HK1019450A - Novel 5-membered ring heterocycles, their preparation, their use and pharmaceutical preparations comprising them - Google Patents

Description

Five-membered heterocyclic compounds, method for the production thereof, and use thereof

And pharmaceutical preparations containing them

The invention relates to compounds of formula (I)B, E, W, Y, Z, R, R therein²、R^2a、R^2b、R³G and h have the following meanings. A compound of formula IAre important pharmaceutically active compounds which are suitable, for example, for the therapy and prophylaxis of inflammatory diseases, such as rheumatoid arthritis, or allergic diseases. The compounds of formula (I) are inhibitors of leukocyte adhesion and migration and/or antagonists of the adhesion receptor VLA-4 belonging to the integrin group. They are generally suitable for the treatment or prophylaxis of diseases which are induced by an adverse degree of leukocyte adhesion and/or migration thereof or by associated causes, or which are caused by cell-cell or cell-matrix interactions based on interactions of VLA-4 with its ligands. The invention further relates to processes for the preparation of the compounds of formula I, their use in the treatment and prophylaxis of the diseases mentioned and pharmaceutical preparations which contain the compounds of formula I.

Integrins are adhesion receptors that play a key role in cell-cell binding and cell-extracellular matrix binding processes. They have α β -heterodimer structures and are widely distributed in cells, and their evolutionary conservation is high. Integrins include, for example: fibrinogen receptors located on platelets and interacting specifically with the RGD (Arg-Gly-Asp) sequence of fibrinogen; or vitronectin receptors located on osteoclasts and interacting specifically with the RGD sequence in vitronectin or osteopontin. Integrins are mainly classified into 3 groups, with the β 2 subfamily, represented by LFA-1 (leukocyte function-associated antigen-1), Mac-1 and p150/95, acting specifically on cell-cell reactions within the immune system, whereas the representatives of β 1 and β 3 primarily mediate the adhesion behavior between cells and extracellular matrix components (Russlahti, annu. rev. biochem.1988,57,375). Integrins of the β 1 subfamily, also known as VLA proteins (very late (activating) antigens), include at least six receptors that act specifically as ligands for fibronectin, collagen and/or laminin. Within the VLA family, the integrin VLA-4(α 4 β 1) is atypical in that it is primarily restricted to lymphoid and myeloid cells only and is responsible for cell-cell interactions with many other cells. For example, VLA-4 mediates interactions between T and B lymphocytes and heparin-II binding fragments of human plasma Fibronectin (FN). The binding of VLA-4 to the heparin II-binding fragment of plasma fibronectin is based on interactions with the LDVP sequence. In contrast to fibrinogen or vitronectin, VLA-4 is not a typical RGD-binding integrin (Kilger & Holzmann, J.mol.meth.1995,73,347).

Leukocytes in the blood circulation normally have a low affinity for vascular endothelial cells lining the blood vessels. However, cytokines released from inflammatory tissues induce endothelial cell activation and thus allow for the expression of cell surface antigens in large quantities. Which comprises the following steps: for example, the adhesion molecule ELAM-1 (endothelial adhesion molecule-1; also known as E-selectin) which specifically binds to neutrophils, ICAM-1 (intercellular adhesion molecule-1) which interacts with LFA-1 (leukocyte function-associated antigen 1) on leukocytes, and VCAM-1 (vascular cell adhesion molecule-1) which binds to various leukocytes, particularly lymphocytes (Osborn et al, cell, 1989,59, 1203). VCAM-1, which is analogous to ICAM-1, is also a member of the immunoglobulin gene superfamily. VCAM-1 (formerly known as INCAM-110) was demonstrated to be an adhesion molecule on endothelial cells induced by inflammatory cytokines such as TNF and IL-1 and Lipopolysaccharide (LPS). Elices et al (cells, 1990,60,577) believe that the receptor-ligand pair formed by VLA-4 and VCAM-1 mediates the adhesive behaviour of lymphocytes and thus activates endothelial cells. At this point VCAM-1 does not bind VLA-4 because of the interaction between VLA-4 and the RGD-sequence; this sequence is not contained in VCAM-1 (Berelson et al, Current Biology, 1995,5, 615). However, VLA-4 is also present in other leukocytes and mediates leukocyte adhesion in addition to lymphocytes also through the VCAM-1/VLA-4 adhesion mechanism. VLA-4 is therefore only an example of a β 1 integrin receptor that has a significant effect on cell-cell interactions and cell-extracellular matrix interactions via the ligands VCAM-1 and fibronectin.

Cytokine-induced adhesion molecules primarily affect leukocyte recruitment into extravascular tissue regions. Leukocytes are recruited to areas of inflamed tissue by cell adhesion molecules that are expressed on the surface of endothelial cells and act as ligands (ligands and receptors are also used interchangeably) for leukocyte surface proteins or protein complexes (receptors). Blood-derived leukocytes must first adhere to endothelial cells before migrating into synovial cells. Since VCAM-1 binds to cells that carry the integrin VLA-4 (. alpha.4beta.1), such as eosinophils, T and B lymphocytes, monocytes or neutrophils, it functions, together with the VCAM-1/VLA-4 mechanism, to recruit such cells to the bloodstream into the foci of infection and inflammation (Elces et al, cells 1990,60, 577; Osborne, cells 1990,62, 3; Issekutz et al, J.exp.Med.1996, 2175).

The mechanism of VCAM-1/VLA-4 adhesion is involved in a number of physiological and pathological processes. In addition to cytokine-induced endothelial cells, VCAM-1 may be expressed in the following cells: myoblasts, lymphoid dendritic cells and tissue macrophages, rheumatoid synovium, cytokine-stimulated nerve cells, epithelial cells of the Bowman's capsule wall, tubular epithelial cells, inflammatory tissue in cardiac and renal transplant rejection, and intestinal tissue in host versus graft disease. VCAM-1 was also found to be expressed in the tissue region of arterial endothelial cells over early atherosclerotic plaques in a rabbit model. In addition, VCAM-1 is expressed on the nodular dendritic cells of human lymph nodes and is found on bone marrow stromal cells, for example in mice. The latter finding suggests a role for VCAM-1 in B-cell development. In addition to cells of hematopoietic origin, VLA-4 was also found on cell lines such as melanoma and the VCAM-1/VLA-4 adhesion mechanism was associated with metastasis of this tumor (Rice et al, science, 1989,246,1303).

VCAM-7D, with 7 immunoglobulin domains, is the predominant form of VCAM-1 on endothelial cells in vivo and is the predominant form in vivo. Domains 4,5 and 6 are similar to domains 1,2 and 3 with respect to amino acid sequence. In another form consisting of 6 domains, the 4 th domain will no longer be present after additional cleavage, and this form is referred to herein as VCAM-6D. VCAM-6D can still bind to VLA-4 expressing cells.

More specific descriptions of VLA-4, VCAM-1, integrins and attachment proteins are described in the literature, for example: kilger and Holzmaan, j.mol.meth.1995,73,347; elece, cell adhesion in human disease, Wiley, chicchester 1995, page 79; kuijpers, Springer semin.

In view of the important role of the VCAM-1/VLA-4 mechanism in cell adhesion processes, e.g., in infection, inflammation, or atherosclerosis, attempts have been made to control diseases, particularly, e.g., inflammation, by methods that intervene in the above-described adhesion processes (Osborn et al, cell, 1989,59, 1203). The method employs monoclonal antibodies directed against VLA-4. Such monoclonal antibodies (mAB) which act as VLA-4 antagonists to block the interaction between VCAM-1 and VLA-4 are known, and thus, for example, anti-VLA-4 mAB HP2/1 and HP1/3 inhibit the adhesion of VLA-4-expressing Ramos cells (B-cell-like cells) to human umbilical endothelial cells and VCAM-1 transfected COS cells. anti-VCAM-1 mAB 489 also inhibited the attachment of Ramos cells, Jurkat cells (T-cell-like cells) and HL60 cells (granulocyte-like cells) to COS cells transfected with genetic constructs for the expression of VCAM-6D and VCAM-7D. For antibodies directed against the α 4 subunit of VLA-4, in vitro data indicate that: adhesion of lymphocytes to synovial endothelial cells is blocked, and this adhesion plays a role in rheumatoid arthritis (van Dinther-Janssen et al, J.Immunol, 1991,147,4207).

In vivo experiments have shown that anti- α 4 mAB can inhibit autoimmune encephalomyelitis used in the experiments. Leukocyte migration into the inflammatory foci is also blocked by monoclonal antibodies directed against the α 4 chain in VLA-4. The effect of VLA-4 on leukocyte recruitment into inflamed lung tissue was verified by studying the effect of antibodies on VLA-4 dependent adhesion mechanisms using an asthmｃA model (USSN 07/821768; EP-A-626861). Administration of anti-VLA-4 antibodies can inhibit late phase reactions and airway hyperreactions in allergic sheep.

The VLA-4 dependent cell adhesion mechanism has also been demonstrated in a primate model with Inflammatory Bowel Disease (IBD). In this model, which corresponds to ulcerative colitis in humans, administration of anti-VLA-4 antibodies significantly reduced acute inflammation.

It has also been shown that VLA-4 dependent cell adhesion may play a role in the following clinical conditions including the following chronic inflammatory processes: rheumatoid Arthritis (Cronstein and Weismann, Arthritis Rheum.1993,36,147; Elices et al, J.Clin.Invest.1994,93,405), diabetes (Yang et al, Proc.Natl.Acad.Sci.USA 1993, 90, 10494), systemic lupus erythematosus (Takeuchi et al, J.Clin.Invest.1993,92,3008), delayed type allergic reactions (type IV allergic reactions) (Elices et al, Clin.Exp.Rheumatoid.1993, 11, S77), multiple sclerosis (Yednock et al, Nature, 1992,356,63), malaria (Ockenhouse et al, J.Exp.Med.1992,176,1183), arteriosclerosis (O' Brien et al, J.Clin.10525, transplant (Iscke. 92,945), Ismobue et al, J.Exp.Med.1992.1992, 7626, Haemon et al, melanoma (Ockenheimoma et al, J.Freukayama et al, J.Clin.,. 1992., 7626, Immunoma et al, J.1992, Immunoma, J.7626, melanoma (Bio-A) and more malignant tumors (Bio-A), E., 18, Bio-A), melanoma (Bio-S. transplantation, Bio-A) and E).

Thus, the VLA-4 blocking effect produced by suitable antagonists may provide effective therapeutic feasibility, particularly, for example, for the treatment of inflammatory diseases including asthma and IBD. The particular relevance of VLA-4 antagonists in the treatment of rheumatoid arthritis is based on the fact that (as described above): blood-derived leukocytes must first adhere to endothelial cells before migrating into the synovium, where the VLA-4 receptor plays a role. The involvement of VCAM-1 in the induction of inflammatory material on endothelial cells (Osborn, cell, 1990,62, 3; Stoolman, cell, 1989,56,907) and recruitment of various leukocytes into the intralesional regions of infection and inflammation has been discussed above. In this regard, T cells adhere to activated endothelium primarily by the mechanisms of LFA-1/CAM-1 and VLA-4/VCAM-1 adhesion (Springer, cells, 1994,76, 301). VLA-4 has an enhanced ability to bind VCAM-1 in rheumatoid arthritis for most synovial T cells (Postigo et al, J.Clin. invest,1992,89, 1445). In addition, enhanced adhesion between synovial T cells and fibronectin has been observed (Laffon et al, J.Clin.Incest,1991,88, 546; Morales-Ducret et al, J.Immunol.1992,149, 1424). VLA-4 is up-regulated both in its expression and on T lymphocytes of the rheumatoid synovium. Blocking the binding between VLA-4 and its physiological ligands, VCAM-1 and fibronectin, may be effective in preventing or alleviating the inflammatory process of the joint. This effect was also demonstrated in the test of antibody HP2/1 in Lewis rats with adjuvant arthritis, where an effective disorder prevention effect was observed (Barbadillo et al, Springer Semin. Immunopathol.1995,16,427). VLA-4 is therefore an important therapeutic target molecule.

The above-mentioned VLA-4 antibodies and the use of these antibodies as VLA-4 antagonists are described in the patent applications WO-A-93/13498, WO-A-93/15764, WO-A-94/16094, WO-A-94/17828 and WO-A-95/19790. Peptide compounds which are VLA-4 antagonists are described in the patent applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581, WO-A-96/06108 and WO-A-96/20216. However, the use of antibody and peptide compounds as pharmaceuticals suffers from disadvantages such as lack of oral effectiveness, susceptibility to degradation, or immunogenic effects after long-term use. There is therefore still a need for VLA-4 antagonists with good properties for use in therapy and prophylaxis.

5-membered heterocycles are described in WO-A-94/21607 and WO-A-95/14008, EP-A-449079, EP-A-530505 (US-A-5389614), WO-A-93/18057, EP-A-566919 (US-A-5397796), EP-A-580008 (US-A-5424293) and EP-A-584694 (US-A-5554594) disclose hydantoin derivatives having platelet aggregation inhibiting activity. EP-A-842934 (German patent application 19647380-2) describes compounds of this type which have ｃA surprising leukocyte adhesion-inhibiting effect and which are inhibitors of VLA-4. Further studies have shown that the compounds of the present invention are also inhibitors of leukocyte adhesion and VLA-4 antagonists.

The present invention relates to compounds of formula I:wherein W is R¹-A-C(R¹³) Or R¹-CH = C; y is a carbonyl, thiocarbonyl or methylene group; z is N (R)⁰) Oxygen, sulfur or methylene; a is a divalent group selected from: (C)₁-C₆) Alkylene group, (C)₃-C₇) -cycloalkylene, phenylene- (C)₁-C₆) Alkyl radicals, (C)₁-C₆) Alkylene-phenyl, phenylene- (C)₂-C₆) -an alkenyl group; or a divalent 5-or 6-membered, saturated or unsaturated heterocyclic radical which contains 1 or 2 nitrogen atoms and may be substituted by (C)₁-C₆) -alkyl or doubly-bound oxygen or doubly-bound sulfur mono-or disubstituted; b is divalent (C)₁-C₆) An alkylene radical which may be unsubstituted or selected from (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenyl, (C)₂-C₈) -alkynyl, (C)₃-C₁₀) -cycloalkyl, (C)₃-C₁₀) -cycloalkyl- (C)₁-C₆) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₆) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₆) -substituent substitution of alkyl; e and E^aIndependently of one another, tetrazolyl, (R)^dO)₂P(O)、HOS(O)₂、R⁹NHS(O)₂Or R¹⁰CO；R⁰Is hydrogen, (C)₁-C₈) Alkyl radicals, (C)₃-C₁₂) -cycloalkyl, (C)₃-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted heteroaryl- (C)₁-C₈) Alkyl, H-CO, (C)₁-C₈) -alkyl-CO, (C)₃-C₁₂) -cycloalkyl-CO, (C)₃-C₁₂) -cycloalkyl- (C)₁-C₈) -alkyl-CO, (C)₆-C₁₂) -bicycloalkyl-CO, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) -alkyl-CO, (C)₆-C₁₂) -tricycloalkyl-CO, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -alkyl-CO, optionally substituted (C)₆-C₁₄) aryl-CO, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl-CO, optionally substituted heteroaryl-CO, heteroaryl optionally substituted heteroaryl- (C) thereof₁-C₈) -alkyl-CO, (C)₁-C₈) alkyl-S (O)_n、(C₃-C₁₂) cycloalkyl-S (O)_n、(C₃-C₁₂) -cycloalkyl- (C)₁-C₈) alkyl-S (O)_n、(C₆-C₁₂) -bicycloalkyl-S (O)_n、(C₆-C₁₂) -bicycloalkyl- (C)₁-C₈) alkyl-S (O)_n、(C₆-C₁₂) -tricycloalkyl-S (O)_n、(C₆-C₁₂) -tricycloalkyl- (C)₁-C₈) alkyl-S (O)_nOptionally substituted (C)₆-C₁₄) aryl-S (O)_nOptionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) alkyl-S (O)_nOptionally substituted heteroaryl-S (O)_nOr heteroaryl optionally substituted with heteroaryl- (C)₁-C₈) alkyl-S (O)_nWherein n is 1 or 2; r, R^a、R^b、R^cAnd R^dIndependently of one another, hydrogen, (C)₁-C₈) Alkyl radicals, (C)₃-C₈) -cycloalkyl, (C)₃-C₈) -cycloalkyl- (C)₁-C₈) -alkyl, optionally substituted (C)₆-C₁₄) Aryl or aryl optionally substituted (C)₆-C₁₄) -aryl- (C)₁-C₈) -an alkyl group; r¹Is X-NH-C (= NH) - (CH)₂)_pOr X¹-NH-(CH₂)_pWhereinp is 0, 1,2 or 3; x is hydrogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkylcarbonyl, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₁₈) -alkylcarbonyloxy- (C)₁-C₆) -alkoxycarbonyl, optionally substituted (C)₆-C₁₄) Arylcarbonyl, optionally substituted (C)₆-C₁₄) Aryloxy carbonyl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₆) -alkoxycarbonyl, (R)^dO)₂P (O), cyano, hydroxy, (C)₁-C₆) Alkoxy, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₆) -alkoxy or amino; x¹Is one of the meanings of X or is R '-NH-C (= N-R "), wherein R' and R" independently of one another have the meaning of X; r²、R^2aAnd R^2dIndependently of one another, hydrogen, (C)₁-C₈) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) Alkyl radicals, (C)₃-C₈) -cycloalkyl or (C)₃-C₈) -cycloalkyl- (C)₁-C₈) -an alkyl group; r³Is R¹¹NH、(C₉-C₁₂) -cycloalkyl, (C)₉-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) Alkyl, CO-N (R)²)-R⁴-E^aOr CO-R⁵-R⁶-R⁷；

