IE892522L - Peptides having bradykinin antagonist action - Google Patents
Peptides having bradykinin antagonist actionInfo
- Publication number
- IE892522L IE892522L IE892522A IE252289A IE892522L IE 892522 L IE892522 L IE 892522L IE 892522 A IE892522 A IE 892522A IE 252289 A IE252289 A IE 252289A IE 892522 L IE892522 L IE 892522L
- Authority
- IE
- Ireland
- Prior art keywords
- arg
- pro
- tic
- ser
- hyp
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 74
- 102000004196 processed proteins & peptides Human genes 0.000 title abstract description 31
- 230000009471 action Effects 0.000 title abstract description 5
- UYRCOTSOPWOSJK-JXTBTVDRSA-N bradykinin antagonist Chemical compound C1C2=CC=CC=C2CC1[C@@H](NC(=O)C(CO)NC(=O)C(NC(=O)CNC(=O)[C@H]1N(C[C@H](O)C1)C(=O)C1N(CCC1)C(=O)C(CCCNC(N)=N)NC(=O)[C@@H](CCCNC(N)=N)NC(=N)CCCCCCC(=N)N[C@H](CCCNC(N)=N)C(=O)NC(CCCNC(N)=N)C(=O)N1C(CCC1)C(=O)N1[C@@H](C[C@@H](O)C1)C(=O)NCC(=O)NC(C1CC2=CC=CC=C2C1)C(=O)NC(CO)C(=O)N[C@H](C1CC2=CC=CC=C2C1)C(=O)N1C2CCCCC2CC1C(=O)NC(CCCNC(N)=N)C(O)=O)C1CC2=CC=CC=C2C1)C(=O)N1C2CCCCC2CC1C(=O)NC(CCCNC(=N)N)C(O)=O UYRCOTSOPWOSJK-JXTBTVDRSA-N 0.000 title description 5
- 239000003152 bradykinin antagonist Substances 0.000 title description 5
- -1 aromatic amino acid Chemical class 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 8
- 102400000967 Bradykinin Human genes 0.000 claims abstract description 7
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 claims abstract description 7
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 claims abstract description 7
- 101800004538 Bradykinin Proteins 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 5
- 101710097732 Bradykinin-related peptides Proteins 0.000 claims abstract description 4
- 230000001575 pathological effect Effects 0.000 claims abstract description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract 2
- 125000006239 protecting group Chemical group 0.000 claims description 22
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 18
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical group NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 210000004899 c-terminal region Anatomy 0.000 claims description 6
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 5
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000012634 fragment Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 241000534944 Thia Species 0.000 claims description 3
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 3
- 229960002591 hydroxyproline Drugs 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 3
- AXEOMQHKTSGLGS-VIFPVBQESA-N (2s)-2-amino-3-(4-hydroxy-2-methylphenyl)propanoic acid Chemical compound CC1=CC(O)=CC=C1C[C@H](N)C(O)=O AXEOMQHKTSGLGS-VIFPVBQESA-N 0.000 claims description 2
- PDELQDSYLBLPQO-JGVFFNPUSA-N (3as,7ar)-2,3,3a,4,5,6,7,7a-octahydro-1h-indole Chemical compound C1CCC[C@H]2NCC[C@@H]21 PDELQDSYLBLPQO-JGVFFNPUSA-N 0.000 claims description 2
- NENLYAQPNATJSU-IUCAKERBSA-N (4as,8ar)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCC[C@@H]2CCCC[C@H]21 NENLYAQPNATJSU-IUCAKERBSA-N 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- CVZZNRXMDCOHBG-UHFFFAOYSA-N 2-azaniumyl-3-(2-chlorophenyl)propanoate Chemical group OC(=O)C(N)CC1=CC=CC=C1Cl CVZZNRXMDCOHBG-UHFFFAOYSA-N 0.000 claims description 2
- NYCRCTMDYITATC-UHFFFAOYSA-N 2-fluorophenylalanine Chemical group OC(=O)C(N)CC1=CC=CC=C1F NYCRCTMDYITATC-UHFFFAOYSA-N 0.000 claims description 2
- NIGWMJHCCYYCSF-UHFFFAOYSA-N Fenclonine Chemical group OC(=O)C(N)CC1=CC=C(Cl)C=C1 NIGWMJHCCYYCSF-UHFFFAOYSA-N 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- VWHRYODZTDMVSS-QMMMGPOBSA-N m-fluoro-L-phenylalanine Chemical group OC(=O)[C@@H](N)CC1=CC=CC(F)=C1 VWHRYODZTDMVSS-QMMMGPOBSA-N 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000008177 pharmaceutical agent Substances 0.000 claims 2
- NENLYAQPNATJSU-DTWKUNHWSA-N (4as,8as)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCC[C@@H]2CCCC[C@@H]21 NENLYAQPNATJSU-DTWKUNHWSA-N 0.000 claims 1
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims 1
- JJDJLFDGCUYZMN-QMMMGPOBSA-N 3-chloro-L-phenylalanine Chemical group OC(=O)[C@@H](N)CC1=CC=CC(Cl)=C1 JJDJLFDGCUYZMN-QMMMGPOBSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 abstract description 25
- 238000010647 peptide synthesis reaction Methods 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 125000001589 carboacyl group Chemical group 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 230000002459 sustained effect Effects 0.000 abstract 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 141
- 239000011347 resin Substances 0.000 description 31
- 229920005989 resin Polymers 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 235000001014 amino acid Nutrition 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 150000003862 amino acid derivatives Chemical class 0.000 description 13
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 230000008878 coupling Effects 0.000 description 10
- 238000010168 coupling process Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- 108010068380 arginylarginine Proteins 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000010532 solid phase synthesis reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 3
- DVBUCBXGDWWXNY-SFHVURJKSA-N (2s)-5-(diaminomethylideneamino)-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C3=CC=CC=C3C2=C1 DVBUCBXGDWWXNY-SFHVURJKSA-N 0.000 description 2
- GOUUPUICWUFXPM-XIKOKIGWSA-N (2s,4r)-1-(9h-fluoren-9-ylmethoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid Chemical compound C1[C@H](O)C[C@@H](C(O)=O)N1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 GOUUPUICWUFXPM-XIKOKIGWSA-N 0.000 description 2
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 2
- ODSNARDHJFFSRH-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-isoindole Chemical compound C1CCCC2CNCC21 ODSNARDHJFFSRH-UHFFFAOYSA-N 0.000 description 2
- OEBIVOHKFYSBPE-UHFFFAOYSA-N 4-Benzyloxybenzyl alcohol Chemical compound C1=CC(CO)=CC=C1OCC1=CC=CC=C1 OEBIVOHKFYSBPE-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HNDVDQJCIGZPNO-RXMQYKEDSA-N D-histidine Chemical compound OC(=O)[C@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-RXMQYKEDSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 description 1
- CNMAQBJBWQQZFZ-LURJTMIESA-N (2s)-2-(pyridin-2-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC=N1 CNMAQBJBWQQZFZ-LURJTMIESA-N 0.000 description 1
- VVQIIIAZJXTLRE-QMMMGPOBSA-N (2s)-2-amino-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound CC(C)(C)OC(=O)NCCCC[C@H](N)C(O)=O VVQIIIAZJXTLRE-QMMMGPOBSA-N 0.000 description 1
- SNZIFNXFAFKRKT-NSHDSACASA-N (2s)-2-azaniumyl-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoate Chemical compound CC(C)(C)OC1=CC=C(C[C@H]([NH3+])C([O-])=O)C=C1 SNZIFNXFAFKRKT-NSHDSACASA-N 0.000 description 1
- MXWMFBYWXMXRPD-YFKPBYRVSA-N (2s)-2-azaniumyl-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoate Chemical compound CC(C)(C)OC(=O)C[C@H](N)C(O)=O MXWMFBYWXMXRPD-YFKPBYRVSA-N 0.000 description 1
- ONOURAAVVKGJNM-SCZZXKLOSA-N (2s,3r)-2-azaniumyl-3-phenylmethoxybutanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])[C@@H](C)OCC1=CC=CC=C1 ONOURAAVVKGJNM-SCZZXKLOSA-N 0.000 description 1
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- ADKDJHASTPQGEO-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[b]pyrrole Chemical compound C1CNC2CCCC21 ADKDJHASTPQGEO-UHFFFAOYSA-N 0.000 description 1
- UZHVXJZEHGSWQV-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole Chemical compound C1NCC2CCCC21 UZHVXJZEHGSWQV-UHFFFAOYSA-N 0.000 description 1
- SBUWIPJHZAJVSM-UHFFFAOYSA-N 1,2,3,3a,4,5,6,7,8,8a-decahydrocyclohepta[b]pyrrole Chemical compound C1CCCCC2NCCC21 SBUWIPJHZAJVSM-UHFFFAOYSA-N 0.000 description 1
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 description 1
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- PDELQDSYLBLPQO-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-indole Chemical compound C1CCCC2NCCC21 PDELQDSYLBLPQO-UHFFFAOYSA-N 0.000 description 1
- MFOUWLGLIHXCOZ-UHFFFAOYSA-N 2,3,3a,4,5,7a-hexahydro-1h-indole Chemical compound C1CC=CC2NCCC21 MFOUWLGLIHXCOZ-UHFFFAOYSA-N 0.000 description 1
- LXUNZSDDXMPKLP-UHFFFAOYSA-N 2-Methylbenzenethiol Chemical compound CC1=CC=CC=C1S LXUNZSDDXMPKLP-UHFFFAOYSA-N 0.000 description 1
- WSSDGZWSPMAECX-UHFFFAOYSA-N 2-azabicyclo[3.1.0]hexane Chemical compound C1CNC2CC21 WSSDGZWSPMAECX-UHFFFAOYSA-N 0.000 description 1
- WTOFYLAWDLQMBZ-UHFFFAOYSA-N 2-azaniumyl-3-thiophen-2-ylpropanoate Chemical compound OC(=O)C(N)CC1=CC=CS1 WTOFYLAWDLQMBZ-UHFFFAOYSA-N 0.000 description 1
- NINJAJLCZUYDGV-UHFFFAOYSA-N 2-azaspiro[4.4]nonane Chemical compound C1CCCC21CNCC2 NINJAJLCZUYDGV-UHFFFAOYSA-N 0.000 description 1
- SFCOKGCNIPSUQF-UHFFFAOYSA-N 2-azaspiro[4.5]decane Chemical compound C1NCCC21CCCCC2 SFCOKGCNIPSUQF-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- GYLMCBOAXJVARF-UHFFFAOYSA-N 3-azabicyclo[2.2.1]heptane Chemical compound C1C2CCC1NC2 GYLMCBOAXJVARF-UHFFFAOYSA-N 0.000 description 1
- KPUSZZFAYGWAHZ-UHFFFAOYSA-N 3-azabicyclo[2.2.2]octane Chemical compound C1CC2CCC1NC2 KPUSZZFAYGWAHZ-UHFFFAOYSA-N 0.000 description 1
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- XWHHYOYVRVGJJY-QMMMGPOBSA-N 4-fluoro-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(F)C=C1 XWHHYOYVRVGJJY-QMMMGPOBSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006418 4-methylphenylsulfonyl group Chemical group 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N Cysteine Chemical compound SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 241001071944 Cyta Species 0.000 description 1
- AGPKZVBTJJNPAG-RFZPGFLSSA-N D-Isoleucine Chemical compound CC[C@@H](C)[C@@H](N)C(O)=O AGPKZVBTJJNPAG-RFZPGFLSSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 description 1
