NO177597B - Analogous Process for Preparing a Therapeutically Active Peptide with Bradykinin Antagonistic Effect - Google Patents
Analogous Process for Preparing a Therapeutically Active Peptide with Bradykinin Antagonistic Effect Download PDFInfo
- Publication number
- NO177597B NO177597B NO893193A NO893193A NO177597B NO 177597 B NO177597 B NO 177597B NO 893193 A NO893193 A NO 893193A NO 893193 A NO893193 A NO 893193A NO 177597 B NO177597 B NO 177597B
- Authority
- NO
- Norway
- Prior art keywords
- arg
- pro
- gly
- tic
- ser
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 60
- 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 title abstract description 9
- 101800004538 Bradykinin Proteins 0.000 title abstract description 8
- 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 title abstract description 8
- 238000004519 manufacturing process Methods 0.000 title description 5
- 102100035792 Kininogen-1 Human genes 0.000 title 1
- 230000003042 antagnostic effect Effects 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims description 21
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 210000004899 c-terminal region Anatomy 0.000 claims description 7
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000012634 fragment Substances 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- OUYCCCASQSFEME-MRVPVSSYSA-N D-tyrosine Chemical compound OC(=O)[C@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-MRVPVSSYSA-N 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 3
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 claims description 3
- DCXYFEDJOCDNAF-UWTATZPHSA-N D-Asparagine Chemical compound OC(=O)[C@H](N)CC(N)=O DCXYFEDJOCDNAF-UWTATZPHSA-N 0.000 claims description 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims description 2
- ZDXPYRJPNDTMRX-GSVOUGTGSA-N D-glutamine Chemical compound OC(=O)[C@H](N)CCC(N)=O ZDXPYRJPNDTMRX-GSVOUGTGSA-N 0.000 claims description 2
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 claims description 2
- 241000534944 Thia Species 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- NSTPXGARCQOSAU-VIFPVBQESA-N N-formyl-L-phenylalanine Chemical compound O=CN[C@H](C(=O)O)CC1=CC=CC=C1 NSTPXGARCQOSAU-VIFPVBQESA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- -1 aromatic amino acid Chemical class 0.000 abstract description 37
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 27
- 150000001413 amino acids Chemical class 0.000 abstract description 24
- 102400000967 Bradykinin Human genes 0.000 abstract description 7
- 238000010647 peptide synthesis reaction Methods 0.000 abstract description 6
- 101710097732 Bradykinin-related peptides Proteins 0.000 abstract description 2
- 230000009471 action Effects 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 2
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- 230000002459 sustained effect Effects 0.000 abstract 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 160
- 239000011347 resin Substances 0.000 description 31
- 229920005989 resin Polymers 0.000 description 31
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- 235000001014 amino acid Nutrition 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 150000003862 amino acid derivatives Chemical class 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
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- 238000010168 coupling process Methods 0.000 description 9
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
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- 238000003776 cleavage reaction Methods 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 210000001147 pulmonary artery Anatomy 0.000 description 4
- 238000010532 solid phase synthesis reaction Methods 0.000 description 4
- 241000283153 Cetacea Species 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000007825 activation reagent Substances 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 3
- DVBUCBXGDWWXNY-SFHVURJKSA-N (2s)-5-(diaminomethylideneamino)-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C3=CC=CC=C3C2=C1 DVBUCBXGDWWXNY-SFHVURJKSA-N 0.000 description 2
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- HNDVDQJCIGZPNO-RXMQYKEDSA-N D-histidine Chemical compound OC(=O)[C@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-RXMQYKEDSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
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- 125000003368 amide group Chemical group 0.000 description 2
- 150000001408 amides 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
- 235000009697 arginine Nutrition 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
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- 125000000524 functional group Chemical group 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- WXEHBUMAEPOYKP-UHFFFAOYSA-N methylsulfanylethane Chemical compound CCSC WXEHBUMAEPOYKP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
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- 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
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- SNZIFNXFAFKRKT-NSHDSACASA-N (2s)-2-azaniumyl-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoate Chemical compound CC(C)(C)OC1=CC=C(C[C@H]([NH3+])C([O-])=O)C=C1 SNZIFNXFAFKRKT-NSHDSACASA-N 0.000 description 1
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- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/18—Kallidins; Bradykinins; Related peptides
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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- A—HUMAN NECESSITIES
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Abstract
Description
Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av nye peptider med bradykinin-antagonistisk virkning. The present invention relates to an analogue method for the production of new peptides with bradykinin-antagonistic action.
Bradykinin-antagonistiske peptider er beskrevet i WO 86/07263 og her ble L-Pro i posisjon 7 i peptidhormonet bradykinin eller andre bradykininanaloger erstattet med en D-aminosyre, så som D-Phe, D-Thi, D-Pal, CDF, D-Nal, MDY, D-Phg, D-His, D-Trp, D-Tyr, D-hPhe, D-Val, D-Ala, D-His, D-Ile, D-Leu og Bradykinin-antagonistic peptides are described in WO 86/07263 and here L-Pro in position 7 of the peptide hormone bradykinin or other bradykinin analogues was replaced with a D-amino acid, such as D-Phe, D-Thi, D-Pal, CDF, D -Nal, MDY, D-Phg, D-His, D-Trp, D-Tyr, D-hPhe, D-Val, D-Ala, D-His, D-Ile, D-Leu and
DOMT. JUDGMENT.
Analogifremgangsmåten ifølge oppfinnelsen for fremstilling av et terapeutisk aktivt peptid med formel I The analogue method according to the invention for the production of a therapeutically active peptide of formula I
hvor where
A er hydrogen, acetyl, D-Arg, D-Tyr, Lys; A is hydrogen, acetyl, D-Arg, D-Tyr, Lys;
B betyr Arg, D-Arg, Arg(Mtr), Arg(N02), Arg(Tos), Lys, B means Arg, D-Arg, Arg(Mtr), Arg(NO2), Arg(Tos), Lys,
Lys(Nic), Lys(PAC), Orn(Nic), Orn(PAC); Lys(Nic), Lys(PAC), Orn(Nic), Orn(PAC);
C betyr en forbindelse fra rekken Hyp-Pro-Gly, Pro-Hyp-Gly, C means a compound from the series Hyp-Pro-Gly, Pro-Hyp-Gly,
Aoc-Pro-Gly, Pro-Aoc-Gly, Opr-Pro-Gly, Pro-Opr-Gly og Pro-Pro-Gly; Aoc-Pro-Gly, Pro-Aoc-Gly, Opr-Pro-Gly, Pro-Opr-Gly and Pro-Pro-Gly;
E betyr Phe, Thia, Aoc, Asp eller Trp; E means Phe, Thia, Aoc, Asp or Trp;
F betyr Ser, D-Ser, Gin, D-Gln, Trp, D-Asn, Opr eller en F means Ser, D-Ser, Gin, D-Gln, Trp, D-Asn, Opr or a
direkte binding; direct binding;
(D)-Tic er en rest med formel V (D)-Tic is a residue of formula V
G betyr Pro, Aoc, Opr, Tic, Oie, D-Oic ellen en direkte G stands for Pro, Aoc, Opr, Tic, Oie, D-Oic or a direct
binding; bonding;
F' betyr Arg, Arg(Mtr) eller en direkte binding; F' means Arg, Arg(Mtr) or a direct bond;
I betyr -0H eller -NH2; I means -OH or -NH2;
K betyr Gly, g<->Ala eller en direkte binding; K means Gly, g<->Ala or a direct bond;
M betyr Phe, Thia eller en direkte binding M means Phe, Thia or a direct bond
samt fysiologiske anvendbare salter derav, kjennetegnet ved at man as well as physiologically usable salts thereof, characterized in that one
a) omsetter et fragment med C-terminal fri karboksylgruppe eller det aktiverte derivatet derav med et tilsvarende a) reacts a fragment with a C-terminal free carboxyl group or the activated derivative thereof with an equivalent
fragment med N-terminal fri aminogruppe eller fragment with N-terminal free amino group or
b) bygger opp peptidet trinnsvis, hvori man avspalter eventuelt den ifølge (a) eller (b) oppnådde forbindelsen i b) builds up the peptide step by step, in which the compound obtained according to (a) or (b) is optionally cleaved in
en eller flere for beskyttelse av andre funksjoner temporært innførte beskyttelsesgrupper og overfører de på denne måten oppnådde forbindelsene med formel I eventuelt til deres fysiologiske anvendbare salter. one or more protective groups temporarily introduced for the protection of other functions and optionally transfer the thus obtained compounds of formula I to their physiologically usable salts.
Hvis ikke annet er angitt står forkortingen av en aminosyre-rest uten en stereodeskriptor for resten i L-form (jfr. Schroder, Lubke, The Peptides, bind I, New York 1965, sidene XXII-XXIII; Houben-Weyl, Methoden der Organischen Chemie, bind XV/l og 2, Stuttgart 1974), som f.eks. Unless otherwise stated, the abbreviation of an amino acid residue without a stereodescriptor stands for the residue in the L form (cf. Schroder, Lubke, The Peptides, Volume I, New York 1965, pages XXII-XXIII; Houben-Weyl, Methoden der Organischen Chemie, volumes XV/1 and 2, Stuttgart 1974), as e.g.
Aad, Abu, "yAbu, ABz, 2ABz, cAca, Ach, Acp, Adpd, Ahb, Aib, PAib, Ala, <p>Ala, Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gin, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hile, hLeu, hLys , hMet, hPhe, hPro, hSer, hThr, hTrp , hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, I va, Kyn, Lant, Len, Leu, Lsg, Lys, eLys, Lys, Met, Mim, Min, nArg, Nie, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, eThi, Thr, Thy, Thx, Tia, Tie, Tly, Trp, Trta, Tyr, Val. Aad, Abu, "yAbu, ABz, 2ABz, cAca, Ach, Acp, Adpd, Ahb, Aib, PAib, Ala, <p>Ala, Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gin, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hile, hLeu, hLys , hMet, hPhe, hPro, hSer, hThr, hTrp , hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, I va, Kyn, Lant, Len , Leu, Lsg, Lys, eLys, Lys, Met, Mim, Min, nArg, Nie, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pro, Pse, Pya, Pyr, Pza , Qin, Ros, Sar, Sec, Sem, Ser, Thi, eThi, Thr, Thy, Thx, Tia, Tie, Tly, Trp, Trta, Tyr, Val.
