LT3375B - Peptides and pharmaceutical composition containing them - Google Patents
Peptides and pharmaceutical composition containing them Download PDFInfo
- Publication number
- LT3375B LT3375B LTIP717A LTIP717A LT3375B LT 3375 B LT3375 B LT 3375B LT IP717 A LTIP717 A LT IP717A LT IP717 A LTIP717 A LT IP717A LT 3375 B LT3375 B LT 3375B
- Authority
- LT
- Lithuania
- Prior art keywords
- arg
- pro
- gly
- ser
- tic
- Prior art date
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims description 62
- 102000004196 processed proteins & peptides Human genes 0.000 title claims description 32
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- -1 hydroxyphenylpropionyl Chemical group 0.000 claims description 57
- 150000001413 amino acids Chemical class 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical group OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 101800004538 Bradykinin Proteins 0.000 claims description 9
- 102400000967 Bradykinin Human genes 0.000 claims description 9
- 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 description 9
- 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 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 241000534944 Thia Species 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 244000137850 Marrubium vulgare Species 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 230000001575 pathological effect Effects 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 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
- 239000003937 drug carrier Substances 0.000 claims description 2
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 claims description 2
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims 2
- 101710097732 Bradykinin-related peptides Proteins 0.000 claims 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims 2
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical group OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 claims 1
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical group NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 157
- 229920005989 resin Polymers 0.000 description 28
- 239000011347 resin Substances 0.000 description 28
- 235000001014 amino acid Nutrition 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 238000000034 method Methods 0.000 description 18
- 150000003254 radicals Chemical class 0.000 description 18
- 125000006239 protecting group Chemical group 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 150000003862 amino acid derivatives Chemical class 0.000 description 9
- 239000004475 Arginine Substances 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 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 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-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
- 239000000203 mixture Substances 0.000 description 6
- 238000010647 peptide synthesis reaction Methods 0.000 description 6
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 5
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 5
- 125000001589 carboacyl group Chemical group 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-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
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 125000003435 aroyl group Chemical group 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 229960003104 ornithine Drugs 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 210000001147 pulmonary artery Anatomy 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 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 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
- PDELQDSYLBLPQO-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-indole Chemical compound C1CCCC2NCCC21 PDELQDSYLBLPQO-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
- 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
- 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
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 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
- 230000003042 antagnostic effect Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- 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 description 2
- 239000003152 bradykinin antagonist Substances 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 150000002168 ethanoic acid esters Chemical class 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 229940050176 methyl chloride Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-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
- 238000001665 trituration Methods 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 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
- KEBBBSYZHVXZIX-UHFFFAOYSA-N (2,2,5,7,8-pentamethyl-3,4-dihydrochromen-6-yl)sulfonyl 2,2,2-trifluoroacetate Chemical compound CC1(OC2=C(C(=C(C(=C2CC1)C)S(=O)(=O)OC(C(F)(F)F)=O)C)C)C KEBBBSYZHVXZIX-UHFFFAOYSA-N 0.000 description 1
- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-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
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Landscapes
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Išradimas priskiriamas naujiems bradikinin-antagonistinio veikimo peptidams, o taip pat farmakologinei kompozicijai, sudarytai jų pagrindu.The present invention relates to novel peptides having bradykinin antagonistic activity, as well as to a pharmaceutical composition based thereon.
PCT paraiškoje Nr. 86/07263 aprašomi bradikininantagonistiniai peptidai, kuriuose, be kitko, peptidinio hormono bradikinino arba jo analogo L-Pro 7 pozicijoje pakeistas D-aminorūgštimi, kaip, pvz. D-Phe, D-Thi, D-Pal, CDP, MDY, D-Phg, D-His, D-Tp, D-Tyr, D-hPhe, D-Val, D-Ala, D-His, D-Ile, D-Leu ir DOMT.PCT application no. No. 86/07263 discloses bradykinin antagonist peptides wherein, inter alia, the L-Pro 7 position of the bradykinin peptide hormone bradykinin or its analog is replaced by a D-amino acid, e.g. D-Phe, D-Thi, D-Pal, CDP, MDY, D-Phg, D-His, D-Tp, D-Tyr, D-hPhe, D-Val, D-Ala, D-His, D- Ile, D-Leu and DOMT.
Šio išradimo esmė buvo - surasti naujus bradikininantagonistėmis savybėmis pasižyminčius peptidus.The object of the present invention was to find novel peptides having bradykinin antagonist properties.
Šis uždavinys išsprendžiamas pagalba peptidų, kurių formulė:This problem is solved by the help of peptides of the formula:
A-B-C-E-F-K-(D)-Tic-G-M-F'-I (I) kuriojeA-B-C-E-F-K- (D) -Tic-G-M-F'-I (I) wherein
A reiškia vandenilį, (C^-Cg) - alkanoilą arba (Cx-C6) alkanoilą, pakeistą karboksilo grupe, arba radikalą, kurio formulė IIA represents hydrogen, (C 1 -C 6 ) alkanoyl or (C x -C 6 ) alkanoyl substituted by a carboxyl group, or a radical of formula II
R -N-CH-C-R -N-CH-C-
(II) kurioje(II) in which
R reiškia vandenilį, C^-Cg - alkanoilą arba C^-Cg alkanoilą, pakeistą hidroksifenilpropionilu;R represents hydrogen, C 1 -C 8 alkanoyl or C 1 -C 8 alkanoyl substituted by hydroxyphenylpropionyl;
R2 reiškia vandenilio atomą; irR 2 represents a hydrogen atom; and
R3 reiškia Cį-Cg - alkilą, pakeistą amino, guanicido grupe, fenilu, pakeistu hidroksilo grupe.R 3 represents C 1 -C 8 alkyl substituted with amino, guanicide, phenyl substituted with hydroxyl.
B reiškia tiesioginę jungtį arba pagrindinę aminorūgštį, esančią L- arba D- konfigūracijoje, minėta aminorūgštis priklauso Arg, Lys ir Orn eilei, ir gali būti pakeistos šoninėje grandinėje benziloksikarbonilu, nitrogrupė, tozilu, nikotinoilu, -CO-NH-C6H6 arba 2, 3,B represents a direct bond or a basic amino acid in the L- or D- configuration, said amino acid belonging to Arg, Lys and Orn and can be substituted in the side chain by benzyloxycarbonyl, nitro, tosyl, nicotinoyl, -CO-NH-C 6 H 6 or 2, 3,
5-trimetil-4-metoksifenilsulfonilu;5-trimethyl-4-methoxyphenylsulfonyl;
C reiškia junginį pagal formulę IllaC represents a compound of formula IIla
G'-G'-C (Illa) kurioje G’ yra nepriklausomas radikalas, kurio formulė IVG'-G'-C (IIla) wherein G 'is an independent radical of formula IV
-N-CH-C--N-CH-C-
(IV) kurioje R4 ir R5 kartu su kitais atomais sudaro heterociklinę, monociklinę sistemą, turinčią 1 azoto atomą ir keturius anglies atomus, sistemą, kuri gali būti pakeista hidroksigrupe arba grupe, turinčią 1 azoto atomą, 3 anglies atomus ir 1 deguonies atomą arba sudarančią heterociklinę, biciklinę žiedinę sistemą, turinčią 1 azoto atomą ir 7 anglies atomus;(IV) wherein R 4 and R 5 together with the other atoms form a heterocyclic, monocyclic system containing 1 nitrogen atom and four carbon atoms, a system which may be substituted by a hydroxy group or a group containing 1 nitrogen atom, 3 carbon atoms and 1 oxygen atom or forming a heterocyclic, bicyclic ring system containing 1 nitrogen atom and 7 carbon atoms;
E reiškia L- arba D- konfigūracijos Phe, Trn arba Thia aromatinės aminorūgšties liekaną;E represents a Phe, Trn or Thia aromatic amino acid residue of the L- or D- configuration;
F reiškia L- arba D- konfigūracijos Ash, Cys, Gln, Orn, Ser, Trp, Phe, Thia aminorūgšties radikalą arba tiesioginę jungtį.F represents the amino acid radical or direct bond of the L- or D- configuration of Ash, Cys, Gln, Orn, Ser, Trp, Phe, Thia.
K reiškia radikalą -NH-(CH2) X-CO, kur X=l-2, arba reiškia tiesioginę jungtį.K represents the radical -NH- (CH 2 ) X -CO, where X = 1-2, or represents a direct bond.
(D) - Tie reiškia grupę, kurios formulė V(D) - Those refer to the group of formula V
(V)(V)
G reiškia tiesioginę jungtį arba formulė IV radikalą, kurioG represents a direct bond or a radical of formula IV having
-N-CH- οι, 1 5 II-N-CH- οι, 1 5 II
R R5 O kurioje R4 ir R5 kartu su kitais atomais sudaro heterociklinę, monociklinę sistemą, turinčią 1 azoto atomą ir keturius anglies atomus, arba sistemą, turinčią 1 azoto atomą, 3 anglies atomus ir 1 deguonies atomą arba sudarančią heterociklinę, biciklinę žiedinę sistemą, turinčią 1 azoto atomą ir 7-9 anglies atomus;RR 5 O wherein R 4 and R 5 together with the other atoms form a heterocyclic, monocyclic system containing 1 nitrogen atom and four carbon atoms, or a system containing 1 nitrogen atom, 3 carbon atoms and 1 oxygen atom or forming a heterocyclic, bicyclic ring system having 1 nitrogen atom and 7-9 carbon atoms;
F’ reiškia liekaną -NH-(CH2)4~, arba L- arba D- konfigūracijos Arg arba Ser aminorūgšties radikalą, kuris gali būti pakeistas ramnozilu arba 2, 3, 5-trimetil-4metoksifenilsulfonilu arba reiškia tiesioginę jungtį;F 'represents a residue of the -NH- (CH 2 ) 4 -, or L- or D- configuration of the Arg or Ser amino acid radical, which may be substituted by rhamnosyl or 2,3,5-trimethyl-4-methoxyphenylsulfonyl or represents a direct bond;
I reiškia amino arba hidroksigrupę, arba fiziologiškai priimtinas jų druskas.I represents an amino or hydroxy group or a physiologically acceptable salt thereof.
Jeigu nieko kito nenurodyta, tai aminorūgšties radikalo pažymėjimas, be stereodeskriptoriaus reiškia, kad radikalas yra L-formoje (Šrioderis, Liubke, Peptidai, 1 tomas, Niujorkas, 1965, psl. ΧΧΙΙ-ΧΧΙΙΙ; Houben-Veil, Organinės chemijos metodai, tomai XV/1 ir 2, Štutgartas 1974) kaip pavyzdžiui:Unless otherwise stated, the designation of an amino acid radical without a stereo descriptor means that the radical is in L-form (Schröder, Lübke, Peptides, Volume 1, New York, 1965, pp. ΧΧΙΙ-ΧΧΙΙΙ; Houben-Veil, Methods in Organic Chemistry, Vol. XV / 1 and 2, Stuttgart 1974) as an example:
Aad, Abu, yAbu, ABz, ξΑΒζ, ξΑσ3, Ach, Acp, Adpd, Ahb, Aib, ĖAib, Ala, PAla, Ala, Alg, Ali, Amą, Apl, Apm,Aad, Abu, yAbu, ABz, ξΑΒζ, ξΑσ3, Ach, Acp, Adpd, Ahb, Aib, AAib, Ala, PAla, Ala, Alg, Ali, Am, Apl, Apm,
Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bhp, Can, Cit, Cys, Cyta, Daad, Dab, Daad, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hClu, His, hlle, hLeu, hLus, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, eHyp, Ile, Ise, Iva, Kyn, Lant, Len, Leu, Lsg, Lys, PLys, Lys, met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pro, Pse, Pyc, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, pThi, Thr, Thy, Thx, Tia, Tie, Tly, Trp,Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bhp, Can, Cit, Cys, Cyta, Daad, Dab, Daad, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hClu, His, hlle, hLeu, hLus, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, eHyp, Ile, Ise, Iva, Kyn, Lant, Len, Leu, Lsg, Lys, PLys, Lys, met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pro, Pse, Pyc, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, pThi, Thr, Thy, Thx, Tia, Tie, Tly, Trp,
Trta, Tyr, Vai.Trta, Tyr, Vai.
