GB2118190A - Peptides with sauvagine-like activity - Google Patents
Peptides with sauvagine-like activity Download PDFInfo
- Publication number
- GB2118190A GB2118190A GB08309547A GB8309547A GB2118190A GB 2118190 A GB2118190 A GB 2118190A GB 08309547 A GB08309547 A GB 08309547A GB 8309547 A GB8309547 A GB 8309547A GB 2118190 A GB2118190 A GB 2118190A
- Authority
- GB
- United Kingdom
- Prior art keywords
- leu
- ser
- pro
- asp
- lle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 54
- 102000004196 processed proteins & peptides Human genes 0.000 title abstract description 23
- 150000008575 L-amino acids Chemical class 0.000 claims abstract description 35
- 230000007935 neutral effect Effects 0.000 claims abstract description 19
- 125000006239 protecting group Chemical group 0.000 claims abstract description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 230000002378 acidificating effect Effects 0.000 claims abstract description 4
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims abstract description 4
- 230000001476 alcoholic effect Effects 0.000 claims abstract description 3
- -1 bonzoyl Chemical group 0.000 claims description 45
- 125000003277 amino group Chemical group 0.000 claims description 14
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 7
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 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 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 claims description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 abstract 1
- 229930195733 hydrocarbon Natural products 0.000 abstract 1
- 150000002430 hydrocarbons Chemical class 0.000 abstract 1
- 159000000000 sodium salts Chemical class 0.000 description 106
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 150000001413 amino acids Chemical class 0.000 description 32
- 235000001014 amino acid Nutrition 0.000 description 31
- 239000011347 resin Substances 0.000 description 28
- 229920005989 resin Polymers 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 25
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 24
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 20
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 14
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 13
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 10
- 229920005654 Sephadex Polymers 0.000 description 10
- 239000012507 Sephadex™ Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- DMBKPDOAQVGTST-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylmethoxypropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)COCC1=CC=CC=C1 DMBKPDOAQVGTST-LBPRGKRZSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000004793 Polystyrene Substances 0.000 description 9
- 229920002223 polystyrene Polymers 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 125000000539 amino acid group Chemical group 0.000 description 8
- 102100024819 Prolactin Human genes 0.000 description 7
- 108010057464 Prolactin Proteins 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 229940097325 prolactin Drugs 0.000 description 7
- 241000700159 Rattus Species 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- SOHLZANWVLCPHK-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-4-phenylmethoxybutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC(=O)OCC1=CC=CC=C1 SOHLZANWVLCPHK-LBPRGKRZSA-N 0.000 description 5
- AJDUMMXHVCMISJ-ZDUSSCGKSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-5-phenylmethoxypentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCC(=O)OCC1=CC=CC=C1 AJDUMMXHVCMISJ-ZDUSSCGKSA-N 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
- 239000005695 Ammonium acetate Substances 0.000 description 5
- 229910021583 Cobalt(III) fluoride Inorganic materials 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 229940043376 ammonium acetate Drugs 0.000 description 5
- 235000019257 ammonium acetate Nutrition 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- WZJQNLGQTOCWDS-UHFFFAOYSA-K cobalt(iii) fluoride Chemical compound F[Co](F)F WZJQNLGQTOCWDS-UHFFFAOYSA-K 0.000 description 5
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 5
- 238000002523 gelfiltration Methods 0.000 description 5
- 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 5
- 238000005406 washing Methods 0.000 description 5
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 4
- 150000003862 amino acid derivatives Chemical class 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000004255 ion exchange chromatography Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 239000007836 KH2PO4 Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 102100038803 Somatotropin Human genes 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- KFUIXDNQSMKKJQ-ZLFMSJRASA-N chembl439883 Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)CNC(=O)[C@H]2NC(=O)CC2)CCC1 KFUIXDNQSMKKJQ-ZLFMSJRASA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 229960000258 corticotropin Drugs 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000037230 mobility Effects 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001817 pituitary effect Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920005990 polystyrene resin Polymers 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 108010086511 sauvagine Proteins 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- VVNYDCGZZSTUBC-LURJTMIESA-N (2s)-5-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCC(N)=O VVNYDCGZZSTUBC-LURJTMIESA-N 0.000 description 1
- CTXPLTPDOISPTE-YPMHNXCESA-N (2s,3r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylmethoxybutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)[C@@H](C)OCC1=CC=CC=C1 CTXPLTPDOISPTE-YPMHNXCESA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- PNLZKVOKOVFGMZ-UHFFFAOYSA-N 1-adamantyl carbonofluoridate Chemical compound C1C(C2)CC3CC2CC1(OC(=O)F)C3 PNLZKVOKOVFGMZ-UHFFFAOYSA-N 0.000 description 1
- BPSNETAIJADFTO-UHFFFAOYSA-N 2-pyridinylacetic acid Chemical compound OC(=O)CC1=CC=CC=N1 BPSNETAIJADFTO-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- RXUBZLMIGSAPEJ-UHFFFAOYSA-N benzyl n-aminocarbamate Chemical compound NNC(=O)OCC1=CC=CC=C1 RXUBZLMIGSAPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 150000001663 caesium Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- KJOZJSGOIJQCGA-UHFFFAOYSA-N dichloromethane;2,2,2-trifluoroacetic acid Chemical compound ClCCl.OC(=O)C(F)(F)F KJOZJSGOIJQCGA-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000008569 process 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
- 210000002966 serum Anatomy 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57509—Corticotropin releasing factor [CRF] (Urotensin)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
There are provided peptides of the formula X-A-Pro-Pro-Ile-Ser-B-C-Leu-D-E-F-G-W wherein X is H, a terminal N atom protecting group, or a residue of a natural L-amino acid, optionally protected by a terminal N atom protecting group; A is a L-amino acid residue or a glycine residue; B is a neutral L-amino acid residue; C is a neutral or acidic L-amino acid residue; D is a L-amino acid residue which contains in the side chain an alcoholic hydroxy group, optionally protected by a conventional hydroxy protecting group; E is a valence bond or a neutral L-amino acid residue; F is a valence bond or a L-amino acid residue; G is a valence bond or a neutral L-amino acid residue; W is OH, NH2, OR, NHR, NR2 or NH-NH-R'; wherein R and R' are optionally substituted hydrocarbon. Pharmaceutically acceptable salts of these peptides are also provided.
Description
SPECIFICATION
Biologically active peptides
The invention relates to biologically active peptides, their pharmaceutically acceptable salts, processes for their preparation and pharmaceutical compositions containing them.
The peptides of the invention are fragments or modified fragments of sauvagine, a natural peptide consisting of 40 amino acid residues (P. C. Montecucchi, A. Henschen -- Int. J. Peptide Protein Res. 18, 113-120, 1981), which shows a series of interesting pharmacological activities, such as release of
ACTH and p-endophin, and inhibition of the release of growth hormone, TSH and prolactin (P. C.
Montecucchi et al., "Hormone Receptor in Digestion and Nutrition", G. Rosselin et al. eds., Elsevier/North-Holiand Biomed. Press, 1979,101-108).
It was surprisingly found that the peptides of the invention maintain totally or partially the biological activity spectrum of sauvagine. The importance of this discovery is evident. The synthesis of a tridecapeptide or a shorter homologue is, obviously, more easily realized than the synthesis of a peptide of 40 amino acid residues. Purer or more easily purifiable products are obtained.
In this specification symbols and abbreviations are those commonly used in peptide chemistry
(see J. Biol. Chem., 1 972, 247, 977-983).