Som salter gjelder spesielt alkali- eller jordalkaliske salter, salter med fysiologisk anvendbare aminer og salter med uorganiske eller organiske syrer som f.eks. HC1, HBr, H2SO4» H3PO4f maleinsyre, fumarsyre, sitronsyre, vinsyre, eddiksyre. As salts, alkali or alkaline earth salts, salts with physiologically usable amines and salts with inorganic or organic acids such as e.g. HC1, HBr, H2SO4» H3PO4f maleic acid, fumaric acid, citric acid, tartaric acid, acetic acid.
Eksempler på spesielt foretrukne peptider med formel I er; H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH. Examples of particularly preferred peptides of formula I are; H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Pro-Gly-Thia- Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH, H-(D )-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH.
Peptidene fremstilt ifølge foreliggende oppfinnelse er blitt fremstilt ifølge kjente metoder innen peptidkjemien, se f.eks. Houben-Weyl, Methoden der organischen Chemie, bind 15/2, fortrinnsvis ved hjelp av fast fasesyntese som f.eks. i B. Merrifield, J.Am.Chem.Soc. 85, 2149 (1963) eller R. C. Sheppard, Int.J.Peptide Protein Res. 21, 118 (1983) eller ved hjelp av ekvivalente kjente metoder. Som a-aminobeskyttelses-gruppe anvendes uretanbeskyttelsesgruppe så som f.eks. tert.-butyloksykarbonyl(Boe)- eller fluorenylmetyloksykarbonyl-(Fmoc)-beskyttelsesgruppe. For å forhindre sidereaksjoner eller hvis det er nødvendig for syntese av spesielle peptider blir de funksjonelle gruppene i sidekjeden til aminosyrene ytterligere beskyttet med egnede beskyttelsesgrupper (se f.eks. T.W. Greene, "Protective Groups in Organic Syn-thesis"), idet først og fremst The peptides produced according to the present invention have been produced according to known methods in peptide chemistry, see e.g. Houben-Weyl, Methoden der organischen Chemie, volume 15/2, preferably by means of solid phase synthesis such as e.g. in B. Merrifield, J. Am. Chem. Soc. 85, 2149 (1963) or R.C. Sheppard, Int. J. Peptide Protein Res. 21, 118 (1983) or using equivalent known methods. As an α-amino protecting group, a urethane protecting group is used such as e.g. tert-butyloxycarbonyl (Boe) or fluorenylmethyloxycarbonyl (Fmoc) protecting group. To prevent side reactions or if necessary for the synthesis of particular peptides, the functional groups in the side chain of the amino acids are further protected with suitable protective groups (see, for example, T.W. Greene, "Protective Groups in Organic Syn-thesis"), as first and foremost
Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMC), Asp(OBzl), Asp(OBut), Cys(4-MeBzl), Cys(Acm), Cys(SBut), Glu(OBzl), Glu(OBut), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(Cl-Z), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr(Bzl), Thr(But), Trp(Mts), Trp(CHO), Tyr(Br-Z), Tyr(Bzl) eller Tyr(But) blir tilsatt. Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMC), Asp(OBzl), Asp(OBut), Cys(4-MeBzl), Cys(Acm), Cys(SBut), Glu(OBzl ), Glu(OBut), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(Cl-Z), Lys(Boc), Met(O), Ser(Bzl), Ser (But), Thr(Bzl), Thr(But), Trp(Mts), Trp(CHO), Tyr(Br-Z), Tyr(Bzl) or Tyr(But) are added.
Fast-fasesyntesen begynner ved den C-terminale enden av peptidet med kobling av en beskyttet aminosyre på et tilsvarende harpiks. Slike utgangsmaterialer kan bli tilveiebragt ved kobling av en beskyttet aminosyre med en med et klormetyl-, hydroksymetyl-, benzhydrylamino(BHA)-, metylbenz-hydrylamino(MBHA)-gruppe modifisert polystyrol- eller polyakrylamid-harpiks over en ester- h.h.v. amidbinding. Harpiks anvendt som baerermateriale er kommersielt til-gjengelig. BHA- og MBHA-harpiks blir vanligvis anvendt når det syntetiserte peptidet skal inneholde en fri amidgruppe i den C-terminale enden. Dersom peptidet skal inneholde en sekundær amidgruppe ved den C-terminale enden anvendes et klormetyl- h.h.v. hydroksymetyl-harpiks og avspaltingen med de tilsvarende aminene blir gjennomført. Hvis man f.eks. vil oppnå etylamidet kan peptidet bli avspaltet fra harpikset med etylamin, hvorved avspaltning av sidekjede-beskyttelsesgrupper deretter tilveiebringes med andre egnede reagenser. Dersom de tert.-butyl-beskyttelsesgruppene til aminosyre-sidekjeden i peptidet skal tilveiebringes blir syntesen gjennomført med Fmoc-beskyttelsesgruppen for temporær blokkering av a-amino-gruppen til aminosyren ved anvendelse av den f.eks. beskrevne metodikken til R.C. Sheppard, J.Chem. Soc., Chem.Comm. 1982. 587, hvorved guanidino-funksjonen til argininene blir beskyttet ved protonering med pyridinium-perklorat og beskyttelse av de andre i sidekjeden funksjonaliserte aminosyrene foregår ved katalytisk transfer-hydrering (A. Felix et al. J. Org. Chem. 13, 4194 (1978) eller med natrium i flytende ammoniakk (W. Roberts, J.Am. Chem.Soc. 76, 6203 (1954)) avspaltbare benzyl-beskyttelsesgruppe. The solid-phase synthesis begins at the C-terminal end of the peptide with the coupling of a protected amino acid on a corresponding resin. Such starting materials can be provided by coupling a protected amino acid with a polystyrene or polyacrylamide resin modified with a chloromethyl, hydroxymethyl, benzhydrylamino (BHA), methylbenzhydrylamino (MBHA) group over an ester or amide bond. Resin used as a carrier material is commercially available. BHA and MBHA resins are usually used when the synthesized peptide is to contain a free amide group at the C-terminal end. If the peptide is to contain a secondary amide group at the C-terminal end, a chloromethyl or hydroxymethyl resin and the cleavage with the corresponding amines is carried out. If you e.g. will obtain the ethyl amide, the peptide can be cleaved from the resin with ethylamine, whereby cleavage of side chain protecting groups is then provided with other suitable reagents. If the tert.-butyl protecting groups for the amino acid side chain in the peptide are to be provided, the synthesis is carried out with the Fmoc protecting group for temporary blocking of the α-amino group of the amino acid by using the e.g. described the methodology of R.C. Sheppard, J. Chem. Soc., Chem.Comm. 1982. 587, whereby the guanidino function of the arginines is protected by protonation with pyridinium perchlorate and protection of the other amino acids functionalized in the side chain takes place by catalytic transfer hydrogenation (A. Felix et al. J. Org. Chem. 13, 4194 ( 1978) or with sodium in liquid ammonia (W. Roberts, J.Am. Chem.Soc. 76, 6203 (1954)) cleavable benzyl protecting group.
Etter avspaltning av amino-beskyttelsesgruppen av den på harpiks koblede aminosyren med et egnet reagens, som f.eks. trifluoreddiksyre i metylenklorid når det gjelder Boc-beskyttelsesgruppen eller en 20% oppløsning av piperidin i dimetylformamid når det gjelder Fmoc-beskyttelsesgruppen, blir de etterfølgende beskyttede aminosyrene koblet av etter hverandre i ønsket rekkefølge. De intermediære N-terminale beskyttede peptidharpiksene blir endeblokkert før kobling med det etterfølgende aminosyrederivatet ved overnevnte reagenser. After removal of the amino-protecting group of the resin-linked amino acid with a suitable reagent, such as e.g. trifluoroacetic acid in methylene chloride in the case of the Boc protecting group or a 20% solution of piperidine in dimethylformamide in the case of the Fmoc protecting group, the subsequent protected amino acids are decoupled one after the other in the desired order. The intermediate N-terminal protected peptide resins are end-blocked prior to coupling with the subsequent amino acid derivative by the above reagents.
Som koblingsreagens kan alle mulige aktiveringsreagenser som anvendes innen peptidsyntesen brukes, se f.eks. Houben-Weyl, Methoden der organischen Chemie, bind 15/2, spesielt karbo-diimider så som f.eks. N-N'-dicykloheksylkarbodiimid, N-N'-diisopropylkarbodiimid eller N-etyl-N'-(3-dimetylamino-propyl)karbodiimid. Koblingen til harpikset kan dermed bli gjennomført direkte ved tilsetning av aminosyrederivat med aktiveringsreagens og eventuelt en tilsetning for undertryk-king av racemisering som f.eks. 1-hydroksybenzotriazol (HOBt) As a coupling reagent, all possible activation reagents used in peptide synthesis can be used, see e.g. Houben-Weyl, Methoden der organischen Chemie, volume 15/2, especially carbo-diimides such as e.g. N-N'-dicyclohexylcarbodiimide, N-N'-diisopropylcarbodiimide or N-ethyl-N'-(3-dimethylamino-propyl)carbodiimide. The connection to the resin can thus be carried out directly by adding an amino acid derivative with an activating reagent and possibly an addition for suppressing racemisation such as e.g. 1-Hydroxybenzotriazole (HOBt)
(W. KSnig, R. Geiger, Chem. Ber. 103. 708 (1970)) eller 3-hydroksy-4-okso-3,4-dihydrobenzotriazin (HOObt) (W. Konig, R. Geiger, Chem.Ber. 103. 2054 (1970) ellers kan foraktiveringen av aminosyrederivatene som symmetrisk anhydrid eller HOBt-h.h.v. HOObt-ester foregå separat og oppløsning av den aktiverte formen i et egnet oppløsningsmiddel kan tilsettes til koblingsdyktig peptidharpiks. (W. KSnig, R. Geiger, Chem. Ber. 103. 708 (1970)) or 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOObt) (W. Konig, R. Geiger, Chem. Ber. 103. 2054 (1970) otherwise, the preactivation of the amino acid derivatives as symmetrical anhydride or HOBt or HOObt ester can take place separately and dissolution of the activated form in a suitable solvent can be added to the coupling-capable peptide resin.
Koblingen h.h.v. aktiveringen av aminosyrederivatene med en av de ovennevnte aktiveringsreagensene kan gjennomføres i dimetylformamid, N-metylpyrrolidon eller metylenklorid eller en blanding av de nevnte oppløsningsmidlene. Det aktiverte aminosyrederivatet blir tilsatt i et 1,5 til 4 ganger overskudd. I de tilfellene hvor en ufullstendig kobling inntreffer gjentas koblingsreaksjonen, uten å på forhånd gjennomføre den for kobling av den påfølgende aminosyre nødvendige endeblokkeringen av a-aminogruppen til peptid-harpikset. The connection or the activation of the amino acid derivatives with one of the above-mentioned activation reagents can be carried out in dimethylformamide, N-methylpyrrolidone or methylene chloride or a mixture of the aforementioned solvents. The activated amino acid derivative is added in a 1.5- to 4-fold excess. In those cases where an incomplete coupling occurs, the coupling reaction is repeated, without first carrying out the end-blocking of the α-amino group of the peptide resin necessary for the coupling of the subsequent amino acid.
Det vellykkede forløpet av koblingsreaksjonen kan overprøves ved hjelp av ninhydrin-reaksjonen som f.eks. er beskrevet av E. Kaiser et al. Anal. Biochem. 34 595 (1970). Syntesen kan også gjennomføres automatisert f.eks. med en peptid-syntese-modell 430A til Fa. Applied Biosystems, hvorved man enten kan anvende synteseprogrammet tilveiebragt fra apparatfabrikanten eller også anvende det som brukeren selv har oppstilt. Sistnevnte anvendes spesielt ved anvendelsen av med Fmoc-gruppe beskyttede aminosyrederivater. The successful course of the coupling reaction can be verified by means of the ninhydrin reaction, which e.g. is described by E. Kaiser et al. Anal. Biochem. 34,595 (1970). The synthesis can also be carried out automatically, e.g. with a peptide synthesis model 430A to Fa. Applied Biosystems, whereby one can either use the synthesis program provided by the device manufacturer or also use the one that the user has set up himself. The latter is used in particular when using amino acid derivatives protected with an Fmoc group.
Etter syntese av peptidene på den ovennevnte "beskrevne måten kan peptidet avspaltes ved harpiksen med reagenser, som f.eks. flytende fluorvannstoff (fortrinnsvis ved de ifølge Boc-metoden fremstilte peptidene) eller trifluoreddiksyre (fortrinnsvis ved den ifølge Fmoc-metode syntetiserte peptider). Disse reagensene spalter ikke bare peptidet fra harpiksen, men også de ytterligere sidekjede-beskyttelsesgruppene til aminosyrederivatene. På denne måten oppnår man dessuten ved anvendelse av BHA- og MBEA-harpikser peptidet i form av den frie syren. Ved BHA- h.h.v. MBHA-harpiksen oppnår man ved spalting med fluorvannstoff eller trifluormetan-sulfonsyre peptidet som syreamid. Ytterligere fremgangsmåte for fremstilling av peptidamider er beskrevet i den tyske patentsøknaden P 37 11 866.8 og P 37 43 620.1. Her foregår avspaltning av peptidamidene fra harpiks ved behandling med de middelsterke syrene som vanligvis anvendes innen peptidsyntesen (f.eks. trifluoreddiksyre) hvorved som kation-fangende substanser som fenol, kresol, tiokresol, anisol, tioanisol, etanditiol, dimetylsulfid, etylmetylsulfid eller lignende i fast-fasesyntese vanlige kationfangere tilsettes enkeltvis eller en blanding av to eller flere av disse hjelpemidlene. Trifluoreddiksyren kan dermed også anvendes fortynnet med egnede oppløsningsmidler, som f.eks. metylenklorid. After synthesis of the peptides in the above-described manner, the peptide can be cleaved at the resin with reagents, such as liquid hydrogen fluoride (preferably in the case of the peptides prepared according to the Boc method) or trifluoroacetic acid (preferably in the case of the peptides synthesized according to the Fmoc method). These reagents not only cleave the peptide from the resin, but also the additional side chain protecting groups of the amino acid derivatives. In this way, moreover, when using BHA and MBEA resins, the peptide is obtained in the form of the free acid. In the case of the BHA or MBHA resin, by splitting with hydrogen fluoride or trifluoromethanesulfonic acid the peptide as an acid amide. Further methods for the production of peptidamides are described in the German patent application P 37 11 866.8 and P 37 43 620.1. Here, cleavage of the peptidamides from resin takes place by treatment with the medium-strong acids that usually used in peptide synthesis (e.g. trifluoroacetic acid) whereby as a cation trap the substances such as phenol, cresol, thiocresol, anisole, thioanisole, ethanedithiol, dimethyl sulphide, ethyl methyl sulphide or the like in solid-phase synthesis common cation scavengers are added individually or a mixture of two or more of these auxiliaries. The trifluoroacetic acid can thus also be used diluted with suitable solvents, such as e.g. methylene chloride.
Dersom tert.-butyl h.h.v. benzylsidekjede-beskyttelsesgruppene til peptidet skal tilveiebringes blir avspaltningen av et på spesielt modifisert bæreharpiks syntetisert peptid gjennomført med 156 trif luoreddiksyre i metylenklorid, som f.eks. beskrevet av R.C. Sheppard J.Chem. Soc, Chem.Comm. 1982. 587. Dersom enkelte tert.-butyl h.h.v. benzylsidekjede-beskyttelsesgrupper skal bli tilveiebragt anvender man en egnet kombinasjon av syntese- og avspaltningsmetoden. If tert.-butyl or the benzyl side chain protecting groups of the peptide are to be provided, the cleavage of a peptide synthesized on a specially modified carrier resin is carried out with 156 trifluoroacetic acid in methylene chloride, which e.g. described by R.C. Sheppard J. Chem. Soc, Chem.Comm. 1982. 587. If certain tert.-butyl or benzyl side chain protecting groups must be provided using a suitable combination of the synthesis and cleavage method.
For syntese av peptider med en C-terminal amidgruppering eller en co-amino- h.h.v. to-guanidinoalkyl-gruppering anvendes det modifiserte bæreharpikset beskrevet av Sheppard. Etter syntesen blir det i sidekjede fullstendig beskyttede peptidet avspaltet fra harpikset og deretter omsatt ved klassisk oppløsningsyntese med det tilsvarende aminet h.h.v. u>-aminoalkylaminet eller u-guanidinoalkylaminet, hvorved eventuelt tilstedeværende ytterligere funksjonelle grupper på kjent måte temporært kan bli beskyttet. For the synthesis of peptides with a C-terminal amide group or a co-amino- or to-guanidinoalkyl group, the modified carrier resin described by Sheppard is used. After the synthesis, the side-chain completely protected peptide is cleaved from the resin and then reacted by classical solution synthesis with the corresponding amine or the u>-aminoalkylamine or the u-guanidinoalkylamine, whereby any additional functional groups present can be temporarily protected in a known manner.
En ytterligere fremgangsmåte for fremstilling av peptider med en cj-aminoalkyl-gruppering er beskrevet i tysk patentsøknad P 36 35 670.0. A further method for the production of peptides with a cj-aminoalkyl grouping is described in German patent application P 36 35 670.0.
Peptidene fremstilt i foreliggende oppfinnelse ble fortrinnsvis syntetisert under anvendelse av fast-faseteknikken ifølge to generelle beskyttelsesgruppe-taktikker: Syntesen forløper med en automatisk peptidsyntese-modell 430 A til Fa. Applied Biosystems under anvendelse av Boc-h.h.v. Fmoc-beskyttelsesgruppen for temporær blokkering av a-aminogruppen. The peptides produced in the present invention were preferably synthesized using the solid-phase technique according to two general protecting group tactics: The synthesis proceeds with an automatic peptide synthesis model 430 A to Fa. Applied Biosystems using Boc-h.h.v. The Fmoc protecting group for temporary blocking of the α-amino group.
Ved anvendelse av Boc-beskyttelsesgruppen ble den for-programmerte syntesesyklusen til fabrikanten av apparatet anvendt for syntesen. When using the Boc protecting group, the pre-programmed synthesis cycle of the apparatus manufacturer was used for the synthesis.
Syntese av peptidene med en fri karboksylgruppe ved den C-terminale enden foregår på et med det tilsvarende Boc-aminosyre funksjonaliserte 4-(hydroksymetyl)fenylacetamido-metylpolystyrol-harpikset (R.B. Merrifield, J.Org.Chem. 43, 2845 (1978)) til Fa. Applied Biosystems. For fremstilling av peptidamidene ble et MBHA-harpiks fra samme firma anvendt. Synthesis of the peptides with a free carboxyl group at the C-terminal end takes place on a 4-(hydroxymethyl)phenylacetamido-methylpolystyrene resin functionalized with the corresponding Boc amino acid (R.B. Merrifield, J.Org.Chem. 43, 2845 (1978)) to Fa. Applied Biosystems. For the preparation of the peptide amides, an MBHA resin from the same company was used.
Som aktiveringsreagenser anvendes As activation reagents are used
N,N'-dicykloheksylkarbodiimid eller N,N'-diisopropylkarbodiimid. Aktiveringen forløp som symmetrisk anhydrid, som EOBt-ester eller HOObt-ester i CE2C12, CH2C12 - DMF-blanding eller NMP. For koblingen ble 2-4 ekvivalenter aktivert aminosyrederivat anvendt. I de tilfellene koblingen forløp ufullstendig ble reaksjonen gjentatt. N,N'-dicyclohexylcarbodiimide or N,N'-diisopropylcarbodiimide. The activation proceeded as symmetrical anhydride, as EOBt ester or HOObt ester in CE2C12, CH2C12 - DMF mixture or NMP. For the coupling, 2-4 equivalents of activated amino acid derivative were used. In those cases where the coupling was incomplete, the reaction was repeated.
Ved anvendelse av Fmoc-beskyttelsesgruppen for temporær beskyttelse av a-aminogruppen ble de for syntese med automatisk peptid-syntesemaskin modell 430A til Fa. Applied Biosystems egne synteseprogrammer anvendt. Syntesen foregår på et p-benzyloksybenzylalkohol-harpisk (S. Wang, J.Am.Chem. Soc. 95., 1328 (1973)) til Fa. Bachem som ifølge kjent metode (E. Atherton et al. J.C.S. Chem. Comm. 1981. 336) var forestret med den tilsvarende aminosyren. Aktivering av aminosyrederivatene som HOBt- eller HOObt-ester foregikk direkte i de aminosyrehylsene fra fabrikanten ved tilsetning av en diisopropylkarbodiimid-oppløsning i DMF til den på forhånd innveide blandingen av aminosyrederivatet og HOBt eller HOObt. Likeledes kan i forbindelse fremstilt Fmoc-aminosyre-OObt ester som beskrevet i Europeisk Patentsøknad 87107634.5 bli tilsatt. Avspaltning av Fmoc-beskyttelsesgruppen foregår med en 20% oppløsning av piperidin i DMF i reaksjonsbeholderen. Det anvendte overskuddet av reaktivt aminosyrederivat utgjorde 1,5 til 2,5 ekvivalenter. Dersom koblingen ikke var fullstendig ble den som ved Boc-metoden gjentatt. Using the Fmoc protecting group for temporary protection of the α-amino group, they became Fa for synthesis with an automatic peptide synthesizer model 430A. Applied Biosystems' own synthesis programs used. The synthesis takes place on a p-benzyloxybenzyl alcohol-harpy (S. Wang, J.Am.Chem. Soc. 95., 1328 (1973)) to Fa. Bachem which according to a known method (E. Atherton et al. J.C.S. Chem. Comm. 1981. 336) was esterified with the corresponding amino acid. Activation of the amino acid derivatives as HOBt or HOObt esters took place directly in the amino acid sleeves from the manufacturer by adding a diisopropylcarbodiimide solution in DMF to the previously weighed mixture of the amino acid derivative and HOBt or HOObt. Similarly, Fmoc-amino acid-OObt ester prepared in connection as described in European Patent Application 87107634.5 can be added. Removal of the Fmoc protection group takes place with a 20% solution of piperidine in DMF in the reaction vessel. The excess of reactive amino acid derivative used was 1.5 to 2.5 equivalents. If the coupling was not complete, it was repeated as in the Boc method.
Peptidene fremstilt ifølge oppfinnelsen har enkeltvis eller i kombinasjon en bradykinin-antagonistisk virkning som i forskjellige modeller kan bli testet (se Handbook of Exp. Pharmacol. Vol. 25, Springer Verlag, 1970, s. 53 - 55 ) som f.eks. fra isolerte rotteuteruser, nisetynntarm eller isolert lungearterie fra niser. The peptides produced according to the invention individually or in combination have a bradykinin-antagonistic effect which can be tested in different models (see Handbook of Exp. Pharmacol. Vol. 25, Springer Verlag, 1970, pp. 53 - 55 ) such as e.g. from isolated rat uteri, porpoise small intestine or isolated porpoise pulmonary artery.
For testingen av peptidene fremstilt ifølge oppfinnelsen på isolerte lungearterier ble niser (Dunkin Hartley) med en vekt på 400—450 g avlivet ved nakkeslag. For the testing of the peptides produced according to the invention on isolated pulmonary arteries, porpoises (Dunkin Hartley) with a weight of 400-450 g were euthanized by neck blow.
Brysthulen blir åpnet og arteria pulmonalis blir forsiktig tatt ut. Det omliggende vevet blir forsiktig fjernet og arteria pulmonalis blir klippet opp spiralformig i en vinkel på 45°. The chest cavity is opened and the pulmonary artery is carefully taken out. The surrounding tissue is carefully removed and the pulmonary artery is cut up spirally at an angle of 45°.
Årestrimler på 2,5 cm lengde og 3 - 4 mm bredde blir fiksert i et 10 ml organbad fylt med Ringeroppløsning. Vein strips of 2.5 cm length and 3 - 4 mm width are fixed in a 10 ml organ bath filled with Ringer's solution.
Sammensetningen av oppløsningen i mmol/1 The composition of the solution in mmol/1
Oppløsningen blir gjennomboblet med 95$ Og og 5$ COg og oppvarmet ved 37°C. pH utgjør 7,4 og forlasten på årestrimlene utgjør 1,0 g. The solution is bubbled through with 95% Og and 5% COg and heated at 37°C. The pH is 7.4 and the load on the vein strips is 1.0 g.
De isotoniske kontraksjonsendringene blir bestemt med en vektsats og et HF-modem (veikniv) til Hugo Sachs og regi-strert på en kompensasjonsskriver (BEC, Goerz Metrawatt SE 460 ). The isotonic contraction changes are determined with a weight set and an HF modem (road knife) to Hugo Sachs and recorded on a compensation recorder (BEC, Goerz Metrawatt SE 460).
Etter ekvilibrering i 1 time blir forsøket påbegynt. Etter at årestrimlene har oppnådd maksimal ømfintlighet overfor 2 x IO-<7> mol/l bradykinin, idet bradykinin fører til en kontrak-sjon av årestrimlene, lar man peptidene i doser på 5 x 10-<8> — 1 x IO-<5> mol/l virke inn i 10 minutter og etter ny porsjon bradykinin blir forfallet av effektene av bradykinin overfor kontrollen sammenlignet. After equilibration for 1 hour, the experiment is started. After the choroid strips have achieved maximum sensitivity to 2 x 10-<7> mol/l bradykinin, as bradykinin leads to a contraction of the choroid strips, the peptides are allowed in doses of 5 x 10-<8> — 1 x 10-< 5> mol/l work for 10 minutes and after a new portion of bradykinin, the decay of the effects of bradykinin compared to the control is compared.
For erkjennelse av en partialagonistisk effekt blir peptidene anvendt i doser på 1 x IO"<5> - 1 x IO"<3> mol/l. For recognition of a partial agonistic effect, the peptides are used in doses of 1 x 10"<5> - 1 x 10"<3> mol/l.
De utregnede ICsg-verdiene av peptidene fremstilt ifølge oppfinnelsen blir regnet ut av dosevirkningskurvene og er ført opp i tabell 1. The calculated ICsg values of the peptides produced according to the invention are calculated from the dose-response curves and are listed in table 1.
Den terapeutiske utnyttelsen av peptidene fremstilt ifølge oppfinnelsen omfatter alle patologiske tilstander som gjennom bradykinin og bradykinin-beslektede peptider blir formidlet, utløst eller understøttet. Disse omfatter bl.a. traumer, så som sår, forbrenning, utslett, erytem, ødem, angina, arthritis, astma, allergier, rhinitis, sjokk, betennelser, lavt blodtrykk, smerter, kløe og forandret sperma-motilitet. Farmasøytiske preparater kan inneholde en virksom mengde av de virksomme stoffene med formel I, enkeltvis eller i kombinasjon, sammen med et uorganisk eller organisk farmasøytisk anvendbart bærerstoff. The therapeutic use of the peptides produced according to the invention includes all pathological conditions which are mediated, triggered or supported through bradykinin and bradykinin-related peptides. These include i.a. trauma, such as wounds, burns, rashes, erythema, oedema, angina, arthritis, asthma, allergies, rhinitis, shock, inflammation, low blood pressure, pain, itching and altered sperm motility. Pharmaceutical preparations can contain an effective amount of the active substances of formula I, individually or in combination, together with an inorganic or organic pharmaceutically usable carrier substance.
Anvendelsen kan være enteral, parenteral, så som f.eks. subkutan, i.m. eller i. v. -, sublingual, epikutan, nasal, rektal, intravaginal, intrabukkal eller pr. inhalasjon. Doseringen av det virksomme stoffet avhenger av den varm-blodige arten, kroppsvekten, alder og applikasjonsform. The application can be enteral, parenteral, such as e.g. subcutaneous, i.m. or i. v. -, sublingual, epicutaneous, nasal, rectal, intravaginal, intrabuccal or per inhalation. The dosage of the active substance depends on the warm-blooded species, body weight, age and form of application.
Fortegnelse over forkortelsene: List of abbreviations:
De for aminosyrene anvendte forkortelsene tilsvarer de innen peptidkjemien vanlige tre bokstav-kode som beskrevet i Europ. J. Biochem. 138. 9 (1984). Ytterligere anvendte forkortelser er oppført nedenfor. The abbreviations used for the amino acids correspond to the usual three-letter code in peptide chemistry as described in Europ. J. Biochem. 138. 9 (1984). Additional abbreviations used are listed below.
