Imidazolidine derivates, their preparation and use, and pharmaceutical compositions containing them

0001The present invention relates to new imidazolidine derivatives of the formula I according to claim 1,<chemistry id="chem0001" num="0001"><img file="EP0903353B1_D0001.tif" /></chemistry>in the B, E, W, Z, R, R⁰, R², R³, e and h have the meanings given below. The compounds of formula I are valuable active pharmaceutical ingredients which are suitable, for example, for the therapy and prophylaxis of inflammatory diseases, for example rheumatoid arthritis, or of allergic diseases. The compounds of formula I are inhibitors of the adhesion and migration of leukocytes and / or antagonists of the adhesion receptor VLA-4, which belongs to the group of integrins. They are generally suitable for the therapy or prophylaxis of diseases which are caused or associated with an undesirable degree of leukocyte adhesion and / or leukocyte migration, or in which cell-cell or cell-matrix interactions play a role, which are based on interactions between VLA-4 receptors are based with their ligands. The invention further relates to processes for the preparation of the compounds of the formula I, their use in the therapy and prophylaxis of the disease states mentioned and pharmaceutical preparations which contain the compounds of the formula I.

0002The integrins are a group of adhesion receptors that are involved in cell-cell-binding and cell-extracellular matrix-binding processes play an important role . They have an αβ-heterodimeric structure and show a wide cellular distribution and a high degree of evolutionary conservation. The integrins include, for example, the fibrinogen receptor on platelets, which primarily interacts with the RGD sequence of the fibrinogen, or the vitronectin receptor on osteoclasts, which primarily interacts with the RGD sequence of vitronectin or osteopontin. The integrins are divided into three large groups, the β2 subfamily with the representatives LFA-1, Mac-1 and p150 / 95, which are responsible in particular for cell-cell interactions of the immune system, and the subfamilies β1 and β3, their representatives mainly mediate cell attachment to components of the extracellular matrix (<nplcit id="ncit0001" npl-type="s"><text>Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375</text></nplcit>). The integrins of the β1 subfamily, also called VLA proteins (very late (activation) antigen), comprise at least six receptors which specifically interact with fibronectin, collagen and / or laminin as ligands. Within the VLA family, the integrin VLA-4 (α4β1) is atypical in that it is mainly limited to lymphoid and myeloid cells and is responsible for cell-cell interactions with a large number of other cells. For example, VLA-4 mediates the interaction of T and B lymphocytes with the heparin II binding fragment of human plasma fibronectin (FN). The binding of VLA-4 with the heparin II binding fragment of plasma fibronectin is based primarily on an interaction with an LDVP sequence. In contrast to the fibrinogen receptor or vitronectin receptor, VLA-4 is not a typical RGD-binding integrin (<nplcit id="ncit0002" npl-type="s"><text>Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347</text></nplcit>).

0003The leukocytes circulating in the blood usually show little affinity for the vascular endothelial cells that line the blood vessels. Cytokines, which are released by inflamed tissue, activate endothelial cells and thus express a large number of cell surface antigens. These include, for example, the adhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; also known as E-selectin), which binds, among other things, neutrophils, ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (leucocyte function -associated antigen 1) interacts with leukocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds various leukocytes, including lymphocytes (<nplcit id="ncit0003" npl-type="s"><text>Osborn et al., Cell 1989, 59, 1203</text></nplcit>). VCAM-1, like ICAM-1, is a member of the immunoglobulin gene superfamily. VCAM-1 (first known as INCAM-110) has been identified as an adhesion molecule induced on endothelial cells by inflammatory cytokines such as TNF and IL-1 and lipopolysaccharides (LPS).<nplcit id="ncit0004" npl-type="s"><text>Elices et al. (Cell 1990, 60, 577</text></nplcit>) showed that VLA-4 and VCAM-1 form a receptor-ligand pair, which mediates the attachment of lymphocytes to activated endothelium. VCAM-1 is not bound to VLA-4 by an interaction of VLA-4 with an RGD sequence, such is not contained in VCAM-1 (<nplcit id="ncit0005" npl-type="s"><text>Bergelson et al., Current Biology 1995, 5, 615</text></nplcit>). VLA-4 also occurs on other leukocytes, and the VCAM-1NLA-4 adhesion mechanism mediates the attachment of leukocytes other than lymphocytes. VLA-4 thus represents a single example of a β1 integrin receptor which plays an essential role in cell-cell interactions as well as in cell-extracellular matrix interactions via the ligands VCAM-1 or fibronectin.

0004The cytokine-induced adhesion molecules play an important role in the recruitment of leukocytes into extravascular tissue areas. Leukocytes are recruited into inflammatory tissue areas by cell adhesion molecules that are expressed on the surface of endothelial cells and serve as ligands for leukocyte-cell surface proteins or protein complexes (receptors) (the terms ligand and receptor can also be used vice versa). Leukocytes from the blood must first attach to endothelial cells before they can migrate into the synovium. Since VCAM-1 binds to cells that carry the integrin VLA-4 (α4β1), such as eosinophils, T and B lymphocytes, monocytes or neutrophils, it has the function and the VCAM-1 / VLA-4 mechanism to recruit such cells from the bloodstream into areas of infection and areas of inflammation (<nplcit id="ncit0006" npl-type="s"><text>Elices et al., Cell 1990, 60, 577</text></nplcit>; <nplcit id="ncit0007" npl-type="s"><text>Osbom, Cell 1990, 62, 3</text></nplcit>; <nplcit id="ncit0008" npl-type="s"><text>Issekutz et al., J. Exp. Med. 1996, 183, 2175</text></nplcit>).

0005The VCAM-1 / VLA-4 adhesion mechanism has been implicated in a number of physiological and pathological processes. In addition to cytokine-induced endothelium, VCAM-1 is also expressed by the following cells, among others: myoblasts, lymphoid dendritic cells and tissue macrophages, rheumatoid synovium, cytokine-stimulated neural cells, parietal epithelial cells of the Bowmans capsule, the renal tubular inflammatory epithelium, the renal tubular inflammatory epithelium, and renal graft rejection and intestinal tissue in graft versus host disease. VCAM-1 is also found expressed on arterial endothelial tissue areas that correspond to early arteriosclerotic plaques of a rabbit model. In addition, VCAM-1 is expressed on follicular dendritic cells from human lymph nodes and is found on bone marrow stromal cells, for example in the mouse. The latter finding indicates a function of VCAM-1 in B cell development. VLA-4 is found not only on cells of haematopoietic origin but also, for example, on melanoma cell lines, and the VCAM-1 / VLA-4 adhesion mechanism is associated with the metastasis of such tumors (<nplcit id="ncit0009" npl-type="s"><text>Rice et al., Science 1989, 246, 1303</text></nplcit>).

0006The main form in which VCAM-1 occurs in vivo on endothelial cells and which is the dominant form in vivo is called VCAM-7D and carries seven immunoglobulin domains. Domains 4, 5 and 6 are similar in their amino acid sequences to domains 1, 2 and 3. The fourth domain is removed by alternative splicing in a further form consisting of six domains, here referred to as VCAM-6D. VCAM-6D can also bind VLA-4 expressing cells.

0007Further information on VLA-4, VCAM-1, integrins and adhesion proteins can be found, for example, in the articles by <nplcit id="ncit0010" npl-type="s"><text>Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347</text></nplcit>; <nplcit id="ncit0011" npl-type="b"><text>Elices, Cell Adhesion in Human Disease, Wiley, Chichester 1995, p. 79</text></nplcit>; <nplcit id="ncit0012" npl-type="s"><text>Kuijpers, Springer Semin. Immunopathol. 1995, 16, 379</text></nplcit>.

0008Due to the role of the VCAM-1 / VLA-4 mechanism in cell adhesion processes, which are important for example in infections, inflammation or atherosclerosis, attempts have been made to combat diseases, in particular, for example, inflammation by intervening in these adhesion processes (<nplcit id="ncit0013" npl-type="s"><text>Osbom et al., Cell 1989, 59, 1203</text></nplcit>). One method of doing this is to use monoclonal antibodies directed against VLA-4. Such monoclonal antibodies (mAb), which block the interaction between VCAM-1 and VLA-4 as VLA-4 antagonists, are known. For example, the anti-VLA-4 mAb HP2 / 1 and HP1 / 3 inhibit the attachment of VLA-4 expressing Ramos cells (B cell-like cells) to human umbilical cord endothelial cells and to VCAM-1 transfected COS cells. Likewise, the anti-VCAM-1 mAb 4B9 inhibits the adhesion of Ramos cells, Jurkat cells (T cell-like cells) and HL60 cells (granulocyte-like cells) to COS cells transfected with genetic constructs that cause that VCAM-6D and VCAM-7D are expressed. In vitro data with antibodies directed against the α4 subunit of VLA-4 show that lymphocyte attachment to synovial endothelial cells is blocked, an adhesion that plays a role in rheumatoid arthritis (<nplcit id="ncit0014" npl-type="s"><text>van Dinther-Janssen et al., J. Immunol. 1991, 147, 4207</text></nplcit>).

0009In vivo experiments have shown that experimental autoimmune encephalomyelitis can be inhibited by anti-α4 mAb. The migration of leukocytes into an inflammatory focus is also blocked by a monoclonal antibody against the α4 chain of VLA-4. Influencing the VLA-4-dependent adhesion mechanism with antibodies was also investigated in an asthma model to investigate the role of VLA-4 in the recruitment of leukocytes into inflamed lung tissue (<patcit id="pcit0001" dnum="USSN07821768A" dnum-type="L"><text>USSN 07 / 821.768</text></patcit>; <patcit id="pcit0002" dnum="EP626861A"><text>EP-A-626 861</text></patcit>). The administration of anti-VLA-4 antibodies inhibited the late phase reaction and the respiratory overreaction in allergic sheep.

0010The VLA-4 dependent cell adhesion mechanism was also examined in a primate model of inflammatory bowel disease (IBD). In this model, which corresponds to ulcerative colitis in humans, the administration of anti-VLA-4 antibodies resulted in a significant reduction in acute inflammation.

0011It was also shown that VLA-4-dependent cell adhesion plays a role in the following clinical conditions, including the following chronic inflammatory processes: Rheumatoid Arthritis (<nplcit id="ncit0015" npl-type="s"><text>Cronstein and Weismann, Arthritis Rheum. 1993, 36, 147</text></nplcit>; <nplcit id="ncit0016" npl-type="s"><text>Elices et al., J. Clin. Invest. 1994, 93, 405</text></nplcit>), Diabetes mellitus (<nplcit id="ncit0017" npl-type="s"><text>Yang et al., Proc. Natl. Acad. Sci. USA 1993, 90, 10494</text></nplcit>), systemic lupus erythematosus (<nplcit id="ncit0018" npl-type="s"><text>Takeuchi et al., J. Clin. Invest. 1993, 92, 3008</text></nplcit>), Delayed type allergies (type IV allergy) (<nplcit id="ncit0019" npl-type="s"><text>Elices et al., Clin. Exp. Rheumatol. 1993, 11, p77</text></nplcit>), multiple sclerosis (<nplcit id="ncit0020" npl-type="s"><text>Yednock et al., Nature 1992, 356, 63</text></nplcit>), Malaria (<nplcit id="ncit0021" npl-type="s"><text>Ockenhouse et al., J. Exp. Med. 1992, 176, 1183</text></nplcit>), Arteriosclerosis (<nplcit id="ncit0022" npl-type="s"><text>O'Brien et al., J. Clin. Invest. 1993, 92, 945</text></nplcit>), Transplant (<nplcit id="ncit0023" npl-type="s"><text>Isobe et al., Transplantation Proceedings 1994, 26, 867-868</text></nplcit>), various malignancies, for example melanoma (<nplcit id="ncit0024" npl-type="s"><text>Renkonen et al., Am. J. Pathol. 1992, 140, 763</text></nplcit>), Lymphoma (<nplcit id="ncit0025" npl-type="s"><text>Freedman et al., Blood 1992, 79, 206</text></nplcit>) and other (<nplcit id="ncit0026" npl-type="s"><text>Albelda et al., J. Cell Biol. 1991, 114, 1059</text></nplcit>).

0012VLA-4 blocking by suitable antagonists then offers effective therapeutic options, in particular for example to treat various inflammatory conditions including asthma and IBD. The particular relevance of VLA-4 antagonists for the treatment of rheumatoid arthritis arises, as already said, from the fact that leukocytes from the blood must first attach to endothelial cells before they can migrate into the synovium, and that at this attachment the VLA-4 receptor plays a role. That inflammatory agents induce VCAM-1 on endothelial cells (<nplcit id="ncit0027" npl-type="s"><text>Osborn, Cell 1990, 62, 3</text></nplcit>; <nplcit id="ncit0028" npl-type="s"><text>Stoolman, Cell 1989, 56, 907</text></nplcit>), and the recruitment of various leukocytes into infection areas and foci of inflammation has already been discussed above. T cells adhere to activated endothelium mainly via the LFA-1 / ICAM-1 and VLA-4 / VCAM-1 adhesion mechanisms (<nplcit id="ncit0029" npl-type="s"><text>Springer, Cell 1994, 76, 301</text></nplcit>). The binding capacity of VLA-4 for VCAM-1 in rheumatoid arthritis is increased on most synovial T cells (<nplcit id="ncit0030" npl-type="s"><text>Postigo et al., J. Clin. Invest. 1992, 89, 1445</text></nplcit>). In addition, increased attachment of synovial T cells to fibronectin was observed (<nplcit id="ncit0031" npl-type="s"><text>Laffon et al., J. Clin. Invest. 1991, 88, 546</text></nplcit>; <nplcit id="ncit0032" npl-type="s"><text>Morales-Ducret et al., J. Immunol. 1992, 149, 1424</text></nplcit>). VLA-4 is therefore upregulated both in terms of its expression and in terms of its function on T lymphocytes in the rheumatoid synovial membrane. Blocking the binding of VLA-4 to its physiological ligands VCAM-1 and fibronectin enables effective prevention or amelioration of articular inflammatory processes. This is also confirmed by experiments with the antibody HP2 / 1 in Lewis rats with adjuvant arthritis, in which effective disease prevention has been observed (<nplcit id="ncit0033" npl-type="s"><text>Barbadillo et al., Springer Semin. Immunopathol. 1995, 16, 427</text></nplcit>). VLA-4 is therefore an important therapeutic target molecule.

0013The above-mentioned VLA-4 antibodies and the use of antibodies as VLA-4 antagonists are in the patent applications <patcit id="pcit0003" dnum="WO9313798A"><text>WO-A-93/13798</text></patcit>, <patcit id="pcit0004" dnum="WO9315764A"><text>WO-A-93/15764</text></patcit>, <patcit id="pcit0005" dnum="WO9416094A"><text>WO-A-94/16094</text></patcit>, <patcit id="pcit0006" dnum="WO9417828A"><text>WO-A-94/17828</text></patcit> and <patcit id="pcit0007" dnum="WO95119790A"><text>WO-A-95119790</text></patcit> described. In the patent applications<patcit id="pcit0008" dnum="WO9415958A"><text>WO-A-94/15958</text></patcit>, <patcit id="pcit0009" dnum="WO9515973A"><text>WO-A-95/15973</text></patcit>, <patcit id="pcit0010" dnum="WO9600581A"><text>WO-A-96/00581</text></patcit>, <patcit id="pcit0011" dnum="WO9606108A"><text>WO-A-96/06108</text></patcit> and <patcit id="pcit0012" dnum="WO9620216A"><text>WO-A-96/20216</text></patcit> peptide compounds are described as VLA-4 antagonists. However, the use of antibodies and peptide compounds as pharmaceuticals has disadvantages, for example a lack of oral availability, easy degradability or immunogenic effects when used over a longer period of time. There is therefore a need for VLA-4 antagonists with a favorable property profile for use in therapy and prophylaxis.

0014In the <patcit id="pcit0013" dnum="WO9514008A"><text>WO-A-95/14008</text></patcit>, of the <patcit id="pcit0014" dnum="WO94121607A"><text>WO-A-94121607</text></patcit>, of the <patcit id="pcit0015" dnum="WO93118057A"><text>WO-A-93118057</text></patcit>, of the <patcit id="pcit0016" dnum="EP449079A"><text>EP-A-449 079</text></patcit>, of the <patcit id="pcit0017" dnum="EP530505A"><text>EP-A-530 505</text></patcit> (<patcit id="pcit0018" dnum="US5389614A"><text>US-A-5 389 614</text></patcit>), of the <patcit id="pcit0019" dnum="EP566919A"><text>EP-A-566 919</text></patcit> (<patcit id="pcit0020" dnum="US5397796A"><text>US-A-5 397 796</text></patcit>), of the <patcit id="pcit0021" dnum="EP580008A"><text>EP-A-580 008</text></patcit> (<patcit id="pcit0022" dnum="US5424293A"><text>US-A-5 424 293</text></patcit>) and the <patcit id="pcit0023" dnum="EP584694A"><text>EP-A-584 694</text></patcit> (<patcit id="pcit0024" dnum="US5554594A"><text>US-A-5 554 594</text></patcit>) Substituted 5-ring heterocycles are described which have an amino, amidino or guanidino function at the N-terminal end of the molecule and which have antiplatelet effects. In the<patcit id="pcit0025" dnum="EP796855A"><text>EP-A-796 855</text></patcit> (European Patent Application <patcit id="pcit0026" dnum="EP97103712A"><text>97103712.2</text></patcit>) further heterocycles are described which are inhibitors of bone resorption. In the<patcit id="pcit0027" dnum="EP842943A"><text>EP-A-842 943</text></patcit>, <patcit id="pcit0028" dnum="EP842945A"><text>EP-A-842 945</text></patcit> and <patcit id="pcit0029" dnum="EP842944A"><text>EP-A-842 944</text></patcit> (German patent applications <patcit id="pcit0030" dnum="DE19647380"><text>19647380.2</text></patcit>, <patcit id="pcit0031" dnum="DE19647381"><text>19647381.0</text></patcit> and <patcit id="pcit0032" dnum="DE19647382"><text>19647382.9</text></patcit>) is described; that certain compounds from this series and certain other compounds surprisingly also inhibit leukocyte adhesion and are VLA-4 antagonists. However, the selected compounds of the formula I, which are notable for their VLA-4 antagonism and / or their inhibitory effect on leukocyte adhesion and leukocyte migration and which are the subject of the present invention, are not specifically disclosed in the applications mentioned.