The invention provides peptides of the general formula: X-A-Pro-Pro-lle-Ser-B-C-Leu-D-E-F-G-W wherein:
X represents a hydrogen atom, a terminal nitrogen protecting group of acyl, aromatic urethane, alkyl, aralkyl or aliphatic urethane type or a residue of a neutral L-amino acid, the free amino group of the residue optionally being protected by a terminal nitrogen atom protecting group of the type cited above;
A represents a L-amino acid residue or a glycine residue;
B represents a neutral L-amino acid residue;
C represents a neutral L-amino acid residue or an acidic L-amino acid residue;
D represents a L-amino acid residue which contains in the side chain an alcoholic hydroxy group, which may be free or protected by a conventional hydroxy protecting group;
E represents a valance bond or a neutral L-amino acid residue;;
F represents a valence bond or a L-amino acid residue:
G represents a valence bond or a neutral L-amino acid residue;
W represents a hydroxy group, an amino group'or a group of the formula OR, NHR, NR2 or NH-NH-R1 wherein R represents a straight chain, branched chain or cyclic (including fused or bridged ring) alkyl group having up to 11 carbon atoms, and being substituted or unsubstituted, a phenyl group or an aralkyl group having from 6 to 8 carbon atoms; and R' represents a hydrogen atom, any of the groups which R may represent, an alkenyl group having 3 to 8 carbon atoms; a straight chain, branched chain or cyclic aliphatic acyl group having from 1 to 11 carbon atoms, unsubstituted or substituted by a hydroxy or amino group or a halogen atom, an aromatic acyl group, unsubstituted or substituted by a hydroxy or amino group or a halogen atom, a straight chain, branched chain or cyclic aliphatic urethane type group having from 3 to 11 carbon atoms, or an aromatic urethane type group.
Preferred terminal nitrogen atom protecting groups which X may represent include (of acyl type) formyl, acetyl, trifluoroacetyl, propionyl and benzoyl groups; (or aromatic urethane type) benzyloxycarbonyl (Z), 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxyca rbonyl, 2,4- dichlorobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 94luornnylmethoxycarbonyl (Fmoc) and 3,5 dimethoxy-a,a'-dimethylbenzyloxycarbonyl (Ddz) groups; (of aliphatic urethane type) t-butoxycarbonyl (Boc), 1 -methyl-cyclobutoxycarbonyl, adamantyloxycarbonyl and isobornyloxycarbonyl groups; and (of alkyl and aralkyl type) trityl, benzyl (Bzl), methyl and isopropyl groups. Preferred neutral L-amino acid resides which X may represent include Pyr, Gln, Pro and 2-oxo-L-pipecolic acid.Preferred L-amino acid residues which A may represent include Glu and Gln. Preferred neutral L-amino acid residues which B may represent include lle, Leu, Nle, Val and Phe. Preferred neutral L-amino acid residues which C may represent include Asn and Gln; preferred acidic L-amino acid residues which C may represent include
Asp and Glu. Preferred L-amino acid residues which D may represent include Ser, Hse, and Thr; if the hydroxy group of a residue represented by D is protected, it is preferably protected by a t-butyl, trityl, benzyl, 2,4-dichlorobenzyl, benzyloxycarbonyl, 2-bromobenzyloxycarbonyl, tetrahydropyranyl or tbutoxycarbonyl group or by a lower acyl group such as a formyl, acetyl, trifluoroacetyl, propionyl or benzoyl group.
Preferred neutral L-amino acid residues which E may represent include Phe, Leu and Nle. Preferred
L-amino acid residues which F may represent include Glu, Gln and His. Preferred neutral L-amino acid residues which G may represent include Leu and Phe.
Preferred groups which R may represent include methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2,2,2-trifluoroethyl, cyclohexyl, adamantyl, phenyl, benzyl and phenethyl groups.
Examples of alkenyl groups which R' may represent include allyl and pentenyl groups. Examples of acyl groups which R' may represent are formyl, acetyl, trifluoroacetyl, propionyl, butyryl, adamantylcarbonyl, benzoyl, phenylacetyl and cinnamyl groups. The aliphatic and aromatic urethane type groups which R' may represent are preferably those groups mentioned as preferred terminal nitrogen protecting groups
X of aliphatic and aromatic urethane type.
Salts of peptides according to the invention with pharmaceutically acceptable acids or bases are within the scope of the invention. Such acid addition salts can be derived from a variety of inorganic and organic acids such as sulphuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, nitric, sulphamic, citric, iactic, pyruvic, oxalic, maleic, succinic, tartaric, cinnamic, acetic, trifluoroacetic, benzoic, salicyclic, gluconic, ascorbic and related acids. Such base addition salts can be derived from a variety of inorganic and organic bases as sodium hydroxide, potassium hydroxide, diethylamine, triethylamine and dicyclohexylamine.
The synthesis of the peptides of the invention may be accomplished either by classical solution methods or by solid phase on polymeric supports. In the classical solution method the synthesis consists essentially in appropriate successive condensations of protected amino acids or peptides. The condensation is carried out so that the resulting peptides have the desired sequence of 9 to 13 amino acid residues. The amino acids and peptides, which are condensed according to methods known in themselves in polypeptide chemistry, have such of their amino and carboxy groups as are not involved in the formation of the peptide linkage blocked by a suitable protecting group. The hydroxy functions of hydroxy amino acids may be protected by suitable protecting groups (throughout all the synthesis or only during a few steps) or may be kept unprotected.
The protecting groups are capable of being removed by acidolysis, saponification or hydrogenolysis. For the protection of the amino groups the following protective groups may for example be employed; benzyloxycarbonyl, t-butoxycarbonyl, trityl, formyl, trifluoroacetyl, o- nitrophenylsulphenyl, 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or 3,5-dimethoxy u.u'-dimethylbenzyloxycarbonyl. For the protection of the carboxy groups the following protective groups may for example be employed: methyl, ethyl, t-butyl, benzyl or p-nitro-benzyl. For the protection of the hydroxy groups the following protecting groups may for example be used: acetyl, tbutoxycarbonyl, benzyloxycarbonyl, 2-bromobenzyloxycarbonyl, tetrahydropyranyl, t-butyl, trityl, benzyl or 2,4-dichlorobenzyl.
The condensation between an amino group of one molecule and a carboxyl group of another molecule to form the peptide linkage may be carried out through an activated acyl-derivative such as a mixed anhydride, an azide or an activated ester, or by direct condensation between a free amino group and a free carboxyl group, in the presence of-a condensing agent such as dicyclohexylcarbodiimide, alone or together with a racemization preventing agent, such as N-hydroxysuccinimide or 1 hydroxybenzotriazole.
Hydrazido or substituted hydrazido derivatives according to the invention are prepared by condensation of the.N-protected peptide or amino acid with a suitably substituted hydrazido such as benzylcarbazate, t-butylcarbazate, adamantylcarbazate, phenylhydrazine or adamantylhydrazine, or reacting the N-protected peptide or amino acid hydrazide with a suitable alkylating agent, such as an alkyl chloride, or with a suitable acylating agent such as benzylchloroformate, t-butylchloroformate, di-t butyldicarbqnate or adamantylfluoroformate.
The condensation may be carried out in a solvent such as dimethylformamide, pyridine, acetonitrile, tetrahydrofuran or N-methyl-2-pyrrolidone. The reaction temperature may be from -300C to ambient temperature. The reaction time is generally from 1 to 120 hours. The scheme of synthesis, the protecting groups and the condensing agents are selected so as to avoid the risk of racemization.
D-protecting reactions are carried out according to methods known per se in polypeptide chemistry. Peptides wherein W represents OR are prepared, for example, starting from the C-terminal amino acid esterified by the appropriate alcohoi. Peptides wherein W represents OH can be prepared, for example, by hydrolysis of peptides wherein W represents OR. Peptides wherein W represents NH2,
NHR or NR2 can be prepared by ammonolysis of the corresponding esters or starting from a C-terminal amino acid amidated by an appropriate amine.
