DK154653B - Fremgangsmaade til fremstilling af pentapeptidet h-arg-x-z-y-tyr-r ved oploesningssyntese - Google Patents
Fremgangsmaade til fremstilling af pentapeptidet h-arg-x-z-y-tyr-r ved oploesningssyntese Download PDFInfo
- Publication number
- DK154653B DK154653B DK415485A DK415485A DK154653B DK 154653 B DK154653 B DK 154653B DK 415485 A DK415485 A DK 415485A DK 415485 A DK415485 A DK 415485A DK 154653 B DK154653 B DK 154653B
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- DK
- Denmark
- Prior art keywords
- group
- carboxy
- fragment
- protected
- arg
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- 230000015572 biosynthetic process Effects 0.000 title claims description 8
- 238000003786 synthesis reaction Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 4
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 16
- -1 β-cyanoethyl Chemical group 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000012634 fragment Substances 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 229930064664 L-arginine Natural products 0.000 claims description 3
- 235000014852 L-arginine Nutrition 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- UOCJDOLVGGIYIQ-PBFPGSCMSA-N cefatrizine Chemical group S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC=1C=NNN=1 UOCJDOLVGGIYIQ-PBFPGSCMSA-N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000005023 xylyl group Chemical group 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims 4
- 230000003213 activating effect Effects 0.000 claims 3
- 150000001412 amines Chemical class 0.000 claims 2
- 150000002081 enamines Chemical class 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 150000001720 carbohydrates Chemical class 0.000 claims 1
- 235000014633 carbohydrates Nutrition 0.000 claims 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical group NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000010532 solid phase synthesis reaction Methods 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical group CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- PSWFFKRAVBDQEG-YGQNSOCVSA-N thymopentin Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PSWFFKRAVBDQEG-YGQNSOCVSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GTFDJMHTJNPQFS-UHFFFAOYSA-N 1-hydroxypiperidine-2,6-dione Chemical compound ON1C(=O)CCCC1=O GTFDJMHTJNPQFS-UHFFFAOYSA-N 0.000 description 1
- FQKFPGMGQXQHLP-UHFFFAOYSA-N 1-hydroxytriazole Chemical compound ON1C=CN=N1 FQKFPGMGQXQHLP-UHFFFAOYSA-N 0.000 description 1
- WSNDAYQNZRJGMJ-UHFFFAOYSA-N 2,2,2-trifluoroethanone Chemical compound FC(F)(F)[C]=O WSNDAYQNZRJGMJ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 102100037644 Kelch-like protein 41 Human genes 0.000 description 1
- 108050003242 Kelch-like protein 41 Proteins 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- VDEUYMSGMPQMIK-UHFFFAOYSA-N benzhydroxamic acid Chemical compound ONC(=O)C1=CC=CC=C1 VDEUYMSGMPQMIK-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- NPKKRSHVJIQBKU-UHFFFAOYSA-N ornogenin Natural products CC(OC(=O)C=Cc1ccccc1)C2(O)CCC3(O)C4(O)CC=C5CC(O)CCC5(C)C4CC(OC(=O)C=Cc6ccccc6)C23C NPKKRSHVJIQBKU-UHFFFAOYSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960004517 thymopentin Drugs 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0819—Tripeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/66—Thymopoietins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06086—Dipeptides with the first amino acid being basic
- C07K5/06095—Arg-amino acid
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Endocrinology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Compounds Of Unknown Constitution (AREA)
Description
Den foreliggende opfindelse angår en fremgangsmåde til frem¬stilling af pentapeptidet H-ARG-X-Z-Y-TYR-R, hvori X er LYS, ogY er VAL, eller X og Y begge er SAR, Z er ASP eller GLU, og Rer OH eller NH2, ved opløsningssyntese.
