DE19504226A1 - New N-(carboxy-alkanoyl) derivs. of hydroxy-quinoxaline carboxamide - Google Patents
New N-(carboxy-alkanoyl) derivs. of hydroxy-quinoxaline carboxamideInfo
- Publication number
- DE19504226A1 DE19504226A1 DE1995104226 DE19504226A DE19504226A1 DE 19504226 A1 DE19504226 A1 DE 19504226A1 DE 1995104226 DE1995104226 DE 1995104226 DE 19504226 A DE19504226 A DE 19504226A DE 19504226 A1 DE19504226 A1 DE 19504226A1
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- alkoxy
- cycloalkyl
- carbamoyl
- aryloxy
- 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- Withdrawn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
- WAOATEWSYYCRLL-UHFFFAOYSA-N 3-oxo-4h-quinoxaline-2-carboxamide Chemical compound C1=CC=C2N=C(O)C(C(=O)N)=NC2=C1 WAOATEWSYYCRLL-UHFFFAOYSA-N 0.000 title 1
- -1 3-hydroxyisoxazolyl Chemical group 0.000 claims abstract description 183
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 110
- 125000003118 aryl group Chemical group 0.000 claims abstract description 40
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 31
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 18
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims abstract description 17
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 14
- 229960003424 phenylacetic acid Drugs 0.000 claims abstract description 13
- 239000003279 phenylacetic acid Substances 0.000 claims abstract description 13
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 12
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 150
- 150000001875 compounds Chemical class 0.000 claims description 77
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 75
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 67
- 229910052757 nitrogen Inorganic materials 0.000 claims description 63
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 56
- 125000003282 alkyl amino group Chemical group 0.000 claims description 53
- 125000005277 alkyl imino group Chemical group 0.000 claims description 39
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 34
- 239000004471 Glycine Substances 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 24
- 125000005116 aryl carbamoyl group Chemical group 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 22
- 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 20
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 150000003254 radicals Chemical class 0.000 claims description 18
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 17
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 16
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 16
- 125000004467 aryl imino group Chemical group 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 102000004079 Prolyl Hydroxylases Human genes 0.000 claims description 15
- 108010043005 Prolyl Hydroxylases Proteins 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 14
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 210000004185 liver Anatomy 0.000 claims description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims description 13
- 125000006625 (C3-C8) cycloalkyloxy group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 10
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 10
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 10
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 10
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 10
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 10
- 125000005239 aroylamino group Chemical group 0.000 claims description 10
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 10
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 10
- 125000005225 alkynyloxycarbonyl group Chemical group 0.000 claims description 9
- 150000005840 aryl radicals Chemical class 0.000 claims description 9
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 9
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 8
- 125000006636 (C3-C8) cycloalkylcarbonyl group Chemical group 0.000 claims description 8
- 125000006323 alkenyl amino group Chemical group 0.000 claims description 8
- 125000005193 alkenylcarbonyloxy group Chemical group 0.000 claims description 8
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
- 125000006319 alkynyl amino group Chemical group 0.000 claims description 8
- 125000005198 alkynylcarbonyloxy group Chemical group 0.000 claims description 8
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 8
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 8
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 8
- 125000001769 aryl amino group Chemical group 0.000 claims description 8
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 8
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 230000003176 fibrotic effect Effects 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 239000000651 prodrug Substances 0.000 claims description 8
- 229940002612 prodrug Drugs 0.000 claims description 8
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 7
- 125000005201 cycloalkylcarbonyloxy group Chemical group 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 6
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 6
- 150000008575 L-amino acids Chemical class 0.000 claims description 6
- 125000003435 aroyl group Chemical group 0.000 claims description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000007127 saponification reaction Methods 0.000 claims description 5
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 4
- KKFDJZZADQONDE-UHFFFAOYSA-N (hydridonitrato)hydroxidocarbon(.) Chemical compound O[C]=N KKFDJZZADQONDE-UHFFFAOYSA-N 0.000 claims description 4
- 150000008574 D-amino acids Chemical class 0.000 claims description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 4
- 125000005087 alkynylcarbonyl group Chemical group 0.000 claims description 4
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 230000036570 collagen biosynthesis Effects 0.000 claims description 4
- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical compound FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 claims description 4
- XEEVLJKYYUVTRC-UHFFFAOYSA-N oxomalonic acid Chemical class OC(=O)C(=O)C(O)=O XEEVLJKYYUVTRC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical class NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000007942 carboxylates Chemical group 0.000 claims description 2
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000004987 o-phenylenediamines Chemical class 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- 125000004001 thioalkyl group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 3
- 150000007650 D alpha amino acids Chemical class 0.000 abstract 2
- 150000007649 L alpha amino acids Chemical class 0.000 abstract 2
- 229910006074 SO2NH2 Inorganic materials 0.000 abstract 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 abstract 2
- 125000000565 sulfonamide group Chemical group 0.000 abstract 2
- GDEWBIJEFBRLIS-UHFFFAOYSA-N 2-[(6,7-dichloro-3-oxo-4h-quinoxaline-2-carbonyl)amino]acetic acid Chemical compound ClC1=C(Cl)C=C2NC(=O)C(C(=O)NCC(=O)O)=NC2=C1 GDEWBIJEFBRLIS-UHFFFAOYSA-N 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 108010035532 Collagen Proteins 0.000 description 14
- 102000008186 Collagen Human genes 0.000 description 14
- 229920001436 collagen Polymers 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229960002429 proline Drugs 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 229960002591 hydroxyproline Drugs 0.000 description 5
- GBCAVSYHPPARHX-UHFFFAOYSA-M n'-cyclohexyl-n-[2-(4-methylmorpholin-4-ium-4-yl)ethyl]methanediimine;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C1CCCCC1N=C=NCC[N+]1(C)CCOCC1 GBCAVSYHPPARHX-UHFFFAOYSA-M 0.000 description 5
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 210000003494 hepatocyte Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- NMOWGWOAPRKWIR-UHFFFAOYSA-N 3-oxo-4h-quinoxaline-2-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=NC2=C1 NMOWGWOAPRKWIR-UHFFFAOYSA-N 0.000 description 3
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 3
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- 102000004266 Collagen Type IV Human genes 0.000 description 3
- 108010042086 Collagen Type IV Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
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- 108010020504 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Proteins 0.000 description 2
- PENXATVRVKUKDH-UHFFFAOYSA-N 3-methoxyquinoxaline-2-carboxylic acid Chemical compound C1=CC=C2N=C(C(O)=O)C(OC)=NC2=C1 PENXATVRVKUKDH-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 108010050808 Procollagen Proteins 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
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- 229940024606 amino acid Drugs 0.000 description 2
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- 230000003510 anti-fibrotic effect Effects 0.000 description 2
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000037319 collagen production Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
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- 230000002440 hepatic effect Effects 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 2
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
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- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 102000001187 Collagen Type III Human genes 0.000 description 1
- 108010069502 Collagen Type III Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- BIMZLRFONYSTPT-UHFFFAOYSA-N N-oxalylglycine Chemical class OC(=O)CNC(=O)C(O)=O BIMZLRFONYSTPT-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 231100000644 Toxic injury Toxicity 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940093740 amino acid and derivative Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
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- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 238000013245 carbon tetrachloride model Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- DBKKFIIYQGGHJO-UHFFFAOYSA-N diethyl 2-oxopropanedioate Chemical compound CCOC(=O)C(=O)C(=O)OCC DBKKFIIYQGGHJO-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- RHXYJLNRQPIYOW-UHFFFAOYSA-N ethyl 3-chloro-7-methoxyquinoxaline-2-carboxylate Chemical compound COC1=CC=C2N=C(Cl)C(C(=O)OCC)=NC2=C1 RHXYJLNRQPIYOW-UHFFFAOYSA-N 0.000 description 1
- YGTZHKWLTOJGOI-UHFFFAOYSA-N ethyl 3-chloroquinoxaline-2-carboxylate Chemical compound C1=CC=C2N=C(Cl)C(C(=O)OCC)=NC2=C1 YGTZHKWLTOJGOI-UHFFFAOYSA-N 0.000 description 1
- XEKIPUVNLOHZNY-UHFFFAOYSA-N ethyl 6-methoxy-3-oxo-4h-quinoxaline-2-carboxylate Chemical compound C1=C(OC)C=C2NC(=O)C(C(=O)OCC)=NC2=C1 XEKIPUVNLOHZNY-UHFFFAOYSA-N 0.000 description 1
- GACPGLJBLJNJFX-UHFFFAOYSA-N ethyl 7-methoxy-3-oxo-4h-quinoxaline-2-carboxylate Chemical compound COC1=CC=C2N=C(O)C(C(=O)OCC)=NC2=C1 GACPGLJBLJNJFX-UHFFFAOYSA-N 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 102000005396 glutamine synthetase Human genes 0.000 description 1
- 108020002326 glutamine synthetase Proteins 0.000 description 1
- 210000000208 hepatic perisinusoidal cell Anatomy 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 0.000 description 1
- STXXGKPYWQIUSQ-UHFFFAOYSA-N n-(2-aminoacetyl)-4-oxo-1h-cinnoline-3-carboxamide Chemical class C1=CC=CC2=C(O)C(C(=O)NC(=O)CN)=NN=C21 STXXGKPYWQIUSQ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001190 organyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 125000005495 pyridazyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- CGJMVNVWQHPASW-UHFFFAOYSA-N quinoxaline-2-carboxamide Chemical class C1=CC=CC2=NC(C(=O)N)=CN=C21 CGJMVNVWQHPASW-UHFFFAOYSA-N 0.000 description 1
- UPUZGXILYFKSGE-UHFFFAOYSA-N quinoxaline-2-carboxylic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CN=C21 UPUZGXILYFKSGE-UHFFFAOYSA-N 0.000 description 1
- 150000003252 quinoxalines Chemical class 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000000352 storage cell Anatomy 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/99—Enzyme inactivation by chemical treatment
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die Erfindung betrifft substituierte Chinoxaline, ihre Herstellung und ihre Verwendung als Inhibitoren der Prolyl-4-hydroxylase und ihre Verwendung als Arzneimittel zur Behandlung von fibrotischen Erkrankungen.The invention relates to substituted quinoxalines, their preparation and their Use as inhibitors of prolyl 4-hydroxylase and their use as Medicines used to treat fibrotic diseases.
Verbindungen, die die Enzyme Prolyl- und Lysylhydroxylase inhibieren, bewirken eine sehr selektive Hemmung der Kollagenbiosynthese durch Beeinflussung der kollagenspezifischen Hydroxylierungsreaktionen. In deren Verlauf wird proteingebundenes Prolin oder Lysin durch die Enzyme Prolyl- bzw. Lysylhydroxylase hydroxyliert. Wird diese Reaktion durch Inhibitoren unterbunden, so entsteht ein nicht funktionsfähiges, unterhydroxyliertes Kollagenmolekül, das von den Zellen nur in geringer Menge in den extrazellulären Raum abgegeben werden kann. Das unterhydroxylierte Kollagen kann außerdem nicht in die Kollagenmatrix eingebaut werden und wird sehr leicht proteolytisch abgebaut. Als Folge dieser Effekte verringert sich insgesamt die Menge des extrazellulär abgelagerten Kollagens.Compounds that inhibit the enzymes prolyl and lysyl hydroxylase a very selective inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reactions. In the course of which protein-bound proline or lysine through the enzymes prolyl or Lysyl hydroxylase hydroxylated. This reaction is caused by inhibitors prevented, so a non-functional, under hydroxylated Collagen molecule that is only present in small amounts in the extracellular cells Space can be given. The under-hydroxylated collagen can also cannot be built into the collagen matrix and becomes proteolytic very easily reduced. As a result of these effects, the amount of extracellularly deposited collagen.
Inhibitoren der Prolylhydroxylase sind deshalb geeignete Substanzen in der Therapie von Erkrankungen, in denen die Ablagerung von Kollagenen maßgeblich zum Krankheitsbild beiträgt. Hierzu gehören u. a. Fibrosen der Lunge, Leber und Haut (Skleroderma) sowie die Atherosklerose.Inhibitors of prolyl hydroxylase are therefore suitable substances in the Therapy of diseases in which the deposition of collagens is essential contributes to the clinical picture. These include a. Fibrosis of the lungs, liver and Skin (scleroderma) and atherosclerosis.
Es ist bekannt, daß das Enzym Prolylhydroxylase durch Pyridin-2,4- und -2,5- dicarbonsäure effektiv gehemmt wird (K. Majamaa et al., Eur. J. Biochem. 138 (1984) 239-245). Diese Verbindungen sind in der Zellkultur allerdings nur in sehr hohen Konzentrationen als Hemmstoffe wirksam (Tschank, G. et al., Biochem. J. 238 (1987) 625 bis 633). It is known that the enzyme prolyl hydroxylase can be isolated by pyridine-2,4- and -2,5- dicarboxylic acid is effectively inhibited (K. Majamaa et al., Eur. J. Biochem. 138 (1984) 239-245). However, these compounds are only found in cell culture very high concentrations as inhibitors (Tschank, G. et al., Biochem. J. 238 (1987) 625-633).
Auch Prodrugs der Pyridin-2,4(5)-dicarboxylate sind bekannt. Diese sind in den älteren deutschen Anmeldungen P 42 33 124.2, P 42 38 506.7 und P 42 09 424.0 beschrieben.Prodrugs of the pyridine-2,4 (5) dicarboxylates are also known. These are in the older German applications P 42 33 124.2, P 42 38 506.7 and P 42 09 424.0.
N-Oxalylglycine als Inhibitoren der Prolyl-4-hydroxylase sind aus J. Med. Chem. 1992, 35, 2652 bis 2658 (Cunliffe et al.), und EP-A-0 457 163 (Baader et al.) bekannt.N-oxalylglycines as inhibitors of prolyl-4-hydroxylase are known from J. Med. Chem. 1992, 35, 2652 to 2658 (Cunliffe et al.), And EP-A-0 457 163 (Baader et al.) known.
Hydroxyisochinoline- und Hydroxycinnolincarbonsäureglycylamide sind aus Biochem. Soc. Trans. 1991, 19, 812 bis 815 (Franklin et al.) bekannt. Aus der WO 92/11245 sind darüberhinaus N-((6,7-Dichlor-3,4-dihydro-3-oxo-2- chinoxalinyl)carbonyl)glycin und α-((6,7-Dichlor-3,4-dihydro-3-oxo-2- chinoxalinyl)carbonyl)amino)phenylessigsäure bekannt.Hydroxyisoquinoline and hydroxycinnoline carboxylic acid glycylamides are made Biochem. Soc. Trans. 1991, 19, 812 to 815 (Franklin et al.). From WO 92/11245 N - ((6,7-dichloro-3,4-dihydro-3-oxo-2- quinoxalinyl) carbonyl) glycine and α - ((6,7-dichloro-3,4-dihydro-3-oxo-2- quinoxalinyl) carbonyl) amino) phenylacetic acid.
Überraschenderweise wurde nun gefunden, daß Chinoxalin-2-carbonsäureamide mit einem Hydroxy-, einem Mercapto-, einem Ether-, oder einem Thioether- Substituenten in ortho-Position zur Amidfunktion stark wirksame Inhibitoren der Prolyl-4-hydroxylase sind.Surprisingly, it has now been found that quinoxaline-2-carboxamides with a hydroxy, a mercapto, an ether, or a thioether Substituents in the ortho position to the amide function are potent inhibitors of Prolyl 4-hydroxylase.
Die erfindungsgemäßen Verbindungen entsprechen der allgemeinen Formel IThe compounds according to the invention correspond to the general formula I.
in welcher
Q O oder S,
X O und S,
A (C₁-C₄)-Alkylen, das gegebenenfalls substituiert ist mit einem oder zwei
Substituenten aus der Reihe Halogen, Cyano, Nitro, Trifluormethyl,
(C₁-C₆)-Alkyl, (C₁-C₆)-Hydroxyalkyl, (C₁-C₆)-Alkoxy,
-O-[CH₂]x-CfH(2f+1-g)Halg, vorzugsweise (C₁-C₈)-Fluoralkoxy, (C₁-C₈)-
Fluoralkenyloxy, (C₁-C₈)-Fluoralkinyloxy, -OCF₂Cl oder -O-CF₂-CHFCl,
(C₁-C₆)-Alkylmercapto, (C₁-C₆)-Alkylsulfinyl, (C₁-C₆)-Alkylsulfonyl,
(C₁-C₆)-Alkylcarbonyl, (C₁-C₆)-Alkoxycarbonyl, Carbamoyl, N-(C₁-C₄)-
Alkylcarbamoyl, N,N-Di-(C₁-C₄)-alkylcarbamoyl, (C₁-C₆)-Alkylcarbonyloxy,
(C₃-C₈)-Cycloalkyl, Phenyl, Benzyl, Phenoxy, Benzyloxy, Anilino,
N-Methylanilino, Phenylmercapto, Phenylsulfonyl, Phenylsulfinyl,
Sulfamoyl, N-(C₁-C₄)-Alkylsulfamoyl, N,N-Di-(C₁-C₄)-alkylsulfamoyl, oder
mit einem substituierten (C₆-C₁₂)-Aryloxy-, (C₇-C₁₁)-Aralkyloxy, (C₆-C₁₂)-
Aryl- oder (C₇-C₁₁)-Aralkyl-Rest, der im Arylteil 1, 2, 3, 4 oder 5 gleiche
oder verschiedene Substituenten aus der Reihe Halogen, Cyano, Nitro,
Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy, -O-[CH₂]x-CfH(2f+1-g)Halg,
-OCF₂Cl,-O-CF₂-CHFCl, (C₁-C₆)-Alkylmercapto, (C₁-C₆)-Alkylsulfinyl,
(C₁-C₆)-Alkylsulfonyl, (C₁-C₆)-Alkylcarbonyl, (C₁-C₆)-Alkoxycarbonyl,
Carbamoyl, N-(C₁-C₄)-Alkylcarbamoyl, N,N-Di-(C₁-C₄)-alkylcarbamoyl,
(C₁-C₆)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkyl, Sulfamoyl, N-(C₁-C₄)-
Alkylsulfamoyl oder N,N-Di-(C₁-C₄)-alkylsulfamoyl trägt, oder
mit den Substituenten R⁵ des α-C-Atoms einer α-Aminosäure, wobei die
natürlichen L-Aminosäuren und ihre D-Isomeren Verwendung finden
können;
B eine saure Gruppierung aus der Reihe -CO₂H, -CONHCOR′′′,
-CONHSOR′′′, CONHSO₂R′′′, -NHSO₂CF₃, Tetrazolyl, Imidazolyl oder
-3-Hydroxyisoxazolyl bedeutet, wobei R′′′ Aryl, Heteroaryl, (C₃-C₇)-
Cycloalkyl oder (C₁-C₄)-Alkyl, gegebenenfalls monosubstituiert mit
(C₆-C₁₂)-Aryl, Heteroaryl, OH, SH, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, (C₁-C₄)-
Thioalkyl, -Sulfinyl oder -Sulfonyl, CF₃, Cl, Br, F, I, NO₂, -COOH, (C₂-C₅)-
Alkoxycarbonyl, NH₂, Mono- oder Di-(C₁-C₄-alkyl)-amino oder (C₁-C₄)-
Perfluoroalkyl bedeutet,
R¹, R², R³ und R⁴ gleich oder verschieden sind und Wasserstoff, Hydroxy,
Halogen, Cyano, Trifluormethyl, Nitro, Carboxy, (C₁-C₂₀)-Alkyl, (C₃-C₈)-
Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkoxy,
(C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkyl,
(C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁ -C₈)-alkyl-
(C₁-C₆)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-
Cycloalkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₈)-
alkoxy-(C₁-C₈)-alkoxy, (C₆-C₁₂)-Aryl, (C₇-C₁₆)-Aralkyl, (C₂-C₂₀)-Alkenyl,
(C₂-C₂₀)-Alkinyl, (C₁-C₂₀)-Alkoxy, (C₂-C₂₀)-Alkenyloxy, (C₂-C₂₀)-
Alkinyloxy, Retinyloxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₁₂)-Alkoxy-
(C₁-C₁₂)-alkoxy, (C₁-C₁₂)-Alkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-
Aryloxy, (C₇-C₁₆)-Aralkyloxy, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxy, (C₇-C₁₆)-
Aralkoxy-(C₁-C₆)-alkoxy, (C₁-C₈)-Hydroxyalkyl, (C₆-C₁₆)-Aryloxy-(C₁-C₈)-
alkyl, (C₇-C₁₆)-Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkoxy-
(C₁-C₆)-alkyl, (C₇-C₁₂)-Aralkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₂-C₂₀)-
Alkenyloxy-(C₁-C₆)-alkyl, (C₂-C₂₀)-Alkinyloxy-(C₁-C₆)-alkyl, Retinyloxy-
(C₁-C₆)-alkyl, -O-[CH₂]xCfH(2f+1-g)Fg, -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂)-Alkylcarbonyl, (C₃-C₈)-Cycloalkylcarbonyl, (C₆-C₁₂)-
Arylcarbonyl, (C₇-C₁₆)-Aralkylcarbonyl, Cinnamoyl, (C₂-C₁₂)-
Alkenylcarbonyl, (C₂-C₁₂)-Alkinylcarbonyl,
(C₁-C₁₂)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl,
(C₆-C₁₂)-Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)-
Cycloalkoxycarbonyl, (C₂-C₂₀)-Alkenyloxycarbonyl, Retinyloxycarbonyl,
(C₂-C₂₀)-Alkinyloxycarbonyl, (C₆-C₁₂)-Aryloxy (C₁-C₆)-alkoxycarbonyl,
(C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)-Cycloalkyl-(C₁-C₆)-
alkoxycarbonyl, (C₃-C₈)-Cycloalkoxy (C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbonyloxy, (C₆-C₁₂)-
Arylcarbonyloxy, (C₇-C₁₆)-Aralkylcarbonyloxy, Cinnamoyloxy, (C₂-C₁₂)-
Alkenylcarbonyloxy, (C₂-C₁₂)-Alkinylcarbonyloxy,
(C₁-C₁₂)-Alkoxycarbonyloxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-
alkoxycarbonyloxy, (C₆-C₁₂)-Aryloxycarbonyloxy, (C₇-C₁₆)-
Aralkyloxycarbonyloxy, (C₃-C₈)-Cycloalkoxycarbonyloxy, (C₂-C₁₂)-
Alkenyloxycarbonyloxy, (C₂-C₁₂)-Alkinyloxycarbonyloxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N,N-Di-(C₁-C₁₂)-alkylcarbamoyl,
N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl,
N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-Cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl-
(C₁-C₆)-alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆)-
alkyl)carbamoyl, N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+)-
dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)-
Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁ -C₁₀)-
Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)-
alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl,
CON(CH₂)h, worin eine CH₂-Gruppe durch O, S, N-(C₁-C₈)-Alkylimino,
N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino,
N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄) -Alkoxy-
(C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet, oder mit
einem Carbamoyl-Rest der allgemeinen Formel IIin which
Q O or S,
X O and S,
A (C₁-C₄) alkylene, which is optionally substituted with one or two substituents from the series halogen, cyano, nitro, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) hydroxyalkyl, (C₁-C₆) -Alkoxy, -O- [CH₂] x -C f H (2f + 1-g) Hal g , preferably (C₁-C₈) fluoroalkoxy, (C₁-C₈) fluoroalkenyloxy, (C₁-C₈) fluoroalkynyloxy, - OCF₂Cl or -O-CF₂-CHFCl, (C₁-C₆) alkyl mercapto, (C₁-C₆) alkylsulfinyl, (C₁-C₆) alkylsulfonyl, (C₁-C₆) alkylcarbonyl, (C₁-C₆) alkoxycarbonyl, carbamoyl , N- (C₁-C₄) alkylcarbamoyl, N, N-di- (C₁-C₄) alkylcarbamoyl, (C₁-C₆) alkylcarbonyloxy, (C₃-C₈) cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino , N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N- (C₁-C₄) alkylsulfamoyl, N, N-di- (C₁-C₄) alkylsulfamoyl, or
with a substituted (C₆-C₁₂) aryloxy, (C₇-C₁₁) aralkyloxy, (C₆-C₁₂) aryl or (C₇-C₁₁) aralkyl radical which is in the aryl part 1, 2, 3, 4 or 5 identical or different substituents from the series halogen, cyano, nitro, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, -O- [CH₂] x -C f H (2f + 1-g) Hal g , -OCF₂Cl, -O-CF₂-CHFCl, (C₁-C₆) alkyl mercapto, (C₁-C₆) alkylsulfinyl, (C₁-C₆) alkylsulfonyl, (C₁-C₆) alkylcarbonyl, (C₁-C₆) -Alkoxycarbonyl, carbamoyl, N- (C₁-C₄) alkylcarbamoyl, N, N-di- (C₁-C₄) alkylcarbamoyl, (C₁-C₆) alkylcarbonyloxy, (C₃-C₈) cycloalkyl, sulfamoyl, N- ( C₁-C₄) - alkylsulfamoyl or N, N-di- (C₁-C₄) alkylsulfamoyl, or
with the substituents R⁵ of the α-C atom of an α-amino acid, whereby the natural L-amino acids and their D-isomers can be used;
B is an acidic group from the series -CO₂H, -CONHCOR ′ ′ ′, -CONHSOR ′ ′ ′, CONHSO₂R ′ ′ ′, -NHSO₂CF₃, tetrazolyl, imidazolyl or -3-hydroxyisoxazolyl, where R ′ ′ ′ aryl, heteroaryl, ( C₃-C₇) - cycloalkyl or (C₁-C₄) alkyl, optionally monosubstituted with (C₆-C₁₂) aryl, heteroaryl, OH, SH, (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁ -C₄) - thioalkyl, sulfinyl or sulfonyl, CF₃, Cl, Br, F, I, NO₂, -COOH, (C₂-C₅) - alkoxycarbonyl, NH₂, mono- or di- (C₁-C₄-alkyl) - amino or (C₁-C₄) - perfluoroalkyl means
R¹, R², R³ and R⁴ are the same or different and are hydrogen, hydroxy, halogen, cyano, trifluoromethyl, nitro, carboxy, (C₁-C₂₀) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkoxy, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkoxy, (C₃-C₈) -cycloalkyloxy- (C₁-C₁₂) alkyl, (C₃ -C₈) -Cycloalkyloxy- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyl- (C₁ -C₈) alkyl- (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈ ) -alkoxy- (C₁-C₆) -alkyl, (C₃-C₈) - cycloalkyloxy- (C₁-C₈) -alkoxy- (C₁-C₆) -alkyl, (C₃-C₈) -cycloalkoxy- (C₁-C₈) - alkoxy- (C₁-C₈) alkoxy, (C₆-C₁₂) aryl, (C₇-C₁₆) aralkyl, (C₂-C₂₀) alkenyl, (C₂-C₂₀) alkynyl, (C₁-C₂₀) alkoxy, (C₂-C₂₀) alkenyloxy, (C₂-C₂₀) alkynyloxy, retinyloxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy, (C -C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) - aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl, (C₆-C₁₆ ) Aryloxy- (C₁-C₈) alkyl, (C₇-C₁₆) aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkoxy- (C₁-C₆) - alkyl, (C₇-C₁₂) aralkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₂-C₂₀) - alkenyloxy- (C₁-C₆) alkyl, (C₂-C₂₀) alkynyloxy- (C₁-C₆) alkyl, retinyloxy- (C₁-C₆) alkyl, -O- [CH₂] x C f H (2f + 1-g) F g , -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂) alkylcarbonyl, (C₃-C₈) cycloalkylcarbonyl, (C₆-C₁₂) arylcarbonyl, (C₇-C₁₆) aralkylcarbonyl, cinnamoyl, (C₂-C₁₂) alkenylcarbonyl, (C₂-C₁₂) alkynylcarbonyl,
(C₁-C₁₂) alkoxycarbonyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) - cycloalkoxycarbonyl, (C₂ -C₂₀) alkenyloxycarbonyl, retinyloxycarbonyl, (C₂-C₂₀) alkynyloxycarbonyl, (C₆-C₁₂) aryloxy (C₁-C₆) alkoxycarbonyl, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxycarbonyl, (C₃- C₈) cycloalkyl (C₁-C₆) alkoxycarbonyl, (C₃-C₈) cycloalkoxy (C₁-C₆) alkoxycarbonyl,
(C₁-C₁₂) alkylcarbonyloxy, (C₃-C₈) cycloalkylcarbonyloxy, (C₆-C₁₂) arylcarbonyloxy, (C₇-C₁₆) aralkylcarbonyloxy, cinnamoyloxy, (C₂-C₁₂) alkenylcarbonyloxy, (C₂-C₁₂oxy) alkynylcarbonyloxy
(C₁-C₁₂) alkoxycarbonyloxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyloxy, (C₆-C₁₂) aryloxycarbonyloxy, (C₇-C₁₆) aralkyloxycarbonyloxy, (C₃-C₈) cycloalkoxycarbonyloxy, (C₂ -C₁₂) - alkenyloxycarbonyloxy, (C₂-C₁₂) alkynyloxycarbonyloxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N - ((C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₁-C₆) alkyl -N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- (C₆-C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁ -C₁₀) - alkyl-N- (C₇-C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆ ) aralkylo xy- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group is represented by O, S, N- (C₁-CAl) alkylimino, N- (C₃-C -C) cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆ ) alkylimino can be replaced and h is 3 to 7, or with
a carbamoyl radical of the general formula II
worin
Rx den Substituenten einer α-Aminosäure bedeutet, zu denen die L-
und D-Aminosäuren zählen,
s 1, 2, 3,4 oder 5 und
T OH, OR oder NR* R** bedeutet, wobei
R*, R** und R*** gleich oder verschieden sind und Wasserstoff (C₆-C₁₂)-
Aryl, (C₇-C₁₁)-Aralkyl, (C₁-C₈)-Alkyl, (C₃-C₈)-Cycloalkyl,
(+)-Dehydroabietyl, (C₁-C₈)-Alkoxy-(C₁-C₈)-alkyl, (C₇-C₁₂)-
Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkyl, (C₁-C₁₀)-
Alkanoyl, ggf. substituiertes (C₇-C₁₆)-Aralkanoyl, ggf.