In the solid-phase method a polymeric support is used. The polymer is preferably a copolymer of styrene with from 1 to 2 percent by weight of divinyl benzene as a cross-linking agent which causes the polystyrene polymer to be completely insoluble in most organic solvents. The synthesis is commenced from the C-terminal end of the peptide, by attaching the required amino acid to a chloromethylated resin, a hydroxymethyl resin, or a benzhydrylamine resin. The amino and side chain protecting groups are those described in the classical solution synthesis.
In the preparation of the compounds of this invention, an amino protected amino acid is coupled to the chloromethylated resin via caesium salt, or to a hydroxymethyl or benzhydrylamine resin, with the aid of a condensing agent such as dicyclohexylcarbodiimide.
After the initial coupling, the amino protecting group is removed by a choice of reagents including trifluoroacetic acid or hydrogen chloride solutions in organic solvents at room temperature. After removal of the amino protecting group, the remaining protected amino acids are coupled stepwise in the desired order to'obtain the desired peptide. Each protected amino acid is generally reacted in)a 3fold excess using an appropriate carboxy group activator such as dicyclohexylcarbodiimide in solution in, for example, methylene dichloride: dimethylformamide mixtures.
After the desired amino acid sequence has been completed, the peptide is removed from the resin support by treatment with a reagent such as hydrogen fluoride, which not only cleaves the peptides from the resin, but also cleaves most of the remaining side-chain protecting groups. When chloromethylated or hydroxymethylated resin is used, hydrogen fluoride treatment results in the formation of the free peptide acid (W = OH). When benzhydrylamine resin is used, hydrogen fluoride treatment results directly in the free peptide amide (W = NH2). Alternatively, when the chloromethylated or hydroxymethylated resin is employed, the side-chain protected peptide can be cleaved by treatment of the peptide resin with ammonia or a mono- or di-alkylamine to give the desired side-chain protected amide, alkylamide or dialkylamide (W = NH2, NHR, NR2).Side-chain protection may then be removed by any of the methods known in the art. In preparing the esters of the present invention (W = OR), the resins used to prepare the acid (W = OH) are employed and the side-chain protected peptide is cleaved with a base and the appropriate alcohol. Side-chain protection is then removed in the usual way.
Alternatively, the peptide acids and amides can be obtained from the peptide esters by saponification or ammonolysis.
The compounds according to the invention show an interesting pharmacological activity on inhibition of prolactin release. In addition some of the compounds of the invention are endowed with the following pharmacological activities: release of ACTH and p-endorphin, inhibition of the release of growth hormone and TSH. The inhibition of prolactin secretion was determined both "in vitro" and "in vivo"; "in vitro" test by using pituitary celis (obtained from rat or beef) suspended in Bio-gel columns, "in vivo" test by measuring the inhibition of serum basal prolactin secretion in male rats and the inhibition of suckening stimulated prolactin secretion in lactating rats.
The inhibition of prolactin release was determined in vitro using the method described by P. J.
Lowry in J. Endocrinol. 63, 1 63 (1974). The peptides synthesized were able to inhibit by 6080% prolactin secretion in isolated and perfused rat pituitary cells at a concentration ranging from 10-4 to 1O0M.
The compounds according to the invention are endowed with anxiolytic activity determined by modifications of the qualitative and quantitative spontaneous activity in rats according to the method described by A. E. Whimbey and V. -H. Denenberg in J. Comparative Physiology and Psychology, 63, 500-504 (1967).
The synthesized compounds, administered subcutaneously to rat at doses ranging from 20 mcg to 100 mcg/kg were-able to decrease the level of anxiety induced by a new environment (open-field), and to increase explorativity in familiar environments (residential cages).
The invention further provides a pharmaceutical composition comprising a compound of the present invention or.a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier; in addition, these preparations can have direct or delayed liberation of the active ingredient.
The preferred peptides according to the invention are the following:
1. H-Pyr-Gly-Prn-P ro-Ile-Ser- le-Asp-Leu-Ser-Leu-Gl u-Leu-OH 2. H-Pyr-G Iy-Pro-P ro-l le-Ser-lie-Asp-Leu-Ser-Leu-G lu-Leu-N Hz 3. H-Pyr-Gly-P ro-P ro-lle-Ser-lle-Asp-Leu-Ser-Leu-G lu-Phe-OH
4. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Phe-NH2 5. H-Pyr-G Iy-P ro-P ro-lle-Ser-l le-Asp-Leu-Ser-Leu-G In-Leu-OH 6. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Gln-Leu-NH2 7. H-Pyr-Gly-P ro-Pro-lle-Ser-l le-Asp-Leu-Ser-Leu-His-Leu-OH
8.H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-His-Leu-N H2
9. H-Pyr-Gly-Pro-Pro-lle-Ser-l le-Asp-Leu-Ser-Phe-Glu-Leu-OH 10. H-Pyr-G ly-P ro-Pro-lle-Ser-lle-Asp-Leu-Ser-Phe-Glu-Leu-NH2 11. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Thr-Leu-Glu-Leu-OH 1 2. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Thr-Leu-Glu-Leu-NH2 13. H-Pyr-Gly-P ro-P ro-lle-Ser-l le-Asn-Leu-Ser-Leu-Glu-Leu-OH 14. H-Pyr-Gly-Pro-P ro-lle-Ser-l le-Asn-Leu-Ser-Leu-G lu-Leu-N H2
1 5.H-Pyr-Gly-Pro-P ro-l le-Ser-l le-Glu-Leu-Ser-Leu-G lu-Leu-OH
1 6. H-Pyr-Gly-Pro-P ro-l le-Ser-lle-G lu-Leu-Ser-Leu-G lu-Leu-NH2 17. H-Pyr-Gly-Pro-Pro-l le-Ser-Leu-Asp-Leu-Ser-Leu-G lu-Leu-OH 1 8. H-Pyr-Gly-Pro-Pro-lle-Ser-Leu-Asp-Leu-Ser-Leu-Glu-Leu-NH2 19. H-Pyr-Gly-P ro-Pro-lle-Ser-P he-Asp-Leu-Ser-Leu-Glu-Leu-OH
20. H-Pyr-Gly-P ro-Pro-lle-Ser-P he-Asp-Leu-Ser-Leu-Glu-Leu-N H2
21. H-Pyr-Glu-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Leu-OH 22.H-Pyr-Glu-P ro-P ro-lle-Ser-l le-Asp-Leu-Ser-Leu-Glu-Leu-NH2
