It was left stirring for 15 minutes at room temperature and then 4.23 g (21.44 mmol) of (R, S) -2-bromo-4-methyl-pentanoic acid t-butyl ester were added. After stirring for 2 hours and allowing to stand overnight at room temperature, the solvent was removed in vacuo, and the residue was chromatographed on silica gel with dichloromethane / methanol (95: 5). 1.2 g (15%) of t-butyl acid ester (R, S) -2- ((R, S) -4- (4-pyridyl) -4-methyl -2,5-dioxo were obtained -imidazolidin-1-yl) -2- (2-methyl-propyl) -acetic acid, which was reacted analogously to Example 1, by reaction with benzyl bromide, to provide compound 6.1. 6b) Acid hydrochloride (R, S) -2- ((R, S) -4- (4-pyridyl) -3- -benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) - 2- (2-methyl-propyl) -acetic (6.2) 1.4 g (3.1 millimoles) of 6.1 in 30 ml of 90% trifluoroacetic acid were stirred at room temperature for 1 hour. Trifluoroacetic acid was removed in vacuo, and the residue was partitioned between diethyl ether and water. The phases were separated, the organic phase was concentrated, and the residue was purified on silica gel with dichloromethane / acetic acid / water (9.5: 0.5: 0.05: 0.05). We obtained 650 mg (47%) of 6.2. 6c) ((R, S) -2 - ((R, S) -4- (4-Pyridyl) -3-benzyl-4-methyl-2, 5-dioxo-s-imidazolidin-1-yl) -2 - (2-methyl-propyl) -acetyl) -L-aspartyl-L- -phenylglycine The compound was prepared in a manner analogous to Example 5 by reaction of 6.2 with H-Asp (OfcBu) -Phg- (OfcBu) x HCl and or subsequent cleavage of the t-butyl ester. ES (+) - MS: 644.3 (M + H) + Example 7 ((R, S) -4-Phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -5-acetyl) -L-aspartyl-L-phenylglycine The compound was prepared by reaction of ((R, S) -4- (4-phenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetic acid (prepared in a manner analogous to Example 1 from (R, S) -4-phenyl-4-methyl-2, 5-dioxo-imidazolidine by alkylation with methyl chloroacetate and then with benzyl bromide and subsequent cleavage of the methyl ester) with H- Asp (OfcBu) -Phg- (OfcBu) x HCl in a manner analogous to Example 1, and subsequent cleavage of the t-butyl ester. ES (+) - MS: 587.1 (M + H) + Example 8 ((S) -4 - (4-Hydroxymethyl-f-enyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetyl) -L-aspartyl-L- phenylglycine 8a) Benzyl ester of ((S) -4- (4-cyanophenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetic acid (8.1) To a solution of 20 g (73.1 mmol) of ((S) -4- (4-cyano-phenyl) -4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetic acid in 120 ml of DMF absolute, 7.73 g (160.8 mmol) of sodium hydride were added under cooling with ice. After stirring for 30 minutes at room temperature, 19 ml (160.8 millimoles) of benzyl bromide were added. The reaction mixture was stirred for 2 hours at room temperature, allowed to stand overnight, the solvent was removed in vacuo, and the residue was chromatographed on silica gel with heptane / ethyl acetate (2: 1). Obtained 11.43 g (35%) of 8.1 8b) Benzyl ester of ((S) -4- (4-formyl-phenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin- 1-il) -acetic (8.2) To a solution of 6.08 g (13.42 millimoles) of 8.1 in 200 ml of pyridine / acetic acid / water (2: 1: 1) were added, at 0 ° C, 24.3 g of sodium hypophosphite x H20 and 4.02 g of Raney nickel, and the reaction mixture was heated for 8 hours at 60 ° C. After cooling to room temperature and filtering, the reaction mixture was concentrated in vacuo, the residue was taken up in ethyl acetate, and the ethyl acetate phase was extracted twice with water, twice with 10% acid solution. citric acid, twice with saturated NaHCO3 solution, and with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, and after filtration the solvent was removed in vacuo. 4.82 g (79%) of 8.2 were obtained. 8c) ((S) -4- (4-Hydroxymethyl-phenyl) -3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -acetic acid (8.3) To a solution of 500 mg (1.1 mmol) of 8.2 in 50 ml of ethanol was added 20 ml of water and then, at 0 ° C, 22 mg (0.6 mmol) of sodium borohydride. After stirring for 40 minutes at 0 ° C, the reaction mixture was concentrated in vacuo, the residue was heated at 50 ° C for 12 hours in 30 ml of 6 N hydrochloric acid / THF (1: 1), and the mixture was allowed to stand. Reaction mixture overnight at room temperature. The mixture was extracted with dichloromethane, and the organic phase was dried over sodium sulfate. After filtration the solvent was removed in vacuo, water was added to the residue, and lyophilized. 440 mg of 8.3 crude were obtained, which was used without further purification in the next synthesis step. 8d) ((S) -4- (4-Hydroxymethyl-phenyl) -3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -acetyl-L-aspartyl-L-phenylglycine To a solution of 200 mg (0.54 millimoles) of 8.3 crude, s 225 mg (0.54 mmol) of H-Asp (OfcBu) -Phg- (OfcBu) x HCl and 178 mg (0.54 mmol) of TOTU were added 185 μl (1.08 millimoles) of diisopropyl-ethylamine. After 1 hour at room temperature, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate, and the ethyl acetate phase was extracted twice with KHS04 / K2S04 solution, saturated NaHCO3 solution, and saturated solution. of sodium chloride. After separating the phases, the organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by chromatography on silica gel with methyl t-butyl ether / heptane (8: 2). after concentrating the fractions with product, the residue was dissolved in 5 ml of 90% trifluoroacetic acid. After 1 hour at room temperature, trifluoroacetic acid was removed in vacuo, and the residue was purified by preparative HPLC or RP-18. 44 mg (13%) of 8.4 were obtained after lyophilization. ES (+) - MS: 617.2 (M + H) + Example 9 s (S) -3- (((S) -4- (4-hydroxymethyl-phenyl) -3-benzyl-4-methyl--2,5-dioxo-imidazolidin-1-yl) -acetylamino acid) -2- (1-adamantylmethyloxycarbonylamino) -propionic The preparation was carried out analogously to Example 8 by coupling 8.3 with (S) -2- (1-adamantylmethyloxycarbonylamino) -3-amino-propionic acid t-butyl ester (see Example 4) instead of H-Asp (O ^ u) -Phg- (OfcBu) x HCl. After cleaving the t-butyl ester with 90% trifluoroacetic acid, the crude product was partitioned between water and dichloromethane. The organic phase was separated, dried over sodium sulfate, and, after filtration, the solvent was removed in vacuo. The residue was purified by preparative HPLC on RP-18. ES (+) - MS: 647.3 (M + H) + Example 10 ((R, S) -4- (Hydroxyphenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazo-lidin-1-yl) -acetyl) -L-aspartyl-L-phenylglycine 10a) 1- (4- (Tetrahydropyran-2-yloxy) -phenyl) -ethanone (10.1) In 100 ml of anhydrous methylene chloride were suspended 13.62 g (100 millimoles) of 4-hydroxyacetophenone and 10.04 ml (110 millimoles) of 3,4-dihydro-2H-pyran. At 0 ° C, 190 mg (1 millimole) of p-toluenesulfonic acid was added with stirring and stirred for 3 hours at 0 ° C. 10.04 ml (110 mmol) of 3,4-dihydro-2H-pyran was added again, and it was stirred at room temperature for another 3 hours. The whole was poured into 150 ml of water, the phases were separated, and the organic phase was extracted with saturated NaHCO 3 solution, with saturated sodium chloride solution, and with water. The organic phase was dried over sodium sulfate, concentrated and, to purify it, chromatographed on silica gel (70-200 μm) with methylene chloride as eluent. 13.65 g (62%) of 10.1 were obtained. 10b) (R, S) -4-Methyl-4- (4-tetrahydropyran-2-yloxy) -phenyl) -2,5-dioxo-imidazolidine (10.2) In 200 ml of 50% ethanol, 11.01 g (50 millimoles) of 10.1 and 42.3 g (440 millimoles) of ammonium carbonate were suspended. To this was added 4.23 g (65 millimoles) of potassium cyanide. It was stirred for 5 hours at a temperature of 50 to 60 ° C. After a short time, a clear solution was obtained. It was left to stand overnight at room temperature, and then stirred at 60 ° C for a further 6 hours. The pH value was adjusted to 6.3 with 6N HCl, and the mixture was stirred for 2 hours, cooling with ice. The precipitate was suction filtered, washed with water, and dried in a desiccator over phosphorus pentoxide. 9.5 g (65%) of 10.2 were obtained. 10c) (R, S) -4-Methyl-4- (4-tetrahydropyran-2-yloxy) -phenyl) -2,5-dioxo-imidazolidin-1-yl) -acetic acid methyl ester (10.3) In 25 ml of anhydrous methanol, 230 mg (10 mmol) of sodium were dissolved under argon. 2.9 g (10 mmol) of 10.2 was added. It was heated to reflux, with stirring, for 2 hours. Then 1.66 g (10 mmol) of potassium iodide was added, and a solution of 0.975 ml (10 mmol) of methyl chloroacetate in 1.1 ml of methanol was added dropwise over the course of 15 minutes. anhydrous. It was heated to reflux for 4 hours, and then allowed to stand overnight at room temperature. Another 0.195 ml (2 millimoles) of methyl chloracetate was added in 0.22 ml of anhydrous methanol, and the whole was stirred at reflux for 4 hours. The precipitate was filtered with suction, and the filtrate was concentrated. The residue was dissolved in methylene chloride, the insoluble portions were filtered off, and chromatographed on silica gel with methylene chloride / ethyl acetate (9: 1). 2.56 g (71%) of 10.3 were obtained. lOd) Acid methyl ester ((R, S) -3-benzyl-4-methyl-4- (4-tetrahydropyran-2-yloxy) -phenyl) -2,5-dioxo-imidazolidin-1-yl) -acetic (10.4) In 8.5 ml of anhydrous DMF, 2.53 g (7 mmol) of 10.3 were dissolved under argon. 370 mg were added at 15 ° C (7.7 mmol) of sodium hydride (50% in oil). It was stirred for 15 minutes at 15 ° C, and then 0.91 ml (7.7 mmol) of benzyl bromide was added dropwise. Stirred at room temperature for 7.5 hours, and allowed to stand overnight at room temperature. The clear solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated, and the aqueous phase was washed once more with ethyl acetate. The organic phases were combined, washed with water, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel with methylene chloride / ethyl acetate (9.5: 0.5). 1.59 g were obtained (50%) of 10.4. 10e) Acid ((R, S) -4- (4-hydroxy-phenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetic acid (10.5) Refluxing for 3 hours was 1.53 g (3.5 mmol) of 10.4, together with 30 ml of concentrated hydrochloric acid. After concentrating the solution in vacuo, the residue was triturated with water, cooled overnight, and then filtered with suction. It was dried over phosphorus pentoxide in a desiccator, and 1.22 g (98%) of 10.5 was obtained. lOf) Di-t-butyl acid ester ((R, S) -4- (4-hydroxy-phenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetyl ester -L - aspartyl-L-phenylglycine (10.6) In 10 ml of DMF 345 mg (1 millimole) of 10.5, 415 mg (1 millimole) of H-Asp (O '? U) -Phg- (OfcBu) x HCl and 135 mg (1 millimole) of HOBt were dissolved. At 0 ° C 0.13 ml (1 milli-mol) of N-ethylmorpholine and 220 mg (1 millimole) of DCC were added. It was stirred at 0 ° C for 1 hour and at room temperature for 3 hours, and allowed to stand overnight at room temperature. It was filtered with suction and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, and washed with NaHCO3 solution, K2SO4 / KHS04 solution, and saturated sodium chloride solution. After drying over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated in vacuo. The oily residue was triturated with diethyl ether, and the organic phase was concentrated. 730 mg (100%) of 10.6 were obtained. lOg) ((R, S) -4- (4-Hydroxy-phenyl) -3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -acetyl-L-aspartyl-L-phenylglycine (10.7) In 4 ml of 90% trifluoroacetic acid they were dissolved 370 mg (0.52 millimoles) of 10.6, and allowed to stand at room temperature for 1 hour. Then he concentrated. The residue was triturated with diethyl ether and filtered with suction. 202 mg (64%) of 10.7 were obtained.