IV formulėje heterociklinės žiedinės sistemos radikalas gali būti sekančių grupių heterociklų radikalai:In formula IV, the radical of the heterocyclic ring system may be the radicals of the following groups of heterocycles:
pirolidinas (A); piperidinas (B); tetrahidroizochinolinas (C) ; dekahidroizochinolinas (D) ; oktahidroindolas (E) ; oktahidrociklopenta (b)-pirolas (F) ; 2-azibiciklo(2.2.3)-oktanas (G); 3-azibiciklo (2.3.1)heptanas (H); 2-azispiro(4.4)-nonanas(J); spiro (biciklo(2.2.1)-heptan)-2,3-pirolidinas) (K); spiro ( (bi — ciklo(2.2.2)oktan)-2,3-pirolidinas) (L);2-azitriciklo (4.3.0.16'9)-dekanas (M); dekahidrociklohepta (b) pirolas (N); oktahidroizoindolas (O); oktahidrociklopenta (c)pirolas (P); 2,3,3a,4,5,7a-heksahidroindolas (O); tetrahidrotiazolas (R); 2-azibiciklo(3.1.0)heksanas (S) ; izoksoazolinas (T) ; pirozolidinas (U) ; hidroksiprolinas (V); kurie esant reikalui gali būti pakeičiami.pyrrolidine (A); piperidine (B); tetrahydroisoquinoline (C); decahydroisoquinoline (D); octahydroindole (E); octahydrocyclopenta (b) -pyrrole (F); 2-azibicyclo (2.2.3) -octane (G); 3-azibicyclo (2.3.1) heptane (H); 2-azispiro (4.4) -nonane (J); spiro (bicyclo (2.2.1) -heptane) -2,3-pyrrolidine) (K); spiro ((bi - cyclo (2.2.2) octane) -2,3-pyrrolidine) (L) 2-azitriciklo (4.3.0.1 6 '9) decane (M); decahydrocyclohepta (b) pyrrole (N); octahydroisoindole (O); octahydrocyclopenta (c) pyrrole (P); 2,3,3a, 4,5,7a-hexahydroindole (O); tetrahydrothiazole (R); 2-azibicyclo (3.1.0) hexane (S); isoxoazoline (T); pyrazolidine (U); hydroxyproline (V); which may be replaced if necessary.
Aukščiau minėtuose radikaluose esantys heterociklai psl.2a žinomi pagal JAV paraiškas Nr. 4344349, 4374847, 4350704, EP paraiškas Nr. 50800, 51741, 51080, 49658, 49605, 29488, 46958, 52870, 271865, VFR paraiškas Nr. 3226768, 3151690, 3210496, 3211397, 3211676, 3227555, 3242151, 2346503 ir 3246757.The heterocycles in the above radicals on page 2a are known from U.S. Pat. 4344349, 4374847, 4350704, EP application no. 50800, 51741, 51080, 49658, 49605, 29488, 46958, 52870, 271865, VFR Application no. 3226768, 3151690, 3210496, 3211397, 3211676, 3227555, 3242151, 2346503 and 3246757.
Be to, kai kurie iš šių heterociklų pateikiami VFR paraiškoje Nr. 3818850.3.In addition, some of these heterocycles are disclosed in VFR application no. 3818850.3.
Jeigu specialiai nepažymėta, alkilas gali turėti tiesią ar besišakojančią atomų grandinę. Tai taip pat galioja ir tokiems radikalams, kaip, pvz. alkokcilas, arilalkilas arba alkanoilas. (C6-C12)-arilas dažniausiai reiškia fenilą, naftilą arba bifenilą. Atitinkamai galima sudaryti ir sudėtingesnius radikalus, kaip, pvz. ariloksilas, arilalkilas arba aroilas.Unless specifically noted, alkyl may have a straight or branched chain of atoms. This also applies to radicals such as alkoxyl, arylalkyl or alkanoyl. (C 6 -C 12 ) -aryl usually represents phenyl, naphthyl or biphenyl. Correspondingly, more complex radicals such as e.g. aryloxyl, arylalkyl or aroyl.
Halogenas reiškia fluorą, chlorą, bromą arba jodą, pirmenybę teikiant chlorui.Halogen means fluorine, chlorine, bromine or iodine, with chlorine being preferred.
Iš druskų pageidautinos šarminių metalų druskos, arba žemės šarminių metalų druskos, druskos su fiziologiškai priimtinais aminais ir druskos, į kurių sudėtį įeina liekanos organinių ir neorganinių rūgščių, kaip druskos rūgštis, bromo vandenilio rūgštis, sieros rūgštis, fumaro rūgštis, citrinos rūgštis, malono rūgštis, acto rūgštis ir kt.Of the salts, the preferred alkali metal salts, or alkaline earth metal salts, salts with physiologically acceptable amines and salts containing residues of organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, citric acid, malonic acid , acetic acid, etc.
Labiau pageidaujami I formulės peptidai, kurMore preferred are peptides of formula I wherein
B reiškia argininą, diaminobutiroilą, arba atitinkamai aminogrupė šoninėje grandinėje gali punktuose aj arba a2) ;B represents arginine, diaminobutyryl, or the amino group in the side chain, respectively, at aj or a 2 );
liziną, ornitiną, 2,4L-homoarginino liekaną, kai arba guanidinogrupė, esanti būti pakeista A, kaip aprašytalysine, ornithine, a 2,4L-homoarginine residue, when either the guanidino group is to be replaced by A as described
E reiškia L- arba D- konfigūracijos aromatinės aminorūgšties liekanos radikalą, kuris arilinėje dalyje gali būti pakeistas halogenu 2-oje, 3-oje arba 4-oje pozicijoje, tirozinas, 0-metiltirozinas, 2-piridilalaninas arba naftilalaninas;E represents a radical of an aromatic amino acid residue of the L- or D- configuration which may be substituted on the aryl portion by halogen at the 2, 3 or 4 position, tyrosine, 0-methyl tyrosine, 2-pyridylalanine or naphthylalanine;
F reiškia L- arba D- konfigūracijos pagrindinės aminorūgšties radikalą, pvz. argininą arba liziną, vienok guanidino grupė arba aminogrupė, esanti šoninėje grandinėje, gali būti pakeista A, kas aprašyta punkte aj arba a2), arba reiškia radikalą -NH-(CH2)n- kur n=28;F represents a radical of the basic amino acid of the L- or D- configuration, e.g. arginine or lysine, a single guanidine group or an amino group on the side chain may be replaced by A as described in aj or a 2 ), or represents -NH- (CH 2 ) n - where n = 28;
K- reiškia radikalą -NH-(CH2) X-CO, kur X=2-4, arba reiškia tiesioginę jungtį. Labiau pageidaujami yra junginiai, kurie atitinka formulę I, kurioje:K- represents the radical -NH- (CH 2 ) X -CO where X = 2-4, or represents a direct bond. More preferred are compounds of formula I wherein:
B reiškia argininą, ornitiną arba liziną, kai guanidino grupė arba aminogrupė, esanti šoninėje grandinėje yra nepakeista arba pakeista (C^-Cg) -alkanoilu, (C7-C10) ariloilu, (C3-C8)-heteroariloilu, (C1-C8)-alkisulfonilu arba (C6-C12)-arilsulfonilu, kai arilo, heteroarilo, ariloilo, arilsulfonilo ir heteroariloilo radikalai, kaip aprašyta punkte a2) gali būti pakeisti 1, 2, 3 arba 4 vienodais ar skirtingais radikalais;B represents arginine, ornithine or lysine when the guanidine group or amino group in the side chain is unsubstituted or substituted by (C 1 -C 8 ) -alkanoyl, (C 7 -C 10 ) aroyl, (C 3 -C 8 ) -heteroaryl, ( C 1 -C 8 ) -alkisulfonyl or (C 6 -C 12 ) -arylsulfonyl, where the aryl, heteroaryl, aroyl, arylsulfonyl and heteroarylyl radicals as described in a2) can be replaced by 1, 2, 3 or 4 radicals which are the same or different ;
E reiškia fenilalaniną, 2-chlorfenilalaniną, 3-chlorfenilalaniną, 4-chlorfenilalaniną, 2-fluorfenilalaniną,E represents phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine,
3-fluorfenilalaniną, 4-fluorfenilalaniną, tiroziną, 0metiltiroziną arba β-(3-tinil)alaniną;3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, 0-methyl tyrosine or β- (3-tinyl) alanine;
F reiškia paprastą jungtį; irF represents a simple bond; and
M reiškia paprastą jungtį.M stands for Simple Connection.
Labiausiai tinka peptidai pagal I formulę, kurioje:Most preferred are peptides of formula I wherein:
A reiškia vandenilį, (D) - arba (L)-H-argininą, (D) arba (L)-H-liziną, arba (D)- arba (L)-H-ornitiną;A represents hydrogen, (D) - or (L) -H-arginine, (D) or (L) -H-lysine, or (D) - or (L) -H-ornithine;
B reiškia argininas, ornitinas arba lizinas, kai guanidino grupė arba aminogrupė, esanti šoninėje grandinėje gali būti pakeista vandeniliu, (C^-Cg)LT 3375 B alkanoilu, (C7-C13) -ariloilu, (C8-C9) -heteroaloilu, (CxC8)-alkilsulfonilu arba (C6-C12) -arilsulfonilu, kur arilo, heteroarilo, ariloilo, arilsulfonilo ir heteroariloilo radikalai, reikalui esant gali būti pakeisti 1, 2, 3 arba 4 vienodais ar skirtingais radikalais, pasirinktais iš metoksilo arba halogeno.B represents arginine, ornithine, or lysine, where the guanidine group or the amino group on the side chain may be replaced by hydrogen, (C 1 -C 8 ) alkanoyl, (C 7 -C 13 ) -aryl, (C 8 -C 9 ). -heteroaloyl, (C x C 8 ) -alkylsulfonyl or (C 6 -C 12 ) -arylsulfonyl wherein aryl, heteroaryl, aroyl, arylsulfonyl and heteroarylyl radicals may be optionally substituted with 1, 2, 3 or 4 radicals, which may be the same or different. , selected from methoxyl or halogen.
C reiškia Pro-Pro-Gly, Hyp-Pro-Gly arba Pro-Hyp-Gly;C represents Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly;
E reiškia Phe arba Thi;E represents Phe or Thi;
F reiškia Ser, Hser, Leu, Lys, Vai, Nle, Ile arba Thr;F represents Ser, Hser, Leu, Lys, Vai, Nle, Ile or Thr;
K reiškia paprastą jungtį; M reiškia paprastą jungtį;K represents a simple bond; M represents a simple bond;
G reiškia IV formulės heterociklinės žiedinės sistemos radikalą, kur geriau tinka heterociklų radikalai, kuriems priklauso pirolodinas (A); piperidinas (B); tetrahidroizochinolinas (C); eis- ir trans-deka20 hidroizochinolinas (D) ; cis-endo oktahidroindolas (E) ; cis-eksi-oktahidroindolas (E); trans-oktahidroindolas (E); cis-endo, cis-eski-, trans-oktahidrociklopentano(b)pirolas (F) arba hidroksiprolinas (V).G represents a radical of the heterocyclic ring system of formula IV, more preferably the heterocycle radicals to which pyrrolodine (A) belongs; piperidine (B); tetrahydroisoquinoline (C); eis and trans-deca20 hydroisoquinoline (D); cis-endo octahydroindole (E); cis-exi-octahydroindole (E); trans-octahydroindole (E); cis-endo, cis-eski-, trans-octahydrocyclopentane (b) pyrrole (F) or hydroxyproline (V).
F' reiškia argininą, irF 'represents arginine, and
I reiškia OH.I stands for OH.
Labiausiai tinkamai I formulės peptidai yra:Most suitably, the peptides of formula I are:
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OHH- (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-OHH- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser (D) -Tic-Oic-Arg-OH
H-(D)-Arg-Arg-Pro-Hyp-Gly-PPhe-Ser(D)-Tic-Oic-Arg-OHH- (D) -Arg-Arg-Pro-Hyp-Gly-PPhe-Ser (D) -Tic-Oic-Arg-OH
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser(D)-Tic-Oic-Arg-OHH- (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-OHH- (D) -Arg-Arg-Pro-Pro-Gly-Phe-Ser (D) -Tic-Oic-Arg-OH
Išradime kalbama apie I formulės peptidų gavybos būdą, kuris apibūdinamas tuo, kadThe present invention relates to a process for the preparation of peptides of formula I which is characterized in that
a) fragmentas su C-galine laisva karboksiline grupe arba jo aktyvuotas darinys sujungiamas su atitinkamu laisvu N-galiniu aminogrupės fragmentu, arba(a) the moiety or the activated derivative thereof is joined to the corresponding free N-terminal amino group moiety of the C-terminal free carboxyl group, or
b) laipsniškai sukuriama peptido struktūra, gautame atitinkamai pagal (a) arba (b) junginyje, reikalui esant, atskeliama, viena ar kelios apsauginės grupės, kurios buvo prijungtos kitų funkcijų apsaugai, ir tokiu būdu gauti I formulės junginiai, reikalui esant, paverčiami i, fiziologiškai įsisavinamas druskas.b) the stepwise formation of the peptide structure obtained in the compound (a) or (b), respectively, if necessary cleaved, by one or more protecting groups which are attached to protect other functions, and thus converting the compounds of formula I thus obtained , physiologically acceptable salts.
uretaninė apsauginė butiloksikarbonilinė pvz. tretinė grupė arbaurethane protective butyloxycarbonyl e.g. a tertiary group or
Šiame išradime pateikti peptidai buvo gauti, naudojant žinomus peptidų cheminius būdus, pvz. pagal Houbenweyl, Methoden der organischen Chemie, Band 15/3, B. Merrifield, J. Am. Chem. Soc. 86, 2149 (1963) arbaThe peptides of the present invention were obtained using known peptide chemical techniques, e.g. by Houbenweyl, Methoden derorganchen Chemie, Band 15/3, B. Merrifield, J. Am. Chem. Soc. 86, 2149 (1963) or
R. C. Shepard, Int. J. Peptide protein Res. 21, 118 (1983) . Kaip α-amino apsauganti grupė yra naudojama grupė, kaip, (Boc) apsauginė fluoretilmetoksikarbonilinė (Fmac). Reikalui esant, pvz. norint išvengti šalutinių reakcijų ar siekiant susintetinti specialius peptidus, funkcinės grupės, esančios aminorūgščių šoninėse grandinėse gali būti apsaugotos atitinkamomis apsauginėmis grupėmis (T.W.Greene, Protective Groups in organic Synthesis), ir pirmiausia tam naudojama Arg(Tos), Arg(Mts), Arg(mir), Arg(PMC), Asp(OBzl), Asp(OBut), Cys(4-MeBlz), Glu(OBzl), Glu(OBut), His(Tos), His(fmoc),R. C. Shepard, Int. J. Peptide Protein Res. 21, 118 (1983). A protecting group such as (Boc) fluoroethylmethoxycarbonyl (Fmac) is used as an α-amino protecting group. If necessary, e.g. in order to prevent side reactions or to synthesize specific peptides, the functional groups in the amino acid side chains may be protected by appropriate protecting groups (TWGreene, Protective Groups in Organic Synthesis), and in particular Arg (Tos), Arg (Mts), Arg ( mir), Arg (PMC), Asp (OBzl), Asp (OBut), Cys (4-MeBlz), Glu (OBzl), Glu (OBut), His (Tos), His (fmoc),
Lys(Cl-z), Lys(Boc), Met(o),Lys (Cl-z), Lys (Boc), Met (o),
Thi(Bzl),Thi (Bzl),
Cys(SBut) His(Dnp), Ser (Būt),Cys (SBut) His (Dnp), Ser (Be),
His(Trt), Ser (Bzl),His (Trt), Ser (Bzl),
Thr(But), Trp(Mts),Thr (But), Trp (Mts),
Trp(CHO), Tyr(Bzl) arba Tyr(But).Trp (CHO), Tyr (Bzl) or Tyr (But).
Kietos fazės sintezė prasideda peptido C-gale, susirišant apsaugotą aminorūgštį su atitinkama derva. Tokios pradinės medžiagos gali būti gautos surišant apsaugomą aminorūgštį su modifikuota chlormetilo, hidroksimetilo, benzhidrilamino (BHA) arba metilbenzhidlamino (MBHA) grupės pagalba polistiroline arba poliakrilamidine derva esterine arba amidine jungtimi. Naudojamos kaip pagrindas dervos gali būti įsigytos komerciniais kanalais.Solid phase synthesis begins at the C-terminus of the peptide by binding the protected amino acid to the corresponding resin. Such starting materials may be obtained by coupling a protected amino acid with a modified polystyrene or polyacrylamide resin ester or amide bond via a modified chloromethyl, hydroxymethyl, benzhydrylamine (BHA) or methylbenzhydlamine (MBHA) group. The resins used as the base can be purchased through commercial channels.
BHA- ir MBHA- dervos paprastai naudojamos tada, kai susintetintas peptidas C-gale turi turėti laisvą amido grupę. Jeigu peptidas C-gale turi turėti antrinę amido grupę, naudojamos chlormetilinė arba hidroksimetilinė derva ir atskėlimas vykdomas atitinkamų aminų pagalba. Jeigu, pavyzdžiui, norima gauti etilamidą, peptidas gali būti atskirtas nuo dervos etilamino pagalba, ir šoninės grandinės apsauginė grupė pašalinama vėliau atitinkamų reagentų pagalba. Jeigu peptido aminorūgšties tretinio butilo apsauginės grupės turi apsaugoti Šoninę grandinę, tai sintezė vykdoma Fmocapsauginės grupės pagalba, siekiant laikinai užblokuoti aminorūgšties α-aminogrupę, naudojant aprašytą pavz. R.C. Sherpard. J. Chem. Soc., Chem. Comm. 1983, 587 metodiką, kai arginino guanidino grupė apsaugoma piridin-perchlorato pagalba, o kitos funkcinės grupės aminorūgščių šoninėje grandinėje apsaugomos apsauginių benzilo grupių pagalba, kurios atskeliamos katalitiškai hidrinant (A. Felix et ai. J. Org. Chem. 13, 4194 (1978)) arba natriu skystame amoniake (W. Robetrts. J. Am. Chem. Soc. 76, 6303 (1954).BHA- and MBHA- resins are commonly used when the synthesized peptide has a free amide group at the C-terminus. If the peptide has a secondary amide group at the C-terminus, a chloromethyl or hydroxymethyl resin is used and the cleavage is carried out with the appropriate amines. If, for example, ethylamide is desired, the peptide may be separated from the resin by ethylamine and the side-chain protecting group subsequently removed by appropriate reagents. If the peptide amino acid tertiary butyl protecting groups are required to protect the side chain, then the synthesis is carried out with the help of a Fmoco protecting group to temporarily block the α-amino group of the amino acid using the procedure described in FIG. R.C. Sherpard. J. Chem. Soc., Chem. Comm. 1983, 587, wherein the guanidine group of arginine is protected by pyridine perchlorate and other functional groups in the amino acid side chain are protected by benzyl protecting groups which are cleaved by catalytic hydrogenation (A. Felix et al., J. Org. Chem. 13, 4194 (1978). )) or sodium in liquid ammonia (W. Robetrts. J. Am. Chem. Soc. 76, 6303 (1954).
Atskėlus sujungtos su derva amonorūgšties apsauginę aminogrupę, atitinkamo reagento, pvz. trifluoracto rūgšties metileno chloride Šesant Boc apsauginei grupei) arba 20 % piperidino dimetilformamide tirpalu (esant Fmoc apsauginei grupei), aminorūgštys nuosekliai sujungiamos norima seka. Tarpiniame etape susidariusios peptidinės dervos prieš susirišimą su sekančiu aminorūgšties dariniu deblokuojamos aukščiau aprašytų reagentų pagalba.Once the protective amino group of the resin bound amino acid is cleaved, the appropriate reagent, e.g. trifluoroacetic acid in methylene chloride With Boc protecting group) or with 20% piperidine in dimethylformamide solution (in the presence of Fmoc protecting group), the amino acids are sequentially linked in the desired sequence. The peptide resins formed in the intermediate step are deprotected with the reagents described above before binding to the subsequent amino acid derivative.
aminorūgšties racemizacij ąamino acid racemization
Kaip reagentai gali būti naudojami visi aktyvuojantys reagentai, naudojami peptidų sintezėje, pvz. HoubenWeil Organinės chemijos metodai, t.15/2, tokie kaip karbodiimidai, kaip N, N'-dicikloheksilkarbodimidas arba N-etil-N’-(3-dimetilaminopropil)karbodiimidas. Sujungimas su derva gali būti vykdomas aktyvuojančio reagento pagalba tiesiogiai prijungiant darini, bei, reikalui esant, su slopinančiu priedu, kaip 1-hidroksibenzotriazolu (HOBt) (W. Konig, R. Geiger, Chem. Ber. 103, 708 (1970) arbaAs reactants all activating reagents used in peptide synthesis can be used, e.g. HoubenWeil Methods of Organic Chemistry, vol.15 / 2 such as carbodiimides such as N, N'-dicyclohexylcarbodimide or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide. Coupling with the resin may be accomplished by direct coupling of the derivative with an activating reagent and, if necessary, with an inhibitory additive such as 1-hydroxybenzotriazole (HOBt) (W. Konig, R. Geiger, Chem. Ber. 103, 708 (1970) or
3-hidroksi-4-okso 3,4-dihidrobenzotriazinu (HOObt) (W. Konig, R. Geiger, Chem. Ber. 103, 2054 (1970)) vienok pradinis aktyvavimas aminorūgšties kaip simetrinio anhidrido arba HOBt- arba HOObt-esterio gali būti vykdomas atskirai ir toks aktyvuotas tirpalas gali būti pridedamas prie peptinės dervos.Initial activation of 3-hydroxy-4-oxo by 3,4-dihydrobenzotriazine (HOObt) (W. Konig, R. Geiger, Chem. Ber. 103, 2054 (1970)) as the amino acid as a symmetric anhydride or HOBt or HOObt ester can may be performed separately and such an activated solution may be added to the peptide resin.
Aminorūgšties sujungimas arba aktyvavimas vienu iš aukščiau paminėtų aktyvuoj ančių reagentų gali būti vykdomas dimetilformamide, N’-metilpirolidone, metileno chloride arba šių tirpiklių mišinyje. Aktyvus aminorūgšties darinys paprastai naudojamas 1,5-4 didesniame, negu reikalinga, kiekyje. Jeigu Įvyksta nepilna sujungimo reakcija, ji yra kartojama, nevykdant peptidinės dervos aminogrupės deblokavimo.The coupling or activation of the amino acid with one of the above activating reagents can be carried out in dimethylformamide, N'-methylpyrrolidone, methylene chloride or a mixture of these solvents. The active amino acid derivative is generally used in an amount of 1.5-4 greater than that required. If an incomplete coupling reaction occurs, it is repeated without deprotection of the amino group of the peptide resin.
Sėkminga reakcijos eiga gali būti kontroliuojama ninhidrino reakcijos pagalba, kaip aprašyta E. Kaiser et ai. Anai. Biochem. 34, 595 (1970). Sintezė taip pat gali būti automatizuota, pvz. panaudojant firmos Applied Biosystems peptidų sintezės programas, tiek sudaryti naujas. Pastarosios reikalingos naudojant aminorūgštis, apsaugotas Fmoc- grupėmis.The successful course of the reaction can be controlled by the reaction of ninhydrin as described by E. Kaiser et al. Anna. Biochem. 34, 595 (1970). Synthesis can also be automated, e.g. using peptide synthesis programs from Applied Biosystems, both to develop new ones. The latter are required using amino acids protected by Fmoc groups.
Po to, kai aukščiau aprašytu būdu susintetinamas peptidas, jis gali būti atskeltas nuo dervos skysto fluoro vandenilio (peptidams, gautiems pagal Boc metodą) arba trifluoracto rūgšties (peptidams, gautiems pagal Fmoc metodą) pagalba. Šie reagentai atskelia ne tik peptidą nuo dervos, bet ir kitas apsaugines šonines grandinės grupes. Tokiu būdu, naudojant BHA- ir MBHAdervas peptidas gaunamas rūgšties formoje. Naudojant BHA- ir MBHA- dervas, atskeliant fluoro vandeniliu ar trifluoracto rūgštimi, peptidas gaunamas rūgšties amido pavidale. Kiti peptido amido gavimo būdai aprašyti patentinėse VFR paraiškose nr. P37 11 866.8 ir P37 43 620.1. Čia peptido amidų atskyrimas nuo dervos vykdomas naudojant paprastai peptidų sintezėje naudojamas vidutinio stiprumo rūgštis (pvz. trifluoracto rūgštį), o katijonams neutralizuoti naudojami tokie junginiai, kaip pvz., fenolas, krezolas, triokrezolas, anizolas, etanditiolas, dimetilsulfidas, etilmetilsulfidas ir kt. naudojami tokiais atvejais, atskirai arba mišinyje. Trifluoracto rūgštis gali būti naudojama ir praskiesta atitinkamais tirpikliais, kai pvz. metilo chloridu.After the peptide is synthesized as described above, it can be separated from the resin by liquid fluorine hydrogen (for peptides obtained by the Boc method) or trifluoroacetic acid (for peptides obtained by the Fmoc method). These reagents also cleave other protective side chain groups in addition to the resin peptide. Thus, using BHA- and MBHAdervas, the peptide is obtained in acid form. Using BHA- and MBHA- resins, the peptide is obtained in the form of an acid amide by cleavage with hydrofluoric acid or trifluoroacetic acid. Other methods for obtaining the peptide amide are described in U.S. Patent Application Ser. P37 11 866.8 and P37 43 620.1. Here, the resin separation of the peptide amides is carried out using moderate acids commonly used in peptide synthesis (e.g. trifluoroacetic acid), and compounds such as phenol, cresol, triocresol, anisole, ethanethiol, dimethylsulfide, ethylmethylsulfide and others are used to neutralize the cations. used in such cases, either singly or in combination. Trifluoroacetic acid can be used and diluted with appropriate solvents, e.g. methyl chloride.
Jeigu turi būti išsaugotos peptidinių šoninių grandininių tretinio butilo arba benzilo apsauginės grupės, susintetinto peptido atskyrimas vykdomasIf peptide side-chain tertiary butyl or benzyl protecting groups are to be retained, then the synthesized peptide is separated.
1-procentinės praskiestos metilo chloride trifluoracto rūgšties pagalba (R. C. Shepard. J. Chem. Soc. Chem. Comm. 1983, 587) . Jeigu turi būti išsaugotos tretinio butilo arba benzilo apsauginės grupės, naudojami atitinkami sintezės atskyrimo būdai.1% dilute in methyl chloride with trifluoroacetic acid (R. C. Shepard. J. Chem. Soc. Chem. Comm. 1983, 587). If tertiary butyl or benzyl protecting groups are to be retained, appropriate synthetic separation techniques are employed.
Sintetinant peptidus C-galinės amidinės grupės, ω-amino- arba ω-guanidinalkilinės grupės pagalba taip pat naudojama Šepardo aprašyta derva.The resin described by Shepard is also used to synthesize the peptides using the C-terminal amide group, the ω-amino or the ω-guanidine alkyl group.
Po sintezės apsaugotos šoninėje grandinėje peptidas atskiriamas nuo dervos ir toliau atitinkamo amino, ω-aminoalkilamino arba ω-guanidinalkilamino pagalba yra perdaromas, ir reikalui esant kitos grupės gali būti laikinai apsaugotos žinomais metodais.After synthesis, the protected side chain peptide is separated from the resin and further rearranged with the appropriate amino, ω-aminoalkylamine or ω-guanidine alkylamine, and if necessary, other groups can be temporarily protected by known methods.
Kitas peptidų gavimo ω-aminoalkilinės grupės pagalba būdas aprašytas VFR patentinėje paraiškoje Nr. 36 35 670.0.Another method for the preparation of peptides by the ω-aminoalkyl group is described in VFR patent application no. 36 35 670.0.
Išradime pateikiami peptidai buvo sintetinami daugiausiai kietoje fazėje reakcijų pagalba, naudojant dvi apsauginių grupių taktikas.The peptides of the invention were synthesized mainly in solid phase by reaction using two protecting group tactics.
Sintezė buvo vykdoma firmos Applied Biosystems peptidų sintezės automatiniu modeliu 430A, panaudojant Boc- ir Fmoc- apsauginių grupių metodą laikinam aaminogrupės blokavimui.The synthesis was carried out by Applied Biosystems Automated Peptide Synthesis Model 430A using the Boc- and Fmoc-protecting group method to temporarily block the amino group.
Naudojant Boc-apsauginę grupę, panaudotos gamintojo sudarytos sintezės programos.Synthetic programs prepared by the manufacturer were used using the Boc-protecting group.
Peptidų su laisva karboksiline grupe C-gale sintezė buvo vykdoma apdorotoje su atitinkama Boc-aminorūgštimiSynthesis of peptides with the free carboxylic group at the C-terminus was carried out on the corresponding Boc-amino acid treated
4- (hidroksimetil) fenilacetamidometilpolistirolo dervoje (R. B. Merrifield. J. Org. Chem. 43, 2845 (1978)), pateiktoje Applied Biosystems firmos. Peptidamidams gauti buvo panaudota tos pačios firmos MBHA-derva.4- (hydroxymethyl) phenylacetamidomethyl-polystyrene resin (R. B. Merrifield. J. Org. Chem. 43, 2845 (1978)) provided by Applied Biosystems. MBHA resin from the same company was used to obtain the peptidamides.
Kai aktyvuoj antys reagentai naudojami N, N'-dicikloheksilkarbodiimidas arba N, N'-diizopropilkarbodiimidas. Aktyvavimas buvo vykdomas simetriniame anhidride, HOBt-eteryje arba NMP. Sujungimui buvo naudojamaWhen the reactants used are N, N'-dicyclohexylcarbodiimide or N, N'-diisopropylcarbodiimide. Activation was performed in symmetric anhydride, HOBt-ether, or NMP. The connection was used
2-4 aktyvuoto aminorūgšties darinio ekvivalentai. Jeigu susijungimo reakcija Įvykdavo nepilnai, ji buvo kartojama.2-4 equivalents of the activated amino acid derivative. If the merger reaction was incomplete, it was repeated.
Naudojant Fmoc- apsauginę grupę laikinam α-amino grupės apsaugojimui sintezės firmos Applied Biosystems modeliu 430A buvo sudarytos naujos sintezės programos. Sintezė vyko ant firmos Bachem p-benziloksibenzilalkoholio dervos (S. Wang. J. Am. Chem. Soc. 95, 1328 (1973)), kuri buvo esterinama pagal žinomą metodiką (E. Atherton et ai. J. C. S. Chem. Comm. 1981, 336) atitinkamos aminorūgšties pagalba. Aminorūgšties darinių HOBt- ir HOObt- esterių pavidale aktyvavimas buvo vykdomas gamintojo pateiktose kapsulėse su aminorūgštimi pridedant diizopropilkarbodiimido tirpalą dimetilformamide į anksčiau gautą HOBt arba HOObt ir aminorūgšties darinio mišinį. Lygiai taip pat substancijoje gali būti naudojami gauti Fmocaminorūgšties-OObt-esteriai, paraiškoje Nr. 87107634.5.Using the Fmoc-protecting group for the temporary protection of the α-amino group, new synthesis programs have been developed for Applied Biosystems Model 430A. The synthesis was carried out on Bachem p-benzyloxybenzyl alcohol resin (S. Wang. J. Am. Chem. Soc. 95, 1328 (1973)), which was esterified according to known procedures (E. Atherton et al., JCS Chem. Comm. 1981). 336) with the aid of the corresponding amino acid. Activation of the amino acid derivatives in the form of HOBt and HOObt esters was accomplished by addition of a solution of diisopropylcarbodiimide in dimethylformamide in the previously prepared mixture of HOBt or HOObt and an amino acid derivative in the capsules provided by the manufacturer. Similarly, the obtained Fmocamino acid-OObt-esters, as disclosed in application no. 87107634.5.
atskėlimas buvo vykdomas kaip aprašyta EP Fmoc- apsauginės grupės 20 % piperidino dimetilforamide tirpalo pagalba reakcijos inde. Aminorūgšties darinio naudotas perteklius sudarė 1,52,5 ekvivalento. Jeigu susijungimas buvo nepilnas, jis, kaip ir Boc- metode, buvo kartojamas.the cleavage was carried out as described in EP Fmoc-protecting group with 20% piperidine dimethylforamide in the reaction vessel. The excess of the amino acid derivative used was 1.52.5 equivalents. If the merger was incomplete, it was repeated, as in the Boc method.
Išradime pateikti peptidai kiekvienas atskirai ar kartu pasižymi bradikinin-antagonistiniu poveikiu, kurį galima patikrinti įvairiais modeliais (Handbook of Exp. Pharmacol., Vol 25, Springer Verlag, 1970, S. 53-55), kaip pvz. izoliuotoje žiurkės gimdoje, jūros kiaulytės žarnoje arba jūros kiaulytės izoliuotoje plaučių arterijoje.The peptides of the invention each individually or in combination exhibit bradykinin-antagonistic activity which can be tested in various models (Handbook of Exp. Pharmacol., Vol. 25, Springer Verlag, 1970, S. 53-55), e.g. isolated rat uterus, guinea pig intestine, or guinea pig isolated pulmonary artery.
Išbandant išradime pateiktus peptidus jūros kiaulytės izoliuotoje plaučių arterijoje (Dunkin. Hartley) 400450 g svorio jūros kiaulytės numarinamos smūgiu į pakaušį.In testing the peptides of the invention, guinea pigs weighing 400450 g in the isolated pulmonary artery (Dunkin. Hartley) are killed by an impact on the occiput.
Atidaroma krūtinės ląsta ir atsargiai išimama plaučių arterija. Supantys audiniai pašalinami ir arterija 45 0 kampu spirališkai supjaustoma.The thorax is opened and the pulmonary artery is carefully removed. Circumjacent tissues 45 are removed and the artery is cut spirally at an angle of 0.
Gautą 2,5 ilgio ir 3-4 cm pločio arterijos juostą fiksuoja 10 ml organinėje vonioje, užpildytoje tirpalu.The resulting arterial strip is 2.5 cm long and 3-4 cm wide and fixed in a 10 ml organic bath filled with solution.
Tirpalo sudėtis mmol/1Composition of solution in mmol / l
NaCl 154 KC1 5,6 CaCl2 1,9 NaHCO3 2,4 gliukozė 5,0NaCl 154 KCl 5.6 CaCl 2 1.9 NaHCO 3 2.4 glucose 5.0
Per tirpalą praleidžiama 95 % O2 ir 5 % CO2 mišinį ir pakaitina jį iki 37 °C. Vandenilio rodiklis yra 7,4, pradinė arterijos juostos apkrova - 1,0 g.Pass 95% O 2 /5% CO 2 through the solution and heat to 37 ° C. Hydrogen index is 7.4 and initial load on arterial bar is 1.0 g.
Izotoniniai susitraukimo pasikeitimai yra registruojami Hugo Zakso aukštadažnio modemo pagalba ir užrašomi kompensografu (BEC, Coerc Metrawatt SE460).Isotonic contractions are recorded using a Hug Zax HF modem and recorded with a compensator (BEC, Coerc Metrawatt SE460).
Po valandos nusistovėjus pusiausvyrai, pradedamas bandymas. Po to, kai juostos pasiekė didžiausią jautrumo laipsnį 2x10 7 mol/1 bradikinino dozei (bradikininas iššaukia arterijų juostų susitraukimą), 10 minučių veikia 5χ10'θ -5xl05 mol/1 peptidų dozė ir po naujos bradikinino dozės nustatomas jo veikimo efektyvumo sumažėjimas, lyginant su kontroliniu mėginiu.After one hour equilibrium is reached, the test begins. After the bands reach the highest sensitivity of 2x10 7 mol / L bradykinin (bradykinin induces contraction of the arterial bands), a dose of 5χ10 ′ θ -5x100 5 mol / L is applied for 10 minutes and a reduction in its efficacy is detected after a new dose of bradykinin. with a control sample.
Dalinio antagonistinio efekto nustatymui peptidai _5 _3 naudojami dozėse 1x10 -1x10 mol/1.Peptides _ 5 _ 3 are used in doses of 1x10 -1x10 mol / l to determine the partial antagonistic effect.
Apskaičiuotos pagal dozių poveikio grafikus IC50 reikšmės išradime pateiktiems peptidams parodytos 1 lentelėje.The calculated IC 50 values for the peptides of the invention based on the dose response graphs are shown in Table 1.
Junginys IC50 Compound IC 50
H-(D) -Arg-Arg-Hyp-Pro-Gly'-Phe-Ser-(D)-Tic-Phe-Arg-OH 4,6xl0~6 H-(D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OH 2,lxl06 H-(D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH 1,2xl0~5 H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Glo-(D)-Tic-Phe-Arg-OH 2,4xl05 H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mts) -OH 2, 5x10’5 H-(D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Pro-Arg-OH 2,5xl0’7 H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH 1,9xl0’7 H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 5,6xl0'8 H- (D) -Arg-Arg-Hyp-Pro-Gl y-lMa-Ser-p-Ala- (D) -Tic-Aoc-Arg-OH 1,7x10 ~6 H- (D) -Arg-Arg-Hyp-Pro-Gly'-Phe-Ser- (D) -Tic-Phe-Arg-OH 4,6x10 ~ 6 H- (D) -Arg-Arg-Hyp-Pro -Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH 2,1x10 6 H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe- Arg-OH 1.2x10 5 H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Glo- (D) -Tic-Phe-Arg-OH 2.4x10 5 H- (D) -Arg -Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mts) -OH 2.5x10 5 H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe- Ser- (D) -Tic-Pro-Arg-OH 2.5x10 7 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH 1 , 9x10 7 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH 5,6x10 7 H- (D) -Arg-Arg- Hyp-Pro-Gly? -Ma-Ser-p-Ala- (D) -Tic-Aoc-Arg-OH 1.7x10 ~ 6
H-(D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- (D) -Tic-Aoc-Arg-OH 3, 9xl0~7 H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Gly-(D)-Oic-Arg-OH 3,2xl07 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- (D) -Tic-AOC-Arg-OH 3, 9xl0 ~ 7 H- (D) -Arg-Arg-Hyp- Pro-Gly-Thia-Gly- (D) -Oic-Arg-OH 3.2x10 7
H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH 4, 810-7H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH 4, 810-7
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Tic-Arg-OH 1,7x10 7 H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 1,ΙχΙΟ'θ H-(D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH 4,6xl08 H-(D)-Tyr-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 6,2xl0’8 H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tie- (D) -Oic-Arg-OH 2, 6xl09 H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH 5,4x10 9 H-(D)-Arg-Lys-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH 3,2x10 7 H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH 6,8xl0’9 H- (D) -Arg-Arg- (N02) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH 6, 4xl0 8 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Tic-Arg-OH 1.7x10 7 H- (D) -Arg-Arg-Pro-Hyp-Gly -Thia-Ser- (D) -Tic-Aoc-Arg-OH 1, ΙχΙΟ'θ H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg -OH 4.6x10 8 H- (D) -Tyr-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH 6.2x10 8 H- (D) -Arg- Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tie- (D) -Oic-Arg-OH 2, 6x10 9 H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser - (D) -Tic-Oic-Arg-OH 5.4x10 9 H- (D) -Arg-Lys-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH 3.2x10 7 H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH 6,8x10 9 H- (D) -Arg-Arg- (NO 2) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH 6,4x10 8
H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH 4,2x10H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH 4,2x10
H-(D)-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH 3,4x10H- (D) -Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH 3.4x10
H-(D)-Arg-(Tos)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Dic-Arg-OH 3,0x10H- (D) -Arg- (Tos) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Dic-Arg-OH 3.0x10
H-(D)-Arg-(Tos)-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Dic-Arg-OH 1,8x10H- (D) -Arg- (Tos) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Dic-Arg-OH 1.8x10
Terapinis išradimo peptidų panaudojimas galimas pataloginėse situacijose, kurias iššaukia bradikininas arba jam giminingi peptidai. Tai apima traumas, kaip, pvz. žaizdos, nudegimai, išbėrimai, nuogulos, anginą, artritus, astmą, alergines būsenas, rinitus, šoką, uždegimus, žemą kraujospūdį, skausmą Ir kt.Therapeutic use of the peptides of the invention is possible in pathological situations caused by bradykinin or related peptides. This includes injuries such as wounds, burns, rashes, bumps, angina, arthritis, asthma, allergic conditions, rhinitis, shock, inflammation, low blood pressure, pain, etc.
Todėl išradimas priskiriamas ir I formulės petidų panaudojimui kaip farmacines gydymo priemones, įjungiančias šiuos peptidus.Therefore, the invention also relates to the use of formula I pethides as pharmaceutical therapeutic agents for the activation of these peptides.
Farmaciniai preparatai turi efektyvų I formulės biologiškai aktyvios medžiagos kiekį - atskiras medžiagas ar jų mišinį - kartu su neorganiniu ar organiniu farmaciškai priimtinu vaistinių preparatų pagrindu.Pharmaceutical formulations contain an effective amount of a Formula I biologically active substance, either alone or in admixture, in combination with an inorganic or organic pharmaceutically acceptable pharmaceutical base.
Preparatai gali būti įvedami enteraliai, parenteraliai, pvz. įvedami po odą, į raumenis ar į veną po liežuviu, per nosį, per tiesiąją žarną, makštį, inhaliacijos būdu. Biologiškai aktyvaus preparato dozavimas priklauso nuo šiltakraujų gyvūnų rūšies, kūno svorio, amžiaus ir įvedimo būdo.The formulations may be administered enterally, parenterally, e.g. administered subcutaneously, intramuscularly or intravenously under the tongue, nose, rectum, vagina, by inhalation. The dosage of the biologically active product depends on the species, body weight, age and route of administration of the warm-blooded animal.
Farmakologiniai preparatai, aprašyti išradime, paruošiami pagal žinomas metodikas kaip tirpalai, mišiniai, granulės arba dražė.The pharmaceutical preparations of the invention are prepared according to known procedures as solutions, formulations, granules or dragees.
įvedant aktyvius junginius per burną arba gleivinius dangalus, junginiai yra sumaišomi su tradicinėmis tam skirtomis medžiagomis, kaip medžiagomis-nešikliais, stabilizatoriais arba inertiniais tirpikliais ir žinomų būdų pagalba realizuojami standartinėmis formomis kaip tabletės, kapsulės, dražė, vandeniniai, spiritiniai arba riebaliniai tirpalai, arba suspencijos nešikliai gali būti naudojami gumiarabikas, magnezija, magnio karbonatas, kalio fosfatas, sacharozė, gliukozė arba krakmolas, pvz. kukurūzų krakmolas. Produktas gali būti tiek sausas tiek šlapias granuliatas. Kaip riebaliniai nešikliai arba tirpikliai gali būti naudojami augaliniai aliejai arba gyvuliniai riebalai, pvz. saulėgrąžų aliejus ir žuvies taukai.when the active compounds are administered orally or in mucous membranes, the compounds are admixed with conventional excipients such as carriers, stabilizers or inert solvents, and are formulated, in known manner, in the form of tablets, capsules, dragees, aqueous, alcoholic or oily solutions or suspensions. carriers include gum arabic, magnesium, magnesium carbonate, potassium phosphate, sucrose, glucose, or starch, e.g. corn starch. The product can be either dry or wet granules. Vegetable oils or animal fats may be used as fat carriers or solvents, e.g. sunflower oil and fish oil.
Vietiniam naudojimui preparatas gali būti realizuotas kaip vandeninis arba riebalinis tirpalas, kremas, emulsija, žele, tepalas, ir, jeigu galima, vandens oro mišinio pavidalu, kada reikalui esant surišimas gali būti pagerintas pridedant polimerinių medžiagų.For topical use, the preparation may be in the form of an aqueous or oily solution, cream, emulsion, gel, ointment and, where appropriate, in the form of a water-air mixture, whereby binding may be improved by the addition of polymeric substances.
Įvedimui per nosį junginiai sumaišomi su tam tikslui naudojamomis medžiagomis, kaip stabilizatoriais ir inertiniais tirpikliais, ir standartinių metodų pagalba paverčiami į atitinkamą pavidalą, kaip vandeninės, spiritinės, riebalinės suspensijos arba vandeniniai, spiritiniai, riebaliniai tirpalai. Į vandeninius preparatus, įvedamus per nosį, gali būti pridėta etillendiamin-N, N, N', N'-tetracto rūgšties, citrinos rūgšties ar jų druskų. Įvedimui per nosį gali būti naudojami dozatoriai-purkštuvai arba galimas realizavimas nosies laįų, nosies kremų pavidalu.For nasal administration, the compounds are mixed with the substances used for this purpose as stabilizers and inert solvents and converted, by standard methods, to aqueous, alcoholic, fatty or aqueous, oily, fatty solutions. Ethylenediamine-N, N, N ', N'-tetracetic acid, citric acid or their salts may be added to aqueous preparations for nasal administration. Nasal delivery can be achieved using dispenser-sprayers or a possible delivery in the form of nasal drops, nasal creams.
Inhaliacijai gali būti naudojami purkštuvai arba suspaustų inertinių dujų balionėliai. Įvedant biologiškai aktyvius preparatus ar jų fiziologiškai įsisavinamas druskas į veną, per odą, po oda ar į odą jie gali būti maišomi su pagalbinėmis medžiagomis.Inhalation may be done using nebulizers or compressed inert gas containers. Intravenous, subcutaneous, subcutaneous or subcutaneous administration of the biologically active agents or their physiologically acceptable salts may be combined with excipients.
Dėl to, kad kai kurių aprašytų vaistinių preparatų skilimo pusperiodis organizame yra trumpas, yra tikslinga naudoti lėtinančias skilimo medžiagas.Due to the short half-life of some of the described medicinal products in the body, it is advisable to use decelerating agents.
Vaistinės preparatų formos gali būti pvz. riebalinės kristalinės suspensijos, mikrokapsulės, lazdelės arba impantantai, kurie gali būti padaryti iš jų biologiškai skaidomų polimerų, kaip polipieno ir poliglikolino rūgšties kopolimerų arba žmogaus albumino.The pharmaceutical forms may be e.g. crystalline fat suspensions, microcapsules, sticks or impantants, which may be made from their biodegradable polymers, such as copolymers of polylactic acid and polyglycolic acid or human albumin.
Tinkama lokalinio ir inhaliacinio preparatų įvedimo tirpalo koncentracija yra 0,01 - 5 mg/ml diapozone, sistemiškai naudojant preparatus tinkamos koncentracijos yra 0,01 - 10 mg/kg.Suitable concentrations for topical and inhalation administration are in the range of 0.01 - 5 mg / ml, and for systemic administration, 0.01 - 10 mg / kg.
Sutrumpinimų sąrašasList of abbreviations
Sutrumpinimuose naudojami aminorūgščių pažymėjimai atitinka chemijoje naudojamų trijų simbolių kodavimą, aprašytą Europ. J. Biochem. 138, 9, (1984). Kiti naudojami sutrumpinimai pateikiami žemiau.The amino acid certificates used in the abbreviations correspond to the three-character coding used in chemistry as described in Europ. J. Biochem. 138, 9, (1984). Other abbreviations used are listed below.
Acm acetamidometilas e-Ahx ε-aminoheksanoilasAcm acetamidomethyl e-Ahx ε-aminohexanoyl
Aoc eis, endo-3-azabiciklo(3.3.0)oktan-3-S-karbonilasAoc eis, endo-3-azabicyclo (3.3.0) octane-3-S-carbonyl
Hoc tretinis butiloksikarbonilasHoc tertiary butyloxycarbonyl
Būt tretinis butilasTo be tertiary butyl
Bzl benzilasBzl Benzyl
Cl-z 4-chlor-benziloksikarbonilasCl-z 4-chloro-benzyloxycarbonyl
DMF dimetilforamidasDMF dimethylforamide
Dnp 2, 4-dinitrofenilasDnp 2,4-dinitrophenyl
FmocFmoc
MeMe
4-Mebzl4-Mebzl
MtrMtr
MtsMts
NMPNMP
OicOic
OprOpr
PmcPmc
T FAT FA
TcsTcs
ThiaThia
TieThey
TrtTrt
9-fluorenilmetiloksikarbonilas metilas9-fluorenylmethyloxycarbonyl methyl
4-metilbenzilas4-methylbenzyl
4-metoksi-2,3,6-trimetilfenilsulfonilas mezitilen-2-sulfonilas4-methoxy-2,3,6-trimethylphenylsulfonyl mesitylene-2-sulfonyl
N-metilpirolidinas cis-endo-oktahidroindol-2-karbonilas izoksazolidin-3-ilkarbonilasN-methylpyrrolidine cis-endo-octahydroindole-2-carbonyl isoxazolidin-3-ylcarbonyl
2,2,5,7,8-pentametilchroman-6-sulfonilas trifluoracto rūgštis2,2,5,7,8-Pentamethylchroman-6-sulfonyl trifluoroacetic acid
4-metilfenilsulfonilas4-methylphenylsulfonyl
2-tienilalanilas2-thienylalanil
1,2,3,4-tetrahidroizochinolin-3-ilkarbonilas tritilas1,2,3,4-Tetrahydroisoquinolin-3-ylcarbonyl trityl
Žemiau pateikti pavyzdžiai paaiškina galimus peptidų sintezės kietoje fazėje metodus pagal išradimą, nesusiaurinant šio išradimo rėmų.The following examples illustrate possible solid phase peptide synthesis methods of the invention without limiting the scope of the present invention.
Buvo naudojami sekantys aminorūgščių dariniai:The following amino acid derivatives were used:
Fmoc-Arg(Mtr)-OH, Boc(D)-Arg-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Hyp-OH, Fmoc-Pro-OObt, Fmoc-Gly-OObt, Fmoc-Phe10 OObt, Fmoc-Ser(tBu)-OObt, Fmoc-(D)-Tic-OH, Fmoc-Gln-OH, Fmoc-Aoc-OH, Fmoc-Thia-OH, Fmoc-Opr-OH, Fmoc-(D)-AsnOH, Fmoc-p-Ala-Oh, Fmoc-Oic-OH.Fmoc-Arg (Mtr) -OH, Boc (D) -Arg-OH, Fmoc-Arg (Pmc) -OH, Fmoc-Hyp-OH, Fmoc-Pro-OObt, Fmoc-Gly-OObt, Fmoc-Phe10 OObt, Fmoc-Ser (tBu) -OObt, Fmoc-(D) -Tic-OH, Fmoc-Gln-OH, Fmoc-Aoc-OH, Fmoc-Thia-OH, Fmoc-Opr-OH, Fmoc- (D) -AsnOH , Fmoc-p-Ala-Oh, Fmoc-Oic-OH.
Pavyzdys 1Example 1
Junginys H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-PheArg-OH buvo susintentintas firmos Applied Biosystems modelio 430A pagalba, naudojant Fmoc- metodą esterinio Fmoc-Arg(Mtr)-OH pagalba p-benziloksibenzilalkoholio dervoje iš firmos Novabiochem (įkrova 0,5 mmol/g dervos) . Buvo naudota 1 g dervos ir sintezė vyko pagal modifikuotą Fmoc- metodui sintezės programą.The compound H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-PheArg-OH was synthesized using Applied Biosystems Model 430A using the Fmoc-method of the Fmoc-Arg (Mtr) ester. -OH in p-benzyloxybenzyl alcohol resin from Novabiochem (loading 0.5 mmol / g resin). 1 g of resin was used and synthesis was carried out according to a modified Fmoc-synthesis program.
Į sintezatoriaus patroną patalpino 1 mmol aminorūgšties darinio su laisva karboksiline grupe. Kartu buvo patalpinta 0,95 mmol HOCbt. Pradinis šių aminorūgščių aktyvavimas buvo atliekamas patrone, ištirpinant 4 ml dimetilforamido ir pridedant 2 ml 0,55 molinio diizopropilkarbodiimido tirpalo dimetilforamide.The synthesizer cartridge contained 1 mmol of an amino acid derivative with a free carboxyl group. 0.95 mmol HOCbt was co-introduced. Initial activation of these amino acids was performed in a cartridge by dissolving 4 mL of dimethylforamide and adding 2 mL of 0.55 molar solution of diisopropylcarbodiimide in dimethylforamide.
Kitų aminorūgščių HOCbt-esteriai buvo ištirpinti 6 ml N-metilpirolidino ir poto, kaip altyvuotos aminorūgštys, buvo sujungti reikiamoje vietoje su deblokuota 20 % piperidino tirpalu dimetilformamidine derva. Pasibaigus sintezei, peptidas, pašalinus šoninių grandinių apsaugines grupes trifluoracto rūgštimi, naudojant tionizolą ir etanditiolą, atskeltas nuo dervos. Gautas nupylus trifluoracto rūgštį produktas daug kartų apdorotas acto rūgšties esterio pagalba ir centifuguojamas. Likęs produktas buvo chromatografuojamas Sefadex ZH20 kolonėlėje, eliuojant 10 %The HOCbt-esters of the other amino acids were dissolved in 6 mL of N-methylpyrrolidine and combined as the activated amino acids with the de-blocked 20% piperidine solution in dimethylformamide resin. Upon completion of the synthesis, the peptide was separated from the resin by removal of the side chain protecting groups with trifluoroacetic acid using thionizole and ethanedithiol. The product obtained after trituration with trifluoroacetic acid was repeatedly treated with acetic acid ester and centrifuged. The remaining product was chromatographed on a Sefadex ZH 2 0 column eluting with 10%
analogiškai kaip pavyzdyje 1.analogously to Example 1.
Pavyzdys 2Example 2
H- (D) -Arg-Arg-Hyp-Pro-Gly-Pro- (D) -Ser- (D) -Tic-Phe-Arg-OHH- (D) -Arg-Arg-Hyp-Pro-Gly-Pro- (D) -Ser- (D) -Tic-Phe-Arg-OH
MS (FAB): 1294 (M+H).MS (FAB): 1294 (M + H) @ +.
Pavyzdys 3Example 3
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH.
MS (FAB) : 1306 (M+H) .MS (FAB): 1306 (M + H) @ +.
Pavyzdys 4Example 4
H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH.
MS (FAB): 1294(M+H).MS (FAB): 1294 (M + H) @ +.
Pavyzdys 5Example 5
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Gly-(D)-Tic-Phe-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Gly- (D) -Tic-Phe-Arg-OH.
MS (FAB) : 1335 (M+H) .MS (FAB): 1335 (M + H) @ +.
Pavyzdys 6Example 6
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Pro-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Pro-Arg-OH.
MS (FAB): 1244 (M+H).MS (FAB): 1244 (M + H) @ +.
Pavyzdys 7Example 7
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Trp-(D)-Tic-Phe-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Trp- (D) -Tic-Phe-Arg-OH.
MS (FAB): 1393 (M+H).MS (FAB): 1393 (M + H) @ +.
Pavyzdys 8Example 8
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH.
MS (FAB): 1250 (M+H).MS (FAB): 1250 (M + H) @ +.
Pavyzdys 9Example 9
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-(D)-Arg-(D)-Tic-Thia-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia- (D) -Arg- (D) -Tic-Thia-Arg-OH.
MS (FAB): 1333 (M+H).MS (FAB): 1333 (M + H) @ +.
Pavyzdys 10Example 10
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Opr-(D)-Tic-Thia-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Opr- (D) -Tic-Thia-Arg-OH.
MS (FAB): 1301 (M+H).MS (FAB): 1301 (M + H) @ +.
Pavyzdys 11Example 11
H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia- (D) -Gln- (D) -Tic-Thia-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia- (D) -Gln- (D) -Tic-Thia-Arg-OH.
MS (FAB) : 1347 (M+H) .MS (FAB): 1347 (M + H) @ +.
Pavyzdys 12Example 12
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly-(D)-Tic-Pro-ArgOH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- (D) -Tic-Pro-ArgOH.
MS (FAB): 1307 (M+H).MS (FAB): 1307 (M + H) @ +.
Pavyzdys 13Example 13
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Phe-OH.
MS (FAB): 1241 (M+H).MS (FAB): 1241 (M + H) @ +.
Pavyzdys 14Example 14
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Phe-Arg-OH.
MS (FAB): 1397 (M+H).MS (FAB): 1397 (M + H) @ +.
Pavyzdys 15Example 15
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-p-Ala-(D)-Tic-Pro-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-p-Ala- (D) -Tic-Pro-Arg-OH.
MS (FAB) : 1321 (M+H) .MS (FAB): 1321 (M + H) @ +.
Pavyzdys 16Example 16
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Gly-(D)-Tic-Pro-Arg-Oh.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Gly- (D) -Tic-Pro-Arg-Oh.
MS (FAB): 1230 (M+H).MS (FAB): 1230 (M + H) @ +.
Pavyzdys 17Example 17
H-(D)-Aoc-Pro-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OH.H- (D) -Aoc-Pro-Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH.
MS (FAB): 1330 (M+H).MS (FAB): 1330 (M + H) @ +.
Pavyzdys 18Example 18
H-(D)-Arg-Arg-Pro-Aoc-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OH.H- (D) -Arg-Arg-Pro-Aoc-Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH.
MS (FAB): 1330 (M+H).MS (FAB): 1330 (M + H) @ +.
Pavyzdys 19Example 19
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1290 (M+H).MS (FAB): 1290 (M + H) @ +.
Pavyzdys 20Example 20
H-(D)-Arg-Arg-Opr-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH.H- (D) -Arg-Arg-Opr-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH.
MS (FAB): 1236 (M+H).MS (FAB): 1236 (M + H) @ +.
Pavyzdys 21Example 21
H-(D)-Arg-Arg-Pro-Opr-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH.H- (D) -Arg-Arg-Pro-Opr-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH.
MS (FAB): 1236 (M+H).MS (FAB): 1236 (M + H) @ +.
Pavyzdys 22Example 22
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Opr-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Opr-Arg-OH.
MS (FAB): 125 (M+H).MS (FAB): 125 (M + H) @ +.
Pavyzdys 23Example 23
H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1290 (M+H).MS (FAB): 1290 (M + H) @ +.
Pavyzdys 24Example 24
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1290 (M+H).MS (FAB): 1290 (M + H) @ +.
Pavyzdžiai 25-27Examples 25-27
H- (D) -Arg-Arg- (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH irH- (D) -Arg-Arg- (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH and
H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mtr) -OH irH- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mtr) -OH and
H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mtr) -OH buvo gaminami analogiškai kaip ir 1, bet apsauginių grupių atskėlimas nuo peptido šoninių grandinių ir peptido atskėlimas nuo dervos trifluoracto rūgšties pagalba buvo apribotas 30 minučių, esant kambario temperatūrai. Esant tokioms sąlygoms, vyksta Mtrapsauginės grupės arginine atskėlimas, i kuri galima nekreipti dėmesio. Dalinai deblokuoti peptidai išskiriami chromatografijos pagalba išvalomi.H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mtr) -OH was prepared analogously to 1 but deprotection of the peptide. cleavage of side chains and peptide from the resin with trifluoroacetic acid was restricted for 30 minutes at room temperature. Under these conditions, an arginine cleavage of the Mt protecting group occurs which can be overlooked. The partially deprotected peptides are purified by chromatography.
25: H-(D)-Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH.25: H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH.
MS (FAB): 1506 (M+H).MS (FAB): 1506 (M + H) @ +.
26: H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Fhe-Sre- (D) -Tic-Ehe-Arg (Mtr) -OH.26: H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Fhe-Sre- (D) -Tic-Ehe-Arg (Mtr) -OH.
MS (FAB): 1718 (M+H).MS (FAB): 1718 (M + H) @ +.
27: H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mtr) -OH.27: H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mtr) -OH.
MS (FAB): 1506 (M+H).MS (FAB): 1506 (M + H) @ +.
Sekančių pavyzdžių 28 - 31 peptidai buvo pagaminti ir išvalyti, kaip pavyzdžiuose 25 - 27.Peptides 28 to 31 of the following Examples were prepared and purified as in Examples 25 to 27.
Pavyzdys 28Example 28
H- (D) -Arg-Arg (Mtr) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH.H- (D) -Arg-Arg (Mtr) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH.
MS (FAB): 1462 (M+H).MS (FAB): 1462 (M + H) @ +.
Pavyzdys 29Example 29
H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg (Mtr) -OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg (Mtr) -OH.
MS (FAB): 1462 (M+H).MS (FAB): 1462 (M + H) @ +.
Pavyzdys 30Example 30
H-(D)-Arg-Arg(Mtr)-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-OH.H- (D) -Arg-Arg (Mtr) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Phe-OH.
MS (FAB): 1453 (M+H).MS (FAB): 1453 (M + H) @ +.
Pavyzdys 31Example 31
H-(D)-Arg-Arg(Mtr)-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg (Mtr) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1502 (M+H).MS (FAB): 1502 (M + H) @ +.
Pavyzdys 32Example 32
H-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-NH-(CH2) 4-NH2 .H-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH 2 ) 4 -NH 2 .
Peptido sintezė buvo vykdoma 1 g aminometilinės dervos, kuri buvo modifikuota pagal EP paraiškoje Nr. 264802 aprašytą metodiką, grupePeptide synthesis was carried out on 1 g of aminomethyl resin which was modified according to EP application no. 264802, group
C /C /
Fmoc-NH-(CH2) 4-NH-CO-O-CH2-C \\Fmoc-NH- (CH 2 ) 4 -NH-CO-O-CH 2 -C
CC
C \C \
C-O-CH2-CH2-CO // cCO-CH 2 -CH 2 -CO // c
ir naudojant Fmoc-aminorūgšties-OOBt esterius automatinio peptidų sintezatoriaus (firmos Applied Biosystems modelis 430A) pagalba bei panaudojant nuosavas modifikuotas sintezės programas. Tam tikslui į sintezatoriaus patroną patalpinta 1 mmol atitinkamo aminorūgšties darinio kartu su 0,95 mmol Fmoc-Arg(Mtr)OH, Fmoc-Hyp-OH ir Fmoc-(D)-Tic-OH. Pradinis reikaLT 3375 B lingos vietos aktyvavimas buvo patrone ištirpinant aminorūgšti, 4 ml dimetilforamido ir pridedant 2 ml 0,55-moliarinio diizopropilkarbodiimido tirpo dimetilformamide. Kitų aminorūgščių HOCbt-esteriai ištirpinti 6 ml N-metilpirolidino ir po to, kaip ir aktyvuotos reikiamoje vietoje aminorūgšties molekulės, buvo dukart sujungti. Po sintezės nuo dervos atskirtas peptid-4amino-butilamidas, kartu pašalinant trifluoracto rūgšties pagalba šonines apsaugines grupes. Katijonams surišti naudojamas tioanizolas ir m-krezolas. Gautas nupylus trifluoracto rūgšti, produktas apdorotas acto rūgšties esterio pagalba ir centrifuguojamas. Likęs produktas buvo chromatografuoj amas Sefadex S25 kolonėlėje, eliuojant viennormaline acto rūgštim. Turinčios švarų peptidą frakcijos buvo sujungtos ir išdžiovintos.and using Fmoc-amino acid-OOBt esters using an automated peptide synthesizer (Applied Biosystems Model 430A) and proprietary modified synthesis programs. For this purpose, 1 mmol of the corresponding amino acid derivative together with 0.95 mmol of Fmoc-Arg (Mtr) OH, Fmoc-Hyp-OH and Fmoc- (D) -Tic-OH was placed in the synthesis cartridge. Initial activation of the reikaLT 3375 B site was accomplished by dissolving the amino acids in the cartridge, adding 4 ml of dimethylforamide and adding 2 ml of a 0.55 molar solution of diisopropylcarbodiimide in dimethylformamide. The HOCbt-esters of the other amino acids were dissolved in 6 ml of N-methylpyrrolidine and then double-coupled, as were the activated amino acid molecules. After synthesis, the peptide-4-amino-butylamide was isolated from the resin, with the removal of side protecting groups with trifluoroacetic acid. Thioanisole and m-cresol are used to bind cations. The product obtained after trituration with trifluoroacetic acid was treated with acetic acid ester and centrifuged. The remaining product was chromatographed on a Sefadex S25 column eluting with 1N acetic acid. Fractions containing the pure peptide were pooled and dried.
