DE3815913A1 - NEW RENINHERMERS, PROCESS FOR THEIR PRODUCTION AND THEIR USE - Google Patents
NEW RENINHERMERS, PROCESS FOR THEIR PRODUCTION AND THEIR USEInfo
- Publication number
- DE3815913A1 DE3815913A1 DE3815913A DE3815913A DE3815913A1 DE 3815913 A1 DE3815913 A1 DE 3815913A1 DE 3815913 A DE3815913 A DE 3815913A DE 3815913 A DE3815913 A DE 3815913A DE 3815913 A1 DE3815913 A1 DE 3815913A1
- Authority
- DE
- Germany
- Prior art keywords
- formula
- group
- cyclohexylmethyl
- butyl
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title claims 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 206010019280 Heart failures Diseases 0.000 claims abstract description 6
- 206010020772 Hypertension Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 239000002461 renin inhibitor Substances 0.000 claims abstract description 5
- 229940086526 renin-inhibitors Drugs 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 4
- -1 amino, hydroxy Chemical group 0.000 claims description 54
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 150000002431 hydrogen Chemical group 0.000 claims description 9
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 150000001413 amino acids Chemical group 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 108090000783 Renin Proteins 0.000 claims description 4
- 102100028255 Renin Human genes 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910052760 oxygen Chemical group 0.000 claims description 4
- 239000001301 oxygen Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 241001430294 unidentified retrovirus Species 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 150000008575 L-amino acids Chemical class 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000002209 hydrophobic effect Effects 0.000 claims description 2
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical group [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 4
- 125000004434 sulfur atom Chemical group 0.000 claims 4
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- BYHXWLQZAJYWMI-UHFFFAOYSA-N C(CCC)NC(CCC(C(CC(CCC(CCC(COCCOCCOCCOC)=S)=O)=O)CC1CCCCC1)O)=O Chemical compound C(CCC)NC(CCC(C(CC(CCC(CCC(COCCOCCOCCOC)=S)=O)=O)CC1CCCCC1)O)=O BYHXWLQZAJYWMI-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- 125000003435 aroyl group Chemical group 0.000 claims 1
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- 125000004057 biotinyl group Chemical group [H]N1C(=O)N([H])[C@]2([H])[C@@]([H])(SC([H])([H])[C@]12[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 abstract 1
- 230000001177 retroviral effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000012043 crude product Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229960005215 dichloroacetic acid Drugs 0.000 description 4
- 229960003512 nicotinic acid Drugs 0.000 description 4
- 235000001968 nicotinic acid Nutrition 0.000 description 4
- 239000011664 nicotinic acid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N alpha-methylpyridine Natural products CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- VHRXHECRJSYLDR-DTWKUNHWSA-N (3r,4s)-4-amino-5-cyclohexyl-2,2-difluoro-3-hydroxypentanoic acid Chemical compound OC(=O)C(F)(F)[C@H](O)[C@@H](N)CC1CCCCC1 VHRXHECRJSYLDR-DTWKUNHWSA-N 0.000 description 1
- LNHSRDSMCWBDOQ-QMMMGPOBSA-N (4s)-4-amino-5-cyclohexyl-2,2-difluoro-3-oxopentanoic acid Chemical compound OC(=O)C(F)(F)C(=O)[C@@H](N)CC1CCCCC1 LNHSRDSMCWBDOQ-QMMMGPOBSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- YJEIOCBNUQFVAY-UHFFFAOYSA-N 2-[2-(2-hydroxyethoxy)ethoxy]ethyl hydrogen carbonate Chemical compound OCCOCCOCCOC(O)=O YJEIOCBNUQFVAY-UHFFFAOYSA-N 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- MNHNHHIHUYPXHP-YFKPBYRVSA-N 3-(trimethylsilyl)-L-alanine Chemical compound C[Si](C)(C)C[C@H](N)C(O)=O MNHNHHIHUYPXHP-YFKPBYRVSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 101000579218 Homo sapiens Renin Proteins 0.000 description 1
- 206010020460 Human T-cell lymphotropic virus type I infection Diseases 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- KCNKJCHARANTIP-SNAWJCMRSA-N allyl-{4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl}-methyl-amine Chemical group C=1OC2=CC(OC/C=C/CN(CC=C)C)=CC=C2C=1C1=CC=C(Br)C=C1 KCNKJCHARANTIP-SNAWJCMRSA-N 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000013216 cat model Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- TWLCEYWYILDCDA-UHFFFAOYSA-N chromium(6+) oxygen(2-) pyridine Chemical compound [O-2].[O-2].[O-2].[Cr+6].C1=CC=NC=C1.C1=CC=NC=C1 TWLCEYWYILDCDA-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005640 glucopyranosyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JLGLQAWTXXGVEM-UHFFFAOYSA-N triethylene glycol monomethyl ether Chemical compound COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N 0.000 description 1
- DUAJIKVIRGATIW-UHFFFAOYSA-N trinitrogen(.) Chemical group [N]=[N+]=[N-] DUAJIKVIRGATIW-UHFFFAOYSA-N 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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Abstract
Description
Die Erfindung betrifft Reninhemmer, Verfahren zu deren Herstellung und deren Verwendung gemäß den Patentansprüchen 1 bis 10.The invention relates to renin inhibitors, process for their preparation and their use according to claims 1 to 10.
Die Verbindungen der Formel I gemäß Patentanspruch 1 werden nachfolgend als Verbindungen gemäß der Erfindung bezeichnet.The compounds of the formula I according to claim 1 are hereinafter referred to as compounds according to the invention.
Falls in der Formel I R₁ für ein geradkettiges oder verzweigtes Alkyl mit 1 bis 10 Kohlenstoffatomen steht, so steht es insbesondere für Methyl, Ethyl, Propyl, Isopropyl, Butyl, tert. Butyl, 2,2-Dimethylethyl, Pentyl, Hexyl usw., insbesondere Methyl, tert. Butyl und 2,2-Dimethyl-ethyl. Sofern es durch Aryloxy substituiert ist, steht es insbesondere für Phenoxymethyl oder 1- oder 2-Naphthyloxymethyl, vorzugsweise 1-Naphthyloxymethyl. Heteroaryl bedeutet insbesondere Pyridyl, Thienyl oder Furyl. Im Heteroarylalkylrest besitzen der Heteroarylteil und der Alkylteil vorzugsweise die vorgenannten Bedeutungen, ein geradekettiger oder verzweigter Alkoxyrest bedeutet insbesondere Ethoxy oder tert. Butoxy und ein (C6-10)Aryl-(C1-5)-alkoxy-Rest besitzt insbesondere die oben für Aryl und Alkyl angegebenen Bedeutungen und steht vorzugsweise für Benzyloxy.If in formula I R₁ is a straight-chain or branched alkyl having 1 to 10 carbon atoms, it is in particular methyl, ethyl, propyl, isopropyl, butyl, tert. Butyl, 2,2-dimethylethyl, pentyl, hexyl, etc., in particular methyl, tert. Butyl and 2,2-dimethyl-ethyl. If it is substituted by aryloxy, it is in particular phenoxymethyl or 1- or 2-naphthyloxymethyl, preferably 1-naphthyloxymethyl. Heteroaryl is especially pyridyl, thienyl or furyl. In the heteroarylalkyl radical, the heteroaryl part and the alkyl part preferably have the abovementioned meanings, a straight-chain or branched alkoxy radical is in particular ethoxy or tert. Butoxy and a (C 6-10 ) aryl (C 1-5 ) alkoxy radical has in particular the meanings given above for aryl and alkyl and is preferably benzyloxy.