Beskrivelsen til USA-patentskrift nr. 4.190.646 og dansk pa¬tentansøgning nr. 1557/80, indleveret d. 11. april 1980, omhandlerforskellige peptider, der er nyttige på thymus-funktionelle og immu¬nologiske områder. Det nævnte patent omhandler “thymopoietin-pen- t tapeptidet" (TP5) og substituerede derivater deraf, hvorimod dennævnte ansøgning omhandler peptidanaloger af TP5, som har størrestyrke end TP5. I det nævnte patent og den nævnte ansøgning blevpeptiderne fremstillet ved fastfase-synteseteknikker, der i alminde¬lighed beskrives som "Merrifield-syntese". Patentet og ansøgningenomtaler også, at klassiske metoder (dvs. opløsnings-synteseteknik-ker) kan anvendes til fremstilling af visse af disse materialer, mender var ikke beskrevet nogen specifik klassisk metode eller syntese¬vej.
Mens fastfase-syntesemetoden "ifølge Merrifield er bekvem tilfremstilling af små mængder peptider i laboratorie-målestok, er denupraktisk og i almindelighed uøkonomisk til fremstilling af storemængder (fx. mere end ca. 100 g) peptid, hvor opløsnings-syntese-teknikken er mere hensigtsmæssig. Endvidere er opløsnings-syntese-metoder i almindelighed langt mindre kostbare end fastfase-metoderp.g.a de langt mindre enheds-omkostninger for visse af de anvendtereagenser. Blandt den store mængde af opløsnings-syntesemetoder,som er tilgængelige for anvendelse ved fremstilling af polypeptider,er der nu fundet bestemte syntesemetoder, som bekvemt og på øko¬nomisk måde giver det ønskede peptid i overraskende højt udbytte.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved de ikravets kendetegnende del anførte træk.
Den alfa-aminobeskyttende gruppe T kan være den samme ellerforskellig for hver af de ovenfor nævnte aminosyrer og bør værestabil mod fjernelse ved de til sammenbinding af aminosyregrupperneanvendte trin samtidig med, at den let skal kunne fjernes ved afslut¬ningen af de forbindende trin under betingelser, som ikke vil spaltenogen af peptidets amid-bindinger. For nogle grupper (fx. BOC)forårsages denne fjernelse af stærk syre (fx. trifluoreddikesyre),hvilket resulterer i et ubeskyttet mellemprodukt, der opnås som dettilsvarende syreadditionssalt (fx. som trifluoracetat).
Den guanidinobeskyttende gruppe T1 kan være en hvilken somhelst passende aminobeskyttende gruppe, som nedenfor beskrevet,eller en nitrogruppe samt syreadditionssalte såsom hydrochloridet.Blandt de aminobeskyttende grupper foretrækkes urethan-beskytten-de grupper (formel a) nedenfor) og substituerede syrederivater så¬som p-methoxybenzensulfonyl og tosyl. Hydrochlorid-saltet foretræk¬kes mest. Denne guanidinobeskyttende gruppe er heri kaldt "omega"-gruppe for at indikere, at den befinder sig ved kædens ende. Dennøjagtige position af mange guanidino-beskyttende grupper på kæ¬den kendes ikke med sikkerhed.
Selvfølgelig skal, hvis X er LYS, dens epsilon-aminogruppe og¬så være passende beskyttet af den amino-beskyttende gruppe T"under fremstilling af fragmenter, som indeholder X, og deres an¬vendelse til fremstilling af slutprodukt-peptidet. T"-gruppen må letkunne fjernes under betingelser, som ikke vil ødelægge det resulte¬rende peptid samtidig med, at den bør være stabil under fjernelsenof T-grupperne.
Den carboxy-beskyttende gruppe U bør let kunne fjernes un¬der betingelser, som ikke vil ødelægge det resulterende peptid sam¬tidig med, at den er stabil under fjernelsen af T-grupperne.
R'-gruppen er enten NH^ (for produkt-peptider, hvor R erNHg) eller OU (for produkt-peptider, hvor R er OH).