The aspartyl-phenylglycine derivatives of Examples 12 to 126 were prepared by solid phase synthesis according to the general method indicated in Example 11.

Example 11 General method for the preparation of aspartyl-phenylglycine derivatives by solid phase synthesis.

General The syntheses on polymer supports were carried out according to the synthesis sequence that is represented in Scheme 1. The radicals R50 to R55 in Scheme 1 have the meaning of the radicals that are in the molecule in the respective position in the Formula I, or they may contain functional groups in protected form or in the form of precursors. R50 corresponds to the radical R. R51 corresponds to the radicals R4 or R15, and the functional groups present in these radicals may be present in protected form or in the form of precursors (ie, for example, the radical -NHR51 may represent the radical of an amino acid which is obtained formally by removal of a hydrogen atom from the amino group). R52, together with the CH group to which this radical is attached, corresponds to group B (ie, R52 corresponds to a substituent on a methylene group represented by B). R53 corresponds to R13. R54 corresponds to the group R1-A, in which the functional groups present therein can be presented in protected form or in the form of precursors. R55 corresponds to the group R °. The synthesis of intermediates on a large scale was carried out in special reaction vessels with frits inserted in the bottom of the reaction vessel, and the synthesis of the compounds of formula I was carried out in syringes or reaction blocks (Act 496, MuitiSyn Tech ). Resin synthesis was followed by the particle analysis method ("on bead") (FT-IR with unit ATR and MAS-NMR) and separation of an analytical sample from the resin (HPLC, MS, NMR). squema 1 Preparation of the structural component of aspartic acid FmocAsp (OH) OAlyl 25 ml of trifluoroacetic acid were added to Fmo-cAsp (OtBu) OAlyl (40 g, 88.7 mmol), and stirred for 30 minutes at room temperature. The solvent was removed in a rotary evaporator. The residue was dried in vacuo. FmocAsp (OH) OAlyl was obtained as a yellow oil (33.9 g, 97%). ES (+) - MS: 395.2 (M + H) + Anchoring to the polymer support (step A in scheme 1) 40 g of polystyrene Wang resin (1.1 millimol / gram, Bachem) was previously expanded for 5 minutes with 20 ml of DMF at room temperature. After adding a solution of 26.0 g (1.5 equivalents) of FmocAsp (OH) OAlyl and 34.3 g (1.5 equivalents) of 1-benzotriazolyloxytri-pyrrolidinophosphonium hexafluorophosphate (PyBOP) and, 3 ml (1.5 equivalents) of diisopropyl-ethylamine in 120 ml of DMF, the mixture was stirred for 10 hours at 40 ° C. After the reaction was complete, the solution was filtered with suction, and the resin was washed with DMF (5 x 20 ml). After adding a solution of acetic anhydride (10 ml) and diisopropyl-ethylamine (9.3 ml, 1.5 equivalents) in 40 ml of DMF, the mixture was stirred again for 30 minutes at room temperature. The solution was suction filtered, and the resin was successively washed three times, with 40 ml each time, with each solvent: DMF, methanol and dichloromethane. The resin was then dried under vacuum. The determination of the charge according to the Fmoc method resulted in a charge of 0.6 mmol / gram.

Removal of the allyl group on the polymer support (step B) The resin was previously expanded, under argon, for 5 minutes in DMF at room temperature. After adding tetrakis (triphenylphosphine) palladium and N-methylpyrrolidine (10 equivalents), the mixture was stirred under argon for 6 hours at 40 ° C. Once the reaction was completed, the solution was suction filtered, the resin was successively washed three times, with 40 ml each time, with each solvent: DMF, methanol, toluene and dichloromethane, and then dried.

Copying with amino compounds on the polymer support (step C) The resin loaded with free carboxyl function was previously expanded, for 5 minutes in DMF at room temperature. After adding a solution of HOBt (1.2 equivalents), TOTU (1.2 equivalents) and diisopropyl-ethylamine (1.2 equivalents) in DMF, the mixture was stirred for 30 minutes at room temperature. The amino compound (1.2 equivalents) dissolved in DMF was added. The suspension was stirred at room temperature until the reaction was complete (HPLC control). After the reaction was completed, the solution was suction filtered and the resin was successively washed three times with each solvent: DMF, methanol, toluene and dichloromethane, and then dried.

Removal of the Fmoc protecting group (step D) To remove the Fmoc protecting group, the resin was previously expanded for 5 minutes in DMF at room temperature. After adding a solution of DMF / piperidine (1: 1) it was stirred at room temperature for 20 minutes. The solution was suctioned and the process repeated. Separation of an analytical sample showed that the reaction had been completed by HPLC / MS analysis. Once the reaction was completed, the resin was washed three times with dichloromethane and used directly in the coupling.

Copying with halogenocarboxylic acids (step E) to 'Copulation with DIC From α-halocarboxylic acids (5 equivalents) the symmetrical anhydrides were formed by reaction for 30 minutes with diisopropylcarbodiimide (2.4 equivalents) in dichloromethane. At the end of this time, 2 equivalents of diisopropyl ethylane were added. The mixture was added to the resin, and stirred for 12 hours at room temperature. After the reaction was completed, the solution was suction filtered and the resin was successively washed three times, with 40 ml each time, with each solvent: DMF, toluene and dichloromethane, and then reacted immediately. b) Copulation with acid halides. o The resin was previously expanded for 5 minutes with dichloromethane at room temperature. Halides of α-halogenocarboxylic acid (1.5 equivalents) were added dissolved in dichloromethane. After adding a catalytic amount of 4-dimethylaminopyridine and diisopropyl-ethylamine (1.5 s equivalents), the mixture was stirred at room temperature for 8 hours. After the reaction was completed, the solution was suction filtered and the resin was successively washed three times, with 40 ml each time, with each solvent: DMF, toluene and dichloromethane, and then reacted immediately.

Copulation of α-halogeno-acyl compounds with hydantoins (step F) The 4,4-disubstituted hydantoins (2 equivalents) 5 were activated in DMF with diazabicycloundecene (DBU) (2 equivalents) at room temperature. The activated solution was added, after 15 minutes, to the resin previously expanded in DMF for 5 minutes. The mixture was stirred at room temperature for 8 hours. Once the reaction was finished, the solution was suction filtered and the resin was successively washed three times, with 40 ml each time, with each solvent: DMF, methanol, toluene and dichloromethane, and then dried.

N-Alkylation of the hydantoin in the polymer support (step G) a) Alkylation with cesium carbonate The resin was previously expanded for 5 minutes in DMF at room temperature. After adding cesium carbonate (3 equivalents) was stirred for 30 minutes at room temperature. After adding the alkylating agent (bromide or iodide) it was stirred for 6 hours at 50 ° C. Once the reaction was completed, the solution was suction filtered and the resin was successively washed three times with each solvent: DMF, methanol / water / DMF (1.5: 1.5: 7), DMF, toluene and dichloromethane, and then dried. b) Alkylation with phosphazenes The resin was previously expanded for 5 minutes in DMF at room temperature. After addition of N, N, N ', N', N "," -hexamethylphosphorimic acid (phosphazene base Pl-t-Bu) (3 equivalents) N '"- t-butyl triamide was stirred at room temperature for 30 minutes. After adding the alkylating agent (bromide or iodide), the mixture was stirred for 4 hours at room temperature, and once the reaction was completed, the solution was suction filtered and the resin was washed successively three times with each solvent: DMF, toluene and dichloromethane, and then dried.

Separation of the resin (step H) To remove the compound from the resin, a mixture of trifluoroacetic acid / dichloromethane (1: 1) was added to the resin. The suspension was stirred for 1 hour. The resin was filtered off. The resulting solution was concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane and ethyl acetate).

