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Indian Patents. 211755:NOVEL HETEROCYCLES AS INHIBITORS OF LEUCOCYTE ADHESION AND AS VLA-4 ANTAGONISTS
NOVEL HETEROCYCLES AS INHIBITORS OF LEUCOCYTE ADHESION AND AS VLA-4 ANTAGONISTS
Novel heterocycles as inhibitors of leucocyte adhesion and as VLA-4 antagonists The present invention relates to compounds of the formula I which are inhibitors of the adhesion and migration of leucocytes and/or antagonists of the adhesion receptor VLA-4 which belongs to the group of integrins. The invention also relates to processes for their preparation, to the use of compounds of the formula I for the treatment or prophylaxis of diseases which are caused by an undesired extent of leucocyte adhesion and/or leucocyte migration or which are associated therewith or in which cell-cell or cell-matrix interactions which are based on interactions of VLA-4 receptors with their ligands play a part, for example of inflammatory processes, of rheumatoid arthritis or of allergic disorders, and also to the use of compounds of the formula I for the production of pharmaceuticals for use in such diseases, and to pharmaceutical preparations which contain the compounds of the formula I.
Novel-heterocycles a£jnhit>itors of leucocyte adhesion and as VLA-4 antagonists
which are inhibitors of the adhesion and migration of leucocytes and/or antagonists of the adhesion receptor VLA-4 which belongs to the group of integrins. The invention also relates to processes for their preparation, to the use of compounds of the formula I for the treatment or prophylaxis of diseases which are caused by an undesired extent of leucocyte adhesion and/or leucocyte migration or which are associated therewith or in ^hich cell-cell or cell-matrix interactions which are based on interactions of VLA-4 receptors with their ligands play a part, for example of inflammatory processes, of rheumatoid arthritis or of allergic disorders, and also to the use of compounds of t-ie formula I for the production of pharmaceuticals for use in such diseases, and to pharmaceutical preparations which contain the compounds of the formula I.
The integrins are a group of adhesion receptors which play an important part in cell-cell-binding and cell-extra:,ellular matrix-binding processes. They have an ap-heterodimeric structure and exhibit a wide cellular distribution and a high extent of evolutive conservation. The integrins include, for example, the fibrinogen receptor on platelets, which interac s especially with the RGD sequence of fibrinogen, or the vitronectin receptor on os aoclasts, which interacts especially with the RGD
sequence of vitronectin or iy osteopontin. The integrins are divided into three major groups, the [32 subfamily with the representatives LFA-1, Mac-1 and p150/95, which are responsible in particulc ' for cell-cell interactions of the immune system, and the subfamilies p1 and [33, whose representatives mainly mediate cell adhesion to components of the extrace ular matrix (Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375). The integrins of the £" subfamily, also called VLA proteins (very late (activation) antigen), include at least six receptors which interact specifically with fibronectin, collagen and/or laminin as ligands. Within the VLA family, the integrin VLA-4 (a4[31) is atypical in so far as it is mainly restricted to lymphoid and myeloid cells and is responsible in ihese for cell-cell interactions with a large number of other cells. For example, Vi.A-4 mediates the interaction of T and B lymphocytes with the heparin ll-binding ,;'agment of human plasma fibronectin (FN). The binding of VLA-4 with the heparin I -binding fragment of plasma fibronectin is especially based on an interaction wtlh an LDVP sequence. In contrast to the fibrinogen or vitronectin receptor, VLA-^ is not a typical RGD-binding integrin (Kilger and Holzmann, J. Mol. Meth 1 .:)95, 73, 347).
The leucocytes circulating in the blood normally exhibit only a low affinity for the vascular endothelial cells vvhich line the blood vessels. Cytokines which are released from inflamed tisd je cause the activation of endothelial cells and thus the expression of a large number of cell surface antigens. These include, for example, the adhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; also designated as E-selectin), which, inter alia, binds neutrophiles, ICAM-1 (intercellular adhesion molecule-1), whi;h interacts with LFA-1 (leucocyte function-associated antigen 1) on leucocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds various leucocytes, inter alia lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1 ( like ICAM-1, is a member of the immunoglobulin gene superfamily, VCAM-1 (first known as INCAM-"1' 0) was identified as an adhesion molecule which is induced on endothelial ce'ls by inflammatory cytokines such as TNF and IL-1 and lipopolysaccharides (LPS!. Elices et al. (Cell 1990, 60, 577) showed that VLA-4 and VCAM-1 form a receptor-licjand pair which mediates the adhesion of lymphocytes to activated endothelium Th \-. binding of VCAM-1 to VLA-4 does not take place here due to an interaction of tt>: VLA-4 with an RGD sequence; such one is not
contained in VCAM-1 (Beroslson et al., Current Biology 1995, 5, 615). VLA-4, however, also occurs on ot 'er leucocytes, and the adhesion of leucocytes other than lymphocytes is also mediated via the VCAM-1 A/LA-4 adhesion mechanism. VLA-4 thus represents an ir dividual example of a pi integrin receptor which, via the ligands VCAM-1 and fibromjctin, plays an important part in cell-cell interactions and in cell-extracellular matrix i ■ teractions
The cytokinennduced adhesion molecules play an important part in the recruitment of leucocytes into extravasrular tissue regions. Leucocytes are recruited into inflammatory tissue region:; by cell adhesion molecules which are expressed on the surface of endothelial cells and serve as ligands for leucocyte cell surface proteins or protein complexes (receptors) (the terms ligand and receptor can also be used vice versa). Leucocytes frcm the blood must first adhere to endothelial cells before ihey can migrate into the synovium. Since VCAM-1 binds to cells which carry the integrin VLA-4 (c The VCAM-1A/LA-4 adhes:on mechanism has been connected with a number of physiological and patholoc.cal processes. Apart from cytokine-induced endothelium, VCAM-1 is additionally expressed, inter alia, by the following cells: myoblasts, lymphoid dendritic cells ard tissue macrophages, rheumatoid synovium, cytokine-stimulated neural cells, parietal epithelial cells of the Bowman's capsule, the renal tubular epithelium, inflamed tissue during heart and kidney transplant rejection and by intestinal tissue in graf:-versus-host disease. VCAM-1 is also found to be expressed on those tissue areas of the arterial endothelium which correspond to early arteriosclerotic plaques of a rabbit model. Additionally, VCAM-1 is expressed on follicular dendritic cell*; of human lymph nodes and is found on stroma cells of the bone marrow, for exanple in the mouse. The latter finding points to a function of VCAM-1 in B-cell development. Apart from cells of hematopoietic origin, VLA-4 is also found, for example, en melanoma cell lines, and the VCAM-1 A/LA-4 adhesion
mechanism is connected w/.h the metastasis of such tumors (Rice et al., Science 1989( 246, 1303).
The main form in which VCAM-1 occurs in vivo on endothelial cells and which is the dominant form in vivo is designated as VCAM-7D and carries seven immunoglobulin domains. The domains 4, £ and 6 are similar in their amino acid sequences to the domains 1, 2 and 3 The fourth domain is removed in a further form, consisting of six domains, designated here i\s VCAM-6D, by alternative splicing. VCAM-6D can also bind VLA-4-expressing eel 5
Further details on VLA-4, VCAM-1, integrins and adhesion proteins are found, for example, in the articles by Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley, Chichester 1995, p. 79; Kuijpers, Springer Semin. Immunopathol. 19^5, 16, 379.
On account of the role of 1 -e VCAM-1A/LA-4 mechanism in cell adhesion processes which are of importance, fi:r example, in infections, inflammations or atherosclerosis, it has betifi attempted by means of interventions into these adhesion processes to control diseases, in particular, for example, inflammations (Osborn et al., Cell 1989, :9, 1203), A method of doing this is the use of monoclonal antibodies which are directed against VLA-4. Monoclonal antibodies (mAB) of this type which as VLA-4 antagonists block the interaction between VCAM-1 and VLA-4, are known. Thus, for examole, the anti-VLA-4 mAB HP2/1 and HP1/3 inhibit the adhesion of VLA-4-expressing Ramos cells (B-cell-like cells) to human umbilical cord endothelial cells and :o VCAM-1 -transfected COS cells.
The anti-VCAM-1 mAB 4E9 likewise inhibits the adhesion of Ramos cells, Jurkat cells (T-cell-like cells) an<: hl60 cells to cos transfected with genetic c instructs which cause vcam-6d and vcam-7d be expressed. in vitro data w. antibodies are directed against the a4 subunit of vla-4 show that adhesion lymphocytes synovial endothe blocked an wh plays a part rheumatoid arthritis dinther-janssen et al. j. immunol>
In vivo experiments have si'own that an experimental autoimmune encephalomyelitis can be inhibited by anti-oc4 mAB. The migration of leucocytes into an inflammatory focus is likewise blocked by a monoclonal antibody against the aA chain of VLA-4. The influer t:ing of the VLA-4-dependent adhesion mechanism by antibodies was also investigated in an asthma model in order to investigate the role of VLA-4 in the recruitment of leucocytes in inflamed lung tissue (USSN 07/821,768; EP-A-626 861). The administration of anti-VLA-4 antibodies inhibited the late-phase reaction and respiratory tr;:.:t overreaction in allergic sheep.
The VLA-4-dependent cell adhesion mechanism was also investigated in a primate model of inflammatory bovv 3l disease (IBD). In this model, which corresponds to ulcerative colitis in man, tho administration of anti-VLA-4 antibodies resulted in a significant reduction in the acute inflammation,
Moreover, it was possible D show that VLA-4-dependent cell adhesion plays a part ]n the following clinical conditions including the following chronic inflammatory processes: rheumatoid art'htis (Cronstein and Weismann, Arthritis Rheum. 1993, 36, 147; Elices et al., J. C-n. Invest. 1994, 93, 405), diabetes mellitus (Yang et al., Proc. Natl. Acad. Sci. US/\ 1993, 90, 10494), systemic lupus erythematosus (Takeuchi et al., J. Clin. In/est. 1993, 92, 3008), allergies of the delayed type (type IV allergy) (Elices et al.p Clin. Exp. Rheumatol. 1993, 11, p.77), multiple sclerosis (Yednock et al., Nature 1^92, 356, 63), malaria (Ockenhouse et al., J, Exo. Med, 1992, 176, 1183), arterio? Xerosis (Obrien et al., J. Clin. Invest. 1993, 92, 945), transplantation (Isobe et ri.( Transplantation Proceedings 1994, 26, 867-868), various malignancies, for ;xample melanoma (Renkonen et al., Am. J. Pathol. 1992, 140, 763), lymphoma (Fre-dman et al., Blood 1992, 79, 206) and others (Albelda et al.. J. Cell Biol. 1991, 114 1059).
VLA-4 blocking by suitabl • antagonists accordingly offers effective therapeutic
possibilities, in particular, :or example, of treating various inflammatory conditions including asthma and IBD. The particular relevance of VLA-4 antagonists for the treatment of rheumatoid cfthritis in this respect results, as already stated, from the fact that leucocytes from ihe blood must first adhere to endothelial cells before they
can migrate into the synovi. mt and that the VLA-4 receptor plays a part in this adhesion. The fact that VC :.M-1 is induced by inflammatory agents on endothelial cells (Osborn, Cell 1990, 6;, 3; Stoolman, Cell 1989, 56, 907), and the recruitment of various leucocytes into c eas of infection and inflammatory foci has already been dealt with above. In this res :>ect, T cells adhere to activated endothelium mainly via the LFA-1/ICAM-1 and VLA-4A/CAM-1 adhesion mechanisms (Springer, Cell 1994, 76, 301), On most synovia1 T cells, the binding capacity of VLA-4 for VCAM-1 is increased in rheumatoid a'lhritis (Postigo et al.( J. Clin. Invest. 1992T 89, 1445). Additionally, an increased fidhesion of synovial T cells to fibronectin has been observed (Laffon et al., J. ;;lin. Invest. 1991, 88, 546; Morales-Ducret et al., J. Immunol. 1992, 149, 1424 ■ VLA-4 is also upregulated both in the course of its expression and with respe: t to its function on T lymphocytes of the rheumatoid synovial membrane. The Mocking of the binding of VLA-4 to its physiological ligands VCAM-1 and fibronectin rr;ikes possible an effective prevention or alleviation of articular inflammatory processes. This is also confirmed by experiments with the antibody HP2/1 on Lewis rats with adjuvant arthritis, in which an effective prevention of illness has been observed (Barbadillo et al., Springer Semin. Immunopathol. 1995, 16, 427), VLA-4 is t" us an important therapeutic target molecule.
The abovementioned VLA-4 antibodies and the use of antibodies as VLA-4 antagonists are describee in the Patent Applications WO-A-93/13798, WO-A-93/15764, WO-A-94/1605M, WO-A-94/17828 and WO-A-95/19790. In the Patent Applications WO-A-94/1f.;i58, WO-A-95/15973, WO-A-96/00581, WO-A-96/06108 and WO-A-96/20216, pej: ide compounds are described as VLA-4 antagonists. The use of antibodies and peo ide compounds as pharmaceuticals, however, is afflicted with disadvantages; for example lack of oral availability, easy degradability or immunogenic action on leiger-term use, and there is thus a need for VLA-4 antagonists having a favo able profile of properties for use in therapy and prophylaxis
W'O-A-95/14008 describes substituted 5-membered ring heterocycles which have an ammo, amidino or guanidino function at the N-terminal end of the molecule and which exhibit platelet aggregation-inhibiting activity. The German Patent Application
19635522.2 describes heterocycles which are inhibitors of bone resorption, WO-A-96/33976 (and the German Patent Application 19515177.1) describes certain Jiydantoin derivatives having a 4-cyanophenyl radical in the 4-position of the hydantoin ring, which are intermediates for the preparation of active compounds which are described in WC-A-95/14008. Pharmacological actions of these cyanophenylhydantoin derivatives, however, are not disclosed. The present invention relates to further heterocyclic compounds which are VLA-4 antagonists and/or inhibitors of leucocye adhesion.
W isR1-A-C(R13)orR1-A-CH=C;
Y is a carbonyl, thiocarbonyl or methylene group;
Z is N(R°), oxygen: sulfu" or a methylene group;
A is a bivalent radical from the group consisting of (C1-C6)-aIkyleneI (C3-C12)-cycloalkylene, (CrC6)-alkylene-(C3-C12)-cycloalkyl, phenylene, phenvlene-(Cr C6)-alkyl, (CrC6)-alky^nephenyl, (CrC6)-alkylenephenyl-(CrC6)-alkyl, phenyIene-(C2-C6)-all B is a bivalent radical frcm the group consisting of (C1-C6)^alkylene) (C2-C6)-alkenylene, phenylene, phenylene-(C1-C3)-alkylf (C1-C3)-alkylenephenyl, where the bivalent (C1-C6)-akylene radical can be unsubstituted or substituted by a radical from the group consisting of (C1-C8)-alkyl, (C2-C8)-a!kenyl, (C2-C8)-aikyny!, (C3-C10)~cyck
aryl radical, optionally substituted heteroaryl and heteroaryl-(C1-C6)-alkyl optionally substituted ir the heteroaryl radical;
D is C(R2)(R3), N(R3) or OH=C(R3);
E is tetrazolyl, (R80)2P(C:, HOS(0)2, R9NHS(0)2 or R10CO;
R is hydrogen, (C1-C8)-all;yl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (Cl5-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(Cr C8)-a!kyl optionally subs.ituted in the heteroaryl radical, where alkyl radicals can be mono- or polysubstit.ted by fluorine;
R° is hydrogen, (C1-C8)-akyl, (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, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted hoteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, CHO, (C1-C8)-alkyl-CO, (C3-C12)-cycloalkyl-CO, (C3-C12)-cycloalkyl-(C1-C8> alkyl-CO, (C6-C12)-bicycloalkyl-CO, (C6-C12)-bicycloalkyl-(C1-C8)-alf;yl-CO, (C6-C12)-tricycloalkyl-CO, (C6-C12)-tricyclcalkyl-(C1-C8)-alkyl-CO, optionally substituted (C6-C14)-aryl-CO, (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted in the aryl radical, optionally substituted heteroaryl-CO, heteror 'yl-(C1-C8)-alkyl-CO optionally substituted in the heteroaryl radical, (Cr08)-alkyl-S(O)n, (C3-C12)-cycloalkyl-S(0)n, (C3-C12)-cycloalkyl-(C1-C8)-alkyl-S(0)n, (C6-C12)-bicycloalkyl-S(0)n, (C6-C12)-bicycloalkyl-(C1-C8)-al R1 is one of the radicals - fi-R21, -S-S-R21, -S(0)-R22, -S(0)2-R22, -S-OR21, -S(O)-OR2\ -S(0)2-OR21. -S-N(R21)-R28, -S(0)-N(R21)-R28, -S(0)2-N(R21)-R28,-S-:(0)-R21,
-S-C(0)-OR22, -S-C(S;-SR22, -S-C(0)-N(R21)-R28, -S-C(S)-N(R21)-R28, -0-C(0)-R21, -O-C(S)-^21, -0-C(0)-OR22, -0-C(0)-N(R21)-R28, -0-C(S)-N(R21)-R28, -0-S(0)2-OR21, -0-S(0)-OR21, -0-S(0)2-N(R21)-R28,
-0-S(0)-N(R21)-R28, -0-S(0)2-R22, -0-S(0)-R22, -0-P(0)(OR21)2, -0-P(C)(OR21)-N(R21)-R28, -0-P(0)(N(R21)-R28)2, -N(R29)-C(0)-OR22, -N(R28)-C(0)-SR22, -N(R28)-C(S)-OR22, -N(R28)-C(S)-SR22, -N( :>28)-C(S)-R21,
-N(R28)-C(0)-N(R21)-R!8,-N(R28)-C(S)-N(R21)-R28. -N(R28)-S(0)2-R22, -N(R28)-S(0)-R22, -N(R28)-S(0)2-0R21,
-N(R28)-S(0)-OR21, -Nt ^28)-S(0)2-N(R21)-R28, -N(R28)-S(0)-N(R21)-R28,
-N(R28)-P(0)(OR21)2, -N(R28)-P(0)(OR21)-N(R21)-R28,
-N(R28)-P(0)(N(R21)-R:8)2, -N(R28)-P(0)(R22)-OR21,
-N(R28)-P(0)(R22)-N(R?1)-R28,-N(R28)-P(0)(R22)2,
-P(0)(OR21)2, -P(0)(0:;:21)-N(R21)-R28, -P(0)(N(R21)-R28)2,
-P(0)(R22)-OR21, -P(Oi(R22)-N(R21)-R28, -P(0)(R22)2,
-C(S)-R21, -C(S)-SR21, -C(S)-N(R21)-R28,
cyano, halogen, nitro 01 methylenedioxy or the radical of an optionally
substituted, 5- to 14-rrk:mbered, mono- or polycyclic, saturated or unsaturated
heterocyclic ring of the formula
Q1 is -C(R21)2-, =C(R:M)-, -N(R28)-, -0- or -S-;
Q2is-S(0)-or-S(0)2-;
Q3is-C(R21)2-, =C(R:!>, -N(R28)-, -0-, -S-, -C(R21)(-)- or -N(-)-,
where the heterocyclic ring can be bonded to the group A via the free bond in
the groups -C(R21)(-)- or -N(-)- representing Q3 or via any other desired ring
carbon atom and whero, if the heterocyclic ring is bonded to a ring system
contained in the group A, the heterocyclic ring can also be fused via two
adjacent atoms to the -ing system in the group A;
R2 is hydrogen, (C1-C8)-:ilkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or (C3-C8)-cycloalkyl;
R3 is hydrogen, (C1-C8)-;ilkyl, optionally substituted (C6-C14)-aryl, (C6~C14)-aryl-(C1-C8)-alkyl optional y substituted in the aryl radical, (C3-C8)-cycloalkyl, (C2-
C8)-a]kenyt, (C1-C8)-all;;/nylt (C2-C8)-alkenylcarbonyl, (C2-C8)-alkynylcarbonyl, pyridyi, R11NH, R4CO, :;00R4, CON(CH3)R4, CONHR4, CSNHR4, CCOR15, CON(CH3)R15orCONHR15;