Eksempler på egnede amino-beskyttende grupper er sådanne med formlen:
hvori R^ betegner aryl, phenyl, tolyl, xylyl, adamantyl, allyl, β-cyanoethyl, fluorenylmethyl, benzyl,benzyl, hvori phenylringen er subsitueret med fra 1-3substituenter udvalgt blandt halogen, nitro, lavere al kylog lavere alkoxy, diisopropylmethyl, diphenylmethyl,cyclohexyl, cyclopentyl, vinyl, t-butyl, t-amyl, dimethyl-trifluormethylmethyl eller dimethylbiphenylmethyl,
, hvori R^ betegner lavere al kyl med 2-4 carbonatomersåsom ethyl, isopropyl og t-butyl eller lavere alkyl med1-4 carbonatomer substitueret med fra 1-5 halogengruppersåsom trifluormethyl, chlormethyl og pentachlorethyl,
hvori V betegner S eller O, og R^ og R^ hver be- tegner benzyl eller lavere alkyl,
d) hvori Rg og Rg hver for sig betegner lavere al kyl eller tilsammen betyder hvori R7 og Rg hver for sig betegner hydrogeneller lavere al kyl, og
hvori Rg betegner hydrogen eller nitro, og hvori R^g er hydrogen, methyl, halogen ellernitro.
Den amino-beskyttende gruppe f), som er bidentat, kan aleneanvendes for α-aminogrupperne i L-arginin eller L-valin eller a-amino-og epsilon-aminogrupperne i L-lysin, men ikke for α-aminogruppen isarcosin. Den amino-beskyttende gruppe på sarcosinets a-aminogruppeskal være monodentat p.g.a. methylsubstituenten på denne aminogrup-pe. De øvrige amino-beskyttende grupper kan anvendes pi alle amino¬syrer.
Som her anvendt, omfatter "halogen" fluor, chlor, brom og iod,men chlor og brom foretrækkes. Udtrykkene "lavere al kyl" og "laverealkoxy" omfatter hhv. mættede alifatiske carbonhydrider med 1-6carbonatomer såsom methyl, ethyl, isopropyl, t-butyl og n-hexylog de tilsvarende alkoxygrupper såsom methoxy, ethoxy, isopropoxy,t-butoxy og n-hexoxy. Methyl er den foretrukne lavere al kyl ogmethoxy er den foretrukne lavere alkoxy.
De til indføring af disse beskyttende grupper anvendte reagen¬ser (sædvanligvis de tilsvarende syrechlorider, selvom andre deriva¬ter kan anvendes), omtales under tiden her som "beskyttelsesgruppe¬reagenser". Andre egnede beskyttende grupper er omhandlet i fx."Protective Groups in Organic Chemistry", J.F.W. McOmie, ed.,
Plenum Press, N.V., 1973.
Det foretrækkes, at hvert T og T" er ens, og at de er benzyl-oxycarboxy (CBZ) eller trifluoracetyl (TFA). Det foretrækkes, atΤ' er hydrochloridsaltet.
En lang række forskellige reagenser kan anvendes til fremstil¬ling af de ovenfor beskrevne carboxy-aktiverede beskyttede amino-syrerester.
En type carboxy-aktiveret beskyttet aminosyrerest er en reaktivester. Eksempler pi midler, som kan anvendes til fremstilling af egne¬de aktive estere er phenol, phenol hvori phenylringen er substitueretmed 1-5 substituenter udvalgt blandt halogen, (fx. chlor eller fluor),nitro, cyano og methoxy, thiophenyl, N-hydroxyphthalimid, N-hydro-xysuccinimid, N-hydroxyglutarimid, N-hydroxybenzamid og 1-hydroxy-triazol. Andre egnede midler er fx. omhandlet i "Protective Groupsin Organic Chemistry", J.F.W. McOmie, ed., omtalt ovenfor. De ne¬denfor givne udførelseseksempler anvender almindeligvis N-hydroxy-succinimid eller 1-hydroxybenzotriazoI.
Andre aktiveringsmetoder, såsom den blandede eller symmetriskeanhydrid-metode, syrechlorid-metoden og azid-metoden er velkendteinden for denne teknik og beskrevet i fx. Bodanszky, et al., "Peptide Synthesis", 2. udgave, 1976, pp 85-128. Disse andre metoderkan også anvendes.
For bekvemmelighedens skyjd anvendes følgende forkortelser heri,som refererer til de forskellige aminosyrer:
Aminosyre Forkortelse
L-lysin LYS
L-valin VAL
L-tyrosin TYR
L-asparaginsyre ASP
L-glutaminsyre GLU
Sarcosin SAR
L-arginin ARG
Fremgangsmåden ifølge opfindelsen er vist skematisk i neden¬stående skema:
I ovenstående skema har de beskyttende grupper U, T, Τ' ogT" de ovenfor omtalte betydninger. Carboxy-aktiveringen af amino-syreresterne er angivet ved bogstaverne OA.