According to the general method described in Example 11, the compounds of Examples 12 to 126 were prepared, having the structure indicated in formula Ib. The meanings of the radicals in the individual compounds are indicated in Tables 1 and 2.

Meanings in tables 1 and 2 Bn = benzyl 3-BrBn = 3-bromobenzyl 4-BrBn = 4-bromobenzyl 4-ClBn = 4-chlorobenzyl 4-Bip = 4-biphenylylmethyl 2-Py = 2-pyridylmethyl 3-Py = 3-pyridylmethyl 4-Py = 4-pyridylmethyl H = hydrogen Me = methyl Et = ethyl nPr = n-propyl iPr = isopropyl nBu = n-butyl iBu = isobutyl nPe = n-pentyl nHe = n-hexyl All = allyl Ph = phenyl The following abbreviations represent radicals that are represented by the -NH-R51 group in the formula Ib. They are radicals of amino acids or derivatives thereof, which can be obtained formally by abstraction of a hydrogen atom from the amino group of the amino acid.

Val = L-Valil Ala = L-Alanyl lie = L-Isoleucil Phg = L-Phenylglycyl PhgMor PhePip PhgPip PhePip Table 1 Ex emp] -o R50 -NH-R51 R52 R53 R54 R55 EN (+) -MS 2 Me Val Bp Me Ph Bn 659 3 Me Val ¡Pr Me Ph 4-Bip 686 4 Me Val H Me Ph Bn 568 5 H Phg H Me Ph 2-Py 589 6 H Phg H Me Ph 3-Py 589 7 H Phg H Me Ph 4-Py 589 8 H Phg Et Me Ph Bn 617 9 H Phg H Ph Ph Bn 651 0 H Phg nBu Me Ph Bn 644 1 H Phg Bu Me Ph Bn 644 H Phg nBu Me Ph 2-Py 645 H Phg nBu Me Ph 3-Py 645 H Phg nBu Me, Ph 4-Py 645 H Phg ¡Bu Me Ph 2-Py 645 H Phg ¡ Bu Me Ph 3-Py 645 H Phg Bu Me Ph 4-Py 645 H lie H Me Ph 4-BrBn 647 H He Bn Me Ph Bn 659 H lie ¡Pr Me Ph Bn 610 H I I Pr Me Ph 4-Bip 686 H He H Me Ph Bn 568 H He nPe Me Ph Bn 639 H He nPe Me Ph 4-Bip 715 H Ala Bn Me Ph Bn 616 H Ala ¡Pr Me Ph Bn 568 H Ala Pr Me Ph 4-Bip 644 H Wing H Me Ph Bn 525 H Wing nPe Me Ph Bn 596 H Wing nPe Me Ph 4-BID 67 H Phg Bn Me Ph Bn 679 H Phg Pr Me Ph Bn 630 H Phg Pr Me Ph 4-Bip 707 H Phg H Me Ph Bn 588 H Phg nPe Me Ph Bn 658 H Phg nPe Me Ph 4-Bip 735 H Phg Et Me Ph 2-Py 618 H Phg Et Me Ph 3-Py 618 H Phg Et Me Ph 4-Py 618 H Phg H Ph Ph 2-Py 651 H Phg H Ph Ph 3-Py 651 H Phg H Ph Ph 4-Py 651 Me Val nPe Me Ph Bn 638 Me Val nPe Me Ph 4-Bip 715 H Val H Me Ph Bn 554 H Val Bn Me Ph Bn 644 H Val ¡Pr Me Ph 4-Bip 672 H Val ¡Pr Me Ph Bn 596 H Val nPe Me Ph Bn 624 H Val nPe Me Ph 4-Bip 701 H PheMor H Me Ph Bn 671 H PheMor Bn Me Ph Bn 762 H PheMor Pr Me Ph 4-Bip 790 H PheMor Pr Me Ph Bn 714 H PheMor nPe Me Ph Bn 742 H PheMor nPe Me Ph 4-Bip 818 H PhePip H Me Ph Bn 670 H PhePip Bn Me Ph Bn 760 H PhePip ¡Pr Me Ph 4-B¡p 788 H PhePip nBu Me Ph Bn 712 H PhePip nPe Me Ph Bn 726 H PhePip nBu Me Ph 4-Bp 802 H PhgMor H Me Ph Bn 658 H PhgMor Bn Me Ph Bn 748 H PhgMor Pr Me Ph Bn 700 H PhgMor nPe Me Ph Bn 728 H PhgMor nPe Me Ph 4-Bip 804 H PhgPip H Me Ph Bn 656 H PhgPip Bn Me Ph Bn 746 H PhgPip Pr Me Ph 4-Bp 774 H PhgPip Pr Me Ph Bn 698 H PhgPip nPe Me Ph Bn 726 H PhgPip nPe Me Ph 4-Bp 802 H Phg 4-CIBn Me Ph Bn 713 H Phg All Me Ph Bn 629 H Phg H Me Ph 4-BrBn 667 H Phg H Me Ph 3-BrBn 667 H Ph (CH2) 3NH- nBu Me Ph Bn 628 H Phg nBu Me Ph nPr 595 H Phg nBu Me Ph Bu 610 H Phg nBu Me Ph nHe 638 H Phg nPr Me Ph Bn 630 H Phg nHe Me Ph Bn 672 H Phg H Me Ph nPr 539 H PheMor H Me Ph nPr 622 96 H PheMor Bu Me Ph Bn 727 97 H Phg H Me Ph Et 525 98 H Phg H Me Ph Bu 553 99 H Phg H Me Ph ¡Pr 539 100 H Phg nBu Me Ph Bn 644 101 H CH3 (CH2) 7NH- nBu Me Ph Bn 621 102 H Phg Et Me Ph ¡Pr 567 103 H Phg nPr Me Ph Bn 630 104 H Phg nPr Me Ph Bu 595 105 H Phg pPr Me Ph ¡Pr 581 Table 2 In all the compounds of Table 2, in the formula Ib the radical Rso represents hydrogen, the radical -NH-R51 represents Phg (= L-phenylglycyl), and the radical R52 represents n-butyl.

Example Rs R3 * R "ES (+) -MS 106 Me 2 - fluorophenyl Bn 661 107 Me 3 -fluorophenyl Bn 661 108 Me 4-fluorophenyl Bn 109 Me 4 -fluorobenzyl Bn 110 Me 3 -trifluoromethylBn phenyl 111 Me 3 -chlorophenyl Bn 112 Bn Bn Bn 113 Me 4 -methoxybenzyl Bn 114 Me cyclohexyl Bn 115 Me Bn Bn 116 Me 2-thienyl Bn 117 Me 3 -trifluoromethyl- Bn benzyl 118 cycloPh Bn propyl 119 cyclo- Ph Bn butyl 120 Me 3,4, 5-trimethoxy- Bn phenyl 121 Me 4-fluorophenyl H 122 Bn Bn H 123 Me 4 -methoxybenzyl H 124 Me 3 -trifluoromethyl-H benzyl 125 cyclo-Ph H butyl 126 Me 3,4, 5-trimethoxy-H benzyl Example 127 (2- ((R, S) -4-Phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2,2-dimethyl-acetyl) -L-aspartyl -L-phenylglycine The compound was obtained by solid phase synthesis in a manner analogous to the general method described in Example 11. ES (+) - MS: 616 The 2,3-diaminopropionic acid derivatives of Examples 129 to 168 were prepared by solid phase synthesis according to the general method indicated in Example 128.

Example 128 General method for preparing, by solid phase synthesis, diaminopropionic acid derivatives General The syntheses on polymer support were carried out according to the synthesis sequence that is represented in scheme 2. Here, likewise, the above general explanations regarding the preparation by solid phase synthesis of aspartyl-phenylglycine derivatives are valid, analogously. to.

Copulation of the -Fmoc-β-Alloc-2, 3-diaminopropionic acid to the polymeric supports (step J in scheme 2) To 1 g of polystyrene Wang resin was added a solution of 0.243 g (1.8 mmol) of HOBt , 0.590 g (1.8 mmol) of TOTU, 0.25 ml (1.8 mmol) of diisopropyl-ethylamine and 0.738 g (1.8 mmol) of acid (S) - -Fmoc-β - Alloc 2, 3 -diaminopropionic acid in 5 ml of DMF, and the mixture was stirred for 12 hours at room temperature. The resin was filtered off and washed three times with 10 ml of DMF each time, once with 10 ml of toluene, once with 10 ml of methanol, and 3 times with 10 ml of dichloromethane. The determination of the load according to the Fmoc method gave a loading result of 0.9 millimoles / gram.

Scheme 2 Removal of the allyloxycarbonyl group from the polymer support (step K) The resin was previously expanded for 5 minutes in DMF, under argon and at room temperature. After adding tetrakis (triphenylphosphine) palladium and N-methylpyrrolidine (10 equivalents), the mixture was stirred under argon for 6 hours at 40 ° C. Once the reaction was completed, the solution was suction filtered, the resin was washed successively, three times with each solvent: DMF, methanol, toluene and dichloromethane, and then dried.

Copulation of α-Fmoc-2,3-diaminopropionic acid with hydantoincarboxylic acids (step L) To 100 mg of resin that had been loaded with α-Fmoc-2,3-diaminopropionic acid (0.9 mmol / gram) was added a solution of 36 mg (0.27 mmol) of HOBt, 88 mg (0.27 mmol) of TOTU, 37 μl (0.27 mmol) of diisopropyl-ethylamine and 0.27 mmol of acid (R, S) 3-benzyl-4-phenyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl-acetic acid in 5 ml of DMF, and the mixture was stirred for 12 hours at room temperature. The resin was filtered off and washed three times with 10 ml of DMF each time, once with 10 ml of toluene, once with 10 ml of methanol, and 3 times with 10 ml of dichloromethane each time.

Removal of the Fmoc protecting group (step M) To remove the Fmoc protecting group, the resin was previously expanded for 5 minutes in DMF at room temperature. After adding a solution of DMF / piperidine (1: 1) it was stirred at room temperature for 20 minutes. The solution was suctioned and the process repeated. The separation of an analytical sample showed that the reaction had been completed by HPLC / MS analysis. After the reaction was completed, the resin was washed three times with dichloromethane, and used directly in the next step.

