NO144928B - Analogifremgangsmaate for fremstilling av fysiologisk aktive zantinderivater - Google Patents
Analogifremgangsmaate for fremstilling av fysiologisk aktive zantinderivater Download PDFInfo
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- NO144928B NO144928B NO754317A NO754317A NO144928B NO 144928 B NO144928 B NO 144928B NO 754317 A NO754317 A NO 754317A NO 754317 A NO754317 A NO 754317A NO 144928 B NO144928 B NO 144928B
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- Prior art keywords
- general formula
- denotes
- carbon atoms
- compound
- alkyl
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- 238000002360 preparation method Methods 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 13
- -1 ethylene, propylene Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-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
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RZQGAZNVNHJIRY-UHFFFAOYSA-N 1,3-diethyl-7-[2-[[3-(2-hexoxyphenoxy)-2-hydroxypropyl]-methylamino]ethyl]purine-2,6-dione;oxalic acid Chemical compound OC(=O)C(O)=O.CCCCCCOC1=CC=CC=C1OCC(O)CN(C)CCN1C(C(=O)N(CC)C(=O)N2CC)=C2N=C1 RZQGAZNVNHJIRY-UHFFFAOYSA-N 0.000 description 1
- OMJXKARLAOMALQ-UHFFFAOYSA-N 1,3-diethyl-7-[2-[ethyl-[2-hydroxy-3-(2-phenylmethoxyphenoxy)propyl]amino]ethyl]purine-2,6-dione;hydrochloride Chemical compound Cl.C1=NC=2N(CC)C(=O)N(CC)C(=O)C=2N1CCN(CC)CC(O)COC1=CC=CC=C1OCC1=CC=CC=C1 OMJXKARLAOMALQ-UHFFFAOYSA-N 0.000 description 1
- ZFDICOQGZFUKNO-UHFFFAOYSA-N 1-(methylamino)-3-(2-phenylmethoxyphenoxy)propan-2-ol Chemical compound C(C1=CC=CC=C1)OC1=C(OCC(CNC)O)C=CC=C1 ZFDICOQGZFUKNO-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- IXYPCFPAFIVIGP-UHFFFAOYSA-N 7-(3-bromopropyl)-1,3-dimethylpurine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CCCBr)C=N2 IXYPCFPAFIVIGP-UHFFFAOYSA-N 0.000 description 1
- YYCFJLRBJHOATJ-UHFFFAOYSA-N 7-[2-(N-[2-hydroxy-3-(2-phenylmethoxyphenoxy)propyl]-4-methylanilino)ethyl]-1,3-dimethylpurine-2,6-dione hydrochloride Chemical compound Cl.C1=CC(C)=CC=C1N(CC(O)COC=1C(=CC=CC=1)OCC=1C=CC=CC=1)CCN1C(C(=O)N(C)C(=O)N2C)=C2N=C1 YYCFJLRBJHOATJ-UHFFFAOYSA-N 0.000 description 1
- ZALZLOKXTMWBPN-UHFFFAOYSA-N 7-[2-(N-[2-hydroxy-3-(2-phenylmethoxyphenoxy)propyl]anilino)ethyl]-1,3-dimethylpurine-2,6-dione hydrochloride Chemical compound Cl.C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCN(C=1C=CC=CC=1)CC(O)COC1=CC=CC=C1OCC1=CC=CC=C1 ZALZLOKXTMWBPN-UHFFFAOYSA-N 0.000 description 1
- NFGVOOCGFHLQLA-UHFFFAOYSA-N 7-[2-[[2-hydroxy-3-(2-phenylmethoxyphenoxy)propyl]-methylamino]ethyl]-1,3-dimethylpurine-2,6-dione;hydrochloride Chemical compound Cl.C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCN(C)CC(O)COC1=CC=CC=C1OCC1=CC=CC=C1 NFGVOOCGFHLQLA-UHFFFAOYSA-N 0.000 description 1
- ZMBAHWGQGJCXNJ-UHFFFAOYSA-N 7-[2-[bis[2-hydroxy-3-(2-phenylmethoxyphenoxy)propyl]amino]ethyl]-1,3-diethylpurine-2,6-dione;hydrochloride Chemical compound Cl.C1=2C(=O)N(CC)C(=O)N(CC)C=2N=CN1CCN(CC(O)COC=1C(=CC=CC=1)OCC=1C=CC=CC=1)CC(O)COC1=CC=CC=C1OCC1=CC=CC=C1 ZMBAHWGQGJCXNJ-UHFFFAOYSA-N 0.000 description 1
- GPKSGFNPIZESBZ-UHFFFAOYSA-N 7-[3-[butyl-[2-hydroxy-3-(2-phenylmethoxyphenoxy)propyl]amino]propyl]-1,3-dimethylpurine-2,6-dione 2,3-dihydroxybutanedioic acid Chemical compound OC(=O)C(O)C(O)C(O)=O.C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(CCCC)CC(O)COC1=CC=CC=C1OCC1=CC=CC=C1 GPKSGFNPIZESBZ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 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
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000047 product 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
- 230000035484 reaction time Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/10—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 3 and 7, e.g. theobromine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Denne oppfinnelse angår fremstilling av nye fysiologisk aktive xantinderivatér med den generelle formel
og syreaddisjonssal-éer derav,.