Isoleringen og rensningen af det resulterende urene produktkan udføres ved en kombination af krystallisation og ionbytnings-kro¬matografi (fortrinsvis under anvendelse af ammoniumacetat-pH5 somelueringsmiddel) under anvendelse af tyndtlags-kromatografi for atbestemme identiteten af materialerne i hver fraktion. Også andreisolerings- og rensningsmetoder end de i eksemplet angivne vil kun¬ne anvendes.
Fremgangsmåden ifølge opfindelsen illustreres nærmere i det ef¬terfølgende eksempel.
Fremstilling af Arg-Lys-Asp-Val-Tyr
Boc(Cbz)sLysONp (2,51 g, 5,00 mmol) opløstes i 4,2 M HCI*di-oxan (15 ml) og omrørtes i 45 min. Derefter inddampede reaktions¬blandingen i vacuum og sønderdeltes i Et^O til dannelse af HCI*(Cbz)-sLysONp som et farveløst fast stof, betegnet 4833-16A.
Til en omrørt opløsning af (Cbz)3Arg (2,25 g, 3,90 mmol) i THF(10 ml) ved -15°C sattes N-methylmorpholin (0,45 ml, 1,1 ækv.) ef¬terfulgt af iBuOCOCI (0,52 ml, 1,02 ækv.). Den resulterende op¬slæmning omrørtes i 15 min., og det pulverformige faste stof beteg¬net 4833-16A (1,71 g, 1,00 ækv.) tilsattes efterfulgt af n-methyl¬morpholin (0,45 ml). Et gelatinøst faststof dannedes næsten med detsamme. Efter 30 min. ved -10°C til -15°C inddampedes reaktions¬blandingen i vacuum ved 30°C. Den faste remanens opslæmmedes i10% citronsyre, filtreredes, vaskedes med H O og lufttørredes. Om- 4 krystallisation fra EtOAc gav (Cbz)3Arg (Cbz)eLysONp·^ H^O somet farveløst faststof betegnet 4833-16 RC, smp. 133-136°C, 3,35 g, 89%.
NMR, IR: AR 1552-84 CHN: AR 1624-84Beregnet % C 61,03 H 5,70 N 9,96Fundet % C 61,03 H 5,63 N 10,09
Til en omrørt opløsning af (Cbz)3Arg-(Cbz)sLys-ONp (4833-16RC, 1,92 g, 2,00 mmol), HCKBzl)pAsp-Val-Tyr-Bzl (DKE 3648-146, 1,22 g, 1,0 ækv. (fremstillet ved behandling af tripeptidet med enopløsning af HCI-gas i eddikesyre)) og 1-hydroxybenzotriazol (0,27 g, 1,0 ækv.) i DMF (10 ml) ved stuetemperatur sattes N-methylmorpholin(0,24 ml, 1,1 ækv.) Efter 4 timer var et tykt bundfald dannet. Det¬te omrørtes med mættet NaHCO^-opIøsning (25 ml). Det faste stoffrafiltreredes og vaskedes med mættet NaHCO^-opløsning, H^O, 10%citronsyre, H^O og Bt^O. Sønderdeling i varm 1% HOAc/EtAOc ogfiltrering gav (Cbz)3-Arg-(Cbz)eLys-(Bzl)pAsp“Val-TyrBzl*~H20,betegnet 4833-17 som et farveløst fast stof, smp. 201-203°C, 2,67 g, 96%.
CHN: AR 1616-84
Beregnet: % C 64,12 H 6,23 N 8,85Fundet % C 64,08 H 6,17 N 8,91
Hvis enhederne i pentapeptidet nummereres som følger:
Arg-Lys-Asp-Val-Tyr1 2 3 4 5 kan fremgangsmåden ifølge opfindelsen illustreres som følger:
medens den konventionelle såkaldte "4 + 1-metode" til opløsningssyn¬tese af peptider kan illustreres som følger:
»
Som det fremgår af de ovenfor anførte data, giver 112+3" kob¬lingen ifølge opfindelsen et udbytte på 96%. Efter fjernelse af de be¬skyttende grupper og rensning af produktet er det resulterende ud¬bytte ca. 85%. Efter fremstilling af pentapeptidet er det samlede ud¬bytte ca. 70%. Til sammenligning giver den kendte "4+1 -metode" kunet udbytte på 23% i det sidste trin.