substituiertes (C₆-C₁₂)-Aroyl bedeuten, oder
R* und R** gemeinsam für -[CH₂]h stehen, worin eine CH₂ Gruppe durch
O, S, SO, SO₂, N-Acylamino, N-(C₁-C₁₀)-Alkoxycarbonylimino,
N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-
Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-
Aralkylimino oder N-(C₁-C₄)-Alkoxy-(C₁-C₆)-alkylimino ersetzt sein
kann und h 3 bis 7 bedeutet, oder mit
Carbamoyloxy, N-(C₁-C₁₂)-Alkylcarbamoyloxy, N,N-Di-
(C₁-C₁₂)-alkylcarbamoyloxy, N-(C₃-C₈)-Cycloalkylcarbamoyloxy,
N-(C₆-C₁₂)-Arylcarbamoyloxy, N-(C₇-C₁₆)-Aralkylcarbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₂)-arylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-
(C₇-C₁₆)-Aralkylcarbamoyloxy, N-((C₁-C₁₀)-alkyl)carbamoyloxy,
N-((C₆-C₁₂)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,-
Amino, (C₁-C₁₂)-Alkylamino, Di-(C₁-C₁₂)-alkylamino, (C₃-C₈)-
Cycloalkylamino, (C₃-C₁₂)-Alkenylamino, (C₃-C₁₂)-Alkinylamino,
N-(C₆-C₁₂)-Arylamino, N-(C₇-C₁ ₁)-Aralkylamino, N-Alkyl-Aralkylamino,
N-Alkyl-Arylamino, (C₁-C₁₂)-Alkoxyamino, (C₁-C₁₂)-Alkoxy-N-(C₁-C₁₀)-
alkylamino,
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino, (C₆-C₁₂)-
Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N-(C₁-C₁₀)-
alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino, (C₆-C₁₂)-Aroyl-
N-(C₁-C₁₀)-alkylamino, (C₇-C₁₁)-Aralkanoyl-N-(C₁-C₁₀)-alkylamino,
(C₁-C₁₂)-Alkanoylamino-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkanoylamino-
(C₁-C₈)-alkyl, (C₆-C₁₂)-Aroylamino-(C₁-C₈)-alkyl, (C₇-C₁₆)-
Aralkanoylamino-(C₁-C₈)-alkyl, Amino-(C₁-C₁₀)-alkyl, N-(C₁-C₁₀)-
alkylamino-(C₁-C₁₀)-alkyl, N,N-Di(C₁-C₁₀)-alkylamino-(C₁-C₁₀)-alkyl,
(C₃-C₈)-Cycloalkylamino-(C₁-C₁₀)-alkyl, (C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)-
Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl, (C₆-C₁₂)-Arylmercapto, (C₆-C₁₂)-
Arylsulfinyl, (C₆-C₁₂)-Arylsulfonyl, (C₇-C₁₆)-Aralkylmercapto, (C₇-C₁₆)-
Aralkylsulfinyl, (C₇-C₁₆)-Aralkylsulfonyl,
Sulfamoyl, N-(C₁-C₁₀)-Alkylsulfamoyl, N,N-Di-(C₁-C₁₀)-alkylsulfamoyl,
(C₃-C₈)-Cycloalkylsulfamoyl,
N-(C₆-C₁₂)-Arylsulfamoyl,
N-(C₇-C₁₆)-Aralkylsulfamoyl,
N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₂)-arylsulfamoyl,
N-(C₁-C₁₀)-Alkyl-N-(C₇-C₁₆)-aralkylsulfamoyl,
(C₁-C₁₀)-Alkyl-sulfonamido,
N-((C₁-C₁₀)-alkyl)-(C₁-C₁₀)-alkylsulfonamido, (C₇-C₁₆)-Aralkylsulfonamido,
N-((C₁-C₁₀)-alkyl-(C₇-C₁₆)-aralkylsulfonamido,
wobei die Reste, die einen Arylrest enthalten ihrerseits am Aryl
substituiert sein können durch 1 bis 5 gleiche oder verschiedene Reste
aus der Reihe:
Hydroxy, Halogen, Cyano, Trifluormethyl, Nitro, Carboxy, (C₁-C₁₂)-Alkyl,
(C₃-C₈)-Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkyl, (C₃-C₈)-
Cycloalkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyloxy-
(C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyl-
(C₁-C₈)-alkyl-(C₁-C₆)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy-(C₁-C₆)-
alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-
Cycloalkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkoxy, (C₆-C₁₂)-Aryl, (C₇-C₁₆)-
Aralkyl, (C₂-C₁₂)-Alkenyl, (C₂-C₁₂)-Alkinyl, (C₁-C₁₂)-Alkoxy, (C₁-C₁₂)-
Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxy, (C₁-C₁₂)-Alkoxy-
(C₁-C₈)-alkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)-Aralkyloxy,
(C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxy, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxy,
(C₁-C₈)-Hydroxyalkyl, (C₆-C₁₆)-Aryloxy-(C₁-C₈)-alkyl, (C₇-C₁₆)-Aralkoxy-
(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₇-C₁₂)-
Aralkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF₂Cl,
-OCF₂-CHFCl,
(C₁-C₁₂)-Alkylcarbonyl, (C₃-C₈)-Cycloalkylcarbonyl, (C₆-C₁₂)-
Arylcarbonyl, (C₇-C₁₆)-Aralkylcarbonyl,
(C₁-C₁₂)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl,
(C₆-C₁₂)-Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)-
Cycloalkoxycarbonyl, (C₂-C₁₂)-Alkenyloxycarbonyl, (C₂-C₁₂)-
Alkinyloxycarbonyl, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxycarbonyl, (C₇-C₁₆)-
Aralkoxy-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)-Cycloalkyl-(C₁-C₆)-
alkoxycarbonyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbonyloxy,
(C₆-C₁₂)-Arylcarbonyloxy, (C₇-C₁₆)-Aralkylcarbonyloxy, Cinnamoyloxy,
(C₂-C₁₂)-Alkenylcarbonyloxy, (C₂-C₁₂)-Alkinylcarbonyloxy,
(C₁-C₁₂)-Alkoxycarbonyloxy, (C₁-C₁₂)-Alkoxy (C₁-C₁₂)-
alkoxycarbonyloxy, (C₆-C₁₂)-Aryloxycarbonyloxy, (C₇-C₁₆)-
Aralkyloxycarbonyloxy, (C₃-C₈)-Cycloalkoxycarbonyloxy, (C₂-C₁₂)-
Alkenyloxycarbonyloxy, (C₂-C₁₂)-Alkinyloxycarbonyloxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N,N-Di-(C₁-C₁₂)-alkylcarbamoyl,
N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl,
N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl-
(C₁-C₆)-alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆)-
alkyl)carbamoyl, N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+)-
dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)-
Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁-C₁₀)-
Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)-
alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl,
CON(CH₂)h, worin eine CH₂-Gruppe durch O, S, N-(C₁-C₈)-Alkylimino,
N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino,
N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄)-Alkoxy-
(C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet,
Carbamoyloxy, N-(C₁-C₁₂)-Alkylcarbamoyloxy, N,N-Di-(C₁-C₁₂)-
alkylcarbamoyloxy, N-(C₃-C₈)-Cycloalkylcarbamoyloxy, N-(C₆-C₁₆)-
Arylcarbamoyloxy, N-(C₇-C₁₆)-Aralkylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-
(C₆-C₁₂)-arylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl N-(C₇-C₁₆)
Aralkylcarbamoyloxy, N-((C₁-C₁₀)-alkyl)carbamoyloxy,
N-((C₆-C₁₂)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N((C₇-C₁₆)-Aralkyloxy-(C₁-C ₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,-
Amino, (C₁-C₁₂)-Alkylamino, Di-(C₁-C₁₂)-alkylamino, (C₃-C₈)-
Cycloalkylamino, (C₃-C₁₂)-Alkenylamino, (C₃-C₁₂)-Alkinylamino,
N-(C₆-C₁₂)-Arylamino, N-(C₇-C₁₁)-Aralkylamino, N-Alkyl-Aralkylamino,
N-Alkyl-Arylamino, (C₁-C₁₂)-Alkoxyamino, (C₁-C₁₂)-Alkoxy-N-(C₁-C₁₀)-
alkylamino,
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino, (C₆-C₁₂)-
Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N-(C₁-C₁₀)-
alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino, (C₆-C₁₂)-Aroyl-
N-(C₁-C₁₀)-alkylamino, (C₇-C₁₁)-Aralkanoyl-N-(C₁-C₁₀)-alkylamino,
(C₁-C₁₂)-Alkanoylamino-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkanoylamino-
(C₁-C₈)-alkyl, (C₆-C₁₂)-Aroylamino-(C₁-C₈)-alkyl, (C₇-C₁₆)-
Aralkanoylamino-(C₁-C₈)-alkyl, Amino-(C₁-C₁₀)-alkyl, N-(C₁-C₁₀)-
Alkylamino-(C₁-C₁₀)-alkyl, N,N-Di-(C₁-C₁₀)-alkylamino-(C₁-C₁₀)-alkyl,
(C₃-C₈)-Cycloalkylamino-(C₁-C₁₀)-alkyl,
(C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)-Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl,
(C₆-C₁₆)-Arylmercapto, (C₆-C₁₆)-Arylsulfinyl, (C₆-C₁₆)-Arylsulfonyl,
(C₇-C₁₆)-Aralkylmercapto, (C₇-C₁₆)-Aralkylsulfinyl, (C₇-C₁₆)-
Aralkylsulfonyl,
R¹ und R², R² und R³ oder R³ und R⁴ eine Kette [CH₂]o bilden können, in
welcher eine oder zwei CH₂-Gruppen der gesättigten oder mit einer
C=C-Doppelbindung ungesättigten Kette gegebenenfalls durch O, S, SO,
SO₂ oder NR′ ersetzt sind, o = 3, 4 oder 5 bedeutet und
R′ Wasserstoff, (C₆-C₁₂)-Aryl, (C₁-C₈)-Alkyl, (C₁-C₈)-Alkoxy-(C₁-C₈)-alkyl,
(C₇-C₁₂)-Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkyl, (C₁-C₁₀)-
Alkanoyl, ggf. substituiertes (C₇-C₁₆)-Aralkanoyl, ggf. substituiertes
(C₆-C₁₂)-Aroyl bedeuten,
R⁵ Wasserstoff oder einen verzweigten oder unverzweigten (C₁-C₂₀)-
Alkylrest, einen (C₆-C₁₆)-Arylrest oder einen (C₇-C₁₆)-Aralkylrest
bedeutet,
wobei diese Reste substituiert sind mit einem oder mehreren Resten aus der
Reihe
Hydroxy, Halogen, Cyano, Trifluormethyl, Nitro, Carboxy, (C₁-C₁₂)-Alkyl,
(C₃-C₈)-Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkoxy,
(C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkyl,
(C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁ -C₈)-alkyl-(C₁-C₆)-
alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-Cycloalkyloxy-
(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkoxy,
(C₆-C₁₂)-Aryl, (C₇-C₁₆)-Aralkyl, (C₂-C₁₂)-Alkenyl, (C₂-C₁₂)-Alkinyl, (C₁-C₁₂)-
Alkoxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxy,
(C₁-C₁₂)-Alkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)-
Aralkyloxy, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxy, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxy,
(C₁-C₈)-Hydroxyalkyl, (C₆-C₁₆)-Aryloxy-(C₁-C₈)-alkyl, (C₇-C₁₆)-Aralkoxy-(C₁-C₈)-
alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₇-C₁₂)-Aralkyloxy-
(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂)-Alkylcarbonyl, (C₃-C₈)-Cycloalkylcarbonyl, (C₆-C₁₂)-Arylcarbonyl,
(C₇-C₁₆)-Aralkylcarbonyl, Cinnamoyl, (C₂-C₁₂)-Alkenylcarbonyl, (C₂-C₁₂)-
Alkinylcarbonyl,
(C₁-C₁₂)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl, (C₆-C₁₂)-
Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)-Cycloalkoxycarbonyl,
(C₂-C₁₂)-Alkenyloxycarbonyl, (C₂-C₁₂)-Alkinyloxycarbonyl, (C₆-C₁₂)-Aryloxy-
(C₁-C₆)-alkoxycarbonyl, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)-
Cycloalkyl-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbonyloxy, (C₆-C₁₂)-
Arylcarbonyloxy, (C₇-C₁₆)-Aralkylcarbonyloxy, Cinnamoyloxy, (C₂-C₁₂)-
Alkenylcarbonyloxy, (C₂-C₁₂)-Alkinylcarbonyloxy,
(C₁-C₁₂)-Alkoxycarbonyloxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyloxy,
(C₆-C₁₂)-Aryloxycarbonyloxy, (C₇-C₁₆)-Aralkyloxycarbonyloxy, (C₃-C₈)-
Cycloalkoxycarbonyloxy, (C₂-C₁₂)-Alkenyloxycarbonyloxy, (C₂-C₁₂)-
Alkinyloxycarbonyloxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N, N-Di-(C₁-C₁₂)-alkylcarbamoyl,
N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl, N-(C₁-C₁₀)-
Alkyl-N-(C₃-C₈)-Cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl-(C₁-C₆)-
alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆)-alkyl)carbamoyl,
N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+)-
dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)-
Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁-C₁₀)-Alkyl-
N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-
alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, CON(CH₂)h,
worin eine CH₂-Gruppe durch O, S, N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)-
Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino,
N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄)-Alkoxy (C₁-C₆)-alkylimino ersetzt sein
kann und h 3 bis 7 bedeutet, oder mit
einem Carbamoyl Rest der allgemeinen Formel IIwherein
R x denotes the substituents of an α-amino acid, which include the L and D amino acids,
s 1, 2, 3, 4 or 5 and
T means OH, OR or NR * R **, where
R *, R ** and R *** are the same or different and are hydrogen (C₆-C₁₂) aryl, (C₇-C₁₁) aralkyl, (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl, ( +) - Dehydroabietyl, (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₇-C₁₂) - aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) -alkyl, (C₁-C₁₀) alkanoyl, optionally substituted (C₇-C₁₆) aralkanoyl, optionally substituted (C₆-C₁₂) aryl, or
R * and R ** together represent - [CH₂] h , in which a CH₂ group is represented by O, S, SO, SO₂, N-acylamino, N- (C₁-C₁₀) alkoxycarbonylimino, N- (C₁-C₈) - Alkylimino, N- (C₃-C₈) -cycloalkylimino, N- (C₃-C₈) - cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆) alkylimino can be replaced and h is 3 to 7, or with
Carbamoyloxy, N- (C₁-C₁₂) alkylcarbamoyloxy, N, N-Di- (C₁-C₁₂) alkylcarbamoyloxy, N- (C₃-C₈) cycloalkylcarbamoyloxy, N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₇ -C₁₆) aralkylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylcarbamoyloxy, N - (( C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy , N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) -aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy, - amino, (C₁- C₁₂) alkylamino, di- (C₁-C₁₂) alkylamino, (C₃-C₈) - cycloalkylamino, (C₃-C₁₂) alkenylamino, (C₃-C₁₂) alkynylamino, N- (C₆-C₁₂) arylamino, N. - (C₇-C₁ ₁) aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C₁- C₁₂) alkoxyamino, (C₁-C₁₂) alkoxy-N- (C₁-C₁₀) alkylamino,
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino, (C₆-C₁₂) aroyl- N- (C₁-C₁₀) alkylamino, (C₇-C₁₁) aralkanoyl-N- (C₁-C₁₀ ) alkylamino,
(C₁-C₁₂) alkanoylamino- (C₁-C₈) alkyl, (C₃-C₈) cycloalkanoylamino- (C₁-C₈) alkyl, (C₆-C₁₂) aroylamino- (C₁-C₈) alkyl, (C₇ -C₁₆) - aralkanoylamino- (C₁-C₈) alkyl, amino- (C₁-C₁₀) alkyl, N- (C₁-C₁₀) alkylamino- (C₁-C₁₀) alkyl, N, N-di (C₁- C₁₀) alkylamino- (C₁-C₁₀) alkyl, (C₃-C₈) cycloalkylamino- (C₁-C₁₀) alkyl, (C₁-C₁₂) alkylmercapto, (C₁-C₁₂) alkylsulfinyl, (C₁-C₁₂) -Alkylsulfonyl, (C₆-C₁₂) arylmercapto, (C₆-C₁₂) - arylsulfinyl, (C₆-C₁₂) arylsulfonyl, (C₇-C₁₆) aralkylmercapto, (C₇-C₁₆) - aralkylsulfinyl, (C₇-C₁onyl) aralkylsulfinyl ,
Sulfamoyl, N- (C₁-C₁₀) alkylsulfamoyl, N, N-di- (C₁-C₁₀) alkylsulfamoyl, (C₃-C₈) cycloalkylsulfamoyl, N- (C₆-C₁₂) arylsulfamoyl, N- (C₇-C₁₆ ) Aralkylsulfamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylsulfamoyl, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylsulfamoyl, (C₁-C₁₀) - Alkyl sulfonamido, N - ((C₁-C₁₀) alkyl) - (C₁-C₁₀) alkylsulfonamido, (C₇-C₁₆) aralkylsulfonamido, N - ((C₁-C₁₀) alkyl- (C₇-C₁₆) aralkylsulfonamido , where the radicals which contain an aryl radical in turn can be substituted on the aryl by 1 to 5 identical or different radicals from the series:
Hydroxy, halogen, cyano, trifluoromethyl, nitro, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkyl, (C₃-C₈) - Cycloalkoxy, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈) alkyl- (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈) alkoxy- (C₁-C₆) - alkyl, (C₃ -C₈) -Cycloalkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₃-C₈) - cycloalkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkoxy, (C₆-C₁₂ ) Aryl, (C₇-C₁₆) aralkyl, (C₂-C₁₂) alkenyl, (C₂-C₁₂) alkynyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) - alkoxy- (C₁-C₁₂) - alkyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy, (C₇-C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl , (C₆-C₁₆) aryloxy- (C₁-C₈) alkyl, (C₇-C₁₆) aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkoxy- ( C₁-C₆) alkyl, (C₇-C₁₂) aralkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, -O- [CH 2- ] x C f H (2f + 1-g) F g , -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂) alkylcarbonyl, (C₃-C₈) cycloalkylcarbonyl, (C₆-C₁₂) arylcarbonyl, (C₇-C₁₆) aralkylcarbonyl,
(C₁-C₁₂) alkoxycarbonyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) - cycloalkoxycarbonyl, (C₂ -C₁₂) alkenyloxycarbonyl, (C₂-C₁₂) alkynyloxycarbonyl, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxycarbonyl, (C₇-C₁₆) - aralkoxy- (C₁-C₆) alkoxycarbonyl, (C₃-C₈ ) -Cycloalkyl- (C₁-C₆) alkoxycarbonyl, (C₃-C₈) -cycloalkoxy- (C₁-C₆) alkoxycarbonyl,
(C₁-C₁₂) alkylcarbonyloxy, (C₃-C₈) cycloalkylcarbonyloxy, (C₆-C₁₂) arylcarbonyloxy, (C₇-C₁₆) aralkylcarbonyloxy, cinnamoyloxy, (C₂-C₁₂) alkenylcarbonyloxy, (C₂-C₁₂), alkynylcarbonyloxy
(C₁-C₁₂) alkoxycarbonyloxy, (C₁-C₁₂) alkoxy (C₁-C₁₂) alkoxycarbonyloxy, (C₆-C₁₂) aryloxycarbonyloxy, (C₇-C₁₆) aralkyloxycarbonyloxy, (C₃-C₈) cycloalkoxycarbonyloxy, (C₂- C₁₂) - alkenyloxycarbonyloxy, (C₂-C₁₂) alkynyloxycarbonyloxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N - ((C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₁-C₆) alkyl -N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- (C₆-C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁-C₁₀) - alkyl-N- (C₇-C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆ ) aralkylox y- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group is represented by O, S, N- (C₁-C₈) alkylimino, N- (C₃-C₈) cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆ ) alkylimino can be replaced and h is 3 to 7,
Carbamoyloxy, N- (C₁-C₁₂) alkylcarbamoyloxy, N, N-Di- (C₁-C₁₂) alkylcarbamoyloxy, N- (C₃-C₈) cycloalkylcarbamoyloxy, N- (C₆-C₁₆) arylcarbamoyloxy, N- (C₇ -C₁₆) aralkylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₁-C₁₀) alkyl N- (C₇-C₁₆) aralkylcarbamoyloxy, N - ((C₁- C₁₀) alkyl) carbamoyloxy, N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N ((C₇-C₁₆) aralkyloxy- (C₁-C ₁₀) alkyl) carbamoyloxy, N - (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy - (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy, - amino, (C₁-C₁₂) Alkylamino, di- (C₁-C₁₂) alkylamino, (C₃-C₈) cycloalkylamino, (C₃-C₁₂) alkenylamino, (C₃-C₁₂) alkynylamino, N- (C₆-C₁₂) arylamino, N- ( C₇-C₁₁) aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C₁- C₁₂) alkoxyamino, (C₁-C₁₂) alkoxy-N- (C₁-C₁₀) alkylamino,
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino, (C₆-C₁₂) aroyl- N- (C₁-C₁₀) alkylamino, (C₇-C₁₁) aralkanoyl-N- (C₁-C₁₀ ) alkylamino,
(C₁-C₁₂) alkanoylamino- (C₁-C₈) alkyl, (C₃-C₈) cycloalkanoylamino- (C₁-C₈) alkyl, (C₆-C₁₂) aroylamino- (C₁-C₈) alkyl, (C₇ -C₁₆) - aralkanoylamino- (C₁-C₈) alkyl, amino- (C₁-C₁₀) alkyl, N- (C₁-C₁₀) alkylamino- (C₁-C₁₀) alkyl, N, N-di- (C₁ -C₁₀) alkylamino- (C₁-C₁₀) alkyl, (C₃-C₈) cycloalkylamino- (C₁-C₁₀) alkyl,
(C₁-C₁₂) alkylmercapto, (C₁-C₁₂) alkylsulfinyl, (C₁-C₁₂) alkylsulfonyl, (C₆-C₁₆) arylmercapto, (C₆-C₁₆) arylsulfinyl, (C₆-C₁₆) arylsulfonyl, (C₆ -C₁₆) aralkylmercapto, (C₇-C₁₆) aralkylsulfinyl, (C₇-C₁₆) aralkylsulfonyl,
R¹ and R², R² and R³ or R³ and R⁴ can form a chain [CH₂] o , in which one or two CH₂ groups of the saturated or unsaturated chain with a C = C double bond optionally by O, S, SO, SO₂ or NR 'are replaced, o = 3, 4 or 5 means and
R ′ is hydrogen, (C₆-C₁₂) aryl, (C₁-C₈) alkyl, (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₇-C₁₂) aralkoxy- (C₁-C₈) - alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkyl, (C₁-C₁₀) alkanoyl, optionally substituted (C₇-C₁₆) aralkanoyl, optionally substituted (C₆-C₁₂) aryl,
R⁵ is hydrogen or a branched or unbranched (C₁-C₂₀) alkyl radical, a (C₆-C₁₆) aryl radical or a (C₇-C₁₆) aralkyl radical,
these radicals being substituted by one or more radicals from the series
Hydroxy, halogen, cyano, trifluoromethyl, nitro, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkyl, (C₃-C₈) - Cycloalkoxy, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkoxy, (C₃-C₈) -cycloalkyl- (C₁-C₈) -alkyl- (C₁-C₆) - alkoxy, (C₃-C₈) -cycloalkyl- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₃ -C₈) -Cycloalkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₃-C₈) -cycloalkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkoxy, (C₆-C₁₂ ) Aryl, (C₇-C₁₆) aralkyl, (C₂-C₁₂) alkenyl, (C₂-C₁₂) alkynyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) - alkyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy, (C₇-C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl, ( C₆-C₁₆) aryloxy- (C₁-C₈) alkyl, (C₇-C₁₆) aralkoxy- (C₁-C₈) - alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkoxy- (C₁- C₆) alkyl, (C₇-C₁₂) aralkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, -O- [CH 2- ] x C f H (2f + 1-g) F g , -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂) alkylcarbonyl, (C₃-C₈) cycloalkylcarbonyl, (C₆-C₁₂) arylcarbonyl, (C₇-C₁₆) aralkylcarbonyl, cinnamoyl, (C₂-C₁₂) alkenylcarbonyl, (C₂-C₁₂) alkynylcarbonyl,
(C₁-C₁₂) alkoxycarbonyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) cycloalkoxycarbonyl, (C₂ -C₁₂) alkenyloxycarbonyl, (C₂-C₁₂) alkynyloxycarbonyl, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxycarbonyl, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxycarbonyl, (C₃-C₈ ) - Cycloalkyl- (C₁-C₆) -alkoxycarbonyl, (C₃-C₈) -cycloalkoxy- (C₁-C₆) -alkoxycarbonyl, (C₁-C₁₂) -alkylcarbonyloxy, (C₃-C₈) -cycloalkylcarbonyloxy, (C₆-C₁₂) - Arylcarbonyloxy, (C₇-C₁₆) aralkylcarbonyloxy, cinnamoyloxy, (C₂-C₁₂) alkenylcarbonyloxy, (C₂-C₁₂) alkynylcarbonyloxy,
(C₁-C₁₂) alkoxycarbonyloxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyloxy, (C₆-C₁₂) aryloxycarbonyloxy, (C₇-C₁₆) aralkyloxycarbonyloxy, (C₃-C₈) - cycloalkoxycarbonyloxy, (C₂ -C₁₂) alkenyloxycarbonyloxy, (C₂-C₁₂) alkynyloxycarbonyloxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) - alkyl-N- (C₃-C₈) -cycloalkylcarbamoyl, N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N- (C₁-C₆) alkyl -N - ((C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- (C₆-C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁-C₁₀) alkyl- N- (C₇-C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆ ) aralkylo xy- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group through O, S, N- (C₁-C₈) alkylimino, N- (C₃-C₈) - cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy (C₁-C₆) -alkylimino can be replaced and h is 3 to 7, or with
a carbamoyl radical of the general formula II
worin
Rx den Substituenten einer α-Aminosäure bedeutet, zu denen die L-
und D-Aminosäuren zählen,
s 1, 2, 3,4 oder 5 und
T OH, OR oder NR*R** bedeutet, wobei
R*, R** und R*** gleich oder verschieden sind und Wasserstoff, (C₆-C₁₂)-
Aryl, (C₇-C₁₁)-Aralkyl, (C₁-C₈)-Alkyl, (C₃-C₈)-Cycloalkyl,
(+)-Dehydroabietyl, (C₁-C₈)-Alkoxy-(C₁-C₈)-alkyl, (C₇-C₁₂)-
Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkyl, (C₁-C₁₀)-
Alkanoyl, ggf. substituiertes (C₇-C₁₆)-Aralkanoyl, ggf.