But wherein, if W is R at the same time¹-A-C(R¹³),R¹-A is 4-amidinophenyl, R¹³Is methyl, Z is NH, Y is carbonyl, B is CH₂R and R²Is hydrogen, E is hydroxycarbonyl, g is 0 and h is 1, and for dioxoimidazolesAsymmetric carbon atoms in the alkane ring and for the ring with R²And R³At a molar ratio of 1: 1 of carbon atoms of the group in R configuration and S configuration, R³Is not 1-adamantyl; r⁴Is divalent (C)₁-C₆) Alkylene, which radical may be chosen from R¹¹NH、(C₉-C₁₂) -cycloalkyl, (C)₉-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -alkyl, and which may also be substituted by one or two other radicals, which may be the same or different (C)₁-C₄) -alkyl substitution; r⁵Is a natural or unnatural amino acid, imino or aza amino acid, in which the free functional group can be protected by protective groups customary in peptide chemistry or is present in the form of an ester or amide, in which amino acid or aza amino acid the N-terminal nitrogen atom carries the group R^b；R⁶Independently of R⁵But having R⁵Or a direct bond; r⁷Is R⁸-NH or Het; r⁸Is (C)₃-C₁₂) -cycloalkyl, (C)₃-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl or (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -an alkyl group; r⁹Is hydrogen, aminocarbonyl, (C)₁-C₁₈) -alkylaminocarbonyl, (C)₃-C₈) -cycloalkylaminocarbonyl, optionally substituted (C)₆-C₁₄) -arylaminocarbonyl, (C)₁-C₁₈) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) Alkyl radicals, (C)₃-C₁₂) -cycloalkyl, (C)₃-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl or (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -an alkyl group; r¹⁰Is hydroxy, (C)₁-C₈) Alkoxy, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkoxy, optionally substituted (C)₆-C₁₄) -aryloxy group, (C)₁-C₈) -alkylcarbonyloxy- (C)₁-C₆) -alkoxy, (C)₆-C₁₄) Aryl carbonyloxy- (C)₁-C₆) -alkoxy, amino, mono-or di- ((C)₁-C₈) -alkyl) -amino, R⁸-NH or Het; r¹¹Is R¹²NH-CO、R¹²-NH-CS、R^14aO-CO、R^14bCO、R^14cS(O)、R^14dS(O)₂、R^14eNH-S (O) or R^14fNH-S(O)₂；R¹²Is optionally substituted (C)₆-C₁₄) Aryl, aryl of which may be substituted (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenyl, (C)₂-C₈) -alkynyl or R¹⁵；R¹³Is hydrogen, (C)₁-C₆) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) Alkyl radicals, (C)₃-C₈) -cycloalkyl or (C)₃-C₈) -cycloalkyl- (C)₁-C₈) -an alkyl group; r^14aIs optionally substituted heteroaryl, heteroaryl wherein heteroaryl is optionally substituted- (C)₁-C₈) -alkyl or R¹⁵；R^14bAnd R^14dIndependently of one another: the aryl group of which is optionally substituted (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₈) -alkyl or R¹⁵；R^14cAnd R^14eIndependently of one another: (C)₁-C₁₈) -alkyl, optionally substituted (C)₆-C₁₄) - - -aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₈) -alkyl or R¹⁵；R^14fIs (C) optionally substituted in the aryl radical₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₈) Alkyl radicals, (C)₉-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -an alkyl group; r¹⁵Is R¹⁶-(C₁-C₆) -alkyl or R¹⁶；R¹⁶Is a 3-to 12-membered monocyclic or 6-to 24-membered bicyclic or tricyclic radical, wherein these radicals are saturated or partially unsaturated and may also contain 1,2,3 or 4 identical or different ring heteroatoms from the group consisting of nitrogen, oxygen, sulfur and may also be selected from the group consisting of (C) by one or more identical or different₁-C₄) -alkyl and oxo; het is a 5-to 10-membered monocyclic or polycyclic heterocyclic group which is bonded via a ring nitrogen atom and which may be aromatic or partially unsaturated or saturated and may contain 1,2,3 and 4 identical or different further ring heteroatoms from the group consisting of oxygen, nitrogen and sulfur and which may be optionally substituted on carbon atoms and further ring nitrogen atoms, wherein the possible substituents on further ring nitrogen atoms thereof may be identical or different and are selected from R^c、R^cCO and R^cO-CO; g and h are independent of each otherAnd is 0 or 1; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Alkyl groups may be straight-chain or branched, and the same applies when they bear substituents or substituents as other groups, for example as substituents in alkoxy, alkoxycarbonyl or arylalkyl groups. The same is true for divalent alkylene groups. Suitably (C)₁-C₁₈) Examples of alkyl groups are: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, heptyl, octyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, isopropyl, isobutyl, isopentyl, isohexyl, 3-methylpentyl, 2,3, 5-trimethylhexyl, sec-butyl, tert-pentyl, neopentyl. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. The two free bonds in the alkylene group may be located on the same carbon atom or may be derived from different carbon atoms. Examples of alkylene are methylene, ethylene (=1, 2-ethylene), tri, tetra, penta and hexamethylene, 1-methylethylene and 2-methylethylene (=1, 2-propylene), 1-dimethylethylene, 2-dimethyl-1, 3-propylene; methylene substituted by alkyl, for example methylene substituted by methyl (= methylmethylene or 1, 1-ethylene), methylene substituted by ethyl, isopropyl, isobutyl or tert-butyl; or two alkyl-substituted methylene groups, such as dimethylmethylene (2, 2-propylene or 2-propylene).

Alkenyl and alkenylene and alkynyl groups may also be straight-chain or branched. Examples of alkenyl are ethenyl, 1-propenyl, 2-propenyl, butenyl, 3-methyl-2-butenyl, examples of alkenylene are ethenylene or propenyl, and examples of alkynyl are ethynyl, 1-propynyl, 2-propynyl (= propargyl) or 6-hexynyl.

Examples of cycloalkyl groups are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl, which may also be substituted,for example, by (C)₁-C₄) -alkyl substitution. Examples of substituted cycloalkyl groups which may be mentioned are 4-methylcyclohexyl and 2, 3-dimethylcyclopentyl. The same applies to cycloalkylene.

If R is¹⁶Is a saturated monocyclic ring containing no ring heteroatoms, which is cycloalkyl. If R is¹⁶Containing one or more ring heteroatoms, it is a heterocyclic group. A 3-to 12-membered ring may contain 3,4,5, 6,7, 8, 9, 10, 11, or 12 ring members. Bicyclic group, tricyclic group and R¹⁶Representative 6-24 membered bicyclic and tricyclic groups are formally derived by removal of one hydrogen atom from a bicyclic or tricyclic ring. As ring members, the bicyclic and tricyclic rings may themselves contain only carbon atoms, and thus they may be bicycloalkanes or tricycloalkanes; but in the radical represented by R¹⁶When they contain 1 to 4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, they may therefore be aza, oxa or thia bicycloalkanes or tricycloalkanes. If a heteroatom is present, preference is given to heteroatoms which contain 1 or 2, in particular nitrogen or oxygen atoms. The same is true for 3-12 membered monocyclic rings. The heteroatoms may occupy any position in the desired bicyclic or tricyclic structure and may be located within the bridge and, in the case of nitrogen atoms, may also be located at the bridgehead. Both bicycloalkanes and tricycloalkanes, as well as heterocyclic analogues thereof, may be fully saturated or contain one or more double bonds; preferably containing 1 or 2 double bonds or preferably being fully saturated. Bicycloalkanes and tricycloalkanes and heterocyclic analogues thereof and saturated and unsaturated representatives thereof may be unsubstituted or substituted in any suitable position by one or more identical or different substituents, for example by one or two oxo and/or one or more (e.g. 1,2,3 or 4) identical or different (C)₁-C₄) Alkyl groups (for example methyl or isopropyl, preferably methyl). The free bond on the bicyclic or tricyclic group can be located at any given position on the molecule, and thus the group can be bonded through the bridgehead atom or the intrabridge atom. The free bond may also be at any selected stereochemical position, for example at the exo (exo) position or the endo (endo) position. The same applies to a single ring.

Can be derivedTo give a bicyclic radical or R¹⁶An example of a bicyclic ring system parent structure of the bicyclic group shown is norbornane (= bicyclo [ 2.2.1)]Heptane), bicyclo [2.2.2]Octane and bicyclo [3.2.1]Octane, the heteroatom-containing, unsaturated or substituted ring system being, for example, 7-azabicyclo [2.2.1]Heptane, bicyclo [2.2.2]Oct-5-ene and camphor (=1,7, 7-trimethyl-2-oxobicyclo [ 2.2.2)]Heptane).

Can be derivatized to form a tricyclic group or R¹⁶An example of a system of tricyclic groups shown is twistane (= tricyclo [ 4.4.0.0)^3,8]Decane), adamantane (= tricyclo [ 3.3.1.1)^3,7]Decane), noradamantane (= tricyclo [ 3.3.1.0)^3,7]Nonane), tricyclo [2.2.1.0^2,6]Heptane, tricyclo [5.3.2.0^4,9]Dodecane, tricyclo [5.4.0.0^2,9]Undecane or tricyclo [5.5.1.0^3,11]Tridecane.

Preference is given to bicyclic radicals, tricyclic radicals and R¹⁶The bicyclic or tricyclic groups shown are prepared from bridged bicyclic or tricyclic rings, i.e., from ring systems containing two or more common atoms. Wherein R is¹⁶Further preferred among the groups shown are 6-to 18-membered rings, more preferably 7-to 12-membered rings. Further preferred specific examples of bicyclic and tricyclic groups are: 2-norbornyl radical (two such radicals with free bonds in the exo-and endo-positions), 2-bicyclo [3.2.1]Octyl, 1-adamantyl, 2-adamantyl, noradamantyl (e.g., 3-noradamantyl), and homoadamantyl. More preferred are 1-and 2-adamantyl.

(C₆-C₁₄) Aryl is for example: phenyl, 1-naphthyl, 2-naphthyl, biphenyl, anthracenyl or fluorenyl, (C)₆-C₁₂) Aryl is, for example, phenyl, naphthyl or biphenyl, (C)₆-C₁₀) Aryl is for example phenyl or naphthyl. Preferred aryl groups are 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl and phenyl. The aryl radicals, in particular the phenyl radical, may be mono-or polysubstituted, preferably mono-, di-or trisubstituted, the substituents of the aryl radicals being identical or different and being selected from (C)₁-C₈) Alkyl, preferably (C)₁-C₄) Alkyl, (C)₁-C₈) Alkoxy, preferably (C)₁-C₄) Alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, methylenedioxy, ethylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C)₁-C₄) Alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R)^dO)₂P(O)、(R^dO)₂P (O) -O-, tetrazolyl. The same applies, for example, to aralkyl or arylcarbonyl groups. Aralkyl is preferably benzyl and 1-and 2-naphthylmethyl, 2-, 3-and 4-biphenylmethyl and 9-fluorenylmethyl, and 1-phenylethyl and 2-phenylethyl, all of which may also be substituted.

Substituted aralkyl radicals are, for example: the aryl part of which may be substituted by one or more (C)₁-C₈) -alkyl, preferably with (C)₁-C₄) -alkyl substituted benzyl and naphthylmethyl; for example 2-, 3-and 4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl, 3, 5-dimethylbenzyl, pentamethylbenzyl, 2-,3-, 4-, 5-, 6-, 7-and 8-methyl-1-naphthylmethyl, 1-, 3-, 4-, 5-, 6-, 7-and 8-methyl-2-naphthylmethyl; the aryl part of which is substituted by one or more (C)₁-C₈) Alkoxy, preferably (C)₁-C₄) Alkoxy-substituted benzyl and naphthylmethyl radicals, such as 4-methoxybenzyl, 4-neopentyloxybenzyl, 3, 5-dimethoxybenzyl, 3, 4-methylenedioxybenzyl, 2,3, 4-trimethoxybenzyl; 2-,3-, and 4-nitrobenzyl; halobenzyl groups, such as 2, 3-and 4-chlorobenzyl, and 2-, 3-and 4-fluorobenzyl, 3, 4-dichlorobenzyl, pentafluorobenzyl, trifluoromethylbenzyl, such as 3-and 4-trifluoromethylbenzyl or 3, 5-bis (trifluoromethyl) benzyl. However, the substituted aralkyl group may also contain different substituents. Examples of the substituted aryl group in the substituted arylalkyl group are the same as those of the substituted aryl group described above.

In monosubstituted phenyl radicals, the substituents may be in the 2-, 3-and 4-positions, preferably in the 3-and 4-positions. When the phenyl group bears two substituents, the substituents may be in the 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-positions. Preferably, the two substituents of the disubstituted phenyl are in the 3, 4-positions. In trisubstituted phenyl, the substituents may be located, for example, in the 2,3, 4-position, 2,3, 5-position, 2,3, 6-position, 2,4, 5-position, 2,4, 6-position or 3,4, 5-position.

The same applies to substituted phenylene radicals. The phenylene group can be, for example, a1, 4-phenylene group or a1, 3-phenylene group.

Phenylene- (C)₁-C₆) Alkyl is preferably phenylenemethyl and phenylenethyl. Phenylene- (C)₂-C₆) Alkenyl is preferably phenylethenyl and phenylethenyl.

Examples of heterocyclic parent structures of bicyclic and tricyclic, 5-to 10-membered monocyclic or polycyclic heterocycles containing one or more ring heteroatoms, which can be derivatized to give a 5-or 6-membered heterocycle, monocyclic or bicyclic 5-to 12-membered heterocycle, 3-to 12-membered monocyclic and 6-to 24-membered bicyclic and tricyclic, are: pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, pyran, thiopyran, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, chroman, 2, 3-naphthyridine, quinoline, isoquinoline, quinoxaline, quinazoline, 1, 2-naphthyridine, aza  or a benzo-, cyclopentyl-, cyclohexyl-or cycloheptyl-fused derivative of these heterocycles. The groups may be bonded at any desired position. In each case, the heterocycle may be present in the maximally unsaturated form or in a partially saturated form (= partially unsaturated form), for example in the dihydro form or in the tetrahydro form, or in a fully saturated form (perhydro form). Unless otherwise indicated, the heterocyclic ring may be substituted, for example, at one or more nitrogen atoms (C)₁-C₇) Alkyl (e.g. methyl or ethyl), phenyl or phenyl- (C)₁-C₄) Alkyl (e.g. benzyl) substituted and/or substituted on one or more of its carbon atoms by (C)₁-C₄) Alkyl, hydrogen, hydroxy, (C)₁-C₄) Alkoxy (e.g. methoxy), phenyl- (C)₁-C₄) Alkoxy (e.g. benzyloxy) or oxo substitution. The nitrogen-containing heterocycle may also be present as an N-oxide.

In particular, heteroaryl is a group derived from a 5-to 12-membered heterocyclic ring containing one or more aromatic ringsThe group contains 1,2,3 or 4 heteroatoms selected from N, O and S. It is preferably obtained from a 5-to 10-membered, i.e. 5-, 6,7-, 8-, 9-or 10-membered, heterocyclic ring, particularly preferably from a 5-to 6-membered heterocyclic ring. Preferably 1,2 or 3 heteroatoms, particularly preferably 1 or 2 heteroatoms. Examples of heteroaryl groups are: pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, 2, 3-naphthyridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, 1, 2-naphthyridinyl, or benzo-, cyclopentyl-, cyclohexyl-, or cycloheptyl-fused derivatives of these heterocycles. The heteroaryl radical may also be mono-or polysubstituted, preferably mono-, di-or trisubstituted, the substituents being identical or different and being selected from (C)₁-C₈) Alkyl, preferably (C)₁-C₄) Alkyl, (C)₁-C₈) Alkoxy, preferably (C)₁-C₄) Alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, methylenedioxy, ethylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C)₁-C₄) Alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R)^dO)₂P(O)、(R^dO)₂P (O) -O-, tetrazolyl.

Such heteroaryl groups may be, for example: 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, phenylpyrrolyl (e.g. 4-or 5-phenyl-2-pyrrolyl), 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, methylimidazolyl (e.g. 1-methyl-2-, -4-or 5-imidazolyl), 1, 3-thiazol-2-yl, 1-tetrazolyl, 5-tetrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-oxy-2-, -3-or-4-pyridyl, 2-pyrazinyl, pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-indolyl, 3-indolyl, 5-indolyl, substituted 2-indolyl (e.g. 1-methyl, 5-methyl-, 5-methoxy-, 5-benzyloxy, 5-chloro or 4, 5-dimethyl-2-indolyl, 1-benzyl-2-or-3-indolyl, 4,5,6, 7-tetrahydro-2-indolyl, cyclohepta [ b ] -5-pyrrolyl, 2-, 3-or 4-quinolinyl, -, 3-or 4-isoquinolinyl, 1-hydroxy-3-isoquinolinyl (= 1-oxo-1, 2-dihydro-3-isoquinolinyl); and pharmaceutically acceptable salts thereof, 2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl or 2-benzothiazolyl.

Examples of partially or fully hydrogenated heterocyclic groups are dihydropyridinyl, tetrahydropyridinyl, pyrrolidinyl (e.g. 2-or 3-or 4- (N-methylpyrrolidinyl)), piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, benzodioxan-2-yl.

The heterocyclic group represented by Het may be unsubstituted or mono-or polysubstituted, e.g. di-, tri-, tetra-or penta-substituted, at carbon atoms and/or at ring nitrogen atoms by identical or different substituents. The carbon atom can be substituted by, for example, (C)₁-C₈) Alkyl, preferably (C)₁-C₄) Alkyl radicals, (C)₁-C₈) Alkoxy, preferably (C)₁-C₄) -alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, oxo, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C)₁-C₄) Alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R)^dO)₂P(O)、(R^dO)₂P (O) -O-, and tetrazolyl. The sulfur atom may be oxidized to a sulfoxide or sulfone. Examples of Het radicals are 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-tetrazolyl, dihydropyridin-1-yl, tetrahydropyridin-1-yl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-substituted 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-oxo-4-thiomorpholinyl, 1-dioxo-4-thiomorpholinyl, perhydroazepin  -1-yl, 2, 5-dimethyl-1-pyrrolyl, 2, 6-dimethyl-1-piperidinyl, 3-dimethyl-4-morpholinyl, 4-isopropyl-2, 2,6, 6-tetramethyl-1-piperazinyl.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

Containing a compound selected from R¹¹NH、(C₉-C₁₂) -cycloalkyl, (C)₉-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl and (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -R substituted by a substituent of an alkyl group⁴The divalent alkylene radical may be, for example, the group-CH₂-CH(NHR¹¹) -or-CH₂-CH₂-CH(NHR¹¹) - (CH therein (NHR)¹¹) With CO-N (R)^a)-R⁴-E^aE in (A)^aRadicals bonded) or-CH₂-CH(NHR¹¹)-CH₂. Furthermore, R⁴The divalent alkylene group shown may be, for example, a group-CH (Cy) -or a group-CH- (Cy) -CH₂-, wherein CH₂Radicals with E^aBonded and Cy group is (C)₉-C₁₂) -cycloalkyl, (C)₉-C₁₂) -cycloalkyl- (C)₁-C₈) -alkyl or (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl or (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -an alkyl group. However, in all the above-mentioned substituent examples, the alkyl group such as methyl group may further contain one or two groups substituted with hydrogen atoms.

R⁵Or R⁶The indicated divalent radicals of amino acids, imino acids or aza amino acids are obtained from the corresponding amino acids, imino acids or aza amino acids in the conventional manner of peptide chemistry by formally eliminating the N-terminal hydrogen atom and the hydroxyl group on the C-terminal carboxylic acid group. By means of the free bond thus formed on the amino or imino group, which can in turn be linked in amide-bonded peptidic manner to the carbonyl group of an adjacent group, R⁵The N-terminal amino or imino group contained in (A) and CO-R⁵-R⁶-R⁷CO bonding in (2). Correspondingly, the CO carbonyl group formally obtained from the carboxylic acid group by elimination of the hydroxyl group is amide-bonded to the adjacent R by means of a free bond⁶Or R⁷To the nitrogen atom of (b). As mentioned above, the nitrogen atom of the amide bond, i.e. CO-N (R)^b) With substitutionRadical R^bThe substituents are, for example, hydrogen, (C)₁-C₄) Alkyl (e.g. methyl), and it is the nitrogen atom, CO-R, passing through the amide bond mentioned above⁵-R⁶-R⁷With the CO group of R⁵Is attached through the nitrogen atom R⁵And R⁶Are connected to each other.

The natural or unnatural amino acid can be present in stereochemistry, e.g., as a D form, L form, or as a mixture of stereoisomers, such as a racemate. Preferred amino acids are alpha-amino acids and beta-amino acids; more preferably alpha-amino acids. Mention may be made of the ability to derive R⁵And R⁶Suitable amino acids for the radicals are, for example, those of Houben-Weyl, Methoden der Organschen Chemie [ methods of organic chemistry]Volumes 15/1 and 15/2, Gerog Thieme Verlag, Stuttgart, 1974): aad, Abu, yAbu, ABz,2ABz, ε Acaa, Ach, Acp, Adpd, Ahb, Aib, β Aib, Ala, β Ala, Δ 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, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hCys, hGln, hGlu, His, blle, hLeu, hLys, hMet, hPro, hSer, hTyr, Hylle, HylSer, hTyVal, hTyr, HylVal, hLys, hVal, hLys, hVal, hPyVal, hThr, hPro, hThr, hVal, hThr, hSer, hVal, hLys, hThr, hPro, hVal, hPro, hVal, hThr, hVal, hLys, hPro, hVal, hThr, hTyr, hPro, h, Neopentyl glycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2-diphenylglycine, 2- (p-tolyl) -2-phenylaminoacetic acid, 2- (p-chlorophenyl) -aminoacetic acid.

If R is⁵And/or R⁶Is a natural or non-natural radical having a hydrogen atom on the alpha-carbon atom, a divalent radical-N (R) is present^b) -CH (SC) -CO-, in which SC is a side chain of an α -amino acid, that is, for example, one of the substituents located at the α -position of the α -amino acid unbranched at the above-mentioned α -position. Examples of side chains are alkyl groups, such as in particular the methyl group of alanine or the isopropyl group of valine, the benzyl group of phenylalanine, the phenyl group of phenylglycine, the 4-aminobutyl group of lysineOr hydroxycarbonylmethyl in aspartic acid. In addition to their chemical structure, the side chains and the resulting amino acids can also be grouped within the meaning of the invention according to their physicochemical properties, for example distinguishing lipophilic side chains from hydrophilic side chains containing polar groups. R⁵And R⁶An example of a lipophilic side chain contained in the amino acids shown is (C)₁-C₆) Alkyl, aryl optionally substituted (C)₆-C₁₂) -aryl- (C)₁-C₄) -alkyl and optionally substituted (C)₆-C₁₂) Aryl, where the above explanations apply to these groups.

An azaamino acid is a natural or unnatural amino acid in which the CH unit is replaced by a nitrogen atom, for example in the case of α -amino acids, the central structural unit:

suitable groups of imino acids are preferably heterocyclic groups selected from the following groups: pyrrolidine-2-carboxylic acid, piperidine-2-carboxylic acid, 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, decahydroisoquinoline-3-carboxylic acid, octahydroindole-2-carboxylic acid, decahydroquinoline-2-carboxylic acid, octahydrocyclopenta [ b ] carboxylic acid]Pyrrole-2-carboxylic acid, 2-azabicyclo [2.2.2]Octane-3-carboxylic acid, 2-azabicyclo [2.2.1]Heptane-3-carboxylic acid, 2-azabicyclo [3.1.0]Hexane-3-carboxylic acid, 2-azaspiro [4.4 ]]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 (bicyclo [2.2.2 ]]Octane) -2, 3-pyrrolidine-5-carboxylic acid, 2-azatricyclo [4.3.0.1^6,9]Decane-3-carboxylic acid, decahydrocycloheptane [ b ]]Pyrrole-2-carboxylic acid, decahydrocyclooctan [ c ]]Pyrrole-2-carboxylic acid, octahydrocyclopentyl [ c ]]Pyrrole-2-carboxylic acid, octahydroisoindole-1-carboxylic acid, 2,3,3a,4,6 a-hexahydrocyclopenta [ b ] carboxylic acid]Pyrrole-2-carboxylic acid, 2,3,3a,4,5,7 a-hexahydroindole-2-carboxylic acid, thiazolidine-4-carboxylic acid, isoxazolidine-3-carboxylic acid, pyrazolidine-3-carboxylic acid, hydroxypyrrolidine-2-carboxylic acid, all of which may be optionally substituted (see general formula below):

heterocycles based on the above groups are disclosed, for example, in U.S. Pat. No. 4,344,949, U.S. Pat. No. 4,374,847, U.S. Pat. No. 3,4,350,704, EP-A29,488, EP-A31,741, EP-A46,953, EP-A49,605, EP-A49,658, EP-A50,800, EP-A51,020, EP-A52,870, EP-A79,022, EP-A84,164, EP-A89,637, EP-A90,341, EP-A90,362, EP-A105,102, EP-A109,020, EP-A111,873, EP-A271,865 and EP-A344,682.

The acid groups in natural or unnatural amino acids, imino acids and aza amino acids may also be present as esters or amides, e.g. (C)₁-C₄) Alkyl esters, such as, in particular, methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, benzyl, unsubstituted amides, methylamides, ethylamides, semicarbazides or omega-amino- (C)₂-C₈) -alkylamides.

The functional groups of amino acids, imino acids, azaamino acids may be present in protected form. Suitable protecting groups, such as urethane protecting groups, carboxyl protecting groups and side chain protecting groups, are disclosed in Hubbuch, Kontakte (Merck)1979, pages 314-23, and Kullesbach, Kontakte (Merck)1980, pages 1, 23-35. The following groups may be mentioned in particular: aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (NO)₂),Z(Hal_n),Bobz,lboc,Adpoc,Mboc,Acm,tert-butyl,OBzl,ONbzl,OMbzl,Bzl,Mob,Pic,Trt.

The compounds of formula i may exist in stereoisomeric forms. If the compounds of the formula I contain one or more chiral centers, these compounds, independently of one another, have the S or R configuration. The present invention includes all possible stereoisomers, such as enantiomers and diastereomers, and mixtures of two or more stereoisomers in any ratio, such as mixtures of enantiomers and/or diastereomers. The invention therefore relates to the enantiomers in enantiomerically pure form (as levorotatory and dextrorotatory enantiomers), in racemic form, in the form of a mixture of the two enantiomers in any ratio. In the case of cis/trans isomers, the invention relates to the cis form and the trans form and mixtures of these forms. Each stereoisomer can, if desired, be prepared in a customary manner by separation of mixtures, for example by chromatography or crystallization, by using homogeneous stereochemical starting materials in the synthesis or by stereoselective synthesis. If appropriate, derivatizations with chiral reagents can be carried out before the separation of the stereoisomers and diastereoisomers, and the compounds thus obtained can then be separated by customary methods, for example crystallization or chromatography. The separation of the mixture of stereoisomers can be carried out at the stage of the compounds of the formula I or at the stage of the starting reactants or at the stage of intermediates in the synthesis.

The present invention also includes all tautomers of the compounds of formula i, such as lactam and lactam tautomers, due to the presence of mobile hydrogen atoms.

If the compounds of the formula I contain one or more acidic or basic groups, the invention also relates to the corresponding physiological or toxicologically or tolerable salts, in particular the pharmaceutically acceptable salts. Thus, compounds of formula I which contain one or more acidic groups, such as carboxyl or sulfonic acid groups, on which groups, for example, alkali metal or alkaline earth metal salts or ammonium salts may be present, are useful in the present invention. Thus, the compounds of the formula I may be, for example, the sodium, potassium, calcium, magnesium salts or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids.

Compounds of formula I containing one or more basic groups, i.e. protonatable groups (e.g. aminoamidino or guanidino), may be present in addition to the acids of inorganic or organic acids and are useful in the present invention, for example, as salts with: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, dimethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid. If the compounds of the formula I contain both acidic and basic groups in the molecule, the invention also encompasses, in addition to the salt forms described above, internal or betaine salts.

The above salts can be prepared from the compounds of formula I by conventional methods known to those skilled in the art, for example in combination with organic or inorganic acids or bases in solvents or dispersants, or else from other salts by anion exchange or cation exchange. The invention also encompasses all salts of the compounds of the formula I which are not suitable for direct use as medicaments because of their poor physiological tolerability but are suitable, for example, as intermediates in chemical reactions or in the preparation of physiologically acceptable salts.

The invention also includes all solvates of the compounds of formula i, such as hydrates or adducts with alcohols, as well as derivatives of the compounds of formula i, such as esters, prodrugs and activated metabolites.

The structural elements in the compounds of the formula I preferably have the following meanings: w is preferably R¹-A-C(R¹³) (ii) a A is preferably methylene, ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexylene, phenylene, phenylenemethyl or phenyleneethyl; y is preferably a carbonyl group; z is preferably N (R)⁰) (ii) a B is preferably a divalent methylene or ethylene (=1, 2-ethylene), especially methylene, both of which may be unsubstituted or substituted. More preferably, both groups are substituted. If the divalent methylene or ethylene (=1, 2-ethylene) represented by B is substituted, preferred substituents are selected from (C)₁-C₈) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl, (C)₃-C₈) Cycloalkyl, preferably (C)₅-C₆) -cycloalkyl, (C)₃-C₈) -cycloalkyl- (C)₁-C₄) Alkyl, preferably (C)₅-C₆) -cycloalkyl- (C)₁-C₄) -alkyl, optionally substituted (C)₆-C₁₀) Aryl, optionally substituted aryl (C)₆-C₁₀) -aryl- (C)₁-C₄) -alkyl, optionally substituted heteroaryl and heteroaryl wherein heteroaryl is optionally substituted- (C)₁-C₄) -an alkyl group. More preferably quilt (C)₁-C₈) -alkyl, preferably (C)₁-C₆) -alkanesBase, (C)₅-C₆) -cycloalkyl, (C)₅-C₆) -cycloalkyl- (C)₁-C₄) -alkyl, phenyl, benzyl, phenethyl substitution; very preferably quilt (C)₁-C₆) Alkyl, i.e. linear or branched alkyl substituted with 1,2,3,4, 5,6,7 or 8 carbon atoms. E and E^aIndependently of one another are R¹⁰CO；R、R^aAnd R^bIndependently of one another, hydrogen, (C)₁-C₆) -alkyl or benzyl, preferably hydrogen, methyl or ethyl; r^cPreferably hydrogen, (C)₁-C₆) Alkyl radicals, (C)₅-C₆) -cycloalkyl, (C)₅-C₆) -cycloalkyl- (C)₁-C₂) Alkyl, optionally substituted phenyl or phenyl in which the phenyl group is optionally substituted- (C)₁-C₂) -an alkyl group; r⁰Preferably hydrogen, (C)₁-C₈) Alkyl radicals, (C)₃-C₁₀) -cycloalkyl, (C)₃-C₁₀) -cycloalkyl- (C)₁-C₆) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₆) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₆) -alkyl, optionally substituted (C)₆-C₁₂) Aryl, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₆) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted heteroaryl- (C)₁-C₆) Alkyl radicals, (C)₁-C₈) -alkyl-CO, (C)₃-C₁₀) -cycloalkyl-CO, (C)₃-C₁₀) -cycloalkyl- (C)₁-C₆) -alkyl-CO, (C)₆-C₁₂) -bicycloalkyl-CO, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₆) -alkyl-CO, (C)₆-C₁₂) -tricycloalkyl-CO, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₆) -alkyl-CO, optionally substituted (C)₆-C₁₂) aryl-CO, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₆) -alkyl-CO, optionally substituted heteroaryl-CO, heteroaryl optionally substituted heteroaryl- (C) thereof₁-C₆) -alkyl-CO, (C)₁-C₈) alkyl-S (O)_n、(C₃-C₁₀) cycloalkyl-S (O)_n、(C₃-C₁₀) -cycloalkyl- (C)₁-C₆) alkyl-S (O)_n、(C₆-C₁₂) -bicycloalkyl-S (O)_n、(C₆-C₁₂) -bicycloalkyl- (C)₁-C₆) alkyl-S (O)_n、(C₆-C₁₂) -tricycloalkyl-S (O)_n、(C₆-C₁₂) -tricycloalkyl- (C)₁-C₆) alkyl-S (O)_nOptionally substituted (C)₆-C₁₂) aryl-S (O)_nOptionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₆) alkyl-S (O)_nOptionally substituted heteroaryl-S (O)_nOr heteroaryl optionally substituted with heteroaryl- (C)₁-C₆) alkyl-S (O)_nWherein n is 1 or 2;

more preferably, R⁰Is (C)₁-C₈) Alkyl radicals, (C)₃-C₁₀) -cycloalkyl, (C)₃-C₁₀) -cycloalkyl- (C)₁-C₆) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₆) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₆) -alkyl, optionally substituted (C)₆-C₁₂) Aryl, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₆) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted heteroaryl- (C)₁-C₆) -an alkyl group; very particular preference is given to: the aryl group of which is optionally substituted (C)₆-C₁₂) -aryl- (C)₁-C₄) -alkyl, heteroaryl optionally substituted heteroaryl- (C) thereof₁-C₄) -alkyl, further preferably (C) optionally substituted in its aryl₆-C₁₂) -aryl- (C)₁-C₄) Alkyl, in particular aryl, unsubstituted or mono-or polysubstituted (C)₆-C₁₂) -aryl- (C)₁-C₂) -an alkyl group. R¹Preferably X-NH-C (= NH), X-NH-C (= NH) -NH or X-NH-CH₂X and X¹Preferably hydrogen, (C)₁-C₆) -alkylcarbonyl, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₁₈) -alkylcarbonacyloxy- (C)₁-C₆) -alkoxycarbonyl or (C)₆-C₁₄) -aryl- (C)₁-C₆) -alkoxycarbonyl, hydroxy; x¹Further is R '-NH-C (= N-R "), wherein R' and R" independently of each other have the preferred meaning of X; r²、R^2aAnd R^2dIndependently of one another, are preferably hydrogen or (C)₁-C₈) -alkyl, more preferably hydrogen; r³Preferably R is¹¹NH、(C₁₀-C₁₂) -cycloalkyl, (C)₁₀-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₈) Alkyl, CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-Het; more preferably R¹¹NH、(C₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) Alkyl, CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-Het; it is highly preferred that R¹¹NH and CO-R⁵-R⁶-Het。R⁴Is preferably divalent (C)₁-C₄) Alkylene, more preferably selected from R¹¹NH、(C₁₀-C₁₂) -cycloalkyl, (C)₁₀-C₁₂) -cycloalkyl- (C)₁-C₆) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₆) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₆) -alkyl substituted by a substituent (C)₁-C₂) Alkylene, and the radical may additionally be substituted by one or two identical or different (C)₁-C₄) -alkyl substitution; r⁵Preference is given to divalent radicals of natural or unnatural amino acids, imino or aza amino acids, in which the free functional groups can be protected by protective groups customary in peptide chemistry or are present in the form of esters or amides, and the nitrogen atom of the N-terminal amino group carries the radical R^bMore preferably R⁵The amino acids represented are alpha-amino acids; r⁶Preferably a direct bond; r¹⁰Preferably hydroxyl, (C)₁-C₆) Alkoxy, optionally substituted aryl (C)₆-C₁₀) -aryl- (C)₁-C₈) -alkoxy, optionally substituted (C)₆-C₁₀) -aryloxy group, (C)₁-C₈) -alkylcarbonyloxy- (C)₁-C₆) -an alkoxy group; r¹¹Preferably R¹²NH-CO、R^14aO-CO、R^14bCO、R^14cS (O) or R^14dS(O)₂；R¹²Preferably optionally substituted (C)₆-C₁₄) Aryl, aryl of which may be substituted (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₈) -alkyl or R¹⁵；R¹³Preferably hydrogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₈) Cycloalkyl or benzyl, more preferably (C)₁-C₆) Alkyl radicals, (C)₃-C₈) Cycloalkyl or benzyl, with R being very particularly preferred¹³Alkyl represented is methyl; r^14aPreferred is heteroaryl- (C) wherein the heteroaryl group is optionally substituted₁-C₂) -alkyl or R¹⁵More preferably R¹⁵；R^14bAnd R^14dIndependently of one another, are preferably (C) whose aryl radical is optionally substituted₆-C₁₀) -aryl- (C)₁-C₄) -alkyl, heteroaryl optionally substituted on heteroaryl- (C)₁-C₄) -alkyl or R¹⁵；R^14cPreferably is (C)₁-C₁₀) Alkyl, aryl optionally substituted (C)₆-C₁₀) -aryl- (C)₁-C₄) -alkyl, heteroaryl optionally substituted on heteroaryl- (C)₁-C₄) -alkyl or R¹⁵；R^14ePreferably is (C)₁-C₁₀) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl or R¹⁵；R^14fPreferably (C) optionally substituted in the aryl radical₆-C₁₄) -aryl- (C)₁-C₈) Alkyl radicals, (C)₉-C₁₀) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl or (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -an alkyl group; r¹⁵Preferably R is¹⁶-(C₁-C₃) -alkyl or R¹⁶More preferably R¹⁶-(C₁) -alkyl or R¹⁶；R¹⁶Preferably a 5-to 10-membered monocyclic radical or a 6-to 14-membered bicyclic or tricyclic radical, where these radicals are saturated or partially unsaturated and may also contain 1,2,3 or 4 identical or different ring heteroatoms from the group consisting of nitrogen, oxygen, sulfur and may also be substituted by one or more identical or different ring heteroatoms from the group consisting of (C)₁-C₄) -substituent substitution of alkyl; het is preferably a 5-to 10-membered monocyclic or polycyclic heterocyclic group which is bonded via a ring nitrogen atom, which heterocyclic group may be aromatic or partially unsaturated or saturated and may contain 1 or 2 identical or different further ring heteroatoms from the group consisting of oxygen, nitrogen and sulfur, and which may be substituted on carbon atoms and on ring nitrogen atomsOptionally substituted, wherein the possible substituents on the further ring nitrogen atom thereof may be the same or different and are selected from R^c、R^cCO and R^cO-CO. More preferably Het is a saturated heterocyclic ring containing no further ring nitrogen atom or containing one further ring heteroatom selected from nitrogen, oxygen and sulphur. If the nitrogen atom in Het carries R^cO-CO, R in this radical^cPreference is given to meanings other than hydrogen.

If R is³Is R¹¹NH, preferably g is 1 and h is 0; if R is³Is cycloalkyl, bicycloalkyl or tricycloalkyl, preferably g is 0 or 1 and h is 1, more preferably g is 0 and h is 1; if R is³Is CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶Het, preferably g is 0 and h is 1.

Preferred compounds of the formula I are those in which one or more radicals have the preferred meanings, the invention being directed to the combination of all preferred meanings of the substituents. More preferred compounds of formula I are those wherein at the same time: w is R¹-A-C(R¹³) (ii) a And A is a divalent radical selected from the group consisting of cyclohexylene, phenylene, and phenylenemethyl; y is a carbonyl group; z is N (R)⁰) (ii) a B is a divalent methylene or ethylene (=1, 2-ethylene), both of which may be unsubstituted or substituted, the substituent when substituted being selected from: (C)₁-C₈) Alkyl radicals, (C)₃-C₈) -cycloalkyl, (C)₃-C₈) -cycloalkyl- (C)₁-C₄) -alkyl, optionally substituted (C)₆-C₁₀) Aryl, optionally substituted aryl (C)₆-C₁₀) -aryl- (C)₁-C₄) -alkyl, optionally substituted heteroaryl and heteroaryl wherein heteroaryl is optionally substituted- (C)₁-C₄) -an alkyl group; e and E^aIndependently of one another are R¹⁰CO；R、R^aAnd R^bIndependently of one another, hydrogen, (C)₁-C₆) -alkyl or benzyl; r^cIs hydrogen, (C)₁-C₆) Alkyl radicals, (C)₅-C₆) -cycloalkyl, (C)₅-C₆) -cycloalkyl- (C)₁-C₂) Alkyl, optionally substituted phenyl or phenyl in which the phenyl group is optionally substituted- (C)₁-C₂) -an alkyl group; r⁰Is (C)₁-C₆) Alkyl radicals, (C)₅-C₁₀) -cycloalkyl, (C)₅-C₁₀) -cycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) -alkyl, optionally substituted (C)₆-C₁₂) Aryl, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₄) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted heteroaryl- (C)₁-C₄) Alkyl radicals, (C)₁-C₆) -alkyl-CO, (C)₅-C₁₀) -cycloalkyl-CO, (C)₅-C₁₀) -cycloalkyl- (C)₁-C₄) -alkyl-CO, (C)₇-C₁₂) -bicycloalkyl-CO, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₄) -alkyl-CO, (C)₁₀-C₁₂) -tricycloalkyl-CO, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) -alkyl-CO, optionally substituted (C)₆-C₁₂) aryl-CO, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₄) -alkyl-CO, optionally substituted heteroaryl-CO, heteroaryl optionally substituted heteroaryl- (C) thereof₁-C₄) -alkyl-CO, (C)₁-C₆) alkyl-S (O)_n、(C₅-C₁₀) cycloalkyl-S (O)_n、(C₅-C₁₀) -cycloalkyl- (C)₁-C₄) alkyl-S (O)_n、(C₇-C₁₂) -bicycloalkyl-S (O)_n、(C₇-C₁₂) -bicycloalkyl- (C)₁-C₄) alkyl-S (O)_n、(C₁₀-C₁₂) -tricycloalkyl-S (O)_n、(C₁₀-C₁₂) -tricycloalkyl radical-(C₁-C₄) alkyl-S (O)_nOptionally substituted (C)₆-C₁₂) aryl-S (O)_nOptionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₄) alkyl-S (O)_nOptionally substituted heteroaryl-S (O)_nOr heteroaryl optionally substituted with heteroaryl- (C)₁-C₄) alkyl-S (O)_nWherein n is 1 or 2; r¹Is X-NH-C (= NH), X-NH-C (= NH) -NH or X-NH-CH₂(ii) a X is hydrogen, (C)₁-C₆) -alkylcarbonyl, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₈) -alkylcarbonyloxy- (C)₁-C₆) -alkoxycarbonyl or (C)₆-C₁₄) -aryl- (C)₁-C₆) -alkoxycarbonyl or hydroxy; r²、R^2aAnd R^2dIndependently of one another, are preferably hydrogen or (C)₁-C₈) -an alkyl group; r³Is R¹¹NH、(C₁₀-C₁₂) -cycloalkyl, (C)₁₀-C₁₂) -cycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) Alkyl, CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-Het；R¹⁰Is hydroxy, (C)₁-C₆) Alkoxy, optionally substituted aryl (C)₆-C₁₀) -aryl- (C)₁-C₈) -alkoxy, optionally substituted (C)₆-C₁₀) -aryloxy group, (C)₁-C₈) -alkylcarbonyloxy- (C)₁-C₆) -an alkoxy group; r¹¹Is R¹²NH-CO、R^14aO-CO、R^14bCO、R^14cS (O) or R^14dS(O)₂；R^14aIs heteroaryl- (C) whose heteroaryl is optionally substituted₁-C₂) -alkyl or R¹⁵；R^14bAnd R^14dIndependently of one another, are aryl radicals thereofOptionally substituted (C)₆-C₁₀) -aryl- (C)₁-C₂) -alkyl, heteroaryl optionally substituted on heteroaryl- (C)₁-C₂) -alkyl or R¹⁵；R^14cIs (C)₁-C₆) Alkyl, aryl optionally substituted (C)₆-C₁₀) -aryl- (C)₁-C₂) -alkyl or R¹⁵；R¹⁵Is R¹⁶-(C₁-C₄) -alkyl or R¹⁶；R¹⁶Is a 5-to 10-membered monocyclic radical or a 6-to 14-membered bicyclic or tricyclic radical, wherein the rings are saturated and may also contain 1 or 2 identical or different ring heteroatoms from the group consisting of nitrogen, oxygen, sulfur and may also be substituted by 1,2,3 and 4 identical or different members selected from the group consisting of (C)₁-C₄) -substituent substitution of alkyl; het is a 5-to 10-membered monocyclic heterocyclic group which is bonded via a ring nitrogen atom and which may be aromatic or partially unsaturated or saturated and may contain 1 or 2 identical or different further ring heteroatoms from the group consisting of oxygen, nitrogen and sulfur and which may be optionally substituted, wherein the possible substituents on their further ring nitrogen atoms may be identical or different and are selected from R^c、R^cCO and R^cO-CO; and one or more of the same or different (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, trifluoromethyl, phenyl and benzyl as substituents on carbon atoms; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Highly preferred compounds of formula I are those wherein: w is R¹-A-C(R¹³)，R¹³Is (C)₁-C₆) Alkyl, aryl optionally substituted (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl or (C)₃-C₈) -a cycloalkyl group; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Further preferred compounds of the formula I are those in which the radicals are simultaneously as defined below: r³Is R¹¹NH、(C₁₀-C₁₂) -cycloalkyl, (C)₁₀-C₁₂) -cycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) Alkyl, CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-Het；R¹¹Is R¹⁵O-CO or R¹⁵S(O)₂；R¹⁵Is R¹⁶-(C₁-C₃) -alkyl or R¹⁶；R¹⁶Is a monocyclic radical of 5 to 6 members or a bicyclic or tricyclic radical of 6 to 12 members, where the rings are saturated and may also contain 1 or 2 identical or different ring heteroatoms from the group consisting of nitrogen, oxygen, sulfur and may also be substituted by 1,2 and 3 identical or different ring heteroatoms from the group consisting of (C)₁-C₄) -substituent substitution of alkyl; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Particularly preferred compounds of the formula I are those in which the radicals are simultaneously as defined below: w is R¹-A-C(R¹³) (ii) a Y is a carbonyl group; z is N (R)⁰) (ii) a A is a divalent group of cyclohexylene, phenylene, and phenylenemethyl; b is a divalent methylene group, which group may be unsubstituted or substituted, the substituents being selected from: (C)₁-C₈) Alkyl radicals, (C)₅-C₆) -cycloalkyl, (C)₅-C₆) -cycloalkyl- (C)₁-C₄) Alkyl, optionally substituted phenyl, phenyl optionally substituted phenyl- (C)₁-C₄) -alkyl, optionally substituted 5-or 6-membered heteroaryl and heteroaryl, the heteroaryl of which is optionally substituted- (C)₁-C₄) -an alkyl group; e and E^aIndependently of one another are R¹⁰CO；R、R^aAnd R^bIndependently of one another, hydrogen or (C)₁-C₄) -an alkyl group; r⁰Is (C)₁-C₆) Alkyl radicals, (C)₅-C₆) -cycloalkyl, (C)₅-C₆) -cycloalkyl- (C)₁-C₂) -alkyl, optionally substituted (C)₆-C₁₂) Aryl, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₂) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted heteroaryl- (C)₁-C₂) Alkyl radicals, (C)₁-C₆) -alkyl-CO, (C)₅-C₆) -cycloalkyl-CO, (C)₅-C₆) -cycloalkyl- (C)₁-C₂) -alkyl-CO, optionally substituted (C)₆-C₁₂) aryl-CO, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₂) -alkyl-CO, (C)₁-C₆) alkyl-S (O)_n、(C₅-C₆) cycloalkyl-S (O)_n、(C₅-C₆) -cycloalkyl- (C)₁-C₂) alkyl-S (O)_nOptionally substituted (C)₆-C₁₂) aryl-S (O)_nOptionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₂) alkyl-S (O)_nWherein n is 1 or 2; r¹Is H²N-C(=NH)、H²N-C(=N-OH)、CH₃O-CO-NH-C(=NH)、H₂N-C (= NH) -NH or H₂N-CH₂；R²、R^2aAnd R^2dIs hydrogen; r³Is R¹¹NH、(C₁₀-C₁₂) -cycloalkyl, (C)₁₀-C₁₂) -cycloalkyl- (C)₁-C₃) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₃) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₃) Alkyl, CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-Het；R¹⁰Is hydroxy, (C)₁-C₄) -alkoxy, phenoxy, benzyloxy, (C)₁-C₄) -alkylcarbonyloxy- (C)₁-C₆) -an alkoxy group; r¹¹Is R¹⁵O-CO or R¹⁵S(O)₂；R¹³Is (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl or benzyl; r¹⁵Is R¹⁶-(C₁-C₃) -alkyl or R¹⁶；R¹⁶Is a 5-to 6-membered monocyclic radical or a 6-to 12-membered bicyclic or tricyclic radical, where the rings are saturated and may also contain 1 or 2 identical or different ring heteroatoms from the group consisting of nitrogen and oxygen and may also be substituted by 1,2 and 3 identical or different (C)₁-C₄) -substituent substitution of alkyl; het is a 5-to 6-membered monocyclic heterocyclic group bonded via a ring nitrogen atom, which heterocyclic group may be aromatic or partially unsaturated or saturated and may contain 1 further ring heteroatom selected from oxygen and sulphur, and which groups may optionally be identical or different (C)₁-C₆) Alkyl radicals, (C)₁-C₄) -substituents of alkoxy, trifluoromethyl, phenyl and benzyl are mono-or di-substituted; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

Very particularly preferred compounds of the formula I are those in which the radicals are at the same time as defined below: w is R¹-A-C(R¹³) And A is a divalent group of phenylene; y is a carbonyl group; z is N (R)⁰) (ii) a B is a divalent methylene group, which may be unsubstituted or substituted, the substituents being selected from (C)₁-C₆) Alkyl radicals, (C)₅-C₆) -cycloalkyl- (C)₁-C₄) -alkyl, phenyl, benzyl and phenethyl; e is R¹⁰CO；R、R^aAnd R^bIndependently of one another, hydrogen or (C)₁-C₉) An alkyl group; r⁰Is (C)₁-C₆) Alkyl, aryl optionally substituted (C)₆-C₁₂) -aryl- (C)₁-C₂) Alkyl radicals, (C)₁-C₆) alkyl-S (O)₂Optionally substituted aryl (C)₆-C₁₂) aryl-S (O)₂；R¹Is H₂N-C(=NH)、H₂N-C(=NOH)、CH₃O-CO-NH-C(=NH)、H₂N-C(=NH)-NH or H₂N-CH₂；R²、R^2aAnd R^2dIs hydrogen; r³Is R¹¹NH or CO-R⁵-Het；R⁵Is a natural or unnatural divalent radical of an alpha-amino acid with a lipophilic side chain, the free functional group of which can be protected by protective groups customary in peptide chemistry or can be present in the form of esters or amides, and which carries the radical R on the nitrogen atom of the N-terminal amino group^b；R¹⁰Is hydroxy, (C)₁-C₄) -alkoxy, phenoxy, benzyloxy, (C)₁-C₄) -alkylcarbonyloxy- (C)₁-C₄) -an alkoxy group; r¹¹Is R¹⁵O-CO or R¹⁵S(O)₂；R¹³Is (C)₁-C₆) -an alkyl group; r¹⁵Is R¹⁶-(C₁-C₃) -alkyl or R¹⁶；R¹⁶Is a 5-to 6-membered monocyclic radical or a 7-to 12-membered bicyclic or tricyclic radical, wherein the rings are saturated and may also contain 1 or 2 identical or different ring heteroatoms from the group consisting of nitrogen and oxygen and may also be substituted by 1 or 2 identical or different ring heteroatoms from the group consisting of (C)₁-C₄) -substituent substitution of alkyl; het is a 5-to 6-membered monocyclic heterocyclic group bonded via a ring nitrogen atom, which heterocyclic group is saturated and may contain 1 further ring heteroatom selected from oxygen and sulphur, and which groups may optionally be substituted by one or two (C)₁-C₄) -substituent substitution of alkyl; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

