SI21800A - Nov postopek sinteze perindoprila - Google Patents
Nov postopek sinteze perindoprila Download PDFInfo
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- SI21800A SI21800A SI200400143A SI200400143A SI21800A SI 21800 A SI21800 A SI 21800A SI 200400143 A SI200400143 A SI 200400143A SI 200400143 A SI200400143 A SI 200400143A SI 21800 A SI21800 A SI 21800A
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- perindopril
- chloride
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- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 15
- 229960002582 perindopril Drugs 0.000 title claims description 18
- 230000015572 biosynthetic process Effects 0.000 title abstract description 12
- 238000003786 synthesis reaction Methods 0.000 title abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- -1 N-butyl Chemical group 0.000 claims description 10
- 229960003767 alanine Drugs 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- CQYBNXGHMBNGCG-FXQIFTODSA-N (2s,3as,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indol-1-ium-2-carboxylate Chemical compound C1CCC[C@@H]2[NH2+][C@H](C(=O)[O-])C[C@@H]21 CQYBNXGHMBNGCG-FXQIFTODSA-N 0.000 claims description 5
- 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 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- AWGBKZRMLNVLAF-UHFFFAOYSA-N 3,5-dibromo-n,2-dihydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=CC(Br)=C1O AWGBKZRMLNVLAF-UHFFFAOYSA-N 0.000 claims 1
- 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 class 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 claims 1
- 238000006664 bond formation reaction Methods 0.000 claims 1
- 150000001805 chlorine compounds Chemical class 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000005541 ACE inhibitor Substances 0.000 abstract 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 4
- 229940086542 triethylamine Drugs 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- AMDDRMIFTJHJGD-WDSKDSINSA-N (2s)-2-[[(1s)-1-carboxyethyl]amino]pentanoic acid Chemical compound CCC[C@@H](C(O)=O)N[C@@H](C)C(O)=O AMDDRMIFTJHJGD-WDSKDSINSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- IYNMDWMQHSMDDE-MHXJNQAMSA-N perindopril erbumine Chemical compound CC(C)(C)N.C1CCC[C@@H]2N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H](C(O)=O)C[C@@H]21 IYNMDWMQHSMDDE-MHXJNQAMSA-N 0.000 description 2
- 229960003929 perindopril erbumine Drugs 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 150000008534 L-alanines Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- ARGCRCXTJMQKNA-KKUMJFAQSA-N benzyl (2s,3as,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indole-2-carboxylate Chemical compound O=C([C@H]1N[C@H]2CCCC[C@H]2C1)OCC1=CC=CC=C1 ARGCRCXTJMQKNA-KKUMJFAQSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- QHCCDDQKNUYGNC-UHFFFAOYSA-N n-ethylbutan-1-amine Chemical compound CCCCNCC QHCCDDQKNUYGNC-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Predlozeni izum se nanasa na nov postopek priprave ACE inhibitorja (2S, 3aS, 7aS)-1-((2S)-2-(((1S)-1-(etoksikarbonil) butil) amino)-1-oksopropil) oktahidro-1H-indol-2-karboksilne kisline in njenih farmacevtsko sprejemljivih soli ter na nov intermediat za omenjeno sintezo.
Description
Nov postopek sinteze perindoprila
Tehnično področje, v katero spada izum
Predloženi izum spada na področje organske kemije in se nanaša na nov postopek sinteze perindoprila in intermediata, ki ga uporabljamo pri njegovi sintezi.
Perindopril, prednostno njegova /-butilaminska sol, je spojina z ACE inhibitomim delovanjem.
Tehnični problem
Obstajala je potreba po izboljšanem, v industrijskem merilu uporabnem postopku, ki bi za sintezo perindoprila uporabljal N-((S)-l-karbetoksibutil)-L-alanin v obliki klorida in s katerim bi dosegali visoke izkoristke in visoko stopnjo čistosti končnega proizvoda, brez nezaželenih stranskih produktov.