Acm Acetamidometyl Acm Acetamidomethyl
c-Ahx c-aminoheksanoyl c-Ahx c-aminohexanoyl
Aoc cis, endo-2-azabicyklo[3,3,0]oktan-3-S-karbonyl Aoc cis, endo-2-azabicyclo[3,3,0]octane-3-S-carbonyl
Boe tert.-butyloksykarbonyl Boe tert-butyloxycarbonyl
But tert.-butyl But tert-butyl
Bzl Benzyl Bzl Benzyl
Cl-Z 4-klor-benzyloksykarbonyl Cl-Z 4-chloro-benzyloxycarbonyl
DMF Dimetylformamid DMF Dimethylformamide
Dnp 2,4-dinitrofenyl Dnp 2,4-dinitrophenyl
Fmoc 9-fluorenylmetyloksykarbonyl Fmoc 9-fluorenylmethyloxycarbonyl
Me Metyl Me Methyl
4-Mebzl 4-metylbenzyl 4-Mebzl 4-methylbenzyl
Mtr 4-metoksy-2,3,6-trimetylfenyllsulfonyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl
Mts Mesitylen-2-sulfonyl Mts Mesitylene-2-sulfonyl
NMP N-metylpyrrolidin NMP N-methylpyrrolidine
Oie cis-endo-oktahydroindol-2-karbonyl Oie cis-endo-octahydroindole-2-carbonyl
Opr Isoksazolidin-3-ylkarbonyl Opr Isoxazolidin-3-ylcarbonyl
Pmc 2,2,5,7,8-pentametylkroman-6-sulfonyl Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl
TFA Trifluoreddiksyre TFA Trifluoroacetic acid
Tes 4-metylfenylsulfonyl Tes 4-methylphenylsulfonyl
Thia 2-tienylalanyl Thia 2-thienylalanyl
Tic 1,2 ,3,4-tetrahydroisochinolin-3-ylkarbonyl Tic 1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl
Trt Trityl Trt Trityl
De følgende eksemplene tydeliggjør de foretrukne fremgangs-måtene for fast fase-syntese av peptidene fremstilt ifølge oppfinnelsen. The following examples clarify the preferred procedures for solid phase synthesis of the peptides produced according to the invention.
Man anvender følgende aminosyre-derivater: The following amino acid derivatives are used:
Fmoc-Årg(Mtr)-0H, Boc-(D)-Arg-OH, Fmoc-Arg(Pmc)-0H, Fmoc-Hyp-OE, Fmoc-Pro-OObt, Fmoc-Gly-OObt, Fmoc-Phe-OObt, Fmoc-Ser(tBu)-00bt, Fmoc-(D)-Tic-OH, Fmoc-Gln-OE, Fmoc-Aoc-OH, Fmoc-Thia-OE, Fmoc-Opr-OE, Fmoc-(D)-Asn-OE, Fmoc-e-Ala-OH, Fmoc-Oic-OH. Fmoc-Årg(Mtr)-OH, Boc-(D)-Arg-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Hyp-OE, Fmoc-Pro-OObt, Fmoc-Gly-OObt, Fmoc-Phe- OObt, Fmoc-Ser(tBu)-00bt, Fmoc-(D)-Tic-OH, Fmoc-Gln-OE, Fmoc-Aoc-OH, Fmoc-Thia-OE, Fmoc-Opr-OE, Fmoc-(D) -Asn-OE, Fmoc-ε-Ala-OH, Fmoc-Oic-OH.
Eksempel 1 Example 1
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OE H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OE
ble dannet med en peptid-synthesizer modell 430 A til Fa. Applied Biosystems ved anvendelse av Fmoc-metoden på en med Fmoc-Arg(Mtr)-0E forestret p-benzyloksybenzylalkohol-harpiks til Fa. Novabiochem (belastning ca. 0,5 mmol/g harpiks). 1 g av harpikset ble tilsatt og syntesen ble gjennomført ved hjelp av en for Fmoc-metoden modifiserte syntese-program. was generated with a peptide synthesizer model 430 A to Fa. Applied Biosystems using the Fmoc method on a p-benzyloxybenzyl alcohol resin esterified with Fmoc-Arg(Mtr)-0E to Fa. Novabiochem (load approx. 0.5 mmol/g resin). 1 g of the resin was added and the synthesis was carried out using a synthesis program modified for the Fmoc method.
I innsatsen til syntesemaskinen ble 1 mmol aminosyrederivat med fri karboksylgruppe tilsatt sammen med 0,95 mmol EOObt. Foraktiveringen av disse aminosyrene foregår direkte i innsatsene ved oppløsning i 4 ml DMF og tilsetning av 2 ml av en 0,55 mol oppløsning av diisopropylkarbodiimid i DMF. De HOObt-esterne til de andre aminosyrene ble oppløst i 6 ml NMP og deretter koblet akkurat som de in situ foraktiverte aminosyrene på det på forhånd med 20$ piper idin i DMF endeblokkerte harpikset. Etter avsluttet syntese ble peptidet avspaltet fra harpikset under samtidig fjerning av sidekjede-beskyttelsesgruppene med trifluoreddiksyre under anvendelse av tioanisol og etanditiol som kationfanger. Resten etter fjerning av trifluoreddiksyre ble flere ganger skylt med eddikester og sentrifugert. Den gjenværende resten ble kromatograf ert på Sephadex LE 20 med 1056 eddiksyre. Frak-sjoner med rene peptider ble slått sammen og frysetørket MS(FAB) : 1294 (M+H) In the input of the synthesizer, 1 mmol amino acid derivative with a free carboxyl group was added together with 0.95 mmol EOObt. The preactivation of these amino acids takes place directly in the inserts by dissolving in 4 ml of DMF and adding 2 ml of a 0.55 mol solution of diisopropylcarbodiimide in DMF. The HOObt esters of the other amino acids were dissolved in 6 mL of NMP and then coupled just like the in situ preactivated amino acids onto the previously 20% piperidine in DMF end-blocked resin. After completion of the synthesis, the peptide was cleaved from the resin while simultaneously removing the side chain protecting groups with trifluoroacetic acid using thioanisole and ethanedithiol as cation scavengers. The residue after removal of trifluoroacetic acid was rinsed several times with vinegar and centrifuged. The remaining residue was chromatographed on Sephadex LE 20 with 1056 acetic acid. Fractions with pure peptides were pooled and freeze-dried MS(FAB): 1294 (M+H)
Peptidene i eksemplene 2 til 24 nedenfor ble fremstilt og renset som i eksempel 1. The peptides in Examples 2 to 24 below were prepared and purified as in Example 1.
Eksempel 2 Example 2
E-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-(D)-Ser-(D)-Tic-Phe-Arg-OH MS(FAB) : 1294 (M+H) E-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-(D)-Ser-(D)-Tic-Phe-Arg-OH MS(FAB) : 1294 (M+H)
Eksempel 3 Example 3
H-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OE MS(FAB) : 1306 (M+H) H-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OE MS(FAB) : 1306 (M+H)
Eksempel 4 Example 4
E-(D)-Arg-Arg-Pro-Eyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OE E-(D)-Arg-Arg-Pro-Eyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OE
MS(FAB) : 1294 (M+E) MS(FAB) : 1294 (M+E)
Eksempel 5 Example 5
E-(D)-Arg-Arg-Eyp-Pro-Gly-Phe-Gln-(D)-Tic-Phe-Arg-OH E-(D)-Arg-Arg-Eyp-Pro-Gly-Phe-Gln-(D)-Tic-Phe-Arg-OH
MS(FAB) : 1335 (M+H) MS(FAB) : 1335 (M+H)
Eksempel 6 Example 6
E-(D )-Arg-Arg-Eyp-Pro-Gly-Phe-Ser-(D)-Tic-Pro-Arg-OE E-(D )-Arg-Arg-Eyp-Pro-Gly-Phe-Ser-(D)-Tic-Pro-Arg-OE
MS(FAB) : 1244 (M+H) MS(FAB) : 1244 (M+H)
Eksempel 7 Example 7
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Trp-(D)-Tic-Phe-Arg-OE H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Trp-(D)-Tic-Phe-Arg-OE
MS(FAB) : 1393 (M+E) MS(FAB) : 1393 (M+E)
Eksempel 8 Example 8
E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OE MS(FAB) : 1250 (M+E) E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OE MS(FAB) : 1250 (M+E)
Eksempel 9 Example 9
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-(D)-Asn-(D)-Tic-Thia-Arg-OH MS(FAB) : 1333 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-(D)-Asn-(D)-Tic-Thia-Arg-OH MS(FAB) : 1333 (M+H)
Eksempel 10 Example 10
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Opr-(D)-Tic-Thia-Arg-OH MS(FAB) : 1301 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Opr-(D)-Tic-Thia-Arg-OH MS(FAB) : 1301 (M+H)
Eksempel 11 Example 11
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-(D)-Gln-(D)-Tic-Thia-Arg-OH MS(FAB) : 1347 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-(D)-Gln-(D)-Tic-Thia-Arg-OH MS(FAB) : 1347 (M+H)
Eksempel 12 Example 12
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H)
Eksempel 13 Example 13
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thla-Ser-(D)-Tic-Pro-Phe-OH MS(FAB) : 1241 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thla-Ser-(D)-Tic-Pro-Phe-OH MS(FAB) : 1241 (M+H)
Eksempel 14 Example 14
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-Arg-OH MS(FAB) : 1397 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-Arg-OH MS(FAB) : 1397 (M+H)
Eksempel 15 Example 15
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-3-Ala-(D)-Tic-Pro-Arg-0H MS(FAB) : 1321 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-3-Ala-(D)-Tic-Pro-Arg-OH MS(FAB) : 1321 (M+H)
Eksempel 16 Example 16
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1220 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1220 (M+H)
Eksempel 17 Example 17