23. H-Pyr--Gln-Prn-Prn-Ile-Ser-lIe-Asp-Leu-Ser-Leu-Glu-Leu-OH 24. H-Pyr-Gln-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Leu-NH2 25. H-Gln-Gly Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Leu-OH 26. H-Gln-Gly-Pro-P ro-lie-Ser-l le-Asp-Leu-Ser-Leu-Glu-Leu-NH2 27. H-Pyr-Gly-P ro-Pro-lle-Ser-l le-Asp-Leu-Ser-P he-His-Leu-OH 28. H-Pyr-G ly-P ro-P ro-l le-Ser-lle-Asp-Leu-Ser-P he-His-Leu-NH2 29. H-Pyr-G ly-Pro-P ro-lle-Ser-lle-Asp-Leu-Thr-P he-His-Leu-OH 30. H-Pyr-Gly-Pro-Pro-Ile-Ser-l Ie-Asp-Leu-Thr-P he-His-Leu-N H2 31. H-Pyr-Gly-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-OH 32.H-Pyr-Gly-Pro-P ro-l le-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-NH2 33. H-Pyr-Glu-Pro-Pro-l le-Ser-Leu-Asp-Leu-Thr-P he-His-Leu-OH 34. H-Pyr-Glu-P ro-P ro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-NH2 35. H-Gln-Glu-Prn-Prn-Ile-Ser-Leu-Asp-LeuJhr-Phe-His-Leu-OH 36. H-Gln-Glu-Prn-Prn-Ile-Ser-Leu-Asp-LeuJhr-Phe-His-Leu-NH2 37. H-Gln-Glu-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Leu-OH 38. H-Gln-Glu-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-Glu-Leu-NH2 39. H-Gln-GIu-P rn-P ro-IIe-Ser-Leu-Asp-Leu-Ser-Leu-Glu-Leu-OH 40. H-Gln-Glu-Pro-Pro-lle-Ser-Leu-Asp-Leu-Ser-Leu-Glu-Leu-NH 41. H-Gln-Glu-P ro-Pro- le-Ser-Leu-Asp-Leu-Thr-Leu-Glu-Leu-OH 42.H-Gln-G lu-P ro-P ro-l le-Ser-Leu-Asp-Leu-Thr-Leu-Glu-Leu-NH2 43. H-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-Glu-Leu-OH 44. H-Gln-Glu-P ro-P ro-lle-Ser-Leu-Asp-Leu-Thr-Phe-G lu-Leu-NH 45. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-OH 46. H-Pyr-Gly-P ro-P ro-lle-Ser-lle-Asp-Leu-Ser-Leu-GI u-NH2 47. H-Pyr-Gly-Pro-P ro-lle-Ser-l le-Asp-Leu-Ser-Leu-His-OH 48. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-His-NH2 49. H-Pyr-G ly-P ro-P ro-l le-Ser-lle-Asp-Leu-Ser-P he-Glu-OH 50. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Phe-Giu-NH2 51. H-Pyr-Gly-Pro-P ro-lle-Ser-lle-Asp-Leu-Thr-Leu-Glu-OH 52. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Thr-Leu-Glu-NH2 53.H-Pyr-Gly-P ro-P ro-lle-Ser-l le-Asn-Leu-Ser-Leu-Glu-OH 54. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asn-Leu-Ser-Leu-Glu-NH2 55. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-GI u-Leu-Ser-Leu-Glu-OH 56. H-Pyr-Gly-P ro-P ro-lle-Ser-lle-G lu-Leu-Ser-Leu-Glu-NH2 57. H-Pyr-Gly-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Ser-Leu-Glu-OH 58. H-Pyr-Gly-Pro-Pro-lle-Ser-Leu-Asp-Leu-Ser-Leu-Glu-NH2 59. H-Pyr-Gly-Pro-P ro-l le-Ser-P he-Asp-Leu-Ser-Leu-G lu-OH 60. H-Pyr-Gly-Pro-Pro-lle-Ser-P.he-Asp-Leu-Ser-Leu-Glu-NH2 61. H-Pyr-Glu-Pro-Pro-lie-Ser Ile-Asp-Leu-Ser-Leu-Glu-OH 62. H-Pyr-Gíu-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-NH2 63. H-Pyr-Gln-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-OH 64.H-Pyr-Gln-P ro-P ro-lle-Ser-l le-Asp-Leu-Ser-Leu-Glu-NH2 65. H-Gln-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Ley-Glu-OH 66. H-Gln-G Iy-P ro-P ro-l le-Ser-lle-Asp-Leu-Ser-Leu-Glu-NH2.
67. H-Gln-Glu-Pro-P ro-lle-Ser-Leu-Asp-Leu-Thr-P he-His-OH 68. H-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-NH2 69. H-Pyr-G Iy-P ro-P ro-lle-Ser-lle-Asp-Leu-Ser-Leu-OH 70. H-Pyr-Gly-P ro-P ro-l le-Ser-lle-Asp-Leu-Ser-Leu-NH2 71. H-Pyr-Gly-P ro-P ro-l le-Ser-l le-Asp-Leu-Ser-Phe-OH 72. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Phe-NH2 73. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-Leu-OH 74. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Thr-Leu-NH2 75. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asn-Leu-Ser-Leu-OH 76. H-Pyr-Gly-P ro-P ro-lle-Ser-lle-Asn-Leu-Ser-Leu-NH2 77. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Glu-Leu-Ser-Leu-OH 78. H-Pyr-Gly-Pro-Pro-lle-Ser-lle-Glu-Leu-Ser-Leu-NH2 79. H-Pyr-Gly-Pro-Pro-lle-Ser-Leu-Asp-Leu-Ser-Leu-OH 80. H-Pyr-Gly-P ro-P ro-ile-Ser-Leu-Asp-Leu-Ser-Leu-N H2 81. H-Pyr-G Iy-P ro-P ro-l le-Ser-P he-Asp-Leu-Ser-Leu-OH 82. H-Pyr-G Iy-P ro-P ro-lle-Ser-P he-Asp-Leu-Ser-Leu-NH2 83. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-OH 84. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-NH2 85. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-OH 86. H-Pyr-Gln-Pro-P ro-lle-Ser-l le-Asp-Leu-Ser-Leu-NH2 87; H-Gln-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-OH 88. H-Gln-G Iy-P ro-P ro-lle-Ser-l le-Asp-Leu-Ser-Leu-NH2 89. H-Pyr-Gly-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-OH 90. H-Pyr-Gly-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-NH2 91. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-OH 92. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-NH2 93. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-OH 94.H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-NH2 95. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asn-Leu-Ser-OH 96. H-Pyr-Giy-Pro-P ro-l le-Ser-lle-Asn-Leu-Ser-NH2 97. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-OH 98. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-NH2 99. H-Pyr-Gly-Pro-P ro-lle-Ser-Leu-Asp-Leu-Ser-OH 100. H-Pyr-Gly-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Ser-NH2 101. H-Pyr-Gly-Pro-Pro-Ile-Ser-Phe-Asp-Leu-Ser-OH 102. H-Pyr-Gly-Pro-Pro-Ile-Ser-Phe-Asp-Leu-Ser-NH2 103. H-Pyr-Glu-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-OH 104. H-Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-NH2 105. H-Pyr-Gln-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-OH 106. H-Pyr-Gln-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Ser-NH2 107. H-Gln-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-OH 108. H-Gln-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-NH2 109.H-Gln-Glu-Pro-Pro-Ile-Ser-Ile-Leu-Asp-Leu-Thr-OH 110. H-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Leu-Asp-Leu-Thr-NH2 111. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-OH 112. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-NH2 113. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-OH 114. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-NH2 115. H-Gly-Pro-Pro-Ile-Ser-Ile-Asn-Leu-Ser-OH 116. H-Gly-Pro-Pro-Ile-Ser-Ile-Asn-Leu-Ser-NH2 117. H-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-OH 118. H-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-NH2 119. H-Gly-Pro-P ro-lle-Ser-Leu-Asp-Leu-Ser-OH 120. H-Gly-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Ser-NH2 121. H-Gly-Pro-Pro-Ile-Ser-Phe-Asp-Leu-Ser-OH 122. H-Gly-Pro-Pro-Ile-Ser-Phe-Asp-Leu-Ser-NH2 123. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-OH 124. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-NH2 125. H-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-OH 126. H-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-NH2 127.H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-OH
128. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-NH2 129. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Phe-OH 139. H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Phe-NH2 131. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-Leu-OH 132. H-Gly-Pro-Pro-lle-Ser-lie-Asp-Leu-Thr-Leu-NH2 133. H-Gly-Pro-Pro-Ile-Ser-Ile-Asn-Leu-Ser-Leu-OH