I denne formel betyr : -.- •
1
R og R en metyl- eller etylgruppe,
Q en etylen-, propylen- eller isopropylengruppe',
A en 3-fenoksy-2-hydroksypropylrest hvor fenylringen kan være substituert i o-stilling med n-heksyloksy eller benzyloksy,
B en alkylgruppe med 1-4 karbonatomer, en fenyl- eller p-metyl-fenylgruppe eller A. De nye forbindelser fremstilles ifølge oppfinnelsen ved at
a) en forbindelse med den generelle formel
(hvor R, R1 og Q har de ovenfor angitte betydninger og D betyr et hydrogenatom, en alkylgruppe med 1-4 karbonatomer, en fenyl-eller p-tolylgruppe) omsettes med en forbindelse med den generelle formel
hvor X betyr en benzyl- eller n-heksylgruppe.
b) Når B er alkyl med 1-4 karbonatomer, omsettes en forbindelse med formelen
(hvor R, R"*" og Q har de ovenfor angitte betydninger, og ' Hal betyr et halogenatom) med en forbindelse med formelen
(hvor Y betyr en alkylgruppe med 1-4 karbonatomer,. og X har
den ovenfor angitte betydning).
Ved fremgangsmåte a) oppvarmes reaksjonskomponentene, eventuelt under tilsetning av et inert oppløsningsmiddel så som benzen, toluen, xylen, mesitylen eller dioksan, til. en temperatur på ca. 160 - 12d°C eller til tilbakeløpstemperatur-. Reaksjonstiden er ca. 15 minutter til noen timer og er avhengig av de til enhver tid anvendte utgangsmaterialer. Efter av- f kjøling til ca. 60 - 80°C settes det til reaksjonsblandingen et egnet oppløsningsmiddel, fortrinnsvis en lavere alkohol, og oppløsningen bringes til en pH-verdi på l ved tilsetning av en syre. Efter vanlig opparbeidelse får man sluttproduktene i almindelighet med utmerkede utbytter.
Omsetning b) foretas ved oppløsning av reaksjonskomponentene i et egnet oppløsningsmiddel så som dioksan/vann, dimetylformamid/vann eller en alkohol, og oppvarmning under tilbakeløpskjøling inntil omsetningen er avsluttet. Også her opparbeides reaksjonsblandingen på vanlig måte.
De således erholdte sluttprodukter med den generelle formel
I kan på vanlig måte overføres til syreaddisjonssaltene derav.
For denne omsetning kan f.eks. anvendes slike syrer som fører til fysiologisk godtagbare salter, f.eks. halogenhydrogensyrer, salpetersyre, svovelsyre, o-fosforsyre, oksalsyre, sitronsyre, vinsyre, maleinsyre, propionsyre, smørsyre, eddiksyre, metan-eller toluensulfonsyre, råvsyre, nikotinsyre eller cykloheksyl-aminsulfonsyre.
Utgangsforbindelsene med den generelle formel II er delvis nye. De kan fremstilles,ved omsetning av dialkylxantinet med en passende kloralkanol, utskiftning av hydroksygruppen med eL kloratom ved hjelp av tionylklorid og påfølgende omsetning av kloralkylxantinet med et passende substituert amin.
De nye forbindelser med den generelle formel I og deres syreaddisjonssalter bevirker en forbedring av den perifere gjen-nomblødning i det mikrosirkulære areal, særlig en forbedring av hjernegjennomblødningen. De er i denne henseende tydelig over-legne i forhold til de kjente handelspreparater, f.eks. 7 [2-hydroksy-3-(N-2-hydroksyetyl-N-metylamino)-propyl]-1,3-dimetylxantin-pyridin-3-karboksylat både med hensyn til virkningsstyrke og virkningsvarighet.