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 1
- OUYCCCASQSFEME-MRVPVSSYSA-N D-tyrosine Chemical compound OC(=O)[C@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-MRVPVSSYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N Glutamine Chemical compound OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101001039684 Homo sapiens mRNA cap guanine-N7 methyltransferase Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- VGALFAWDSNRXJK-VIFPVBQESA-N L-aspartic acid beta-benzyl ester Chemical compound OC(=O)[C@@H](N)CC(=O)OCC1=CC=CC=C1 VGALFAWDSNRXJK-VIFPVBQESA-N 0.000 description 1
- QEFRNWWLZKMPFJ-YGVKFDHGSA-N L-methionine S-oxide Chemical compound CS(=O)CC[C@H](N)C(O)=O QEFRNWWLZKMPFJ-YGVKFDHGSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001484259 Lacuna Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Chemical compound CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- KAFHLONDOVSENM-HNNXBMFYSA-N O-Benzyl-L-tyrosine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1OCC1=CC=CC=C1 KAFHLONDOVSENM-HNNXBMFYSA-N 0.000 description 1
- GEYBMYRBIABFTA-VIFPVBQESA-N O-methyl-L-tyrosine Chemical compound COC1=CC=C(C[C@H](N)C(O)=O)C=C1 GEYBMYRBIABFTA-VIFPVBQESA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 240000002390 Pandanus odoratissimus Species 0.000 description 1
- 235000005311 Pandanus odoratissimus Nutrition 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 208000012866 low blood pressure Diseases 0.000 description 1
- 102100040949 mRNA cap guanine-N7 methyltransferase Human genes 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- MSWIFFGHKBTPMY-VFUQPONKSA-L magnesium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O MSWIFFGHKBTPMY-VFUQPONKSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N methionine Chemical compound CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- IOPLHGOSNCJOOO-UHFFFAOYSA-N methyl 3,4-diaminobenzoate Chemical compound COC(=O)C1=CC=C(N)C(N)=C1 IOPLHGOSNCJOOO-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001681 protective effect Effects 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
- 230000005588 protonation Effects 0.000 description 1
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000019100 sperm motility Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- ZERULLAPCVRMCO-UHFFFAOYSA-N sulfure de di n-propyle Natural products CCCSCCC ZERULLAPCVRMCO-UHFFFAOYSA-N 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N tryptophan Chemical compound C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/18—Kallidins; Bradykinins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Genetics & Genomics (AREA)
- Cardiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Peptides of the formula I A-B-C-E-F-K-(D)-Tic-G-M-F'-I (I> in which A is hydrogen, alkyl, alkanoyl, alkoxycarbonyl, alkylsulphonyl, cycloalkyl, aryl, arylsulphonyl, heteroaryl or an amino acid, each of which can optionally be substituted, B is a basic amino acid, C is a di- or tripeptide, E is the residue of an aromatic amino acid, F is, independently of one another, an amino acid which is optionally substituted in the side chain or is a direct bond, G is an amino acid, F' is defined as F, can be -NH-(CH2)2-8 or optionally a direct bond, I is -OH, -NH2 or -NHC2H5 and K is a radical -NH(CH2)-1-4-CO- or is a direct bond, have bradykinin-antagonistic action. Their therapeutic uses comprise all pathological states which are promoted, induced or sustained by bradykinin and bradykinin- related peptides. The peptides of the formula I are prepared by known methods of peptide synthesis.
Description
The invention relates to novel peptides having bradykinin antagonist action and to a process for their preparation.
Bradykinin antagonist peptides are described in WO 86/07263 in which, inter alia, L-Pro in position 7 of 5 the peptide hormone bradykinin or other bradykinin analogs is replaced by a D-amino acid, such as D-Phe, D-Thi, D-Pal, CDF, D-Nal, MDY, D-Phg, D-His, D-Trp, D-Tyr, D-hPhe, D-Val, D-Ala, D-His, D-Ile, D-Leu and DOMT.
The invention is based on the object of finding novel active peptides having bradykinin antagonist action.
This object is achieved by the peptides of the formula I A-B-C-E-F-K-(D)-Tic-G-M-F-I (I) ' in which A ax) is hydrogen, (C^-Cg) -alkyl, (C^-Cg) -alkanoyl, (Cx-C8) -alkoxycarbonyl or (C1-C8) - alkyl sulfonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or three identical or different radicals from the group comprising carboxyl, amino, (C^-C^)-alkyl, (C1-C4)-alkylamino, hydroxyl, (C1-C3)-alkoxy, halogen, di- (C1-C4) - alkylamino, carbamoyl, sulfamoyl, (C1-C4) -alkoxycarbonyl , (C6-C12) -aryl and (C6-C12)-aryl-(C1-C5)-alkyl, or in which in each case 1 hydrogen atom is optionally replaced by a radical from the group comprising (C3-C8 ) - cycloalkyl, (C1-C4)- alkylsulfonyl, (C1-C4)-alkylsulfynyl, (c6-c12)-aryl-(ci"c4)-alkylsuifonyl, (C6"C12^ " aryl-(C^-C^) -alkylsulfynyl, (Cg-C12)-aryloxy, (C3-C9)-heteroaryl and (C3-C9)-heteroaryloxy and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals from the group comprising carboxyl, amino, (C-^-C^) -alkylamino, hydroxyl, (C^-C^)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (C1-C4) -alkoxycarbonyl, (C6 -C12) -aryl and (Cg-C12)-aryl-(C^-C^) -5 alkyl, a2) is (C3-C8) -cycloalkyl, carbamoyl, which can optionally be substituted on the nitrogen by (C^-C6) -alkyl or (C6-C12)-aryl, (C6-C12) -aryl, (C7-C18) aryloyl, (C6"C12^ -aryl- sulfonyl or (C3-Cg)-heteroaryl, or (C3-Cg)-heter- oaryloyl, where in the radicals defined tinder aa) and a2) in each case hetroaryl, arlyloyl, arylsulfonyl and heteroaryloyl is optionally substituted by 1, 2, 3 or 4 different 15 radicals from the group comprising carboxyl, amino, nitro, (C1-C4)-alkylamino, hydroxyl, (C1-C4)-alkyl, (Cx-C4) -alkoxy, halogen, cyano, di-(C1-C4) -alkylamino, carbamoyl, sulfamoyl and (C^-C^) -alkoxycarbonyl, or a-,) is a radical of the formula II R ( 1 ) N—CH —C (II) I I H R(2) *(5)0 defined as A under ax) or a2) , hydrogen or methyl, hydrogen or (C^-Cg) -alkyl, preferably (C^-C^)-alkyl,which is optionally monosubstituted by amino, substituted amino, hydroxyl, carboxyl, carbamoyl, guanidino, substituted guanidino, u r e i d o , mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitro-phenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3rpyridyl or cyclohexyl, 3 5 where substituted amino is a compound -NH-A- and substituted guanidino is a compound -NH-C(NH) -NH-A, in which A is defined, as under ax) or a2) ; where R(1) is R(2) is R(3) is B is Arg, lys, Orn, 2,4-diaminobutyroyl or an L- homoginine radical, where in each case the amino or the guanidino group of the side chain can be substituted by A as described under ax) or a2) ; C is a compound of the formula Ilia or Illb G'-G'-Gly G*-NH-(CH2)n-CO ("la) (Mb), where G' independently of one another are a radical of the formula IV . „ ._ .
R(4)R(5) © I I II N —CH —C — (IV) in which R(4* and Rt5^ together with the atoms carrying them form a heterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms, and n is 2 to 8; E is the radical of phenylalanine, which is optionally substituted by halogen in the 2-,3- or 4-position, tyrosine, O-methyltyrosine, 2-thieny-lalanine, 2-pyridylalanine or naphthylalanine; F independently of one another is the radical of a neutral, acidic or basic, aliphatic or aromatic amino acid, which can be substituted in the side chain, or is a direct bond; (D)-Tic is the radical of the formula V (V) G is as defined for G' or is a direct bond; F' is the radical of the basic amino acids Arg or Lys in the L- or D-form, or a direct bond, where the guanidino group or amino group of the side chain can be substituted by A as defined under ax) or a2) , or a radical -NH-(CH2)n- with n = 2-8, or is a direct bond: I is -OH, -NH2 or -NHC2H5; K is the radical -NH- (CH2)x-CO with x = 1-4 or is a direct bond; M is as defined for F, and their physiologically tolerable salts.
If not stated otherwise, the abbreviation of an amino acid radical without a stereodescriptor stands for the radical in the L-fonn (compare Schroder, Lubke, The Peptides, Volume I, New York 1965, pages XXII-XXIII; Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Volume XV/1 and 2, Stuttgart 1974), such as, for example, Aad, Abu, TAbu, ABz, 2ABz, cAca, Ach, Acp, Adpd, Abb, Alb, (Aib, Ala, &Ala, Ala, Alg, All, Aaa, Amt, Ape, Apa, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Clt, Cya, Cyta, Daad, Dab, Dadd, Dap, Dapa, Dasu, Djen, Dpa, Dtc, Fel, Gin, Clu, Gly, Cuv, hAla, hArg, hCys, hGln, hGlu, His hlle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr Hyl, Hyp, 3Hyp, lie, Ise, Iva, Kyn, Lant, Lcn, Leu, Lag, Lys, fiLys, Lys, Met, Mia, Win, nArg, Kle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pro, Pae, Pya, Pyr, Pza, Qin, Rob, Sar, Sec, Sea, Ser, Thl, fThi, Thr, Thy, Thx, *Tia, Tie, Tly, Trp, Trta, Tyr, Val.
Suitable radicals of a heterocyclic ring system of the formula IV are in particular radicals of heterocycles of the group below: Pyrrolidine (A) ; piperidine (B); tetrahydroisoquinoline (C); decahydroisoquinoline (D) ; octahydroindole (E); octahydrocyclopenta[b]pyrrole (F) ; 2-aza-bicyclo[2.2.2]-octane (G) ; 2-azabicyclo[2.2.1]heptane (H) ; 2-azaspiro-[4.5]decane (I); 2-azaspiro[4.4]nonane (J); spiro[(bi-cyclo[2.2.1]heptane)-2,3-pyrrolidine] (K) ; spiro[(bi-cyclo[2.2.2]octane)-2,3-pyrrolidine] (L) ; 2-azatricyclo- [4 . 3 . 0 .16'9] decane (M) ; decahydrocyclohepta [b] pyrrole (N) ; octahydroisoindole (0) ; octahydrocyclopenta[c]pyrrole (P) ; 2,3,3a,4,5,7a-hexahydroindole (Q); tetrahydrothia-zole (R) ; 2-azabicyclo [3.1.0]hexane (S) ; isoxazolidine (T) ; pyrazolidine (U) ; hydroxyproline (V) ; all of which may be optionally substituted.