134. H-Gly-Pro-Pro-Ile-Ser-Ile-Asn-Leu-Ser-Leu-NH2 135. H-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-Leu-OH 136.H-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-Leu-NH2 137. H-Gly-Pro-Pro-lle-Ser-Leu-Asp-Leu-Ser-Leu-OH 138. H-Gly-Pro-Pro-lle-Ser-Leu-Asp-Leu-Ser-Leu-NH2 139. H-Gly-Pro-Pro-lle-Ser-Phe-Asp-Leu-Ser-Leu-OH 140. H-Gly-Pro-Pro-lle-Ser-Phe-Asp-Leu-Ser-Leu-NH2 141. H-Glu-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-OH 142. H-Glu-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-NH2 143. H-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-Oh 144. H-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-NH2 145. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-Glu-OH 146. H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-NH2 147. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-His-OH 148. H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-His-NH2 149. H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Phe-Glu-OH 150.H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Phe-Glu-NH2 151. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-Leu-Glu-OH 152. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Thr-Leu-Glu-NH2 1 53. H-Gly-Pro-Pro-lle-Ser-lle-Asn-Leu-Ser-Leu-Glu-OH 154. H-Gly-Pro-Pro-Ile-Ser-Ile-Asn-Leu-Ser-Leu-Glu-NH2 155. H-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-Leu-Glu-OH 156. H-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-Leu-Glu-NH2 157. H-Gly-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Ser-Leu-Glu-OH
1 58. H-Gly-P ro-Pro-i le-Ser-Leu-Asp-Leu-Ser-Leu-Glu-NH2
159. H-Gly-Pro-Pro-Ile-Ser-Phe-Asp-Leu-Ser-Leu-Glu-OH
160. H-Gly-Pro-Pro-Ile-Ser-Phe-Asp-Leu-Ser-Leu-Glu-NH2
161. H-Glu-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-Glu-OH
1 62. H-Glu-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-NH2
163.H-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-OH
1 64. H-Glu-Pro-P ro-l le-Ser-Leu-Asp-Leu-Thr-Phe-His-NH2 165. H-Gly-P ro-P ro-lle-Ser-l le-Asp-Leu-Ser-Leu-Glu-Leu-OH 166. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-Glu-Leu-NH2
167. H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-Glu-Phe-OH
1 68. H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Phe-N2 169. H-Gly-P ro-P ro-l le-Ser-Ile-Asp-Leu-Ser-Leu-His-Leu-OH
170. H-Gly-P ro-P ro-l le-Ser-l le-Asp-Leu-Ser-Leu-His-Leu-NH2
171.H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Phe-Glu-Leu-OH
172. H-Gly-Pro-Pro-l le-Ser-l le-Asp-Leu-Ser-Phe-Glu-Leu-NH2 173. H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Thr-Leu-Glu-Leu-OH 1 74. H-Gly-P ro-P ro-l le-Ser-lle-Asp-Leu-Thr-Leu-Giu-Leu-NH2 1 75. H-Gly-P ro-P ro-lle-Ser-l le-Asn-Leu-Ser-Leu-Glu-Leu-OH 176. H-Gly-Pro-Pro-Ile-Ser-Ile-Asn-Leu-Ser-Leu-Glu-Leu-NH2
177. H-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-Leu-Glu-Leu-OH
178. H-Gly-Pro-Pro-Ile-Ser-Ile-Glu-Leu-Ser-Leu-Glu-Leu-NH2
179. H-Gly-Pro-Pro-lle-Ser-Leu-Asp-Leu-Ser-Leu-Glu-Leu-OH 1 80. H-Gly-Pro-Pro-lle-Ser-Leu-Asp-Leu-Ser-Leu-Glu-Leu-NH2
1 81. H-Gly-Pro-P ro-lIo-Ser-Phe-Asp-Leu-Ser-Leu-Glu-Leu-OH 1 82.H-Gly-Pro-Pro-lle-Ser-Phe-Asp-Leu-Ser-Leu-Glu-Leu-NH2
1 83. H-Glu-P ro-P ro-IIo-Sor-lIo-Asp-Leu-Ser-Leu-Glu-Lou-0H 1 84. H-Glu-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Leu-NH2
185. H-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-OH
186. H-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-NH2
The following Examples illustrate the invention. The.Rf values were determined on pre-coated plates of silica gel 60 F254 (Merck) Layer thickness 0.25 mm, length 20 cm, using the following development systems:
System A: n-butanol:acetic acid water (4:1:1 by volume)
System B: chloroform: methanol: 32% ammonium hydroxide (65:45:20 by volume).
"Merck" is a Trade Mark.
TLC analyses were carried out at temperatures ranging from 18 to 250 C. The Rf values can therefore change by +5%.
High pressure liquid chromatography (HPLC) analysis were carried out Qn Hibar Lichrosorb R9-1 8 (5 y) columns using:
Eluent A: KH2PO4 0.02 M, pH 7, 10% acetonitrile
Eluent B: KH2PO4 0.02 M; pH 7, 60% acetonitrile
Mobile phase: mix A and B to obtain solution containing 10% B. Increase percent of B from 10% to 60% in 25 minutes.
High voltage paper electrophoresis is carried out with a Pherograph-Original-Frankful l Type 64 apparatus on Schleicher and Schull paper No. 2317 at pH 5.8 (pyridine acetic acid water 45:5:450 by volume) 32.5 V/cm). Electrophoretic mobilities (E5.8) are given relative to glutamic acid.
Synthesis on a polymeric support can be carried out, for example, by one of the following procedures.
Procedure A. Preparation of Boc-(AA)n-(AA)n-1... (AA)1-Hydroxymethyl Polystyrene Ester
Chloromethylated polystyrene resin is esterified with the first Boc-amino acid (Boc-AA1-OH) according to Gisin, Helv. Chim. Acta, 56, 1476 (1973). The polystyrene ester is treated according to schedule A for incorporation of Boc-(AA)2-OH... Boc(AA)n-OH to give the title resin.
Schedule A
-1. Wash 3 times with dichloromethane.
2. Treat twice for 1 minute with trifluoroacetic acid : dichloromethane (40:60 by volume).
3. Treat for 30 minutes with trifluoroacetic acid: dichloromethane (40:60 by volume).
4. Wash 4 times with dichloroethane.
5. Treat twice for 1 minute with 10% N-methylmorpholine in dichloromethane.
6. Treat for 5 minutes with 10% N-methylmorpholine in dichloromethane.
7. Wash 8 times with dichloromethane.
8;Add or 3 equivalents of the symmetric anhydride of the corresponding amino acid derivative, prepared according to Hagenmayer and Frank, Hoppe-Seyler's Z Physiol. Chem., 353, 1973 (1972), dissolved in dichloromethane. Reaction time 0.5 to 2 hours.
9. Wash 3 times with dichloromethane.
10. Wash 3 times with isopropanol.
11. Wash 3 times with dichloromethane.
12. Test by the ninhydrin reaction according to Kaiser et al., Annal. Biochem., 34, 595 (1970). In case of incomplete reaction repeat steps 4 to 11.
Procedure B. Preparation of H-(AA),--(AA),~,... (AA)1-Hydroxyrnethyi Polystyrene Ester
After introduction of the last amino acid derivative according to schedule A (procedure A), repeat steps 1 to 7 of schedule A, and wash 4 times with isopropanol.
Procedure C. Preparation of Boc-(AA)n-(AA)n-1... (AA)1-Benzhydrylamine Resin
Boc-(AA)1-OH is attached to a benzhydrylamine resin via dicyclohexylcarbodiimide, as described by Pietta et al., J. Org. Chem. 39,44 (1974). Unreacted amino groups are acetylated with acetic anhyddde : pyridine : dichloromethane (2 :1:1 0 by volume). The polystyrene amide is then treated according to schedule A (procedure A) for high voltage paper electrophoresis is carried out with a
Pherograph-Original-Frankfurt Type 64 apparatus on Schleicher and Schull paper No. 231 7 at pH 5.8 (pyridine:acetic acid:water 45:5:450 by volume) 32.5 V/cm. Electrophoretic mobilities (E5.6) are given relative to glutamic acid.
