NO159017B - Analogifremgangsmaate for fremstilling av terapeutisk aktive 1,2,3,4-tetrahydroisokinolin-3-karboksylsyre-derivater. - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive 1,2,3,4-tetrahydroisokinolin-3-karboksylsyre-derivater. Download PDFInfo
- Publication number
- NO159017B NO159017B NO813359A NO813359A NO159017B NO 159017 B NO159017 B NO 159017B NO 813359 A NO813359 A NO 813359A NO 813359 A NO813359 A NO 813359A NO 159017 B NO159017 B NO 159017B
- Authority
- NO
- Norway
- Prior art keywords
- tetrahydro
- carboxylic acid
- acid
- amino
- isoquinoline
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title claims description 11
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
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- 239000002253 acid Substances 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims abstract description 3
- -1 N-substituted amino Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
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- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
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- 239000007858 starting material Substances 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
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 102000005686 Serum Globulins Human genes 0.000 description 1
- 108010045362 Serum Globulins Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 125000001243 alanino group Chemical group 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Chemical class OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- HYKDEPCVBMNYCM-UHFFFAOYSA-N benzyl 1,2,3,4-tetrahydroisoquinolin-2-ium-3-carboxylate;chloride Chemical compound Cl.C1C2=CC=CC=C2CNC1C(=O)OCC1=CC=CC=C1 HYKDEPCVBMNYCM-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- ZLZXSWNRZFMSSS-UHFFFAOYSA-N ethyl 2-bromo-4-phenylbutanoate Chemical compound CCOC(=O)C(Br)CCC1=CC=CC=C1 ZLZXSWNRZFMSSS-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Chemical class 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N gamma-phenylbutyric acid Natural products OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002333 glycines Chemical class 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000001630 malic acid Chemical class 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- NNKSEUBQDFHGAC-UHFFFAOYSA-N tert-butyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate;hydrochloride Chemical compound Cl.C1=CC=C2CNC(C(=O)OC(C)(C)C)CC2=C1 NNKSEUBQDFHGAC-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
Description
Denne oppfinnelse angår fremstilling av substituerte acylderivater av 1,2,3,4-tetrahydroisokinolin-3-karboksylsyre-(S,S,S)-forbindelser med formelen
hvor
R er hydrogen, t-butyl eller benzyl;
er hydrogen eller lavere alkyl; ■
R2 er hydrogen, metyl eller etyl, og
X og Y er uavhengig av hverandre hydrogen, lavere alkyl,
lavere alkoksy eller hydroksy; og de farmasøytisk godtagbare salter derav.
Betegnelsene "lavere alkyl" og "lavere alkoksy" betyr en lineær eller forgrenet alkyl- eller alkoksygruppe med fra 1 til 4 karbonatomer.
Spesielt foretrekkes forbindelsene
2 - [2 - [ (l-karboksy-3-f eny lpropy 1) ami no ] - 1-oksopropyl!] -1,2,3,4-tetrahydro-3-isokinolin-karboksylsyre; 2-[2 -[[1-(etoksykarbonyl)- 3-fenylpropy1]amino]-1-oksopropyl]-1,2,3,4-tetrahydro-3-isokinolin-karboksylsyre; 2 - [2- [ {1-kar bo ksy-3-f eny lpropy 1) ami no] - 1-oksopropyl,] -1,2,3,4-tetrahydro-6,7-dimetoksy-3 isokinolin-karboksylsyre;
2-[2-[[1-(etoksykarbonyl)-3-fenylpropy1]amino]-1-oksopropyl]-1,2,3,4-tetrahydro-6,7-dimetoksy-3-isokinolin-karboksylsyré;
og farmasøytisk godtagbare syreaddisjonssalter derav.
Forbindelsene med formel I har asymmetriske karbonatomer be-tegnet med stjerner. 1,2,3,4-tetrahydroisokinolin-3-karboksyl-syren som anvendes ifølge oppfinnelsen, har L (S) konfigurasjon. Denne konfigurasjon er vist å være nødvendig for å oppnå biologisk aktivitet, og de aktive forbindelser er således avledet fra enten (L(-) eller DL-1,2,3,4-tetrahydroisokinolin-3-karboksylsyre.
Optiske isomerer og diastereo-isomerer oppstår på grunn av chiralitet i de sentre som er merket med en stjerne i formel I, og forbindelsene som fremstilles ifølge oppfinnelsen, har S-konfigurasjonen i disse sentere.
Forbindelsene som fremstilles ifølge oppfinnelsen, kan eksistere i vannfri form såvel som i solvatisert form, inn-befattet hydratiserte former. Vanligvis er de hydratiserte former og de solvatiserte former med farmasøytisk godtagbare oppløsningsmidler likeverdige med den vannfrie eller ikke-solvatiserte form for denne oppfinnelses formål.
Forbindelsene med formel I fremstilles fra 1,2,3,4-tetra-hydroisokinolin-3-karboksylsyre ved først å beskytte karboksyl-syregruppen, fortrinnsvis som en ester, f.eks. med en lavere alkyl-, benzyl- eller trimetylsilylgruppe (Formel II):
hvor
X og Y er som ovenfor og R^ er en passende blokkert karboksylsyregruppe.
