NO168247B - Analogifremgangsmaate for fremstilling av terapeutisk aktive 5-metoksy-alkyl-ammonium-tetrahydrofuraner. - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive 5-metoksy-alkyl-ammonium-tetrahydrofuraner. Download PDFInfo
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- NO168247B NO168247B NO882336A NO882336A NO168247B NO 168247 B NO168247 B NO 168247B NO 882336 A NO882336 A NO 882336A NO 882336 A NO882336 A NO 882336A NO 168247 B NO168247 B NO 168247B
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- Prior art keywords
- preparation
- ammonium
- compound
- alkyl
- tetrahydrofuranes
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- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- -1 2-tridecyl-5-dimethylamino-ethoxymethyl-tetrahydrofuran Chemical compound 0.000 description 5
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000283977 Oryctolagus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MYNRDUPGBPOWQT-IDTAVKCVSA-N (2r,3r,4s,5r)-2-(6-aminopurin-9-yl)-5-[[3-hydrazinylpropyl(methyl)amino]methyl]oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](CN(CCCNN)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MYNRDUPGBPOWQT-IDTAVKCVSA-N 0.000 description 1
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- LYLBPWMEXRLSFP-UHFFFAOYSA-M 6-pyridin-1-ium-1-ylhexan-1-ol;chloride Chemical compound [Cl-].OCCCCCC[N+]1=CC=CC=C1 LYLBPWMEXRLSFP-UHFFFAOYSA-M 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 206010022714 Intestinal ulcer Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 230000002804 anti-anaphylactic effect Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- AITBHTAFQQYBHP-UHFFFAOYSA-N benzene;pyridine Chemical compound C1=CC=CC=C1.C1=CC=NC=C1 AITBHTAFQQYBHP-UHFFFAOYSA-N 0.000 description 1
- 108010015046 cell aggregation factors Proteins 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000012332 laboratory investigation Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Animal Behavior & Ethology (AREA)
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- Diabetes (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Furan Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pyridine Compounds (AREA)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av nye 5-metoksy-alkyl-ammonium-tetrahydrofuraner
med den generelle formel:
hvor
m er et helt tall fra 1 til 12,
A er:
et pyridiniumsalt med formlene:
hvor R betyr H eller CH3,
et ammoniumsalt med formlene:
og
Z~ er et farmasøytisk godtagbart anion.
Disse forbindelser kan være i form av de mulige stereo-isomerer eller som en blanding av disse.
Disse forbindelser er særlig interessante som anti-PAF-midler (PAF betyr blodplateaggregasjons-faktor) med den tilsvarende aktivitet som anti-anafylaktisk middel, anti-trombotisk middel, anti-ischemisk middel, immunodepressor og virker også mot immun-forandringer i nyren, mot forskjellige sjokk, mot hud-allergier og tarmsår fremkalt f.eks. av endotoksin.
Fremgangsmåten ifølge oppfinnelsen består i at en forbindelse med formel I
omsettes med en forbindelse med formel II
hvor B er forløperen for A inneholdende en aminogruppe, eller B = A.
Omsetningen utføres hensiktsmessig i et oppløsningsmiddel så som dimetylformamid ved en> temperatur på 60-80°C. Når B betyr en forløper for A som, inneholder en aminogruppe, metyleres denne på kjent måte.
Utgangsmaterialene med formel I kan fremstilles ved at en forbindelse med formel III:
omsettes med metansulfonylklorid i benzen-pyridin fulgt av klassisk behandling.
Forbindelsen med formel II fremstilles ved at natriumhydrid omsettes med den tilsvarende aminoalkohol BOH i DMF ved 50-60°C.