0015The present invention thus relates to compounds of the formula I according to claim 1,<chemistry id="chem0002" num="0002"><img file="EP0903353B1_D0002.tif" /></chemistry>wherein<dl id="dl0001" compact="compact"><dt>W</dt><dd>for R¹-AC (R¹³) or R¹-CH = C;</dd><dt>Z.</dt><dd>represents oxygen or sulfur;</dd><dt>A</dt><dd>for a direct bond or (C₁-C₂) Alkylene;</dd><dt>B</dt><dd>a divalent residue from the series (C₁-C₆) Alkylene, (C₂-C₆) Alkenylene, phenylene, phenylene (C₁-C₃) alkyl, (C₁-C₃) -Alkylene-phenyl, the divalent (C₁-C₆) Alkylene radical unsubstituted or by a radical from the series (C₁-C₈) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, (C₃-C₁₀) Cycloalkyl, (C₃- C₁₀) -Cycloalkyl- (C₁-C₆) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₆) alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl in the heteroaryl radical (C₁-C₆) alkyl may be substituted;</dd><dt>E</dt><dd>Tetrazolyl, (R⁸O)₂P (O), HOS (O)₂, R⁹NHS (O), or R¹⁰Means CO;</dd><dt>R</dt><dd>Hydrogen, (C₁-C₈) Alkyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) alkyl, optionally substituted heteroaryl or heteroaryl optionally substituted in the heteroaryl radical (C₁- C₈) alkyl;</dd><dt>R⁰</dt><dd>for hydrogen, (C₁-C₈) Alkyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) - alkyl, (C₆-C₁₂) Bicycloalkyl, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂) - tricycloalkyl, (C₆-C₁₂) -Tricycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₄) Aryl (C₁-C₈) - alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) -alky), H-CO, (C₁-C₈) -Alkyl-CO, (C₃-C₁₂) - Cycloalkyl-CO, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) alkyl-CO, (C₆-C₁₂) Bicycloalkyl-CO, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl-CO, (C₆-C₁₂) - tricycloalkyl-CO, (C₆-C₁₂) - Tricycoalkyl- (C₁-C₈) alkyl-CO, optionally substituted (C₆-C₁₄) -Aryl-CO, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl-CO, optionally substituted heteroaryl-CO, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl-CO, (C₁-C₈) -Alkyl-S (O)_n, (C₃-C₁₂) - Cycloalkyl-S (O)_n, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) alkyl-S (O)_n, (C₈-C₁₂) -Bicycloalkyl- S (O)_n, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl-S (O)_n, (C₆-C₁₂) Tricycloalkyl-S (O)_n, (C₆- C₁₂) -Tricycloalkyl- (C₁-C₈) alkyl-S (O)_n, optionally substituted (C₆-C₁₄) - Aryl-S (O)_n, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl- S (O)_n, optionally substituted heteroaryl-S (O)_n or in the heteroaryl radical optionally substituted heteroaryl (C₁-C₈) alkyl-S (O)_n where n is 1 or 2;</dd><dt>R¹</dt><dd>represents an optionally substituted radical from the series phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, where each of these radicals can also be benzanellated;</dd><dt>R²</dt><dd>Hydrogen, (C₁-C₈) Alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) alkyl or (C₃-C₈) - means cycloalkyl;</dd><dt>R³</dt><dd>Hydrogen, (C₁-C₈) Alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl, (C₃-C₈) Cycloalkyl, (C₃-C₈) -Cycloalkyl- (C₁-C₈) alkyl, (C₆- C₁₂) Bicycloalkyl, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂) - tricycloalkyl, (C₆- C₁₂) -Tricycloalkyl- (C₁-C₈) alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, R¹¹NH, CON (CH₃) R⁴, CONHR⁴, COOR¹⁵, CON (CH₃) R¹⁵ or CONHR¹⁵ means;</dd><dt>R⁴</dt><dd>Hydrogen or (C₁-C₁₀) -Alkyl means that optionally one or more times by identical or different radicals from the series Hydroxy, (C₁- C₈) Alkoxy, R⁵, optionally substituted (C₃-C₈) Cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di - ((C₁-C₁₈) aikyl) aminocarbonyl, (C₆-C₁₄) Aryl (C₁-C₈) -alkoxycarbonyl, which can also be substituted in the aryl radical, (C₁-C₈) Alkoxycarbonyl, Het-CO, R⁶-CO, tetrazolyl and trifluoromethyl may be substituted;</dd><dt>R⁵</dt><dd>optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl or an optionally substituted monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulfur , means;</dd><dt>R⁶</dt><dd>the rest of a natural or unnatural amino acid, imino acid, optionally N- (C₁-C₈) alkylated or N - ((C₆-C₁₄) Aryl (C₁-C₈) -alkylated) azaamino acid, which can also be substituted in the aryl radical, or represents the rest of a dipeptide, and their esters and amides, it being possible for free functional groups to be protected by protective groups customary in peptide chemistry;</dd><dt>R⁸</dt><dd>Hydrogen, (C₁-C₁₈) Alkyl, optionally substituted (C₆-C₁₄) Aryl or (C₆- C₁₄) Aryl (C₁-C₈) -alkyl, which can also be substituted in the aryl radical, means;</dd><dt>R⁹</dt><dd>Hydrogen, aminocarbonyl, (C₁-C₁₈) Alkylaminocarbonyl, (C₃-C₈) - Cycloalkylaminocarbonyl, optionally substituted (C₆-C₁₄) - arylaminocarbonyl, (C₁-C₁₈) Alkyl, optionally substituted (C₆-C₁₄) Aryl or (C₃-C₈) Means cycloalkyl;</dd><dt>R¹⁰</dt><dd>Hydroxy, (C₁-C₁₈) Alkoxy, (C₆-C₁₄) Aryl (C₁-C₈) -alkoxy, which can also be substituted in the aryl radical, optionally substituted (C₆-C₁₄) Aryloxy, (C₁-C₈) - alkylcarbonyloxy- (C₁-C₆) alkoxy, (C₆-C₁₄) -Arylcarbonyloxy- (C₁-C₆) alkoxy, amino or mono- or di - ((C₁C.₁₈) -alkykl) -amino means;</dd><dt>R¹¹</dt><dd>for hydrogen, R^12a, R^12a-CO, H-CO, R¹²-O-CO, R^12b-CO, R^12b-CS, R^12a-SO)₂ or R^12b-SO)₂ stands;</dd><dt>R^12a</dt><dd>(C.₁-C₁₈) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) - Cycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl or the radical R¹⁵ means;</dd><dt>R^12b</dt><dd>Amino, Di - ((C₁-C₁₈) alkyl) amino or R^12a-NH means;</dd><dt>R¹³</dt><dd>Hydrogen, (C₁-C₆) Alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₆) alkyl, (C₃-C₈) - cycloalkyl or (C₃-C₈) -Cyclo- (C₁-C₆) alkyl;</dd><dt>R¹⁵</dt><dd>for R¹⁶- (C₁-C₆) alkyl or for R¹⁶ stands;</dd><dt>R¹⁶</dt><dd>represents a 6-membered to 24-membered bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different heteroatoms from the series nitrogen, oxygen and sulfur and which can also be substituted by one or several identical or different substituents from the series (C₁-C₄) Alkyl and oxo may be substituted;</dd><dt>Het</dt><dd>represents the remainder of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a ring nitrogen atom, which may contain one, two, three or four identical or different additional ring hetero atoms from the series consisting of oxygen, nitrogen and sulfur and which may be optionally substituted on carbon atoms and on additional ring nitrogen atoms, where identical or different radicals from the series hydrogen, R^H, HCO, R^HCO and R^HO-CO can stand as substituents and R^H for (C₁- C₈) Alkyl, (C₃-C₈) Cycloalkyl, (C₃-C₈) -Cycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl or optionally substituted (C₆- C₁₄) Aryl (C₁-C₈) alkyl;</dd><dt>e and h</dt><dd>independently represent 0 or 1;</dd></dl>

0016in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically acceptable salts.

0017Alkyl radicals can be straight-chain or branched. This also applies if they carry substituents or occur as substituents of other radicals, for example in alkoxy radicals, alkoxycarbonyl radicals or arylalkyl radicals. The same applies to alkylene residues. Examples of suitable (C₁-C₁₈) -Alkyl radicals are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n- Pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, isopropyl, isobutyl, isopentyl, isohexyl, 3-methylpentyl, neopentyl, neohexyl, 2,3,5-trimethylhexyl, sec-butyl, tert-butyl, tert-pentyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. Examples of alkylene radicals are methylene, ethylene, tri, tetra, penta- and hexamethylene or methylene or ethylene substituted by an alkyl radical, for example methylene which is represented by a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group or an n-hexyl group is substituted, or for example ethylene, which can be substituted both on one and on the other carbon atom or also on both carbon atoms.

0018Alkenyl residues and alkenylene residues as well as alkynyl residues can also be straight-chain or branched. Examples of alkenyl radicals are vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl, examples of alkenylene radicals are vinylene or propenylene, for alkynyl radicals ethinyl, 1-propynyl or propargyl.

0019Cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl, which are also, for example, by (C₁-C₄) Alkyl may be substituted. Examples of substituted cycloalkyl radicals are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl. The same applies to cycloalkylene radicals.

0020Bicycloalkyl residues, tricycloalkyl residues and those for R¹⁶ standing 6-membered to 24-membered bicyclic and tricyclic radicals are obtained formally by abstraction of a hydrogen atom from bicyclic or tricyclic. The underlying bicycles and tricycles can contain only carbon atoms as ring members, so they can be bicycloalkanes or tricycloalkanes, but in the case of those for R¹⁶ radicals also contain one to four identical or different heteroatoms from the series nitrogen, oxygen and sulfur, so it can be aza-, oxa- and thiabicyclo- and -tricycloalkanes. If heteroatoms are contained, one or two heteroatoms, in particular nitrogen atoms or oxygen atoms, are preferably contained. The heteroatoms can have any positions in the bicyclic or tricyclic structure, they can be located in the bridges or, in the case of nitrogen atoms, on the bridgeheads. The bicycloalkanes and tricycloalkanes as well as their hetero-analogues can be completely saturated or contain one or more double bonds; they preferably contain one or two double bonds or, in particular, are completely saturated. Both the bicycloalkanes and tricycloalkanes and the hetero-analogs and both the saturated and the unsaturated representatives can be unsubstituted or in any suitable positions by one or more oxo groups and / or one or more identical or different (C₁-C₄) Alkyl groups, for example methyl groups or isopropyl groups, preferably methyl groups. The free bond of the bicyclic or tricyclic radical can be in any position of the molecule, that is to say the rest can be bonded via a bridgehead atom or an atom in a bridge. The free bond can also be in any stereochemical position, for example in an exo position or an endo position.

0021Examples of basic bodies of bicyclic ring systems from which a bicyclic radical can be derived are norbornane (= bicyclo [2.2.1] heptane), bicyclo [2.2.2] octane and bicyclo [3.2.1] octane, examples of heteroatoms Containing, for unsaturated or for substituted ring systems are 7-azabicylo [2.2.1] heptane, bicyclo [2.2.2] oct-5-ene and camphor (= 1,7,7-trimethyl-2-oxobicyclo [2.2 .1] heptane).

0022Examples of systems from which a tricyclic radical can be derived are the Twistan (= tricyclo [4.4.0.0^3.8] decane), the adamantane (= tricyclo [3.3.1.1^3,7] decane), the noradamantane (= tricyclo [3.3.10^3,7] nonane), the tricyclo [2.2.1.0^2,6] heptane, the tricyclo [5.3.2.0^4,9] dodecane, the tricyclo [5.4.0.0^2,9] undecane or the tricyclo [5.5.1.0^3,11] tridecan.

0023Bicyclic or tricyclic radicals are preferably derived from bridged bicycles or tricycles, that is to say from systems in which rings have two or more than two atoms in common. Unless stated otherwise, bicyclic or tricyclic radicals having 6 to 18 ring members are also preferred, particularly preferably those having 6 to 14 ring members, very particularly preferably those having 7 to 12 ring members.

0024Particularly preferred bicyclic and tricyclic radicals are the 2-norbornyl radical, both the one with the free bond in the exo position and the one with the free bond in the endo position, the 2-bicyclo [3.2.1] octyl radical, the Adamantyl, both the 1-adamantyl and the 2-adamantyl, the homoadamantyl and the noradamantyl, for example the 3-noradamantyl. The 1- and 2-adamantyl radicals are also preferred.

0025(C.₆-C₁₄) Aryl groups are, for example, phenyl, naphthyl, for example 1-naphthyl and 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl, (C₆-C₁₀) Aryl groups, for example 1-naphthyl, 2-naphthyl and especially phenyl. Aryl radicals, in particular phenyl radicals, can be substituted one or more times, preferably once, twice or three times, by identical or different radicals from the series (C₁-C₈) Alkyl, especially (C₁-C₄) Alkyl, (C₁-C₈) Alkoxy, especially (C₁-C₄) -Alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy- (C₁-C₄) -alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C₁-C₄) -Alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl. The same applies, for example, to radicals such as arylalkyl or arylcarbonyl. Arylalkyl radicals are in particular benzyl and 1- and 2-naphthylmethyl, 2-, 3- and 4-biphenylylmethyl and 9-fluorenylmethyl, which can also be substituted. Substituted arylalkyl radicals are, for example, by one or more (C₁-C₈) Alkyl residues, especially (C₁-C₄) -Alkyl radicals, benzyl radicals and naphthylmethyl radicals substituted in the aryl part, 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, by one or several (C₁-C₈) Alkoxy radicals, in particular (C₁-C₄) -Alkoxy radicals, benzyl radicals and naphthylmethyl radicals substituted in the aryl part, for example 4-methoxybenzyl, 4-neopentyloxybenzyl, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 2,3,4-trimethoxybenzyl, nitrobenzyl radicals, for example 2-, 3- and 4-nitrobenzyl, halobenzyl radicals, for example 2-, 3- and 4-chlorobenzyl and 2-, 3- and 4-fluorobenzyl, 3,4-dichlorobenzyl, pentafluorobenzyl, trifluoromethylbenzyl radicals, for example 3- and 4-trifluoromethylbenzyl or 3, 5-bis (trifluoromethyl) benzyl. However, substituted arylalkyl radicals can also have different substituents.

0026In monosubstituted phenyl radicals, the substituent can be in the 2-, 3- or 4-position, with the 3- and the 4-position being preferred. If phenyl is substituted twice, the substituents can be in the 1,2-, 1,3- or 1,4-position to one another. Thus, doubly substituted phenyl can be in the 2,3-position, the 2,4-position, the 2,5-position, the 2,6-position, the 3,4-position or the 3,5-position, based on the linkage point may be substituted. In two-substituted phenyl radicals, the two substituents are preferably arranged in the 3-position and the 4-position, based on the point of attachment. In triple-substituted phenyl radicals, the substituents can be, for example, in the 2,3,4 position, the 2,3,5 position, the 2,4,5 position, the 2,4,6 position, the 2,3 , 6-position or the 3,4,5-position. The same applies to phenylene radicals, which can be present, for example, as 1,4-phenylene or as 1,3-phenylene.

0027Phenylene (C₁-C₃) alkyl is especially phenylene methyl (-C₆H₄-CH₂-) and phenylene ethyl, (C₁-C₃) -Alkylene-phenyl, especially methylenephenyl (-CH₂-C₆H₄-). Phenylene (C₂-C₆) -alkenyl is especially phenylene ethenyl and phenylene propenyl.

0028Heteroaryl stands for a monocyclic or polycyclic aromatic radical with 5 to 14 ring members, which contains 1, 2, 3, 4 or 5 heteroatoms as ring members. Examples of heteroatoms are N, O and S. If several heteroatoms are contained, these can be the same or different. Heteroaryl residues can also be single or multiple, preferably single, double or triple, by the same or different residues from the series (C₁-C₈) Alkyl, especially (C₁-C₄) Alkyl, (C₁-C₆) Alkoxy, especially (C₁-C₄) -Alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy- (C₁-C₄) -alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C₁-C₄) -Alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl. Heteroaryl preferably represents a monocyclic or bicyclic aromatic radical which contains 1, 2, 3 or 4, in particular 1, 2 or 3, identical or different heteroatoms from the series N, O and S and which is represented by 1, 2, 3 or 4 , in particular 1, 2 or 3, identical or different substituents from the series (C₁-C₆) Alkyl, (C₁-C₆) -Alkoxy, fluorine, chlorine, nitro, amino, trifluoromethyl, hydroxy, hydroxy- (C₁-C₄) alkyl, (C₁-C₄) Alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl may be substituted. Heteroaryl particularly preferably represents a monocyclic or bicyclic aromatic radical having 5 to 10 ring members, in particular a 5-membered to 6-membered monocyclic aromatic radical, the 1, 2 or 3, in particular 1 or 2, identical or different heteroatoms from the series Contains N, O and S and by 1 or 2 identical or different substituents from the series (C₁-C₄) Alkyl, (C₁-C₄) Alkoxy, phenyl, phenoxy, benzyloxy and benzyl may be substituted.

0029Heterocycles which stand for monocyclic or bicyclic 5-membered to 12-membered heterocyclic rings can be aromatic or partially or completely saturated. They can be unsubstituted or substituted on one or more carbon atoms or on one or more nitrogen atoms by the same or different substituents, as indicated for the rest of heteroaryl. In particular, the heterocyclic ring on carbon atoms can be replaced one or more times by identical or different radicals from the series (C₁-C₈) Alkyl, for example (C₁-C₄) Alkyl, (C₁-C₈) Alkoxy, for example (C₁-C₄) Alkoxy such as methoxy, phenyl- (C₁-C₄) -alkoxy, for example benzyloxy, hydroxy, oxo, halogen, nitro, amino or trifluoromethyl, and / or ring nitrogen atoms in heterocyclic rings as well as in heteroaryl radicals by (C₁-C₈) Alkyl, for example (C₁-C₄) -Alkyl such as methyl or ethyl, by optionally substituted phenyl or phenyl- (C₁-C₄) alkyl, for example benzyl.

0030Examples of heterocycles which can form the basis of the heteroaryl radical or the radical of the monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, pyridine, Pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, β-carboline or benzanellated, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles.

0031Nitrogen heterocycles can also be present as N-oxides.

0032Residues which can represent heteroaryl or the residue of a monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring are, for example, 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2- Furyl, 3-furyl, 2-thienyl, 3-thienyl, 4-imidazolyl, methylimidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, N-oxido-2-, -3- or -4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3-or 5-indolyl, substituted 2-indolyl, for example 1-methyl, 5-methyl, 5-methoxy, 5-benzyloxy, 5-chloro or 4,5-dimethyl-2-indolyl, 1 -Benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta [b] -5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3-or4 Isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl or 2-benzothiazolyl or, as residues of partially hydrogenated or fully hydrogenated heterocyclic rings, for example also dihydropyridinyl, pyrrolidinyl, for example 2- or 3- (N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, benzodioxolanyl.

0033Heterocyclic radicals representing the radical Het can be unsubstituted on carbon atoms and / or ring nitrogen atoms or substituted one or more times, for example twice, three times, four times or five times, by identical or different substituents. For example, carbon atoms can be identified by (C₁-C₈) Alkyl, especially (C₁-C₄) Alkyl, (C₁-C₈) Alkoxy, especially (C₁-C₄) Alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, oxo, cyano, hydroxycarbonyl, aminocarbonyl, (C₁-C₄) Alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl, in particular by (C₁-C₄) Alkyl, for example methyl, ethyl or tert-butyl, (C₁-C₄) Alkoxy, for example methoxy, hydroxy, oxo, phenyl, phenoxy, benzyl, benzyloxy. Sulfur atoms can be oxidized to sulfoxide or sulfone. Examples of the rest Het are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-substituted 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-oxo-4-thiomorpholinyl, 1,1-dioxo-4-thiomorpholinyl , Perhydroazepin-1-yl, 2,6-dimethyl-1-piperidinyl, 3,3-dimethyl-4-morpholinyl, 4-isopropyl-2,2,6,6-tetramethyl-1-piperazinyl, 4-acetyl-1 -piperazinyl, 4-ethoxycarbonyl-1-piperazinyl.

0034The for R¹ standing heteroaromatic radicals furyl, thienyl, pyrrolyl, imidazolyl and pyridyl can be bonded via any of the carbon atoms, so the radicals 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2 -Imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-pyridyl, 3-pyridyl and 4-pyridyl are present. The one for R¹ standing phenyl radical and the heteroaromatic radicals can also be benzanellated, R¹ can also stand for naphthyl, benzo [b] furyl (= benzofuryl), benzo [c] furyl, benzo [b] thienyl (= benzothienyl), benzo [c] thienyl, indolyl, benzimidazolyl, quinolyl and isoquinolyl, in particular for naphthyl , Benzofuryl, benzothienyl, indolyl, benzimidazolyl, quinolyl and isoquinolyl. The for R¹ standing benzanellated radicals are preferably bonded via a carbon atom in the heterocyclic ring, which in turn can be bonded via any of these carbon atoms. Examples of such for R¹ standing benzanellated residues are 1-naphthyl, 2-naphthyl, 2-benzofuryl, 3-benzofuryl, 2-benzothienyl, 3-benzothienyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7- Indolyl, 2-benzimidazolyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl.

0035The for R¹ standing radicals can be unsubstituted or substituted in any position by one or more, for example one, two, three or four, identical or different substituents. The explanations above apply, for example to the substituent positions in phenyl radicals and heterocyclic radicals, correspondingly also for those for R.¹ standing leftovers. For example, (C₁-C₈) Alkyl, especially (C₁-C₄) Alkyl, (C₁-C₈) Alkoxy, especially (C₁-C₄) -Alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy- (C₁-C₄) -alkyl such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, cyano, formyl, acetyl, hydroxycarbonyl, aminocarbonyl, (C₁-C₄) Alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy and tetrazolyl into consideration, where these substituents can be on carbon atoms in the heterocyclic ring and / or on carbon atoms in a fused benzene ring. Nitrogen atoms in pyrrolyl residues, imidazolyl residues and their benzanellated analogues can be unsubstituted or in particular, for example, by (C₁-C₈) Alkyl, for example (C₁-C₄) -Alkyl such as methyl or ethyl, by optionally substituted phenyl or phenyl- (C₁-C₄) alkyl, for example benzyl, or for example by (C₁-C₄) Alkyl-CO may be substituted.

0036The substituent on a substituted alkylene radical representing B can contain a cycle if it is a substituent from the series (C₃-C₁₀) Cycloalkyl, (C₃-C₁₀) -Cycloalkyl- (C₁-C₆) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₆) alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl in the heteroaryl radical (C₁-C₆), and on the other hand it can be acyclic if it is a substituent from the series (C₁-C₈) Alkyl, (C₂-C₈) Alkenyl and (C₂-C₈) Alkynyl. The acyclic substituents can contain 2, 3, 4, 5, 6, 7 or 8 carbon atoms or, in the case of the saturated alkyl radical, also 1 carbon atom. In the case of alkenyl residues and alkynyl residues, the double bond or triple bond can be in any position and in the case of the double bond can have a cis configuration or a trans configuration. As explained above, these alkyl radicals, alkenyl radicals and alkynyl radicals can be straight-chain or branched.

0037As examples of substituents that stand for B (C₁-C₆) -Alkylene radical may be mentioned, in particular methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, isopentyl, isohexyl, sec-butyl, tert -Butyl, tert-pentyl, neopentyl, neohexyl, 3-methylpentyl, 2-ethylbutyl, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, ethynyl, 1-propynyl, 2 Propynyl, 6-hexynyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-biphenylylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, Cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclooctylpropyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyridylmethyl, 2- (4-pyridyl) ethyl, 2-furylmethyl, 2-thienylmethyl, 3-thienylmethyl or 2 - (3-indolyl) ethyl.

0038Halogen represents fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.

0039The remainder of an amino acid, imino acid or azaamino acid or a dipeptide is obtained, as is customary in peptide chemistry, from the corresponding amino acid, imino acid or azaamino acid or the dipeptide by formally removing a hydrogen atom from the N-terminal amino group or from the imino group. Via the free bond on the amino group or the imino group thus formed, this group is then peptide-like by an amide bond with the CO group in the R group⁶-CO linked.

0040The natural and unnatural amino acids can be present in all stereochemical forms, for example in the D form, the L form or in the form of a mixture of stereoisomers, for example in the form of a racemate. Preferred amino acids are α-amino acids and β-amino acids, particularly preferred are α-amino acids. Examples of amino acids that can be considered are (cf.<nplcit id="ncit0034" npl-type="b"><text>Houben-Weyl, Methods of Organic Chemistry, Volume 15/1 and 15/2. Georg Thieme Verlag, Stuttgart, 1974</text></nplcit>): <ul id="ul0001" list-style="none" compact="compact"><li>Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, ​​Aib, βAib, Ala, βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)₂, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet , hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, βLys, ΔLys, Met, Mim, Min, nArg, Nle , Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, βThi, Thr, Thy , Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), neopentylglycine (Npg), Cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2- (p-tolyl) -2-phenylaminoacetic acid, 2- (p-chlorophenyl) aminoacetic acid.</li></ul>

0041Stands R⁶ for the remainder of a natural or unnatural α-amino acid which is not branched on the α-carbon atom, that is to say which has a hydrogen atom on the α-carbon atom, then the remainder is -N (R^b) -CH (SC) -CO-L, in which CO-L represents the acid group of the amino acid or a derivative thereof, for example an ester group or an amide group, R^b stands for hydrogen and SC for the side chain of the α-amino acid, for example for one of the substituents which are contained in the α-position of the abovementioned α-amino acids which are unbranched in the α-position. Examples of side chains are alkyl radicals, for example the methyl group in alanine or the isopropyl group in valine, the benzyl radical in phenylalanine, the phenyl radical in phenylglycine, the 4-aminobutyl radical in lysine or the hydroxycarbonylmethyl group in aspartic acid. In the sense of the present invention, such side chains and thus the amino acids can be combined into a group in addition to their chemical structure, for example also on the basis of their physicochemical properties, for example lipophilic side chains can be distinguished from hydrophilic side chains which contain polar groups. Examples of lipophilic side chains that are used for R⁶ standing amino acids can be contained are alkyl radicals, arylalkyl radicals or aryl radicals.