Acylation of the 2,3-diaminopropionic acid a-amino group (Step N) a) Preparation of carboxylic acid amides (acylation with carboxylic acids) To 100 mg of resin that had been charged with the 2,3-diaminopropionic acid component was added a solution of 36 mg (0.27 mmol) of HOBt, 88 mg (0.27 mmol) of TOTU, 37 μl (0.27 mmol) of diisopropyl-ethylamine and 0.27 mmol of the corresponding carboxylic acid of formula R60-COOH in 5 ml of DMF, and the mixture was stirred for 12 hours. hours at room temperature. The resin was filtered off and washed 3 times with 10 ml of DMF each time, once with 10 ml of toluene, once with 10 ml of methanol, and 3 times with 10 ml of dichloromethane each time. b) Preparation of ureas (acylation with isocyanates) To 100 mg of resin that had been charged with the 2,3-diaminopropionic acid component was added a solution of 0.27 mmol of the corresponding isocyanate of formula R60-N = C = O and a catalytic amount (1 mg) of 4-dimethylaminopyridine in 5 ml of DMF, and the mixture was stirred for 8 hours at room temperature. The resin was filtered off and washed 3 times with 10 ml of DMF each time, once with 10 ml of toluene, once with 10 ml of methanol, and 3 times with 10 ml of dichloromethane each time. c) Preparation of carbamates (acylation with carbonic acid derivatives) The corresponding alcohol (0.27 mmol) of formula R60-OH was stirred for 5 hours at 40 ° C with, in each case, equivalent amounts of di- ( N-succinimidyl) and diisopropyl-ethylamine. The solution was added to 100 mg of resin that had been charged with the 2,3-diaminopropionic acid component, and the mixture was stirred for 8 hours at room temperature. The resin was filtered off and washed 3 times with 10 ml of DMF each time, once with 10 ml of toluene, once with 10 ml of methanol, and 3 times with 10 ml of dichloromethane each time. s Separation of the resin (step P) To separate the compound from the resin, a mixture of trifluoroacetic acid and dichloromethane (1: 1) was added to the resin. The suspension was stirred for 1 hour and then the resin was filtered off. The resulting solution or solution was concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane and ethyl acetate).

The 3-benzyl-4-phenyl-4-methyl-2, 5-dioxo-imidazolidin-l-yl-acetic acid used in step L was obtained according to the following general working method for preparing hydantoincarboxylic acids 4, 4-Disubstituted: To 3.0 millimoles of acetophenone and 3.0 g of ammonium carbonate in 3.8 ml of ethanol was added by pipette a solution of 288 mg of potassium cyanide in 3.8 ml of water. The mixture was stirred for 5 hours at 55 ° C. Subsequently, 8 ml of 6 N hydrochloric acid were metered in slowly, and the mixture was stirred for a further 2 hours at 55 ° C. After adding 6.0 ml of water, the mixture was cooled to room temperature over the course of 2 hours. The product was filtered with suction, washed with water and dried in air. The (R, S) -4-methyl-4-phenyl-hydantoin was suspended with an equivalent of cesium carbonate in DMF (20 ml / g of hydantoin derivative), and stirred for 20 minutes at room temperature. After adding an equivalent of t-butyl ester of or bromoacetic acid, the mixture was stirred for 1 hour at room temperature. Water was then added and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The hydantoacetic acid ester was obtained in the form of an oil. The hydantoacetic acid ester, together with an equivalent of cesium carbonate and one equivalent of benzyl bromide, was suspended in DMF (20 ml / g of hydantoin derivative). The mixture was stirred for 1 hour at room temperature. Water was then added and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (hexane / ethyl acetate). The 3-benzyl-hydanto-acetic acid ester was obtained in the form of an oil. The t-butyl ester group was then cleaved with trifluoroacetic acid, under standard conditions, to obtain the carboxylic acid. The compounds of Examples 129 to 168, which have the structure indicated in the formula le, were prepared according to the general method described in Example 128. The meaning of the groups X and R60 in the individual compounds of the formula is indicated in Table 3. If X represents a direct bond, this means that the R60 group is directly bonded to the carbonyl group.

Table 3 Example -X- R ° ES- (+) -MS 129 direct link 3-methylphenyl 543 130 direct link 2-methylphenyl 543 131 direct link 2, 4-dimethoxyphenyl 589 132 direct link 3, 5-dinitrophenyl 619 133 direct link 4-t-butylphenyl 585 134 direct link 2, 4, 5-trimethylphenyl 571 135 -. 135-NH-4-chlorophenyl 579 136 -. 136 -NH- 4-isopropylphenyl 586 137 -. 137 -NH- 2-nitrophenyl 589 138 direct link 4-chlorophenyl 564 139 direct link 4-methylphenyl 543 140 direct link 4-methoxyphenyl 559 141 direct link 4-nitrophenyl 574 142 -. 142 -NH- 4- (trifluoromethoxy) -628 phenyl 143 -NH-2-methoxyphenyl 574 144 -. 144-NH-3, 5-bis (trifluoro-680 methyl) phenyl 145 - -NH-benzyl 558 146 -. 146 -0- 2-methoxyethyl 527 147 -. 147 -O- prop-2-inyl 507 148 -. 148 -O- 2, 2, 2-trifluoroethyl 551 149 -. 149 -O- cyclopentyl 537 150 -. 150 -0- 2-cyclohexylethyl 580 151 -. 151 -O-prop-2-enyl 510 152 -. 152 -O- 2- (4-fluorophenyl) ethyl 591 153 -. 153 -O- 2- (4-nitrophenyl) ethyl 618 154 -. 154 -0- 2- (3-methoxyphenyl) ethyl 604 155 -. 155 -O- cyclopropylmethyl 523 156 -. 156 -O- isobutyl 525 157 -. 157 -0-, 2, 2-dimethylpropyl 539 158 -. 158 -0- cyclobutylmethyl 537 159 -0 2-ethylbutyl 553 160 -. 160 -0 cyclopentylmethyl 551 161 -. 161 -0 2- (4-methylphenyl) ethyl 589 162 -. 162 -0 4-benzylbenzyl 650 163 -. 163 -0 4-nitrobenzyl 604 164 -. 164 -0 2-phenylethyl 573 165 -. 165 -0 2- (4-methoxyphenyl) ethyl 604 166 -. 166 -O 2- (1-naphthyl) ethyl 624 167 -. 167 -0 2- (2-naphthyl) ethyl 624 168 -. 168 -0 2- (4-t-butylphenyl) ethyl 630 Example 169 (S) -3- ((S) -2- ((S) -4-phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -2- acid ( 2-methyl-propyl) -acetylamino) -3- (3,4-methylenedioxy-phenyl) -propionic 169a) (S) -2-amino-2- (4-bromo-phenyl) -propionic acid methyl ester (169.1) In 107 ml of 3 N sodium hydroxide solution, 15 g (55.7 mmol) of (S) -4- (4-bromophenyl) -4-methyl-2, 5-dioxo-imidazolidine were suspended and the suspension was heated. for 2 hours at 145 ° C in an autoclave. It was allowed to cool to room temperature, the precipitate was filtered off, dissolved in water, and pH = 1 was adjusted with 1 N hydrochloric acid. After lyophilization, the solid was suspended in 150 ml of absolute methanol. The suspension was cooled to -15 ° C, and 8.8 ml of thionyl chloride was added. After stirring for 6 hours at room temperature and allowing to stand overnight, another 100 ml of absolute methanol and 8.8 ml of thionyl chloride were added. The mixture was stirred for 8 hours at room temperature and again allowed to stand overnight. After removing the volatile portions in vacuo, the residue was adjusted to pH 9.3 with sodium hydrogencarbonate solution and sodium carbonate solution, and then the aqueous phase was extracted 2 times with ethyl acetate. After drying over sodium sulfate, filtering and removing the solvent in vacuo, 11.4 g (79%) of 169.1 were obtained. 169b) (S) -2- ((S) -4- (4-bromo-phenyl) -4-methyl-2, 5-dioxo-imidazolidin-1-yl) -2- () S-t-butyl ester ( 2-methyl-propyl) -acetic (169.2) To a solution of 5.8 g (22.5 mmol) of 169.1 in 50 ml of DMF was added 4.8 g of L-leucine t-butyl ester isocyanate (prepared from L-t-butyl ester). leucine analogously to JS Nowick et al., J. Org. Chem. 1996, 61, 3929). After stirring for 4 hours at room temperature, the solvent was removed, and the residue was chromatographed on silica gel with heptane / t-butylmethylether = 6/4. The fractions containing the intermediate product were pooled, the solvent was removed in vacuo, the residue was dissolved again in 90 ml of DMF, and 775 mg of a 55-65% dispersion were added to the solution at 0 ° C. of sodium hydride in oil. After stirring for 3 hours at room temperature, the solvent was removed in vacuo, and the residue was chromatographed on silica gel with heptane / t-butylmethylether = 1 / l. After concentrating the fractions with product, 7.8 g (79%) of 169.2 were obtained as a colorless solid. 169c) (S) -2- ((S) -4- (4-bromo-phenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl t-butyl ester) -2- (2-methyl-propyl) -acetic (169.3) To a solution of 1.75 g (4 mmol) of 169.2 in 20 ml of absolute DMF was added 540 μl (4.4 mmol) of benzyl bromide and then, at 0 ° C, 140 mg of an aqueous dispersion. 55-65% sodium hydride in oil, and stirred for 15 minutes at 0 ° C and for 3 hours at room temperature. After allowing to stand overnight, the solvent was removed in vacuo and the residue was chromatographed on silica gel with heptane / ethyl acetate = 8/2. The fractions were combined with product and the solvent was removed in vacuo. 1.97 g (93%) of 169.3 were obtained. 169d) (S) -2- ((S) -4-phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -2- (2-) t-butyl ester methyl-propyl) - acetic (169.4) They were hydrogenated for 2 hours over 76 mg of 10% shovel-dio / carbon, 1.9 g (3.59 mmol) of 169.3 in 190 ml of ethanol. The catalyst was filtered off, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with a 10% sodium hydrogencarbonate solution. The phases were separated and the organic phase was dried over sodium sulfate. After filtering, 1.3 g (80%) of 169.4 were obtained. 169e) (S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -2- (2-methyl-propyl) - acid acetic acid (169.5) 1.3 g (2.89 mmol) of 169.4 were heated at reflux for 4 hours in a mixture of 10 ml of 6 N hydrochloric acid and 2 ml of tetrahydrofuran. After removing the solvent in vacuo and chromatographing the residue with heptane / ethyl acetate = 3/2, 510 mg (45%) of 169.5 were obtained. 169f) (S) -3- ((S) -2- ((S) -4-phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -2- ( 2-methyl-propyl) -acetylamino) -3-- (3,4-methylenedioxy-phenyl) -propionic The compound was prepared in a manner analogous to Example 1, by reaction of 169.5 with (S) -3-amino-3- (3,4-methylenedioxy-phenyl) -propionic acid t-butyl ester (prepared analogously to SG). Davis et al., Tetrahedron Asymmetry 1991, 2, 183), cleavage of the t-butyl ester with trifluoroacetic acid as described in Example 1, and subsequent purification of the crude product by preparative HPLC (RP18, eluent: acetonitrile / water = 50/120). ES (+) - MS: 586.4 (M + H) + Analogously to Example 169, the following two compounds can also be prepared: Acid (S) -3- ((S) -2- ((S) -4-phenyl-3-benzyl-4-methyl-2, 5-dioxo-imidazolidin-1-yl) -2- (2 - methyl-propyl) -acetylamino) -3 - (2,4-dimethoxy-phenyl) -propionic (by reaction of 169.5 with (S) -3-amino-3- (2,4-dimethoxy-phenyl) -propionic acid t-butyl ester and subsequent cleavage of the t-butyl ester with trifluoroacetic acid) Acid (S) - 3- ((S) -2- ((S) -4-phenyl-3- ((4-biphenylyl) -methyl) -4-methyl-2, 5-dioxo-imidazole idin-1-yl) -2 - (2-methyl-propyl) -acetylamino) -3- (3,4-methylenedioxy-phenyl) -propionic (by reaction of (S) -2- ((S) -4-phenyl-3- (4-biphenylyl) -methyl) -4-methyl-2, 5-dioxo-imidazolidin-1-yl) -2 - (2-methyl-propyl) -acetic (which can be obtained by reaction of 169.2 with 4-phenyl-benzyl bromide analogously to the synthesis of 169.3, and subsequent consecutive reaction in a manner analogous to the preparation of 169.5) with (S) -3-amino-3- (3,4-methylenedioxy-phenyl) -propionic acid t-butyl ester and subsequent cleavage of the t-butyl ester with trifluoroacetic acid) EXAMPLE 170 Acid (S) -3- ((R, S) -2- ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin- l-il) -2- (2-methyl-propyl) -acetylamino) -2- (1-adamantylmethyloxycarbonylamino) -propionic The compound was prepared analogously to Example 5 by reaction of 6.2 (see Example 6) with (S) -2- (1-adamantylmethyloxycarbonylamino) -3-aminopropionic acid t-butyl ester (for preparation see Example 4) and subsequent cleavage of the t-butyl ester with trifluoroacetic acid. ES (+) - MS: 674.5 (M + H) + Example 171 General method for preparing 2- (N- ((2,5-dioxo-imidazolidin-1-yl) -acetyl) -N-alkyl-amino) -propionic acids 171a) General method for preparing N-alkylated ß-alanine t-butyl esters The primary alkylamine (50 mmol) was dissolved in 80 ml of methanol (if the alkylamine was used in the form of the hydrochloride, the amine was first released by the addition of potassium t-butylate (45 mmol), 7.25 ml of ester was added. t-butyl of acrylic acid and, after effective mixing, was allowed to stand at room temperature for 2 days, then the solids eventually present were filtered off, concentrated on a rotary evaporator at 60 [deg.] C. and co-evaporated twice with toluene The residue was taken up in 100 ml of diethyl ether, filtered, and the filtrate was extensively concentrated.The product so obtained was presented as an oil or solid, and was used without further purification in the next reaction step. 171b) General working method for the acylation with hydantoincarboxylic acids of N-alkylated ß-alanine t-butyl esters and cleavage of the ß-alanine t-butyl ester In 2 ml of absolute DMF, the hydan-toincarboxylic acid (0.5 mmol) (see Example 128), 114 mg of N-ethyl-N 1 - (3-dimethylaminopropyl) carbodiimide hydrochloride (0.6 mmol) were dissolved, 70 mg of 1-hydroxybenzo-triazole (0.6 mmol) and the N-alkylated β-alanine t-butyl ester (1.0 mmol), and stirred for 8 hours at room temperature. The reaction mixture was taken up in 100 ml of ethyl acetate and washed three times with KHS04 solution (10%), three times with KHC03 solution, and three times with water. The ethyl acetate phase was dried with MgSO 4 and concentrated to dryness. 3 ml of trifluoroacetic acid was added to the residue, and allowed to stand for 1 hour at room temperature. The trifluoroacetic acid was removed in vacuo and the residue was co-evaporated with toluene and diethylether.