The heterocycles based on the abovementioned radicals are known, for example, from US-A-4,344,949, US-A-4,374,847, US - A-4,350,704, EP-A-50,800, EP-A-31,741, EP-A-51,020, EP-A-49,658, EP-A-49,605, EP-A-29,488, EP-A-46,953, EP-A-52,870, EP-A-271,865, DE-A-3,226,768, DE-A-3,151,690, DE-A-3,210,496, DE-A-3,211,397, DE-A-3,211,676 , DE-A-3,227,055, DE-A-3,242,151, DE-A-3,246,503 and DE-A-3,246,757.
Some of these heterocycles are furthermore proposed in DE-A-3,818,850.3.
If not stated otherwise in the individual case, alkyl can be straight-chain or branched. The same applies to radicals derived therefrom such as alkoxy, aralkyl or alkanoyl.
(C6-C12) -Aryl preferably denotes phenyl, naphtyl or biphenylyl. Radicals derived therefrom, such as aryloxy, aralkyl or aroyl, are to be formulated correspondingly.
Halo stands for fluorine, chlorine, bromine or iodine, preferably for chlorine.
Possible salts are, in particular, alkali metal or alkaline earth metal salts, salts with physiologically tolerable amines and salts with inorganic or organic acids such as, for example, HC1, HBr, H2S04, H3P04, maleic acid, fumaric acid, citric acid, tartaric acid and acetic acid.
Preferred peptides of the formula I are those in. which: B is Arg, Orn or Lys, where the guanidino group or the amino group of the side chain is unsubstituted or can be substituted by (C1-C8) -alkanoyl, (C7-C13)-aryl-oyl, (C3-C9)-heteroaryloyl, (Ci-C8)-alkyl- sulfonyl or (C6-C12)-arylsulfonyl, where the aryl, heteroaryl, aryloyl, -arylsulfonyl and heteroaryloyl radicals can be substituted as described under a2) by optionally 1, 2, 3 or 4 5 identical or different radicals; E is phenylalanine, 2-chlorophenylalanine, 3-chlor©phenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, 0-methyltyrosine 10 or /S-(2-thienyl) alanine; K is a direct bond; M is a direct bond.
Particularly preferred peptides of the formula I are those in which: A is hydrogen, (D) - or (L) -H-Arg, (D) - or (L) -H-Lys or (D)- or (L)-H-Oro; B is Arg, Orn or Lys, where the guanidino group or the amino group of the side chain can be substituted by hydrogen, 20 (C^-Cg) -alkanoyl, (C7-C13)-aryloyl, (C3-Cg)-het eroaryloyl, (C^-Cg) -alkylsulfonyl or (Cg-C12) -arylsulfonyl, where the aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl radicals 2 5 can optionally be substituted by 1, 2, 3 or 4 identical or different radicals from the group comprising methyl, methoxy and halogen; C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly; 3 0 E is Phe or Thia; F is Ser, Hser, Lys, Leu, Val, Nle, lie or Thr; K is a direct bond; M is a direct bond; G is the radical of a heterocyclic ring system of 3 5 the formula IV, selected from the radicals of the heterocycles pyrrolidine (A) , piperidine (B) , tetrahydroisoquinoline (C) , cis- oi' trans-decahydroisoquinoline (D) , cis-endo-octa-hydroindole (E), cis-exo-octahydroindole (E), trans-octahydroindole (E) , cis-endo-, cis-exo- or trans-octahydrocyclopentano [b] pyrrole (F) , or hydroxyproline (V) ; F' is Arg; I is OH.
Very particularly preferred is a peptide, which is selected from the group comprising: H-(D)-Arg-Arg-Pro-Hyp-Gly_thia_ser-(d)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-ARG-ARG-Pro-Hyp-Gly-Phe-Ser-(d)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Hyp-ProOGly-Phe-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH.
The invention furthermore relates to a process for the preparation of peptides of the formula I, which comprises a) reacting a fragment having a C-terminal free carboxyl group or its activated derivative with an appropriate fragment having an N- terminal free amino group or b) synthesizing the peptide stepwise, optionally splitting off one or more protective groups temporarily introduced for the protection of other functions in the compound obtained according to (a) or (b) and optionally converting the compounds of the formula I thus obtained into their physiologically tolerable salt.
The peptides of the present invention were prepared by generally known methods of peptide chemistry, see, for example, Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume 15/2, preferably by means of solid phase synthesis such as described, for example, by B. Merrifield, J.Am.Chem.Soc. .85., 2149 (1963) or R. C. Sheppard, Int. J. Peptide Protein Res. 21, 118 (19 83) or by equivalent known methods. Urethane protective groups such as, for example, the tert-butyloxy-carbonyl(Boc) or fluorenylmethoxycarbonyl(Fmoc) protec- tive group are used as a-amino protective group. If necessary for the prevention of side reactions or for the synthesis of specific peptides, the functional groups in the side chain of amino acids are additionally protected 5 by suitable protective groups (see, for example, T.W.
Greene, "Protective Groups in Organic Synthesis"), where primarily, Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMC), Asp(OBzl), Asp(OBut), Cys(4-MeBzl) , Cys(Acm), Cys(SBut), Glu(OBzl), 10 Glu(OBut), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(Cl-Z), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts), Trp(CHO), Tyr(Br-Z), Tyr(Bzl) or Tyr(But) are employed.
Solid phase synthesis begins at the C-terminal end of the 15 peptide with the coupling of a protected amino acid to an appropriate resin. Starting materials of this type may be obtained by linking a protected amino acid via an ester or amide bond to a polystyrene or polyacrylamide resin modified with a chloromethyl, hydroxymethyl, benzhydryl- 2 0 amino (BHA) or me thy lb enzhy dry 1 amino (MBHA) group. The resins used as support materials are commercially obtainable. BHA and MBHA resins are usually used if the peptide synthesized is intended to have a free amide group at the C-terminus. If the peptide is intended to have a second-25 ary-amide group at the C-terminal end, a chloromethyl or hydroxymethyl resin is used and the splitting off is carried out using the corresponding amines. If it is wished to obtain, for example, the ethylamide, the peptide can be split off from the resin using ethylamine, 3 0 the splitting off of the side chain protective groups subsequently being carried out by means of other suitable reagents. If it is intended to retain the tert-butyl protective groups of the amino acid side chain in the peptide, the synthesis is carried out using the Fmoc 3 5 protective group for temporary blocking of the a-amino group of the amino acid using the method described, for example, in R.C. Sheppard, J.Chem.Soc., Chem.Comm 1982. 5 87, the guanidino function of the arginine being protected by protonation with pyridinium percblorate and the protection of the other functionalized amino acids in the side chain being carried out using benzyl protective groups which can be split off by means of catalytic transfer hydrogenation (A. Felix et al. J. Org. Chem. 13., 4194 (1978) or by means of sodium in liquid ammonia (W. Roberts, J.Am.Chem.Soc. 7_6r 6203 (1954)).
After splitting off the amino protective group of the amino acid coupled to the resin using a suitable reagent, such as, for example, trifluoroacetic acid in methylene chloride in the case of the Boc protective group or a 2 0% strength solution of piperidine in dimethylformamide in the case of the Fmoc protective group, the subsequently protected amino acids are successively coupled in the desired sequence. The intermediately resulting N-terminal protected peptide resins are deblocked by means of the reagents described above before linkage with the subsequent amino acid derivative.
All possible activating reagents used in peptide synthesis can be used as coupling reagents, see, for example, Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume 15/2, in particular, however, carbodiimides such as, for example, N,N'-dicyclohexyl carbodiimide, N,N'-diisopropylcarbodi-imide or N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide. The coupling can in this case be carried out directly by addition of amino acid derivative and the activating reagent and, if desired, a racemization-suppressing additive such as, for example, 1-hydroxybenzotriazole (HOBt) (W. Konig, R. Geiger, Chem. Ber. 103. 708 (1970)) or 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOObt) (W. Konig, R. Geiger, Chem.Ber. 103, 2054 (1970)) to the resin or, however, the preactivation of the amino acid derivative as symmetrical anhydride or HOBt or HOObt ester can be carried out separately and the solution of the activated species in a suitable solvent can be added to the peptide resin capable of coupling.
The coupling or activation of the amino acid derivative with one of the abovementioned activating reagents can be carried out in dimethylf ormamide, N-methylpyrrolidone or methylene chloride or a mixture of the solvents men-5 tioned. The activated amino acid derivative is custom arily employed in a 1.5 to 4 fold excess. In cases in which an incomplete coupling takes place, the coupling reaction is repeated without previously carrying out the deblocking of the a-amino group of the peptide resin 10 necessary for the coupling of the following amino acid.
The successful course of the coupling reaction can be monitored by means of the ninhydrin reaction, such as described, for example, by E. Kaiser et al. Anal. Biochem. 34 595 (1970). The synthesis can also be automated, for example using a peptide synthesizer model 43 OA from Applied Biosystems, it being possible either to use the synthesis program provided by the apparatus manufacturer or else, however, one set up by the user himself. The latter are in particular employed in the use of amino acid derivatives protected with the Fmoc group.
After synthesis of the peptides in the previously described manner, the peptide can be split off from the resin using reagents, such as, for example, liquid hydrogen fluoride (preferably in the peptides prepared 2 5 according to the Boc method) or trifluoroacetic acid (preferably in the peptides synthesized according to the Fmoc method). These reagents not only cleave the peptide from the resin but also the other side chain protective groups of the amino acid derivative. In this manner, the 3 0 peptide is obtained in the form of the free acid in addition using BOA and MBHA resins. With the BHA or MBHA resins, the peptide is obtained as acid amide when splitting off is carried out using hydrogen fluoride or trifluoromethanesulfonic acid. Additional processes for 3 5 the preparation of peptide amides are described in German Patent Applications P 37 11 866.8 and P 37 43 620.1. The splitting off of the peptide amides from the resin here is carried out by treatment with medium strength acids (for example trifluoroacetic acid) usually used in peptide synthesis, cation entrainer substances such as phenol, cresol, thiocresol, anisole, thioanisole, ethane-dithiol, dimethyl sulfide, ethyl methyl sulfide or similar cation entrainers customary in solid phase synthesis being added individually or as a mixture of two or more of these auxiliaries. In this case, the tri-fluoroacetic acid can also be used diluted by suitable solvents, such as, for example, methylene chloride.
If the tert-butyl or benzyl side chain protective groups of the peptides are to be retained, the splitting off of the peptide synthesized on a particularly modified support resin is carried out using 1% trifluoroacetic acid in methylene chloride, such as described, for example, in R.C. Sheppard J.Chem. Soc., Chem. Comm. 1982. 587. If individual tert-butyl or benzyl side chain protective groups are to be retained, a suitable combination of synthesis and splitting off methods is used.