Falls R₄ für ein geradekettiges oder verzweigtes Alkyl steht, bedeutet es insbesondere Alkyl mit 1 bis 5 Kohlenstoffatomen vorzugsweise Äthyl, Propyl oder Isobutyl der glykosidisch gebundene Zuckerrest steht, beispielsweise für Glucopyranosyl, das gegebenenfalls O-acyliert sein kann z. B. Tetra-O-Acetylglucopyranosyl, eine gegebenenfalls substituierte gesättigte oder ungesättigte (C2-30)Alkylcarbonylgruppe steht insbesondere für eine entsprechende (C4-20)Alkylcarbonylgruppe beispielsweise für einen Palmitoyl-, einen Oleyl-, Linoyl-, Stearoyl- oder Pivaloyl-Rest wobei die Alkylcarbonylgruppe durch einen Cyclopentaphenanthren-Rest substituiert und für einen Cholyl-Rest stehen kann, ein (C3-6)Polyhydroxyalkylcarbonyl-Rest steht, beispielsweise für einen Glycerinoyl- oder einen Gluconoyl-Rest die gegebenenfalls substituiert sein können und beispielsweise einen Penta-O-acetylgluconoyl- oder einen Dibutyroylglycerinoyl-Rest bedeuten, ein Aroylrest steht beispielsweise für den Benzoyl-, ein Heteroaroyl-Rest steht, beispielsweise für den 2-, 3-, oder 4-Pyridinoyl-Rest, ein Arylalkyl-Rest steht beispielsweise für den Benzyl-, Phenethyl-, Naphthylmethyl-, p-Chlorphenoxy-propyl-2-Rest, ein Arylalkylcarbonyl-Rest steht, beispielsweise für einen Phenylacetyl-, Bis(1-Naphthylmethyl)acetyl- oder einen p-Chlorophenoxy- 1,1-dimethylacetyl-Rest, ein Heteroarylalkylcarbonylgruppe steht beispielsweise für einen Bis-(3-Pyridylmethyl)acetyl- oder einen Bis(4-Chinolinylmethyl)acetyl-Rest.If R₄ is a straight-chain or branched alkyl, it means, in particular, alkyl having 1 to 5 carbon atoms, preferably ethyl, propyl or isobutyl, the glycosidically bound sugar moiety, for example glucopyranosyl, which may optionally be O-acylated z. For example, tetra-O-acetylglucopyranosyl, an optionally substituted saturated or unsaturated (C 2-30 ) alkylcarbonyl group is especially for a corresponding (C 4-20 ) alkylcarbonyl group, for example, a palmitoyl, an oleyl, linoyl, stearoyl or pivaloyl Wherein the alkylcarbonyl group substituted by a cyclopentaphenanthrene radical and may stand for a cholyl radical, a (C 3-6 ) polyhydroxyalkylcarbonyl radical, for example, a glycerinoyl or a gluconoyl radical which may be optionally substituted and, for example, a Penta-O-acetylgluconoyl or a dibutyroylglycerinoyl radical, an aroyl radical is, for example, the benzoyl radical, a heteroaroyl radical, for example the 2-, 3- or 4-pyridinoyl radical, an arylalkyl radical is, for example for the benzyl, phenethyl, naphthylmethyl, p-chlorophenoxy-propyl-2 radical, an arylalkylcarbonyl radical, for example a phenylacetyl, Bi s (1-naphthylmethyl) acetyl or a p-chlorophenoxy-1,1-dimethylacetyl radical, a heteroarylalkylcarbonyl group is, for example, a bis (3-pyridylmethyl) acetyl or a bis (4-quinolinylmethyl) acetyl radical.
In R₅ steht eine Seitenkette einer D- oder L-Aminosäure insbesondere für Methyl, Isopropyl, Isobutyl, Benzyl, Hydroxy(C1-5)alkyl, 4-Aminobutyl oder 2-Carboxyethyl.In R₅ is a side chain of a D or L-amino acid in particular methyl, isopropyl, isobutyl, benzyl, hydroxy (C 1-5 ) alkyl, 4-aminobutyl or 2-carboxyethyl.
Eine hydrophile oder hydrophobe Aminosäureseitenkette in der Bedeutung von R₂ kann vorzugsweise Cyclohexylmethyl, Phenylmethyl, Trimethylsilylmethyl, p-Methoxyphenylmethyl, 1-Adamantylmethyl oder Isobutyl sein.A hydrophilic or hydrophobic amino acid side chain in the Meaning of R₂ may preferably cyclohexylmethyl, phenylmethyl, Trimethylsilylmethyl, p-methoxyphenylmethyl, 1-adamantylmethyl or isobutyl.
Die hydrophile oder lipophile Aminosäure-Seitenkette in der Bedeutung von R₈ kann vorzugsweise ein n-Butyl-, Isobutyl-, (E-2- Butenyl), Benzyl-, 4-Imidazolylmethyl-, 2-Methylthioethyl- oder -methyl-, Trimethylsilylmethyl-, Cyclohexylmethyl-, ein Azido- oder einen Pyridylmethyl-Rest sein. The hydrophilic or lipophilic amino acid side chain in meaning of R₈ may preferably be an n-butyl, isobutyl, (E-2) Butenyl), benzyl, 4-imidazolylmethyl, 2-methylthioethyl or methyl, trimethylsilylmethyl, cyclohexylmethyl, an azido or a pyridylmethyl radical.
Bevorzugte Verbindungen der Verbindungen gemäß der Erfindung besitzen die Formel IY Preferred compounds of the compounds according to the invention have the formula I Y
worin WY für -CH₂-CH₂- oder eine Gruppe der Formelwherein W Y is -CH₂-CH₂- or a group of the formula
steht, wobei
XY die Bedeutung von X besitzt, jedoch besonders bevorzugt Schwefel
bedeutet,
VY für Sauerstoff, NR₃Y worin R₃Y Wasserstoff oder einen geradekettigen
oder verzweigten (C1-5)Alkylrest insbesondere jedoch
Wasserstoff oder Methyl bedeutet, oder für eine Bindung steht,
R₁Y für tert.-Butyl, Benzyloxy, ω-Aminopentyl oder Isopropyl
steht oder
R₁Y eine Gruppe der Formelstands, where
X Y has the meaning of X, but particularly preferably denotes sulfur,
V Y is oxygen, NR₃ Y in which R₃ Y is hydrogen or a straight-chain or branched (C 1-5 ) alkyl radical but especially hydrogen or methyl, or represents a bond,
R₁ Y is tert-butyl, benzyloxy, ω- aminopentyl or isopropyl or
R₁ Y is a group of the formula
R₄Y-O-(CH₂CH₂O) m Y-(CH₂) n Y-R₄ Y is -O- (CH₂CH₂O) m Y - (CH₂) n Y -
bedeutet, worin
R₄Y für Wasserstoff, Methyl, Pyridinoyl oder 3,4,5-Trimethoxybenzoyl
steht,
m Y eine ganze Zahl von 2-7 und
n Y eine ganze Zahl von 0-2 bedeutet,
R₂Y Cyclohexylmethyl, Phenylmethyl, Trimethylsilylmethyl, p-Methoxyphenylmethyl,
a-Adamantylmethyl oder Isobutyl bedeutet,
Z die im Anspruch 1 angegebene Bedeutung besitzt,
AY Gruppen der Formelnmeans, in which
R₄ Y is hydrogen, methyl, pyridinoyl or 3,4,5-trimethoxybenzoyl,
m Y is an integer from 2-7 and
n Y is an integer from 0-2,
R₂ Y is cyclohexylmethyl, phenylmethyl, trimethylsilylmethyl, p-methoxyphenylmethyl, a- adamantylmethyl or isobutyl,
Z has the meaning given in claim 1,
A Y groups of formulas
bedeutet worin
R₃Y für Wasserstoff oder Methyl steht und
R₈Y für n-Butyl, Isobutyl, E-2-Butenyl, Benzyl, 4-Imidazolylmethyl,
Pyridylmethyl, Trimethylsilylmethyl oder einen Azido-Rest
steht,
BY eine Gruppe der Formelmeans in which
R₃ Y is hydrogen or methyl and
R₈ Y is n-butyl, isobutyl, E-2-butenyl, benzyl, 4-imidazolylmethyl, pyridylmethyl, trimethylsilylmethyl or an azido radical,
B Y is a group of the formula
bedeutet worin R₉Y für Isobutyl, Benzyl oder Cyclohexylmethyl
steht und entweder
R₁₀Y einen Hydroxyl-Rest und
R₁₁Y Wasserstoff bedeuten, falls R₁₂Y und R₁₃Y jeweils für Wasserstoff
stehen, oder
R₁₀Y und R₁₁Y zusammen die Oxogruppe bilden, insbesondere falls
R₁₂Y und R₁₃Y jeweils für Fluor stehen.wherein R₉ Y is isobutyl, benzyl or cyclohexylmethyl and either
R₁₀ Y is a hydroxyl radical and
R₁₁ Y is hydrogen, if R₁₂ Y and R₁₃ Y are each hydrogen, or
R₁₀ Y and R₁₁ Y together form the oxo group, especially if
R₁₂ Y and R₁₃ Y are each fluorine.
R₁₄Y und R₁₅Y sind gleich oder verschieden und bedeuten jeweils Wasserstoff, Methyl, i-Propyl, i-Butyl, 2-Butyl oder eine Gruppe der FormelR₁₄ Y and R₁₅ Y are the same or different and each represents hydrogen, methyl, i-propyl, i-butyl, 2-butyl or a group of the formula
worin
R₁₆Y für i-Butyl oder 2-Butyl und
R₁₇Y für Aminomethylpyridyl stehen;
YY für eine Bindung oder eine Gruppe der Formelwherein
R₁₆ Y is i-butyl or 2-butyl and
R₁₇ Y is aminomethylpyridyl;
Y Y is a bond or a group of the formula
steht, wobei
R₁₈Y und R₁₉Y unabhängig voneinander Wasserstoff, Fluor, Chlor,
eine Azido-Gruppe, n-Butyl, Isobutyl, E-2-Butenyl, Methylthiomethyl,
Methyl, Benzyl, Isopropyl bedeuten.
stands, where
R₁₈ Y and R₁₉ Y independently of one another are hydrogen, fluorine, chlorine, an azido group, n-butyl, isobutyl, E-2-butenyl, methylthiomethyl, methyl, benzyl, isopropyl.