H-(D)-Arg-Arg-Aoc-Pro-Gly-Thia-Ser-(D)-Tic-Thla-Arg-OH MS(FAB) : 1330 (M+H) H-(D)-Arg-Arg-Aoc-Pro-Gly-Thia-Ser-(D)-Tic-Thla-Arg-OH MS(FAB) : 1330 (M+H)
Eksempel 18 Example 18
E-(D)-Arg-Arg-Pro-Aoc-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OE MS(FAB) : 1330 (M+E) E-(D)-Arg-Arg-Pro-Aoc-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OE MS(FAB) : 1330 (M+E)
Eksempel 19 Example 19
E-(D) -Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Ti c-Aoc-Arg-OE MS(FAB) : 1290 (M+E) E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Ti c-Aoc-Arg-OE MS(FAB) : 1290 (M+E)
Eksempel 20 Example 20
E-(D)-Arg-Arg-Opr-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-0E MS(FAB) : 1236 (M+E) E-(D)-Arg-Arg-Opr-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-0E MS(FAB) : 1236 (M+E)
Eksempel 21 Example 21
E-(D)-Arg-Arg-Pro-Opr-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OE MS(FAB) : 1236 (M+E) E-(D)-Arg-Arg-Pro-Opr-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OE MS(FAB) : 1236 (M+E)
Eksempel 22 Example 22
E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Opr-Arg-OE MS(FAB) : 1252 (M+E) E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Opr-Arg-OE MS(FAB) : 1252 (M+E)
Eksempel 23 Example 23
E-(D)-Arg-(D)-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1290 (M+E) E-(D)-Arg-(D)-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1290 (M+E)
Eksempel 24 Example 24
H-(D)-Arg-Arg-Pro-Eyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1290 (M+E) H-(D)-Arg-Arg-Pro-Eyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1290 (M+E)
Eksemplene 25 - 27 Examples 25 - 27
E-(D)-Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-0E og E-(D)-Arg-Arg-Pro-Eyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg(Mtr)-0E og E-(D)-Arg-Arg(Mtr)-Pro-Eyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg(Mtr)-0H E-(D)-Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-0E and E-(D)-Arg-Arg-Pro-Eyp-Gly -Phe-Ser-(D)-Tic-Phe-Arg(Mtr)-0E and E-(D)-Arg-Arg(Mtr)-Pro-Eyp-Gly-Phe-Ser-(D)-Tic-Phe -Arg(Mtr)-OH
blir fremstilt analogt med eksempel 1, idet avspaltningen av sidekjede-beskyttelsesgruppene og peptidet fra harpikset ved hjelp av trifluoreddiksyrer ble innskrenket til 30 minutter ved romtemperatur. Under de slik valgte betingelsene foregår det bare en neglisjerbar avspaltning av Mtr-beskyttelses- is prepared analogously to example 1, in that the cleavage of the side chain protecting groups and the peptide from the resin by means of trifluoroacetic acids was limited to 30 minutes at room temperature. Under the conditions chosen in this way, only a negligible cleavage of the Mtr protective
gruppen ved arginin. De delvis deblokkerte peptidene ble adskilt og renset ved kromatografi på revers-fase-materiale. the group at arginine. The partially deblocked peptides were separated and purified by chromatography on reverse-phase material.
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+E) MS(FAB): 1506 (M+E)
26: H-(D)-Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg(Mtr)-0H 26: H-(D)-Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-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)-0H 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)
Peptidene i eksemplene 28 - 31 nedenfor ble fremstilt og renset analogt med eksemplene 25 - 27. The peptides in examples 28 - 31 below were prepared and purified analogously to examples 25 - 27.
Eksempel 28 Example 28
H-(D)-Arg-Arg(Mtr )-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH MS(FAB) : 1462 (M+H) H-(D)-Arg-Arg(Mtr )-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH MS(FAB) : 1462 (M+H)
Eksempel 29 Example 29
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D )-Tic-Pro-Arg(Mtr)-0H MS(FAB): 1462 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D )-Tic-Pro-Arg(Mtr)-OH MS(FAB): 1462 (M+H)
Eksempel 30 Example 30
H-(D)-Arg-Arg(Mtr )-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-OH MS(FAB) : 1453 (M+H) H-(D)-Arg-Arg(Mtr )-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-OH MS(FAB) : 1453 (M+H)
Eksempel 31 Example 31
H-(D)-Arg-Arg(Mtr)-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1502 (M+H) H-(D)-Arg-Arg(Mtr)-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1502 (M+H)
Eksempel 32 Example 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-(CH2)4-NH2.
Petidsyntesen foregår på 1 g aminometylharpiks, som er modifisert med en i EP-A 264 802 beskrevet ankergruppe av typen under anvendelse av Fmoc-aminosyre-OObt estere med en automatisk peptidsynthesizer (modell 430A til Fa. Applied Biosystems) og egne modifiserte synteseprogram. Hver gang ble 1 mMol av det tilsvarende aminosyrederivatet innveid i innsatsene til fabrikanten, samt Fmoc-Arg(Mtr)-0H, Fmoc-Eyp-OH og Fmoc-(D)-Tic-OH ble sammen med 0,95 mMol HOObt tilsatt i innsatsene. Den in situ-foraktiveringen av disse aminosyrene foregår direkte i innsatsene ved oppløsning i 4 ml DMF og tilsetning av 2 ml av en 0,55 M oppløsning av diisopropylkarbodiimid i DMF. HOObt-esterne til de andre aminosyrene ble løst opp i 6 ml NMP og deretter koblet som de in situ foraktiverte aminosyrene på det på forhånd med 2056 piperidin i DMF endeblokkerte harpikset, hvorved de in situ aktiverte aminosyrene ble koblet dobbelt. Etter avsluttet syntese ble peptidet 4-amino-butylamid avspaltet under samtidig fjerning av sidekjede-beskyttelsesgruppene med trifluoreddiksyre som inneholder tioanisol og m-kresol som kationfanger, fra harpikset. Etter uttrekning av trifluoreddiksyren ble den oppnådde resten flere ganger senket ned i eddikester og sentrifugert. Det gjenværende råpeptidet ble kromatografert på Sephadex G25 med IN eddiksyre. Fraksjonene som inneholdt rene peptider ble slått sammen og frysetørket. The peptide synthesis takes place on 1 g of aminomethyl resin, which is modified with an anchor group of the type described in EP-A 264 802 using Fmoc-amino acid-OObt esters with an automatic peptide synthesizer (model 430A from Fa. Applied Biosystems) and its own modified synthesis program. Each time, 1 mmol of the corresponding amino acid derivative was weighed into the inserts of the manufacturer, and Fmoc-Arg(Mtr)-OH, Fmoc-Eyp-OH and Fmoc-(D)-Tic-OH were added together with 0.95 mmol of HOObt in the stakes. The in situ preactivation of these amino acids takes place directly in the inserts by dissolving in 4 ml of DMF and adding 2 ml of a 0.55 M solution of diisopropylcarbodiimide in DMF. The HOObt esters of the other amino acids were dissolved in 6 ml of NMP and then coupled as the in situ preactivated amino acids on the resin previously end-blocked with 2056 piperidine in DMF, whereby the in situ activated amino acids were doubly coupled. After completion of the synthesis, the peptide 4-amino-butylamide was cleaved while simultaneously removing the side chain protecting groups with trifluoroacetic acid containing thioanisole and m-cresol as cation scavengers from the resin. After extraction of the trifluoroacetic acid, the obtained residue was immersed several times in acetic acid and centrifuged. The remaining crude peptide was chromatographed on Sephadex G25 with 1N acetic acid. The fractions containing pure peptides were pooled and freeze-dried.
Forbindelsene i eksemplene 33 - 35 ble fremstilt analogt med eksempel 32: Eksempel 33 The compounds in examples 33 - 35 were prepared analogously to example 32: Example 33
H-D-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-NH-(CE2)4-NE2H-D-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-NH-(CE2)4-NE2
Eksempel 34 Example 34
E00C-(C<H>2)2-C0-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-NH-(CH2)4-NH2E00C-(C<H>2)2-C0-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-NH-(CH2)4-NH2
Eksempel 35 Example 35
HOOC-( CH2 )2-CO-(D )-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-NH-(CH2)4-NH2: Eksemplene 36 til 161 ble syntetisert ifølge metoden beskrevet i eksempel 1. HOOC-( CH2 )2-CO-(D )-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-NH-(CH2)4-NH2: Examples 36 to 161 were synthesized according to the method described in example 1.