Stanje tehnike
Perindopril, s kemijskim imenom (2S,3aS,7aS)-l-((2S)-2-(((lS)-l-(etoksikarbonil) butil) amino)-l-oksopropil)oktahidro-l//-indol-2-karboksilna kislina, je opisan v EP 49658. Sinteza je večstopenjska in vključuje ločevanje izomer s kolonsko kromatografijo. EP 308341 opisuje izboljšano sintezo perindoprila v obliki Z-butilaminske soli v industrijskem merilu. Reakcija poteka med p-toluensulfonsko soljo benzilnega estra (2S, 3aS, 7aS)-oktahidroindol2-karboksilne kisline in N-((S)-l-karbetoksibutil)-L-alaninom v prisotnosti trietil amina, N,Ndicikloheksilkarbodiimida ter 1-hidroksibenztriazola. Po končani reakciji dobijo benzilni ester perindoprila, ki ga reducirajo, liofilizirajo in nato s /-butilaminom v etilacetatu pretvorijo v sol.
Za zmanjšanje nastajanja stranskih produktov reakcije med benzilnim estrom perindoprila in Ν,Ν-dicikloheksilkarbodiimidom, je v prijavi WO 01/58868 opisano nižje razmerje med ptoluensulfonsko soljo benzilnega estra (2S,3aS,7aS)-oktahidroindol-2-karboksilne kisline, N((S)-l-karbetoksibutil)-L-alaninom, trietil aminom, Ν,Ν-dicikloheksil- karbodiimidom in 1hidroksibenztriazolom. Kljub zmanjšanemu razmerju pa sta še vedno prisotna stranska produkta reakcije med benzilnim estrom perindoprila in Ν,Ν-dicikloheksilkarbodiimidom.
W0 03/064388 opisuje sintezo perindoprila brez stranskih produktov reakcij N,Ndicikloheksilkarbodiimida. Reakcija poteka med (2S,3aS,7aS)-oktahidroindol-2-karboksilno kislino in kloridom N-acil zaščitenega N-((S)-l-karbetoksibutil)-L-alanina. Kislinski klorid pripravijo z uporabo tionilklorida in predhodno zaščitenega N-((S)-l-karbetoksibutil)-Lalanina. Slaba stran opisanega postopka je nizek izkoristek pri kondenzaciji in odstranjevanju zaščitne skupine, 35 do 55 %.
Pri naših raziskavah smo presenetljivo ugotovili, da se s predloženim izumom, ki opisuje sintezo perindoprila po metodi kislinskega klorida z nezaščitenim N-((S)-1-karbetoksibutil)L-alaninom, izognemo zgoraj navedenim pomanjkljivostim.
Prednosti opisanega izuma so v zagotavljanju visoke kakovosti in čistosti perindoprila in visokega izkoristka reakcije, brez stranskih produktov.
Opis izuma
Predmet predloženega izuma je postopek za pripravo perindoprila ali njegovih farmacevtsko sprejemljivih soli s formulo I:
h3<
HOOC
H5C2OOC CH, -v H
I tako, daN-((S)-l-karbetoksibutil)-L-alanin s formulo II:
h5c2ooc ch3
H,C
OH pretvorimo v kislinski klorid s formulo III:
H5C2OOC ch-
ki nato reagira z (2S,3aS,7aS)-oktahidroindol-2-karboksilno kislino s formulo IV:
H
-7-N H Ri
COOR
IV kjer R pomeni zaščitno skupino, kot je benzilna, /-butilna, trimetilsilililna skupino ali vodik ali kation, kot je kalij, litij ali natrij in Ri pomeni vodik ali zaščitno skupino, kot je trimetilsililna skupina v spojino s formulo V
ROOC
H,C,OOC CH3 v kateri ima R zgoraj navedeni pomen, ki jo v primeru, da R ni vodik, s hidrogenolizo ali hidrolizo pretvorimo v perindopril s formulo I
Sama reakcija kondenzacije oziroma tvorba peptidne vezi med spojino ΙΠ in spojino s formulo IV poteka v organskih topilih, kot acetonu, acetonitrilu, dioksanu, kloroformu, metilenkloridu, tetrahidrofuranu ali opcijsko v kombinaciji le-teh z vodo, v prisotnosti baze, v temperaturnem območju od -20°C do +20°C, prednostno pri temperaturi 0°C do -20°C.
Predmet izuma je nadalje tudi kislinski klorid s formulo III in njegove soli. Spojino s formulo III pripravimo iz N-((S)-l-karbetoksibutil)-L-alanina z reagenti za pripravo kloridov, kot so fosforpentaklorid, fosfortriklorid, fosforil klorid ali tionilklorid. Za pripravo klorida lahko uporabimo 10 do 50 % prebitek reagenta, reakcijo izvajamo v inertnem topilu, kot je metilenklorid, v temperaturnem območju od -30°C do 30°C, prednostno pri 0°C do 10°C.
uporabimo 10 do 50 % prebitek reagenta, reakcijo izvajamo v inertnem topilu, kot je metilenklorid, v temperaturnem območju od -30°C do 30°C, prednostno pri 0°C do 10°C.