is hydrogen or (C1-C28)-alkyl which can optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or di-((C1-C18)-alkyl)-aminocarbonylt amino-(C2-C18)-a!kylarr:nocarbonyl, amino-(C1-C3)-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (C. -C18)-alkylcarbonylamino-(CrC3)-alkylphenyl-(C1-C3)-alkylaminocarbonyl, (CrC18)-alkylcarbonylamino-(C2-C18)-aIkylaminocaoonyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl which can also be substituted in tKie aryl radical, amino, mercapto, (Cj-C^J-alkoxy, (Cr C18)-alkoxycarbonyl, H»:t-CO, optionally substituted (C3-C8)-cycloalkyl, HOS(0)2-(CrC3)-alkyl R9NHS(0)2-(CrC3)-alkyl, (R80)2P(0)-(C1-C3)^alkyll tetrazolyU(CrC3)-atkyl, halogen, nitro, trifluoromethyl or the radical R5; is optionally substitutec; (C6-C14)-aryi, (C6-Cl4)-aryl-(C1-C8)-alkv| optiona'ly
substituted in the aryl radical, a mono- or bicyclic 5- 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 group consisting of nitrogen, oxygen and sulfur, a radical R6 or a radical R6CO, *vhere the aryl radical and, independently thereof, the heterocyclic radical car; be mono- or polysubstituted by identical or different radicals from the group consisting of (CrC18)-alkyl, (C1-C18)-alkoxy, halogen, nitro, amino and trifluoromethyl;
is R7R8N, R70 or R7S »:r an amino acid side cnain, a natural or unnatural amino acid, imino acid, optionally N-(C1-C8)-alkylated or N-((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid or a dipeptide radical which can also be substituted in the aryl radical and/or reduced in the peptide bond to -NH-CH2-, and their esters and amides, where hyc-iogen or hydroxymethyl can optionally stand in place of
of free functional group andfor where free functional groups can be protected
by protective groups customary in peptide chemistry;
is hydrogen, (CrC18)-
can optionally be subst :uted by an amino group and/or where the aryl radicals can be mono- or polysi instituted, preferably monosubstituted, by identical or different radicals from 'e group consisting of (C1-C8)-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino c \d trifluoromethyl, or is a natural or unnatural amino acid, imino acid, optionally N(C1-C8)-alkylated or N-((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid or a dip : ptide radical which can also be substituted in the aryl radical and/or reduced in the peptide bond to -NH-CH2-; R8 is hydrogen, (CrC18)-:i kyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-
(C1-C8)-alkyl which ca*i also be substituted in the aryl radical; R9 is hydrogen, aminocari'nnyl, (CrC18)-alkylaminocarbonyl, (C3-C8)-cycloalkylamiri-jcarbonyl, optionally substituted
(C6-C14)-arylaminocarlonyl, (Cl-C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8)-cycloalkyl; R10 is hydroxy!, (C1"C18)-i-:lkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryi adical, optionally substituted (C6-C14)-aryloky, amino or mono- or di-((C,-C18; -alkyljamino; R11 is hydrogen, R12a R1':a-CO, H-CO. R12a-0-CO, R12b-CO, R12b-CS,
R17a-S(0)2orR12b-SO)2; R12a is (CrC18)-alkyl, (C;- -C8)-alkenyl, (C2-C8)-alkynyl, (CrC12)-cycloalkyl, (C3-C12)-cycloalkyl-(Cr;;8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alky! optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical or he radical R15; R12b is amino, di-((CrC1: -alkyl)-amino or R12a-NH;
R13 is hydrogen, (C1-C6; alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionu ly substituted in the aryl radical, (C3-C8)-cycloalkyl or (C3-C8)-cycloalkyl-(C1-C8)-alkyl; R15 is R16- R16 is a 6- to 24-membe'3d bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one, two, three or four identical or different leteroatoms from the group consisting of nitrogen, oxygen and sulfur z ■ d which can also be substituted by one or more identical or different substitutes from the group consisting of (C1-C4)-alkyl and oxo;
R21 is hydrogen, (C1-C8)-;:lkyl, hydroxy-(C1-C8)-alkyl, (C1-C8)-alkenyl, (C3-C12)-cycloalkyl, (C3-C12)-C'Cloalkyl-(C1-C8)-alkyll optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C -C8)~alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-a!kyl optionally substituted in the heteroaryl radical, where alkyl radicals can also be monosubstituted or pclysubstituted by fluorine and the radicals R21 can be identical or different il they occur two or more times; R22 is (C1-C8)-alkyl, hydmxy-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C3-C12)-cycloalkyl, (CrC12)-cycloalkyl-(OrC8)-alkylt optionally substituted (C6-C14)-aryl) (C6-C14)-aryl-(C1-C8)-alk:'l optionally substituted in the aryl radical, optionally substituted heteroar> or heteroaryl-(C1-C8)-a!kyl optionally substituted in the heteroaryl radical, whare alkyl radicals can be monosubstituted or polysubstituted by fk::>rine and the radicals R22 can be identical or different if they occur two or moi >a times;
R28 is one of the radicals ^21-, R21N(R21)-, R21C(0)-, R220-C(0)-, R21N(R21)-C(0)-orR21N(R21)-C(=N(R21))--;
R29 is one of the radicals R22-, R21N(R21)-, R21C(0)-, R220-C(0)-, R21N(R21)-C(O)- or R21N(R21)-i;.(=N(R21))-;
Het is the radical of a 5- to 10-membered, monocyclic or polycyclic heterocycle bonded via a nitroger atom, which can be eromatic or partially unsaturated or saturated and which : an contain one, two, three or four identical or different additional ring heterc atoms from the group consisting of oxygen, nitrogen and sulfur and which car ue optionally substituted on carbon atoms and on additional ring nitrogen atoms, where there can be identical or different radicals Rh, RhCO o, RhO-CO as substituents on additional ring nitrogen atoms and Rh is hyd ogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl? (C3-C8)~ cycIoalkyl-(C1-C8)-ai *yl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8}-alkyl optionally substituted in the aryl radical;
b, c. d and 1 independentiv of one another are 0 or 1, but cannot all simultaneously
in all their stereoisomer^ orms and mixtures thereof in any ratio, and their
physiologically tolerable Stilts;
where, however, if simultaneously W is 4-cyanophenyl-C(R13), Y is a carbonyl group, 2 is NR0a, B is an ur substituted methylene group, R is Ra, b, c and d are 1 and e, f and g are 0, then D cannot be C(R2a)(R3a), where R0a, Ra and R2a independently of one another are hydrogen, (C^-C^-alkyl,
optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally
substituted in the ary radical or (C3-C8)-cycloalkyl and R3a is hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-
(C1-C8}-alkyl options: y substituted in the aryl radical, (C3-C8)-cycloalkyl or 2-,
3- or 4-pyridyl.
Alkyl radicals can be straic it-chain or branched. This also applies if they carry substituents or occur as suostituents of other radicals, for example in alkoxy, alkoxycarbonyi or aralkyi i radicals. The same applies to alkylene radicals. Examples of suitable (C1-C28)-aikyl radicals are: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, undec-J, dodecyl, tridecyl, pentadecyl, hexader.yl, heptadecyl, nonadecyl, eicosyl, docosyl, tricosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, isopropyl, isobutyl, isoper.1:/!, neopentyl, isohexyl, 3-methylpentyl, 2,3,5-trimethylhexyl, sec-butyl, tfirt-butyl, tert-pentyl. Preferred alkyl radicals are methyl, ethyl, propyl, isopropyl, bUyl, isobutyl, sec-butyl and tert-butyl. Examples of alkylene radicals are methylene, ethylene, tri-, tetra-, penta- and hexamethylene or methylene substituted by sn alkyl radical, for example methylene which is substituted by a methyl group, an ethyl group, an isopropyl group, an isobutyl group or a tert-butyl group.
Alkenyl and alkenylene radicals as well as alkynyl radicals 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 and examples of alkynyl radicals are ethynyl, 1-propynyl or propargyl.
Cycloalkyl radicals are, ir particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycioheptyl, cyclooctyl, cy:lononyl, cyclodecyl, cycloundecyl and cyclododecyl, but which can also be substiUted by, for example, (C1-C4)-alkyl. Examples of substituted cycloalkyl radicals which may be mentioned are 4-methylcyclohexyl and
2,3-dimethylcyclopentyl. Th3 same applies to cycioalkylene radicals.
The 6- to 24-membered bicyclic and tricyclic radicals R16 are formally obtained by abstraction of a hydrogen ;;itom from bicyclic systems or tricyclic systems. The bicyclic systems and tricyclic systems on which they are based can cdntain only carbon atoms as ring memi;ers, i. e, they can be bicycloalkanes or tricycloalkanes, but they can also contain one, two, three or four identical or different heteroatoms from the group consisting c-,: nitrogen, oxygen and sulfur, i. e, they can be aza-, oxa-and thiabicyclo- and -tricycloalkanes. If heteroatoms are present, preferably one or two heteroatoms, in partici ar nitrogen or oxygen atoms, are present. The heteroatoms can assume z -ly desired positions in the bi- or tricyclic structure; they can be located in the bridges, or in the case of nitrogen atoms, also at the bridgeheads. Both the bicyclo- and tricycloalkanes and their heterocyclic analogs can be completely saturated or can contain one or more double bonds, Tney preferably contain one or t//o double bonds or, in particular, are completely saturated. Both the bicycle- and tricycloalkanes and the heterocyclic analogs and both the saturated and the unsaturated representatives can be unsubstituted or substituted in any desired suitable positions by one or more oxo groups and/or one or more identical or different (C1-C4)-alkyl groups, for example methyl or isopropyl groups, preferably methyl groups. The free bond of the bi- or tricyclic radical can be located in any desired position of the molecule; the radical can thus be bonded via a bridgehead atom or an atc:m in a bridge. The free bond can also be located in any desired stereochemical position, for example in an exo or an endo position.
Examples of parent structures of bicyclic ring systems from which a bicyclic radical can be derived are norbonane (= bicyclo[2.2.1]heptane), bicyclo[2.2,2]octane and bicyclo[3.2.1]octane, examples of unsaturated or substituted systems or systems containing heteroatoms an* 7-azabicyclo[2.2.1]- heptane, bicyclo[2.2.2]oct-5-ene
ana camphor (= 1,7l7-tnm:ithyl-2-oxobic/clo[2.2.1]heptane).
Examples of systems frorr which a tricyclic radical can be derived are twistane (= tricyclo[4.4,0.03,8]decane:, adamantane (= tricyclo[3.3.1.13,7]- decane), noradamantane (= tricyclo;3.3.1.03'7]nonane), tricyclo[2.2.1.02,6]- heptane,
tricyc!o[5.3.2.04,9]dodecano( tricyclo[5.4.0.02,9]undecane or tricyclo[5.5.1.03,11]tridecan:i
Preferably, bicyclic or tricyclic radicals representing R16 are derived from bridged bicyclic systems or tricyclic systems, i.e. from systems in which rings together have two or more than two atom":, Bicyclic or tricyclic radicals having 6 to 18 ring members are additionally [referred, particularly preferably those having 7 to 12 ring members.
Specifically particularly pro 'erred bi- and tricyclic radicals are the 2-norbornyl radical, both that with the *'ee bond in the exo position and also that with the free bond in the endo position, fhe 2-bicyclo[3.2.1]octyl radical, the 1-adamantyl radical, the 2-adamantyl radical ard the noradamantyl radical, for example the 3-noradamantyl radical. The 1- and the 2-adamantyl radicals are moreover preferred.
(C6-C14)-aryl groups ere, f:>r example, phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, where 1-naphthyl, 2-naphthyl and in particular phenyl are preferred. Aryl radicals, in particular pheryl radicals, can be mono- or polysubstituted, preferably mono-, di- or trisubstitutec, by identical or different radicals from the group consisting of (C1-C8)-alkyl, in particular (C1-C4)-alkyll (C1-C8)-alkoxv, in particular (CrC4)-alkoxy, halogen, 'vtro, amino, trifluoromethyl, hydroxyl, methylenedioxy, ethylenedioxy, cyano, hyclroxycarbonyl, aminocarbonyl, (CrC4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, kenzyloxy, (R80)2P(0), (R80)2P(0)-0-, tetrazolyl. The same applies, for exampk to radicals such as aralkyl or arylcarbonyl. Aralkyl radicals are, in particular, benzyl as well as 1- and 2-naphthylmethyl, 2-, 3- and 4-biphenylylmethyl and 9-fluorenylmethyl which can also be substituted. Substituted aralkyl radicals are, for example, benzyl and naphthylmethyl substituted in the aryl : ioiety by one or more (C -C8)-aIkyl radicals, in particular (C1-C4)-alkyl radicals, for example 2-, 3- and 4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl( 3,5-dimetfT'lbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-methyl-1 -naphthylmethyl, 1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthyImethyl, or benzyl and naphthylmethyl substituted in the aryl moiety by one or more (C1-C8)~ alkoxy radicals, in particular (CrC4)-alkoxy radicals, for example 4-methoxybenzyl,
4-neopentyloxybenzyl, 3,5-;iimethoxybenzyl, 3,4-methylenedioxybenzyl, 2,3,4-trimethoxybenzyl, further 2*, 3- and 4-nitrobenzyl, halobenzyl, for example 2-, 3- and 4-chloro- and 2-, 3- and 4-:;jorobenzyl, 3,4-dichlorobenzyl, pentafluorobenzyl, trifluoromethylbenzyl, for example 3- and 4-trifluoromethylbenzyl or 3,5-bis(trifIuoromethyi)beni:yl. Substituted aralkyl radicals, however, can also have different substituents, Exan.ples of pyridyl are 2-pyridyl, 3-pyridyl and 4-pyridyl.
In monosubstituted phenyl -adicals, the substituent can be located in the 2-, the 3-or the 4-position, the 3- an : Phenylene-(C1-C6)-alkyl is in particular, phenylenemethyl (-C6H4-CH2-) and phenyleneethyl, (C1-C6)-alkylenephenyl is, in particular, methylenephenyl (-CH2-C6H4-). Phenylene-(C2-C6)-alkenyl is, in particular, phenyleneethenyl and phenylenepropenyl.
Heteroaryl is a mono- or polycyclic aromatic radical having 5 to 14 ring members, which contains 1 to 5 hete '■oatoms as ring members. Examples of heteroatoms are N, 0 and S. If several heteroatoms are contained, these can be identical or different. Heteroaryl radicals can a»:o be mono- or polysubstituted, preferably mono-, di- or irisubstituteci, by tdentica' or different radicals from the group consisting of (C1-C8)-alkyi, in particular (CrC4; -alkyl, (C1-C8)-alkoxy, in particular (CrC4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, ethylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl) phenyl, phenoxy, benzyl, benzyloxy, (R80) ,P(0), (R80)2P(0)-0-, tetrazolyl. Preferably, heteroaryl is a
mono- or bicyclic aromatic 'adical which contains 1, 2, 3 or 4, in particular 1 to 3, identical or different heterontoms from the group consisting of N, O and S and which can be substituted by 1, 2, 3 or 4, in particular 1 to 3, identical or different substituents from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, chlorine, nitro, amino, triflu:>romethyl, hydroxy!, (CrCt)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy and btnzyl. Particularly preferably, heteroaryl is a mono- or bicyclic aromatic radical having 5 to 10 ring members, in particular a 5- to 6-membered monocyclic aromatic radical which contains 1, 2 or 3, in particular 1 or 2, identical or different hetercatoms from the group consisting of N, 0 and S and can be substituted by 1 or 2 identical or different substituents from the group consisting of (CrC4)-alkyl, (CrC4)-alkoxy, phenyl, phenoxy, benzyloxy and benzyl.
which can represent the gfoup R1, can be completely saturated in the ring or can contain one or more double bonds. In addition to the substituents in the groups Q1 and Q3, these heterocyclic rings can additionally carry one or more further, identical or different radicals R21 ar j/or halogen atoms as substituents. The meanings -C(R21)(-)- and -N(-)- contained in the definition of Q3 are to be understood as meaning that two of the ttrse free bonds of the carbon atom or of the nitrogen atom are directed toward the adjacent ring members and the third free bond is directed toward the group A, such I hat in this case the heterocyclic ring is thus bonded to the group A via the group Q3. If the heterocyclic ring is fused to the ring system in the group A via two adjacent c '.oms of the ring system, a condensed ring system is present. The fusion can take place via the group Q3 and the adjacent carbon atom or via any two desired adjacent carbon atoms. Examples of condensed ring systems of this type are the radicals-.
which then represent the g'oup R1~A in the formula I.
Heterocycles which represent the mono- or bicyclic 5- to 12-membered heterocyclic rings mentioned in the definition of R5 can be aromatic or partially or completely saturated and can be substituted, in particular on a nitrogen atom, by (CrC7)-alkyl, for example methyl or ethy phenyl or phenyl-(C1-C4)-alkyl, for example benzyl, and/or on one or more cari;on atoms by (C1-C4)-alkylr halogen, hydroxyl, (C^C^)-alkoxy, for example metho: Examples of heterocycles :>n which the group heteroaryl or the mono- or bicyclic 5-to 12-membered heterocyclic ring can be based are pyrrole, furan, thiophene, imidazole, pyrazole, oxazc:!e, isoxazole, thiazole, isothiazole, tetrazole, pyridine, pyrazine, pyrimidine, indole:, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, :]uinazoline, cinnoline, p-carboline or benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivatives of these heterocycles. Nitrogen heterocycles can also be present as N-oxides.
Radicals which can repres ant heteroaryl or the radical of a mono- or bicyclic 5- to 12-membered heterocyclic: ring are, for example, 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-:>yrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl, for example 1 -methyl-2-, -: - or -5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide, 2-;:iyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyi, for sample 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro or 4>dimethyl~2~ 'idolyl, 1-benzyl-2- or -3-indolyl, 4,5,6,74etrahydro-2-indolyl, cyclohepta[b]-5-pyTolyl, 2-, 3-or 4-quinolyl, 1-, 3-or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl 2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl or benzothiazolyl or, as radicals of partially hydrogenated or completely hydrogenated leterocyclic rings, for example also dihydropyridinyl,
pyrrolidinyl, for example 2- or 3-(N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl, tetrahydro::*iienyl, benzodioxolanyl.
Heterocyclic radicals representing the radical Het can be unsubstituted on carbon atoms and/or ring nitrogen atoms or monosubstituted or polysubstituted, for example disubstituted, trisubstituted, tetrasubstituted or pentasubstituted, by identical or different substituents. Carl:on atoms can be substituted, for example, by (C^C^-alkyl, in particular (CrC4)- ?ilkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, oxo, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R80)2P(0), (R-0)2P(0)-CK tetrazolyl. Sulfur atoms can be oxidized to the sulfoxide or to the sulfone. Examples of the radical Het are 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-tctrazolyl, 1 -dihydropyridin-1 -yl, tetrahydropyridin-1-yl, 1-pyrrolidinyl, 1-piperidinyl, ' -piperazinyl, 4-substituted 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-oxo-4-:hiomorpholinyl, 1,1-dioxothiomorpholinyl, perhydroazepin-1-yl, 2,5-dimethyl-1-pyrrolyl, 2,6-dimethyl-1-piperidinyl, 3,3-dimethyl-4-morpholinyl, 4- .sopropyl-2,2,6,6-tetramethyM -piperazinyl, 4-acetyl-1-piperazinyl, 4-ethoxycarbcnyM -piperazinyl.