Eksempel 36 Example 36
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H)
Eksempel 37 Example 37
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H) H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H)
Eksempel 38 Example 38
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-OH MS(FAB) : 1241 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-OH MS(FAB) : 1241 (M+H)
Eksempel 39 Example 39
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-e-Ala-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1361 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-e-Ala-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1361 (M+H)
Eksempel 40 Example 40
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-p<->Ala-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1361 (M+H) H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-p<->Ala-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1361 (M+H)
Eksempel 41 Example 41
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-Arg-OH MS(FAB) : 1397 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Phe-Arg-OH MS(FAB) : 1397 (M+H)
Eksempel 42 Example 42
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Pro-Phe-Arg-OH MS(FAB) : 1397 (M+E) H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Pro-Phe-Arg-OH MS(FAB) : 1397 (M+E)
Eksempel 43 Example 43
E-(D)-Arg-Arg-Pro-Eyp-Gly-Thia-Gly-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1260 (M+E) E-(D)-Arg-Arg-Pro-Eyp-Gly-Thia-Gly-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1260 (M+E)
Eksempel 44 Example 44
E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Gly-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1260 (M+E) E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Gly-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1260 (M+E)
Eksempel 45 Example 45
E-(D)-Arg-(D)-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1290 (M+E) E-(D)-Arg-(D)-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1290 (M+E)
Eksempel 46 Example 46
E-(D)-Arg-(D)-Arg-Pro-Eyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1290 (M+E) E-(D)-Arg-(D)-Arg-Pro-Eyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1290 (M+E)
Eksempel 47 Example 47
E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Tic-Arg-OE MS(FAB) : 1312 (M+E) E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-Ser-(D)-Tic-Tic-Arg-OE MS(FAB) : 1312 (M+E)
Eksempel 48 Example 48
H-(D)-Arg-Arg-Pro-Eyp-Gly-Thia-Ser-(D)-Tic-Tic-Arg-OE MS(FAB) : 1312 (M+E) H-(D)-Arg-Arg-Pro-Eyp-Gly-Thia-Ser-(D)-Tic-Tic-Arg-OE MS(FAB) : 1312 (M+E)
Eksempel 49 Example 49
E-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1274 (M+E) E-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1274 (M+E)
Eksempel 50 Example 50
E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1203 (M+H) E-(D)-Arg-Arg-Eyp-Pro-Gly-Thia-(D)-Tic-Aoc-Arg-OE MS(FAB) : 1203 (M+H)
Eksempel 51 Example 51
H-(D)-Arg-Arg-Hyp-Pro-Gly-Aoc-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Aoc-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H)
Eksempel 52 Example 52
H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-P-Ala-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-P-Ala-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H)
Eksempel 53 Example 53
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-P-Ala-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H) H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-P-Ala-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H)
Eksempel 54 Example 54
H-(D)-Arg-Arg-Hyp-Pro-Gly-Asp-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1252 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Asp-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1252 (M+H)
Eksempel 55 Example 55
H-(D)-Arg-Arg-Pro-Hyp-Gly-Asp-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1252 (M+H) H-(D)-Arg-Arg-Pro-Hyp-Gly-Asp-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1252 (M+H)
Eksempel 56 Example 56
H-(D)-Arg-Arg-Hyp-Pro-Gly-Trp-Ser-(D)-Tlc-Aoc-Arg-OH MS(FAB) : 1323,7 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Trp-Ser-(D)-Tlc-Aoc-Arg-OH MS(FAB) : 1323.7 (M+H)
Eksempel 57 Example 57
H-(D)-Tyr-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1297,7 (M+H) H-(D)-Tyr-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1297.7 (M+H)
Eksempel 58 Example 58
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-(D)-Oic-Arg-OH MS(FAB) : 1304,6 (M+H) H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-(D)-Oic-Arg-OH MS(FAB) : 1304.6 (M+H)
Eksempel 59 Example 59
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1304,6 (M+H) H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1304.6 (M+H)
Eksempel 60 Example 60
H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-01c-Arg-0H MS(FAB) : 1289 (M+H) H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-O1c-Arg-OH MS(FAB) : 1289 (M+H)
Eksempel 61 Example 61
H-(D)-Arg-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tlc-Aoc-Arg-OH MS(FAB) : 1262 (M+H) H-(D)-Arg-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tlc-Aoc-Arg-OH MS(FAB) : 1262 (M+H)
Eksempel 62 Example 62
H-(D)-Arg-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1276 (M+H) H-(D)-Arg-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1276 (M+H)
Eksempel 63 Example 63
H-(D)-Arg-Lys-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1260 (M+H) H-(D)-Arg-Lys-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1260 (M+H)
Eksempel 64 Example 64
H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1298 (M+H) H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1298 (M+H)
Eksempel 65 Example 65
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1298 (M+H) H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1298 (M+H)
Eksempel 66 Example 66
H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1282 (M+H) H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1282 (M+H)
Eksempel 67 Example 67
H-(D)-Arg-Arg(N02 )-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1329,7 (M+H) H-(D)-Arg-Arg(NO2 )-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1329.7 (M+H)
Eksempel 68 Example 68
H-(D)-Arg-Arg(N02)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1343 (M+H) H-(D)-Arg-Arg(NO2)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1343 (M+H)
Eksempel 69 Example 69
H-(D)-Arg-Arg(N02)-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1327 (M+H) H-(D)-Arg-Arg(NO2)-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1327 (M+H)
Eksempel 70 Example 70
H-(D)-Arg-Arg(N02)-Pro-Pro-Gly-Thla-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1333 (M+H) H-(D)-Arg-Arg(NO2)-Pro-Pro-Gly-Thla-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1333 (M+H)
Eksempel 71 Example 71
H-(D)-Arg-Arg(N02)-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1349 (M+H) H-(D)-Arg-Arg(NO2)-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1349 (M+H)
Eksempel 72 Example 72
H-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH H-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) : 1302 (M+H) MS(FAB) : 1302 (M+H)
Eksempel 73 Example 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) : 1142 (M+H) MS(FAB) : 1142 (M+H)
Eksempel 74 Example 74
H-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1233 (M+H) H-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1233 (M+H)
Eksempel 75 Example 75
H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH
MS(FAB) : 1296 (M+H) MS(FAB) : 1296 (M+H)
Eksempel 76 Example 76
H-Lys(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1219 (M+H) H-Lys(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1219 (M+H)
Eksempel 77 Example 77
H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH
MS(FAB) : 1282 (M+H) MS(FAB) : 1282 (M+H)
Eksempel 78 Example 78
Ac-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1324 (M+H) Ac-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1324 (M+H)
Eksempel 79 Example 79
H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1438 (M+H) H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1438 (M+H)
Eksempel 80 Example 80
H-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1302 (M+H) H-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1302 (M+H)
Eksempel 81 Example 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)
Eksempel 82 Example 82
H-Lys(-CO-NH-C6H5)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1233 (M+H) H-Lys(-CO-NH-C6H5)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1233 (M+H)
Eksempel 83 Example 83
H-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1296 (M+H) H-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1296 (M+H)
Eksempel 84 Example 84
H-Lys(Nicotinoyl)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1219 (M+H) H-Lys(Nicotinoyl)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1219 (M+H)
Eksempel 85 Example 85
H-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1282 (M+H) H-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1282 (M+H)
Eksempel 86 Example 86
Ac-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1324 (M+H) Ac-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1324 (M+H)
Eksempel 87 Example 87
H-D-Arg-Arg(Tos )-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1438 (M+H) H-D-Arg-Arg(Tos )-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1438 (M+H)
Eksempel 88 Example 88
H-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1286 (M+H) H-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1286 (M+H)
Eksempel 89 Example 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)
Eksempel 90 Example 90
H-Lys(-CO-NH-C6H5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1217 (M+H) H-Lys(-CO-NH-C6H5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1217 (M+H)
Eksempel 91 Example 91
H-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1280 (M+H) H-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1280 (M+H)
Eksempel 92 Example 92
H-Lys(Nlcotinoyl )-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1203 (M+H) H-Lys(Nlcotinoyl )-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1203 (M+H)
Eksempel 93 Example 93
H-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1266 (M+H) H-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1266 (M+H)
Eksempel 94 Example 94
Ac-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tlc-Aoc-Arg-OH MS(FAB) : 1308 (M+H) Ac-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tlc-Aoc-Arg-OH MS(FAB) : 1308 (M+H)
Eksempel 95 Example 95
H-D-Arg-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1422 (M+H) H-D-Arg-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1422 (M+H)
Eksempel 96 Example 96
H-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH H-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) : 1148 (M+H) MS(FAB) : 1148 (M+H)
Eksempel 97 Example 97
H-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1239 (M+H) H-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1239 (M+H)
Eksempel 98 Example 98
H-Lys(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H) H-Lys(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H)
Eksempel 99 Example 99
H-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1288 (M+H) H-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1288 (M+H)
Eksempel 100 Example 100
Ac-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1330 (M+H) Ac-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1330 (M+H)
Eksempel 101 Example 101
H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1444 (M+H) H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1444 (M+H)
Eksempel 102 Example 102
H-Arg-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH H-Arg-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) : 1148 (M+H) MS(FAB) : 1148 (M+H)
Eksempel 103 Example 103
H-Lys(-CO-NH-C6H5)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1239 (M+H) H-Lys(-CO-NH-C6H5)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1239 (M+H)
Eksempel 104 Example 104
H-Lys(Nicotinoyl)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H) H-Lys(Nicotinoyl)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H)
Eksempel 105 Example 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) : 1288 (M+H) MS(FAB) : 1288 (M+H)
Eksempel 106 Example 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)
Eksempel 107 Example 107
H-D-Arg-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1440 (M+H) H-D-Arg-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1440 (M+H)
Eksempel 108 Example 108
H-Lys(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H) H-Lys(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H)