Ved å sammenknytte en 2-(4-fenylsmørsyre)-del med en glycin-eller L-alanin-del, som kan beskyttes som en ester, dannes et N-[2-(4-fenylsmørsyre)]-substituert glycin- eller L-alanin-derivat med formel III:
hvor
og R2 er som ovenfor.
Efter en eventuell selektiv avblokkering av syredelen på glycin- eller alanin-delen av produktet med formel III/ kan den resulterende monosyre kobles, via standard peptidkoblings-metoder til 1,2,3,4-tetrahydro-3-isokinolin-karboksylatet, beskyttet som en ester. Selektiv eller fullstendig fjernelse av estergruppene kan benyttes for å oppnå den ønskede forbindelse med formel I.
Forbindelsene oppnås typisk som en blanding av diastereoisomerer som kan separeres ved standard metoder for fraksjonert krystallisasjon eller kromatografi.
Forbindelsene som fremstilles ifølge oppfinnelsen, danner syresalter med forskjellige uorganiske og organiske syrer. De farmasøytisk godtagbare syreaddisjonssalter som fremstilles ifølge oppfinnelsen, kan fremstilles ved vanlige reaksjoner hvor først den frie aminosyre eller aminoester-formen av produktet omsettes med én eller flere ekvivalenter av den passende syre
for å oppnå det ønskede anion i et oppløsningsmiddel eller et medium hvor saltet er uoppløselig, eller i vann efterfulgt av fjernelse av vannet ved frysetørring. Saltene av sterke syrer foretrekkes. Farmasøytisk godtagbare syreaddisjonssalter er f.eks. saltene av saltsyre, bromhydrogensyre, svovelsyre, salpetersyre, eddiksyre, fumarsyre, eplesyre, maleinsyre og sitronsyre.
Virkningen av enzymet renin på angiotensinogen, et pseudoglobulin i blodplasma, fører til dekapeptidet angiotensin I. Angiotensin I omdannes ved hjelp av angiotensin-omdannende enzym (ACE) til oktapeptidet angiotensin II. Sistnevnte er en aktiv pressor-substans som man har antydet er det stoff som forårsaker forskjellige former for hypertensjon i forskjellige pattedyr, f.eks. rotter og hunder. Forbindelsene som fremstilles ifølge oppfinnelsen, griper inn i renin —> angiotensin I —> angiotensin II-forløpet ved å hemme angiotensin I-omdannende enzym og redusere eller eliminere dannelsen av pressor-substansen angiotensin II, og er derfor nyttige til å redusere eller lindre hypertensjon. Ved administrering av et preparat inneholdende én av eller en kombinasjon av forbindelser med formel I eller farmasøytisk godtagbare salter derav, lindres hypertensjon hos slike pattedyr som har denne lidelse. En enkelt dose, eller fortrinnsvis to til fire separate daglige doser, administrert i en mengde på ca. 0,1 til 100 mg pr. kg. pr. dag, fortrinnsvis ca. 1 til 50 mg pr. kg pr. dag, er passende for å redusere blodtrykket. Forbindelsen admini-streres fortrinnsvis oralt, men man kan også anvende parenteral administrering, så som subkutan, intramuskulær, intravenøs eller intraperitoneal.
In vitro ACE måling: Hemmende virkning på angiotensin-omdannende enzym (ACE) ble bestemt ved å måle marsvin-serum ACE i nærvær og fravær av prøveforbindelsen. ACE fra marsvin-serum og prøveforbindelsene ble forhåndsinkubert i 10 minutter før tilsetning av det merkede substrat <3>H-hippuryl-glycyl-glycin. Efter 60 minutters inkubering ved 37°C ble reaksjonen, stanset ved tilsetning av 0,IN HC1. ACE spalter hippuryl-glycyl-bindingen for å danne dipeptidet glycy1-glycin og 3 H-hippursyre. <3>H-hippursyren ble derefter ekstrahert med etylacetat og ACE for en gitt prøve ble beregnet som mengden av dannet ^n-hippursyre.
Forbindelsene som fremstilles ifølge oppfinnelsen, kan anvendes for å oppnå reduksjon av blodtrykk ved anvendelse i slike preparater som tabletter, kapsler eller eliksirer for oral administrering, eller i sterile oppløsninger eller suspensjoner for parenteral administrering. Ca. 10 til 500 mg av en forbindelse eller blanding av forbindelser med formel I eller II eller fysiologisk godtagbare salter derav blandes med en fysiologisk godtagbar bærer, hjelpestoff, bindemiddel, konserveringsmiddel, stabilisator, smaksstoff osv., i en egnet enhetsdoseform i henhold til vanlig farmasøytisk praksis. Mengden av aktivt stoff i disse preparater er slik at man opp-når en passende dosemengde i det angitte område.
Illustrerende eksempler på hjelpestoffer som kan anvendes
i tabletter, kapsler o.l., er de følgende: et bindemiddel så som tragakantgummi, akasiegummi, maisstivelse eller gelatin;
et hjelpestoff så som dikalsiumfosfat; et sprengmiddel så
som maisstivelse, potetstivelse, alginsyre o.l., et smøremiddel så som magnesiumstearat; et søtningsmiddel så som sukrose, laktose eller sakkarin; et smaksstoff så som peppermynte, vintergrøntolje eller kirsebær. Når enhetsdoseformen er en kapsel, kan den i tillegg til materialer av ovennevnte type inneholde et flytende bæremiddel så som en fet olje. Forskjellige andre materialer kan være til stede som belegg eller for på annen måte å modifisere enhetsdosens fysikalske form. For eksempel kan tabletter være belagt med skjellakk, sukker eller begge. En sirup eller eliksir kan inneholde den aktive bestanddel, sukrose som søtningsmiddel, metyl- og propyl-parabener som konserveringsmidler, ét farvestoff og et smaksstoff så som kirsebær- eller appelsin-smaksstoff.
Sterile preparater for injeksjon kan tilberedes i henhold til vanlig farmasøytisk praksis ved å oppløse eller suspendere den aktive forbindelse i et bæremiddel så som vann for injeksjon, en naturlig forekommende vegetabilsk olje så som sesam-olje, kokos-olje, jordnøttolje, bomullsfrøolje osv., eller et syntetisk, fett bæremiddel så som etyloleat eller lignende. Buffere, konserveringsmidler, antioksydasjonsmidler og lignende kan innføres i den grad det er nødvendig.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere. Eksempel 1-4 viser fjernelse av beskyt-telsesgruppen, Eksempel 5-7 viser omsetning av II + III, og eksempel 8 og eksempel 9-11 viser fremstilling av henholdsvis III og II.
Eksempel 1
2-[ 2-[[ 1-( etoksykarbonyl)- 3- fenylpropyl] amino]- 1- oksopropyl]-1, 2, 3, 4- tetrahydro- 6, 7- dimetoksy- 3- isokinolin- karboksylsyre-hydroklorid- hydrat ( S, S, S).
En mengde på 0,0079 mol av hydrokloridet av 2-[2-[Il-te toksykarbonyl) -3-f enylpropyl] amino]-1-oksopropyl]-1,2,3,4-tetrahydro-6,7-dimetoksy-3-isokinolin-karboksylsyre-fenylmetylester (S,S,S) oppløst i 100 ml tetrahydrofuran ble katalytisk debenzylsrt med hydrogen og 0,5 g 20% Pd/kull ved lavt trykk. Katalysatoren ble' frafiltrert, og produktet ble utfelt som et forholdsvis ikke-hydroskopt, fast stoff ved tilsetning av en 10-dobbelt mengde eter; vekt 3,7 g (88%), sm.p. 120-140°C,
TLC (20% MeOH-CHCl3/Si02) én flekk, Rf 0,5-0,7;
[a]^<3>= + 31,6° (1,05% EtOH).
Analyse:
Beregnet for C27H34N2°7*HC1"H20: C 58'63' H 6'74' N'5,07 Funnet: C 58,59, H 6,38, N 5,06.
Det ikke-krystallinske diester-hydroklorid-utgangsmateriale som ble anvendt ovenfor, ble fremstilt ved behandling av 5,54 g (0,0079 mol) av maleatsaltet (fremstilt ved fremgangsmåten
ifølge eksempel 5) med et overskudd av mettet natriumbikarbonat, ekstraksjon av den frie base inn i 50% eter-etylacetat,
behandling av denne oppløsning med overskudd av hydrogenklorid og konsentrering ved redusert trykk.
Eksempel 2
2- [ 2- [ [ 1- ( etoksykarbonyl)- 3- fenylpropyl] amino]- 1- oksopropyl]-1, 2, 3, 4- tetrahydro- 3- isokinolinkarboksylsyre- hydroklorid-
hydrat ( S, S, S).
Fremgangsmåte A: Debenzylering.
2-[2-[[1-(etoksykarbonyl)-3-fenylpropyl]amino]-1-oksopropyl] -1,2,3,4-tetrahydro-3-isokinolinkarboksylsyre-fenylmetylester-maleat (S,S,S) (fremstilt ved fremgangsmåten ifølge eksempel 6) ble katalytisk debenzylert ved fremgangsmåten beskrevet i eksempel 1 for å gi produktet, sm.p. 105-120°C, utbytte 56%; TLC (20% Me0II-CHCl3/Si02) én flekk, Rf 0,5-0,6;
[a]p3= +10,9° (1,03% EtOH).
Analyse:
Beregnet for C^H^N^ • HC1-H20: C 60,90, H 6,75, N 5,68 Funnet: C 61,00, H 6,37, N 5,59.
Fremgangsmåte B: Via spaltning av 1,1-dimetyletylester.
En mengde på 100 g av tri fluoreddiksyre ble satt til 11,6 g (0,023 mol) 2-[2-[ [1-etoksykarbony1)-3-fenylpropyl]amino]-1-oksopropyl]-1,2,3,4-tetrahydro-3-isokinolinkarboksylsyre-1,1-dimetyletylester (S,S,S) (fremstilt ved fremgangsmåten ifølge eksempel 7). Blandingen ble omrørt til oppløsning,
og 1 time ved romtemperatur. Mesteparten av trifluoreddiksyren ble fjernet på en rotasjonsinndamper, og gjenværende spor ble fjernet ved suksessiv tilsetning og fjerning på rotasjonsinndamper av 2 x 50 ml THF. Den gjenværende olje ble oppløst i ca. 400 ml tørr eter, og hydrokloridet ble utfelt ved tilsetning av en oppløsning av 1,0 g (overskudd) av tørt hydrogenklorid opp-løst i 20 ml tørr eter. Efter filtrering og vasking med tørr eter ble filterkaken oppløst i ca. 250 ml vann. Denne opp-løsning ble filtrert gjennom celite og frysetørret for å gi produktet som et partielt hydrat, 10,0 g (90%), sm.p. 113-120°C. Analyse: Beregnet for C25H3Q<N>2<0>5•<H>C1•3/4 H20: C 61,55, H 6,70, N 5,74 Funnet: C 61,51, H 6,49, N 5,70
Eksempel 3
2-[ 2-[( 1- karboksy- 3- fenylpropyl) amino]- 1- oksopropyl]- 1, 2, 3, 4-tetrahydro- 6, 7- dimetoksy- 3- isokinolinkarboksylsyre- hydroklorid-hydrat ( S, S, S).