substituiertes (C₆-C₁₂)-Aroyl bedeuten, oder
R* und R** gemeinsam für -[CH₂]h stehen, worin eine CH₂ Gruppe durch
O, S, SO, SO₂, N-Acylamino, N-(C₁-C₁₀)-Alkoxycarbonylimino,
N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-
Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-
Aralkylimino oder N-(C₁-C₄)-Alkoxy-(C₁-C₆)-alkylimino ersetzt sein
kann und h 3 bis 7 bedeutet, oder mit
Carbamoyloxy, N-(C₁-C₁₂)-Alkylcarbamoyloxy, N,N-Di-
(C₁-C₁₂)-alkylcarbamoyloxy, N-(C₃-C₈)-Cycloalkylcarbamoyloxy,
N-(C₆-C₁₂)-Arylcarbamoyloxy, N-(C₇-C₁₆)-Aralkylcarbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₂)-arylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-
(C₇-C₁₆)-aralkylcarbamoyloxy, N-((C₁-C₁₀)-alkyl)carbamoyloxy,
N-((C₆-C₁₂)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,-
Amino, (C₁-C₁₂)-Alkylamino, Di-(C₁-C₁₂)-alkylamino, (C₃-C₈)-
Cycloalkylamino, (C₃-C₁₂)-Alkenylamino, (C₃-C₁₂)-Alkinylamino,
N-(C₆-C₁₂)-Arylamino, N-(C₇-C₁₁)-Aralkylamino, N-Alkyl-Aralkylamino,
N-Alkyl-Arylamino, (C₁-C₁₂)-Alkoxyamino, (C₁-C₁₂)-Alkoxy-N-(C₁-C₁₀)-
alkylamino,
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino, (C₆-C₁₂)-
Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N-(C₁-C₁₀)-
alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino, (C₆-C₁₂)-Aroyl-
N-(C₁-C₁₀)-alkylamino, (C₇-C₁₁)-Aralkanoyl-N-(C₁-C₁₀)-alkylamino,
(C₁-C₁₂)-Alkanoylamino-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkanoylamino-
(C₁-C₈)-alkyl, (C₆-C₁₂)-Aroylamino-(C₁-C₈)-alkyl, (C₇-C₁₆)-
Aralkanoylamino-(C₁-C₈)-alkyl, Amino-(C₁-C₁₀)-alkyl, N-(C₁-C₁₀)-
alkylamino-(C₁-C₁₀)-alkyl, N,N-Di(C₁-C₁₀)-alkylamino-(C₁-C₁₀)-alkyl,
(C₃-C₈)-Cycloalkylamino-(C₁-C₁₀)-alkyl,
(C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)-Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl,
(C₆-C₁₂)-Arylmercapto, (C₆-C₂)-Arylsulfinyl, (C₆-C₁₂)-Arylsulfonyl,
(C₇-C₁₆)-Aralkylmercapto, (C₇-C₁₆)-Aralkylsulfinyl, (C₇-C₁₆)-
Aralkylsulfonyl,
Sulfamoyl, N-(C₁-C₁₀)-Alkylsulfamoyl, N,N-Di-(C₁-C₁₀)-alkylsulfamoyl,
(C₃-C₈)-Cycloalkylsulfamoyl,
N-(C₆-C₁₂)-Arylsulfamoyl,
N-(C₇-C₁₆)-Aralkylsulfamoyl,
N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₂)-arylsulfamoyl,
N-(C₁-C₁₀)-Alkyl-N-(C₇-C₁₆)-aralkylsulfamoyl,
(C₁-C₁₀)-Alkyl-sulfonamido,
N-((C₁-C₁₀)-Alkyl)-(C₁-C₁₀)-alkylsulfonamido, (C₇-C₁₆)-
Aralkylsulfonamido, N-((C₁-C₁₀)-Alkyl (C₇-C₁₆)-aralkylsulfonamido,
wobei die Reste, die einen Arylrest enthalten ihrerseits am Aryl
substituiert sein können durch 1 bis 5 gleiche oder verschiedene Reste
aus der Reihe:
Hydroxy, Halogen, Cyano, Trifluormethyl, Nitro, Carboxy, (C₁-C₁₂)-Alkyl,
(C₃-C₈)-Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkyl, (C₃-C₈)-
Cycloalkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyloxy-
(C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyl-
(C₁-C₈)-alkyl-(C₁-C₆)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy-(C₁-C₆)-
alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-
Cycloalkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkoxy, (C₆-C₁₂)-Aryl, (C₇-C₁₆)-
Aralkyl, (C₂-C₁₂)-Alkenyl, (C₂-C₁₂)-Alkinyl, (C₁-C₁₂)-Alkoxy, (C₁-C₁₂)-
Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxy, (C₁-C₁₂)-Alkoxy-
(C₁-C₈)-alkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)-Aralkyloxy,
(C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxy, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxy,
(C₁-C₈)-Hydroxyalkyl, (C₆-C₁₆)-Aryloxy-(C₁-C₈)-alkyl, (C₇-C₁₆)-Aralkoxy-
(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₇-C₁₂)-
Aralkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF₂Cl,
-OCF₂-CHFCl,
(C₁-C₁₂)-Alkylcarbonyl, (C₃-C₈)-Cycloalkylcarbonyl, (C₆-C₁₂)-
Arylcarbonyl, (C₇-C₁₆)-Aralkylcarbonyl,
(C₁-C₁₂)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl,
(C₆-C₁₂)- Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)-
Cycloalkoxycarbonyl, (C₂-C₁₂)-Alkenyloxycarbonyl, (C₂-C₁₂)-
Alkinyloxycarbonyl, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxycarbonyl, (C₇-C₁₆)-
Aralkoxy-(C₁-C₆)-alkoxycarbonyl, (C₃- C₈)-Cycloalkyl-(C₁-C₆)-
alkoxycarbonyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbonyloxy,
(C₆-C₁₂)-Arylcarbonyloxy, (C₇-C₁₆)-Aralkylcarbonyloxy, Cinnamoyloxy,
(C₂-C₁₂)-Alkenylcarbonyloxy, (C₂-C₁₂)-Alkinylcarbonyloxy,
(C₁-C₁₂)-Alkoxycarbonyloxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-
alkoxycarbonyloxy, (C₆-C₁₂)-Aryloxycarbonyloxy, (C₇-C₁₆)-
Aralkyloxycarbonyloxy, (C₃-C₈)-Cycloalkoxycarbonyloxy, (C₂-C₁₂)-
Alkenyloxycarbonyloxy, (C₂-C₁₂)-Alkinyloxycarbonyloxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N, N-Di-(C₁-C₁₂)-alkylcarbamoyl,
N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl,
N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl-
(C₁-C₆)-alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆)-
alkyl)carbamoyl, N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+ )-
dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)-
Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁-C₁₀)-
Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)-
alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl,
CON(CH₂)h, worin eine CH₂-Gruppe durch O, S, N-(C₁-C₈)-Alkylimino,
N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino,
N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄)-Alkoxy-
(C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet,
Carbamoyloxy, N-(C₁-C₁₂)-Alkylcarbamoyloxy, N,N-Di-(C₁-C₁₂)-
alkylcarbamoyloxy, N-(C₃-C₈)-Cycloalkylcarbamoyloxy, N-(C₆-C₁₆)-
Arylcarbamoyloxy, N-(C₇-C₁₆)-Aralkylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-
(C₆-C₁₂)-arylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-(C₇-C₁₆)-
Aralkylcarbamoyloxy, N-((C₁-C₁₀)-alkyl)carbamoyloxy,
N-((C₆-C₁₂)-Aryloxy-(C₁-C₁₀)-alkyl)-carbamoyloxy,
N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)-carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,
N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁ ₀)-alkyl)carbamoyloxy,
Amino, (C₁-C₁₂)-Alkylamino, Di-(C₁-C₁₂)-alkylamino, (C₃-C₈)-
Cycloalkylamino, (C₃-C₁₂)-Alkenylamino, (C₃-C₁₂)-Alkinylamino, N-(C₆-
C₁₂)-Arylamino, N-(C₇-C₁₁)-Aralkylamino, N-Alkyl-Aralkylamino, N-Alkyl-
Arylamino, (C₁-C₁₂)-Alkoxyamino, (C₁-C₁₂)-Alkoxy-N-(C₁-C₁₀)-
alkylamino,
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino,
(C₆-C₁₂)-Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N-
(C₁-C₁₀)-alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino,
(C₆-C₁₂)-Aroyl-N-(C₁-C₁₀)-alkylamino, (C₇-C₁₁)-Aralkanoyl-N-(C₁-C₁₀)-
alkylamino,
(C₁-C₁₂)-Alkanoylamino-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkanoylamino-
(C₁-C₈)-alkyl, (C₆-C₁₂)-Aroylamino-(C₁-C₈)-alkyl, (C₇-C₁₆)-
Aralkanoylamino-(C₁-C₈)-alkyl, Amino-(C₁-C₁₀)-alkyl, N-(C₁-C₁₀)-
Alkylamino-(C₁-C₁₀)-alkyl, N,N-Di-(C₁-C₁₀)-alkylamino-(C₁-C₁₀)-alkyl,
(C₃-C₈)-Cycloalkylamino-(C₁-C₁₀)-alkyl,
(C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)-Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl,
(C₆-C₁₆)-Arylmercapto, (C₆-C₁₆)-Arylsulfinyl, (C₆-C₁₆)-Arylsulfonyl,
(C₇-C₁₆)-Aralkylmercapto, (C₇-C₁₆)-Aralkylsulfinyl, (C₇-C₁₆)-
Aralkylsulfonyl,
und
f = 1 bis 8,
g = 0,1 bis (2f+1),
x = 0 bis 3,
h = 3 bis 6 bedeuten
einschließlich der physiologisch wirksamen Salze,
wobei N-((6,7-Dichlor-3,4-dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α-
((6,7-Dichlor-3,4-dihydro-3-oxo-2-chinoxalinyl)carbonyl)amino)phenyl-essigsäure
ausgenommen sind.wherein
R x denotes the substituents of an α-amino acid, which include the L and D amino acids,
s 1, 2, 3, 4 or 5 and
T means OH, OR or NR * R **, where
R *, R ** and R *** are the same or different and are hydrogen, (C₆-C₁₂) aryl, (C₇-C₁₁) aralkyl, (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl, (+) - Dehydroabietyl, (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₇-C₁₂) - aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈ ) alkyl, (C₁-C₁₀) alkanoyl, optionally substituted (C₇-C₁₆) aralkanoyl, optionally substituted (C₆-C₁₂) aroyl, or
R * and R ** together represent - [CH₂] h , in which a CH₂ group is represented by O, S, SO, SO₂, N-acylamino, N- (C₁-C₁₀) alkoxycarbonylimino, N- (C₁-C₈) - Alkylimino, N- (C₃-C₈) -cycloalkylimino, N- (C₃-C₈) - cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆) alkylimino can be replaced and h is 3 to 7, or with
Carbamoyloxy, N- (C₁-C₁₂) alkylcarbamoyloxy, N, N-Di- (C₁-C₁₂) alkylcarbamoyloxy, N- (C₃-C₈) cycloalkylcarbamoyloxy, N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₇ -C₁₆) aralkylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylcarbamoyloxy, N - (( C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy , N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) -aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy, - amino, (C₁- C₁₂) alkylamino, di- (C₁-C₁₂) alkylamino, (C₃-C₈) - cycloalkylamino, (C₃-C₁₂) alkenylamino, (C₃-C₁₂) alkynylamino, N- (C₆-C₁₂) arylamino, N. - (C₇-C₁₁) aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C₁-C ₁₂) alkoxyamino, (C₁-C₁₂) alkoxy-N- (C₁-C₁₀) alkylamino,
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino, (C₆-C₁₂) aroyl- N- (C₁-C₁₀) alkylamino, (C₇-C₁₁) aralkanoyl-N- (C₁-C₁₀ ) alkylamino,
(C₁-C₁₂) alkanoylamino- (C₁-C₈) alkyl, (C₃-C₈) cycloalkanoylamino- (C₁-C₈) alkyl, (C₆-C₁₂) aroylamino- (C₁-C₈) alkyl, (C₇ -C₁₆) - aralkanoylamino- (C₁-C₈) alkyl, amino- (C₁-C₁₀) alkyl, N- (C₁-C₁₀) alkylamino- (C₁-C₁₀) alkyl, N, N-di (C₁- C₁₀) alkylamino- (C₁-C₁₀) alkyl, (C₃-C₈) cycloalkylamino- (C₁-C₁₀) alkyl,
(C₁-C₁₂) alkylmercapto, (C₁-C₁₂) alkylsulfinyl, (C₁-C₁₂) alkylsulfonyl, (C₆-C₁₂) arylmercapto, (C₆-C₂) arylsulfinyl, (C₆-C₁₂) arylsulfonyl, (C₇ -C₁₆) aralkylmercapto, (C₇-C₁₆) aralkylsulfinyl, (C₇-C₁₆) aralkylsulfonyl,
Sulfamoyl, N- (C₁-C₁₀) alkylsulfamoyl, N, N-di- (C₁-C₁₀) alkylsulfamoyl, (C₃-C₈) cycloalkylsulfamoyl, N- (C₆-C₁₂) arylsulfamoyl, N- (C₇-C₁₆ ) Aralkylsulfamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylsulfamoyl, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylsulfamoyl, (C₁-C₁₀) - Alkylsulfonamido, N - ((C₁-C₁₀) alkyl) - (C₁-C₁₀) alkylsulfonamido, (C₇-C₁₆) aralkylsulfonamido, N - ((C₁-C₁₀) alkyl (C₇-C₁₆) aralkylsulfonamido, where the radicals which contain an aryl radical in turn can be substituted on the aryl by 1 to 5 identical or different radicals from the series:
Hydroxy, halogen, cyano, trifluoromethyl, nitro, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkyl, (C₃-C₈) - Cycloalkoxy, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈) alkyl- (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈) alkoxy- (C₁-C₆) - alkyl, (C₃ -C₈) -Cycloalkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₃-C₈) - cycloalkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkoxy, (C₆-C₁₂ ) Aryl, (C₇-C₁₆) aralkyl, (C₂-C₁₂) alkenyl, (C₂-C₁₂) alkynyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) - alkoxy- (C₁-C₁₂) - alkyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy, (C₇-C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl , (C₆-C₁₆) aryloxy- (C₁-C₈) alkyl, (C₇-C₁₆) aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkoxy- ( C₁-C₆) alkyl, (C₇-C₁₂) aralkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, -O- [CH 2- ] x C f H (2f + 1-g) F g , -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂) alkylcarbonyl, (C₃-C₈) cycloalkylcarbonyl, (C₆-C₁₂) arylcarbonyl, (C₇-C₁₆) aralkylcarbonyl,
(C₁-C₁₂) alkoxycarbonyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) - cycloalkoxycarbonyl, (C₂ -C₁₂) alkenyloxycarbonyl, (C₂-C₁₂) - alkynyloxycarbonyl, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxycarbonyl, (C₇-C₁₆) - aralkoxy- (C₁-C₆) alkoxycarbonyl, (C₃- C₈ ) -Cycloalkyl- (C₁-C₆) alkoxycarbonyl, (C₃-C₈) -cycloalkoxy- (C₁-C₆) alkoxycarbonyl,
(C₁-C₁₂) alkylcarbonyloxy, (C₃-C₈) cycloalkylcarbonyloxy, (C₆-C₁₂) arylcarbonyloxy, (C₇-C₁₆) aralkylcarbonyloxy, cinnamoyloxy, (C₂-C₁₂) alkenylcarbonyloxy, (C₂-C₁₂), alkynylcarbonyloxy (C₁-C₁₂) alkoxycarbonyloxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyloxy, (C₆-C₁₂) aryloxycarbonyloxy, (C₇-C₁₆) aralkyloxycarbonyloxy, (C₃-C₈) cycloalkoxycarbonyloxy, (C₂ -C₁₂) - alkenyloxycarbonyloxy, (C₂-C₁₂) alkynyloxycarbonyloxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N - ((C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₁-C₆) alkyl -N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- (C₆-C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁-C₁₀) - alkyl-N- (C₇-C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆ ) aralkyl oxy- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group is represented by O, S, N- (C₁-C₈) alkylimino, N- (C₃-C₈) cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆ ) alkylimino can be replaced and h is 3 to 7,
Carbamoyloxy, N- (C₁-C₁₂) alkylcarbamoyloxy, N, N-Di- (C₁-C₁₂) alkylcarbamoyloxy, N- (C₃-C₈) cycloalkylcarbamoyloxy, N- (C₆-C₁₆) arylcarbamoyloxy, N- (C₇ -C₁₆) aralkylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N-
(C₆-C₁₂) arylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylcarbamoyloxy, N - ((C₁-C₁₀) alkyl) carbamoyloxy,
N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀ ) -Alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀ ) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁ ₀) alkyl) carbamoyloxy,
Amino, (C₁-C₁₂) alkylamino, di- (C₁-C₁₂) alkylamino, (C₃-C₈) - cycloalkylamino, (C₃-C₁₂) alkenylamino, (C₃-C₁₂) alkynylamino, N- (C₆- C₁₂ ) Arylamino, N- (C₇-C₁₁) aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C₁-C₁₂) alkoxyamino, (C₁-C₁₂) alkoxy-N- (C₁-C₁₀) - alkylamino,
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino, (C₆-C₁₂) aroyl-N- (C₁-C₁₀) alkylamino, (C₇-C₁₁) aralkanoyl-N- (C₁-C₁₀ ) - alkylamino,
(C₁-C₁₂) alkanoylamino- (C₁-C₈) alkyl, (C₃-C₈) cycloalkanoylamino- (C₁-C₈) alkyl, (C₆-C₁₂) aroylamino- (C₁-C₈) alkyl, (C₇ -C₁₆) - aralkanoylamino- (C₁-C₈) alkyl, amino- (C₁-C₁₀) alkyl, N- (C₁-C₁₀) alkylamino- (C₁-C₁₀) alkyl, N, N-di- (C₁ -C₁₀) alkylamino- (C₁-C₁₀) alkyl, (C₃-C₈) cycloalkylamino- (C₁-C₁₀) alkyl,
(C₁-C₁₂) alkylmercapto, (C₁-C₁₂) alkylsulfinyl, (C₁-C₁₂) alkylsulfonyl, (C₆-C₁₆) arylmercapto, (C₆-C₁₆) arylsulfinyl, (C₆-C₁₆) arylsulfonyl, (C₆ -C₁₆) aralkylmercapto, (C₇-C₁₆) aralkylsulfinyl, (C₇-C₁₆) aralkylsulfonyl,
and
f = 1 to 8,
g = 0.1 to (2f + 1),
x = 0 to 3,
h = 3 to 6 mean
including the physiologically active salts,
where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α- ((6,7-dichloro-3,4-dihydro-3-oxo-2 -chinoxalinyl) carbonyl) amino) phenyl-acetic acid are excluded.
Unter Aryl werden im allgemeinen carbocyclische und heterocyclische aromatische Ringsysteme verstanden. Insbesondere versteht man hierunter Phenyl-, Biphenyl- oder Naphthyl- bzw. unsubstituierte 5- und 6-gliedrige heteroaromatische Ringe mit 1, 2 oder 3 Stickstoff- und/oder Sauerstoff und/oder Schwefelatomen, wie Pyridyl-, Pyridazyl-, Pyrimidyl-, Pyrazyl-, Imidazolyl-, Triazolyl-, Thienyl-, Oxazolyl-, und Thiazolyl-Derivate, und deren benzoannellierte Derivate. Bevorzugt sind Phenyl, Pyridyl und Thienyl.Aryl is generally carbocyclic and heterocyclic understood aromatic ring systems. This is understood in particular Phenyl, biphenyl or naphthyl or unsubstituted 5- and 6-membered heteroaromatic rings with 1, 2 or 3 nitrogen and / or oxygen and / or sulfur atoms, such as pyridyl, pyridazyl, pyrimidyl, pyrazyl, Imidazolyl, triazolyl, thienyl, oxazolyl, and thiazolyl derivatives, and their benzo-fused derivatives. Phenyl, pyridyl and thienyl are preferred.
Die Erfindung umfaßt weiterhin Salze der Verbindungen der allgemeinen Formel I.The invention further encompasses salts of the compounds of the general Formula I.
Die Salzbildung mit basischen Reagenzien kann ein-, zwei- oder dreifach an den aciden Gruppen der Verbindungen der Formel I erfolgen, insbesondere an den Resten B und R⁵.Salt formation with basic reagents can be done once, twice or three times at the Acid groups of the compounds of formula I take place, in particular on the Residues B and R⁵.
Zur Anwendung kommende Reagenzien sind beispielsweise Alkoholate,
Hydroxide, Carbonate, Hydrogencarbonate, Hydrogenphosphate, Metallorganyle
der Alkali- und Erdalkalielemente, der Elemente der 3. und 4. Hauptgruppe des
Periodensystems und der Elemente der Übergangsmetalle,
Amine, ggf. 1- bis 3-fach substituiert mit (C₁-C₈)-Hydroxyalkyl, (C₁-C₄)-Alkoxy-
(C₁-C₈)-alkyl, Phenyl, Benzyl oder (C₁-C₈)-Alkyl, welches 1- bis 3-fach
substituiert sein kann mit Hydroxy oder (C₁-C₄)-Alkoxy,
beispielsweise Tromethan (Tris-Puffer), 2-Aminoethanol, 3-Aminopropanol,
Hydroxylamin, Dimethylhydroxylamin, 2-Methoxyethylamin,
3-Ethoxypropylamin, und
basische Aminosäuren und -derivate, wie Aminosäureester, Histidin, Arginin und
Lysin und deren Derivate, sowie
Arzneimittel, die eine basische Gruppe enthalten, wie beispielsweise ®Amilorid,
®Verapamil und Betablocker.Reagents used are, for example, alcoholates, hydroxides, carbonates, hydrogen carbonates, hydrogen phosphates, metal organyls of the alkali and alkaline earth elements, the elements of the 3rd and 4th main group of the periodic table and the elements of the transition metals,
Amines, optionally 1 to 3 times substituted with (C₁-C₈) hydroxyalkyl, (C₁-C₄) alkoxy- (C₁-C₈) alkyl, phenyl, benzyl or (C₁-C₈) alkyl, which 1 - Can be substituted up to 3 times with hydroxy or (C₁-C₄) alkoxy, for example tromethane (Tris buffer), 2-aminoethanol, 3-aminopropanol, hydroxylamine, dimethylhydroxylamine, 2-methoxyethylamine, 3-ethoxypropylamine, and basic amino acids and derivatives, such as amino acid esters, histidine, arginine and lysine and their derivatives, and
Medicines containing a basic group, such as ®Amilorid, ®Verapamil and beta blockers.
Die Erfindung betrifft weiterhin die Verbindungen, gemäß Formel I, zuzüglich N-((6,7-Dichlor-3,4-dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α-((6,7- Dichlor-3,4-dihydro-3-oxo-2-chinoxalinyl)carbonyl)amino)phenylessigs-äure zur Anwendung der Arzneimittel.The invention further relates to the compounds according to formula I, plus N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7- Dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) amino) phenylacetic acid for Use of medicines.
Bevorzugt sind Verbindungen der Formel I, in der
Q O oder S,
X O,
A (C₁-C₃)-Alkylen, das gegebenenfalls einfach substituiert ist mit Halogen,
Cyano, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Hydroxyalkyl, (C₁ -C₆)-
Alkoxy, -O-[CH₂]x-CfH(2f+1-g)Fg oder
A -CHR⁶- bedeutet, wobei R⁶ einen der Substituenten des α-C-Atoms einer
α-Aminosäure bedeutet, insbesondere einer natürlichen L-Aminosäure und
ihres D-Isomeren,
B CO₂H
R¹, R², R³ und R⁴ gleich oder verschieden sind und Wasserstoff, (C₁-C₂₀)-Alkyl,
(C₂-C₂₀)-Alkenyloxy, (C₂-C₂₀)-Alkinyloxy, Retinyloxy, (C₂-C₂₀)-
Alkenyloxy-(C₁-C₃)-alkyl, Retinyloxy-(C₁-C₃)-alkyl, (C₂-C₂₀)-Alkinyloxy-
(C₁-C₃)-alkyl, (C₁-C₂₀)-Alkoxy, Halogen, Cyano, Trifluormethyl, (C₁-C₈)-
Hydroxyalkyl, (C₁-C₁₀)-Alkanoyl, (C₇-C₁₂)-Aralkanoyl, (C₆-C₁₂)-Aroyl,
-O-[CH₂]xCfH(2f+1-g)Fg, (C₁-C₁₀)-Alkylmercapto, (C₁-C₁₀)-Alkylsulfinyl,
(C₁-C₁₀)-Alkylsulfonyl, (C₆-C₁₂)-Arylmercapto, (C₆-C₁₂)-Arylsulfinyl,
(C₆-C₁₂)-Arylsulfonyl, (C₇-C₁₂)-Aralkylmercapto, (C₇-C₁₂)-Aralkylsulfinyl,
(C₇-C₁₂)-Aralkylsulfonyl, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)-Aralkyloxy, Carboxy,
(C₁-C₂₀)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl,
(C₆-C₁₂)-Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)-
Cycloalkoxycarbonyl, (C₂-C₂₀)-Alkenyloxycarbonyl, Retinyloxycarbonyl,
(C₂-C₂₀)-Alkinyloxycarbonyl, (C₃-C₈)-Cycloalkyl-(C₁-C₆)-alkoxycarbonyl,
(C₃-C₈)-Cycloalkoxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-
alkoxycarbonyl, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₈)-Alkoxy-(C₁-C₁₂)-alkoxy, (C₁-C₁₂)-
Alkoxy-(C₁-C₈)-alkoxy-(C₂-C₆)-alkyl, (C₇-C₁₁)-Aralkyloxy, (C₃-C₈)-
Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkyloxy,
(C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy, (C₃-C₈)-Cycloalkyloxy-(C₁-C₈)-alkyl,
(C₃-C₈)-Cycloalkyloxy-(C₁-C₈)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁ -C₆)-alkyl-
(C₁-C₆)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-
Cycloalkoxy-(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, NRYRZ, substituiertes (C₆-C₁₂)-
Aryloxy-(C₁-C₆)-alkyl, (C₇-C₁₁)-Aralkoxy-(C₁-C₆)-alkyl, (C₆-C₁₂)-Aryloxy-
(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, (C₇-C₁₁)-Aralkyloxy-(C₁-C₆)-alkoxy-(C₁-C₆)-
alkyl, (C₆-C₁₂)-Aryloxy, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxy oder (C₇-C₁₁)-
Aralkoxy-(C₁-C₆)-alkoxy bedeuten, wobei ein aromatischer Rest mit 1, 2,
3, 4 oder 5 gleichen oder verschiedenen Substituenten aus der Reihe
Wasserstoff, Halogen, Cyano, Nitro, Trifluormethyl, (C₁-C₆)-Alkyl,
(C₁-C₆)-Hydroxyalkyl, (C₁-C₆)-Alkoxy, -O-[CH₂]xCfH(2f+1-g)Fg, -OCF₂Cl,
-O-CF₂-CHFCl, (C₁-C₆)-Alkylmercapto, (C₁-C₆)-Alkylsulfinyl, (C₁-C₆)-
Alkylsulfonyl, (C₁-C₆)-Alkylcarbonyl, (C₁-C₆)-Alkoxycarbonyl, Carbamoyl,
N-(C₁-C₄)-Alkylcarbamoyl, N,N-Di-(C₁-C₄)-alkylcarbamoyl, (C₁-C₆)-
Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbamoyl, Phenyl, Benzyl, Phenoxy,
Benzyloxy, NRYRZ, Phenylmercapto, Phenylsulfonyl, Phenylsulfinyl,
Sulfamoyl, N-(C₁-C₄)-Alkylsulfamoyl oder N,N-Di-(C₁-C₄)-alkylsulfamoyl
trägt, oder gegebenenfalls bis zu 3 der vorstehend genannten gleichen
oder verschiedenen Substituenten trägt und zwei benachbarte C-Atome
des Aralkyloxyrestes gemeinsam eine Kette -[CH₂-] und/oder
-CH=CH-CH=CH- tragen, wobei eine CH₂-Gruppe der Kette
gegebenenfalls durch O, S, SO, SO₂ oder NR′ ersetzt ist,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N, N-Di-(C₁-C₁₂)-alkylcarbamoyl,
N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo(C₃-C₈)-alkylcarbamoyl,
N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-cycloalkylcarbamoyl, N-(C₃-C₈)-Cycloalkyl-
(C₁-C₆)-alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆)-
alkyl)carbamoyl, N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+)-
dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)-
Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁ -C₁₀)-
Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)-
alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl,N-(C₁-C₁₀)-Alkyl-N-
((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl,
CON(CH₂)h, worin eine CH₂-Gruppe durch O, S, N-(C₁-C₈)-alkylimino,
N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino,
N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄)-Alkoxy-
(C₁-C₆)-alkylimino ersetzt ein kann und h 3 bis 7 bedeutet,
R¹ und R² oder R² und R³ oder R³ und R⁴ eine Kette [CH₂]o bilden können,
wobei o = 3, 4 oder 5 bedeutet,
R⁵ Wasserstoff oder einen verzweigten oder unverzweigten (C₁-C₁₂)-
Alkylrest, der bis zu 3 C-C-Mehrfachbindungen enthalten kann, einen (C₆-
C₁₆)-Arylrest oder einen (C₇-C₁₆)-Aralkylrest, der bis zu 2 C-C-
Mehrfachverbindungen enthalten kann, bedeutet, wobei diese Reste
substituiert sind mit einem oder mehreren Resten aus der Reihe Hydroxy,
Fluor, Chlor, Cyano, Trifluormethyl, Carboxy, (C₁-C₁₂)-Alkyl, (C₃-C₈)-
Cycloalkyl, (C₃-C₈)-Cycloalkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy,
(C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₆-C₁₂)-Aryl, (C₇-C₁₆)-Aralkyl,
(C₂-C₁₂)-Alkenyl, (C₂-C₁₂)-Alkinyl, (C₁-C₁₂)-Alkoxy, (C₁-C₁₂)-Alkoxy-
(C₁-C₁₂)-alkoxy, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)-Aralkyloxy, (C₆-C₁₂)-Aryloxy-
(C₁-C₆)-alkoxy, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxy, (C₁-C₈)-Hydroxyalkyl, -
O-[CH2-]xCfH(2f+1-g)Fg,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N,N-Di-(C₁-C₁₂)-alkylcarbamoyl,
N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl,
N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl-
(C₁-C₆)-alkyl)carbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)-
Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁-C₁₀)-
Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)-
alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyl,
N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, CON(CH₂)h, worin eine
CH₂-Gruppe durch O, N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)-Cycloalkylimino,
N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino oder
N-(C₇-C₁₆)-Aralkylimino ersetzt sein kann und h 3 bis 6 bedeutet, oder mit
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino, (C₆-C₁₂)-
Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N-(C₁-C₁₀)-
alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino,
wobei die Reste, die einen Arylrest enthalten ihrersei 25664 00070 552 001000280000000200012000285912555300040 0002019504226 00004 25545ts am Aryl
substituiert sein können durch 1 bis 5 gleiche oder verschiedene Reste
aus der Reihe:
Hydroxy, Fluor, Chlor, Cyano, Trifluormethyl, Carboxy, (C₁-C₁₂)-Alkyl,
(C₃-C₈)-Cycloalkyl, (C₂-C₁₂)-Alkenyl, (C₁-C₁₂)-Alkoxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N, N-Di-(C₁-C₁₂)-alkylcarbamoyl,
N-(C₃-C₈)-Cycloalkylcarbamoyl, oder (C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)-
Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl,
wobei
RY und RZ gleich oder verschieden sind und Wasserstoff, (C₆-C₁₂)-Aryl,
(C₁-C₁₀)-Alkyl, (C₃-C₁₀)-Cycloalkyl, (C₁-C₈)-Alkoxy-(C₁-C₈)-alkyl,
(C₇-C₁₂)-Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkyl, (C₁-C₁₀)-
Alkanoyl, ggf. substituiertes (C₇-C₁₆)-Aralkanoyl, ggf. substituiertes
(C₆-C₁₂)-Aroyl bedeuten oder
RY und RZ gemeinsam für -[CH₂]h- stehen, worin eine CH₂-Gruppe durch O, S,
N-(C₁-C₄)-Alkanoylimino oder N-(C₁-C₄)-Alkoxycarbonylimino ersetzt sein
kann, und
f 1 bis 8,
g 0, 1 bis (2f+1),
h 3 bis 6,
x 0 bis 3, und
n 3 oder 4 ist,
einschließlich der physiologisch wirksamen Salze wobei N-((6,7-Dichlor-3,4-
dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α-((6,7-Dichlor-3,4-dihydro-3-
oxo-2-chinoxalinyl)carbonyl)amino) ausgenommen sind.Preferred compounds of the formula I are those in which
QO or S,
XO,
A (C₁-C₃) alkylene, which is optionally monosubstituted with halogen, cyano, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) hydroxyalkyl, (C₁ -C₆) alkoxy, -O- [CH₂ ] x -C f H (2f + 1-g) F g or
A means -CHR⁶-, where R⁶ means one of the substituents of the α-C atom of an α-amino acid, in particular a natural L-amino acid and its D isomer,
B CO₂H
R¹, R², R³ and R⁴ are the same or different and are hydrogen, (C₁-C₂₀) alkyl, (C₂-C₂₀) alkenyloxy, (C₂-C₂₀) alkynyloxy, retinyloxy, (C₂-C₂₀) - alkenyloxy- (C₁ -C₃) alkyl, retinyloxy- (C₁-C₃) alkyl, (C₂-C₂₀) alkynyloxy- (C₁-C₃) alkyl, (C₁-C₂₀) alkoxy, halogen, cyano, trifluoromethyl, (C₁-C₈ ) - Hydroxyalkyl, (C₁-C₁₀) alkanoyl, (C₇-C₁₂) aralkanoyl, (C₆-C₁₂) aroyl, -O- [CH₂] x C f H (2f + 1-g) F g , (C₁ -C₁₀) alkylmercapto, (C₁-C₁₀) alkylsulfinyl, (C₁-C₁₀) alkylsulfonyl, (C₆-C₁₂) arylmercapto, (C₆-C₁₂) arylsulfinyl, (C₆-C₁₂) arylsulfonyl, (C₇-C₁ ) Aralkylmercapto, (C₇-C₁₂) aralkylsulfinyl, (C₇-C₁₂) aralkylsulfonyl, (C₆-C₁₂) aryloxy, (C₇-C₁₆) aralkyloxy, carboxy, (C₁-C₂₀) alkoxycarbonyl, (C₁-C₁₂ ) Alkoxy- (C₁-C₁₂) alkoxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) - cycloalkoxycarbonyl, (C₂-C₂₀) - Alkenyloxycarbonyl, retinyloxycarbonyl, (C₂-C₂₀) alkynyloxycarbonyl, (C₃-C₈) cycloalkyl- (C₁-C₆) alkoxycarbonyl, (C₃-C₈) -cycloalkoxy- (C₁-C₆) alkoxycarbonyl, (C₆-C₁₂) - Aryloxy- (C₁-C₆) alkoxycarbonyl, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxycarbonyl,
(C₁-C₁₂) alkoxy- (C₁-C₁₂) alkyl, (C₁-C₈) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₂ -C₆) alkyl, (C₇-C₁₁) aralkyloxy, (C₃-C₈) - cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₈) alkyl, (C₃-C₈) cycloalkyloxy, (C₃-C₈ ) -Cycloalkyl- (C₁-C₈) -alkoxy, (C₃-C₈) -cycloalkyloxy- (C₁-C₈) -alkyl, (C₃-C₈) -cycloalkyloxy- (C₁-C₈) -alkoxy, (C₃-C₈) - Cycloalkyl- (C₁-C₆) -alkyl- (C₁-C₆) -alkoxy, (C₃-C₈) -cycloalkyl- (C₁-C₆) -alkoxy- (C₁-C₆) -alkyl, (C₃-C₈) -cycloalkoxy- (C₁-C₆) alkoxy- (C₁-C₆) alkyl, NR Y R Z , substituted (C₆-C₁₂) aryloxy- (C₁-C₆) alkyl, (C₇-C₁₁) aralkoxy- (C₁-C₆ ) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy- (C₁-C₁) alkyl, (C₇-C₁₁) aralkyloxy- (C₁-C₆) alkoxy- (C₁-C₆) - are alkyl, (C₆-C₁₂) aryloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy or (C₇-C₁₁) - aralkoxy- (C₁-C₆) alkoxy, an aromatic radical having 1, 2, 3, 4 or 5 identical or different substituents from the series hydrogen, halogen, cyano, nitro, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) hydroxyalkyl, (C₁-C₆) alkoxy, -O- [CH₂] x C f H (2f + 1-g) F g , -OCF₂Cl, -O-CF₂-CHFCl, (C₁-C₆) alkyl mercapto, (C₁-C₆) alkylsulfinyl, (C₁-C₆) alkylsulfonyl, (C₁-C₆ ) -Alkylcarbonyl, (C₁-C₆) -alkoxycarbonyl, carbamoyl, N- (C₁-C₄) -alkylcarbamoyl, N, N-di- (C₁-C₄) -alkylcarbamoyl, (C₁-C₆) - alkylcarbonyloxy, (C₃-C₈ ) -Cycloalkylcarbamoyl, phenyl, benzyl, phenoxy, benzyloxy, NR Y R Z , phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N- (C₁-C₄) alkylsulfamoyl or N, N-di- (C₁-C₄) -alkylsulfamoyl, or optionally carries up to 3 of the same or different substituents mentioned above and two adjacent C atoms of the aralkyloxy radical together bear a chain - [CH₂-] and / or -CH = CH-CH = CH-, one CH₂ group of the chain optionally replaced by O, S, SO, SO₂ or NR ' is
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo (C₃-C₈) alkylcarbamoyl, N - (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N- (C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₁-C₆) alkyl-N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- (C₆ -C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁ -C₁₀) - alkyl-N- (C₇ -C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N- ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) - aralkylox y- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group is represented by O, S, N- (C₁-C₈) alkylimino, N- (C₃-C₈) cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆ ) alkylimino can be replaced and h is 3 to 7,
R¹ and R² or R² and R³ or R³ and R⁴ can form a chain [CH₂] o , where o = 3, 4 or 5,
R⁵ is hydrogen or a branched or unbranched (C₁-C₁₂) alkyl radical which can contain up to 3 CC multiple bonds, a (C₆- C₁₆) aryl radical or a (C₇-C₁₆) aralkyl radical which contains up to 2 CC multiple compounds can contain means, where these radicals are substituted with one or more radicals from the series hydroxy, fluorine, chlorine, cyano, trifluoromethyl, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) - cycloalkyl, (C₃-C₈ ) -Cycloalkoxy, (C₃-C₈) -cycloalkyl- (C₁-C₁₂) -alkoxy, (C₃-C₈) -cycloalkyloxy- (C₁-C₁₂) -alkoxy, (C₆-C₁₂) -aryl, (C₇-C₁₆) - Aralkyl, (C₂-C₁₂) alkenyl, (C₂-C₁₂) alkynyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₆-C₁₂) aryloxy, (C₇-C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl, - O - [CH 2- ] x C f H (2f + 1-g) F g ,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N - ((C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₆-C₁₂) arylcarbamoyl , N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁-C₁₀) - alkyl-N- (C₇-C₁₆) aralkylcarbamoyl , N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₇-C₁₆ ) Aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group is substituted by O, N- (C₁-C₈) alkylimino, N- (C₃-C₈) cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino or N- (C₇-C₁₆) aralkylimino can be replaced and h is 3 to 6, or with
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino,
where the residues containing an aryl residue are 25664 00070 552 001000280000000200012000285912555300040 0002019504226 00004 25545ts on the aryl may be substituted by 1 to 5 identical or different residues from the series:
Hydroxy, fluorine, chlorine, cyano, trifluoromethyl, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, (C₂-C₁₂) alkenyl, (C₁-C₁₂) alkoxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, or (C₁-C₁₂) alkylmercapto, (C₁-C₁₂) - alkylsulfinyl, (C₁-C₁₂) alkylsulfonyl,
in which
R Y and R Z are the same or different and are hydrogen, (C₆-C₁₂) aryl, (C₁-C₁₀) alkyl, (C₃-C₁₀) cycloalkyl, (C₁-C₈) alkoxy- (C₁-C₈) - alkyl, (C₇-C₁₂) aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkyl, (C₁-C₁₀) alkanoyl, optionally substituted (C₇-C₁₆) Aralkanoyl, optionally substituted (C₆-C₁₂) aroyl or
R Y and R Z together represent - [CH₂] h -, in which a CH₂ group can be replaced by O, S, N- (C₁-C₄) alkanoylimino or N- (C₁-C₄) alkoxycarbonylimino, and
f 1 to 8,
g 0.1 to (2f + 1),
h 3 to 6,
x 0 to 3, and
n is 3 or 4,
including the physiologically active salts where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7-dichloro-3,4-dihydro- 3-oxo-2-quinoxalinyl) carbonyl) amino) are excluded.
