DK167532B1 - 2-(1-pyridylalkanoyloxymethylen)tetrahydrofuran- og -tetrahydrothiophensalte, fremgangsmaade til fremstilling deraf og laegemidler indeholdende saadanne salte - Google Patents
2-(1-pyridylalkanoyloxymethylen)tetrahydrofuran- og -tetrahydrothiophensalte, fremgangsmaade til fremstilling deraf og laegemidler indeholdende saadanne salte Download PDFInfo
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- DK167532B1 DK167532B1 DK291088A DK291088A DK167532B1 DK 167532 B1 DK167532 B1 DK 167532B1 DK 291088 A DK291088 A DK 291088A DK 291088 A DK291088 A DK 291088A DK 167532 B1 DK167532 B1 DK 167532B1
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- Prior art keywords
- salts
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- tetrahydrothiophenal
- pyridylalkanoyloxymythylene
- tetrahydrofurane
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- 238000000034 method Methods 0.000 title claims description 5
- 150000003839 salts Chemical class 0.000 title claims 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 4
- HRBGUGQWTMBDTR-UHFFFAOYSA-N 2,3,4-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC=C(S(Cl)(=O)=O)C(C(C)C)=C1C(C)C HRBGUGQWTMBDTR-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229910052770 Uranium Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 150000003572 thiolanes Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- DNYWZCXLKNTFFI-UHFFFAOYSA-N uranium Chemical compound [U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U] DNYWZCXLKNTFFI-UHFFFAOYSA-N 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000283977 Oryctolagus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical group C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 2
- ORLMQXIHXJVFKP-UHFFFAOYSA-N (5-tridecyloxolan-2-yl)methanol Chemical compound CCCCCCCCCCCCCC1CCC(CO)O1 ORLMQXIHXJVFKP-UHFFFAOYSA-N 0.000 description 1
- CRVONYYEQXCNKZ-UHFFFAOYSA-N (5-tridecyloxolan-2-ylidene)methyl 5-chloropentanoate Chemical compound CCCCCCCCCCCCCC1CCC(=COC(=O)CCCCCl)O1 CRVONYYEQXCNKZ-UHFFFAOYSA-N 0.000 description 1
- JOFZZWXVLLDHOV-UHFFFAOYSA-N (5-tridecylthiolan-2-yl)methanol Chemical compound CCCCCCCCCCCCCC1CCC(CO)S1 JOFZZWXVLLDHOV-UHFFFAOYSA-N 0.000 description 1
- -1 2,4,6-trimethylphenyl Chemical group 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- YSXDKDWNIPOSMF-UHFFFAOYSA-N 5-chloropentanoic acid Chemical compound OC(=O)CCCCCl YSXDKDWNIPOSMF-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-M Arachidonate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC([O-])=O YZXBAPSDXZZRGB-DOFZRALJSA-M 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 229910003556 H2 SO4 Inorganic materials 0.000 description 1
- 206010022714 Intestinal ulcer Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000002804 anti-anaphylactic effect Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940114078 arachidonate Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 108010015046 cell aggregation factors Proteins 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 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
- 150000002367 halogens Chemical group 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000001680 trimethoxyphenyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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- 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
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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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 Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Den foreliggende opfindelse angår hidtil ukendte 2-(l- pyridylalkanoyloxymethy len )tetrahydrof uran- og -tetrahy- drothiophensalte med den almene formel: .-Or* «—s ch2_o_c_ (CH2)n-M-;> } . z o 10 hvori: X betegner 0 eller S; n er et helt tal fra 1-6; R betegner lineær eller forgrenet C^-C^ alkyl, C^-C^q cycloalkyl, eller phenyl eller phenylalkyl med 1-5 car-15 bonatomer i alkyldelen, som i phenylringen kan være substitueret med CH3 eller OCH^, og Z® betegner en farmaceutisk acceptabel anion.
Opfindelsen angår disse forbindelser for hver af dem i 20 form af deres mulige stereoisomerer eller en vilkårlig blanding af disse.
Disse forbindelser er ganske særligt interessante som anti-PAF midler (PAF betyder blodplade-aggregerings-fak-25 tor) med den dertil svarende aktivitet, som anti-anaphy-lactisk middel, antithrombotisk middel, anti-ischemisk middel, immunodepressorer og ligeledes som indvirkende imod immunændring i nyren, overfor forskellige chocktil-stande, overfor hudallergier og tarm-ulcera fremkaldt 30 f.eks. ved endotoxin. Derudover kan disse forbindelser p.g.a. deres kraftige anticholinesterase-aktivitet være nyttige ved behandlingen af Alzheimers sygdom.
Opfindelsen angår også en fremgangsmåde til fremstilling 35 af forbindelserne ifølge krav 1, hvilken fremgangsmåde er ejendommelig ved det i krav 2's kendetegnende del angivne.
5 2
Forbindelserne ifølge opfindelsen kan således fremstilles ved, at man omsætter en forbindelse med formlen: X CH2 oh med en forbindelse med formlen:
10 l · HO_C_(CH ) _Y II
II
o hvori X, n og R har den ovenfor anførte betydning, og Y 15 betegner halogen.
Denne reaktion gennemføres bedst i et inert opløsningsmiddel, såsom tørt CHCl^, ved stuetemperatur i nærvær af triisopropylbenzensulfonylchlorid og pyridin, og den 20 fører til mellemproduktet med formlen: R_T1 ih
x'^CH2_0_C_(CH2)n_Y 25 O
hvori X, n, R og Y har den ovenfor anførte betydning. Denne forbindelse behandles yderligere med pyridin til opnåelse af de omhandlede forbindelser.
30
Forbindelsen med formlen (I) kan fremstilles i en flertrinsproces, som fører til følgende triol med formlen:
R I - CH-OH IV
35 2
OH
OH
3 hvori R har den ovenfor anførte betydning som kan cycli-seres til en tetrahydrofuran- eller tetrahydrothiophen-ring under anvendelse af beskyttelsesgrupper, mesylering og behandling med henholdsvis H20 eller Na2S.
5
Opfindelsen angår også et lægemiddel, der er ejendommeligt ved det i krav 3's kendetegnende del angivne.
Den foreliggende opfindelse belyses nærmere ved de efter-10 følgende eksempler.
EKSEMPEL 1 2-tridecyl-5-(5-pyridiniumpentanoyloxymethylen) tetrahy-15 drofuran chlorid X = 0, n = 4, R = CH3(CH2)12,Z~ = Cl" 20 Trin a: Fremstilling af 2-tridecyl-5-(5-chlorpentanoyl- oxymethylen) tetrahydrofuran. III n = 4, X=0, Y = Cl.
Man omrørte ved stuetemperatur i 24 timer en blanding af 2 g (7 mmol) 2-tridecyl-tetrahydrofur-5-yl-methanol, 1,43 25 g (10,5 mmol) 5-chlor-pentansyre og 4,24 g (14 mmol) tri-isopropylbenzensulfonylchlorid i tørt CHClg (20 ml)/pyri-din (10).
Reaktionen blev udslukket ved tilsætning af 50 ml H20 og 30 derpå gjort alkalisk (Na2C03), og det vandige lag blev genekstraheret med CHClg. Efter vaskning successivt med H20, IN, H2S0^, H20, Na2C03 og H20, blev organiske lag tørret (MgSO^) og opkoncentreret under vacuum. Inddamp-ningsresten blev derpå chromatograferet på en silicagel-35 søjle under anvendelse af 5 og 10% ether i petroleum ether til dannelse af 1,42 g af den i overskriften nævnte forbindelse i form af en olie. IR (film) 2950, 2880 (C- 4 Η), 1750 (C=0), 1190, 1110 (C-O) cm -1. 1HNMR (80 MHz, CDClg, HMDS), 6 4,02 (m, 4H, CH20C0 + CH-0), 3,55 (t, 2H, CH2C1), 2,35 (t, 2H, CH2C0), 2,22-1,37 (m, 10H, CH2-C-0, CH2-C-C0 + CH2-C-C1), 1,22 (stor s, 22H, 1(CH2)i:l), 0,81 5 (t, 3H, CH3).
Trin b: Fremstilling af 2-tridecyl-5-(5-pyridiniumpenta-noyloxymethylen) tetrahydrofuranchlorid.
