MXPA97005585A - New cyclalacyl derivatives as inhibitors of bone resortion and vitronect receptor antagonists - Google Patents
New cyclalacyl derivatives as inhibitors of bone resortion and vitronect receptor antagonistsInfo
- Publication number
- MXPA97005585A MXPA97005585A MXPA/A/1997/005585A MX9705585A MXPA97005585A MX PA97005585 A MXPA97005585 A MX PA97005585A MX 9705585 A MX9705585 A MX 9705585A MX PA97005585 A MXPA97005585 A MX PA97005585A
- Authority
- MX
- Mexico
- Prior art keywords
- alkanediyl
- cycloalkyl
- alkyl
- aryl
- substituted
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 19
- 239000003112 inhibitor Substances 0.000 title claims abstract description 16
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- 150000003839 salts Chemical class 0.000 claims description 27
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- 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 claims description 6
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- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 101700082140 clc-2 Proteins 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000001143 conditioned Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
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- 230000003628 erosive Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- CKTNHGVJKUQEBM-UHFFFAOYSA-N ethylazanide Chemical class CC[NH-] CKTNHGVJKUQEBM-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000002319 fibrinogen receptor antagonist Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
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- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 201000002980 hyperparathyroidism Diseases 0.000 description 1
- LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 description 1
- 150000007928 imidazolide derivatives Chemical class 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 101700045377 mvp1 Proteins 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 230000030991 negative regulation of bone resorption Effects 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 230000000790 osteoblast Effects 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 235000015108 pies Nutrition 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- VNUORQWNUXXHLX-UHFFFAOYSA-N pyrazolidine-3-carboxylic acid Chemical compound OC(=O)C1CCNN1 VNUORQWNUXXHLX-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002441 reversible Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 150000003349 semicarbazides Chemical class 0.000 description 1
- 230000001953 sensory Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
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- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
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- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
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Abstract
Cycloalkyl derivatives of the formula I R1-Y-A-B-D-E-F-G are described in which R1, Y, A, B, D, E, F and G have the meanings indicated in the claims, their preparation and their use as medicaments. The compounds according to the invention are used as antagonists of vitronectin receptors and as inhibitors of resorption
Description
New cycloalkyl derivatives as inhibitors of bone resorption and antagonists of vitronectin receptors
The subject of the present invention are compounds of the formula I as well as their physiologically compatible salts and pharmaceutical preparations containing such compounds, their preparation and use as medicaments, especially as inhibitors of bone resorption by osteoclasts, as inhibitors of the growth of tumors and of the metastatization of tumors, as inhibitors of inflammations, for the treatment or prophylaxis of cardiovascular diseases, such as arteriosclerosis or restenosis, for the treatment or prophylaxis of nephropathies and retinopathies, such as p. ex. diabetic retinopathy, as well as antagonists of vitronectin receptors for the treatment and prophylaxis of diseases, which are based on the interaction between vitronectin receptors and their ligands in processes of cell-to-cell or cell-to-cell interaction. The invention also concerns the use of the compounds of the formula I as well as their physiologically compatible salts and of pharmaceutical preparations containing such compounds as medicaments for relieving or curing diseases that are partially conditioned by an undesired degree of bone resorption, angiogenesis, or proliferation of vascular smooth muscle cells. Human bones undergo a continuous dynamic process of reform, which involves bone resorption and bone formation. These processes are controlled by cell types that specialize for it. The osseous constitution is based on the deposition of bone matrix by osteoblasts, the bone resorption is based on the decomposition of bone matrix by osteoclasts. Most bone diseases are based on a disturbed balance between bone formation and bone resorption. Osteoporosis is characterized by a loss of bone matrix. Activated osteoclasts are plurinuclear cells with a diameter up to 400 μm, which spend the bone matrix. Activated osteoclasts are deposited on the surface of the bone matrix and secrete proteolytic enzymes and acids in the so-called "sealing zone", ie the zone between its cell membrane and the bone matrix. The acidic environment and the proteases give rise to bone decomposition. The compounds of the formula I according to the invention inhibit bone resorption by osteoclasts. Diseases of the bones, against which the compounds according to the invention can be used, are above all osteoporosis, hypercalcemia, osteopenia, p. ex. caused by metastasis, diseases of the teeth, hyperparathyroidism, periarticular erosions in the case of rheumatoid arthritis, and Paget's disease. In addition, the compounds of formula I can be used for the relief, avoidance or therapy of bone diseases, which are caused by a glucocorticoid, steroid or corticosteroid therapy, or by a lack of sex hormone (s) ( is). All these diseases are characterized by bone loss, which is based on the imbalance between the constitution of bones and the decomposition of bones. Studies have shown that the deposition of osteoclasts in bones is controlled by integrin receptors located on the osteoclast cell surface. Integrins are a superfamily of receptors, to which among others belong the fibrinogen receptor d? T ^? 3 in blood platelets and the vitronectin receptor av /? 3. The vitronectin receptor avjß3 is a glycoprotein located in the membranes, which is expressed on the cell surface of a series of cells, such as endothelial cells, vascular smooth muscle cells, osteoclasts and tumor cells. The vitronectin receptor Qtv ^ 3, which is expressed on the osteoclast membrane, controls the process of bone deposition and bone resorption and thus contributes to osteoporosis.
Av / 83 binds in this case to bone matrix proteins, such as osteopontin, the bone sialoprotein and the thromboespona, which contain the tripeptide motif Arg-Gly-Asp (or RGD). Horton et al. Disclose RGD peptides and an anti-vitronectin receptor antibody (23C6), which inhibit osteoclast bone breakdown and osteoclast displacement (Horton et al., Exp. Cell. Res. 1991, 195, 368). . Sato et al. Describe in J. Cell. Biol. 1990, 111, 1. 713 echistatin, which is an RGD peptide from snake venom, as a potent inhibitor of bone resorption in a tissue culture and as an inhibitor of osteoclast adhesion to bones. Fischer et al. (Endocrinolog ?, 1993, 132, 1411) could show in a rat that echistatin also inhibits bone resorption in vivo. The avr 33 vitronectin receptor in human cells of the vascular smooth muscle of the aorta stimulates the displacement of these cells to the neointimal layer, which eventually leads to arteriosclerosis and restenosis after angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815). The compounds of the formula I can also serve as vehicles for active substances, for deliberately transporting the active substance to the site where it has its effect (= Drug Targeting, see eg Targeted Drug Deli very, R.C. Juliano , Handbook of Experimental Pharmacolgy, volume 100, Born compiler, GVR et al., Edi torial Springer Verlag). When referring to the active substances, they are those that can be used for the treatment of the aforementioned diseases. Brooks et al. (Cell 1994, 79, 1157) showed that antibodies against avjS3 or cvjS3 antagonists can produce a contraction of tumors, inducing apoptosis of blood vascular cells during angiogenesis. Chersh et al. (Science 1995, 270, 1,500) describe anti-av3 antibodies or av33 antagonists, which inhibit angiogenesis processes induced by bFGF in the eye of a rat, which could be useful therapeutically in the case of the treatment of retinopa-aunts. In PCT patent application WO 94/12181, substituted or aromatic ring systems are described, substituted heterocycles are described in WO 94/08577 as antagonists of fibrinogen receptors and inhibitors of platelet aggregation. From the European patent documents EP-A-518,586 and EP-A-528,587 there are known phenylalanine derivatives, substituted with aminoalkyl or heterocyclyl, and from WO 95/3? 710 aryl derivatives are known as inhibitory substances of bone resorption by osteoclasts. WO 96/00574 discloses benzodiazepines, and WO 96/00730 molds of fibrinogen receptor antagonists, especially benzodiazepines, which are attached to a 5-membered ring carrying a nitrogen, as antagonists of vitronectin receptors. The subject of the present invention are cycloalkyl derivatives of the formula I
R1-Y-A-B-D-E-F-G I,
where they mean: A direct bond, alkanediyl (C ^ Cg), -NR2-C (0) -NR2- -NR2-C (0) 0-, -NR2-C (0) S-, -NR2- C (S) -NR2-, -NR2-C (S) -0- -NR2-C (S) -S-, -NR-S (0) n-NR2-, -NR2-S (O) n- 0-, -NR2-S (O) n-cycloalkanediyl (C3-C12), -Cs-C-, -NR2-C (0) -, -C (0) -NR2- -arylene (C5-C14) - C (O) -NR2-, -O-, -S (0) n-, -arylene (C5-C14) - -CO-, -arylene (C5-C14) -CO-, -NR2-, -S02- NR2-, -C02-, -CR2 = CR3-, -arylene (C5-C14) -S (0) n-, which in each case may be substituted once or twice with alkanediyl (CL-Cg), such as p. ex. -alkanodiil (C ^ Cg) -CO-NR2-alkanediyl (C1-C8), -alkanodiil (C ^ Cg) -CO-NR2- or -CO-NR2-alkanediyl (C- ^ Cg);
B a direct bond, alkanediyl (Ci-C ^), -CR2 = CR3- or -CsC-, which in each case can be substituted once or twice with alkanediyl (C ^ Cg), such as p. ex. -CH2-C = C-CH2- or -CH2-CR2 = CR3-;
D a direct bond, alkanediyl (C1-C8) or -0-, -NR2-, -C0-NR2-, -NR2-C0-, -NR2-C (0) -NR2-, -NR -C (S) -NR2-, -0C (0) -, -C (0) 0-, -CO-, -CS-, -S (0) -, -S (0) 2-, -S (0) 2-NR2 -, -NR2-S (0) -, -NR2-S (0) 2-, -S-, -CR2 = CR3-, -C-sC- or -CH (OH) -, which in each case can be replaced once or twice with alkanediyl (C ^ Cg); »
E a 6-membered aromatic ring system, which eventually contains up to 4 N atoms and is optionally substituted with 1-4 radical (s), the same or different, taken from the series consisting of R2, R3, fluoro, Cl, Br, I, N02 or OH;
F is as defined D;
R4 (CH2) q-R9 R
And a direct link or -NR2-;
R1 R2-C (= NR2) -NR2-, R2R3N-C (= NR2) -, R2R3N-C (= NR2) -NR2-, or a ring system (s), aromatic or non-aromatic, monocyclic or polycyclic, of 4-10 links, which may eventually contain 1-4 heteroatom (s) taken from the series consisting of N, O and S and may possibly be substituted once or multiple times with substituents of the series formed by R11, R12, R13 and R14;
R3 independently of one another, H, (C1-C10) alkyl, which is optionally substituted once or multiple times with fluoro, or means cycloalkyl (C3-C12), cycloalkyl (C3-C12) -alkanediyl (Cx-C8), aryl (C5-C14), aryl (C5-C14) -alkanediyl (-C8), H2N, (R80) R8NR7, R8OR7, R8OC (0) R7, R8-arylene (C5-C14) -R7, R8R8NR7, HO- alkanediyl (-C8) -NR8R7, R8R8NC (0) R7, R8C (0) NR8R7, R8C (0) R7, R8R8N-C (= NR8) -, R8R8N-C (= NR8) -NR8- or alkyl (c? "c? ß) -carbonyloxy-alkanediyl (C ^ Cg) -oxycarbonyl;
R4 cycloalkyl (C10-C18), cycloalkyl (C10-C18) -alkanediyl (Cx-C8), the cycloalkyl radicals can be monopclic or polycyclic, be saturated or unsaturated once or multiple times and be substituted as described in the case of RG, or R60R7, R6SR7, R6C02R7, R60C (0) R7, R6-arylene (C5-C14) -R7, R6N (R2) R7, R6R8NR7, R6N (R2) C (0) OR9, R6S (0 ) nN (R2) R7, R60C (O) N (R2) R7, R6C (0) N (R2) R7, R6N (R2) C (0) N (R2) R7, R6N (R2) S (O) nN (R2) R7, R6S (0) nR7, R6SC (0) N (R2) R7, R6C (0) R7, R6N (R2) C (O) R7 or R6N (R2) S (0) nR7;
R5 H, fluoro, alkyl (C ^^ - Cg), cycloalkyl (C3-C12), cycloalkyl (C3-C12) -alkanediyl (C1-C8), aryl (C5-C14), aryl (C5-C14) -alcanediyl (C ^ Cg) the alkyl radicals being able to be substituted once or multiply with fluoro;