Za pripravo spojine s formulo ΙΠ lahko uporabimo tudi spojine s formulo Π v obliki soli, prednostno v obliki hidroklorida. Hidroklorid spojine s formulo lije poznan iz Tetr. Lett. 1982, 23 (16) 1677-1680, Drug Design and Discovery 1992, 9 (1) 11-28 in EP 1403278.
Spojino s formulo ΙΠ v obliki soli, prednostno hidrokloridne, lahko izoliramo tako, da delno odparimo topilo in jo izoborimo z antitopilom, kot npr. z različnimi etri ali ogljikovodiki.
Derivat L-alanina s formulo lije opisan v patentih dokumentih: EP 308340, EP 308341, EP 309324, EP 1362845, EP 1400431, EP 1400531, WO 01/56353 in WO 01/56972.
Oktahidroindol-2-karboksilna kislina s formulo IV pa je poznana iz patentih dokumentov: EP 37231, EP 308339, EP 308341, EP 1323729, US 5258525 in EP 1338591.
Trimetilsililni derivati amino kislin se uporabljajo za izboljšanje topnosti, zaščito karboksilne skupine in izboljšanje reakcij acilacije (Leo A. Paquette, Encyclopedia of reagents for Organic Synthesis, Volume 2, page 1234).
Spojine s formulo I izoliramo po znanih ali konvencionalnih postopkih. Spojino lahko izoliramo v obliki Z-butilaminske soli, ki je poznana iz EP 308341 in lahko nastopa v različnih polimorfnih oblikah, kot so opisane na primer v WO 01/87835 (alfa polimorf), WO 01/87836 (beta polimorf) in WO 01/83439 (gama polimorf).
Spojino I lahko izoliramo tudi v obliki drugih farmacevtsko sprejemljivih soli, kot je na primer argininska sol, opisana v WO 03/087050.
Predloženi izum je ponazoijen z naslednjimi izvedbenimi primeri, ne da bi bil omejen z njimi.
Primeri
Primer 1
Priprava hidroklorid N-((S)-l-karbetoksibutil)-L-alanil klorida
V suspenzijo ob mešanju pri 20 - 25°C, 13,2 gN-((S)-l-karbetoksibutil)-L-alanina v 80 mL diklorometana uvajamo HC1 toliko časa, da dobimo bistro raztopino. Bistro raztopino ohladimo na -5°C do 0°C in dodamo 12,9 g PCI5 ter nadaljujemo z mešanjem pri isti temperaturi še pet ur. Suspenziji odparimo približno polovico diklorometana, dodamo 180 mL diizopropil etra in nadaljujemo z mešanjem pri temperaturi 10 - 25°C še eno uro. Izpadle kristale odfiltriramo in speremo z 90 mL diizopropil etra.
Dobimo 15,1 g hidroklorid N-((S)-l-karbetoksibutil)-L-alanil klorida.