Synthesis on a polymeric support can be carried out, for example, by one of the following procedures.
Procedure A. Preparation of Boc-(AA)n-(AA)n-1... . . (AA)1-Hydroxymethyl Polystyrene Ester
Chloromethylated polystyrene resin is esterified with the first Boc-amino acid (Boc-AA1-OH) according to Gisin, Helv. Chim. Acta, 56, 1476 (1973). The polystyrene ester is treated according to schedule A for incorporation of Boc-(AA)2-OH... Boc(AA)n-OH to give the title resin.
Schedule A
1. Wash 3 times with dichloromethane.
2. Treat twice for 1 minute with trifluoroacetic acid dichloromethane (40:60 by volume).
3. Treat for 30 minutes with trifluoroacetic acid : dichloromethane (40:60 by volume).
4. Wash 4 times with dichloroethane.
5, Treat twice for 1 minute with 10% N-methylmorpholine in dichloromethane.
6. Treat for 5 minutes with 10% N-methylmorpholine in dichloromethane.
9. Wash 8 times with dichloromethane.
8. Add 2 or 3 equivalents of the symmetric anhydride of the corresponding amino acid derivative, prepared according to Hagenmayer and Frank, Hoppe-Seyler's Z Physiol. Chem., 353, 1973 (1972), dissolved in dichloromethane. Reaction time 0.5 to 2 hours.
9. Wash 3 times with dichloromethane.
10. Wash 3 times with isopropanol.
11. Wash 3 times with dichloromethane.
12. Test by the ninhydrin reaction according to Kaiser et al., Annal. Biochem., 34,595 (1970). In case of incomplete reaction repeat steps 4 to 11.
Procedure B. Preparation of H-(AA)n-(AA)n-1.. (AA)1-Hydroxymethyl Polystyrene Ester
After introduction of the last amino acid derivative according to schedule A (procedure A), repeat steps 1 to 7 of schedule A, and wash 4 times with isopropanol.
Procedure C.)reparation of Boc-(AA)n-(AA)n-1... (AA)1-Benzhydrylamine Resin
Boc-(AA)1-OH is attached to a benzhydrylamine resin via dicyclohexylcarbodiimide, as described by Pietta et al., J. Org. Chem. 39,44 (1974). Unreated amino groups are acetylated with acetic anhydride;pyridine: dichloromethane (2 :1:10 by volume).The polystyrene amide is then treated according to schedule A (procedure A) for
EXAMPLE 1
Pyr-Giy-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Leu-OH Sodium Salt (1)
1 g of peptide resin deteained by procedure A with the required sequence of amino acid residues (introduced as Boc-Leu-OH, Boc-Glu(OBz1)-OH, Boc-Leu-OH, Boc-Ser(Bzl)-OH Boc-Leu-OH, Boc Asp(OBzl)-OH, Boc-lle-OH, Boc-Ser(Bzl)-OH, Boc-lle-OH, Boc-Pro-OH, Boc-Pro-OH, Boc-Gly-OH, H-Pyr
OH in that ordine) was suspended for 1 hour at 0 C in 10 ml of anhydrous (distilled over 500 mg of cobalt trifluoride) hydrogen fluoride containing 1 ml of anisole. The hydrogen fluoride was removed under reduced pressure and the anisole was removed by washing with diisopropyl ether (3 x 10 ml).
The crude peptido was extracted from the resin with dimethylformamide (3 x 10 ml) and purified by gel filtration on Sephadex LH-20 using dimethylformamide as eluent, and by an exchange chromatography on DEAE-Sephadex A-25 using as eluent ammonium acetate buffer at pH 6. The product was then transformed to the sodium salt with an excess of sodium bicarbonate, desalted on Sephadex C-1 5, and lyophilized.
0.120 g of the peptide (1 ) were obtained.
RIA 0.17; RfB 0.44; E56 0.60 Clu; R, (HPLC) ca. 15'
Amino acid ratio:
Asp 0.99; Ser 1.94; Glu 1.96; Pro 1.96; Gly 1.01; Leu 2.96; lle 1.97.
EXAMPLE 2
Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Leu-NH2 Sodium Salt (2)
1 g of peptide resin obtained by procedure C with the required sequence of amino acid residues (introduced as Boc-Leu-OH, Boc-Glu(OBzl)-OH, Boc-Leu-OH, Boc-Ser-(Bzl)-OH, Boc-Leu-OH, Boc
Asp(OBzl)-OH, Boc-lle-OH, Boc-Ser(Bzl)-OH, Boc-lle-OH, Boc-Pro-OH, Boc-Pro-OH, Boc-Gly-OH, H-Pyr
OH, in that order) was suspended for 1 hour in 10 ml of anhydrous (distilled over 500 mg of cobalt trifluoride) hydrogen fluoride containing 1 ml of anisole. The hydrogen fluoride was removed under reduced pressure and the anisole was removed by washing with diisopropyl ether (3 x 10 ml).The crude peptido was extracted from the resin with dimethylformamide (3 x 10 ml) and purified by gel filtration on Sephadex LH-20 using dimethylformamide as fluent, and by ion exchange chromatography on DEAE-Sephadex A-25 using as eluent ammonium acetate buffer at pH 6. The product was then transformed to the sodium salt with an excess of sodium bicarbonate, desalted on Sephadex G-1 5 and lyophilized.
0.130 g of the peptide (2) were obtained.
E5 , 0.30.
Amino acid ratio:
Asp 0.98; Ser 1.95; Glu 1.97; Pro 1.96; Gly 1.00; Leu 2.94; lle 1.98.
EXAMPLE 3 H-Giy-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Leu-OH Sodium Salt (1 65) 1 g of peptide resin obtained by procedure B with the required sequence of amino acid residues (introduced as Boc-Leu-OH, Boc-Glu(OBzl)-OH, Boc-Leu-OH, Boc-Ser-(Bzl)-OH, Boc-Leu-OH, Boc
Asp(OBzl)-OH, Boc-lle-OH, Boc-Ser(Bzl)-OH, Boc-lle-OH, Boc-Pro-OH, Boc-Pro-OH, Boc-Gly-OH in that
order) was suspended for 1 hour at OOC in 10 ml of anhydrous (distilled over 500 mg of cobalt trifluoride) hydrogen fluoride containing 1 ynl of anisole. The hydrogen fluoride was removed under reduced pressure and:the anisole was removed by washing with diisopropyl ether (3 x 10 ml).The curde peptide was extracted from the resin with dimethylformamide (3 x 10 -mI) and purified by gel filtration on Sephadex LH-20 using dimethylformamide as eluent and by ion exchange chromatograph on CH-Sephadex C-25 using as eluent ammonium acetate buffer at pH 4. The product was then transformed to the sodium salt with an excess of sodium bicarbonate, desalted on Sephadex Ct-1 5 and lyophilized.
0.110 g of the peptide (16.5) were obtained.
RfA 0.16, RfB 0.44, E58 0;34; Rt (HP'LC) Ca. 17'
Amino acid ratio:
Asp 0.98; Ser 1.97; Glu 1.00; Pro 1.99; Gly 0.99 Leu 2.97; lle 1.98.