Besonders bevorzugt sind Verbindungen der Formel I, in der
Q O oder S,
X O,
A -CHR⁶-, wobei R⁶ den Substituenten des α-C-Atoms einer α-Aminosäure
bedeutet, insbesondere einer natürlichen L-Aminosäure oder ihr
D-Isomeres,
B CO₂H,
R¹, R², R³ und R⁴ gleich oder verschieden sind und Wasserstoff, (C₁-C₁₂)-Alkyl,
(C₃-C₇)-Cycloalkyl, (C₁-C₁₂)-Alkoxy, (C₃-C₇)-Cycloalkyloxy, (C₃-C₇)-
Cycloalkyl-(C₁-C₂)-alkoxy, -O-[CH₂]x-CfH(2f+1-g)Fg, (C₁-C₄)-Alkoxy-
(C₁-C₄)-alkoxy, substituiertes (C₆-C₁₂)-Phenoxy, (C₇-C₁₁)-Phenylalkyloxy,
(C₆-C₁₂)-Phenoxy-(C₁-C₄)-alkoxy, (C₇-C₁₁)-Phenylalkoxy-(C₁-C₄)-alkoxy,
Fluor, Trifluormethyl, Chlor, N-(C₁-C₁₀)-Alkylcarbamoyl, N, N-Di-(C₁-C₈)-
alkylcarbamoyl, N-(C₃-C₇)-Cycloalkylcarbamoyl, N-Phenylcarbamoyl,
N-Phenyl-(C₁-C₄)-alkylcarbamoyl, Carboxy, (C₁-C₁₆)-Alkoxycarbonyl,
(C₂-C₁₆)-Alkenyloxycarbonyl, Retinyloxycarbonyl, (C₃-C₇)-
Cycloalkoxycarbonyl, bedeutet, wobei ein aromatischer Rest mit 1, 2
oder 3 gleichen oder verschiedenen Substituenten aus der Reihe Fluor,
Chlor, Cyano, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy substituiert ist
R⁵ Wasserstoff oder einen verzweigten oder unverzweigten (C₁-C₁₂)-
Alkylrest, der eine oder zwei C-C-Mehrfachbindungen enthalten kann, und
f 1 bis 4
g 0,1 bis (2f+1)
x 0 und 1 bedeutet,
einschließlich der physiologisch wirksamen Salze, wobei N-((6,7-Dichlor-3,4-
dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α-((6,7-Dichlor-3,4-dihydro-3-
oxo-2-chinoxalinyl)carbonyl)amino)phenylessigsäure ausgenommen sind.Compounds of the formula I in which
QO or S,
XO,
A -CHR⁶-, where R⁶ is the substituent of the α-C atom of an α-amino acid, in particular a natural L-amino acid or its D isomer,
B CO₂H,
R¹, R², R³ and R⁴ are the same or different and are hydrogen, (C₁-C₁₂) alkyl, (C₃-C₇) cycloalkyl, (C₁-C₁₂) alkoxy, (C₃-C₇) cycloalkyloxy, (C₃-C₇ ) - Cycloalkyl- (C₁-C₂) alkoxy, -O- [CH₂] x -C f H (2f + 1-g) F g , (C₁-C₄) alkoxy- (C₁-C₄) alkoxy, substituted (C₆-C₁₂) phenoxy, (C₇-C₁₁) phenylalkyloxy, (C₆-C₁₂) phenoxy- (C₁-C₄) alkoxy, (C₇-C₁₁) phenylalkoxy- (C₁-C₄) alkoxy, fluorine, Trifluoromethyl, chlorine, N- (C₁-C₁₀) alkylcarbamoyl, N, N-di- (C₁-C₈) alkylcarbamoyl, N- (C₃-C₇) cycloalkylcarbamoyl, N-phenylcarbamoyl, N-phenyl- (C₁-C₄ ) -alkylcarbamoyl, carboxy, (C₁-C₁₆) alkoxycarbonyl, (C₂-C₁₆) alkenyloxycarbonyl, retinyloxycarbonyl, (C₃-C₇) - cycloalkoxycarbonyl, where an aromatic radical having 1, 2 or 3 identical or different substituents from the Series fluorine, chlorine, cyano, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy is substituted
R⁵ is hydrogen or a branched or unbranched (C₁-C₁₂) alkyl radical, which can contain one or two CC multiple bonds, and
f 1 to 4
g 0.1 to (2f + 1)
x means 0 and 1,
including the physiologically active salts, where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7-dichloro-3,4-dihydro -3-oxo-2-quinoxalinyl) carbonyl) amino) phenylacetic acid are excluded.
Ganz besonders bevorzugt sind Verbindungen der Formel I, in der
Q O,
X O,
A eine -CH₂-Gruppe bedeutet, die mit einer Methylgruppe substituiert sein
kann,
B CO₂H,
R¹, R², R³ und R⁴ gleich oder verschieden sind und Wasserstoff, (C₁-C₁₂)-Alkyl,
(C₃-C₇)-Cycloalkyl, (C₁-C₁₂)-Alkoxy, (C₃-C₇)-Cycloalkyloxy, (C₃-C₇)-
Cycloalkyl-(C₁-C₂)-alkoxy, -O-[CH₂]x-CfH(2f+1-g)Fg, (C₁-C₄)-Alkoxy-
(C₁-C₄)-alkoxy, substituiertes (C₆-C₁₂)-Phenoxy, (C₇-C₁₁ )-Phenylalkyloxy,
(C₆-C₁₂)-Phenoxy-(C₁-C₄)-alkoxy, (C₇-C₁₁)-Phenylalkoxy-(C₁-C₄)-alkoxy,
Fluor, Trifluormethyl, Chlor, N-(C₁-C₁₀)-Alkylcarbamoyl, N,N-Di-(C₁-C₈)-
alkylcarbamoyl, N-(C₃-C₇)-Cycloalkylcarbamoyl, N-Phenylcarbamoyl,
N-Phenyl-(C₁-C₄)-alkylcarbamoyl, Carboxy, (C₁-C₁₆)-Alkoxycarbonyl,
(C₂-C₁₆)-Alkenyloxycarbonyl, Retinyloxycarbonyl, (C₃-C₇)-
Cycloalkoxycarbonyl, bedeutet, wobei ein aromatischer Rest mit 1, 2
oder 3 gleichen oder verschiedenen Substituenten aus der Reihe Fluor,
Chlor, Cyano, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy substituiert ist
und
R⁵ Wasserstoff oder einen verzweigten oder unverzweigten (C₁-C₆)-Alkylrest
bedeutet und
f 1 bis 4,
g 0,1 bis (2f+1) und
x 0 und 1 bedeuten,
einschließlich der physiologisch wirksamen Salze, wobei N-((6,7-Dichlor-3,4-
dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α-((6,7-Dichlor-3,4-dihydro-3-
oxo-2-chinoxalinyl)carbonyl)amino)phenylessigsäure ausgenommen sind.Compounds of the formula I in which
QO,
XO,
A represents a -CH₂ group which can be substituted by a methyl group,
B CO₂H,
R¹, R², R³ and R⁴ are the same or different and are hydrogen, (C₁-C₁₂) alkyl, (C₃-C₇) cycloalkyl, (C₁-C₁₂) alkoxy, (C₃-C₇) cycloalkyloxy, (C₃-C₇ ) - Cycloalkyl- (C₁-C₂) alkoxy, -O- [CH₂] x -C f H (2f + 1-g) F g , (C₁-C₄) alkoxy- (C₁-C₄) alkoxy, substituted (C₆-C₁₂) phenoxy, (C₇-C₁₁) phenylalkyloxy, (C₆-C₁₂) phenoxy- (C₁-C₄) alkoxy, (C₇-C₁₁) phenylalkoxy- (C₁-C₄) alkoxy, fluorine, Trifluoromethyl, chlorine, N- (C₁-C₁₀) alkylcarbamoyl, N, N-di- (C₁-C₈) alkylcarbamoyl, N- (C₃-C₇) cycloalkylcarbamoyl, N-phenylcarbamoyl, N-phenyl- (C₁-C₄ ) -alkylcarbamoyl, carboxy, (C₁-C₁₆) alkoxycarbonyl, (C₂-C₁₆) alkenyloxycarbonyl, retinyloxycarbonyl, (C₃-C₇) - cycloalkoxycarbonyl, where an aromatic radical having 1, 2 or 3 identical or different substituents from the Series fluorine, chlorine, cyano, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy is substituted and
R⁵ is hydrogen or a branched or unbranched (C₁-C₆) alkyl radical and
f 1 to 4,
g 0.1 to (2f + 1) and
x means 0 and 1,
including the physiologically active salts, where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7-dichloro-3,4-dihydro -3-oxo-2-quinoxalinyl) carbonyl) amino) phenylacetic acid are excluded.
ln höchst besonderem Maße bevorzugt sind Verbindungen der Formel I, in der
Q O,
X O,
A eine -CH₂-Gruppe und,
B CO₂H bedeutet, und
R¹ und R⁴ gleich oder verschieden sind und Wasserstoff, Fluor, Chlor und
(C₁-C₄)-Alkyl bedeuten,
R² und R³ gleich oder verschieden sind und Wasserstoff, Fluor, Chlor, (C₁-C₁₂)-
Alkoxy, (C₃-C₇)-Cycloalkoxy, -O-[CH₂]x-CfH(2f+1-g)Fg, (C₁-C₄)-Alkyl,
Benzyloxy, gegebenenfalls substituiert mit bis zu 3 Substituenten aus der
Reihe Fluor, Chlor, Trifluormethyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkyl,
O[CH₂)x-CfH(2f+1-g)Fg bedeuten,
R⁵ Wasserstoff oder (C₁-C₆)-Alkyl bedeutet und
f 1 bis 4,
g 0,1 bis (2f+1),
x 0 und 1 bedeuten und
deren physiologisch wirksamen Salze, wobei N-((6,7-Dichlor-3,4-dihydro-3-oxo-
2-chinoxalinyl)carbonyl)glycin und α-((6,7-Dichlor-3,4-dihydro-3-oxo-2-
chinoxalinyl)carbonyl)amino)phenylessigsäure ausgenommen sind.Compounds of the formula I in which
QO,
XO,
A is a -CH₂ group and,
B means CO₂H, and
R¹ and R⁴ are identical or different and are hydrogen, fluorine, chlorine and (C₁-C₄) alkyl,
R² and R³ are the same or different and are hydrogen, fluorine, chlorine, (C₁-C₁₂) alkoxy, (C₃-C₇) cycloalkoxy, -O- [CH₂] x -C f H (2f + 1-g) F g , (C₁-C₄) alkyl, benzyloxy, optionally substituted with up to 3 substituents from the series fluorine, chlorine, trifluoromethyl, (C₁-C₆) alkoxy, (C₁-C₆) alkyl, O [CH₂) x -C f H (2f + 1-g) F g mean
R⁵ is hydrogen or (C₁-C₆) alkyl and
f 1 to 4,
g 0.1 to (2f + 1),
x mean 0 and 1 and
their physiologically active salts, where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7-dichloro-3,4-dihydro- 3-oxo-2-quinoxalinyl) carbonyl) amino) phenylacetic acid are excluded.
Die Erfindung umfaßt weiterhin Prodrugs zu den Verbindungen der Formel (I), die eine Hemmung der Kollagenbiosynthese in vivo durch Freisetzung von Verbindungen der Formel I oder deren Salzen bewirken.The invention further comprises prodrugs for the compounds of the formula (I) which inhibit collagen biosynthesis in vivo by releasing Effect compounds of formula I or their salts.
Schließlich umfaßt die Erfindung auch Prodrugs, die in vivo durch Freisetzung von Verbindungen der Formel I oder deren Salzen eine inhibitorische Wirkung auf die Prolyl-4-hydroxylase bewirken.Finally, the invention also encompasses prodrugs released in vivo of compounds of formula I or their salts have an inhibitory effect on the prolyl 4-hydroxylase.
Prodrug-Gruppierungen sind chemische Gruppen, die in vivoProdrug groupings are chemical groups that are in vivo
- - zur Carboxylatgruppe der Verbindungen der Formel I umgewandelt werden und/oder- Converted to the carboxylate group of the compounds of formula I. be and / or
- - vom Amid-N-Atom abgespalten werden können und/oder- Can be split off from the amide N atom and / or
- - zu einem Pyridinring umgewandelt werden können.- Can be converted to a pyridine ring.
Die in Betracht kommenden Prodrug-Gruppen sind dem Fachmann bekannt.The prodrug groups in question are known to the person skilled in the art.
Insbesondere sind folgende Prodrug-Gruppierungen genannt:
für die Carboxylatgruppe Ester-, Amid-, Hydroxymethyl- und Aldehydgruppen
und deren Abkömmlinge für das Pyridin-N-Atom N-Oxide und N-Alkylderivate
und für den Pyridinring 1,4-Dihydropyridin-Derivate.
The following prodrug groups are mentioned in particular:
for the carboxylate group ester, amide, hydroxymethyl and aldehyde groups and their derivatives for the pyridine N atom, N-oxides and N-alkyl derivatives and for the pyridine ring 1,4-dihydropyridine derivatives.
Die Erfindung betrifft die Verwendung von Verbindungen der allgemeinen Formel I sowie die physiologisch verträglichen Salze zur Inhibierung der Kollagenbiosynthese.The invention relates to the use of compounds of the general formula I and the physiologically tolerable salts for inhibiting the Collagen biosynthesis.
Die Erfindung betrifft die Verwendung von Verbindungen der allgemeinen Formel I sowie die physiologisch verträglichen Salze zur Hemmung der Prolyl-4- hydroxylase.The invention relates to the use of compounds of the general formula I and the physiologically tolerable salts for inhibiting prolyl-4 hydroxylase.
Weiterhin betrifft die Erfindung die Verwendung von Verbindungen der allgemeinen Formel I sowie die physiologisch verträglichen Salze zur Herstellung eines Arzneimittels gegen fibrotische Erkrankungen.The invention further relates to the use of compounds of general formula I and the physiologically tolerable salts for the preparation a medicine for fibrotic diseases.
Weiterhin betrifft die Erfindung die Verwendung von Verbindungen der allgemeinen Formel I sowie die physiologisch verträglichen Salze zur Herstellung eines Arzneimittels gegen fibrotische Erkrankungen der Leber, der Lunge und der Haut.The invention further relates to the use of compounds of general formula I and the physiologically tolerable salts for the preparation a medicine for fibrotic diseases of the liver, lungs and Skin.
Schließlich betrifft die Erfindung die Verbindungen der allgemeinen Formel I zur Verwendung als Arzneimittel.Finally, the invention relates to the compounds of general formula I for Use as a medicine.
Insbesondere betrifft die Erfindung die Verbindungen der Formel I zur Anwendung als Fibrosuppressiva.In particular, the invention relates to the compounds of formula I for Use as a fibrosuppressant.
Weiterhin betrifft die Erfindung ein Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I.The invention further relates to a method for producing compounds of the general formula I.
Die Herstellung der Verbindungen der Formel I, in denen A einen Alkylenteil,
B = CO₂H und X = 0 bedeutet erfolgt wie in Schema I veranschaulicht:
3,4-Dihydro-3-oxo-chinoxalin-2-carbon-säureester der Formel 5 werden erhalten,
indemThe compounds of the formula I in which A is an alkylene part, B = CO₂H and X = 0 are prepared as illustrated in Scheme I:
3,4-Dihydro-3-oxo-quinoxaline-2-carboxylic acid esters of the formula 5 are obtained by
- i1) substituierte o-Phenylendiamine der Formel 4 mit Mesoxalsäureestern der Formel 2 oderi1) substituted o-phenylenediamines of the formula 4 with mesoxalic acid esters of Formula 2 or
- i2) substituierte 2-Nitroaniline der Formel 1 mit Mesoxalsäureestern der Formel 2 zu den Iminen der Formel 3 umgesetzt werden, die bei der anschließenden Reduktion der Nitrogruppe unter den Reaktionsbedingungen zu den Verbindungen der Formel 5 ringschließen; undi2) substituted 2-nitroanilines of formula 1 with mesoxalic acid esters of Formula 2 are implemented to the imines of formula 3, which in the subsequent reduction of the nitro group among the Ring reaction conditions to the compounds of formula 5; and
- ii1) die Verbindungen der Formel 5 verseift werden zu Verbindungen der Formel 7, wobei R⁵ = H gilt, oderii1) the compounds of the formula 5 are saponified to give the compounds Formula 7, where R⁵ = H, or
- ii2) die Verbindungen der Formel 5 halogeniert werden z. B. mit SOCl₂ oder (COCl)₂ und anschließend umgesetzt werden zu Verbindungen der Formel 7, wobei R⁵, die Bedeutung gemäß der Ansprüche außer H hat, undii2) the compounds of formula 5 are halogenated z. B. with SOCl₂ or (COCl) ₂ and then reacted to compounds of the formula 7, wherein R⁵ has the meaning according to the claims except H, and
- iii) die Verbindungen der Formel 7 mit den Aminoestern der Formel 8 zu Verbindungen der Formel 9 umgesetzt werden, wobei anschließend ggf.iii) the compounds of formula 7 with the amino esters of formula 8 Compounds of formula 9 are reacted, with subsequent
- iv1) eine Verseifung zu Verbindungen der Formel I und/oderiv1) saponification to give compounds of the formula I and / or
- iv2) die Salzbildung in den physiologisch wirksamen Salzen mit N-((6,7- Dichlor-3,4-dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α-((6,7- Dichlor-3,4-dihydro-3-oxo-2-chinoxalinyl)carbonyl)amino)phenylessigs-äure erfolgt.iv2) the salt formation in the physiologically active salts with N - ((6,7- Dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7- Dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) amino) phenylacetic acid he follows.
Die substituierten 2-Nitroaniline der Formel 1 sind beispielsweise aus EP-A-0 166 287 bekannt. The substituted 2-nitroanilines of the formula 1 are, for example, from EP-A-0 166 287 known.
Geeignete Verfahren zur Amidbildung sind die Methoden der Carboxylaktivierung (iii) und die aus der Peptidchemie bekannten Kondensationsreaktionen.Suitable methods for amide formation are the methods of carboxy activation (iii) and the condensation reactions known from peptide chemistry.
An Reagenzien zur Carbonsäureaktivierung können die dem Fachmann bekannten Substanzen, wie Thionylchlorid, Oxalylchlorid, Pivaloylchlorid, Chlorameisensäureester-Derivate oder N,N′-Carbonyldimidazol Verwendung finden. Die aktivierten Derivate der Verbindungen der Formel II werden nach Herstellung in situ mit den Amidderivaten der Formel III umgesetzt.The person skilled in the art can use reagents for carboxylic acid activation known substances, such as thionyl chloride, oxalyl chloride, pivaloyl chloride, Chloroformic acid ester derivatives or N, N'-carbonyldimidazole use Find. The activated derivatives of the compounds of formula II are after Production implemented in situ with the amide derivatives of the formula III.
Ein geeignetes Kondensationsmittel ist beispielsweise die Kombination von N,N′-Dicyclohexylcarbodiimid/N-Hydroxy-1H-benzotriazol, N-Ethylmorpholin und N-Cyclohexyl-N′-(2-morpholinoethyl)carbodiimid-methyl-p-toluol-sulfo-nat (CMC).A suitable condensing agent is, for example, the combination of N, N'-dicyclohexylcarbodiimide / N-hydroxy-1H-benzotriazole, N-ethylmorpholine and N-Cyclohexyl-N '- (2-morpholinoethyl) carbodiimide-methyl-p-toluenesulfonate (CMC).
Geeignete Lösungsmittel sind Dichlormethan, Tetrachlormethan, Butylacetat, Ethylacetat, Toluol, Tetrahydrofuran, Dimethoxyethan, 1,4-Dioxan, Acetonitril, N,N-Dimethylformamid, N,N-Dimethylacetamid, Dimethylsulfoxid, Nitromethan und/oder Pyridin.Suitable solvents are dichloromethane, carbon tetrachloride, butyl acetate, Ethyl acetate, toluene, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, nitromethane and / or pyridine.
Die Verbindungen der Formel I sind Inhibitoren der Prolyl-4-hydroxylase. Die Hemmung dieses Enzyms wurde, wie von Kaule und Günzler in Annal. Biochem. 184, 291 bis 297 (1990) beschrieben, bestimmt.The compounds of formula I are inhibitors of prolyl 4-hydroxylase. The Inhibition of this enzyme has been described by Kaule and Günzler in Annal. Biochem. 184, 291 to 297 (1990).
Die erfindungsgemäßen Verbindungen der Formel I besitzen wertvolle pharmakologische Eigenschaften und zeigen insbesondere antifibrotische Wirksamkeit.The compounds of formula I according to the invention have valuable pharmacological properties and in particular show antifibrotic Effectiveness.
Die antifibrotische Wirkung kann im Modell der Tetrachlorkohlenstoff-induzierten Leberfibrose bestimmt werden. Dazu werden Ratten mit CCl₄ (1 ml/kg) - gelöst in Olivenöl - zweimal wöchentlich behandelt. Die Prüfsubstanz wird täglich, gegebenenfalls sogar zweimal täglich per os oder intraperitoneal - gelöst in einem geeigneten verträglichen Lösungsmittel - verabreicht. Das Ausmaß der Leberfibrose wird histologisch bestimmt und der Anteil Kollagen in der Leber per Hydroxyprolinbestimmung - wie bei Kivirikko et al. (Anal. Biochem. 19, 249 f. (1967)) beschrieben - analysiert. Die Aktivität der Fibrogenese kann durch radioimmunologische Bestimmung von Kollagenfragmenten und Prokollagenpeptiden im Serum bestimmt werden. Die erfindungsgemäßen Verbindungen sind in diesem Modell in Konzentrationen von 1 bis 100 mg/kg wirksam.The antifibrotic effect can be induced in the carbon tetrachloride model Liver fibrosis can be determined. For this, rats are dissolved with CCl₄ (1 ml / kg) in olive oil - treated twice a week. The test substance is possibly even twice a day by os or intraperitoneally - dissolved in a suitable compatible solvent. The extent of Liver fibrosis is determined histologically and the percentage of collagen in the liver per Hydroxyproline determination - as in Kivirikko et al. (Anal. Biochem. 19, 249 f. (1967)) - analyzed. The activity of fibrogenesis can be caused by radioimmunological determination of collagen fragments and Procollagen peptides can be determined in serum. The invention Compounds are in this model in concentrations of 1 to 100 mg / kg effective.
Die Aktivität der Fibrogenese kann durch radioimmunologische Bestimmung des N-terminalen Propeptids des Kollagen Typ-III oder der N- bzw. C-terminalen Quervernetzungsdomäne des Kollagen-Typ-IV (7s-Kollagen bzw. Typ-IV-Kollagen NC₁) im Serum bestimmt werden.The activity of fibrogenesis can be determined by radioimmunological determination of the N-terminal propeptide of type III collagen or the N- or C-terminal Cross-linking domain of collagen type IV (7s collagen or type IV collagen NC₁) can be determined in the serum.