Natural or unnatural amin;: acids can be present in all stereochemical forms, if chiral, tor example in the I> or L-form or in the form of a mixture of stereoisomers, for example in the form of w racemate. oc-Amino acids and p-amino acids are preferred, particularly pre:sarred are a-amino acids. Examples of suitable amino acids which may be menti : Aad, Abu, yAbu, ABz, 2AI:z, eAca, Ach, Acp, Adpd, Ahb, Aib, PAib, Ala, ISAIa, AAla, Alg, All, Ama, Amt. Ape, Ppm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fe', Gin, Glu, Gly, Guv, hAla, hArg hCys, hGIn, hGlu, His, hlle, hLeu, hLys, hMet, hPhe,
hPro, hSer, hThr, hTrp, hTy, Hyl, Hyp, 3Hyp, lie, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsy, Lys, ftLys, ALys, Met, Mim Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, APro, Pse, Pya, Fyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, liThi, Thr, Thy, Thx, Tia, Tie, 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-chloropheny!)-amino acetic acid.
As customary in peptide chamistry, the radical of an amino acid, imino acid orx azaamino acid or of a dipeutide is obtained 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 or formally removing the hydroxyl group from the carboxylic acid group, Amino acid side chains are understood as meaning side chains of natural or unnatural amino acids. Azaamino acids are natural or unnatural amino acids in which a CH unit is replaced by a nitrogen atom, for example in a-amino acids the central unit
Suitable radicals of an imi * o acid are, in particular, radicals of heterocycles from the following group; pyrrolidim-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-c;3rboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carbox;'lic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrole-2-carboxylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid; 2-azabicy:;lo[2.2.1]heptane-3-carboxylic acid; 2-azabicycio[3,1.0]hexane-" carboxylic acid; 2-azaspiro[4.4]nonane-3-carboxylic acid; 2-azaspiro[4.5]decane-3-rrole-2-carboxylicacid; decahydrocycloocta[c]pyrrole-2-
carboxylic acid; octahydroc /clopenta[c]pyrro!e-2~carboxylic acid; octahydroisoindole-1 -carboxylic acid; 2,3;3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid; 213,3at4,57a-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 following formulae).
The heterocycles on which the abovementioned radicals are based are disclosed, for example, in US-A-4,34-1,949; US-A 4,374,847; US-A 4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,95:: EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,02:; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109.C 20; EP-A 111,873; EP-A 271,865 and EP-A 344,682.
Dipeptides can contain na jral or unnatural amino acids, imino acids as well as azaamino acids as structural units. The natural or unnatural amino acids, imino acids, azaamino acids anc dipeptides can further be present also as esters or amides, such as, for example, as the methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl es er, benzyl ester, unsubstituted amide, ethylamide, semicarbazide or u-amino-(C2-C8)-alkylamide,
Functional groups of the cvnino acids, imino acids and dipeptides can be present in protected form. Suitable p elective groups such as, for example, urethane protective groups, carboxyl protective groups and side chain protective groups are described in Hubbuch, Kontakte (Me*rck) 1979, No. 3, pages 14 to 23, and in Bullesbach, Kontakte (Merck) 1980, l\k 1, pages 23 to 35. The following may be mentioned in
particular: Aloe, Pyoc, Fmcc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(N02), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.
Physiologically tolerable salts of the compounds of the formula 1 are, in particular, pharmaceutical^ utilizable or nontoxic salts.
Such salts are formed, for example, from compounds of the formula I which contain acidic groups, for example :arboxylic acid or sulfonic acid or phosphonic acid groups, with inorganic bas^s, for example alkali metal or alkaline earth metal compounds or ammonia. 1 he salts of the compounds of the formula I can thus be, for example, sodium, potassium, magnesium, calcium or ammonium salts. Salts of compounds of the formula with physiologically tolerable organic bases can also be formed, for example with physiologically tolerable organic amines such as triethylamine, ethanoiaminB or tris(2-hydroxyethyl)amine.
Compounds of the formuk- I which contain basic groups, for example an amino group or a guanidino grouo, form salts with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulfonic acids, such as, fc example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric; acid, methanesulfonic acid or p-toluenesulfonic acid.
Salts can be obtained fror, the compounds of the formula I by customary methods known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in >* solvent or dispersant, or alternatively from other salts by anion exchange or cation exchange.
The compounds of the formula I can be present in stereoisomer^ 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 stereoisomer^ forms, for example mixtures of enantiomers and/or diastereomers, in all ratios. The invention thus
relates to enantiomers in e ';antiomerically pure form, both as Ievo- and as dextrorotatory antipodes, iri the form of racemates and in the form of mixtures of the two enantiomers in ail ratios. If cis/trans isomerism is present, the invention relates to both the cis form and thii: trans form and mixtures of these forms.
The compounds of the formula I according to the invention can moreover contain mobile hydrogen atoms, i.e can be present in various tautomeric forms. The present invention also relates to al! these tautomers. The present invention furthermore includes all solvates of corvpounds of the formula I, for example hydrates or adducts with alcohols, as well as derivatives of the compounds of the formula I, for example esters, prodrugs and meta :olites which act like the compounds of the formula I.
The individual structural e1 foments in the formula I preferably have the following meanings.
Wis preferably R1-A-C(Ri;).
A is preferably methylene, ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexylene, phenylene, methylenephenyl, methylenephenylmethyl, phenylenemethyl or phenyleneethyl. Y is preferably a carbonyl ;iroup. Z is preferably N(R°)
B is preferably methylene, ethylene, trimethylene, tetramethylene, vinylene, phenylene or substituted methylene or ethylene. B is particularly preferably a bivalent methylene radical or ethylene radical (= 1,2-ethylene), where each of these radicals can be unsubstituted or substituted and in particular is substituted. Very particularly preferably, B is a substituted or unsubstituted methylene radical, in particular a substituted methylene radical. If a bivalent methylene radical or ethylene radical (= 1,2-ethylene) re:resenting B is substituted, it is preferably substituted by a radical from the group consisting of (C^C^-alkyl, (C2-C6)-alkeny!t (C2-C6)~alkynyl, (C3-C8)-cycloalkyl, in part oilar (C5-C6)-cycloalkylt (C3-C8)-cycloalkyl-(CrC4)-alkylI in particular (C5-C6)-cyclo-ilkyl-(C1-C4)*alkyll optionally substituted (C6-C10)-aryl, (C6-C10)-aryl-(CrC4)-alkyl optionally substituted in the aryl radical, optionally substituted heteroary! or I* steroaryl-(CrC4)-alkyl optionally substituted in the
heteroaryl radical, and it is particularly preferably substituted by (C1-C8)-aIkyl, i.e.
by a straight-chain or branded alkyl radical having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
R is preferably hydrcgen, (^rC6)-alkyl or benzyl, in particular hydrogen, methyl or
R° is preferably (C1-C8)-all optionally substituted (C6-C.14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally
substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-
(C1-C8)-alkyl optionally substituted in the heteroaryl radical, particularly preferably
optionally substituted (C6-014)-aryl, (C6-C14)-aryl-(C1-C8)-alkyt optionally
substituted in the aryl radical or heteroaryl-(C1-C8)-alkyl optionally substituted in the
heteroaryl radical, very particularly preferably optionally substituted (C6-C14)-aryl-
(CrC4)-alkyl optionally substituted in the aryl radical or heteroaryl-(CrC4)~alkyl
optionally substituted in th-s heteroaryl radical, moreover preferably (C6-C14)-aryl-
(C1-C4)-alkyl optionally substituted in the aryl radical. It is specifically preferred if R°
is biphenylylmethyl, napht'iylmethyl or benzyl, each of which is unsubstituted or
mono- or polysubstituted i '\ the aryl radical.
R1 is preferably one of the; radicals -S(0)-N(R21)-R28, -S(0)2-N(R21)-R28f
~OC(0)~R2\ -0-C(0)-OR?2, -0-C(0)-N(R21)-R28, -0-C(S)-N(R21)-R28,
-0-S(0)2-N(R21)-R28, -0-:?(0)-N(R21)-R28,
-N(R29)-C(OK)R22( -N(R:,)-C(S)-R21,
-N(R28)-C(0)-N(R21)-R28, N(R28)-C(S)-N(R21)-R28,
-N(R28)-S(0)rR22( -N(R2f>S(0)-R22, -N(R28)-S(0)2-OR21, -N(R28)-S(0)-OR21,
-N(R28VS(0)2-N(R21)-R28,-N(R28)-S(0)-N(R21)-R28l
-C(S)-R21, -C(S)-N(R21)-R28 or cyano or the radical of an optionally substituted, 5-
io 14-membered, mono- c:t polycyclic, saturated or unsaturated heterocyclic ring of
Q1 is -C(R21)r, =C(R21)-, N(R28)-, -0- or -S-;
Q3 is -C(R21)2-, =C(R21)-, -N(R28)-, -0-, -S-, -C(R21)(-)- or -N(-)-,
where the heterocyclic rincj can be bonded to the group A via the free bond in the
groups -C(R21)(-)- or -N(-) ■ representing Q3 or via any other desired ring carbon
atom and where, if the heterocyclic ring is bonded to a ring system contained in the
group A, the heterocyclic ring can also be fused via two adjacent atoms to the ring
system in the group A
Particularly preferably, R1 s one of the radicals -0-C(0)-R21, -0-C(0)-OR22, -O-
C(0)-N(R21)-R28, -N(R29)-C(0)-OR22, -N(R28)-C(0)-N(R21)-R28,
-N(R28)-C(S)-N(R21)-R28 o' cyano.
R3 is preferably (C1-C8)-ai' R11 is preferably hydrogen, R12a, R12a-CO, H-CO, R12a-0-CO, R12b-CO, R12b-CS or R12a-S(0)2, particularly p aferably hydrogen, R12a, R12a-C0, R12a-0-C0, R12b-C0, R12b-CS or R12a-S(0)2, ir particular a radical from the group consisting of hydrogen, (CrC18)-alkyl, R12cC0, optionally substituted (C6-C14)-aryl-S(0)2, (CrC18)-alkyl-S(0)2, (C6-C14)-aryl-(C1-i;-8)-alkyl optionally substituted in the aryl radical, R9NHS(0)2 and R15, where RC is hydrogen, (CrC18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, optionally substi .ited (C6-C14)-aryl, (CrC18)-alkoxy, (C6-C14)-aryl-(C1-C8)-
alkoxy, which can also be ; jbstituted in the aryl radical, optionally substituted (C6-Cu)-aryIoxy, amino or moro- or di-((CrC18)~alkyl)-amino, the radical R15 or the radical R15-CK Ver/ particularly preferably, R11 is R12a, R12a-CO, R12a-0-CO, R12b-CO, R12b-CS or R12a-3(0)2, moreover particularly preferably for R12a, R12a-CO, R12a-0-CO, R12b-CO ,T R12a-S(0)2.
R12a is preferably (CrC10)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)--cycloalkyl, (C3~C12)-eycloai-alkyi optionally substituted .n the aryl radical, optionally substituted heteroaryl, heturoaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical or the ra:iical R15 R12b is preferably R12a-NK
R13 is preferably hydrogef. (C1-C6)-alkyl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or (C3-C8)-cycloalkyl, particularly preferably hydrogen or m particular (C1-C6)-alf* /I, (C3-C8)-cycloalkyl or benzyl, where a very particularly preferred alkyl radical representing R13 is the methyl radical. R15 is preferably R16-(Crr: 3)-alkyl or R16( particularly preferably R^C^-alkyl or R16. Moreover, when R3 \ He* is preferably the radical of a 5- to 10-membered, saturated monocyclic or polycyclic heterocycle bonded via a nitrogen atom, which can contain one or two identical or different addit onal ring heteroatoms from the group consisting of oxygen, nitrogen and sulkr and can optionally be substituted on carbon atoms and on ring nitrogen atoms, w 'ere there can be identical or different radicals R , R CO or RhO-CO as subsVituen's on additional ring nitrogen atoms. Particularly preferably, Het is a heterocycle of tht? type which contains no additional ring heteroatom or
which contains one additional ring heteroatom from the group consisting of nitrogen,
oxygen and sulfur, very particularly preferably Het is the radical of a 5-, 6- or 7-
membered, saturated monocyclic heterocycle bonded via a nitrogen atom, which
contains no additional ring heteroatom or which contains one additional ring
heteroatom from the group consisting of nitrogen, oxygen and sulfur, where in these
cases too the radical Het can be unsubstituted or can be substituted on carbon
atoms and/or on additiona' "ing nitrogen atoms
b, c and d preferably independently of one another are 1
e, g and h preferably independently of.one another are the numbers Q, 1, 2 or 3.
Preferred compounds of tho formula I are those in which, simultaneously
W is R1-A-C(R13) or R1-A-CH=C;
Y is a carbonyl, thiocarbc lyI or methylene group;
Z is N(R°), oxygen, sulfu' or a methylene group,
A is a bivalent radical fro'i the group consisting of (C1-C6)-alkylene, (C3-C12)-cycloalkylene, (C1-C6)-.alkylene-(C3-C12)-cycloalkyll phenylene, phenylene-(Cr C6)-alkyl, (C1-C6)-alkylenephenyl, (C1-C6)-alkylenephenyl-(C1-C6)-alkyll phenylene-(C2-C6)-alk.E nyl or a bivalent radical of a 5- or 6-membered saturated or unsaturated ring wh :h can contain 1 or 2 nitrogen atoms and can be mono-or disubstituted by (C1 -C6)-alkyl or doubly bonded oxygen or sulfur, or is a direct bond;
B is a bivalent radical frcm the group consisting of (C1-C6)-alkylene, (C2-C6)-alkenylene, phenylene phenylene-(CrC3)-alkyl, (C1-C3)-alkylene-phenyl;
D isC(R2)(R3), N(R3)orCH==C(R3);
E is tetrazolyl, (R80)2P(0), HOS(0)2, R9NHS(0)2 or R10CO;
R and R° independently d one another are hydrogen, (C1-C8)-alkyl,
(CrC12)-cycloalkyi, iC3-Cl2)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-ary!, (C6-C14)-aryi-(C1-C8)-alkyl optionally substituted in the aryl ^ddicai, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl jtionally substituted in the he;;eroaryl radical, where alkyl radicals can be mono- or polysubstituted by f.jorine;
R1 is one of the radicals -S-R21, -S-S-R21, ^S(0)-R22, -S(0)2-R22,
-S-OR21, -S(0)-ORM, -S(0)2-OR21, -S-N(R21)-R28, -S(0)-N(R21)-R28,
-S(0)2-N(R21)-R28, -I3-C(0)-R21, -S-C(0)-OR22, -S-C(S)-SR22, -S-C(0)-N(R21)-R28, -S-C(S)-N(R21)-R28, -0-C(0)-R21, -0-C(S)-R21, -0-C(0)-OR22, -0-C(0)-N(R21)-R28, -0-C(S)-N(R21)-R28, -0-S(0)2-OR21, -0-S,0)-OR21, -0-S(0)2-N(R21)-R28, -0-S(0)-N(R21)-R28, 0-S(0)2-R22, -0-S(0)-R22, -0-P(0)(OR21)2, -0-i:'(0)(OR21)-N(R21)-R28, -0-P(0)(N(R21)-R28)2, -N(R29)-C(0)-OR22, N(R28)-C(0)-SR22, -N(R28)-C(S)-OR22, -N(R28)-C(S)-SR22, -N(R28)-C(S)-R21, -N(R28)-C(0)-N(R21)-R28, -N(R28)-C(S)-N(R21)-R28, -N(R28)-S(0)2-R22, ~N(R28)-S(0)-R22, -N(R28)-S(0)2-OR21, -N(R28)-S(0)-OR21, -N(R28)-S(0)2-N(R21)-R28, -N(R28)-S(0)-N(R21)-R28, -N(R28)-P(0)(OR21):;, -N(R28)-P(0)(OR21)-N(R21)-R28, -N(R28)-P(0)(N(R21)-R28)2, -N(R28)-P(0)(R22)-OR21, -N(R28)-P(0)(R22)-N;R21)-R28, -N(R28)-P(0)(R22)2, -P(0)(OR21)2, -P(0);OR21)-N(R21)-R28, -P(0)(N(R21)-R28)2, -P(0)(R22)-OR21, -f-0)(R22)-N(R21)-R28, -P(0)(R22)2, -C(S)-R21, -C(S)-SR:!1, -C(S)-N(R21)-R28,
cyano, halogen, nitre or methylenedioxy or the radical of an optionally substituted, 5- to 14-rnembered, mono- or polycyclic, saturated or unsaturated heterocyclic ring of t" e formula
Q1 is -C(R21)r. =C(R21)-, -N(R28)-, -0- or -S-;
Q2 is-S(0)-or-S(OV;
Q3 is -C(R21)2~, =C(I;21)-, -N(R28)-, -0-, -S-, -C(R21)(-)- or -N(-)-,
where the heterocyc c ring can be bonded to the group A via the free bond in
the groups -C(R21)(■■'.- or -N(-)- representing Q3 or via any other desired ring
carbon atom and whare, if the heterocyclic ring is bonded to a ring system
contained in the grc .ip A, the heterocyclic ring can also be fused via two
adjacent atoms to th; ring system in the group A;
R2 is hydrogen, (C^CgJ-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or (C3-C8)-cycloalkyl;
R3 is hydrogen, (C1-C8)-:ilkyll optionally substituted (C6~C14)-aryl, (C6-Cl4)-aryl-(C1-C8)-alkyl optiona !y substituted in the aryl radical, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl, (C2-C8)-nlkyny|(.(C2-C8)-alkenylcarbonyl, (C2-C8)-alkynylcarbonyl, pyridyl, R11NH, R4CO, CQOR4, CON(CH3)R4, CONHR4, CSNHR4, COOR15, CON(CH3)R15orCCNIHR15;
R4 is hydrogen or {C1-C,8)-alkyl which can optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy!, hydroxycarbonyl, arr, nocarbonyl. mono- or di-((C1-C18)-alkyl)-aminocarbonyl, amino-(C2-C18)-alkyi:;minocarbonyl, amino-(C1-C3)-alkylphenyl-(C1-C3)-alkylaminocc'-bonyll (CrC18)-alkylcarbonylamino-(C1-C3)-alkylphenyl-(CrC3)-alkylaminocc!^bony|, (C1-C18)-alkylcarbonylamino-(C2-C18)-alkylaminocarbonyl, C6-C14j-aryl-(C1-C8)-alkoxycarbonyl which can also be substituted in tne aryl radical, amino, mercapto, (C^C^-alkoxy, (C^-C-^)-alkoxycarbonyl, optionally substituted (C3-C8)-cyclcalkyl, HOS(0)2-(C1-C3)-alkyl, R9NHS(0)2-(CrC3)-a|kyl, (R80)2P(0)-(CrC3)-alkyl, tetrazolyi-(CrC3)-alkyl, halogen, nitro, trifluoromethyl or the radical R5;
R5 is optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the ary. radical, a mono- or bicyclic 5- to 12-membered heterocyclic ring whi:;h can be aromatic, partially hydrogenated or completely hydrogenated and wMich can contain one, two or three identical or different heteroatoms from tt>: group consisting of nitrogen, oxygen and sulfur, a radical R6 or a radical R6CC-, where the aryl radical and, independently thereof, the heterocyclic radical can be mono- or polysubstituted by identical or different radicals from the gro.;p consisting of (C1-C18)'alkyl, (C1-C18)-alkoxy, halogen, nitro, amino or trifluo'omethyl;