Eksempel 1
2-( 2'- tredecyl- tetrahvdrofuran- 5'- metyloksy)- etvl- trimetyl-ammoniumi odid
+
X=0, m=2,A=-N- (CH3)3, I"
Trinn a: Fremstilling av 2-tredecyl-5-dimetylamino-etoksymetyl-tetrahydrofuran. A = (CH2)2N(CH3)2
Til 1,13 g (12,7 mmol) dimetylaminoetanol i 100 ml tørr dimetylformamid ble satt 0,51 g (12,7 mmol) NaH (60% dispersjon i olje). Blandingen ble oppvarmet i 30 minutter ved 60°C med omrøring, hvorefter 2,3 g (6,35 mmol) 2-tredecyl-tetrahydrofuran-5-metanol-metan-sulfonat ble tilsatt. Efter oppvarmning i ytterligere 2 timer ved 80°C med omrøring, ble blandingen avkjølt, og overskudd av NaH ble dekomponert ved tilsetning av 5 ml MeOH. Avdampning av mesteparten av DMF førte til et residuum som ble fortynnet med vann og ekstrahert tre ganger med dietyleter. Det organiske lag ble vasket med vann inntil nøytralitet var oppnådd, tørret (MgS04) og inndampet i vakuum. Den rå tittelforbindelse ble derefter renset ved kromatografi
på silikagel under anvendelse av 1 til 5% MeOH i CHC13 som elueringsmiddel for å gi 0,9 g (40%) som en olje.
IR (film): 2930, 2860 (C-H), 2780 (N-CH3), 1120 (C-O-C) cm<-1>, <1->HNMR (80 MHZ, CDCl3 , HMDS) S: 3,95 (m, 2H, CH-O) , 3,58 (t, 2H, 0CH2-C-N), 3,42 (d, 2H, CH2-0), 2,5 (t, 2H, CH2N), 2,25 (s, 6H, N(CH3)2) , 2,06-1,35 (m, 6H, CH2-C-0) , 1,22 (stor s, 22H, (CH2) 1±), 0,82 (t, 3H, CH3).
Trinn b: Fremstilling av 2-(2-tredecyl-tetrahydrofuran-5-metyloksy)-etyl-trimetylammoniumj odid.
0,5 g (1,4 mmol) av forbindelsen fremstilt i trinn a) ovenfor og et overskudd av metyljodid (2 g, 14 mmol) i 50 ml tørr aceton ble omrørt i 2 timer ved romtemperatur. Efter fjernelse av oppløsningsmidlet og av overskudd av Mel, ble residuet kromatografert på en silikagelkolonne under anvendelse
av 5% til 20% MeOH i CHC13 som elueringsmiddel, hvilket førte til tittelforbindelsen som et gult, fast stoff, sm.p. = 104°C. IR (KBr) 2940, 2860 (C-H), 1120, 1070 (C-O-C) cm-<1>.
^-HNMR (80 MHz, CDCI3 , HMDS) S: 4.00 (m, 5H, CH2-0 + O-CH-C-O) , 3,77 (m, 3H, CH-0 + CH2N), 3,56 (s, 9H, N(CH3)3), 2,25-1,50 (m, 6H, CH2-C-0), 1,25 (stor s, 22H (CH2)11), 0,85 (t, 3H, CH3).
Eksempel 2
2- f 2'- tredecyl- tetrahydrofuran- 5'- metoksy)- tolyl- p- trimetyl-ammoniumi odid
X = 0, m = 1,
N(CH3)3, I-
Fremstillingen ble foretatt som i eksempel 1 a) og b),
idet man startet med den samme metansulfonyl-forbindelse og p-dimetylaminobenzylalkohol fremstilt ved reduksjon med NaBH4 av kommersielt p-dimetylaminobenzaldehyd i EtOH for å oppnå tittelforbindelsen som et gult, fast stoff, sm.p. = 124-126°C. IR (KBr): 3000 (aromatisk C-H), 2910, 2820 (C-H), 1100, 1080 (C-O-C) cm<-1>.
<1>HNMR (80 MHz, CDCI3, HMDS) S: 8,07 (m, 2H, CH=C-N), 7,66 (m, 2H, CH=C-C) , 4,65 (s, 2H, 0-CH2-cp) , 4,05 (stor s, 11H, N(CH3)3 + CH-O), 3,49 (d, 2H, 0CH2-C-0), 2,12-1,42 (m, 6H, CH2-C-0), 1,22 (stor s, 22H, (CH2)1:L), <0,>82 (t, 3H, CH3) .