"En oppløsning av 0,553 g (0,001 mol) 2-[2-[[ 1-(etoksy-karbonyl) -3-fenylpropyl]amino]-1-oksopropyl]-1,2,3,4-tetrahydro-6,7-dimetoksy-3-isokinolirikarboksylsyre-hydroklorid-hydrat (S,S,S)
(fremstilt ved fremgangsmåten ifølge eksempel 1) i 4 ml (0,004 mol) IN natriumhydroksyd og 4 ml metanol fikk stå ved romtemperatur i 20 timer. Reaksjonsblandingen ble satt til 5 ml IN saltsyre og konsentrert under redusert trykk. De siste mengder vann ble fjernet ved to påfølgende tilsetninger og fjerning under redusert trykk av 25 ml porsjoner av etanol. Den organiske del av residuet ble oppløst i 0,5 ml metanol. Kloroform (30 ml)
ble tilsatt, og oppløsningen ble tørret over natriumsulfat, behandlet med trekull, filtrert og konsentrert for å gi 0,45 g produkt. Dette amorfe materiale ble oppløst i 20 ml tetrahydrofuran, og 100 ml eter ble tilsatt for å felle ut et nesten hvitt, fast produkt, vekt 0,4 g, sm.p. 145-170°C, utbytte 80%,
TLC (20% Me0H-CHCl3/Si02), Rf 0,1 [a]^<3>= +37,8° (1,09% MeOH). Analyse: Beregnet for C25<H>30<N>2°7'<H>C1'H2°: C 57'19' H 6'34' N 5,34 Funnet: C 57,17, H 6,10, N 5,51
Eksempel 4
2-[ 2 - [ ( l- karboksy- 3- fenylpropy1) amino]- 1- oksopropyl]- 1, 2, 3, 4-tetrahydro- 3- isokinolinkarboksylsyre- hydroklorid- hemihydrat
( S, S, S)
2-[2-[[1-(etoksykarbonyl)-3-fenylpropyl]amino]-1-oksopropyl]-1,2,3,4-tetrahydro-3-isokinolin-karboksylsyre-hydroklorid-hydrat (S,S,S) ble behandlet ved fremgangsmåten beskrevet i eksempel 3 for å gi produktet, sm.p. 140-170°C, utbytte 39%, [a]^3= V+|4,5° (1,08% MeOH).
Analyse:
Beregnet for <C>2gN205•HC1•1/2 H20:
C 60,59, H 5,97, N 6,15, Cl 7,77 Funnet: C 60,58, H 6,04, N 5,89, Cl 7,04
Eksempel 5
2- [ 2- [ [ 1- ( etoksykarbonyl)- 3- fenylpropyl] amino]- 1- oksopropyl]-1, 2, 3, 4- tetrahydro- 6, 7- dimetoksy- 3- isokinolin- karboksylsyre-fenylmetylester- maleat ( S, S, S)
En omrørt oppløsning av 5,0 g -(0,0158 mol) etyl-a-[(l-karboksyetyl)amino]benzenbutanoat-hydroklorid (S,S) (fremstilt ved fremgangsmåten ifølge eksempel 8) i 200 ml metylenklorid ble behandlet suksessivt med 1,60 g (0,0158 mol) trietylamin,
2,14 g (0,0158 mol) 1-hydroksybenzotriazol, 5,16 g (0,0158 mol) 1,2,3,4-tetrahydro-6,7-dimetoksy-3-isokinolin-karboksylsyre-fenylmetylester, fri base (S-form) (fremstilt ved fremgangsmåten ifølge eksempel 9), og derefter med 3,26 g (0,0158 mol) dicykloheksylkarbodiimid i 10 ml metylendiklorid. Dicykloheksyl-
urinstoff ble gradvis utskilt. Blandingen fikk stå ved romtemperatur natten over. Heksan (300 ml) ble tilsatt, og urinstoffet filtrert. Filtratet ble vasket med 250 ml mettet natriumbikarbonat, tørret over natriumsulfat og konsentrert for å fjerne oppløsningsmidde1. Det viskøse residuum ble utgnidd med 50 ml eter og filtrert for å fjerne uoppløselig stoff. Filtratet ble konsentrert for å gi 9,2 g (99%) urenset base.
Fremstilling av maleatsaltet: En oppløsning av 9,0 g (0,015 mol) av den urensede basen ovenfor i 50 ml etylacetat ble behandlet med en varm (40°C) oppløsning av 1,86 g (0,016 mol) maleinsyre i 50 ml etylacetat. Hvite krystaller ble utskilt, vekt 7,2 g (65%), sm.p. 139-141°C; TLC av basen (dannet
med vandig natriumbikarbonat-behandling av saltet og etylacetat-ekstraksjon) viste én flekk, Rf 0,7 (EtOAc/SiO.,) . Omkrystallisering fra etylacetat ga rent. materiale med samme smeltepunkt, [a]^<3> = +3,4° (1,05% EtOH).