Das Verfahren gemäß Verfahrensstufe a) des Patentanspruches 3 wird vorzugsweise so durchgeführt, daß man ein Amin der Formel II mit einer Säure der Formel III, unter Verwendung von, in der Peptidchemie bekannten Verfahren, z. B. in Ggenwart von N,N′- Dicyclohexyl-carbodiimid (unter Zusatz von 1-Hydroxybenzotriazol) in einem geeigneten Lösungsmittel wie z. B. Methylenchlorid bei Temperaturen zwischen 0° und Raumtemperatur umsetzt. Die hierbei erhaltenen Verbindungen der Formel Ia sind ein Spezialfall von Verbindungen der Formel I, worin W fürThe method according to process step a) of claim 3 is preferably carried out so that an amine of the formula II with an acid of formula III, using, in Peptide chemistry known methods, eg. In the presence of N, N ' Dicyclohexylcarbodiimide (with the addition of 1-hydroxybenzotriazole) in a suitable solvent such. For example, methylene chloride at temperatures between 0 ° and room temperature. The compounds of the formula Ia obtained in this case are a special case of compounds of the formula I in which W is
steht, und -V ein Bindung und X=0 bedeuten.and -V is a bond and X = 0.
Das Verfahren gemäß Verfahrensstufe b) des Patentanspruches 3 wird vorzugsweise so durchgeführt, daß man ein Amin der Formel II direkt mit einem aktivierten Säurederivat der Formel IV worin Q beispielsweise für einen p-Nitro-Phenyl- oder einen Alkoxyrest steht, gegebenenfalls unter Zusatz von Dimethylaminopyridin bei 20°-80° in einem geeigneten Lösungsmittel wie z. B. Dimethylformamid umsetzt.The method according to process step b) of claim 3 is preferably carried out so that an amine of the formula II directly with an activated acid derivative of formula IV wherein Q is for example a p-nitro-phenyl or an alkoxy radical is, if appropriate, with the addition of dimethylaminopyridine 20 ° -80 ° in a suitable solvent such. B. dimethylformamide implements.
Die hierbei erhaltenen Verbindungen der Formel Ib sind ein Spezialfall von Verbindungen der Formel I, worin W fürThe compounds of the formula Ib obtained in this case are a special case of compounds of the formula I in which W is
steht, worin V und X die im Anspruch 1 angegebenen Bedeutungen besitzen.wherein V and X are as defined in claim 1 Own meanings.
Das Verfahren gemäß Verfahrensstufe c) ist eine reduktive Alkylierung der primären Aminogruppe der Verbindungen der Formel II, die zweckmäßigerweise in einem Lösungsmittel wie Methanol bei einem pH-Wert der Lösung von 6 bis 7 und einer Temperatur von 20° bis 30°C erfolgt, wobei als Reduktionsmittel NaBH₃CN bevorzugt wird. The process according to process step c) is a reductive alkylation the primary amino group of the compounds of the formula II, Conveniently in a solvent such as methanol at a pH of the solution of 6 to 7 and a temperature of 20 ° to 30 ° C, with preference as a reducing agent NaBH₃CN becomes.
Die hierbei erhaltenen Verbindungen der Formel Ic sind ein Spezialfall von Verbindungen der Formel I, worin W für -CH₂-CH₂- steht.The compounds of the formula Ic obtained in this case are a special case of compounds of the formula I in which W is -CH₂-CH₂- stands.
Das Verfahren gemäß Verfahrensstufe d) des Patentanspruches 3 wird so durchgeführt, daß man Verbindungen der Formel Ie mit einem Chromtrioxyd-dipyridin-komplex (Collin's Reagens) in ein Lösungsmittel wie Methylenchlorid oder Dimethylformamid zum entsprechenden Keton umsetzt. Alternativ können, insbesondere wenn X=S, auch andere geeignete Verfahren, wie z. B. Oxidation mit/in Dimethylsulfoxid in Gegenwart von Dicyclohexylcarbodiimid und einer katalytischen Menge von Dichloressigsäure verwendet werden.The method according to process step d) of claim 3 is carried out so that compounds of the formula Ie with a chromium trioxide-dipyridine complex (Collin's reagent) in a Solvents such as methylene chloride or dimethylformamide for corresponding ketone. Alternatively, in particular if X = S, other suitable methods, such as. B. oxidation with / in dimethyl sulfoxide in the presence of dicyclohexylcarbodiimide and a catalytic amount of dichloroacetic acid become.
Die hierbei erhaltenen Verbindungen der Formel If sind ein Spezialfall von Verbindungen der Formel I, worin B für eine Gruppe der FormelThe compounds of the formula If obtained in this case are a special case of compounds of formula I wherein B is a group the formula
steht, worin R₉, R₁₂ bis R₁₅, Y und X die im Anspruch 1 angegebene Bedeutung besitzen und R₁₀ und R₁₁ zusammen für eine Oxo-Gruppe stehen.wherein R₉, R₁₂ to R₁₅, Y and X are as defined in claim 1 Have meaning and R₁₀ and R₁₁ together for an oxo group stand.
Die in den obigen Verfahren verwendeten Ausgangsverbindungen sind entweder bekannt oder können auf an sich bekannte Verfahren, beispielsweise wie in den nachfolgenden Beispielen beschrieben, hergestellt werden. The starting compounds used in the above processes are either known or can be based on methods known per se, for example, as described in the examples below, getting produced.
Die erfindungsgemäß hergestellten Verbindungen der Formel I können auf an sich bekannte Verfahren isoliert und gereinigt werden. Racemische und/oder diastereomere Gemische können auf an sich bekannte Weise aufgetrennt werden.The compounds of the formula I prepared according to the invention can be isolated and purified by methods known per se become. Racemic and / or diastereomeric mixtures can be used on to be separated in a known manner.
Falls die Verbindungen der Formel I saure oder basische Gruppen enthalten, so können diese gegebenenfalls auch Salze bilden, beispielsweise Metallsalze wie Natriumsalze oder Säureadditionssalze wie Hydrochloride.If the compounds of formula I acidic or basic groups may optionally form salts, for example, metal salts such as sodium salts or acid addition salts like hydrochlorides.
In den nachfolgenden Beispielen sind alle Temperaturen in Celsiusgraden angegeben und sind nicht korrigiert. In the following examples, all temperatures are in degrees centigrade indicated and are not corrected.
In den nachfolgenden Beispielen werden folgende Abkürzungen verwendet:The following abbreviations are used in the following examples:
373 mg Me-2eg-p-Nitrophenylester und 620 mg H-Cha(O)Bly-Cha- (OH)Bly-NHBu werden in 3 ml Dimethylformamid gelöst und 2 Stunden bei 35° umgesetzt. Man verdünnt das Reaktionsgemisch mit Essigester, extrahiert mehrmals mit wäßriger Natriumbicarbonat-Lösung, trocknet die org. Phase mit Magnesiumsulfat und dampft ein. Das Rohprodukt wird aus Methylenchlorid/Ether/Hexan kristallisiert. Die erhaltene Titelverbindung besitzt ein373 mg of Me-2eg p-nitrophenyl ester and 620 mg of H-Cha (O) Bly-Cha (OH) Bly-NHBu are dissolved in 3 ml of dimethylformamide and 2 hours reacted at 35 °. Dilute the reaction mixture with ethyl acetate, extracted several times with aqueous sodium bicarbonate solution, the org dries. Phase with magnesium sulfate and evaporated. The Crude product is crystallized from methylene chloride / ether / hexane. The title compound obtained has a
=-5.0° (c=0.1 in CH₂Cl₂).= -5.0 ° (c = 0.1 in CH₂Cl₂).
50 mg Me-3egr-I, 100 mg H-Phe-Nle-Cha(OH)Bly-NHBu und 355 µl Ethyldiisopropylamin werden in wenig Dimethylformamid gelöst und 3 Tage bei Raumtemperatur stehen gelassen, wobei die Umsetzung stattfindet. Das Produkt wird wie in Bsp. 1 isoliert und mit Methanol in Methylenchlorid (3-6%) an Kieselgel chromatographiert. Die erhaltene Titelverbindung besitzt ein50 mg Me-3egr-I, 100 mg H-Phe-Nle-Cha (OH) Bly-NHBu and 355 μl Ethyldiisopropylamin are dissolved in a little dimethylformamide and Allowed to stand for 3 days at room temperature, the reaction takes place. The product is isolated as in Ex. 1 and with Methanol in methylene chloride (3-6%) chromatographed on silica gel. The title compound obtained has a
=-46.5° (c=0.15 in CH₂Cl₂). = -46.5 ° ( c = 0.15 in CH₂Cl₂).
38 mg 3EGS-OEt und 82 mg H-Phe-Nle-Cha(OH)Bly-NHBu werden analog Bsp. 1 umgesetzt. Das Rohprodukt wird mit Methanol in Methylenchlorid (5%) chromatographiert. Die erhaltene Titelverbindung besitzt ein38 mg 3EGS-OEt and 82 mg H-Phe-Nle-Cha (OH) Bly-NHBu are analogous Example 1 implemented. The crude product is treated with methanol in methylene chloride (5%) chromatographed. The title compound obtained owns one
=-11.0° (c =0.2 in CH₂Cl₂).= -11.0 ° ( c = 0.2 in CH₂Cl₂).
150 mg 3EGS-OEt und 315 mg H-Cha(O)Bly-Cha(OH)Bly-NHBu werden analog Bsp. 1 umgesetzt. Das Rohprodukt wird mit Methanol in Methylenchlorid (2-4%) chromatographiert. Die erhaltene Titelverbindung besitzt ein150 mg 3EGS-OEt and 315 mg H-Cha (O) Bly-Cha (OH) Bly-NHBu analogously Ex 1 implemented. The crude product is mixed with methanol Methylene chloride (2-4%) chromatographed. The title compound obtained owns one
=-32.5° (c =0.1 in CH₂Cl₂).= -32.5 ° ( c = 0.1 in CH₂Cl₂).