R6 is R'R'-'N R70 or R7$ or an ammo acid side chain, a natural or unnatural amino
acid, mm acid, oplK^ally N^C^CgVaikylatedor N*((C6-Gu)-aryl-(C1-C8)-
alkylated) azaamino acid or a dipeptide radical which can also be substituted in the aryl radical and/c in which the peptide bond can be reduced to -NH-CH2-, and their esters and amides, where hydrogen or hydroxymethyl can optionally stand in place of of fr-:;e functional groups and/or where free functional groups
can be protected by pr ;tective groups customary in peptide chemistry; R7 is hydrogen, (CrC18)-nlkyl, (C6-C14)-aryl-(C1-C8)-alkyl, (CrC18)-alkylcarbonylF (CrC18)-alkoxycarbon,l, (C6-C14)-arylcarbonyl, (C6~C14)-aryl-(C1-C8)-alkylcarbonyl or (C6-C 4)-aryl-(C1-C18)-alkyloxycarbonyI, where the alkyl groups can optionally be subs', tuted by an amino group and/or where the aryl radicals can be mono- or polys.bstituted, preferably monosubstituted, by identical or different radicals from :.ne group consisting of (C1-C8)-alkyl, (C1-C8)-alkoxy, hglogen, nitro, amino and trifluoromethyl, or is a natural or unnatural amino acid, imino acid, optionally N-(C1-C8)-alkylated or N-((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid or a dipeptide radical which can also be substituted in the aryl radical and/or in which the peptide bond can be reduced to -NH-CH2~; R8 is hydrogen, (CrC18)':ilky|, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-
(C1-C8)-alkyl which can also be substituted in the aryl radical; R9 is hydrogen, aminocaroonyl, (CrC18)-alkylaminocarbonyl, (C3-C8)-
cycloalkylaminocarborvl, optionally substituted (C6-C14)-arylaminocarbonyl, (CrC18)-alkyi, optionally substituted (C6-C14)-aryl or (C3-C8)-cycloalkyl; R10 is hydroxyl, (CrC18)-aikoxy, (Cg-C^-aryl-^-C^-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6~C14)-aryloxy, amino or mono- or di-((CrC18)alkyl)amino; R11 is hydrogen, (CrC18)-3lky|, R12CO, optionally substituted (C6-C14)-aryl-S(0)2, (CrC18)-alkyl-S(0)2, ;C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, R9NHS(G)2 or the radical R15; R12 is hydrogen, (Cl-C18)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, optionally
substituted (C6-C14)-e the aryl radical or (C:i-C8)-cycloalkyl; R15 :sR16-(C1-C6)-alkylcr R16;
R]0 is a 6- to 24-member<:d bicyclic or tricyclic radical which is saturated partially unsaturated and can also contain one to four identical different heteroatoms from the group consisting of nitrogen oxygen sulfur>
can also be substitute:! by one or more identical or different substituents from the group consisting c (C1-C4)-alkyl and oxo;
R21 is hydrogen, (C1-C8)-alkylJ hydroxy-(C1-C8)-alkylt (C2-C8)-alkeny1, (C3-C12)-cycloalkyl, (C3-C12)-cM;loalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6'C^4)-ary\-{C^ -38)-alkyl optionally substituted in the aryl radical, optionally substituted l-eteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the hete'oaryl radical, where alkyl radicals can also be monosubstituted or pclysubstituted by fluorine and the radicals R21 can be identical or different if they occur two or more times;
R22 is(C1-C8)-alkyl, hydro>:y-(C1-C8)-a|kyl, (C2-C8)-alkenyl, (C3-C12)'Cycloalkyl[ (C3-C12)-cycloalkyl-(C--C8)-alky|, optionally substituted (C6-C14)-aryl, (C6-C14)-;;ary|V(C1-C8)-a)kyl optionally substituted in the aryl radical, optionally substituted Ineteroaryl or heteroaryl-tCj-C^-alkyl optionally substituted in the heteroaryl radical, where alky! radicals can be monosubstituted or polysubstituted by fluorine and the radicals R22 can be identical or different if they occur two or more times;
R28 is one of the radicals :!21-, R21N(R21h R21C(0)-, R22O-C(0)-, R21N(R21)-C(0)-orR21N(R21)-C(^N(Fi'M))-,
R29 is one of the radicals :l22-, R21N(R21)-, R21C(Oh R220-C(0)-, R21N(R21)-C(0)-orR21N(R21)-C(=N(F:'1))-;
b, c, d and f independently of one another are 0 or 1, but cannot all simultaneously
beO;
e, g and h independently in all their stereoisomer^ -'orms and mixtures thereof in any ratio, and their
physiologically tolerable s*ilts,
where, if simultaneously W is 4-cyanophenyl-C(R13), Y is a carbonyl group, Z is
NR0a, B is an unsubstitute d methylene group, R is Ra, b, c and d are' 1 and e, f and
g are 0 then D cannot be 0(R2a)(R3a), where
H d, Ra and R indopenointly of one another are hydrogen, (C1-C8)-alkyl, optionally substitutes (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the ary: radical or (C3-C8)-oycloalkyl and
R3a is hydrogen, (C1-C8) alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, (C3-C8)-cycloalkyl or 2-,
3- or 4-pyridyl,
Particularly preferred compounds of the formula I are those in which simultaneously
W is R1-A-CH"C and therein A is a phenylene radical or a methylenephenyl radical,
or W is R1-A-C(R13) and therein A is a bivalent radical from the group consisting of
methylene, ethylene, trime:hylene, tetramethylene, pentamethylene, cyclohexylene,
phenylene, phenylenemet'iyl, methylenephenyl, methylenephenylmethyl;
B is a bivalent radical from the group consisting of methylene, ethylene,
trimethylene, tetramethylere, vinylene, phenylene, or substitued methylene or
EisR10CO,
R is hydrogen, (C^CgJ-alkyl or benzyl;
R° is (C1-C8)-alkyl, (C3-C8;-cycloalkyl, optionally substituted (C6-C14)-aryl or (C6-
C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical;
R1 is preferably one of the radicals -S(0)-N(R21)-R28, -S(0)2-N(R21)-R28,
-0-C(0)-R21,-0-C(0)-OR'>2, -0-C(0)-N(R21)-R28,-0-C(S)-N(R21)-R28,
-0-S(0)2-N(R21)-R28, -0-i:(0)-N(R21)-R28,
-N(R29)-C(0)-OR22, -N(R';j)-C(S)-R21,
-N(R2B)-C(0)-N(R21 )-R28 N(R28)-C(S)-N(R21 )-R28,
-N(R28)-S(0)2-R22, -N(R2B)-S(0)-R22, -N(R28)-S(0)2-OR21, -N(R28)-S(0)-OR21,
-N(R28)-S(0)2-N(R21)-R2{!,-N(R28)-S(0)-N(R21)-R26,
-C(S)-R21, -C(S)-N(R21)-f;.28 or cyano or the radical of an optionally substituted, 5-
to 14-membered, mono- c; polycyclic, saturated or unsaturated heterocyclic ring of
Q1 is -C(R21)2- =C(R21)-: -N(R28)-; -0- or -S-; Q2 is -S(0)-or-S(0)2-,
Q3 is -C(R21)2-, =C(R21)- -N(R28)-, -0-, -S-, -C(R21)(-)- or -N(-)-,
where the heterocyclic ring can be bonded to the group A via the free bond in the
groups -C(R21)(-)- or -N(-)- representing Q3 or via any other desired ring carbon
atom and where, if the heterocyclic ring ig bonded to a ring system contained in the
system in the group A;
R2 is hydrogen or (C1-C8)-8lky|;
R3 is (C1-C8)-alky|, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl,
(Cs-CeJ-cycloalky!, (C2-C8)-alkenyl, (C2-C8)-alkynyl, pyridyl, R11NH, R4CO, COCR4,
CONHR4, CSNHR4, COOR15 and GONHR15;	a
in all tfieir stereoisomer^ forms and mxtures thereof in any ratio, and their
physiologically tolerable st ts.
Very particularly preferred compounds of the formula I are those in which W is R1-A-C(R13) and R13 is (C1-C6)-alky|, (C6»C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical or (C3-C8)-cycloalkyl;
in all their stereoisomer^ forms and mixtures thereof in any ratio, and their physiologically tolerable saits.
A series of specifically preferred compounds of the formula I are those in which R3 is optionally substituted (CrC14)-aryl, COOR4, R11NH or CONHR14, where -NHR14 is the radical of an a-aminci acid, its (i)-amino-(C2-C8)-alkylamide, its (C^C^-alkyl ester, its (Cs-C^-aryl-^ C4)-alkyl ester, or its derivative in which the carboxylic acid group is converted into the group Het-CO, in all their stereoisomer^ forms and mixtures thereof in any ratio, and their physiologically tolerable salts. The radical of an cc-amino acid -NHR14 i« formally obtained by abstraction of a hydrogen atom from the amino group of the amino acid, It is specifically preferred in this series if R3 is CONHR4, where -NHR4 is the radical of the a-amino acids valine, lysine, phenylglycine, phenylalan ne or tryptophan or their (Cj-C^-alkyl esters, (C6-C14)-aryl-(CrC4)-alkyl esters o Moreover preferred compounds of the formula I in this series are those in which
WisR1-A-C(R13);
Z isN(R°);
A is ethylene, trimethylene tetramethylene, pentamethylene, cyclohe^ylene,
phenylene, phenylenemethyl, methylenephenyl c.r methylenephenylmethyl;
EisR10CO;
R° is (C1-C8)-alkyl, (C3-Ct)-cycloalkyl, optionally substituted (C6-C14)-aryl or (C6-
C^-aryKCj-CgJ-alkyl opt onally substituted in the aryl radical;
R1 is one of the radicals -0-C(0)-R21, -0-C(0)-OR22 , -0-C(0)-N(R21)-R28,
-N(R29)-C(0)-OR22, -N(R2i)-C(0)-N(R21)-R28, -N(R28)-C(S)-N(R21)-R28 or cyano;
R4 is methyl which is subs: tuted by hydroxycarbonyl and a radical from the group
consisting of (CrC4)-alkyl phenyl and benzyl, or is methyl which is substituted by
(Cj-CgJ-alkoxycarbonyl, pteferably (CrC4)-alkoxycarbonyl, and a radical from the
group consisting of (CrC4'-alkyl, phenyl and benzyl, or is methyl which is
substituted by Het-CO and a radical from the group consisting of (C1-C4)-alkyl,
phenyl and benzyl;
R10 is hydroxyl or (C1-C8)alkoxy, preferably (CrC4)-alkoxy;
R13 is (C1-C6)-alkyl, (C3-Cr)-cycloalkyl or benzyl, in particular methyl;
b, c and d are 1 and e, f at'.d g are 0;
in all their stereoisomer'^ "brms and mixtures thereof in any ratio, and their
If -NHR4 is a (C1-C8)-alkyi ester of an a-amino acid or R4 contains an alkoxycarbonyl radical, the methyl, ethyl, isopropyl, isobutyl or tert-butyl ester is preferred, if -NHR4 is a (Crs-C14)-aryr-(C1-C4)-alkyl ester of an a-amino acid, the benzyl ester is preferred.
A further series of specific-ally preferred compounds of the formula I are those
compounds in which simultaneously
W is R1-A-CH=Q and therein A is a phenylene radical or a methylenephenyl radical,
methylene, ethylene, trime'hylene, tetramethylene, pentamethylene, cyclohexylene,
phenylene, pheriylenemeth/j, methylenephenyl, methylenephenylmethyl;
B is a bivalent radical from he group consisting of methylene, ethylene,
trimethylene, tetramethylena, vinylene, phenylene or substituted methylene or
EisR10CO;	9	:
R is hydrogen or (C^CgJ-aikyl;
R° js (C1-C8)-alkyl, (C3-C *)-cycloalkyl, optionally substituted (C6-C14)-aryl or (C6-
cu)*a'7|-(Ci-C8)-alkyroptionally substituted in the aryl radical;
R1 is preferably one of the -adicais -S(0)-N(R21)-R28, -S(0)rN(R21)-R28,
-0-C(0)-R21, -0-C'(0)-ORa2, -0-C(0)-N(R21)-R28, -0-C(S)-N(R21)-R28,
-0-S(0)2-N(R21 )-R28 -0-S{0)-N(R21 )-R28,
-N(R29)-C(0)-OR22, -N(R2ti)-C(S)-R21,
-N(R28)-C(0)-N(R21)-R28, • N(R28)-C(S)-N(R21)-R28,
-NfRfj-SCO^-R22, -N(R2! -S(0)-R22 -N(R28)-S(0)2-OR21, -N(R28)-S(0)-OR21,
~N(R28j-S(0)2-N(R21 )-R28, -N(R28)-S(0)-N(R21 )-R28,
-C(S)-R21, -C(S)-N(R21)-R -8 or cyano or the radical of an optionally substituted, 5-
tq "14-membered, mono- cr polycyclic, saturated or unsaturated heterocyclic ring of
Q1 is -C(R21 )2-, =C(R21)- -N(R28)-, -0- or -S-;
Q2 is -S(0)- or -S(0)2-;
where the heterocyclic rinj can be bonded to the group A via the free bond in the
groups -C(R21)(-)- or -N(-;- representing Q3 or via any other desired ring carbon
group A, the heterpcyclic» ig can also be fused via two adjacent atoms to the ring
systemin the group A;
R2 is hydrogen or (C1-C8)-n|kyl;
R3 is CONHR15 or CONHH* where R4 herein is a (C1-C8)-alkyl radical which is
unsubstituted or substitutetj by one or more (C6-C14)-aryl radicals;
R15 js R16.(C1-C6)-alkyl o- B16, where R16 is a 7- to 12-membered bridged bicyclic
or tricyclic radical which is saturated or partially unsaturated and which can also
contain one to four identical or different heteroatoms from the group consisting of
nitrogen, oxygen and sulfiK and which can also be substituted by one or more
identical or different substituents from the group consisting of (C1-C4)-alkyl and oxo,
and in particular R15 is an adamantyl radical or an adamantylmethyl radical;
and e, g and h independently of one another are the numbers 0,1, 2 or 3 and b, c
and d are 1;
in all their stereoisomeric loans and mixtures thereof in any ratio, and their
physiologically tolerable salts;	Moreover preferred compounds of the formula I in this series are those in which simultaneously, Wis R1-A-C(R13); Y is a carbony) group;
ZisN(R°);
A is ethylene, trimethylerw, tetramethylene, pentamethylene, cyclohexylene,
phenylene, phenylenemefhyl, methylenephenyl or methylenephenylmethyl;
B js an unsubstituted or substituted methylene radical;
R is hydrogen or (C1-C4>alkyl, in particular hydrogen, methyl or ethyl;
R° is (C1-C8)-alkyl, (C3-C8)-cycloalkyl, optionally substituted (C6-C14)-aryl or (C6-
R1 is one of the radicals 0-C(0)-R21, -0-C(0)-OR22 , -0-C(0)-N(R21)-R28,
-N(R29)-C(0)-OR22, -N(R28)-C(0)-N(R21)-R28, -N(R28)-C(S)-N(R21)-R28 or cyano;
R3 is CONHR15 or CONI-iR4 where R4 herein is a (C1-C6)-alkyl radical which is
unsubstltuted or substitute!! by one or more (C6-C10)-aryl radicals;
R10 is hydroxyl or (C1-C8)-;;lkoxy, preferably (CrC4)-alkoxy;
R13 is (C1-C6)-alkyl, (C3-C:)-cycloalkyl or benzyl, in particular methyl;
R15 is an adamantyf radical or an adamantylmethyl radical;
b, c and d are 1 and e, f ard g are 0;
in all tfieir stereoisomeric f; rms and mixtures thereof in any ratio, and their
Furthermore, a series of specifically preferred compounds of the formula I are those
in which simultaneously
A is ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexylene,
phenylene, phenylenemetlyl, fnethylenephenyl, methylenephenylmethyl;
B is an unsubstituted or suos'tituted methylene radical or ethylene radical;
R° is (C1-C8)-alkyl, (C3-C; i-cycloalkyl, optionally substituted (C6-C14)-aryl or (C6-
C14)-aryl-(C1-C8)-alkyl whish is optionally substituted in the aryl radical;
-0-C(0)-R21, -0-C(0)-OFI:!2, -0-C(0)-N(R21)-R28, -0-C(S)-N(R21)-R28,
-0-S(0)2-N(R21)-R28, -0-:-.(0)-N(R21)-R28,
-N(R29)-C(0)-OR22,-N(R;:3)-C(S)-R21,
-N(R28)-C(0)-N(R21)-R28 -N(R28)-C(S)-N(R21)-R28,
-N(R28)-S(0)2-R22, -N(R21)-S(0)-R22, -N(R28)-SfO)2-OR21, -N(R28)-S(0)-OR21,
-N(R28)-S(0)2-N(R21 )-R2i, -N(R28)-S(0)-N(R21 )-R28,
-C(S)-R21, -C(S)-N(R21)-F!28 or cyano or the radical of an optionally substituted, 5-
to 14-membered, mono- c' polycyclic, saturated or unsaturated heterocyclic ring of
Q1 is -C(R21)2-f -C(R21)-, -N(R28)-, -0- or -S-;
Q3 is -C(R21)2-t =C(R21)-, N(R28)-, -0-, -S-, -C(R21)(-)- or -N(-)-,
where the heterocyclic rinc; can be ponded to the group A via the free bond in the
groups -C(R21)(-)- or -N(-)' representing Q3 or via any other desired ring carbon
group A, the heterocyclic nng can also be fused via two adjacent atoms to the ring
system in the group A;	®
R3 is an unsubstituted phenyl radical or naphthyl radical, a phenyl radical or
naphthyl radical substitute: by one, two or three identical or different radicals from
the group consisting of (Ct -C4)-alkyl, (CrC4)-alkoxy, hydroxyl, halogen,
trifluoromethyl, nitro, methylenedioxy, ethylenedioxy, hydroxycarbonyl, (C^C^-
alkoxycarbonyl, aminocart onyl, cyano, phenyl, phenoxy and benzyloxy, a pyridyl
radical, a (C,-C4)-alkyl rancal, a (C2-C4)-alkenyl radical, a (C2-C4)-alkynyl radical or
a (C5-C6)-cycloalkyl radio , and in particular R3 is an unsubstituted or substituted
phenyl radical or naphthyl radical;
R*° is hydroxyl or (C1-C8) -alkoxy, in particular ((^-C^-alkoxy, and preferably R10 is
a radical from the group consisting of hydroxyl, methoxy, ethoxy, propoxy and
isoprbpoxy;
R13 is (C1-C6)-alkyl, (C3-C:/)-cycloalkyl or benzyl, in particular methyl;
in all their stereoisomer^ 1'orms and mixtures thereof in any ratio, and their
physiologically tolerable sr^lts.
Finally, a series of specifically preferred compounds of the formula I are those compounds in which simL'.aneously
WisR'-A-C(R1J);
Z is N(R°);
A is ethylene, trimethylene tetramethylene, pentamethylene, cyclohexylene,
phenylene, phenylenemethyj, methylenephenyl, methylenephenylmethyl;
B is an unsubstituted or substitute^ methylene radical or ethylene radical;
D Is C(R2)(R3); '
R is hydrogen or (C1-C4)-alky|l in particular hydrogen, methyl or ethyl;
R° is (C1-C8)-alkyl, ^-Cgi-cycloalkyl, optionally substituted (C6-C14)-aryl or (C6-
C14)-aryI-(C1-C8)-alkyl optionally substituted in the aryl radical;
-Q-C(0)-R21, -O-C(O)-0R:i2, -6-C(0)-N(R21 )-R28, -0-C(S)-N(R21 )-R28,
-0-S(0)2-N(R21 )-R28, -Q-S(0)-N(R21 )-R28,
~N(R29)-C(0)-OR22, -N(R^)-C(S)-R21,
-N(R28)-S(0)2-R22, -N(R28)~S(0)-R22, -N(R28)-S(0)2-OR21, -N(R28)-S(0)-OR21,
-N(R28)-S(0)2-N(R21 )-R28, -N(R28)-S(Q)-N(R21 )-R28,
-C(S)-R21, -C(S)-N(R21)-R18 or cyano or the radical of an optionally substituted, 5-
to 14-membered, mono- or polycyclic, saturated or unsaturated heterocyclic ring of
Q1 is -C(R21)2-, =C(R21)-, -N(R2£)-, -0- or -S-;
Q3 is -C(R21)2-, =C(R21)-, .N(R28)-, -0-, -S-, -C(R21)(-)- or -N(-)-,
where the heterocyclic rin;.j can be bonded to the group A via the free bond in the
groups -C(R21)(-)- or -N(-}- representing Q3 or via any other desired ring carbon
group A, the heterocyclic r ng can also be fused via two adjacent atoms to the ring
R3isR11NH;
R10 is hydroxyl or (C1-C8)-alkoxyl in particular (CrC4)~alkoxy, and preferably R10 is
isopropoxy;
R13 is (C-pC^-alkyl, (C3-G7)-cycloalkyl or benzyl, in particular methyl;
b, ct d and e are 1 and f'ard g are 0;
in all their stereoisomer^ forms and mixtures thereof in any ratio, and their
physiologically tolerable s hits.