Analyse:
Beregnet for C34<H>4Q<N>2<0>7•C4H404: C 64,74, H 6,29, N 3,98 Funnet: C 64,48, H 6,30, N 3,99.
Eksempel 6
2-[ 2-[[ 1-( etoksykarbonyl)- 3- fenylpr opyl] amino]- 1- oksopropyl]-1, 2, 3, 4- tetrahydro- 3- isokinolinkarboksylsyre- fenylmetylester-maleat ( S, S, S)
Etyl-a-[(1-karboksyetyl)amino]-benzenbutanoat-hydroklorid (S,S) (fremstilt ved fremgangsmåten ifølge eksempel 8) ble koblet med 1,2,3,4-tetrahydro-3-isokinolin-karboksylsyre-feny1-metylester, fri base (S-form) (fremstilt ved fremgangsmåten ifølge eksempel 10) ved samme fremgangsmåte som ble anvendt i eksempel 5; utbytte, 61%; sm.p- 151-153°C (omkrystallisert fra etylacetat); TLC av basen viste én flekk, Rf 0,8 (EtOAc/Si02); [a]^<3> = -11,7° (1,0% MeOH).
Analyse:
Beregnet for <C>32<H>36<N>2°5'<C>4<H>4°4<:> C 67'°7' H 6'25' N 4'35 Funnet: C 66,58, H 6,09, N 4,25
Eksempel 7
2-[ 2-[[ 1- etoksykarbonyl)- 3- fenylpropyl] amino]- 1- oksopropyl]-1, 2, 3, 4- tetrahydro- 3- isokinolin- karboksylsyre- l, 1- dimetyletylester ( S, S, S)
En blanding av 8,38 g (0,03 mol) etyl-a-[(1-karboksyetyl)-amino]benzenbutanoat (fri aminosyre (S,S) (fremstilt ved fremgangsmåten ifølge eksempel 8), 8,09 g (0,03 mol) 1,2,3,4-tetrahydro-3-isokinolin-karboksylsyre-l,1-dimetyletylester-hydroklorid (S-form) (fremstilt ved fremgangsmåten ifølge eksempel 11), 4,05 g (0,03 mol) 1-hydroksybenzotriazol og 250 ml THF ble avkjølt i et isbad til 3-5°C. Under omrøring ble 3,04 g (0,03 mol) trietylamin tilsatt, og derefter ble en oppløsning av 6,92 g (0,0335 mol) dicykloheksylkarbodiimid i 30 ml THF langsomt tilsatt dråpevis i løpet av 20 minutter. Reaksjonsblandingen ble omrørt ved 3-5°C i 1 time. Isbadet ble fjernet, og reaksjonsblandingen ble omrørt i ytterligere
3 timer. Den separerte blanding av trietylamin-hydroklorid og dicykloheksylurinstoff ble fjernet ved filtrering og vasket med THF. Filtratet ble inndampet ved rotasjonsinndampning for å fjerne alle flyktige stoffer. Den resulterende gummi ble oppløst i ca. 300 ml etylacetat. Efter filtrering gjennom celite ble etylacetatoppløsningen ekstrahert 2 ganger med 100 ml av en mettet natriumbikarbonatoppløsning, en gang med 7 5 ml av en 2N sitronsyreoppløsning, en gang med 100 mi av en mettet natriumbikarbonatoppløsning og en gang med 100 ml av en mettet natriumkloridoppløsning. Efter tørring med vannfritt MgSO^
og filtrering, ble etylacetat fjernet ved rotasjonsinndampning for å gi 16,9 g av en lysebrun gummi. Denne gummi ble oppløst i 350 ml kokende heksan og dekantert gjennom celite. Heksan-oppløsningen ble avkjølt i is, kimpodet og omrørt inntil krystallisering var godt igang. Produktet ble filtrert, vasket med kald heksan og tørret, vekt 11,6 g (78%), sm.p. 68,5-71°C, [a]^3= -12,2° (2% MeOH). Rent materiale hadde sm.p. 71-72°C, [a] 3= -12,6° (2% MeOH). Maleatsaltet hadde sm.p. 127,5-128,5°C, [a]^<3>= +46,4 (2% MeOH).
Eksempel 8
Etyl- a-[ ( 1- karboksyetyl) amino] benzenbutanoat- hydroklorid ( S, S)
En oppløsning av 2,0 g t-butylalanin (S-form) og 3,78 g etyl-2-brom-4-fenylbutanoat i 25 ml dimetylformamid ble behandlet med 1,8 ml trietylamin, og oppløsningen ble oppvarmet ved 70°C
i 18 timer. Oppløsningsmidlet ble fjernet under redusert trykk, og residuet ble blandet med vann og ekstrahert med etyleter.
Det organiske lag ble vasket med vann og tørret over magnesium-sulfat. Konsentrering av oppløsningen under redusert trykk ga den oljeaktige t-butylester av mellomproduktet som ved gass-væske-kromatografi ble funnet å være tilstrekkelig ren for videre anvendelse.