Analogiška 32 pavyzdžio procedūra buvo panaudota ir pavyzdžiuose 33-35.An analogous procedure to Example 32 was also used in Examples 33-35.
Pavyzdys 33Example 33
H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH2) 4-NH2.H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH 2 ) 4 -NH 2 .
Pavyzdys 34Example 34
HOOC- (CH2) 2-O0-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH2) 4-NH2.HOOC- (CH 2 ) 2 -O-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH 2 ) 4 -NH 2 .
Pavyzdys 35Example 35
H3DC- (CEį) 2—CD— (D) -Arg-Hyp-Pro-Gly-Ehe-Ser- (D) -Tic-Fhe^H- (Clį) 4-Nfį.H3DC- (CE) 2 -CD- (D) -Arg-Hyp-Pro-Gly-Ehe-Ser- (D) -Tic-Fhe ^ H- (Cl) 4 -Nfis.
Pavyzdžiai 36-161 buvo sintetinami pagal pavyzdyje 1 aprašytą metodiką.Examples 36-161 were synthesized according to the procedure described in Example 1.
Pavyzdys 36Example 36
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- (D) -Tic-Pro-Arg-OH.
MS (FAB): 1307 (M+H).MS (FAB): 1307 (M + H) @ +.
Pavyzdys 37Example 37
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser-Gly- (D) -Tic-Pro-Arg-OH.
MS (FAB) : 1307 (M+H) .MS (FAB): 1307 (M + H) @ +.
Pavyzdys 38Example 38
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Phe-OH.
MS (FAB): 1241 (M+H).MS (FAB): 1241 (M + H) @ +.
Pavyzdys 39Example 39
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-p-Ala-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-p-Ala- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1361 (M+H).MS (FAB): 1361 (M + H) @ +.
Pavyzdys 40Example 40
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-p-Ala-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser-p-Ala- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1361 (M+H).MS (FAB): 1361 (M + H) @ +.
Pavyzdys 41Example 41
H- (D) -Arg-Arg-Hyp-Pro)Gly-Thia-Ser- (D) -Tic-Pro-Phe-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro) Gly-Thia-Ser- (D) -Tic-Pro-Phe-Arg-OH.
MS (FAB): 1397 (M+H).MS (FAB): 1397 (M + H) @ +.
Pavyzdys 42Example 42
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Pro-Phe-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Pro-Phe-Arg-OH.
MS (FAB) : 1397 (M+H) .MS (FAB): 1397 (M + H) @ +.
Pavyzdys 43Example 43
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Gly-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Gly- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1260 (M+H).MS (FAB): 1260 (M + H) @ +.
Pavyzdys 44Example 44
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Gly-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Gly- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1260 (M+H).MS (FAB): 1260 (M + H) @ +.
Pavyzdys 4 5Example 4 5
H-(D)-Arg-(D)-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1390 (M+H).MS (FAB): 1390 (M + H) @ +.
Pavyzdys 46Example 46
H-(D)-Arg-(D)-Arg-Phe-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg- (D) -Arg-Phe-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1290 (M+H).MS (FAB): 1290 (M + H) @ +.
Pavyzdys 47Example 47
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Tic-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Tic-Arg-OH.
MS (FAB): 1312 (M+H).MS (FAB): 1312 (M + H) @ +.
Pavyzdys 48Example 48
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Tic-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Tic-Arg-OH.
MS (FAB): 1312 (M+H).MS (FAB): 1312 (M + H) @ +.
Pavyzdys 49Example 49
H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1274 (M+H).MS (FAB): 1274 (M + H) @ +.
Pavyzdys 50Example 50
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Aoc-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Aoc-Arg-OH.
MS (FAB): 1203 (M+H).MS (FAB): 1203 (M + H) @ +.
Pavyzdys 51Example 51
H-(D)-Arg-Arg-Hyp-Pro-Gly-Aoc-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Aoc-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1274 (M+H).MS (FAB): 1274 (M + H) @ +.
Pavyzdys 52Example 52
H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-p-Ala- (D) -Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-p-Ala- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1274 (M+H).MS (FAB): 1274 (M + H) @ +.
Pavyzdys 53Example 53
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-p-Ala-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-p-Ala- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1274 (M+H).MS (FAB): 1274 (M + H) @ +.
Pavyzdys 54Example 54
H-(D)-Arg-Arg-Hyp-Pro-Gly-Asp-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Asp-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1252 (M+H).MS (FAB): 1252 (M + H) @ +.
Pavyzdys 55Example 55
H-(D)-Arg-Arg-Pro-Hyp-Gly-Asp-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Asp-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1252 (M+H).MS (FAB): 1252 (M + H) @ +.
Pavyzdys 56Example 56
H-(D)-Arg-Arg-Hyp-Pro-Gly-Trp-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Arg-Arg-Hyp-Pro-Gly-Trp-Ser- (D) -Tic-Aoc-Arg-OH.
MS FAB): 1323.7 (M+H).MS FAB): 1323.7 (M + H).
Pavyzdys 57Example 57
H-(D)-Tyr-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H- (D) -Tyr-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1297.7 (M+H).MS (FAB): 1297.7 (M + H) @ +.
Pavyzdys 58Example 58
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tia-(D)-Oic-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tia- (D) -Oic-Arg-OH.
MS (FAB): 1304.6 (M+H).MS (FAB): 1304.6 (M + H) @ +.
Pavyzdys 59Example 59
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1304.6 (M+H).MS (FAB): 1304.6 (M + H) @ +.
H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH.H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
Pavyzdys 60Example 60
MS (FAB): 1289 (M+H).MS (FAB): 1289 (M + H) @ +.
Pavyzdys 61Example 61
H-(D)-Arg-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-Oh.H- (D) -Arg-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-Oh.
MS (FAB): 1262 (M+H).MS (FAB): 1262 (M + H) @ +.
Pavyzdys 62Example 62
H-(D)-Arg-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH.H- (D) -Arg-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1276 (M+H).MS (FAB): 1276 (M + H) @ +.
Pavyzdys 63Example 63
H-(D)-Arg-Lys-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH.H- (D) -Arg-Lys-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1260 (M+H).MS (FAB): 1260 (M + H) @ +.
Pavyzdys 64Example 64
H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH.H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1298 (M+H).MS (FAB): 1298 (M + H) @ +.
Pavyzdys 65Example 65
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH>H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH>
MS (FAB): 1298 (M+H).MS (FAB): 1298 (M + H) @ +.
Pavyzdys 66Example 66
H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH.H- (D) -Arg-Arg-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1282 (M+H).MS (FAB): 1282 (M + H) @ +.
Pavyzdys 67Example 67
H- (D) -Arg-Arg- (N02) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH.H- (D) -Arg-Arg- (NO 2 ) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1329.7 (M+H).MS (FAB): 1329.7 (M + H) @ +.
Pavyzdys 68Example 68
H- (D) -Arg-Arg- (NO2) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.H- (D) -Arg-Arg- (NO 2 ) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1343 (M+H).MS (FAB): 1343 (M + H) @ +.
Pavyzdys 69Example 69
H-(FAB): 1327 (M+H).H - (FAB): 1327 (M + H).
Pavyzdys 70Example 70
H- (D) -Arg-Arg- (NO2) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.H- (D) -Arg-Arg- (NO 2 ) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1333 (M+H).MS (FAB): 1333 (M + H) @ +.
Pavyzdys 71Example 71
H- (D) -Arg-Arg (NO2) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.H- (D) -Arg-Arg (NO 2 ) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 13449 (M+H).MS (FAB): 13449 (M + H) @ +.
Pavyzdys 72Example 72
Η-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH.Η-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1302 (M+H).MS (FAB): 1302 (M + H) @ +.
Pavyzdys 73Example 73
H-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-Oh.H-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-Oh.
MS (FAB): 1147 (M+H).MS (FAB): 1147 (M + H) @ +.
Pavyzdys 74Example 74
Η-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-D-Tic-Oic-Arg-OH.Η-Lys (-CO-NH-C 6 H 5 ) -Pro-Hyp-Gly-D-Tic-Oic-Arg-OH.
MS (FAB): 1233 (M+H).MS (FAB): 1233 (M + H) @ +.
Pavyzdys 75Example 75
Η-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.Η-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1296 (M+H).MS (FAB): 1296 (M + H) @ +.
Pavyzdys 76Example 76
Η-Lys(nikotinoilas)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.Β-Lys (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1219 (M+H).MS (FAB): 1219 (M + H) @ +.
Pavyzdys 77Example 77
Η-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.Η-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1282 (M+H).MS (FAB): 1282 (M + H) @ +.
Pavyzdys 78Example 78
Ac-Arg-(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc—Arg-OH.Ac-Arg- (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1324 (M+H).MS (FAB): 1324 (M + H) @ +.
Pavyzdys 79Example 79
H-D-Arg-Arg(Tos)-Phe-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.H-D-Arg-Arg (Tos) -Phe-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1438 (M+H).MS (FAB): 1438 (M + H) @ +.
Pavyzdys 60Example 60
H-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1303 (M+H).MS (FAB): 1303 (M + H) @ +.
Pavyzdys 81Example 81
H-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB) : 1142 (M+H) .MS (FAB): 1142 (M + H) @ +.
Pavyzdys 82Example 82
Η-Lys (-CO-NH-C6H5) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.Η-Lys (-CO-NH-C 6 H 5 ) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1233 (M+H).MS (FAB): 1233 (M + H) @ +.
Pavyzdys 83Example 83
Η-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.Η-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1296 (M+H).MS (FAB): 1296 (M + H) @ +.
Pavyzdys 84Example 84
Η-Lys(nikotinoilas)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.Η-Lys (nicotinoyl) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1219 (M+H).MS (FAB): 1219 (M + H) @ +.
Pavyzdys 85Example 85
H-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.H-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1282 (M+H).MS (FAB): 1282 (M + H) @ +.
Pavyzdys 86Example 86
Ac-Arg(Tos)-Hyp-Pr)-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.Ac-Arg (Tos) -Hyp-Pr) -Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): (M+H).MS (FAB): (M + H) @ +.
Pavyzdys 87Example 87
H-D-Arg-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.H-D-Arg-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB) : (M+H) .MS (FAB): (M + H) @ +.
Pavyzdys 88Example 88
H-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB) : (M+H) .MS (FAB): (M + H) @ +.
Pavyzdys 89Example 89
H-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1126 (M+H).MS (FAB): 1126 (M + H) @ +.
Pavyzdys 90Example 90
Η-Lys (-CO-NH-C6H5) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.Η-Lys (-CO-NH-C 6 H 5 ) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1217 (M+H).MS (FAB): 1217 (M + H) @ +.
Pavyzdys 91Example 91
Η-Arg(Tos)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.Ar-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1280 (M+H).MS (FAB): 1280 (M + H) @ +.
Pavyzdys 92Example 92
Η-Lys(nikotinoilas)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.Η-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1203 (M+H).MS (FAB): 1203 (M + H) @ +.
Pavyzdys 93Example 93
Η-Arg(Tos)-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.Η-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1266 (M+H).MS (FAB): 1266 (M + H) @ +.
Pavyzdys 94Example 94
Ac-Arg(Tos)-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.Ac-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1308 (M+H).MS (FAB): 1308 (M + H) @ +.
Pavyzdys 95Example 95
Η-Arg-Arg(Tos)-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.Η-Arg-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1422 (M+H).MS (FAB): 1422 (M + H) @ +.
Pavyzdys 96Example 96
H-Arg-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Arg-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1148 (M+H).MS (FAB): 1148 (M + H) @ +.
Pavyzdys 97Example 97
Η-Lys (-CO-NH-C6H5) -Pro-Hyp-Gly-Thia) Ser-D-Tic-Oic-Arg-OH.Η-Lys (-CO-NH-C 6 H 5 ) -Pro-Hyp-Gly-Thia) Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1239 (M+H).MS (FAB): 1239 (M + H) @ +.
Pavyzdys 98Example 98
Η-Lys(nikotinoilas)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.Α-Lys (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB) : (M+H) .MS (FAB): (M + H) @ +.
Pavyzdys 99Example 99
H-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.H-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1288 (M+H).MS (FAB): 1288 (M + H) @ +.
Pavyzdys 100Example 100
Ac-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.Ac-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1330 (M+H).MS (FAB): 1330 (M + H) @ +.
Pavyzdys 101Example 101
H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.H-D-Arg-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1444 (M+H).MS (FAB): 1444 (M + H) @ +.
Pavyzdys 102Example 102
H-Arg-Hyp-Pro-Thia-Ser-Tic-Oic-Arg-OH.H-Arg-Hyp-Pro-Thia-Ser-Tic-Oic-Arg-OH.
MS (FAB): 1148 (M+H).MS (FAB): 1148 (M + H) @ +.
Pavyzdys 103Example 103
Η-Lys (-CO-NH-C6H5) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.Η-Lys (-CO-NH-C 6 H 5 ) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1239 (M+H).MS (FAB): 1239 (M + H) @ +.