220 mg des Produktes aus Bsp. 1 werden 2 Stunden in Anwesenheit von 20 mg eines Palladium-Kohle Katalysators in Ethanol bei Raumtemperatur und Normaldruck hydriert. Der Katalysator wird abfiltriert und das Filtrat eingedampft. Die erhaltene Titelverbindung besitzt ein220 mg of the product from Ex. 1 are in the presence for 2 hours of 20 mg of a palladium-carbon catalyst in ethanol at room temperature and normal pressure hydrogenated. The catalyst is filtered off and the filtrate evaporated. The title compound obtained owns one
=-13.5° (c =0.1 in CH₂Cl₂). = -13.5 ° ( c = 0.1 in CH₂Cl₂).
175 mg Me-3egS-SMe werden analog Bsp. 1 mit 400 mg H-Tmsal- His-Cha(OH)Bly-NHBu unter Zusatz von 100 mg Imidazol 15 Stunden miteinander reagieren gelassen. Das erhaltene Rohprodukt wird mit Methanol in Methylenchlorid (2-10%) chromatographiert. Die erhaltene Titelverbindung besitzt ein175 mg of Me-3egS-SMe are analogously to Example 1 with 400 mg of H-Tmsal- His-Cha (OH) Bly-NHBu with the addition of 100 mg imidazole 15 hours react with each other. The resulting crude product is with Methanol in methylene chloride (2-10%) chromatographed. The obtained Title compound has one
=-49.8° (c =0.2 in CH₂Cl₂).= -49.8 ° ( c = 0.2 in CH₂Cl₂).
300 mg Me-7egS-SMe werden analog Bsp. 1 mit 330 mg H-Cha(O)- Bly-Cha(OH)Ala-NHBu unter Zusatz von 15 mg Dimethylaminopyridin während 15 Stunden umgesetzt. Das Rohprodukt wird mit Methanol in Methylenchlorid (2-5%) chromatographiert. Die erhaltene Titelverbindung besitzt ein300 mg of Me-7egS-SMe are analogously to Example 1 with 330 mg of H-Cha (O) - Bly-Cha (OH) Ala-NHBu with the addition of 15 mg dimethylaminopyridine implemented during 15 hours. The crude product is mixed with methanol Methylene chloride (2-5%) chromatographed. The title compound obtained owns one
=-23.3° (c =0.15 in CH₂Cl₂).= -23.3 ° ( c = 0.15 in CH₂Cl₂).
160 mg 4-Pyridyl-CH₂O(CS)SMe werden analog Bsp. 1 mit 410 mg H-Tmsal-Nle-F₂-Chatin-NHiBu umgesetzt. Das Rohprodukt wird mit Methanol in Methylenchlorid (1-5%) chromatographiert. Die erhaltene Titelverbindung besitzt ein160 mg of 4-pyridyl-CH₂O (CS) SMe are analogous Ex. 1 with 410 mg H-Tmsal-Nle-F₂-Chatin-NHiBu implemented. The crude product is with Methanol in methylene chloride (1-5%) chromatographed. The obtained Title compound has one
=-53.0° (c =0.1 in CH₂Cl₂). = -53.0 ° ( c = 0.1 in CH₂Cl₂).
115 mg MPA-(CS)SMe werden analog Bsp. 1 mit 400 mg H-Tmsal- Nle-Chatin-leu-α-Picolin umgesetzt. Das Rohprodukt wird aus Essigester/Ether gefällt. Die erhaltene Titelverbindung besitzt ein115 mg of MPA (CS) SMe are reacted analogously to Example 1 with 400 mg of H-Tms-Nle-Chatin-leu- α- picoline. The crude product is precipitated from ethyl acetate / ether. The title compound obtained has a
=-68.6° (c =0.2 in CH₂Cl₂).= -68.6 ° ( c = 0.2 in CH₂Cl₂).
325 mg Me-7egS-SCH₃ werden analog Bsp. 1 mit 400 mg H-Cha- Nle-Cha(OH)Nle-NHBu unter Zusatz von 20 mg Dimethylaminopyridin während 15 Stunden reagieren gelassen. Das Rohprodukt wird mit Methanol in Methylenchlorid (2-5%) chromatographiert. Die erhaltene Titelverbindung besitzt ein325 mg Me-7egS-SCH₃ are analogously Ex. 1 with 400 mg H-Cha Nle-Cha (OH) Nle-NHBu with the addition of 20 mg dimethylaminopyridine allowed to react for 15 hours. The crude product is with Methanol in methylene chloride (2-5%) chromatographed. The obtained Title compound has one
=-39.4° (c =0.2 in CH₂Cl₂).= -39.4 ° ( c = 0.2 in CH₂Cl₂).
Analog Bsp. 1 werden 1 g Me-PegS-SMe mit 400 mg H-Cha-Nle- Cha(OH)Nle-NHBu unter Zusatz von 20 mg Dimethylaminopyridin während 24 Stunden reagieren lassen. Das Rohprodukt wird mit Methanol in Methylenchlorid (2-5%) chromatographiert. Man erhält die Titelverbindung als Gemisch verschiedener Oligomere.Analogously to Example 1, 1 g of Me-PegS-SMe with 400 mg of H-Cha-NLE Cha (OH) Nle-NHBu with the addition of 20 mg dimethylaminopyridine to react for 24 hours. The crude product is with Methanol in methylene chloride (2-5%) chromatographed. You get the title compound as a mixture of different oligomers.
300 mg der Titelverbindung aus Bsp. 8 werden in einem Gemisch von Benzol und Dimethylsulfoxid 1 : 1 gelöst. Bei 0-5° gibt man 433 mg Dicyclohexylcarbodiimid und 17 µl Dichloressigsäure zu und rührt 24 Stunden bei Raumtemperatur. Bei 0° wird eine Lösung von 200 mg Oxalsäure in wenig Methanol zugetropft, 1 Stunde gerührt, von ausgefallenem Dicyclohexylharnstoff abfiltriert und das Filtrat zwischen Essigester und ges. wäßriger Natriumbicarbonat-Lösung verteilt. Die org. Phase wird getrocknet (MgSO₄) und eingedampft. Die erhaltene Titelverbindung besitzt ein300 mg of the title compound from Ex. 8 are dissolved in a mixture of Benzene and dimethyl sulfoxide 1: 1 dissolved. At 0-5 ° gives 433 mg Dicyclohexylcarbodiimide and 17 ul dichloroacetic acid and stirred 24 hours at room temperature. At 0 °, a solution of 200 mg Oxalic acid added dropwise in a little methanol, stirred for 1 hour, from precipitated dicyclohexylurea and the filtrate between ethyl acetate and sat. aqueous sodium bicarbonate solution distributed. The org. Phase is dried (MgSO₄) and evaporated. The title compound obtained has a
=-19.1° (c = 1 in CH₂Cl₂).= -19.1 ° ( c = 1 in CH₂Cl₂).
302 mg Niacin-2egS-SMe werden analog Bsp. 1 mit 514 mg H-Tmsal- Nle-F₂Chatin-NHiBu unter Zusatz von 40 mg Dimethylaminopyridin während 36 Stunden reagieren gelassen. Das Rohprodukt wird mit Methanol in Methylenchlorid (10-5%) chromatographiert. Die erhaltene Titelverbindung besitzt ein302 mg of niacin-2egS-SMe are prepared analogously to Example 1 with 514 mg of H-Tmsal Nle-F₂Chatin-NHiBu with the addition of 40 mg dimethylaminopyridine allowed to react for 36 hours. The crude product is with Methanol in methylene chloride (10-5%) chromatographed. The obtained Title compound has one
=-71.3° (c =0.1 in CH₂Cl₂).= -71.3 ° ( c = 0.1 in CH₂Cl₂).
28 mg der Titelverbindung aus Bsp. 13 werden analog Bsp. 12 mit Dimethylsulfoxid in Anwesenheit von 35 mg Dicyclohexylcarbodiimid und 2 mg Dichloressigsäure oxidiert. Die erhaltene Titelverbindung besitzt ein28 mg of the title compound from Ex. 13 are analogous Ex. 12 with Dimethyl sulfoxide in the presence of 35 mg dicyclohexylcarbodiimide and 2 mg of dichloroacetic acid oxidized. The obtained Title compound has one
=-13.5° (c =0.05 in CH₂Cl₂). = -13.5 ° ( c = 0.05 in CH₂Cl₂).
500 mg Tmpac-2egS-SMe werden analog Bsp. 1 mit 610 mg H- Tmsal-Nle-F₂Chatin-NHiBu unter Zusatz von 100 mg Dimethylaminopyridin während 15 Stunden reagieren gelassen. Das Rohprodukt wird mit Methanol in Methylenchlorid (0-5%) chromatographiert. Die erhaltene Titelverbindung besitzt ein500 mg Tmpac-2egS-SMe are prepared analogously to Ex. 1 with 610 mg H- Tmsal-Nle-F₂Chatin-NHiBu with the addition of 100 mg dimethylaminopyridine allowed to react for 15 hours. The crude product is chromatographed with methanol in methylene chloride (0-5%). The title compound obtained has a
=-49.1° (c =0.1 in CH₂Cl₂).= -49.1 ° ( c = 0.1 in CH₂Cl₂).