In this series, moreover preferred compounds of the formula I are those in which R11 is R12a, R12a-CO, R12a-0-CO, R12b-CO, R12b-CS or R12a-S(0)2, in particular R12a, R12a-CO, R12a-0-CO, R12b-CO or R12a-S(0)2;
R12a is (CrC10)-alkyl, (C1-C8)-alkenyl, (C2-C8)-alkynyl, (C3-C12)-cycloalkyl, (Cr C12)-cycloalkyl-(C1-C8)-a!kyl, optionally substituted (C6-C14)-aryl, (Ce-C14)-aryl-(Cr C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-^-C^-alkyl optionally substituted in the heteroaryl radical or the radical
R12b js R12a.NH;
in all their stereoisomers Very specifically preferred compounds of the formula I are those in which a substituted methylene radical or substituted ethylene radical representing the group B carries as a substituen? a radical from the group consisting of (Cj-C^-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkyryl, (C3-C8)-cycloalkyl, in particular (C5-C6)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-all
preferred compounds of tha formula I are those in which B is an unsubstituted methylene radical or a methylene radical which is substituted by a (C|-C8)-alkyl radical, in particular by a (Cj-C^-alkyl radical, in all their stereoisomer^ forms and mixtures thereof in any ratio, and their physiologically tolerable salts.
Generally, compounds of the formula I are preferred which have a uniform
configuration at chiral centers, e.g. at the chiral carbon atom representing D and at the center W in the 5-membered ring heterocycle in the formula I.
The compounds of the formula I can be prepared, for example, by fragment condensation of a compound of the formula II
with a compound of the formula III,
where W, Y, Z, B, D, E, R and b, d, e, f, g, and h are defined as indicated above and G is hydroxycarbonyl, (C1-C6)-alkoxycarbonyl, activated carboxylic acid derivatives, such as acid chlorides or active esters, or isocyanato.
For the condensation of the compounds of the formula II with those of the formula III, the coupling methods of peptide chemistry known per se (see, for example, Houben-Weyl, Methoden der Org-mischen Chemie, [Methods of organic chemistry], Volume 15/1 and 15/2, Georg Th-sme Verlag, Stuttgart, 1974) are advantageously used. To
do this, as a rule it is necessary that nonreacting amino groups present are protected by reversible proactive groups during the condensation. The same applies to carboxyl groups not participating in the reaction, which are preferably present as (C1-C6)-alkyl, b-rizyl or tert-butyl esters. Amino group protection is unnecessary if the amino groups to be generated are still present as nitro or cyano groups and are formed, for gxample, by hydrogenation only after the coupling. After the coupling, the protective! groups present are removed in a suitable manner. For example, N02 groups (guanjdino protection), benzyloxycarbonyl groups and benzyl esters can be removed by 'lydro^enation. The protective groups of the tert-butyl type are removed under acicjic conditions, while the 9-fluorenylmethyloxycarbonyl radical is removed by secondary amines.
Compounds of the formula I (in which W is R1-A-C(R13), Y is a carbonyl group and Z is NR° can be prepared, fo* example, by first reacting compounds of the formula IV
in a Bucherer reaction to (jive compounds of the formula V,
in which just as in the formula IV R1, R13 and A are defined as indicated above (H. T. Bucherer, V. A. Lieb, J. Prakt. Chem. 141(1934), 5). Compounds of the formula V),
in which R1, R13, A, B and G are defined as indicated above can then be obtained by fjr$t reacting the compounds of the formula V, for example, with an alkylating reagent which introduces tf e radical -B-G into the molecule. The reaction of compounds of the formula */l with a second reagent of the formula R°-LG, in which R° has the meanings indicated above and LG is a nucleophilically substitutable leaving group, for example* nalogen, in particular chlorine or bromine, (C^-C^)-alkoxy, optionally substituted phenoxy or a heterocyclic leaving group such as, for example, imjdazoiyl, leads :p the corresponding compounds of the formula II. These reactions can be carried out analogously to known methods familiar to the person skilled in the art. Depending on the individual case, it may be appropriate here, as in all steps in the synthesis cf the compounds of the formula I, temporarily to block functional groups which could lead to side reactions or undesired reactions by means of a protective groin strategy adapted to the synthesis problem, what is known to the person skilled in the art.
If W is R1-A~CH=C, this stiuctural element can be introduced, for example, by
* condensing an aldehyde with a 5-membered ring heterocycle which contains a
methylene group in the position corresponding to the group W analogously to known methods.
Compounds of the formula | in which the 5-membered ring heterocycle is a dioxo- or thioxo-oxo-substituted imitJazolidine ring in which W is R1-A-C(R13) can also be obtained as follows:
by reaction of a-amino acids or N-substituted a-amino acids or preferably their esters, for example the methyl, ethyl, tert-butyl or benzyl esters, for example of a compound of the formula VII,
to the compounds of the fo*jiula |a 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
During the cyclization, gua^idino groups can be blocked by protective groups, for example N02- Afrnino groups in the side chain can be present in protected form or still as an N02 or cyano function whicfi can later be reduced to the amino group or, in the case of the cyano group, also be converted into the formamidino group.
Compounds of the formula i in which the 5-membered ring heterocycle is a dioxo- or thioxo-oxo-substituted imioazolidine ring in which W is R1-A-C(R13) and c is 1 can also be obtained by reacting a compound of the formula VII with an isocyanate or isothiocyanate of the formula X
in which B, AJ and b are defined as indicated above for the formula VIII and L is an alkoxy group, for example a (C1-C4)-alkoxygroup such as methoxy, ethoxy or tert-butoxy, a (C6-C14)-aryloxy group, for example phenoxy, or a (C6-C14)-aryl-(CrC4)-alkoxy group, for example henzyloxy. In this case, a compound of the formula XI
is obtained in which A, B, 7, L, R°, R1, R13 and b are defined as indicated above for the formulae IX and X, which is then cyclized under the influence of an acid or of a base, such as described &oove for the cyclization of the compounds of the formula
IX, to a compound of the fcrmula XII
in which B, L, V, W, R° and b are defined as indicated above for the formulae la and X From the compound of tcte formula XII, a compound of the formula la is then obtained by hydrolysis of the group CO-l to give the carboxylic acid COOH and subsequent coupling with n compound of the formula III, as described above for the coupling of the compound!! of the formulae Hand III. Here too, during the cyclization functional groups can be present in protected form or in the form of precursors, for example guanidino groups; are blocked by N02 or amino groups are present in protected form or still as ar. N02 or cyano function which can later be reduced to the amino group or, in the cas* of the cyano group, also be converted into the formamidino group.
A further method for the pioparation of compounds of the formula la is, for example, the reactionof compounds of the formula XIII,
in which W is R1-A-C(R13 and for which otherwise the definitions indicated above apply, with phosgene, thic: phosgene or corresponding equivalents (analogously to S. Goldschmidt and M. W ok, Liebigs Ann. Chem. 575 (1952), 217-231 and C. Tropp, Chem. Ber. 61 (15:8), 1431-1439).
A conversion of an amino iunction into a guanidino function can be carried out using the following reagents:
1.	O-Methylisourea (S. Wsiss and H- Krommer, Chemiker Zeitung 98 (1974), 617-618)
2.	S-Methylisothiourea (F!f. Borne, M.L. Forrester and I.W, Waters, J. Med. Chem. 20 (1977), 77 3.	Nitro-S-methylisothiou-sa (L.S. Hafner and R.E. Evans, J. Org. Chem. 24 (1959) 57)
4.	Formamidinosulfonic &;id (K. Kim, Y.-T. Lin and H.S. Mosher, Tetrah. Lett. 29 (1988), 3183-3186)
5.	3,5-Dimethyl-1-pyrazcHy|formamidinium nitrate (F.L. Scott, D.G. O'Donovan and J. Reil'ly, J. Amer. Chem. !i;oc. 75 (1953), 4053-4054)
6.	N.N'-Di-tert-butyloxycf-i'bonyl-S-methylisothiourea (R. J. Bergeron and J. S. McManis, J. Org. Chem. 5;: (1987), 1700-1703)
7.	N-Alkoxycarbonyl-, N, T-dialkoxycarbonyl-, N-alkylcarbonyl-and N.N'-dialkylcarbonyl-S-mehylisothiourea (H. Wollweber, H. Killing, E. Niemers, A. Widdig, P. Andrews, H.-P. Schulz and H. Thomas, Arzneim. Forsch./Drug Res. 34 (1984), 531-542).
With respect to the preparation of the compounds of the formula I, the details on the synthesis of the molacula,' structure which are contained in the following documents are fully incorporated by r -ference: WO-A-95/14008, German Patent Application 19515177.1 and WO-A-9 For the preparation of cor'pounds of the formula I in which R1 is -S-R21, the starting materials used can be the corresponding compounds of the formula IV in which R1 is -S-R21. If compounds o: the formula IV in which R^ is a protected SH group are employed in the Bucherer reaction, compounds of the formula I in which R1 is -SH are obtained after the rerr oval of the protective group. These compounds can in turn
be converted into compounds of the formula I in which R1 is -S-R21 (with meanings of R21 other than hydroge-i) by introduction of the radical R21, or alternatively serve as intermediates for the preparation of other compounds of the formula I in which the atom bonded to the group A of the radical R*1 is a sulfur atom.
Compounds of the formuls | in which R1 is -S(0)2-R21 can be prepared, for example, by oxidizing compounds o- the formula I in which R1 is -S-R21 to the sulfones according to methods kno^n from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie [MeHods of Organic Chemistry], Vol. E12/2, Georg Thieme Verlag, Stuttgart 1985, p. 1058 ff.), i.e. to the compounds of the formula I in which R1 is -S(0)2-R2i. Correspondingly, compounds of the formula I in which R1 is -S-R21 can be oxidized to the sulfoxides under suitable reaction conditions familiar to the person skilled in the art according to methods known per se (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1, Georg Thieme Verlag, Stuttgart 1985, p. 702 ff.), i.e. to thi- compounds of the formula I in which R1 is -S(0)-R21. If necessary, in the oxidations to the sulfoxides or to the sulfones, oxidation-sensitive groups in the molecule am protected by suitable protective groups before carrying out the oxidation.
Compounds of the formuUi I in which R1 is -S(0)2-OR21 or -S(0)2-N(R21)-R28 can be prepared, for example, by oxidizing compounds of the formula I in which R1 is -SH according to methods known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol E12/2, Georg Thieme Verlag, Stuttgart 1985, p. 1058 ff.) for the preparation of sulfonic acid derivatives to compounds of the formula I in which R1 is -S(0)2-OH. The compounds of the formula I in which R1 is -S(0)2-OR21 or -S(0)2-N(R21)-R28 can then be obtained from these sulfonic acids directly or via corresponding sulfonyl halides by esterification or linkage of an amide bond.
Compounds of the formula I in which R1 is -S(0)-OR21 or -S(0)-N(R21)-R28 can be prepared, for example, by converting compounds of the formula I in which R1 is -SH into the corresponding si *ides, i.e. into the salts in which R1 is -S* and the counterion is, for example, an alkali metal ion or an alkaline earth metal ion, and then oxidizing these salts for example using meta-chloroperbenzoic acid, to the
sulfinic acids, i.e. to the co ipdunds of the formula I in which R1 is -S(0)-OH (cf. Houben-Weyl, Methoden c jr Organischen Chemie, Vol. E11/1, Georg Thieme Verlag, Stuttgart 1985, p. fc |8 ff.). The corresponding sulfinic acid esters and sulfinamides, i.e. the compounds of the formula I in which R1 is -S(0)-OR21 or -S(0)-N(R21)-R28, can be p'eparecj from the sulfinic acids by methods5 known per se.
If necessary, also in the preparation of sulfonic acid derivatives and sulfinic acid derivatives by oxidation, oxidation-sensitive groups in the molecule are protected by suitable protective groups :efore carrying out the oxidation.
Apart from the methods rrhntioned, for the preparation of the compounds of the formula I in which R1 is -S!0)-R22 -S(0)rR22, -S(0)-OR21, -S(0)2-OR21, -S(O)-N(R21)-R28 or -S(0)2-N(R2' )-R28 other processes described in the literature for preparing such types of compounds can generally also be used (cf. Houben-Weyl, Methoden der Organische■• Chemie, Georg Thieme Verlag, Stuttgart, Vol. E11/1, 1985, p. 618 ff. or Vol. E1' 2, 1985, p. 1055 ff.).
Compounds of the formula I in which R1 is further sulfur-containing groups, for example -N(R28)-C(S)-OR!2, -N(R28)-C(S)-SR22, -N(R28)-C(S)-R21, -N(R28)-S(0)2-R22, -N(R28)-S(0)-R22, -N(R28)-S(0)2-OR21, -N(R28)-S(0)-OR21, -N(Ri: • )-S(0)2-N(R21 )-R28, -N(R28)-S(0)-N(R21 )-R28, -0-C(S)-N(R21)-R28, -0-SiO)2-OR21, -0-S(0)-OR21, -0-S(0)2-N(R21)-R28, -0-!»(0)-N(R21)-R28, -0-S(0)2-R22, -O-SfOJ-R22, -C(S)-R21, -C(S)-N(R21)-I!28, can be synthesized from suitable precursors by methods known per se am described in the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1 and E11/2, Georg Thieme Verlag, Stuttgart 1985), the adaptation of tr 3 selected synthesis method to the particular target molecule presenting no problems to the person skilled in the art. This also applies to further methods for the preparation of compounds of the formula I in which R1 is -S-
The latter also applies to the preparation of the compounds of the formula I in which R1 is one of the phosphor. s-containing radicals mentioned in the definition of R , for
example a phosphonic acid derivative or a phosphoric acid derivative. These compounds can be synthesized analogously to methods known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E1 and E2, Georg Thieme Verlag, Stuttgart 1082) for the preparation of such compounds from suitable precursors.
Compounds of the formula I in which R1 is -N(R28)-C(0)-NH-R28 can be prepared, for example, by reacting thu corresponding compounds of the formula I in which R1 is -NH-R28 with isocyanateu of the formula 0=C=N-R28 according to methods known from the literature (cf. Hot ;en-Wey|, Methoden der Organischen Chemie, Vol. VIII, Georg Thieme Verlag, Stu.gart 1952, p. 132). Analogously, compounds of the formula I in which R1 is -N Compounds of the formula I in which R1 is -N(R29)-C(0)-OR22 can be prepared, for example, by reacting compounds of the formula I in which R1 is -NHR29 with chlorocarbonic acid ester:; of the formula CI-C(0)-OR22 according to methods known from the literature [rf. Houben-Weyl, Methoden der Organischen Chemie, Vol. VIII, Georg Thieme Vnrlag, Stuttgart 1952, p. 138). Generally, other methods known from the literature :;an also be used for the preparation of compounds of the formula I in which R1 is -N{R29)-C(0)-OR22 (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. VIII, Georg Thieme Verlag, Stuttgart 1952). Compounds of the formula I in which R' is -N(R28)-C(0)-SR22 can be prepared analogously.
Compounds of the formula I in which R1 is -0-C(0)-NH-R28 can be prepared, for example, by reacting compounds of the formula I in which R1 is -OH with isocyanates of the formula 0=C=N-R28 according to methods known from the literature (cf. Houben-Wew|, Methoden der Organischen Chemie, Vol. VIII, Georg
example a phosphonic aciii derivative or a phosphoric acid derivative. These compounds can be synthe sized analogously to methods known from the literature (cf. Houben-Weyl, Methoc&n der Organischen Chemie, Vol. E1 and E2, Georg Thieme Verlag, Stuttgart 1 -82) for the preparation of such compounds from suitable precursors.
Compounds of the formula 1 in which.R1 is -N(R28)-C(0)-NH-R28 can be prepared, for example, by reacting thu corresponding compounds of the formula I in which R1 is -NH-R28 with isocyanate:; of the formula 0=C=N-R28 according to methods known from the literature (cf. Hou: en-Weyj, Methoden der Organischen Chemie, Vol. VIM, Georg Thieme Verlag, Stu gart 1952, p. 132). Analogously, compounds of the formula I in which R1 is -Ni =*28)-C(S)-NH-R28 can be prepared, for example, by reacting the corresponding compounds of the formula I in which R1 is -NHR28 with isothiocyanates of the formula S=C-N-R28. Generally, for the preparation of compounds of the formula i in which R1 is -N(R28)-C(0)-N(R21)-R28or -N(R28)-C(S)-N(R21)-R28, methods Compounds of the formula I in which R1 is -N(R29)-C(0)-OR22 can be prepared, for example, by reacting compounds of the formula I in which R1 is -NHR29 with chlorocarbonic acid esters of the formula CI-C(0)-OR22 according to methods known from the literature (:,f. Houben-Weyl, Methoden der Organischen Chemie, Vol. VIII, Georg Thieme Varlag, Stuttgart 1952, p. 138). Generally, other methods known from the literature c an also be used for the preparation of compounds of the formula I in which R1 is -N(R29)-C(0)-OR22 (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. VIII, Georg Thieme Verlag, Stuttgart 1952). Compounds of the formula I in which F.' is -N(R28)-C(0)-SR22 can be prepared analogously.,,
Compounds of the formula I in which R1 is -0-C(0)-NH-R28 can be prepared, for example, by reacting compounds of the formula I in which R1 is -OH with isocyanates of the formula 0=C=N-R28 according to methods known from the literature (cf. Houben-Wey, Methoden der Organischen Chemie, Vol. VIM, Georg
Thieme Verlag, Stuttgart 1!;52, p. 141). Analogously, compounds of the formula I in which R1 is -S-C(0)-NH-R': * can be prepared, for example, by reacting compounds of the formula | in which R1 is -SH with isocyanates of the formula 0=C=N-R28. Analogously isothiocyanatns of the formula S=C=N-R28 can be reacted. Generally, for the preparation of compounds of the formula I in which R1 is -0-C(0)-N(R21)-R28 or -S--C(0)-N(R21)-R28, methods known from the literature for the preparation of such carbonic acid derivatives can be used, for example reactions with carbamoyl halides.
Compounds of the formula I in which R1 is -0-C(0)-R21 can be prepared, for example, by reacting compounds of the formula I in which R1 is -OH according to methods known per se am:i described in the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, »'ol. VIII, Georg Thieme Verlag, Stuttgart 1952, p. 508 ft), for example, with reactive ;arboxylic acid derivatives. Correspondingly, for example, compounds of the formula f in which R1 is - 0-C(0)-OR22 can be obtained from compounds of the formula i in which R1 is -OH using suitable carbonic acid derivatives such as, for ex-Triple, chlorocarbonic acid esters.
In accordance with the above details, the compounds of the formula I in which the radicals W, Z, Y, B, R, D, li- and b, c, d, e, f, g and h have the meanings indicated at the outset can also be employed as intermediates for the preparation of other compounds, in particular further pharmaceutical active compounds which are obtainable from the compcunds of the formula I, for example, by modification or introduction of radicals or' jnctional groups.