Pavyzdys 104Example 104
Η-Lys(nikotinoilas)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.Β-Lys (nicotinoyl) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1225 (M+H).MS (FAB): 1225 (M + H) @ +.
Pavyzdys 105Example 105
H-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.H-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1289 (M+H).MS (FAB): 1289 (M + H) @ +.
Pavyzdys 106Example 106
Ac-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.Ac-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1330 (M+H).MS (FAB): 1330 (M + H) @ +.
Pavyzdys 107Example 107
H-D-Arg-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.H-D-Arg-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1440 (M+H).MS (FAB): 1440 (M + H) @ +.
Pavyzdys 108Example 108
Η-Lys (-CO-NH-C6H5) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.Η-Lys (-CO-NH-C 6 H 5 ) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1225 (M+H).MS (FAB): 1225 (M + H) @ +.
Pavyzdys 109Example 109
Η-Lys(nikotinoilas)-Pro-Pro-Gly-Thia-Ser-D-Oic-Arg-OH.Β-Lys (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Oic-Arg-OH.
MS (FAB): 1209 (M+H).MS (FAB): 1209 (M + H) @ +.
Pavyzdys 110Example 110
Η-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tip-Aoc-Arg-OH.Η-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tip-Aoc-Arg-OH.
MS (FAB) : 1272 (M+H) .MS (FAB): 1272 (M + H) @ +.
Pavyzdys 111Example 111
Ac-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg)OH.Ac-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg) OH.
MS (FAB): 1314 (M+H).MS (FAB): 1314 (M + H) @ +.
Pavyzdys 112Example 112
H-D-Arg-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.H-D-Arg-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.
MS (FAB): 1428 (M+H).MS (FAB): 1428 (M + H) @ +.
Pavyzdys 113Example 113
H-D-Arg-Lys(nikotinoilas)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Lys (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1365 (M+H).MS (FAB): 1365 (M + H) @ +.
Pavyzdys 114Example 114
H-D-Arg-Lys (-OD-NH-CgHs) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Lys (-OD-NH-CgHs) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1379 (M+H).MS (FAB): 1379 (M + H) @ +.
Pavyzdys 115Example 115
H-D-Arg-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1442 (M+H).MS (FAB): 1442 (M + H) @ +.
Pavyzdys 116Example 116
H-Lys-Lys-(nokotinoilas)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Lys-Lys- (Nocotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1337 (M+H).MS (FAB): 1337 (M + H) @ +.
Pavyzdys 117Example 117
H-Lys-Lys (-CO-NH-CgHį) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Lys-Lys (-CO-NH-CgH1) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1351 (M+H).MS (FAB): 1351 (M + H) @ +.
Pavyzdys 118Example 118
H-Lys-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Lys-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1414 (M+H).MS (FAB): 1414 (M + H) @ +.
Pavyzdys 119Example 119
H-D-Arg-Lys (nikotinoilas) -Pro-Hyp-Gly-Thia-Ser-D-Oic-Arg-OH.H-D-Arg-Lys (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Oic-Arg-OH.
MS (FAB): 1381 (M+H).MS (FAB): 1381 (M + H) @ +.
Pavyzdys 120Example 120
H-D-Arg-Lys (-OO-NH-CgHj) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Lys (-OO-NH-CgHj) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1395 (M+H).MS (FAB): 1395 (M + H) @ +.
Pavyzdys 121Example 121
H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB):1458 (M+H).MS (FAB): 1458 (M + H) @ +.
Pavyzdys 122Example 122
H-Lys-Lys (-GO-NH-CgHs) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Lys-Lys (-GO-NH-CgHs) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB) : 1367 (M+H) .MS (FAB): 1367 (M + H) @ +.
Pavyzdys 123Example 123
H-Lys-Lys (nikotinoilas) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Lys-Lys (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1353 (M+H).MS (FAB): 1353 (M + H) @ +.
Pavyzdys 124Example 124
H-Lys-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Lys-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1420 (M+H).MS (FAB): 1420 (M + H) @ +.
Pavyzdys 125Example 125
H-D-Arg-Lys(nikotinoilas)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1359 (M+H).MS (FAB): 1359 (M + H) @ +.
Pavyzdys 126Example 126
H-D-Arg-Lys (-CO-NH-C6H5) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.HD-Arg-Lys (-CO-NH-C 6 H 5 ) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB) : 1373 (M+H) .MS (FAB): 1373 (M + H) @ +.
Pavyzdys 127Example 127
H-D-Arg-Arg(Tos)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1436 (M+H).MS (FAB): 1436 (M + H) @ +.
Pavyzdys 128Example 128
H-Lys-Lys(nikotinoilas)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Lys-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1331 (M+H).MS (FAB): 1331 (M + H) @ +.
Pavyzdys 129Example 129
H-Lys-Lys (-CO-NH-C6H5) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Lys-Lys (-CO-NH-C 6 H 5 ) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1345 (M+H).MS (FAB): 1345 (M + H) @ +.
Pavyzdys 130Example 130
H-Lys-Arg(Tos)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Lys-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1408 (M+H).MS (FAB): 1408 (M + H) @ +.
Pavyzdys 131Example 131
H-D-Arg-Lys(nikotinoilas)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Lys (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB0: 1375 (M+H).MS (FABO: 1375 (M + H) @ +).
Pavyzdys 132Example 132
H-D-Arg-Lys (-OO-NH-C6H5) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.HD-Arg-Lys (-OO-NH-C 6 H 5 ) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1389 (M+H).MS (FAB): 1389 (M + H) @ +.
Pavyzdys 133Example 133
H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1452 (M+H).MS (FAB): 1452 (M + H) @ +.
Pavyzdys 134Example 134
H-Lys-Lys(nikotinoilas)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Lys-Lys (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB) : 1347 (M+H) .MS (FAB): 1347 (M + H) @ +.
Pavyzdys 135Example 135
H-Lys-Lys (-CO-NH-C6H5) -Pro-Hyp-Gly-Phe-Ser-S-Tic-Oic-Arg-OH.H-Lys-Lys (-CO-NH-C 6 H 5 ) -Pro-Hyp-Gly-Phe-Ser-S-Tic-Oic-Arg-OH.
MS (FAB): 1361 (M+H).MS (FAB): 1361 (M + H) @ +.
Pavyzdys 136Example 136
H-Lys-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Lys-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1424 (M+H).MS (FAB): 1424 (M + H) @ +.
Pavyzdys 137Example 137
H-D-Arg-Om (nikotinoilas) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg)OH.H-D-Arg-Om (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg) OH.
MS (FAB): 1351 (M+H).MS (FAB): 1351 (M + H) @ +.
Pavyzdys 138Example 138
H-D-Arg-Om (Tos) -CD-NH-CgHs) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.HD-Arg-Om (Tos) -CD-NH-CgHs) - Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1428 (M+H).MS (FAB): 1428 (M + H) @ +.
Pavyzdys 139Example 139
H-Lys-Om (nikotinoilas) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Lys-Om (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB) : 1328 (M+H) .MS (FAB): 1328 (M + H) @ +.
Pavyzdys 140Example 140
Η-Lys-Orn (-αθ-ΝΗ-ΟθΗ5) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.Η-Lys-Orn (-αθ-ΝΗ-ΟθΗ 5 ) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1337 (M+H).MS (FAB): 1337 (M + H) @ +.
Pavyzdys 141Example 141
H-D-Arg-Om (nikotinoilas) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Om (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB) : 1367 (M+H) .MS (FAB): 1367 (M + H) @ +.
Pavyzdys 142Example 142
H-D-Arg-Orn-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Orn-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1381 (M+H).MS (FAB): 1381 (M + H) @ +.
Pavyzdys 143Example 143
H-Lys-Om (nikotinoilas) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.H-Lys-Om (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1339 (M+H).MS (FAB): 1339 (M + H) @ +.
Pavyzdys 144Example 144
H-Lys-Orn (CO-NH-C6H5) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Arg-OH.H-Lys-Orn (CO-NH-C 6 H 5 ) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Arg-OH.
MS (FAB): 1353 (M+H).MS (FAB): 1353 (M + H) @ +.
Pavyzdys 145Example 145
H-D-Arg-Om (nikotinoilas) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Om (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1345 (M+H).MS (FAB): 1345 (M + H) @ +.
Pavyzdys 146Example 146
H-D-Arg-Orn (OO-NH-CgHį) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Orn (OO-NH-CgH1) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1359 (M+H).MS (FAB): 1359 (M + H) @ +.
Pavyzdys 147Example 147
H-Lys-Orn (nikotinoilas) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Lys-Orn (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1317 (M+H).MS (FAB): 1317 (M + H) @ +.
Pavyzdys 148Example 148
H-Lys-Orn (CO-NH-C6H5) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Lys-Orn (CO-NH-C 6 H 5 ) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1331 (M+H).MS (FAB): 1331 (M + H) @ +.
Pavyzdys 149Example 149
H-D-Arg-Om (nikotinoilas) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-D-Arg-Om (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1361 (M+H).MS (FAB): 1361 (M + H) @ +.
Pavyzdys 150Example 150
H-D-Arg-Orn (CO-NH-C6H5) -Pro-Hyp-Gly-Phe-Ser-Tic-Oic-Arg-OH.HD-Arg-Orn (CO-NH-C 6 H 5 ) -Pro-Hyp-Gly-Phe-Ser-Tic-Oic-Arg-OH.
MS (FAB): 1375 (M+H).MS (FAB): 1375 (M + H) @ +.
Pavyzdys 151Example 151
H-Lys-Om (nikotinoilas) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Lys-Om (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1333 (M+H).MS (FAB): 1333 (M + H) @ +.
Pavyzdys 152Example 152
H-Lys-Orn (CO-NH-C6H5) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.H-Lys-Orn (CO-NH-C 6 H 5 ) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.
MS (FAB): 1347 (M+H).MS (FAB): 1347 (M + H) @ +.
Pavyzdys 153Example 153
H-Lys-Lys-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H-Lys-Lys-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB) : 1218 (M+H) .MS (FAB): 1218 (M + H) @ +.
Pavyzdys 154Example 154
H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB) : 1234 (M+H) .MS (FAB): 1234 (M + H) @ +.
Pavyzdys 155Example 155
H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH.H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1234 (M+H).MS (FAB): 1234 (M + H) @ +.
Pavyzdys 156Example 156
H-Lys-Lys-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH.H-Lys-Lys-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1212 (M+H).MS (FAB): 1212 (M + H) @ +.
Pavyzdys 157Example 157
H-Lys-Lys-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH.H-Lys-Lys-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH.
MS (FAB): 1228 (M+H).MS (FAB): 1228 (M + H) @ +.
Pavyzdys 158Example 158
H-Lys-Lys-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH.H-Lys-Lys-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1232 (M+H).MS (FAB): 1232 (M + H) @ +.
Pavyzdys 159Example 159
H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH.H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1248 (M+H).MS (FAB): 1248 (M + H) @ +.
Pavyzdys 160Example 160
H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH.H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1226 (M+H).MS (FAB): 1226 (M + H) @ +.
Pavyzdys 161Example 161
H-Lys-Lys-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH.H-Lys-Lys-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.
MS (FAB): 1243 (M+H).MS (FAB): 1243 (M + H) @ +.
162 - 164 pavyzdžiai gauti pagal analogiją su 31 pavyzdžiu, naudojant aprašytą EP paraiškoje Nr. 322348 dervą, kurios struktūraExamples 162-164 were obtained by analogy to Example 31 using the method described in EP application no. 322348 resin having a structure
PolistirolasPolystyrene
Pavyzdys 162Example 162
H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH2.HD-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH 2 .
MS (FAB): 1283 (M+H).MS (FAB): 1283 (M + H) @ +.
Pavyzdys 163Example 163
H-D-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH2.HD-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH 2 .
MS (FAB): 1283 (M+H).MS (FAB): 1283 (M + H) @ +.
Pavyzdys 164Example 164
H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH2.HD-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH 2 .
MS (FAB): 1267 (M+H).MS (FAB): 1267 (M + H) @ +.
Claims (8)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3839581 | 1988-11-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LTIP717A LTIP717A (en) | 1995-01-31 |
| LT3375B true LT3375B (en) | 1995-08-25 |
Family
ID=6367743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LTIP717A LT3375B (en) | 1988-11-24 | 1993-06-25 | Peptides and pharmaceutical composition containing them |
Country Status (5)
| Country | Link |
|---|---|
| BR (1) | BR1100648A (en) |
| DD (1) | DD284030A5 (en) |
| LT (1) | LT3375B (en) |
| RU (1) | RU2083586C1 (en) |
| ZA (1) | ZA896068B (en) |
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Also Published As
| Publication number | Publication date |
|---|---|
| DD284030A5 (en) | 1990-10-31 |
| RU2083586C1 (en) | 1997-07-10 |
| BR1100648A (en) | 2000-02-08 |
| ZA896068B (en) | 1991-01-30 |
| LTIP717A (en) | 1995-01-31 |
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