Enkeltdosen ved anvendelse av forbindelsene med den generelle formel I utgjør ved oral administrering 10-500, fortrinnsvis 50-200 mg, den daglige dose er tilsvarende 30-1500, fortrinnsvis 150-600 mg. For injeksjon foreslås en dosering på 5-200, fortrinnsvis 10-100 mg pr. dose.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere.
Eksempel 1
7-( 2 - [ N- [ 3-( o- benzyloksyfenoksy)- 2- hydroksy- l- propyl]- N- metyl-amino 1- etyl)- 1, 3- dietylxantin- hydroklorid
113 g 1,3-dietyl-7-(3-metylaminoetyl)-xantin (sm.p. 101-104°C) blandes godt med 114,8 g l-epoksypropyl-2-benzyloksy-fenyleter og holdes i 30 minutter ved en temperatur mellom 180°C og 190°C. Man lar den klare, brungule smelte avkjøles til 80°C og oppløser den i alkohol. Den alkoholiske oppløsning bringes til pH 1 med alkoholisk saltsyre, avkjøles til romtemperatur og fortynnes med litt absolutt eter. De erholdte krystaller avsuges efter tre timers henstand ved romtemperatur og vaskes med etanol/eter 3:1.
Utbytte: 190,6 = 11. 1% av det teoretiske, sm.p. 85-90°C
Eksempel 2
7-( 3-[ N- 3-( o- benzyloksyfenoksy)- 2- hydroksy- l- propyl]- N- metyl-amino]- 1- propyl)- 1, 3- dimetylxantin- hydroklorid
15,1 g 1,3-dimetyl-7-(y-brompropyl)-xantin, 11,5 g N-[3-(o-benzyloksyfenoksy)-2-hydroksypropyl]-N-metylamin og
4,2 g natriumhydrogenkarbonat omrøres under ,tilbakeløpskjøling
i en blanding av 100 ml dioksan og 30 ml vann i 15 timer.
Residuet inndampes til tørrhet i vakuum, opptas i 500 ml
2N saltsyre og utrystes med kloroform. Efter tørring over magnesiumsulfat inndampes kloroformfasen i vakuum, residuet oppløses i 500 ml vann, og oppløsningen innstilles ved tilsetning av natriumhydroksydoppløsning på en pH-verdi >10. Derefter"utrystes det med kloroform, oppløsningen tørres over magnesiumsulfat og kloroformen avdampes i vakuum. For omdannelse av basen til hydrokloridet oppløses residuet i 1000 ml 2N saltsyre og utrystes flere ganger med kloroform. Kloroformekstraktene tørres over magnesiumsulfat og kloroformen avdampes.- Det gjenværende residuum oppløses i etanol og innstilles med alkoholisk saltsyre på en pH-verdi på mellom'1 og 2..<
Man oppnår den i overskriften angitte forbindelse i et utbytte på 8,7 g (40% av det teoretiske), sm.p. 150-153°C.
Analogt med de angitte fremstillingsmetoder ble følgende forbindelser fremstilt: 7- (2- [N,N-bis- [3- (o-benzyloksyfenoksy.) -2-hydroksy-l-propyl]-amino]-etyl)-1,3-dimetylxantin, sm.p. 132-138°C.
7-(2-[N-[3-(o-benzyloksyfenoksy)-2-hydroksy-l-propyl]-N-fenyl-amino]-etyl)-1,3-dimetylxantin-hydroklorid, sm.p. 102°C.
7-(2-[N-[3-(o-benzyloksyfenoksy)-2-hydroksy-l-propyl]-N-(p-tolyl) - amino]-etyl)-1,3-dimetylxantin-hydroklorid, sm.p. 176-179°C.
7-(2-[N-[3-(o-benzoyloksyfenoksy)-2-hydroksy-l-propyl]-N-n-butylamino]-etyl)-1,3-dimetylxantin-hydroklorid, sm.p. 176-180°C.
7-(2-[N-[3-(o-benzoyloksyfenoksy)-2-hydroksy-l-propyl]-N-ety1-amino]-etyl)-1,3-dimetylxantin-hydroklorid, sm.p. 166-169°C.
7-(2-[N,N-bis-[3- (o-benzyloksyfenoksy)-2-hydroksy-l-propyl]-amino]-etyl)-1,3-dietylxantin-hydroklorid, sm.p. 60°C.
7-(2-[N-[3-(o-benzyloksyfenoksy)-2-hydroksy-l-propyl]-N-etylamino]-etyl)-1, 3-dietylxantin-hydroklorid., sm.p. 115-116°C.
7-(2-[N-[3-(o-n-heksyloksyfenoksy)-2-hydroksy-l-propyl]-N-etyl-amino]-etyl)-1,3-dietylxantin-dihydroklorid, sm.p. 149-151°C.
7- (2-[N-[3- (o-n-heksyloksyfenoksy)-2-hydroksy-l-propyl]-N-metyl-amino]-etyl)-1,3-dietylxantin-oksalat, sm.p. 118-122°C.
7- (3-[N-[3-(o-benzyloksyfenoksy)-2-hydroksy-l-propyl]-N-n-buty1-amino]-l-propyl)-1,3-dimetylxantin-tartrat, sm.p. 91°C (spaltn.).
7-(2-[N-[3-(o-benzyloksyfenoksy)-2-hydroksy-l-propyl]-N-metyl-amino]-etyl)-1,3-dimetylxantin-hydroklorid, sm.p. 156-158°C.
Claims (1)
- Analogifremgangsmåte for fremstilling av fysiologisk aktive xantinderivater med den generelle formelog syreaddisjonssalter derav, hvor R qg R"*"-betegner metyl eller etyl, Q betegner en etylen-, propylen- eller isopropylengruppe, A betegner 3-fenoksy-2-hydroksypropyl hvor fenylringen kan være substituert i o-stilling med n-heksyloksy eller benzyloksy, B betegner alkyl med 1-4 karbonatomer, fenyl eller p-metylfenyl eller A,karakterisert ved at a) man omsetter en forbindelse med den generelle formel hvor R, R"*" og Q har de ovenfor angitte betydninger, og D betyr hydrogen,alkyl med 1-4 karbonatomer, fenyl eller p-tolyl, med en forbindelse med. den generelle formel hvor X betegner benzyl eller n-heksyl, eller b) når B er alkyl med 1-4 karbonatomer, omsetter man en forbindelse med den generelle formel hvor R, R"1" og Q har de ovenfor angitte betydninger, og Hal er halogen, med en forbindelse med den generelle formel hvor X har den ovenfor angitte betydning, og Y er alkyl med 1-4 karbonatomer, og eventuelt overføres den oppnådde forbindelse med formel I til et syreaddisjonssalt derav.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742460929 DE2460929A1 (de) | 1974-12-21 | 1974-12-21 | Neue xanthinderivate, verfahren zu ihrer herstellung und ihre anwendung |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO754317L NO754317L (no) | 1976-06-22 |
| NO144928B true NO144928B (no) | 1981-08-31 |
| NO144928C NO144928C (no) | 1981-12-09 |
Family
ID=5934312
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO754317A NO144928C (no) | 1974-12-21 | 1975-12-19 | Analogifremgangsmaate for fremstilling av fysiologisk aktive zantinderivater. |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US3998953A (no) |
| JP (1) | JPS5188995A (no) |
| AT (1) | AT341540B (no) |
| AU (1) | AU501889B2 (no) |
| BE (1) | BE836898A (no) |
| BG (1) | BG25518A3 (no) |
| CA (1) | CA1036159A (no) |
| CH (1) | CH628346A5 (no) |
| CS (1) | CS191289B2 (no) |
| DD (1) | DD124984A5 (no) |
| DE (1) | DE2460929A1 (no) |
| DK (1) | DK137677C (no) |
| ES (2) | ES443738A1 (no) |
| FI (1) | FI62089C (no) |
| FR (1) | FR2294706A1 (no) |
| GB (1) | GB1517710A (no) |
| GR (1) | GR59204B (no) |
| HU (1) | HU174673B (no) |
| IE (1) | IE43208B1 (no) |
| IL (1) | IL48697A (no) |
| LU (1) | LU73972A1 (no) |
| NL (1) | NL7514837A (no) |
| NO (1) | NO144928C (no) |
| NZ (1) | NZ179599A (no) |
| PH (1) | PH11810A (no) |
| PL (1) | PL99165B1 (no) |
| RO (1) | RO68381A (no) |
| SE (1) | SE420493B (no) |
| SU (1) | SU603340A3 (no) |
| YU (1) | YU39004B (no) |
| ZA (1) | ZA757865B (no) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4337254A (en) * | 1977-08-23 | 1982-06-29 | Burroughs Wellcome Co. | Pharmaceutical compositions |
| DE3113880A1 (de) * | 1981-04-07 | 1982-10-21 | Basf Ag, 6700 Ludwigshafen | Verfahren zur herstellung von coffein |
| IT1174773B (it) * | 1983-07-29 | 1987-07-01 | Medosan Ind Biochimi | Attivita' antiaggregante piastrinica e broncolitica della 7-(1-metil-5-p-metilbenzoilpirrol-2-acetamidoetil)teofillina |
| US5446046A (en) * | 1993-10-28 | 1995-08-29 | University Of Florida Research Foundation | A1 adenosine receptor agonists and antagonists as diuretics |
| US5736528A (en) * | 1993-10-28 | 1998-04-07 | University Of Florida Research Foundation, Inc. | N6 -(epoxynorborn-2-yl) adenosines as A1 adenosine receptor agonists |
| US5620676A (en) * | 1994-03-08 | 1997-04-15 | The United States Of America As Represented By The Department Of Health And Human Services | Biologically active ATP analogs |
| US5789416B1 (en) * | 1996-08-27 | 1999-10-05 | Cv Therapeutics Inc | N6 mono heterocyclic substituted adenosine derivatives |
| WO1999031101A1 (en) * | 1997-12-17 | 1999-06-24 | University Of South Florida | Adenosine receptor antagonists with improved bioactivity |
| US6576619B2 (en) | 1999-05-24 | 2003-06-10 | Cv Therapeutics, Inc. | Orally active A1 adenosine receptor agonists |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1230663A (no) * | 1968-12-10 | 1971-05-05 | ||
| US3728346A (en) * | 1971-07-16 | 1973-04-17 | Degussa | Hydroxyphenylhydroxyalkylaminoalkyltheophyllines |
| JPS5132638B2 (no) * | 1972-07-13 | 1976-09-14 |
-
1974
- 1974-12-21 DE DE19742460929 patent/DE2460929A1/de active Granted
-
1975
- 1975-11-28 AT AT904575A patent/AT341540B/de not_active IP Right Cessation
- 1975-12-09 LU LU73972A patent/LU73972A1/xx unknown
- 1975-12-11 SU SU752197999A patent/SU603340A3/ru active
- 1975-12-12 DD DD190116A patent/DD124984A5/xx unknown
- 1975-12-15 AU AU87547/75A patent/AU501889B2/en not_active Expired
- 1975-12-16 DK DK571875A patent/DK137677C/da active
- 1975-12-16 FI FI753543A patent/FI62089C/fi not_active IP Right Cessation
- 1975-12-17 US US05/641,550 patent/US3998953A/en not_active Expired - Lifetime
- 1975-12-17 GR GR49628A patent/GR59204B/el unknown
- 1975-12-18 YU YU03234/75A patent/YU39004B/xx unknown
- 1975-12-18 RO RO7584245A patent/RO68381A/ro unknown
- 1975-12-18 CH CH1643275A patent/CH628346A5/de not_active IP Right Cessation
- 1975-12-18 CS CS758669A patent/CS191289B2/cs unknown
- 1975-12-19 SE SE7514477A patent/SE420493B/xx not_active IP Right Cessation
- 1975-12-19 NZ NZ179599A patent/NZ179599A/xx unknown
- 1975-12-19 BG BG7500032887A patent/BG25518A3/xx unknown
- 1975-12-19 IL IL48697A patent/IL48697A/xx unknown
- 1975-12-19 ZA ZA757865A patent/ZA757865B/xx unknown
- 1975-12-19 IE IE2787/75A patent/IE43208B1/en unknown
- 1975-12-19 CA CA242,131A patent/CA1036159A/en not_active Expired
- 1975-12-19 GB GB52168/75A patent/GB1517710A/en not_active Expired
- 1975-12-19 NL NL7514837A patent/NL7514837A/xx not_active Application Discontinuation
- 1975-12-19 FR FR7539174A patent/FR2294706A1/fr active Granted
- 1975-12-19 PH PH17894A patent/PH11810A/en unknown
- 1975-12-19 HU HU75BO1590A patent/HU174673B/hu unknown
- 1975-12-19 NO NO754317A patent/NO144928C/no unknown
- 1975-12-19 BE BE162965A patent/BE836898A/xx not_active IP Right Cessation
- 1975-12-19 JP JP50151721A patent/JPS5188995A/ja active Pending
- 1975-12-20 PL PL1975185740A patent/PL99165B1/pl unknown
- 1975-12-20 ES ES443738A patent/ES443738A1/es not_active Expired
-
1976
- 1976-09-11 ES ES451457A patent/ES451457A1/es not_active Expired
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