The compounds of the formula I in which the radicals W, Z, Y, B, R, D, E and b, c, d, e, f, g and h have the meanings indicated at the outset are antagonists of the adhesion receptor VLA-4 und/or inhibitors of leucocyte adhesion. This applies to the same extent also to the ccmpounds already described in WO-A-96/33976, which are excluded according to the definition given at the outset of those compounds which are claimed per se in the present application, but for which no pharmacological action or pharmaceutical use is described in WO-A-9S/33976. The following details
of the pharmacological act on and use also apply to the last-mentioned compounds. For the preparation of the last-mentioned compounds, reference is made to WO-A-96/33976 and German Patent Application 19515177,1, whose contents are inasmuch part of the present disclosure. With respect to the use of compounds and with respect to pharmaceuvcal preparations, the present invention thus relates on the one hand to the compounds of the formula I in which the radicals W, Z, Y, B, R, D, E and b, c, d, e, f, g anc h have the meanings indicated at the outset, but on the other hand also to the conrtf jounds which are excluded according to the definition of the claimed compounds inoicated at the outset and which are described in WO-A-96/33976. With respect to the use and pharmaceutical preparation described in the following, the preser. invention thus relates to compounds of the formula lb,
W isR1-A-C(R13)orR1-ACH=C;
Z is NCR0), oxygen, sulfur or a methylene group;
A is a bivalent radical frc i the group consisting of ((^-C^-alkylene, (C3-C12)-cycloalkylene, (C1-C6)-^lkylene-(C3-C12)-cycloalkyl, phenylene, phenylene-(C1-C6)-alkyl, (C1-C6)-irtkyIenephenyl, (C1-C6)-alkylenephenyl-(C1-C6)-alkyl, phenylene-(C2-C6)-alk*nyl or a bivalent radical of a 5- or 6-membered, saturated or unsaturated ring wh oh can contain 1 or 2 nitrogen atoms and can be mono-or disubstituted by (C-j -36)-alkyl or doubly bonded oxygen or sulfur or is a direct bond;
B is a bivalent radical from the group consisting of (Cj-CsJ-alkylene, (C2-C6)-alkenylene, phenylene, phenylene-(CrC3)-alkyll (C1-C3)-alkylenephenyl where the bivalent (C1-C6)-aUylene radical can be unsubstituted or substituted by a
radical from the group consisting of (C^-CgJ-alkyl, (C2-C8)-a!kenyl, (C2-C8)-alkynyl, (C3-C10)-cyclo;ilkyl, (Cj-C^-cycloalkyKC^C^-alkyl, optionally substituted (C6-C14)-arfl, (C6-C14)-aryl-(C1-C6)-alkyl optionally substituted in the aryl radical, optionally iiubstituted heteroaryl and heteroaryKC^-CgJ-alkyl optionally substituted in the heteroaryl radical;
D is C(R2)(R3), N(R3) or ■:; H=C(R3);
E is tetrazolyl, (R80)2P(C i, HOS(0)2, R9NHS(0)2 or R10CO;
R is hydrogen, (C1-C8)-a:yl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (i*6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl r -:dical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, where alkyl radicals can be mono- or polysu ostituted by fluorine;
R° is hydrogen, (C1-C8)-akyl, (C3-C12)-cycloaikyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyll (C6-C12)-bicycloalkyl, (';6-C12)-bicycloalkyl-(C1-C8)-alkyl, (C6-C12)-tricycloalkyl, (C6-C12)-tricycloalkyl-(':',1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl ..ptionally substituted in the aryl radical, optionally substituted heteroaryl, •,eteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, CHO, (C1-C8)-alkyl-CO, (C3-C12)-cycloalkyl-CO, (C3-C12)-cycloalkyl-(C1-C8)-alk> CO, (C6-C12)-bicycloalkyl-CO, C6-C12)-bicycloalkyl-(C1-C8)-alkyl-CO, (C6-::12)"tricycloalkyl-CO, (C6-C12)-tricycloalkyl-(C1-C8)-alkyl-CO, optionally substitulod (C6-C14)-aryl-CO, (C6-C14)-aryl-(C1-C8)-alkyl-CO optionally substituted i i the aryl radical, optionally substituted heteroaryl-CO, heteroaryl-(C|-C8)-alkyl-CO optionally substituted in the heteroaryj radical, (C^ C8)-alkyl-S(0)n, (C3-Cr:)-cycloalkyl-S(0)n, (C3-C12)-cycloalkyl-(C1-C8)-alkyl-S(0)n,(C6-C12)-bicyclcHlkyl-S(0)n, (C6-C12)-bicycloalkyl-(C1-C8)-alkyl-S(0)n, (C6-C12)-tricycloalkyl-S(0)n,(C6-C12)-tricycloalkyl-(C1-C8)-alkyl-S(0)n, optionally substituted (C6-C14)-ar,l-S(0)n, (C6-C14)-aryl-(C1-C8)-alkyl-S(0)n optionally substituted in the aryl r; dical, optionally substituted heteroaryl-S(0)n or heteroaryl-(C1-C8)-alky[-S(0)n optionally substituted in the heteroaryl radical, *,:ii' where n is 1 or 2;
R1 is one of the radicals -c^-R21, -S-S-R21, -S(0)-R22, -S(0)2-R22, -S-OR21, -S(O)-OR21, -S(0)2-OR21, -S-N(R21)-R28, -S(0)-N(R21)-R28, -S(0)2-N(R21)-R28, -S-<:>
-S-C(0)-N(R21)-R28, -S-C(S)-N(R21)-R28,
-0-C(0)-R21, -0-C(S)-R21, -0-C(0)-OR22, -0-C(O)-N(R21)-R28,
-0-C(S)-N(R21)-R28, -0-S(0)2-OR2\ -0-S(0)-OR21,
-0-S(0)2-N(R21)-R28, -.0-S(0)-N(R21)-R28, -0-S(0)2-R22, -0-S(0)-R22,
-0-P(0)(OR21)2, -0-PO)(OR21)-N(R21)-R28,-0-P(0)(N(R21)-R28)2,
-N(R29)-C(0)-OR22, -N(R28)-C(0)-SR22, -N(R28)-C(S)-OR22,
-N(R28)-C(S)-SR22, -N'R28)-C(S)-R21, -N(R28)-C(0)-N(R21)-R28,
-N(R28)-C(S)-N(R21 )-R28, -N(R28)-S(0)2-R22, -N(R28)-S(0)-R22,
-N(R28)-S(0)2-OR21, -N(R28)-S(0)-OR21,
-N(R28)-S(0)2-N(R21)- H28, -N(R28)-S(0)-N(R21)-R28,
-N(R28)-P(0)(OR21)2, ;M(R28)-P(0)(OR21)-N(R21)-R28,
-N(R28)-P(0)(N(R21)-F.'8)2, -N(R28)-P(0)(R22)-OR21,
-N(R28)-P(0)(R22)-N(R21)-R28, -N(R28)-P(0)(R22)2,
-P(0)(OR21)2, -P(0)(C^21)-N(R21)-R28, -P(0)(N(R21)-R28)2,
-P(0)(R22)-OR21, -P(C')(R22)-N(R21)-R28, -P(0)(R22)2,
cyano, halogen, nitro i:r methylenedioxy or the radical of an optionally
substituted, 5- to 14-rv smbered, mono- or polycyclic, saturated or unsaturated
Q1 is -C(R21)2-, =C(RM)-, -N(R28)-, -0- or -S-; Q2 is -S(0)- or -S(0)r;
Q3 is -C(R21)r, =C(R;1)-, -N(R28)-, -0-, -S-, -C(R21)(-)- or -N(-)-, where the heterocyclic ring can be bonded to the group A via the'free bond in the groups -C(R21 )(-)•• or -N(-)- representing Q3 or via any other desired ring carbon atom and where, if the heterocyclic ring is bonded to a ring system contained in the groun A, the heterocyclic ring can also be fused via two adjacent atoms to the ring system in the group A; R2 is hydrogen, (C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-
(C1-C8)-alkyl optionally ■ ubstituted in the aryl radical or (C3-C8)-cycloalkyl; is hydrogen, (C1-C8)-alk'I, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optinally substituted in the aryl radical, (C3-C8)-cycloalkyl, (C2-C8)~ alkenyl, (C1-C8)-alkynyi, (C2-C8)-alkenylcarbonyl, (C2-C8)-alkynylcarbonyl, pyridyl, R11NH, R4CO, ;OOR4, CON(CH3)R4, CONHR4, CSNHR4, COOK15, CON(CH3)R15orCONHR15;
is hydrogen or (CrC28;alkyl which can optionally be mono- or polysubstituted by identical or different : adicals from the group consisting of hydroxyl, hydroxycarbonyl, amin^arbonyl, mono- or di-((CrC18)-alkyl)aminocarbonyl, amino-(C2-C18)-a!kylamnocarbonyl, amino-(CrC3)-alkylphenyl-(CrC3)-aikylaminocarbonyl, (C onyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl which can also be substituted in t' e aryl radical, amino, mercapto, (C^-C^-alkoxy, (Cr C18)-alkoxycarbonyl, I- ot-CO, optionally substituted (C3-C8)-cycloalkyl, HOS(0)r(C1-C3)-alky!l R9NHS(0)2-(CrC3)-alkyl, (R80)2P(0)-(CrC3)-alkyl, tetrazolyl-(CrC3)-alky halogen, nitro, trifluoromethyl or the radical R5; is optionally substitute: (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl adical, a mono- or bicyclic 5- 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 :.roup consisting of nitrogen, oxygen and sulfur, a radical R6 or a radical R6CO- where the aryl radical and, independently thereof, the heterocyclic radical ci i be mono- or polysubstituted by identical or different radicals from the group consisting of (C^C^J-alkyl, (C1-C18)-alkoxy, halogen, nitro, amino and triflu.romethyl;
is R7R8N, R70 or R7J- or an amino acid side chain, a natural or unnatural amino acid, imino acid, optionally N-(C1-C8)-alkyIated or N~((C6-C14)-aryl-(C1-C8)-alkylated) azaamino E ;id or a dipeptide radical which can also be substituted in the aryl radical and/o in which the peptide bond can be reduced to -NH-CH2-, and their esters and c, nides, where hydrogen or hydroxymethyl can optionally stand in place of of fr ■ e functional groups and/or where free functional ^roups can be protected by i> otective groups customary in peptide chemistry;
R7 is hydrogen, (CrC18H;ikyl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C18)-alkylcarbonyll (CrC18)-alkoxycarbony , (C6-C14)-arylcarbonyl, (C6-C14)-aryl-(C1-C8)-alkylcarbonyl or (C6-C1i)-aryl-(Cl-C18)-alkyloxycarbonyl, where the alkyl groups can optionally be subs; :uted by an amino group and/or where the aryl iddicals can be mono- or polysi^stituted, preferably monosubstituted, by identical or different radicals from tie group consisting of (C1-C8)-alkyl, (C1-C8)~alkoxy, halogen, nitro, amino and trifluoromethyl, or is a natural or unnatural amino acid, imino acid, optionally N (C1-C8)-alkylated or N-((C6-C14)-aryl-(C1-C8)-alkylated) azaamino acid or a dip;*ptide radical which can also be substituted in the aryl radical and/or in which 'he peptide bond can be reduced to -NH-CH2-; R8 is hydrogen, (CrC18)-tilkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl~
(C1-C8)-alkyl which can also be substituted in the aryl radical; R9 is hydrogen, aminocar:;onyl, (CrC18)-alkylaminocarbonyl, (C3-C8)-
cycloalkylaminocarborij'l, optionally substituted (C6-C14)-arylaminocarbonyl, (Cr C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-"8)-cycloaIkyl; R10 is hydroxyl, (CrC18 -alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can also be substituted in the ai ,l radical, optionally substituted (C6-C14)-aryloxy, amino or mono- or di-((Cr ,';18)-alkyl)amino; R11 is hydrogen, R12a, R,2a-CO, H-CO, R12a-0-CO, R12b-CO, R12bi-CS,
R12a-S(0)2orR12b-i;(0)2; R12a is (CrC18)-alkyl, (C: -C8)-alkenyl, (C1-C8)-alkynyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalky!-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroar.l, heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical or :he radical R15; R12b is amino, di-((C1-C1,,)-alkyl)-amino or R12a-NH;
R13 is hydrogen, (C1-C6' alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, (C3-C8)-cycloalkyl or (C3-C8)-cycloalkyl-(!:rC8)-alkyl; R15 is R16~(C1-C6)-alkyl :>r R16,
R16 is a 6- to 24-membered, bicyclic or tricyclic radical which is saturated or partially unsaturate:! and which can also contain one, two, three or four identical or differeni heteroatoms from the group consisting of nitrogen,
oxygen and sulfur and which can also be substituted by one or more identical or different substituer.ts from the group consisting of (C1-C4)-alkyl and oxo;
R21 is hydrogen, (C1-C8)-alkylI hydroxy-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C3-C12)-cycloalkyl, (C3-C12)-c:/cloalkyl-(C1-C8)-alkyL optionally substituted (C6-C14)-aryl, (C6-C14)-aryl-(Cl-C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-fCj-C^-alkyl optionally substituted in the heteroaryl radical, where alkyl radicals can also be monosubstituted or polysubstituted by fluorine and the radicals R21 can be identical or different if they occur two or more times;
R22 is (C1-C8)-alkyl, hydioxy-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C3-C12)~cycloalkyl, (C3-C12)-cydoalkyl-i;OrC8)-alkyl, optionally substituted (C6-C14)-arylr (C6~ C14)'aryl-(C1-C8)-ar- /I optionally substituted in the aryl radical, optionally substituted heteroar/l or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, wnere alkyl radicals can be monosubstituted or polysubstituted by fkorine and the radicals R22 can be identical or different if they occur two or more times;
R28 is one of the radicals R21-, R21N(R21)-, R21C(0)-, R220-C(OK R21N(R21)-C(O)- or R21N(R21)- C(=N(R21))-;
R29 is one of the radicals R22-, R21N(R21)-, R21C(0)-, R220-C(0)-, R21N(R21)-C(O)- or R21N(R21)- C(=N(R21))-;
Het is the radical of a 5- ;o 10-membered, monocyclic or polycyclic heterocycle bonded via a nitrogen atom, which can be aromatic or partially unsaturated or saturated and whicl can contain one, two, three or four identical or different additional ring heteroatoms from the group consisting of oxygen, nitrogen and sulfur and which car be optionally substituted on carbon atoms and on additional ring nitrogen atoms, where there can be identical or different radicals Rh, RhCO c' RhO-CO as substituents on additional ring nitrogen atoms and Rh is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-c, kyl, optionally substituted (C6-C14)-aryi or (C6-C14)-aryl-(C1-C8)-alkyl optior-ally substituted in the aryl radical;
b, c, d and f independent! / of one another can be 0 or 1, but cannot all
simultaneously be 0;
e, g and h independently of one another are the numbers 0, 1,2, 3, 4, 5 or 6;
in all their stereoisomer^ f::rms and mixtures thereof in any ratio, and their physiologically tolerable sots.