Talilno območje = 89 - 98 °C ( razpad)
IR (cm1) : 2972, 1793, 1742, 1470 in 1206
IH NMR ( 300 MHz, DMSO-i/6) δ 0,90 ( 3 H, t, J= 7,15 Hz), 1,24 ( 3 H, t, J= 7,14 Hz), 1,40( 2 H, m ), 1,51( 3 H, d, J= 7,14 Hz), 1,86 ( 2 H, m ), 4,07 ( 2 H, m ), 4,21 ( 2 H, m, 7 = 7,14 Hz) in 9,71 (2 H, š)
Primer 2
Priprava perindopril erbumina
2-metilpropan-2-aminska sol (2S,3aS,7aS)-1 -((2S)-2-((( 1 S)-1 -(etoksikarbonil)butil)amino)-1 oksopropil)oktahidro- lH-indol-2-karboksilne kisline
K 3,72 g (2S, 3aS, 7aS)-oktahidroindol-2-karboksilne kisline v 60 ml diklorometana pri 20 25°C dodamo 2,86 mL trimetilklorsilana in 3,08 mL trietilamina ter mešamo pri 20 - 25°C dve uri. Po dveh urah dodamo 2,8 mL trietilamina, suspenzijo ohladimo na -15°C in dolijemo ohlajeno na -15°C suspenzijo 5,5 g hidroklorid N-((S)-l-karbetoksibutil)-L-alanil klorida v 60 mL diklorometana ter nadaljujemo z mešanjem pri -15°C dve uri. Reakcijsko raztopino segrejemo na 0°C in dodamo 25 mL slanice, v kateri smo raztopili 0,8 g NaOH, ter naravnamo pH na 4,2 z 20 % raztopino NaOH. Organsko fazo ločimo in vodni sloj še enkrat speremo z 20 mL diklorometana. Združene diklorometanske sloje uparimo, preostanek raztopimo v 100 mL etilacetata, neraztopljeni del odfiltriramo in filtratu dodamo 2,2 mL tbutilamina. Izpadle kristale raztopimo pri vrelišču raztopine in bistro raztopino ohladimo na
- 20 °C in nadaljujemo z mešanjem dve uri. Po dveh urah izpadle kristale odfiltriramo, speremo z 12 mL etilacetata in posušimo pri 35 - 40°C v zračnem sušilniku.
Dobimo 7,1 g (80 %) perindopril erbumina a oblike in čistosti več kot 99 % ter posamezne nečistote nobene več kot 0,1 %.
Claims (10)
- Patentni zahtevki1.Postopek za pripravo perindoprila ali njegovih farmacevtsko sprejemljivih soli s formuloI:HOOCH5C2OOC CH3 7-HI označen s tem, daN-((S)-l-karbetoksibutil)-L-alanin s formulo II:h5c2ooc ch3OH presnovimo v kislinski klorid s formulo III:H5C2OOC ch3 η3<Χ»^νH O ki nato reagira z (2S, 3aS, 7aS)-oktahidroindol-2-karboksilno kislino s formulo IV:HIV kjer R pomeni zaščitno skupino, kot je benzilna, /-butilna, trimetilsililna skupina ali vodik ali kation kot je kalij, litij ali natrij in Rj pomeni vodik ali zaščitno skupino, kot je trimetilsililna skupina v spojino s formulo VV v kateri ima R zgoraj navedeni pomen, ki jo v primeru , da R ni vodik, s hidrogenolizo ali hidrolizo pretvorimo v perindopril s formulo I-
- 2. Postopek po zahtevku 1, označen s tem, da reakcija tvorba peptidne vezi poteka v organskih topilih, kot acetonu, acetonitrilu, dioksanu, kloroformu, metilenkloridu, tetrahidrofuranu ali v kombinaciji le-teh z vodo, v prisotnosti baze.
- 3. Postopek po zahtevku 1, označen s tem, da reakcija poteka v temperaturnem območju od 20°C do +20°C, prednostno pri temperaturi od 0°C do -20°C.
- 4. Spojina s formulo ΙΠ in njene soli h5c2ooc ch3H O
- 5. Spojina s formulo III v obliki hidrokloridne soli.
- 6. Postopek za pripravo spojine iz zahtevka 4, označen s tem, da uporabimo spojino s formulo II in reagente za pripravo kloridov, kot so fosforpentaklorid, fosfortriklorid, fosforil klorid ali tionilklorid.
- 7. Postopek za pripravo spojine iz zahtevka 4, označen s tem, da uporabimo spojine s formulo Π v obliki soli, prednostno v obliki hidroklorida.
- 8. Postopek za pripravo spojine iz zahtevka 4, označen s tem, da reakcijo izvajamo v inertnem topilu, prednostno metilenkloridu.
- 9. Postopek za pripravo spojine iz zahtevka 4, označen s tem, da reakcijo izvajamo v temperaturnem območju od -30°C do 30°C, prednostno pri 0°C do 10°C.
- 10. Uporaba spojine s formulo III in njenih soli za pripravo perindoprila ali njegovih farmacevtsko sprejemljivih soli.