30 mg der Titelverbindung des Beispiels 15 werden analog Beispiel 12 mit Dimethylsulfoxid in Anwesenheit von 33 mg Dicyclohexylcarbodiimid und 2 mg Dichloressigsäure oxidiert. Die erhaltene Titelverbindung besitzt ein30 mg of the title compound of Example 15 are analogous to Example 12 with dimethyl sulfoxide in the presence of 33 mg dicyclohexylcarbodiimide and 2 mg of dichloroacetic acid oxidized. The title compound obtained owns one
=+1.8° (c =0.1 in CH₂Cl₂).= + 1.8 ° ( c = 0.1 in CH₂Cl₂).
130 mg 3EGS-OEt werden analog Beispiel 1 mit 233 mg H-Phe (N-Me)Leu-Cha(OH)Bly-NHBu in Gegenwart von 15 mg Dimethylaminopyridin umgesetzt. Das Rohprodukt wird mit Methanol in Methylenchlorid (5%) chromatographiert. Die erhaltene Titelverbindung besitzt ein130 mg of 3EGS-OEt are analogously to Example 1 with 233 mg of H-Phe (N-Me) Leu-Cha (OH) Bly-NHBu in the presence of 15 mg dimethylaminopyridine implemented. The crude product is treated with methanol in methylene chloride (5%) chromatographed. The title compound obtained owns one
=-58.8° (c =0.25 in CH₂Cl₂). = -58.8 ° ( c = 0.25 in CH₂Cl₂).
200 mg 3EGS-OEt werden analog Bsp. 1 mit 350 mg H-Cha(OH)Bly- Cha(OH)Bly-NHBu unter Zusatz von 20 mg Dimethylaminopyridin während 4 Stunden reagieren gelassen. Das Rohprodukt wird mit Methanol in Methylenchlorid (2-4%) chromatographiert. Die erhaltene Titelverbindung besitzt ein200 mg of 3EGS-OEt are analogously to Example 1 with 350 mg of H-Cha (OH) Bly- Cha (OH) Bly-NHBu with the addition of 20 mg dimethylaminopyridine allowed to react for 4 hours. The crude product is with Methanol in methylene chloride (2-4%) chromatographed. The obtained title compound has a
=-74.5° (c =0.2 in CH₂Cl₂).= -74.5 ° ( c = 0.2 in CH₂Cl₂).
15 mg Niacin-2egS-SMe werden analog Beispiel 1 mit 25 mg H- Tmsal-Nle-Cha(OH)-CF₂-CF₂-CF₃ während 72 Stunden reagieren gelassen. Das Rohprodukt wird mit Methanol in Methylenchlorid (5-10%) chromatographiert. Die erhaltene Titelverbindung besitzt ein15 mg niacin-2egS-SMe are analogously to Example 1 with 25 mg H- Tmsal-Nle-Cha (OH) -CF₂-CF₂-CF₃ allowed to react for 72 hours. The crude product is washed with methanol in methylene chloride (5-10%) Chromatograph. The title compound obtained has a
=-38.5° (c =0.7 in CH₂Cl₂).= -38.5 ° ( c = 0.7 in CH₂Cl₂).
70 mg Me-3eg-H und 200 mg H-Cha(OH)Bly-Cha(OH)Bly-NHBu werden in wenig Methanol gelöst und mit ca. 20 mg NaBH₃CN versetzt. Nach 1 Stunde wird zwischen Essigester und ges. wäßriger Natriumbicarbonat-Lösung verteilt, die org. Phase getrocknet und eingedampft. Der Rückstand wird mit Methanol in Methylenchlorid (1-3%) an Kieselgel chromatographiert. Die erhaltene Titelverbindung besitzt ein70 mg Me-3eg-H and 200 mg H-Cha (OH) Bly-Cha (OH) Bly-NHBu are dissolved in dissolved a little methanol and treated with about 20 mg NaBH₃CN. After 1 hour is between ethyl acetate and sat. aqueous sodium bicarbonate solution distributed, the org. Phase dried and evaporated. The residue is treated with methanol in methylene chloride (1-3%) Silica gel chromatographed. The title compound obtained has on
=-40° (c =0.1 in CH₂Cl₂). = -40 ° ( c = 0.1 in CH₂Cl₂).
130 mg 3EGS-OEt werden analog Bsp. 1 mit 256 mg H-Phe- O-Nle-Cha(OH)Nle-NHB in Gegenwart von 20 mg Dimethylaminopyridin umgesetzt. Mit Methanol in Methylenchlorid (3%) wird chromatographiert. Die erhaltene Titelverbindung besitzt ein130 mg of 3EGS-OEt are prepared analogously to Example 1 with 256 mg of H-phe- O-Nle-Cha (OH) NLE-NHB in the presence of 20 mg dimethylaminopyridine implemented. It is chromatographed with methanol in methylene chloride (3%). The title compound obtained has a
=-21.7° (c =0.25 in CH₂Cl₂).= -21.7 ° ( c = 0.25 in CH₂Cl₂).
Die erfindungsgemäßen Verbindungen weisen pharmakologische Aktivität auf. Sie können als Arzneimittel verwendet werden. Wie Resultaten von Standard-Tests entnommen werden kann, weisen sie insbesondere für Enzymhemmer typische Wirkungen auf. Die hemmende Wirkung in Bezug auf ein spezifisches Enzym hängt selbstverständlich von der Peptidstruktur gesamthaft ab. Die obigen, besonders als Hemmer der Reninaktivität geeigneten Verbindungen bewirken am humanen synthetischen Tetradekapeptidsubstrat bei einer Konzentration von 10-5M bis 10-11M eine 50%ige Hemmung der Enzymaktivität von reinem Humanrenin nach der Methode von F. Cumin et al. (Bioch. Biophys. Acta 913, 10-19 [1987]) oder mittels Renin Binding Assay (Fundamental and Clin. Pharmacol. in Press).The compounds according to the invention have pharmacological activity. They can be used as medicines. As can be seen from standard tests, they have typical effects especially for enzyme inhibitors. The inhibitory effect on a specific enzyme will of course depend on the overall peptide structure. The above compounds particularly useful as inhibitors of renin activity cause a 50% inhibition of the enzyme activity of pure human renin in the human synthetic tetradecapeptide substrate at a concentration of 10 -5 M to 10 -11 M by the method of F. Cumin et al. (Bioch., Biophys., Acta 913, 10-19 [1987]) or by Renin Binding Assay (Fundamental and Clin. Pharmacol., Press).
In der "antibody-trapping"-Methode von K. Poulsen und J. Jorgensen (J. Clin. Endocrin. Metab. 39 [1974] 816-825) hemmen sie die Humanplasmareninaktivität bei einer Konzentration von 10-5M bis 10-11M.In the "antibody-trapping" method of K. Poulsen and J. Jorgensen (J.Clin.Endocrin.Metab.39 [1974] 816-825) they inhibit human plasma renin activity at a concentration of 10 -5 M to 10 -11 M.
Die erfindungsgemäßen Verbindungen sind daher zur Verwendung für die Prophylaxe und Behandlung von Zuständen geeignet, die durch eine enzymatische Dysfunktion charakterisiert sind und für die eine Hemmung der enzymatischen Aktivität angezeigt ist.The compounds of the invention are therefore for use suitable for the prophylaxis and treatment of conditions that characterized by an enzymatic dysfunction and for an inhibition of enzymatic activity is indicated.
Als Reninhemmer sind sie z. B. zur Verwendung bei der Prophylaxe und Behandlung der Hypertonie und Herzinsuffizienz ("congestive heart failure") geeignet.As renin inhibitors they are z. For use in prophylaxis and treatment of hypertension and heart failure ("congestive heart failure ").
Bevorzugt für die Prophylaxe und Behandlung der Hypertonie und der Herzinsuffizienz sind die Titelverbindungen der Beispiele 1 bis 5, 9 bis 12, 16, 20 und 21 insbesondere der Beispiele 1 bis 4, 9 bis 12 und 21 und ganz besonders der Beispiele 3, 10 und 21. Preferred for the prophylaxis and treatment of hypertension and Heart failure are the title compounds of Examples 1 to 5, 9 to 12, 16, 20 and 21 in particular of examples 1 to 4, 9 to 12 and 21 and more particularly Examples 3, 10 and 21.