Example 172 2- (N- (((R, S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetyl) -N- (benzylamino) acid -propionic The compound was prepared starting from benzylamine, according to the method of Example 171. Yield: 183 mg (73%) of colorless powder.

EXAMPLE 173 2- (N- (((R, S) -4-Phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetyl) -N-octylamino) acid propionic The compound was prepared starting from n-octylamine, according to the method of Example 171. Yield: 293 mg (99%) of colorless oil.

Investigation of biological activity As a test method for determining the activity of the compounds of formula I on the interaction between VCAM-1 and VLA-4, a determination is used that is specific for this interaction. The cellular coparticipants in the binding, ie the integrins VLA-4, are offered in their natural form as surface molecules on human U937 cells (ATCC CRL 1593), which belong to the group of leukocytes. As specific partners in the binding recombinant soluble fusion proteins are used, produced by genetic engineering, composed of the extrakitoplasmatic domains of human VCAM-1 and the constant region of a human immunoglobulin of subclass IgGl.

Test methods Assay for measurement of adhesion of U937 cells (ATCC CRL 1593) to hVCAM-1 (1-3) -IgG 1. Preparation of human VCAM-1 (1-3) -IgG and human CD4-IgG A genetic construct was used for the expression of the extracellular domains of human VCAM-1, linked to the genetic sequence of the immunoglobulin heavy chain IgGl Human (Hinge, CH2, and CH3 regions) (by Dr Brian Seed, Massachusetts General Hospital, Boston, USA, see Damle and Aruffo, Proc.Nat.Ac. Sci. USA 1991, 88, 6403-6407). The soluble fusion protein hVCAM-1 (1-3) -IgG contained the three amino-terminal extracellular domains, similar to the immunoglobulin, of human VCAM-1 (Damle and Aruffo, Proc. Nati, Acad. Sci. USA 1991, 88, 6403). For negative controls it served as a CD4-IgG fusion protein (Zettlmeissl et al., DNA and Cell Biology 1990, 9, 347). The recombinant proteins were expressed as soluble proteins after transfection of DNA in COS cells (ATCC CRL 1651), induced by DEAE / dextran, according to standard procedures (Ausubel et al., Current Protocols in Molecular Biology, -John Wiley &Sons , Inc., 1994). 2. Assay for the measurement of the adhesion of U937 cells to hVCAM-1 (1-3) -IgG 2. 1 96-well microtiter plates (Nunc Maxisorb) were incubated at room temperature for 1 hour with 100 μl / well of goat anti-human IgG-antibody solution (10 μg / ml in 50 mM Tris, pH 9 ,5) . After removing the antibody solution, it was washed once with PBS. 2. 2 150 μl / well of a blocking buffer (1% BSA in PBS) was incubated on the plates for 0.5 hour at room temperature. After removing the blocking buffer, it was washed once with PBS. 2. 3 100 μl / well of a cell culture supernatant of transfected COS cells was incubated on the plates for 1.5 hours at room temperature. The COS cells had been transfected with a plasmid coding for the three N-terminal domains, similar to immunoglobulin, of VCAM-1, coupled to the Fe part of human IgGx (hVCAM-1 (1-3) -IgG ). The content of hVCAM-1 (1-3) -IgG was approximately 0.5 - 1 μg / ml. After removing the culture supernatant, it was washed once with PBS. 2. 4 Plates were incubated for 20 minutes at room temperature with 100 μl / well of a Fe receptor buffer (β-globulin 1 mg / ml, 100 mM NaCl, 100 μM MgCl 2, or 100 μM MnCl 2, 100 μM CaCl 2, BSA 1 mg / ml in 50 mM HEPES, pH 7.5). After removing the blocking buffer from the Fe receptor, it was washed once with PBS. 2. 5 20 μl of binding buffer (100 mM NaCl, 100 μM MgCl 2, 100 μM MnCl 2, 100 μM CaCl 2, 1 mg / ml BSA in HEPES were discarded. 50 mM, pH 7.5), the substances to be tested were added in 10 μl of binding buffer, and incubated for 20 minutes. Antibodies against VCAM-1 (BBT, number BBA6) and against VLA-4 (Immunotech, number 0764) were used as controls. 0 2.6 U937 cells were incubated in Fe receptor blocking buffer for 20 minutes, and then added by pipette at a concentration of 1 x 106 / ml and in an amount of 100 μl per well (final volume 125 5 μl / well). 2. 7 The plates were slowly immersed, at a 45 ° angle, in stop buffer (100 mM NaCl, 100 μM MgCl 2, 100 μM MnCl 2, 100 μM CaCl 2, in 25 mM Tris, pH 7.5), and extracted. The process was repeated. 2. 8 Then 50 μl / well of a dye solution (16.7 μg / ml Hoechst Farbstoff 33258 dye, 4% formaldehyde, 0.5% Triton-X-100 in PBS) was incubated on the plates for 15 minutes. ) 2.9 The plates were removed and slowly immersed, at a 45 ° angle, in stop buffer (100 mM NaCl, 100 μM MgCl 2, 100 μM MnCl 2, 100 μM CaCl 2, in 25 mM Tris, pH 7.5). The process was repeated. It was then measured with the liquid in a cytofluorimeter (Millipore) (sensitivity: 5, filters: excitation wavelength: 360 nm, emission wavelength: 460 nm). The intensity of the light emitted by stained U-937 cells is a measure of the number of U937 cells remaining in the plate, adhered to hVCAM-1 (1-3) IgG, and therefore represents a measure of the capacity of the test substance added to inhibit this adhesion. From the inhibition of the adhesion to different concentrations of the test substance, the ICS0 concentration was calculated, which leads to a 50% inhibition of the adhesion. The following test results were obtained: Example Cell adhesion assay U937 / VCAJM-1 ICS0 (μM) 4 45 7 4.5 9 4 10 9.5

