NO153730B - Analogifremgangsmaate ved fremstilling av terapeutisk aktivt 10-brom-e-homo-eburnan. - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk aktivt 10-brom-e-homo-eburnan. Download PDFInfo
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- NO153730B NO153730B NO802403A NO802403A NO153730B NO 153730 B NO153730 B NO 153730B NO 802403 A NO802403 A NO 802403A NO 802403 A NO802403 A NO 802403A NO 153730 B NO153730 B NO 153730B
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- Prior art keywords
- acid
- general formula
- homo
- compound
- preparation
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- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- -1 methyl- Chemical group 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000017531 blood circulation Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000002792 vascular Effects 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 2
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical class C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- 241000320529 Allobates femoralis Species 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- DDPMGIMJSRUULN-UHFFFAOYSA-N buphedrone Chemical compound CCC(NC)C(=O)C1=CC=CC=C1 DDPMGIMJSRUULN-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000004004 carotid artery internal Anatomy 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- ZHGASCUQXLPSDT-UHFFFAOYSA-N cyclohexanesulfonic acid Chemical compound OS(=O)(=O)C1CCCCC1 ZHGASCUQXLPSDT-UHFFFAOYSA-N 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960002726 vincamine Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Description
Oppfinnelsen angår en analogifremgangsmåte ved fremstilling av terapeutisk aktivt 10-brom-E-homo-eburnan, dets epimerer, optisk aktive antipoder og fysiologisk akseptable syreaddisjonssalter.
Den nye forbindelse svarer til den generelle formel I
Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at et racemisk eller optisk aktivt 9-halogen-octahydro-indolochinolizin-derivat av generell formel II
hvori R"*" betegner en alkylgruppe med 1-6 carbonatomer, eller syreaddisjonssalter av disse forbindelser, behandles med en sterk base, og, om ønsket, at den erholdte forbindelse av generell formel I separeres i sine 15-epimerer og/eller sine optisk aktive antipoder, og/eller omdannes til fysiologisk akseptable syreaddisjonssalter.
Forbindelsen av generell formel I utviser en
verdifull karutvidende virkning.
Alkylgruppen R i forbindelsene av generell
formel II er rettkjedede eller forgrenede alkylgrupper,
f.eks. methyl-, ethyl-, n-propyl-, i-propyl-, n-butyl-, sek.-butyl-, tert.-butyl-, n-pentyl-, i-pentyl-, n-hexyl-eller i-hexylgruppe.
Utgangsforbindelsene av generell formel II kan fremstilles som beskrevet i norsk patent 147 340.
Denne fremgangsmåte består i at et 9-halogen-l,2,3,4,6,7-hexahydro-indol-[2,3-a]chinolisin-derivat omsettes med 2-acyloxyacrylsyreestere, og de erholdte 1-(2'-acyloxy-2'-alkyloxycarbonyl-ethyl)-9-halogen-l,2,3,4,6,7-hexahydro-indol-[2,3-a]chinolizin-derivater reduseres enten først og deretter desacyleres, eller desacyleres først og reduseres deretter.
Forbindelsene av generell formel II omsettes med sterke baser. Som sterke baser anvendes eksempelvis føl-gende: Alkalihydrider slik som natriumhydrid, eller alkali-alkoholater slik som natriummethylat, natriumethylat, natrium-tert..-butylat, kalium-tert.-butylat osv., alkali-amider slik som f.eks. natriumamid, kaliumamid osv., eller alkalidialkylamider slik som f.eks. lithiumdiisopropylamid.
Den alkaliske behandling utføres i et inert aprotisk apolart organisk løsningsmiddel. Som løsningsmid-del anvendes eksempelvis aromatiske hydrocarboner slik som benzen, toluen eller xylen.
Den alkaliske behandling utføres fortrinnsvis ved en temperatur nær det anvendte løsningsmiddels kokepunkt.
Ved fremgangsmåten erholdes 15-epimerblandingen
av forbindelsen av generell formel I. Denne blanding kan om ønsket spaltes i de enkelte epimerer. Dette skjer hen-siktsmessig ved hjelp av preparativ tynnskiktskromatografi.
Forbindelsen av generell formel I kan omsettes
med egnede syrer til sine syreaddisjonssalter.