0042Azaamino acids are natural or unnatural amino acids in which a CH unit is replaced by a nitrogen atom, for example in α-amino acids the central building block<chemistry id="chem0003" num="0003"><img file="EP0903353B1_D0003.tif" /></chemistry>is replaced.

0043In particular, residues of heterocycles from the following group come into consideration as the residue of an imino acid: pyrrolidine-2-carboxylic acid; Piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinotine-3-carboxylic acid; Decahydroisoquinoline-3-carboxylic acid; Octahydroindole-2-carboxylic acid; Decahydroquinoline-2-carboxylic acid; Octahydrocyclopenta [b] pyrrole-2-carboxylic acid; 2-azabicyclo [2.2.2] octane-3-carboxylic acid; 2-azabicyclo [2.2.1] heptane-3-carboxylic acid; 2-azabicyclo [3.1.0] hexane-3-carboxylic acid; 2-azaspiro [4.4] 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; Decahydrocyclohepta [b] pyrrole-2-carboxylic acid; Decahydrocycloocta [c] pyrrole-2-carboxylic acid; Octahydrocyclopenta [c] pyrrole-2-carboxylic acid; Octahydroisoindole-1-carboxylic acid; 2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole-2-carboxylic acid; 2,3,3a, 4,5,7a-hexahydroindole-2-carboxylic acid; Tetrahydrothiazole-4-carboxylic acid; Isoxazolidine-3-carboxylic acid; Pyrazolidine-3-carboxylic acid, hydroxypyrrolidine-2-carboxylic acid, all of which can optionally be substituted (see the following formulas):<chemistry id="chem0004" num="0004"><img file="EP0903353B1_D0004.tif" /></chemistry><chemistry id="chem0005" num="0005"><img file="EP0903353B1_D0005.tif" /></chemistry><chemistry id="chem0006" num="0006"><img file="EP0903353B1_D0006.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP0903353B1_D0007.tif" /></chemistry><chemistry id="chem0008" num="0008"><img file="EP0903353B1_D0008.tif" /></chemistry><chemistry id="chem0009" num="0009"><img file="EP0903353B1_D0009.tif" /></chemistry><chemistry id="chem0010" num="0010"><img file="EP0903353B1_D0010.tif" /></chemistry><chemistry id="chem0011" num="0011"><img file="EP0903353B1_D0011.tif" /></chemistry>

0044The heterocycles on which the above-mentioned radicals are based are known, for example, from <patcit id="pcit0033" dnum="US4344949A"><text>US-A-4,344,949</text></patcit>; <patcit id="pcit0034" dnum="US4374847A"><text>US-A 4,374,847</text></patcit>; <patcit id="pcit0035" dnum="US4350704A"><text>US-A 4,350,704</text></patcit>; <patcit id="pcit0036" dnum="EP29488A"><text>EP-A 29,488</text></patcit>; <patcit id="pcit0037" dnum="EP31741A"><text>EP-A 31,741</text></patcit>; <patcit id="pcit0038" dnum="EP46953A"><text>EP-A 46,953</text></patcit>; <patcit id="pcit0039" dnum="EP49605A"><text>EP-A 49,605</text></patcit>; <patcit id="pcit0040" dnum="EP49658A"><text>EP-A 49,658</text></patcit>; <patcit id="pcit0041" dnum="EP50800A"><text>EP-A 50,800</text></patcit>; <patcit id="pcit0042" dnum="EP51020A"><text>EP-A 51,020</text></patcit>; <patcit id="pcit0043" dnum="EP52870A"><text>EP-A 52,870</text></patcit>; <patcit id="pcit0044" dnum="EP79022A"><text>EP-A 79,022</text></patcit>; <patcit id="pcit0045" dnum="EP84164A"><text>EP-A 84,164</text></patcit>; <patcit id="pcit0046" dnum="EP89637A"><text>EP-A 89,637</text></patcit>; <patcit id="pcit0047" dnum="EP90341A"><text>EP-A 90,341</text></patcit>; <patcit id="pcit0048" dnum="EP90362A"><text>EP-A 90,362</text></patcit>; <patcit id="pcit0049" dnum="EP105102A"><text>EP-A 105,102</text></patcit>; <patcit id="pcit0050" dnum="EP109020A"><text>EP-A 109,020</text></patcit>; <patcit id="pcit0051" dnum="EP111873A"><text>EP-A 111,873</text></patcit>; <patcit id="pcit0052" dnum="EP271865A"><text>EP-A271,865</text></patcit> and <patcit id="pcit0053" dnum="EP344682A"><text>EP-A344,682</text></patcit>.

0045Dipeptides can contain natural or unnatural amino acids, imino acids and azaamino acids as building blocks. Furthermore, the natural or unnatural amino acids, imino acids, azaamino acids and dipeptides can also be in the form of derivatives of the carboxylic acid group, for example as esters or amides, such as, for example, as methyl esters, ethyl esters, n-propyl esters, isopropyl esters, isobutyl esters, tert-butyl esters, benzyl esters , unsubstituted amides, methylamides, ethylamides, semicarbazides or ω-amino- (C₂-C₈) alkyl amides.

0046Functional groups in residues of amino acids, imino acids, azaamino acids and dipeptides as well as in other parts of the molecules of the formula I can be present in protected form. Suitable protecting groups such as urethane protecting groups, carboxyl protecting groups and side chain protecting groups are among<nplcit id="ncit0035" npl-type="s"><text>Hubbuch, contacts (Merck) 1979, No. 3, pages 14 to 23</text></nplcit>, and at <nplcit id="ncit0036" npl-type="s"><text>Büllesbach, contacts (Merck) 1980, No. 1, pages 23 to 35</text></nplcit>, described. The following may be mentioned in particular: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (NO₂), Z (Hal_n); Bobz, Iboc, Adpoc, Mboc, Acm, tert-Butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

0047Physiologically acceptable salts of the compounds of the formula I are in particular pharmaceutically usable or non-toxic salts. Such salts are, for example, in the case of compounds of the formula I which contain acidic groups, for example carboxylic acid groups, alkali metal salts or alkaline earth metal salts and salts with ammonia and physiologically compatible organic amines. Such compounds of the formula I can therefore be present, for example, as sodium salts, potassium salts, calcium salts, magnesium salts or as acid addition salts with amines such as, for example, triethylamine, ethanolamine, tris (2-hydroxyethyl) amine or amino acids, in particular basic amino acids.

0048Compounds of the formula I which contain basic groups, for example an amino group or a guanidino group, form with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid , Fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid salts. If the compounds of the formula I simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms described, internal salts or betaines.

0049Salts can be obtained from the compounds of the formula I by customary processes known to those skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or else by anion exchange or cation exchange from other salts. The present invention also encompasses all salts of the compounds of the formula I which, because of their low physiological tolerance, are not directly suitable for use in medicaments, but are suitable, for example, as intermediates for chemical reactions or for the preparation of physiologically tolerable salts.

0050The compounds of formula I can exist in stereoisomeric forms. If the compounds of the formula I contain one or more centers of asymmetry, these can independently of one another have the S configuration or the R configuration. The invention includes all possible stereoisomers, for example enantiomers and diastereomers, and mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and / or diastereomers, in all ratios. Enantiomers are therefore the subject of the invention in all ratios in enantiomerically pure form, both as left-handed and as right-handed antipodes, in the form of racemates and in the form of mixtures of the two enantiomers. In the presence of a cis / trans isomerism, both the cis form and the trans form and mixtures of these forms are the subject of the invention. If desired, individual stereoisomers can be prepared by separating a mixture by customary methods, for example by chromatography or crystallization, by using stereochemically uniform starting substances in the synthesis or by stereoselective synthesis. If necessary, derivatization can take place before separation of stereoisomers. A stereoisomer mixture can be separated at the stage of the compounds of the formula I or at the stage of a starting substance or of an intermediate in the course of the synthesis.

0051The compounds of the formula I according to the invention can furthermore contain mobile hydrogen atoms, that is to say they can exist in various tautomeric forms. These tautomers are also the subject of the present invention. The present invention further comprises all solvates of compounds of the formula I, for example hydrates or adducts with alcohols, and derivatives of the compounds of the formula I, for example esters, pro-drugs and active metabolites.

0052The individual structural elements in the formula I preferably have the following meanings, independently of one another.

0053W preferably represents R¹-AC (R¹³).

0054Z preferably represents oxygen.

0055A preferably represents a direct bond or methylene, particularly preferably a direct bond.

0056B is preferably a divalent radical from the series consisting of methylene, ethylene, trimethylene, tetramethylene, vinylene, phenylene or a substituted (C₁-C₄) Alkylene radical. B particularly preferably represents a divalent methylene radical or ethylene radical (= 1,2-ethylene), in particular a methylene radical, it being possible for each of these radicals to be unsubstituted or substituted. B very particularly preferably represents a substituted methylene radical or ethylene radical, in particular a substituted methylene radical. If a divalent alkylene radical for B, in particular a methylene radical or ethylene radical (= 1,2-ethylene), is substituted, it is preferably substituted by a radical from the series (C₁-C₈) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, (C₃-C₇) Cycloalkyl, especially (C₅-C₆) Cycloalkyl, (C₃-C₇) -Cycloalkyl- (C₁-C₄) alkyl, especially (C₅-C₆) -Cycloalkyl- (C₁-C₄) alkyl, optionally substituted (C₆-C₁₀) Aryl, optionally substituted (C₆-C₁₀) Aryl (C₁-C₄) alkyl, optionally substituted heteroaryl or heteroaryl optionally substituted in the heteroaryl radical (C₁-C₄) alkyl. A substituted alkylene radical for B is particularly preferably substituted by (C₁-C₈) Alkyl, that is, by a straight-chain or branched alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

0057E preferably represents tetrazolyl or R.¹⁰CO, particularly preferred for R¹⁰CO.

0058R preferably represents hydrogen, (C₁-C₈) Alkyl or benzyl, particularly preferably for hydrogen or (C₁-C₈) Alkyl, very particularly preferably for hydrogen or (C₁-C₄) Alkyl, especially for hydrogen, methyl or ethyl.

0059R⁰ preferably stands for (C₁-C₈) Alkyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂Bicycloalkyl, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂) - tricycloalkyl, (C₆-c₁₂) -Tricycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) alkyl, optionally substituted heteroaryl or heteroaryl optionally substituted in the heteroaryl radical (C₁-C₈) alkyl, particularly preferred for (C₁-C₈) Alkyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) -Cycloalkyl- (C₁-C₄) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₄) alkyl, optionally substituted heteroaryl or heteroaryl optionally substituted in the heteroaryl radical (C₁-C₄) alkyl, very particularly preferably for optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₄) alkyl, optionally substituted heteroaryl or heteroaryl optionally substituted in the heteroaryl radical (C₁-C₄) alkyl, furthermore preferred for (C₆-C₁₄) Aryl (C₁-C₄) alkyl or heteroaryl- (C₁-C₄) alkyl. It is particularly preferred if R⁰ for optionally substituted in the aryl radical (C₆-C₁₄) Aryl (C₁-C₄) -alkyl, in particular for biphenylylmethyl, naphthylmethyl or benzyl which is unsubstituted or mono- or polysubstituted in the aryl radical.

0060R¹ preferably represents a radical from the series phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, which is not benzanellated. R is particularly preferably¹ for a phenyl radical, a 2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a 3-thienyl radical, a 3-pyrrolyl radical, a 4-imidazolyl radical, a 3-pyridyl radical or a 4-pyridyl radical, very particularly preferably for a phenyl radical , a 2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a 3-thienyl radical, a 4-imidazolyl radical or a 4-pyridyl radical, moreover preferably for a phenyl radical or a 4-pyridyl radical. A for R is preferred¹ standing radical unsubstituted or substituted by one, two or three, in particular by one or by two, identical or different of those radicals which are considered as substituents on carbon atoms and nitrogen atoms in R¹ are specified. A for R is particularly preferred¹ standing rest unsubstituted. Preferred substituents on carbon atoms in the radical R¹ are (C₁-C₄) Alkyl, (C₁-C₄) -Alkoxy, halogen, amino, trifluoromethyl, hydroxy, hydroxy- (C₁-C₄) -alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy, in particular as substituents on carbon atoms one for R¹ standing heteroaryl residues. Particularly preferred substituents on carbon atoms in R¹, especially on carbon atoms one for R¹ standing phenyl residues, are (C₁-C₄) Alkyl, (C₁-C₄) Alkoxy, halogen, trifluoromethyl, hydroxy, hydroxy- (C₁-C₄) alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy.

0061R² preferably represents hydrogen or (C₁-C₈) Alkyl, particularly preferably for hydrogen or (C₁-C₄) Alkyl.

0062R³ preferably stands for (C₁-C₈) Alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₄) alkyl, (C₃-C₈) Cycloalkyl, (C₃-C₈) -Cycloalkyl- (C₁-C₄) alkyl, (C₆-C₁₂) Bicycloalkyl, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₄) alkyl, (C₆-C₁₂) Tricycloalkyl, (C₆-C₁₂) -Tricycloalkyl- (C₁-C₄) alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) -Alkynyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₄) alkyl, R¹¹NH, CON (CH₃)^R, CONHR⁴, CON (CH₃) R¹⁵ or CONHR¹⁵, particularly preferably for optionally substituted (C₆-C₁₄) Aryl, especially optionally substituted (C₆-C₁₀) -Aryl, optionally substituted 5-membered or 6-membered heteroaryl with one or two identical or different heteroatoms from the series nitrogen, oxygen and sulfur, in particular pyridyl, R.¹¹NH, CON (CH₃) R⁴, CONHR⁴, CON (CH₃) R¹⁵ or CONHR¹⁵, very particularly preferably for optionally substituted (C₆-C₁₀) Aryl, R¹¹NH, CON (CH₃) R⁴, CONHR⁴, CON (CH₃) R¹⁵ or CONHR¹⁵

0063R⁴ preferably stands for (C₁-C₈) Alkyl, which is optionally as described above in the definition of R⁴ may be substituted, particularly preferably for (C₁-C₈) Alkyl, especially (C₁-C₆) Alkyl, which is represented by one or two of the in the above definition of R⁴ specified substituent is substituted. It is very particularly preferred if one of the substituents is bonded in the 1-position of the alkyl group, that is to that carbon atom of the alkyl group to which the nitrogen atom in the CONHR group is also attached⁴ or in the group CON (CH₃) R⁴ is bound, and if this substituent in the 1-position of one of the residues hydroxycarbonyl, aminocarbonyl, mono- or di - ((C₁-C₁₈) alkyl) aminocarbonyl, (C₆-C₁₄) Aryl (C₁-C₈) -alkoxycarbonyl, which can also be substituted in the aryl radical, Het-CO, R⁶-CO, (C₁-C₈) Alkoxycarbonyl or tetrazolyl. In this particularly preferred case, the rest is -NHR⁴ or the rest -N (CH₃) R⁴ thus for the remainder of an α-amino acid or an N-methyl-α-amino acid or a derivative thereof, this formally being obtained by abstraction of a hydrogen atom from the amino group of the amino acid. Particularly preferred α-amino acids are those with a lipophilic side chain, for example phenylglycine, phenylalanine, valine, leucine, isoleucine and homologues thereof, and derivatives of these amino acids such as esters, amides or the derivatives in which the carboxylic acid group in the rest of Het-CO is transferred.

0064R¹¹ preferably represents hydrogen, R^23a, R^12a-CO, H-CO, R^12a-O-CO, R^12b-CO, R^12b-CS or R^12a-SO)₂, particularly preferred for hydrogen, R^12a, R^12a-CO, R^12a-O-CO, R^12b-CO, R^12b-CS or R^12aSO)₂, very particularly preferred for R^12a, R^12a-CO, R^12a-O-CO, R^12b-CO, R^12b-CS or R^12a-SO)₂, also preferred for R¹², R¹²-CO, R^12a-O-CO, R^12b-CO or R^12a-SO)₂.

0065R^12a preferably stands for (C₁-C₁₀) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl or the radical R¹⁵.

0066R^12b preferably represents R.^12a-NH.

0067R¹³ preferably represents hydrogen, (C₁-C₆) Alkyl, (C₃-C₈) Cycloalkyl or benzyl, particularly preferably for hydrogen or (C₁-C₆) Alkyl, very particularly preferably for hydrogen or (C₁-C₄) Alkyl, especially for (C₁-C₄) Alkyl, with a preferred alkyl radical for the R¹³ stands, is the methyl radical.

0068R¹⁵ preferably represents R.¹⁶- (C₁-C₃) alkyl or for R¹⁶, particularly preferred for R¹⁶- (C₁) alkyl or R¹⁶. R is also preferably¹⁵ then when R³ for COOR¹⁵ represents the exo-2-norbornyl radical, the endo-2-norbornyl radical or the bicyclo [3.2.1] octyl radical, and R represents¹⁵ then when R³ for CONHR¹⁵ stands for the exo-2-norbornyl radical, the endo-2-norbornyl radical, the 3-noradamantyl radical and in particular the 1-adamantyl radical, the 2-adamantyl radical, the 1-adamantylmethyl radical or the 2-adamantylmethyl radical.

0069R¹⁶ preferably represents a 6-membered to 14-membered, in particular a 7-membered to 12-membered, bridged bicyclic or tricyclic radical which is saturated or partially unsaturated and which also has one to four, in particular one, two or three, especially one or contain two, identical or different heteroatoms from the series nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the series (C₁-C₄) Alkyl and oxo may be substituted.

0070Het preferably represents the remainder of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a ring nitrogen atom, which may contain one or two identical or different additional ring hetero atoms from the series oxygen, nitrogen and sulfur and on Carbon atoms and optionally substituted on ring nitrogen atoms, where identical or different radicals from the series hydrogen, R^H, HCO, R^HCO or R^HO-CO can stand as substituents. Het particularly preferably represents such a heterocycle which does not contain an additional ring heteroatom or which contains an additional ring heteroatom from the series consisting of nitrogen, oxygen and sulfur, very particularly preferably Het represents the remainder of a 5-membered bond via a nitrogen atom, 6-membered or 7-membered, saturated monocyclic heterocycle, which contains no additional ring heteroatom or which contains an additional ring heteroatom from the series nitrogen, oxygen and sulfur, in which case the rest Het may also be unsubstituted or substituted on carbon atoms and / or on additional ring nitrogen atoms.

0071Stands R³ for one of the residues (C₁-C₈) Alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl, (C₃-C₈) Cycloalkyl, (C₃-C₈) -Cycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂) Bicycloalkyl, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂) Tricycloalkyl, (C₆-C₁₂) -Tricycloalkyl- (C₁-C₈) alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, CON (CH₃) R⁴, CONHR⁴, COOR¹⁵, CON (CH₃) R¹⁵ or CONHR¹⁵, preferably e stands for 0 and h for 1. If R³ for R¹¹NH, e is preferably 1 and h is 0.