Claims (17)

1. Compounds of formula I, wherein W represents R ^ A-CÍR13) or R1-CH = C; s Z represents oxygen or sulfur; A represents a direct bond or alkylene Cx-C2; B means a divalent radical of the Cx-C6 alkylene series, C2-C6 alkenylene, phenylene, phenylene-alkyl (Cx-Cs), alkylene (C3-C3) -phenyl, wherein the alkylene radical is C6-C6. divalent unsubstituted or substituted with a radical from the series of C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C10 cycloalkyl, (C3-C10) cycloalkyl (C? -C3) alkyl, C6 aryl -C14 optionally substituted, aryl (C6-C14) -alkyl (Cx-C6) optionally substituted on the aryl radical, optionally substituted heteroaryl and heteroaryl-C (-C6) alkyl, optionally substituted on the heteroaryl radical; E means tetrazolyl, (R80) 2P (0), HOS (0) 2, R9NHS (O) 2 or R10CO; R means hydrogen, C?-C8 alkyl, C3-C12 cycloalkyl, (C3-C12) cycloalkyl (C?-C8) alkyl, optionally or substituted C6-C14 aryl, aryl (C6-C ?4) -alkyl (C) C8) optionally substituted on the aryl radical, optionally substituted heteroaryl or heteroaryl (Cx-Cg) alkyl optionally substituted on the heteroaryl radical; R ° represents hydrogen, C? -C8 alkyl, C3-C12 cycloalkyl, C3-C12 cycloalkyl-alkyl (Cx-Cg), C6-C12 bicycloalkyl, (C6-C12) bicycloalkyl (Cx-Cg), C3-C12 tricycloalkyl, (C6-C2) tricycloalkyl (C? -C8) alkyl, optionally substituted C6-C? 4 aryl, (C6-C? 4) aryl-(C? -C8) alkyl optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, H-CO, (C? -8) -CO alkyl, (C3-C? 2) -CO cycloalkyl, cycloalkyl (C3-C12) -alkyl (C? -C8) -CO, bicycloalkyl -CO, bicycloalkyl (C6-C? 2) -alkyl (C? -8) -CO, tricycloalkyl (C6-C? 2) -CO , (C6-C12) tricycloalkyl (C? -C8) -CO, aryl (C6-C14) -CO optionally substituted, aryl (C6-C? 4) -alkyl (C? -8) -CO optionally substituted in the aryl radical, optionally substituted heteroaryl -CO, heteroaryl (C? -C8) -CO alkyl optionally substituted on the heteroaryl radical, (C? -C8) -S (O) n alkyl, (C3-C?) cycloalkyl ) --S ( 0) n, (C3-C2) cycloalkyl-alkyl (C? -C8) -S (O) n, bicycloalkyl (C6-C? 2) -S (0) n, bicycloalkyl (C6-C? 2) -alkyl (C? -C8) -S (0) n, tricycloalkyl (C6-C12) -S (0) n, tricycloalkyl (C6-C12) -alkyl (C? -C8) -S (O) n, optionally substituted aryl (C6-C14) -S (O) n, aryl (C6-C? 4) -alkyl (C? -C8) -S (O) n optionally substituted on the aryl radical, heteroaryl-S ( O) n optionally substituted, or heteroaryl-alkyl (C? -C8) -S (O) n optionally substituted on the heteroaryl radical, wherein n represents 1 or 2; R1 represents an optionally substituted radical of the phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl series, each of these radicals being also benzo-condensed; R means hydrogen, C?-C8 alkyl, optionally substituted C 6 -C 14 aryl, (C 6 -C 14) aryl (C?-C 8) alkyl optionally substituted on the aryl radical, or C 3 -C 8 cycloalkyl; R 3 is hydrogen, C 1 -C 8 alkyl, optionally substituted C 6 -C 14 aryl, (C 6 -C 14) aryl (C 1 -C 8) alkyl optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl-alkyl (C 1 - C8) optionally substituted on the heteroaryl radical, C3-C8 cycloalkyl, (C3-C8) cycloalkyl-(C? -8) alkyl, C6-C12 bicycloalkyl, (C6-C? 2) bicycloalkyl (C? -8) alkyl , C6-C12 tricycloalkyl, (C6-C12) tricycloalkyl (C? -C8), C2-C8 alkenyl, C2-C8 alkyloxy, R1: LNH, CON (CH3) R4, CONHR4, COOR15, CON (CH3) ) R15 or CONHR15; R4 means hydrogen or C? -C? 0 alkyl which may optionally be substituted once or several times with the same or different radicals, from the series of hydroxy, C? -C8 alkoxy, Rs, optionally substituted C3-C8 cycloalkyl, hydroxycarbonyl, aminocarbonyl , mono- or di- (C 1 -C 18 alkyl) -aminocarbonyl, aryl (C 6 -C 4) -alkoxy (C 1 -C 8) -carbonyl which may also be substituted on the aryl radical; (C 1 -C 8) alkoxycarbonyl, Het-CO, R 6 -C 0, tetrazolyl and trifluoromethyl; Rs means optionally substituted C6-C ?4 aryl, aryl (C6-C14) -alkyl (C? -C8) optionally substituted on the aryl radical, or a possibly substituted 5 to 12 membered monocyclic or bicyclic ring, which may be substituted aromatic, partially or totally hydrogenated, and which may contain one, two or three heteroatoms equal or different from the series of nitrogen, oxygen and sulfur; R6 means the radical of a natural or non-natural amino acid, an imino acid, an aza-amino acid (optionally N-alkyl (C? -8) -substituted or N-aryl (C6-C14) -alkyl (C? -8) - -substituted), which may also be substituted on the aryl radical, or the radical of a dipeptide, as well as its esters and amides, whereby free functional groups may be protected by protective groups customary in peptide chemistry; R8 means hydrogen, C? -C18 alkyl, optionally substituted C6-C1 aryl, or aryl (C6-Cx) -alkyl (C? -C8) which may also be substituted on the aryl radical; R9 means hydrogen, aminocarbonyl, alkyl (C? -C? 8) -aminocarbonyl, (C3-C8) cycloalkyl-aminocarbonyl, optionally substituted aryl (C6-C14) -aminocarbonyl, C? -C18 alkyl, C6-C14 aryl optionally substituted, or C3-C8 cycloalkyl; R 10 is hydroxy, C 1 -C 18 alkoxy, aryl (C 6 -C 14) -alkoxy (C x -C 8), which may also be substituted on the aryl radical, optionally substituted C 6 -C 14 aryloxy, (C 1 -C 8) alkylcarbonyloxy -alkoxy (C? -C3), aryl (C6-C14) -carbonyloxy-alkoxy (C? -C6), amino, or mono- or di- ((C? -C18) alkyl-amino; R11 represents hydrogen, R12a, R12a-CO, H-CO, R12aO-CO, R12b-CO, R12b-CS, R12a-S (0) 2 or R12b-S (0) 2; R12a means C6-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C2 cycloalkyl, (C3-C2) cycloalkyl- (C6-8) alkyl, optionally substituted C6-C14 aryl, aryl (C6-C1) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, or the radical R15; R 12b means amino, di- (C 1 -C 18 alkyl) -amino, or R 12a-NH; R 13 is hydrogen, C 1 -C 6 alkyl, optionally substituted C 6 -C 4 aryl, aryl (C 6 -C 14) -alkyl (C 6 -C 6) optionally substituted on the aryl radical, C 3 -C 8 cycloalkyl or (C 3 -C 8) cycloalkyl ) -alkyl (C? -C6); R15 represents R16-alkyl (C? -C6) or represents Rld; R16 represents a bicyclic or tricyclic radical of 6 to 24 members, which is saturated or partially unsaturated, and which may also contain one, two, three or four identical or different heteroatoms, of the series of nitrogen, oxygen and sulfur, and which may also being substituted with one or more substituents, the same or different, of the alkyl series Het represents the radical of a saturated, monocyclic or 5- to 10-membered polycyclic heterocycle, attached via a ring nitrogen atom, which may contain one, two, three or four additional heteroatoms in the ring, the same or different, of the oxygen, nitrogen, and sulfur series, and which may eventually be substituted on the carbon atoms and on the additional nitrogen atoms of the ring, being able to there are radicals of the same or different series of hydrogen, Rh, HCO, RhCO and RhO-CO, as substituents on additional nitrogen atoms of the ring, and Rh represents alkyl C? -C8, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C? -C8) alkyl, optionally substituted C6-C? 4 aryl or (C6-C14) aryl-(C? -C8) alkyl optionally substituted on the aryl radical; e and h represent, independently of one another, 0 or 1; in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.