Zu diesem Zweck wurden die Hydroxyprolin-, Prokollagen-III-Peptid-, 7s-Kollagen- und Typ-IV-Kollagen-NC-Konzentrationen in der Leber vonFor this purpose the hydroxyproline, procollagen III peptide, 7s collagen and type IV collagen NC concentrations in the liver of
- a) unbehandelten Ratten (Kontrolle)a) untreated rats (control)
- b) Ratten, denen Tetrachlorkohlenstoff verabreicht wurden (CCl₄-Kontrolle)b) rats to which carbon tetrachloride was administered (CCl₄ control)
- c) Ratten, denen zunächst CCl₄ und anschließend eine erfindungsgemäße Verbindung verabreicht wurdec) rats, which first CCl₄ and then an inventive Compound was administered
gemessen (diese Testmethode wird beschrieben von Rouiller, C., experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, 5. 335 bis 476, New York, Academic Press, 1964).measured (this test method is described by Rouiller, C., experimental toxic injury of the liver; in The Liver, C. Rouiller, Vol. 2, 5, 335 to 476, New York, Academic Press, 1964).
Weiterhin kann eine Wirksamkeit der erfindungsgemäßen Verbindungen in folgenden Systemen nachgewiesen werden.Furthermore, the compounds according to the invention can be effective in following systems can be demonstrated.
Hemmung der hepatischen Prolyl-4-hydroxylase in vivo:
Dieses Modell dient zum Nachweis der akuten Hemmung der Prolyl-4-
hydroxylase in vivo. Dazu werden Ratten beiderlei Geschlechts (gesund bzw.
mit induzierter Leberfibrose) die Prüfsubstanz bzw. das entsprechende Vehikel
appliziert (intraperitoneal, intravenös, per os) und nach Substanzgabe
¹⁴C-L-Prolin (250 µCi/kg Körpergewicht) intraperitoneal verabreicht. Danach
erfolgt erneut eine intraperitoneale Applikation von ¹⁴C-L-Prolin (250 µCi/kg
Körpergewicht). Schließlich werden die Tiere unter Pentobarbitalnarkose
entblutet und die Leber entnommen. Die Aufreinigung des hepatischen Kollagens
durch Pepsinverdau und fraktionierte Ammoniumsulfatfällung erfolgte
entsprechend publizierten Protokollen (Ref. 1, 2). Das gereinigte Leberkollagen
wurde hydrolysiert und der Gehalt an ¹⁴C-Hydroxyprolin und ¹⁴C-Prolin durch
Aminosäureanalyse mittels Ionenaustauschchromatografie bestimmt. Eine
Hemmung der Prolyl-4-hydroxylase ergibt sich aus einer Absenkung des
Quotienten ¹⁴C-Hydroxyprolin/[¹⁴C-Hydroxyprolin + ¹⁴C-Prolin]. Als
Referenzsubstanz wird 2,2′-Dipyridyl verwendet. (1: Chojkier, M. 1986.
Hepatocyte collagen production in vivo in normal rats. J. Clin. Invest. 78 : 333-
339 und 2: Ogata I., et al. 1991. Minor contribution of hepatocytes of
hepatocytes to collagen production in normal and early fibrotic livers.
Hepatology 14 : 361-367).Inhibition of hepatic prolyl 4-hydroxylase in vivo:
This model serves to demonstrate the acute inhibition of prolyl 4-hydroxylase in vivo. For this purpose, rats of both sexes (healthy or with induced liver fibrosis) are administered the test substance or the corresponding vehicle (intraperitoneally, intravenously, per os) and administered intraperitoneally after administration of substance ¹⁴C-L-proline (250 µCi / kg body weight). Then an intraperitoneal application of ¹⁴C-L-proline (250 µCi / kg body weight) again. Finally, the animals are bled under pentobarbital anesthesia and the liver removed. The hepatic collagen was purified by pepsin digestion and fractionated ammonium sulfate precipitation in accordance with published protocols (Ref. 1, 2). The purified liver collagen was hydrolyzed and the content of ¹⁴C-hydroxyproline and ¹⁴C-proline was determined by amino acid analysis using ion exchange chromatography. An inhibition of prolyl-4-hydroxylase results from a lowering of the quotient ¹⁴C-hydroxyproline / [¹⁴C-hydroxyproline + ¹⁴C-proline]. 2,2'-Dipyridyl is used as the reference substance. (1: Chojkier, M. 1986. Hepatocyte collagen production in vivo in normal rats. J. Clin. Invest. 78: 333-339 and 2: Ogata I., et al. 1991. Minor contribution of hepatocytes of hepatocytes to collagen production in normal and early fibrotic livers. Hepatology 14: 361-367).
Hemmung der Prnlyl-4-hydroxylase in Zellkulturen:
Für die Testung von Prolyl-4-hydroxylasehemmstoffen in Zellkulturen werden
folgende Zelltypen verwendet:
Normale humane Hautfibrolasten (Normal human fibrolasts, NHDF), Rattenleber-
Epithelzellen (rat liver epithelial cells, Ref. 1) und primäre Fettspeicherzellen aus
der Rattenleber (fat storing cells, Ref. 2). Dazu werden die Zellen in Gegenwart
von Hemmstoffen kultiviert. Gleichzeitig wird das in dieser Zeit neu
synthetisierte Kollagen durch 4-³H-L-Prolin und ¹⁴C-Prolin metabolisch markiert.
Der Einfluß der Testsubstanzen auf den Hydroxylierungsgrad des Kollagens wird
anschließend entsprechend der Methode von Chojkier et al (Ref. 3) bestimmt.
Als Referenzsubstanz wird 2,2′-Dipyridyl eingesetzt. (1.: Schrode, W., Mecke,
D., Gebhard, R. 1990. Induction of glutamine synthetase in periportal
hepatocytes by co-cultivation with a liver epithelial cell line. Eur. J. Cell. Biol.
53 : 35-41, 2. Blomhoff, R., Berg T. 1990. Isolation and cultivation of rat liver
stellate cells. Methods Enzymol. 190 : 59-71 und 3.: Chojkier, M. Peterkofsky,
B. Bateman,, J. 1980. A new method for determining the extent of proline
hydroxylation by measuring changes in the ration of [4-³H] : [¹⁴C] proline in
collagenase digests. Anal. Biochem. 108: 385-393).Inhibition of Prnlyl-4-hydroxylase in cell cultures:
The following cell types are used for testing prolyl-4-hydroxylase inhibitors in cell cultures:
Normal human skin fibrolasts (NHDF), rat liver epithelial cells (ref. 1) and primary fat storage cells from the rat liver (fat storing cells, ref. 2). For this purpose, the cells are cultivated in the presence of inhibitors. At the same time, the collagen newly synthesized during this time is metabolically marked by 4-³H-L-proline and ¹⁴C-proline. The influence of the test substances on the degree of hydroxylation of the collagen is then determined according to the method of Chojkier et al (Ref. 3). 2,2'-Dipyridyl is used as the reference substance. (1 .: Schrode, W., Mecke, D., Gebhard, R. 1990. Induction of glutamine synthetase in periportal hepatocytes by co-cultivation with a liver epithelial cell line. Eur. J. Cell. Biol. 53: 35- 41, 2. Blomhoff, R., Berg T. 1990. Isolation and cultivation of rat liver stellate cells. Methods Enzymol. 190: 59-71 and 3 .: Chojkier, M. Peterkofsky, B. Bateman, J. 1980. A new method for determining the extent of proline hydroxylation by measuring changes in the ration of [4-³H]: [¹⁴C] proline in collagenase digests. Anal. Biochem. 108: 385-393).
Die Verbindungen der Formel I können als Medikamente in Form von pharmazeutischer Präparate Verwendung finden, welche sie gegebenenfalls mit verträglichen pharmazeutischen Trägern enthalten. Die Verbindungen können als Heilmittel, z. B. in Form pharmazeutischer Präparate Verwendung finden, welche diese Verbindungen in Mischung mit einem für die enterale, perkutane oder parenterale Applikation geeigneten pharmazeutischen, organischen oder anorganischen Träger, wie z. B. Wasser, Gummi arabicum, Gelatine, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Polyalkylenglykole, Vaseline usw. enthalten.The compounds of formula I can be used as drugs in the form of pharmaceutical preparations are used, which they may be used with compatible pharmaceutical carriers. The connections can be made as Remedies, e.g. B. find use in the form of pharmaceutical preparations these compounds mixed with one for enteral, percutaneous or parenteral application of suitable pharmaceutical, organic or inorganic carriers, such as. B. water, gum arabic, gelatin, Milk sugar, starch, magnesium stearate, talc, vegetable oils, Contain polyalkylene glycols, petroleum jelly, etc.
Sie können zu diesem Zweck oral in Dosen von 0,1 bis 25 mg/kg/Tag, vorzugsweise 1 bis 5 mg/kg/Tag oder parenteral in Dosen von 0,01 bis 5 mg/kg/Tag, vorzugsweise 0,01 bis 2,5 mg/kg/Tag, insbesondere 0,5 bis 1,0 mg/kg/Tag, appliziert werden. Die Dosierung kann in schweren Fällen auch erhöht werden. In vielen Fällen genügen jedoch auch geringere Dosen. Diese Angaben beziehen sich auf einen Erwachsenen von etwa 75 kg Gewicht.For this purpose you can take orally in doses of 0.1 to 25 mg / kg / day, preferably 1 to 5 mg / kg / day or parenterally in doses of 0.01 to 5 mg / kg / day, preferably 0.01 to 2.5 mg / kg / day, in particular 0.5 to 1.0 mg / kg / day. The dosage can also be severe increase. In many cases, however, lower doses are sufficient. These Figures refer to an adult weighing approximately 75 kg.
Verbindungen der Formel I sind als substituierte N-(Chinoxalinyl-2- carbonyl)glycine klassifiziert.Compounds of the formula I are substituted N- (quinoxalinyl-2- classified carbonyl) glycine.
Unter dieser Bezeichnungsweise werden substituierte Chinoxalin-2-carbonsäure- N-(carboxymethyl)amide verstanden.Substituted quinoxaline-2-carboxylic acid Understand N- (carboxymethyl) amides.
-
a) N-((3,4-Dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycinethylester
4,8 g (25 mmol) 3-Hydroxychinoxalin-2-carbonsäure wurden in 500 ml wasserfreiem Dichlormethan suspendiert und bei 20°C unter Rühren nacheinander mit 3,5 g (25 mmol) Glycinethylester-Hydrochlorid, 7,2 ml (55 mmol) N-Ethylmorpholin, 3,6 g (27 mmol) 1-Hydroxy-1-H-benzotriazol und 11,4 g (27 mmol) N-Cyclohexyl-N′-(2-morpholinoethyl)-carbodiimid-methyl-p- toluolsulfonat (Abkürzung CMC) versetzt und 20 h bei Raumtemperatur gerührt. Dann wurde vom Ungelösten abfiltriert, die organische Phase je 1 mol mit gesättigter wäßriger HCl und mit Wasser ausgeschüttelt, über Magnesiumsulfat getrocknet, i.Vak. eingeengt und der Rückstand mit Diethylether zur Kristallisation gebracht. Man erhielt 1,4 g Produkt, Fp. 224-227°C.a) N - ((3,4-Dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine ethyl ester
4.8 g (25 mmol) of 3-hydroxyquinoxaline-2-carboxylic acid were suspended in 500 ml of anhydrous dichloromethane and successively at 20 ° C. with 3.5 g (25 mmol) of glycine ethyl ester hydrochloride, 7.2 ml (55 mmol ) N-ethylmorpholine, 3.6 g (27 mmol) of 1-hydroxy-1-H-benzotriazole and 11.4 g (27 mmol) of N-cyclohexyl-N ′ - (2-morpholinoethyl) carbodiimide-methyl-p- toluenesulfonate (abbreviation CMC) and stirred for 20 h at room temperature. The undissolved material was then filtered off, the organic phase was shaken out in each case with 1 mol of saturated aqueous HCl and with water, dried over magnesium sulfate, in vacuo. concentrated and the residue brought to crystallization with diethyl ether. 1.4 g of product were obtained, mp. 224-227 ° C. - b) Die Titelverbindung wurde erhalten, indem 0,69 g (25 mmol) der vorstehenden Verbindung bei 20°C unter Rühren in eine Mischung von 0,12 g (5 mmol) LiOH in 40 ml Methanol/Wasser (3 : 1) eingetragen wurden. Nach 1 h wurde i.Vak. eingeengt, der Rückstand in 60 ml Wasser gelöst, 1× mit Dichlormethan extrahiert, die wäßrige Phase mit konz. wäßriger HCl auf pH 1 gebracht. Das ausgefallene Produkt wurde abgesaugt, mit Wasser gewaschen und getrocknet. Man erhielt 0,5 g, Fp. 283-285°C.b) The title compound was obtained by adding 0.69 g (25 mmol) of the the above compound at 20 ° C with stirring in a mixture of 0.12 g (5 mmol) LiOH in 40 ml methanol / water (3: 1) were added. After 1 h became i.Vak. concentrated, the residue dissolved in 60 ml of water, 1 × with Extracted dichloromethane, the aqueous phase with conc. aqueous HCl to pH 1 brought. The precipitated product was filtered off, washed with water and dried. 0.5 g, mp. 283-285 ° C. was obtained.
- a) 3-Chlorchinoxalin-2-carbonsäurechlorid wurde aus 3-Hydroxychinoxalin-2- carbonsäure mit SOCl₂/katalytische Menge DMF erhalten, Fp. 125°C aus Diethylether. a) 3-chloroquinoxaline-2-carboxylic acid chloride was obtained from 3-hydroxyquinoxaline-2 carboxylic acid with SOCl₂ / catalytic amount of DMF obtained, mp. 125 ° C. Diethyl ether.
- b) 3-Methoxychinoxalin-2-carbonsäure durch Reaktion mit Na-methylat in Methanol und Verseifung mit 1,5 N methanolischer NaOH. Fp. 128-130°C aus wäßriger Salzsäure).b) 3-methoxyquinoxaline-2-carboxylic acid by reaction with Na methylate in Methanol and saponification with 1.5 N methanolic NaOH. Mp 128-130 ° C aqueous hydrochloric acid).
-
c) N-((3-Methoxy-2-chinoxalinyl)carbonyl)glycinethylester
2,0 g (10 mmol) 3-Methoxychinoxalin-2-carbonsäure wurden analog Beispiel 1a) mit Glycinethylester kondensiert. Man erhielt 1,9 g Produkt, Fp. 113- 115°C (aus Diisopropylether).c) N - ((3-methoxy-2-quinoxalinyl) carbonyl) glycine ethyl ester
2.0 g (10 mmol) of 3-methoxyquinoxaline-2-carboxylic acid were condensed with glycine ethyl ester analogously to Example 1a). 1.9 g of product were obtained, mp 113-115 ° C. (from diisopropyl ether). - d) Die Titelverbindung wurde erhalten, indem 0,8 g des vorstehenden Esters mit 1,5 N methanolischer NaOH verseift wurden. Man erhielt nach Ansäuern mit wäßriger Salzsäure und Einengen 0,27 g Produkt, Fp. 199-201°C.d) The title compound was obtained by 0.8 g of the above ester were saponified with 1.5 N methanolic NaOH. One obtained after acidification aqueous hydrochloric acid and concentration 0.27 g of product, mp. 199-201 ° C.
- a) 3-Ethoxy-2-chinoxalin-2-carbonsäure wurde aus 3-Chlorchinoxalin-2- carbonsäureethylester und ethanolischer Na-ethanolat Lösung und anschließender Esterverseifung erhalten, Fp. 119-120°C (aus wäßriger Salzsäure).a) 3-ethoxy-2-quinoxaline-2-carboxylic acid was obtained from 3-chloroquinoxaline-2- carboxylic acid ethyl ester and ethanolic Na ethanolate solution and subsequent ester hydrolysis obtained, mp. 119-120 ° C (from aqueous Hydrochloric acid).
- b) N-((3-Ethoxy-2-chinoxalinyl)carbonyl)glycinethylester 2,2 g (10 mmol) der vorstehenden Carbonsäure wurden analog Beispiel 1a) mit Glycinethylester-Hydrochlorid kondensiert. Man erhielt 1,9 g Produkt, Fp. 126-127°C (aus Diisopropylether).b) N - ((3-Ethoxy-2-quinoxalinyl) carbonyl) glycine ethyl ester 2.2 g (10 mmol) of the above carboxylic acid were added as in Example 1a) Glycine ethyl ester hydrochloride condensed. 1.9 g of product, mp. 126-127 ° C (from diisopropyl ether).
- c) Die Titelverbindung wurde aus 0,5 g des vorstehenden Esters durch Verseifung mit 1 ,5 N ethanolischer Natronlauge erhalten. Man isolierte 0,37 g aus wäßriger Salzsäure (pH 2-3), Fp. 198-200°C.c) The title compound was obtained from 0.5 g of the above ester Saponification obtained with 1.5 N ethanolic sodium hydroxide solution. 0.37 g was isolated from aqueous hydrochloric acid (pH 2-3), mp. 198-200 ° C.
-
a) 6-Methoxy-3,4-dihydro-3-oxo-chinoxalin-2-carbonsäureethylester
12 g (71,4 mmol) 4-Methoxy-2-nitroanilin wurden in 250 Toluol gelöst, mit 12,5 g (11 ml, 72 mmol) Mesoxalsäurediethylester und mit einer Spatelspitze p- TosOH versetzt und 2 h am Wasserabscheider erhitzt. Nach dem Abkühlen wurde mit gesättigter wäßriger Na-Bicarbonat extrahiert, getrocknet, im Vakuum eingeengt, der Rückstand in Ethanol gelöst und mit Raney-Nickel in der Schüttelente hydriert (H₂-Aufnahme: 4,9 l). Dann wurde vom Katalysator abgesaugt, das Filtrat im Vakuum auf 100 ml eingeengt und 2,6 g Produkt erhalten, Fp. 220-222°C. Aus dem Filtrat erhielt man durch Behandeln des Rückstandes mit Ethylacetat weitere 4 g Produkt, Fp. 218-220°C.a) 6-Methoxy-3,4-dihydro-3-oxo-quinoxaline-2-carboxylic acid ethyl ester
12 g (71.4 mmol) of 4-methoxy-2-nitroaniline were dissolved in 250 toluene, 12.5 g (11 ml, 72 mmol) of diethyl mesoxalate and a spatula tip of p-TosOH were added and the mixture was heated for 2 hours on a water separator. After cooling, the mixture was extracted with saturated aqueous Na bicarbonate, dried, concentrated in vacuo, the residue was dissolved in ethanol and hydrogenated with Raney nickel in the shaking duck (H₂ uptake: 4.9 l). The catalyst was then filtered off with suction, the filtrate was concentrated to 100 ml in vacuo and 2.6 g of product were obtained, mp. 220-222 ° C. A further 4 g of product, mp 218-220 ° C., were obtained from the filtrate by treating the residue with ethyl acetate. -
b) 6-Methoxy-3,4-dihydro-3-oxo-chinaxolin-2-carbonsäure
2,6 g des vorstehenden Esters wurden mit 150 ml 1,5 N methanolischer Natronlauge (Man versetzte mit 100 ml Tetrahydrofuran und Wasser, bis eine klare Lösung entstand) verseift. Man erhielt 2,66 g Produkt aus wäßriger Salzsäure, Fp. 239-241°C (unter Gasentwicklung).b) 6-methoxy-3,4-dihydro-3-oxo-quinaxoline-2-carboxylic acid
2.6 g of the above ester were saponified with 150 ml of 1.5 N methanolic sodium hydroxide solution (100 ml of tetrahydrofuran and water were added until a clear solution formed). 2.66 g of product were obtained from aqueous hydrochloric acid, mp. 239-241 ° C. (with evolution of gas). -
c) N-((6-Methoxy-3,4-dihydro-3-oxo-chinoxalinyl)carbonyl)glycinoctylest-er
2,2 g (10 mmol) der vorstehenden Carbonsäure wurden analog Beispiel 1a) mit Hilfe von 3,75 ml (30 mmol) N-Ethylmorpholin, 1,8 g (12 mmol) 1-Hydroxy-1H- benzotriazol und 4,2 g (10 mmol) CMC mit 3,6 g (10 mmol) Glycin-octylester- Tosylat kondensiert. Nach Aufarbeitung (Beispiel 1a)) erhielt man durch Kristallisation mit Diethylether 2,2 g Produkt, Fp. 203-206°C (sintern bei 190°C).c) N - ((6-methoxy-3,4-dihydro-3-oxo-quinoxalinyl) carbonyl) glycinoctyl ester
2.2 g (10 mmol) of the above carboxylic acid were analogous to Example 1a) using 3.75 ml (30 mmol) of N-ethylmorpholine, 1.8 g (12 mmol) of 1-hydroxy-1H-benzotriazole and 4.2 g (10 mmol) CMC condensed with 3.6 g (10 mmol) glycine octyl ester tosylate. After working up (Example 1a)), 2.2 g of product, mp 203-206 ° C. (sintering at 190 ° C.) was obtained by crystallization with diethyl ether. - d) Die Titelverbindung wurde erhalten, indem 0,58 g (15 mmol) des obigen Esters mit 1,5 N methanolischer Natronlauge (Wasserzugabe bis zur klaren Lösung) verseift wurden. Nach dem Einengen wurde der Rückstand in Wasser gelöst und mit konz. wäßriger HCl auf pH 1 gebracht. Man isolierte 0,35 g der Titelverbindung, Fp. 310°C (unter Zersetzung).d) The title compound was obtained by adding 0.58 g (15 mmol) of the above Ester with 1.5 N methanolic sodium hydroxide solution (water until clear Solution) were saponified. After concentration, the residue was in water solved and with conc. aqueous HCl brought to pH 1. 0.35 g of the was isolated Title compound, mp. 310 ° C (with decomposition).
- a) 7-Methoxy-3,4-dihydro-3-oxo-chinoxalin-2-carbonsäureethylester, Fp. 167-168°C (aus Diisopropylether).a) ethyl 7-methoxy-3,4-dihydro-3-oxo-quinoxaline-2-carboxylate, Mp 167-168 ° C (from diisopropyl ether).
- b) 7-Methoxy-3,4-dihydro-3-oxo-chinoxalin-2-carbonsäure, Fp. 222-223°C (unter Zersetzg., aus wäßriger Salzsäure).b) 7-methoxy-3,4-dihydro-3-oxo-quinoxaline-2-carboxylic acid, Mp 222-223 ° C (with decomposition, from aqueous hydrochloric acid).
- c) N-((7-Methoxy-3,4-dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycinethyle-ster, Fp. 233-234°C (aus Diisopropylether).c) N - ((7-methoxy-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine ethyl ester, Mp 233-234 ° C (from diisopropyl ether).
- d) Die Titelverbindung wurde nach alkalischer Verseifung des vorstehenden Esters (350 mg) aus wäßriger Salzsäure erhalten, Ausbeute 340 mg, Fp. 292°C (unter Zersetzung).d) The title compound was obtained after alkaline saponification of the above Ester (350 mg) obtained from aqueous hydrochloric acid, yield 340 mg, mp. 292 ° C. (with decomposition).
- a) 3-Chlor-7-methoxychinoxalin-2-carbonsäureethylestera) Ethyl 3-chloro-7-methoxyquinoxaline-2-carboxylate
- b) 3-Ethoxy-7-methoxychinoxalin-2-carbonsäure, Fp. 156-158°C (aus wäßriger Salzsäure)b) 3-ethoxy-7-methoxyquinoxaline-2-carboxylic acid, Mp 156-158 ° C (from aqueous hydrochloric acid)
- c) N-((3-Ethoxy-7-methoxy-2-chinoxalinyl)carbonyl)glycinethylester, Fp. 131-132°C (aus Diisopropylether) c) N - ((3-ethoxy-7-methoxy-2-quinoxalinyl) carbonyl) glycine ethyl ester, Mp 131-132 ° C (from diisopropyl ether)
- d) 0,8 g des vorstehenden Esters wurden mit 1,5 N ethanolischer NaOH verseift. Man erhielt 0,7 g der Titelverbindung, Fp. 203-204°C (aus wäßriger Salzsäure, dann mit Dichlormethan behandelt).d) 0.8 g of the above ester was treated with 1.5 N ethanolic NaOH saponified. 0.7 g of the title compound, mp. 203-204 ° C. (from aqueous Hydrochloric acid, then treated with dichloromethane).