0072Preferred compounds of the formula I are those compounds in which one or more of the radicals have preferred meanings, all combinations of preferred substituent meanings being the subject of the present invention. Particularly preferred compounds of formula 1 are those in which simultaneously<dl id="dl0002" compact="compact"><dt>W</dt><dd>for R¹-AC (R¹³) stands;</dd><dt>Z.</dt><dd>represents oxygen or sulfur;</dd><dt>A</dt><dd>represents a direct bond or methylene;</dd><dt>B</dt><dd>represents a divalent methylene radical or ethylene radical, both of which may be unsubstituted or may be substituted by a radical from the series (C₁-C₈) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, (C₃-C₁₀) Cycloalkyl, (C₃- C₁₀) -Cycloalkyl- (C₁-C₆) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₆) alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl in the heteroaryl radical (C₁-C₆) alkyl;</dd><dt>E</dt><dd>Tetrazolyl or R¹⁰Means CO;</dd><dt>R</dt><dd>Hydrogen or (C₁-C₈) Means alkyl;</dd><dt>R⁰</dt><dd>for hydrogen, (C₁-C₈) Alkyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) - alkyl, (C₆-C₁₂) Bicycloalkyl, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂) - tricycloalkyl, (C₆-C₁₂) -Tricycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) - alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl, H-CO, (C₁-C₈) -Alkyl-CO, (C₃-C₁₂) -Cycloalkyl-CO, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) alkyl-CO, (C₆-C₁₂) - bicycloalkyl-CO, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl-CO, (C₆-C₁₂) Tricycloalkyl CO, (C₆-C₁₂) -Tricycloalkyl- (C₁-C₈) alkyl-CO, optionally substituted (C₆- C₁₄) -Aryl-CO, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) - alkyl-CO, optionally substituted heteroaryl-CO, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl-CO, (C₁-C₈) -Alkyl-S (O)_n, (C₃-C₁₂) -Cycloalkyl-S (O)_n, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) alkyl-S (O)_n, (C₆-C₁₂) - Bicycloalkyl-S (O)_n, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl-S (O)_n, (C₆-C₁₂) - tricycloalkyl-S (O)_n, (C₆-C₁₂) -Tricycloalkyl- (C₁-C₈) alkyl-S (O)_n, optionally substituted (C₆-C₁₄) -Aryl-S (O)_n, optionally substituted (C₆- C₁₄) Aryl (C₁-C₈) alkyl-S (O)_n, optionally substituted heteroaryl-S (O)_n or in the heteroaryl radical optionally substituted heteroaryl (C₁-C₈) -alkyl- S (O)_n where n is 1 or 2;</dd><dt>R¹</dt><dd>represents an optionally substituted radical from the series phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl, where each of these radicals can also be benzanellated;</dd><dt>R²</dt><dd>Hydrogen or (C₁-C₈) Means alkyl;</dd><dt>R³</dt><dd>Hydrogen, (C₁-C₈) Alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl, (C₃-C₈) Cycloalkyl, (C₃-C₈) -Cycloalkyl- (C₁-C₈) alkyl, (C₆- C₁₂) Bicycloalkyl, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂) Tricycloalkyl, (C₆- C₁₂) -Tricycloalkyl- (C₁-C₈) alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, R¹¹NH, CON (CH₃) R⁴, CONHR⁴, COOR¹⁵, CON (CH₃) R¹⁵ or CONHR¹⁵ means;</dd><dt>R⁴</dt><dd>(C.₁-C₈) -Alkyl means that optionally one or more times by identical or different radicals from the series Hydroxy, (C₁-C₈) Alkoxy, R⁵, optionally substituted (C₃-C₈) Cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di - ((C₁-C₁₈) alkyl) aminocarbonyl, (C₆-C₁₄) Aryl (C₁- C₈) -alkoxycarbonyl, which can also be substituted in the aryl radical, (C₁-C₈) - alkoxycarbonyl, Het-CO, R⁶-CO, tetrazolyl and trifluoromethyl may be substituted;</dd><dt>R⁵</dt><dd>optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl or an optionally substituted monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulfur , means;</dd><dt>R⁶</dt><dd>the rest of a natural or unnatural amino acid, imino acid, optionally N- (C₁-C₈) alkylated or N - ((C₆-C₁₄) Aryl (C₁-C₈) -alkylated) azaamino acid, which can also be substituted in the aryl radical, or represents the rest of a dipeptide, and their esters and amides, it being possible for free functional groups to be protected by protective groups customary in peptide chemistry;</dd><dt>R¹⁰</dt><dd>Hydroxy, (C₁-C₁₈) Alkoxy, (C₆-C₁₄) Aryl (C₁-C₈) -alkoxy, which can also be substituted in the aryl radical, optionally substituted (C₆-C₁₄) Aryloxy, (C₁-C₈) - alkylcarbonyloxy- (C₁-C₆) alkoxy, (C₆-C₁₄) -Arylcarbonyloxy- (C₁-C₆) alkoxy,</dd><dt>R¹¹</dt><dd>Amino or Mono- or Di - ((C₁-C₁₈) -alkyl) -amino; for hydrogen, R^12a, R^12a-CO, R^12a-O-CO, R^12b-CO, R^12b-CS or R^12a-SO)₂ stands;</dd><dt>R^12a</dt><dd>(C.₁-C₁₈) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) - Cycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl or the radical R¹⁵ means;</dd><dt>R^12b</dt><dd>Amino, Di - ((C₁-C₁₈) alkyl) amino or R^12a-NH means;</dd><dt>R¹³</dt><dd>Hydrogen or (C₁-C₆) Means alkyl;</dd><dt>R¹⁵</dt><dd>for R¹⁶- (C₁-C₆) alkyl or for R¹⁶ stands;</dd><dt>R¹⁶</dt><dd>represents a 6-membered to 14-membered bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different heteroatoms from the series consisting of nitrogen, oxygen and sulfur and which can also be substituted by one or several identical or different substituents from the series (C₁-C₄) Alkyl and oxo may be substituted;</dd><dt>Het</dt><dd>represents the remainder of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a ring nitrogen atom, which may contain one, two, three or four identical or different additional ring hetero atoms from the series consisting of oxygen, nitrogen and sulfur and which may be optionally substituted on carbon atoms and on additional ring nitrogen atoms, where identical or different radicals from the series hydrogen, R^H, HCO, R^HCO or R^HO-CO can stand as substituents and R^H for (C₁- C₈) Alkyl, (C₃-C₈) Cycloalkyl, (C₃-C₈) -Cycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl or optionally substituted (C₆- C₁₄) Aryl (C₁-C₈) alkyl;</dd><dt>e and h</dt><dd>independently represent 0 or 1;</dd></dl>in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically acceptable salts.

0073Very particularly preferred compounds of the formula I are those in which at the same time<dl id="dl0003" compact="compact"><dt>W</dt><dd>for R¹-AC (R¹³) stands;</dd><dt>Z.</dt><dd>represents oxygen;</dd><dt>A</dt><dd>represents a direct bond or methylene;</dd><dt>B</dt><dd>represents a divalent methylene radical or ethylene radical, both of which may be unsubstituted or may be substituted by a radical from the series (C₁-C₈) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, (C₃-C₁₀) Cycloalkyl, (C₃- C₁₀) -Cycloalkyl- (C₁-C₆) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₆) alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl in the heteroaryl radical (C₁-C₆) alkyl;</dd><dt>E</dt><dd>R¹⁰Means CO;</dd><dt>R</dt><dd>Hydrogen or (C₁-C₄) Means alkyl;</dd><dt>R⁰</dt><dd>for (C₁-C₈) Alkyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) -Cycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂) - bicycloalkyl, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₈) alkyl, (C₆-C₁₂) Tricycloalkyl, (C₆-C₁₂) - Tricycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) alkyl, optionally substituted heteroaryl or heteroaryl optionally substituted in the heteroaryl radical (C₁-C₈) alkyl;</dd><dt>R¹</dt><dd>represents an optionally substituted radical from the series phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl;</dd><dt>R²</dt><dd>Hydrogen or (C₁-C₄) Means alkyl;</dd><dt>R³</dt><dd>(C.₁-C₈) Alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₄) -alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₄) alkyl, (C₃-C₈) Cycloalkyl, (C₃-C₈) -Cycloalkyl- (C₁-C₄) alkyl, (C₆- C₁₂) Bicycloalkyl, (C₆-C₁₂) -Bicycloalkyl- (C₁-C₄) alkyl, (C₆-C₁₂) Tricycloalkyl, (C₆- C₁₂) -Tricycloalkyl- (C₁-C₄) alkyl, R¹¹NH, CON (CH₃) R⁴, CONHR⁴, COOR¹⁵, CON (CH₃) R¹⁵ or CONHR¹⁵ means;</dd><dt>R⁴</dt><dd>(C.₁-C₈) -Alkyl means that, if necessary, one or more times by the same</dd><dt>R⁵</dt><dd>or various residues from the series Hydroxy, (C₁-C₈) Alkoxy, R⁵, optionally substituted (C₃-C₈) Cycloalkyl, hydroxycarbonyl, aminocarbonyl, mono- or di - ((C₁-C₈) alkyl) aminocarbonyl, (C₆-C₁₄) Aryl (C₁- C₈) -alkoxycarbonyl, which can also be substituted in the aryl radical, (C₁-C₈) - alkoxycarbonyl, Het-CO, R⁶-CO, tetrazolyl and trifluoromethyl may be substituted; optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl or an optionally substituted monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulfur , means;</dd><dt>R⁶</dt><dd>the remainder of a natural or unnatural amino acid, imino acid or optionally N- (C₁-C₈) alkylated or N - ((C₆-C₁₄) Aryl (C₁-C₈) -alkylated) azaamino acid, which can also be substituted in the aryl radical, and their esters and amides, where free functional groups can be protected by protective groups customary in peptide chemistry;</dd><dt>R¹⁰</dt><dd>Hydroxy, (C₁-C₈) Alkoxy, (C₆-C₁₄) Aryl (C₁-C₈) -alkoxy, which can also be substituted in the aryl radical, optionally substituted (C₆-C₁₄) Aryloxy, (C₁-C₈) - alkylcarbonyloxy- (C₁-C₆) alkoxy, (C₆-C₁₄) -Arylcarbonyloxy- (C₁-C₆) alkoxy, amino or mono- or di - ((C₁-C₈) -alkyl) -amino;</dd><dt>R¹¹</dt><dd>for R^12a, R^12a-CO, R^12a-O-CO, R^12b-CO or R^12a-SO)₂ stands;</dd><dt>R^12a</dt><dd>(C.₁-C₁₀) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl; (C.₃-C₁₂) Cycloalkyl, (C₃-C₁₂) - Cycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl or the radical R¹⁵ means;</dd><dt>R^12b</dt><dd>Amino, Di - ((C₁-C₁₀) alkyl) amino or R^12a-NH means;</dd><dt>R¹³</dt><dd>Hydrogen or (C₁-C₄) Means alkyl;</dd><dt>R¹⁵</dt><dd>for R¹⁶- (C₁-C₃) alkyl or for R¹⁶ stands;</dd><dt>R¹⁶</dt><dd>for a 7-membered to 12-membered bicyclic or tricyclic radical</dd><dt>Het</dt><dd>which is saturated or partially unsaturated and which can also contain one or two identical or different heteroatoms from the series nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the series (C₁-C₄) Alkyl and oxo may be substituted; represents the remainder of a 5-membered to 10-membered, saturated monocyclic or polycyclic heterocycle which is bonded via a ring nitrogen atom and which may contain one or two identical or different additional ring hetero atoms from the series consisting of oxygen, nitrogen and sulfur and which is attached to carbon atoms and additional ring nitrogen atoms may optionally be substituted, where identical or different radicals from the series hydrogen, R^H, HCO, R^HCO or R^HO-CO can stand as substituents and R^H for (C₁- C₆) Alkyl, (C₃-C₈) Cycloalkyl, (C₃-C₈) -Cycloalkyl- (C₁-C₄) alkyl, optionally substituted (C₆-C₁₄) Aryl or optionally substituted (C₆- C₁₄) Aryl (C₁-C₄) alkyl;</dd><dt>e and h</dt><dd>independently represent 0 or 1;</dd></dl>in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically acceptable salts.

0074Furthermore preferred compounds of formula I are those in which simultaneously<dl id="dl0004" compact="compact"><dt>W</dt><dd>for R¹-AC (R¹³) stands;</dd><dt>Z.</dt><dd>represents oxygen;</dd><dt>A</dt><dd>represents a direct bond or methylene;</dd><dt>B</dt><dd>represents an unsubstituted methylene radical or a methylene radical which is replaced by a radical from the series (C₁-C₈) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, (C₃-C₇) Cycloalkyl, (C₃-C₇) -Cycloalkyl- (C₁-C₄) alkyl, optionally substituted (C₆-C₁₀) Aryl, optionally substituted (C₆-C₁₀) - Aryl- (C₁-C₄) alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl in the heteroaryl radical (C₁-C₄) alkyl is substituted;</dd><dt>E</dt><dd>R¹⁰Means CO;</dd><dt>R</dt><dd>Hydrogen or (C₁-C₄) Means alkyl;</dd><dt>R⁰</dt><dd>for optionally substituted in the aryl radical (C₆-C₁₄) Aryl (C₁-C₄) alkyl or heteroaryl (C₁-C₄) alkyl;</dd><dt>R¹</dt><dd>represents an optionally substituted radical from the series phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl;</dd><dt>R²</dt><dd>Hydrogen or (C₁-C₄) Means alkyl;</dd><dt>R³</dt><dd>for an unsubstituted phenyl radical or naphthyl radical or one by one, two or three identical or different radicals from the series (C₁-C₄) Alkyl, (C₁- C₄) Alkoxy, hydroxy, halogen, trifluoromethyl, nitro, methylenedioxy, ethylenedioxy, hydroxycarbonyl, (C₁-C₄) -Alkoxycarbonyl, aminocarbonyl, cyano, phenyl, phenoxy, benzyl and benzyloxy substituted phenyl radical or naphthyl radical or R³ for pyridyl, (C₁-C₄) Alkyl, (C₂-C₄) Alkenyl, (C₂-C₄) - alkynyl, (C₅-C₆) Cycloalkyl, R¹¹NH, CON (CH₃) R⁴, CONHR⁴, CON (CH₃) R¹⁵ or CONHR¹⁵ stands;</dd><dt>R⁴</dt><dd>(C.₁-C₈) -Alkyl means that by one or two identical or different radicals from the series Hydroxy, (C₁-C₈) Alkoxy, R⁵, optionally substituted (C₃-C₈) Cycloalkyl, hydroxycarbonyl, aminocarbonyl, (C₆-C₁₀) Aryl (C₁-C₄) - alkoxycarbonyl, which can also be substituted in the aryl radical, (C₁-C₆) - alkoxycarbonyl, Het-CO, R⁶-CO, tetrazolyl and trifluoromethyl is substituted;</dd><dt>R⁵</dt><dd>optionally substituted (C₆-C₁₀) Aryl, optionally substituted (C₆-C₁₀) Aryl (C₁-C₄) -alkyl or an optionally substituted monocyclic or bicyclic 5-membered to 10-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms from the series nitrogen, oxygen and sulfur , means;</dd><dt>R¹⁰</dt><dd>Hydroxy, (C₁-C₈) Alkoxy, (C₆-C₁₀) Aryl (C₁-C₄) -alkoxy, which can also be substituted in the aryl radical, optionally substituted (C₆-C₁₀) Aryloxy, (C₁-C₈) - alkylcarbonyloxy- (C₁-C₄) alkoxy, (C₈-C₁₀) -Arylcarbonyloxy- (C₁-C₄) alkoxy, amino or mono- or di - ((C₁-C₈) -alkyl) -amino;</dd><dt>R¹¹</dt><dd>for R^12a, R^12a-CO, R^12a-O-CO, R^12b-CO or R^12a-SO)₂ stands;</dd><dt>R^12a</dt><dd>(C.₁-C₁₀) Alkyl, (C₂-C₈) Alkenyl, (C₂-C₈) Alkynyl, (C₃-C₁₂) Cycloalkyl, (C₃-C₁₂) - Cycloalkyl- (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄) Aryl, optionally substituted (C₆-C₁₄) Aryl (C₁-C₈) -alkyl, optionally substituted heteroaryl, in the heteroaryl radical optionally substituted heteroaryl- (C₁-C₈) alkyl or the radical R¹⁵ means;</dd><dt>R^12b</dt><dd>Amino, Di - ((C₁-C₁₀) alkyl) amino or R^12a-NH means;</dd><dt>R¹³</dt><dd>Hydrogen or (C₁-C₄) Means alkyl;</dd><dt>R¹⁵</dt><dd>for R¹⁶- (C₁-C₃) alkyl or for R¹⁶ stands;</dd><dt>R¹⁶</dt><dd>represents a 7-membered to 12-membered bicyclic or tricyclic radical which is saturated and which can also contain one or two identical or different heteroatoms from the series consisting of nitrogen, oxygen and sulfur and which also consists of one or more identical or different substituents the series (C₁-C₄) Alkyl and oxo may be substituted;</dd><dt>Het</dt><dd>represents the remainder of a 5-membered to 7-membered, saturated monocyclic heterocycle bonded via a ring nitrogen atom, which may contain one or two identical or different additional ring hetero atoms from the series consisting of oxygen, nitrogen and sulfur, and that on carbon atoms and on additional ring nitrogen atoms can optionally be substituted, the same or different radicals from the series hydrogen, R. on additional ring nitrogen atoms^H, HCO, R^HCO or R^HO-CO can stand as substituents and R^H (C.₁-C₆) Alkyl, (C₃-C₈) - cycloalkyl, (C₃-C₈) -Cycloalkyl- (C₁-C₄) alkyl, optionally substituted (C₆- C₁₀) Aryl or optionally substituted (C₆-C₁₀) Aryl (C₁-C₄) - alkyl;</dd><dt>e and h</dt><dd>independently represent 0 or 1;</dd></dl>in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically acceptable salts.

0075Particularly preferred compounds of the formula I are those in which B is unsubstituted methylene or is methylene which is substituted by a (C₁-C₈) -Alkylrest is substituted, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts. Particularly particularly preferred compounds of the formula I are those in which B is methylene which is replaced by a (C₁-C₈) -Alkylrest is substituted, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts.

0076On the other hand, particularly preferred compounds of the formula I are those in which R¹ represents a radical from the series phenyl, furyl, thienyl, pyrrolyl, imidazolyl and pyridyl which is unsubstituted or by one, two or three identical or different substituents from the series (C₁-C₄) Alkyl, (C₁-C₄) -Alkoxy, halogen, amino, trifluoromethyl, hydroxy, hydroxy- (C₁-C₄) alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy is substituted, in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically acceptable salts.

0077Particularly particularly preferred compounds of the formula I are those in which R¹ represents a radical from the series phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 4-imidazolyl and 3-pyridyl and 4-pyridyl, the phenyl radical being unsubstituted or by one or two identical or different residues from the series (C₁-C₄) Alkyl, (C₁-C₄) Alkoxy, halogen, trifluoromethyl, hydroxy, hydroxy- (C₁-C₄) -alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy and the heteroaromatic radicals are unsubstituted or by one or two identical or different radicals from the series (C₁-C₄) Alkyl, (C₁-C₄) -Alkoxy, halogen, amino, trifluoromethyl, hydroxy, hydroxy- (C₁-C₄) alkyl, methylenedioxy, ethylenedioxy, phenyl, phenoxy, benzyl and benzyloxy are substituted, in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerable salts.

0078Very particularly particularly preferred compounds of the formula I are those in which R¹ represents an unsubstituted radical from the series phenyl, 2-euryl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 4-imidazolyl, 3-pyridyl and 4-pyridyl, in all their stereoisomeric forms and mixtures thereof all conditions, and their physiologically acceptable salts.

0079Even more particularly preferred compounds of the formula I are those in which R¹ represents an unsubstituted radical from the series phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 4-imidazolyl and 4-pyridyl, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable Salts.

0080In general, preference is given to compounds of the formula I which are located at centers of chirality, for example with appropriate substitution at which the radicals R² and R³ bearing chiral carbon atom and / or at the center W in the imidazolidine ring in the formula I, have a uniform configuration.

0081The compounds of formula I can be prepared, for example, by fragment condensation of a compound of formula II<chemistry id="chem0012" num="0012"><img file="EP0903353B1_D0012.tif" /></chemistry>with a compound of formula III,<chemistry id="chem0013" num="0013"><img file="EP0903353B1_D0013.tif" /></chemistry>where in formulas II and III the groups W, Z, B, E, R, R⁰, R² and R³ and e and h are as defined above or functional groups in protected form or in the form of precursors may also be present in these groups, and where G is hydroxycarbonyl, (C₁-C₆) -Alkoxycarbonyl or activated carboxylic acid derivatives such as acid chlorides or active esters. In the compounds of the formula III, if compounds of the formula I are to be prepared in which, for example, R³ in the formula I stands for or contains a carboxylic acid derivative, but for example also the radical R³ initially stand for or contain a hydroxycarbonyl group in protected form, and then only after the condensation of the compounds of the formulas II and III in one or more further steps the desired final group R³ being constructed.

0082For the condensation of the compounds of the formula II with those of the formula III, the coupling methods of peptide chemistry which are well known to the person skilled in the art are advantageously used (see for example <nplcit id="ncit0037" npl-type="b"><text>Houben-Weyl, Methods of Organic Chemistry, Vol. 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974</text></nplcit>). Examples of condensing agents are carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide or diisopropylcarbodiimide, the O - ((cyano (ethoxycarbonyl) methylene) amino) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TOTA) or propylphosphonic (PPO) acid (PPH) acid in propylphosphonic acid (PPO) . In the case of condensation, it is generally necessary for existing, unreactive amino groups to be protected by reversible protective groups. The same applies to carboxyl groups not involved in the reaction, which during the condensation preferably as (C₁-C₆) Alkyl esters, for example tert-butyl ester, or benzyl ester. Protection of amino groups is superfluous if the amino groups are still in the form of precursors, for example as nitro groups, and are only formed after coupling, for example by hydrogenation. After the coupling, the existing protective groups are split off in a suitable manner. For example, NO₂-Groups (guanidino protection in amino acids), benzyloxycarbonyl groups and benzyl groups in benzyl esters. The protecting groups of the tert-butyl type are split off with acid, while the 9-fluorenylmethyloxycarbonyl radical is removed by secondary amines. The compounds of the formula I can also be prepared, for example, by gradually building up the compounds on a solid phase by customary methods, it being possible for the individual components of the molecule to be introduced in a different order.

0083Compounds of the formula II in which W represents R¹-AC (R¹³) and Z stands for oxygen can be prepared, for example, by first using compounds of the formula IV<chemistry id="chem0014" num="0014"><img file="EP0903353B1_D0014.tif" /></chemistry>in a Bucherer reaction to compounds of the formula V,<chemistry id="chem0015" num="0015"><img file="EP0903353B1_D0015.tif" /></chemistry>in the same as in Formula IV R¹, R¹³ and A are as defined above,<nplcit id="ncit0038" npl-type="s"><text>HT Bucherer, VA Lieb, J. Prakt. Chem. 141 (1934), 5</text></nplcit>). Compounds of the formula VI,<chemistry id="chem0016" num="0016"><img file="EP0903353B1_D0016.tif" /></chemistry>in the R¹, R¹³A, B and G as defined above can then be obtained by first reacting the compounds of the formula V, for example, with an alkylating reagent which introduces the remainder of the -BG into the molecule. The reaction of compounds of formula VI with a second reagent of formula R.⁰-LG, in the R⁰ has the meanings given above and LG has a nucleophilically substitutable leaving group, for example halogen, in particular chlorine or bromine, (C₁-C₄) -Alkoxy, optionally substituted phenoxy or a heterocyclic leaving group such as imidazolyl, leads to the corresponding compounds of formula II. These reactions can be carried out analogously to known methods known to the person skilled in the art. Depending on the individual case, it can be appropriate, as with all steps in the synthesis of the compounds of the formula I, to temporarily block functional groups which could lead to side reactions or undesired reactions by a protective group strategy adapted to the synthesis problem, which is known to the person skilled in the art . With regard to the preparation of the compounds of the formulas V and VI in racemic form and in enantiomerically pure form, reference is made here in particular to the corresponding statements in the <patcit id="pcit0054" dnum="WO9633976A"><text>WO-A-96/33976</text></patcit>that form part of the present disclosure.

0084W stands for R¹-A-CH = C, this structural element can be introduced, for example, by condensing an aldehyde with a dioxoimidazolidine or thioxo-oxo-imidazolidine, which contains an unsubstituted methylene group in the position corresponding to group W, analogously to known methods.

0085The amino compounds of the formula III can be synthesized from starting compounds which are commercially available or can be obtained according to or analogously to literature procedures by or analogously to well-known standard processes.