Priority Applications (19)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200400143A SI21800A (sl) | 2004-05-14 | 2004-05-14 | Nov postopek sinteze perindoprila |
| SI200400235A SI21852A (sl) | 2004-05-14 | 2004-08-05 | Nov postopek sinteze perindoprila |
| PCT/EP2005/005048 WO2005113500A1 (en) | 2004-05-14 | 2005-05-10 | Process for the preparation of perindopril and salts thereof |
| EP05748048.5A EP1753720B1 (en) | 2004-05-14 | 2005-05-10 | Process for the preparation of perindopril and salts thereof |
| PL05748048T PL1753720T3 (pl) | 2004-05-14 | 2005-05-10 | Proces wytwarzania peryndoprylu i jego soli |
| UAA200613250A UA83139C2 (uk) | 2004-05-14 | 2005-05-10 | Спосіб одержання периндоприлу або його солей (варіанти), проміжна сполука, спосіб її одержання (варіанти) та її застосування |
| PT57480485T PT1753720E (pt) | 2004-05-14 | 2005-05-10 | Processo para a preparação de perindopril e sais do mesmo |
| CA2566754A CA2566754C (en) | 2004-05-14 | 2005-05-10 | Process for the preparation of perindopril and salts thereof |
| US11/568,908 US7674814B2 (en) | 2004-05-14 | 2005-05-10 | Process for the preparation of perindopril and salts thereof |
| EA200602117A EA011322B1 (ru) | 2004-05-14 | 2005-05-10 | Способ получения периндоприла и его солей |
| AU2005245087A AU2005245087B2 (en) | 2004-05-14 | 2005-05-10 | Process for the preparation of perindopril and salts thereof |
| SI200531867T SI1753720T1 (sl) | 2004-05-14 | 2005-05-10 | Postopek za pripravo perindoprila in njegovih soli |
| DK05748048.5T DK1753720T3 (da) | 2004-05-14 | 2005-05-10 | Fremgangsmåde til fremstilling af perindopril og salte deraf |
| HRP20140487TT HRP20140487T1 (hr) | 2004-05-14 | 2005-05-10 | Postupak dobivanja perindoprila i njegovih soli |
| ES05748048.5T ES2466248T3 (es) | 2004-05-14 | 2005-05-10 | Procedimiento para la preparación de perindopril y de sus sales |
| JP2007512069A JP5032983B2 (ja) | 2004-05-14 | 2005-05-10 | ペリンドプリルまたはおよびその塩の調製のための方法 |
| ZA200609915A ZA200609915B (en) | 2004-05-14 | 2006-11-28 | Process for the preparation of Perindopril and salt thereof |
| NO20065695A NO337892B1 (no) | 2004-05-14 | 2006-12-11 | Fremgangsmåte for fremstilling av perindopril og salter derav |
| CY20141100483T CY1115222T1 (el) | 2004-05-14 | 2014-07-01 | Μεθοδος για την παρασκευη περινδοπριλης και αλατων αυτης |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200400143A SI21800A (sl) | 2004-05-14 | 2004-05-14 | Nov postopek sinteze perindoprila |
| SI200400235A SI21852A (sl) | 2004-05-14 | 2004-08-05 | Nov postopek sinteze perindoprila |
| PCT/EP2005/005048 WO2005113500A1 (en) | 2004-05-14 | 2005-05-10 | Process for the preparation of perindopril and salts thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SI21800A true SI21800A (sl) | 2005-12-31 |
Family
ID=34969318
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI200400143A SI21800A (sl) | 2004-05-14 | 2004-05-14 | Nov postopek sinteze perindoprila |
| SI200400235A SI21852A (sl) | 2004-05-14 | 2004-08-05 | Nov postopek sinteze perindoprila |
| SI200531867T SI1753720T1 (sl) | 2004-05-14 | 2005-05-10 | Postopek za pripravo perindoprila in njegovih soli |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SI200400235A SI21852A (sl) | 2004-05-14 | 2004-08-05 | Nov postopek sinteze perindoprila |
| SI200531867T SI1753720T1 (sl) | 2004-05-14 | 2005-05-10 | Postopek za pripravo perindoprila in njegovih soli |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US7674814B2 (sl) |
| EP (1) | EP1753720B1 (sl) |
| JP (1) | JP5032983B2 (sl) |