All the above explanations or the compounds of the formula I, for example with
respect to alkyl radicals, aiyl radicals, etc., apply to the compounds of the formula lb
correspondingly. All the stereoisomers are also included here. Likewise, all the
preferred meanings and preferred compounds indicated above expressly also refer
here to the compounds of ie formula lb correspondingly. With respect to the use
and the pharmaceutical pi iparations, preferred compounds of the formula lb, for
example, are thus in turn t- ose compounds in which
Y is a carbonyl, thiocarb.myl or methylene group;
Z is N(R°), oxygen, sulfur or a methylene group;
A is a bivalent radical frc;m the group consisting of (C1-C6)-alkylene, (C3-C12)-cycloalkylene, (C1-C6 3ikylene-(C3-C12)-cycloalkyll phenylene, phenylene-(Cr C6)-alkyl, (C1-C6)-alky snephenyl, (C1-C6)-alkylenephenyI-(C1-C6)-alkylt phenylene-(C2-C6)-aH;onyi or a bivalent radical of a 5- or 6-membered saturated or unsaturated ring wh ch can contain one or two nitrogen atoms and can be mono- or disubstitutec oy (C1-C6)-alkyl or doubly bonded oxygen or sulfur, or is a direct bond;
B is a bivalent radical fron the group consisting of (C1-C6)-alkylenel (C2~C6)-alkenylene, phenylen;; phenyIene»(C1-C3)-alkyl, (C1-C3)-alkylenephenyl;
D is C(R2)(R3), N(R3) or :H=C(R3);
E is tetrazolyl, (R80)2P(:))f HOS(0)2, R9NHS(0)2 or R10CO;
R and R° independently ;r one another are hydrogen, (C1-C8)-alkylI
(CrC12)-cycloalkyl, (:;3-C12)-cycloalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-aryl, (C6-C14)-arJ-(C1-C8)-alkyl optionally substituted in the aryl radical, optionally substitutec heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radi ;..al, where alkyl radicals can be mono- or polysubstituted by fluorine;
R1 is one of the radicals -S-R21, -S-S-R21, -S(0)-R22, -S(0)2-R22, -S-OR21, -S(O)-OR21, -S(0)2-OR21, '!;-N(R21)-R28, -S(0)-N(R21)-R28, -S(0)2-N(R21)-R28, -i;.C(0)-R21, -S-C(0)~OR22, -S-C(S)-SR22
-S-C(0)-N(R21)-R28( -S C(S)-N(R21)-R28,
-0-C(0)-R21, -0-C(S)-F:21, -0-C(0)-OR22, -0-C(0)-N(R21)-R28,
-0-C(S)-N(R21)-R28, -0-S(0)2-OR21, -0-S(0)-OR21, -0-S(0)2-N(R21)-R^8,
-0-S(0)-N(R21)-R28, -C-S(0)2-R22, -0-S(0)-R22,
-0-P(0)(OR21)2, -0-P(::>)(OR21)-N(R21)-R28, -0-P(0)(N(R21)-R28)2,
-N(R29)-C(0)-OR22, -NtR28)-C(0)-SR22, -N(R28)-C(S)-OR22,
-N(R28)-C(S)-SR22, -Ni'*28)-C(S)-R21, -N(R28)-C(0)-N(R21)-R28,
-N(R28)-C(S)-N(R21)-R::3, -N(R28)-S(0)2-R22, -N(R28)-S(0)-R22
-N(R28)-S(0)2-OR21, -M(R28)-S(0)-OR21,
-N(R28)-S(0)rN(R21 )-F!28, -N(R28)-S(0)-N(R21 )-R28,
-N(R28)-P(0)(OR21)2, ■ 1(R28)-P(0)(OR21)-N(R21)-R28,
-N(R28)-P(0)(N(R21 )-R?8)2, -N(R28)-P(0)(R22)-OR21,
-N(R28)-P(0)(R22)-N(R'1 )-R28, -N(R28)-P(0)(R22)2,
-P(0)(OR21)2, -P(0)(C:i21)-N(R21)-R28, -P(0)(N(R21)-R28)2,
-P(0)(R22)-OR21; -P(0)(R22)-N(R21)-R28, -P(0)(R22)2,
cyano, halogen, nitro c methylenedioxy or the radical of an optionally
substituted, 5- to 14-rr limbered, mono- or polycyclic, saturated or unsaturated
heterocyclic ring of the; formula
Q1 is-C(R21)2-. -C(R2>, -N(R28K -0- or -S-;
Q2is-S(0)-or-!3(0)2-;
Q3is-C(R21)2-? =C(R2,K -N(R28)-, -0-, -S-, -C(R21)(-)-or-N(-)-,
where the heterocyclic ring can be bonded to the group A via the free bond in the groups -C(R21)(-)~ or -N(-)- representing Q3 or via any other desired ring carbon atom and wher«3, if the heterocyclic ring is bended to a ring system contained in the group A, the heterocyclic ring can also be fused via two adjacent atoms to the ring system in the group A; R2 is hydrogen, (C1-C8)-ulkylI optionally substituted (C6-Cu)-aryl, (C6-C14)-aryl-
(C1-C8)-alkyl optionally substituted in the aryl radical or (C3-C8)-cycloalkyl; is hydrogen, (C1-C8)-ai is hydrogen or (C1-C28; alkyl which can optionally be mono- or polysubstituted by identical or different :adicals from the group consisting of hydroxyl, hydroxycarbonyl, amin icarbonyl, mono- or di-((CrC18)-alkyl)aminocarbonyll amino-(C2-C18)-alkylam;nocarbonyl, amino-(CrC3)-alkylphenyl-(CrC3)-alkylaminocarbonyl, (C ,-C18)-alkylcarbonylamino-(C1-C3)-alkylphenyl--(C1-C3)-alkylaminocarLiDnyl, (CrC18)-alkylcarbonylamino~ (C2-C18)-alkylaminoca' Donyl, (C6-C14)-aryl-(C1-C8)-alkoxycarbonyl which can also be substituted in the aryl radical, amino, mercapto, (C-j-C^-alkoxy, (C^ C18)-alkoxycarbonyl, Of;tionally substituted (C3-C8)-cycloalkyl, HOS(0)2-(C1-C3)-alkyl, R9NHS(0)2-(Cr::3)'alkyl, (R80)2P(0)-(CrC3)-alkyl, tetrazolyKCrC3)~ alkyl, halogen, nitro, tr/uoromethyl and the radical R5 ; is optionally substituted (C6-C14)~aryl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in the aryl radical, a mono- or bicyclic 5- to 12-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated and whicn can contain one, two or three identical or different heteroatoms from the c/oup consisting of nitrogen, oxygen and sulfur, a radical R6 or a radical R6CO-, where the aryl radical and, independently thereof, the heterocyclic radical car, be mono- or polysubstituted by identical or different radicals from the grou^ consisting of (CrC18)-alkyl, (C1-C18)-alkoxy) halogen^ nitro, amino or trifluorc riethyl;
is R7R8N, R70 or R7S :ir an amino acid side chain, a natural or unnatural amino acid, imino acid, optionally N-(C1-C8)-alkylated or N-((C6-C14)-aryl-(C1-C8)« alkylated) azaamino a;d or a dipeptide radical which can also be substituted in the aryl radical and/or 1 which the peptide bond can be reduced to -NH-CH2-( and their esters and anides, where hydrogen or hydroxymethyl can optionally stand in place of of fre ? functional groups and/or where free functional groups can be protected by protective groups customary in peptide chemistry;
R' is hydrogen, (C1-C18)-£.lkyll (C6-C14)-aryl-(CrG8)-alkyl, (CrC18j-alkylcarbonyll (Cj-C^-alkoxycarbony, (C6-C14)-arylcarbonyl, (C6-C14)-aryl-(C1-C8)-alkylcarbonyl or (C6-C- J~aryl-(CrC18)~alkyloxycarbonyl, where the alkyl groups can optionally be subsisted by an amino group and/or where the aryl radicals can be mono- or polysuostituted, preferably monosubstituted, by identical or different radicals from :ne group consisting of (C^-C^-alkyl, (C1-C8)-alkoxy, halogen, nitro, amino and trifluoromethyl, or is a natural or unnatural amino acid, imino acid, optionally N"(C1-C8)-alkylated or N-((C6-C14)-aryl-(C1-p8)-alkylated) azaamino acid or a dip ■ ptide radical which can also be substituted in the aryl radical and/or in which the peptide bond can be reduced to -NH-CH2-; R8 is hydrogen, (CrC18)^vkyl, optionally substituted (C6-C14)-aryl or (C6-C14)-aryl-
(C^-Cg^alky! which can also be substituted in the aryl radical; R9 is hydrogen, aminocarbonyl, (CrC18)-alkylaminocarbonyl, (C3-C8)~
cycloalkylaminocarbonH, optionally substituted (C6-C14)-arylaminocarbonyl, (Cy C18)-alkyl, optionally substituted (C6-C14)-aryl or (C3-C8)-cydoalkyl; R10 is hydroxyl, (CrC18)-riikoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryl adical, optionally substituted (C6-C14)~aryloxy, amino or mono- or di-((CrC18) '3lkyl)amino; R11 is hydrogen, (CrC18;-alkyi, R12CO, optionally substituted (C6-C14)-aryl-S(0)2, (CrC18)-alkyl-S(0)2, (C6-C14)-aryl-(C1-C8)-aikyl optionally substituted in the aryl radical, R9NHS(0)2 or the radical R15; R,z is hydrogen, (CrC18i-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, optionally
substituted (C6-C14)-^ryl, (CrC18)-alkoxy, (C6-C14)-aryl-(C1-C8)-alkoxy which can also be substituted in the aryl radical, optionally substituted (C6-C14)-aryloxy, amino or mono- or di-((C1-Cl8)-alkyl)amino, the radical R15 or the radical R15-0~; R13 is hydrogen, (C1-C6)--:lkyl, (C6-C14)-aryl-(C1-C8)-alkyl optionally substituted in
the aryl radical or (C3-C8)-cycloalkyl; R15 is R16~(C1-C6)-alkyl oi R16;
R16 is a 6- to 24-memberr?d, bicyclic or tricyclic radical which is saturated or partially unsaturated und which can also contain one to four identical or different heteroatom* from the group consisting of nitrogen, oxygen and sulfur and which can also lt> substituted by one or more identical or different
substituents from the Cj 'oup consisting of (C1-C4)-aIkyl and oxo;
R21 is hydrogen, (C1-C8)-elkyl, hydroxy-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C3-C12)-cycloalkyl, (C3-C12)~c>doalkyl-(C1-C8)-alkyl, optionally substituted (C6-C14)-arY|. (Off-Cu)-Bry\-{C^ C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, where alkyl radicals can alsq be monosubstituted or pc ^substituted by fluorine and the radicals R21 can be identical or different if Ahey occur two or more times;
R22 is (C1-C8)-alkyl, hydrc: R28 is one of the radicals f R29 is one of the radicals R22-, R21N(R21)-, R21C(0)-, R220-C(0)-, R21N(R21)-C(0)-orR21N(R21)-C(=N(R21))-;
e, g and h independently cf one another are 0, 1, 2, 3, 4, 5 or 6;
in all their stereoisomeric forms and mixtures thereof in any ratio, and their
physiologically tolerable Halts.
The compounds of the formula lb according to the above definition have t' ) ability to inhibit the adhesion receptor VLA-4 and to inhibit ceil-cell and cell-matrix interaction processes in which interactions between VLA-4 and its ligands play a part. The activity of the compounds of the formula lb can be demonstrated, for example, in an assay in wnich the binding of cells which contain the VLA-4 receptor, for example leucocytes.. I; ligands of this receptor is measured, for example to VCAM-1, which for this purpose can advantageously also be prepared by genetic engineering. Details of such an assay are described below. In particular, the
compounds of the formula o are able to inhibit the adhesion and the migration of leucocytes, for example thn adhesion of leucocytes to endothelial cells which - as explained above - is controlled via the VCAM-1/VLA-4 adhesion mechanism.
The compounds of the formula lb and their physiologically tolerable salts are therefore suitable for the treatment and prophylaxis of diseases which are based on the interaction between the; VLA-4 receptor and its ligands or can be influenced by inhibition of this interaction and in particular they are suitable for the treatment and prophylaxis of diseases wh ch are caused at least partially by an undesired extent of leucocyte adhesion and/or eucocyte migration or which are associated therewith, and for whose prevention, .alleviation or cure the adhesion and/or migration of leucocytes should be reduced. They can thus be employed, for example, as antiinflammatory agents in the case of inflammatory symptoms having very different causes. The compounds of the formula lb according to the present invention are used, for example, for the reatment or prophylaxis of rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis), systemic lupus erythematosus or for the treatment or prophylaxis of inflammatory disorders of the central nervous system, such as, for example, multiple sclerosis, for the treatment or prophylaxis of asthma or of allergies, for example allergies of the delayed type (type IV allergy), furthermore for the treatment or prophylaxis of cardiovascular disorders, arteriosclerosis, restenosis, for the treatment or prophylaxis of diabetes, for the prevention of damage to organ transplants, for the inhibition of tumor growth or tumor metastasis in varioi.j malignancies, for the therapy of malaria, and also of other diseases in which blocking of the integrin VLA-4 and/or influencing of the leucocyte activity appears appropriate for prevention, alleviation or cure. The compounds of the formula lb and their salts can furthermore be employed for diagnostic purposes, e. g, in in vitro diagnoses, and as tools in biochemical investigations in which VLA-4 blocking or influencing of cell-cell or cell-matrix interactions is intended.
The compounds of the foimula lb and their physiologically tolerable salts can be administered according t:> the invention, as pharmaceuticals for therapy or prophylaxis, to animals, \:. eferably to mammals, and in particular to man. They can
be administered per se, in nixtures with one another or in the form of pharmaceutical preparations which permit enteral or parenteral use and which as active constituents contair. an efficacious dose of at least one compound of the formula lb and/or its physi ;J ogically tolerable salts in addition to customary, pharmaceutical^ innocuous excipients and/or additives. The pharmaceutical preparations normally contain approximately 0.5 to 90% by weight of the therapeutically active compounds of the formula lb and/or their physiologically tolerable salts.
The present invention relays to the compounds of the formula lb and/or their physiologically tolerable salts for use as pharmaceuticals, the use of the compounds of the formula lb and/or tht-ir physiologically tolerable salts for the production of pharmaceuticals for the inhibition of the adhesion and/or migration of leucocytes or for the inhibition of the VLA-4 receptor, i.e. of pharmaceuticals for the treatment or prophylaxis of diseases in which leucocyte adhesion and/or leucocyte migration has an undesired extent, or of diseases in which VLA-4-dependent adhesion processes play a part, in particular for the production of pharmaceuticals for the inhibition of inflammation, and also tht- use of the compounds of the formula lb and/or their physiologically tolerable s alts in the treatment and prophylaxis of diseases of this type. The present invention furthermore relates to pharmaceutical preparations which contain an efficacious dose of at least one compound of the formula lb and/or its physiologically tolerab i. salts in addition to customary pharmaceutical^ innocuous excipients andior additives.
The pharmaceuticals can he administered orally, for example in the form o» pills, tablets, film-coated tablets sugar-coated tablets, granules, hard and soft gelatin capsules, solutions, syrup;, emulsions or suspensions. However, administration can also take place rectally, fcr example in the form of suppositories, or parenterally, for example in the form of injection or infusion solutions, microcapsules or rods, or percutaneously, for examile in the form of ointments or tinctures, or by other routes, for example in the form of nasal sprays or aerosol mixtures.
The pharmaceutical preparations to be employed according to the invention are
prepared in a manner known per se, pharmaceutically inert inorganic and/or organic excipients being used in addition to the compound(s) of the formula lb ana/or its/their physiologically tolerable salts. For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, com starch or derivatives thereof, talc, stearic acid or its salts, etc. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable excipients for the preparation of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable excipients for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.
In addition to the active compounds and excipients the pharmaceutical preparations can additionally contain additives, such as, for example, fillers, disintegrants, binders, lubricants, wettin;i agents, stabilizers, emulsifiers, preserv3tives, sweeteners, colorants, flavorings or aromatizers, thickeners, diluents, buffer substances, and also solvents or solubilizers or agents for achieving a depot effect, as well as salts for changing the osmotic pressure, coatings or antioxidants. They can also contain two or mere compounds of the formula lb and/or their physiologically tolerable suits. In addition to at least one compound of the formula lb and/or its physiologically tolerable salts, they can further contain one or more other therapeutically or prophylactically active substances, for example substances having antiinflammatory action.
The dose can vary within ^/ide limits and is to be adapted to the individual conditions in each individual case. 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 rf body weight is adequate to achieve effective results. In the case of intravenous administration, the daily dose is in general approximately 0.01 to 50 mg/kg, preferably 0.01 to 10 mg/kg of body weight. The daily dose can be subdivided, in particular, ■• the case of administration of relatively large amounts, into a number of, for example 2, 3 or 4, part administrations. Where appropriate, it may be necessary, depending on individual behavior, to deviate upwards or
downwards from the indicatad daily dose. Pharmaceutical preparations normally contain 0.2 to 500 rng, preforably 1 to 100 mg, of active compound of the formula lb and/or its physiologically tc erable salts per dose
The products were identified by means of mass spectra (MS) and/or NMR spectra. Compounds which were p.rified by chromatography using an eluent which contained, for example, acetic acid or trifluoroacetic acid and were then freeze-dried partly still contained, depending on the freeze-drying procedure, the acid contained in the eluent, and were thus partially or completely obtained in the form of a salt, for example in the form of the acetic acid salt or trifluoroacetic acid salt.
The abbreviations have ttv: following meanings:
THF	Tetrahydrcfuran
DCC	N.N'-Dicyclohexycarbodiimide
HOBt	1 -Hydroxybenzo "iazole
((R.SH^-lCyanophenyl.^-methyl-a^-naphthylmethyl^.S-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-pl ,anylglycine
1 a) (R,S)-4-(4-Cyanophen>l)-4-methyl-2,5-dioxoimidazoIidine 20 g {138 mmol) of p--acety; oenzonitrile, 115.6 g of ammonium carbonate (1.21 mol) and 11.6 g of potassium cyanide (178 mmol) were dissolved in 600 ml of a mixture of 50% ethanol and 50% water. The mixture was stirred at 55°C for 5 hours and allowed to stand at room temperature overnight. The solution was adjusted to pH = 6.3 using 6 N HCI and ther. stirred at room temperature for 2 hours. The precipitate was filtered off with suctior washed with water and dried over phosphorus pentoxide in a high vacuur. Yield: 22.33 g (75%). FAB-MS: 216.1 (M + H)+
1b) Methyl ((RlS)-4-(4-cya'ophenyl)-4-methyl-2,5-dioxoimida20lidin-1-yl)acetate
1.068 g of sodium (46,47 r mol) were dissolved in 110 ml of abs. methanol under nitrogen. The clear solution was treated with 10 g of (R,S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidne (46.47 mmol) and the mixture was boiled under reflux for 2 h. 7.75 g (46,68 mmc ■) of potassium iodide were added and a solution of 4.53 ml of methyl chloroacetate (51.3 mmol) in 5 ml of methanol was added dropwise in the course of 1 hour. The fixture was heated to boiling for 6 hours, allowed to stand at room temperature overnight and concentrated. The oily residue was chromatographed on silica gel using methylene chloride/ethyl acetate (9:1). Yield: 8.81 g (66%). FAB-MS: 288 (M + H)+
1 c) Methyl ((R(S)-4-(4-cyanophenyI)-4-methyl-3-(2-naphthylmethyl-2,5-dioxoimidazolidin-1-yl)ace?ate
5 g of methyl ((R,S)-4'(4^:vanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate (17.4 mmoi) were dissolved in 20 ml of anhydrous DMF under argon. 920 mg of a sodium hydride dispersion in mineral oil (19.14 mmol) were added in an argon countercurrent. The reaction mixture was stirred at room temperature for 15 minutes. A solution of 3.85 g of 2~bromomethylnaphthalene (19.14 mmol) in 10 ml of anhydrous DMF was then added. The mixture was stirred at room temperature for 4 hours and then allowed t
concentrated. For purification, the substance was chromatographed on silica gel using methylene chloride/ethyl acetate (9.75:0.25). The fractions containing the pure substance were concentrated. Yield: 5,15 g of oil (69%). FAB-MS: 428.3 (M + H)+
1d) ((R,S)-4-(4-Cyanopherv/l)-4-methyl-3-(2-naphthylmethyl)-2l5-dioxoimidazolidin-1-yl)acetic acid
1.1 g of methyl ((R,S)-4-(4 oyanophenyO^-methyl^^-naphthylmethyl)^^-dioxoimidazolidin-1-yl)aceiate (2.57 mmol) were dissolved in a mixture of 20 ml of 6 N HCI and 10 ml of dioxan?;. The solution was stirred at 70°C for 3 hours and then concentrated. Yield: 1.2 g of crude product, FAB-MS: 414.2 (M + H)+
1e) ((R,S)-4-(4-Cyanophet-yl)-4-methyl-3-(2-naphthylmethyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-ph3nyIglycine di-tert-butyl ester
515 mg of DCC (2.34 mmcl) were added at 0 °C to a solution of 1,2 g of ((R,S)-4-(4-cyanophenyl)-4-methyl-3- 2-naphthylmethyl)-2,5-dioxoimidazolidin-1 -yl)acetic acid (crude product), 0.97 g of H-Asp(OBut)-Phg-OBut hydrochloride (2.34 mmol) and 320 mg of HOBt (2.34 mmol) in 25 ml of DMF, The mixture was stirred at 0 °C for 1 hour and at room temperature for 3 hours. The batch was then allowed to stand at room temperature overnicht, the precipitate was filtered off with suction and the filtrate was concentrated. For purification, the substance was chromatographed on silica gel, first with methyiene chloride/methanol/glacial acetic acid (9.5:0.5:0.05) and then with methylene ;nloride/ethyl acetate (8:2). Yield: 620 mg of an oil (34.4%). FAB-MS: 774.3 (M + H)+
1f) ((RlS)-4-(4-Cyanophe'1yl)-4-methyl-3-(2-naphthylmethyl)-2t5-dioxoimidazolidin" 1 -yl)acetyl-L-aspartyl-L-p **enylglycine
250 mg of ((R,S)-4-(4-cy:inophenyl)-4^methyl-3-(2-naphthylmethyl)-2,5-
dioxoimidazoIidin-1 -yl)acety'l-L-aspartyl-L-phenylglycine di-tert-butyl ester were dissolved in a mixture of 2.25 ml of trifluoroacetic acid and 0.25 ml of water. The mixture was allowed to sta";d at room temperature for one hour and was concentrated in a water-jet vacuum. For purification, the substance was chromatographed on Sephadex LH20 using a mixture of glacial acetic acid, n-butanol and water. The fractions containing the pure substance were concentrated. The residue was dissolved in water, freeze-dried and, for further purification, chromatographed on silica gel using methylene chloride/methanol/glacial acetic acid/water (9; 1:0.01:0.1). Yield: 78 mg (36.8%). FAB-MS: 662.2 (M + H)+
{(RfS)-3-BenzyM-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine
2a) (R(S)-4-Methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidine
A mixture of 20 g (121 mnol) of 4-nitroacetophenone, 101.65 g (1.06 mol) of ammonium carbonate anc 10,2 g (156 mmol) of potassium cyanide in 400 ml of ethanol/water (1:1) was heated at 50 °C for 5 h. The solution was then adjusted to pH = 6.3 using 6 N hydrochloric acid and stirred at room temperature for 2 h. The precipitate was filtered off with suction, washed with water and dried over phosphorus pentoxide in >\ high vacuum. Yield: 27,37 g (96%) of colorless solid.
2b) ((R(S)-3-Benzyl-4-meth;/l-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-1-yl)aceticacid
The compound was prepared analogously to Example 1 by reaction of (R,S)-4~ methyl-4-(4-nitrophenyl)-2.T'-dioxoimidazolidine with methyl bromoacetate and then benzyl bromide (instead of 2-bromomethylnaphthalene) and cleavage of the methyl ester with 6 N hydrochloric, acid.
2c) ((R,S)-3-Benzyl-4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine
A solution of 383 mg (1 mrol) of ((R.SJ-S-benzyM-methyM^-nitrophenyO^.S-dioxoimidazolidin-1-yl)acelic acid, 414 mg (1 mmol) of H-Asp(OtBu)-Phg-(OtBu) x HCI and 135 mg (1 mmol) :f HOBt in 5 ml of absolute DMF was treated at X with 220 mg (1.1 mmol) of DCC After stirring at 0 °C for 60 minutes and at room temperature for 60 minutes, the precipitate was filtered off with suction, the filtrate was concentrated and the residue was taken up in ethyl acetate. After filtration, the ethyl acetate solution was washed in succession with saturated NaHC03 solution, KHS04/K2S04 solution, Scuurated NaHC03 solution and water. After phase separation, the organic phase was dried over sodium sulfate. The drying agent was filtered off, the solvent war; removed in vacuo and the residue was chromatographed on silica gel using dichlorc.nethane/ethyl acetate (9:1). After concentration of the product fractions, the residue was treated with 10 ml of 90% strength trifluoroacetic acid. After 1 h at room ten- oerature, the trifluoroacetic acid was removed in vacuo and the residue was chromatographed on silica gel using dichloromethane/methanol/glacial acetic acid/water (9:1:0.1:0.1) and then on Sephadex LH20 using wavsr/butanol/acetic acid (43:4.3:3.5). After freeze-drying of the product fractions, 23 mg (4%) of the title compound were obtained, ES(+)-MS: 632 (M+H)+
((R,S)-3-Benzyl-4-methyl-4-(4-(3-(2-methylphenyl)ureido)pheny!)-2(5-dioxoimidazolidin-1-yl)acotyl"L-aspartyl-L-phenyIglycine
3a) Methyl ((RIS)-3-benzyl'4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-1»
3b) Methyl ((R,S)-4-(4-aminophenyl)-3-benzyl-4-methyl-2,5'dioxoimidazolidin-1-
A solution of 8.92 g (22.4!: mmol) of methyl ((R,S)-3-benzyl-4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-1-yl)acetate in 280 ml of absolute methanol was treated with 17 g (90 mmol) of tin chloride and 3 drops of acetic acid and heated at 50 °C. After starting material was no longer detectable according to HPLC checking, the reaction mixture was concentrated in vacuo and the residue was filtered through silica gel using methanol. After concentration, 6.39 g (78%) of the title compound were obtained,
3c) Methyl ((R,S)-3-benzyl4~methyl-4-(4-(3"(2-methylphenyl)ureido)-phenyl)-2,5-dioxoimidazolidin-1-yl)ao: ate
0.91 g (6.8 mmol) of orthc tolyl isocyanate in 2 ml of THF was added to a solution of 2 5 g (6.8 mmol) of methyl ((R,S)-4-(4-aminophenyl)-3-benzyl-4-methyl~2,5-dioxoimidazolidin-1 -yl)acotate in 20 ml of THF. After healing under reflux for 5 h, the reaction mixture was allowed to stand at room temperature overnight, a further 0.18
g (1.36 mmol) of ortho-toly isocyanate was added and it was stirred under reflux for 3 h. The reaction mixture vas concentrated and the residue was purified on silica gel by means of MPLC usk-g heptane/ethyl acetate (1:1). After concentration of the product fractions, 1.35 g (■■ J%) of the title compound were obtained.
3d)((R)S)-3-Benzyl-4-metryl-4-(4-(3-(2-methylphenyl)ureido)phenyl)-2l5-dioxoimidazolidin-1 -yl)ace /l-L-aspartyl-L-phenylglycine
The synthesis was carriec Dut analogously to Example 2 by coupling of ((RtS)-3-ben2yl-4-methyl-4-(4-(3'(2-methylphenyl)ureido)phenyI)-2t5-dioxoimidazolidin-1» yl)acetic acid (prepared b} cleavage of methyl ((R,S)-3-benzyl-4-methyl-4-(4-(3-(2-methylphenyl)ureido)phertjl)-2t5-dioxoimidazolidin-1-yl)acetate with 6 N hydrochloric acid analogously to Example 1) and H-Asp(OtBu)-Phg-(OtBu) x HCI, After cleavage of the tert-tutyl ester with 90% strength trifluoroacetic acid, the crude product was purified by preparative HPLC on RP-18. ES(+)-MS: 735 (M+H)+
((R,S)-3-Benzyl'4-(4-(3-b^nzylureidomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-p-'i3nylglycine
4a) Methyl ((R,S)-3-benzyl- H4-cyanophenyl)-4-methyl-2l5-dioxoimidazolidin-1 -yl)acetate
28.7 g (100 mmol) of methy. ((RIS)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acet;ite were dissolved in 160 ml of anhydrous DMF under argon. 5,28 g (110 mmol) c :NaH were added in portions with stirring at 0 °C. The mixture was stirred at 0 °C lor 30 minutes. 13 ml of benzyl bromide were then slowly added dropwise. The mixture was stirred at room temperature for 5 hours and allowed to stand at room t 4b) Methyl ((R,S)-4-(4-(arrinomethyl)phenyl)-3-benzyl-4-methyl-2?5-dioxo-imidazolidin-1 -yl)acetate
15.2 g (40 mmol) of methyl ((RpS)-3-benzyl-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazo!idin-1-yl)ace;ate (4a) were dissolved in 160 ml of a mixture of ethanol and 50% strength acetic a: id (8:2), treated with 3 g of Pd/carbon and hydrogenated for 7 hours in an autoclave at 3 bar of H2. The catalyst was filtered off with suction and the filtrate was conce Crated. The residue was dissolved in dichloromethane and chromatographed on nlica gel (70-200 pm) using dichloromethane and then dichloromethane/methano; (8:2). 15.3 g (100%) of the title compound were obtained.
4c) Methyl ((R,S)-3-benzy 4-(4-(3~benzylureidomethyl)phenyl)-4-methyl-2,5--dioxoimidazolidin-1-yl)act;iate
3.80 g (10 mmol) of methy ((RIS)-4-(4»(aminomethyl)phenyl)-3-benzyl-4-methyl'2,5-dioxoimidazolidin-1 -yl)ace ate (4b) were dissolved in 20 ml of anhydrous dichloromethane under ar;jon. 1.85 ml (2 g; 15 mmol) of benzyl isocyanate and 2
drops of triethylamine were added. The mixture was stirred at room temperature for 2 hours and the solution w;=s concentrated a little. It was diluted with ethyl acetate and washed 2 x with 5% st angth citric acid, 2 x with saturated NaHC03 solution and 1 x with water/NaCI solution. The solution was dried over anhydrous sodium sulfate and concentrated. 5.09 g (\ 8.9%) of the title compound were obtained as an oil.
4d)((R)S)-3-Ben2yl-4-(4-(:":-benzylureidomethyl)phenyl)-4-methyl-215-dioxoimidazolidin-1-yl)acelic acid
1 g (1.94 mmol) of methyl t.R(S)-3-benzyl-4-(4-(3-benzylureidomethyl)-phenyl)-4-methyI-2,5-dioxoimidazolic;n-1-yl)acetate (4c) were refluxed for 5 hours with 20 ml of concentrated hydrochloi >c acid. The mixture was then concentrated. The residue was triturated with water, cooled and filtered off with suction. 700 mg (72%) of the title compound were obtained.
4e) ((R.SJ-S-Benzyl^^^H-benzylureidomethyOphenyO^-methyl^.S-dioxoimidazolidin-1-yl)ace./l-L-aspartyl-L-phenylglycine di-tert-butyl ester
500 mg (1 mmol) of ((R,S) -3-benzyl-4-(4-(3-benzylureidomethyl)phenyl)-4-methyI-2,5-dioxoimidazolidin-1-yl;acetic acid (4d), 414.9 mg (1 mmol) of H-Asp(OtBu)-Phg-(C^Bu) x HCI and 135 mg j I mmol) of HOBt were dissolved in 10 ml of absolute DMF. 0.13 ml (1 mmol) of AJ-ethylmorpholine and 220 mg (1.1 mmol) of DCC were added at 0 PC. The mixturo was stirred at 0 °C for 1 hour and at room temperature for 3 hours. It was allowed to stand at room temperature overnight, the urea precipitate was filtered off vvith suction and the filtrate was concentrated in a high vacuum. The residue was laken up in ethyl acetate, and washed with'saturated NaHC03 solution, KHS04' AT) ((R)S)-3-3enzyl-4-(4-(.!-benzylureidomethyl)phenyl)-4-methyl-2I5-* dioxoimidazolidin-1-yl)ac':*:yl-L-aspartyl-L'phenylglycine
800 mg (0.93 mmol) of ((R,f>)-3-benzyl-4-(4-(3-benzylureidomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester (4e) were dissolved 'v 8 ml of 90% strength trifluoroacetic acid and allowed to stand at room temperature "'or 1 hour. The mixture was then concentrated and the residue was triturated with diethyl ether. The crude product was purified by chromatography on silica c 3l using dichloromethane/methanol/acetic acid/water (9:1:0.1:0.1). 527 mg (76 CA) of the title compound were obtained. ES(+)-MS: 749.3 (M+H)+
((R,S)-3-Benzyl-4-methyl—(4-(3-phenylureidom 1-yl)acetyl-L-aspartyl-L-phf!nylglycine
The synthesis was carried out analogously to Example 4. After cleavage of the tert-butyl ester using 90% strength trifluoroacetic acid, the crude product was purified by chromatography on silica :iel using dichloromethane/methanol/acetic acid/water (9:1:0.1:0.1). ES(+)-MS: 735.2 (M+H)+
((RfS)-3-BenzyM-methyl-4-(4-(3-(2-methylphenyl)ureidomethyl)phenyl)^215-dioxoimidazolidin-1-yl)ace:yl-L-aspartyl-L-phenylglycine
The synthesis was carried out analogously to Example 4. After cleavage of the tert-butyl ester using 90% strength trifluoroacetic acid, the crude product was purified by chromatography on silica •;131 using dichloromethane/methanol/acetic acid/water (9:1:0,1:0.1). ES(+)-MS: 749.3 (M+H)+
((RJS)-3-BenzyI-4-methyU4-(4-(3-(2-phenylethyl)ureidomethyl)phenyI)-2,5-dioxoimidazolidin-1-yl)ace :/l-L-aspartyl-L-phenylglycine
The synthesis was carrie :l out analogously to Example 4. After cleavage of the tert-butyl ester using 90% stnngth trifluoroacetic acid, the crude product was purified by chromatography on silica *jel using dichloromethane/methanol/acetic acid/water
(9:1:0.1:0.1). ES(+)-MS: 763.3 (M+H)+
Investigation of the biological activity
As a test method for the activity of the compounds of the formula lb on the interaction between VCAM-1 and VLA-4, an assay is used which is specific for this interaction. The cellular binding components, i.e. 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 :»f leucocytes. As specific binding components, recombinant soluble fusior proteins prepared by genetic engineering and consisting of the extracytoplasmic domains of human VCAM-1 and the constant region of a human immunoglobulin of ne subclass lgG1 are used.
Assay for the measuremen: of the adhesion of U937 cells (ATCC CRL 1593) to hVCAM-1(1-3)-lgG
1. Preparation of human VCAM-1 (1-3)-lgG and human CD4-lgG
A genetic construct for the expression of the extracellular domains of human VCAM-1 was employed, associated with the genetic sequence of the heavy chain of human immunoglobulin Ig3-1 (hinge, CH2 and CH3 regions), from Dr. Brian Seed, Massachusetts General Hospital, Boston, USA. The soluble fusion protein hVCAM-1(1-3)-lgG contained the three amino-terminal extracellular immunoglobulin-like domains of human VCAM-1 (Damle and Aruffo, Proc. Natl. Acad, Sci, USA 1991, 88, 6403). CD4-lgG (Zettlmeissl et al., DNA and Cell Biology 1990, 9, 347) served as a fusion protein for negativf controls. The recombinant proteins were expressed as soluble proteins after DEAE/dextran-mediated DNA-transfection in COS cells (ATCC CRL1651) according to standard procedures (Ausubel et al., Current protocols in molecular biology, John Vv'iley & Sons, Inc., 1994).
2. Assay for measurement of the adhesion of U937 cells to hVCAIvM (1 -3)-lgG
2.1	96-well microtiter test plates (Nunc Maxisorb) were incubated at room temperature for 1 hour with 100 ul/well of a goat-anti-human IgG antibody solution (10 pg/ml in 50 mM Tris, pH 9.5). After removing the antibody solution, washing was carried out once with PBS.
2.2	150 ul/well of a blocking buffer (1 % BSA in PBS) was incubated on the plates at room temperature for 0.5 hours. After removing the blocking buffer, washing was carried out once with PBS.
2.3	100 pi per well of a cell culture supernatant of transfected COS cells were incubated on the plates at room temperature for 1.5 hours. The COS cells were transfected with a plasmid which codes for the three N-terminal immunoglobulin-like domains of VCAM-1, coupled to the Fc part of human lgG1 (hVCAM-1(1-3)-lgG). The content of hVCAM-1 (1 -3)-lgG was about 0.5-1 ug/ml. After removing the culture supernatant, washing was carried out once with PBS.
2.4	The plates were incubated at room temperature for 20 minutes with 100 ul/well of Fc receptor blocking buffer (1 mg/ml of v-globulin, 100 mM NaCI, 100 uM MgCI2, 100 uM MnCI2, 100 uM CaCI2, 1 mg/ml BSA in 50 mM HEPES, pH 7.5). After removing the Fc receptor blocking buffer, washing was carried out once with PBS.
2.5	20 pi of binding buffer (100 mM NaCI, 100 uM MgCI2,100 uM MnCI2, 100 pM CaCI2, 1 mg/ml BSA in 50 mM HEPES, pH 7.5), were initially introduced, the substances to be tested w« re added in 10 ul of binding buffer and the mixture was incubated for 20 minutes. As controls, antibodies against VCAM-1 (BBT, No. BBA6) and against VLA-4 (Immu-iotech, No. 0764) were used.
2.6	U937 cells were incubated in Fc receptor blocking buffer for 20 minutes and then pipetted in at a concmtration of 1 x 106/ml and in an amount of 100 pi per well (final volume 125 pl/well).
2.7	The plates were slow!/ immersed at an angle of 45° in stop buffer (100 mM NaCI, 100 pM MgCI2, 100 gM MnCI2, 100 pM CaCI2 in 25 mM Trisf pH 7.5) and shaken off. The process wis repeated.
2.8	50 pi/well of a dye solution (167 pg/mi of Hoechst dye 33258, 4% formaldehyde, 0.5% Triton X-100 in PBS) were then incubated on the plates for 15 minutes,
2.9	The plates were shaken off and slowly immersed at an angle of 45° in stop
buffer (100 mM NaClt 100 |JM MgCI2, 100 pM MnCI2, 100 pM CaCI2 in 25 mM tris,
pH 7.5). The process was repeated. Then, with the liquid, measurements were made
in a cytofluorimeter (Millipore) (sensitivity: 5; filter: excitation wavelength: 360 nm,
emission wavelength: 460 nm).
The intensity of the light emitted by the stained U937 cells is a measure of the number of the U937 cells adhered to the hVCAM-1(1-3)-lgG and remaining on the plate and thus a measure tf the ability of the added test substance to inhibit this adhesion. From the inhibit on of the adhesion at various concentrations of the test substance, the concentrat on IC50 which leads to an inhibition of adhesion by 50% was calculated.
phenylene, phenylenemethyl, methylenephenyl or methylenephenylmethyl;
B is an unsubstituted methylene radical or a methylene radical which is substituted
by a (Ci-C8)-alkyl radical;
D isC(R2)(R3);
E isR10CO;
R is hydrogen or (CrC4)-alkyl;
R° is (CrC8)-alkyl, (C3-C8)-cycloalkyl, optionally substituted (C6-Ci4)-aryl or (C6-C14)-
aryl-(CrC8)-alkyl optionally substituted in the aryl radical;
R1 is one of the radicals -0-C(0)-R21, -0-C(0)-OR22, -0-C(0)-N(R21)-R28,
R4 is methyl which is substituted by hydroxycarbonyl and a radical from the group
consisting of (Ci-C4)-alkyl, phenyl and benzyl, or is methyl which is substituted by
(CrCs)-alkoxycarbonyl and a radical from the group consisting of (CrC4)-alkyl,
phenyl and benzyl, or is methyl which is substituted by Het-CO and a radical from the
group consisting of (Ci-C4)-alkyl, phenyl and benzyl;
R10 is hydroxy or (CrC8)-alkoxy;
R13 is (CrC6)-alkyl, (C3-C7)-cycloalkyl or benzyl;
R21 is hydrogen, (C1-C8)-alkyl, hydroxy-(d-C8)-alkyl, (C2-C8)-alkenyl, (C3-C12)-
cycloalkyl, (Ca-C^J-cycloalkyHCrCaValkyl, optionally substituted (Ce-CuJ-aryl, (C6-
Ci4)-aryl-(d-C8)-alkyl optionally substituted in the aryl radical, optionally substituted
heteroary] or heteroaryl-(CrC8)-alkyl optionally substituted in the heteroaryl radical,
where alkyl radicals can also be monosubstituted or polysubstituted by fluorine and
the radicals R21 can be identical or different if they occur two or more times;
R22 is (C1-C8)-alkyl, hydroxy-(C1-C8)-alkyl, (C2-C8)-alkenyl, (C3-Ci2)-cycloalkyl, (C3-
Ci2)*cycloalkyl-(CrC8)-alkylf optionally substituted (C6-Ci4)-arylt (C6-Cu>aryl-(Ci-
C8)-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl or
heteroaryl-(C1-C8)-alkyl optionally substituted in the heteroaryl radical, where alkyl
radicals can be monosubstituted or polysubstituted by fluorine and the radicals R22
can be identical or different if they occur two or more times;
R28 is one of the radicals R21-, R21N(R21K R21C(0)-, R220-C(Oh R21N(R21)-C(0)- or
R21N(R2>C(=N(R21))-;
R29 is one of the radicals R22-, R21N(R21)-, R21C(0)-, R220-C(0)-f R21N(R21)-C(0)- or
R21N(R21)-C(*N(R21))-;
Het is the radical of a 5- to 10-membered, monocyclic or polycyclic heterocycle
bonded via a nitrogen atom, which can be aromatic or partially unsaturated or
saturated and which can contain one, two, three or four identical or different
additional ring heteroatoms from the group consisting of oxygen, nitrogen and sulfur
and which can be optionally substituted on carbon atoms and on additional ring
nitrogen atoms, where there can be identical or different radicals Rh, RhCO or RhO-
CO as substituents on additional ring nitrogen atoms and Rh is hydrogen, (CrC8)-
alkyl, (C3-C8)-cycloalkyl, (C3*C8)-cycloalkyl-(CrC8)-alkyl, optionally substituted (C6-
Ci4)-aryl or (C6-Ci4)-aryl-(CrC8)-alkyI optionally substituted in the aryl radical;
in all its stereoisomer^ forms and mixtures thereof in any ratio, or its physiologically
tolerable salts.
2.	A process for the preparation of compounds of the formula I as claimed in claims 1,
which comprises carrying out a fragment condensation of a compound of the formula II
where W, Y, Z, B, D, E and R, and b, ds e, f, g, and h are defined as indicated in claims 1 and G is hydroxycarbonyl, (Ci-C6)-alkoxycarbonyl, activated carboxylic acid derivatives, such as acid chlorides, active esters or mixed anhydrides, or isocyanato.
3.	A pharmaceutical preparation which comprises one or more compounds of the formula I
as claimed in claim 1 and/or their physiologically tolerable salts in addition to pharmaceutically
innocuous excipients and/or additives.
2414-mas-1997-abstract.pdf
2414-mas-1997-claims filed.pdf
2414-mas-1997-claims granted.pdf
2414-mas-1997-correspondnece-others.pdf
2414-mas-1997-correspondnece-po.pdf
2414-mas-1997-description(complete)filed.pdf
2414-mas-1997-description(complete)granted.pdf
2414-mas-1997-form 1.pdf
2414-mas-1997-form 19.pdf
2414-mas-1997-form 26.pdf
2414-mas-1997-form 3.pdf
2414-mas-1997-form 4.pdf
2414-mas-1997-form 5.pdf
2414-mas-1997-otehr documents.pdf
2414/MAS/1997
D-65926 FRANKFURT,
1 DR CHRISTOPH HULS RHEINBLICK 19, 55263 WACKERNHEIM,
2 DR DIRK SEIFFGE KOSTHEIMER LANDSTRASSE 11, 55246 MAINZ-KOSTHEIM,
3 DR HANS ULRICH STILZ JOHANNESALLEE 18, 65929 FRANKFURT,
4 DR VOLKMAR WEHNER LINDENSTRASSE 1, 97657 SANDBERG,
C07 K 5/023
1 19647381.0 1996-11-15 Germany