0086Compounds of the formula I in which W represents R¹-AC (R¹³) can also be obtained as follows:

0087By reaction of α-amino acids or N-substituted α-amino acids obtainable by standard processes or preferably their esters, for example the methyl, ethyl, tert-butyl or benzyl ester, for example a compound of the formula VII,<chemistry id="chem0017" num="0017"><img file="EP0903353B1_D0017.tif" /></chemistry>where R⁰, R¹, R¹³ and A are as defined above, with an isocyanate or isothiocyanate, for example of the formula VIII,<chemistry id="chem0018" num="0018"><img file="EP0903353B1_D0018.tif" /></chemistry>where B, E, R, R², R³, e and h are defined as indicated above and U represents isocyanato or isothiocyanato, urea derivatives or thiourea derivatives of the formula IX are obtained,<chemistry id="chem0019" num="0019"><img file="EP0903353B1_D0019.tif" /></chemistry>to which the definitions given above apply and which by heating with acid with saponification of the ester functions to give compounds of the formula Ia<chemistry id="chem0020" num="0020"><img file="EP0903353B1_D0020.tif" /></chemistry>be cyclized for which the meanings given above apply. The cyclization of the compounds of the formula IX to the compounds of the formula Ia can also be carried out by treatment with bases in inert solvents, for example by treatment with sodium hydride in an aprotic solvent such as dimethylformamide. Functional groups can in turn be present in protected form during the cyclization.

0088Compounds of the formula I in which W represents R¹-AC (R¹³) can also be obtained by using a compound of formula VII with an isocyanate or isothiocyanate of formula X<chemistry id="chem0021" num="0021"><img file="EP0903353B1_D0021.tif" /></chemistry>in which B and U are as defined above for formula VIII and Q is an alkoxy group, for example a (C₁-C₄) Alkoxy group such as methoxy, ethoxy or tert-butoxy, a (C₆-C₁₄) Aryloxy group, for example phenoxy, or a (C₆-C₁₄) Aryl (C₁-C₄) -alkoxy group, for example benzyloxy. A compound of formula XI<chemistry id="chem0022" num="0022"><img file="EP0903353B1_D0022.tif" /></chemistry>received in the Z, A, B, Q, R⁰, R¹ and R¹³ as defined above for the formulas IX and X, which then under the influence of an acid or a base, as described above for the cyclization of the compounds of the formula IX, to a compound of the formula XII,<chemistry id="chem0023" num="0023"><img file="EP0903353B1_D0023.tif" /></chemistry>in the W for R¹-AC (R¹³) stands and Z, B, Q, and R⁰ as defined above for the formulas la and x, is cyclized. A compound of the formula Ia is then obtained from the compound of the formula XII by hydrolysis of the group CO-Q to the carboxylic acid COOH and subsequent coupling with a compound of the formula III, as described above for the coupling of the compounds of the formulas II and III. Here too, functional groups can be present in protected form or in the form of precursors during the cyclization.

0089Another method for producing compounds of the formula Ia is, for example, the reaction of compounds of the formula XIII,<chemistry id="chem0024" num="0024"><img file="EP0903353B1_D0024.tif" /></chemistry>in the W for R¹-AC (R¹³) and for which the definitions given above apply otherwise, with phosgene or thiophosgene or corresponding equivalents (analog <nplcit id="ncit0039" npl-type="s"><text>S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575 (1952), 217-231</text></nplcit> and <nplcit id="ncit0040" npl-type="s"><text>C. Tropp, Chem. Ber. 61 (1928), 1431-1439</text></nplcit>).

0090With regard to the preparation of the compounds of formula I, full reference is further made to the <patcit id="pcit0055" dnum="WO9514008A"><text>WO-A-95/14008</text></patcit>, on the <patcit id="pcit0056" dnum="EP796855A"><text>EP-A-796 855</text></patcit> (European Patent Application <patcit id="pcit0057" dnum="EP97103712A"><text>97103712.2</text></patcit>) and the corresponding registrations, as well as on the <patcit id="pcit0058" dnum="WO9633976A"><text>WO-A-96/33976</text></patcit>.

0091The compounds of formula I are valuable active pharmaceutical ingredients which are suitable, for example, for the therapy and prophylaxis of inflammatory diseases, allergic diseases or asthma. According to the invention, the compounds of the formula I and their physiologically tolerable salts can be administered to animals, preferably to mammals, and in particular to humans, as medicaments for therapy or prophylaxis. They can be administered on their own, in mixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral use and which, as an active ingredient, contain an effective dose of at least one compound of the formula I and / or its physiologically tolerable salts in addition to the usual pharmaceutically acceptable ones Contain carriers and / or additives.

0092The present invention therefore also relates to the compounds of the formula I and / or their physiologically tolerable salts for use as medicaments, the use of the compounds of the formula I and / or their physiologically tolerable salts for the manufacture of medicaments for the therapy and prophylaxis of the above or diseases described below, for example for the therapy and prophylaxis of inflammatory diseases, and the use of the compounds of formula I and / or their physiologically tolerable salts in the therapy and prophylaxis of these diseases. The present invention furthermore relates to pharmaceutical preparations which contain an effective dose of at least one compound of the formula I and / or its physiologically tolerable salts in addition to customary pharmaceutically acceptable carriers and / or additives.

0093The medicaments can be administered orally, for example in the form of pills, tablets, film-coated tablets, dragees, granules, hard and soft gelatin capsules, solutions, syrups, emulsions or suspensions. However, the administration can also be rectal, for example in the form of suppositories, or parenteral, for example in the form of injection solutions or infusion solutions, microcapsules or rods, or percutaneously, for example in the form of ointments, solutions or tinctures, or in another way Example in the form of nasal sprays or aerosol mixtures.

0094The pharmaceutical preparations according to the invention are prepared in a manner known per se, in addition to the compound or compounds of the formula I and / or their physiologically tolerable salts, pharmaceutically inert inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. can be used for the production of pills, tablets, dragees and hard gelatin capsules. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, etc. Carriers for the production of solutions, for example injection solutions, or emulsions or syrups are, for example, water, alcohols, glycerol, Polyols, sucrose, invert sugar, glucose, vegetable oils etc. For example, copolymers of glycolic acid and lactic acid are suitable as carriers for microcapsules, implants or rods. The pharmaceutical preparations normally contain about 0.5 to 90% by weight of the compounds of the formula I and / or their physiologically tolerable salts.

0095In addition to the active ingredients and carriers, the pharmaceutical preparations can also contain additives such as fillers, explosives, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colors, flavors or aromatizers, Thickeners, diluents, buffer substances, furthermore solvents or solubilizers or agents for achieving a depot effect, as well as salts for changing the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I and / or their physiologically tolerable salts. In addition to at least one compound of the formula I and / or its physiologically tolerable salts, they can also contain one or more other therapeutically or prophylactically active substances, for example substances with an anti-inflammatory effect. The pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1 to 100 mg, of active ingredient of the formula I and / or its physiologically tolerable salts.

0096The 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 activity of the compounds of the formula I can be demonstrated, for example, in an assay in which the binding of cells which have the VLA-4 receptor, for example leukocytes, to ligands of this receptor is measured, for example to VCAM-1, which can advantageously also be produced genetically for this purpose. Details of such an assay are described below. In particular, the compounds of the formula I are able to inhibit the adhesion and migration of leukocytes, for example the attachment of leukocytes to endothelial cells, which - as explained above - is controlled by the VCAM-1 / VLA-4 adhesion mechanism. In addition to being anti-inflammatory agents, the compounds of the formula I and their physiologically tolerable salts are therefore generally suitable for the therapy and prophylaxis of diseases which are based on the interaction between the VLA-4 receptor and its ligands or can be influenced by inhibiting this interaction, and they are particularly suitable for the therapy and prophylaxis of diseases, which are at least partially caused by or are associated with an undesirable degree of leukocyte adhesion and / or leukocyte migration, or for the prevention, alleviation or healing of which the adhesion and / or migration of leukocytes is to be reduced.

0097The compounds of the formula I can be used as anti-inflammatory agents in the case of inflammatory symptoms of various causes. They are used, for example, for the therapy or prophylaxis of rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis), systemic lupus erythematosus or for the therapy or prophylaxis of inflammatory diseases of the central nervous system such as, for example, multiple sclerosis, for the therapy or prophylaxis of asthma or of allergies, for example allergies of the delayed type (type IV allergy). Furthermore, they are suitable for the therapy or prophylaxis of cardiovascular diseases, arteriosclerosis, restenosis, for the therapy or prophylaxis of diabetes, for preventing damage to organ transplants, for inhibiting tumor growth or tumor metastasis in the case of various malignancies, for treating malaria and other diseases in which the integrin VLA-4 is blocked and / or the leukocyte activity is influenced for prevention, Relief or healing appears appropriate.

0098The dose when using the compounds of the formula I can vary within wide limits and, as usual, must be adapted to the individual circumstances in each individual case. It depends, for example, on the compound used or on the type and severity of the disease to be treated or on whether an acute or chronic condition is being treated or whether prophylaxis is being carried out. In general, in the case of oral administration, a daily dose of approximately 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg, in particular 0.3 to 2 mg / kg (in each case per kg of body weight) is approximately 75 kg heavy adults appropriate for effective results. When administered intravenously, the daily dose is generally about 0.01 to 50 mg / kg, preferably 0.01 to 10 mg / kg body weight. The daily dose can be divided into several, for example 2, 3 or 4, partial administrations, in particular when larger amounts are applied. Depending on individual behavior, it may be necessary to deviate upwards or downwards from the specified daily dose.

0099The present invention therefore also relates to the compounds of the formula I for inhibiting the adhesion and / or migration of leukocytes or for inhibiting the VLA-4 receptor and the use of the compounds of the formula I for the production of medicaments therefor, ie medicaments for therapy or prophylaxis of diseases in which the leukocyte adhesion and / or leukocyte migration is undesirable, or of diseases, in which VLA-4-dependent adhesion processes play a role, and the use of the compounds of the formula I and / or their physiologically tolerable salts in the therapy and prophylaxis of such diseases.

0100The compounds of the formula I and their salts can furthermore be used for diagnostic purposes, for example in in-vitro diagnoses, and as aids in biochemical studies in which VLA-4 blocking or an influencing of cell-cell or cell Matrix interactions is sought. Furthermore, they can serve as intermediates for the preparation of other compounds, in particular other active pharmaceutical ingredients which can be obtained from the compounds of the formula I, for example by modification or introduction of radicals or functional groups.

Examples

0101The compounds were identified by mass spectra (MS) and / or NMR spectra. Compounds which were purified by chromatography using an eluent which contained, for example, acetic acid or trifluoroacetic acid and were subsequently freeze-dried, in some cases still contained, depending on the freeze-drying procedure, the acid originating from the eluent, that is to say partially or completely in the form of a salt of used acid, for example in the form of the acetic acid salt or trifluoroacetic acid salt.

0102It means:<tables id="tabl0001" num="0001"><table frame="none"><tgroup cols="2" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="14mm" /><colspec colnum="2" colname="col2" colwidth="126mm" /><tbody><row><entry>DMF</entry><entry>N, N-dimethylformamide</entry></row><row><entry>THF</entry><entry>Tetrahydrofuran</entry></row><row><entry>DCC</entry><entry>N, N'-dicyclohexylcarbodiimide</entry></row><row><entry>HOBt</entry><entry>1-hydroxybenzotriazole</entry></row><row><entry>TOTU</entry><entry>O- (cyan (ethoxycarbonyl) methylenamino) -1,1,3,3-tetramethyluronium tetrafluoroborate</entry></row></tbody></tgroup></table></tables>

example 1

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

0103<chemistry id="chem0025" num="0025"><img file="EP0903353B1_D0025.tif" /></chemistry>

1a) (R, S) -2-bromo-4-methylpentanoic acid tert-butyl ester (1.1)

0104To a solution of 2.5 g (12.8 mmol) of (R, S) -2-bromo-4-methylpentanoic acid in 80 ml of chloroform and 80 ml of tert-butyl acetate, 1.96 ml of concentrated sulfuric acid and 0.515 ml of oleum ( 20%) and the mixture was stirred for 3 h at room temperature. Then it was made by adding 10% NaHCO₃- Solve a pH of 4. The aqueous phase was separated off and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate. After filtration and concentration of the filtrate in vacuo, 2.62 g (82%) 1.1 were obtained.

1b) (R, S) -2 - ((S) -4- (4-bromophenyl) -4-methyl-2,5-dioxo-imidazolidin-1-yl) -4-methyl-pentanoic acid tert- butyl ester (1.2)

0105A solution of 2.08 g (7.72 mmol) of (S) -4- (4-bromophenyl) -4-methyl-2,5-dioxo-imidazolidine in 20 ml of absolute DMF was added under argon 0 ° C 213 mg (8.87 mmol) sodium hydride, stirred for 1 h at room temperature, added 1.94 g (7.72 mmol) 1.1, stirred for 5 h at room temperature and left the mixture overnight at room temperature. The solvent was removed in vacuo, the residue was taken up in ethyl acetate and the ethyl acetate solution was washed with water. The organic phase was dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using heptane / ethyl acetate (2: 1). After concentrating the product fractions, 2.45 g (72%) 1.2 were obtained.

1c) (R, S) -2 - ((S) -4- (4-bromophenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -4-methyl- pentanoic acid tert-butyl ester (1.3)

0106126 mg (5.24 mmol) of sodium hydride were added to a solution of 1.92 g (4.37 mmol) of 1.2 in 10 ml of absolute DMF under argon at 0 ° C., the mixture was stirred at room temperature for 1 h, and 570 μl (4 , 8 mmol) of benzyl bromide and allowed to stir again at room temperature for 1 h. The solvent was removed in vacuo, the residue was partitioned between water and ethyl acetate and, after phase separation, the water phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated in vacuo. 2.17 g (94%) of 1.3 were obtained.

1d) (R, S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -4-methyl-pentanoic acid (1.4)

0107A solution of 1 g (1.88 mmol) 1.3 in 100 ml ethanol was hydrogenated over 40 mg 10% Pd / C. After 2 h the catalyst was filtered off, the filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate and the solution with 10% NaHCO₃Solution and water washed and dried over sodium sulfate. After filtration and removal of the solvent in vacuo, 10 ml of 90% trifluoroacetic acid were added to the residue. After 15 min at room temperature, the trifluoroacetic acid was removed in vacuo and the residue was concentrated twice with toluene. 740 mg (100%) 1.4 were obtained.

1e) ((R, S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl-propyl) -acetyl) -L-aspartyl-L-phenylglycine (1.5)

0108To a solution of 200 mg (0.507 mmol) 1.4 and 210 mg (0.507 mmol) H-Asp (O^tBu) -Phg-O^tBu hydrochloride in 10 ml of absolute DMF was added with 166 mg (0.507 mmol) of TOTU and 172 μl (1.014 mmol) of diisopropylethylamine. After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuo, the residue was taken up in ethyl acetate and the organic phase twice with saturated NaHCO₃-Solution and water washed. After drying over sodium sulfate, filtration and concentration of the filtrate in vacuo, 393 mg of crude product were obtained, which was chromatographed on silica gel using heptane / ethyl acetate (3: 1). After concentrating the product fractions, the residue was dissolved in 5 ml of 90% trifluoroacetic acid, after 15 min at room temperature the trifluoroacetic acid was removed in vacuo and the residue was dissolved in 20% acetic acid and freeze-dried. 219 mg (67%) 1.5 were obtained. ES (+) - MS: 643.3 (M + H)⁺

Example 2

(S) -3 - ((R, S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2- methyl-propyl) -acetylamino) -2-benzyloxycarbonylamino-propionic acid

0109<chemistry id="chem0026" num="0026"><img file="EP0903353B1_D0026.tif" /></chemistry>

0110The compound was obtained by reaction of (R, S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -4-methyl-pentanoic acid ( 1.4) and (S) -3-Amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester prepared analogously to the preparation of 1.4, wherein after cleavage of the tert-butyl ester and removal of the trifluoroacetic acid in vacuo, the residue with dichloromethane / methanol / acetic acid / water (9: 1: 0.1: 0.1) was chromatographed on silica gel. ES (+) - MS: 615.4 (M + H)⁺

0111The (S) -3-amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester was prepared as follows. 10 g (42 mmol) of (S) -3-amino-2-benzyloxycarbonylamino-propionic acid were concentrated in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml. H₂SO₄ 3 days at 20 atm N₂-Shaking pressure in the autoclave. Excess isobutylene was blown off and the remaining solution was 150 ml of diethyl ether and 150 ml of saturated NaHCO₃-Solution given. The phases were separated and the aqueous phase was extracted twice with 100 ml of diethyl ether. The combined organic phases were washed with 2 x 100 ml of water and over Na₂SO₄ dried. After removal of the solvent in vacuo, 9.58 g (78%) of (S) -3-amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester were obtained as a pale yellow oil.

Example 3

(R, S) -3 - ((R, S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- ( 2-methyl-propyl) -acetylamino) -3- (3,4-methylenedioxy-phenyl) -propionic acid

0112<chemistry id="chem0027" num="0027"><img file="EP0903353B1_D0027.tif" /></chemistry>

0113The compound was prepared by reacting 1.4 with (R, S) -3-amino-3- (3,4-methylenedioxy-phenyl) propionic acid tert-butyl ester hydrochloride and subsequent cleavage of the tert-butyl ester as described in Example 1 . ES (+) - MS: 586.3 (M + H)⁺

0114The (R, S) -3-amino-3- (3,4-methylenedioxy-phenyl) propionic acid tert-butyl ester hydrochloride was prepared by analog <nplcit id="ncit0041" npl-type="s"><text>WM Radionow, EAPostovskaya, J. Am. Chem. Soc. 1929, 51, 841</text></nplcit> (see also <nplcit id="ncit0042" npl-type="b"><text>Houben-Weyl, Methods of Organic Chemistry, Volume XI / 2, Georg Thieme Verlag, Stuttgart, 1958, p. 497</text></nplcit>), the corresponding β-amino acid was first prepared. This was converted into the benzyloxycarbonylamino derivative, from which the tert-butyl ester was then obtained according to the following synthesis instructions: 1.5 mmol of oxalyl chloride were added to 1 mmol of the 3-benzyloxycarbonylamino-carboxylic acid in 13 ml of absolute dichloromethane. After 4 hours of stirring at room temperature, the reaction mixture was concentrated and 6.5 ml of tert-butanol were added to the residue. The mixture was stirred at room temperature for 1 h and the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and twice with saturated NaHCO₃- Solution and water extracted. The organic phase was dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. To produce the β-amino acid tert-butyl ester hydrochloride, the benzyloxycarbonyl group was then hydrogenated over 10% Pd / C in methanol / HCl.

Example 4

(S) -3 - ((R, S) -2 - ((R, S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2-isopropyl -acetylamino) -2- (1-adamantylmethyloxycarbonylamino) propionic acid

0115<chemistry id="chem0028" num="0028"><img file="EP0903353B1_D0028.tif" /></chemistry>

0116The compound was prepared by reacting (R, S) -2 - ((R, S) -3-benzyl-4-phenyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2-isopropyl acetic acid (prepared analogously to the instructions in Example 1 from (R, S) -4-methyl-4-phenyl-2,5-dioxo-imidazolidine) with (S) -3-amino-2- (1-adamantylmethyloxycarbonylamino) - tert-butyl propionate and subsequent cleavage of the tert-butyl ester as described in Example 1. The crude product was purified by means of preparative HPLC on RP-18. ES (+) - MS: 659.4 (M + H)⁺

0117The (S) -3-amino-2- (1-adamantylmethyloxycarbonylamino) propionic acid tert-butyl ester was prepared as follows.

0118A solution of 10 g (34 mmol) of tert-butyl (S) -3-amino-2-benzyloxycarbonylaminopropionate (see Example 2) in 600 ml of THF / water (2: 1) at 0 ° C. was 8.9 g (40.8 mmol) of di-tert-butyl dicarbonate and then in portions 1 N NaOH, so that the pH of the solution was between 9 and 10 (consumption of 1 N NaOH: 32 ml). After 3 h of stirring at room temperature, 1 l of water was added and the mixture was extracted 3 times with diethyl ether. After drying the organic phase over sodium sulfate, filtration and removal of the solvent in vacuo, the residue was chromatographed on silica gel with dichloromethane / methanol (20: 1). 13.19 g (98%) of (S) -2-benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester were obtained.

011913.1 g (S) -2-benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester were hydrogenated in methanol / HCl over 10% Pd / C. After 1.5 h, the mixture was filtered and the filtrate was concentrated in vacuo. 9.77 g (99%) of (S) -2-amino-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester hydrochloride were obtained as a colorless solid.

0120A solution of 10.9 g (65.4 mmol) of 1-hydroxymethyl adamantane and 10.6 g (65.4 mmol) of carbonyldiimidazole in 60 ml of THF was stirred at 50 ° C. for 1.5 h. 9.7 g (32.7 mmol) of (S) -2-amino-3-tert-butoxycarbonylamino-propionic acid tert-butyl ester hydrochloride in 25 ml of THF and 5.6 ml (32.7 mmol) of diisopropylethylamine were added , stirred for 4 h at 60 ° C and left overnight at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane / ethyl acetate (7: 3). 8.7 g (59%) of (S) -2- (1-adamantylmethyloxycarbonylamino) -3-tert-butoxycarbonylamino-propionic acid tert-butyl ester were obtained as a colorless oil.

0121A solution of 8.7 g (19.22 mmol) of (S) -2- (1-adamantylmethyloxycarbonylamino) -3-tert-butoxycarbonylamino-propionic acid tert-butyl ester in 180 ml of trifluoroacetic acid / dichloromethane (1: 1) was added 1 min in 1.5 l ice-cold NaHCO₃Solution was given, the mixture was extracted three times with dichloromethane and the dichloromethane phases were then dried over sodium sulfate. After filtration and removal of the solvent in vacuo, 6.35 g (94%) of (S) -3-amino-2- (1-adamantylmethyloxycarbonylamino) propionic acid tert-butyl ester were obtained as a colorless solid.