For the synthesis of peptides having a C-terminal amide grouping or an to-amino or w-guanidinoalkyl grouping, the modified support resin described by Sheppard is likewise used. After the synthesis, the peptide fully protected in the side chain is split off from the resin and subsequently reacted with the appropriate amine or to-amino-alkylamine or w-guanidinoalkylamine in classical solution synthesis, it being possible for optionally present additional functional groups to be temporarily protected in a known manner.
An additional process for the preparation of peptides having an w-aminoalkyl grouping is described in German Patent Application P 36 35 670.0.
The peptides of the present invention were preferably synthesized by two general protective group tactics using the solid phase technique: The synthesis was carried out using an automatic peptide synthesizer model 43 0 A from Applied Biosysterns, with Boc or Fmoc protective groups for temporary blockage of the 5 cc-amino group.
When using the Boc protective group, the synthesis cycles pre-programmed by the manufacturer of the apparatus were used for the synthesis.
The synthesis of the peptides having a free carboxyl group on the C-terminal end was carried out on a 4-(hydroxymethyl)phenylacetamidomethylpolystyrene resin functionalized with the corresponding Boc amino acid (R.B. Merrifield, J. Org. Chem. 43., 2845 (1978)) from Applied Biosystems. An MBHA resin from the same firm was used for the preparation of the peptide amides. N,N' -Dicyclohexylcarbodiimide orN,N' -diisopropylcarbodi-imide were used as activating reagents. Activation was carried out as the symmetrical anhydride, as the HOBt ester or HOObt ester in CH2C12, CH2Cl2 - DMF mixtures or NMP. 2-4 equivalents of activated eimino acid derivative were employed for the coupling. In cases in which the coupling took place incompletely, the reaction was repeated.
During the use of the Fmoc protective group for the 2 5 temporary protection of the a-amino group, our own synthesis programs were used for synthesis using the automatic peptide synthesizer model 43 OA from Applied Biosystems. The synthesis was carried out on a p-ben-zyloxybenzyl alcohol resin (S. Wang, J.Am.Chem.Soc. 95. 30 1328 (1973)) from Bachem which was esterified by.a known method (E. Atherton et al. J.C.S. Chem. Comm. 1981. 33 6) using the appropriate amino acid. The activation of the amino acid derivatives as HOBt or HOObt esters was carried out directly in the amino acid cartridges pro- 3 5 vided by the apparatus manufacturer by addition of a solution of diisopropylcarbodiimide in DMF to the previously weighed-in mixture of amino acid derivative and HOBt or HOObt. Fmoc-amino acid-OObt esters prepared in substance can likewise be employed as described in European Patent Application 87,107,634.5. The splitting off of the Fmoc protective group was carried out using a 2 0% strength solution of piperidine in DMF in the reaction vessel. The excess of reactive amino acid derivative used was 1.5 to 2.5 equivalents. If the coupling was not complete, it was repeated as in the Boc method.
The peptides according to the invention have, individually or in combination, a bradykinin antagonist action which can be tested in various models (see Handbook of Exp. Pharmacol. Vol. 25, Springer Verlag, 1970, p. 53-55) , for example on the isolated rat uterus, on the guinea pig ileum or on the isolated pulmonal artery of the guinea pig.
For testing the peptides according to the invention on the isolated arteria pulmonalis, guinea pigs (Dunkin Hartley) having a weight of 400 - 450 g are sacrificed by a blow to the back of the neck.
The thorax is opened and the arteria pulmonalis is carefully dissected out. The surrounding tissue is carefully removed and the arteria pulmonalis is cut spirally at an angle of 45°.
The vessel strip of 2.5 cm length and 3-4 mm width is fixed in a 10 ml capacity organ bath which is filled with Ringer solution.
Composition of the solution in mmol/1 NaCl 154 KC1 .6 CaCl2 NaHC03 2.4 1.9 Glucose .0 95% 02 and 5% C02 is bubbled through the solution, which is warmed to 37°C. The pH is 7.4 and the preload on the vessel strip is 1.0 g.
The isotonic contraction changes are detected using a 5 lever arrangement and an EF modem (position sensor) from Eugo Sachs and recorded on a compensating recorder (BEC, Goerz Metrawatt SE 460).
After equilibration for 1 hour, the experiment is begun. After the vessel strips have achieved their maximum 10 sensitivity to 2 x 10~7 mol/1 of bradykinin - bradykinin leads to a contraction of the vessel strips - the peptides are allowed to act for 10 minutes in each case in the doses 5 x 10~8 - 1 x 10"5 mol/1 and, after adding bradykinin again, the decrease in the effect of bradykin-15 in as opposed to the control is compared.
For the detection of a partial agonistic effect, the peptides are used in the doses 1 x 10~5 - 1 x 10"3 mol/1.
The IC50 values of the peptides according to the invention calculated from the dose-effect curves are shown in Table 1.
Table 1: Compound 1^-50 [M] H-(D -Arg-Arg-Hyp-Pro-Gly-Phe-5er-(D)-T1c-Ph*-Arg-0H 4,6 • 10* • 6 H-(D -Arg-Arg-Hyp-Pro-Gly-Th1a-5er-(D)-Tic-Th1a-Arg-0H 2.1 • 10" ■6 H-(D -Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH 1.2 • 10" •5 H-(D -Arg-Arg-Hyp-Pro-Gly-Phe-G1o-(D)-Tic-Phe-Arg-0H 2,4 • 10" ■5 H-(D -Arg-Arg-Pro-Hyp-Gly-Phe-5er-(D)-T1c-Phe-Arg(Mtr)-0H 2,5 • 10" •5 H-(D -Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Pro-Arg-OH 2,5 • 10* 7 H-(D -Arg-Arg-Hyp-Pro-G1y-TMa-5er-(D)-T1c-Pro-Arg-0H 1.9 • 10" 7 1 0 H-(D -Arg-Arg-Hyp-Pro-Gly-Th1a-Ser-(D)-Tic-Aoc-Arg-0H ,6 • 10" 8 H-(D -Arg-Arg-Hyp-Pro-G1y-Thia-5er-£-A1a-(0)-T1c-Aoc-Arg-0H 1.7 • 10- 6 H- (D -Arg-Arg-Hyp-Pro-Gly-Th1a-Ser-Gly-(D)-Tic-Aoc-Arg-OH 3.9 • 10" 7 H-(D -Arg-Arg-Hyp-Pro-G1y-Thia-Gly-(D)-T1c-(D,L)-01c-Arg-0H 3.2 • 10" 7 H-(D -Arg-(D)-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 4.8 • 10" 7 H-(D -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-T1c-Tie-Arg-0H 1.7 • 10" 7 H-(D -Arg-Arg-Pro-Hyp-Gly-Th1a-Str-(D)-Tic-Aoc-Arg-0H 1.1 • 10* 8 H-(D -Arg-Arg-Pro-Hyp-G1y-Phe-5er-(D)-T1c-Aoc-Arg-0H 4.6 • 10" 8 H-(0 -Tyr-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 6.2 • 10" 8 H-(D -Arg-Arg-Pro-Hyp-Gly-Th1a-Ser-(D)-Hc-(D)-Dic-Arg-0H 2.6 • 10" H- (D - Arg-Arg-Pro-Hyp-Gly-Th\a-Ser-(D)-Ti c- 01 c-Arg-OH .4 • 10- 9 H-(D -Arg-Lys-Pro-Hyp-Gly-Phe-Ser-(D)-T1c-Aoc-Arg-0H 3.2 • 10" 7 H-(D -Arg-Arg-Pro-Hyp-G1y-Phe-Ser-(D)-T1c-01c-Arg-0H 6.8 • 10- 9 H-(D -Arg-Arg-(N02)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-0H 6.4 • 10- 8 H-(D -Ar.g-Arg-Pro-Pro-Gly-TMa-Ser-(D)-T1c-Dic-Arg-0H 4.2 • 10" 9 H-(D -Arg-Pro-Hyp-Gly-Phe-5er-(D)-Tic-01c-Arg-0H 3,4 • 10" 7 H-Arg-(Tcs)-Pro-Hyp-Gly-Phe-Ser-(D)-T1c-D1c-Arg-0H 3,0 • 10 -8 H-Arg-(Tos)-Pro-Hyp-G1y-Th1a-Ser-(D)-T1c-D1c-Arg-0H 1,8 • 10 -8 The therapeutic utility of the peptides according to the invention includes all pathological states which are mediated, caused or supported by bradykinin and brady-kinin-related peptides. This includes, inter alia, traumas, such as wounds, burns, rashes, erythemas, edemas, angina, arthritis, asthma, allergies, rhinitis, shock, inflammations, low blood pressure, pain,. pruritus and changed sperm motility.
The invention therefore also relates to the use of peptides of the formula I as medicaments, and to pharmaceutical preparations which contain these compounds.
Pharmaceutical preparations contain an effective amount 5 of the active substance of the formula X - individually or in combination - together with an inorganic or organic pharmaceutically utilizable excipient.
Administration can be carried out enterally, parenterally - such as, for example, subcutaneously, i.m. or i.v. -, 10 sublingually, epicutaneously, nasally, rectally, intra- vaginally, intrabuccally or by inhalation. The dosage of the active substance depends on the mammal species, the body weight, age and on the manner of administration.
The pharmaceutical preparations of the present invention 15 are prepared in solution, mixing, granulating or tablet coating processes known per se.
For oral administration or application to the mucosa, the active compounds are mixed with the customary additives for this, such as excipients, stabilizers or inert 2 0 diluents, and brought into suitable forms for admini stration, Buch as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions, by customary methods. Inert excipients which may be used are, for 25 example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular maize starch. In this case, the preparation may be present both as dry and moist granules. Suitable oily excipients or solvents are, 3 0 for example, vegetable or animal oils, such as sunflower oil and cod liver oil.
A preparation for topical application may be present as an aqueous or oily solution, lotion, emulsion or gel, ointment or fatty ointment or, if possible, in spray form, it being possible to improve the adhesion, If desired, by addition of a polymer.
For the intranasal form of administration, the compounds are mixed with the customary auxiliaries for this, such as stabilizers or inert diluents, and brought into suitable forms for administration, such as aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions, by customary methods. Chelating agents, ethylenediamine-N,N,N',N'-tetraacetic acid, citric acid, tartaric acid or their salts may be added to aqueous intranasal preparations. Administration of the nasal solutions can be carried out by means of metered atomizers or as nasal drops, having a viscosity-increasing component, or nasal gels or nasal creams.
For administration by inhalation, atomizers or pressurized gas packs using inert carrier gases can be used.
For intravenous, subcutaneous, epicutaneous or intradermal administration, the active compounds or their physiologically tolerable salts, if desired with the pharmaceutically customary auxiliaries, for example for isotonisizing or adjusting pH, and Bolubilizers, emul-sifiers or other auxiliaries, are brought into solution, suspension or emulsion.
Because of the short half-lives of some of the medicaments described in body fluids, the use of injectable sustained release preparations is efficient. Medicament forms which may be used are, for example, oily crystal suspensions, microcapsules, rods or implants, it being possible to synthesize the latter from tissue-compatible polymers, in particular biodegradable polymers, such as, for example, those based on polylactic acid/polyglycolic acid copolymers or human albumin.