Die Verbindungen gemäß der Erfindung besitzen ferner eine antiretrovirale Wirkung und können deshalb zur Behandlung von durch Retroviren, inbegriffen HTLV-I und -III-Viren, hervorgerufenen Krankheiten verwendet werden. Diese Wirkung zeigt sich im FeLV- Katzenmodell [Cerny und Essex, CPC Press IN 1979, Seiten 233-256; Cockerell et al. J. Natl. Cancer Inst. 57, Seiten 1095-1099 (1976); Cotter et al. J. AM. VET. MED. ASSOC. 166, Seiten 449-453 (1975); ESSEX et al. SCIENCE 190, 790-792 (1975)]. - einem Modell zur Untersuchung der AIDS-Krankheit. Es wurde berichtet (beispielsweise am 25 ICAAC in Minneapolis vom 30. September bis 2. Oktober), daß bei Verabreichung von 30 mg 3′-Azido-3′-deoxythymidin während 14 Tagen eine Reduktion des FeLV-Titers um einen Faktor von 10 gezeigt werden konnte, jedoch keine Heilung stattfand. Nach Verabreichung der Verbindungen gemäß der Erfindung konnte eine Vernichtung der Viren beobachtet werden.The compounds according to the invention also have an antiretroviral Effect and therefore can be used to treat Retroviruses, including HTLV-I and -III viruses, evoked Diseases are used. This effect is evident in the FeLV Cat Model [Cerny and Essex, CPC Press IN 1979, pp. 233-256; Cockerell et al. J. Natl. Cancer Inst. 57, pp. 1095-1099 (1976); Cotter et al. J. AM. VET. MED. ASSOC. 166, pages 449-453 (1975); ESSEX et al. SCIENCE 190, 790-792 (1975)]. - a model for the study of AIDS disease. It has been reported (for example at the 25th ICAAC in Minneapolis from 30th September to 2nd October) that when administered 30 mg of 3'-azido-3'-deoxythymidine during 14 days a reduction of the FeLV titer a factor of 10 could be shown, but no cure took place. After administration of the compounds according to the invention a destruction of the viruses could be observed.
Die zur Erreichung der antiviralen Wirkung benötigten Dosen entsprechen denjenigen die üblicherweise verwendet werden und liegen beispielsweise in der Größenordnung von 5 bis 20 mg/kg/Tag.The doses required to achieve the antiviral effect correspond those that are commonly used and are lying for example, on the order of 5 to 20 mg / kg / day.
Für obige Anwendungen hängt die zu verabreichende Dosis von der jeweils verwendeten Verbindung, der Art der Verabreichung und der gewünschten Behandlung ab. Im allgemeinen werden zufriedenstellende Resultate erhalten, falls die Verbindungen in einer täglichen Dosis von 0,02 mg/kg bis ca. 20 mg/kg Tierkörpergewicht verabreicht werden. Für größere Säugetiere beträgt die empfohlene tägliche Dosis von etwa 1 mg bis etwa 500 mg, zweckmäßigerweise verabreicht z. B. oral in Dosen von 0,25 mg bis ca. 500 mg 1-4mal täglich oder in Retard-Form. For the above applications, the dose to be administered depends on the dose each used compound, the route of administration and the desired treatment. In general, will be satisfactory Get results in case the compounds are in a daily Dose from 0.02 mg / kg to about 20 mg / kg animal body weight be administered. For larger mammals, the recommended daily dose of about 1 mg to about 500 mg, conveniently administered z. B. orally in doses of 0.25 mg to about 500 mg 1-4 times daily or in delayed-release form.
Die erfindungsgemäßen Verbindungen können in freier Form oder, sofern saure oder basische Gruppen anwesend sind, in pharmakologisch verträglicher Salzform verabreicht werden. Solche Salzformen weisen eine Wirkung in derselben Größenordnung wie die freien Formen auf und können auf bekannte Weise hergestellt werden. Die vorliegende Erfindung betrifft ebenfalls pharmazeutische Zubereitungen enthaltend eine erfindungsgemäße Verbindung in freier Form oder in pharmazeutisch verträglicher Salzform, gegebenenfalls zusammen mit pharmazeutisch verträglichen Hilfs- und/oder Trägerstoffen. Solche pharmazeutischen Zubereitungen können zur Verwendung bei enteraler, vorzugsweise oraler Verabreichung formuliert werden, z. B. als Tabletten, oder zur Verwendung bei parenteraler Verabreichung, z. B. als injizierbare Lösungen oder Suspension.The compounds of the invention may be in free form or, if acidic or basic groups are present, pharmacologically be administered in a compatible salt form. Such salt forms have an effect of the same order of magnitude as the free forms and can be prepared in a known manner. The present invention also relates to pharmaceutical Preparations containing a compound of the invention in free form or in pharmaceutically acceptable salt form, optionally together with pharmaceutically acceptable auxiliary and / or Excipients. Such pharmaceutical preparations can for use in enteral, preferably oral, administration be formulated, for. As tablets, or for use in parenteral administration, e.g. B. as injectable solutions or Suspension.
Claims (10)
R₁ eine Gruppe der FormelR₄-O(CH₂CH₂O) m -(CH₂) n -bedeutet, worin R₄ für Wasserstoff, einen geradkettigen oder verzweigten (C1-20)Alkyl- oder einen glykosidisch gebundenen Zuckerrest, eine gegebenenfalls substituierte, gesättigte oder ungesättigte, geradekettige oder verzweigte (C2-30)Alkylcarbonylgruppe, eine (C3-6)Polyhydroxy-alkylcarbonyl-, eine Phosphoroyl-, eine Bis-(dimethyl-amino)-phosphoroyl-, eine Sulfo-, eine Aroyl-, eine Heteroaroyl-, worin der Heteroarylrest oben definiert ist, eine (C7-11)Arylalkyl-, eine (C7-11)Arylalkylcarbonyl- oder eine Heteroarylalkylcarbonylgruppe, worin der Heteroarylrest oben definiert ist, oder die Biotinoyl-Gruppe steht,
m =eine ganze Zahl von 1-20 und
n = eine ganze Zahl von 0-5 bedeuten
oder
R₄ eine Gruppe der Formel bedeutet, worin R₅ für Wasserstoff oder eine Seitenkette einer D- oder L-Aminosäure steht und R₆ und R₇ gleich oder verschieden sind und jeweils Wasserstoff, (C1-5)Alkyl, (C2-5)Hydroxyalkyl oder (C2-5)Amino-alkyl bedeuten oder
R₄ eine Gruppe der Formel bedeutet, worin
R₆ und R₇ obige Bedeutung besitzen,
p für eine ganze Zahl von 0 bis 5 steht und
E eine Bindung oder die Gruppe bedeutet oder
R₄ eine Gruppe der FormelF-(CH₂) p -E-bedeutet, worin
p und E obige Bedeutung besitzen und
F für Gruppen der Formeln steht, worin R₃ obige Bedeutung besitzt;
R₂ für eine hydrophile oder hydrophobe Aminosäureseitenkette steht,
Z für Gruppen der Formeln steht,
A Gruppen der Formeln oder bedeutet, worin
R₈ eine hydrophile oder lipophile Aminosäureseitenkette bedeutet und
R₃ obige Bedeutung besitzt,
B eine Gruppe der Formel bedeutet, worin X die obige Bedeutung hat,
R₉ die gleiche Bedeutung wie R₈ besitzt,
R₁₀ für eine Hydroxyl- oder Aminogruppe und
R₁₁ für Wasserstoff stehen oder
R₁₀ und R₁₁ zusammen eine Oxo-Gruppe bilden,
R₁₂ und R₁₃ unabhängig voneinander Fluor oder Wasserstoff bedeuten,
R₁₄ und R₁₅ gleich oder verschieden sind und jeweils Wasserstoff, einen geradekettigen oder verzweigten (C1-6)Alkylrest, oder jeweils eine Gruppe der Formel bedeuten, worin
R₁₆ einen geradekettigen oder verzweigten (C1-5)Alkylrest oder einen geradekettigen oder verzweigten (C1-5)Hydroxylalkylrest bedeutet,
R₁₇ für einen Hydroxylrest, eine geradekettige oder verzweigte (C1-5)Alkoxygruppe, eine Amino- oder eine (C1-5)Alkylaminogruppe, eine Aminomethyl-pyridylgruppe, eine Benzylgruppe oder für eine geschützte oder ungeschützte Aminosäure steht,
Y eine Bindung bedeutet oder für -O-, NH oder die Gruppe steht,
worin R₁₈ und R₁₉ unabhängig voneinander für Wasserstoff, Fluor oder Chlor stehen oder die für R₈ oben angegebene Bedeutung besitzen, oder
B eine Gruppe der Formel bedeutet, worin
R₉, R₁₀, R₁₁ und n die oben angegebenen Bedeutungen besitzen. 1. renin inhibitor of the formula I. wherein W is -CH₂-CH₂ or a group of formula wherein X is sulfur or oxygen, and V is O, NR₃ wherein R₃ is hydrogen or a straight or branched (C 1-5 ) alkyl group, or a bond, R₁ is a straight-chained or branched (C 1-10 ) alkyl group which may optionally be substituted by amino, hydroxy or (C 2-5 ) alkyl or (C 6-10 ) aryloxy, a 5- or 6-membered one or two nitrogen atoms, oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and or a heteroaryl radical containing a sulfur atom or a heteroaryl (C 1-5 ) -alkyl radical in which the heteroaryl part is 5- or 6-membered and contains one or two nitrogen atoms, oxygen or sulfur atoms or a nitrogen atom and an oxygen atom and / or a sulfur atom , a straight-chain or branched (C 1-5 ) alkoxy radical or a (C 6-10 ) aryl- (C 1-5 ) alkoxy radical or
R₁ represents a group of the formula R₄-O (CH₂CH₂O) m - (CH₂) n -, in which R₄ represents hydrogen, a straight-chain or branched (C 1-20 ) alkyl or glycosidically bonded sugar residue, an optionally substituted, saturated or unsaturated, straight-chain or branched (C 2-30 ) alkylcarbonyl group, a (C 3-6 ) polyhydroxyalkylcarbonyl, a phosphoroyl, a bis (dimethylamino) phosphoroyl, a sulfo, an aroyl, a heteroaroyl wherein the heteroaryl radical is defined above, a (C 7-11 ) arylalkyl, a (C 7-11 ) arylalkylcarbonyl or a heteroarylalkylcarbonyl group wherein the heteroaryl radical is defined above, or the biotinoyl group is
m = an integer of 1-20 and
n = an integer from 0-5
or
R₄ is a group of the formula in which R₅ is hydrogen or a side chain of a D- or L-amino acid and R₆ and R₇ are the same or different and are each hydrogen, (C 1-5 ) alkyl, (C 2-5 ) hydroxyalkyl or (C 2-5 ) Amino-alkyl or
R₄ is a group of the formula means, in which
R₆ and R₇ have the above meaning,
p is an integer from 0 to 5 and
E a bond or the group means or
R₄ is a group of the formula F- (CH₂) p -E-, in which
p and E have the above meaning and
F for groups of formulas wherein R₃ has the above meaning;
R₂ is a hydrophilic or hydrophobic amino acid side chain,
Z for groups of formulas stands,
A groups of formulas or means, in which
R₈ represents a hydrophilic or lipophilic amino acid side chain and
R₃ has the above meaning,
B is a group of the formula in which X has the above meaning,
R₉ has the same meaning as R₈,
R₁₀ for a hydroxyl or amino group and
R₁₁ are hydrogen or
R₁₀ and R₁₁ together form an oxo group,
R₁₂ and R₁₃ independently of one another denote fluorine or hydrogen,
R₁₄ and R₁₅ are the same or different and each is hydrogen, a straight-chain or branched (C 1-6 ) alkyl radical, or in each case a group of the formula mean, in which
R₁₆ represents a straight-chain or branched (C 1-5 ) alkyl radical or a straight-chain or branched (C 1-5 ) hydroxylalkyl radical,
R₁₇ represents a hydroxyl radical, a straight-chain or branched (C 1-5 ) alkoxy group, an amino or a (C 1-5 ) alkylamino group, an aminomethylpyridyl group, a benzyl group or represents a protected or unprotected amino acid,
Y represents a bond or -O-, NH or the group stands,
wherein R₁₈ and R₁₉ independently of one another are hydrogen, fluorine or chlorine or have the meaning given above for R₈, or
B is a group of the formula means, in which
R₉, R₁₀, R₁₁ and n have the meanings given above.