EXAMPLE 4 H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Sers Leu-Glu-Leu-NH2 Sodium Salt (166)
1 g of peptide resin obtained by procedure D with the required sequence of amino acid residues (introduced as Boc-Leu-OH, Boc-Glu (OBzl)-OH, Boc-Leu-OH, Boc-Ser(Bzl)-OH, Boc-Leu-OH, Boc
Asp(OBzl)-OH, Boc-lle-OH, Boc-Ser(Bzl)-OH, Boc-lle-OH, Boc-Pro-OH, Boc-Pro-OH, Boc-Gly-OH in that order) was suspended for 1 hour at OOC in 10 ml of anhydrous (distilled over 500 mg of cobalt trifluoride) hydrogen fluoride containing 1 ml of anisole. The hydrogen fluoride wes removed under reduced pressure and the anisole was removed by washing with diisopropyl ether.The crude peptido was extracted from the resin with dimethylformamide (3 x 10 ml) and purified by gel filtration on
Sephadex LH-20 using dimethylformamide as eluent and by ion exchange chromatography on CH
Sephadex C-25 using as eluent ammonium acetate buffer at pH 4. The product was then transformed to the sodium salt with an excess of sodium bicarbonate, desalted on Sephadex G-1 5 and lyophilized.
0.110 g of the peptide (1 66) were obtained.
ES.e." 0
Amino acid ratio:
Asp 0.98; Ser 1.97; Glu 0.99; Pro 1.97; Gly 1.00; Leu 2.96; lle 1.96.
EXAMPLE 5
Preparation of H-Gln-Glu-Pro-Pro-lle-Ser-Leu-Asp-Leu-Thr-Phe-OH Sodium Salt (89)
1 g of peptide-resin obtained by procedure B with the required sequence of amino acid residues (Boc-Phe-OH, Boc-Thr(Bzl)-OH, Boc-Leu-OH, Boc-Asp (OBzl)-OH, Boc-Leu-OH, Boc-Ser(Bzl)-OH, Boc
lle-OH, Boc-Pro-OH, Boc-Pro-OH, Boc-Glu(OBzl)-OH, Boc-Gln-OH, in that order) was suspended for 1 hr at OOC in 1.0 ml of anhydrous (distilled over 500 mg of cobalt trifluoride) hydrogen fluoride containing 1 ml of anisole. The hydrogen fluoride was removed under reduced pressure and the anisole was removed by washing with diisopropyl ether (3 x 10 ml).The crude peptide was extracted from the resin with dimethylformamide (3 x 10 ml) and purified by gel filtration on Sephadex LH-20 using dimethylformamide as eluent and by ion exchange chromatography on CH-Sephadex C-25 using as eluent ammonium acetate at pH 4. The product was then converted to the sodium salt with an excess of sodium bicarbonate, desalted on Sephadex G-1 5 and lyophilized.
0.130 g of the peptide (89) were obtained.
RfA 0.22, Rfs 0.45, E58 0.75 Rt (HPLC) Ca. 12'
Amino acid ratio:
Asp 0.99; Thr 0.88; Ser 0.96, Glu 1.98, Pro 1.98, Leu 2.00; Ile 0.98; Phe 0.99
In similar way the following compounds were prepared:
VI) Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-Glu-OH Sodium Salt (45) E5,8 0.63
Amino acid ratio:
Asp 0.98; Ser 1.96; Glu 1.98; Pro 1.99; Gly 1.00; Leu 1.97; lle 1.98.
VII) Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-Glu-NH2 Sodium Salt (46) E5.8 0.30.
Amino acid ratio:
Asp 0.99; Ser 1.95; Glu 1.97; Pro 1.98; Gly 1.00; Leu 1.98; lle 1.97.
VIII) Pyr-Gly-P ro-Pro-ile-Ser-lle-Asp-Leu-Ser-Leu-OH Sodium Salt (69) E5.8 0.32
Amino acid ratio:
Asp 0.98; Ser 1.97; Glu 0.98; Pro 1.98, Gly 1.00, Leu 1.99.
IX) Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-NH2 Sodium Salt (70)
E5.8 0.15.
Amino acid ratio:
Asp 0.99, Ser 1.98; Glu 0.99; Pro 1.97; Gly 1.00; Leu 1.99; lle 1.99;
X) Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-OH Sodium Salt (91) E5.ss 0.35.
Amino acid ratio:
Asp: 0.97; Ser 1.96; Glu 0.97; Pro 1.96; Gly 0.99; Leu 1.00; lie 1.98.
XI) Pyr-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-NH2 Sodium Salt (92)
E5.8 0.16.
Amino acid ratio:
Asp 0.98, Ser 1.97; Glu 1.01; Pro 1.97; Gly 1.00; Leu 1.00; lle 1.97.
XII) H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-OH Sodium Salt (111)
E5,8 0.18.
Amino acid ratio:
Asp 0.99; Ser 1.98; Pro 1.99; Gly 1.01; Leu 1.00; Ile 1.99.
XIII) H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-NH2 Sodium Salt (112) E5.8 ca. O.
Amino acid ratio:
Asp 0.98; Ser 1.98; Pro 1.98; Gly 0.99; Leu 1.00; lie 1.98.
XIV) H-Gly-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-OH Sodium Salt(127) E580.15 Amino acid ratio:
Asp 0.99; Ser 1.97; Pro 1.99; Gly 1.00; Leu 1.99; Ile 1.98.
XV) H-Gly-Pro-Pro-lle-Ser-ile-Asp-Leu-Ser-Leu-NH2 Sodium Salt (128) E5.8 ca. O.
Amino acid ratio:
Asp 0.98; Ser 1.97; Pro 1.97; Gly 1.00; Leu 2.00; Ile 1.99.
XVI) H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-OH Sodium Salt (145)
E5.8 0.32.
Amino acid ratio:
Asp 0.99; Ser 1.98; Glu 0.97; Pro 1.98; Gly 1.00; Leu 2.01; lIe 1.99.
XVII) H-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-NH2 Sodium Salt (146) E5.B 0.16.
Amino acid ratio:
Asp 0.98; Ser 1.98; Glu 0.98; Pro 1.99; Gly 1.00; Leu 1.98; lle 1.98.
XVIII) Pyr-Gly-Pro-Pro-lle-Ser-lle-Asn-Leu-Ser-Leu-Glu-OH Sodium Salt (13) E5 8 0.28.
Amino acid ratio:
Asp 0.99; Ser 1.99; Glu 1.99; Pro 1.98; Gly 1.00; Leu 2.97; lle 1.97.
XIX) Pyr-Gly-Pro-Pro-lle-Ser-lle-Asn-Leu-Ser-Leu-Glu-Leu-NH2 Sodium Salt (11) E5.8 0.14.
Amino acid ratio:
Asp 0.99; Ser 1.97; Glu 1.97; Pro 1.99; Gly 1.00; Leu 2.98; lle 1.99.
XX) Pyr-Gly-Pro-Pro-lle-Ser-ile-Asp-Leu-Ser-Leu-Gln-Leu-OH Sodium Salt (5) E5 8 0.28.
Amino acid ratio:
Asp 0.97; Ser 1.98; Glu 1.96; Pro 1.97; Gly 1.00; Leu 2.97; lle 1.97.
XXI) Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Gln-Leu-NH2 Sodium Salt (6) E58 0.14.
Amino acid ratio:
Asp 0.98; Ser 1.97; Glu 1.97; Pro 1.99; Gly 1.00; Leu 3.01; lle 1.99.
XXII) Pyr-Gly-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Giu-Phe-OH Sodium Salt (3)
RfA 0.16; Rf5 0.42; E58 0.60.
Amino acid ratio:
Asp 0.99; Ser 1.95; Glu 1.99; Pro 1.98; Gly 1.00; Leu 1.97; lle 1.98; Phe 1.00.
XXIII) Pyr-Giy-Pro-Pro-lle-Ser-lle-Asp-Leu-Ser-Leu-Glu-Phe-NH2 Sodium Salt (4) E5.a 0.30.
Amino acid ratio:
Asp 0.98; Ser 1.98; Glu 1.96; Pro 1.98; Gly 1.01; Lou 1.99; lle 1.98; Phe 1.00.
EXAMPLES 24 TO 186
Using corresponding starting materials and by way of corresponding intermediates, the peptides
identified above by the numbers 7 to 12, 15to44,47 to 68,71 to 90, 93 to 110, 1 13 to 126,129 to - 144. 147 to 1 86 are obtained analogously to the aforegoing Examples.