The most preferred compounds of the formula I are those in which the radicals are simultaneously as defined below: w is R¹-A-C(R¹³) And A is a divalent phenylene group; y is a carbonyl group; z is N (R)⁰) (ii) a B is a divalent methylene group, which may be unsubstituted or substituted, the substituents being selected from (C)₁-C₆) Alkyl radicals, (C)₅-C₆) -cycloalkyl- (C)₁-C₄) -alkyl, phenyl, benzyl and phenethyl; e is R¹⁰CO；R、R^aAnd R^bIndependently of one another, hydrogen or methyl; r⁰Is (C)₁-C₆) Alkyl, aryl optionally substituted (C)₆-C₁₂) -aryl- (C)₁-C₂) -an alkyl group; r¹Is H₂N-C(=NH)、H₂N-C(=NOH)、CH₃O-CO-NH-C(=NH)、H₂N-C (= NH) -NH or H₂NH-CH₂；R²、R^2aAnd R^2dIs hydrogen; r³Is R¹¹NH or CO-R⁵-Het；R⁵Is a natural or unnatural divalent radical of an alpha-amino acid with a lipophilic side chain, the free functional group of which can be protected by protective groups customary in peptide chemistry or can be present in the form of esters or amides, and which carries the radical R on the nitrogen atom of the N-terminal amino group^b；R¹⁰Is hydroxy, (C)₁-C₄) -alkoxy, phenoxy, benzyloxy or (C)₁-C₄) -alkylcarbonyloxy- (C)₁-C₄) -an alkoxy group; r¹¹Is R¹⁵O-CO；R¹³Is (C)₁-C₆) -an alkyl group; r¹⁵Is R¹⁶-CH₂Or R¹⁶；R¹⁶Is cyclopentyl, cyclohexyl, 1-adamantyl, 2-adamantyl or noradamantyl; het is a 5-to 6-membered monocyclic heterocyclic group bonded via a ring nitrogen atom, which heterocyclic group is saturated and may contain 1 oxygen as further ring heteroatom, and which groups may optionally be substituted by one or two identical or different (C)₁-C₄) -alkyl substitution; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

In general, the compounds of formula I preferably have a uniform configuration at the chiral center, for example with R in formula I²And R³Chiral carbon atoms of the group and/or the center of W in a 5-membered heterocyclic ring.

The compounds of formula I can be prepared, for example, by reacting a compound of formula II:carrying out fragment condensation with a compound of a formula III,wherein, formula IIIn thing III, W, Y, Z, B, E, R, R²、R^2a、R^2bAnd R³And G and h have the abovementioned meanings or functional groups in these radicals are present in their protected form or as precursors, and where G is hydroxycarbonyl, (C)₁-C₆) Alkoxycarbonyl or activated carboxylic acid derivatives such as acid chlorides or activated esters. When prepared from compounds of formula I, e.g. R in formula I³Is CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-R⁷A compound of formula III, R in the compound of formula III³It is also possible for the radicals to be initially hydroxycarbonyl in protected form and then to give the desired R in one or more syntheses after condensation of the compounds of the formulae II and III³。

For the condensation of the compounds of the formula II with the compounds of the formula III, coupling methods known per se to the expert in peptide chemistry are advantageously employed (see, for example, Houben-Weyl, Methodender Organischen Chemie [ methods of organic Synthesis]Volumes 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). Possible condensation reagents are, for example, carbonyldiimidazole, carbodiimides (e.g. dicyclohexylcarbodiimide or diisopropylcarbodiimide), O- ((cyano (ethoxycarbonyl) -methylene) amino) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TOTU) or propylphosphonic anhydride (PPA). In general, reversible protecting groups are required to protect unreacted amino groups in condensation reactions. The same applies to carboxyl groups which do not participate in the reaction, the carboxyl groups in the condensation preferably being represented by (C)₁-C₆) Alkyl esters (e.g. tert-butyl esters) or benzyl esters. An amino protecting group is not necessary if the amino group is still present in its precursor form, for example nitro or cyano, and is only formed after coupling, for example by hydrogenation. After coupling the protecting groups can be removed by suitable means. For example, NO₂(guanidino protection), benzyloxycarbonyl and benzyl ester can be removed by hydrogenation. The tert-butyl type protecting group is removed under acidic conditions, while the 9-fluorenylmethoxycarbonyl group is removed by a secondary amine.

W is R¹-A-C(R¹³) Y is carbonyl and Z is NR⁰Formula IIThe compounds can be prepared, for example, by first reacting a compound of formula IV:carrying out a Bucherer reaction to provide a compound of formula V:wherein and in the formula IV, R¹、R¹³And a has the above meaning (h.t. bucher, v.a. lieb, j.prakt.chem.141(1934), 5). The compound of formula VI can then be prepared:wherein R is¹、R¹³A, B and G have the abovementioned meanings, by first reacting the compounds of the formula V with, for example, alkylating agents to introduce the groups-B-G into the molecule. Compounds of formula VI and formula R⁰Reaction of a second reagent represented by LG to give the corresponding compound of formula II, wherein R⁰Having the above-mentioned meaning and LG is a nucleophilically substituted leaving group, e.g. halogen (especially chlorine or bromine), (C)₁-C₄) -alkoxy, optionally substituted phenoxy, or a heterocyclic leaving group, such as imidazolyl. The above reaction can be accomplished by similar methods known to those skilled in the art. It is appropriate, as the case may be, to temporarily block functional groups which may lead to secondary or adverse reactions by protecting groups in all steps of the synthesis of the compounds of the formula I, as is known to the person skilled in the art. In particular, reference is made to the corresponding examples of WO-A-96/33976, which is also part of the disclosure of the present invention, in the preparation of compounds of the formulae V and VI in racemic form and in the form of the pure enantiomers.

If W is R¹-a-CH = C, which structural unit can be introduced by, for example, condensing an aldehyde with a 5-membered heterocyclic compound containing a methylene group in a position corresponding to the W group (analogously to known methods).

The amino compounds of formula III are synthesized according to or analogously to known standard methods, from compounds which are commercially available or prepared in the same or analogous literature methods.

For a 5-membered heterocyclic ring, W is R¹-A-C(R¹³) Of (2) aThe compounds of formula I in the case of substituted-or thio-oxo-substituted imidazolidines can also be prepared by the following process:

the α -amino acids or N-substituted α -amino acids obtained according to standard methods or preferably with their esters (e.g., methyl, ethyl, tert-butyl or benzyl esters), such as compounds of formula VII:wherein R is⁰、R¹、R¹³And A has the above-mentioned meaning, with isocyanates or isothiocyanates, such as the compounds of the formula VIII:wherein, B, E, R, R²、R^2a、R^2b、R³G and h have the abovementioned meanings and U is isocyanate or isothiocyanate, urea derivatives or thiourea derivatives can be obtained, for example compounds of the formula IX:wherein the radicals have the abovementioned meanings and V is oxygen or sulfur, and which is cyclized by heating with an acid by hydrolysis of the ester function to give the compounds of the formula Ia:wherein V is oxygen or sulfur, W is R¹-A-C(R¹³) And other groups which have the above-mentioned meanings. The compound of formula IX may also be cyclized to the compound of formula Ia by treatment with a base in an inert solvent, for example, sodium hydride in an aprotic solvent such as dimethylformamide.

In the cyclization, guanidino groups may be blocked by protecting groups, such as nitro groups. The amino groups may be present in protected form, for example again as nitro or cyano functions, which groups can subsequently be reduced to amino groups, which in the case of cyano groups can also be converted into amidino groups.

In the compounds of formula I the 5-membered heterocycle is W is R¹-A-C(R¹³) With a dioxo-or thioxo-oxo-substituted imidazolidine ring, the compounds of formula I can also be prepared by reacting a compound of formula VII with an isocyanate or isothiocyanate of formula X：Wherein B and U have the meaning given above for formula VIII and Q is alkoxy, e.g. (C)₁-C₄) Alkoxy (e.g. methoxy, ethoxy or tert-butoxy), (C)₆-C₁₄) Aryloxy (e.g. phenoxy), or (C)₆-C₁₄) -aryl- (C)₁-C₄) Alkoxy (such as benzyloxy). In this case, a compound of formula XI is prepared:v, A, B, Q, R therein⁰、R¹And R¹³Having the meaning given above under formula IX and X, which is then cyclized under the action of an acid or base, e.g. as in the case of compounds of formula IX, to give compounds of formula XIIWherein W is R¹-A-C(R¹³) And V, B, Q and R⁰Having the meanings given above under formulae Ia and X. Starting from the compound of formula XII, the compound of formula Ia can be obtained by hydrolysis of the group CO-Q to COOH and subsequent coupling with the compound of formula III, as described above for the coupling of the compounds of formulae II and III. Also, during cyclization, the functional groups may be present in protected or precursor form.

Another process for preparing compounds of the formula Ia is, for example, the reaction of a compound of the formula XIII:wherein W is R¹-A-C(R¹³) And the other groups have the meaning described above, with phosgene, triphosgene or the corresponding equivalents (analogously to S.Goldschmidt and M.Wick, Liebigs Ann. chem.575(1952), 217-.

The reaction for converting the amino function into the guanidino function can be carried out using the following reagents: o-methylisourea (S.Weiss and H.Krommer, Chemiker Zeitung 98(1974), 617-776) 2. S-methylisothiourea (R.F.Borne, M.L.Forrester and I.W.Waters, J.Pharma.Chem.20 (1977), 771-776); 3. nitro-S-methylisothiourea (l.s.hafner and r.e.evans, journal of organic chemistry, 24(1959) 57); 4. formamidinesulfonic acid (K.Kim, Y. -T.Lin and H.S.Mosher, Tetrah.lett.29(1988), 3183-3186); 5. nitric acid 3, 5-dimethyl-1-pyrazolyl formamidine (f.l. scott, d.g.o' donovan and j.reilly, j.amer.chem.soc.75(1953), 4053-; n, N' -di-tert-butoxycarbonyl-S-methylisothiourea (R.J.Bergeron and J.S.McManis, J.org.chem., 52(1987) 1700-); n-alkoxycarbonyl-, N '-dialkoxycarbonyl, N-alkylcarbonyl-and N, N' -dialkylcarbonyl-S-methylisothiourea (H.Wollweber, H.Kolling, E.Niemers, A.Widdig, P.Andrews, H. -P.Schulz and H.Thomas, Arzneim.Forsch./Drug Res.34(1984),531 542).

Amidine compounds can be prepared from the corresponding cyano compounds by addition of an alcohol (e.g. methanol or ethanol) and subsequent aminolysis in an acidic anhydrous medium (dioxane, methanol or ethanol), for example by treatment with ammonia in an alcohol (e.g. isopropanol, methanol or ethanol) (g.wagner, p.richter and ch.garbe, Pharmazie 29(1974), 12-55). Another method for preparing amidines is the addition of H2S to a cyano group, followed by methylation of the resulting thioamide and further reaction with ammonia (GDR patent 235866). Furthermore, hydroxylamine can be added to the cyano group to form an N-hydroxyamidine which can then be converted, if desired, to an amidine, for example by hydrogenation.

For the preparation of compounds of formulA I, reference is further made to WO-A-96/33976 in its entirety and the following patents in which the compounds have platelet aggregation inhibiting action: WO-A-94/21607, WO-A-95/14008, EP-A-449079, EP-A-530505 (US-A-5389614), WO-A-93/18057, EP-A-566919 (US-A5397796), EP-A-580008 (US-A-5424293) and EP-A-584694 (US-A-5554594).

The compounds of the formula I are valuable pharmaceutical active compounds which are suitable, for example, for the treatment and prophylaxis of inflammatory disorders, allergic disorders or asthma. In the present invention, the compounds of formula I and their physiologically acceptable salts can be administered to animals, preferably mammals, more preferably humans, as therapeutic and prophylactic agents. They can be administered as such, or in a mixture with other substances or in the form of pharmaceutical preparations, which allow for gastro-intestinal or parenteral administration and which, in addition to customary pharmaceutically acceptable, nontoxic excipients and/or additives, should contain an effective amount of at least one compound of the formula I and/or physiologically acceptable salts thereof as active ingredient.

The invention therefore also relates to the use of compounds of the formula I and/or their physiologically acceptable salts as medicaments, to the use of compounds of the formula I and/or their physiologically acceptable salts for the preparation of medicaments for the treatment and prophylaxis of the abovementioned or following diseases, for example for the treatment and prophylaxis of inflammation, and to the use of compounds of the formula I and/or their physiologically acceptable salts for the treatment and prophylaxis of these diseases. The invention further relates to pharmaceutical preparations which contain an effective amount of at least one compound of the formula I and/or physiologically acceptable salts thereof in addition to customary pharmaceutically nontoxic excipients and/or additives.

These medicaments can be administered orally, for example in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions. However, rectal administration is also possible, for example suppositories; parenteral administration, such as injection or infusion solutions, microcapsules or sticks (rod); or transdermal administration, such as ointments, solutions or tinctures; or by other routes, such as nasal sprays or aerosol mixtures.

The pharmaceutical preparations of the invention can be prepared in a manner known per se using pharmaceutically inert organic or organic excipients other than the compounds of the formula I and/or their physiologically acceptable salts. For the preparation of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts and the like. Excipients for soft gelatine capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils and the like. Suitable excipients for the preparation of solutions, for example injection solutions, emulsions or syrups, are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils and the like. Suitable excipients for microcapsules, implants or sticks are for example copolymers of glycolic acid and lactic acid. Pharmaceutical preparations generally contain from about 0% to about 5% to about 90% by weight of the compound of formula I and/or their physiologically acceptable salts.

In addition to the active compounds and excipients, the pharmaceutical preparations can contain additives, such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavors or fragrances, thickeners, diluents, buffer substances, and solvents or solubilizers or substances for achieving a depot effect, and also salts for regulating the osmotic pressure, coating agents or antioxidants. They may also comprise two or more compounds of the formula I and/or their physiologically acceptable salts. In addition, they may contain, in addition to at least one compound of the formula I and/or a physiologically acceptable salt, one or more other therapeutically and prophylactically active substances, for example substances having an anti-inflammatory action. The pharmaceutical preparations generally contain from 0 to 2 to 500mg, preferably from 1 to 100mg, of the active compound of the formula I and/or a physiologically acceptable salt thereof.

The compounds of formula I have the ability to inhibit cell-cell and cell-matrix interaction processes in which interactions between VLA-4 and its ligands play a role. The effectiveness of the compounds of the formula I can be demonstrated, for example, in binding assays of cells containing the VLA-4 receptor (e.g.leukocytes) with ligands for this receptor (e.g.VCAM-1, which can also advantageously be prepared by genetic techniques). Such tests are described in detail below. In particular, the compounds of formula I inhibit leukocyte adhesion and migration, e.g., the effect of leukocyte adhesion to endothelial cells (as described above) may be modulated by the VCAM-1/VLA-4 adhesion mechanism. In addition to being anti-inflammatory, the compounds of the formula I and their physiologically acceptable salts are generally suitable for the treatment and prophylaxis of diseases which are based on the interaction of VLA-4 receptors with their ligands or which can be influenced by inhibiting this interaction, in particular for the treatment and prophylaxis of diseases which are induced at least in part by an inappropriate degree of leukocyte adhesion and/or leukocyte migration or factors associated therewith or for which leukocyte adhesion and/or migration should be reduced in the prophylaxis, alleviation or cure.

The compounds of formula I may be used as anti-inflammatory agents in inflammation of various origins. They can be used, for example, for the treatment and prophylaxis of rheumatoid arthritis, inflammatory bowel diseases (ulcerative colitis), systemic lupus erythematosus; or for the treatment and prevention of inflammatory diseases of the central nervous system, such as multiple sclerosis; for the treatment or prevention of asthma or allergic reactions, such as delayed type strain (type IV strain). They are further suitable for the treatment or prophylaxis of cardiovascular diseases, arteriosclerosis, restenosis; for the treatment or prophylaxis of diabetes, for the prevention of damage to organ transplants, for the inhibition of tumor growth or the occurrence of tumor metastases of various malignancies, for the treatment of malaria and other diseases in which blockade of the integrin VLA-4 and/or influence on leukocyte activity can be brought to an appropriate extent for the prevention, alleviation or cure.

When using the compounds of the formula I, the dosages employed can vary within wide limits and should be adapted to the individual case in each particular case as is customary. Depending on, for example, the compound used, the nature and severity of the disease to be treated, the acute or chronic nature of the disease to be treated, whether prophylaxis is to be achieved. In general, in the case of oral administration, a daily dose of about 0.01 to 100mg/kg, preferably 0.1 to 10mg/kg, more preferably 0.3 to 2mg/kg (each per kg body weight) is suitable for an adult weighing 75kg to achieve effective therapeutic effects. In the case of intravenous administration, the daily dose is usually about 0.01 to 50mg/kg, preferably 0.01 to 10mg/kg of body weight. In particular in the case of relatively large amounts, the daily dose can be divided, for example, into 2,3 or 4 partial doses. If appropriate, the above-mentioned daily doses may be deviated upwardly or downwardly, as the case may be.

The invention also relates to the use of compounds of the formula I for inhibiting leukocyte adhesion and/or migration or for inhibiting the VLA-4 receptor, and to the preparation of medicaments for the treatment or prophylaxis of diseases which are induced to an adverse extent by leukocyte adhesion and/or migration or in which the VLA-4-dependent adhesion process has an influence, and to the use of compounds of the formula I and/or their physiologically acceptable salts for the treatment or prophylaxis of these diseases.

The compounds of formula i and their salts can further be used for diagnostic purposes, for example in vitro diagnostics, and as adjuvants in biochemical studies with the aim of blocking or influencing VLA-4 on cell-cell or cell-matrix interactions. They are also useful as intermediates for the preparation of other compounds, in particular other pharmaceutically active compounds, which can be prepared from compounds of formula I, for example by modification or introduction of groups or functional groups.

Examples

The identification of the compounds is carried out by means of Mass Spectrometry (MS) and/or nuclear magnetic resonance spectroscopy (NMR). The compounds are purified, for example, by chromatography using an eluent comprising, for example, acetic acid or trifluoroacetic acid, followed by lyophilization, in some cases still containing the acid from the eluent, depending on how the lyophilization is carried out, thereby producing a partially or fully salt form of the acid used, e.g., the acetate or trifluoroacetate salt. The abbreviations have the following meanings: DMF N, N-dimethylformamide THF tetrahydrofuran DCC N, N' -dicyclohexylcarbodiimide HOBt 1-hydroxybenzotriazole HOOBt 3-hydroxy-4-oxo-3, 4-dihydro-1, 2, 3-benzotriazole example 1(S) -3- (((R, S) -4- (4- (amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2- (1-adamantylmethoxy-carbonamide) propionic acid1a) (R, S) -4- (4-cyanophenyl) -4-methyl-2, 5-dioxoimidazolidine

20g (138mmol) of p-acetylbenzonitrile, 115.6g (1.21mol) of ammonium carbonate and 11.6g (178mmol) of potassium cyanide are dissolved in 600ml of a mixture of 50% ethanol and 50% water. The compound was stirred at 55 ℃ for 5 hours and left to stand overnight. The solution was adjusted to pH 6.3 with 6N hydrochloric acid and stirred at room temperature for 2 hours. The precipitate is filtered off with suction, washed with water and dried under high vacuum with phosphorus pentoxide. Yield: 22.33g (75%). 1b) ((R, S) -4- (4-cyanophenyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetic acid methyl ester

1.068g (46.47mmol) of sodium were dissolved in anhydrous methanol under nitrogen. The clear solution was treated with 10g (R, S) -4- (4-cyanophenyl) -4-methyl-2, 5-dioxoimidazolidine (46.47mmol) and the mixture was refluxed for 2 hours. 7.75g (46.68mmol) of potassium iodide are added and 4.53ml (51.3mmol) of methyl chloroacetate in 5ml of methanol are added dropwise over a period of 1 h. The mixture was boiled under heating for 6 hours, allowed to stand overnight at room temperature and concentrated. The oily residue was chromatographed on silica gel eluting with methylene chloride/ethyl acetate (9: 1). Yield: 8.81g (66%). 1c) ((R, S) -4- (4-cyanophenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetic acid methyl ester

754mg (17.27mmol) of sodium hydride are added at 0 ℃ to a solution of 4.5g (15.7mmol) of methyl ((R, S) -4- (4-cyanophenyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetate in 25ml of anhydrous DMF under hydrogen. The mixture was stirred at room temperature for 15 minutes, 2.05ml (17.27mmol) of benzyl bromide were added and the mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane/ethyl acetate (7: 3). The product containing fractions were concentrated to give 9.81g (76%) of compound. 1d) ((R, S) -4- (4-amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetic acid methyl ester hydrochloride

A suspension of 4.42g (11.7mmol) methyl ((R, S) -4- (4-cyanophenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetate in 80ml of anhydrous ethanol is cooled to 0 ℃. Dry hydrogen chloride gas was passed through the suspension and the reaction temperature was maintained at 10 ℃ until the nitrile band disappeared in the IR spectrum. The ethanol solution was concentrated to half of the original and treated with 1L of diethyl ether. The suspension was concentrated under vacuum and the residue was dried under high vacuum. The resulting intermediate was dissolved in 60ml of anhydrous isopropanol and treated with 13.7ml of a 1.9N solution of ammonia in isopropanol at 50 ℃. After stirring for 5 hours at 50 ℃, the reaction mixture was cooled and poured into 1L of diethyl ether. The precipitate was removed by suction filtration, the filtrates concentrated, and the residues combined and subjected to silica gel chromatography, eluting with methylene chloride/methanol/acetic acid/water (9: 1: 0.1). 2.94g (64%) of the title compound are obtained. 1e) ((R, S) -4- (4-amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetate

2.82g (7.2mmol) ((R, S) -4- (4-amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetic acid methyl ester hydrochloride are heated under reflux in 60ml concentrated hydrochloric acid for 5 hours. The solution was concentrated under vacuum and the residue was diluted with water and lyophilized. 1.885g (63%) of the title compound are obtained. 1f) (S) -3-amino-2-benzyloxycarbonylaminopropionic acid tert-butyl ester

In an autoclave, 10g (42mmol) of (S) -3-amino-2-benzyloxycarbonylaminopropionic acid were placed under 20 atm N₂Under atmospheric pressure and shaking in a mixture of 100ml dioxane, 100ml isobutene and 8ml concentrated sulphuric acid. Excess isobutylene was purged and 150ml of diethyl ether and 150ml of saturated sodium bicarbonate solution were added to the residual solution. The phases were separated and the aqueous phase was extracted twice with 100 ml/time of diethyl ether. The combined organic phases are washed with 2X 100ml of water and dried over sodium sulfate. After removal of the solvent in vacuo, 9.58g (78%) of the title compound are obtained as a pale yellow oil. 1g) (S) -2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester

To a solution of 10g (34mmol) of tert-butyl (S) -3-amino-2-benzyloxycarbonylaminopropionate in 600ml of THF/water (2: 1) at 0 ℃ were added 8.9g (40.8mmol) of di-tert-butyl dicarbonate and subsequently 1N NaOH solution was added portionwise again in order to bring the solution to a pH of between 9 and 10 (NaOH consumption; 32 ml). After stirring at room temperature for 3 hours, 1L of water was added and the mixture was extracted 3 times with diethyl ether. After drying over sodium sulfate, filtration and removal of the solvent in vacuo, the residue is chromatographed on silica gel, eluting with dichloromethane/methanol (20: 1). Yield 13.19g (98%) of the title compound. 1h) (S) -2-amino-3-tert-butoxycarbonylaminopropionic acid tert-butyl ester hydrochloride

13.1g of (S) -2-benzyloxycarbonylamino-3-tert-butoxycarbonylaminopropionic acid tert-butyl ester was hydrogenated with 10% Pd/C in methanol/HCl. After 1.5 hours the mixture was filtered and the filtrate was concentrated in vacuo. 9.77g (99%) of the title compound are obtained as a colorless solid. 1i) (S) -tert-butyl 2- (1-adamantylmethoxycarbonylamino) -3-tert-butoxycarbonylamino-propionate

A solution of 10.9g (65.4mmol) of 1- (hydroxymethyl) adamantane and 10.6g (65.4mmol) of carbonyldiimidazole in 60ml THF was stirred at 50 ℃ for 1.5 hours. A solution of 9.7g (32.7mmol) of tert-butyl (S) -2-amino-3-tert-butoxycarbonylaminopropionate in 25ml of THF and 5.6ml (32.7mmol) of diisopropylethylamine were added to the solution, and the mixture was stirred at 60 ℃ for 4 hours and allowed to stand at room temperature overnight. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with heptane/ethyl acetate (7: 3). 8.7g (59%) of the title compound are obtained as a colourless oil. lj) (S) -tert-butyl 2- (1-adamantylmethoxycarbonylamino) -3-aminopropionate

A solution of 8.7g (19.22mmol) of tert-butyl (S) -2- (1-adamantylmethoxycarbonylamino) -3-tert-butoxycarbonylamino-propionate in 180ml of trifluoroacetic acid in dichloromethane (1: 1) was added over the course of 1 minute to 1.5L of ice-cold sodium hydrogencarbonate solution, the mixture was extracted 3 times with dichloromethane and the dichloromethane phases were combined and dried over sodium sulfate. After filtration and removal of the solvent in vacuo, 6.35g (94%) of the title compound are obtained as a colourless solid. 1k) (S) -3- (((R, S) -4- (4- (amino-imino-methyl) phenyl) 3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2- (1-adamantylmethoxycarbonylamino) propionic acid

417mg (1mmol) ((R, S) -4- (4-amino-imino-methyl) -phenyl) -3-benzyl-4-methyl-2, 5-di-oxoimidazolidin-1-yl) acetic acid hydrochloride and 163mg (1mmol) HOOBt are suspended in 5ml DMF and treated with 220mg (1.1mmol) DCC at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour and at room temperature for 1 hour, then 353mg (1mmol) of tert-butyl (S) -2- (1-adamantylmethoxycarbonylamino) -3-aminopropionate and 11.7. mu.l (0.9mmol) of N-ethylmorpholine were added, and the mixture was stirred at room temperature for 2 hours and left to stand at room temperature overnight. After filtration, the filtrate was concentrated in vacuo and the residue was chromatographed on silica gel, eluting with dichloromethane/methanol/glacial acetic acid (9: 1: 0.1). After concentration of the product-containing fractions, the residue is dissolved in 4ml of 90% strength trifluoroacetic acid and stirred at room temperature for 1 hour. Trifluoroacetic acid was removed in vacuo, the residue partitioned between ether and water, the aqueous phase concentrated and the residue purified by silica gel chromatography eluting with dichloromethane/methanol/glacial acetic acid/water (9: 1: 0.1) and then purified by preparative HPLC on RP-18. After concentration of the product fractions and freeze-drying, 26.3mg (4%) of standard are obtainedThe title compound. FAB-MS 659.4(M + H)⁺Example 2(S) -3- ((S) -4- (4- (amino-hydroxyimino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-di-oxoimidazolidin-1-yl) acetylamino) -2- (1-adamantylmethoxycarbonylamino) propionic acid2a) ((S) -4- (4-cyanophenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetic acid 2-Naphthalenemethyl ester

5.28g (110mmol) of sodium hydride are added to a solution under ice bath of 13.66g (50mmol) of ((S) -4- (4-cyanophenyl) -4-methyl-2, 5-di-oxoimidazolidin-1-yl) acetic acid in 100ml of anhydrous DMF. The mixture was stirred at room temperature for 1 hour, and 24.3g (110mmol) of 2-bromomethylnaphthalene were added over 1 hour. The reaction mixture was stirred at room temperature for 20 hours, and then ethyl acetate/water was poured into the mixture. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed 2 times with water and dried over sodium sulfate. After filtration and removal of the solvent in vacuo, the residue is chromatographed on silica, eluting with heptane/ethyl acetate (2: 1). 8.51g (56%) of the title compound are obtained. 2b) ((S) -4- (4- (amino-hydroxyimino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetic acid 2-naphthylmethyl ester

1.67g (24mmol) of hydroxylamine hydrochloride and 5.04ml (35mmol) of triethylamine are added to a solution of 6.64g (12mmol) of 2-naphthylmethyl ((S) -4- (4-cyanophenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetate in 120ml of anhydrous ethanol, and the mixture is heated under reflux for 2.5 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and dried over magnesium sulfate. After filtration, the solvent was evaporated in vacuo to yield 6.08g (86%) of the title compound. 2c) ((S) -4- (4- (amino-hydroxyimino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetic acid

A solution of 2g (3.4mmol) of 2-naphthalenemethyl ((S) -4- (4- (amino-hydroxyimino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetate in 200ml of anhydrous methanol is hydrogenated with palladium hydroxide/barium sulfate for 4 hours. The catalyst was filtered off, the filtrate was concentrated in vacuo and the residue was stirred with ethyl acetate. The product is filtered off with suction and dried under high vacuum. 0.56g (37%) of the title compound are obtained. 2d) (S) -3- ((S) -4- (4- (amino-hydroxyimino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2- (1-adamantylmethoxycarbonylamino) propionic acid tert-butyl ester

164mg (0.5mmol) of TOTU (O- (cyano (ethoxycarbonyl) -methyleneamino) -1,1,3, 3-tetramethyluronium tetrafluoroborate) and 165mg (1.26mmol) of diisopropylethylamine are added to a solution of 223mg (0.5mmol) of ((S) -4- (4- (amino-hydroxyimino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetic acid and 176mg (0.5mmol) of tert-butyl (S) -2- (1-adamantylmethoxycarbonylamino) -3-aminopropionate (cf. example 1) in 10ml of DMF. Stir at room temperature for 2 hours and stand overnight, concentrate the reaction mixture under vacuum and partition the residue into ethyl acetate and water. The phases were separated, the aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated sodium bicarbonate solution and water. Drying over sodium sulfate, filtering and concentrating the filtrate in vacuo, ethyl acetate is added to the residue and the solution is taken up in KHSO₄/K₂SO₄Solution, saturated NaHCO₃The solution and water are washed successively and dried over magnesium sulfate to yield 240mg (62%) of the title compound. 2e) (S) -3- ((S) -4- (4- (amino-hydroxyimino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2- (1-adamantylmethoxycarbonylamino) propionic acid

220mg (0.28mmol) of tert-butyl (S) -3- ((S) -4- (4- (amino-hydroxyimino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2- (1-adamantylmethoxycarbonylamino) propionate are dissolved in 20ml of 90% strength trifluoroacetic acid. After 1 hour at room temperature, the trifluoroacetic acid is removed in vacuo and the residue is stirred with diethyl ether. The product is filtered off with suction, washed with diethyl ether and dried under high vacuum. 110mg (54%) of the title compound (as trifluoroacetate salt) are obtained. ES (+) -MS 725.4(M + H)⁺Example 3(S) -3- (((R, S) -4- (4- (amino-hydroxyimino) -4-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2-benzylaminocarbonylaminopropionic acid3a) (S) -3- (((R, S) -4- (4- (amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2-aminopropionic acid dihydrochloride

A100 ml solution of 4.4g (6.7mmol) of (S) -3- (((R, S) -4- (4- (amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2-benzyloxycarbonylaminopropionic acid [ prepared in analogy to example 1 by coupling ((R, S) -4- (4-amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetic acid hydrochloride and (S) -3-amino-2-phenoxy-carbonylaminopropionic acid tert-butyl ester and subsequent cleavage of the tert-butyl ester ] in methanol at room temperature was prepared using palladium hydroxide/barium sulfate Hydrogenation for 1 hour. The catalyst is filtered off, the solvent is removed in vacuo, and the residue is stirred for 30 minutes at 40 ℃ in 40ml of 6N hydrochloric acid. The solution was concentrated in vacuo, diluted with water and lyophilized to give 2.39g (77%) of the title compound. 3b) (S) -3- (((R, S) -4- (4- (amino-hydroxyimino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2-benzylaminocarbonylaminopropionic acid

0.4ml (2.4mmol) of diisopropylethylamine and 0.15ml (1.2mmol) of benzyl isocyanate are added to a solution of 570mg (1.2mmol) of (S) -3- (((R, S) -4- (4- (amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2-aminopropionic acid dihydrochloride in 20ml of anhydrous DMF. After stirring at room temperature for 4 hours, the solvent was removed in vacuo and the crude product was purified by chromatography on silica gel eluting with dichloromethane, dichloromethane/methanol (8: 2) and methanol. After concentration of the product-containing fractions, the residue was dissolved in water and lyophilized. 70mg (10%) of the title compound are obtained. FAB-MS 600.3(M + H)⁺Example 4(S) - ((R, S) -4- (4- (amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) acetylamino) -2-benzylaminothiocarbonylaminopropionic acid dihydrochloride