Analog Beispiel 4 wurden die folgenden Verbindungen hergestellt:The following compounds were prepared analogously to Example 4:
Claims (16)
Q O oder S,
X O und S,
A (C₁-C₄)-Alkylen, das gegebenenfalls substituiert ist mit einem oder zwei Substituenten aus der Reihe Halogen, Cyano, Nitro, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Hydroxyalkyl, (C₁-C₆)-Alkoxy, -O-[CH₂]x-CfH(2f+1-g)Halg, vorzugsweise (C₁-C₈)-Fluoralkoxy, (C₁-C₈)- Fluoralkenyloxy, (C₁-C₈)-Fluoralkinyloxy, -OCF₂Cl oder -O-CF₂-CHFCl, (C₁-C₆)-Alkylmercapto, (C₁-C₆)-Alkylsulfinyl, (C₁-C₆)-Alkylsulfonyl, (C₁-C₆)-Alkylcarbonyl, (C₁-C₆)-Alkoxycarbonyl, Carbamoyl, N-(C₁-C₄)- Alkylcarbamoyl, N,N-Di-(C₁-C₄)-alkylcarbamoyl, (C₁-C₆)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkyl, Phenyl, Benzyl, Phenoxy, Benzyloxy, Anilino, N-Methylanilino, Phenylmercapto, Phenylsulfonyl, Phenylsulfinyl, Sulfamoyl, N-(C₁-C₄)-Alkylsulfamoyl, N,N-Di-(C₁-C₄)-alkylsulfamoyl, oder
mit einem substituierten (C₆-C₁₂)-Aryloxy-, (C₇-C₁₁)-Aralkyloxy, (C₆-C₁₂)- Aryl- oder (C₇-C₁₁)-Aralkyl-Rest, der im Arylteil 1, 2, 3, 4 oder 5 gleiche oder verschiedene Substituenten aus der Reihe Halogen, Cyano, Nitro, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy, -O-[CH₂]x-CfH(2f+1-g)Halg, -OCF₂Cl,-O-CF₂-CHFCl, (C₁-C₆)-Alkylmercapto, (C₁-C₆)-Alkylsulfinyl, (C₁-C₆)-Alkylsulfonyl, (C₁-C₆)-Alkylcarbonyl, (C₁-C₆)-Alkoxycarbonyl, Carbamoyl, N-(C₁-C₄)-Alkylcarbamoyl, N,N-Di-(C₁-C₄)-alkylcarbamoyl, (C₁-C₆)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkyl, Sulfamoyl, N-(C₁-C₄)- Alkylsulfamoyl oder N,N-Di-(C₁-C₄)-alkylsulfamoyl trägt, oder
mit den Substituenten R⁵ des α-C-Atoms einer α-Aminosäure, wobei die natürlichen L-Aminosäuren und ihre D-Isomeren Verwendung finden können;
B eine saure Gruppierung aus der Reihe -CO₂H, -CONHCOR′′′,
-CONHSOR′′′, CONHSO₂R′′′, -NHSO₂CF₃, Tetrazolyl, Imidazolyl oder 3-Hydroxyisoxazolyl bedeutet, wobei R′′′ Aryl, Heteroaryl, (C₃-C₇)- Cycloalkyl oder (C₁-C₄)-Alkyl, gegebenenfalls monosubstituiert mit (C₆-C₁₂)-Aryl, Heteroaryl, OH, SH, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, (C₁-C₄)- Thioalkyl, -Sulfinyl oder -Sulfonyl, CF₃, Cl, Br, F, I, NO₂, -COOH, (C₂-C₅)- Alkoxycarbonyl, NH₂, Mono- oder Di-(C₁-C₄-alkyl)-amino oder (C₁-C₄)- Perfluoroalkyl bedeutet,
R¹, R², R³ und R⁴ gleich oder verschieden sind und Wasserstoff, Hydroxy, Halogen, Cyano, Trifluormethyl, Nitro, Carboxy, (C₁-C₂₀)-Alkyl, (C₃-C₈)- Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁ -C₈)-alkyl- (C₁-C₆)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)- Cycloalkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₈)- alkoxy-(C₁-C₈)-alkoxy, (C₆-C₁₂)-Aryl, (C₇-C₁₆)-Aralkyl, (C₂-C₂₀)-Alkenyl, (C₂-C₂₀)-Alkinyl, (C₁-C₂₀)-Alkoxy, (C₂-C₂₀)-Alkenyloxy, (C₂-C₂₀)- Alkinyloxy, Retinyloxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₁₂)-Alkoxy- (C₁-C₁₂)-alkoxy, (C₁-C₁₂)-Alkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)- Aryloxy, (C₇-C₁₆)-Aralkyloxy, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxy, (C₇-C₁₆)- Aralkoxy-(C₁-C₆)-alkoxy, (C₁-C₈)-Hydroxyalkyl, (C₆-C₁₆)-Aryloxy-(C₁-C₈)- alkyl, (C₇-C₁₆)-Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkoxy- (C₁-C₆)-alkyl, (C₇-C₁₂)-Aralkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₂-C₂₀)- Alkenyloxy-(C₁-C₆)-alkyl, (C₂-C₂₀)-Alkinyloxy (C₁-C₆)-alkyl, Retinyloxy- (C₁-C₆)-alkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂)-Alkylcarbonyl, (C₃-C₈)-Cycloalkylcarbonyl, (C₆-C₁₂)- Arylcarbonyl, (C₇-C₁₆)-Aralkylcarbonyl, Cinnamoyl, (C₂-C₁₂)- Alkenylcarbonyl, (C₂-C₁₂)-Alkinylcarbonyl,
(C₁-C₁₂)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl, (C₆-C₁₂)-Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)- Cycloalkoxycarbonyl, (C₂-C₂₀)-Alkenyloxycarbonyl, Retinyloxycarbonyl, (C₂-C₂₀)-Alkinyloxycarbonyl, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxycarbonyl, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)-Cycloalkyl-(C₁-C₆)- alkoxycarbonyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbonyloxy, (C₆-C₁₂)- Arylcarbonyloxy, (C₇-C₁₆)-Aralkylcarbonyloxy, Cinnamoyloxy, (C₂-C₁₂)- Alkenylcarbonyloxy, (C₂-C₁₂)-Alkinylcarbonyloxy,
(C₁-C₁₂)-Alkoxycarbonyloxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)- alkoxycarbonyloxy, (C₆-C₁₂)-Aryloxycarbonyloxy, (C₇-C₁₆)- Aralkyloxycarbonyloxy, (C₃-C₈)-Cycloalkoxycarbonyloxy, (C₂-C₁₂)- Alkenyloxycarbonyloxy, (C₂-C₁₂)-Alkinyloxycarbonyloxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N,N-Di-(C₁-C₁₂)-alkylcarbamoyl, N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-Cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl- (C₁-C₆)-alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆)- alkyl)carbamoyl, N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+)- dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆) Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁-C₁₀)- Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)- alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy (C₁-C₁₀)-alkyl)carbamoyl, N-((C₇-C₁₆)-Aralkyloxy (C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy (C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, CON(CH₂)h, worin eine CH₂-Gruppe durch O, S, N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄)-Alkoxy- (C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet, oder mit
einem Carbamoyl-Rest der allgemeinen Formel II worin
Rx den Substituenten einer α-Aminosäure bedeutet, zu denen die L- und D-Aminosäuren zählen,
s 1, 2, 3, 4 oder 5 und
T OH, OR oder NR*R** bedeutet, wobei
R*, R** und R*** gleich oder verschieden sind und Wasserstoff (C₆-C₁₂)- Aryl, (C₇-C₁₁)-Aralkyl, (C₁-C₈)-Alkyl, (C₃-C₈)-Cycloalkyl, (+)-Dehydroabietyl, (C₁-C₈)-Alkoxy-(C₁-C₈)-alkyl, (C₇-C₁₂)- Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkyl, (C₁-C₁₀)- Alkanoyl, ggf. substituiertes (C₇-C₁₆)-Aralkanoyl, ggf. substituiertes (C₆-C₁₂)-Aroyl bedeuten, oder
R* und R** gemeinsam für -[CH₂]h stehen, worin eine CH₂ Gruppe durch O, S, SO, SO₂, N-Acylamino, N-(C₁-C₁₀)-Alkoxycarbonylimino, N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)- Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)- Aralkylimino oder N-(C₁-C₄)-Alkoxy-(C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet, oder mit
Carbamoyloxy, N-(C₁-C₁₂)-Alkylcarbamoyloxy, N,N-Di- (C₁-C₁₂)-alkylcarbamoyloxy, N-(C₃-C₈)-Cycloalkylcarbamoyloxy, N-(C₆-C₁₂)-Arylcarbamoyloxy, N-(C₇-C₁₆)-Aralkylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₂)-arylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N- (C₇-C₁₆)-Aralkylcarbamoyloxy, N-((C₁-C₁₀)-alkyl)carbamoyloxy, N-((C₆-C₁₂)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,-
Amino, (C₁-C₁₂)-Alkylamino, Di-(C₁-C₁₂)-alkylamino, (C₃-C₈)- Cycloalkylamino, (C₃-C₁₂)-Alkenylamino, (C₃-C₁₂)-Alkinylamino, N-(C₆-C₁₂)-Arylamino, N-(C₇-C₁₁)-Aralkylamino, N-Alkyl-Aralkylamino, N-Alkyl-Arylamino, (C₁-C₁₂)-Alkoxyamino, (C₁-C₁₂)-Alkoxy-N-(C₁-C₁₀)- alkylamino,
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino, (C₆-C₁₂)- Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N-(C₁-C₁₀)- alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino, (C₆-C₁ ₂)-Aroyl- N-(C₁-C₁₀)-alkylamino, (C₇-C₁₁)-Aralkanoyl-N-(C₁-C₁₀)-alkylamino,
(C₁-C₁₂)-Alkanoylamino-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkanoylamino- (C₁-C₈)-alkyl, (C₆-C₁₂)-Aroylamino-(C₁-C₈)-alkyl, (C₇-C₁₆)- Aralkanoylamino-(C₁-C₈)-alkyl, Amino-(C₁-C₁₀)-alkyl, N-(C₁-C₁₀)- alkylamino-(C₁-C₁₀)-alkyl, N,N-Di-(C₁-C₁₀)-alkylamino-(C₁-C₁₀)-alkyl, (C₃-C₈)-Cycloalkylamino-(C₁-C₁₀)-alkyl, (C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)- Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl, (C₆-C₁₂)-Arylmercapto, (C₆-C₁₂)- Arylsulfinyl, (C₆-C₁₂)-Arylsulfonyl, (C₇-C₁₆)-Aralkylmercapto, (C₇-C₁₆)- Aralkylsulfinyl, (C₇-C₁₆)-Aralkylsulfonyl,
Sulfamoyl, N-(C₁-C₁₀)-Alkylsulfamoyl, N,N-Di-(C₁-C₁₀)-alkylsulfamoyl, (C₃-C₈)-Cycloalkylsulfamoyl, N-(C₆-C₁₂)-Arylsulfamoyl, N-(C₇-C₁₆)-Aralkylsulfamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₂)-arylsulfamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₇-C₁₆)-aralkylsulfamoyl, (C₁-C₁₀)-Alkyl-sulfonamido, N-((C₁-C₁₀)-alkyl)-(C₁-C₁₀)-alkylsulfonamido, (C₇-C₁₆)-Aralkylsulfonamido, N-((C₁-C₁₀)-alkyl)-(C₇-C₁₆)-aralkylsulfonamido,
wobei die Reste, die einen Arylrest enthalten ihrerseits am Aryl substituiert sein können durch 1 bis 5 gleiche oder verschiedene Reste aus der Reihe:
Hydroxy, Halogen, Cyano, Trifluormethyl, Nitro, Carboxy, (C₁-C₁₂)-Alkyl, (C₃-C₈)-Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkyl, (C₃-C₈)- Cycloalkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyloxy- (C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyl- (C₁-C₈)-alkyl-(C₁-C₆)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy-(C₁-C₆)- alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)- Cycloalkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkoxy, (C₆-C₁₂)-Aryl, (C₇-C₁₆)- Aralkyl, (C₂-C₁₂)-Alkenyl, (C₂-C₁₂)-Alkinyl, (C₁-C₁₂)-Alkoxy, (C₁-C₁₂)- Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxy, (C₁-C₁₂)-Alkoxy- (C₁-C₈)-alkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)-Aralkyloxy, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxy, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxy, (C₁-C₈)-Hydroxyalkyl, (C₆-C₁₆)-Aryloxy-(C₁-C₈)-alkyl, (C₇-C₁₆)-Aralkoxy- (C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₇-C₁₂)- Aralkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, -O-[CH2-]xC₂H(2f+1-g)Fg, -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂)-Alkylcarbonyl, (C₃-C₈)-Cycloalkylcarbonyl, (C₆-C₁₂)- Arylcarbonyl, (C₇-C₁₆)-Aralkylcarbonyl,
(C₁-C₁₂)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl, (C₆-C₁₂)-Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)- Cycloalkoxycarbonyl, (C₂-C₁₂)-Alkenyloxycarbonyl, (C₂-C₁₂)- Alkinyloxycarbonyl, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxycarbonyl, (C₇-C₁₆)- Aralkoxy-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)-Cycloalkyl-(C₁-C₆)- alkoxycarbonyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbonyloxy, (C₆-C₁₂)-Arylcarbonyloxy, (C₇-C₁₆)-Aralkylcarbonyloxy, Cinnamoyloxy, (C₂-C₁₂)-Alkenylcarbonyloxy, (C₂-C₁₂)-Alkinylcarbonyloxy,
(C₁-C₁₂)-Alkoxycarbonyloxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)- alkoxycarbonyloxy, (C₆-C₁₂)-Aryloxycarbonyloxy, (C₇-C₁₆)- Aralkyloxycarbonyloxy, (C₃-C₈)-Cycloalkoxycarbonyloxy, (C₂-C₁₂)- Alkenyloxycarbonyloxy, (C₂-C₁₂)-Alkinyloxycarbonyloxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N, N-Di-(C₁-C₁₂)-alkylcarbamoyl, N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl- (C₁-C₆)-alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆)- alkyl)carbamoyl, N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+)- dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)- Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁ -C₁₀)- Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)- alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)-carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, CON(CH₂)h, worin eine CH₂ Gruppe durch O, S, N-(C₁-C₈)-Alkylimino, N-(C₃-C₈) Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄)-Alkoxy- (C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet,
Carbamoyloxy, N-(C₁-C₁₂)-Alkylcarbamoyloxy, N,N-Di-(C₁-C₁₂)- alkylcarbamoyloxy, N-(C₃-C₈)-Cycloalkylcarbamoyloxy, N-(C₆-C₁₆)- Arylcarbamoyloxy, N-(C₇-C₁₆)-Aralkylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N- (C₆-C₁₂)-arylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-(C₇-C₁₆)- Aralkylcarbamoyloxy, N-((C₁-C₁₀)-alkyl)carbamoyloxy, N-((C₆-C₁₂)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,-
Amino, (C₁-C₁₂)-Alkylamino, Di-(C₁-C₁₂)-alkylamino, (C₃-C₈)- Cycloalkylamino, (C₃-C₁₂)-Alkenylamino, (C₃-C₁₂)-Alkinylamino, N-(C₆-C₁₂)-Arylamino, N-(C₇-C₁₁)-Aralkylamino, N-Alkyl-Aralkylamino, N-Alkyl-Arylamino, (C₁-C₁₂)-Alkoxyamino, (C₁-C₁₂)-Alkoxy-N-(C₁-C₁₀)- alkylamino,
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino, (C₆-C₁₂)- Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N-(C₁-C₁₀)- alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino, (C₆-C₁₂)-Aroyl- N-(C₁-C₁₀)-alkylamino, (C₇-C₁₁)-Aralkanoyl-N-(C₁-C₁₀)-alkylamino,
(C₁-C₁₂)-Alkanoylamino-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkanoylamino- (C₁-C₈)-alkyl, (C₆-C₁₂)-Aroylamino-(C₁-C₈)-alkyl, (C₇-C₁₆)- Aralkanoylamino-(C₁-C₈)-alkyl, Amino-(C₁-C₁₀)-alkyl, N-(C₁-C₁₀)- Alkylamino-(C₁-C₁₀)-alkyl, N,N-Di-(C₁-C₁₀)-alkylamino-(C₁-C₁₀)-alkyl, (C₃-C₈)-Cycloalkylamino-(C₁-C₁₀)-alkyl,
(C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)-Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl, (C₆-C₁₆)-Arylmercapto, (C₆-C₁₆)-Arylsulfinyl, (C₆-C₁₆)-Arylsulfonyl, (C₇-C₁₆)-Aralkylmercapto, (C₇-C₁₆)-Aralkylsulfinyl, (C₇-C₁₆)- Aralkylsulfonyl,
R¹ und R², R² und R³ oder R³ und R⁴ eine Kette [CH₂]o bilden können, in welcher eine oder zwei CH₂-Gruppen der gesättigten oder mit einer C=C-Doppelbindung ungesättigten Kette gegebenenfalls durch O, S, SO, SO₂ oder NR′ ersetzt sind, o = 3, 4 oder 5 bedeutet und
R′ Wasserstoff, (C₆-C₁₂)-Aryl, (C₁-C₈)-Alkyl, (C₁-C₈)-Alkoxy-(C₁-C₈)-alkyl, (C₇-C₁₂)-Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkyl, (C₁-C₁₀)- Alkanoyl, ggf. substituiertes (C₇-C₁₆)-Aralkanoyl, ggf. substituiertes (C₆-C₁₂)-Aroyl bedeuten,
R⁵ Wasserstoff oder einen verzweigten oder unverzweigten (C₁-C₂₀)- Alkylrest, einen (C₆-C₁₆)-Arylrest oder einen (C₇-C₁₆)-Aralkylrest bedeutet,
wobei diese Reste substituiert sind mit einem oder mehreren Resten aus der Reihe
Hydroxy, Halogen, Cyano, Trifluormethyl, Nitro, Carboxy, (C₁-C₁₂)-Alkyl, (C₃-C₈)-Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁ -C₈)-alkyl-(C₁-C₆)- alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-Cycloalkyloxy- (C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkoxy, (C₆-C₁₂)-Aryl, (C₇-C₁₆)-Aralkyl, (C₂-C₁₂)-Alkenyl, (C₂-C₁₂)-Alkinyl, (C₁-C₁₂)- Alkoxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxy, (C₁-C₁₂)-Alkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)- Aralkyloxy, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxy, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxy, (C₁-C₈)-Hydroxyalkyl, (C₆-C₁₆)-Aryloxy-(C₁-C₈)-alkyl, (C₇-C₁₆)-Aralkoxy-(C₁-C₈)- alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₇-C₁₂)-Aralkyloxy- (C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂)-Alkylcarbonyl, (C₃-C₈)-Cycloalkylcarbonyl, (C₆-C₁₂)-Arylcarbonyl, (C₇-C₁₆)-Aralkylcarbonyl, Cinnamoyl, (C₂-C₁₂)-Alkenylcarbonyl, (C₂-C₁₂)- Alkinylcarbonyl,
(C₁-C₁₂)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl, (C₆-C₁₂)- Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)-Cycloalkoxycarbonyl, (C₂-C₁₂)-Alkenyloxycarbonyl, (C₂-C₁₂)-Alkinyloxycarbonyl, (C₆-C₁₂)-Aryloxy- (C₁-C₆)-alkoxycarbonyl, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)- Cycloalkyl-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbonyloxy, (C₆-C₁₂)- Arylcarbonyloxy, (C₇-C₁₆)-Aralkylcarbonyloxy, Cinnamoyloxy, (C₂-C₁₂)- Alkenylcarbonyloxy, (C₂-C₁₂)-Alkinylcarbonyloxy,
(C₁-C₁₂)-Alkoxycarbonyloxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyloxy, (C₆-C₁₂)-Aryloxycarbonyloxy, (C₇-C₁₆)-Aralkyloxycarbonyloxy, (C₃-C₈)- Cycloalkoxycarbonyloxy, (C₂-C₁₂)-Alkenyloxycarbonyloxy, (C₂-C₁₂)- Alkinyloxycarbonyloxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N,N-Di-(C₁-C₁₂)-alkylcarbamoyl, N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl, N-(C₁-C₁₀)- Alkyl-N-(C₃-C₈)-Cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl-(C₁-C₆)- alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆) alkyl)carbamoyl, N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+)- dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)- Aralkylcarbamcyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁-C₁₀)-Alkyl- N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy (C₁-C₁₀)-alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)- alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, CON(CH₂)h, worin eine CH₂-Gruppe durch O, S, N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)- Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄)-Alkoxy-(C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet, oder mit
einem Carbamoyl-Rest der allgemeinen Formel II worin
Rx den Substituenten einer α-Aminosäure bedeutet, zu denen die L- und D-Aminosäuren zählen,
s 1, 2, 3,4 oder 5 und
T OH, OR oder NR*R** bedeutet, wobei
R*, R** und R*** gleich oder verschieden sind und Wasserstoff, (C₆-C₁₂)- Aryl, (C₇-C₁₁)-Aralkyl, (C₁-C₈)-Alkyl, (C₃-C₈)-Cycloalkyl, (+)-Dehydroabietyl, (C₁-C₈)-Alkoxy-(C₁-C₈)-alkyl, (C₇-C₁₂)- Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkyl, (C₁-C₁₀)- Alkanoyl, ggf. substituiertes (C₇-C₁₆)-Aralkanoyl, ggf. substituiertes (C₆-C₁₂)-Aroyl bedeuten, oder
R* und R** gemeinsam für -[CH₂]h stehen, worin eine CH₂ Gruppe durch O, S, SO, SO₂, N-Acylamino, N-(C₁-C₁₀)-Alkoxycarbonylimino, N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)- Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)- Aralkylimino oder N-(C₁-C₄)-Alkoxy-(C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet, oder mit
Carbamoyloxy, N-(C₁-C₁₂)-Alkylcarbamoyloxy, N,N-Di- (C₁-C₁₂)-alkylcarbamoyloxy, N-(C₃-C₈)-Cycloalkylcarbamoyloxy, N-(C₆-C₁₂)-Arylcarbamoyloxy, N-(C₇-C₁₆)-Aralkylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₂)-arylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N- (C₇-C₁₆)-aralkylcarbamoyloxy, N-((C₁-C₁₀)-alkyl)carbamoyloxy, N-((C₆-C₁₂)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,-
Amino, (C₁-C₁₂)-Alkylamino, Di-(C₁-C₁₂)-alkylamino, (C₃-C₈)- Cycloalkylamino, (C₃-C₁₂)-Alkenylamino, (C₃-C₁₂)-Alkinylamino, N-(C₆-C₁₂)-Arylamino, N-(C₇-C₁₁)-Aralkylamino, N-Alkyl-Aralkylamino, N-Alkyl-Arylamino, (C₁-C₁₂)-Alkoxyamino, (C₁-C₁₂)-Alkoxy-N-(C₁-C₁₀)- alkylamino,
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino, (C₆-C₁₂)- Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N-(C₁-C₁₀)- alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino, (C₆-C₁₂)-Aroyl- N-(C₁-C₁₀)-alkylamino, (C₇-C₁₁)-Aralkanoyl-N-(C₁-C₁₀)-alkylamino,
(C₁-C₁₂)-Alkanoylamino-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkanoylamino- (C₁-C₈)-alkyl, (C₆-C₁₂)-Aroylamino-(C₁-C₈)-alkyl, (C₇-C₁₆)- Aralkanoylamino-(C₁-C₈)-alkyl, Amino-(C₁-C₁₀)-alkyl, N-(C₁-C₁₀)- alkylamino-(C₁-C₁₀)-alkyl, N,N-Di-(C₁-C₁₀)-alkylamino-(C₁-C₁₀)-alkyl, (C₃-C₈)-Cycloalkylamino-(C₁-C₁₀)-alkyl,
(C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)-Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl, (C₆-C₁₂)-Arylmercapto, (C₆-C₁₂)-Arylsulfinyl, (C₆-C₁₂)-Arylsulfonyl, (C₇-C₁₆)-Aralkylmercapto, (C₇-C₁₆)-Aralkylsulfinyl, (C₇-C₁₆)- Aralkylsulfonyl,
Sulfamoyl, N-(C₁-C₁₀)-Alkylsulfamoyl, N,N-Di-(C₁-C₁₀)-alkylsulfamoyl, (C₃-C₈)-Cycloalkylsulfamoyl, N-(C₆-C₁₂)-Arylsulfamoyl, N-(C₇-C₁₆)-Aralkylsulfamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₂)-arylsulfamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₇-C₁₆)-aralkylsulfamoyl, (C₁-C₁₀)-Alkyl-sulfonamido, N-((C₁-C₁₀)-Alkyl)-(C₁-C₁₀)-alkylsulfonamido, (C₇-C₁₆)- Aralkylsulfonamido, N-((C₁-C₁₀)-Alkyl-(C₇-C₁₆)-aralkylsulfonamido,
wobei die Reste, die einen Arylrest enthalten ihrerseits am Aryl substituiert sein können durch 1 bis 5 gleiche oder verschiedene Reste aus der Reihe:
Hydroxy, Halogen, Cyano, Trifluormethyl, Nitro, Carboxy, (C₁-C₁₂)-Alkyl, (C₃-C₈)-Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkyl, (C₃-C₈)- Cycloalkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyloxy- (C₁-C₁₂)-alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyl- (C₁-C₈)-alkyl-(C₁-C₆)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy-(C₁-C₆)- alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)- Cycloalkoxy-(C₁-C₈)-alkoxy-(C₁-C₈)-alkoxy, (C₆-C₁₂)-Aryl, (C₇-C₁₆)- Aralkyl, (C₂-C₁₂)-Alkenyl, (C₂-C₁₂)-Alkinyl, (C₁-C₁₂)-Alkoxy, (C₁-C₁₂)- Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxy, (C₁-C₁₂)-Alkoxy- (C₁-C₈)-alkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)-Aralkyloxy, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxy, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxy, (C₁-C₈)-Hydroxyalkyl, (C₆-C₁₆)-Aryloxy-(C₁-C₈)-alkyl, (C₇-C₁₆)-Aralkoxy- (C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, (C₇-C₁₂)- Aralkyloxy-(C₁-C₈)-alkoxy-(C₁-C₆)-alkyl, -O-[CH2-]xCfH(2f+1-g)Fg, -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂)-Alkylcarbonyl, (C₃-C₈)-Cycloalkylcarbonyl, (C₆-C₁₂)- Arylcarbonyl, (C₇-C₁₆)-Aralkylcarbonyl,
(C₁-C₁₂)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl,
(C₆-C₁₂)-Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)- Cycloalkoxycarbonyl, (C₂-C₁₂)-Alkenyloxycarbonyl, (C₂-C₁₂)- Alkinyloxycarbonyl, (C₆-C₁₂)-Aryloxy-(C₁-C₆)-alkoxycarbonyl, (C₇-C₁₆)- Aralkoxy-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)-Cycloalkyl-(C₁-C₆)- alkoxycarbonyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbonyloxy, (C₆-C₁₂)-Arylcarbonyloxy, (C₇-C₁₆)-Aralkylcarbonyloxy, Cinnamoyloxy, (C₂-C₁₂)-Alkenylcarbonyloxy, (C₂-C₁₂)-Alkinylcarbonyloxy,
(C₁-C₁₂)-Alkoxycarbonyloxy, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)- alkoxycarbonyloxy, (C₆-C₁₂)-Aryloxycarbonyloxy, (C₇-C₁₆)- Aralkyloxycarbonyloxy, (C₃-C₈)-Cycloalkoxycarbonyloxy, (C₂-C₁₂)- Alkenyloxycarbonyloxy, (C₂-C₁₂)-Alkinyloxycarbonyloxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N,N-Di-(C₁-C₁₂)-alkylcarbamoyl, N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl- (C₁-C₆)-alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆)- alkyl)carbamoyl, N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+)- dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)- Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁-C₁₀)- Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)- alkyl)-carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)-carbamoyl, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, CON(CH₂)h, worin eine CH₂-Gruppe durch O, S, N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄)-Alkoxy- (C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet,
Carbamoyloxy, N-(C₁-C₁₂)-Alkylcarbamoyloxy, N,N-Di-(C₁-C₁₂)- alkylcarbamoyloxy, N-(C₃-C₈)-Cycloalkylcarbamoyloxy, N-(C₆-C₁₆)- Arylcarbamoyloxy, N-(C₇-C₁₆)-Aralkylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N- (C₆-C₁₂)-arylcarbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-(C₇-C₁₆)- Aralkylcarbamoyloxy, N-((C₁-C₁₀)-alkyl)carbamoyloxy, N-((C₆-C₁₂)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyloxy, N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyloxy,-
Amino, (C₁-C₁₂)-Alkylamino, Di-(C₁-C₁₂)-alkylamino, (C₃-C₈)- Cycloalkylamino, (C₃-C₁₂)-Alkenylamino, (C₃-C₁₂)-Alkinylamino, N-(C₆- C₁₂)-Arylamino, N-(C₇-C₁₁)-Aralkylamino, N-Alkyl-Aralkylamino, N-Alkyl- Arylamino, (C₁-C₁₂)-Alkoxyamino, (C₁-C₁₂)-Alkoxy-N-(C₁-C₁₀)- alkylamino,
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino, (C₆-C₁₂)-Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N- (C₁-C₁₀)-alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino, (C₆-C₁₂)-Aroyl-N-(C₁-C₁₀)-alkylamino, (C₇-C₁₁)-Aralkanoyl-N-(C₁-C₁₀)- alkylamino,
(C₁-C₁₂)-Alkanoylamino-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkanoylamino- (C₁-C₈)-alkyl, (C₆-C₁₂)-Aroylamino-(C₁-C₈)-alkyl, (C₇-C₁₆)- Aralkanoylamino-(C₁-C₈)-alkyl, Amino-(C₁-C₁₀)-alkyl, N-(C₁-C₁₀)- Alkylamino-(C₁-C₁₀)-alkyl, N,N-Di-(C₁-C₁₀)-alkylamino-(C₁-C₁₀)-alkyl, (C₃-C₈)-Cycloalkylamino-(C₁-C₁₀)-alkyl,