| AU (1) | AU2005245087B2 (sl) |
| CA (1) | CA2566754C (sl) |
| CY (1) | CY1115222T1 (sl) |
| DK (1) | DK1753720T3 (sl) |
| EA (1) | EA011322B1 (sl) |
| ES (1) | ES2466248T3 (sl) |
| HR (1) | HRP20140487T1 (sl) |
| NO (1) | NO337892B1 (sl) |
| PL (1) | PL1753720T3 (sl) |
| PT (1) | PT1753720E (sl) |
| SI (3) | SI21800A (sl) |
| UA (1) | UA83139C2 (sl) |
| WO (1) | WO2005113500A1 (sl) |
| ZA (1) | ZA200609915B (sl) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HRP20161602T1 (hr) * | 2004-03-29 | 2016-12-30 | Les Laboratoires Servier | Postupak priprave čvrstog farmaceutskog pripravka |
| US7291745B2 (en) | 2005-03-21 | 2007-11-06 | Glenmark Pharmaceuticals Limited | Process for the preparation of perindopril |
| JP2006290825A (ja) * | 2005-04-13 | 2006-10-26 | Shiono Chemical Co Ltd | アルファ型ペリンドプリルエルブミンの製造法 |
| SI22543A (sl) | 2007-06-27 | 2008-12-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Nove soli perindoprila |
| WO2016178591A2 (en) | 2015-05-05 | 2016-11-10 | Gene Predit, Sa | Genetic markers and treatment of male obesity |
| PH12018502155B1 (en) | 2016-04-20 | 2024-03-27 | Servier Lab | Pharmaceutical composition comprising a beta blocker, a converting enzyme inhibitor and an antihypertensive or an nsaid |
Family Cites Families (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2503155A2 (fr) | 1980-10-02 | 1982-10-08 | Science Union & Cie | Nouveaux imino diacides substitues, leurs procedes de preparation et leur emploi comme inhibiteur d'enzyme |
| US4508729A (en) | 1979-12-07 | 1985-04-02 | Adir | Substituted iminodiacids, their preparation and pharmaceutical compositions containing them |
| IE52663B1 (en) | 1980-04-02 | 1988-01-20 | Warner Lambert Co | Substituted acyl derivatives of octahydro-1h-indole-2-carboxylic acids |
| US4350704A (en) | 1980-10-06 | 1982-09-21 | Warner-Lambert Company | Substituted acyl derivatives of octahydro-1H-indole-2-carboxylic acids |
| US4425355A (en) | 1981-02-17 | 1984-01-10 | Warner-Lambert Company | Substituted acyl derivatives of chair form of octahydro-1H-indole-2-carboxylic acids |
| US4743450A (en) | 1987-02-24 | 1988-05-10 | Warner-Lambert Company | Stabilized compositions |
| FR2620700B1 (fr) | 1987-09-17 | 1990-06-01 | Adir | Procede de synthese d'alpha amino acides n alkyles et leurs esters. application a la synthese de carboxyalkyl dipeptides |
| FR2620703B1 (fr) | 1987-09-17 | 1991-10-04 | Adir | Procede de synthese industrielle de l'acide perhydroindole carboxylique - 2(2s, 3as, 7as). application a la synthese de carboxyalkyl dipeptides |
| FR2620699B1 (fr) | 1987-09-17 | 1990-06-01 | Adir | Procede de synthese d'alpha amino acides n alkyles et de leurs esters. application a la synthese de carboxyalkyl dipeptides |
| FR2620709B1 (fr) | 1987-09-17 | 1990-09-07 | Adir | Procede de synthese industrielle du perindopril et de ses principaux intermediaires de synthese |
| US5258525A (en) | 1991-03-27 | 1993-11-02 | Mcneilab, Inc. | Processes for preparing [2S-(2α,3aβ,7aβ)]octahydro-1H-indole-2-carboxylic acid and esters |
| SI9111842A (sl) | 1991-11-25 | 1998-04-30 | Krka | Stabilna formulacija soli enalaprila, postopek za njeno pripravo in njena uporaba |
| SI9600169A (en) * | 1996-05-22 | 1997-12-31 | Krka Tovarna Zdravil | Process for preparation of compounds with ace inhibitory effect |
| FR2771010B1 (fr) | 1997-11-19 | 2003-08-15 | Adir | Utilisation d'une combinaison d'un inhibiteur de l'enzyme de conversion de l'angiotensine et d'un diuretique pour le traitement des desordres microcirculatoires |