Eksempel 3
( 2 '- tredecvl- tetrahvdrofuran- 5/- metyloksy)- metyl- 3- N- metyl-pyridiniumi odid
X = 0, m = 1,
Denne fremstilling ble foretatt som i eksempel 1 a) og b), idet man startet med den samme metansulfonylforbindelse og 3-pyridylmetanol for å oppnå tittelforbindelsen som et gult, fast stoff, sm.p.: 76°C.
IR |KBr), 3080, 3060 (aromatisk C-H), 2940, 2870 (C-H), 1645 (C=N), 1130, 1080 (C-O-C) cm-<1>.
<1->HNMR (80 MHz, CDC13 , HMDS) S: 9,38 (d, 1H, Ha) , 9,26 (s, 1H, Hp), 8,57 (d, 1H, HT), 8,17 (t, 1H, H§), 4,90 (s, 2H, 0-CH2-pyridin), 4,68 (s, 3H, CH3-N), 4,36-3,72 (m, 2H, CH-0), 3,62 (d, 2H, 0-CH2-C-0), 2,21-1,55 (m, 6H, CH2-C-0), 1,25 (stor s, 22H, (CH2)11), 0,82 (t, 3H, CH3).
Eksempel 4
6-( 2'- tredecyl- tetrahydrofuran- 5'- metvloksy)- heksyl- pyridinium-klorid
X = 0, m = 6,
Cl-
Analogt med eksempel 1 startet man med den samme metan-sulf onylf orbindelse og 6-pyridinio-heksanolklorid for å oppnå tittelforbindelsen som en hygroskopisk olje.
<1->HNMR (80 MHz, CDCI3 , HMDS) S: 9,55 (d, 2H, CH=N) , 8,55 (m, 1H,
+ <+>
8,17 (t, 2H, CH=C-N), 4,97 (m, 2H, CH2N), 4,47-3,67
(m, 4H, CH-0 + O-CH2-C-0), 3,33 (m, 2H, CH20), 2,2-1,32 (m, 10H, CH2-C-0 + CH2-C-N) , 1,2 (stor s, 26H, (CH2)1:L <+> 0-C2-(CH2)2-C2-N), 0,82 (t, 3H, CH3).
Toksikologi
Forbindelsene fremstilt ifølge oppfinnelsen ble administrert til mus for å bestemme akutt LD50. For alle forbindelsene fremstilt ifølge oppfinnelsen var LD50 over 300 mg/kg (ip eller sc) og 600 mg/kg (po).
Farmakologi
Et bevis på den farmakologiske virkning av forbindelsene fremstilt ifølge oppfinnelsen fremgår av følgende farmasøytiske forsøk.
Hemning av blodplateaggregasjon på New Zealand- kaniner
Forsøket ble foretatt på blodplater med plasma fra New Zealand-kaniner.
Blodprøver ble tatt fra øre-arterien og anbragt i citrat-buffer (3,8%, pH 7,4); og blodet ble derefter sentrifugert i 15 minutter ved 1200 opm.
Forsøksprøven ble tilberedt i DMSO, og derefter hellet på blodplaterik plasma i 1 minutt hvorefter en dose på 2,5 nM PAF ble tilsatt.
Bestemmelsen ble foretatt på et Cronolog Coultronics apparat som bestemmer transmisjonsprosenten svarende til maksimum høyde av toppen før deaggregering.
Den prosentvise variasjon av hemningen i henhold til transmisjonsprosenten beregnes (kontroll: ren DMSO).
Denne metode er beskrevet i detalj i Laboratory Investigations, vol. 41, nr. 3, s. 275, 1979. Jean-Pierre Cazenave, Dr. Med.,
Jacques Benveniste, Dr. Med., og J. Fraser Mustard, M.D., "Aggregation of Rabbits Platelets by Platelet-Activating Factor is independent of the Release Reaction and the Arachidonate Pathway and inhibited by Membrane-Active Drugs".
Resultatene viser at forbindelsene hemmer aggregasjonen fremkalt av 2,5 nM PAF. Fem forsøk foretatt med 5 forskjellige kaniner gjorde det mulig å beregne IC50 for de forskjellige forbindelser under anvendelse av lineær regresjonstest.