(C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)-Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl, (C₆-C₁₆)-Arylmercapto, (C₆-C₁₆)-Arylsulfinyl, (C₆-C₁₆)-Arylsulfonyl, (C₇-C₁₆)-Aralkylmercapto, (C₇-C₁₆)-Aralkylsulfinyl, (C₇-C₁₆)- Aralkylsulfonyl,
und
f = 1 bis 8,
g = 0,1 bis (2f+1),
x = 0 bis 3,
h = 3 bis 6 bedeuten
einschließlich der physiologisch wirksamen Salze, wobei N-((6,7-Dichlor-3,4-dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α- ((6,7-Dichlor-3,4-dihydro-3-oxo-2-chinoxalinyl)carbonyl)amino)phenyl-essigsäure ausgenommen sind.1. Compounds of the general formula I in which
Q O or S,
X O and S,
A (C₁-C₄) alkylene, which is optionally substituted with one or two substituents from the series halogen, cyano, nitro, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) hydroxyalkyl, (C₁-C₆) -Alkoxy, -O- [CH₂] x -C f H (2f + 1-g) Hal g , preferably (C₁-C₈) fluoroalkoxy, (C₁-C₈) fluoroalkenyloxy, (C₁-C₈) fluoroalkynyloxy, - OCF₂Cl or -O-CF₂-CHFCl, (C₁-C₆) alkyl mercapto, (C₁-C₆) alkylsulfinyl, (C₁-C₆) alkylsulfonyl, (C₁-C₆) alkylcarbonyl, (C₁-C₆) alkoxycarbonyl, carbamoyl , N- (C₁-C₄) alkylcarbamoyl, N, N-di- (C₁-C₄) alkylcarbamoyl, (C₁-C₆) alkylcarbonyloxy, (C₃-C₈) cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino , N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N- (C₁-C₄) alkylsulfamoyl, N, N-di- (C₁-C₄) alkylsulfamoyl, or
with a substituted (C₆-C₁₂) aryloxy, (C₇-C₁₁) aralkyloxy, (C₆-C₁₂) aryl or (C₇-C₁₁) aralkyl radical which is in the aryl part 1, 2, 3, 4 or 5 identical or different substituents from the series halogen, cyano, nitro, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, -O- [CH₂] x -C f H (2f + 1-g) Hal g , -OCF₂Cl, -O-CF₂-CHFCl, (C₁-C₆) alkyl mercapto, (C₁-C₆) alkylsulfinyl, (C₁-C₆) alkylsulfonyl, (C₁-C₆) alkylcarbonyl, (C₁-C₆) -Alkoxycarbonyl, carbamoyl, N- (C₁-C₄) alkylcarbamoyl, N, N-di- (C₁-C₄) alkylcarbamoyl, (C₁-C₆) alkylcarbonyloxy, (C₃-C₈) cycloalkyl, sulfamoyl, N- ( C₁-C₄) - alkylsulfamoyl or N, N-di- (C₁-C₄) alkylsulfamoyl, or
with the substituents R⁵ of the α-C atom of an α-amino acid, whereby the natural L-amino acids and their D-isomers can be used;
B is an acidic group from the series -CO₂H, -CONHCOR ′ ′ ′,
-CONHSOR ''',CONHSO₂R''', -NHSO₂CF₃, tetrazolyl, imidazolyl or 3-hydroxyisoxazolyl, where R '''aryl, heteroaryl, (C₃-C₇) - cycloalkyl or (C₁-C₄) -alkyl, optionally monosubstituted with (C₆-C₁₂) aryl, heteroaryl, OH, SH, (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) thioalkyl, sulfinyl or sulfonyl, CF₃, Cl, Br , F, I, NO₂, -COOH, (C₂-C₅) - alkoxycarbonyl, NH₂, mono- or di- (C₁-C₄-alkyl) -amino or (C₁-C₄) - perfluoroalkyl,
R¹, R², R³ and R⁴ are the same or different and are hydrogen, hydroxy, halogen, cyano, trifluoromethyl, nitro, carboxy, (C₁-C₂₀) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkoxy, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkoxy, (C₃-C₈) -cycloalkyloxy- (C₁-C₁₂) alkyl, (C₃ -C₈) -Cycloalkyloxy- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyl- (C₁ -C₈) alkyl- (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈ ) -alkoxy- (C₁-C₆) -alkyl, (C₃-C₈) - cycloalkyloxy- (C₁-C₈) -alkoxy- (C₁-C₆) -alkyl, (C₃-C₈) -cycloalkoxy- (C₁-C₈) - alkoxy- (C₁-C₈) alkoxy, (C₆-C₁₂) aryl, (C₇-C₁₆) aralkyl, (C₂-C₂₀) alkenyl, (C₂-C₂₀) alkynyl, (C₁-C₂₀) alkoxy, (C₂-C₂₀) alkenyloxy, (C₂-C₂₀) alkynyloxy, retinyloxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy, (C -C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) - aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl, (C₆-C₁₆ ) Aryloxy- (C₁-C₈) alkyl, (C₇-C₁₆) aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkoxy- (C₁-C₆) - alkyl, (C₇-C₁₂) aralkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₂-C₂₀) - alkenyloxy- (C₁-C₆) alkyl, (C₂-C₂₀) alkynyloxy ( C₁-C₆) alkyl, retinyloxy- (C₁-C₆) alkyl, -O- [CH 2- ] x C f H (2f + 1-g) F g , -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂) alkylcarbonyl, (C₃-C₈) cycloalkylcarbonyl, (C₆-C₁₂) arylcarbonyl, (C₇-C₁₆) aralkylcarbonyl, cinnamoyl, (C₂-C₁₂) alkenylcarbonyl, (C₂-C₁₂) alkynylcarbonyl,
(C₁-C₁₂) alkoxycarbonyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) - cycloalkoxycarbonyl, (C₂ -C₂₀) alkenyloxycarbonyl, retinyloxycarbonyl, (C₂-C₂₀) alkynyloxycarbonyl, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxycarbonyl, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxycarbonyl, (C₃ -C₈) cycloalkyl- (C₁-C₆) alkoxycarbonyl, (C₃-C₈) cycloalkoxy- (C₁-C₆) alkoxycarbonyl,
(C₁-C₁₂) alkylcarbonyloxy, (C₃-C₈) cycloalkylcarbonyloxy, (C₆-C₁₂) arylcarbonyloxy, (C₇-C₁₆) aralkylcarbonyloxy, cinnamoyloxy, (C₂-C₁₂) alkenylcarbonyloxy, (C₂-C₁₂oxy) alkynylcarbonyloxy
(C₁-C₁₂) alkoxycarbonyloxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyloxy, (C₆-C₁₂) aryloxycarbonyloxy, (C₇-C₁₆) aralkyloxycarbonyloxy, (C₃-C₈) cycloalkoxycarbonyloxy, (C₂ -C₁₂) - alkenyloxycarbonyloxy, (C₂-C₁₂) alkynyloxycarbonyloxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N - ((C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₁-C₆) alkyl -N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- (C₆-C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁-C₁₀) - alkyl-N- ( C₇-C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy (C₁-C₁₀) alkyl) carbamoyl, N- ((C₇-C₁₆) aralkyloxy (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) aralkyloxy - (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group by O, S, N- (C₁-C₈) alkylimino, N- (C₃-C₈) -cycloalkylimino, N- ( C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆) -alkylimino can be replaced and h is 3 to 7, or with
a carbamoyl radical of the general formula II wherein
R x denotes the substituents of an α-amino acid, which include the L and D amino acids,
s 1, 2, 3, 4 or 5 and
T means OH, OR or NR * R **, where
R *, R ** and R *** are the same or different and are hydrogen (C₆-C₁₂) aryl, (C₇-C₁₁) aralkyl, (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl, ( +) - Dehydroabietyl, (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₇-C₁₂) - aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) -alkyl, (C₁-C₁₀) alkanoyl, optionally substituted (C₇-C₁₆) aralkanoyl, optionally substituted (C₆-C₁₂) aryl, or
R * and R ** together represent - [CH₂] h , in which a CH₂ group is represented by O, S, SO, SO₂, N-acylamino, N- (C₁-C₁₀) alkoxycarbonylimino, N- (C₁-C₈) - Alkylimino, N- (C₃-C₈) -cycloalkylimino, N- (C₃-C₈) - cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆) alkylimino can be replaced and h is 3 to 7, or with
Carbamoyloxy, N- (C₁-C₁₂) alkylcarbamoyloxy, N, N-Di- (C₁-C₁₂) alkylcarbamoyloxy, N- (C₃-C₈) cycloalkylcarbamoyloxy, N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₇ -C₁₆) aralkylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylcarbamoyloxy, N - (( C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy , N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) -aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy, -
Amino, (C₁-C₁₂) alkylamino, di- (C₁-C₁₂) alkylamino, (C₃-C₈) - cycloalkylamino, (C₃-C₁₂) alkenylamino, (C₃-C₁₂) alkynylamino, N- (C₆-C₁₂ ) Arylamino, N- (C₇-C₁₁) aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C₁-C₁₂) alkoxyamino, (C₁-C₁₂) alkoxy-N- (C₁-C₁₀) - alkylamino,
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino, (C₆-C₁ ₂) aroyl- N- (C₁-C₁₀) alkylamino, (C₇-C₁₁) aralkanoyl-N- (C₁- C₁₀) alkylamino,
(C₁-C₁₂) alkanoylamino- (C₁-C₈) alkyl, (C₃-C₈) cycloalkanoylamino- (C₁-C₈) alkyl, (C₆-C₁₂) aroylamino- (C₁-C₈) alkyl, (C₇ -C₁₆) - aralkanoylamino- (C₁-C₈) alkyl, amino- (C₁-C₁₀) alkyl, N- (C₁-C₁₀) alkylamino- (C₁-C₁₀) alkyl, N, N-di- (C₁ -C₁₀) alkylamino- (C₁-C₁₀) alkyl, (C₃-C₈) -cycloalkylamino- (C₁-C₁₀) alkyl, (C₁-C₁₂) alkylmercapto, (C₁-C₁₂) alkylsulfinyl, (C₁-C₁₂ ) Alkylsulfonyl, (C₆-C₁₂) arylmercapto, (C₆-C₁₂) arylsulfinyl, (C₆-C₁₂) arylsulfonyl, (C₇-C₁₆) aralkylmercapto, (C₇-C₁₆) aralkylsulfinyl, (C₇-C₁₆) - Aralkylsulfonyl,
Sulfamoyl, N- (C₁-C₁₀) alkylsulfamoyl, N, N-di- (C₁-C₁₀) alkylsulfamoyl, (C₃-C₈) cycloalkylsulfamoyl, N- (C₆-C₁₂) arylsulfamoyl, N- (C₇-C₁₆ ) Aralkylsulfamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylsulfamoyl, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylsulfamoyl, (C₁-C₁₀) - Alkyl sulfonamido, N - ((C₁-C₁₀) alkyl) - (C₁-C₁₀) alkylsulfonamido, (C₇-C₁₆) aralkylsulfonamido, N - ((C₁-C₁₀) alkyl) - (C₇-C₁₆) - aralkylsulfonamido,
where the radicals which contain an aryl radical in turn can be substituted on the aryl by 1 to 5 identical or different radicals from the series:
Hydroxy, halogen, cyano, trifluoromethyl, nitro, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkyl, (C₃-C₈) - Cycloalkoxy, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈) alkyl- (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈) alkoxy- (C₁-C₆) - alkyl, (C₃ -C₈) -Cycloalkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₃-C₈) - cycloalkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkoxy, (C₆-C₁₂ ) Aryl, (C₇-C₁₆) aralkyl, (C₂-C₁₂) alkenyl, (C₂-C₁₂) alkynyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) - alkoxy- (C₁-C₁₂) - alkyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy, (C₇-C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl , (C₆-C₁₆) aryloxy- (C₁-C₈) alkyl, (C₇-C₁₆) aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkoxy- ( C₁-C₆) alkyl, (C₇-C₁₂) aralkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, -O- [CH 2- ] x C₂H (2f + 1-g) F g , -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂) alkylcarbonyl, (C₃-C₈) cycloalkylcarbonyl, (C₆-C₁₂) arylcarbonyl, (C₇-C₁₆) aralkylcarbonyl,
(C₁-C₁₂) alkoxycarbonyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) - cycloalkoxycarbonyl, (C₂ -C₁₂) alkenyloxycarbonyl, (C₂-C₁₂) alkynyloxycarbonyl, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxycarbonyl, (C₇-C₁₆) - aralkoxy- (C₁-C₆) alkoxycarbonyl, (C₃-C₈ ) -Cycloalkyl- (C₁-C₆) alkoxycarbonyl, (C₃-C₈) -cycloalkoxy- (C₁-C₆) alkoxycarbonyl,
(C₁-C₁₂) alkylcarbonyloxy, (C₃-C₈) cycloalkylcarbonyloxy, (C₆-C₁₂) arylcarbonyloxy, (C₇-C₁₆) aralkylcarbonyloxy, cinnamoyloxy, (C₂-C₁₂) alkenylcarbonyloxy, (C₂-C₁₂), alkynylcarbonyloxy
(C₁-C₁₂) alkoxycarbonyloxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyloxy, (C₆-C₁₂) aryloxycarbonyloxy, (C₇-C₁₆) aralkyloxycarbonyloxy, (C₃-C₈) cycloalkoxycarbonyloxy, (C₂ -C₁₂) - alkenyloxycarbonyloxy, (C₂-C₁₂) alkynyloxycarbonyloxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N - ((C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₁-C₆) alkyl -N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- (C₆-C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁ -C₁₀) - alkyl-N- (C₇-C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇- C₁₆) aralky loxy- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , wherein a CH₂ group through O, S, N- (C₁-C₈) alkylimino, N- (C₃-C₈) cycloalkylimino, N- (C₃ -C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆) - alkylimino can be replaced and h represents 3 to 7,
Carbamoyloxy, N- (C₁-C₁₂) alkylcarbamoyloxy, N, N-Di- (C₁-C₁₂) alkylcarbamoyloxy, N- (C₃-C₈) cycloalkylcarbamoyloxy, N- (C₆-C₁₆) arylcarbamoyloxy, N- (C₇ -C₁₆) aralkylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylcarbamoyloxy, N - (( C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy , N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) -aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy, -
Amino, (C₁-C₁₂) alkylamino, di- (C₁-C₁₂) alkylamino, (C₃-C₈) - cycloalkylamino, (C₃-C₁₂) alkenylamino, (C₃-C₁₂) alkynylamino, N- (C₆-C₁₂ ) Arylamino, N- (C₇-C₁₁) aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C₁-C₁₂) alkoxyamino, (C₁-C₁₂) alkoxy-N- (C₁-C₁₀) - alkylamino,
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino, (C₆-C₁₂) aroyl- N- (C₁-C₁₀) alkylamino, (C₇-C₁₁) aralkanoyl-N- (C₁-C₁₀ ) alkylamino,
(C₁-C₁₂) alkanoylamino- (C₁-C₈) alkyl, (C₃-C₈) cycloalkanoylamino- (C₁-C₈) alkyl, (C₆-C₁₂) aroylamino- (C₁-C₈) alkyl, (C₇ -C₁₆) - aralkanoylamino- (C₁-C₈) alkyl, amino- (C₁-C₁₀) alkyl, N- (C₁-C₁₀) alkylamino- (C₁-C₁₀) alkyl, N, N-di- (C₁ -C₁₀) alkylamino- (C₁-C₁₀) alkyl, (C₃-C₈) cycloalkylamino- (C₁-C₁₀) alkyl,
(C₁-C₁₂) alkylmercapto, (C₁-C₁₂) alkylsulfinyl, (C₁-C₁₂) alkylsulfonyl, (C₆-C₁₆) arylmercapto, (C₆-C₁₆) arylsulfinyl, (C₆-C₁₆) arylsulfonyl, (C₆ -C₁₆) aralkylmercapto, (C₇-C₁₆) aralkylsulfinyl, (C₇-C₁₆) aralkylsulfonyl,
R¹ and R², R² and R³ or R³ and R⁴ can form a chain [CH₂] o , in which one or two CH₂ groups of the saturated or unsaturated chain with a C = C double bond optionally by O, S, SO, SO₂ or NR 'are replaced, o = 3, 4 or 5 means and
R ′ is hydrogen, (C₆-C₁₂) aryl, (C₁-C₈) alkyl, (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₇-C₁₂) aralkoxy- (C₁-C₈) - alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkyl, (C₁-C₁₀) alkanoyl, optionally substituted (C₇-C₁₆) aralkanoyl, optionally substituted (C₆-C₁₂) aryl,
R⁵ is hydrogen or a branched or unbranched (C₁-C₂₀) alkyl radical, a (C₆-C₁₆) aryl radical or a (C₇-C₁₆) aralkyl radical,
these radicals being substituted by one or more radicals from the series
Hydroxy, halogen, cyano, trifluoromethyl, nitro, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkyl, (C₃-C₈) - Cycloalkoxy, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkoxy, (C₃-C₈) -cycloalkyl- (C₁-C₈) -alkyl- (C₁-C₆) - alkoxy, (C₃-C₈) -cycloalkyl- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₃ -C₈) -Cycloalkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₃-C₈) -cycloalkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkoxy, (C₆-C₁₂ ) Aryl, (C₇-C₁₆) aralkyl, (C₂-C₁₂) alkenyl, (C₂-C₁₂) alkynyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) - alkyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy, (C₇-C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl, ( C₆-C₁₆) aryloxy- (C₁-C₈) alkyl, (C₇-C₁₆) aralkoxy- (C₁-C₈) - alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkoxy- (C₁- C₆) alkyl, (C₇-C₁₂) aralkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, -O- [CH 2- ] x C f H (2f + 1-g) F g , -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂) alkylcarbonyl, (C₃-C₈) cycloalkylcarbonyl, (C₆-C₁₂) arylcarbonyl, (C₇-C₁₆) aralkylcarbonyl, cinnamoyl, (C₂-C₁₂) alkenylcarbonyl, (C₂-C₁₂) alkynylcarbonyl,
(C₁-C₁₂) alkoxycarbonyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) cycloalkoxycarbonyl, (C₂ -C₁₂) alkenyloxycarbonyl, (C₂-C₁₂) alkynyloxycarbonyl, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxycarbonyl, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxycarbonyl, (C₃-C₈ ) - cycloalkyl- (C₁-C₆) alkoxycarbonyl, (C₃-C₈) cycloalkoxy- (C₁-C₆) alkoxycarbonyl,
(C₁-C₁₂) alkylcarbonyloxy, (C₃-C₈) cycloalkylcarbonyloxy, (C₆-C₁₂) arylcarbonyloxy, (C₇-C₁₆) aralkylcarbonyloxy, cinnamoyloxy, (C₂-C₁₂) alkenylcarbonyloxy, (C₂-C₁₂oxy) alkynylcarbonyloxy
(C₁-C₁₂) alkoxycarbonyloxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyloxy, (C₆-C₁₂) aryloxycarbonyloxy, (C₇-C₁₆) aralkyloxycarbonyloxy, (C₃-C₈) - cycloalkoxycarbonyloxy, (C₂ -C₁₂) alkenyloxycarbonyloxy, (C₂-C₁₂) alkynyloxycarbonyloxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) - alkyl-N- (C₃-C₈) -cycloalkylcarbamoyl, N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N- (C₁-C₆) alkyl -N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- ( C₆-C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamcyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁-C₁₀) alkyl- N- ( C₇-C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) - aralkylox y- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group by O, S, N- (C₁-C₈) alkylimino, N- (C₃-C₈) - cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆ ) alkylimino can be replaced and h is 3 to 7, or with
a carbamoyl radical of the general formula II wherein
R x denotes the substituents of an α-amino acid, which include the L and D amino acids,
s 1, 2, 3, 4 or 5 and
T means OH, OR or NR * R **, where
R *, R ** and R *** are the same or different and are hydrogen, (C₆-C₁₂) aryl, (C₇-C₁₁) aralkyl, (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl, (+) - Dehydroabietyl, (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₇-C₁₂) - aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈ ) alkyl, (C₁-C₁₀) alkanoyl, optionally substituted (C₇-C₁₆) aralkanoyl, optionally substituted (C₆-C₁₂) aroyl, or
R * and R ** together represent - [CH₂] h , in which a CH₂ group is represented by O, S, SO, SO₂, N-acylamino, N- (C₁-C₁₀) alkoxycarbonylimino, N- (C₁-C₈) - Alkylimino, N- (C₃-C₈) -cycloalkylimino, N- (C₃-C₈) - cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆) alkylimino can be replaced and h is 3 to 7, or with
Carbamoyloxy, N- (C₁-C₁₂) alkylcarbamoyloxy, N, N-Di- (C₁-C₁₂) alkylcarbamoyloxy, N- (C₃-C₈) cycloalkylcarbamoyloxy, N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₇ -C₁₆) aralkylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylcarbamoyloxy, N - (( C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy , N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) -aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy, -
Amino, (C₁-C₁₂) alkylamino, di- (C₁-C₁₂) alkylamino, (C₃-C₈) - cycloalkylamino, (C₃-C₁₂) alkenylamino, (C₃-C₁₂) alkynylamino, N- (C₆-C₁₂ ) Arylamino, N- (C₇-C₁₁) aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C₁-C₁₂) alkoxyamino, (C₁-C₁₂) alkoxy-N- (C₁-C₁₀) - alkylamino,
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino, (C₆-C₁₂) aroyl- N- (C₁-C₁₀) alkylamino, (C₇-C₁₁) aralkanoyl-N- (C₁-C₁₀ ) alkylamino,
(C₁-C₁₂) alkanoylamino- (C₁-C₈) alkyl, (C₃-C₈) cycloalkanoylamino- (C₁-C₈) alkyl, (C₆-C₁₂) aroylamino- (C₁-C₈) alkyl, (C₇ -C₁₆) - aralkanoylamino- (C₁-C₈) alkyl, amino- (C₁-C₁₀) alkyl, N- (C₁-C₁₀) alkylamino- (C₁-C₁₀) alkyl, N, N-di- (C₁ -C₁₀) alkylamino- (C₁-C₁₀) alkyl, (C₃-C₈) cycloalkylamino- (C₁-C₁₀) alkyl,
(C₁-C₁₂) alkylmercapto, (C₁-C₁₂) alkylsulfinyl, (C₁-C₁₂) alkylsulfonyl, (C₆-C₁₂) arylmercapto, (C₆-C₁₂) arylsulfinyl, (C₆-C₁₂) arylsulfonyl, (C₆ -C₁₆) aralkylmercapto, (C₇-C₁₆) aralkylsulfinyl, (C₇-C₁₆) aralkylsulfonyl,
Sulfamoyl, N- (C₁-C₁₀) alkylsulfamoyl, N, N-di- (C₁-C₁₀) alkylsulfamoyl, (C₃-C₈) cycloalkylsulfamoyl, N- (C₆-C₁₂) arylsulfamoyl, N- (C₇-C₁₆ ) Aralkylsulfamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylsulfamoyl, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylsulfamoyl, (C₁-C₁₀) - Alkyl sulfonamido, N - ((C₁-C₁₀) alkyl) - (C₁-C₁₀) alkylsulfonamido, (C₇-C₁₆) aralkylsulfonamido, N - ((C₁-C₁₀) alkyl- (C₇-C₁₆) aralkylsulfonamido ,
where the radicals which contain an aryl radical in turn can be substituted on the aryl by 1 to 5 identical or different radicals from the series:
Hydroxy, halogen, cyano, trifluoromethyl, nitro, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkyl, (C₃-C₈) - Cycloalkoxy, (C₃-C₈) cycloalkyl- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyloxy- (C₁-C₁₂) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈) alkyl- (C₁-C₆) alkoxy, (C₃-C₈) cycloalkyl- (C₁-C₈) alkoxy- (C₁-C₆) - alkyl, (C₃ -C₈) -Cycloalkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, (C₃-C₈) - cycloalkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkoxy, (C₆-C₁₂ ) Aryl, (C₇-C₁₆) aralkyl, (C₂-C₁₂) alkenyl, (C₂-C₁₂) alkynyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) - alkoxy- (C₁-C₁₂) - alkyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy, (C₇-C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl , (C₆-C₁₆) aryloxy- (C₁-C₈) alkyl, (C₇-C₁₆) aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkoxy- ( C₁-C₆) alkyl, (C₇-C₁₂) aralkyloxy- (C₁-C₈) alkoxy- (C₁-C₆) alkyl, -O- [CH 2- ] x C f H (2f + 1-g) F g , -OCF₂Cl, -OCF₂-CHFCl,
(C₁-C₁₂) alkylcarbonyl, (C₃-C₈) cycloalkylcarbonyl, (C₆-C₁₂) arylcarbonyl, (C₇-C₁₆) aralkylcarbonyl,
(C₁-C₁₂) alkoxycarbonyl, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyl,
(C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) - cycloalkoxycarbonyl, (C₂-C₁₂) alkenyloxycarbonyl, (C₂-C₁₂) alkynyloxycarbonyl, (C₆-C₁₂) aryloxy- (C₁ -C₆) -alkoxycarbonyl, (C₇-C₁₆) - aralkoxy- (C₁-C₆) -alkoxycarbonyl, (C₃-C -C) -cycloalkyl- (C₁-C₆) - alkoxycarbonyl, (C₃-C₈) -cycloalkoxy- (C₁-C₆ ) alkoxycarbonyl,
(C₁-C₁₂) alkylcarbonyloxy, (C₃-C₈) cycloalkylcarbonyloxy, (C₆-C₁₂) arylcarbonyloxy, (C₇-C₁₆) aralkylcarbonyloxy, cinnamoyloxy, (C₂-C₁₂) alkenylcarbonyloxy, (C₂-C₁₂), alkynylcarbonyloxy
(C₁-C₁₂) alkoxycarbonyloxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxycarbonyloxy, (C₆-C₁₂) aryloxycarbonyloxy, (C₇-C₁₆) aralkyloxycarbonyloxy, (C₃-C₈) cycloalkoxycarbonyloxy, (C₂ -C₁₂) - alkenyloxycarbonyloxy, (C₂-C₁₂) alkynyloxycarbonyloxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N - ((C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₁-C₆) alkyl -N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- (C₆-C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁-C₁₀) - alkyl-N- (C₇-C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) - carbamoyl, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) - alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇ -C₁₆) aralkyl oxy- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group is represented by O, S, N- (C₁-C₈) alkylimino, N- (C₃-C₈) cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆ ) alkylimino can be replaced and h is 3 to 7,
Carbamoyloxy, N- (C₁-C₁₂) alkylcarbamoyloxy, N, N-Di- (C₁-C₁₂) alkylcarbamoyloxy, N- (C₃-C₈) cycloalkylcarbamoyloxy, N- (C₆-C₁₆) arylcarbamoyloxy, N- (C₇ -C₁₆) aralkylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₂) arylcarbamoyloxy, N- (C₁-C₁₀) alkyl-N- (C₇-C₁₆) aralkylcarbamoyloxy, N - (( C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy , N- (C₁-C₁₀) alkyl-N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) -aryloxy- (C₁-C₁₀) alkyl) carbamoyloxy, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyloxy, -
Amino, (C₁-C₁₂) alkylamino, di- (C₁-C₁₂) alkylamino, (C₃-C₈) cycloalkylamino, (C₃-C₁₂) alkenylamino, (C₃-C₁₂) alkynylamino, N- (C₆- C₁₂ ) Arylamino, N- (C₇-C₁₁) aralkylamino, N-alkyl-aralkylamino, N-alkyl-arylamino, (C₁-C₁₂) alkoxyamino, (C₁-C₁₂) alkoxy-N- (C₁-C₁₀) - alkylamino,
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino, (C₆-C₁₂) aroyl-N- (C₁-C₁₀) alkylamino, (C₇-C₁₁) aralkanoyl-N- (C₁-C₁₀ ) - alkylamino,
(C₁-C₁₂) alkanoylamino- (C₁-C₈) alkyl, (C₃-C₈) cycloalkanoylamino- (C₁-C₈) alkyl, (C₆-C₁₂) aroylamino- (C₁-C₈) alkyl, (C₇ -C₁₆) - aralkanoylamino- (C₁-C₈) alkyl, amino- (C₁-C₁₀) alkyl, N- (C₁-C₁₀) alkylamino- (C₁-C₁₀) alkyl, N, N-di- (C₁ -C₁₀) alkylamino- (C₁-C₁₀) alkyl, (C₃-C₈) cycloalkylamino- (C₁-C₁₀) alkyl,
(C₁-C₁₂) alkylmercapto, (C₁-C₁₂) alkylsulfinyl, (C₁-C₁₂) alkylsulfonyl, (C₆-C₁₆) arylmercapto, (C₆-C₁₆) arylsulfinyl, (C₆-C₁₆) arylsulfonyl, (C₆ -C₁₆) aralkylmercapto, (C₇-C₁₆) aralkylsulfinyl, (C₇-C₁₆) aralkylsulfonyl,
and
f = 1 to 8,
g = 0.1 to (2f + 1),
x = 0 to 3,
h = 3 to 6 mean
including the physiologically active salts, where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α- ((6,7-dichloro-3,4-dihydro -3-oxo-2-quinoxalinyl) carbonyl) amino) phenyl-acetic acid are excluded.