2. Compounds of formula I according to claim 1, wherein W represents R1-A-C (R13); Z represents oxygen or sulfur; A represents a direct bond, or methylene; B represents a divalent methylene or ethylene radical, both radicals being unsubstituted or substituted by a radical from the series of C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C10 cycloalkyl, cycloalkyl (C3-C) ?) -alkyl (C? -C6), optionally substituted C6-C? 4 aryl, aryl (C6-C1) -alkyl (C? -C6) optionally substituted on the aryl radical, optionally substituted heteroaryl and heteroaryl-alkyl (C? ~ -C6) optionally substituted on the heteroaryl radical; E means tetrazolyl or R10CO; R means hydrogen or C? -C3 alkyl; R represents hydrogen, C? -C8 alkyl, C3-C12 cycloalkyl (C3-C12) cycloalkyl (C? -8) alkyl, C6-C12 bicycloalkyl, (C6-C12) bicycloalkyl (Cx-C8) alkyl, C6-Cl2 tricycloalkyl, (C6-C2) tricycloalkyl (C? -C8) alkyl, optionally substituted C6-C14 aryl, (C6-C14) aryl (C? -C8) alkyl optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, H-CO, (C? -8) alkyl-CO, (C3-C? 2) -CO cycloalkyl, (C3-C) cycloalkyl 2) -alkyl (C? -C8) -CO, bicycloalkyl (C6-C? 2) -CO, bicycloalkyl (C6-C? 2) -alkyl (C? -8) -CO, tricycloalkyl (C6-C? 2) -CO, tricycloalkyl (C6-C12) -alkyl (C? -C8) -CO, aryl (C6-C? 4) -CO optionally substituted, aryl (C6-C14) -alkyl (C? -8) -CO optionally substituted on the aryl radical, optionally substituted heteroaryl-CO, heteroaryl (C? -C8) -CO alkyl optionally substituted on the heteroaryl radical, (C? -C8) alkyl (-S), cycloalkyl (C3) --C ? 2) -S (0) n, (C3-C? 2) cycloalkyl- (C? -C8) -S (0) n, bicycloalkyl (Cg-Cxa) -S (O) n, bicycloalkyl ( C6-C12) -alkyl (C? -C8) -S (O) n, tricycloalkyl (C6-C? 2) -S (O) n, tricycloalkyl (C6-C12) -alkyl- (C? -8) -S (O) n, aryl (C6-C? 4) -S (O) n optionally substituted, aryl (C6-CX4) -alkyl (C? -C8) -S (0) n optionally substituted on the aryl radical , optionally substituted heteroaryl -S (O) n, or heteroaryl-C 1 -C 8 alkyl -S (O) n optionally substituted on the heteroaryl radical, wherein n represents 1 or 2; R1 represents an optionally substituted radical of the phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl series, each of these radicals also being benzocondensates; R2 means hydrogen or C? -C8 alkyl; R 3 is hydrogen, C 1 -C 8 alkyl, optionally substituted C 6 -C 4 aryl, aryl (C 6 -C 6) -alkyl (C 1 -C 8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl-alkyl ( C? -C8) optionally substituted on the heteroaryl radical, C3-C8 cycloalkyl, (C3-C8) cycloalkyl-(C? -8) alkyl, C6-C? Bicycloalkyl, (C6-C12) bicycloalkyl-alkyl ( C? -C8), C6-C12 tricycloalkyl, (C6-C12) tricycloalkyl (C? -C8), C2-C8 alkenyl, C2-C8 alkynyl, R11NH, CON (CH3) R4, CONHR4, COOR15, CON (CH3) R15 or CONHR15; R4 means C?-C8 alkyl which may be optionally substituted once or several times with the same or different radicals from the series of hydroxy, C?-C8 alkoxy, R5, optionally substituted C3-C8 cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di- (C 1 -C 8 alkyl) -aminocarbonyl, aryl (C 6 -C 14) -alkoxy (C 1 -C 8) -carbonyl which may also be substituted on the aryl radical, alkoxy (C 8 -C 8) ) -carbonyl, Het-CO, Rd-CO, tetrazolyl and trifluoromethyl: R5 means optionally substituted C6-C1 aryl, aryl (C6-C? 4) -alkyl (C? -C8) optionally substituted on the aryl radical, or a possibly substituted 5 to 12 membered monocyclic or bicyclic heterocyclic ring, which may be aromatic, partially or totally hydrogenated, and which may contain one, two or three heteroatoms which are the same or different from the series of nitrogen, oxygen and sulfur; R6 means the radical of a natural or non-natural amino acid, an imino acid, an aza-amino acid (optionally N-alkyl (C? -8) -substituted or N-aryl (C6-C14) -alkyl (C? -8) - -substituted), which may also be substituted on the aryl radical, or the radical of a dipeptide, as well as its esters and amides, whereby free functional groups may be protected by protective groups customary in peptide chemistry; R 10 denotes hydroxy, C 1 -C 8 alkoxy, aryl (C 6 -C 14) -alkoxy (C 1 -C 8) which may also be substituted on the aryl radical, optionally substituted C 6 -C 4 aryloxy, alkyl (C 1 -) C8) -carbonyloxy-alkoxy (C? -C3), aryl (C6-C14) -carbonyloxy-alkoxy (C? -C3), amino or mono- or di- ((C? -C18) alkyl) -amino; R11 represents hydrogen, R12a, R1a-CO, R12a-0-CO, R12b-CO, R12b-CS or R12a-S (0) 2; R12a means C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 cycloalkyl, (C3-C12) cycloalkyl (C?-C8) alkyl, optionally substituted C6-C14 aryl, aryl (C6-C14) ) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, or the radical R15; R 12b means amino, di- (C 1 -C 8 alkyl) amino, or R 12a-NH; R 13 is hydrogen or C 1 -C 6 alkyl; R15 represents R16-alkyl (Cx-C6) or represents R16; R16 represents a bicyclic or tricyclic radical of 6 to 14 members, which is saturated or partially unsaturated, and which may also contain one, two, three or four same or different heteroatoms, of the series of nitrogen, oxygen and sulfur, and which may also being substituted with one or more substituents, the same or different, of the alkyl series Het represents the radical of a saturated, monocyclic or 5- to 10-membered polycyclic heterocycle, attached via a ring nitrogen atom, which may contain one, two, three or four additional heteroatoms in the ring, the same or different, of the oxygen, nitrogen, and sulfur series, and which may eventually be substituted on the carbon atoms and on the additional nitrogen atoms of the ring, being able to to exist as substituents on additional nitrogen atoms of the ring radicals, the same or different, from the series of hydrogen, Rh, HCO, RhCO or RhO-CO, and Rh represents alkyl C? -C8, C3-C8 cycloalkyl, (C3-C8) cycloalkyl- (C? -C8) alkyl, optionally substituted C6-C14 aryl or (C6-C? 4) aryl-(C? -C8) alkyl optionally substituted on the aryl radical; e and h represent, independently of one another, 0 or 1; in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.

3. Compounds of formula I according to claim 1 and / or 2, wherein W represents R1-A-C (R13); Z represents oxygen; A represents a direct bond, or methylene; B represents a divalent methylene or ethylene radical, both radicals being unsubstituted or substituted with a radical of the series C C-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C ciclocycloalkyl, cycloalkyl (C3) -C? 0) -alkyl (C? -C6), optionally substituted C6-C? 4 aryl, aryl (C6-C? 4) -alkyl (C? -C6) optionally substituted on the aryl radical, optionally substituted heteroaryl and heteroaryl-C 1 -C 6 alkyl optionally substituted on the heteroaryl radical; E means R10CO; R means hydrogen or C 1 -C 4 alkyl; R ° represents C? -C8 alkyl, C3-C12 cycloalkyl, cycloalkyl (C3-C? 2) -alkyl (C? -8), C6-C12 bicycloalkyl, bicycloalkyl (C? -C? 2) -alkyl (Cx) -C8), C6-C12 tricycloalkyl, (C6-C2-C2) tricycloalkyl (Cx-C8), optionally substituted C6-C14 aryl, aryl (C6-C1) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, or heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical; R1 represents an optionally substituted radical of the phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl series; R 2 means hydrogen or C 1 -C 4 alkyl; s R3 is C alquilo-C4 alkyl, optionally substituted C6-C1 aryl, (C6-C14) aryl (C?-C4) alkyl optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl-alkyl (C?-C) optionally substituted on the heteroaryl radical, C3-C8 cycloalkyl, (C3-C8) cycloalkyl-0-alkyl (C? -C4), C6-C12 bicycloalkyl, (C6-C? 2) -alkyl (C? -C4) bicycloalkyl ), C6-C12 tricycloalkyl, (C6-C12) -cycloalkyl-(C? -C4) alkyl, R NH, CON (CH3) R4, CONHR4, COOR15, CON (CH3) R15 OR CONHR15; R4 means C?-C8 alkyl which may optionally be substituted once or several times with the same or different radicals, from the series of hydroxy, C?-C8 alkoxy, Rs, optionally substituted C3-C8 cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di- (C 1 -C 18 alkyl) -aminocarbonyl, (C 6 -C 14) aryl-alkoxy (C 1 -C 8) -carbonyl which may also be 0 substituted on the aryl radical, (C 1 -C 8) alkoxy carbonyl, Het-CO, R6-CO, tetrazolyl and trifluoromethyl; R5 means optionally substituted C6-C ?4 aryl, aryl (C6-C?) -alkyl (C?-C8) optionally substituted on the aryl radical, or a 5- to 12-membered monocyclic or bicyclic heterocyclic ring, optionally substituted , which may be aromatic, be partially or totally hydrogenated, and which may contain one, two or three heteroatoms which are the same or different from the series of nitrogen, oxygen and sulfur; R6 means the radical of a natural or non-natural amino acid, an imino acid or an aza-amino acid (optionally N-alkyl (C? -8) -substituted or N-aryl (C6-C14) -alkyl (C? -8) - substituted), which may also be substituted on the aryl radical, as well as its esters and amides, free functional groups being protected by usual protecting groups in peptide chemistry; R10 means hydroxy, C?-C8 alkoxy, (C6-C14) aryl-(C?-C8) alkoxy, which may also be substituted on the aryl radical, optionally substituted C6-C? Ar aryloxy, alkyl (C?-C8) ) -carbonyloxy-alkoxy (C? -C6), aryl (C6-C14) -carbonyloxy-alkoxy (C? -C6), amino or mono- or di- ((C? -C8) alkyl) -amino; s R11 represents R12a, R12a-CO, R12a-0-CO, R12b-CO, or R12a-S (0) 2; R 12a means C 1 -C 10 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 2 cycloalkyl, (C 3 -C 12) cycloalkyl (C 1 -C 8) alkyl, optionally substituted C 6 -C 14 aryl, aryl ( C6-C14) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, or the radical R15; R 12b means amino, di- (C 1 -C 0 alkyl) -amino, or R 12 -NH; R 13 is hydrogen or C 1 -C 4 alkyl; R15 represents R16-alkyl (C? -C3) or represents Rld; R1S represents a bicyclic or tricyclic radical of 7 to 12 members, which is saturated or partially unsaturated, and which may also contain one or two identical or different heteroatoms, of the series of nitrogen, oxygen and sulfur, and which may also be substituted with one or more substituents, the same or different, of the C? -C4 alkyl and oxo series; Het represents the radical of a 5- to 10-membered monocyclic or polycyclic heterocycle, saturated, linked through a ring nitrogen atom, which may contain one or two additional ring heteroatoms, the same or different, from the series of Oxygen, nitrogen, and sulfur, and which may optionally be substituted on the carbon atoms and additional nitrogen atoms of the ring, and may exist as substituents on additional nitrogen atoms of the ring, the same or different radicals of the series of hydrogen, Rh, HCO, RhCO and RhO-CO, and Rh represents C? -C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl- (C? -C4) alkyl, optionally substituted C6-C? or aryl (C6-C14) -alkyl (Cx-C4) optionally substituted on the aryl radical; 5 e and h represent, independently of one another, 0 or 1; in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.