A suitable dose range for forms for topical application and administration by inhalation are solutions containing 0.01-5 mg/ml, and with forms for systemic administration 0.01-10 mg/kg is suitable.
List of abbreviations: The abbreviations used for amino acids correspond to the 5 three-letter code customary in peptide chemistry as described in Europ. J. Biochem. 138, 9 (1984). Additionally used abbreviations are listed below.
Acm Acetamidomethyl e -Ahx £ -Aminohexanoyl Aoc cis, endo-2-Azabicyclo [3.3.0] octane-3-S- carbonyl Boc tert-Butyloxycarbonyl But tert-Butyl Bzl Benzyl Cl-Z 4-Chlorobenzyloxycarbonyl DMF Dime thy lformamide Dnp 2,4-Dinitrophenyl Fmoc 9-Fluorenylmethoxycarbonyl Me Methyl 2 0 4-Mebzl 4-Methylbenzyl Mtr 4-Methoxy-2, 3 , 6- trimethylphenyllsulf onyl Mts Mesitylene-2-sulfonyl NMP N-Methylpyrrolidine Oic• cis-endo-octahydroindol-2-carbonyl Opr Isoxazolidin-3-ylcarbonyl Pmc 2,2,5,7,8-Pentamethylchroman-6-sulfonyl TFA Trifluoroacetic acid Tcs 4-Methylphenylsulfonyl Thia 2-Thienylalanyl 3 0 Tic l,2,3,4-Tetrahydroisoquinolin-3-ylcarbonyl Trt Trityl The following examples are intended to illustrate the preferred methods for solid phase synthesis of the peptides according to the invention, without limiting the 35 invention thereto.
The amino acid derivatives below were used: Fmoc-Ary(Mtr)-OH, Boc-(D)-Arg-OH, Fmoc-Ary(Pmc)-OH, Fmoc-Hyp-OH, Fmoc-Pro-OObt, Fmoc-Gly-OObt, F»oc-Phe-OObt, Fmoc-Ser(tBu)-OObt, Fmoc-(D)-Tic-OH, Flaoc-Gla-OH, Fmoc-Aoc-OH, Fmoc-Thia-OH, Faoc-Opr-OH, Fmoc- (D)-Aan-OH, Fttoc-ft-Ala-OH, Faoc-Oic-OH.
Example 1: H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH was synthesized stepwise using a peptide synthesizer model 43 0 A from Applied Biosystems by the Fmoc method on a p-benzyloxybenzyl alcohol resin from Novabiochem (loading about 0.5 mmol/g of resin) esterified with Fmoc-Arg(Mtr)-OH. 1 g of the resin was employed and the synthesis was carried out with the aid of a synthesis program modified for the Fmoc method.
Xn each case 1 mmol of the amino acid derivative having a free carboxyl group together with 0.95 mmol of HOObt was weighed into the cartridges of the synthesizer. The preactivation of these amino acids was carried out 15 directly in the cartridges by dissolving in 4 ml of DMF and- adding 2 ml of a 0.55 mol solution of diisopropyl-carbodiimide in DMF.
The HOObt esters of the other amino acids were dissolved in 6 ml of NMP and then similarly coupled to the resin 20 previously deblocked using 20% piperidine in DMF, like the amino acids preactivated in situ. After completion of the synthesis, the peptide was split off from the resin using thioanisole and ethanedithiol as cation entrainers, with simultaneous removal of the side chain protective 2 5 groups using trifluoroacetic acid. The residue obtained after stripping off the trifluoroacetic acid was repeatedly digested with ethyl acetate and centrifuged. The residue which remained was chromatographed on ,®Sephadex LH 20 using 10% strength acetic acid. The fractions containing the pure peptide were combined and freeze-dried.
MS(FAB) : 1294 (M+H) The peptides of Examples 2 to 24 below were prepared and purified analogously to Example 1.
Example 2: H- (d)-Arg-Arg-Hyp-Pro-Gly-Phe- (D)-Ser- (D)-Tic-Phe-Arg-OH MS(FAB) : 1294 (M+H) Example 3: H- (D) - Arg- Arg- Hyp- Pro- Gly- Thia- Ser- (D)-Tic-Thia-Arg-OH MS(FAB) : 1306 (M+H) Example 4: H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH MS(FAB) : 1294 (M+H) Example 5: H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Gin-(D)-Tic-Phe-Arg-OH MS(FAB) : 1335 (M+H) Example 6: H- (D)-Arg-Arg-Hyp-Pro-Gly- : H- (D)-Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser- (D)-Tic-Phe-Arg-OH MS(FAB): 1506 (M+H) 26: H- (D)-Arg- Arg (Mtr)-Pro-Hyp- Cly- Phe- Ser- (D)-Tic-Phe-Arg(Mtr)-OH MS(FAB): 1718 (M+H) 27: H- (D) - Ar g- Arg- Pro- Hyp- Gly- Phe- Ser- (D ) - Tic- Phe- Arg (Mtr) -OH MS(FAB): 1506 (M+H) The peptides of Examples 28 - 31 below were prepared and purified analogously to Examples 25 - 27.
Example 28: H- (D)-Arg- Arg (Mtr)-Hyp-Pro- Gly-Thia- Ser- (D)-Tic-Pro-Arg-OH MS(FAB) : 1462 (M+H) Example 29: H- (D) - Arg- Arg- Hyp- Pro- Cly- Thia- Ser- (D)-Tic-Pro-Arg (Mtr)-OH MS(FAB) : 1462 (M+H) Example 30: H- (D)-Arg-Arg (Mtr)-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Pro-Phe-OH MS(FAB) : 1453 (M+H) Example 31: H- (D)-Arg-Arg (Mtr)-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1502 (M+H) Example 32: H-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH2) 4-NH2 .
The peptide synthesis was carried out on 1 g of an amino-methyl resin which was modified with an attachment group of the type C=C Fmoc-NH- (CH9)A-NH-C0-0-CH-,-C JD-0-CH2-C0- V/ described in EP-A 264,802, using Fmoc-amino acid-OObt esters with an automatic peptide synthesizer (model 43OA from Applied Biosystems) and synthesis programs which have themselves been modified. To this end, in each case 1 mmol of the appropriate amino acid derivative was weighed into the cartridges provided by the manufacturer, and Fmoc-Arg(Mtr)-OH, Fmoc-Hyp-OH and Fmoc-(D)-Tic-OH were weighed into the cartridges together with 0.95 mmol of HOObt. The preactivation of these amino acids in situ was carried out directly in the cartridges by dissolving in 4 ml of DMF and adding 2 ml of a 0.55 M solution of diisopropylcarbodiimide in DMF. The HOObt esters of the other amino acids were dissolved in 6 ml of NMP and then coupled to the resin previously deblocked using 2 0% piperidine in DMF, like the amino acids preactivated in situ, the amino acids activated in situ being doubly coupled. After completion of synthesis, the peptide 4-aminobutylamide was split off from the resin with simultaneous removal of the side chain protective groups with trifluoroacetic acid which contained thioanisole and m-cresol as cation entrainers. The residue obtained after stripping off the trifluoroacetic acid was repeatedly digested with ethyl acetate and centrifuged. The crude peptide which remained was chromatographed on ®Sephadex G25 using IN acetic acid. The fractions containing the pure peptide were combined and freeze-dried.
The compounds of Examples 33 - 35 were prepared analogously to Example 32: Example 33: H-D-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-NH-(CH2)4-HH2 Example 34: H00C-(CH2)2"CO-Arg-Hyp-Pro-Cly-Phe-Ser-(D)-Tic-Phe-NH-(CH2)4-NH2 Example 35: HOOC- (CH2)2-CO- (D) - Arg- Hyp- Pro- Cly-She- Ser- (D)-Tic-Phe-NH- (ch2)4-nh2 Examples 36 to [lacuna] were synthesized in accordance with the method described in Example 1.