This compound is prepared analogously to example 3 and by replacing the isocyanate with benzyl isothiocyanate. ES (+) -MS 616.3(M + H)⁺EXAMPLE 5((R, S) -4- (4- (amino-imino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetyl-L- (N-methylaspartyl) -L-valylmorpholine5a) L-valyl morpholine

3.93g (12mmol) of TOTU (cf. example 2) and 2.04ml of diisopropylethylamine were added to 30ml of anhydrous DMF containing 3.01g (12ml) of N-benzyloxycarbonyl-L-valine and 1.04g (12mmol) of morpholine. After stirring for 2 hours at room temperature, the solvent was removed in vacuo, ethyl acetate was added to the residue and the solution was taken up in 3 XKHSO₄/K₂SO₄Aqueous solution, 3 × saturated sodium bicarbonate solution and 3 × water wash. After drying over sodium sulfate, filtration and removal of the solvent in vacuo, 3.88g N-benzyloxycarbonyl-L-valylmorpholine crude was obtained which was hydrogenated in methanol with 10% Pd/C for 3 hours to remove the benzyloxycarbonyl group. 2.11g (95%) of the title compound are obtained. 5b) L- (N-methylaspartyl (OtBu)) -L-valylmorpholine

The compound is prepared by reacting L-Z-N (CH)₃) Coupling of-Asp (OtBu) -OH and L-valylmorpholine and subsequent removal of the Z group (benzyloxycarbonyl) by hydrogenation as described under a). From 1.39g (7.5mmol) L-valylmorpholine, 2.4g (86%) of the title compound are obtained. 5c) ((R, S) -4- (4- (amino-imino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetyl-L- (N-methylaspartyl) -L-valylmorpholine

This compound was prepared by contacting ((R, S) -4- (4- (amino-imino-methyl) phenyl) -3- (2-naphthylmethyl) -4-methyl-2, 5-dioxoimidazolidin-1-yl) acetate hydrochloride [ prepared in a manner analogous to example 1 and substituting 2-bromomethylnaphthalene for benzyl bromide]And L-N-methyl-aspartyl (OtBu) -L-valylmorpholine and subsequent reaction with 90% trifluoroacetic acid in an analogous manner to example 2Cracking tert-butyl ester by the method. ES (+) MS:728.4(M + H)⁺

Preparation of other carbamates can be prepared analogously to the preparation of the compound of example 1, e.g. (S) -3- (((S) -4- (4- (amino-imino-methyl) phenyl) -3-benzyl-4-methyl-2, 5-dioxoimidazolidin-1-yl) - ((R, S) -2- (2-methylpropyl) acetylamino) -2- (cyclohexylmethoxycarbonylamino) propanoic acid, of the formula, using 2-bromo-4-methylvalerate instead of chloroacetate in step b) of example 1.Study of biological Activity

The assay used to study the activity of the compounds of formula I on the interaction of VCAM-1 and VLA-4 is a specific assay for this type of interaction. The VLA-4 integrin, a cell-binding component in its native form, is used, which is a surface molecule located on human U937 cells (ATCC CRL1593), which belong to the leukocyte group. The specific binding component used was a genetically engineered recombinant soluble fusion protein consisting of the extracytoplasmic domain of human VCAM-1 and the constant region of human immunoglobulin subclass IgG 1. Test method

Determination of adhesion between U937 cells (ATCC CRL1593) and hVCAM-1(1-3) -IgG test 1 preparation of human VCAM-1- (1-3) -IgG and human CD4-IgG

The assay used a gene construct for expression of the extracellular domain of human VCAM-1 (from Dr. brain Seed, Massachusetts General Hospital, Boston, USA) in combination with the gene sequence of the heavy chain of human immunoglobulin IgG1 (hinge region, CH2 and CH3 regions), see Damle and Aruffo, Proc. Natl. Acad. Sci. USA 1991,88, 6403-6407. The soluble fusion protein hVCAM-1(1-3) -IgG contains the three amino-terminal extracellular immunoglobulin-like domains of human VCAM-1 (Damie and Aruffo, Proc. Natl. Acad. Sci. U.S. 1991,88, 6403). CD4-IgG (Zettlmeissl et al, DNA and cell biology, 1990,9,347) was used as a fusion protein for the negative control. According to the conventional method (Ausubel et al, modern methods in Molecular Biology, Current Protocols in Molecular Biology, John Wiley)&Sons, Inc,1994), expressing recombinant proteins as soluble proteins in COS cells (ATCC CRL1651) by DEAE/dextran-mediated DNA transfection. Adhesion assay of U937 cells with hVCAM-1(1-3) -IgG test 2.1 test plates of 96 wells (Nunc Maxisorb) were incubated with 100. mu.l/well goat-anti-human IgG antibody solution (10. mu.g/ml in 50mM tris, pH 9.5) at room temperature for 1 hour. The antibody solution was removed and washed 1 time with PBS. 2.2 mu.l/well blocking buffer (1% BSA in PBS) were incubated on the plate for 0.5 h at room temperature. The blocking buffer was removed and washed 1 time with PBS. 2.3 100. mu.l/well of cell culture supernatant from transfected COS cells was incubated on the plate for 1.5 hours at room temperature. Using a code and human IgG₁The Fc portion of (2) VCAM-1 three amino-terminal immunoglobulin-like domains (hVCAM-1(1-3) -IgG) plasmid transfected COS cells. The content of hVCAM-1(1-3) -IgG is 0.5-1 μ g/ml. The culture supernatant was removed and washed 1 time with PBS. 2.4 plates were incubated with 100. mu.l/well Fc receptor blocking buffer (containing 1 mg/ml. gamma. -globulin, 100mM NaCl, 100. mu.M MgCl)₂,100μM MnCl₂,100μM CaCl₂1mg/ml BSA in 50mM HEPES, pH7.5) was incubated at room temperature for 20 minutes. The blocking buffer was removed and washed 1 time with PBS. 2.5 mu.l of binding buffer (containing 100mM NaCl, 100. mu.M MgCl) was added first₂,100μM MnCl₂,100μM CaCl₂1mg/ml BSA in 50mM HEPES, pH7.5), and the test substance was added to 10. mu.l of the binding buffer and incubated for 20 minutes. The controls used were antibodies against VCAM-1(BBT, No. BBA6) and against VLA-4 (immunological technique, No. 0764). 2.6 culturing U937 cells in Fc in blocking buffer for 20 min, then pipette to a concentration of 1X 10⁶A volume of 100. mu.l per well (final volume of 125. mu.l/well). 2.7 plates were slowly immersed in stop buffer (containing 100mM NaCl, 100. mu. MMgCl) at an angle of 45 °₂,100μM MnCl₂,100μM CaCl₂25mM Tris, pH7.5) and shaken. The process is repeated. 2.8 mu.l/well of Dye solution (16.7. mu.l/ml of Hoechst Dye 33258, 4% formaldehyde, 0.5% Triton X-100 in PBS) were incubated on the plate for 15 minutes. 2.9 plates were slowly immersed in stop buffer (containing 100mM NaCl, 100. mu. MMgCl) at an angle of 45 °₂,100μM MnCl₂,100μM CaCl₂25mM Tris, pH7.5) and shaken. The process is repeated. The liquid was then measured using a cytofluorometer (Millipore) (sensitivity; 5, filter: excitation wavelength: 360 nm; emission wavelength: 460 nm).

The intensity of light emitted by the stained U937 cells adhered to the hVCAM-1(1-3) -IgG and the number of U937 cells remaining on the plate was also a measure of the ability of the test substance added to inhibit this adhesion. From the inhibitory activity of the test substances at different concentrations on the adhesion, the IC giving 50% inhibition of adhesion can be calculated₅₀And (4) concentration. The test results obtained are as follows: example U937/VCAM-1 cell adhesion assay

IC₅₀(μM)1 1.253 11.54 10.55 0.73

Claims (15)

1. A compound of formula IWherein W is R¹-A-C(R¹³) Or R¹-CH = C; y is a carbonyl, thiocarbonyl or methylene group; z is N (R)⁰) Oxygen, sulfur or methylene; a is a divalent group selected from: (C)₁-C₆) Alkylene group, (C)₃-C₇) -cycloalkylene, phenylene- (C)₁-C₆) Alkyl radicals, (C)₁-C₆) Alkylene-phenyl, phenylene- (C)₂-C₆) -chainAn alkenyl group; or a divalent 5-or 6-membered, saturated or unsaturated heterocyclic radical which contains 1 or 2 nitrogen atoms and may be substituted by (C)₁-C₆) -alkyl or doubly-bound oxygen or doubly-bound sulfur mono-or disubstituted; b is divalent (C)₁-C₆) An alkylene radical which may be unsubstituted or selected from (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenyl, (C)₂-C₈) -alkynyl, (C)₃-C₁₀) -cycloalkyl, (C)₃-C₁₀) -cycloalkyl- (C)₁-C₆) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₆) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₆) -substituent substitution of alkyl; e and E^aIndependently of one another, tetrazolyl, (R)^dO)₂P(O)、HOS(O)₂、R⁹NHS(O)₂Or R¹⁰CO；R⁰Is hydrogen, (C)₁-C₈) Alkyl radicals, (C)₃-C₁₂) -cycloalkyl, (C)₃-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted heteroaryl- (C)₁-C₈) Alkyl, H-CO, (C)₁-C₈) -alkyl-CO, (C)₃-C₁₂) -cycloalkyl-CO, (C)₃-C₁₂) -cycloalkyl- (C)₁-C₈) -alkyl-CO, (C)₆-C₁₂) -bicycloalkyl-CO, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) -alkyl-CO, (C)₆-C₁₂) -tricycloalkyl-CO, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -alkyl-CO, optionally substituted (C)₆-C₁₄) aryl-CO, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl-CO, optionally substituted heteroaryl-CO, heteroaryl optionally substituted heteroaryl- (C) thereof₁-C₈) -alkyl-CO, (C)₁-C₈) alkyl-S (O)_n、(C₃-C₁₂) cycloalkyl-S (O)_n、(C₃-C₁₂) -cycloalkyl- (C)₁-C₈) alkyl-S (O)_n、(C₆-C₁₂) -bicycloalkyl-S (O)_n、(C₆-C₁₂) -bicycloalkyl- (C)₁-C₈) alkyl-S (O)_n、(C₆-C₁₂) -tricycloalkyl-S (O)_n、(C₆-C₁₂) -tricycloalkyl- (C)₁-C₈) alkyl-S (O)_nOptionally substituted (C)₆-C₁₄) aryl-S (O)_nOptionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) alkyl-S (O)_nOptionally substituted heteroaryl-S (O)_nOr heteroaryl optionally substituted with heteroaryl- (C)₁-C₈) alkyl-S (O)_nWherein n is 1 or 2; r, R^a、R^b、R^cAnd R^dIndependently of one another, hydrogen, (C)₁-C₈) Alkyl radicals, (C)₃-C₈) -cycloalkyl, (C)₃-C₈) -cycloalkyl- (C)₁-C₈) -alkyl, optionally substituted (C)₆-C₁₄) Aryl or aryl optionally substituted (C)₆-C₁₄) -aryl- (C)₁-C₈) -an alkyl group; r¹Is X-NH-C (= NH) - (CH)₂)_pOr X¹-NH-(CH₂)_pWherein p is 0, 1,2 or 3; x is hydrogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkylcarbonyl, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₁₈) -alkylcarbonyloxy- (C)₁-C₆) Alkoxycarbonyl, optionally substituted (C)₆-C₁₄) Arylcarbonyl, optionally substituted (C)₆-C₁₄) Aryloxy carbonyl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₆) -alkoxycarbonyl, (R)^dO)₂P (O), cyano, hydroxy, (C)₁-C₆) Alkoxy, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₆) -alkoxy or amino; x¹Is one of the meanings of X or is R '-NH-C (= N-R "), wherein R' and R" independently of one another have the meaning of X; r²、R^2aAnd R^2dIndependently of one another, hydrogen, (C)₁-C₈) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) Alkyl radicals, (C)₃-C₈) -cycloalkyl or (C)₃-C₈) -cycloalkyl- (C)₁-C₈) -an alkyl group; r³Is R¹¹NH、(C₉-C₁₂) -cycloalkyl, (C)₉-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) Alkyl, CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-R⁷；

But wherein, if W is R at the same time¹-A-C(R¹³),R¹-A is 4-amidinophenyl, R¹³Is methyl, Z is NH, Y is carbonyl, B is CH₂R and R²Is hydrogen, E is hydroxycarbonyl, g is 0 and h is 1, and for the asymmetric carbon atom in the dioxoimidazolidine ring and for the ring with R²And R³At a molar ratio of 1: 1 of carbon atoms of the group in R configuration and S configuration, R³Is not 1-adamantyl; r⁴Is divalent (C)₁-C₆) An alkylene group ofThe group can be selected from R¹¹NH、(C₉-C₁₂) -cycloalkyl, (C)₉-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -alkyl, and which may also be substituted by one or two other radicals, which may be the same or different (C)₁-C₄) -alkyl substitution; r⁵Is a natural or unnatural amino acid, imino or aza amino acid, in which the free functional group can be protected by protective groups customary in peptide chemistry or is present in the form of an ester or amide, in which amino acid or aza amino acid the N-terminal nitrogen atom carries the group R^b；R⁶Independently of R⁵But having R⁵Or a direct bond; r⁷Is R⁸-NH or Het; r⁸Is (C)₃-C₁₂) -cycloalkyl, (C)₃-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl or (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -an alkyl group; r⁹Is hydrogen, aminocarbonyl, (C)₁-C₁₈) -alkylaminocarbonyl, (C)₃-C₈) -cycloalkylaminocarbonyl, optionally substituted (C)₆-C₁₄) -arylaminocarbonyl, (C)₁-C₁₈) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -cycloalkyl, (C)₃-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₃-C₁₂) -tricycloalkyl or(C₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -an alkyl group; r¹⁰Is hydroxy, (C)₁-C₈) Alkoxy, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkoxy, optionally substituted (C)₆-C₁₄) -aryloxy group, (C)₁-C₈) -alkylcarbonyloxy- (C)₁-C₆) -alkoxy, (C)₆-C₁₄) Aryl carbonyloxy- (C)₁-C₆) -alkoxy, amino, mono-or di- ((C)₁-C₈) -alkyl) -amino, R⁸-NH or Het; r¹¹Is R¹²NH-CO、R¹²-NH-CS、R^14aO-CO、R^14bCO、R^14cS(O)、R^14dS(O)₂、R^14eNH-S (O) or R^14fNH-S(O)₂；R¹²Is optionally substituted (C)₆-C₁₄) Aryl, aryl of which may be substituted (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₈) Alkyl radicals, (C)₂-C₈) -alkenyl, (C)₂-C₈) -alkynyl or R¹⁵；R¹³Is hydrogen, (C)₁-C₆) -alkyl, optionally substituted (C)₆-C₁₄) Aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) Alkyl radicals, (C)₃-C₈) -cycloalkyl or (C)₃-C₈) -cycloalkyl- (C)₁-C₈) -an alkyl group; r^14aIs optionally substituted heteroaryl, heteroaryl wherein heteroaryl is optionally substituted- (C)₁-C₈) -alkyl or R¹⁵；R^14bAnd R^14dIndependently of one another: the aryl group of which is optionally substituted (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₈) -alkyl or R¹⁵；R^14cAnd R^14eIndependently of one another: (C)₁-C₁₈) -alkyl, optionally substituted (C)₆-C₁₄)

- - -aryl, optionally substituted aryl (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₈) -alkyl or R¹⁵；R^14fIs (C) optionally substituted in the aryl radical₆-C₁₄) -aryl- (C)₁-C₈) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted with (C)₁-C₈) Alkyl radicals, (C)₉-C₁₂) -cycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -bicycloalkyl, (C)₆-C₁₂) -bicycloalkyl- (C)₁-C₈) Alkyl radicals, (C)₆-C₁₂) -tricycloalkyl, (C)₆-C₁₂) -tricycloalkyl- (C)₁-C₈) -an alkyl group; r¹⁵Is R¹⁶-(C₁-C₆) -alkyl or R¹⁶；R¹⁶Is a 3-to 12-membered monocyclic or 6-to 24-membered bicyclic or tricyclic radical, wherein these radicals are saturated or partially unsaturated and may also contain 1,2,3 or 4 identical or different ring heteroatoms from the group consisting of nitrogen, oxygen, sulfur and may also be selected from the group consisting of (C) by one or more identical or different₁-C₄) -alkyl and oxo; het is a 5-to 10-membered monocyclic or polycyclic heterocyclic group which is bonded via a ring nitrogen atom and which may be aromatic or partially unsaturated or saturated and may contain 1,2,3 and 4 identical or different further ring heteroatoms from the group consisting of oxygen, nitrogen and sulfur and which may be optionally substituted on carbon atoms and further ring nitrogen atoms, wherein the possible substituents on further ring nitrogen atoms thereof may be identical or different and are selected from R^c、R^cCO and R^cO-CO; g and h are each independently of the other and are 0 or 1; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