Example 5

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

0122<chemistry id="chem0029" num="0029"><img file="EP0903353B1_D0029.tif" /></chemistry>

5a) (R, S) -4- (4-pyridyl) -4-methyl-2,5-dioxo-imidazolidine (5.1)

012336.34 g (300 mmol) of 4-acetylpyridine and 259.2 g (2.694 mol) of ammonium carbonate were suspended in 400 ml of 50% ethanol. 25.5 g (392 mmol) of potassium cyanide were added. The mixture was stirred at 50-60 ° C. for 5 hours, the mixture was allowed to cool to room temperature, the pH was adjusted to 6.3 by adding 6N HCl and the mixture was left to stand at room temperature overnight. The pH was again adjusted to 6.3 and the solvent was removed in vacuo. The residue was slurried several times with dichloromethane. The insoluble portions were each filtered off and the combined filtrates were concentrated in vacuo. The residue was chromatographed on silica gel with dichloromethane / methanol. After concentration of the product fractions, 37.53 g (65%) 5.1 were obtained.

5b) ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetyl-L-aspartyl-L-phenylglycine (5.2)

0124A solution of 50 mg (0.133 mmol) of ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) acetic acid was added -hydrochloride (prepared by cleavage of ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetic acid tert-butyl ester with 90 % trifluoroacetic acid and subsequent conversion into the hydrochloride, where the ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) acetic acid tert-butyl ester by alkylating 5.1 only with bromoacetic acid tert-butyl ester and then with benzyl bromide as in Example 1) and 55 mg (0.133 mmol) of H-Asp (O^tBu) -Phg- (O^tBu) x HCl in 10 ml absolute DMF 43.6 mg TOTU and 68 µl diisopropyl-ethylamine. After 3 d at room temperature, the solvent was removed in vacuo, the residue was taken up in ethyl acetate, the solution with saturated NaHCO₃-Solution, water and KHSO₄/ K₂SO₄solution washed and dried over sodium sulfate. After filtration, the solvent was removed in vacuo and 10 ml of 90% trifluoroacetic acid were added to the residue. After 1 h at room temperature, the trifluoroacetic acid was removed in vacuo, the residue was partitioned between diethyl ether and water, the aqueous phase was freeze-dried and the residue was purified by chromatography on silica gel twice. 19.5 mg (25%) of 5.2 were obtained. ES (+) - MS: 588.3 (M + H)⁺

Example 6

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

0125<chemistry id="chem0030" num="0030"><img file="EP0903353B1_D0030.tif" /></chemistry>

6a) (R, S) -2 - ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2nd -methyl-propyl) -acetic acid tert-butyl ester (6.1)

0126A solution of 4.1 g (21.44 mmol) of (R, S) -4- (4-pyridyl) -4-methyl-2,5-dioxo-imidazolidine (see Example 5) in 30 ml of absolute was added DMF with ice cooling 1.03 g (23.58 mmol) sodium hydride. The mixture was stirred at room temperature for 15 min and then 4.23 g (21.44 mmol) of tert-butyl (R, S) -2-bromo-4-methyl-pentanoate were added. After stirring for 2 h and standing overnight at room temperature, the solvent was removed in vacuo and the residue was chromatographed on silica gel using dichloromethane / methanol (95: 5). This gave 1.2 g (15%) (R, S) -2 - ((R, S) -4- (4-pyridyl) -4-methyl-2,5-dioxo-imidazolidin-1-yl) - 2- (2-methyl-propyl) -acetic acid tert-butyl ester, which was reacted analogously to Example 1 by reaction with benzyl bromide to 6.1.

6b) (R, S) -2 - ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2nd -methyl-propyl) -acetic acid hydrochloride (6.2)

01271.4 g (3.1 mmol) of 6.1 in 30 ml of 90% trifluoroacetic acid were stirred at room temperature for 1 h. The trifluoroacetic acid was removed in vacuo and the residue was partitioned between diethyl ether and water. The phases were separated, the organic phase was concentrated and the residue was purified over silica gel with dichloromethane / methanol / acetic acid / water (9.5: 0.5: 0.05: 0.05). 650 mg (47%) 6.2 were obtained.

6c) ((R, S) -2 - ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- ( 2-methyl-propyl) -acetyl) -L-aspartyl-L-phenylglycine

0128The compound was prepared analogously to Example 5 by reacting 6.2 with H-Asp (O^tBu) -Phg- (O^tBu) x HCl and subsequent cleavage of the tert-butyl ester. ES (+) - MS: 644.3 (M + H)⁺

Example 7

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

0129<chemistry id="chem0031" num="0031"><img file="EP0903353B1_D0031.tif" /></chemistry>

0130The compound was prepared by reacting ((R, S) -4- (4-phenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) acetic acid (prepared analogously to Example 1) (R, S) -4-phenyl-4-methyl-2,5-dioxo-imidazolidine by alkylation with methyl chloroacetate and then with benzyl bromide and subsequent cleavage of the methyl ester) with H-Asp (O^tBu) -Phg- (O^tBu) x HCl analogously to Example 1 and subsequent cleavage of the tert-butyl ester. ES (+) - MS: 587.1 (M + H)⁺

Example 8 (comparative example)

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

0131<chemistry id="chem0032" num="0032"><img file="EP0903353B1_D0032.tif" /></chemistry>

8a) ((S) -4- (4-cyanophenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetic acid benzyl ester (8.1)

0132A solution of 20 g (73.1 mmol) of ((S) -4- (4-cyanophenyl) -4-methyl-2,5-dioxo-imidazolidin-1-yl) acetic acid in 120 ml of absolute DMF was added with ice cooling 7.73 g (160.8 mmol) sodium hydride. After stirring at room temperature for 30 min, 19 ml (160.8 mmol) of benzyl bromide were added. The reaction mixture was stirred at room temperature for 2 h, left to stand overnight, the solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane / ethyl acetate (2: 1). 11.43 g (35%) 8.1 were obtained.

8b) ((S) -4- (4-formylphenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetic acid benzyl ester (8.2)

013324.3 g of sodium hypophosphite × H were added to a solution of 6.08 g (13.42 mmol) of 8.1 in 200 ml of pyridine / acetic acid / water (2: 1: 1) at 0 ° C.₂O and 4.02 g of Raney nickel and heated the reaction mixture to 60 ° C. for 8 h. After cooling to room temperature and filtration, the reaction mixture was concentrated in vacuo, the residue was taken up in ethyl acetate and the ethyl acetate phase twice with water, twice with 10% citric acid solution, twice with saturated NaHCO₃Solution and extracted with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and, after filtration, the solvent was removed in vacuo. 4.82 g (79%) 8.2 were obtained.

8c) ((S) -4- (4-hydroxymethylphenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) acetic acid (8.3)

013420 ml of water were added to a solution of 500 mg (1.1 mmol) of 8.2 in 50 ml of ethanol and then 22 mg (0.6 mmol) of sodium borohydride at 0 ° C. After stirring at 0 ° C. for 40 min, the reaction mixture was concentrated in vacuo, the residue was heated in 30 ml of 6N hydrochloric acid / THF (1: 1) at 50 ° C. for 12 h and the reaction mixture was left to stand at room temperature overnight. The mixture was extracted with dichloromethane and the organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo, the residue was mixed with water and freeze-dried. 440 mg of crude 8.3 were obtained, which was used in the next synthesis step without further purification.

8d) ((S) -4- (4-hydroxymethylphenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetyl-L-aspartyl-L-phenylglycine (8.4)

0135A solution of 200 mg (0.54 mmol) crude 8.3, 225 mg (0.54 mmol) H-Asp (O^tBu) -Phg- (O^t185 μl (1.08 mmol) of diisopropylethylamine were added to Bu) × HCl and 178 mg (0.54 mmol) of TOTU. After 1 h at room temperature, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the ethyl acetate phase in each case twice with KHSO₄K₂SO₄Solution, saturated NaHCO₃Solution and saturated saline solution extracted. After phase separation, the organic phase was dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by chromatography with methyl tert-butyl ether / heptane (8: 2) on silica gel. After concentrating the product fractions, the residue was dissolved in 5 ml of 90% trifluoroacetic acid. After 1 h at room temperature, the trifluoroacetic acid was removed in vacuo and the residue was purified by preparative HPLC on RP-18. After freeze-drying, 44 mg (13%) 8.4 were obtained. ES (+) - MS: 617.2 (M + H)⁺

Example 9 (comparative example)

(S) -3 - (((S) -4- (4-hydroxymethylphenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) acetylamino) -2- (1 -adamantylmethyloxycarbonylamino) -propionic acid

0136<chemistry id="chem0033" num="0033"><img file="EP0903353B1_D0033.tif" /></chemistry>

0137The preparation was carried out analogously to Example 8 by coupling 8.3 with (S) -2- (1-adamantylmethyloxycarbonylamino) -3-amino-propionic acid tert-butyl ester (see Example 4) instead of H-Asp (O^tBu) -Phg- (O^tBu) x HCl. After cleavage of the tert-butyl ester with 90% trifluoroacetic acid, the crude product was partitioned between water and dichloromethane. The organic phase was separated off, dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. The residue was purified by preparative HPLC on RP-18. ES (+) - MS: 647.3 (M + H)⁺

Example 10 (comparative example)

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

0138<chemistry id="chem0034" num="0034"><img file="EP0903353B1_D0034.tif" /></chemistry>

10a) 1- (4- (tetrahydropyran-2-yloxy) phenyl) ethanone (10.1)

013913.62 g (100 mmol) of 4-hydroxyacetophenone and 10.04 ml (110 mmol) of 3,4-dihydro-2H-pyran were suspended in 100 ml of anhydrous methylene chloride. At 0 ° C., 190 mg (1 mmol) of p-toluenesulfonic acid were added with stirring and the mixture was stirred at 0 ° C. for 3 hours. Another 10.04 ml (110 mmol) of 3,4-dihydro-2H-pyran were added and the mixture was stirred for a further 3 hours at room temperature. The mixture was poured into 150 ml of water, the phases were separated and the organic phase was washed with saturated NaHCO₃Solution, saturated NaCl solution and extracted with water. The organic phase was dried over sodium sulfate, concentrated and, for purification, chromatographed on silica gel (70-200 μm) using methylene chloride as the eluent. 13.65 g (62%) 10.1 were obtained.

10b) (R, S) -4-methyl-4- (4- (tetrahydropyran-2-yloxy) phenyl) -2,5-dioxo-imidazolidine (10.2)

014011.01 g (50 mmol) 10.1 and 42.3 g (440 mmol) ammonium carbonate were suspended in 200 ml 50% ethanol. 4.23 g (65 mmol) of potassium cyanide were added. The mixture was stirred at 50 to 60 ° C for 5 hours. A clear solution emerged after a short time. The mixture was left to stand at room temperature overnight and then stirred at 60 ° C. for 6 hours. The pH was adjusted to 6.3 with 6 N HCl and the mixture was allowed to stir for 2 hours while cooling with ice. The precipitate was filtered off, washed with water and dried over phosphorus pentoxide in a desiccator. 9.5 g (65%) 10.2 were obtained.

10c) ((R, S) -4-methyl-4- (4- (tetrahydropyran-2-yloxy) phenyl) -2,5-dioxo-imidazolidin-1-yl) -acetic acid methyl ester (10.3)

0141230 mg (10 mmol) sodium was dissolved in 25 ml of anhydrous methanol under argon. 2.9 g (10 mmol) 10.2 were added. The mixture was heated to reflux with stirring for 2 hours. Then 1.66 g (10 mmol) of potassium iodide were added and a solution of 0.975 ml (10 mmol) of methyl chloroacetate in 1.1 ml of anhydrous methanol was added dropwise over the course of 15 minutes. The mixture was heated to reflux for 4 hours and then left to stand at room temperature overnight. Another 0.195 ml (2 mmol) of methyl chloroacetate in 0.22 ml of anhydrous methanol was added and the mixture was stirred under reflux for 4 hours. The precipitate was filtered off and the filtrate was concentrated. The residue was dissolved in methylene chloride, the insolubles were filtered off and the residue was chromatographed on silica gel using methylene chloride / ethyl acetate (9: 1). 2.56 g (71%) 10.3 were obtained.

10d) ((R, S) -3-benzyl-4-methyl-4- (4- (tetrahydropyran-2-yloxy) phenyl) -2,5-dioxo-imidazolidin-1-yl) methyl acetate ( 10.4)

01422.53 g (7 mmol) 10.3 were dissolved in 8.5 ml of anhydrous DMF under argon. At 15 ° C 370 mg (7.7 mmol) sodium hydride (50% in oil) were added. The mixture was stirred at 15 ° C. for 15 minutes and then 0.91 ml (7.7 mmol) of benzyl bromide was added dropwise. The mixture was stirred at room temperature for 7.5 hours and left to stand at room temperature overnight. The clear solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase washed again with ethyl acetate. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel using methylene chloride / ethyl acetate (9.5: 0.5). 1.59 g (50%) 10.4 was obtained.

10e) ((R, S) -4- (4-hydroxyphenyl) -3-benzyl-4-methy / -2,5-dioxo-imidazolidin-1-yl) -acetic acid (10.5)

01431.53 g (3.5 mmol) 10.4 were refluxed with 30 ml concentrated hydrochloric acid for 3 h. After concentrating the solution in vacuo, the residue was triturated with water, cooled overnight and then suction filtered. It was dried over phosphorus pentoxide in a desiccator and 1.22 g (98%) 10.5 was obtained.

10f) ((R, S) -4- (4-hydroxyphenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -acetyl-L-aspartyl-L-phenylglycine- di-tert-butyl ester (10.6)

0144354 mg (1 mmol) 10.5, 415 mg (1 mmol) H-Asp (O^tBu) -Phg-O^tBu x HCl and 135 mg (1 mmol) HOBt were dissolved in 10 ml DMF. At 0 ° C 0.13 ml (1 mmol) of N-ethylmorpholine and 220 mg (1 mmol) of DCC were added. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 3 hours and left to stand at room temperature overnight. It was suctioned off and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and with NaHCO₃Solution, K₂SO₄KHSO₄Solution and saturated saline. After drying over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated in vacuo. The oily residue was triturated with diethyl ether and the organic phase was concentrated. 730 mg (100%) 10.6 were obtained.

10g) ((R, S) -4- (4-hydroxyphenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) acetyl-L-aspartyl-L-phenylglycine ( 10.7)

0145370 mg (0.52 mmol) 10.6 were dissolved in 4 ml of 90% trifluoroacetic acid and left to stand for 1 hour at room temperature. Then it was narrowed. The residue was triturated with diethyl ether and suction filtered. 202 mg (64%) were obtained 10.7.

0146The aspartyl phenylglycine derivatives of Examples 12 to 126 were prepared by solid phase synthesis according to the general procedure given in Example 11.

Example 11

General instructions for the preparation of aspartyl-phenylglycine derivatives by solid phase synthesis

General

0147The syntheses on the polymeric support were carried out according to the synthesis sequence shown in Scheme 1. The leftovers R⁵⁰ to R⁵⁵ in Scheme 1 have the meaning of the radicals which are in the relevant position in the molecule in the formula I, or they can contain functional groups in protected form or in the form of precursors. R⁵⁰ corresponds to the rest R. R⁵¹ corresponds to the radicals R⁴ or R¹⁵, where functional groups present in these residues can be in protected form or in the form of precursors (the rest -NHR⁵¹ can thus represent, for example, the residue of an amino acid which is formally obtained by removing a hydrogen atom from the amino group). R⁵² together with the CH group to which this residue is attached corresponds to group B (R⁵² corresponds to a substituent on a methylene group representing B). R⁵³ corresponds to R¹³, R⁵⁴ corresponds to group R¹-A, being in it<chemistry id="chem0035" num="0035"><img file="EP0903353B1_D0035.tif" /></chemistry>existing functional groups can be present in protected form or in the form of precursors. R⁵⁵ corresponds to group R⁰.

0148The synthesis of intermediates on a larger scale was carried out in special reaction vessels with embedded frits at the bottom of the reaction vessel, the synthesis of the compounds of the formula I was carried out in syringes or reaction blocks (Act 496, MultiSynTech). The syntheses on the resin were followed by on-bead analysis (FT-IR with ATR unit and MAS-NMR) and cleavage of an analytical sample from the resin (HPLC, MS, NMR).

0149Preparation of the Aspartic Acid Building Block FmocAsp (OH) OAllyl FmocAsp (OtBu) OAllyl (40 g, 88.7 mmol) was mixed with 25 ml of trifluoroacetic acid and stirred for 30 min at room temperature. The solvent was removed on a rotary evaporator. The residue was dried in vacuo. FmocAsp (OH) OAllyl was obtained as a yellow oil (33.9 g, 97%). ES (+) - MS: 395.2 (M + H)⁺

Attachment to the polymeric support (step A in Scheme 1)

015040 Wang polystyrene resin (1.1 mmol / g; Bachem) was preswollen for 5 min with 20 ml DMF at room temperature. After adding a solution of 26.0 g (1.5 equivalents) of FmocAsp (OH) OAllyl and 34.3 g (1.5 equivalents) of 1-benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and 9.3 ml (1.5 equivalents) Düsopropyl-ethylamine in 120 ml DMF, the mixture was shaken at 40 ° C for 10 h. After the reaction had ended, the solution was filtered off with suction and the resin was washed with DMF (5 × 20 ml). After adding a solution of acetic anhydride (10 ml) and diisopropyl-ethylamine (9.3 ml, 1.5 equivalents) in 40 ml of DMF, the mixture was shaken again for 30 min at room temperature. The solution was filtered off with suction and the resin was washed three times in succession with 40 ml of DMF, methanol and dichloromethane. The resin was then dried in vacuo. The determination of the loading by the Fmoc method resulted in a loading of 0.6 mmol / g.

Cleavage of the allyl group on the polymeric carrier (step B)

0151The resin was pre-swollen under argon in DMF at room temperature for 5 min. After adding tetrakis (triphenylphosphine) palladium and N-methylpyrrolidine (10 equivalents), the mixture was shaken under argon at 40 ° C. for 6 h. After the reaction had ended, the solution was filtered off with suction and the resin was washed three times in succession with DMF, methanol, toluene and dichloromethane and then dried.

Coupling with amino compounds on the polymeric carrier (step C)

0152The loaded resin with free carboxyl function was pre-swollen in DMF at room temperature for 5 min. A solution of HOBt (1.2 equivalents), TOTU (1.2 equivalents) and diisopropylethylamine (1.2 equivalents) in DMF was added and the mixture was shaken at room temperature for 30 min. The amino compound (1.2 equivalents) was added dissolved in DMF. The suspension was shaken at room temperature until the reaction was complete (HPLC control). After the reaction had ended, the solution was filtered off with suction and the resin was washed three times in succession with DMF, methanol, toluene and dichloromethane and then dried.

Cleavage of the Fmoc protective group (step D)

0153To remove the Fmoc protective group, the resin was preswollen in DMF at room temperature for 5 min. After adding a solution of DMF / piperidine (1: 1), the mixture was shaken at room temperature for 20 min. The solution was suctioned off and the process repeated. The cleavage of an analytical sample showed complete conversion after HPLC / MS examination. After the reaction was complete, the resin was washed three times with dichloromethane and used directly in the coupling.

Coupling with α-halocarboxylic acids (step E)

a) Coupling with DIC

0154The symmetrical anhydrides were formed from α-halocarboxylic acids (5 equivalents) by reaction with diisopropylcarbodiimide (2.4 equivalents) in dichloromethane for 30 minutes. After this time, 2 equivalents of diisopropylethylamine were added. The mixture was added to the resin and shaken at room temperature for 12 hours. After the reaction had ended, the solution was filtered off with suction and the resin was washed three times in succession with DMF, toluene and dichloromethane and then immediately reacted further.

b) Coupling with acid halides

0155The resin was pre-swollen with dichloromethane at room temperature for 5 minutes. The α-halocarboxylic acid halides (1.5 equivalents) were added in solution in dichloromethane. After adding a catalytic amount of 4-dimethylaminopyridine and diisopropylethylamine (1 equivalent), the mixture was shaken for 8 hours at room temperature. After the reaction had ended, the solution was filtered off with suction and the resin was washed three times in succession with DMF, toluene and dichloromethane and then immediately reacted further.

Coupling of the α-haloacyl compounds with hydantoins (step F)

0156The 4,4-disubstituted hydantoins (2 equivalents) were activated in DMF with diazabicycloundecene (DBU) (2 equivalents) at room temperature. The activated solution was added after 15 minutes to the resin pre-swollen in DMF for 5 minutes. The mixture was shaken at room temperature for 8 hours. After the reaction had ended, the solution was filtered off with suction and the resin was washed three times in succession with DMF, methanol, toluene and dichloromethane and then dried.

N-alkylation of the hydantoin on the polymeric support (step G)

a) Alkylation with cesium carbonate

0157The resin was pre-swollen in DMF at room temperature for 5 minutes. After adding cesium carbonate (3 equivalents), the mixture was shaken at room temperature for 30 min. After the addition of the alkylating agent (bromide or iodide), the mixture was shaken at 50 ° C. for 6 h. After the reaction had ended, the solution was filtered off with suction and the resin was washed three times in succession with DMF, methanol / water / DMF (1.5: 1.5: 7), DMF, toluene and dichloromethane and then dried.

b) alkylation with phosphazenes

0158The resin was pre-swollen in DMF at room temperature for 5 minutes. After addition of N "'- tert-butyl-N, N, N', N ', N", N "-hexamethylphosphorimidic acid triamide (phosphazene base P1-t-Bu) (3 equivalents), the mixture was shaken at room temperature for 30 min Addition of the alkylating agent (bromide or iodide) was shaken at room temperature for 4 h, after the reaction had ended, the solution was filtered off with suction and the resin was washed three times in succession with DMF, toluene and dichloromethane and then dried.

Cleavage from the resin (step H)

0159A mixture of trifluoroacetic acid / dichloromethane (1: 1) was added to the resin to split off the compound from the resin. The suspension was shaken for 1 hour. The resin was filtered off. The remaining solution was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane and ethyl acetate).