| FR2807037B1 (fr) | 2000-03-31 | 2002-05-10 | Adir | NOUVEAU PROCEDE DE SYNTHESE DES ESTERS DE LA N-[(s)-1- CARBOXYBUTYL]-(S)-ALANINE ET APPLICATION A LA SYNTHESE DU PERINDOPRIL |
| FR2807431B1 (fr) | 2000-04-06 | 2002-07-19 | Adir | Nouveau procede de synthese du perindopril et de ses sels pharmaceutiquement acceptables |
| FR2807430B1 (fr) | 2000-04-11 | 2002-05-17 | Adir | Nouveau procede de synthese des esters de la n-[(s)-1- carboxybutyl]-(s)-alanine et application a la synthese du perindopril |
| FR2811318B1 (fr) | 2000-07-06 | 2002-08-23 | Adir | Nouvelle forme cristalline gamma du sel de tert-butylamine du perindopril, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| FR2811319B1 (fr) | 2000-07-06 | 2002-08-23 | Adir | Nouvelle forme cristalline beta du sel de tert-butylamine du perindopril, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| FR2811320B1 (fr) | 2000-07-06 | 2002-08-23 | Adir | Nouvelle forme cristalline alpha du sel de tert-butylamine du perindopril, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| DE10131217A1 (de) | 2001-06-28 | 2003-01-09 | Solvay Pharm Gmbh | 3-Phenyl-3,7-diazabicyclo 3,3,1 nonan-Verbindungen sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
| ATE371442T1 (de) | 2001-10-12 | 2007-09-15 | Elan Pharma Int Ltd | Zusammensetzungen mit einer kombination aus eigenschaften sofortiger freisetzung und kontrollierter freisetzung |
| EP1513555B1 (en) | 2002-01-15 | 2007-03-28 | Actavis Group hf. | Formulations of quinapril and related ace inhibitors |
| EP1333026B1 (en) * | 2002-01-30 | 2007-06-27 | Les Laboratoires Servier | Process for the preparation of high purity perindopril and intermediates useful in the synthesis |
| WO2003075842A2 (en) | 2002-03-08 | 2003-09-18 | Teva Pharmeceuticals Usa, Inc. | Stable formulations of angiotensin converting enzyme (ace) inhibitors |
| FR2838648B1 (fr) | 2002-04-18 | 2004-05-21 | Servier Lab | Nouveau sel de perindopril et les compositions pharmaceutiques qui le contiennent |
| AU2003241477A1 (en) | 2002-06-10 | 2003-12-22 | Elan Pharma International, Ltd. | Nanoparticulate polycosanol formulations and novel polycosanol combinations |
| WO2004061462A1 (en) * | 2002-12-23 | 2004-07-22 | Power Measurement Ltd. | Power monitoring integrated circuit with communication interface |
| EP1603558B1 (en) * | 2003-02-28 | 2008-05-21 | Les Laboratoires Servier S.A. | Process for preparation of perindopril and salts thereof |
| ATE307801T1 (de) | 2003-02-28 | 2005-11-15 | Servier Lab | Verfahren zur synthese des (2s,3as,7as)- perhydroindol-2-carbonsäures und seiner estern, verwendung in der synthese von perindopril |
| ES2231760T3 (es) | 2003-03-12 | 2005-05-16 | Les Laboratoires Servier | Nuevo procedimiento de sintesis del acido(2s, 3as,7as)perhidroindol-2-carboxilico y de sus esteres, y su aplicacion a la sintesis de perindopril. |
| SI1367061T1 (sl) * | 2003-06-30 | 2006-04-30 | Servier Lab | Nov postopek za sintezo perindoprila in njegovih farmacevtsko sprejemljivih soli |
| US6869963B2 (en) | 2003-07-11 | 2005-03-22 | Sandoz Ag | Stable pharmaceutical compositions containing an ACE inhibitor |
| GB2404336A (en) | 2003-07-30 | 2005-02-02 | Cipla Ltd | Stabilisation of therapeutic agents using a carbonate salt of an amino acid, preferably in the presence of a saccharide, & pharmaceutical compositions thereof |
| ES2271497T3 (es) * | 2003-07-31 | 2007-04-16 | Les Laboratoires Servier | Nuevo procedimiento de sintesis de perindopril y de sus sales farmaceuticamente aceptables. |