For saltdannelsen vil eksempelvis følgende syrer komme i betraktning: uorganiske syrer slik som hydrogenhalo-genider (saltsyre, hydrobromsyre), svovelsyre, fosforsyre, salpetersyre, perhalogensyrer (f.eks. perklorsyre), organiske carbonsyrer slik som maursyre, eddiksyre, propionsyre, glycolsyre, maleinsyre, hydroxymaleinsyre, fumarsyre. salicylsyre, melkesyre, kanelsyre, benzoesyre, fenyleddik-syre, p-aminobenzoesyre, p-hydroxybenzoesyre, p-aminosali-cylsyre osv., alkylsulfonsyrer (f.eks. methansulfonsyre, ethansulfonsyre osv.), cycloalifatiske sulfonsyrer (f.eks. cyclohexylsulfonsyre), arylsulfonsyrer (f.eks. p-toluen-sulfonsyre, nafthylsulfonsyre, sulfanilsyre osv.), og amino-syrer (f.eks. asparaginsyre, glutaminsyre osv.).
Racematet av forbindelsen av generell formel I kan på kjent måte separeres i de optiske antipoder. For fremstilling av optisk aktive forbindelser av generell formel I kan man imidlertid også utgå fra optisk aktive forbindelser av generell formel II.
Den ifølge oppfinnelsen fremstilte forbindelse av generell formel I (som racemat eller optisk aktive forbindelser) , sine epimerer eller syreaddisjonssalter kan om ønsket ytterligere renses, f.eks. ved omkrystallisering. Valget av egnet løsningsmiddel for omkrystalliseringen av-henger av løselighets- og krystalliseringsegenskapene til den enkelte substans.
Forbindelsen av generell formel I erholdes i en godt identifiserbar form. IR- og massespektrene for den fremstilte forbindelse er i overensstemmelse med den angitte struktur.
Virkningen av forbindelsen av generell formel I på blodkretsløpet ble undersøkt.
Undersøkelsene ble foretatt med kloralose-urethan-narkotiserte hunder. Det arterielle blodtrykk, puls, blod-strømning i Arteria femoralis og Arteria carotis interna såvel som karmotstand i begge karområder (Karmotstand = blodtrykk: blodstrømning i de angjeldende karområder) ble målt. Den vandige løsning av substansen ble administrert intravenøst i en dose på 1 mg/kg kroppsvekt. Pr. substans ble det foretatt 5-6 forsøk. Som referanseforbindelse ble det anvendt det kjente vincamin. Forsøksresultatene er opp-ført i de etterfølgende tabeller.
Betydning av forkortelser:
MABP = midlere arterielt blodtrykk (mmHg9
HR = Puls (min<-1>)
CBF = Blodstrømning i A. carotis interna (ml min "*")
CVR = Karmotstand i området ved A. carotis mmHg min ml FBF = Blodstrømning i A. fermoralis (ml min ^)
FVR = Karmotstand i området ved A. Femoralis (mmHg min ml "*")
Fra de i tabellen angitte data er det tydelig at 10-brom-14-oxo-15-hydroxy-E-homo-eburnan(3a,17a) intravenøst på narkotiserte hunder i en dose på 1 mg/kg neppe påvirker blodtrykket og pulsen, dvs. at den systemiske virkning på kretsløpet er fordelaktig liten. I karområdet for A. carotis forårsaker forbindelsen en 25 %-ig karutvidelse, som svarer til en 21 %-ig blodgjennomstrømningsøkning. Særlig fordelaktig er det at forbindelsen praktisk talt ikke har noen annen virkning på kretsløpet.
Forbindelsen av generell formel I er på grunn av deres karutvidende virkning egnet for anvendelse innen tera-pien .
Virkestoffet av generell formel I kan formuleres
med de innen farmasien vanlige, ikke-toksiske, inerte faste eller flytende bærer og/eller hjelpestoffer for parenteral eller enteral administrering.
Oppfinnelsen belyses ytterligere i det etter-følgende eksempel.
Eksempel
10- brom- 14- oxo- 15- hydroxy- E- homo- eburnan ( 3a, 17a)
Til en suspensjon av 3,0 g (6,9 mmol) 9-brom-la-ethyl-1-[2-hydroxy-2-(methoxycarbonyl)-ethyl]-1,2,3,4,5,6,7,12-octahydro-12ba-H-indol[2,3-a]-chinolizin i 200 ml tørr toluen og 2,8 ml (2,6 g) acetofenon ble tilsatt 0,30 g (2,7 mmol) kaliumtert.-butylat. Reaksjonsblandingen ble kokt under tilbakeløpskjøling under argonatmosfære og under stadig omrøring i 4 timer. Deretter ble blandingen avkjølt til 0° C og deretter utristet fire ganger med 3 0 ml kald 2,5 %-ig vandig svovelsyre. De forenede vandige faser ble under av-kjøling gjort alkalisk til pH 10 med 25 %-ig vandig ammoniakk og ble deretter ekstrahert tre ganger med 30 ml diklormethan. De organiske faser ble tørket over magnesiumsulfat, filtrert hvorpå filtratet ble inndampet i vakuum og residuet ble omkrystallisert fra 10 ml methanol. 1,85 g (66,6 %) produkt i form av epimerblanding ble erholdt. Smeltepunkt: 2 06 -
208° C. Bruttoformel: C2oH23BrN202 (M = 403,33).