4. Compounds of formula I according to one or more of claims 1 to 3, in which W represents R1-A-C (R13); Z represents oxygen; A represents a direct bond, or methylene; B represents an unsubstituted methylene radical or a methylene radical which is substituted with a radical from the series of C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, (C3-C7) cycloalkyl-alkyl (C? -C4), optionally substituted C6-C10 aryl, aryl (C6-C? 0) -alkyl (C? -C4) optionally substituted on the aryl radical, optionally substituted heteroaryl and heteroaryl-alkyl (C? -C4) optionally substituted on the heteroaryl radical; E means R10CO; R means hydrogen or C 1 -C 4 alkyl; R ° means aryl (C6-C14) -alkyl (C? -C4) optionally substituted on the aryl radical or heteroaryl (C? -C4) alkyl optionally substituted on the heteroaryl radical; R1 represents an optionally substituted radical of the series of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl; R 2 means hydrogen or C 1 -C 4 alkyl; R3 represents a phenyl radical or naphthyl radical, unsubstituted, or a phenyl radical or naphthyl radical substituted with one, two or three radicals, the same or different, from the series of C C-C4 alkyl, C?-C4 alkoxy, hydroxy , halogen, trifluoromethyl, nitro, methylenedioxy, ethylenedioxy, hydroxycarbonyl, (C 1 -C 4) alkoxycarbonyl, aminocarbonyl, cyano, phenyl, phenoxy, benzyl and benzyloxy, or R 3 represents pyridyl, C 1 -C 4 alkyl, C 2 alkenyl C4, C2-C4 alkynyl, C5-C6 cycloalkyl, RX1NH, CON (CH3) R4, CONHR4, CON (CH3) Rls or CONHR15; R4 means C?-C8 alkyl which may optionally be substituted with one or two radicals, the same or different, from the series of hydroxy, C?-C8 alkoxy, Rs, optionally substituted C3-C8 cycloalkyl, hydroxycarbonyl, aminocarbonyl, aryl (C6) -C? 0) -alkoxy (C? -C4) -carbonyl which may also be substituted on the aryl radical, (C? -C6) alkoxycarbonyl, Het-CO, tetrazolyl and trifluoromethyl; R5 means C6-C? 0 optionally substituted aryl, aryl (C6-C10) -alkyl (C?-C4) optionally substituted on the aryl radical, or a possibly substituted 5 to 10-membered monocyclic or bicyclic heterocyclic ring, which may be substituted be or aromatic, be partially or totally hydrogenated, and which may contain one, two or three heteroatoms, the same or different, from the series of nitrogen, oxygen and sulfur; R 10 denotes hydroxy, C 1 -C 8 alkoxy, aryl (C 6 -C 10) -alkoxy (C 1 -C 4), which may also be substituted on the aryl radical, optionally substituted C 6 -C 10 aryloxy, alkyl (C x C 8) - carbonyloxy-alkoxy (C? -C4), aryl (C6-C? 0) -carbonyloxy-alkoxy (C? -C4), amino or mono- or di- ((C-C8) alkyl-amino; R11 represents R12a, R12a-C0, R12a-0-C0, R12b-C0, or R12a-S (0) 2; R 12a means C 1 -C 10 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 0 C 3 -C 2 cycloalkyl, (C 3 -C 2) cycloalkyl- (C 1 -C 8) alkyl, optionally substituted C 6 -C 14 aryl , aryl (C6-C? 4) -alkyl (C? -C8) optionally substituted on the aryl radical, optionally substituted heteroaryl, heteroaryl (C? -C8) alkyl optionally substituted on the heteroaryl radical, or the radical R15; R12b means amino, di- (alkyl (C? -C? 0)) -amino, or R12-NH; R 13 is hydrogen or C 1 -C 4 alkyl; R15 represents Rld-alkyl (Cx-C3) or represents Rld; Rld represents a bicyclic or tricyclic radical of 7 to 12 members, which is saturated, and which may also contain one or two heteroatoms of the same or different series of nitrogen, oxygen and sulfur, and which may also be substituted by one or more substituents , the same or different, from the C? -C4 alkyl and oxo series; Het represents the radical of a saturated 5-7 membered monocyclic heterocycle, linked through a ring nitrogen atom, which may contain one or two additional heteroatoms in the ring, same or different, from the series of oxygen, nitrogen, and sulfur, and which may eventually be substituted on the carbon atoms and on the additional nitrogen atoms of the ring, and there may exist as substituents on additional nitrogen atoms of the ring, the same or different radicals of the hydrogen series , Rh, HCO, RhCO or RhO-CO, and Rh represents C?-C6 alkyl, C3-C8 cycloalkyl, (C3-C8) cycloalkyl (C?-C4) alkyl, optionally substituted C6-C10 aryl or aryl (C6) -C? 0) -alkyl (C? ~ -C4) optionally substituted on the aryl radical; e and h represent, independently of one another, 0 or 1; in all its stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.

5. Compounds of formula I according to one or more of claims 1 to 4, in which B represents unsubstituted methylene or methylene which is substituted with a C? -C8 alkyl radical, in all its stereoisomeric forms and mixtures of the same in all proportions, and their physiologically tolerable salts.

6. Compounds of formula I according to one or more of claims 1 to 5, in which R1 represents a radical of the series of phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, which is unsubstituted or substituted by one, two or three substituents, the same or different, from the series of C C-C4 alkyl, C?-C4 alkoxy, halogen, amino, trifluoromethyl, hydroxy, hydroxy -alkyl (C?-C4), methylenedioxy, ethylenedioxy , phenyl, phenoxy, benzyl and benzyloxy, in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.

7. Compounds of formula I according to one or more of claims 1 to 6, in which R1 represents a radical from the series of phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3- pyrrolyl, 4-imidazolyl and 3-pyridyl and 4-pyridyl, the phenyl radical being unsubstituted or substituted by one or two radicals, the same or different, from the series of C C-C4 alkyl, C?-C4 alkoxy, halogen, trifluoromethyl, hydroxy, hydroxy (C? -C4) alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, and the heteroaromatic radicals being unsubstituted or substituted with one or two substituents, the same or different, from the C? -C4 alkyl, C? -C4 alkoxy, halogen, amino, trifluoromethyl, hydroxy, hydroxy (C? -C4), methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy groups, in all their stereoisomeric and mixtures thereof in all proportions, and their physiologically tolerable salts.

8. Compounds of formula I according to one or more of claims 1 to 7, in which R1 represents an unsubstituted radical, of the series of phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl , 3-pyrrolyl, 4-imidazolyl, 3-pyridyl and 4-pyridyl, in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.

9. Compounds of formula I according to one or more of claims 1 to 8, in which R1 represents an unsubstituted radical, of the series of phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl , 4-imidazolyl and 4-pyridyl, in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.

10. Process for preparing compounds of formula I according to one or more of claims 1 to 9, characterized in that condensation of fragments of a compound of formula II is carried out. with a compound of formula III, wherein, in the formulas II and III, the groups W, Z, B, E, R, R °, R2 and R3, as well as e and h, are defined as in claims 1 to 9, or groups may also be included functional in protected form or in the form of precursors, and wherein G represents hydroxycarbonyl, (C6C6) alkoxycarbonyl or activated carboxylic acid derivatives.

11. Compounds of formula I according to one or more of claims 1 to 9 and / or their physiologically tolerable salts, for use as medicaments. Pharmaceutical preparation characterized in that it contains, together with excipient substances and / or pharmaceutically acceptable additives, one or more compounds of formula I according to one or more of claims 1 to 9 and / or their physiologically tolerable salts. 13. Compounds of formula I according to one or more of claims 1 to 9 and / or their physiologically tolerable salts, for use as inflammation-inhibiting substances. 14. Compounds of formula I according to one or more of claims 1 to 9 and / or their physiologically tolerable salts, for use in the therapy or prophylaxis of rheumatoid arthritis, of inflammatory bowel disease, of systemic lupus erythematosus, or of inflammatory diseases of the central nervous system. 15. Compounds of formula I according to one or more of claims 1 to 9 and / or their physiologically tolerable salts, for use in the therapy or prophylaxis of asthma or allergies. 16. Compounds of formula I according to one or more of claims 1 to 9 and / or their physiologically tolerable salts, for use in the therapy or prophylaxis of cardiovascular diseases, arteriosclerosis, restenosis, or diabetes, for prevent the deterioration of transplanted organs, to inhibit tumor growth or tumor metastasis, or for the therapy of malaria. 17. Compounds of formula I according to one or more of claims 1 to 9 and / or their physiologically tolerable salts, for use as inhibitors of the adhesion and / or migration of leukocytes, or as substances inhibiting the receptor VLA-4.