Claims (1)
- Fremgangsmåde til fremstilling af pentapeptidet H-ARG-X-Z-Y-TYR-R, hvori X er LYS, og Y er VAL, eller X og Y begge er SAR,Z er ASP eller GLU, og R er OH eller NHg, ved opløsningssyntese,KENDETEGNET ved, at man a) danner fragment I, som består af H-Y-TYR-R', hvori R1 erOU eller NH2, ved i) beskyttelse af a-aminogruppen af Y-aminosyren ved atlade den reagere med et reagens, som vil indføre den be¬skyttende gruppe T, ii) aktivering af den i trin i) dannede, beskyttede Y medhensyn til nukleofilt angreb ved carboxygruppen af enamin, til dannelse af en carboxy-aktiveret, beskyttet Y-aminosyre, iii) omsætning af den carboxy-aktiverede beskyttede Y medTYR-R', og iv) fjernelse af den beskyttende gruppe T, b) danner fragment IV, som består af alfa-T-omega-U-Z-Y-TYR-R1, ved i) beskyttelse af alfa-amino- og omega-carboxygrupperne afZ-aminosyren ved at lade den reagere med reagenser, somvil indføre de beskyttende grupper T og U, ii) aktivering af den i trin i) dannede, beskyttede Z med hen¬syn til nukleofilt angreb ved alfa-carboxygruppen af enamin, til dannelse af en carboxy-aktiveret, beskyttet Z-aminosyre, og iii) omsætning af den carboxy-aktiverede, beskyttede Z-amino-syre med fragment I, c) danner fragment IVA, som består af H-omega-U-Z-Y-TYR-R',ved fjernelse af den beskyttende gruppe T fra fragment IV, d) danner fragment V, som består af alfa-T-omega-T'-ARG-epsilon-T"-X-OH, ved i)’ beskyttelse af alfa-aminogruppen og guanidinogruppen afL-argininen ved at lade den reagere med reagenser, somvil indføre de beskyttende grupper T og T1, H) aktivering af den i trin i) dannede, beskyttede ARG medhensyn til nukleofilt angreb ved alfa-carboxygruppen afen amin, til dannelse af en carboxy-akti veret, beskyttetARG, og iii) omsætning af den carboxy-aktiverede, beskyttede ARG med X-aminosyre (beskyttet på epsilon-aminogruppen., hvorX er LYS), e) aktiverer X-aminosyreresten af fragment V med hensyn tilnukleofilt angreb ved carboxygruppen af en amin, til dannelse af etcarboxy-aktiveret fragment V, f) lader det i trin e) dannede, carboxy-aktiverede fragment Vreagere med det i trin c) dannede fragment IVA til dannelse af alfa-T-omega-T,-ARG-epsilon-Ti,-X-omega-U-Z-Y-TYR-R,, g) fjerner U, T, Τ' og T" grupperne til dannelse af peptidetH-ARG-X-Z-Y-TYR-R, og h) isolerer og renser det resulterende peptid, hvori T* og, nårX er LYS, T" hver er en gnuppe udvalgt fra gruppen bestående af a)hvori R^ betegner phenyl, tolyl, xylyl, adaman-tyl, allyl, β-cyanoethyl, fluorenylmethyl, benzyl, benzyl,hvori phenylringen er substitueret med fra 1-3 substituen-ter udvalgt blandt halogen, nitro, lavere al kyl og laverealkoxy, diisopropyilmethyl, diphenylmethyl, cyclohexyl,cyclopentyl, vinyl, t-butyl, t-amyl, dimethyltrifluorme-thylmethyl eller dimethylbiphénylmethyl, b)hvori Rg betegner lavere al kyl med 2-4 carborrato-mer eller lavere al kyl med 1-4 carbonatomer substitueretmed fra 1-5 halogengrupper, c)hvori V betegner S eller O, og R3 og R^ hver be¬tegner benzyl eller lavere al kyl, d) hvori R._ og R- hver for sig betegner lavereo b al kyl eller tilsammen betyderhvori Ry og Rg hver for sig betegner hydrogeneller lavere al kyl,e) hvori Rg betegner hydrogen eller nitro, ogf) hvori R1g betegner hydrogen, methyl, halogen eller nitro, under