Epimerblandingen ble separert ved hjelp av preparativ tynnskiktskromatografi i de enkelte epimerer. Som adsorbent ble anvendt en kiselgelplate (<p>F254+366 ^ 20 x 20 x 1,5 mm, og som drivmiddel ble det anvendt en 14:3-blanding av benzen-methanol. Produktet ble eluert med diklormethan. Epimer A ble omkrystallisert fra 5 ml methanol og epimer B
fra 10 ml methanol.
Fra den øvre flekk ble det erholdt 0,4 g epimer A. Utbytte: 21,6 %. Sm.p.: 177 - 178° C. IR-spektrum (i KBr): Y maks 4400 cm"<1> (-OH), 1660 cm"<1> (Amid-CO).
MS(m/e): 404, 403, 402, 401, 376, 360, 358, 347, 345,
332, 339, 317, 315, 303, 301, 277, 275, 180, 167, 153, 140.
Fra den nedre flekk ble det erholdt 1,25 g epimer B. Utbytte: 67,6 %. Sm.p.: 214 - 216° C. IR-spektrum
(i KBr): Ymaks 3400 cm"<1> (-OH), 1685 cm"<1> (Amid-CO).
MS (m/e): 404, 403, 402, 401, 376, 374, 360, 358, 347,
345, 332, 339, 303, 301, 277, 275, 180, 167,
153, 140.
NMR-spektrum (i deuteroklorform):
6 ': 0,96 (t, 3H, -CH3)
6 : 7,39 - 8,24 (m, 3H, aromat. H)
Cg-H = 7,51 ppm J^2 g = 0,2 Hz (para)
C-q-H = 7,39 ppm 12 = 8,7 Hz (ortho)
C12"H = 8,24 ppm J^ g = 2,8 Hz (meta).
Claims (1)
- Analogifremgangsmåte ved fremstilling av terapeutisk aktivt10-brom-E-homo-eburnan av generell formel Isåvel som epimerer, optisk aktive antipoder og fysiologisk akseptable syreaddisjonssalter av denne forbindelse, karakterisert ved at et racemisk eller optisk aktivt 9-halogen-octahydro-indolochinolizin-derivat av generell formel II hvori R<1> betegner en alkylgruppe med 1-6 carbonatomer, eller syreaddisjonssalter av disse forbindelser, behandles med en sterk base, og, om ønsket, at den erholdte forbindelse av generell formel I separeres i sine 15-epimerer og/eller sine optisk aktive antipoder, og/eller omdannes til fysiologisk akseptable syreaddisjonssalter.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU79RI723A HU181496B (en) | 1979-08-13 | 1979-08-13 | Process for preparing 10-bromo-15-hydroxy-e-homo-eburnanes |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO802403L NO802403L (no) | 1981-02-16 |
| NO153730B true NO153730B (no) | 1986-02-03 |
| NO153730C NO153730C (no) | 1986-05-14 |
Family
ID=11001106
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO802403A NO153730C (no) | 1979-08-13 | 1980-08-12 | Analogifremgangsmaate ved fremstilling av terapeutisk aktivt 10-brom-e-homo-eburnan. |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4285950A (no) |
| JP (1) | JPS5629590A (no) |
| AT (1) | AT375940B (no) |
| AU (1) | AU541869B2 (no) |
| BE (1) | BE884472A (no) |
| CA (1) | CA1140121A (no) |
| CH (1) | CH644123A5 (no) |
| DE (1) | DE3026584A1 (no) |
| DK (1) | DK154431C (no) |
| ES (1) | ES494211A0 (no) |
| FI (1) | FI67382C (no) |
| FR (1) | FR2463141A1 (no) |
| GB (1) | GB2058759B (no) |
| HU (1) | HU181496B (no) |
| IL (1) | IL60827A (no) |
| IT (1) | IT1132404B (no) |
| NL (1) | NL8004565A (no) |
| NO (1) | NO153730C (no) |
| NZ (1) | NZ194654A (no) |
| PH (1) | PH16023A (no) |
| SE (1) | SE436881B (no) |
| SU (1) | SU993819A3 (no) |
| ZA (1) | ZA804922B (no) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU180927B (en) * | 1979-07-13 | 1983-05-30 | Richter Gedeon Vegyeszet | Process for producing 1k-hydroximino-e-homoe-eburane de rivatives |
| HU180929B (en) * | 1979-08-13 | 1983-05-30 | Richter Gedeon Vegyeszet | Process for producing new bromo-vincamone derivatives |