En oppløsning av 143,7 g av denne t-butylester i 630 ml .trifluoreddiksyre ble omrørt ved romtemperatur i 1 time. Opp-løsningsmidlet ble fjernet under redusert trykk, og residuet ble oppløst i etyleter og inndampet påny. Denne operasjon ble gjentatt. Derefter ble eteroppløsningen behandlet dråpevis med en oppløsning av hydrogenklorid-gass i etyleter inntil utfelling opphørte. Det faste stoffet, som ble oppsamlet ved filtrering, var en blanding av diastereoisomerer,
sm.p. 153-165°C, [a]^<3>= +3,6° (1% MeOH).
For å fraskille den foretrukne S,S-isomer ble en suspensjon av 10,0 g av blandingen i 200 ml metylenklorid omrørt ved romtemperatur i 5 minutter og filtrert, det faste stoff ble vasket med ytterligere metylenklorid og til slutt med eter. Det faste materialet, sm.p. 202-208°C (spaltn.), [a]^<3>= -29,3° (1% MeOH) var den mindre foretrukne diastereoisomer med R,S-konfigurasjon
(S angir delen avledet fra L-alanin). Den foretrukne S,S-diastereoisomer ble erholdt fra filtratet efter konsentrering og utgnidning av resiudet med eter, sm.p. 137-139°C, [alD = +31,3°
(1% MeOH).
Den frie aminosyre (S,S-form) ble fremstilt ved behandling av en vandig.oppløsning av hydrokloridet med mettet natrium-acetat. Produktet ble filtrert, vasket godt med kaldt vann og omkrystallisert fra etylacetat, sm.p. 149-151°C,
[a]^<3>= +29,7° (1% 0,1N HC1).
Eksempel 9
1, 2, 3, 4- tetrahydro- 6, 7- dimetoksy- S- isokinolin- karboksylsyre-fenylmetylester- hydroklorid ( S- form)
En blanding av 1,2,3,4-tetrahydro-6,7-dimetoksy-3-isokinolinkarboksylsyre-hydroklorid (S-form) og 600 ml benzylalkohol ble mettet med hydrogenkloridgass. Temperaturen steg til 45°C. Blandingen ble omrørt ved romtemperatur i 3 dager. En relativt liten mengde av det faste stoffet ble frafiltrert> og filtratet ble behandlet med ca. 2 liter eter for å felle ut råproduktet, vekt 37,5 g, utbytte 83%. Rensning ble utført ved behandling med overskudd av mettet natriumbikarbonat, ekstraksjon av basen inn i etylacetat og utfelling av hydroklorid-saltet med HCl-gass. Omkrystallisering fra metanol-eter ga renset produkt, sm.p. 255-260°C, [a]p<3>= -81,3° (1,0% MeOH),
TLC (20% Me0H-CHCl3/Si02), én flekk Rf 0,8.
Analyse:
Beregnet for CigH21N04 • HC1: C 62 ,72 , H 6,10, N 3,85
Funnet: C 62,54, H 5,99, N 4,00.
Eksempel 10
1, 2, 3, 4- tetrahydro- 3- isokinolin- karboksylsyre- fenylmetylester-hydroklorid ( S- form)
Benzylalkohol, 750 ml, ble behandlet med 150 g kommersiell polyfosforsyre og oppvarmet og omrørt ved 90°C for å få en homogen blanding. Fast 1,2,3,4-tetrahydro-3-isokinolin-karboksylsyre (S-form), 165,2 g, ble tilsatt. Blandingen ble omrørt i 4 timer ved 95-105°C og fikk derefter stå ved romtemperatur i 18 timer. En oppløsning av 18,5 g gassformig saltsyre i 2,5 1 vannfri eter ble tilsatt, og produktet ble langsomt utskilt ved avkjøling natten over. Filtrering ga det rå benzyl-1,2,3,4-tetrahydro-3-isokinolin-karboksylat-hydroklorid. Dette ble renset ved omkrystallisering to ganger fra etanol for å gi materialet med sm.p. 190,5-191°C,
[a]^<3>= -83,3° (1% 1:1 metanol/lN saltsyre).
Eksempel 11
1, 2, 3, 4- tetrahydro- 3- isokinolinkarboksylsyre- l, 1- dimetyletylester- hydroklorid ( S- form)
Denneforbindelsen ble fremstilt ved at 447 g isobutylen ble ført inn i en 0°C oppløsning av 63,5 g 1,2,3,4-tetrahydro-3-isokinolin-karboksylsyre (S-form) i 650 ml tørr dioksan og 65 ml konsentrert svovelsyre under nitrogen. Reaksjonskaret ble forseglet og rystet i 17 timer ved romtemperatur. Reaksjonskaret ble luftet, og reaksjonsblandingen ble hellet-over i 25 1 kald 2N natriumhydroksyd. Produktet ble ekstrahert inn i eter. Eteroppløsningen ble vasket med vann, tørret og konsentrert til ca. 500 ml. Denne oppløsning ble behandlet med overskudd av 6N isopropanolisk saltsyre for å felle ut produktet, som ble oppsamlet ved filtrering. En prøve som var renset ved omkrystallisering fra etanol/eter hadde sm.p. 190-192°C (spaltn.), [a]<p3> = -88,7° (2% MeOH).