Verdiene for IC50 på blodplater er funnet å være som følger:
Claims (1)
- Analogifremgangsmåte for fremstilling av nye terapeutisk aktive tetrahydrofuraner med den generelle formel:hvorm er et helt tall fra 1 til 12,A er: - et pyridiniumsalt med formlene: hvor R betyr H eller CH3, - et ammoniumsalt med formlene:og Z~ er et farmasøytisk godtagbart anion,karakterisert ved at en forbindelse med formel I omsettes med forbindelsen NaOB hvor B betyr enten A eller forløperen for A som inneholder en aminogruppe, i et oppløsnings-middel så som dimetylformamid ved en temperatur på 60-80°C, og når B betyr en forløper for A som inneholder en aminogruppe, metyleres denne på kjent måte.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878712694A GB8712694D0 (en) | 1987-05-29 | 1987-05-29 | Tetrahydrofurans etc |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO882336D0 NO882336D0 (no) | 1988-05-27 |
| NO882336L NO882336L (no) | 1988-11-30 |
| NO168247B true NO168247B (no) | 1991-10-21 |
| NO168247C NO168247C (no) | 1992-01-29 |
Family
ID=10618140
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO882336A NO168247C (no) | 1987-05-29 | 1988-05-27 | Analogifremgangsmaate for fremstilling av terapeutisk aktive 5-metoksy-alkyl-ammonium-tetrahydrofuraner. |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US4888338A (no) |
| JP (1) | JPS63310880A (no) |
| KR (1) | KR960012371B1 (no) |
| AR (1) | AR244223A1 (no) |
| AT (1) | AT396471B (no) |
| AU (1) | AU605717B2 (no) |
| BE (1) | BE1002145A3 (no) |
| CA (1) | CA1318673C (no) |
| CH (1) | CH675123A5 (no) |
| DE (1) | DE3818122C2 (no) |
| DK (1) | DK167678B1 (no) |
| ES (1) | ES2009925A6 (no) |
| FI (1) | FI89354C (no) |
| FR (2) | FR2615855B1 (no) |
| GB (2) | GB8712694D0 (no) |
| GR (1) | GR1000146B (no) |
| HK (1) | HK100490A (no) |
| IE (1) | IE61385B1 (no) |
| IN (1) | IN169649B (no) |
| IT (1) | IT1219697B (no) |
| LU (1) | LU87230A1 (no) |
| MA (1) | MA21288A1 (no) |
| MY (1) | MY103731A (no) |
| NL (1) | NL192573C (no) |
| NO (1) | NO168247C (no) |
| NZ (1) | NZ224776A (no) |
| OA (1) | OA08740A (no) |
| PT (1) | PT87586B (no) |
| SE (1) | SE466448B (no) |
| SG (1) | SG83090G (no) |
| TN (1) | TNSN88050A1 (no) |
| ZA (1) | ZA883732B (no) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8701727D0 (en) * | 1987-01-27 | 1987-03-04 | Scras | Tetrahydrofuran derivatives |
| GB8712693D0 (en) * | 1987-05-29 | 1987-07-01 | Scras | Tetrahydrofurans etc |
| ES2010568A6 (es) * | 1988-08-04 | 1989-11-16 | Uriach & Cia Sa J | Procedimiento para la obtencion de derivados 2,5-disustituidos de tetrahidrofurano. |
| JP2805006B2 (ja) * | 1991-08-29 | 1998-09-30 | 財団法人 工業技術研究院 | チオフェン系化合物及びその薬理的に許容できる塩類よりなる医薬 |
| KR100836547B1 (ko) * | 2002-01-11 | 2008-06-10 | 상꾜 가부시키가이샤 | 아미노 알코올 유도체 또는 포스폰산 유도체 및 이들을함유하는 의약 조성물 |
| WO2005079788A1 (ja) | 2004-02-24 | 2005-09-01 | Sankyo Company, Limited | アミノアルコール化合物 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1088880A (en) * | 1964-11-18 | 1967-10-25 | Vantorex Ltd | ª‡-cycloalkyleneimino-substituted esters |
| US4289884A (en) * | 1979-01-08 | 1981-09-15 | Shell Oil Company | Herbicidal tetrahydrofuran derivatives |
| DK162882A (da) * | 1981-04-13 | 1982-10-14 | Searle & Co | Imidazolderivater eller syreadditionssalte deraf,deres fremstilling og anvendelse |
| DE3408879A1 (de) * | 1984-03-10 | 1985-09-12 | Basf Ag, 6700 Ludwigshafen | Pyridiniumsalze und diese enthaltende fungizide und bakterizide |
| GB8701727D0 (en) * | 1987-01-27 | 1987-03-04 | Scras | Tetrahydrofuran derivatives |
| GB8712693D0 (en) * | 1987-05-29 | 1987-07-01 | Scras | Tetrahydrofurans etc |
| NZ227287A (en) * | 1987-12-21 | 1992-01-29 | Merck & Co Inc | 2,5-diaryl tetrahydrofurans and medicaments |
-
1987
- 1987-05-29 GB GB878712694A patent/GB8712694D0/en active Pending
-
1988
- 1988-05-20 NL NL8801314A patent/NL192573C/nl not_active IP Right Cessation
- 1988-05-20 AR AR88310911A patent/AR244223A1/es active
- 1988-05-23 IN IN452/DEL/88A patent/IN169649B/en unknown
- 1988-05-23 GR GR880100341A patent/GR1000146B/el not_active IP Right Cessation
- 1988-05-25 NZ NZ224776A patent/NZ224776A/en unknown
- 1988-05-25 ZA ZA883732A patent/ZA883732B/xx unknown
- 1988-05-25 CH CH1981/88A patent/CH675123A5/fr not_active IP Right Cessation
- 1988-05-25 SE SE8801945A patent/SE466448B/sv not_active IP Right Cessation
- 1988-05-26 PT PT87586A patent/PT87586B/pt not_active IP Right Cessation
- 1988-05-26 GB GB8812487A patent/GB2205315B/en not_active Expired - Fee Related
- 1988-05-26 FI FI882476A patent/FI89354C/fi not_active IP Right Cessation
- 1988-05-26 MY MYPI88000562A patent/MY103731A/en unknown
- 1988-05-27 TN TNTNSN88050A patent/TNSN88050A1/fr unknown
- 1988-05-27 ES ES8801675A patent/ES2009925A6/es not_active Expired
- 1988-05-27 IE IE160088A patent/IE61385B1/en not_active IP Right Cessation
- 1988-05-27 LU LU87230A patent/LU87230A1/fr unknown
- 1988-05-27 US US07/199,939 patent/US4888338A/en not_active Expired - Lifetime
- 1988-05-27 IT IT20772/88A patent/IT1219697B/it active
- 1988-05-27 MA MA21530A patent/MA21288A1/fr unknown
- 1988-05-27 DK DK291188A patent/DK167678B1/da not_active IP Right Cessation
- 1988-05-27 OA OA59369A patent/OA08740A/xx unknown
- 1988-05-27 AU AU16721/88A patent/AU605717B2/en not_active Ceased
- 1988-05-27 CA CA000567991A patent/CA1318673C/en not_active Expired - Fee Related
- 1988-05-27 BE BE8800599A patent/BE1002145A3/fr active
- 1988-05-27 DE DE3818122A patent/DE3818122C2/de not_active Expired - Fee Related
- 1988-05-27 JP JP63128594A patent/JPS63310880A/ja active Granted
- 1988-05-27 NO NO882336A patent/NO168247C/no not_active IP Right Cessation
- 1988-05-28 KR KR1019880006344A patent/KR960012371B1/ko not_active IP Right Cessation
- 1988-05-30 FR FR888807165A patent/FR2615855B1/fr not_active Expired - Fee Related
- 1988-05-30 FR FR888807166A patent/FR2615736B1/fr not_active Expired - Fee Related
- 1988-05-30 AT AT0140688A patent/AT396471B/de not_active IP Right Cessation
-
1990
- 1990-10-12 SG SG830/90A patent/SG83090G/en unknown
- 1990-11-29 HK HK1004/90A patent/HK100490A/xx not_active IP Right Cessation
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| MM1K | Lapsed by not paying the annual fees |
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