| FR2487836A1 (fr) * | 1980-07-31 | 1982-02-05 | Richter Gedeon Vegyeszet | Nouveaux derives halogenes du 15-hydroxy-e-homoeburnane et leur procede de preparation |
| HU190399B (en) * | 1982-06-30 | 1986-08-28 | Richter Gedeon Vegyeszeti Gyar Rt,Hu | Process for the production of e-homo-eburnane-derivatives |
| AT383599B (de) * | 1982-06-30 | 1987-07-27 | Richter Gedeon Vegyeszet | Verfahren zur herstellung von neuen racemischen und optisch aktiven e-homo-eburnan-derivaten sowievon saeureadditions-salzen derselben |
| US4481204A (en) * | 1983-06-29 | 1984-11-06 | Richter Gedeon Vegyeszeti Gyar R.T. | E-Homo-eburnane derivatives, process for their preparation, and pharmaceutical compositions containing these compounds |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3770724A (en) * | 1970-03-31 | 1973-11-06 | Roussel Uclaf | Process for preparing pentacyclic alkaloids |
| FR2206090A1 (en) * | 1972-11-16 | 1974-06-07 | Omnium Chimique Sa | Homovincamone-contg. medicaments - with vasodilating, spasmolytic anti-arrhythmic and anti-ischaemic properties |
| GB2010833B (en) * | 1977-11-25 | 1982-04-15 | Scras | Homoerburnamine preparation |
| DE2922316A1 (de) * | 1978-06-12 | 1979-12-20 | Omnium Chimique Sa | Neue halogenderivate des vincamins, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
| HU177732B (en) * | 1978-12-15 | 1981-12-28 | Richter Gedeon Vegyeszet | Process for producing 10-bromo-vincamine and acid additional salts thereof,and 10-bromo-14-epivincamine |
| HU180927B (en) * | 1979-07-13 | 1983-05-30 | Richter Gedeon Vegyeszet | Process for producing 1k-hydroximino-e-homoe-eburane de rivatives |
-
1979
- 1979-08-13 HU HU79RI723A patent/HU181496B/hu not_active IP Right Cessation
-
1980
- 1980-07-14 DE DE19803026584 patent/DE3026584A1/de not_active Withdrawn
- 1980-07-22 PH PH24325A patent/PH16023A/en unknown
- 1980-07-25 BE BE1/9906A patent/BE884472A/fr not_active IP Right Cessation
- 1980-08-05 US US06/175,383 patent/US4285950A/en not_active Expired - Lifetime
- 1980-08-11 GB GB8026072A patent/GB2058759B/en not_active Expired
- 1980-08-12 AU AU61370/80A patent/AU541869B2/en not_active Ceased
- 1980-08-12 CA CA000358098A patent/CA1140121A/en not_active Expired
- 1980-08-12 NZ NZ194654A patent/NZ194654A/xx unknown
- 1980-08-12 SU SU802957550A patent/SU993819A3/ru active
- 1980-08-12 DK DK348080A patent/DK154431C/da not_active IP Right Cessation
- 1980-08-12 SE SE8005687A patent/SE436881B/sv not_active IP Right Cessation
- 1980-08-12 NL NL8004565A patent/NL8004565A/nl not_active Application Discontinuation
- 1980-08-12 NO NO802403A patent/NO153730C/no unknown
- 1980-08-12 JP JP10989380A patent/JPS5629590A/ja active Granted
- 1980-08-12 AT AT0412780A patent/AT375940B/de not_active IP Right Cessation
- 1980-08-12 FR FR8017733A patent/FR2463141A1/fr active Granted
- 1980-08-12 FI FI802535A patent/FI67382C/fi not_active IP Right Cessation
- 1980-08-12 ZA ZA00804922A patent/ZA804922B/xx unknown
- 1980-08-12 IL IL60827A patent/IL60827A/xx unknown
- 1980-08-12 CH CH608480A patent/CH644123A5/de not_active IP Right Cessation
- 1980-08-13 ES ES494211A patent/ES494211A0/es active Granted
- 1980-08-13 IT IT24151/80A patent/IT1132404B/it active
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