Claims (3)
1. Analogifremgangsmåte for fremstilling av et terapeutisk aktivt substituert acylderivat av 1,2,3,4-tetrahydro-isokinolin-3-karboksylsyre (S,S,S) med formelen
hvor
R er hydrogen, t-butyl eller benzyl,
Ri er hydrogen eller lavere alkyl,
R2 er hydrogen, metyl eller etyl, og
X og Y er uavhengig av hverandre hydrogen, lavere alkyl, lavere alkoksy eller hydroksy,
hvor lavere alkyl og lavere alkoksy inneholder 1 til 4 lineære eller forgrenede karbonatomer;
og de farmasøytisk godtagbare salter derav, karakterisert ved peptidkobling av et passende substituert 1,2,3,4-tetrahydro-isokinolin-3-karboksylat med formelen
med en N-substituert aminosyre med formelen
hvor Rj_, R2, X og Y er som definert ovenfor, og R 3 er en passende blokkert karboksylsyregruppe, og eventuelt fjernelse av beskyttelsesgruppe(r), idet utgangsmaterialene eventuelt anvendes som salt, eller den fremstilte forbindelse omdannes til salt.
2. Fremgangsmåte som angitt i krav 1 for fremstilling av 2~[2~[[1-(etoksykarbonyl)-3-fenylpropyl]amino]-1-oksopropyl]-1,2,3,4-tetrahydro-6,7-dimetoksy-3-isokinolinkarboksylsyre-hydroklorid-hydrat (S,S,S), karakterisert ved at det anvendes utgangsmaterialer hvor R2 er etyl, R^ er metyl, og X og Y er hver metoksy.
3. Fremgangsmåte som angitt i krav 1 for fremstilling av 2_[2-[[1-(etoksykarbonyl)-3-fenylpropyl]amino]-1-oksopropyl]-1,2,3,4-tetrahydro-3-isokinolinkarboksylsyre-hydroklorid-hydrat (S,S,S)', karakterisert ved at det anvendes utgangsmaterialer hvor R2 er etyl, er metyl og X og Y er hver hydrogen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US19376780A | 1980-10-03 | 1980-10-03 | |
| US06/236,397 US4344949A (en) | 1980-10-03 | 1981-02-20 | Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO813359L NO813359L (no) | 1982-04-05 |
| NO159017B true NO159017B (no) | 1988-08-15 |
| NO159017C NO159017C (no) | 1988-11-23 |
Family
ID=26889329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO813359A NO159017C (no) | 1980-10-03 | 1981-10-02 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 1,2,3,4-tetrahydroisokinolin-3-karboksylsyre-derivater. |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4344949A (no) |
| EP (2) | EP0096157B1 (no) |
| JP (1) | JPS5788164A (no) |
| KR (1) | KR880001326B1 (no) |
| AT (2) | ATE25974T1 (no) |
| AU (2) | AU551239B2 (no) |
| CA (3) | CA1341330C (no) |
| DD (1) | DD201787A5 (no) |
| DE (3) | DE3176010D1 (no) |
| DK (1) | DK163120C (no) |
| ES (1) | ES505960A0 (no) |
| FI (2) | FI78690C (no) |
| GR (1) | GR75353B (no) |
| HK (1) | HK43389A (no) |
| IE (2) | IE52666B1 (no) |
| IL (1) | IL63806A (no) |
| LU (1) | LU88321I2 (no) |
| MX (1) | MX155144A (no) |
| MY (1) | MY100440A (no) |
| NL (2) | NL930077I2 (no) |
| NO (1) | NO159017C (no) |
| PH (1) | PH17740A (no) |
| SG (1) | SG15689G (no) |
Families Citing this family (169)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4460775A (en) * | 1979-08-09 | 1984-07-17 | Norwich Eaton Pharmaceuticals, Inc. | 2-(3-Mercapto-1-oxopropyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid derivatives |
| US4595675A (en) * | 1979-09-19 | 1986-06-17 | Hoechst Aktiengesellschaft | Bicyclic α-iminocarboxylic acid compounds having hypotensive activity |
| 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 |
| US4616030A (en) * | 1979-12-07 | 1986-10-07 | Adir | Perhydroindole-2-carboxylic acids as antihypertensives |
| US4644008A (en) * | 1979-12-07 | 1987-02-17 | Adir | Perhydroindole-2-carboxylic acids as antihypertensives |
| US4508729A (en) * | 1979-12-07 | 1985-04-02 | Adir | Substituted iminodiacids, their preparation and pharmaceutical compositions containing them |
| US4565819A (en) * | 1979-12-07 | 1986-01-21 | Adir | Substituted imino diacids, their preparation and pharmaceutical compositions which contain them |
| US4616031A (en) * | 1979-12-07 | 1986-10-07 | Adir | Perhydroindole-2-carboxylic acids as antihypertensives |
| US4616029A (en) * | 1979-12-07 | 1986-10-07 | Adir | Perhydromdole-2-carboxylic acids as antihypertensives |
| DE3177311D1 (de) * | 1980-08-30 | 1994-06-09 | Hoechst Ag | Aminosäurederivate, Verfahren zu ihrer Herstellung, diese enthaltende Mittel und deren Verwendung. |
| ZA817261B (en) * | 1980-10-23 | 1982-09-29 | Schering Corp | Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them |