- (2R,4S,5S,8R,11S)-6,12-Diaza-2,8-di(E-2-butenyl)-N-butyl-5,11-di-
(cyclohexylmethyl)-4-hydroxy-14,17,20,23-tetraoxa-7,10,13-trioxo-
tetracosansäureamid.
(2R,4S,5S,8S,11S)-6,9,12-Triaza-2-(E-2-butenyl)-8,N-dibutyl-11- benzyl-5-cyclohexylmethyl-4-hydroxy-15,18,21-trioxa-7,10-dioxo- docosansäureamid.
(2R,4S,5S,8S,11S)-6,9,12-Triaza-11-benzyl-2-(E-2-butenyl)-8,N- butyl-5-cyclohexylmethyl-4-hydroxy-15,18,21,24-tetraoxa-7,10- dioxo-13-thioxo-pentacosansäureamid.
(2R,4S,5S,8R,11S)-6,12-Diaza-2,8-di-(E-2-butenyl)-N-butyl-5,11- di-(cyclohexylmethyl)-4-hydroxy-15,18,21,24-tetraoxa-7,10-dioxo- 13-thioxo-pentacosansäureamid.
(2R,4S,5S,8R,11S)-6,12-Diaza-2,8N-tributyl-5,11-di(cyclohexylmethyl)-- 4-hydroxy-14,17,20,23-tetraoxa-7,10,13-trioxo-tetracosansäureamid.
(2R,4S,5S,8S,11R)-6,9,12-Triaza-2-(E-2-butenyl)-N-butyl-5-cyclohexyl-methyl- 4-hydroxy-8-(3-imidazolylmethyl)-14,17,20,23-tetraoxa- 7,10-dioxo-13-thioxo-11-trimethylsilylmethyl-tetracosansäureamid.
(2R,4S,5S,8R,11S)-6,12-Diaza-8-(E-2-butenyl)-N-butyl-5,11-di(cyclohe-xylmethyl)- 4-hydroxy-2-methyl-14,17,20,23,26,29,32,35-oktaoxa- 7,10-dioxo-13-thioxo-dotriacontansäureamid.
(3R,4S,7S,10R)-5,8,11-Triaza-7-butyl-4-cyclohexylmethyl-2,2-di- fluoro-3-hydroxy-N-isobutyl-13-oxa-6,9-dioxo-14-(4-pyridyl)-12- thioxo-tetradecansäureamid.
(2S,6S,7S,10S,13R)-3,8,11,14,16-Pentaaza-10-butyl-7-cyclohexylmethyl-- 5-hydroxy-2-isobutyl-18-morpholino,4,9,12-trioxo-N-(2-pyridylmethyl)-- 15-thioxo-13-trimethyl-silylmethyl-oktadecansäureamid.
(2R,4S,5S,8S,11S)-6,9,12-Triaza-2,8,N-butyl-5,11-di(cyclohexylmethyl-- 4-hydroxy-14,17,20,23,26,29,32,35-oktaoxa-7,10-dioxo-13- thioxo-dotriacontansäureamid.
(4S, 7S,10R)-5,8,11-Triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro- N-isobutyl-13-oxa-3,6,9-trioxo-14-(4-pyridyl)-12-thioxo-tetradecansä-ureamid.
(3R,4S,7S,10R)-5,8,11-Triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-- 3-hydroxy-N-isobutyl-19-nicotinoyl-13,16,19-trioxa-6,9- dioxo-12-thioxo-nonadecansäureamid.
(4S,7S,10R)-5,8,11-Triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro- N-isobutyl-19-nicotinoyl-13,16,19-trioxa-3,6,9-trioxo-12-thioxo- nonadecansäureamid.
(3R,4S,7S,10R)-5,8,11-Triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-- 3-hydroxy-N-isobutyl-19-(3,4,5-trimethoxyphenylacetyl)-13,16,19- trioxa-6,9-dioxo-12-thioxo-nonadecansäureamid.
(4S,7S,10R)-5,8,11-Triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro- N-isobutyl-19-(3,4,5-trimethoxyphenylacetyl)-13,16,19-trioxa-3,6,9- trioxo-12-thioxo-nonadecansäureamid.
(2R,4S,5S,8S,11S)-6,9,12-Triaza-2-(E-2-butenyl)-N-butyl-5-cyclohexyl-methyl- 4-hydroxy-8-isobutyl-9-methyl-15,18,21,24-tetraoxa-7,10- dioxo-11-phenyl-13-thioxo-pentacosansäureamid.
(2R,4S,5S,8R,10S,11S)-6,12-Diaza-2,8-di(E-2-butenyl)-N-butyl-5,11- di(cyclohexylmethyl-4,10-dihydroxy-15,18,21,24-tetraoxa-7-oxo- 13-thioxo-pentacosansäureamid.
(4R,5S,8S,11R)-6,9,12-Triaza-8-butyl-5-cyclohexylmethyl-1,1,1,2,2,3,-3- heptafluoro-4-hydroxy-20-nicotinoyl-14,17,20-trioxa-7,10- dioxo-13-thioxo-eicosan.
(2R,4S,5S,8R,10S,11S)-6,12-Diaza-2,8-di(E-2-butenyl)-N-butyl-5,11- di(cyclohexylmethyl)-4,10-dihydroxy-15,18,21-trioxa-7-oxo-docosansäu-reamid.
(2R,4S,5S,8S,11S)-6,12-Diaza-2,8,N-tributyl-5-cyclohexylmethyl-4- hydroxy-9,15,18,21,24-pentaoxa-7,10-dioxo-11-phenyl-13-thioxo-pentac-osansäureamid.
- (2R, 4S, 5S, 8R, 11S) -6,12-diaza-2,8-di (E-2-butenyl) -N-butyl-5,11-di (cyclohexylmethyl) -4-hydroxy-14 , 17,20,23-tetraoxa-7,10,13-trioxotetracosansäureamid.
(2R, 4S, 5S, 8S, 11S) -6,9,12-triaza-2- (E-2-butenyl) -8, N-dibutyl-11-benzyl-5-cyclohexylmethyl-4-hydroxy-15, 18,21-trioxa-7,10-dioxo-docosansäureamid.
(2R, 4S, 5S, 8S, 11S) -6,9,12-triaza-11-benzyl-2- (E-2-butenyl) -8, N-butyl-5-cyclohexylmethyl-4-hydroxy-15, 18,21,24-tetraoxa-7,10-dioxo-13-thioxo-pentacosanoic acid amide.
(2R, 4S, 5S, 8R, 11S) -6,12-diaza-2,8-di- (E-2-butenyl) -N-butyl-5,11-di (cyclohexylmethyl) -4-hydroxy 15,18,21,24-tetraoxa-7,10-dioxo-13-thioxo-pentacosanoic acid amide.