RG cycloalkyl (C10-C18), cycloalkyl (C10-C18) -alkanediyl (Ci-Cg), the cycloalkyl radicals can be monocyclic or polycyclic, can be saturated or unsaturated once or multiply, and can be substituted once or multiple times with (Cx-C10) alkyl, which is optionally substituted once or multiple times with fluoro, or with (C3-C12) cycloalkyl, (C3-C12) cycloalkyl-alkanediyl (C ^ Cg), aryl (C5-) C14), aryl (C5-C14) -alkanediyl (C ^ Cg), alkoxy (C1-C8), aryl (C5-C14) -alkanediyl (CLC ^ -OXI, aryl (C5-C14) -oxi, alkyl (C ^ Cg) -carbonyloxy-alkanediyl (C 1 -C 4) -oxi, NH 2, mono- or di- (C 1 -Cg alkyl) -amino, aryl (C 5 -C 14) -alkanediyl (C x -C 8) -amino, aryl (C 5) -C14) -amino, = 0, = S, N02, OH, fluoro, Cl, Br or I;
R7 a direct bond or alkanediyl (C-L-Cg);
R8 H, alkyl (CL-Cg), cycloalkyl (C3-C12), cycloalkyl (C3-C12) -alkanediyl (Cx-C8), aryl (C5-C14), aryl (C5-C14) -alkanediyl (C ^ Cg) ), the alkyl radicals being able to be substituted once or multiple times, with fluoro;
R9 C (0) R10, C (S) R10, S (0) nR10, P (0) (R10) n, or a four to eight link heterocycle, saturated or unsaturated, which contains 1, 2, 3 or 4 heteroatom (s) taken from the series consisting of N, O and S, such as p. ex. triazolyl, imidazolyl, pyrazolyl, oxazolyl or thiadiazolyl;
R10 OH, alkoxy (CL-Cg), aryl (C5-C14) -alkanediyl (C ^ Cgl-oxy, aryl (C5-C14) -oxi, alkyl (C ^ Cg) -carbonyloxy-alkanediyl (C1-C4) - oxy, aryl (C5-C14) -alkanodiyl (CL-Cg) -carbonyloxy-alkanediyl (C ^ Cg) -oxi, NH2, mono- or di- (C ^ Cg alkyl) -amino, aryl (C5-C14) - alkanediyl (C ^ Cg) -amino, di- (C ^ Cg alkyl) -aminocarbonyl-methyleneoxy, aryl (C5-C14) -di- (C1-C8 alkyl) -aminocarbonyl-methyleneoxy or aryl (C5-C14) -amino or a radical of an L or D-amino acid;
R11, R12, R13, R14 independently of each other, H, (C1-C10) alkyl which is optionally substituted once or multiply with fluoro, or signify (C3-C12) cycloalkyl, (C3-C12) cycloalkyl-alkanediyl ( Ci-Cg), aryl (C5-C14), aryl (C5-C14) -alkanediyl (C ^ CQ), H2N, (R80) R8NR7, R80R7, R80C (0) R7, R8R8NR7, R8-arylene (C5-C14) ) -R7, HO-alkanediyl (Cx-C8) -N (R2) R7, R8N (R2) C (0) R7, R8C (0) N (R2) R7, R8C (0) R7, R2R3N-C (= NR2) -NR2-, R2R3N-C (= NR2) -, = 0 OR = S;
n 1 6 2;
q 0 or 1,
in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts. Alkyl radicals that occur in substituents can be linear or branched, saturated or unsaturated once or multiple times. The corresponding is valid for the radicals that are derived from these, such as p. ex. alkoxy The cycloalkyl radicals in R2, R3, R5, R8 as well as in R11-R14 can be mono-, bi- or tri-cyclic. The monocyclic cycloalkyl radicals in R2, R3, R5, R8 as well as in R11-R14 are especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, which however can also be substituted for example by alkyl (C ^ C ^. Examples of substituted cycloalkyl radicals are 4-methyl-cyclohexyl and 2,3-dimethyl-cyclopentyl Examples of basic frameworks of monocyclic (C 10 -C 18) cycloalkyl radicals in R 4 or R 6 are, for example, cyclodecane or cyclododecane. bicyclic and tricyclic cycloalkyl in R2, R3, R5, R8 as well as in R11-R14 may be unsubstituted or substituted in any appropriate positions with one or more oxo groups and / or with one or more alkyl groups (CL-J) the same or different, eg methyl or isopropyl groups, preferably methyl groups The bicyclic and tricyclic cycloalkyl radicals (C 10 -C 18) in R 4 or R 6 can be substituted as described therein. The free bond of the bicyclic or tricyclic radical can be found in any position of the molecule, and therefore the radical can be linked through a bridgehead atom or an atom in a bridge. The free bond can also be found in any stereochemical position, for example in an exo or endo position. An example of a bicyclic ring system is decalin (decahydronaphthalene), and an example of a system substituted with an oxo group is 2-decalone. Examples of fundamental frameworks of tricyclic systems are the tuistano (= tricyclo [4.4.0.03,8] ecano, adamantane (= tricyclo [3.3.1.13,7] decane, noradamantane (= tricyclo [3.3.1.03,7] nonane) , the tricycle [2.2.1.02,6] heptane, the tricycle [5.3.2.04,9] dodecane, the tricycle [5.4.0. O2,9] -undecane or the tricycle [5.5.1.03,11] tridecane. Fundamental frameworks of tricyclic cycloalkyl (C10-C18) radicals in R4 or R6 are tuistane (= tricyclo [4.4.0.O3,8] decane, adamantane (= tricyclo- [3.3.1.13,7] decane, noradamantane ( = tricycle [3.3.1.03'7] -nonano), the tricyclo [5.3.2.O4,9] dodecane, the tricycle- [5.4.0. O2,9] undecane or the tricycle [5.5.1.03,11] tridecane Examples of 6-membered aromatic ring systems are phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl and tetrazinyl. for example phenyl, naphthyl, biphenylyl anthryl or fluorenyl, with 1-n being preferred aftyl, 2-naphthyl and especially phenyl. Aryl radicals, especially phenyl radicals, may be substituted once or multiply, preferably once, twice or three times, with the same or different radicals taken from the series consisting of (C x C 8) alkyl, especially alkyl (C). ^ Cj), alkoxy (Ci-Cg), especially (C 1 -C 4) alkoxy, halogen, such as fluoro, chloro and bromo, nitro, amino, trifluoromethyl, hydroxy, methylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl, alkoxy (Cj) ^ j) -carbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R170) 2P (0) -, (R170) 2P (0) -O-, wherein R17 = H, (C-C10) alkyl, (C6-C14) aryl or (C6-C14) aryl ) -alkyl (Cx-C8), or with tetrazolyl. In monosubstituted phenyl radicals the substitution can be found in the 2, 3 or 4 position, with positions 3 and 4 being preferred. If the phenyl is substituted twice, the substituents may be in the 1,2-, 1,3-positions. -1.4 one with respect to the other. Preferably, in two-substituted phenyl radicals the two substituents are arranged in positions 3 and 4, referred to the binding site. The aryl groups can also constitute monocyclic or polycyclic aromatic ring systems, in which from 1 to 5 atom (s) of C can be (are) replaced by 1 to 5 heteroatom (s), such as p. ex. 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinolinyl, 3-carbolinyl, or a derivative, condensed with benzo or condensed with cyclo-penta, cyclohexa or cyclohepta, of these radicals. These heterocycles can be substituted with the same substituents as the aforementioned carbocyclic aryl systems. In the series of these aryl groups, monocyclic or bicyclic aromatic systems with 1-3 heteroatom (s) taken from the series consisting of N, 0 and S, which may be substituted by 1-3 substituent (s), are preferred. taken (s) from the series consisting of (C1-C6) alkyl, alkoxy (CL-Cg), fluoro, Cl, N02, NH2, trifluoromethyl, OH, (C1-C4) alkoxycarbonyl, phenyl, phenoxy, benzyloxy and benzyl Especially preferred in this case are monocyclic or aromatic bicyclic ring systems of 5-10 links with 1-3 heteroatom (s) taken from the series consisting of N, 0 and S, which may be substituted by 1 - 2 substituent (s) taken from the series consisting of alkyl), (C 1 -C 4) alkoxy, phenyl, phenoxy, benzyl or benzyloxy.
The L- or D-amino acids can be natural or non-natural amino acids. Ar-amino acids are preferred. By way of example they will be mentioned (compare Houben-Weyl, Methoden der organischen Chemie, volumes XV / 1 and 2, edi torial Georg Thi eme Verlag, Stuttgart, 1974): Aad, Abu,? Abu, ABz, 2ABz, eAca, Ach , Acp, Adpd, Ahb, Aib, jßAib, Ala, jdAla,? Ala, Alg, All, Ama, Amt, Ape, Apm, Apr,
Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys,
(Cys) 2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dte, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hile, hLeu , hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Lie, Ise, Iva, Kyn, Lant, Len, Leu, Lsg, Lys, 0Lys,? Lys, Met, Mim, nArg, Nle, Nva, Oly, Orn, Bread, Pee, Pen, Phe, Phg, Foot, Pro,? Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, 0Thi , Thr, Thy, Thx, Aunt, Tie, Tly, Trp, Trta, Tyr, Val, tere. -butyl glycine (Tbg), neopentyl-glycine (Npg), cyclohexyl-glycine (Chg), cyclohexyl-alanine (Cha), 2-thienyl-alanine (Thia), 2,2-diphenylaminoacetic acid, 2- acid (p-tolyl) -2-phenylamino-acetic acid and 2- (p-chloro-phenyl) -aminoacetic acid. In addition: pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; 1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid; decahydro-isoquinoline-3-carboxylic acid; octahydro-indole-2-carboxylic acid; decahydro-quinoline-2-carboxylic acid; octahydro-cyclopenta [b] pyrrole-2-carboxylic acid; 2-azabicyclo [2.2.2] octane-3-carboxylic acid; 2-azabicyclo [2.2.1] -heptane-3-carboxylic acid; 2-azabicyclo [3.1.0] hexane-3-carboxylic acid; 2-aza-spiro [4.4] nonane-3-carboxylic acid; 2-aza-spiro [4.5] decane-3-carboxylic acid, - spiro- (bicyclo [2.2.1] heptane) -2,3-pyrrolidine-5-carboxylic acid; Spiro acid (bicyclo [2.2.2] octane) -2, 3-pyrrolidine-5-carboxylic acid; 2-aza-tricyclo [4.3.0.l6,9] decane-3-carboxylic acid; decahydro-cyclohepta [b] pyrrole-2-carboxylic acid; decahydro-cycloocta [c] pyrrole-2-carboxylic acid; octahydro-cyclopentafc] -pyrrole-2-carboxylic acid; octahydro-isoindol-1-carboxylic acid; 2,3, 3a, 4, 5, 6a-hexahydro-cyclopenta [b] pyrrole-2-carbo-xylic acid; 2, 3, 3a, 4, 5, 7a-hexahydro-indole-2-carboxylic acid; tetrahydro-thiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine-3-carboxylic acid and hydroxypyrrolidine-2-carboxylic acid, all of which may be optionally substituted (see the following formulas):
The heterocycles which form the basis of the aforementioned radicals are known, for example, from US Pat. No. 4,344,949; US-A 4,374,847; US-A 4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682. In addition, amino acids can also be present as esters or amides, such as p. ex. methyl esters, ethyl esters, isopropyl esters, isobutyl esters, esters tere. -butyls, benzyl esters, ethylamides, semicarbazides or? -amino-alkyl (C2-C8) -amides. The functional groups of the amino acids can be present in the protected state. Suitable protective groups such as p. ex. Urethane protective groups, urethane protecting groups, carboxyl protecting groups and side chain protecting groups are described in the literature references of Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23 and in Búllesbach, Kontakte (Merck). ) 1980, n "1, pages 23 to 35. Especially will be mentioned: Aloe, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (N02), Z (Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tere.-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pie and Trt The physiologically compatible salts of the compounds of the formula I are especially pharmaceutically usable or non-toxic salts. they are formed, for example, by compounds of the formula I, which contain acid groups, p. ex. carboxy, with alkali or alkaline earth metals, such as p. ex. Na, K, Mg and Ca, as well as with physiologically compatible organic amines, such as p. ex. triethylamine, ethanolamine or tris- (2-hydroxy-ethyl) -amine. The compounds of the formula I, which contain basic groups, p. ex. an amino group, an amidino group or a guanidinq group, form salts with inorganic acids, such as p. ex. hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulfonic acids, such as p. ex. acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. The compounds of the formula I according to the invention can contain optically active carbon atoms, which, independently of one another, can have R or S configurations, and consequently occur in the form of pure enantiomers or pure diastereoisomers, p in the form of mixtures of enantiomers or mixtures of diastereomers. Both the pure enantiomers and the mixtures of enantiomers as well as the diastereomers and the mixtures of diastereomers are object of the present invention. The invention encompasses mixtures of two stereoisomers and of more than two stereoisomers of the formula I and all the ratios in which the stereoisomers can be present in the mixtures. The compounds of the formula I according to the invention can be present in the form of mixtures of E and Z isomers, in case A, D or F, independently of one another, are -CR2 = CR3-. Both pure E or Z isomers and mixtures of E and Z isomers in all ratios are subject of the present invention. The diastereoisomers, including the E and Z isomers, can be separated into the individual isomers by chromatography. The racemates can be separated into both enantiomers either by chromatography on chiral phases or by splitting racemates. The compounds of the formula I according to the invention can also contain mobile hydrogen atoms, that is to say they can be present in different tautomeric forms. Also these tautomers are object of the present invention. Preferred are the compounds of the formula I, in which they mean:
To a direct bond, alkanediyl (CL-Cg), -NR2-C (0) -NR2-, -NR2-C (0) 0-, -NR2-C (0) S-, -NR2-C (S) -NR2-, NR2-C (S) -O-, '-NR2-C (S) -S-, -NR2-S (0) n-NR2-, -NR-S (O) n-0-, -NR2-S (O) n-, cycloalkanediyl (C3-C8), -CSC-, -NR2-C (0) -, -C (0) -NR2-, arylene (C5-C12) -C (O) -NR2-, -0-, -S (0) n-, -arylene (C5-C12) -, -CO-, -arylene (C5-C12) -CO-, -NR2-, -S02-NR2-, -C02-, -CR2 = CR3-, arylene (C5-C12) -S (O) n-, which in each case may be substituted once or twice with alkanediyl (C1-C8), -
B a direct bond, alkanediyl (C ^ Cg), -CR2 = CR3- or -C-BC-, which in each case may be substituted once or twice with alkanediyl (C ^ Cg);
D a direct bond, alkanediyl (Cx-C8) or -0-, - NR2-, -CO-NR2-, -NR2-C0-, -NR2-C (0) -NR2-, -NR2-C (S ) -NR2-, -0C (0) -, -C (0) -0-, -CO-, -CS-, -S (O) -, -S (0) 2-, -S (0) 2 -NR2-, -NR2-S (0) -, -NR2-S (0) 2-, -S-, -CR2 = CR3-, -CsC-, which in each case may be substituted once or twice with alkanediyl (C ^ Cg),
E is a 6-membered aromatic ring system (s), which optionally contains 1 or 2 atom (s) of N and is optionally substituted by 1-3 radicals, identical or different, taken from the series formed by
R2, R3, fluoro, Cl or OH;
F is as defined D;
And a direct link or -NR2-;
R1 R2-C (= NR2) -NR2-, R2R3N-C (= NR2) -, R2R3N-C (= NR2) -NR2-, or an aromatic or non-aromatic ring system, monocyclic or polycyclic, 4-10 links, which may optionally contain 1-4 heteroatom (s) taken from the series consisting of N, O and S and optionally may be substituted once or multiple times with substituents of the series consisting of R 11, R12, R13 and R14;
R2, R3 independently of one another, H, (C1-C8) alkyl, which may optionally be substituted once or multiple times with fluoro, or mean (C3-C8) cycloalkyl, (C3-C8) cycloalkyl-alkanediyl (C ^) Cg), aryl (C5-C12), aryl (C5-C12) -alkanediyl (C ^ Cg), H2N, (R80) R8NR7, R8pR7, R80C (0) R7, R8-arylene (C5-C12) -R7, R8R8NR7, HO-alkanediyl (-Cg) -NR8R7, R8R8NC (0) R7, R8C (0) NR8R7, R8C (0) R7, R8R8N-C (= NR8) -, R8R8N-C (= NR8) -NR8- or (C 1 -C 10) alkylcarbonyloxy-alkanediyl (CLC 4 -oxocarbonyl;
R4 cycloalkyl (C10-C16) or (C10-C16) cycloalkyl-alkanediyl (CL-Cg), the cycloalkyl radicals can be monocyclic or polycyclic, can be saturated or unsaturated once or multiple times and be substituted as described in the case of Re o mean R60R7, R6SR7, R6SR7, R6C02R7, R60C (0) R7, R6-arylene (C5-C12) -R7, R6N (R2) R7, R6R8NR7, R6N (R2) C (O) OR7, R6S (O ) nN (R2) R7, R6OC (0) N (R2) R7, R6C (O) N (R2) R7, R6N (R2) C (O) N (R2) R7, R6N (R2) S (0) nN (R) R7, R6S (0) nR7, R6SC (O) N (R2) R7, R6C (0) R7, R6N (R2) C (0) R7 or R6N (R2) S (0) nR7,
R5 H, alkyl (C ^ Cg), cycloalkyl (C3-C8), cycloalkyl (C3-C8) -alkanediyl (Cx-C6), aryl (C5-C10), aryl (C5-C10) -alkanediyl (CL-Cg) ), the arylalkyl radicals being able to be substituted with fluoro once or multiple times;
R6 cycloalkyl (C10-C16) or (C10-C16) cycloalkyl-alkanediyl (CL-Cg), the cycloalkyl radicals being bicyclic or tricyclic, being saturated or unsaturated once or multiple times, and substituted once or multiple times with alkyl (CL-Cg), which is optionally substituted once or multiple times with fluoro, or means cycloalkyl (C5-C6), cycloalkyl (C5-C6) -alkanediyl (C ^ Cg), aryl (C5-C10), aryl (C5-C10) -alkanediyl (C ^ Cg), alkoxy (Cx-Cg), aryloxy (C5-C10), aryl (C5-C10) -alkanediyl (Cx-Cg) -oxi, NH2, mono- or di - (C1-C6 alkyl) -amino, = 0, OH, fluoro or Cl;
R7 a direct bond or alkanediyl (C-L-Cg);
R8 H, alkyl (C ^ Cg), cycloalkyl (C3-C8), cycloalkyl (C3-C8) -alkanediyl (Cx-C6), aryl (C5-C12), aryl (C5-C12) -alkanediyl (C ^ Cg) ), the alkyl radicals being able to be substituted once or multiply with fluoro;
R9 C (0) R10, C (S) R10, S (0) nR10, P (O) (R10) not a saturated or unsaturated heterocycle, of four to eight links, which contains 1, 2, 3 or 4 heteroatom (s) taken from the series consisting of N, 0 and S;
R10 OH, (C1-C6) alkoxy, aryl (C5-C12) -alkanediyl (C ^ Cg) -oxi, aryl (C5-C12) -oxi, alkyl (C ^ Cg) -carbonyloxy-alkanediyl (CLC ^ -OXÍ , aryl (C5-C12) -alkanodiyl (C ^ Cg) -carbonyl-oxy-alkanediyl (Ci-CgJ-oxy, NH2, mono- or di- (C-Cg alkyl) -amino, aryl (C5-C12) - alkanediyl (C ^ Cg) -amino or di- (alkyl ^ -Cg) -aminocarbonylmethyleneoxy;
R11, R12, R13, R14 independently of each other, H, alkyl (Cj ^ -Cg), which is optionally substituted once or multiply with fluoro, or means cycloalkyl (C3-C8), cycloalkyl (C3-C8) - alkanediyl (Cj ^ -Cg), aryl (C5-C12), aryl (C5-C12) -alkanediyl (Ci-Cg), H2N, (R80) R8NR7, R80R7, R80C (0) R7, R8-aryl (C5-) C12) -R7, R8R8NR7, HO-alkyl (C ^ Cg) -N (R2) R7, R8N (R2) C (0) R7, R8C (0) N (R2) R7, R8C (0) R7, R2R3N- C (= NR2) R2R3N-C (= NR3) -NR2-, = 0 OR = S;
1 OR 2;
0 or 1;
in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts. Especially preferred are compounds of formula I, in which they mean:.
To a direct bond, alkanediyl (C1-C6), -NR2-C (0) -NR2-,
-NR2-C (0) 0-, -NR2-S (0) n-NR2, -NR2-S (0) n-, cycloalkanediyl (C3-C6), -CSC-, -NR2-C (0) - , -C (0) -NR2-,
-0-, -CO-, -NR2-, -0-, -CO-, -NR2-, -C02-, -CR2 = CR3, which may be substituted in each case once or twice with alkanediyl (Cx) -C6);
B a direct bond, alkanediyl (Cx-C6), -CR2 = CR3-, which may be substituted once or twice with alkanediyl (C - ^ - C8);
D a direct bond, alkanediyl (C ^ Cg) or -0-, - NR2-, -NR2-C0-, -C (0) NR2-, -NR2-C (0) -NR2-, -0C (0 ) -, -C (0) -, -S (0) 2-NR2-, -NR2-S (0) -, -NR2-S (0) 2-, which in each case may be substituted once or twice with alkanediyl (C ^ Cg);
E phenylene or pyridinediyl, which is optionally substituted with 1-3 radical (s), the same or different, taken from the series consisting of R2 and R3, -
F a direct bond, alkanediyl (Cx-C6), or -0-, -CO-NR2-, -NR2-C0-, -NR2-C (0) -NR2-, -0C (0) -, -C (0) 0-, -CO-, -S (0) 2-, -S (0) 2-NR2, -NR-S (0) 2-, -CR2 = CR3-, -CsC-, which in each case may be substituted once or twice, sometimes with alkanediyl (C ^ Cg); a direct link or -NH-, R | -
R3 independently of one another, alkyl (CL-Cg), which is optionally substituted once or multiply, preferably 1-6 times, with fluoro, or means (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-alkanediyl ( Cx-C4), aryl (C5-C10), aryl (C5-C10) -alkanediyl (CLC ^, H2N, R8OR7, Rd-arylene (C5-C10) -R7, R8NHR7, R8R8NR7, R8NHC (0) R7, H2N -C (= NH) -, H2N-C (= NH) -NH-;
cycloalkyl (C10-C14) or cycloalkyl (C10-C14) -alkanediyl (C ^ Cg), the cycloalkyl radicals being bicyclic or tricyclic, and substituted 1-3 times with alkyl (Cx-C6), trifluoromethyl, pentaf luoroethyl , phenyl, benzyl, alkoxy (C ^ Cg), phenoxy, benzyloxy, NH2, = 0 or mono- or di- (C ^ -Cg alkyl) -amino; or they mean R60R7, R6C02R7, R60C (0) R7, R6NHR7, R6R8NR7, R6NHC (0) 0R7, R6S (0) nNHR7, R6OC (0) NHR7, R6C (0) NHR7, R6C (0) R7, R6NHC (0) NHR7 OR R6NHC (0) R7;
R 5 H, (C 1 -C 6) alkyl, (C 5 -C 6) cycloalkyl, (C 5 -C 6) cycloalkyl (C 1 -C 6) alkanediyl, trifluoromethyl, pentafluoroethyl, phenyl or benzyl;
R6 cycloalkyl (C10-C14) or cycloalkyl (C10-C14) -alkanediyl (Cx-C6), the cycloalkyl radicals being bicyclic or tricyclic, and substituted 1-3 times with alkyl (C ^ Cg), trifluoromethyl, pentafluoroethyl , phenyl, benzyl, (Cx-Cg) alkoxy, phenoxy, benzyloxy, NH2, = 0 or mono- or di- (Cj-.Cg) alkylamino;
R7 a direct bond or alkanediyl (Cx-C8);
R8 H, alkyl (C ^ Cg), cycloalkyl (C3-C6), cycloalkyl (C3-C6) -alkanediyl (Cx-C4), aryl (C5-C10), aryl (C5-C10) -alkanediyl (C ^ - C ^, the alkyl radicals being able to be substituted by 1-6 fluorine atoms, -
R9 C (O) R10;
R10 OH, alkoxy (Ci-Cg), aryl (C5-C10) -alkanediyl (Cx-C6) -oxi, aryl (C5-C10) -oxi, alkyl (CL-Cg) -carbonyloxy-alkanediyl (Ci-C4) -oxi, aryl (C5-C10) -alkanediyl (Cx-C4) -carbonyloxy-(C1-C4) alkanediyl-oxy, NH2, mono- or di- (Cx-alkyl) -amino;
R11 H, (Cx-C6) alkyl, which is optionally substituted with fluoro once or multiple times, (C3-C6) cycloalkyl, (C3-C6) cycloalkyl-alkanediyl (CLC ^, aryl (C5-C10), aryl (C5-C10) -alkanaldi (Cx-C4), H2N, R80R7, R8OC (0) R7, R8-arylene (C5-C10) -R7, R8R8NR7, R8NHC (0) R7, R8C (0) NHR7, H2N- C (= NH) -, H2N-C (= NH) -NH-, = 0;
n 1 or 2;
q O or 1;
in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts. Especially preferred are the compounds of the formula I, in which they mean: A direct bond, alkanediyl (Cx-C4), -NR2-C (0) -NR2-, -NR2-C (0) 0-, - NR2-S (0) n-, -NR2-S (0) n-NR2- OR -NR2-CO-, -NR2-, which may be substituted in each case once or twice with alkanediyl (Cx-C4 );
B a direct bond or alkanediyl (C-L-Cg);
D a direct bond, alkanediyl (Cx-C4), or -O-, -NR2-, -NR2-CO-, -C (0) -NR2-, -NR2-C (O) -NR2-, which in each case they may be substituted once or twice with alkanediyl (CLC ^;
E phenylene or pyridinadiyl, which is optionally substituted with 1 or 2 radicals taken from R2 and R3, -
F a direct bond, alkanediyl (Cx-C6), or -O-, -CO-NR2-, -NR2-CO-, -NR2-C (0) -NR2-, -S (0) 2-NR2- , -NR2-S (0) 2-, -CR2 = CR3-, -CsC-, which in each case may be substituted once or twice with alkanediyl (Cx-C4), -
a direct link or -NH;
R2R3N-C (= NR2)
R2, R3 independently of one another, H, (Cx-C6) alkyl, trifluoromethyl, pentaf luoroe yl, (C5-C6) cycloalkyl, (C5-C6) cycloalkyl-alkanediyl (CLC ^, phenyl, benzyl, H2N, R8OR7, R8R8NR7, R8NHC (0) R7, H2N-C (= NH) -, H2N-C (= NH) -NH-;
R4 cycloalkyl (C10-C12), (C10-C12) cycloalkyl-alkanediyl (Ci-Cg), or R60R7, R6R8NR7, R6NHC (0) OR7, R6S (0) nNHR7, R6OC (0) NHR7, the cycloalkyl radicals being 1-adamantyl or 2-adamantyl preference and the cycloalkyl-alkanediyl radicals preferably adamantyl-1-alkanediyl (Cx-C3) or adamantyl-2-alkanediyl (Cx-C3) and may be substituted 1 or 2 times with alkyl (C x) -C4), trifluoromethyl, phenyl, benzyl, alkoxy (CLC ^, phenoxy, benzyloxy, = 0 or mono- or di- (CX-C4 alkyl) -amino, with adamantyl radicals being substituted once or twice as especially preferred. The cycloalkyl radicals (Cxl-C12) unsubstituted or substituted 1 or 2 times as described above are described above;
R5 H, (Cx-C4) alkyl or trifluoromethyl;
R6 cycloalkyl (C10-C12), (C10-C12) cycloalkyl-alkanediyl (Ci-Cg), the cycloalkyl radicals being preferably l-adamantyl or 2-adamantyl and the cycloalkyl-alkanediyl radicals preferably adamantyl-1-alkanediyl (Cx-C3 ) or adamantyl-2-alkanediyl (C ^ C- ^) and may be substituted once or twice with (Cx-C4) alkyl, trifluoromethyl, phenyl, benzyl, alkoxy (CLC ^, phenoxy, benzyloxy, = 0 or mono or di- (C 1 -C 4 alkyl) -amino, with adamantyl radicals substituted 1 or 2 times as described above or the cycloalkyl radicals (C x 1 -C 12) unsubstituted or substituted 1 or 2 times as is described above;
R7 a direct bond or alkanediyl (C ^ Cg);
R8 H, (Cx-C6) alkyl, (C5-C6) cycloalkyl, (C5-C6) cycloalkyl-alkanediyl (Cx-C2), (C5-C6) aryl or (C5-C6) aryl-alkanediyl (C1-C2) '> • C (0) R10;
R 10 OH, (C 1 -C 6) alkoxy, phenoxy, benzyloxy, C 1 -C 4 alkylcarbonyloxy-(C 1 -C 4) alkoxy, NH 2 or mono- or di- (C 1 -C 4 alkyl) amino; 1 or 2;
q 0 6 1;
in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts. . Especially preferred are the compounds of the formula I, in which they mean: A -NH-C (O); B alkanediyl (Cx-C4); D -O-, -NR2-C (0) -, -C (0) -NR2- or a direct bond; E phenylene or pyridinadiyl; F -CH2- or -C (O) NHCH, - R4
a direct link; H2N-C (= NH) -,
R ^ H or alkyl (Cx-C4); R6OC (0) NH-; R5 H; adamantyl-1-alkylene (C1-C3), adamantyl-2-alkylene (C1-C3), 1-adamantyl, 2-adamantyl, adamantyl being preferably substituted once or twice with (Cx-C4) alkyl, trifluoromethyl, phenyl, benzyl, (Cx-C4) alkoxy, phenoxy or benzyloxy, or (C11-C12) cycloalkyl, which may be substituted 1 or 2 times as above; R9 C (0) R10; R10 OH, (Cx-C6) alkoxy, phenoxy, benzyloxy or (Cx-C4) alkoxy-carbonyloxy-(C1-C4) alkanediyl-oxy; in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts. The compounds of the formula I can be prepared in general terms, for example in the course of a convergent synthesis, by joining two or more fragments, which can be derived retrosynthetically from the formula I. In the case of the preparation of the compounds of the formula I it may generally be necessary, in the course of the synthesis, to temporarily block functional groups, which in the respective stage of synthesis could lead to unwanted reactions or secondary reactions, by means of a protective group strategy which is adapted to the problem of synthesis, which is known to a person skilled in the art. The method of binding fragments is not limited to the following Examples, but can be applied in general terms for synthesis of the compounds of the formula I. For example, compounds of the formula I of the type,
R1-Y-A-B-D-E-C (O) NR2-G,
wherein F in formula I represents -C (0) NR2-, can be prepared by condensation of a compound of formula II,
R ^ Y-A-B-D-E-M II,
representing M-hydroxycarbonyl, (C ^ Cg) -carbonyl alkoxy, activated carboxylic acid derivatives such as acid chlorides, active esters or mixed anhydrides, with HNR2-G. For the condensation of two fragments with the formation of an amide bond, the known coupling methods of peptide chemistry are advantageously used (see, for example, Houben-Weyl, Methoden der Organischen Chemie, vol. 15/1 and 15). / 2, Georg Thieme Verlag, Stuttgart, 1974). For this purpose, it is generally necessary that the amino groups present, which have not reacted, be protected during condensation by reversible protective groups. The same is true for carboxyl groups that do not participate in the reaction, which are preferably used in the form of esters of alkyl (Ci-Cg), benzyl or tere. -butyl. A protection of amino groups becomes unnecessary when the amino groups to be generated are still present as nitro or cyano groups and are formed by hydrogenation only after coupling. After coupling, the protective groups present are separated in an appropriate manner. For example, N02 groups (for guanidino protection), benzyloxycarbonyl groups and benzylic esters can be removed by hydrogenation. The protective groups of the type of tere. -butyl are separated under acidic conditions, while the 9-fluorenylmethyloxycarbonyl group is removed by means of secondary amines. The compounds of the formula I, in which R1 has the indicated meaning, Y represents -NR2- and A represents -C (0) -, can be prepared according to the generally known coupling methods of peptide chemistry, by coupling of R1-NR2H with H02C-BDEFG. The compounds of the formula I, in which R9 = S02R10, are prepared for example by oxidizing compounds of the formula I with R9 = SH according to procedures known from the literature (cf. Houben-lVeyl, Methoden der Organischen Chemie, volume E12 / 2, Georg Thieme Verlag Verlag, Stuttgart 1985, pages 1, 058 et seq.) To form compounds of the formula I with R9 = S03H, from which they are subsequently prepared directly or through corresponding sulphonic acid halides, by esterification
0 coupling of an amide bond, the compounds of formula I wherein R9 = S02R10 (R10? OH). The sensory groups for oxidation existing in the molecule, such as p. ex. amino, amidino or guanidino groups are protected, if necessary, prior to carrying out the oxidation by appropriate protective groups. The compounds of the formula I in which R9 = S (0) R10 are prepared, for example, by converting compounds of the formula
1 in which R9 = SH in the corresponding sulfide (R9 = S?) And then oxidizing it with meta-chloroperbenzoic acid to give the sulfinic acids (R9 = S02H) (cf. Houben-Weyl, Methoden der Organischen Chemie, volume Ell / 1, edi torial Georg Thieme Verlag, Stuttgart 1985, pages 618 et seq.) from which, according to methods known from the literature, the corresponding esters or amides of sulfinic acids in which R9 = S ( 0) R10
(R10? OH). In general terms, other methods known from the literature can also be used for the preparation of compounds of the formula I in which R9 = S (0) nR10 (n = 1.2) (cf. Houben-Weyl, Methoden der Organischen Chemie, volume Ell / 1, editorial Georg Thieme Verlag, Stuttgart 1985, page 618 et seq. Or volume The 1/2, Stuttgrart 1985, pages 1. 055 et seq.). The compounds of the formula I in which R9 = P (O) (R10) n (n = 1.2) are constituted from suitable precursor compounds according to methods known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie , volumes El and E2, editorial Georg Thieme Verlag, Stuttgart 1982), having to adapt the chosen synthesis method to the target molecule. The compounds of the formula I in which R9 = C (S) R10 can be prepared according to procedures of the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, volumes E5 / 1 and E5 / 2, Georg Editorial Thieme Verlag, Stuttgart 1985).
The compounds of the formula I in which R9 = S (0) nR10 (n = 1.2), P (0) (R10) n (n = 1.2) or C (S) R10 can also be prepared naturally by fragment coupling as described above, which is advisable for example when in FG of formula I they are contained p. ex. an aminosulfonic acid, aminosulfinic acid, aminophosphonic acid or aminophosphonic acid (commercial) or derivatives obtained therefrom, such as esters or amides. The compounds of the formula I, in which R1-Y-A represents
R2R3N C (= NR2) -N-C (O) - ° cyclic acylguanidines of the type,
R
can be prepared for example
reacting a compound of formula III,
Q (O) C-B-D-E-F-G m
wherein Q represents a labile group easily substituted nucleophilically, with the corresponding guanidine (or one of its derivatives) of the type
or with cyclic guanidine (or one of its derivatives) of the type
The activated acid derivatives of the formula III, wherein Q means an alkoxy group, preferably methoxy, a phenoxy group, or a phenylthio group, methylthio, 2-pyridylthio, a heterocycle with nitrogen, preferably 1-imidazolyl, are advantageously obtained in a manner known per se from the carboxylic acids (Q = OH) or chlorides of carboxylic acids (Q = Cl) which constitute its basis. The latter are obtained in turn in a manner known per se from the carboxylic acids (Q = OH) which constitute their basis, for example by reaction with thionyl chloride.
In addition to the carboxylic acid chlorides (Q = Cl), other activated derivatives of the Q (0) C-type acids can also be prepared in a manner known per se directly from the carboxylic acids (Q = OH) which constitute its base, such as for example the methyl esters (Q = OCH3) by treatment with gaseous HCl in methanol, the imidazolides (Q = 1-imidazolyl) by treatment with carbonyl-diimidazole [cf. Staab, Angew. Chem. International Edition in English 1, 351 -367 (1962)], mixed anhydrides (Q = C2H5COC (0) 0 or TosO) with C1-C002H5 or tosyl chloride (toluenesulfonyl) in the presence of triethylamine in a inert solvent. Activation of the carboxylic acids can also be carried out with dicyclohexylcarbo-diimide (DCC1) or with 0 - [(cyano- (ethoxycarbonyl) methylene) amino] -1,3,3,3-tetramethyl-uronium tetrafluoroborate or ("TOTü" ) [Weiss and Krommer, Chemiker Zeitung 98, 817 (1974)] and with other activation reagents that are common in the chemistry of peptides. A number of methods suitable for the preparation of activated carboxylic acid derivatives of the formula II are indicated, with reference to the source literature, in J. March, Advanced Organic Chemistry, third edition (John Wiley &Sons, 1985), page 350. The reaction of an activated carboxylic acid derivative of the formula III with the respective guanidine (or one of its derivatives) is carried out in a manner known per se in a polar protic or aprotic organic solvent, but inert . In such a context in the case of reaction of esters
methyl (Q = 0CH3) with the respective guanidines, methanol, isopropanol or THF at a temperature of from 20 ° C to the boiling point of these solvents. In the majority of the reactions of compounds of the formula III with guanidines free of salts, it is advantageously employed in
the sine of inert aprotic solvents such as THF, dimethoxyethane or dioxane. Na However, water can also be used with the use of a base (such as for example NaOH) as solvent in the case of the reaction of compounds of formula III with guanidines. When Q means Cl, it
advantageously works with the addition of an acid trapping agent, e.g. ex. in the form of guanidine (or one of its derivatives) in excess, for the fixation and separation of the halogenated hydrazide. The compounds of the formula I, in which R1-Y-A-25 represents R2-C (= NR2) -C (0) - or a system containing a monocyclic or polycyclic radical of the type
3 - . 3 -.n0 C (O) - can be used in a similar way. The compounds of the formula I, in which R1-Y-A- represents a sulfonyl- or sulfoxyl-guanidine of the type
R2R3N-C (= NR2) -NR-S (0) n- (n = 1.2) or a sulphonyl- or sulfoxyl aminoguanidine of the type R2R3N-C (= NR2) -NR2-NR2-S (0) n - (n = 1,2)
or
they are obtained according to processes known from the literature by reacting R2R3N-C (= NR2) NR2H or R2R3N-C (= NR2) -NR2v-NR2H or else.
with sulfinic or sulphonic acid derivatives of the formula IV,
Q-S (O) n-B-D-E-F-G IV
in which Q means p. ex. Cl or NH2, analogously to S. Birtwell et al. , J. Chem. Soc. (1946), 491 or Houben-Weyl, Methoden der Organischen Chemie, volume E4, Georg Thieme Verlag, Stuttgart 1983, pages 620 et seq. The compounds of the formula I, in which R1-YA-represents R2-C (= NR2) -S (0) n- (n = 1.2) or R2-C (= NR2) -NR-NR2-S (0) n- (n = 1,2) or a system containing a monocyclic or polycyclic radical of the type
(n = 1,2), can be obtained analogously. The compounds of the formula I, in which Y has the indicated meaning, A represents -NR2-C (0) -NR2-,, -NR2-C (0) 0-, -NR2-C (0) S- and R1 represents R2R3N-C (= NR2) -, R2C (= NR2) - or a ring system (s), aromatic or non-aromatic, monocyclic or polycyclic, of 4-10 links, which is specified such as - described above and may be substituted as described therein, p. ex. by reacting a compound of the formula V
Q-B-D-E-F-G V
wherein Q represents HNR2-, HO- or HS-, with an appropriate derivative of carbonic acid, preferably phosgene, diphosgene (trichloromethyl ester of chloroformic acid), triphosgene (bis-trichloromethyl carbonic acid ester), chloroformic acid ethyl ester , iso-butyl ester of chloroformic acid, bis- (1-hydroxy-1H-benzo-triazolyl) carbonate or N, N '-carbonyl-diimidazole, in a solvent inert to the reagents used, preferably DMF, THF or toluene, at a temperature comprised between -20 ° C and the boiling point of the solvent, preferably between 0 ° C and 60 ° C, first to form a substituted carbonic acid derivative of the formula VI
VI wherein R represents -NR2-, -O- or -S- and Q ', depending on the carbonic acid derivative used, represents chloro, ethoxy, isobutoxy, benzotriazole-1-oxy or 1-imidazolyl. The reaction of these derivatives - in the case where Y means a direct bond - with R2R3N-C (= NR2) -NR2H or
R2-C (= NR2) -NR2H or, in the case where Y represents -NR2-, with R2R3N-C (= NR2) -NR2-NR2H or R2-C (= NR2) -NR2-NRH or with the systems containing a monocyclic or polycyclic radical of the type
it is carried out as described above in the case of the preparation of acylguanidines (or their derivatives). The compounds of the formula I, in which F represents -R2N-C (0) -NR2- or -R2N-C (S) -NR2-, are prepared for example by reacting a compound of the formula VII
R1-Y-A-B-D-E-NHR2 Vil
with an OCN-G isocyanate or SCN-G isothiocyanate according to methods known from the literature. The compounds of the formula I, in which F represents -C (0) NR2-, -S02NR2- or -C (0) 0-, can be obtained according to procedures of the literature p. ex. by reaction of R1-Y-A-B-D-E-C (O) Q R1-Y_A-B-D-E-SO2Q
(Q is a leaving group, easily substituted nucleophilically, such as eg OH, Cl, OCH3, etc.) with HR2N-G or HO-G. The compounds of the formula I, in which Y is a bond and R- ^ A- contain a monocyclic or polycyclic radical of the type
can be prepared, for example,
reacting a compound of the formula VIII \ HR2N-B-D-E-F-G Vlll
with a monocyclic or polycyclic radical of the type
wherein X represents a nucleophilically substitutable leaving group, such as p. ex. Halogen or SH, SCH3, SOCH3, S02CH3 or HN-N02, according to methods known from the literature (see, for example, AF Mckay et al., J. Med. Chem. 6 (1963) 587, MN Buchman et al., J. Am. Chem. Soc. 71 (1949), 766, F. Jung. Et al., J. Med. Chem. 34 (1991) 1 .110 or G. Sorba et al., Eur. J. Med. Chem. 21 (1986), 391). The compounds of the formula I, in which Y is a bond and Rx-A- contains a monocyclic or polycyclic radical of the type e can be prepared, for example, by reacting a compound of the formula VIII with a compound of the type
to a labile group,
according to known methods of the literature (cf., eg, R. Hiroki et al., Synthesis (1984) 703, or M. Purkayastha et al., Indian J. Chem. Sect. B 30 (1991) 646). The compounds of the formula I, in which D represents -CsC-, can be prepared, for example, by reacting a compound of the formula IX, X-E-F-G IX
where X means I or Br, with a compound of the type
R1-Y-A-B-C- "CH in a palladium catalyzed reaction, as described p. ex. in the bibliographic citations of A.
Arcadi et al. , Tetrahedron Lett. 1993, 34, 2. 813 or E.C.
Taylor et al. , J. Org. Chem. 1990, 55, 3, 222. Analogously, compounds of the formula I, in which F is equal to -CsC-, can be prepared, for example by coupling compounds of the formula X,
R1-Y-A-B-D-E-X X
wherein X means I or Br, with a compound of the type HC = C-G in a palladium catalyzed reaction. The known preparation methods of the literature are described p. ex. in the work of < J. March, Advanced Organic Chemistry, third edition (John Wiley &Sons, 1985). The compounds of the formula I and their physiologically compatible salts can be administered to an animal, preferably to a mammalian animal, and especially to a human being, as a medicine on their own, in mixtures with one another or in the form of pharmaceutical preparations, which allow an enteral or parenteral application, and which contain as an active constituent an effective dose of at least one compound of the formula I or one of its salts together with pharmaceutically acceptable vehicle substances and additives. The preparations normally contain about 0.5 to 90% by weight of the therapeutically active compound. Medications can be administered orally, p. ex. in the form of pills, tablets, varnished tablets, dragees, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or mixtures for aerosols. The administration can be carried out, however, also by the rectal route, e.g. ex. in the form of suppositories, or via the parenteral route, p. ex. in the form of solutions for injection or infusion, microcapsules or rods, percutaneously, p. ex. in the form of ointments or tinctures, nasally, p. ex. in the form of nasal nebulization. The production of the pharmaceutical preparations is carried out in a manner known per se, using pharmaceutically inert inorganic or organic carrier materials. For the manufacture of pills, tablets, dragees and hard gelatin capsules, p. ex. lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. The carrier materials for soft gelatin capsules and suppositories are p. ex. fats, waxes, semi-solid and liquid polyols, natural or hardened oils, etc. As carrier materials for the preparation of solutions and syrups, p. ex. water, sucrose, invert sugars, glucose, polyols, etc. As vehicle materials for the preparation of injectable solutions, water, alcohols, glycerol, polyols, vegetable oils, etc. are suitable. As carrier materials for microcapsules, implants or rods, for example, copolymers of glycolic acid and lactic acid are suitable.
The pharmaceutical preparations, together with the active and vehicle substances, may also contain additive substances, such as p. ex. fillers, spreading agents, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, dyes, flavorings or flavoring agents, thickeners, diluents, buffer substances, in addition solvents or solubilizers or agents to achieve a deposition effect ( delayed release), as well as salts for the modification of osmotic pressure, coating agents or antioxidants. These may also contain two or more compounds of the formula I or their physiologically compatible salts; in addition, together with at least one compound of the formula I may also contain one or more other therapeally active substances. The dose can vary within wide limits and has to be adapted in each individual case to the individual circumstances. In the case of an oral administration, the daily dose generally amounts to values between 0.01 and 50 mg / kg, preferably between 0.1 and 5 mg / kg, preferably between 0.3 and 0.5 mg / kg of body weight, in order to achieve effective results. In the case of an intravenous application, the daily dose is generally about 0.01 to 100 mg / kg, preferably 0.05 to 10 mg / kg of body weight. The daily dose, especially in the case of the application of high amounts, can be subdivided into several, p. ex. 2, 3 or 4, partial administrations. Eventually, depending on the individual behavior, it may be necessary to move towards higher values or towards lower values of the indicated daily dose.
Examples
The products were identified by mass spectra and / or nuclear magnetic resonance (NMR) spectra.
Acid (2SJ? "F (aTtii) -3- (4- (3-guanidino-guanidino-carbonyl-prop? Lox?) - phen? L) 3 (4 carbonyl-propyloxy) -phenyl) -propionic (1.5 )
The synthesis was carried out according to the following sequence of reactions:
la) Ester tere. -butylic acid (2S) -2-benzyloxycarbonylamino-3- (4- (3-ethoxycarbonyl-propyloxy) phenyl) -propionic acid (1.1) To 21.5 g (57.9 mmol) of ester tere. of N-benzyloxycarbonyl-tyrosine in 280 ml of acetone were added 8.29 ml (57.9 mmol) of 4-bromo-butanoic acid ethyl ester and 28.21 g (86.58 mmol) of sodium carbonate. cesium and heated to reflux with stirring. After 2 h, 2 ml of 4-bromo-butanoic acid ethyl ester and 2 g of cesium carbonate were again added, after another 2 h, another 2 ml of 4-bromo-butanoic acid ethyl ester and 3 g were added. of cesium carbonate, and after reapplying at room temperature overnight, was again added 9 ml of 4-bromo-butanoic acid ethyl ester and the mixture was heated at reflux for another 6 h. After cooling, it was filtered, the residue was washed with acetone and the filtrate was concentrated. The residue was taken up in diethyl ether and the organic phase was washed consecutively with a 3% solution of citric acid, 3 x H20 and with a saturated solution of NaCl. The ether phase was dried over
MgSO4, the drying agent was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed with CH2C12 and with a mixture of CH2C12 and MeOH
(99/1) on silica gel. 31.3 g of a pale yellow oil were obtained, which was used without further purification for the synthesis of the compound (1.2).
ib) Ester tere. -butylic acid (2S) -2-benzyloxycarbonyl 1 amino-3- (4- (3-guanidinocarbonyl-propyloxy) phenyl) -propionic acid (1.2) To a solution of 20 g (41.23 mmol) of the compound ( 1.1) in THF, a solution of 3.64 g (61.69 mmol) of guanidine in 150 ml of tertiary butanol was added and stirred for 18 h at room temperature. Subsequently, another 4.5 g of guanidine were added in 150 ml of tertiary butanol, the mixture was stirred for 7 h at room temperature, the reaction solution was concentrated to approximately half volume and stirring was continued for a further 18 h at room temperature. ambient. The solvent was removed in vacuo and the residue was first filtered with a mixture of CH2C12, MeOH and H20 (95/5 / 0.5) over basic A1203 and then chromatographed by MPLC with a mixture of CH2C12, MeOH and acid. acetic (90/10 / 0.5) on silica gel. 8.6 g (42%) of the compound (1.2) were obtained. lc) (2S) -2-amino-3- (4- (3-guanidinocarbonyl-propyloxy) phenyl) -propionic acid hydrochloride (1.3). To 8.6 g (17.3 mmol) of the compound (1.2) were added 30 ml of 95% trifluoroacetic acid and allowed to stir at room temperature for 25 min. The reaction mixture was concentrated by rotary evaporation and then concentrated twice with toluene. The residue was taken up in dilute acetic acid, mixed with water and lyophilized. The colorless solid, thus obtained, was purified by MPLC with a mixture of CH2C12, MeOH and acetic acid (90/10 / 0.5) on silica gel. After concentrating and lyophilizing, 5.5 g (72%) of a colorless solid was obtained. 400 mg of this substance were dissolved in 30 ml of MeOH and after adding methanolic hydrochloric acid was separated by hydrogenolysis on 10% Pd / C the benzyloxycarbonyl protecting group. The precipitated product was brought to solution by addition of DMF, the catalyst was removed by filtration, the filtrate was concentrated and the residue was lyophilized. 320 mg of the compound (1.3) was obtained as a colorless solid material.
ld) (1-Adamantylmethyl) -4-nitro-phenyl carbonate (1.4) To a solution of 499 mg (3 mmol) of 1-hydroxymethylambaraine in 7 ml of pyridine were added 605 mg (3 mmol) of ester 4-Nitro-phenyl of chloroformic acid and allowed to stir at room temperature overnight. After concentrating under high vacuum, the residue was used directly for the preparation of the compound (1.5).
le) (2S) -2- (l-adamantylmethyloxycarbonylamino) -3- (4- (3-guanidinocarbonyl-propyloxy) phenyl) -propionic acid (1.'5)
To a solution of 146 mg (0.35 mmol) of the compound (1.3) in 2 ml of DMF were added 114.5 mg of the compound (1.4) and stirred overnight at room temperature. 0.059 ml of diisopropyl-ethylamine was added and the mixture was stirred again at room temperature overnight. After removing the solvent in vacuo, the residue was partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, concentrated and then mixed with diisopropyl ether. The precipitate was separated by filtration and purified by preparative thin layer chromatography with a mixture of CH2C12, MeOH and acetic acid (100/25/2). 10 mg of the compound (1.5) were obtained.
Example 2 (2S) -2- (2- (1-adamantyl) -ethyloxycarbonylamino) -3- (4- (3-guanidinocarbonyl-propyloxy) phenyl) -propionic acid (2.2) The synthesis was carried out according to the following sequence of reactions:
(2.2) The synthesis of the compound (1.3) was carried out as described in Example 1, lc). Compound (2.1) was prepared analogously to compound (1.4) (Example 1, ld)) from 1- (2-hydroxy-ethyl) adamantane and chloroformic acid 4-nitro-phenyl ester and was used directly for the synthesis of the compound (2.2).
(2S) -2- (2- (1-adamantyl) -ethyloxy-carbonylamino) -3- (4- (3-guanidinocarbonyl-propyloxy) phenyl) -propionic acid (2.2) To a solution of 146 mg (0.35) mmol) of compound (1.3) in 2 ml of DMF was added 119 mg of compound (2.1) and stirred overnight at room temperature. 2.3 g of imidazole and 0.3 ml of pyridine were added and it was stirred again overnight at room temperature. The solution was concentrated, the residue was partitioned between water and ethyl acetate, the organic phase was dried over MgSO 4 and after filtering, the solvent was removed in vacuo, the residue was separated by preparative thin-layer chromatography with a mixture. of CH2C12, MeOH and acetic acid (100/25/2) There were obtained 19 mg of the compound (2.2).
EXAMPLE 3 (2S) -2- (1-Adamantylmethyloxycarbonylamino) -3- (4- (2- (1, 4,5,6-tetrahydro-pyrimidin-2-yl-carbamoyl) -ethyl) benzoyl-amino acid -propionic (g) The synthesis was carried out according to the following sequence of reactions
a) 4- (2-Methoxycarbonyl-vinyl) enzoic acid 18.74 g (0.12 mol) of the potassium salt of the malonic acid monomethyl ester in 18 ml of pyridine were suspended. While stirring, 15.01 g (0.1 mol) of 4-carboxy-benzaldehyde and 0.85 g (0.01 mol) of piperidine were added at room temperature (RT) and boiled under reflux until completion of the evolution. of C02 (approximately during 2 h). Another 60 ml of pyridine was added and stirring was continued at reflux for 1 h. The reaction mixture was mixed while stirring with 500 ml of ice and 110 ml of concentrated HCl. After the addition was complete, it was still followed for 20 min, the product was filtered with suction, washed with water and recrystallized from isopropanol. Yield: 12.85 g (62%)? E NMR (200 MHz, DMSO): d 3.75 (s, 3H, 0CH3); 6.76 (d, J = 15 Hz, 1H, CHC00CH3, 7.73 (d, J = 15 Hz, 1H, Ar-CJI), 7.84 (d, J = 9 Hz, 2H, Ar-H) 7.98 (d, J = 9 Hz, 2H, Ar-H), 13.11 (s, broad, 1H, COOH) MS: Cl +, m / e = 207.2 (M + H +, 100% HPLC: (RP18: Nucleosil 300-5-C18, 250 X 4 mm), Buffer A: H20, 0.1% TFA, Buffer B: Acetonitrile (80% v / v), H20 (20% v / v) ), 0.1% TFA, Gradient: (1) for 5 min, 10% of buffer B, (2) for 20 min, up to 90% of buffer B, (3) for 5 min, 90% of buffer B; Flow rate 1 ml / min, -Rt = 18, 05 min.
b) 4- (2-Methoxycarbonyl-ethyl) enzoic acid 8 g (38.8 mmol) of 4- (2-methoxycarbonyl) benzoic acid were suspended (Example a) in 250 ml of dioxane and hydrogenated during 7 ha TA on Pd (at 10%) / C with 1 bar of H2. It was filtered and the solvent was removed by evaporation in vacuo. Yield: 8.5 g (100%)? K NMR (200 MHz, DMSO): d 2.67 (t, J = 8 Hz, 2H, £ H2-COOMe); 2.93 (t, J = 8 Hz, 2H, Ar-CH2); 3.59 (s, 3H, 0CH3); 7.35 (d, 2H, Ar-H); 7.86 (d, J = 9 Hz, 2H, Ar-H); 12.80 (s, broad, 1H, COOH). MS: Cl +, m / e = 209.2 (M + H +, 100%) HPLC: (RP18 Nucleosil 300-5-C18, 250 x 4 mm), Buffer A: H20, 0.1% TFA; Buffer B: acetonitrile (80% v / v); H20 (20% v / v); 0.1% TFA; gradient: (1) for 5 min, 10% of buffer B; (2) for 20 min, up to 90% of buffer B, (3) for 5 min, 90% of buffer B; Flow rate 1 ml / min; Rt = 17.03 min.
c) Ester tere. -butylic acid (2S) -2-benzyloxy-carbonylamino-3- (4- (2-methoxycarbonyl-yl) -benzoylamino) -propionic acid 354 mg (1.7 mmol) of 4- (2-methoxy) acid were dissolved -carbonyl-ethyl) -benzoic acid (Example b) and 500 mg (1.7 mmol) of tere ester. -butyl 2S-benzyloxy-carbonylamino-3-amino-propionic acid in 3 ml of DMF and mixed with 557 mg
(1.7 mmol) of 0- [(cyano (ethoxycarbonyl) -methylidene) amino] -1,3,3-tetramethyl-uronium tetrafluoroborate (TOTU) and 204 mg
(1.7 mmol) of diisopropyl-ethylamine (DIPEA) and stirred for 7 h at RT. The solvent was removed by evaporation in vacuo, the residue was dissolved in ethyl acetate (EA) and washed in neutral conditions in each case three times with a solution of KHS04 and NaHCO3. The organic phase was separated, dried and the solvent was distilled off in vacuo, yield: 770 mg (93%), MS: ES +, m / e = 485.2 (M + H +, 100%) td) Ester tere . -butylic acid (2S) -2-benzyloxycarbonylamino-3- (4- (2- (1, 4,5,6-tetrahydro-pyrimidin-2-yl-carbamoyl) -ethyl) benzoylamino) -propionic acid were dissolved 1.25 g (& 2 mmol) of 2-amino-1, 4,5,6-tetrahydro-pyrimidine hydrochloride and 1.03 g (9.2 mmol) of tere, potassium-butylate in 3 ml of absolute DMF and stirred at RT for 30 min. Then 740 mg (1.53 mmol) of tere ester was added. -butyl (2S) -2-benzyloxycarbonylamino-3- (4- (2-methoxycarbonyl-ethyl) -benzoylamino) -propionic acid or (Example c) in 1 ml of DMF and stirred for 4 h at RT. It was adjusted to pH 4 with glacial acetic acid, the solvent was removed by evaporation in vacuo, the residue was chromatographed on silica gel (in a mixture of dichloromethane, methanol, glacial acetic acid and water (9/1 / 0.1 / 0.1)). Yield: 190 mg (38%) MS: ES +, m / e = 552.3 (M + H +, 100%)
e) (2S) -2-Benzyloxycarbonylamino-3- (4- (2- (1,4,5,6-tetrahydro-pyrimidin-2-yl-carbamoyl) -ethyl) -enzoylamino) -propionic acid. mg (0.34 mmol) of the (2S) -2-benzyloxycarbonylamino-3- (4- (2- (1,4,5,6-tetrahydro-pyrimidin-2-yl-carbamoyl) tert-butyl ester) ) -ethyl) enzoylamino) -propionic (Example d) in 5 ml of 95% trifluoroacetic acid and stirred for 1 h at RT. The trifluoroacetic acid was distilled off in vacuo, coevaporated with toluene, the residue was dissolved in glacial acetic acid, diluted with water and lyophilized. Yield: 170 mg (100%) MS: ES +, m / e = 496.3 (M + H +, 100%)
f) (2S) -2-amino-3- (4- (2- (1, 4, 5, 6-tetrahydro-pyridin-2-yl-carbamoyl) -ethyl) enzoylamino) -propionic acid
100 mg (0.2 mmol) of (2S) -2-benzyloxycarbonylamino-3- (4- (2- (1,4,5,6-tetrahydro-pyrimidin-2-yl-carbamoyl) - was dissolved. ethyl) benzoylamino) -propionic or
(Example e) in 15 ml of dioxane, were mixed with 0.012 ml of glacial acetic acid and hydrogenated over Pd (5%) / C at RT and 1 bar of H2. After 2 h, 15 ml of methanol was added and another 5 h was hydrogenated at RT and 1 bar of H2. It was filtered and the solvent was removed by evaporation in vacuo.
Yield: 67.4 mg (93%). MS: ES +, m / e = 362.2 (M + H +, 30%); 173.0 (100).
g) Acid (2S) -2- (l-adamantylmethyloxycarbonylamino) -3- (4- (2- (1, 4,5,6-tetrahydro-pyrimidin-2-yl-carbamoyl) -ethyl) -benzoylamino) -propionic 67.4 mg (0.186 mmol) of (2S) -2-amino-3- (4- (2- (1,4,5,6-tetrahydro-pyrimidin-2-yl-carbamoyl) - ethyl) benzoylamino) -propionic (Example f) in 4 ml of dioxane. With stirring, 4 ml of a saturated solution of NaHCO 3, then 57 mg of (1-adamantylmethyl) -ester (2,5-dioxo-pyrrolidin-1-yl) ester of carbonic acid were added at RT. It was stirred for 24 h at RT, adjusted to pH 4 with glacial acetic acid, the solvent was removed by evaporation in vacuo and the residue was chromatographed on RP-18 (Lichrospher C18) (20% (v / v) acetonitrile in water , 0.1% trifluoroacetic acid, up to 40% (v / v) acetonitrile). Yield: 30 mg (30%). MS: ES +, m / e = 554.4 (M + H +, 100%) Example 4 (2S) -2- (1-adamantylmethyloxycarbonylamino) -3- (4-. {3- (1, 4) acid , 5,6-tetrahydro-pyrimidin-2-yl-carbamoyl) -propyloxy) -phenyl) -propionic acid.
(1.1) (4.2)
a) Ester ester hydrochloride. -butylic acid (2S) -2- amino-3- (4- (3-ethoxycarbonyl-propyloxy) phenyl) -propionic acid (4.2) 100 g (0.206 mol) of tert-butyl ester of (2S) acid were dissolved - 2-Benzyloxycarbonylamino-3- (4- (3-ethoxycarbonyl-propyloxy) phenyl) -propionic acid (II) of Example i in 1 of methanol was mixed with methanolic hydrochloric acid and with 10 g of palladium hydroxide at 20 ° C. % / carbon and hydrogen was introduced for 6 hours. The catalyst was then filtered off, the solution was concentrated and the residue was mixed with di-tert. -butyl ether. The resulting precipitate was filtered with suction. 72 g (90%) of an amorphous powder were obtained.
b) Ester tere. -butyl (2S) -2- (1-adamantyl-methyloxy-earbonylamino) -3- (4- (3-ethoxycarbonyl-propyloxy) phenyl) -propionic acid (4.3). To a solution of 830 mg (5 mmol) of 1-hydroxymethyl-adamantane in 10 ml of tetrahydrofuran was added 892 mg (5.5 mmol) of carbonyl-imidazole (CDI) and left to stir at RT overnight. It was then mixed with 1 g of tere ester hydrochloride. -butylic acid (2S) -amino-3- (4- (3-ethoxycarbonyl-propyloxy) phenyl) -propionic acid and 442 μl (2.57 mmol) of diisopropyl-ethylamine (DIPEA) and allowed to stir at 50 ° C. C for one night. After cooling, it was taken up in ethyl acetate and the organic phase was washed consecutively with a 3% solution of citric acid, a solution of sodium hydrogencarbonate, 3 x H20 and a saturated solution of NaCl. The organic phase was dried with MgSO 4, the drying agent was removed by filtration and the filtrate was concentrated. The residue was chromatographed with a mixture of CH2C12 and CH30H (99/1) on silica gel. 1.19 g (85%) of an oil was obtained, which was used without further purification for the synthesis of the compound (4.4).
c) Ester tere. -butylic acid (2S) -2- (l-adamantyl-methyloxy-carbonylamino) -3- (4- (3- (1,4,5,6-te rahydro-pyrimidin-2-yl-carbamoyl) -propoxy) ) phenyl) -propionic or
(4.4) 398 mg (2.94 mmol) of 2-amino-1,4,5,6-tetrahydro-pyrimidine hydrochloride were dissolved in 7 ml of methanol and mixed with 330 mg (2.94 mmol) of terephthalate. . -butyrate of potassium. After 40 min, the precipitated salts were filtered off and the filtrate was concentrated. The residue was dissolved in 3 ml of dimethylformamide and added to a solution of 365 mg tere ester. -butyl (2S) -2- (l-adamantylmethyloxycarbonylamino) -3- (4- (.3-ethoxycarbonyl-propyloxy) phenyl) -propionic acid (4.3). It was heated at 40 ° C for 5 hours, the solvent was removed in vacuo, taken up in ethyl acetate and the organic phase was washed 3 times with H 2 O and a saturated solution of sodium chloride. The organic phase was concentrated and the residue was chromatographed with a mixture of CH2C12, CH30H, EtOAc and H20 (90: 10: 0.5: 0.5) on silica gel. 100 mg of an amorphous powder was obtained, which was used for the synthesis of (4.5).
d) (2S) -2- (1-adamantylmethyloxycarbonylamino) -3- (4- (3- (1, 4,5,6-tetrahydro-pyrimidin-2-yl-carbamoyl) -propyloxy) phenyl) - propionic (4.5) 100 mg of the compound of Example 4.4 was dissolved in 10 ml of a mixture of trifluoroacetic acid and H20 (95: 5). After 30 min, the reaction solution was concentrated and the residue was digested with diisopropyl ether. Subsequent lyophilization gave 85 mg of the compound (4.5).
Example 5 Acid. (2S) -2- (1- (adamantylmethyloxycarbonylairu.no) -3- (4- (3- (4,5-dihydro-imidazol-2-yl-carbamoyl) -propyloxy) phenyl-propionic acid (5.2)
The preparation was carried out analogously to Example 4. a) Ester tere. -butylic acid (2S) -2- (1- (adamantyl-methyloxy-carbonylamino) -3- (4- (3- (4,5-dihydro-imidazol-2-yl-carbamoyl-propyloxy) phenyl) -propionic acid (5.1) 436 mg (0.8 mmol) of (2S) -2- (1-adamantylmethyloxycarbonylamino) -3- (4- (3-ethoxycarbonyl-propyloxy) phenyl) tere .butylic acid ester were added. propionic to a solution of 388 mg (3.2 mmol) of 2-amino-4,5-dihydro-imidazole hydrochloride and 3.59 mg (3.2 mmol) of potassium tere. -butylate in 10 ml of DMF. The mixture was left stirring overnight, after the reaction had ended, it was treated analogously to Example 4c and chromatographed with the same mixture of eluents on silica gel, 188 mg (0.32 mmol) of the compound were obtained ( 5.1).
b) (2S) -2- (1- (Adamantylmethyloxycarbonylamino) -3- (4- (3 - (4,5-dihydro-imidazol-2-yl-carbamoyl) -propyloxy) phenyl) -propionic acid (5.2) 188 mg (0.32 mmol) of compound (5.1) were dissolved in 10 ml of a mixture of trifluoroacetic acid and H20 (95: 5) After 30 min, the solvent was removed in vacuo and the residue was digested with diisopropyl ether After having lyophilized 168 mg of an amorphous powder of the compound (5.2) were obtained.
Pharmacological investigations The inhibition of bone resorption by the compounds according to the invention can be determined, for example, with the aid of the osteoclast resorption test (from
"PIT ASSAY" (hole analysis)) for example analogously to WO 95/32710. The inhibitory effect of the compounds according to the invention against the vitronectin av33 receptor can be determined for example. ex. as described below.
Assay for the measurement of the inhibition of the binding of 293 cells to human vitronectin (in the test results, abbreviated as cell assay Vn / 293)
1. Purification of human vitronectin Human vitronectin is isolated from a human plasma and purified by affinity chromatography according to the method of Yatohyo et al. , Cell Structure and Function, 1988, 23, 281-292.
2. Cell assay Cells 293, which are a cell line of human embryonic kidneys, and which have been cotransfected with DNA sequences for the avr and jS3 subunits of the 0 ^ 3 vitronectin receptor, are selected according to the FACS method under point in view of obtaining a high expression regime (> 500,000 avJ3 / cell receptors). The selected cells are further cultured and screened by FACS, in order to obtain a stable (15 D) cell line with > 1,000,000 copies of cxvß3 per cell.
A 96-well flat-bottomed Linbro tissue culture plate is covered with human vitronectin (0.01 mg / ml, 0.05 ml / well) in a phosphate buffered sodium chloride (PBS) solution overnight at 4 ° C and then blocked with 0.5% BSA. Solutions of the test substances concentrated in 10"10 - 2 x 10" 3 mol / 1 are prepared in a DMEM medium containing glucose and in each case 0.05 ml / well of the solution is poured onto the plate. The cells, which express a high level of cxvßj (eg 15 D) are suspended in a DMEM medium containing glucose and the suspension is adjusted to a content of 25,000 cells / 0.05 ml of medium. 0.05 ml of this cell suspension is poured into each well and the plate is incubated for 90 min at 37 ° C. The plate is washed 3 times with tempered PBS, in order to eliminate unfixed cells. The fixed cells are lysed in a citrate buffer (25 mmol, * pH 5.0), containing 0.25% Triton X-100. The substrate for hexose-amidase p-nitrophenyl-N-acetyl- | S-glucosaminide is then added and the plate is incubated for 90 min at 37 ° C. The reaction is stopped with a glycine buffer (50 mmol) / EDTA (5 mmol) (pH 10.4) and the absorption of each well is measured at 405-650 nm. The data is evaluated according to classical procedures. The following test results were obtained:
Cell assay Vn / 293 Cl 50 (μm) Compound of Example 1 0.032 Compound of Example 3 0.032
Claims (11)
1.- Compound of formula I, R1-Y-A-B-D-E-F-G I, where they mean: A direct bond, alkanediyl (C ^ Cg), -NR2-C (0) -NR2 -NR2-C (0) 0-, -NR2-C (0) S-, -NR2-C (S) -NR2-, -NR2-C (S) -0-NR2-C (S) -S-, -NR2-S (0) n-NR2-, -NR2-S (0) n-0- , -NR2-S (0) n cycloalkanediyl (C3-C12), -CSC-, -NR2-C (0) -, -C (0) -NR2 -arylene (C5-C14) -C (O) -NR2 , -O-, -S (0) n-, -arylene (C5-C14) -CO-, -arylene (C5-C14) -CO-, -NR2-, -S02-NR2-, -C02-, -CR2 = CR3-, -arylene (C5-C14) -S (0) n-, which in each case may be substituted once or twice with alkanediyl (CL-Cg), such as p. ex. -alkanediyl "(C ^ Cg) -CO-Nfe2-alkanediyl (C ^ Cg), -alkanediyl (C-L-Cg) -CO-NR2- or -CO-NR2-alkanediyl (C ^ Cg); B a direct bond, alkanediyl (C - ^ - C ^), -CR2 = CR3- or -CsC-, which in each case may be substituted once or twice with alkanediyl (C ^ Cg), such as p. ex. -CH2-Cf-iC-CH2- or -CH2-CR2 = CR3-; D a direct bond, alkanediyl (C ^ Cg) or -0-, -NR2-, -CO-NR2-, -NR2-C0-, -NR2-C (0) -NR2-, -NR2-C (S) -NR2-, -0C (0) -, -C (0) 0-, -C0-, -CS-, -S (0) -, -S (0) 2-, -S (0) 2-NR2 -, -NR2-S (0) -, -NR2-S (0) 2-, -S-, -CR2 = CR3-, -CsC- or -CH (OH) -, which in each case may be substituted once or twice with alkanediyl (C ^ Cg); E is a 6-membered aromatic ring system, which optionally contains up to 4 N atoms and is optionally substituted with 1-4 radical (s), the same or different, taken from the series consisting of R2, R3, fluoro, Cl, Br, I, N02 or OH; it is as defined D; And a direct link or -NR2-; R1 R2-C (= NR2) -NR2-, R2R3N-C (= NR2) -, R2R3N-C (= NR2) -NR2-, or a ring system (s), aromatic or non-aromatic, monocyclic or polycyclic, of 4-10 links, which can eentually contain 1-4 heteroatom (s) taken from the series consisting of N, O and S and may possibly be substituted once or multiple times with substituents of the series formed by R11, R12, R13 and R14; R2, R3 independently of one another, H, alkyl (C ^ -C-LO), which is optionally substituted once or multiply with fluoro, or means (C3-C12) cycloalkyl, (C3-C12) cycloalkyl-alkanediyl ( C ^ Cg), aryl (C5-C14), aryl (C5-C14) -alkanediyl (C1-C8), H2N, (R80) R8NR7, R80R7, R80C (0) R7, R8-arylene (C5-C14) - R7, R8R8NR7, HO-alkanediyl (C ^ Cg) -NR8R7, R8R8NC (0) R7, R8C (0) NR8R7, R8C (0) R7, R8R8N-C (= NR8) -, R8R8N-C (= NR8) - NR 8 - O alkyl 1-c 8 -cy8) -carbonyloxy-alkanediyl (CL-Cg) -oxycarbonyl; R4 cycloalkyl (C10-C18), cycloalkyl (C10-C18) -alkanediyl (C ^ Cg), the cycloalkyl radicals being able to be monocyclic or polycyclic, be saturated or unsaturated once or multiple times and be substituted as described in the case of R6, or R60R7, R6SR7, R6C02R7, R0C (0) R7, R6-arylene (C5-C14) -R7, R6N (R2) R7, R6R8NR7, R6N (R2) C (0) 0R9, R6S (0 ) nN (R2) R7, R60C (O) N (R2) R7, R6C (0) N (R2) R7, R6N (R2) C (O) N (R2) R7, R6N (R2) S (0) nN (R2) R7, R6S (0) nR7, R6SC (0) N (R2) R7, R6C (0) R7, R6N (R2) C (O) R7 or R6N (R2) S (0) nR7; R5 H, fluoro, alkyl (Cx-Cg), cycloalkyl (C3-C12), cycloalkyl (C3-C12) -alkanediyl (C ^ -Cg), aryl (C5-C14), aryl (C5-C14) -alkanediyl ( C1-C8) the alkyl radicals being able to be substituted once or multiply with fluoro; R6 cycloalkyl (C10-C18), cycloalkyl (C10-C18) -alkanediyl (Ci-Cg), the cycloalkyl radicals can be monocyclic or polycyclic, be saturated or unsaturated once or multiple times, and be replaced once or multiple times with alkyl (CLC- ^), which is optionally substituted once or multiple times with fluoro, or with (C3-C12) cycloalkyl, (C3-C12) cycloalkyl-alkanediyl (C ^ Cg), aryl (C5-C14) , aryl (C5-C14) -alkanediyl (C ^ Cg), alkoxy (C ^ Cg), aryl (C5-C14v) -alkanodiyl- (Cj ^ -Cg) -oxi, aryl (C5-C14) -oxi, alkyl (Ci-Cg) -carbonyloxy-alkanediyl (CLC ^ -oxi, NH2, mono- or di- (C ^ Cg alkyl) -amino, aryl (C5-C14) -alkanediyl (C ^^ - Cg) -amino, aryl (C5-C14) -amino, = 0, = S, N02, OH, fluoro, Cl, Br or I; R7 a direct bond or alkanediyl (C ^ Cg); R8 H, alkyl (C ^ Cg), cycloalkyl (C3-C12), cycloalkyl (C3-C12) -alkanediyl (C ^ Cg), aryl (C5-C14), aryl (C5-C14) -alkanediyl (CL-Cg) ), the alkyl radicals being able to be substituted once or multiply with fluoro; R9 C (0) R10, C (S) RX0, S (0) nR10, P (O) (R10) n, or a four to eight link heterocycle, saturated or unsaturated, which contains 1, 2, 3 or 4 heteroatom (s) taken from the series consisting of N, O and S, such as p. ex. triazolyl, imidazolyl, pyrazolyl, oxazolyl or thiadiazolyl; R10 OH, alkoxy (q-C8), aryl (C5-C14) -alkanediyl (-CGJ-oxy, aryl (C5-C14) -oxi, alkyl (-Cg) -carbonyloxy-alkanediyl (Cx-C4) -oxi, aryl (C5-C14) -alkanodiyl (-Cg) -carbonyloxy-alkanediyl (-Cg) -oxi, NH2, mono- or di- (alkyl-Cg) -amino, aryl (C5-C14) -alkanediyl (-Cg) -amino, di- (C 1 -Cg alkyl) -aminocarbonylmethyleneoxy, aryl (C 5 -C 14) -di- (alkyl CL-C 8) -aminocarbonylmethyleneoxy or aryl (C 5 -C 14) -amino or a radical of an L or D-amino acid; R11, R12, R13, R14 independently of each other,, H, (C1-C10) alkyl which is optionally substituted once or multiply with fluoro, or mean (C3-C12) cycloalkyl, (C3-C12) cycloalkyl-alkanediyl (CL-Cg), aryl (C5-C14), "aryl (C5-C14) -alkanediyl (C ^ Cg), H2N, (R80) R8NR7, R8OR7, R8 c (0) R7, R8R8NR7, R8-arylene ( C5-C14) -R7, HO-alkanediyl (-C8) -N (R2) R7, R8N (R2) C (0) R7, R8C (0) N (R2) R7, R8C (0) R7, R2R3N-C (= NR2) -NR2-, R2R3N-C (= NR2) -, = 0 Ó = S; n 1 or 2; q 0 or 1, in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts.
2. Compound of formula I according to claim 1, in which they mean: A direct bond, alkanediyl (C ^ Cg), -NR2-C (0) -NR2-, -NR2-C (0) 0- , -NR -C (0) S-, -NR2-C (S) -NR2-, NR2-C (S) -0-, -NR2-C (S) -S-, -NR2-S (0) n-NR2-, -NR2-S (0) n-0-, -NR2-S (0) n-, cycloalkanediyl (C3-C8), -CSC-, -NR2-C (0) -, -C ( 0) -NR2-, arylene (C5-C12) -C (0) -NR2-, -O-, -S (0) n-, -arylene (C5-C12) -, -CO-, -arylene (C5) -C12) -CO-, -NR2-, -S02-NR2-, -C02-, -CR2 = CR3-, arylene (C5-C12) -S (0) n-, which in each case may be substituted once p twice with alkanediyl (-Cg); B a direct bond, alkanediyl (C1-C8), -CR2 = CR3- or -CsC-, which in each case may be substituted once or twice with alkanediyl (-Cg); D a direct bond, alkanediyl (C ^ CQ) Either -0 -, - NR2-, -CO-NR2-, -NR2-C0-, -NR2-C (0) -NR2-, -NR -C (S ) -NR2-, -OC (O) -, -C (0) -0-, -CO-, -CS-, -S (O) -, -S (0) 2-, -S (0) 2 -NR2-, -NR -S (0) -, -NR2-S (0) 2-, -S-, -CR2 = CR3-, -CSC-, which in each case may be substituted once or twice with alkanediyl (-Cg), E is a 6-membered aromatic ring system (s), which optionally contains 1 or 2 atom (s) of N and is optionally substituted by 1-3 radicals, identical or different, taken from the series formed by R2, R3, fluoro, Cl or OH; it is as defined D; 4 G R (CH2) (R And a direct link or -NR2-; R1 R2-C (= NR2) -NR2-, R2R3N-C (= NR2) -, R2R3N-C (= NR2) -NR2-, or an aromatic or non-aromatic, monocyclic or polycyclic ring system (s), 4-10 links, which may optionally contain 1-4 heteroatom (s) taken from the series consisting of N, 0 and S and optionally may be substituted once or multiple times with substituents of the series consisting of R 11, R12, R13 and R14; R2, R3 independently of one another, H, alkyl (q-C8), which may optionally be substituted once or multiple times with fluoro, or mean cyclo (C3-C8) alkyl, (C3-C8) cycloalkyl-alkanediyl (q-) C6), aryl (C5-C12), aryl (C5-C12) -alkanediyl (q-C6), H2N, (R80) R8NR7, R80R7, R80C (0) R7, R8-arylene (C5-C12) -R7, R8R8NR7, HO-alkanediyl (q-C8) -NR8R7, R8R8NC (0) R7, R8C (0) NR8R7, R8C (0) R7, R8R8N-C (= NR8) -, R8R8N-C (= NR8) -NR8- O alkyl (c? "? O) -carbonyloxy-alkanediyl (q-C4) -oxycarbonyl; R4 cycloalkyl (q0-q6) or (C10-C16) cycloalkyl-alkanediyl (q-C8), the cycloalkyl radicals (being monocyclic or polycyclic, being saturated or unsaturated once or multiple times and substituted as described in US Pat. case of R6 or mean R60R7, R6SR7, R6C02R7, R < QC (0) R7, R6-arylene (C5-C12) -R7, R6N (R2) R7, R6R8NR7, R6N (R2.) .C (O) OR7, R6S (O) nN (R2) R7, R6OC (0 ) N (R2) R7, R6C (0) N (R2) R7, R6N (R2) C (O) N (R2) R7, R6N (R2) S (0) nN (R2) R7, R6S (0) nR7 , R6SC (O) N (R2) R7, R6C (0) R7, R6N (R2) C (0) R7 or R6N (R2) S (0) nR7; R5 H, alkyl (q-C6), cycloalkyl (C3-C8), cycloalkyl (C3-C8) -alkanediyl (q-C6), aryl (C5-C10), aryl (C5-C10) -alkanediyl (q-C6) ), the arylalkyl radicals being able to be substituted with fluoro once or multiple times, - R6 cycloalkyl (q0-q6) or cycloalkyl (C10-C16) -alkanediyl (C1-C6), the cycloalkyl radicals being bicyclic or tricyclic, saturated or unsaturated once or multiple times, and substituted once or multiple times with alkyl (q-C8), which is optionally substituted once or multiple times with fluoro, or means cycloalkyl (C5-C6), cycloalkyl (C5-C6) -alkanediyl (q-C6), aryl (C5-C10), aryl (C5-C10) -alkanediyl (q-C6), alkoxy (q-C6), aryloxy (C5-C10), aryl (C5-C10) -alkanediyl (q-C6) -oxi, NH2, mono- or di - (alkyl q-C6) -amino, = 0, OH, fluoro or Cl; R7 a direct bond or alkanediyl (q-C6); R8 H, alkyl (q-C6), cycloalkyl (C3-C8), cycloalkyl (C3-C8) -alkanediyl (q-C6), aryl (C5-C12), aryl (C5-C12) -alkanediyl (q-C6) ), the alkyl radicals being able to be substituted once or multiply with fluoro; R9 C (0) R10, C (S) R10, S (0) nR10, P (O) (R10) not a saturated or unsaturated heterocycle, of four to eight links, which contains 1, 2, 3 or 4 heteroatom (s) taken from the series consisting of N, 0 and S; R10 OH, alkoxy (q-Cg), aryl (C5-C12) -alkanediyl (C1-C6) -oxi, aryl (C5-C12) -oxi, alkyl (q-C6) -carbonyloxy-alkanediyl (q-C4) -oxi, aryl (C5-C12) -alkanediyl (q-C6) -carbonyl-oxy-alkanediyl (C1-C6) -oxi, NH2, mono- or di- (alkyl q-Cg) -amino, aryl (C5-) C12) -alkanodiil (q-C6) -amino or di- (alkyl q-C6) -aminocarbonyl-methyleneoxy; R11, R12, R13, R14 independently of each other, H, (Cx-C8) alkyl, which is optionally substituted once or multiple times with fluoro, or means cycloalkyl (C3-C8), cycloalkyl (C3-C8) -alkaneldiyl (q-C6), aryl (C5-C12), aryl (C5-C12) -alkanediyl (q-Cg), H2N, (R80) R8NR7, R80R7, R80C (0) R7, R8-aryl (C5-C12) -R7, R8R8NR7, HO-alkyl (q-C8) -N (R2) R7, R8N (R2) C (0) R7, R8C (0) N (R2) R7, R8C (0) R7, R2R3N-C ( -NR2) -, R2R3N-C (= NR3) -NR2-, = 0 OR = S; n 1 or 2; q 0 or 1; in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts.
3. Compound of the formula I according to claims 1 and / or 2, in which they mean: A direct bond, alkanediyl (q-C6), -NR2-C (0) -NR2-, -NR2-C ( 0) 0-, -NR2-S (0) n-NR2, -NR2-S (0) n-, cycloalkanediyl (C3-C6), -CSC-, -NR2-C (0) -, -C (0) ) -NR2-, -0-, -CO-, -NR2-, -0-, -CO-, -NR2-, -C02-, -CR2 = CR3, which may be substituted in each case once or twice sometimes with alkanediyl (C1-C6); t B a direct bond, alkanediyl (q-C6), -CR2 = CR3-, which may be substituted once or twice with alkanediyl (q-C6); D a direct link, alkandi (q-C6) or -0 -, - NR2-, -NR2-C0-, -C (0) NR2-, -NR2-C (0) -NR2-, -0C (0) -, -C (0) -, -S (0) 2-NR2-, - NR-S (0) -, -NR2-S (0) 2-, which in each case may be substituted once or twice with alkanediyl (q-C6); E phenylene or pyridinediyl, which is optionally substituted with 1-3 radical (s), the same or different, taken from the series consisting of R2 and R3, - F a direct bond, alkanediyl (q-C6), or -0-, -CO-NR2-, -NR2-C0-, -NR2-C (0) -NR2-, -0C (0) -, -C (0) 0-, -CO-, -S (0) 2-, -S (0) 2-NR2, -NR2-S (0) 2-, -CR2 = CR3-, -CsC-, which in each case may be substituted once or twice with alkanediyl (q-C6), - 4 (CH2) q-R9 a direct bond or -NH- R -C (= NR2) -NR2-, R2R3N-C (= NR2) -, R2, R3 independently of one another, alkyl (q-C6), which is optionally substituted once or multiply times, preferably 1-6 times, with fluoro, or means (C3-C6) cycloalkyl, (C3-C6) cycloalkyl- alkanediyl (C1-C4), aryl (C5-C10), aryl (C3-C10) -alkanediyl (C1-C4), H2N, R80R7, R8-arylene (C5-C10) -R7, R8NHR7, R8R8NR7, R8NHC (0 ) R7,, H2N-C (= NH) -, H2N-C (= NH) -NH-; R4 cycloalkyl (q0-C14) or cycloalkyl (C10-C14) -alkanediyl (q-C6) ^ being able cycloalkyl radicals to be bicyclic or tricyclic, as well as being substituted 1-3 times with alkyl (q-C6), trifluoromethyl, pentafluoroethyl , phenyl, benzyl, alkoxy (q-C6), phenoxy, benzyloxy, NH2, = 0 or mono- or di- (alkyl q-C6) -amino; or they mean R60R7, R6C02R7, R60C (0) R7, R6NHR7, R6R8NR7, R6NHC (0) 0R7, R6S (0) nNHR7, R6OC (0) NHR7, R6C (0) NHR7, R6C (0) R7, R6NHC (0) NHR7 or R6NHC (0) R7; R5 H, alkyl (q-C6), cycloalkyl (C5-C6), cycloalkyl (C5-C6) -alkanediyl (q-C6), trifluoromethyl, pentafluoroethyl, phenyl or benzyl; R6 (C10-C14) cycloalkyl or (C10-C14) cycloalkyl-alkanediyl (q-C6), the cycloalkyl radicals being bicyclic or tricyclic, and substituted 1-3 times with alkyl (q-C6), trifluoromethyl , pentafluoroethyl, phenyl, benzyl, alkoxy (q-C6), phenoxy, benzyloxy, NH2, = 0 or mono- or di- (alkyl q-C6) -amino, - R7 a direct bond or alkanediyl (q-C6); R8 H, alkyl (q-C6), cycloalkyl (C3-C6), cycloalkyl (C3-C6) -alkanediyl (q-C4), aryl (C5-C10), aryl (C5-C10) -alkanediyl (q-C4) ), the alkyl radicals being able to be substituted with 1-6 fluorine atoms, - R9 C (0) R10; R10 OH, alkoxy (q-C8), aryl (C3-C10) -alkanediyl (q-C6) -oxi, aryl (C5-C10) -oxi, alkyl (q-C6) -carbonyloxy-alkanediyl (C1-C4) -oxi, aryl (C5-C10) -alkanodiyl (q-C4) -carbonyloxy-alkanediyl (q-C4) -oxi, NH2, mono-, di- (C1-C6 alkyl) -amino, -R11 H, alkyl (q-C6), which is optionally substituted once multiple times with fluoro, or means cycloalkyl (C3-C6), cycloalkyl (C3-C6) -alkanediyl (q-C4), aryl (C5-C10), aryl ( C5-C10) -alkanaldi (q-C4), H2N, R80R7, R8OC (0) R7, R8-arylene (C5-C10) -R7, R8R8NR7, R8NHC (0) R7, R8C (0) NHR7, H2N-C (= NH) -, H2N-C (= NH) -NH-, = 0; n 1 or 2; q 0 6 1; in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts.
4. Compound of formula I according to one or more of claims 1 to 3, in which they mean: A direct bond, alkanediyl (q-C4), -NR2-C (0) -NR2-, -NR- C (0) 0-, -NR2-S (0) n-, -NR2-S (0) n-NR2- or -NR2-C0-, -NR2-, which can be substituted in each case once or twice with alkanediyl (q-C4), - B a direct bond or alkanediyl (q-C6), -D a direct bond, alkanediyl (q-C4), or -0-, -NR2-, -NR2-C0-, -C (0) -NR2-, -NR2-C (0) -NR2-, which in each case may be substituted once or twice with alkanediyl (q-C4); E phenylene or pyridinadiyl, which is optionally substituted with 1 or 2 radicals taken from R2 and R3, - a direct bond, alkanediyl (q-C6), or -0-, -CO-NR2-, -NR2-C0-, -NR2-C (0) -NR2-, -S (0) 2-NR2-, -NR2-S (0) 2-, -CR2 = CR3-, -CsC-, which in each case may be substituted once or twice, with alkanella (q-C4), - And a direct link or -NH; R1 R2R3N-C (= NR2) R3 independently of one another, H, alkyl (q-C6), trifluoromethyl, pentafluoroethyl, cycloalkyl (C5-C6), cycloalkyl (C5-C6) -alkanediyl (C1-C2), phenyl, benzyl, H2N, R80R7, R8R8NR7, R8NHC (0) R7, H2N-C (= NH) -, H2N-C (= NH) -NH-; cycloalkyl (C10-C12) / (C10-C12) cycloalkyl-alkanediyl (q-Cg), OR R60R7, R6R8NR7, R6NHC (0) OR7, R6S (0) nNHR7, R6OC (0) NHR7, the cycloalkyl radicals being preferred 1-adamantyl or 2-adamantyl and the cycloalkyl-alkanediyl radicals preferably adamantyl-1-alkanediyl (q-C3) or adamantyl-2-alkanediyl (C1-C3) and may be substituted 1 or 2 times with alkyl (q- C4), trifluoromethyl, phenyl, benzyl, alkoxy (q-C4), phenoxy, benzyloxy, = 0 or mono- or di- (alkyl q-C4) -amino, with adamantyl radicals substituted 1 or 2 times as such being especially preferred. as described above or the cycloalkyl radicals (C 1 -C 12) unsubstituted or substituted 1 or 2 times as described above, -R 5 H, alkyl (q-C 4) or trifluoromethyl; R6 cycloalkyl (C10-C12), (C10-C12) cycloalkyl-alkanediyl (q-C8), the cycloalkyl radicals preferably being 1-adamantyl or 2-adamantyl and the cycloalkyl-alkanediyl radicals preferably adamantyl-1-alkanediyl (C1-C3) or adamantyl-2 -alkanodiyl (C1-C3) and can be substituted once or twice with alkyl (q-C4), trifluoromethyl, phenyl, benzyl, alkoxy (q-C4), phenoxy, benzyloxy, = 0 or mono- or di- ( alkyl q-C4) -amino, with the substituted adamantyl radicals being 1 or 2 times as described above or the cycloalkyl radicals (C 11 -C 12) unsubstituted or substituted 1 or 2 times as described above being especially preferred. , - R7 a direct bond or alkanediyl (C1-C6), - R8 H, alkyl (q-C6), cycloalkyl (C5-C6), cycloalkyl (C5-C6) -alkanediyl (q-C2), aryl (C5-C6) or aryl (C5-C6) -alkanodiyl (C1-C2), - R9 C (0) R10; R10 OH, alkoxy (q-Cg), phenoxy, benzyloxy, alkyl (q-C4) -carbonyloxy-alkanediyl (q-C4) -oxi, NH2 or mono- or di- (alkyl (q-C6) -amino, - n 1 6 2; q 0 or 1; in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts.
5. Compound of the formula I according to one or more of claims 1 to 4, in which they mean: A -NH-C (O); B alkanediyl (q-C4), -D -O-, -NR2-C (0) -, -C (0) -NR2- or a direct bond; E phenylene or pyridinadiyl; a straight d bond, - H2N-C (= NH) -, R2 H or alkyl (q-C4); R4 R60C (0) NH-; R5 H; Re adamantyl-1-alkylene (q-C3), adamantyl-2-alkylene (q-C3), 1-adamantyl, 2-adamantyl, adamantyl being preferably substituted 1-fold or 2-fold with alkyl (q-C4), trifluoromethyl , phenyl, benzyl, alkoxy (q-C4), phenoxy or benzyloxy, or cycloalkyl (C11-C12), which may be substituted 1 or 2 times as above; R9 C (0) R10; R 10 OH, alkoxy (q-C 6), phenoxy, benzyloxy or alkoxy (q-C 4) -carbonyloxy-alkanediyl (C 1 -C 4) -oxy; in all its stereoisomeric forms and mixtures thereof in all ratios, and their physiologically compatible salts.
6. - Process for the preparation of a compound of the formula I according to one or more of claims 1 to 5, characterized in that two or more fragments that can be retrosynthetically derived from formula I are coupled.
7. - Compound of formula I according to one or more of claims 1 to 5 and / or its physiologically compatible salts for use as medicaments.
8. Compound of formula I according to one or more of claims 1 to 5 and / or its physiologically compatible salts as inhibitors of bone resorption by osteoclasts, as inhibitors of tumor growth and tumor metastasis, as inhibitors of inflammations, for the treatment or prophylaxis of cardiovascular diseases, for the treatment or prophylaxis of nephropathies and retinopathies as well as as antagonists of vitronectin receptors for the treatment and prophylaxis of diseases that are based on the interaction between vitronectin receptors and its ligands in the case of cell to cell or cell to cell interaction processes.
9.- Pharmaceutical preparation, which contains at least one compound of formula I according to one or more of claims 1 to 5 and / or its physiologically compatible salts together with pharmaceutically irreproachable carriers and additives.
10. Use of a compound of the formula I according to one or more of claims 1 to 5 and / or its physiologically compatible salts as medicaments.
11. Use of a compound of formula I according to one or more of claims 1 to 5 and / or its physiologically compatible salts as inhibitors of bone resorption by osteoclasts, as inhibitors of tumor growth and tumor metastasis, as inhibitors of inflammations, for the treatment or prophylaxis of cardiovascular diseases, for the treatment or prophylaxis of nephropathies and retinopathies as well as as antagonists of vitronectin receptors for the treatment and prophylaxis of diseases, which are based on the interaction between vitronectin receptors and their ligands in the case of cell-to-cell or cell-to-matrix interaction processes. RESU IN Cycloalkyl derivatives of the formula I are described R ^ Y-A-B-D-E-F-G (I) wherein R1, Y, A, B, D, E, F and G possess the meanings indicated in the claims, their preparation and their use as medicaments. The compounds according to the invention are used as antagonists of vitronectin receptors and as inhibitors of bone resorption.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE19629816.4 | 1996-07-24 |
Publications (1)
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MXPA97005585A true MXPA97005585A (en) | 1998-11-16 |
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