Claims (4)
1. A peptide of the general formula: X-A-Pro-Pro-lle-Ser-B-C-Leu-D-E-F-G-W wherein:
X represents a hydrogen atom, a terminal nitrogen protecting group of acyl, aromatic urethane,
alkyl, aralkyl or aliphatic urethane type or a residue of a neutral L-amino acid, the free amino group of
the residue optionally being protected by a terminal nitrogen atom protecting group of the type cited
above,
A represents an L-amino acid residue or a glycine residue;
B represents a neutral L-amino acid residue;
C represents a neutral L-amino acid residue or an acidic L-amino acid residue;
D represents an L-amino acid residue which contains in the side chain an alcoholic hydroxy group,
which may be free or protected by a conventional hydroxy protecting group;
E represents a valence bond or a neutral L-amino acid residue;;
F represents a valence bond or an L-amino acid residue;
G represents a valence bond or a neutral L-amino acid residue;
W represents a hydroxy group, an amino group or a group of the formula OR, NHR, NR2 or NH-NH
R' wherein R represents a straight chain, branched chain or cyclic (including fused or bridged ring) alkyl
group having up to 1 1 carbon atoms, and being substituted or unsubstituted, a phenyl group or an
aralkyl group having from 6 to 8 carbon atoms; and R' represents a hydrogen atom, any of the groups
which R may represent, an alkenyl group having from 3 to 8 carbon atoms; a straight chain, branched
chain or cyclic aliphatic acyl group having from 1 to 11 carbon atoms, unsubstituted or substituted by
hydroxy or an amino group or a halogen atom, an aromatic acyl group, unsubstituted or substituted by a hydroxy or amino group or a halogen atom, a straight chain, branched chain or cyclic aliphatic urethane type group having from 3 to 11 carbon atoms, or an aromatic urethane type group; or a pharmaceutically acceptable salt thereof.
2. A peptide according to claim 1, wherein, X represents hydrogen atom, a formyl, acetyl, trifluoroacetyl, propionyl, bonzoyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 9- fluorenylmethoxycarbonyl, methoxy-cr,a'-dimethylbenzyloxywarbonyl, t-butoxycarbonyl, 1 - methyl-cyclobutoxyca rbonyl, adamantyloxycarbonyl, isobornyloxycarbonyl, trityl, benzyl, methyl or isopropyl group or a Pyr, Gln, Pro or 2-oxo-L-pipecolic acid residue,
A represents a Glu, Gln or Gly residue,
B represents an lle, Leu, Nle, Val or Phe residue,
C represents an Asn, Gln, Asp or Glu residue,
D represents a Ser, Hse and Tlr residue and if the hydroxy group of the residue represented by D is protected, it is protected by a t-butyl, trityl, benzyl, 2,4-dichlorobenzyl, benzyloxycarbonyl, 2bromobenzyloxycarbonyl, tetrahydropyranyl, t-butoxyca rbonyl, formyl, acetyl, trifluoroacetyl, propionyl or benzoyl group,
E represents a Phe, Leu or Nle residue or a valence bond,
F represents a Glu, Gln or His residue or a valence bond,
G represents a Leu or Phe residue or a valence bond, and
W represents a hydroxy group, an amino group or a group of the formula OR, NHR, NR2 or NH-NH
R' wherein R represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2,2,2- trifluoroethyl, cyclohexyl, adamantyl, phenyl, bonzyl or phenethyl group and R' represents a hydrogen atom or an allyl, pentenyl, formyl, acetyl, trifluoroacetyl, propionyl, butyryl, adamantylcarbonyl, benzoyl, phenylacetyl, cinnamyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 3,5 dimethoxy-ct,a'-dimethyibenzyloxywarbonyl, t-butoxycarbonyl group, or any of the groups specifically named in this claim as values for R; or a pharmaceutically acceptable salt thereof.
3. Any of the peptidos numbered herein from 1 to 186, or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a peptido according to any preceding claim or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08309547A GB2118190B (en) | 1982-04-13 | 1983-04-08 | Peptides with sauvagine-like activity |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8210696 | 1982-04-13 | ||
| GB08309547A GB2118190B (en) | 1982-04-13 | 1983-04-08 | Peptides with sauvagine-like activity |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8309547D0 GB8309547D0 (en) | 1983-05-11 |
| GB2118190A true GB2118190A (en) | 1983-10-26 |
| GB2118190B GB2118190B (en) | 1985-05-01 |
Family
ID=26282536
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08309547A Expired GB2118190B (en) | 1982-04-13 | 1983-04-08 | Peptides with sauvagine-like activity |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2118190B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1986001209A3 (en) * | 1984-08-02 | 1986-03-27 | Boehringer Mannheim Gmbh | New p-phenylenediamine peptides and reactance containing them for the determination of proteases of the blood coagulation system |
| EP0122798A3 (en) * | 1983-04-14 | 1986-09-03 | The Salk Institute For Biological Studies | Rcrf and analogs |
-
1983
- 1983-04-08 GB GB08309547A patent/GB2118190B/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0122798A3 (en) * | 1983-04-14 | 1986-09-03 | The Salk Institute For Biological Studies | Rcrf and analogs |
| WO1986001209A3 (en) * | 1984-08-02 | 1986-03-27 | Boehringer Mannheim Gmbh | New p-phenylenediamine peptides and reactance containing them for the determination of proteases of the blood coagulation system |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2118190B (en) | 1985-05-01 |
| GB8309547D0 (en) | 1983-05-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4350627A (en) | Biologically active peptides | |
| US4897445A (en) | Method for synthesizing a peptide containing a non-peptide bond | |
| US4803261A (en) | Method for synthesizing a peptide containing a non-peptide | |
| US5229489A (en) | Parathyroid hormone antagonists | |
| US4211693A (en) | Peptides with para-substituted phenylalanine | |
| US4659693A (en) | N,N'-dialkyl substituted guanidino amino acyl residue substituted GRF-analog peptides | |
| US5807986A (en) | Methods of making and screening betide libraries | |
| DK167361B1 (en) | GRF ANALOGUE PEPTIDES, PHARMACEUTICAL ACCEPTABLE SALTS AND PROCEDURES FOR THE PRODUCTION OF THESE | |
| JPH085916B2 (en) | New calcitonin derivative | |
| EP0363589A2 (en) | Somatostatin analogues | |
| EP0082568B1 (en) | Retro-inverso analogues of c-terminal penta and hexapeptides of substance p. | |
| Fujii et al. | Total synthesis of bovine pancreatic ribonuclease A. Part 1. Synthesis of the protected pentadecapeptide ester (positions 110–124) | |
| EP0225020A2 (en) | Peptides comprising, in sequence, units selected from the amino-acid residues 17 to 24 of ViP | |
| US4473555A (en) | Nona- and dodecapeptides for augmenting natural killer cell activity | |
| US4774319A (en) | Synthesis of a derivative of GRF and intermediate peptides | |
| US6673769B2 (en) | Lanthionine bridged peptides | |
| US4474765A (en) | Biologically active peptides | |
| US4491541A (en) | Peptides | |
| CZ1021084A3 (en) | Gonadoliberin derivatives and process for preparing thereof | |
| GB2130590A (en) | Peptides | |
| GB2118190A (en) | Peptides with sauvagine-like activity | |
| US4820804A (en) | Analogs of [1,7-di-alanine, des-19-leucine]calcitonin | |
| Kaur et al. | Synthesis and Biological Evaluation of Dehydrophenylalanine Containing Substance P Fragments. | |
| US5252705A (en) | Peptide derivatives | |
| Boissonnas et al. | Chemistry of the neurohypophysial hormones |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |