NO882888L - PROCEDURE FOR THE PREPARATION OF HETEROAROMATIC DERIVATIVES OF ADENOSIN. - Google Patents
PROCEDURE FOR THE PREPARATION OF HETEROAROMATIC DERIVATIVES OF ADENOSIN.Info
- Publication number
- NO882888L NO882888L NO882888A NO882888A NO882888L NO 882888 L NO882888 L NO 882888L NO 882888 A NO882888 A NO 882888A NO 882888 A NO882888 A NO 882888A NO 882888 L NO882888 L NO 882888L
- Authority
- NO
- Norway
- Prior art keywords
- compound according
- adenosine
- mol
- thien
- phenethyl
- Prior art date
Links
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical class C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 title claims description 31
- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 45
- -1 nitro, amino Chemical group 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- XHRJGHCQQPETRH-KQYNXXCUSA-N (2r,3r,4s,5r)-2-(6-chloropurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(Cl)=C2N=C1 XHRJGHCQQPETRH-KQYNXXCUSA-N 0.000 claims description 16
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 229960005305 adenosine Drugs 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 208000028017 Psychotic disease Diseases 0.000 claims description 4
- 230000000561 anti-psychotic effect Effects 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
- 125000004001 thioalkyl group Chemical group 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 150000003456 sulfonamides Chemical class 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000003573 thiols Chemical group 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 239000011877 solvent mixture Substances 0.000 claims 1
- 150000001412 amines Chemical class 0.000 description 24
- 229910052799 carbon Inorganic materials 0.000 description 14
- RPMXALUWKZHYOV-UHFFFAOYSA-N nitroethene Chemical compound [O-][N+](=O)C=C RPMXALUWKZHYOV-UHFFFAOYSA-N 0.000 description 14
- 239000002777 nucleoside Substances 0.000 description 14
- 150000003833 nucleoside derivatives Chemical class 0.000 description 14
- 229910010082 LiAlH Inorganic materials 0.000 description 11
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- PIAOLBVUVDXHHL-UHFFFAOYSA-N 2-nitroethenylbenzene Chemical compound [O-][N+](=O)C=CC1=CC=CC=C1 PIAOLBVUVDXHHL-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 150000003838 adenosines Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- JRGGUPZKKTVKOV-UHFFFAOYSA-N 1-bromo-3-chlorobenzene Chemical compound ClC1=CC=CC(Br)=C1 JRGGUPZKKTVKOV-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000008259 solid foam Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 2
- FQMUKFCUWXBGSC-UHFFFAOYSA-N 2-phenyl-2-thiophen-2-ylethanamine Chemical compound C=1C=CC=CC=1C(CN)C1=CC=CS1 FQMUKFCUWXBGSC-UHFFFAOYSA-N 0.000 description 2
- RBIGKSZIQCTIJF-UHFFFAOYSA-N 3-formylthiophene Chemical compound O=CC=1C=CSC=1 RBIGKSZIQCTIJF-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 208000027753 pain disease Diseases 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 description 1
- XKUZPQVASVQVKJ-UHFFFAOYSA-N 2,2-dithiophen-2-ylethanamine Chemical compound C=1C=CSC=1C(CN)C1=CC=CS1 XKUZPQVASVQVKJ-UHFFFAOYSA-N 0.000 description 1
- WVUICGOYGDHVBH-ONEGZZNKSA-N 2-[(e)-2-nitroethenyl]furan Chemical group [O-][N+](=O)\C=C\C1=CC=CO1 WVUICGOYGDHVBH-ONEGZZNKSA-N 0.000 description 1
- WBFUBNWKSDINIX-UHFFFAOYSA-N 2-methylfuran-3-carbaldehyde Chemical compound CC=1OC=CC=1C=O WBFUBNWKSDINIX-UHFFFAOYSA-N 0.000 description 1
- DSMRYCOTKWYTRF-UHFFFAOYSA-N 3-methylfuran-2-carbaldehyde Chemical compound CC=1C=COC=1C=O DSMRYCOTKWYTRF-UHFFFAOYSA-N 0.000 description 1
- BSQKBHXYEKVKMN-UHFFFAOYSA-N 3-methylthiophene-2-carbaldehyde Chemical compound CC=1C=CSC=1C=O BSQKBHXYEKVKMN-UHFFFAOYSA-N 0.000 description 1
- VAUMDUIUEPIGHM-UHFFFAOYSA-N 5-Methyl-2-thiophenecarboxaldehyde Chemical compound CC1=CC=C(C=O)S1 VAUMDUIUEPIGHM-UHFFFAOYSA-N 0.000 description 1
- 101150007969 ADORA1 gene Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003257 anti-anginal effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 230000005792 cardiovascular activity Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- LJWKFGGDMBPPAZ-UHFFFAOYSA-N ethoxyethane;toluene Chemical compound CCOCC.CC1=CC=CC=C1 LJWKFGGDMBPPAZ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
De hittil ukjente forbindelser ifølge foreliggende oppfinnelse er beslektet med de N<6->substituerte adenosiner ifølge verserende US-patentsøknad nr. 756.922 som er en "continuation" av den nå oppgitte US-patentsøknad nr. 621.943, som igjen er en "continuation" av den nå oppgitte US-patentsøknad nr. 519.284. Dessuten er den samtidig med denne innleverte søknad PD nr. 3576 beslektet med foreliggende oppfinnelse, og den inkorporeres herved i den foreliggende beskrivelse med hele sitt innhold. The hitherto unknown compounds according to the present invention are related to the N<6->substituted adenosines according to pending US patent application no. 756,922 which is a "continuation" of the now issued US patent application no. 621,943, which is again a "continuation" of the now issued US Patent Application No. 519,284. Moreover, the application PD No. 3576 submitted at the same time as this one is related to the present invention, and it is hereby incorporated into the present description with its entire content.
Foreliggende forbindelser er sterkere N<6->substituerte adenosin-analoger som har både Al- og A2-selektiv reseptor-binding, i forhold til hva som tidligere er funnet blant adenosin-analoger.Forbindelsene har spesielt fordelaktige sentralnervesystem- og kardiovaskulære-aktiviteter, så som analgetiske, antipsykotiske, sedative, antihypertensive og kardiotoniske, spesielt antianginale og vasodilatoriske aktiviteter. Særlig er de sterkt antipsykotiske og kardiovaskulære virkninger ifølge foreliggende oppfinnelse, uventede. The present compounds are stronger N<6->substituted adenosine analogues that have both A1- and A2-selective receptor binding, compared to what has previously been found among adenosine analogues. The compounds have particularly beneficial central nervous system and cardiovascular activities, such as analgesic, antipsychotic, sedative, antihypertensive and cardiotonic, especially antianginal and vasodilatory activities. In particular, the strong antipsychotic and cardiovascular effects according to the present invention are unexpected.
Den ovennevnte verserende US-patentsøknad nr. 756.922 og referanser angitt i denne, gir bakgrunn for foreliggende oppfinnelse, herunder litteraturbeskrivelser av undersøkelser, som har vist at forbindelsen ifølge foreliggende oppfinnelse er i besittelse av den her beskrevne aktivitet. Verserende US-søknad nr. 756.922 inkorporeres derfor herved med hele sitt innhold som en del av den foreliggende beskrivelse. The above-mentioned pending US patent application no. 756,922 and references stated therein provide background for the present invention, including literature descriptions of investigations, which have shown that the compound according to the present invention possesses the activity described here. Pending US application No. 756,922 is therefore hereby incorporated with its entire content as part of the present description.
Foreliggende oppfinnelse angår en forbindelse med formel eller et farmasøytisk akseptabelt syreaddisjonssalt derav, hvor Ar<1>og Ar<2>uavhengig er fenyl, som er usubstituert eller substituert med halogen, hydroksy, tiol, lavere alkoksy, lavere tioalkyl, lavere alkanoyloksy, lavere karboksyalkyl, lavere alkyl, nitro, amino, lavereS(0)n-alkyl, hvor n er 0, 1 eller 2, sulfonamid eller trifluormetyl, eller en heteroaryl valgt blant 2- eller 3-tienyl eller 2- eller 3-furanyl, hvor tienyl eller furanyl er usubstituert eller substituert med lavere alkyl eller halogen. The present invention relates to a compound of formula or a pharmaceutically acceptable acid addition salt thereof, where Ar<1> and Ar<2> are independently phenyl, which is unsubstituted or substituted with halogen, hydroxy, thiol, lower alkoxy, lower thioalkyl, lower alkanoyloxy, lower carboxyalkyl, lower alkyl, nitro, amino, lower S(0)n-alkyl, where n is 0, 1 or 2, sulfonamide or trifluoromethyl, or a heteroaryl selected from 2- or 3-thienyl or 2- or 3-furanyl, where thienyl or furanyl is unsubstituted or substituted by lower alkyl or halogen.
Det er en generell forutsetning at minst én av Ar<1>ellerIt is a general condition that at least one of Ar<1>or
Ar<2>er heteroarylgruppen og at hverken Ar<1>eller Ar<2>har merAr<2> is the heteroaryl group and that neither Ar<1> nor Ar<2> has more
enn én substituent.than one substituent.
R2' , R3' og R5' er hver uavhengig hydrogen, alkanoyl medR2', R3' and R5' are each independently hydrogen, alkanoyl with
to til tolv karbonatomer i en rett eller forgrenet alkylkjede, som kan være substituert med amino, benzoyl eller benzoyl substituert med lavere alkyl, lavere alkoksy, halogen eller trifluormetyl, idet ytterligere R2' og R3' kan være bundet sammen for å danne en fem-leddet alkylidenring med i alt inntil 20 karbonatomer, som for eksempel isopropyliden eller en cyklisk fosfatdiester, og R5' kan være et fosfat, hydrogen eller dihydrogenfosfat, eller et alkalimetall- eller ammonium-eller dialkali- eller diammoniumsalt derav, som for eksempel P03Na2. two to twelve carbon atoms in a straight or branched alkyl chain, which may be substituted with amino, benzoyl or benzoyl substituted with lower alkyl, lower alkoxy, halogen or trifluoromethyl, further R2' and R3' may be linked together to form a five- membered alkylidene ring with a total of up to 20 carbon atoms, such as isopropylidene or a cyclic phosphate diester, and R5' can be a phosphate, hydrogen or dihydrogen phosphate, or an alkali metal or ammonium or dialkali or diammonium salt thereof, such as PO3Na2.
Den foreliggende oppfinnelse omhandler også en farmasøytisk sammensetning som omfatter en terapeutisk effektiv mengde av en forbindelse med den ovenstående formel I med et farmasøytisk akseptabelt bæremiddel, samt en fremgangsmåte til behandling av pattedyr ved administrering til slike pattedyr en doseform av en forbindelse med ovenstående formel og som er definert ovenfor. The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula I with a pharmaceutically acceptable carrier, as well as a method for treating mammals by administering to such mammals a dosage form of a compound of the above formula and which is defined above.
I forbindelsene med formel I er det hensikten at uttrykket "lavere alkyl" skal inkludere en rett eller forgrenet alkylgruppe med fra 1 til 6 karbonatomer, som for eksempel metyl, etyl, propyl, isopropyl, butyl, sek-butyl, isobutyl, tert-butyl, In the compounds of formula I, the term "lower alkyl" is intended to include a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl ,
amyl, isoamyl, neopentyl, heksyl og lignende.amyl, isoamyl, neopentyl, hexyl and the like.
Halogen inkluderer særlig fluor, klor eller brom.Halogen includes in particular fluorine, chlorine or bromine.
Lavere alkoksy og tioalkyl er 0-alkyl eller S-alkyl medLower alkoxy and thioalkyl are O-alkyl or S-alkyl with
fra 1 til 6 karbonatomer som definert ovenfor for "lavere alkyl". from 1 to 6 carbon atoms as defined above for "lower alkyl".
Lavere alkanoyloksy er en rettkjedet eller forgrenetLower alkanoyloxy is a straight chain or branched chain
0 0
11 11
O-C-alkylgruppe med fra 1 til 6 karbonatomer i alkylkjeden, som definert ovenfor. O-C alkyl group with from 1 to 6 carbon atoms in the alkyl chain, as defined above.
0 0
i) Lavere karboalkoksy er en rettkjedet eller forgrenet C-0-alkylgruppe med fra 1 til 6 karbonatomer i alkylkjeden, som definert ovenfor. i) Lower carboalkoxy is a straight or branched C-0 alkyl group having from 1 to 6 carbon atoms in the alkyl chain, as defined above.
Forbindelsene med formel I er nyttige både i den frie baseform og i form av syreaddisjonssalter. Begge former faller innenfor oppfinnelsens rammer. I praksis svarer anvendelse av saltformen til anvendelse av baseformen. Passende farmasøytisk akseptable salter som faller innenfor oppfinnelsens rammer er slike som er avledet av mineralsyrer, så som saltsyre og svovelsyre, samt organiske syrer, så som etansulfonsyre, benzensulfonsyre, p-toluensulfonsyre og lignende som gir henholdsvis hydrokloridet, sulfamatet, etansulfonatet, benzen-sulf onatet, p-toluensulfonatet og lignende. (Se for eksempel "Pharmaceutical Salts," J. Pharm. Sei., (1977) 66(1):1-19). The compounds of formula I are useful both in the free base form and in the form of acid addition salts. Both forms fall within the scope of the invention. In practice, use of the salt form corresponds to use of the base form. Suitable pharmaceutically acceptable salts that fall within the scope of the invention are those derived from mineral acids, such as hydrochloric acid and sulfuric acid, as well as organic acids, such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like which respectively give the hydrochloride, sulfamate, ethanesulfonate, benzenesulfonate onate, p-toluenesulfonate and the like. (See, for example, "Pharmaceutical Salts," J. Pharm. Sci., (1977) 66(1):1-19).
Syreaddisjonssaltene av de nevnte basiske forbindelser fremstilles enten ved å oppløse den frie base i vandig oppløsning eller vandig alkoholoppløsning eller andre egnede oppløsnings-midler, inneholdende den passende syre, og isolere saltet ved inndampning av oppløsningen, eller ved å omsette den frie base og syre i et organisk oppløsningsmiddel, hvorved saltet utskilles direkte eller oppnås ved konsentrering av oppløsningen. The acid addition salts of the aforementioned basic compounds are prepared either by dissolving the free base in aqueous solution or aqueous alcohol solution or other suitable solvents, containing the appropriate acid, and isolating the salt by evaporation of the solution, or by reacting the free base and acid in an organic solvent, whereby the salt is precipitated directly or obtained by concentrating the solution.
I alminnelighet fremstilles forbindelsene med formel I ifølge den foreliggende oppfinnelse, ved hjelp av en fremgangsmåte ifølge Skjema I. In general, the compounds of formula I according to the present invention are prepared using a method according to Scheme I.
Den i Skjema I viste fremgangsmåte omdanner arylaldehydet med formel VI til den tilsvarende w-nitrostyren med formel V. Forbindelsene med formel V omsettes deretter med en organo-metallisk arylforbindelse med formel IV (fortrinnsvis et Grignard- eller et litiumderivat) i et aprotisk oppløsnings-middelsystem (fortrinnsvis toluen-eter) ved en lav temperatur (fortrinnsvis -10°til -40°C). Den således fremstillede diarylnitroetan med formel III reduseres deretter til den tilsvarende diaryletylamin med formel II (fortrinnsvis med LiAlH4i eter) som deretter kobles med 6-klorpurin-ribosid som beskrevet i den tidligere angitte US-patentsøknad nr. 756.922. På denne måte fremstilles de ønskede forbindelser med formel I. The method shown in Scheme I converts the aryl aldehyde of formula VI into the corresponding w-nitrostyrene of formula V. The compounds of formula V are then reacted with an organometallic aryl compound of formula IV (preferably a Grignard or a lithium derivative) in an aprotic solvent medium system (preferably toluene-ether) at a low temperature (preferably -10° to -40°C). The thus prepared diarylnitroethane of formula III is then reduced to the corresponding diarylethylamine of formula II (preferably with LiAlH4i ether) which is then coupled with 6-chloropurine riboside as described in the previously cited US Patent Application No. 756,922. In this way, the desired compounds of formula I are prepared.
Utgangsmaterialene for den ovenfor beskrevne fremgangsmåte for fremstilling av forbindelser med formel I er i alminnelighet kjente, kommersielt tilgjengelige eller kan fremstilles ved hjelp av fremgangsmåter som enten er kjente eller analoge med kjente fremgangsmåter. The starting materials for the above-described method for preparing compounds of formula I are generally known, commercially available or can be prepared using methods that are either known or analogous to known methods.
Variasjoner i de omtalte fremgangsmåter som er kjente for en vanlig utdannet fagmann, faller innenfor oppfinnelsens rammer. Variations in the described methods which are known to a normally trained professional fall within the scope of the invention.
Produktene fra fremgangsmåtene kan isoleres ved hjelp av konvensjonelle midler, så som ekstraksjon, destillasjon, kromatografi og lignende. The products from the methods can be isolated using conventional means, such as extraction, distillation, chromatography and the like.
Forbindelsene med formel I tilveiebringer de mest selektive potente Al-reseptor- ogA2-reseptorbindende adenosiner, som nå er funnet, og har derfor overraskende og uventet aktivitet. Særlig bemerkelsesverdig er den større intraperitoneale MAST-aktivitet til de omtalte forbindelser. Beskrivelse av prøver for å oppnå slike data finnes i den inkorporerte US-patentsøknad nr. 756.922. The compounds of formula I provide the most selective potent A1 receptor and A2 receptor binding adenosines yet found and therefore have surprising and unexpected activity. Particularly noteworthy is the greater intraperitoneal MAST activity of the mentioned compounds. Description of tests for obtaining such data can be found in incorporated US Patent Application No. 756,922.
Data er vist i de følgende tabeller. Data are shown in the following tables.
Eksempel 6 har en ED50-verdi på 1,75 mg/kg for unngåelses-blokade i SIDRAT. Example 6 has an ED50 value of 1.75 mg/kg for avoidance blockade in SIDRAT.
Prøvingen tilpasses for å vise prosentuell nedsettelse av det gjennomsnittlige arterielle blodtrykk, hvor A er mer enn 20% og C er 10-20% nedsettelse. I begge tilfelle med en varighet på minst 2 timer. The test is adapted to show a percentage reduction in mean arterial blood pressure, where A is more than 20% and C is 10-20% reduction. In both cases with a duration of at least 2 hours.
Den foreliggende oppfinnelse inkluderer derfor også en farmasøytisk sammensetning til behandling av psykoser, søvn-forstyrrelser, smerte eller kardiovaskulære sykdommer, omfattende en antipsykotisk, sedativ, analgetisk eller kardiovaskulær effektiv mengde av en forbindelse med formel I som definert ovenfor, sammen med et farmasøytisk akseptabelt bæremiddel. The present invention therefore also includes a pharmaceutical composition for the treatment of psychoses, sleep disorders, pain or cardiovascular diseases, comprising an antipsychotic, sedative, analgesic or cardiovascular effective amount of a compound of formula I as defined above, together with a pharmaceutically acceptable carrier .
Den foreliggende oppfinnelse inkluderer ytterligere en fremgangsmåte til behandling av psykoser, søvnforstyrrelser, smerte eller kardiovaskulære sykdommer i pattedyr med slike lidelser, omfattende administrering til slike pattedyr enten oralt eller parenteralt, en tilsvarende farmasøytisk sammensetning med en forbindelse med formel I som definert ovenfor, i passende doseform. The present invention further includes a method for the treatment of psychoses, sleep disorders, pain or cardiovascular diseases in mammals with such disorders, comprising administering to such mammals either orally or parenterally, a corresponding pharmaceutical composition with a compound of formula I as defined above, in appropriate dosage form.
Sammensetningene og administreringsmåtene skal forstås i overensstemmelse med teknikkens stand, for eksempel som beskrevet i US-patentsøknad nr. 756.922. The compositions and methods of administration are to be understood in accordance with the state of the art, for example as described in US patent application no. 756,922.
Mengden aktiv forbindelse i et enhetsdosepreparat kan varieres eller justeres fra 0,1 mg til 200 mg, fortrinnsvis 1 mg til 100 mg i henhold til den særlige anvendelse og til styrken av den aktive bestanddel. Sammensetningene kan om ønsket også inneholde andre kompatible terapeutiske midler. The amount of active compound in a unit dose preparation may be varied or adjusted from 0.1 mg to 200 mg, preferably 1 mg to 100 mg according to the particular application and to the strength of the active ingredient. If desired, the compositions may also contain other compatible therapeutic agents.
I terapeutisk bruk som beskrevet ovenfor, er doseintervallet for et individ på 70 kg fra 0,1 til 150 mg/kg legemsvekt per dag, eller fortrinnsvis 0,1 til 10 mg/kg legemsvekt per dag. Dosene kan imidlertid varieres, avhengig av pasientens krav, tilstandens alvor og forbindelsen som anvendes. In therapeutic use as described above, the dosage range for a 70 kg subject is from 0.1 to 150 mg/kg body weight per day, or preferably 0.1 to 10 mg/kg body weight per day. However, the doses can be varied, depending on the patient's requirements, the severity of the condition and the compound used.
Bestemmelse av den passende dose for en spesiell situasjon er fagmessig. I alminnelighet påbegynnes behandling med mindre doser som er mindre enn den optimale dose av forbindelsen. Deretter økes dosen med små mengder, inntil den optimale virkning oppnås. Av bekvemmelighetsgrunner kan den totale daglige dose deles og administreres i porsjoner i løpet av dagen, om ønsket. Determining the appropriate dose for a particular situation is a professional matter. In general, treatment is initiated with smaller doses that are less than the optimal dose of the compound. The dose is then increased by small amounts, until the optimal effect is achieved. For convenience, the total daily dose may be divided and administered in portions during the day, if desired.
De følgende eksempler belyser oppfinnelsen ytterligere. The following examples further illustrate the invention.
EKSEMPEL 1 EXAMPLE 1
N, 6-( 2-( tien- 2- yl)- 2- fenetyl) adenosinN, 6-(2-(thien-2-yl)-2-phenethyl)adenosine
Nitrostyren (12,65 g, 33%) ble fremstillet fra 2-tiofen-karboksaldehyd (23,4 ml, 0,25 mol) og nitrometan (15,3 g, Nitrostyrene (12.65 g, 33%) was prepared from 2-thiophene-carboxaldehyde (23.4 mL, 0.25 mol) and nitromethane (15.3 g,
0,25 mol) som beskrevet i Eksempel 10 nedenfor.0.25 mol) as described in Example 10 below.
Aminet (0,90 g, 32%) ble fremstillet fra E,2-(tien-2-yl)nitroeten (2,16 g, 0,014 mol) og fenylmagnesiumbromid (7,2 ml, 0,021 mol) etterfulgt av LiAlH4-reduksjon (1,60 g, 0,042 mol) som beskrevet i Eksempel 10 nedenfor. The amine (0.90 g, 32%) was prepared from E,2-(thien-2-yl)nitroethene (2.16 g, 0.014 mol) and phenylmagnesium bromide (7.2 mL, 0.021 mol) followed by LiAlH 4 reduction (1.60 g, 0.042 mol) as described in Example 10 below.
Nukleosidet (0,22 g, 20%) ble fremstillet fra aminet (0,47 g, 0,0023 mol), 6-klorpurin-ribosid (0,66 g, 0,0023 mol) og trietylamin (0,3 ml, 0,0025 mol) som et skum, smp. 68-72°C, som beskrevet i Eksempel 10 nedenfor. The nucleoside (0.22 g, 20%) was prepared from the amine (0.47 g, 0.0023 mol), 6-chloropurine riboside (0.66 g, 0.0023 mol) and triethylamine (0.3 mL, 0.0025 mol) as a foam, m.p. 68-72°C, as described in Example 10 below.
EKSEMPEL 2 EXAMPLE 2
N, 6-( 2-( tien- 3- yl)- 2- fenetyl) adenosinN, 6-(2-(thien-3-yl)-2-phenethyl)adenosine
Nitrostyrenet (27,2 g, 70%) ble fremstillet fra 3-tiofen-karboksaldehyd (22,0 ml, 0,25 mol) og nitrometan (15,3 g, The nitrostyrene (27.2 g, 70%) was prepared from 3-thiophene-carboxaldehyde (22.0 mL, 0.25 mol) and nitromethane (15.3 g,
0,25 mol) som beskrevet i Eksempel 10 nedenfor.0.25 mol) as described in Example 10 below.
Aminet (3,28 g, 29%) ble fremstillet fra E,2-(tien-3-yl)nitroeten (8,50 g, 0,055 mol) og fenylmagnesiumbromid (28,5 ml, 0,0855 mol) etterfulgt av LiAlH4-reduksjon (6,5 g, 0,17 mol), som beskrevet i Eksempel 10 nedenfor. The amine (3.28 g, 29%) was prepared from E,2-(thien-3-yl)nitroethene (8.50 g, 0.055 mol) and phenylmagnesium bromide (28.5 mL, 0.0855 mol) followed by LiAlH4 -reduction (6.5 g, 0.17 mol), as described in Example 10 below.
Nukleosidet (1,21 g, 37%) ble fremstillet fra aminet (1,44 g, 0,007 mol), 6-klorpurin-ribosid (2,00 g, 0,007 mol) og trietylamin (1,0 ml, 0,0077 mol) som et hvitt skum, smp. 80-100°C, som beskrevet i Eksempel 10 nedenfor. The nucleoside (1.21 g, 37%) was prepared from the amine (1.44 g, 0.007 mol), 6-chloropurine riboside (2.00 g, 0.007 mol) and triethylamine (1.0 mL, 0.0077 mol ) as a white foam, m.p. 80-100°C, as described in Example 10 below.
EKSEMPEL 3 EXAMPLE 3
N, 6-( 2-( 3- metoksyfenyl)- 2-( tien- 2- yl) etyl) adenosin N, 6-( 2-( 3- methoxyphenyl)- 2-( thien- 2- yl) ethyl) adenosine
Nitrostyrenet (16,8 g, 77%) ble fremstillet fra 2-tiofen-karboksaldehyd (13,0 ml, 0,14 mol) og nitrometan (8,5 g, The nitrostyrene (16.8 g, 77%) was prepared from 2-thiophene-carboxaldehyde (13.0 mL, 0.14 mol) and nitromethane (8.5 g,
0,14 mol), som beskrevet i Eksempel 10 nedenfor.0.14 mol), as described in Example 10 below.
Aminet (1,69 g, 20%) ble fremstillet fra E,2-(tein-2-yl)nitroeten (5,64 g, 0,036 mol), 3-metoksybrombenzen (9,2 ml, 0,073 mol), magnesium (1,40 g, 0,058 mol) etterfulgt av LiAlH4-reduksjon (5,46 g, 0,144 mol), som beskrevet i Eksempel 10 nedenfor. The amine (1.69 g, 20%) was prepared from E,2-(thein-2-yl)nitroethene (5.64 g, 0.036 mol), 3-methoxybromobenzene (9.2 mL, 0.073 mol), magnesium ( 1.40 g, 0.058 mol) followed by LiAlH 4 reduction (5.46 g, 0.144 mol), as described in Example 10 below.
Nukleosidet (0,83 g, 23%) ble fremstillet fra aminet (1,69 g, 0,0073 mol), 6-klorpurin-ribosid (1,86 g, 0,0065 mol) og trietylamin (0,95 ml, 0,0072 mol) som et faststoff, smp. 71-80°C, som beskrevet i Eksempel 10 nedenfor. The nucleoside (0.83 g, 23%) was prepared from the amine (1.69 g, 0.0073 mol), 6-chloropurine riboside (1.86 g, 0.0065 mol) and triethylamine (0.95 mL, 0.0072 mol) as a solid, m.p. 71-80°C, as described in Example 10 below.
EKSEMPEL 4 EXAMPLE 4
N, 6-( 2-( 3- klorfenyl)- 2-( tien- 2- yl) etyl) adenosinN, 6-( 2-( 3- chlorophenyl)- 2-( thien- 2- yl) ethyl) adenosine
Nitrostyrenet (12,65 g, 33%) ble fremstillet fra 2-tiofen-karboksaldehyd (23,4 ml, 0,25 mol) og nitrometan (15,3 g, The nitrostyrene (12.65 g, 33%) was prepared from 2-thiophene-carboxaldehyde (23.4 mL, 0.25 mol) and nitromethane (15.3 g,
0,25 mol), som beskrevet i Eksempel 10 nedenfor.0.25 mol), as described in Example 10 below.
Aminet (1,71 g, 36%) ble fremstillet fra E,2-(tien-2-yl)nitroeten (3,1 g, 0,02 mol), 3-klorbrombenzen (4,7 ml, The amine (1.71 g, 36%) was prepared from E,2-(thien-2-yl)nitroethene (3.1 g, 0.02 mol), 3-chlorobromobenzene (4.7 mL,
0,04 mol), magnesium (0,77 g, 0,032 mol) etterfulgt av LiAlH4-reduksjon (2,30 g, 0,06 mol), som beskrevet i Eksempel 10 nedenfor. 0.04 mol), magnesium (0.77 g, 0.032 mol) followed by LiAlH 4 reduction (2.30 g, 0.06 mol), as described in Example 10 below.
Nukleosidet (1,12 g, 37%) ble fremstillet fra aminet (1,47 g, 0,006 mol), 6-klorpurin-ribosid (1,72 g, 0,006 mol) og trietylamin (0,9 ml, 0,0066 mol), som et faststoff, smp. 99-104°C, som beskrevet i Eksempel 10 nedenfor. The nucleoside (1.12 g, 37%) was prepared from the amine (1.47 g, 0.006 mol), 6-chloropurine riboside (1.72 g, 0.006 mol) and triethylamine (0.9 mL, 0.0066 mol ), as a solid, m.p. 99-104°C, as described in Example 10 below.
EKSEMPEL 5 EXAMPLE 5
N, 6-( 2-( 3- klorfenyl)- 2-( tien- 3- yl) etyl) adenosin N, 6-( 2-( 3- chlorophenyl)- 2-( thien- 3- yl) ethyl) adenosine
Nitrostyrenet (27,2 g, 70%) ble fremstillet fra 3-tiofen-karboksaldehyd (22,0 ml, 0,25 mol) og nitrometan (15,3 g, The nitrostyrene (27.2 g, 70%) was prepared from 3-thiophene-carboxaldehyde (22.0 mL, 0.25 mol) and nitromethane (15.3 g,
0,25 mol), som beskrevet i Eksempel 10 nedenfor.0.25 mol), as described in Example 10 below.
Aminet (0,87 g, 18%) ble fremstillet fra E,2-(tien-3-yl)nitroeten (3,1 g, 0,02 mol), 3-klorbrombenzen (4,7 ml, The amine (0.87 g, 18%) was prepared from E,2-(thien-3-yl)nitroethene (3.1 g, 0.02 mol), 3-chlorobromobenzene (4.7 mL,
0,04 mol), magnesium (0,77 g, 0,032 mol) etterfulgt av LiAlH4-reduksjon (2,30 g, 0,06 mol), som beskrevet i Eksempel 10 nedenfor. 0.04 mol), magnesium (0.77 g, 0.032 mol) followed by LiAlH 4 reduction (2.30 g, 0.06 mol), as described in Example 10 below.
Nukleosidet (0,86 g, 49%) ble fremstillet fra aminet (0,87 g, 0,0037 mol), 6-klorpurin-ribosid (1,00 g, 0,0035 mol) og trietylamin (0,5 ml, 0,0039 mol) som et faststoff, smp. 104-110°C, som beskrevet i Eksempel 10 nedenfor. The nucleoside (0.86 g, 49%) was prepared from the amine (0.87 g, 0.0037 mol), 6-chloropurine riboside (1.00 g, 0.0035 mol) and triethylamine (0.5 mL, 0.0039 mol) as a solid, m.p. 104-110°C, as described in Example 10 below.
EKSEMPEL 6 EXAMPLE 6
N, 6-( 2, 2- ditien- 2- yletyl) adenosinN, 6-(2,2-dithien-2-ylethyl)adenosine
Aminet (1,11 g, 53%) ble fremstillet fra E,2-tien-2-yl-nitroeten (1,55 g, 10 mmol, se Eksempel 1), 2-bromtiofen (2,45 g, 15 mmol) og magnesium (0,48 g, 20 mmol) etterfulgt av LiAlH4-reduksjon (1,11 g, 30 mol), som beskrevet i Eksempel 10 nedenfor. The amine (1.11 g, 53%) was prepared from E,2-thien-2-yl-nitroethene (1.55 g, 10 mmol, see Example 1), 2-bromothiophene (2.45 g, 15 mmol) and magnesium (0.48 g, 20 mmol) followed by LiAlH 4 reduction (1.11 g, 30 mol), as described in Example 10 below.
Nukleosidet (1,29 g, 53%) ble fremstillet fra 2,2-ditien-2-yletylamin (1,11 g, 5,3 mmol), 6-klorpurin-ribosid (1,45 g, 5 mmol) og trietylamin (1,01 g, 10 mmol) som et lyst kakifarvet fast skum, smp. 89-97°C, som beskrevet i Eksempel 10 nedenfor. The nucleoside (1.29 g, 53%) was prepared from 2,2-dithien-2-ylethylamine (1.11 g, 5.3 mmol), 6-chloropurine riboside (1.45 g, 5 mmol) and triethylamine (1.01 g, 10 mmol) as a pale khaki colored solid foam, m.p. 89-97°C, as described in Example 10 below.
EKSEMPEL 7 EXAMPLE 7
N, 6-( 2-( tien- 2- yl)- 2-( tien- 3- yl) etyl) adenosinN, 6-( 2-( thien-2- yl)- 2-( thien-3- yl) ethyl) adenosine
Aminet (1,68 g, 32%) ble fremstillet fra E,2-(tien-3-yl)nitroeten (3,88 g, 0,025 mol, se Eksempel 2), 2-bromtiofen (5,2 ml, 0,05 mol), magnesium (0,96 g, 0,04 mol) etterfulgt av LiAlH4-reduksjon (2,88 g, 0,076 mol), som beskrevet i Eksempel 10 nedenfor. The amine (1.68 g, 32%) was prepared from E,2-(thien-3-yl)nitroethene (3.88 g, 0.025 mol, see Example 2), 2-bromothiophene (5.2 mL, 0, 05 mol), magnesium (0.96 g, 0.04 mol) followed by LiAlH 4 reduction (2.88 g, 0.076 mol), as described in Example 10 below.
Nukleosidet (1,34 g, 50%) ble fremstillet fra aminet (1,20 g, 0,0057 mol), 6-klorpurin-ribosid (1,63 g, 0,0057 mol) og trietylamin (0,8 ml, 0,0063 mol) som et faststoff, smp. 94-105°C, som beskrevet i Eksempel 10 nedenfor. The nucleoside (1.34 g, 50%) was prepared from the amine (1.20 g, 0.0057 mol), 6-chloropurine riboside (1.63 g, 0.0057 mol) and triethylamine (0.8 mL, 0.0063 mol) as a solid, m.p. 94-105°C, as described in Example 10 below.
EKSEMPEL 8 EXAMPLE 8
N, 6-( 2-( furan- 2- yl)- 2- fenetyl) adenosinN, 6-(2-(furan-2-yl)-2-phenethyl)adenosine
Nitrostyrenet (8,25 g, 49%) ble fremstillet fra 2-furaldehyd The nitrostyrene (8.25 g, 49%) was prepared from 2-furaldehyde
(11,3 g, 0,12 mol) og nitrometan (7,3 g, 0,12 mol), som beskrevet i Eksempel 10 nedenfor. (11.3 g, 0.12 mol) and nitromethane (7.3 g, 0.12 mol), as described in Example 10 below.
Aminet (2,02 g, 54%) ble fremstillet fra E,2-(furan-2-yl)nitroeten (2,78 g, 0,02 mol), fenylmagnesiumbromid (10,3 ml, 0,03 mol) etterfulgt avLiAlH4-reduksjon (2,30 g, 0,06 mol), som beskrevet i Eksempel 10 nedenfor. The amine (2.02 g, 54%) was prepared from E,2-(furan-2-yl)nitroethene (2.78 g, 0.02 mol), phenylmagnesium bromide (10.3 mL, 0.03 mol) followed by of LiAlH 4 reduction (2.30 g, 0.06 mol), as described in Example 10 below.
Nukleosidet (0,22 g, 9%) ble fremstillet fra aminetThe nucleoside (0.22 g, 9%) was prepared from the amine
(0,94 g, 0,005 mol), 6-klorpurin-ribosid (1,43 g, 0,005 mol) og trietylamin (0,7 ml, 0,0055 mol) som et beigefarvet faststoff, smp. 74-83°C, som beskrevet i Eksempel 10 nedenfor. (0.94 g, 0.005 mol), 6-chloropurine riboside (1.43 g, 0.005 mol), and triethylamine (0.7 mL, 0.0055 mol) as a beige solid, m.p. 74-83°C, as described in Example 10 below.
EKSEMPEL 9 EXAMPLE 9
N, 6-( 2-( 3- klorfenyl)- 2- furan- 2- yl) etyl) adenosinN, 6-( 2-( 3- chlorophenyl)- 2- furan- 2- yl) ethyl) adenosine
Aminet (2,60 g, 29%) ble fremstillet fra E,2-(furan-2-yl)nitroeten (5,56 g, 0,04 mol, se Eksempel 8), 3-klorbrombenzen (9,4 ml, 0,08 mol), magnesium (1,54 g, 0,064 mol) etterfulgt av LiAlH4-reduksjon (4,60 g, 0,12 mol), som beskrevet i Eksempel 10 nedenfor. The amine (2.60 g, 29%) was prepared from E,2-(furan-2-yl)nitroethylene (5.56 g, 0.04 mol, see Example 8), 3-chlorobromobenzene (9.4 mL, 0.08 mol), magnesium (1.54 g, 0.064 mol) followed by LiAlH 4 reduction (4.60 g, 0.12 mol), as described in Example 10 below.
Nukleosidet (2,21 g, 67%) ble fremstillet fra aminetThe nucleoside (2.21 g, 67%) was prepared from the amine
(1,58 g, 0,007 mol), 6-klorpurin-ribosid (2,01 g, 0,007 mol) og trietylamin (1 ml, 0,0077mol) som et faststoff, smp. 87-103°C, som beskrevet i Eksempel 10 nedenfor. (1.58 g, 0.007 mol), 6-chloropurine riboside (2.01 g, 0.007 mol) and triethylamine (1 mL, 0.0077 mol) as a solid, m.p. 87-103°C, as described in Example 10 below.
EKSEMPEL 10 EXAMPLE 10
N6-( 2-( 5- metyltien- 2- yl)- 2- fenetyl) adenosinN6-( 2-( 5- methylthien- 2- yl)- 2- phenethyl) adenosine
a) E,2-(5-metyltien-2-yl)nitroeten.a) E,2-(5-methylthien-2-yl)nitroethene.
Vandig natriumhydroksyd (5M, 15 ml) ble i løpet av 15 Aqueous sodium hydroxide (5M, 15 ml) was added during 15
minutter dråpevis tilsatt til en oppløsning av 5-metyltiofen-2-karboksaldehyd (9,45 g, 0,075 mol) og nitrometan (4,58 g, minutes added dropwise to a solution of 5-methylthiophene-2-carboxaldehyde (9.45 g, 0.075 mol) and nitromethane (4.58 g,
0,075 mol) i metanol (28 ml). Etter ytterligere 10 minutter ble reaksjonsblandingen avkjølt ved å helles ut på fortynnet saltsyre (0,5M, 165 ml), og ble så ekstrahert med eter (2 x 50 ml). De samlede ekstraktene ble vasket med vann og mettet saltvann og tørket (MgS04). Oppløsningsmidlet ble fjernet under redusert trykk, og den gjenværende olje ble oppløst i CH2C12(120 ml) og omrørt under N2ved 0°C. Mesylklorid (4,9 ml, 0,063 mol) i CH2C12(15 ml) ble tilsatt i løpet av 10 minutter, og deretter ble trietylamin (15 ml, 0,11 mol) i CH2Cl2(15 ml) tilsatt i 0.075 mol) in methanol (28 mL). After an additional 10 minutes, the reaction mixture was cooled by pouring onto dilute hydrochloric acid (0.5M, 165 mL) and then extracted with ether (2 x 50 mL). The combined extracts were washed with water and saturated brine and dried (MgSO 4 ). The solvent was removed under reduced pressure and the remaining oil was dissolved in CH 2 Cl 2 (120 mL) and stirred under N 2 at 0°C. Mesyl chloride (4.9 mL, 0.063 mol) in CH 2 Cl 2 (15 mL) was added over 10 min, and then triethylamine (15 mL, 0.11 mol) in CH 2 Cl 2 (15 mL) was added in
løpet av 20 minutter. Etter 10 minutter ble reaksjonsblandingen helt over i fortynnet saltsyre (0,5M, 135 ml). Lagene ble adskilt og det vandige lag ekstrahert med CH2C12(2 x 25 ml). De samlede organiske faser ble vasket med vann, mettet saltvann og tørket (Na2S04). Oppløsningsmidlet ble fjernet under redusert trykk for å oppnå nitrostyrenet (4,42 g, 35%) som et gult faststoff. NMR (CDC13) 5 8,1 (d, 1H); 7,2-7,3 (2H, m); 6,80 within 20 minutes. After 10 minutes, the reaction mixture was poured into dilute hydrochloric acid (0.5M, 135 ml). The layers were separated and the aqueous layer extracted with CH 2 Cl 2 (2 x 25 mL). The combined organic phases were washed with water, saturated brine and dried (Na 2 SO 4 ). The solvent was removed under reduced pressure to afford the nitrostyrene (4.42 g, 35%) as a yellow solid. NMR (CDCl 3 ) δ 8.1 (d, 1H); 7.2-7.3 (2H, m); 6.80
(1H, d); 2,57 (s, 3H). (1H, d); 2.57 (p, 3H).
b) 2-(5-metyltien-2-yl)-2-fenyletylaminb) 2-(5-methylthien-2-yl)-2-phenylethylamine
Fenylmagnesiumbromid (3M i eter, 7 ml, 0,021 mol) ble Phenylmagnesium bromide (3M in ether, 7 mL, 0.021 mol) was
dråpevis tilsatt til en oppløsning av E,2-(5-metyl-tien-2-yl)nitroeten (3,14 g, 0,019 mol) i toluen (100 ml), og omrørt under N2ved -30°C. Etter 1 time ble reaksjonsblandingen avkjølt ved å helles over i fortynnet saltsyre (0,5M, 60 ml). Lagene ble adskilt og det vandige lag ekstrahert med eter (2 x 25 ml). De samlede organiske faser ble vasket med vann (2 x added dropwise to a solution of E,2-(5-methyl-thien-2-yl)nitroethene (3.14 g, 0.019 mol) in toluene (100 mL), and stirred under N2 at -30°C. After 1 hour, the reaction mixture was cooled by pouring into dilute hydrochloric acid (0.5M, 60 mL). The layers were separated and the aqueous layer extracted with ether (2 x 25 mL). The combined organic phases were washed with water (2 x
25 ml, emulsjoner vanlig på dette trinn), mettet saltvann (25 ml) og tørket (MgS04). Oppløsningsmidlet ble fjernet under redusert trykk for å oppnå det rå diarylnitroetan (2,79 g) som en olje. Oljen ble oppløst i eter (130 ml) og i løpet av 20 minutter dråpevis tilsatt til en suspensjon av LiAlH4(2,88 g, 76 mmol) i eter (325 ml) omrørt under N2ved 25°C. Kraftig gassutvikling og mild eksoterm! Etter 20 timer ble reaksjonsblandingen avkjølt ved forsiktig sekvensiell dråpevis tilsetning av vann (3 ml), vandig natriumhydroksydoppløsning (10% vekt/vol., 3 ml) og vann (9 ml). Kraftig gassutvikling og eksoterm! Blandingen ble vakuumfiltrert og residuet vasket med eter (100 ml). De samlede filtrater ble ekstrahert med fortynnet saltsyre (0,1M, 2 x 100 ml). Det vandige lag ble vasket med eter (2 x 50 ml), gjort basisk med NaOH-pellets (1,0 g 25 mmol) og ekstrahert med eter (2 x 25 ml). De samlede ekstraktene ble vasket med vann (2 x 25 ml, ofte emulsjoner), mettet saltvann (25 ml) og tørket (MgS04). Oppløsningsmidlet ble fjernet under redusert trykk for å gi det ønskede amin (1,36 g, 31%) som en olje. NMR (CDCI3) 6 7,3 (5H, s); 6,55-6,7 (2H, m); 4,10 (2H, t, J=7Hz); 3,27 (2H, d, J=7Hz); 2,43 (3H, s); 1,40 (2H, br. s). c) N,6-(2-(5-metyltien-2-yl)-2-fenyletyl)adenosin 6-klorpurin-ribosid (1,61 g, 5,6 mmol), 2-(5-metyltien-2-yl)-2-fenyletylamin (1,36 g, 6,3 mmol) og trietylamin (0,8 ml, 6,2 mmol) ble tilbakeløpsbehandlet i etanol (50 ml) under N2i 48 timer. Oppløsningsmidlet ble fjernet under redusert trykk for å gi et fast skum som ble renset ved silikagel-kromato-grafering under eluering med 6/1 CHCl3/MeOH. Oppløsningsmidlet ble fjernet under redusert trykk og det resulterende skum omkrystallisert fra metanol for å gi det ønskede nukleosid som et faststoff, smp. 107-111°C. 25 ml, emulsions common at this stage), saturated brine (25 ml) and dried (MgSO 4 ). The solvent was removed under reduced pressure to afford the crude diarylnitroethane (2.79 g) as an oil. The oil was dissolved in ether (130 mL) and over 20 minutes added dropwise to a suspension of LiAlH 4 (2.88 g, 76 mmol) in ether (325 mL) stirred under N 2 at 25°C. Powerful gas evolution and mild exothermic! After 20 hours, the reaction mixture was cooled by careful sequential dropwise addition of water (3 mL), aqueous sodium hydroxide solution (10% w/v, 3 mL) and water (9 mL). Powerful gas development and exothermic! The mixture was vacuum filtered and the residue washed with ether (100 mL). The combined filtrates were extracted with dilute hydrochloric acid (0.1M, 2 x 100 ml). The aqueous layer was washed with ether (2 x 50 mL), basified with NaOH pellets (1.0 g 25 mmol) and extracted with ether (2 x 25 mL). The combined extracts were washed with water (2 x 25 ml, often emulsions), saturated saline (25 ml) and dried (MgSO 4 ). The solvent was removed under reduced pressure to give the desired amine (1.36 g, 31%) as an oil. NMR (CDCl 3 ) δ 7.3 (5H, s); 6.55-6.7 (2H, m); 4.10 (2H, t, J=7Hz); 3.27 (2H, d, J=7Hz); 2.43 (3H, s); 1.40 (2H, br. p). c) N,6-(2-(5-methylthien-2-yl)-2-phenylethyl)adenosine 6-chloropurine riboside (1.61 g, 5.6 mmol), 2-(5-methylthien-2-yl)-2-phenylethylamine (1.36 g, 6.3 mmol) and triethylamine (0.8 mL , 6.2 mmol) was refluxed in ethanol (50 mL) under N 2 in 48 h. The solvent was removed under reduced pressure to give a solid foam which was purified by silica gel chromatography eluting with 6/1 CHCl 3 /MeOH. The solvent was removed under reduced pressure and the resulting foam recrystallized from methanol to give the desired nucleoside as a solid, m.p. 107-111°C.
Beregnet for C23H25N504S . 0 ,15H20Calculated for C23H25N504S. 0.15H2O
C, 58,75; H, 5,42; N, 14,89 C, 58.75; H, 5.42; N, 14.89
Funnet: C, 58,38; H, 5,34; N, 14,85 Found: C, 58.38; H, 5.34; N, 14.85
EKSEMPEL 11 EXAMPLE 11
N, 6-( 2-( 3- metyltien- 2- yl)- 2- fenetyl) adenosinN, 6-( 2-( 3- methylthien- 2- yl)- 2- phenethyl) adenosine
Nitrostyrenet (6,65 g, 53%) ble fremstillet fra 3-metyl-2-tiofenkarboksaldehyd (9,45 g, 0,075 mol) og nitrometan (4,58 g, 0,075 mol), som beskrevet i Eksempel 10. The nitrostyrene (6.65 g, 53%) was prepared from 3-methyl-2-thiophenecarboxaldehyde (9.45 g, 0.075 mol) and nitromethane (4.58 g, 0.075 mol), as described in Example 10.
Aminet (1,50 g, 19%) ble fremstillet fra E,2-(3-metyltien-2- yl)nitroeten (6,00 g, 0,0355 mol) og fenylmagnesiumbromid (18,7 ml, 0,056 mol), etterfulgt av LiAlH4-reduksjon (5,41 g, 0,14 mol) som beskrevet i Eksempel 10. The amine (1.50 g, 19%) was prepared from E,2-(3-methylthien-2-yl)nitroethene (6.00 g, 0.0355 mol) and phenylmagnesium bromide (18.7 mL, 0.056 mol), followed by LiAlH4 reduction (5.41 g, 0.14 mol) as described in Example 10.
Nukleosidet (0,90 g, 31%) ble fremstillet fra aminetThe nucleoside (0.90 g, 31%) was prepared from the amine
(1,50 g, 0,0069 mol), 6-klorpurin-ribosid (1,78 g, 0,0062 mol) og trietylamin (0,9 ml, 0,0068 mol) som et faststoff, smp. 93-100°C, som beskrevet i Eksempel 10. (1.50 g, 0.0069 mol), 6-chloropurine riboside (1.78 g, 0.0062 mol) and triethylamine (0.9 mL, 0.0068 mol) as a solid, m.p. 93-100°C, as described in Example 10.
EKSEMPEL 12 EXAMPLE 12
N, 6-( 2-( 2- metylfuran- 3- yl)- 2- fenetyl) adenosinN, 6-( 2-( 2- methylfuran-3- yl)- 2- phenethyl) adenosine
Nitrostyrenet (1,86 g, 25%) ble fremstillet fra 2-metyl-3-furaldehyd (5,38 g, 0,049 mol) og nitrometan (3,00 g, 0,049 mol) som beskrevet i Eksempel 10. The nitrostyrene (1.86 g, 25%) was prepared from 2-methyl-3-furaldehyde (5.38 g, 0.049 mol) and nitromethane (3.00 g, 0.049 mol) as described in Example 10.
Aminet (0,44 g, 44%) ble fremstillet fra E,2-(2-metylfuran-3- yl)nitroeten (0,77 g, 0,005 mol) og fenylmagnesiumbromid (2,7 ml, 0,008 mol), etterfulgt av LiAlH4-reduksjon (0,66 g, 0,017 mol) som beskrevet i Eksempel 10. The amine (0.44 g, 44%) was prepared from E,2-(2-methylfuran-3-yl)nitroethene (0.77 g, 0.005 mol) and phenylmagnesium bromide (2.7 mL, 0.008 mol), followed by LiAlH4 reduction (0.66 g, 0.017 mol) as described in Example 10.
Nukleosidet (0,66 g, 73%) ble fremstillet fra aminetThe nucleoside (0.66 g, 73%) was prepared from the amine
(0,44 g, 0,0022 mol), 6-klorpurin-ribosid (0,57 g, 0,002 mol)(0.44 g, 0.0022 mol), 6-chloropurine riboside (0.57 g, 0.002 mol)
og trietylamin (0,3 ml, 0,0022 mol) som et lysebrunt faststoff, smp. 93-96°C, som beskrevet i Eksempel 10. and triethylamine (0.3 mL, 0.0022 mol) as a light brown solid, m.p. 93-96°C, as described in Example 10.
EKSEMPEL 13 EXAMPLE 13
N, 6-( 2-( 3- metylfuran- 2- yl)- 2- fenetyl) adenosinN, 6-( 2-( 3- methylfuran- 2- yl)- 2- phenethyl) adenosine
Nitrostyrenet (0,59 g, 48%) ble fremstillet fra 3-metyl-2-furaldehyd (0,92 g, 0,008 mol) og nitrometan (0,49 g, 0,008 mol), som beskrevet i Eksempel 10. The nitrostyrene (0.59 g, 48%) was prepared from 3-methyl-2-furaldehyde (0.92 g, 0.008 mol) and nitromethane (0.49 g, 0.008 mol), as described in Example 10.
Aminet (0,08 g, 10%) ble fremstillet fra E,2-(3-metylfuran-2-yl)nitroeten (0,59 g, 0,0039 mol) og fenylmagnesiumbromid (2,1 ml, 0,0063 mol), etterfulgt av LiAlH4-reduksjon (0,18 g, 0,0047 mol), som beskrevet i Eksempel 10. The amine (0.08 g, 10%) was prepared from E,2-(3-methylfuran-2-yl)nitroethene (0.59 g, 0.0039 mol) and phenylmagnesium bromide (2.1 mL, 0.0063 mol) ), followed by LiAlH 4 reduction (0.18 g, 0.0047 mol), as described in Example 10.
Nykleosidet (0,12 g, 74%) ble fremstillet fra aminetThe nucleoside (0.12 g, 74%) was prepared from the amine
(0,08 g, 0,0004 mol), 6-klorpurin-ribosid (0,10 g, 0,00036 mol) og trietylamin (0,1 ml, 0,0008 mol) som et faststoff, smp. 68-78°C, som beskrevet i Eksempel 10. (0.08 g, 0.0004 mol), 6-chloropurine riboside (0.10 g, 0.00036 mol) and triethylamine (0.1 mL, 0.0008 mol) as a solid, m.p. 68-78°C, as described in Example 10.
EKSEMPEL 14 EXAMPLE 14
N, 6-( 2-( 5- bromtien- 2- yl)- 2- fenetyl) adenosin N, 6-( 2-( 5- bromothien- 2- yl)- 2- phenethyl) adenosine
E,2-(tien-2-yl)nitroeten (12,65 g, 33%) ble fremstilletE,2-(thien-2-yl)nitroethene (12.65 g, 33%) was prepared
fra tiofen-2-karboksaldehyd (23,4 ml, 0,25 mol) og nitrometan (15,3 g, 0,25 mol) som beskrevet i Eksempel 10. from thiophene-2-carboxaldehyde (23.4 ml, 0.25 mol) and nitromethane (15.3 g, 0.25 mol) as described in Example 10.
2-tien-2-yl-2-fenetylamin (0,90 g, 32%) ble fremstillet2-thien-2-yl-2-phenethylamine (0.90 g, 32%) was prepared
fra E,2-(tien-2-yl)nitroeten (2,16 g, 14 mmol) og fenylmagnesiumbromid (7,2 ml, 21 mmol) etterfulgt av LiAlH4-reduksjon (1,60 g, 42 mmol), som beskrevet i Eksempel 10. from E,2-(thien-2-yl)nitroethene (2.16 g, 14 mmol) and phenylmagnesium bromide (7.2 mL, 21 mmol) followed by LiAlH 4 reduction (1.60 g, 42 mmol), as described in Example 10.
2-(5-bromtien-2-yl)-2-fenetylamin. En oppløsning av brom (1,12 g, 7 mmol) i CHC13(25 ml) ble dråpevis i løpet av 20 minutter tilsatt til en oppløsning av 2-tien-2-yl-2-fenetylamin (1,19 g, 6,5 mmol) i CHC13(25 ml) og omrørt under N2ved 0°C. Etter ytterligere 20 minutter ble reaksjonsblandingen ekstrahert med fortynnet saltsyre (0,1M, 2 x 50 ml). Det vandige lag ble vasket med CHC13(2 x 25 ml), deretter gjort basisk med NaOH-pellets (1,2 g, 30 mmol), og ble deretter ekstrahert med eter (3 x 25 ml). De samlede ekstraktene ble vasket med vann (2 x 25 ml), mettet saltvann (25 ml) og tørket (MgSOj. Oppløsnings- 2-(5-Bromothien-2-yl)-2-phenethylamine. A solution of bromine (1.12 g, 7 mmol) in CHCl 3 (25 mL) was added dropwise over 20 minutes to a solution of 2-thien-2-yl-2-phenethylamine (1.19 g, 6, 5 mmol) in CHCl 3 (25 mL) and stirred under N 2 at 0°C. After an additional 20 minutes, the reaction mixture was extracted with dilute hydrochloric acid (0.1M, 2 x 50 mL). The aqueous layer was washed with CHCl 3 (2 x 25 mL), then basified with NaOH pellets (1.2 g, 30 mmol), and then extracted with ether (3 x 25 mL). The combined extracts were washed with water (2 x 25 ml), saturated brine (25 ml) and dried (MgSO 4 . Solution-
midlet ble fjernet under redusert trykk for å oppnå det ønskede bromid (0,85 g, 49%) som en lysegul olje. the solvent was removed under reduced pressure to afford the desired bromide (0.85 g, 49%) as a pale yellow oil.
Nukleosidet (1,26 g, 72%) ble fremstillet fra 2-(5-bromtien-2-yl)-2-fenetylamin (0,85 g, 3,3 mmol), 6-klorpurin-ribosid (0,96 g, 3,3 mmol) og trietylamin (0,61 g, 6 mmol) som et hvitaktig fast skum, smp. 101-109°C, som beskrevet i Eksempel 10. The nucleoside (1.26 g, 72%) was prepared from 2-(5-bromothien-2-yl)-2-phenethylamine (0.85 g, 3.3 mmol), 6-chloropurine riboside (0.96 g , 3.3 mmol) and triethylamine (0.61 g, 6 mmol) as a whitish solid foam, m.p. 101-109°C, as described in Example 10.
Claims (21)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92602886A | 1986-10-31 | 1986-10-31 | |
| PCT/US1987/002725 WO1988003148A2 (en) | 1986-10-31 | 1987-10-19 | Heteroaromatic derivatives of adenoside |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO882888L true NO882888L (en) | 1988-06-29 |
| NO882888D0 NO882888D0 (en) | 1988-06-29 |
Family
ID=26776348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO882888A NO882888D0 (en) | 1986-10-31 | 1988-06-29 | PROCEDURE FOR THE PREPARATION OF HETEROAROMATIC DERIVATIVES OF ADENOSIN. |
Country Status (2)
| Country | Link |
|---|---|
| DK (1) | DK357888A (en) |
| NO (1) | NO882888D0 (en) |
-
1988
- 1988-06-29 DK DK357888A patent/DK357888A/en not_active Application Discontinuation
- 1988-06-29 NO NO882888A patent/NO882888D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK357888D0 (en) | 1988-06-29 |
| DK357888A (en) | 1988-06-29 |
| NO882888D0 (en) | 1988-06-29 |
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