(2R, 4S, 5S, 8R, 11S) -6,12-diaza-2,8N-tributyl-5,11-di (cyclohexylmethyl) -4-hydroxy-14,17,20,23-tetraoxa-7, 10,13-trioxo-tetracosansäureamid.
(2R, 4S, 5S, 8S, 11R) -6,9,12-triaza-2- (E-2-butenyl) -N-butyl-5-cyclohexylmethyl-4-hydroxy-8- (3-imidazolylmethyl ) -14,17,20,23-tetraoxa-7,10-dioxo-13-thioxo-11-trimethylsilylmethyl-tetracosanoic acid amide.
(2R, 4S, 5S, 8R, 11S) -6,12-diaza-8- (E-2-butenyl) -N-butyl-5,11-di (cyclohexylmethyl) -4-hydroxy-2-methyl -14,17,20,23,26,29,32,35-octaoxa-7,10-dioxo-13-thioxo-dotriacontanoic acid amide.
(3R, 4S, 7S, 10R) -5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-di-fluoro-3-hydroxy-N-isobutyl-13-oxa-6,9- dioxo-14- (4-pyridyl) -12-thioxo-tetradecanoic acid amide.
(2S, 6S, 7S, 10S, 13R) -3,8,11,14,16-pentaaza-10-butyl-7-cyclohexylmethyl-5-hydroxy-2-isobutyl-18-morpholino, 4,9,12 trioxo-N- (2-pyridylmethyl) -15-thioxo-13-trimethyl-silylmethyl-octadecanoic acid amide.
(2R, 4S, 5S, 8S, 11S) -6,9,12-triaza-2,8, N -butyl-5,11-di (cyclohexylmethyl-4-hydroxy-14,17,20,23,26 , 29,32,35-octaoxa-7,10-dioxo-13-thioxo-dotriacontanamide.
(4S, 7S, 10R) -5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-N-isobutyl-13-oxa-3,6,9-trioxo-14- (4 pyridyl) -12-thioxo-tetradecansä-acid amide.
(3R, 4S, 7S, 10R) -5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-3-hydroxy-N-isobutyl-19-nicotinoyl-13,16,19 trioxa-6,9-dioxo-12-thioxo-nonadecanoic acid amide.
(4S, 7S, 10R) -5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-N-isobutyl-19-nicotinoyl-13,16,19-trioxa-3,6, 9-trioxo-12-thioxononadecanoic acid amide.
(3R, 4S, 7S, 10R) -5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-3-hydroxy-N-isobutyl-19- (3,4,5-) trimethoxyphenylacetyl) -13,16,19-trioxa-6,9-dioxo-12-thioxo-nonadecanoic acid amide.
(4S, 7S, 10R) -5,8,11-triaza-7-butyl-4-cyclohexylmethyl-2,2-difluoro-N-isobutyl-19- (3,4,5-trimethoxyphenylacetyl) -13,16, 19-trioxa-3,6,9-trioxo-12-thioxo-nonadecanoic acid amide.
(2R, 4S, 5S, 8S, 11S) -6,9,12-triaza-2- (E-2-butenyl) -N-butyl-5-cyclohexyl-methyl-4-hydroxy-8-isobutyl-9- methyl-15,18,21,24-tetraoxa-7,10-dioxo-11-phenyl-13-thioxo-pentacosanoic acid amide.
(2R, 4S, 5S, 8R, 10S, 11S) -6,12-diaza-2,8-di (E-2-butenyl) -N-butyl-5,11-di (cyclohexylmethyl-4,10-dihydroxy -15,18,21,24-tetraoxa-7-oxo-13-thioxo-pentacosanoic acid amide.
(4R, 5S, 8S, 11R) -6,9,12-triaza-8-butyl-5-cyclohexylmethyl-1,1,1,2,2,3,3-heptafluoro-4-hydroxy-20-nicotinoyl -14,17,20-trioxa-7,10-dioxo-13-thioxo-eicosane.
(2R, 4S, 5S, 8R, 10S, 11S) -6,12-diaza-2,8-di (E-2-butenyl) -N-butyl-5,11-di (cyclohexylmethyl) -4,10- dihydroxy-15,18,21-trioxa-7-oxo-docosansäu-acid amide.
(2R, 4S, 5S, 8S, 11S) -6,12-diaza-2,8, N-tributyl-5-cyclohexylmethyl-4-hydroxy-9,15,18,21,24-pentaoxa-7,10- dioxo-11-phenyl-13-thioxo-PENTAC-osansäureamid.
- a) eine Verbindung der Formel II
worin A, B, Z und R₂ die in Anspruch 1 angegebenen Bedeutungen
besitzen,
mit einer Verbindung der Formel worin R₁ die in Anspruch 1 angegebenen Bedeutungen besitzt, umsetzt
wobei man zu Verbindungen der Formel Ia gelangt, worin R₁, R₂, Z, A und B die im Anspruch 1 beschriebenen Bedeutungen besitzen, - b) eine Verbindung der Formel II gemäß Verfahrensstufe a) mit einer Verbindung der Formel worin R₁, V und X die im Anspruch 1 angegebene Bedeutung besitzen und Q die Abgangsgruppe eines aktiven Esters bedeutet, umsetzt wobei man zu Verbindungen der Formel gelangt, worin R₁, V, X, R₂, Z, A und B die im Anspruch 1 angegebene Bedeutung besitzen,
- c) eine Verbindung der Formel II gemäß Verfahrensstufe a) mit einer Verbindung der Formel worin R₁ die im Anspruch 1 angegebene Bedeutung besitzt, steht in Anwesenheit eines Reduktionsmittels, umsetzt, wobei man zu Verbindungen der Formel worin R₁, R₂, Z, A und B die im Anspruch 1 angegebene Bedeutung besitzen, gelangt und
- d) eine Verbindung der Formel Ie worin R₁, R₂, R₉, R₁₁ bis R₁₅, W, Z, A, Y und X die im Anspruch 1 angegebene Bedeutung besitzen und R₁₀′ für eine Hydroxylgruppe steht, zu einer Verbindung der Formel If worin R₁, R₂, R₉, R₁₂ bis R₁₅, W, Z, A, Y und X die im Anspruch 1 angegebene Bedeutung besitzen, oxidiert.
- a) a compound of formula II wherein A, B, Z and R₂ have the meanings given in claim 1,
with a compound of the formula wherein R₁ has the meanings given in claim 1, is reacted
being given to compounds of the formula Ia wherein R₁, R₂, Z, A and B have the meanings described in claim 1, - b) a compound of the formula II according to process step a) with a compound of the formula wherein R₁, V and X have the meaning given in claim 1 and Q is the leaving group of an active ester, reacting to give compounds of the formula wherein R₁, V, X, R₂, Z, A and B have the meaning given in claim 1,
- c) a compound of the formula II according to process step a) with a compound of the formula wherein R₁ has the meaning given in claim 1, is in the presence of a reducing agent, reacting to give compounds of the formula wherein R₁, R₂, Z, A and B have the meaning given in claim 1, passes and
- d) a compound of the formula Ie wherein R₁, R₂, R₉, R₁₁ to R₁₅, W, Z, A, Y and X have the meaning given in claim 1 and R₁₀ 'is a hydroxyl group, to a compound of formula If wherein R₁, R₂, R₉, R₁₂ to R₁₅, W, Z, A, Y and X have the meaning given in claim 1, oxidized.
Priority Applications (4)
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DE3815913A DE3815913A1 (en) | 1988-05-10 | 1988-05-10 | NEW RENINHERMERS, PROCESS FOR THEIR PRODUCTION AND THEIR USE |
JP1505450A JPH02504152A (en) | 1988-05-10 | 1989-05-09 | Renin inhibitors, their preparation and uses |
PCT/EP1989/000509 WO1989010917A2 (en) | 1988-05-10 | 1989-05-09 | Renin inhibitors, process for producing them and use thereof |
EP89906087A EP0387309A1 (en) | 1988-05-10 | 1989-05-09 | Renin inhibitors, process for producing them and use thereof |
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IT1177379B (en) * | 1984-12-11 | 1987-08-26 | Anic Spa | DERIVATIVES OF THE SUBSTANCE P AND ITS FRAGMENTS |
FR2585708B1 (en) * | 1985-07-31 | 1989-07-07 | Sanofi Sa | RESIN AND ACID PROTEIN INHIBITOR AMINOALCOHOL DERIVATIVES, PREPARATION METHOD THEREOF AND THERAPEUTIC APPLICATION THEREOF |
KR870005013A (en) * | 1985-11-29 | 1987-06-04 | 가와무라 요시부미 | Lenin-inhibiting oligopeptides, methods of making and uses thereof |
-
1988
- 1988-05-10 DE DE3815913A patent/DE3815913A1/en not_active Withdrawn
-
1989
- 1989-05-09 EP EP89906087A patent/EP0387309A1/en not_active Withdrawn
- 1989-05-09 WO PCT/EP1989/000509 patent/WO1989010917A2/en not_active Application Discontinuation
- 1989-05-09 JP JP1505450A patent/JPH02504152A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
WO1989010917A2 (en) | 1989-11-16 |
JPH02504152A (en) | 1990-11-29 |
WO1989010917A3 (en) | 1989-12-28 |
EP0387309A1 (en) | 1990-09-19 |
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