0160The compounds of Examples 12 to 126, which have the structure given in the formula Ib, were prepared by the general method described in Example 11. The meanings of the radicals in the individual compounds are given in Tables 1 and 2.<chemistry id="chem0036" num="0036"><img file="EP0903353B1_D0036.tif" /></chemistry>

0161In Tables 1 and 2:<tables id="tabl0002" num="0002"><table frame="none"><tgroup cols="4" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="18mm" /><colspec colnum="2" colname="col2" colwidth="33mm" /><colspec colnum="3" colname="col3" colwidth="18mm" /><colspec colnum="4" colname="col4" colwidth="28mm" /><tbody><row><entry>Bn =</entry><entry>Benzyl</entry><entry>3-BrBn =</entry><entry>3-bromobenzyl</entry></row><row><entry>4-BrBn =</entry><entry>4-bromobenzyl</entry><entry>4-CIBn =</entry><entry>4-chlorobenzyl</entry></row><row><entry>4-Bip =</entry><entry>4-biphenylylmethyl</entry><entry>2-Py =</entry><entry>2-pyridylmethyl</entry></row><row><entry>3-Py =</entry><entry>3-pyridylmethyl</entry><entry>4-Py =</entry><entry>4-pyridylmethyl</entry></row><row><entry>H =</entry><entry>hydrogen</entry><entry>Me =</entry><entry>methyl</entry></row><row><entry>Et =</entry><entry>Ethyl</entry><entry>nPr =</entry><entry>n-propyl</entry></row><row><entry>iPr =</entry><entry>Isopropyl</entry><entry>nBu =</entry><entry>n-butyl</entry></row><row><entry>iBu =</entry><entry>Isobutyl</entry><entry>nPe =</entry><entry>n-pentyl</entry></row><row><entry>nHe =</entry><entry>n-hexyl</entry><entry>All =</entry><entry>Allyl</entry></row><row><entry>Ph =</entry><entry>Phenyl</entry><entry /><entry /></row></tbody></tgroup></table></tables>

0162The following abbreviations stand for residues that belong to the group -NH-R⁵¹ are in the formula Ib. They are residues of amino acids or derivatives thereof, which are formally obtained by abstraction of a hydrogen atom from the amino group of the amino acid.<chemistry id="chem0037" num="0037"><img file="EP0903353B1_D0037.tif" /></chemistry><chemistry id="chem0038" num="0038"><img file="EP0903353B1_D0038.tif" /></chemistry><chemistry id="chem0039" num="0039"><img file="EP0903353B1_D0039.tif" /></chemistry><chemistry id="chem0040" num="0040"><img file="EP0903353B1_D0040.tif" /></chemistry><chemistry id="chem0041" num="0041"><img file="EP0903353B1_D0041.tif" /></chemistry><chemistry id="chem0042" num="0042"><img file="EP0903353B1_D0042.tif" /></chemistry><tables id="tabl0003" num="0003"><table frame="none"><title>Table 1</title><tgroup cols="8" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="17mm" /><colspec colnum="2" colname="col2" colwidth="10mm" /><colspec colnum="3" colname="col3" colwidth="26mm" /><colspec colnum="4" colname="col4" colwidth="16mm" /><colspec colnum="5" colname="col5" colwidth="10mm" /><colspec colnum="6" colname="col6" colwidth="10mm" /><colspec colnum="7" colname="col7" colwidth="16mm" /><colspec colnum="8" colname="col8" colwidth="21mm" /><thead><row><entry valign="top">example</entry><entry valign="top">R⁵⁰</entry><entry valign="top">-NH-R⁵¹</entry><entry valign="top">R⁵²</entry><entry valign="top">R⁵³</entry><entry valign="top">R⁵⁴</entry><entry valign="top">R⁵⁵</entry><entry valign="top">ES (+) - MS</entry></row></thead><tbody><row><entry>12</entry><entry>Me</entry><entry>Val</entry><entry>Bn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>659</entry></row><row><entry>13</entry><entry>Me</entry><entry>Val</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>686</entry></row><row><entry>14</entry><entry>Me</entry><entry>Val</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>568</entry></row><row><entry>15</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>2-Py</entry><entry>589</entry></row><row><entry>16</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>3-Py</entry><entry>589</entry></row><row><entry>17</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>4-Py</entry><entry>589</entry></row><row><entry>18</entry><entry>H</entry><entry>Phg</entry><entry>Et</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>617</entry></row><row><entry>19</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Ph</entry><entry>Ph</entry><entry>Bn</entry><entry>651</entry></row><row><entry>20</entry><entry>H</entry><entry>Phg</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>644</entry></row><row><entry>21</entry><entry>H</entry><entry>Phg</entry><entry>iBu</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>644</entry></row><row><entry>22</entry><entry>H</entry><entry>Phg</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>2-Py</entry><entry>645</entry></row><row><entry>23</entry><entry>H</entry><entry>Phg</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>3-Py</entry><entry>645</entry></row><row><entry>24</entry><entry>H</entry><entry>Phg</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>4-Py</entry><entry>645</entry></row><row><entry>25</entry><entry>H</entry><entry>Phg</entry><entry>iBu</entry><entry>Me</entry><entry>Ph</entry><entry>2-Py</entry><entry>645</entry></row><row><entry>26</entry><entry>H</entry><entry>Phg</entry><entry>iBu</entry><entry>Me</entry><entry>Ph</entry><entry>3-Py</entry><entry>645</entry></row><row><entry>27</entry><entry>H</entry><entry>Phg</entry><entry>iBu</entry><entry>Me</entry><entry>Ph</entry><entry>4-Py</entry><entry>645</entry></row><row><entry>28</entry><entry>H</entry><entry>Ile</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>4-BrBn</entry><entry>647</entry></row><row><entry>29</entry><entry>H</entry><entry>Ile</entry><entry>Bn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>659</entry></row><row><entry>30</entry><entry>H</entry><entry>Ile</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>610</entry></row><row><entry>31</entry><entry>H</entry><entry>Ile</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>686</entry></row><row><entry>32</entry><entry>H</entry><entry>Ile</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>568</entry></row><row><entry>33</entry><entry>H</entry><entry>Ile</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>639</entry></row><row><entry>34</entry><entry>H</entry><entry>Ile</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>715</entry></row><row><entry>35</entry><entry>H</entry><entry>Ala</entry><entry>Bn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>616</entry></row><row><entry>36</entry><entry>H</entry><entry>Ala</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>568</entry></row><row><entry>37</entry><entry>H</entry><entry>Ala</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>644</entry></row><row><entry>38</entry><entry>H</entry><entry>Ala</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>525</entry></row><row><entry>39</entry><entry>H</entry><entry>Ala</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>596</entry></row><row><entry>40</entry><entry>H</entry><entry>Ala</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>672</entry></row><row><entry>41</entry><entry>H</entry><entry>Phg</entry><entry>Bn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>679</entry></row><row><entry>42</entry><entry>H</entry><entry>Phg</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>630</entry></row><row><entry>43</entry><entry>H</entry><entry>Phg</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>707</entry></row><row><entry>44 H</entry><entry /><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>588</entry></row><row><entry>45</entry><entry>H</entry><entry>Phg</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>658</entry></row><row><entry>46</entry><entry>H</entry><entry>Phg</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>735</entry></row><row><entry>47</entry><entry>H</entry><entry>Phg</entry><entry>Et</entry><entry>Me</entry><entry>Ph</entry><entry>2-Py</entry><entry>618</entry></row><row><entry>48</entry><entry>H</entry><entry>Phg</entry><entry>Et</entry><entry>Me</entry><entry>Ph</entry><entry>3-Py</entry><entry>618</entry></row><row><entry>49</entry><entry>H</entry><entry>Phg</entry><entry>Et</entry><entry>Me</entry><entry>Ph</entry><entry>4-Py</entry><entry>618</entry></row><row><entry>50</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Ph</entry><entry>Ph</entry><entry>2-Py</entry><entry>651</entry></row><row><entry>51</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Ph</entry><entry>Ph</entry><entry>3-Py</entry><entry>651</entry></row><row><entry>52</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Ph</entry><entry>Ph</entry><entry>4-Py</entry><entry>651</entry></row><row><entry>53</entry><entry>Me</entry><entry>Val</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>638</entry></row><row><entry>54</entry><entry>Me</entry><entry>Val</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>715</entry></row><row><entry>55</entry><entry>H</entry><entry>Val</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>554</entry></row><row><entry>56</entry><entry>H</entry><entry>Val</entry><entry>Bn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>644</entry></row><row><entry>57</entry><entry>H</entry><entry>Val</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>672</entry></row><row><entry>58</entry><entry>H</entry><entry>Val</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>596</entry></row><row><entry>59</entry><entry>H</entry><entry>Val</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>624</entry></row><row><entry>60</entry><entry>H</entry><entry>Val</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>701</entry></row><row><entry>61</entry><entry>H</entry><entry>PheMor</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>671</entry></row><row><entry>62</entry><entry>H</entry><entry>PheMor</entry><entry>Bn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>762</entry></row><row><entry>63</entry><entry>H</entry><entry>PheMor</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>790</entry></row><row><entry>64</entry><entry>H</entry><entry>PheMor</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>714</entry></row><row><entry>65</entry><entry>H</entry><entry>PheMor</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>742</entry></row><row><entry>66</entry><entry>H</entry><entry>PheMor</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>818</entry></row><row><entry>67</entry><entry>H</entry><entry>PhePip</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>670</entry></row><row><entry>68</entry><entry>H</entry><entry>PhePip</entry><entry>Bn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>760</entry></row><row><entry>69</entry><entry>H</entry><entry>PhePip</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>788</entry></row><row><entry>70</entry><entry>H</entry><entry>PhePip</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>712</entry></row><row><entry>71</entry><entry>H</entry><entry>PhePip</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>726</entry></row><row><entry>72</entry><entry>H</entry><entry>PhePip</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>802</entry></row><row><entry>73</entry><entry>H</entry><entry>PhgMor</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>658</entry></row><row><entry>74</entry><entry>H</entry><entry>PhgMor</entry><entry>Bn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>748</entry></row><row><entry>75</entry><entry>H</entry><entry>PhgMor</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>700</entry></row><row><entry>76</entry><entry>H</entry><entry>PhgMor</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>728</entry></row><row><entry>77</entry><entry>H</entry><entry>PhgMor</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>804</entry></row><row><entry>78</entry><entry>H</entry><entry>PhgPip</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>656</entry></row><row><entry>79</entry><entry>H</entry><entry>PhgPip</entry><entry>Bn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>746</entry></row><row><entry>80</entry><entry>H</entry><entry>PhgPip</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>774</entry></row><row><entry>81</entry><entry>H</entry><entry>PhgPip</entry><entry>iPr</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>698</entry></row><row><entry>82</entry><entry>H</entry><entry>PhgPip</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>726</entry></row><row><entry>83</entry><entry>H</entry><entry>PhgPip</entry><entry>nPe</entry><entry>Me</entry><entry>Ph</entry><entry>4-bip</entry><entry>802</entry></row><row><entry>84</entry><entry>H</entry><entry>Phg</entry><entry>4-CIBn</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>713</entry></row><row><entry>85</entry><entry>H</entry><entry>Phg</entry><entry>Alles</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>629</entry></row><row><entry>86</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>4-BrBn</entry><entry>667</entry></row><row><entry>87</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>3-BrBn</entry><entry>667</entry></row><row><entry>88</entry><entry>H</entry><entry>Ph (CH₂)₃NH-</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>628</entry></row><row><entry>89</entry><entry>H</entry><entry>Phg</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>nPr</entry><entry>595</entry></row><row><entry>90</entry><entry>H</entry><entry>Phg</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>iBu</entry><entry>610</entry></row><row><entry>91</entry><entry>H</entry><entry>Phg</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>nHe</entry><entry>638</entry></row><row><entry>92</entry><entry>H</entry><entry>Phg</entry><entry>nPr</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>630</entry></row><row><entry>93</entry><entry>H</entry><entry>Phg</entry><entry>nHe</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>672</entry></row><row><entry>94</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>nPr</entry><entry>539</entry></row><row><entry>95</entry><entry>H</entry><entry>PheMor</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>nPr</entry><entry>622</entry></row><row><entry>96</entry><entry>H</entry><entry>PheMor</entry><entry>iBu</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>727</entry></row><row><entry>97</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>Et</entry><entry>525</entry></row><row><entry>98</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>iBu</entry><entry>553</entry></row><row><entry>99</entry><entry>H</entry><entry>Phg</entry><entry>H</entry><entry>Me</entry><entry>Ph</entry><entry>iPr</entry><entry>539</entry></row><row><entry>100</entry><entry>H</entry><entry>Phg</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>644</entry></row><row><entry>101</entry><entry>H</entry><entry>CH₃(CH₂)₇NH-</entry><entry>nBu</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>621</entry></row><row><entry>102</entry><entry>H</entry><entry>Phg</entry><entry>Et</entry><entry>Me</entry><entry>Ph</entry><entry>iPr</entry><entry>567</entry></row><row><entry>103</entry><entry>H</entry><entry>Phg</entry><entry>nPr</entry><entry>Me</entry><entry>Ph</entry><entry>Bn</entry><entry>630</entry></row><row><entry>104</entry><entry>H</entry><entry>Phg</entry><entry>nPr</entry><entry>Me</entry><entry>Ph</entry><entry>iBu</entry><entry>595</entry></row><row><entry>105</entry><entry>H</entry><entry>Phg</entry><entry>nPr</entry><entry>Me</entry><entry>Ph</entry><entry>iPr</entry><entry>581</entry></row></tbody></tgroup></table></tables><tables id="tabl0004" num="0004"><table frame="none"><title>Table 2</title><tgroup cols="5" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="32mm" /><colspec colnum="2" colname="col2" colwidth="33mm" /><colspec colnum="3" colname="col3" colwidth="34mm" /><colspec colnum="4" colname="col4" colwidth="34mm" /><colspec colnum="5" colname="col5" colwidth="35mm" /><thead><row><entry namest="col1" nameend="col5" align="left" valign="top">In formula Ib, the radical R is in all compounds of table 2⁵⁰ for hydrogen, the rest -NH-R⁵¹ for Phg (= L-phenylglycyl) and the rest R⁵² for n-butyl.</entry></row><row><entry valign="top">example</entry><entry valign="top">R⁵³</entry><entry valign="top">R⁵⁴</entry><entry valign="top">R⁵⁵</entry><entry valign="top">ES (+) - MS</entry></row></thead><tbody><row><entry>106</entry><entry>Me</entry><entry>2-fluorophenyl</entry><entry>Bn</entry><entry>661</entry></row><row><entry>107</entry><entry>Me</entry><entry>3-fluorophenyl</entry><entry>Bn</entry><entry>661</entry></row><row><entry>108</entry><entry>Me</entry><entry>4-fluorophenyl</entry><entry>Bn</entry><entry /></row><row><entry>109</entry><entry>Me</entry><entry>4-fluorobenzyl</entry><entry>Bn</entry><entry /></row><row><entry>110</entry><entry>Me</entry><entry>3-trifluoromethylphenyl</entry><entry>Bn</entry><entry /></row><row><entry>111</entry><entry>Me</entry><entry>3-chlorophenyl</entry><entry>Bn</entry><entry /></row><row><entry>112</entry><entry>Bn</entry><entry>Bn</entry><entry>Bn</entry><entry /></row><row><entry>113</entry><entry>Me</entry><entry>4-methoxybenzyl</entry><entry>Bn</entry><entry /></row><row><entry>114</entry><entry>Me</entry><entry>Cyclohexyl</entry><entry>Bn</entry><entry /></row><row><entry>115</entry><entry>Me</entry><entry>Bn</entry><entry>Bn</entry><entry /></row><row><entry>116</entry><entry>Me</entry><entry>2-thienyl</entry><entry>Bn</entry><entry /></row><row><entry>117</entry><entry>Me</entry><entry>3-trifluoromethylbenzyl</entry><entry>Bn</entry><entry /></row><row><entry>118</entry><entry>Cyclopropyl</entry><entry>Ph</entry><entry>Bn</entry><entry /></row><row><entry>119</entry><entry>Cyclobutyl</entry><entry>Ph</entry><entry>Bn</entry><entry /></row><row><entry>120</entry><entry>Me</entry><entry>3,4,5-trimethoxyphenyl</entry><entry>Bn</entry><entry /></row><row><entry>121</entry><entry>Me</entry><entry>4-fluorophenyl</entry><entry>H</entry><entry /></row><row><entry>122</entry><entry>Bn</entry><entry>Bn</entry><entry>H</entry><entry /></row><row><entry>123</entry><entry>Me</entry><entry>4-methoxybenzyl</entry><entry>H</entry><entry /></row><row><entry>124</entry><entry>Me</entry><entry>3-trifluoromethylbenzyl</entry><entry>H</entry><entry /></row><row><entry>125</entry><entry>Cyclobutyl</entry><entry>Ph</entry><entry>H</entry><entry /></row><row><entry>126</entry><entry>Me</entry><entry>3,4,5-trimethoxybenzyl</entry><entry>H</entry><entry /></row></tbody></tgroup></table></tables>

Example 127

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

0163<chemistry id="chem0043" num="0043"><img file="EP0903353B1_D0043.tif" /></chemistry>

0164The compound was prepared analogously to the general procedure described in Example 11 by solid phase synthesis. ES (+) - MS: 616

0165The 2,3-diaminopropionic acid derivatives of Examples 129 to 168 were prepared by solid phase synthesis according to the general procedure given in Example 128.

Example 128

General procedure for the preparation of diaminopropionic acid derivatives by solid phase synthesis

General

0166The syntheses on the polymeric support were carried out according to the synthesis sequence shown in Scheme 2. The above general explanations for the preparation of aspartyl-phenylglycine derivatives by solid phase synthesis apply here accordingly.

Coupling of α-Fmoc-β-Alloc-2,3-Diaminopropionic Acid to the Polymeric Support (Step J in Scheme 2)

0167To 1 g of Wang polystyrene resin was added a solution of 0.243 g (1.8 mmol) of HOBt, 0.590 g (1.8 mmol) of TOTU, 0.25 ml (1.8 mmol) of diisopropylethylamine and 0.738 g (1.1 8 mmol) (S) -α-Fmoc-β-Alloc-2,3-diaminopropionic acid in 5 ml DMF and the mixture was shaken at room temperature for 12 h. The resin was filtered off and washed 3 times with 10 ml of DMF, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml of dichloromethane. The determination of the loading according to the Fmoc method gave a loading of 0.9 mmol / g.

Cleavage of the allyloxycarbonyl group on the polymeric support (step K)

0168The resin was pre-swollen under argon in DMF at room temperature for 5 min. After adding tetrakis (triphenylphosphine) palladium and N-methylpyrrolidine (10 equivalents), the mixture was shaken under argon at 40 ° C. for 6 h. After the reaction had ended, the solution was filtered off with suction and the resin was washed three times in succession with DMF, methanol, toluene and dichloromethane and then dried.<chemistry id="chem0044" num="0044"><img file="EP0903353B1_D0044.tif" /></chemistry>

Coupling of α-Fmoc-2,3-diaminopropionic acid with hydantoin carboxylic acids (step L)

0169A solution of 36 mg (0.27 mmol) HOBt, 88 mg (0.27 mmol) TOTU was added to 100 mg of resin loaded with the α-Fmoc-2,3-diaminopropionic acid (0.9 mmollg) , 37 µl (0.27 mmol) diisopropylethylamine and 0.27 mmol (R, S) -3-benzyl-4-phenyl-4-methyl-2,5-dioxo-imidazolidin-1-yl-acetic acid in 5 ml of DMF and the mixture was shaken at room temperature for 12 h. The resin was filtered off and washed 3 times with 10 ml of DMF, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml of dichloromethane.

Cleavage of the Fmoc protective group (step M)

0170To remove the Fmoc protective group, the resin was preswollen in DMF at room temperature for 5 min. After adding a solution of DMF / piperidine (1: 1), the mixture was shaken at room temperature for 20 min. The solution was suctioned off and the process repeated. The cleavage of an analytical sample showed complete conversion after HPLC / MS examination. After completion of the reaction, the resin was washed three times with dichloromethane and used directly in the next step.

Acylation of the α-amino group of 2,3-diaminopropionic acid (step N)

a) Preparation of carboxamides (acylation with carboxylic acids)

0171A solution of 36 mg (0.27 mmol) of HOBt, 88 mg (0.27 mmol) of TOTU, 37 μl (0.27 mmol) of diisopropyl was added to 100 mg of resin loaded with the 2,3-diaminopropionic acid building block -ethylamine and 0.27 mmol of the corresponding carboxylic acid of the formula R.⁶⁰-COOH in 5 ml DMF and let the mixture shake at room temperature for 12 h. The resin was filtered off and washed 3 times with 10 ml of DMF, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml of dichloromethane.

b) Production of ureas (acylation with isocyanates)

0172A solution of 0.27 mmol of the corresponding isocyanate of the formula R was added to 100 mg of resin which was loaded with the 2,3-diaminopropionic acid unit⁶⁰-N = C = O and a catalytic amount (1 mg) of 4-dimethylaminopyridine in 5 ml of DMF and allowed to shake the mixture for 8 hours at room temperature. The resin was filtered off and washed 3 times with 10 ml of DMF, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml of dichloromethane.

c) Production of carbamates (acylation with carbonic acid derivatives)

0173The corresponding alcohol (0.27 mmol) of the formula R⁶⁰-OH was shaken at 40 ° C. for 5 hours with equivalent amounts of di- (N-succinimidyl) carbonate and diisopropyl-ethylamine. The solution was added to 100 mg of resin loaded with the 2,3-diaminopropionic acid building block and the mixture was shaken at room temperature for 8 hours. The resin was filtered off and washed 3 times with 10 ml of DMF, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml of dichloromethane.

Cleavage from the resin (step P)

0174A mixture of trifluoroacetic acid and dichloromethane (1: 1) was added to the resin to remove the compound from the resin. The suspension was shaken for 1 hour and then the resin was filtered off. The remaining solution was concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane and ethyl acetate).

0175The 3-benzyl-4-phenyl-4-methyl-2,5-dioxo-imidazolidin-1-yl-acetic acid used in step L was obtained according to the following general procedure for the preparation of 4,4-disubstituted hydantoincarboxylic acids.

0176A solution of 288 mg of potassium cyanide in 3.8 ml of water was pipetted into 3.0 mmol of acetophenone and 3.0 g of ammonium carbonate in 3.8 ml of ethanol. The mixture was stirred at 55 ° C for 5 h. 8 ml of 6N hydrochloric acid were then slowly metered in and the mixture was stirred at 55 ° C. for a further 2 h. After adding 6.0 ml of water, the mixture was cooled to room temperature over 2 hours. The product was suction filtered, washed with water and air dried.