den forudsætning, at T er monodentat, når X og Y er SAR,og T“ er hydrogen, når X er SAR, og U er benzyl eller benzyl,hvori phenylgruppen er substitueret med fra 1-3 substituenter hverudvalgt blandt halogen, nitro, C^_galkyl og C^_galkoxy, og Τ' er en gruppe udvalgt blandt, hvori R^ er som defineret ovenfor, nitro, hydrochlorid, p-methoxybenzylsulfonyl og tosyl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/160,241 US4298523A (en) | 1980-06-17 | 1980-06-17 | Methods and compositions for preparation of H-ARG-X-Z-Y-TYR-R |
| US16024180 | 1980-06-17 | ||
| DK263781 | 1981-06-16 | ||
| DK263781A DK151968C (da) | 1980-06-17 | 1981-06-16 | Fremgangsmaade til fremstilling af pentapeptidet h-arg-x-asp-y-tyr-r ved oploesningssyntese |
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| DK415485D0 DK415485D0 (da) | 1985-09-12 |
| DK415485A DK415485A (da) | 1985-09-12 |
| DK154653B true DK154653B (da) | 1988-12-05 |
| DK154653C DK154653C (da) | 1989-05-01 |
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| DK263781A DK151968C (da) | 1980-06-17 | 1981-06-16 | Fremgangsmaade til fremstilling af pentapeptidet h-arg-x-asp-y-tyr-r ved oploesningssyntese |
| DK415485A DK154653C (da) | 1980-06-17 | 1985-09-12 | Fremgangsmaade til fremstilling af pentapeptidet h-arg-x-z-y-tyr-r ved oploesningssyntese |
| DK227787A DK154437C (da) | 1980-06-17 | 1987-05-04 | Fremgangsmaade til fremstilling af pentapeptidet h-arg-x-z-y-tyr-r ved oploesningssyntese |
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| DK263781A DK151968C (da) | 1980-06-17 | 1981-06-16 | Fremgangsmaade til fremstilling af pentapeptidet h-arg-x-asp-y-tyr-r ved oploesningssyntese |
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| EP (3) | EP0042291B1 (da) |
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| AT (2) | ATE24183T1 (da) |
| AU (3) | AU562807B2 (da) |
| CA (6) | CA1188297A (da) |
| DE (2) | DE3177306T2 (da) |
| DK (3) | DK151968C (da) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4369137A (en) * | 1980-06-17 | 1983-01-18 | Ortho Pharmaceutical Corporation | N-Protected pentapeptides useful as intermediates in the preparation of thymopoietin pentapeptide |
| US4499079A (en) * | 1982-11-18 | 1985-02-12 | E. R. Squibb & Sons, Inc. | Carboxy and substituted carboxy alkanoyl and cycloalkanoyl peptides |
| DE3401545A1 (de) * | 1983-08-03 | 1985-02-14 | Hoechst Ag, 6230 Frankfurt | Neue peptide mit immunstimulierender wirkung, verfahren zu deren herstellung und deren verwendung |
| US4505853A (en) * | 1983-11-18 | 1985-03-19 | Ortho Pharmaceutical Corporation | Enzyme-resistant immunomodulatory peptides |
| AU602483B2 (en) * | 1985-01-18 | 1990-10-18 | Immunetech Pharmaceuticals | Immunoregulatory peptides |
| US4749690A (en) * | 1986-01-27 | 1988-06-07 | Ortho Pharmaceutical Corporation | Treatment of allergy with thymopentin |
| US4732970A (en) * | 1986-06-13 | 1988-03-22 | American Cyanamid Company | Antitumor amino acid and peptide derivatives of 1,4-bis(aminoalkyl and hydroxy-aminoalkyl)amino)-5,8-dihydroxyanthraquinones |
| US5200506A (en) * | 1987-03-19 | 1993-04-06 | Eniricerche S.P.A. | Process for preparing new thymopentin retro-inverso analogs and fragments thereof and the intermediates obtained therein |