2．A compound of formula I as claimed in claim 1, wherein W is R¹-A-C(R¹³) (ii) a And A is a divalent radical selected from the group consisting of cyclohexylene, phenylene, and phenylenemethyl; y is a carbonyl group; z is N (R)⁰) (ii) a B is a divalent methylene or ethylene (=1, 2-ethylene), both of which may be unsubstituted or substituted, the substituent when substituted being selected from: (C)₁-C₈) Alkyl radicals, (C)₃-C₈) -cycloalkyl, (C)₃-C₈) -cycloalkyl- (C)₁-C₄) -alkyl, optionally substituted (C)₆-C₁₀) Aryl, optionally substituted aryl (C)₆-C₁₀) -aryl- (C)₁-C₄) -alkyl, optionally substituted heteroaryl and heteroaryl wherein heteroaryl is optionally substituted- (C)₁-C₄) -an alkyl group; e and E^aIndependently of one another are R¹⁰CO；R、R^aAnd R^bIndependently of one another, hydrogen, (C)₁-C₆) -alkyl or benzyl; r^cIs hydrogen, (C)₁-C₆) Alkyl radicals, (C)₅-C₆) -cycloalkyl, (C)₅-C₆) -cycloalkyl- (C)₁-C₂) Alkyl, optionally substituted phenyl or phenyl in which the phenyl group is optionally substituted- (C)₁-C₂) -an alkyl group; r⁰Is (C)₁-C₆) Alkyl radicals, (C)₅-C₁₀) -cycloalkyl, (C)₅-C₁₀) -cycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) -alkyl, optionally substituted (C)₆-C₁₂) Aryl, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₄) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted heteroaryl- (C)₁-C₄) Alkyl radicals, (C)₁-C₆) -alkyl-CO, (C)₅-C₁₀) -cycloalkyl-CO, (C)₅-C₁₀) -cycloalkyl-(C₁-C₄) -alkyl-CO, (C)₇-C₁₂) -bicycloalkyl-CO, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₄) -alkyl-CO, (C)₁₀-C₁₂) -tricycloalkyl-CO, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) -alkyl-CO, optionally substituted (C)₆-C₁₂) aryl-CO, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₄) -alkyl-CO, optionally substituted heteroaryl-CO, heteroaryl optionally substituted heteroaryl- (C) thereof₁-C₄) -alkyl-CO, (C)₁-C₆) alkyl-S (O)_n、(C₅-C₁₀) cycloalkyl-S (O)_n、(C₅-C₁₀) -cycloalkyl- (C)₁-C₄) alkyl-S (O)_n、(C₇-C₁₂) -bicycloalkyl-S (O)_n、(C₇-C₁₂) -bicycloalkyl- (C)₁-C₄) alkyl-S (O)_n、(C₁₀-C₁₂) -tricycloalkyl-S (O)_n、(C₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) alkyl-S (O)_nOptionally substituted (C)₆-C₁₂) aryl-S (O)_nOptionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₄) alkyl-S (O)_nOptionally substituted heteroaryl-S (O)_nOr heteroaryl optionally substituted with heteroaryl- (C)₁-C₄) alkyl-S (O)_nWherein n is 1 or 2; r¹Is X-NH-C (= NH), X-NH-C (= NH) -NH or X-NH-CH₂(ii) a X is hydrogen, (C)₁-C₆) -alkylcarbonyl, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₈) -alkylcarbonyloxy- (C)₁-C₆) -alkoxycarbonyl or (C)₆-C₁₄) -aryl- (C)₁-C₆) -alkoxycarbonyl or hydroxy; r²、R^2aAnd R^2dIndependently of one another, are preferably hydrogen or (C)₁-C₈) -an alkyl group; r³Is R¹¹NH、(C₁₀-C₁₂) -RingAlkyl, (C)₁₀-C₁₂) -cycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) Alkyl, CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-Het；R¹⁰Is hydroxy, (C)₁-C₆) Alkoxy, optionally substituted aryl (C)₆-C₁₀) -aryl- (C)₁-C₈) -alkoxy, optionally substituted (C)₆-C₁₀) -aryloxy group, (C)₁-C₈) -alkylcarbonyloxy- (C)₁-C₆) -an alkoxy group; r¹¹Is R¹²NH-CO、R^14aO-CO、R^14bCO、R^14cS (O) or R^14dS(O)₂；R^14aIs heteroaryl- (C) whose heteroaryl is optionally substituted₁-C₂) -alkyl or R¹⁵；R^14bAnd R^14dIndependently of one another, are (C) whose aryl radical is optionally substituted₆-C₁₀) -aryl- (C)₁-C₂) -alkyl, heteroaryl optionally substituted on heteroaryl- (C)₁-C₂) -alkyl or R¹⁵；R^14cIs (C)₁-C₆) Alkyl, aryl optionally substituted (C)₆-C₁₀) -aryl- (C)₁-C₂) -alkyl or R¹⁵；R¹⁵Is R¹⁶-(C₁-C₄) -alkyl or R¹⁶；R¹⁶Is a 5-to 10-membered monocyclic radical or a 6-to 14-membered bicyclic or tricyclic radical, wherein the rings are saturated and may also contain 1 or 2 identical or different ring heteroatoms from the group consisting of nitrogen, oxygen, sulfur and may also be substituted by 1,2,3 and 4 identical or different members selected from the group consisting of (C)₁-C₄) -substituent substitution of alkyl; het is a 5-to 10-membered monocyclic heterocyclic group bonded via a ring nitrogen atom, which heterocyclic group may be aromatic or partially unsaturated or saturated and may contain 1 or 2 identical or different members selected from the group consisting of oxygen, nitrogen and sulfurAnd which group may be optionally substituted, wherein the possible substituents on the further ring nitrogen atom thereof may be the same or different and are selected from R^c、R^cCO and R^cO-CO; and one or more of the same or different (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, trifluoromethyl, phenyl and benzyl as substituents on carbon atoms; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

3. A compound of formula I as claimed in claim 1 and/or 2, wherein W is R¹-A-C(R¹³),R¹³Is (C)₁-C₆) Alkyl, aryl optionally substituted (C)₆-C₁₄) -aryl- (C)₁-C₈) -alkyl or (C)₃-C₈) -a cycloalkyl group; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

4. A compound of formula i according to one or more of claims 1 to 3, wherein: r³Is R¹¹NH、(C₁₀-C₁₂) -cycloalkyl, (C)₁₀-C₁₂) -cycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₄) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₄) Alkyl, CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-Het；R¹¹Is R¹⁵O-CO or R¹⁵S(O)₂；R¹⁵Is R¹⁶-(C₁-C₃) -alkyl or R¹⁶；R¹⁶Is a monocyclic radical of 5 to 6 members or a bicyclic or tricyclic radical of 6 to 12 members, where the rings are saturated and may also contain 1 or 2 identical and different ring heteroatoms from the group consisting of nitrogen, oxygen, sulfur, and may also be substituted by 1,2 and 3 identical atomsOr are different from (C)₁-C₄) -substituent substitution of alkyl; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

5. A compound of formula I as claimed in one or more of claims 1 to 4, wherein W is R¹-A-C(R¹³) (ii) a Y is a carbonyl group; z is N (R)⁰) (ii) a A is a divalent group of cyclohexylene, phenylene, and phenylenemethyl; b is a divalent methylene group, which group may be unsubstituted or substituted, the substituents being selected from: (C)₁-C₈) Alkyl radicals, (C)₅-C₆) -cycloalkyl, (C)₅-C₆) -cycloalkyl- (C)₁-C₄) Alkyl, optionally substituted phenyl, phenyl optionally substituted phenyl- (C)₁-C₄) -alkyl, optionally substituted 5-or 6-membered heteroaryl and heteroaryl, the heteroaryl of which is optionally substituted- (C)₁-C₄) -an alkyl group; e and E^aIndependently of one another are R¹⁰CO；R、R^aAnd R^bIndependently of one another, hydrogen or (C)₁-C₄) -an alkyl group; r⁰Is (C)₁-C₆) Alkyl radicals, (C)₅-C₆) -cycloalkyl, (C)₅-C₆) -cycloalkyl- (C)₁-C₂) -alkyl, optionally substituted (C)₆-C₁₂) Aryl, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₂) -alkyl, optionally substituted heteroaryl, heteroaryl optionally substituted heteroaryl- (C)₁-C₂) Alkyl radicals, (C)₁-C₆) -alkyl-CO, (C)₅-C₆) -cycloalkyl-CO, (C)₅-C₆) -cycloalkyl- (C)₁-C₂) -alkyl-CO, optionally substituted (C)₆-C₁₂) aryl-CO, optionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₂) -alkyl-CO, (C)₁-C₆) alkyl-S (O)_n、(C₅-C₆) cycloalkyl-S (O)_n、(C₅-C₆)-Cycloalkyl- (C)₁-C₂) alkyl-S (O)_nOptionally substituted (C)₆-C₁₂) aryl-S (O)_nOptionally substituted aryl (C)₆-C₁₂) -aryl- (C)₁-C₂) alkyl-S (O)_nWherein n is 1 or 2; r¹Is H₂N-C(=NH)、H₂N-C(=N-OH)、CH₃O-CO-NH-C(=NH)、H₂N-C (= NH) -NH or H₂N-CH₂；R²、R^2aAnd R^2dIs hydrogen; r³Is R¹¹NH、(C₁₀-C₁₂) -cycloalkyl, (C)₁₀-C₁₂) -cycloalkyl- (C)₁-C₃) Alkyl radicals, (C)₇-C₁₂) -bicycloalkyl, (C)₇-C₁₂) -bicycloalkyl- (C)₁-C₃) Alkyl radicals, (C)₁₀-C₁₂) -tricycloalkyl, (C)₁₀-C₁₂) -tricycloalkyl- (C)₁-C₃) Alkyl, CO-N (R)^a)-R⁴-E^aOr CO-R⁵-R⁶-Het；R¹⁰Is hydroxy, (C)₁-C₄) -alkoxy, phenoxy, benzyloxy, (C)₁-C₄) -alkylcarbonyloxy- (C)₁-C₆) -an alkoxy group; r¹¹Is R¹⁵O-CO or R¹⁵S(O)₂；R¹³Is (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl or benzyl; r¹⁵Is R¹⁶-(C₁-C₃) -alkyl or R¹⁶；R¹⁶Is a 5-to 6-membered monocyclic radical or a 6-to 12-membered bicyclic or tricyclic radical, where the rings are saturated and may also contain 1 or 2 identical or different ring heteroatoms from the group consisting of nitrogen and oxygen and may also be substituted by 1,2 and 3 identical or different (C)₁-C₄) -substituent substitution of alkyl; het is a 5-to 6-membered monocyclic heterocyclic group bonded via a ring nitrogen atom, which heterocyclic group may be aromatic or partially unsaturated or saturated and may contain 1 further ring heteroatom selected from oxygen and sulphur, and which groups may optionally be identical or different (C)₁-C₆) Alkyl radicals, (C)₁-C₄) -substituents of alkoxy, trifluoromethyl, phenyl and benzyl are mono-or di-substituted; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

6. Compounds of formula I as claimed in one or more of claims 1 to 5, wherein W is R¹-A-C(R¹³) And A is a divalent phenylene group; y is a carbonyl group; z is N (R)⁰) (ii) a B is a divalent methylene group, which may be unsubstituted or substituted, the substituents being selected from (C)₁-C₆) Alkyl radicals, (C)₅-C₆) -cycloalkyl, (C)₅-C₆) -cycloalkyl- (C)₁-C₄) -alkyl, phenyl, benzyl and phenethyl; e is R¹⁰CO；R、R^aAnd R^bIndependently of one another, hydrogen or (C)₁-C₄) -an alkyl group; r⁰Is (C)₁-C₆) Alkyl, aryl optionally substituted (C)₆-C₁₂) -aryl- (C)₁-C₂) Alkyl radicals, (C)₁-C₆) alkyl-S (O)_nOptionally substituted aryl (C)₆-C₁₂) aryl-S (O)_n；R¹Is H₂N-C(=NH)、H₂N-C(=N-OH)、CH₃O-CO-NH-C(=NH)、H₂N-C (= NH) -NH or H₂N-CH₂；R²、R^2aAnd R^2dIs hydrogen; r³Is R¹¹NH or CO-R⁵-Het；R⁵Is a natural or unnatural divalent radical of an alpha-amino acid with a lipophilic side chain, the free functional group of which can be protected by protective groups customary in peptide chemistry or can be present in the form of esters or amides, and which carries the radical R on the nitrogen atom of the N-terminal amino group^b；R¹⁰Is hydroxy, (C)₁-C₄) -alkoxy, phenoxy, benzyloxy, (C)₁-C₄) -alkylcarbonyloxy- (C)₁-C₄) -an alkoxy group; r¹¹Is R¹⁵O-CO or R¹⁵S(O)₂；R¹³Is (C)₁-C₆) -an alkyl group; r¹⁵Is R¹⁶-(C₁-C₃) -alkyl or R¹⁶；R¹⁶Is a 5-to 6-membered monocyclic radical or a 6-to 12-membered bicyclic or tricyclic radical, where the rings are saturated and may also contain 1 or 2 identical and different ring heteroatoms from the group consisting of nitrogen and oxygen and may also be identical or different by 1 and 2 (C)₁-C₄) -alkyl substitution; het is a 5-to 6-membered monocyclic heterocyclic group bonded via a ring nitrogen atom, which heterocyclic group is saturated and may contain 1 further ring heteroatom selected from oxygen and sulphur, and which groups may optionally be substituted by one or two (C)₁-C₄) -alkyl substitution; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

7. A compound of formula I as claimed in one or more of claims 1 to 6, wherein W is R¹-A-C(R¹³) And A is a divalent phenylene group; y is a carbonyl group; z is N (R)⁰) (ii) a B is a divalent methylene group, which may be unsubstituted or substituted, the substituents being selected from (C)₁-C₆) Alkyl radicals, (C)₅-C₆) -cycloalkyl- (C)₁-C₄) -alkyl, phenyl, benzyl and phenethyl; e is R¹⁰CO；R、R^aAnd R^bIndependently of one another, hydrogen or methyl; r⁰Is (C)₁-C₆) Alkyl, aryl optionally substituted (C)₆-C₁₂) -aryl- (C)₁-C₂) -an alkyl group; r¹Is H₂N-C(=NH)、H₂N-C(=NOH)、CH₃O-CO-NH-C(=NH)、H₂N-C (= NH) -NH or H₂NH-CH₂；R²、R^2aAnd R^2dIs hydrogen; r³Is R¹¹NH or CO-R⁵-Het；R⁵Is a natural or unnatural divalent radical of an alpha-amino acid with a lipophilic side chain, the free functional group of which can be protected by protective groups customary in peptide chemistry or can be present in the form of esters or amides, and which carries the radical R on the nitrogen atom of the N-terminal amino group^b；R¹⁰Is hydroxy, (C)₁-C₄) -alkoxy, benzeneOxy, benzyloxy or (C)₁-C₄) -alkylcarbonyloxy- (C)₁-C₄) -an alkoxy group; r¹¹Is R¹⁵O-CO；R¹³Is (C)₁-C₆) -an alkyl group; r¹⁵Is R16-CH₂Or R¹⁶；R¹⁶Is cyclopentyl, cyclohexyl, 1-adamantyl, 2-adamantyl or noradamantyl; het is a 5-to 6-membered monocyclic heterocyclic group bonded via a ring nitrogen atom, which heterocyclic group is saturated and may contain 1 oxygen as further ring heteroatom, and which groups may optionally be substituted by one or two identical or different (C)₁-C₄) -alkyl substitution; all of their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

8. A process for the preparation of a compound of formula i according to one or more of claims 1 to 7, which process comprises reacting a compound of formula ii:carrying out fragment condensation with a compound of a formula III,wherein, in the compound III of the formula II, W, Y, Z, B, E, R, R²、R^2a、R^2bAnd R³And G and h have the meanings stated in claims 1 to 7, or functional groups in these radicals are present in their protected form or as precursors, and where G is hydroxycarbonyl, (C)₁-C₆) -alkoxycarbonyl or activated carboxylic acid derivatives.

9. A compound of the formula i and/or a physiologically acceptable salt according to one or more of claims 1 to 7 for use as a medicament.

10. Pharmaceutical preparations which, in addition to pharmaceutically nontoxic excipients and/or additives, contain one or more compounds of the formula i according to one or more of claims 1 to 7 and/or physiologically acceptable salts thereof.

11. A compound of the formula i according to one or more of claims 1 to 7 and/or its physiologically acceptable salts for use as an anti-inflammatory agent.

12. A compound of the formula i and/or its physiologically acceptable salts according to one or more of claims 1 to 7 for the treatment or prophylaxis of rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, inflammatory diseases of the central nervous system.

13. A compound of the formula i and/or a physiologically acceptable salt according to one or more of claims 1 to 7 for use in the treatment or prophylaxis of asthma or allergic reactions.

14. A compound of the formula i and/or its physiologically acceptable salts according to one or more of claims 1 to 7 for the treatment or prophylaxis of cardiovascular diseases, arteriosclerosis, restenosis or diabetes, for the prevention of organ transplant damage, for the inhibition of tumor growth or tumor metastasis, for the treatment of malaria.

15. A compound of the formula i and/or its physiologically acceptable salts according to one or more of claims 1 to 7 for use as an inhibitor of leukocyte adhesion and/or migration or as an inhibitor of the VLA-4 receptor.