0177The (R, S) -4-methyl-4-phenylhydantoin was suspended with one equivalent of cesium carbonate in DMF (20 ml / g hydantoin derivative) and stirred for 20 min at room temperature. After adding one equivalent of tert-butyl bromoacetate, the mixture was stirred for 1 h at room temperature. Then water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The hydantoin acetic acid ester was obtained as an oil.

0178The hydantoin acetic acid ester was suspended with one equivalent of cesium carbonate and one equivalent of benzyl bromide in DMF (20 ml / g hydantoin derivative). The mixture was stirred at room temperature for 1 h. Then water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (hexane / ethyl acetate). The 3-benzyl-hydantoinic acid ester was obtained as an oil. The tert-butyl ester group was then cleaved under standard conditions with trifluoroacetic acid to give the carboxylic acid.

0179According to the general procedure described in example 128, the compounds of examples 129 to 168 were produced which have the structure given in formula Ic. The meaning of groups X and R⁶⁰ in the individual compounds of formula Ic are given in Table 3. If X stands for a direct bond, this means that the group R⁶⁰ is bonded directly to the carbonyl group and thus a group R⁶⁰CO is present.<chemistry id="chem0045" num="0045"><img file="EP0903353B1_D0045.tif" /></chemistry><tables id="tabl0005" num="0005"><table frame="none"><title>Table 3</title><tgroup cols="4" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="17mm" /><colspec colnum="2" colname="col2" colwidth="28mm" /><colspec colnum="3" colname="col3" colwidth="45mm" /><colspec colnum="4" colname="col4" colwidth="21mm" /><thead><row><entry valign="top">example</entry><entry valign="top">-X-</entry><entry valign="top">R⁶⁰</entry><entry valign="top">ES - (+) - MS</entry></row></thead><tbody><row><entry>129</entry><entry>direct bond</entry><entry>3-methylphenyl</entry><entry>543</entry></row><row><entry>130</entry><entry>direct bond</entry><entry>2-methylphenyl</entry><entry>543</entry></row><row><entry>131</entry><entry>direct bond</entry><entry>2,4-dimethoxyphenyl</entry><entry>589</entry></row><row><entry>132</entry><entry>direct bond</entry><entry>3,5-dinitrophenyl</entry><entry>619</entry></row><row><entry>133</entry><entry>direct bond</entry><entry>4-tert-butylphenyl</entry><entry>585</entry></row><row><entry>134</entry><entry>direct bond</entry><entry>2,4,5-trimethylphenyl</entry><entry>571</entry></row><row><entry>135</entry><entry>-NH-</entry><entry>4-chlorophenyl</entry><entry>579</entry></row><row><entry>136</entry><entry>-NH-</entry><entry>4-isopropylphenyl</entry><entry>586</entry></row><row><entry>137</entry><entry>-NH-</entry><entry>2-nitrophenyl</entry><entry>589</entry></row><row><entry>138</entry><entry>direct bond</entry><entry>4-chlorophenyl</entry><entry>564</entry></row><row><entry>139</entry><entry>direct bond</entry><entry>4-methylphenyl</entry><entry>543</entry></row><row><entry>140</entry><entry>direct bond</entry><entry>4-methoxyphenyl</entry><entry>559</entry></row><row><entry>141</entry><entry>direct bond</entry><entry>4-nitrophenyl</entry><entry>574</entry></row><row><entry>142</entry><entry>-NH-</entry><entry>4- (trifluoromethoxy) phenyl</entry><entry>628</entry></row><row><entry>143</entry><entry>-NH-</entry><entry>2-methoxyphenyl</entry><entry>574</entry></row><row><entry>144</entry><entry>-NH-</entry><entry>3,5-bis (trifluoromethyl) phenyl</entry><entry>680</entry></row><row><entry>145</entry><entry>-NH-</entry><entry>Benzyl</entry><entry>558</entry></row><row><entry>146</entry><entry>-O-</entry><entry>2-methoxyethyl</entry><entry>527</entry></row><row><entry>147</entry><entry>-O-</entry><entry>Prop-2-ynyl</entry><entry>507</entry></row><row><entry>148</entry><entry>-O-</entry><entry>2,2,2-trifluoroethyl</entry><entry>551</entry></row><row><entry>149</entry><entry>-O-</entry><entry>Cyclopentyl</entry><entry>537</entry></row><row><entry>150</entry><entry>-O-</entry><entry>2-cyclohexylethyl</entry><entry>580</entry></row><row><entry>151</entry><entry>-O-</entry><entry>Prop-2-enyl</entry><entry>510</entry></row><row><entry>152</entry><entry>-O-</entry><entry>2- (4-fluorophenyl) ethyl</entry><entry>591</entry></row><row><entry>153</entry><entry>-O-</entry><entry>2- (4-nitrophenyl) ethyl</entry><entry>618</entry></row><row><entry>154</entry><entry>-O-</entry><entry>2- (3-methoxyphenyl) ethyl</entry><entry>604</entry></row><row><entry>155</entry><entry>-O-</entry><entry>Cyclopropylmethy)</entry><entry>523</entry></row><row><entry>156</entry><entry>-O-</entry><entry>Isobutyl</entry><entry>525</entry></row><row><entry>157</entry><entry>-O-</entry><entry>2,2-dimethylpropyl</entry><entry>539</entry></row><row><entry>158</entry><entry>-O-</entry><entry>Cyclobutylmethyl</entry><entry>537</entry></row><row><entry>159</entry><entry>-O-</entry><entry>2-ethylbutyl</entry><entry>553</entry></row><row><entry>160</entry><entry>-O-</entry><entry>Cyclopentylmethyl</entry><entry>551</entry></row><row><entry>161</entry><entry>-O-</entry><entry>2- (4-methylphenyl) ethyl</entry><entry>589</entry></row><row><entry>162</entry><entry>-O-</entry><entry>4-benzylbenzyl</entry><entry>650</entry></row><row><entry>163</entry><entry>-O-</entry><entry>4-nitrobenzyl</entry><entry>604</entry></row><row><entry>164</entry><entry>-O-</entry><entry>2-phenylethyl</entry><entry>573</entry></row><row><entry>165</entry><entry>-O-</entry><entry>2- (4-methoxyphenyl) ethyl</entry><entry>604</entry></row><row><entry>166</entry><entry>-O-</entry><entry>2- (1-naphthyl) ethyl</entry><entry>624</entry></row><row><entry>167</entry><entry>-O-</entry><entry>2- (2-naphthyl) ethyl</entry><entry>624</entry></row><row><entry>168</entry><entry>-O-</entry><entry>2- (4-tert-butylphenyl) ethyl</entry><entry>630</entry></row></tbody></tgroup></table></tables>

Example 169

(S) -3 - ((S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl- propyl) acetylamino) -3- (3,4-methylenedioxy-phenyl) propionic acid

0180<chemistry id="chem0046" num="0046"><img file="EP0903353B1_D0046.tif" /></chemistry>

169a) (S) -2-amino-2- (4-bromophenyl) propionic acid methyl ester (169.1)

018115 g (55.7 mmol) (S) -4- (4-bromophenyl) -4 methyl-2,5-dioxo-imidazolidine were suspended in 107 ml of 3 N sodium hydroxide solution and the suspension was heated in an autoclave at 145 ° C. for 2 h. The mixture was allowed to cool to room temperature, the precipitate was filtered off, dissolved in water and adjusted to pH 1 with 1N hydrochloric acid. After freeze-drying, the solid was suspended in 150 ml of absolute methanol. The suspension was cooled to -15 ° C. and 8.8 ml of thionyl chloride were added. After stirring for 6 hours at room temperature and standing overnight, a further 100 ml of absolute methanol and 8.8 ml of thionyl chloride were added. The mixture was stirred at room temperature for 8 h and allowed to stand again overnight. After removal of volatile constituents in vacuo, the residue was adjusted to pH 9.3 with sodium hydrogen carbonate solution and sodium carbonate solution and then the aqueous phase was extracted twice with ethyl acetate. After drying over sodium sulfate, filtration and removal of the solvent in vacuo, 11.4 g (79%) 169.1 were obtained.

169b) (S) -2 - ((S) -4- (4-bromophenyl) -4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl-propyl) - tert-butyl acetate (169.2)

01824.8 g of L-leucine tert-butyl ester isocyanate (prepared analogously from L-leucine tert-butyl ester) were added to a solution of 5.8 g (22.5 mmol) of 169.1 in 50 ml of DMF <nplcit id="ncit0043" npl-type="s"><text>JS Nowick et al., J. Org. Chem. 1996, 61, 3929</text></nplcit>). After 4 hours of stirring at room temperature, the solvent was removed and the residue was chromatographed on silica gel using heptane / tert-butyl methyl ether = 6/4. The fractions containing the intermediate were combined, the solvent was removed in vacuo, the residue was redissolved in 90 ml of absolute DMF and the solution at 0 ° C. was mixed with 775 mg of a 55-65% sodium hydride dispersion in oil. After stirring for 3 h at room temperature, the solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane / tert-butyl methyl ether = 1/1. After concentration of the product fractions, 7.8 g (79%) of 169.2 were obtained as a colorless solid.

169c) (S) -2 - ((S) -4- (4-bromophenyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl -propyl) -acetic acid tert-butyl ester (169.3)

0183540 μl (4.4 mmol) of benzyl bromide were added to a solution of 1.75 g (4 mmol) of 169.2 in 20 ml of absolute DMF and then 140 mg of a 55-65% sodium hydride dispersion in oil at 0 ° C., and the mixture was left Stir for 15 min at 0 ° C and 3 h at room temperature. After standing overnight, the solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane / ethyl acetate = 8/2. The product fractions were combined and the solvent removed in vacuo. 1.97 g (93%) 169.3 were obtained.

169d) (S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl-propyl) -acetic acid- tert-butyl ester (169.4)

01841.9 g (3.59 mmol) 169.3 in 190 ml ethanol were hydrogenated over 76 mg 10% palladium / carbon for 2 h. The catalyst was filtered off, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the solution was washed with a 10% sodium hydrogen carbonate solution. The phases were separated and the organic phase was dried over sodium sulfate. After filtration, 1.3 g (80%) 169.4 was obtained.

169e) (S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl-propyl) -acetic acid ( 169.5)

01851.3 g (2.89 mmol) 169.4 in a mixture of 10 ml of 6N hydrochloric acid and 2 ml of tetrahydrofuran were heated under reflux for 4 h. Removal of the solvent in vacuo and chromatography of the residue with heptane / ethyl acetate = 3/2 gave 510 mg (45%) 169.5.

169f) (S) -3 - ((S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2- methyl-propyl) -acetylamino) -3- (3,4-methylenedioxy-phenyl) -propionic acid

0186The compound was prepared analogously to Example 1 by reacting 169.5 with (S) -3-amino-3- (3,4-methylenedioxyphenyl) propionic acid tert-butyl ester (prepared analogously<nplcit id="ncit0044" npl-type="s"><text> SG Davis et al., Tetrahedron Asymmetry 1991, 2, 183</text></nplcit>), Cleavage of the tert-butyl ester with trifluoroacetic acid as described in Example 1, and subsequent purification of the crude product by means of preparative HPLC (RP18, eluent: acetonitrile / water = 501120). ES (+) - MS: 586.4 (M + H)⁺

0187The following two compounds can also be prepared analogously to Example 169:

(S) -3 - ((S) -2 - ((S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl- propyl) acetylamino) -3- (2,4-dimethoxyphenyl) propionic acid

0188<chemistry id="chem0047" num="0047"><img file="EP0903353B1_D0047.tif" /></chemistry>(by reaction of 169.5 with (S) -3-amino-3- (2,4-dimethoxyphenyl) propionic acid tert-butyl ester and subsequent cleavage of the tert-butyl ester with trifluoroacetic acid)

(S) -3 - ((S) -2 - ((S) -4-phenyl-3 - ((4-biphenylyl) methyl) -4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methyl-propyl) -acetylamino) -3- (3,4-methylenedioxy-phenyl) -propionic acid

0189<chemistry id="chem0048" num="0048"><img file="EP0903353B1_D0048.tif" /></chemistry>(by reaction of (S) -2 - ((S) -4-phenyl-3 - ((4-biphenylyl) methyl) -4-methyl-2,5-dioxo-imidazotidin-1-yl) -2- (2-methyl-propyl) acetic acid (obtainable by reacting 169.2 with 4-phenyl-benzylbromide analogously to the synthesis of 169.3 and subsequent subsequent reactions analogously to the preparation of 169.5) with (S) -3-amino-3- (3,4 -methylendioxy-phenyl) -propionic acid tert-butyl ester and subsequent cleavage of the tert-butyl ester with trifluoroacetic acid)

Example 170

(S) -3 - ((R, S) -2 - ((R, S) -4- (4-pyridyl) -3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) -2- (2-methylpropyl) acetylamino) -2- (1-adamantylmethyloxycarbonylamino) propionic acid

0190<chemistry id="chem0049" num="0049"><img file="EP0903353B1_D0049.tif" /></chemistry>

0191The compound was prepared analogously to Example 5 by reacting 6.2 (see Example 6) with (S) -2- (1-adamantylmethyloxycarbonylamino) -3-amino-propionic acid tert-butyl ester (preparation see Example 4) and subsequent cleavage of the tert- Butyl ester with trifluoroacetic acid. ES (+) - MS: 674.5 (M + H)⁺

Example 171

General instructions for the preparation of 2- (N - ((2,5-dioxo-imidazolidin-1-yl) -acetyl) -N-alkylamino) propionic acids

171 a) General procedure for the preparation of N-alkylated β-alanine tert-butyl esters

0192The primary alkylamine (50 mmol) was dissolved in 80 ml of methanol (when the alkylamine was used in the form of the hydrochloride, the amine was first released by the addition of potassium tert-butoxide (45 mmol)). 7.25 ml of tert-butyl acrylate (50 mmol) were added and, after mixing, the mixture was left to stand at room temperature for 2 days. Any solids present were then filtered off, concentrated on a rotary evaporator at 60 ° C. and coevaporated twice with toluene. The residue was taken up in 100 ml of absolute diethyl ether, filtered and the filtrate was concentrated sharply. The product obtained in this way was obtained as an oil or solid and was used in the next reaction step without further purification.

171 b) General procedure for the acylation of N-alkylated β-alanine tert-butyl esters with hydantoin carboxylic acids and cleavage of the β-alanine tert-butyl ester

0193The hydantoin carboxylic acid (0.5 mmol) (see Example 128), 114 mg of N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.6 mmol), 70 mg of 1-hydroxybenzotriazole (0.6 mmol) and the N-alkylated β- Alanine tert-butyl ester (1.0 mmol) was dissolved in 2 ml of absolute DMF and stirred at room temperature for 8 h. The reaction mixture was taken up in 100 ml of ethyl acetate and three times each with KHSO₄Solution (10%), KHCO₃-Solution and water washed. The ethyl acetate phase was washed with MgSO₄ dried and evaporated to dryness. The residue was mixed with 3 ml of trifluoroacetic acid and left to stand at room temperature for 1 h. The trifluoroacetic acid was removed in vacuo and the residue was coevaporated with toluene and diethyl ether.

Example 172

2- (N - (((R, S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) acetyl) -N-benzylamino) propionic acid

0194<chemistry id="chem0050" num="0050"><img file="EP0903353B1_D0050.tif" /></chemistry>

0195The compound was prepared starting from benzylamine according to the procedure in Example 171. Yield: 183 mg (73%) colorless powder.

Example 173

2- (N - (((R, S) -4-phenyl-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl) acetyl) -N-octylamino) propionic acid

0196<chemistry id="chem0051" num="0051"><img file="EP0903353B1_D0051.tif" /></chemistry>

0197The compound was prepared starting from n-octylamine according to the procedure in Example 171. Yield: 293 mg (99%) colorless oil.

Examination of biological activity

0198An assay that is specific for this interaction is used as a test method for the effectiveness of the compounds of the formula I on the interaction between VCAM-1 and VLA-4. The cellular binding partners, ie the VLA-4 integrins, are offered in their natural form as surface molecules on human U937 cells (ATCC CRL 1593), which belong to the group of leukocytes. Genetically engineered recombinant soluble fusion proteins consisting of the extracytoplasmic domain of human VCAM-1 and the constant region of a human immunoglobulin of the IgG1 subclass are used as specific binding partners.

Test method

Assay for measuring the adhesion of U937 cells (ATCC CRL 1593) to hVCAM-1 (1-3) -IgG

1. Production of human VCAM-1 (1-3) IgG and human CD4 IgG

0199A genetic construct was used to express the extracellular domain of human VCAM-1, linked to the genetic sequence of the heavy chain of human immunoglobulin IgG1 (Hinge, CH2 and CH3 regions) (by Dr. Brian Seed, Massachusetts General Hospital, Boston, USA) ; see. <nplcit id="ncit0045" npl-type="s"><text>Damle and Aruffo, Proc. Natl. Acad. Sci. USA 1991, 88, 6403-6407</text></nplcit>). The soluble fusion protein hVCAM-1 (1-3) -IgG contained the three amino terminal extracellular immunoglobulin-like domains of human VCAM-1 (<nplcit id="ncit0046" npl-type="s"><text>Damle and Aruffo, Proc. Natl. Acad. Sci. USA 1991, 88, 6403</text></nplcit>). CD4-IgG (<nplcit id="ncit0047" npl-type="s"><text>Zettlmeissl et al., DNA and Cell Biology 1990, 9, 347</text></nplcit>) served as a fusion protein for negative controls. The recombinant proteins were expressed as soluble proteins after DEAE / dextran-mediated DNA transfection in COS cells (ATCC CRL1651) according to standard procedures (<nplcit id="ncit0048" npl-type="b"><text>Ausubel et al., Current Protocols in Molecular Biology, John Wiley &amp; Sons, Inc., 1994</text></nplcit>).

2nd Assay to measure the adhesion of U937 cells to hVCAM-1 (1-3) -IgG

0200<ul id="ul0002" list-style="none"><li>2.1 96-well microtitre test plates (Nunc Maxisorb) were incubated with 100 μl / well of a goat anti-human IgG antibody solution (10 μg / ml in 50 mM Tris, pH 9.5) for 1 hour at room temperature. After removal of the antibody solution, it was washed once with PBS.</li><li>2.2 150 µl / well of a blocking buffer (1% BSA in PBS) was incubated on the plates for 0.5 hours at room temperature. After removal of the blocking buffer, washing was carried out once with PBS.</li><li>2.3 100 μl per well of a cell culture supernatant from transfected COS cells were incubated on the plates for 1.5 hours at room temperature. The COS cells were transfected with a plasmid, which for the three N-terminal immunoglobulin-like domains of VCAM-1, coupled to the Fc part of human IgG₁ (hVCAM-1 (1-3) -IgG). The content of hVCAM-1 (1-3) -IGG was approx. 0.5 - 1 µg / ml. After removal of the culture supernatant, it was washed once with PBS.</li><li>2.4 The plates were washed with 100 μl / well Fc receptor block buffer (1 mg / ml γ-globulin, 100 mM NaCl, 100 μM MgCl₂, 100 µM MnCl₂, 100 µM CaCl₂, 1 mg / ml BSA in 50 mM HEPES, pH 7.5) for 20 minutes at room temperature. After removal of the Fc receptor block buffer, washing was carried out once with PBS.</li><li>2.5 20 µl binding buffer (100 mM NaCl, 100 µM M₉Cl₂, 100 µM MnCl₂, 100 µM CaCl₂, 1 mg / ml BSA in 50 mM HEPES, pH 7.5) were presented, the substances to be tested were added in 10 μl binding buffer and incubated for 20 minutes. Antibodies against VCAM-1 (BBT, No. BBA6) and against VLA-4 (Immunotech, No. 0764) served as controls.</li><li>2.6 U937 cells were incubated in Fc receptor block buffer for 20 minutes and then at a concentration of 1 x 10⁶/ ml and pipetted in an amount of 100 µl per well (final volume 125µl / well).</li><li>2.7 The plates were placed at a 45 ° angle in stop buffer (100 mM NaCl, 100 µM M₉Cl₂, 100 µM MnCl₂, 100 µM CaCl₂ slowly immersed in 25 mM Tris, pH 7.5) and knocked out. The process was repeated.</li><li>2.8 50 µl / well of a staining solution (16.7 µg / ml Hoechst dye 33258, 4% formaldehyde, 0.5% Triton-X-100 in PBS) were then incubated on the plates for 15 minutes.</li><li>2.9 The plates were knocked out, at a 45 ° angle in stop buffer (100 mM NaCl, 100 µM MgCl₂, 100 µM MnCl₂, 100 µM CaCl₂ slowly immersed in 25 mM Tris, pH 7.5). The process was repeated. The liquid was then measured in a cytofluorimeter (Millipore) (sensitivity: 5, filter: excitation wavelength: 360 nm, emission wavelength: 460 nm).</li></ul>

0201The intensity of the light emitted by the stained U937 cells is a measure of the number of U937 cells remaining on the plate and adhering to the hVCAM-1 (1-3) -IgG and thus a measure of the ability of the added test substance to inhibit this adhesion. The inhibition of adhesion at different concentrations of the test substance became the concentration IC₅₀ calculated, which leads to an inhibition of adhesion by 50%.

0202The following test results were obtained:<tables id="tabl0006" num="0006"><table frame="none"><tgroup cols="2" colsep="0" rowsep="0"><colspec colnum="1" colname="col1" colwidth="17mm" /><colspec colnum="2" colname="col2" colwidth="64mm" /><thead><row><entry valign="top">example</entry><entry align="center" valign="top">U937NCAM-1 cell adhesion test IC₅₀ (µM)</entry></row></thead><tbody><row><entry>4</entry><entry align="center">45</entry></row><row><entry>7</entry><entry align="center">8</entry></row><row><entry>8</entry><entry align="center">4,5</entry></row><row><entry>9</entry><entry align="center">4</entry></row><row><entry>10</entry><entry align="center">9,5</entry></row></tbody></tgroup></table></tables>