| US5656601A (en) * | 1987-06-19 | 1997-08-12 | Berlin-Chemie Ag | Acylated splenopentins, methods for their synthesis and their use |
| HU199878B (en) * | 1987-06-19 | 1990-03-28 | Berlin Chemie Veb | Process for producing acylated splenopentynes and pharmaceutical compositions comprising such compounds as active ingredient |
| FR2622587B1 (fr) * | 1987-10-30 | 1990-12-21 | Inst Vaisseaux Sang | Peptide lysyl-arginyl-aspartyl-serine et ses applications en tant que medicament, notamment antithrombotique |
| NZ229004A (en) * | 1988-05-19 | 1993-09-27 | Immunobiology Res Inst Inc | Tetrapeptides having t cell helper acitivity |
| JPH01264767A (ja) * | 1988-11-17 | 1989-10-23 | G N Tool Kk | 砥石自動交換ｃｎｃ工具研削盤 |
| CN101168560B (zh) * | 2006-10-23 | 2012-09-05 | 江苏正大天晴药业股份有限公司 | N-取代肽酰胺，其药物组合物与用途 |
| JP5647146B2 (ja) | 2008-12-29 | 2014-12-24 | トレベナ・インコーポレイテッドＴｒｅｖｅｎａ， Ｉｎｃ． | β−アレスチンエフェクターおよび組成物およびその使用方法 |
| JP2017506235A (ja) | 2014-02-07 | 2017-03-02 | トレベナ・インコーポレイテッドＴｒｅｖｅｎａ， Ｉｎｃ． | ベータ−アレスチンエフェクターの結晶性および非晶質形態 |
| CA2948858A1 (en) | 2014-05-19 | 2015-11-26 | Trevena, Inc. | Synthesis of beta-arrestin effectors |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3317559A (en) * | 1963-08-23 | 1967-05-02 | American Cyanamid Co | alpha-amino acid esters of n-hydroxysuccinimide and preparation and use in peptide synthesis |
| DE1593830A1 (de) * | 1967-05-24 | 1971-03-11 | Akad Wissenschaften Ddr | Verfahren zur Herstellung von Peptiden |
| US3560503A (en) * | 1968-09-18 | 1971-02-02 | Council Scient Ind Res | Di-lower alkyl-substituted octahydropyrazinopyrimidinones |
| JPS4826010B1 (da) * | 1969-11-11 | 1973-08-03 | ||
| CH611878A5 (da) * | 1974-07-04 | 1979-06-29 | Takeda Chemical Industries Ltd | |
| DE2544348C3 (de) * | 1975-10-03 | 1979-12-13 | Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V., 3400 Goettingen | L-Leucin-13-Motilin, Verfahren zu dessen Herstellung und dasselbe enthaltendes Mittel |
| US4190646A (en) * | 1975-11-11 | 1980-02-26 | Sloan-Kettering Institute For Cancer Research | Polypeptide compositions and methods |
| SE446867B (sv) * | 1977-11-15 | 1986-10-13 | Sloan Kettering Inst Cancer | Sett att framstella en polypeptid med formaga att inducera differentiering av t-lymfocyter men inte av komplementreceptor (cr?72+) b-lymfocyter |
| US4215112A (en) * | 1979-03-14 | 1980-07-29 | Ortho Pharmaceutical Corporation | Tripeptides and methods |
| US4215111A (en) * | 1979-03-14 | 1980-07-29 | Ortho Pharmaceutical Corporation | Peptides having ubiquitin-like activity |
| CA1156220A (en) * | 1979-04-26 | 1983-11-01 | George Heavner | Method and composition for preparation of h-sar-lys-sar-gln-nh.sub.2 |
| DE2938420A1 (de) * | 1979-09-22 | 1981-04-09 | Hoechst Ag, 6000 Frankfurt | Neue peptide und verfahren zu ihrer herstellung |
| US4309340A (en) * | 1980-03-31 | 1982-01-05 | American Home Products Corporation | Polypeptide compositions |
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1980
- 1980-06-17 US US06/160,241 patent/US4298523A/en not_active Expired - Lifetime
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1981
- 1981-06-03 NZ NZ197294A patent/NZ197294A/en unknown
- 1981-06-08 CA CA000379207A patent/CA1188297A/en not_active Expired
- 1981-06-12 GR GR65234A patent/GR74546B/el unknown