Example 36: H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Cly- (D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H) Example 37: H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H) Example 38: H-(D)-Arg-Arg-Hyp-Pro-Cly-Thia-Ser-(D)-Tic-Pro-Phe-OH MS(FAB) : 1241 (M+H) Example 39: H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-ft- A1a-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1361 (M+H) Example 40: -H-(D)-Arg-Arg-Pro-Hyp-Cly-Thia-Ser-ft- Ala-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1361 (M+H) Example 41: H- (D)-Arg-Arg-Hyp-Pro-Cly-Thia-Ser- (D)-Tic-Pro-Phe-Arg-OH MS(FAB) : 1397 (M+H) Example 42: H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Pro-Phe-Arg-OH MS(FAB) : 1397 (M+H) Example 43: H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Gly- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1260 (M+H) Example 44: H-{D)-Arg-Arg-Hyp-Pro-Cly-Thia-Gly-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1260 (M+H) Example 45: H-(D)-Arg-(D)-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1290 (M+H) Example 46: H-(D)-Arg-(D)-Arg-Pro-Hyp-Cly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1290 (M+H) Example 47: H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Tic-Arg-OH MS(FAB) : 1312 (M+H) Example 48: H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)«Tic-Tic-Arg-OH MS(FAB) : 1312 (M+H) Example 49: H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H) Example 50: H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1203 (M+H) Example 51: H-(D)-Arg-Arg-Hyp-Pro-Gly-Aoc-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H) Example 52: H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-fc-Ala- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H) Example 53: H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-ft-Ala- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H) Example 54: H-(D)-Arg-Arg-Hyp-Pro-Gly-Asp-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1252 (M+H) Example 55: H-(D)-Arg-Arg-Pro-Hyp-Cly-Asp-Ser- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1252 (M+H) Example 56: H-(D)-Arg-Arg-Hyp-Pro-Gly-Trp-Ser- (P)-Tic-Aoc-Arg-OH MS(FAB) : 1323,7 (M+H) Example 57: K- (D) - Tyr- Arg- Pro^Hyp- Gly- Thia- Ser—(D) - Tic- Aoc-Arg- OH MS(FAB) : 1297,7 (M+H) Example 58: H- (D) - Arg-Arg- Pro-Hyp- Gly-Thia- Ser- (D)-Tic- (D)-Oic-Arg-OH MS(FAB) : 1304,6 (M+H) Example 59: 2o H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D)-Tic-Oic-Arg-OH MS(FAB) : 1304,6 (M+H) Example 60: H- (D)-Arg-Arg-Pro-Pro-Cly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1289 (M+H) 2 5 Example 61: H- (D)-Arg-Lys-Pro-Hyp-Cly-Thia-Ser- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1262 (M+H) Example 62: H- (D)-Arg-Lys-Pro-Hyp-Cly-Thia-Ser- (D)-Tic-Oic-Arg-OH 30 MS(FAB) : 1276 (M+H) Example 63: H- (D)-Arg-Lye-Pro-Pro-Gly-Thia-Ser- (D)-Tic-Oic-Arg-OH MS(FAB) : 1260 (M+H) Example 64: H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1298 (M+H) Example 65: H-(D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D)-Tic-Oic-Arg-OH MS(FAB) : 1298 (M+H) 1 q Example 66: H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1282 (M+H) Example 67: H- (D)-Arg-Arg (NO2)-Pro-Hyp-Gly-Phe-Ser- (D)-Tic-Aoc-Arg-OH 15 MS(FAB) : 1329,7 (M+H) Example 68: H- (D)-Arg-Arg(NO2)-Pro-Hyp-Gly-Phe-Ser- (D)-Tic-Oic-Arg-OH MS(FAB): 1343 (M+H) Example 69: h- (D)-Arg-Arg(N02)-Pro-Pro-Gly-Phe-Ser- (D)-Tic-Oic-Arg-OH MS(FAB) : 1327 (M+H) Example 70: H- (D)-Arg-Arg(N02)-Pro-Pro-Gly-Thi%-Ser- (D)-Tic-Oic-Arg-OH MS(FAB) : 1333 (M+H) Example 71: 2 5 H-(D)-Arg-Arg(NO2)-Pro-Hyp-Gly-Thie-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1349 (M+H) Example 72: H-Arg(Tos)- Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1302 (M+H) Example 73: H-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH - -MS(FAB) : 1142 (M+H) Example 74: H-Lys(-CO-NH-CgH5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1233 (M+H) Example 75: H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS (FAB) : 1296 (M+H) Example 76: H-Lys(Ni cotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1219 (M+H) Example 77: H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH 15 MS(FAB) : 1282 (M+H) Example 78: Ac-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1324 (M+H) Example 79: H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1438 (M+H) Example 80: H-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1302 (M+H) Example 81: H-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1142 (M+H) Example 82: H- Ly b (- CO- NH- CfeH5) - Hyp- Pro- Gly- Phe- Ser-D-Tic- Oic- Arg- OH MS(FAB) : 1233 (M+H) Example 83: H-Arg(Toe)-Hyp-Pro-Cly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1296 (M+H) Example 84: H- Lys (Nicotinoyl) -Hyp-Pro- Cly-Phe- Ser-X>- Tic- Oic-Arg- OH MS(FAB) : 1219 (M+H) Example 85: H-Arg(Tob)-Hyp-Pro-Cly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1282 (M+H) 1 o Example 86 : Ac- Arg (To*) -Hyp-Pro-Cly-Phe- Ser-D-Tic-Aoc- Arg- OH MS(FAB) : 1324 (M+H) Example 87: H-D-Arg-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser- D-Tic-Aoc-Arg-OH 15 MS(FAB) : 1438 (M+H) Example 88: H-Arg(Tos)-Pro-Pro-Gly-This-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1286 (M+H) Example 89: 2q " h-Arg-Pro-Pro-Cly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1126 (M+H) Example 90: H-Lys(-CO-NH-C6H5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1217 (M+H) Example 91: H- Arg (Tos) - Pr o- Pro- Gly- Phe- Ser- D- Tic- Oic- Arg- OH MS (FAB) : .1280 (M+H) Example 92: H-Lys(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH 3 0 MS(FAB) : 1203 (M+H) Example 93: H-Arg(Tob)-Pro-Pro-Cly-Phe-Ser-D-Tic-Aoc-Arg- OH MS(FAB) : 1266 (M+H) Example 94: Ac-Arg (To*)-Pro- Pro-Cly-Phe-Ser-D-Tic-Aoc- Arg-OH MS(FAB) : 1308 (M+H) ; Example 95: H-D-Arg-Arg(Tos)-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1422 (M+H) Example 96: H-Arg-Pro-Hyp-Cly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1148 (M+H) Example 97: H-Lys(- CO-NH-C6H5)"Pr 1HyP"Thia-Ser-D-Tic-Oic-Arg-OH 15 MS(FAB) : 1239 (M+H) Example 98: H-Lys(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H) Example 99: 2 0 H-Arg(Tos)-Pro-Hyp-Cly-Thia-Ser-D-Tic- Aoc-Arg-OH MS(FAB) : 12B8 (M+H) Example 10 0: Ac-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1330 (M+H) Example 101: H- D- Arg- Arg (Tos) - Pro- Hyp- Gly- Thia- Ser-D- Tic- Aoc- Arg- OH MS(FAB) : 1444 (M+H) Example 102: H-Arg-Hyp-Pro-Cly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1148 (M+H) Example 103: - H- Lys (- CO- NH- CgHs) - Hyp- Pro- CI y- Thi a- Ser- D- Tic- Oic- Arg- OH MS(FAB) : 1239 (M+H) Example 104: H- Ly s (N i cot inoyl) - Hyp- Pro- Cly- Thi a- Ser- D- Tic- Oic- Arg- OH MS(FAB) : 1225 (M+H) Example 105: H-Arg (Tos)-Hyp- Pro-Cly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1288 (M+H) Example 106: Ac-Arg(Tob)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1330 (M+H) Example 107: H-D- Arg- Arg ( Toe ) - Hyp- Pro- Gly- Thi a- Ser- D- Tic- Aoc- Arg- OH MS(FAB) : 1440 (M+H) Example 108: H-Lye(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H) Example 109: H-Lys(Ni cotinoyl)-Pro-Pro-Cly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1209 (M+H) Example 110: H- Arg (Tos) - Pro- Pro- Cly- Thia- Ser-D- Tic- Aoc- Arg- OH MS(FAB): 1272 (M+H) Example 111: Ac-Arg(Tob)-Pro-Pro-Cly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1314 (M+H) Example 112: H-D-Arg-Arg(Tob)-Pro-Pro-Cly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1428 (M+H) Example 113: H-D-Arg-Lys (Nicotinoyl )-Pro-Pro-Cly-Thi*-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1365 (M+H) Example 114: H- D- Arg- Ly * (- CO- NH- CgHg ) - Pr o- Pro- Cly- Thi*- S er- D- Tic- Oic-Arg-OH MS(FAB) : 1379 (M+H) Example 115: H-D-Arg-Arg(To*)-Pro-Pro-Cly-Thi*-Ser-D-Tic-Oic-Arg-OH MS(FAB) s 1442 (M+H) Example 116: H- Lys- Lys- (Ni cotinoyl) - Pro- Pro- Cly-Kiia- Ser- D- Tic- Oic- Arg- OH MS(FAB) : 1337 (M+H) Example 117: H- Ly s- Ly * (- CO- NH- CgH5 ) - Pro- Pro- Cly-Thi*- Ser-D- Tic- Oic- Arg- OH MS(FAB) : 1351 (M+H) Example 118: H- Lys- Arg (Tos) - Pro- Pro- Cly- Thi*- Ser-D- Tic- Oic- Arg- OH MS(FAB) : 1414 (M+H) Example 119: H-D-Arg-Lye (Nicotinoyl)-Pro-Hyp-Cly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1381 (M+H) Example 120: H- D- Arg- Lys- (CO- NH- C6H£) - Pro- Hyp- Cly- Thia- Ser- D- Tic- Oic-Arg-OH MS(FAB) : 1395 (M+H) Example 121: H- D- Arg- Arg (Toe) - Pro-Hyp- Cly- Thia- Ser-D-Tic- Oic-Arg- OH MS(FAB) : 1458 (M+H) Example 122: H- Ly s- Ly* (- CO- NH- C6H5) - Pro- Hyp- Cly- Thia- Ser-D- Tic- Oic-Arg-OH MS(FAB) ; 1367 (M+H) Example 123: H-Lys-Lys(Nicotinoyl)-Pro-Hyp-Cly-Thia-Ser-D-Tic-Oic-Arg- OH MS(FAB) s 1353 (M+H) Example 124: H- Lys- Arg (Tob ) - Pro- Hyp- Cly- Thia- Ser-D- Tic- Oic- Arg- OH MS(FAB) : 1430 (M+H) Example 125: H- D- Arg- Lys (Nicotinoyl) - Pro- Pro- Cly- Phe- Ser- D- Tic- Oic- Arg- OH MS(FAB) : 1359 (M+H) Example 126: H-D-Arg-Lys(-CO-NH-CgHg)-Pro-Pro-Cly-Phe-Ser-D-Tic-Oic-Arg- OH MS(FAB) : 1373 (M+H) Example 127: H- D-Arg-Arg(Tob)-Pro-Pro-Cly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1436 (M+H) Example 128: K-Lys- Lys (Nicotinoyl) - Pro-Pro- Cly- Phe- Ser-D- Tic- Oic- Arg- OH MS(FAB) : 1331 (M+H) Example 129: H- Ly s- Lys (- CO- NH- CfiH5 ) - Pro- Pro- Cly- Phe- Ser- D- Tic- Oic- Arg- OH MS(FAB) : 1345 (M+H) Example 13 0: H-Lys-Arg(Tob)-Pro-Pro-Cly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1406 (M+H) Example 131: H-D-Arg-Lya (Nicotinoyl)-Pro-Hyp-Cly-Phe-Ser-D-Tic-Oic-Arg- OH MS(FAB) : 1375 (M+H) Example 132: H- D- Arg- Lyb (- CO- NH- C6H5) - Pro- Hyp- Cly- Phe- Ser- D- Tic- Oic- Arg-OH MS(FAB) : 1389 (M+H) Example 133: . H- D- Arg- Arg ( Tob ) - Pro- Hyp- Cly- Phe- S er- D- Tic- Oic- Arg- OH MS(FAB) : 1452 (M+H; Example 134: H-Lys-Lys (Nicotinoyl)-Pro-Hyp-Cly-Phe-Ser-D-Tic-Oic-Arg-OH MS (FAB) : 1347 .