| ATE337332T1 (de) * | 2003-07-31 | 2006-09-15 | Servier Lab | Verfahren für die synthese von perindopril und seiner pharmazeutischen annehmbaren salzen |
| DK1362845T3 (da) | 2003-09-01 | 2010-01-18 | Servier Lab | Ny fremgangsmåde til fremstilling af estere af N-((S)-1-carboxybutyl)-(S)-alanin og deres anvendelse ved fremstilling af perindopril |
| EP1400531B1 (fr) | 2003-09-30 | 2006-01-04 | Les Laboratoires Servier | Procédé de synthèse de la N-[(S)-1-carbéthoxybutyl]-(S)-alanine et application à la synthèse du perindopril |
| ATE297407T1 (de) | 2003-09-30 | 2005-06-15 | Servier Lab | Verfahren zur herstellung von n-((s)-1- (ethoxycarbonyl)butyl)-(s)-alanin und verwendung in der synthese von perindopril |
| GB2394660A (en) | 2003-12-17 | 2004-05-05 | Niche Generics Ltd | Stabilisation of pharmaceutical compositions comprising ACE inhibitor by absence of acidic excipients having large specific surface area, eg silicon dioxide |
| HRP20161602T1 (hr) | 2004-03-29 | 2016-12-30 | Les Laboratoires Servier | Postupak priprave čvrstog farmaceutskog pripravka |
-
2004
- 2004-05-14 SI SI200400143A patent/SI21800A/sl not_active IP Right Cessation
- 2004-08-05 SI SI200400235A patent/SI21852A/sl not_active IP Right Cessation
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2005
- 2005-05-10 SI SI200531867T patent/SI1753720T1/sl unknown
- 2005-05-10 AU AU2005245087A patent/AU2005245087B2/en not_active Ceased
- 2005-05-10 US US11/568,908 patent/US7674814B2/en not_active Expired - Fee Related
- 2005-05-10 UA UAA200613250A patent/UA83139C2/uk unknown
- 2005-05-10 WO PCT/EP2005/005048 patent/WO2005113500A1/en not_active Ceased
- 2005-05-10 ES ES05748048.5T patent/ES2466248T3/es not_active Expired - Lifetime
- 2005-05-10 EA EA200602117A patent/EA011322B1/ru not_active IP Right Cessation
- 2005-05-10 JP JP2007512069A patent/JP5032983B2/ja not_active Expired - Fee Related
- 2005-05-10 CA CA2566754A patent/CA2566754C/en not_active Expired - Fee Related
- 2005-05-10 DK DK05748048.5T patent/DK1753720T3/da active
- 2005-05-10 EP EP05748048.5A patent/EP1753720B1/en not_active Expired - Lifetime
- 2005-05-10 HR HRP20140487TT patent/HRP20140487T1/hr unknown
- 2005-05-10 PL PL05748048T patent/PL1753720T3/pl unknown
- 2005-05-10 PT PT57480485T patent/PT1753720E/pt unknown
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- 2006-11-28 ZA ZA200609915A patent/ZA200609915B/en unknown
- 2006-12-11 NO NO20065695A patent/NO337892B1/no not_active IP Right Cessation
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Also Published As
| Publication number | Publication date |
|---|---|
| NO337892B1 (no) | 2016-07-04 |
| JP5032983B2 (ja) | 2012-09-26 |
| AU2005245087B2 (en) | 2010-12-16 |
| CY1115222T1 (el) | 2017-01-04 |
| US7674814B2 (en) | 2010-03-09 |
| SI1753720T1 (sl) | 2014-08-29 |
| AU2005245087A1 (en) | 2005-12-01 |
| EA011322B1 (ru) | 2009-02-27 |
| EP1753720B1 (en) | 2014-05-07 |
| PT1753720E (pt) | 2014-08-04 |
| NO20065695L (no) | 2006-12-11 |
| CA2566754C (en) | 2012-09-18 |
| ZA200609915B (en) | 2008-05-28 |
| ES2466248T3 (es) | 2014-06-09 |
| SI21852A (sl) | 2006-02-28 |
| JP2007537189A (ja) | 2007-12-20 |
| UA83139C2 (uk) | 2008-06-10 |
| EA200602117A1 (ru) | 2007-04-27 |
| WO2005113500A1 (en) | 2005-12-01 |
| US20080051584A1 (en) | 2008-02-28 |
| CA2566754A1 (en) | 2005-12-01 |
| PL1753720T3 (pl) | 2014-09-30 |
| EP1753720A1 (en) | 2007-02-21 |
| HRP20140487T1 (hr) | 2014-07-04 |
| DK1753720T3 (da) | 2014-06-30 |
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