- 1981-06-12 ES ES503012A patent/ES8207513A1/es not_active Expired
- 1981-06-16 EP EP81302685A patent/EP0042291B1/en not_active Expired
- 1981-06-16 DK DK263781A patent/DK151968C/da not_active IP Right Cessation
- 1981-06-16 IL IL72392A patent/IL72392A/xx unknown
- 1981-06-16 ZA ZA814061A patent/ZA814061B/xx unknown
- 1981-06-16 FI FI811883A patent/FI79329C/fi not_active IP Right Cessation
- 1981-06-16 IE IE940518A patent/IE940518L/xx unknown
- 1981-06-16 IE IE133681A patent/IE62213B1/en not_active IP Right Cessation
- 1981-06-16 JP JP9163881A patent/JPS5728036A/ja active Granted
- 1981-06-16 NO NO812035A patent/NO161744C/no unknown
- 1981-06-16 EP EP93200564A patent/EP0565148A2/en not_active Withdrawn
- 1981-06-16 PT PT73201A patent/PT73201B/pt not_active IP Right Cessation
- 1981-06-16 IL IL63108A patent/IL63108A/xx not_active IP Right Cessation
- 1981-06-16 DE DE3177306T patent/DE3177306T2/de not_active Expired - Fee Related
- 1981-06-16 AT AT81302685T patent/ATE24183T1/de active
- 1981-06-16 DE DE8181302685T patent/DE3175701D1/de not_active Expired
- 1981-06-16 EP EP84201633A patent/EP0144103B1/en not_active Expired - Lifetime
- 1981-06-16 IL IL72393A patent/IL72393A/xx unknown
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- 1981-06-17 YU YU152881A patent/YU45852B/sh unknown
- 1981-06-17 PH PH25768A patent/PH16501A/en unknown
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1982
- 1982-05-31 ES ES512721A patent/ES8303298A1/es not_active Expired
- 1982-05-31 ES ES512722A patent/ES8304541A1/es not_active Expired
- 1982-12-03 PH PH28221A patent/PH21622A/en unknown
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1984
- 1984-07-12 IL IL72394A patent/IL72394A0/xx unknown
- 1984-07-12 IL IL72392A patent/IL72392A0/xx unknown
- 1984-07-12 IL IL72393A patent/IL72393A0/xx unknown
- 1984-08-31 CA CA000462320A patent/CA1282550C/en not_active Expired - Lifetime
- 1984-08-31 CA CA000462321A patent/CA1285099C/en not_active Expired - Lifetime
- 1984-11-12 AT AT84201633T patent/ATE99327T1/de not_active IP Right Cessation
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1985
- 1985-07-31 AU AU45666/85A patent/AU562807B2/en not_active Ceased
- 1985-07-31 AU AU45667/85A patent/AU562808B2/en not_active Ceased
- 1985-07-31 AU AU45668/85A patent/AU563303B2/en not_active Ceased
- 1985-09-12 DK DK415485A patent/DK154653C/da not_active IP Right Cessation
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1987
- 1987-05-04 DK DK227787A patent/DK154437C/da not_active IP Right Cessation
-
1988
- 1988-06-08 IE IE172088A patent/IE62614B1/en not_active IP Right Cessation
- 1988-12-20 NO NO885646A patent/NO164245C/no unknown
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1989
- 1989-04-17 JP JP1095437A patent/JPH01308297A/ja active Granted
- 1989-04-17 JP JP1095438A patent/JPH01308298A/ja active Granted
- 1989-07-12 CA CA000605518A patent/CA1315042C/en not_active Expired - Fee Related
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- 1989-07-12 CA CA000605516A patent/CA1315040C/en not_active Expired - Fee Related
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1990
- 1990-01-22 NO NO900294A patent/NO166532C/no unknown
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| PBP | Patent lapsed |