| US4532342A (en) * | 1981-02-20 | 1985-07-30 | Warner-Lambert Company | N-substituted amino acids as intermediates in the preparation of acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids |
| IN156096B (no) * | 1981-03-19 | 1985-05-11 | Usv Pharma Corp | |
| EP0065301A1 (en) * | 1981-05-18 | 1982-11-24 | Merck & Co. Inc. | Isoquinoline carboxylic acid derivates, process for preparing and pharmaceutical composition containing the same |
| DE3134933A1 (de) * | 1981-09-03 | 1983-03-31 | Hoechst Ag, 6230 Frankfurt | "harnstoffderivate, verfahren zu ihrer herstellung und diese enthaltende medikamente sowie deren verwendung" |
| DE3226768A1 (de) * | 1981-11-05 | 1983-05-26 | Hoechst Ag, 6230 Frankfurt | Derivate der cis, endo-2-azabicyclo-(3.3.0)-octan-3-carbonsaeure, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung |
| EP0081094A1 (en) * | 1981-11-12 | 1983-06-15 | Merck & Co. Inc. | Substituted omega-amino-carboxymethyldipeptide antihypertensive agents |
| CA1341296C (en) * | 1981-12-29 | 2001-09-25 | Hansjorg Urbach | 2-azabicycloalkane-3-carboxylic acid derivatives, processes for their preparation, agents containing these compounds and their use |
| IE54551B1 (en) * | 1982-01-22 | 1989-11-22 | Ici Plc | Amide derivatives |
| US4665087A (en) * | 1982-02-22 | 1987-05-12 | Ciba-Geigy Corporation | 1-(carbamyl, thiocarbamyl, and iminocarbamyl)-indoline derivatives |
| US4483850A (en) * | 1982-05-10 | 1984-11-20 | Merck & Co., Inc. | N-Terminal substituted oligopeptide converting enzyme inhibitors |
| US4617291A (en) * | 1982-05-14 | 1986-10-14 | Mead Johnson & Company | Angiotensin-converting enzyme inhibiting dipeptide derivatives |
| US4427665A (en) | 1982-05-19 | 1984-01-24 | E. R. Squibb & Sons, Inc. | Phosphinylalkanoyl substituted imino acids and their use in hypotensive compositions |
| AU560285B2 (en) * | 1982-07-19 | 1987-04-02 | Imperial Chemical Industries Plc | Heterocyclyl carbonyl sulphonamides |
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-
1981
- 1981-02-20 US US06/236,397 patent/US4344949A/en not_active Expired - Lifetime
- 1981-09-09 IE IE1566/87A patent/IE52666B1/en not_active IP Right Cessation
- 1981-09-09 IE IE2097/81A patent/IE52665B1/en not_active IP Right Cessation
- 1981-09-11 IL IL63806A patent/IL63806A/xx not_active IP Right Cessation
- 1981-09-17 AU AU75416/81A patent/AU551239B2/en not_active Expired
- 1981-09-18 PH PH26222A patent/PH17740A/en unknown
- 1981-09-28 GR GR66144A patent/GR75353B/el unknown
- 1981-09-30 CA CA000387002A patent/CA1341330C/en not_active Expired - Lifetime
- 1981-09-30 FI FI813033A patent/FI78690C/fi not_active IP Right Cessation
- 1981-10-01 JP JP56154900A patent/JPS5788164A/ja active Granted
- 1981-10-01 DE DE8181304541T patent/DE3176010D1/de not_active Expired
- 1981-10-01 EP EP83102092A patent/EP0096157B1/en not_active Expired
- 1981-10-01 EP EP81304541A patent/EP0049605B1/en not_active Expired
- 1981-10-01 DK DK436081A patent/DK163120C/da not_active IP Right Cessation
- 1981-10-01 AT AT81304541T patent/ATE25974T1/de active
- 1981-10-01 DE DE8383102092T patent/DE3176029D1/de not_active Expired
- 1981-10-01 AT AT83102092T patent/ATE26120T1/de active
- 1981-10-01 DE DE1995175041 patent/DE19575041I2/de active Active
- 1981-10-02 MX MX7585A patent/MX155144A/es unknown
- 1981-10-02 ES ES505960A patent/ES505960A0/es active Granted
- 1981-10-02 NO NO813359A patent/NO159017C/no not_active IP Right Cessation
- 1981-10-02 KR KR1019810003713A patent/KR880001326B1/ko active
- 1981-10-02 DD DD81233850A patent/DD201787A5/de not_active IP Right Cessation
-
1986
- 1986-02-04 AU AU52991/86A patent/AU563683C/en not_active Expired
-
1987
- 1987-09-16 MY MYPI87001697A patent/MY100440A/en unknown
-
1988
- 1988-04-27 FI FI881985A patent/FI79839C/fi not_active IP Right Cessation
-
1989
- 1989-03-13 SG SG156/89A patent/SG15689G/en unknown
- 1989-05-25 HK HK433/89A patent/HK43389A/xx not_active IP Right Cessation
-
1992
- 1992-06-23 CA CA000616411A patent/CA1331614C/en not_active Expired - Lifetime
- 1992-06-23 CA CA000616412A patent/CA1331615C/en not_active Expired - Lifetime
-
1993
- 1993-06-17 NL NL930077C patent/NL930077I2/nl unknown
- 1993-06-22 LU LU88321C patent/LU88321I2/fr unknown
-
1996
- 1996-05-14 NL NL960012C patent/NL960012I2/nl unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK1K | Patent expired |
Free format text: EXPIRED IN OCTOBER 2001 |