Eksempel 109 Example 109
H-Lys(Nicotinoyl )-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1209 (M+H) H-Lys(Nicotinoyl )-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1209 (M+H)
Eksempel 110 Example 110
H-Arg(Tos )-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH H-Arg(Tos )-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH
MS(FAB) : 1272 (M+H) MS(FAB) : 1272 (M+H)
Eksempel 111 Example 111
Ac-Arg(Tos )-Pro-Pro-Gly-Thla-Ser-D-Tic-Aoc-Arg-OH Ac-Arg(Tos )-Pro-Pro-Gly-Thla-Ser-D-Tic-Aoc-Arg-OH
MS(FAB) : 1314 (M+H) MS(FAB) : 1314 (M+H)
Eksempel 112 Example 112
H-D-Arg-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1428 (M+H) H-D-Arg-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1428 (M+H)
Eksempel 113 Example 113
H-D-Arg-Lys(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1365 (M+H) H-D-Arg-Lys(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1365 (M+H)
Eksempel 114 Example 114
H-D-Arg-Lys(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH H-D-Arg-Lys(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) : 1379 (M+H) MS(FAB) : 1379 (M+H)
Eksempel 115 Example 115
H-D-Arg-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1442 (M+H) H-D-Arg-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1442 (M+H)
Eksempel 116 Example 116
H-Lys-Lys-(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1337 (M+H) H-Lys-Lys-(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1337 (M+H)
Eksempel 117 Example 117
H-Lys-Lys(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1351 (M+H) H-Lys-Lys(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1351 (M+H)
Eksempel 118 Example 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)
Eksempel 119 Example 119
H-D-Arg-Lys(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1381 (M+H) H-D-Arg-Lys(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1381 (M+H)
Eksempel 120 Example 120
H-D-Arg-Lys-(C0-NH-C6H5)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-0H H-D-Arg-Lys-(C0-NH-C6H5)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) : 1395 (M+H) MS(FAB) : 1395 (M+H)
Eksempel 121 Example 121
H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1458 (M+H) H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1458 (M+H)
Eksempel 122 Example 122
H-Lys-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1367 (M+H) H-Lys-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1367 (M+H)
Eksempel 123 Example 123
H-Lys-Lys(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1353 (M+H) H-Lys-Lys(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1353 (M+H)
Eksempel 124 Example 124
H-Lys-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tlc-Oic-Arg-OH H-Lys-Arg(Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tlc-Oic-Arg-OH
MS(FAB) : 1430 (M+H) MS(FAB) : 1430 (M+H)
Eksempel 125 Example 125
H-D-Arg-Lys(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1359 (M+H) H-D-Arg-Lys(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1359 (M+H)
Eksempel 126 Example 126
H-D-Arg-Lys(-C0-NH-C6H5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1373 (M+H) H-D-Arg-Lys(-C0-NH-C6H5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1373 (M+H)
Eksempel 127 Example 127
H-D-Arg-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1436 (M+H) H-D-Arg-Arg(Tos )-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1436 (M+H)
Eksempel 128 Example 128
H-Lys-Lys(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1331 (M+H) H-Lys-Lys(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1331 (M+H)
Eksempel 129 Example 129
H-Lys-Lys(-C0-NH-C6H5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1345 (M+H) H-Lys-Lys(-C0-NH-C6H5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1345 (M+H)
Eksempel 130 Example 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)
Eksempel 131 Example 131
H-D-Arg-Lys(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1375 (M+H) H-D-Arg-Lys(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1375 (M+H)
Eksempel 132 Example 132
H-D-Arg-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1389 (M+H) H-D-Arg-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1389 (M+H)
Eksempel 133 Example 133
H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1452 (M+H) H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1452 (M+H)
Eksempel 134 Example 134
H-Lys-Lys(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1347 (M+H) H-Lys-Lys(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1347 (M+H)
Eksempel 135 Example 135
H-Lys-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1361 (M+H) H-Lys-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1361 (M+H)
Eksempel 136 Example 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)
Eksempel 137 Example 137
H-D-Arg-Orn(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1351 (M+H) H-D-Arg-Orn(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1351 (M+H)
Eksempel 138 Example 138
H-D-Arg-Orn(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH H-D-Arg-Orn(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) : 1428 (M+H) MS(FAB) : 1428 (M+H)
Eksempel 139 Example 139
H-Lys-Orn(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1323 (M+H) H-Lys-Orn(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1323 (M+H)
Eksempel 140 Example 140
H-Lys-Orn(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1337 (M+H) H-Lys-Orn(-CO-NH-C6H5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1337 (M+H)
Eksempel 141 Example 141
H-D-Arg-Orn(Nicotinoyl)-Pro-Eyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1367 (M+E) H-D-Arg-Orn(Nicotinoyl)-Pro-Eyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1367 (M+E)
Eksempel 142 Example 142
E-D-Arg-Orn(-CO-NH-C6E5)-Pro-Eyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OE E-D-Arg-Orn(-CO-NH-C6E5)-Pro-Eyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OE
MS(FAB) : 1381 (M+E) MS(FAB) : 1381 (M+E)
Eksempel 143 Example 143
E-Lys-Orn(Nicotinoyl)-Pro-Eyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1339 (M+E) E-Lys-Orn(Nicotinoyl)-Pro-Eyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1339 (M+E)
Eksempel 144 Example 144
E-Lys-Orn(-CO-NE-C6E5)-Pro-Eyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1353 (M+E) E-Lys-Orn(-CO-NE-C6E5)-Pro-Eyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1353 (M+E)
Eksempel 145 Example 145
E-D-Arg-Orn(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1345 (M+E) E-D-Arg-Orn(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1345 (M+E)
Eksempel 146 Example 146
E-D-Arg-Orn(-CO-NE-C6E5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1359 (M+E) E-D-Arg-Orn(-CO-NE-C6E5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1359 (M+E)
Eksempel 147 Example 147
E-Lys-Orn(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1317 (M+E) E-Lys-Orn(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1317 (M+E)
Eksempel 148 Example 148
E-Lys-0rn(-C0-NE-C6E5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1331 (M+E) E-Lys-0rn(-C0-NE-C6E5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1331 (M+E)
Eksempel 149 Example 149
E-D-Arg-Orn(Nicotinoyl)-Pro-Eyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1361 (M+E) E-D-Arg-Orn(Nicotinoyl)-Pro-Eyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OE MS(FAB) : 1361 (M+E)
Eksempel 150 Example 150
H-D-Arg-Orn(CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tlc-Oic-Arg-OH MS(FAB) : 1375 (M+H) H-D-Arg-Orn(CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tlc-Oic-Arg-OH MS(FAB) : 1375 (M+H)
Eksempel 151 Example 151
H-Lys-Orn(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1333 (M+H) H-Lys-Orn(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1333 (M+H)
Eksempel 152 Example 152
H-Lys-Orn(-CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1347 (M+H) H-Lys-Orn(-CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1347 (M+H)
Eksempel 153 Example 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)
Eksempel 154 Example 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)
Eksempel 155 Example 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)
Eksempel 156 Example 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)
Eksempel 157 Example 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)
Eksempel 158 Example 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)
Eksempel 159 Example 159
H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-01c-Arg-0H H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-01c-Arg-0H
MS(FAB) : 1248 (M+E) MS(FAB) : 1248 (M+E)
Eksempel 160 Example 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)
Eksempel 161 Example 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) : 1242 (M+H) MS(FAB) : 1242 (M+H)
Eksemplene 162 - 164 ble fremstilt som i eksempel 32 ved anvendelse av harpikset beskrevet i EP-A 322348 med struk-turen Examples 162 - 164 were prepared as in Example 32 using the resin described in EP-A 322348 with the structure
Eksempel 162 Example 162
H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-NHg MS(FAB) : 1283 (M+H) H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-NHg MS(FAB) : 1283 (M+H)
Eksempel 163 Example 163
H-D-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NHg MS(FAB) : 1283 (M+H) H-D-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NHg MS(FAB) : 1283 (M+H)
Eksempel 164 Example 164
H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH2 MS(FAB) : 1267 (M+H) H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH2 MS(FAB) : 1267 (M+H)
Nedenfor følger ICF5ø(M) verdiene i de angitte eksemplene: Below are the ICF5ø(M) values in the given examples:
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| NO893193D0 NO893193D0 (en) | 1989-08-08 |
| NO893193L NO893193L (en) | 1990-05-25 |
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| NO2008016C NO2008016I2 (en) | 1988-11-24 | 2008-10-30 | icatibant |
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| AU (1) | AU612054B2 (en) |
| CA (1) | CA1340667C (en) |
| CY (2) | CY2028A (en) |
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| WO1991009055A1 (en) * | 1989-12-08 | 1991-06-27 | Boston University | Acylated bradykinin antagonists and uses therefor |
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| WO1993017701A1 (en) * | 1992-03-12 | 1993-09-16 | The Administrators Of The Tulane Educational Fund | Endothelin receptor-binding peptides |
| TW258739B (en) * | 1992-04-04 | 1995-10-01 | Hoechst Ag | |
| FR2692581B1 (en) * | 1992-06-18 | 1994-08-19 | Adir | New peptide derivatives with bradykinin antagonist activity, their preparation process and the pharmaceutical compositions containing them. |
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| US6355613B1 (en) | 1996-07-31 | 2002-03-12 | Peptor Limited | Conformationally constrained backbone cyclized somatostatin analogs |
| DE19642289A1 (en) * | 1996-10-14 | 1998-04-16 | Hoechst Ag | Use of bradykinin antagonists for the manufacture of medicaments for the treatment and prevention of Alzheimer's disease |
| DE10304994A1 (en) * | 2003-02-07 | 2004-09-02 | Aventis Pharma Deutschland Gmbh | The use of antagonists of the bradykinin B2 receptor for the treatment of osteoarthrosis |
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| CN104043101B (en) * | 2014-05-23 | 2016-04-20 | 杭州阿德莱诺泰制药技术有限公司 | A kind of icatibant composition for injection and preparation method thereof and preparation |
| KR102099509B1 (en) | 2018-07-27 | 2020-04-09 | 강경순 | Supports for fruit trees |
| CN111944016B (en) * | 2020-08-25 | 2022-04-29 | 台州吉诺生物科技有限公司 | Preparation method of icatibant acetate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3044236A1 (en) * | 1980-11-25 | 1982-06-16 | Hoechst Ag, 6000 Frankfurt | AMINO ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| FR2487829A2 (en) * | 1979-12-07 | 1982-02-05 | Science Union & Cie | NOVEL SUBSTITUTED IMINO ACIDS, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS AN ENZYME INHIBITOR |
| DE3227055A1 (en) * | 1982-07-20 | 1984-01-26 | Hoechst Ag, 6230 Frankfurt | NEW DERIVATIVES OF 2-AZA-BICYCLO (2.2.2) OCTAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF, AND 2-AZA-BICYCLO (2.2.2) OCTAN-3-CARBONIC ACID AS ANSWER FOR THEIR PRODUCTION |
| FR2575753B1 (en) * | 1985-01-07 | 1987-02-20 | Adir | NOVEL PEPTIDE DERIVATIVES WITH NITROGEN POLYCYCLIC STRUCTURE, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| US4693993A (en) * | 1985-06-13 | 1987-09-15 | Stewart John M | Bradykinin antagonist peptides |
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