Q O oder S,
X O,
A (C₁-C₃)-Alkylen, das gegebenenfalls einfach substituiert ist mit Halogen, Cyano, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Hydroxyalkyl, (C₁-C₆)- Alkoxy, -O-[CH₂]x-CfH(2f+1-g)Fg oder
A -CHR⁶- bedeutet, wobei R⁶ einen der Substituenten des α-C-Atoms einer α-Aminosäure bedeutet, insbesondere einer natürlichen L-Aminosäure und ihres D-Isomeren,
B CO₂H
R¹, R², R³ und R⁴ gleich oder verschieden sind und Wasserstoff, (C₁-C₂₀)-Alkyl, (C₂-C₂₀)-Alkenyloxy, (C₂-C₂₀)-Alkinyloxy, Retinyloxy, (C₂-C₂₀)- Alkenyloxy-(C₁-C₃)-alkyl, Retinyloxy-(C₁-C₃)-alkyl, (C₂-C₂₀)-Alkinyloxy- (C₁-C₃)-alkyl, (C₁-C₂₀)-Alkoxy, Halogen, Cyano, Trifluormethyl, (C₁-C₈)- Hydroxyalkyl, (C₁-C₁₀)-Alkanoyl,(C₇-C₁₂)-Aralkanoyl, (C₆-C₁₂)-Aroyl, -O-[CH₂]xCfH(2f+1-g)Fg, (C₁-C₁₀)-Alkylmercapto, (C₁-C₁₀)-Alkylsulfinyl, (C₁-C₁₀)-Alkylsulfonyl, (C₆-C₁₂)-Arylmercapto, (C₆-C₁₂)-Arylsulfinyl, (C₆-C₁₂)-Arylsulfonyl, (C₇-C₁₂)-Aralkylmercapto, (C₇-C₁₂)-Aralkylsulfinyl, (C₇-C₁₂)-Aralkylsulfonyl, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)-Aralkyloxy, Carboxy, (C₁-C₂₀)-Alkoxycarbonyl, (C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkoxycarbonyl, (C₆-C₁₂)-Aryloxycarbonyl, (C₇-C₁₆)-Aralkoxycarbonyl, (C₃-C₈)- Cycloalkoxycarbonyl, (C₂-C₂₀)-Alkenyloxycarbonyl, Retinyloxycarbonyl, (C₂-C₂₀)-Alkinyloxycarbonyl, (C₃-C₈)-Cycloalkyl-(C₁-C₆)-alkoxycarbonyl, (C₃-C₈)-Cycloalkoxy-(C₁-C₆)-alkoxycarbonyl, (C₆-C₁₂)-Aryloxy-(C₁-C₆)- alkoxycarbonyl, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxycarbonyl,
(C₁-C₁₂)-Alkoxy-(C₁-C₁₂)-alkyl, (C₁-C₈)-Alkoxy-(C₁-C₁₂)-alkoxy, (C₁-C₁₂)- Alkoxy-(C₁-C₈)-alkoxy-(C₂-C₆)-alkyl, (C₇-C₁₁)-Aralkyloxy, (C₃-C₈)- Cycloalkyl, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkyloxy, (C₃-C₈)-Cycloalkyl-(C₁-C₈)-alkoxy, (C₃-C₈)-Cycloalkyloxy-(C₁-C₈)-alkyl, (C₃-C₈)-Cycloalkyloxy-(C₁-C₈)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₆)-alkyl- (C₁-C₆)-alkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, (C₃-C₈)- Cycloalkoxy-(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, NRYRZ, substituiertes (C₆-C₁₂)- Aryloxy-(C₁-C₆)-alkyl, (C₇-C₁₁)-Aralkoxy-(C₁-C₆)-alkyl, (C₆-C₁₂)-Aryloxy- (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, (C₇-C₁₁)-Aralkyloxy-(C₁-C₆)-alkoxy (C₁-C₆)- alkyl, (C₆-C₁₂)-Aryloxy, (C₆-C₁₂)-Aryloxy (C₁-C₆)-alkoxy oder (C₇-C₁₁)- Aralkoxy-(C₁-C₆)-alkoxy bedeuten, wobei ein aromatischer Rest mit 1, 2, 3, 4 oder 5 gleichen oder verschiedenen Substituenten aus der Reihe Wasserstoff, Halogen, Cyano, Nitro, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Hydroxyalkyl, (C₁-C₆)-Alkoxy, -O-[CH₂]xCfH(2f+1-g)Fg, -OCF₂Cl, -O-CF₂-CHFCl, (C₁-C₆)-Alkylmercapto, (C₁-C₆)-Alkylsulfinyl, (C₁ -C₆)- Alkylsulfonyl, (C₁-C₆)-Alkylcarbonyl, (C₁-C₆)-Alkoxycarbonyl, Carbamoyl, N-(C₁-C₄)-Alkylcarbamoyl, N,N-Di-(C₁-C₄)-alkylcarbamoyl, (C₁-C₆)- Alkylcarbonyloxy, (C₃-C₈)-Cycloalkylcarbamoyl, Phenyl, Benzyl, Phenoxy, Benzyloxy, NRYRZ, Phenylmercapto, Phenylsulfonyl, Phenylsulfinyl, Sulfamoyl, N-(C₁-C₄)-Alkylsulfamoyl oder N,N-Di-(C₁-C₄)-alkylsulfamoyl trägt, oder gegebenenfalls bis zu 3 der vorstehend genannten gleichen oder verschiedenen Substituenten trägt und zwei benachbarte C-Atome des Aralkyloxyrestes gemeinsam eine Kette -[CH₂-] und/oder -CH=CH-CH=CH- tragen, wobei eine CH₂-Gruppe der Kette gegebenenfalls durch O, S, SO, SO₂ oder NR′ ersetzt ist,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N, N-Di-(C₁-C₁₂)-alkylcarbamoyl, N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo(C₃-C₈)-alkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-cycloalkylcarbamoyl, N-(C₃-C₈)-Cycloalkyl- (C₁-C₆)-alkyl)carbamoyl, N-(C₁-C₆)-Alkyl-N-((C₃-C₈)-cycloalkyl-(C₁-C₆)- alkyl)carbamoyl, N-(+)-Dehydroabietylcarbamoyl, N-(C₁-C₆)-Alkyl-N-(+)- dehydroabietylcarbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)- Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁-C₁₀)- Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)- alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁ ₀)-alkyl)carbamoyl, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl,N-(C₁-C₁₀)-Alkyl-N- ((C₁-C₁₀)-alkoxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₆-C₁₂)-aryloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-(C₁-C₁₀)-Alkyl-N-((C₇-C₁₆)-aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, CON(CH₂)h, worin eine CH₂-Gruppe durch O, S, N-(C₁-C₈)-alkylimino, N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino, N-(C₇-C₁₆)-Aralkylimino oder N-(C₁-C₄)-Alkoxy- (C₁-C₆)-alkylimino ersetzt sein kann und h 3 bis 7 bedeutet,
R¹ und R² oder R² und R³ oder R³ und R⁴ eine Kette [CH₂]o bilden können, wobei o = 3, 4 oder 5 bedeutet,
R⁵ Wasserstoff oder einen verzweigten oder unverzweigten (C₁-C₁₂)- Alkylrest, der bis zu 3 C-C-Mehrfachbindungen enthalten kann, einen (C₆- C₁₆)-Arylrest oder einen (C₇-C₁₆)-Aralkylrest, der bis zu 2 C-C- Mehrfachverbindungen enthalten kann, bedeutet, wobei diese Reste substituiert sind mit einem oder mehreren Resten aus der Reihe Hydroxy, Fluor, Chlor, Cyano, Trifluormethyl, Carboxy, (C₁-C₁₂)-Alkyl, (C₃-C₈)- Cycloalkyl, (C₃-C₈)-Cycloalkoxy, (C₃-C₈)-Cycloalkyl-(C₁-C₁₂)-alkoxy, (C₃-C₈)-Cycloalkyloxy-(C₁-C₁₂)-alkoxy, (C₆-C₁₂)-Aryl, (C₇-C₁ ₆)-Aralkyl, (C₂-C₁₂)-Alkenyl, (C₂-C₁₂)-Alkinyl, (C₁-C₁₂)-Alkoxy, (C₁-C₁₂)-Alkoxy- (C₁-C₁₂)-alkoxy, (C₆-C₁₂)-Aryloxy, (C₇-C₁₆)-Aralkyloxy, (C₆-C₁₂)-Aryloxy- (C₁-C₆)-alkoxy, (C₇-C₁₆)-Aralkoxy-(C₁-C₆)-alkoxy, (C₁-C₈)-Hydroxyalkyl, - O-[CH2-]xCfH(2f+1-g)Fg,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N, N-Di-(C₁-C₁₂)-alkylcarbamoyl, N-(C₃-C₈)-Cycloalkylcarbamoyl, N,N-Dicyclo-(C₃-C₈)-alkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₃-C₈)-cycloalkylcarbamoyl, N-((C₃-C₈)-Cycloalkyl- (C₁-C₆)-alkyl)carbamoyl, N-(C₆-C₁₂)-Arylcarbamoyl, N-(C₇-C₁₆)- Aralkylcarbamoyl, N-(C₁-C₁₀)-Alkyl-N-(C₆-C₁₆)-arylcarbamoyl, N-(C₁-C₁₀)- Alkyl-N-(C₇-C₁₆)-aralkylcarbamoyl, N-((C₁-C₁₀)-Alkoxy-(C₁-C₁₀)- alkyl)carbamoyl, N-((C₆-C₁₆)-Aryloxy-(C₁-C₁₀)-alkyl)carbamoyl, N-((C₇-C₁₆)-Aralkyloxy-(C₁-C₁₀)-alkyl)carbamoyl, CON(CH₂)h, worin eine CH₂-Gruppe durch O, N-(C₁-C₈)-Alkylimino, N-(C₃-C₈)-Cycloalkylimino, N-(C₃-C₈)-Cycloalkyl-(C₁-C₄)-alkylimino, N-(C₆-C₁₂)-Arylimino oder N-(C₇-C₁₆)-Aralkylimino ersetzt sein kann und h 3 bis 6 bedeutet, oder mit
(C₁-C₁₂)-Alkanoylamino, (C₃-C₈)-Cycloalkanoylamino, (C₆-C₁₂)- Aroylamino, (C₇-C₁₆)-Aralkanoylamino, (C₁-C₁₂)-Alkanoyl-N-(C₁-C₁₀)- alkylamino, (C₃-C₈)-Cycloalkanoyl-N-(C₁-C₁₀)-alkylamino,
wobei die Reste, die einen Arylrest enthalten ihrerseits am Aryl substituiert sein können durch 1 bis 5 gleiche oder verschiedene Reste aus der Reihe:
Hydroxy, Fluor, Chlor, Cyano, Trifluormethyl, Carboxy, (C₁-C₁₂)-Alkyl, (C₃-C₈)-Cycloalkyl, (C₂-C₁₂)-Alkenyl, (C₁-C₁₂)-Alkoxy,
Carbamoyl, N-(C₁-C₁₂)-Alkylcarbamoyl, N, N-Di-(C₁-C₁₂)-alkylcarbamoyl, N-(C₃-C₈)-Cycloalkylcarbamoyl, oder (C₁-C₁₂)-Alkylmercapto, (C₁-C₁₂)- Alkylsulfinyl, (C₁-C₁₂)-Alkylsulfonyl,
wobei
RY und RZ gleich oder verschieden sind und Wasserstoff, (C₆-C₁₂)-Aryl, (C₁-C₁₀)-Alkyl, (C₃-C₁₀)-Cycloalkyl, (C₁-C₈)-Alkoxy-(C₁-C₈)-alkyl, (C₇-C₁₂)-Aralkoxy-(C₁-C₈)-alkyl, (C₆-C₁₂)-Aryloxy-(C₁-C₈)-alkyl, (C₁-C₁₀)- Alkanoyl, ggf. substituiertes (C₇-C₁₆)-Aralkanoyl, ggf. substituiertes (C₆-C₁₂)-Aroyl bedeuten oder
RY und RZ gemeinsam für -[CH₂]h- stehen, worin eine CH₂-Gruppe durch O, S, N-(C₁-C₄)-Alkanoylimino oder N-(C₁-C₄)-Alkoxycarbonylimino ersetzt sein kann, und
f 1 bis 8,
g 0, 1 bis (2f+1),
h 3 bis 6,
x 0 bis 3, und
n 3 oder 4 ist,
einschließlich der physiologisch wirksamen Salze wobei N-((6,7-Dichlor-3,4- dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α-((6,7-Dichlor-3,4-dihydro-3- oxo-2-chinoxalinyl)carbonyl)amino) ausgenommen sind.2. Compounds of formula I according to claim 1, in which
QO or S,
XO,
A (C₁-C₃) alkylene, which is optionally monosubstituted with halogen, cyano, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) hydroxyalkyl, (C₁-C₆) alkoxy, -O- [CH₂ ] x -C f H (2f + 1-g) F g or
A means -CHR⁶-, where R⁶ means one of the substituents of the α-C atom of an α-amino acid, in particular a natural L-amino acid and its D isomer,
B CO₂H
R¹, R², R³ and R⁴ are the same or different and are hydrogen, (C₁-C₂₀) alkyl, (C₂-C₂₀) alkenyloxy, (C₂-C₂₀) alkynyloxy, retinyloxy, (C₂-C₂₀) - alkenyloxy- (C₁ -C₃) alkyl, retinyloxy- (C₁-C₃) alkyl, (C₂-C₂₀) alkynyloxy- (C₁-C₃) alkyl, (C₁-C₂₀) alkoxy, halogen, cyano, trifluoromethyl, (C₁-C₈ ) - Hydroxyalkyl, (C₁-C₁₀) alkanoyl, (C₇-C₁₂) aralkanoyl, (C₆-C₁₂) aroyl, -O- [CH₂] x C f H (2f + 1-g) F g , (C₁ -C₁₀) alkylmercapto, (C₁-C₁₀) alkylsulfinyl, (C₁-C₁₀) alkylsulfonyl, (C₆-C₁₂) arylmercapto, (C₆-C₁₂) arylsulfinyl, (C₆-C₁₂) arylsulfonyl, (C₇-C₁ ) Aralkylmercapto, (C₇-C₁₂) aralkylsulfinyl, (C₇-C₁₂) aralkylsulfonyl, (C₆-C₁₂) aryloxy, (C₇-C₁₆) aralkyloxy, carboxy, (C₁-C₂₀) alkoxycarbonyl, (C₁-C₁₂ ) -Alkoxy- (C₁-C₁₂) alkoxycarbonyl, (C₆-C₁₂) aryloxycarbonyl, (C₇-C₁₆) aralkoxycarbonyl, (C₃-C₈) - cycloalkoxycarbonyl, (C₂-C₂₀) -A lkenyloxycarbonyl, retinyloxycarbonyl, (C₂-C₂₀) alkynyloxycarbonyl, (C₃-C₈) cycloalkyl- (C₁-C₆) alkoxycarbonyl, (C₃-C₈) -cycloalkoxy- (C₁-C₆) alkoxycarbonyl, (C₆-C₁₂) - Aryloxy- (C₁-C₆) alkoxycarbonyl, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxycarbonyl,
(C₁-C₁₂) alkoxy- (C₁-C₁₂) alkyl, (C₁-C₈) alkoxy- (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₈) alkoxy- (C₂ -C₆) alkyl, (C₇-C₁₁) aralkyloxy, (C₃-C₈) - cycloalkyl, (C₃-C₈) cycloalkyl- (C₁-C₈) alkyl, (C₃-C₈) cycloalkyloxy, (C₃-C₈ ) -Cycloalkyl- (C₁-C₈) -alkoxy, (C₃-C₈) -cycloalkyloxy- (C₁-C₈) -alkyl, (C₃-C₈) -cycloalkyloxy- (C₁-C₈) -alkoxy, (C₃-C₈) - Cycloalkyl- (C₁-C₆) -alkyl- (C₁-C₆) -alkoxy, (C₃-C -C) -cycloalkyl- (C₁-C₆) -alkoxy- (C₁-C₆) -alkyl, (C₃-C₈) -cycloalkoxy- (C₁-C₆) alkoxy- (C₁-C₆) alkyl, NR Y R Z , substituted (C₆-C₁₂) aryloxy- (C₁-C₆) alkyl, (C₇-C₁₁) aralkoxy- (C₁-C₆ ) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy- (C₁-C₆) alkyl, (C₇-C₁₁) aralkyloxy- (C₁-C₆) alkoxy (C₁-C₆) - alkyl , (C₆-C₁₂) aryloxy, (C₆-C₁₂) aryloxy (C₁-C₆) alkoxy or (C₇-C₁₁) aralkoxy- (C₁-C₆) alkoxy, an aromatic radical having 1, 2, 3, 4 or 5 identical or different substituents from the series hydrogen, halogen, cyano, nitro, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) hydroxyalkyl, (C₁-C₆) alkoxy, -O- [CH₂] x C f H (2f + 1-g) F g , -OCF₂Cl, -O-CF₂-CHFCl, (C₁-C₆) alkylmercapto, (C₁-C₆) alkylsulfinyl, (C₁ -C₆) alkylsulfonyl, (C₁-C₆ ) -Alkylcarbonyl, (C₁-C₆) -alkoxycarbonyl, carbamoyl, N- (C₁-C₄) -alkylcarbamoyl, N, N-di- (C₁-C₄) -alkylcarbamoyl, (C₁-C₆) - alkylcarbonyloxy, (C₃-C₈ ) -Cycloalkylcarbamoyl, phenyl, benzyl, phenoxy, benzyloxy, NR Y R Z , phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N- (C₁-C₄) alkylsulfamoyl or N, N-di- (C₁-C₄) -alkylsulfamoyl, or optionally carries up to 3 of the same or different substituents mentioned above and two adjacent C atoms of the aralkyloxy radical together bear a chain - [CH₂-] and / or -CH = CH-CH = CH-, one CH₂ group of the chain optionally replaced by O, S, SO, SO₂ or NR ' is
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo (C₃-C₈) alkylcarbamoyl, N - (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N- (C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₁-C₆) alkyl-N - ((C₃-C₈) -cycloalkyl- (C₁-C₆) - alkyl) carbamoyl, N - (+) - dehydroabietylcarbamoyl, N- (C₁-C₆) alkyl-N - (+) - dehydroabietylcarbamoyl, N- (C₆ -C₁₂) arylcarbamoyl, N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁-C₁₀) - alkyl-N- (C₇ -C₁₆) aralkylcarbamoyl, N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁ ₀) alkyl) carbamoyl, N - ((C₇-C₁₆) aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N- ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl , N- (C₁-C₁₀) alkyl-N - ((C₆-C₁₂) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N- (C₁-C₁₀) alkyl-N - ((C₇-C₁₆) -aralkylox y- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group is represented by O, S, N- (C₁-C₈) alkylimino, N- (C₃-C₈) cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino, N- (C₇-C₁₆) aralkylimino or N- (C₁-C₄) alkoxy- (C₁-C₆ ) alkylimino can be replaced and h is 3 to 7,
R¹ and R² or R² and R³ or R³ and R⁴ can form a chain [CH₂] o , where o = 3, 4 or 5,
R⁵ is hydrogen or a branched or unbranched (C₁-C₁₂) alkyl radical which can contain up to 3 CC multiple bonds, a (C₆- C₁₆) aryl radical or a (C₇-C₁₆) aralkyl radical which contains up to 2 CC multiple compounds can contain means, where these radicals are substituted with one or more radicals from the series hydroxy, fluorine, chlorine, cyano, trifluoromethyl, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) - cycloalkyl, (C₃-C₈ ) -Cycloalkoxy, (C₃-C₈) -cycloalkyl- (C₁-C₁₂) -alkoxy, (C₃-C₈) -cycloalkyloxy- (C₁-C₁₂) alkoxy, (C₆-C₁₂) aryl, (C₇-C₁ ₆) -Aralkyl, (C₂-C₁₂) alkenyl, (C₂-C₁₂) alkynyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkoxy- (C₁-C₁₂) alkoxy, (C₆-C₁₂) aryloxy , (C₇-C₁₆) aralkyloxy, (C₆-C₁₂) aryloxy- (C₁-C₆) alkoxy, (C₇-C₁₆) aralkoxy- (C₁-C₆) alkoxy, (C₁-C₈) hydroxyalkyl, - O- [CH 2- ] x C f H (2f + 1-g) F g ,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, N, N-dicyclo- (C₃-C₈) alkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₃-C₈) cycloalkylcarbamoyl, N - ((C₃-C₈) cycloalkyl- (C₁-C₆) alkyl) carbamoyl, N- (C₆-C₁₂) arylcarbamoyl , N- (C₇-C₁₆) aralkylcarbamoyl, N- (C₁-C₁₀) alkyl-N- (C₆-C₁₆) arylcarbamoyl, N- (C₁-C₁₀) - alkyl-N- (C₇-C₁₆) aralkylcarbamoyl , N - ((C₁-C₁₀) alkoxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₆-C₁₆) aryloxy- (C₁-C₁₀) alkyl) carbamoyl, N - ((C₇-C₁₆ ) Aralkyloxy- (C₁-C₁₀) alkyl) carbamoyl, CON (CH₂) h , in which a CH₂ group is substituted by O, N- (C₁-C₈) alkylimino, N- (C₃-C₈) cycloalkylimino, N- (C₃-C₈) cycloalkyl- (C₁-C₄) alkylimino, N- (C₆-C₁₂) arylimino or N- (C₇-C₁₆) aralkylimino can be replaced and h is 3 to 6, or with
(C₁-C₁₂) alkanoylamino, (C₃-C₈) cycloalkanoylamino, (C₆-C₁₂) aroylamino, (C₇-C₁₆) aralkanoylamino, (C₁-C₁₂) alkanoyl-N- (C₁-C₁₀) alkylamino, (C₃-C₈) cycloalkanoyl-N- (C₁-C₁₀) alkylamino,
where the radicals which contain an aryl radical in turn can be substituted on the aryl by 1 to 5 identical or different radicals from the series:
Hydroxy, fluorine, chlorine, cyano, trifluoromethyl, carboxy, (C₁-C₁₂) alkyl, (C₃-C₈) cycloalkyl, (C₂-C₁₂) alkenyl, (C₁-C₁₂) alkoxy,
Carbamoyl, N- (C₁-C₁₂) alkylcarbamoyl, N, N-di- (C₁-C₁₂) alkylcarbamoyl, N- (C₃-C₈) cycloalkylcarbamoyl, or (C₁-C₁₂) alkylmercapto, (C₁-C₁₂) - alkylsulfinyl, (C₁-C₁₂) alkylsulfonyl,
in which
R Y and R Z are the same or different and are hydrogen, (C₆-C₁₂) aryl, (C₁-C₁₀) alkyl, (C₃-C₁₀) cycloalkyl, (C₁-C₈) alkoxy- (C₁-C₈) - alkyl, (C₇-C₁₂) aralkoxy- (C₁-C₈) alkyl, (C₆-C₁₂) aryloxy- (C₁-C₈) alkyl, (C₁-C₁₀) alkanoyl, optionally substituted (C₇-C₁₆) Aralkanoyl, optionally substituted (C₆-C₁₂) aroyl or
R Y and R Z together represent - [CH₂] h -, in which a CH₂ group can be replaced by O, S, N- (C₁-C₄) alkanoylimino or N- (C₁-C₄) alkoxycarbonylimino, and
f 1 to 8,
g 0.1 to (2f + 1),
h 3 to 6,
x 0 to 3, and
n is 3 or 4,
including the physiologically active salts where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7-dichloro-3,4-dihydro- 3-oxo-2-quinoxalinyl) carbonyl) amino) are excluded.
Q O oder S,
X O,
A -CHR⁶-, wobei R⁶ den Substituenten des α-C-Atoms einer α-Aminosäure bedeutet, insbesondere einer natürlichen L-Aminosäure oder ihr D-Isomeres,
B CO₂H,
R¹, R², R³ und R⁴ gleich oder verschieden sind und Wasserstoff, (C₁-C₁₂)-Alkyl, (C₃-C₇)-Cycloalkyl, (C₁-C₁₂)-Alkoxy, (C₃-C₇)-Cycloalkyloxy, (C₃-C₇)- Cycloalkyl-(C₁-C₂)-alkoxy, -O-[CH₂]x-CfH(2f+1-g)Fg, (C₁-C₄)-Alkoxy- (C₁-C₄)-alkoxy, substituiertes (C₆-C₁₂)-Phenoxy, (C₇-C₁₁)-Phenylalkyloxy, (C₆-C₁₂)-Phenoxy-(C₁-C₄)-alkoxy, (C₇-C₁₁)-Phenylalkoxy-(C₁-C₄)-alkoxy, Fluor, Trifluormethyl, Chlor, N-(C₁-C₁₀)-Alkylcarbamoyl, N, N-Di-(C₁-C₈)- alkylcarbamoyl, N-(C₃-C₇)-Cycloalkylcarbamoyl, N-Phenylcarbamoyl, N-Phenyl-(C₁-C₄)-alkylcarbamoyl, Carboxy, (C₁-C₁₆)-Alkoxycarbonyl, (C₂-C₁₆)-Alkenyloxycarbonyl, Retinyloxycarbonyl, (C₃-C₇)- Cycloalkoxycarbonyl, bedeutet, wobei ein aromatischer Rest mit 1, 2 oder 3 gleichen oder verschiedenen Substituenten aus der Reihe Fluor, Chlor, Cyano, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy substituiert ist
R⁵ Wasserstoff oder einen verzweigten oder unverzweigten (C₁-C₁₂)- Alkylrest, der eine oder zwei C-C-Mehrfachbindungen enthalten kann, und
f 1 bis 4
g 0,1 bis(2f+1)
x 0 und 1 bedeutet,
einschließlich der physiologisch wirksamen Salze, wobei N-((6,7-Dichlor-3,4- dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α-((6,7-Dichlor-3,4-dihydro-3- oxo-2-chinoxalinyl)carbonyl)amino)phenylessigsäure ausgenommen sind.3. Compounds of formula I according to claims 1 or 2, in which
QO or S,
XO,
A -CHR⁶-, where R⁶ is the substituent of the α-C atom of an α-amino acid, in particular a natural L-amino acid or its D isomer,
B CO₂H,
R¹, R², R³ and R⁴ are the same or different and are hydrogen, (C₁-C₁₂) alkyl, (C₃-C₇) cycloalkyl, (C₁-C₁₂) alkoxy, (C₃-C₇) cycloalkyloxy, (C₃-C₇ ) - Cycloalkyl- (C₁-C₂) alkoxy, -O- [CH₂] x -C f H (2f + 1-g) F g , (C₁-C₄) alkoxy- (C₁-C₄) alkoxy, substituted (C₆-C₁₂) phenoxy, (C₇-C₁₁) phenylalkyloxy, (C₆-C₁₂) phenoxy- (C₁-C₄) alkoxy, (C₇-C₁₁) phenylalkoxy- (C₁-C₄) alkoxy, fluorine, Trifluoromethyl, chlorine, N- (C₁-C₁₀) alkylcarbamoyl, N, N-di- (C₁-C₈) alkylcarbamoyl, N- (C₃-C₇) cycloalkylcarbamoyl, N-phenylcarbamoyl, N-phenyl- (C₁-C₄ ) -alkylcarbamoyl, carboxy, (C₁-C₁₆) alkoxycarbonyl, (C₂-C₁₆) alkenyloxycarbonyl, retinyloxycarbonyl, (C₃-C₇) - cycloalkoxycarbonyl, where an aromatic radical having 1, 2 or 3 identical or different substituents from the Series fluorine, chlorine, cyano, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy is substituted
R⁵ is hydrogen or a branched or unbranched (C₁-C₁₂) alkyl radical, which can contain one or two CC multiple bonds, and
f 1 to 4
g 0.1 to (2f + 1)
x means 0 and 1,
including the physiologically active salts, where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7-dichloro-3,4-dihydro -3-oxo-2-quinoxalinyl) carbonyl) amino) phenylacetic acid are excluded.
Q O,
X O,
A eine -CH₂-Gruppe bedeutet, die mit einer Methylgruppe substituiert sein kann,
B CO₂H,
R¹, R², R³ und R⁴ gleich oder verschieden sind und Wasserstoff, (C₁-C₁₂)-Alkyl, (C₃-C₇)-Cycloalkyl, (C₁-C₁₂)-Alkoxy, (C₃-C₇)-Cycloalkyloxy, (C₃-C₇)- Cycloalkyl-(C₁-C₂)-alkoxy, -O-[CH₂]x-CfH(2f+1-g)Fg, (C₁-C₄)-Alkoxy- (C₁-C₄)-alkoxy, substituiertes (C₆-C₁₂)-Phenoxy, (C₇-C₁₁)-Phenylalkyloxy, (C₆-C₁₂)-Phenoxy-(C₁-C₄)-alkoxy, (C₇-C₁₁)-Phenylalkoxy-(C₁-C₄)-alkoxy, Fluor, Trifluormethyl, Chlor, N-(C₁-C₁₀)-Alkylcarbamoyl, N, N-Di-(C₁-C₈)- alkylcarbamoyl, N-(C₃-C₇)-Cycloalkylcarbamoyl, N-Phenylcarbamoyl, N-Phenyl-(C₁-C₄)-alkylcarbamoyl, Carboxy, (C₁-C₁₆)-Alkoxycarbonyl, (C₂-C₁₆)-Alkenyloxycarbonyl, Retinyloxycarbonyl, (C₃-C₇)- Cycloalkoxycarbonyl, bedeutet, wobei ein aromatischer Rest mit 1, 2 oder 3 gleichen oder verschiedenen Substituenten aus der Reihe Fluor, Chlor, Cyano, Trifluormethyl, (C₁-C₆)-Alkyl, (C₁-C₆)-Alkoxy substituiert ist und
R⁵ Wasserstoff oder einen verzweigten oder unverzweigten (C₁-C₆)-Alkylrest bedeutet und
f 1 bis 4,
g 0,1 bis (2f+1) und
x 0 und 1 bedeuten,
einschließlich der physiologisch wirksamen Salze, wobei N-((6,7-Dichlor-3,4- dihydro-3-oxo-2-chinoxalinyl)carbonyl)glycin und α-((6,7-Dichlor-3,4-dihydro-3- oxo-2-chinoxalinyl)carbonyl)amino)phenylessigsäure ausgenommen sind.4. Compounds of formula I according to one or more of claims 1 to 3, in which
QO,
XO,
A represents a -CH₂ group which can be substituted by a methyl group,
B CO₂H,
R¹, R², R³ and R⁴ are the same or different and are hydrogen, (C₁-C₁₂) alkyl, (C₃-C₇) cycloalkyl, (C₁-C₁₂) alkoxy, (C₃-C₇) cycloalkyloxy, (C₃-C₇ ) - Cycloalkyl- (C₁-C₂) alkoxy, -O- [CH₂] x -C f H (2f + 1-g) F g , (C₁-C₄) alkoxy- (C₁-C₄) alkoxy, substituted (C₆-C₁₂) phenoxy, (C₇-C₁₁) phenylalkyloxy, (C₆-C₁₂) phenoxy- (C₁-C₄) alkoxy, (C₇-C₁₁) phenylalkoxy- (C₁-C₄) alkoxy, fluorine, Trifluoromethyl, chlorine, N- (C₁-C₁₀) alkylcarbamoyl, N, N-di- (C₁-C₈) alkylcarbamoyl, N- (C₃-C₇) cycloalkylcarbamoyl, N-phenylcarbamoyl, N-phenyl- (C₁-C₄ ) -alkylcarbamoyl, carboxy, (C₁-C₁₆) alkoxycarbonyl, (C₂-C₁₆) alkenyloxycarbonyl, retinyloxycarbonyl, (C₃-C₇) - cycloalkoxycarbonyl, where an aromatic radical having 1, 2 or 3 identical or different substituents from the Series fluorine, chlorine, cyano, trifluoromethyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy is substituted and
R⁵ is hydrogen or a branched or unbranched (C₁-C₆) alkyl radical and
f 1 to 4,
g 0.1 to (2f + 1) and
x means 0 and 1,
including the physiologically active salts, where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7-dichloro-3,4-dihydro -3-oxo-2-quinoxalinyl) carbonyl) amino) phenylacetic acid are excluded.
Q O,
X O,
A eine -CH₂-Gruppe und,
B CO₂H bedeutet, und
R¹ und R⁴ gleich oder verschieden sind und Wasserstoff, Fluor, Chlor und (C₁-C₄)-Alkyl bedeuten,
R² und R³ gleich oder verschieden sind und Wasserstoff, Fluor, Chlor, (C₁-C₁₂)- Alkoxy, (C₃-C₇)-Cycloalkoxy, -O-[CH₂]x-CfH(2f+1-g)Fg, (C₁-C₄)-Alkyl, Benzyloxy, gegebenenfalls substituiert mit bis zu 3 Substituenten aus der Reihe Fluor, Chlor, Trifluormethyl, (C₁-C₆)-Alkoxy, (C₁-C₆)-Alkyl, O[CH₂)x-CfH(2f+1-g)Fg bedeuten,
R⁵ Wasserstoff oder (C₁-C₆)-Alkyl bedeutet und
f 1 bis 4,
g 0,1 bis (2f+1),
x 0 und 1 bedeuten und
deren physiologisch wirksamen Salze, wobei N-((6,7-Dichlor-3,4-dihydro-3-oxo- 2-chinoxalinyl)carbonyl)glycin und α-((6,7-Dichlor-3,4-dihydro-3-oxo-2- chinoxalinyl)carbonyl)amino)phenylessigsäure ausgenommen sind.5. Compounds of formula I according to one or more of claims 1 to 4, in which
QO,
XO,
A is a -CH₂ group and,
B means CO₂H, and
R¹ and R⁴ are identical or different and are hydrogen, fluorine, chlorine and (C₁-C₄) alkyl,
R² and R³ are the same or different and are hydrogen, fluorine, chlorine, (C₁-C₁₂) alkoxy, (C₃-C₇) cycloalkoxy, -O- [CH₂] x -C f H (2f + 1-g) F g , (C₁-C₄) alkyl, benzyloxy, optionally substituted with up to 3 substituents from the series fluorine, chlorine, trifluoromethyl, (C₁-C₆) alkoxy, (C₁-C₆) alkyl, O [CH₂) x -C f H (2f + 1-g) F g mean
R⁵ is hydrogen or (C₁-C₆) alkyl and
f 1 to 4,
g 0.1 to (2f + 1),
x mean 0 and 1 and
their physiologically active salts, where N - ((6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxalinyl) carbonyl) glycine and α - ((6,7-dichloro-3,4-dihydro- 3-oxo-2-quinoxalinyl) carbonyl) amino) phenylacetic acid are excluded.
- i1) substituierte o-Phenylendiamine der Formel 4 mit Mesoxalsäureestern der Formel 2 zu Verbindungen der Formel 5 oder
- i2) substituierte 2-Nitroaniline der Formel 1 mit Mesoxalsäureestern der Formel 2 zu den Iminen der Formel 3 umgesetzt werden und anschließend nach Reduktion der Nitrogruppe der Ring zur Verbindung der Formel 5 geschlossen wird und
- ii1) die Verbindungen der Formel 5 zu Verbindungen der Formel 7 verseift werden (R⁵=H) oder
- ii2) die Verbindungen der Formel 5 zu Verbindungen der Formel 6 halogeniert werden und diese anschließend zu Verbindungen der Formel 7 umsetzt und
- iii) die Verbindungen der Formel 7 mit Verbindungen der Formel 8 zu Verbindungen der Formel 9 umsetzt und ggf.
- iv1) eine Verseifung zu Verbindungen der Formel I und/oder
- iv2) die Salzbildung erfolgt.
- i1) substituted o-phenylenediamines of the formula 4 with mesoxalic acid esters of the formula 2 to give compounds of the formula 5 or
- i2) substituted 2-nitroanilines of the formula 1 are reacted with mesoxalic acid esters of the formula 2 to give the imines of the formula 3 and then, after reduction of the nitro group, the ring for the compound of the formula 5 is closed and
- ii1) the compounds of formula 5 are saponified to give compounds of formula 7 (R⁵ = H) or
- ii2) the compounds of formula 5 are halogenated to compounds of formula 6 and these are subsequently converted to compounds of formula 7 and
- iii) reacting the compounds of the formula 7 with compounds of the formula 8 to give compounds of the formula 9 and optionally
- iv1) saponification to give compounds of the formula I and / or
- iv2) salt formation occurs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1995104226 DE19504226A1 (en) | 1995-02-09 | 1995-02-09 | New N-(carboxy-alkanoyl) derivs. of hydroxy-quinoxaline carboxamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1995104226 DE19504226A1 (en) | 1995-02-09 | 1995-02-09 | New N-(carboxy-alkanoyl) derivs. of hydroxy-quinoxaline carboxamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19504226A1 true DE19504226A1 (en) | 1996-08-22 |
Family
ID=7753520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1995104226 Withdrawn DE19504226A1 (en) | 1995-02-09 | 1995-02-09 | New N-(carboxy-alkanoyl) derivs. of hydroxy-quinoxaline carboxamide |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE19504226A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1020453A4 (en) * | 1997-09-01 | 2000-11-08 | Kyorin Seiyaku Kk | 6,7-ASYMMETRICAL DISUBSTITUTED QUINOXALINECARBOXYLIC ACID DERIVATIVES, ADDITION SALTS THEREOF, AND PROCESSES FOR PREPARING THESE DERIVATIVES AND SALTS |
-
1995
- 1995-02-09 DE DE1995104226 patent/DE19504226A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1020453A4 (en) * | 1997-09-01 | 2000-11-08 | Kyorin Seiyaku Kk | 6,7-ASYMMETRICAL DISUBSTITUTED QUINOXALINECARBOXYLIC ACID DERIVATIVES, ADDITION SALTS THEREOF, AND PROCESSES FOR PREPARING THESE DERIVATIVES AND SALTS |
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