(M+H) Example 135: H- Ly s- Lys (- CO- NH- CfiH5) - Pro-Hyp- Cly- Phe- Ser- D- Tic- Oic- Arg- OH 1Q MS(FAB) : 1361 (M+H) Example 13 6: H-Lys-Arg(Tob)-Pro-Hyp-Cly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1424 (M+H) Example 137: 1 H-D-Arg-Orn(Nicotinoyl)-Pro-Pro-Cly-Thi*-Ser-D-Tic-Oic-Arg- OH MS(FAB) : 1351 (M+H) Example 13 8: H-D-Arg-Orn(-CO-NH-CfeHs)-Pro-Pro-Cly-Thia-Ser-D-Tic-Oic-20 ' Arg-OH MS(FAB) : 1428 (M+H) Example 13 9: H-Lys-Om(Nicotinoyl)-Pro-Pro-Cly-Thia-Ser-D-Tic-Oic-Arg- OH MS(FAB) : 1323 (M+H) Example 140: H-Lys-Orn(-CO-NH-C6H5)-Pro-Pro-Cly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1337 (M+H) Example 141: H-D- Arg- Orn (Nicotinoyl)-Pro-Hyp-Cly-Thia- Ser-D-'Tic- Oic-Arg- OH MS(FAB) : 1367 (M+H) Example 142: H-D-Arg-Orn(- CO-NH-CgHs)-Pro-Hyp-Cly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1381 (M+H) Example 143 : H- Lys- Om (Nicotinoyl) - Pro- Hyp- Cly- Thia- Ser-D- Tic- Oic- Arg- OH MS(FAB) : 1339 (M+H) Example 144: H- Lys- Om (- CO-NH- CgHs) - Pro-Hyp- Cly- Thia- Ser-D- Tic- Oic- Arg- OH MS(FAB) : 1353 (M+H) Example 145: H- D- Arg- Om (Nicotinoyl) - Pro- Pro- Cly- Phe- Ser-D-Tic- Oic-Arg- 0H MS(FAB) : 1345 (M+H) Example 146: H-D- Arg- Orn (- CO- NH- CgH^ ) - Pro- Pro- Cly- Phe- Ser- D- Tic-Oic- Arg-OH MS(FAB) : 1359 (M+H) Example 147: H- Lys- Orn (Ni cot inoyl) - Pro- Pro- Cly- Phe- Ser- D- Tic- Oic-Arg- OH MS(FAB) : 1317 (M+H) Example 148: 2 0 H- Ly s - Om (- CO- NH- C6H5) - Pro- Pro- Cly- Phe- Ser- D- Tic- Oic- Arg- OH MS(FAB) : 1331 (M+H) Example 149: H- D- Arg- Om (Nicotinoyl) - Pro-Hyp- Cly- Phe- Ser-D-Tic- Oic-Arg- 0H MS(FAB) : 1361 (M+H) Example 150: H- D- Arg- Om (CO- NH- C6H5) - Pro- Hyp- Cly- Phe- Ser-D- Tic- Oic- Arg- OH 3 0 MS(FAB) : 1375 (M+H) H- Lys^Orn (Nicotinoyl) -Pro-Hyp- Cly-Phe- Ser-D-Tic- Oic-Arg- OH MS(FAB) : 1333 (M+H) Example 152: 3 5 H- Ly s - Om (- CO- NH- C6H5) - Pr o- Hyp- Cly- Phe- Ser- D- Ti c - Oic- Arg- OH MS(FAB) : 1347 (M+H) Example 153: H-Lys-Lys-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1218 (M+H) Example 154: H-Lys-Lys-Pro-Hyp-Cly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1234 (M+H) Example 155: H-Lys-Lys-Hyp-Pro-Cly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1234 (M+H) Example 156: 1 0 H- Lys- Lys- Pro- Pro- Cly- Phe- Ser- (D) - Tic-Aoc- Arg- OH MS(FAB) : 1212 (M+H) Example 157: H-Lys-Lys-Pro-Hyp-Cly-Phe-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1228 (M+H) Example 158: H-Lys-Lys-Pro-Pro-Cly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1232 (M+H) Example 159: 2Q H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1248 (M+H) Example 160: H-Lys-Lys-Hyp-Pro-Cly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1226 (M+H) Example 161: H- Lys- Lys- Pro- Hyp- Gly- Phe- Ser- (D) - Tic- Oic- Arg- OH MS(FAB) : 1242 (M+H) Examples 162 - 164 were prepared analogously to Example 32 using the resin described in EP-A-322348 having the structure Fm.e-NH och3 OCH3 ch2 I ch2 c-o I NH och3 ch2 Example 162: H-D- Arg- Arg- Pro- Hyp- Gly- Phe- Ser-D- Tic- Aoc- Arg- NH2 •MS(FAB) : 1283 (M+H) Example 163: H-D- Arg- ARg-Hyp-Pro- Gly-Phe- Ser-D-Tic-Aoc-Arg-NH2 MS(FAB): 1283 (M+H) Example 164: H- D- Arg- Arg- Pro- Pro- Gly- Phe- Ser-D- Tic- Aoc- Arg- NH2 MS(FAB): 1267 (M+H)
Claims (12)
1. A peptide of the formula I A-B-C-E-F-K-(D)-Tic-G-M-F'-I I, in which A ax) is hydrogen, (C^-Cg) -alkyl, (C^-C8) -alkanoyl, ( Ci-C8)-alkoxycarbonyl or (ci~c8^~ alkylsulfonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or three identical or different radicals from the group comprising carboxyl, amino, (C1-C4)-alkyl, (C^C^)-alkylamino, hydroxyl, (C1-C3)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (C^-C4) -alkoxycarbonyl, (C6-C12) -aryl and (C6-C12) -aryl- (Cx-C5) -alkyl, or in which in each case 1 hydrogen atom is optionally replaced by a radical from the group comprising (C3-C8)-cycloalkyl, (C^-C^) -alkylsulfonyl, (C1-C4)-alkyl- sulfinyl, (Cg-C12) -aryl- (C1-C4) -alkylsul-f onyl, (C g-Ci2 ) -aryl- (CX-CA) -alkyl- sulfinyl, (C6-C12)-aryloxy, (C3-Cs)-heteroaryl and (C3-Cg)-heteroaryloxy and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals from the group comprising carboxyl, amino, (C1-C4) -alkylamino, hydroxyl, (Cx-C4)-alkoxy, halogen, di-(C-^-C^) -alkylamino, carbamoyl, sulfamoyl, _(C1-C4) -alkyloxycarbonyl, (cg-C12^ ~aryl an
2. A peptide of the formula I as claimed in claim 1, in which B is Arg, Orn or Lys, where the guanidino group or the amino group of the side chain is unsubstituted or can be substituted by (C^Cg) -alkanoyl, (C7-C13)-aryloyl, (C3-C9) -heteroaryloyl, (C1-C8)-alkyl-sulfonyl or (C6-C12)-arylsulf onyl, where the aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl radicals can be substituted as described under a2) by optionally 1, 2, 3 or 4 identical or different radicals; E is phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluor©phenylalanine, tyrosine, 0-methyltyrosine or £-(2-thienyl)alanine; K is a direct bond; M is a direct bond.
3. A peptide of the formula I as claimed in claim 1, in which A is hydrogen, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or (D)- or (L)-H-Orn; B is Arg, Orn or Lys, where the guanidino group or the amino group of the side chain can be substituted by hydrogen, - 45 - (C^-Cg)-alkanoyl, (C7-C13)-aryloyl, (C3-C9)-heteroaryloyl, (^-Cg)-alkylsulfonyl or (C6-C12) -arylsulf onyl, where the aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl radicals can optionally be substituted by 1, 2, 3 or 4 identical or different radicals from the group comprising methyl, methoxy and halogen; c is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly; E is Phe or Thia; F is Ser, Hser, Lys, Leu, Val, Nle, lie or Thr; K is a direct bond; M is a direct bond; G is the radical of a heterocyclic ring system of the formula IV, selected from the radicals of the heterocycles pyrrolidine (A) , piperidine (B) , tetrahydroisoquinoline (C) , cis- or trans-decahydroisoquinoline (D) , cis-endo-octa-hydroindole (E), cis-exo-octahydroindole (E), trans-octahydroindole (E) , cis-endo-, cis-exo- or trans-octahydrocyclopentano [b]pyrrole (F) , or hydroxyproline (V); F' is Arg; I is OH.
4. A peptide of the formula I as claimed in claim 1, which is selected from the group comprising: H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H- (D) - Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, H- (D) - Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, H- (D) -Arg-Arg-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.
5. A process for the preparation of a peptide of the formula I as claimed in one or more of claims 1 to 4, which comprises a) reacting a fragment having a C-terminal free carboxyl group or its activated derivative with an appropriate fragment having an N-terminal free amino group or b) synthesizing the peptide stepwise, optionally splitting off one or more protective groups temporarily introduced for the protection of other functions in the compound obtained according to (a) or (b) and optionally converting the compounds of the formula I thus obtained into their physiologically tolerable salts.
6. Use of a peptide of the formula I as claimed in one of claims 1 to 4 for the preparation of a medicament for the treatment of pathological states which are mediated, caused or supported by bradykinin and bradykinin-related peptides.
7. A pharmaceutical agent containing a peptide of the formula I as claimed in one or more of claims 1 to 4 .
8. A peptide of the formula (I) given and defined in claim 1, or a physiologically tolerable salt thereof, substantially as hereinbefore described and exemplified.
9. A process for the preparation of a peptide of the formula (I) given and defined in claim 1, or a physiologically tolerable salt thereof, substantially as hereinbefore described and exemplified. - 47 -
10. A peptide of the formula (I) given and defined in claim 1, or a physiologically tolerable salt thereof, whenever prepared by a process claimed in a preceding claim. 5
11. Use according to claim 6, substantially as hereinbefore described.
12. A pharmaceutical agent according to claim 7, 10 substantially as hereinbefore described. F. R. KELLY & CO. AGENTS FOR THE APPLICANTS
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3839581 | 1988-11-24 | ||
| DE3916291 | 1989-05-19 | ||
| DE3918225 | 1989-06-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE892522L true IE892522L (en) | 1990-05-24 |
| IE63490B1 IE63490B1 (en) | 1995-05-03 |
Family
ID=27198531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE252289A IE63490B1 (en) | 1988-11-24 | 1989-08-03 | Peptides having bradykinin antagonist action |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0370453B1 (en) |
| JP (1) | JPH07121956B2 (en) |
| KR (1) | KR0139632B1 (en) |
| CN (1) | CN1035006C (en) |
| AT (1) | ATE107318T1 (en) |
| AU (1) | AU612054B2 (en) |
| CA (1) | CA1340667C (en) |
| CY (2) | CY2028A (en) |
| CZ (1) | CZ282384B6 (en) |
| DE (3) | DE58907889D1 (en) |
| DK (1) | DK175344B1 (en) |
| ES (1) | ES2057071T3 (en) |
| FI (1) | FI94353C (en) |
| HK (1) | HK1006716A1 (en) |
| HU (2) | HU210566B (en) |
| IE (1) | IE63490B1 (en) |
| IL (1) | IL91298A (en) |
| LU (1) | LU91499I2 (en) |
| LV (1) | LV10720B (en) |
| MX (1) | MX9203277A (en) |
| NL (1) | NL300359I2 (en) |
| NO (2) | NO177597C (en) |
| NZ (1) | NZ230244A (en) |
| PH (1) | PH31009A (en) |
| PT (1) | PT91692B (en) |
| SK (1) | SK279315B6 (en) |
Families Citing this family (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5648333A (en) * | 1988-11-24 | 1997-07-15 | Hoechst Aktiengesellschaft | Peptides having bradykinin antagonist action |
| DE4013270A1 (en) * | 1990-04-26 | 1991-10-31 | Hoechst Ag | PEPTIDES WITH BRADYKININ ANTAGONISTIC EFFECT |
| DE69012142D1 (en) * | 1989-12-08 | 1994-10-06 | Univ Boston | ACYLATED BRADYKIN ANANTAGONISTS AND THEIR USE. |
| MX9100717A (en) * | 1990-08-24 | 1992-04-01 | Syntex Inc | BRADIQUININE ANTAGONISTS |
| US5843900A (en) * | 1991-04-01 | 1998-12-01 | Cortech, Inc. | Bradykinin antagonists |
| US5416191A (en) * | 1991-04-01 | 1995-05-16 | Cortech, Inc. | Bradykinin antagonists |
| US6770741B1 (en) | 1991-04-19 | 2004-08-03 | Scios Inc. | Bradykinin antagonist peptides |
| JP3465000B2 (en) | 1991-04-19 | 2003-11-10 | シオス・ノヴァ・インコーポレイティット | Bradykinin-type peptide |
| CA2106762C (en) * | 1991-04-19 | 2000-10-10 | Donald J. Kyle | Bradykinin antagonist peptides |
| HUT63060A (en) * | 1991-08-22 | 1993-07-28 | Hoechst Ag | Process for producing pharmaceutical compositions locally applicable on nose and eye, comprising bradykinin antagonists |
| US6117974A (en) * | 1991-10-02 | 2000-09-12 | Peptor Limited | Libraries of backbone-cyclized peptidomimetics |
| WO1993011789A1 (en) * | 1991-12-12 | 1993-06-24 | Scios Nova Inc. | Modified position (7) bradykinin antagonist peptides |
| TW199863B (en) * | 1991-12-21 | 1993-02-11 | Hoechst Ag | |
| WO1993017701A1 (en) * | 1992-03-12 | 1993-09-16 | The Administrators Of The Tulane Educational Fund | Endothelin receptor-binding peptides |
| TW258739B (en) * | 1992-04-04 | 1995-10-01 | Hoechst Ag | |
| FR2692581B1 (en) * | 1992-06-18 | 1994-08-19 | Adir | New peptide derivatives with bradykinin antagonist activity, their preparation process and the pharmaceutical compositions containing them. |
| US5541286A (en) * | 1992-10-08 | 1996-07-30 | Scios Nova Inc. | Bradykinin antagonist pseudopeptide derivatives of olefinic aminoalkanoic acids |
| US5610142A (en) * | 1992-10-08 | 1997-03-11 | Scios Inc. | Bradykinin antagonist pseudopeptide derivatives of substituted 4-keto-1,3,8-triazaspiro[4.5]decan-3-alkanoic acids |
| US5686565A (en) * | 1992-10-08 | 1997-11-11 | Scios Inc. | Bradykinin antagonist pseudopeptide derivatives of aminoalkanoic acids and related olefins |
| US5521158A (en) * | 1992-10-08 | 1996-05-28 | Scios Nova Inc. | Pseudopeptide bradykinin receptor antagonists |
| IL107400A0 (en) * | 1992-11-10 | 1994-01-25 | Cortech Inc | Bradykinin antagonists |
| WO1994019372A1 (en) * | 1993-02-17 | 1994-09-01 | Scios Nova Inc. | Cyclic bradykinin antagonist peptides |
| US5817756A (en) * | 1993-09-09 | 1998-10-06 | Scios Inc. | Pseudo- and non-peptide bradykinin receptor antagonists |
| DE4345062A1 (en) * | 1993-12-31 | 1995-07-13 | Hoechst Ag | Use of bradykinin antagonists for the manufacture of medicaments for the treatment of viral diseases |
| DE69533704D1 (en) * | 1994-03-09 | 2004-12-02 | Cortech Inc | BRADYKININ ANTAGONIST PEPTIDE WITH N-SUBSTITUTED GLYCINES |
| IL109943A (en) | 1994-06-08 | 2006-08-01 | Develogen Israel Ltd | Conformationally constrained backbone cyclized peptide analogs |
| US6407059B1 (en) | 1994-06-08 | 2002-06-18 | Peptor Limited | Conformationally constrained backbone cyclized peptide analogs |
| EP0832106A2 (en) * | 1995-06-05 | 1998-04-01 | Cortech, Inc. | Compounds having bradykinin antagonistic activity and mu-opioid agonistic activity |
| US5770687A (en) * | 1995-06-07 | 1998-06-23 | Peptor Limited | Comformationally constrained backbone cyclized somatostatin analogs |
| US6051554A (en) * | 1995-06-07 | 2000-04-18 | Peptor Limited | Conformationally constrained backbone cyclized somatostatin analogs |
| FR2737408B1 (en) * | 1995-07-31 | 1997-09-05 | Oreal | USE OF A BRADYKININE ANTAGONIST IN A COSMETIC, PHARMACEUTICAL OR DERMATOLOGICAL COMPOSITION AND COMPOSITION OBTAINED |
| US5849863A (en) * | 1995-09-08 | 1998-12-15 | University Of Colorado | Cytolytic bradykinin antagonists |
| US5834431A (en) * | 1995-09-08 | 1998-11-10 | Cortech, Inc. | Des-Arg9 -BK antagonists |
| FR2739553B1 (en) * | 1995-10-06 | 1998-01-02 | Oreal | USE OF BRADYKININE ANTAGONISTS TO STIMULATE OR INDUCE HAIR GROWTH AND / OR STOP THE HAIR LOSS |
| US6841533B1 (en) | 1995-12-07 | 2005-01-11 | Peptor Limited | Conformationally constrained backbone cyclized interleukin-6 antagonists |
| DE19612067A1 (en) * | 1996-03-27 | 1997-10-02 | Hoechst Ag | Use of bradykinin antagonists for the manufacture of medicaments for the treatment of chronic fibrogenetic liver diseases and acute liver diseases |
| US6355613B1 (en) | 1996-07-31 | 2002-03-12 | Peptor Limited | Conformationally constrained backbone cyclized somatostatin analogs |
| DE19642289A1 (en) * | 1996-10-14 | 1998-04-16 | Hoechst Ag | Use of bradykinin antagonists for the manufacture of medicaments for the treatment and prevention of Alzheimer's disease |
| DE10304994A1 (en) * | 2003-02-07 | 2004-09-02 | Aventis Pharma Deutschland Gmbh | The use of antagonists of the bradykinin B2 receptor for the treatment of osteoarthrosis |
| CN102532267B (en) * | 2012-02-09 | 2014-06-18 | 深圳翰宇药业股份有限公司 | Method for preparing icatibant |
| CN104043101B (en) * | 2014-05-23 | 2016-04-20 | 杭州阿德莱诺泰制药技术有限公司 | A kind of icatibant composition for injection and preparation method thereof and preparation |
| KR102099509B1 (en) | 2018-07-27 | 2020-04-09 | 강경순 | Supports for fruit trees |
| CN111944016B (en) * | 2020-08-25 | 2022-04-29 | 台州吉诺生物科技有限公司 | Preparation method of icatibant acetate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3044236A1 (en) * | 1980-11-25 | 1982-06-16 | Hoechst Ag, 6000 Frankfurt | AMINO ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| FR2487829A2 (en) * | 1979-12-07 | 1982-02-05 | Science Union & Cie | NOVEL SUBSTITUTED IMINO ACIDS, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS AN ENZYME INHIBITOR |
| DE3227055A1 (en) * | 1982-07-20 | 1984-01-26 | Hoechst Ag, 6230 Frankfurt | NEW DERIVATIVES OF 2-AZA-BICYCLO (2.2.2) OCTAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF, AND 2-AZA-BICYCLO (2.2.2) OCTAN-3-CARBONIC ACID AS ANSWER FOR THEIR PRODUCTION |
| FR2575753B1 (en) * | 1985-01-07 | 1987-02-20 | Adir | NOVEL PEPTIDE DERIVATIVES WITH NITROGEN POLYCYCLIC STRUCTURE, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| US4693993A (en) * | 1985-06-13 | 1987-09-15 | Stewart John M | Bradykinin antagonist peptides |
-
1989
- 1989-08-03 IE IE252289A patent/IE63490B1/en not_active IP Right Cessation
- 1989-08-04 DK DK198903840A patent/DK175344B1/en active Protection Beyond IP Right Term
- 1989-08-08 NZ NZ230244A patent/NZ230244A/en unknown
- 1989-08-08 NO NO893193A patent/NO177597C/en not_active IP Right Cessation
- 1989-08-08 FI FI893738A patent/FI94353C/en active Protection Beyond IP Right Term
- 1989-08-09 AU AU39431/89A patent/AU612054B2/en not_active Expired
- 1989-08-09 CA CA000607853A patent/CA1340667C/en not_active Expired - Lifetime
- 1989-08-11 IL IL9129889A patent/IL91298A/en unknown
- 1989-08-21 SK SK4906-89A patent/SK279315B6/en unknown
- 1989-08-21 CZ CS894906A patent/CZ282384B6/en not_active IP Right Cessation
- 1989-08-23 HU HU894323A patent/HU210566B/en unknown
- 1989-08-28 JP JP1218758A patent/JPH07121956B2/en not_active Expired - Lifetime
- 1989-09-11 PT PT91692A patent/PT91692B/en not_active IP Right Cessation
- 1989-09-11 CN CN89107065A patent/CN1035006C/en not_active Expired - Lifetime
- 1989-09-11 KR KR1019890013102A patent/KR0139632B1/en not_active IP Right Cessation
- 1989-11-21 DE DE58907889T patent/DE58907889D1/en not_active Expired - Lifetime
- 1989-11-21 AT AT89121498T patent/ATE107318T1/en active
- 1989-11-21 EP EP89121498A patent/EP0370453B1/en not_active Expired - Lifetime
- 1989-11-21 DE DE3938751A patent/DE3938751A1/en not_active Withdrawn
- 1989-11-21 DE DE122008000066C patent/DE122008000066I2/en active Active
- 1989-11-21 ES ES89121498T patent/ES2057071T3/en not_active Expired - Lifetime
-
1990
- 1990-07-30 PH PH40920A patent/PH31009A/en unknown
-
1992
- 1992-06-24 MX MX9203277A patent/MX9203277A/en active IP Right Grant
- 1992-12-23 LV LVP-92-701A patent/LV10720B/en unknown
-
1995
- 1995-01-20 HU HU95P/P00069P patent/HU210712A9/en active Protection Beyond IP Right Term
-
1998
- 1998-02-20 CY CY202898A patent/CY2028A/en unknown
- 1998-06-22 HK HK98105867A patent/HK1006716A1/en not_active IP Right Cessation
-
2008
- 2008-09-09 NL NL300359C patent/NL300359I2/en unknown
- 2008-10-30 NO NO2008016C patent/NO2008016I2/en unknown
- 2008-11-19 LU LU91499C patent/LU91499I2/en unknown
- 2008-12-30 CY CY200800022C patent/CY2008022I2/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1340667C (en) | Peptides having bradykinin antagonist action | |
| CA2023194C (en) | Peptides having bradykinin antagonist action | |
| US5648333A (en) | Peptides having bradykinin antagonist action | |
| US5597803A (en) | Bradykinin peptides with modifications at the N terminus | |
| JP2552402B2 (en) | Bradykinin antagonistic peptide | |
| CN1034416Y (en) | Preparation method of peptide with bradykinin antagonism | |
| LT3375B (en) | Peptides and pharmaceutical composition containing them | |
| LT3872B (en) | Novel peptides and pharmaceutical compositions containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| SPCF | Request for grant of supplementary protection certificate |
Free format text: SPC035/2008: 20090119 Spc suppl protection certif: SPC035/2008 Filing date: 20090119 |
|
| SPCG | Supplementary protection certificate granted |
Free format text: SPC035/2008: 20090811, EXPIRES: 20140802 Spc suppl protection certif: SPC035/2008 Filing date: 20090811 Expiry date: 20140802 |
|
| MK9A | Patent expired |