10 Man opvarmer under tilbagesvaling natten over i 5 ml tør pyridin 0,5 g (1,24 mmol) af den ovenfor i trin a) fremstillede forbindelse. Efter opkoncentrering under vacuum blev den brune inddampningsrest renset over en silicagel-søjle under anvendelse af successivt 1, 2, 5 og 10% MeOH 15 i CHC13, hvilket fører til 0,4 g af den i overskriften nævnte forbindelse i form af et hygroskopisk, voksagtigt produkt.
IR (film) 3060 (aromatisk C-H), 2860, 2950 (C-H), 1740 20 C=0), 1640 (C=N), 1590 (C=C), 1180, 1100 (C-0) cm"1.
0 1HNMR (80 MHz, CDClg, HMDS) 6 9,71 (d, 2H, CH=N), 8,65 © y-- Θ 25 (t, IH, -N ^ 'V-H), 8,25 (t, 2H, 2CH = C-N), 5,12 Φ (t, 2H, CH2N), 3,97 (m, 4H, CH^QCO + 2CH-0), 2,42 (t, 2H CH2C0), 2,27-1,42 (m, 10H, CH2-C-0, CH2-C-CO + CH2-C-30 ø N), 1,22 (stor s, 22H, (CH2)l;L), 0,82 (t, eH,l CH3).
35 5 EKSEMPEL 2 2-(3, 4, 5, trimethoxyphenyl)-5-(pyridiniumpentanoyloxy- methylen) tetrahydrofuranchlorid 5 H3C0 ^ v Θ Θ X = 0, n = 4, R = H3CO-^_, Z = Cl h3co>=^ 10
Idet man går frem analogt med eksempel 1 afsnit a) og b), og idet man går ud fra 2-(3, 4, 5-trimethoxyphenyl)-te-trahydrofur-5-yl-methanol, opnår man den i overskriften 15 nævnte forbindelse i form af et meget hygroskopisk stof.
IR (KBR) 3060 (aromatisk C-H), 2920 (C-H), 1735 4C=0), 1635 (C=N), 1595 (C=C), 1180, 1130, 1035 (C-0) cm"1.
20 ©
«NMR (80 MHz, CDClg, HMDS) 6:9,71 (d, 2H, CH = N
—λ © 8,48 (t, IH, 8,08 (t, 2H, CH = C-N), © 25 6,62 (s, 2H, aromatisk H), 5,52-4,77 (m, 3H, CH2N + *- CH-0), 4,42 (m, IH, CH-0), 4,17 (t, 2H, CH20C0), 3,87 (s, 9H, CHgO), 2,63-1,55 (m, 10H, CH2CO + CH2-C-C0 + 30 @ ch2-c-n + ch2-c-o).
35 6 EKSEMPEL 3 2-(2,4,6-trimethylphenyl )-5-( 5-pyridiniumpentanoyloxyme-thylen)-tetrahydrofuranchlorid 5 /ch3 θ θ X = 0, n = 4, R = H3C , Z » Cl 'ch3 10 Man går frem analogt med eksempel 1 afsnit a) og b), idet man går ud fra 2-(2,4,6,-trimethylphenyl)-tetrahydrofur- 5-yl-methanol til opnåelse af den i overskriften nævnte forbindelse i form af et meget hygroskopisk stof.
Θ 15 1HNMR (80MHz, CDC13, HMDS) 6 9,28 (d, 2H, CH=N), 8,42 © © (m, IH, -N H) , 7,98 (m, 2H, CH=C - N), 6,75 (s, 2H, aromatisk H), 5,25 (m, IH, Φ-CH-O), 4,90 (m, 2H, 20 © CH2N), 4,60-3,96 (m, 3H, CH20C0 + CH-0), 2,57-1,37 (m, © 10H, CH2-C0 + CH2-C-0 + CH2-C-N), 2,27 (s, 6H, ortho-25 CH3), 2/17 (s, 3H, para-CH3).
EKSEMPEL 4 2-tridecyl-5-(5-pyridiniumpentanoyloxymethylen)-tetra-30 hydrothiophenchlorid θ Θ X = S, n = 4, R = C13H27, Z = Cl 35
Man går frem analogt med eksempel 1 afsnit a) og b), idet man går ud fra 2-tridecyl-tetrahydrothien-5-yl-methanol til opnåelse af den i overskriften nævnte forbindelse i form af et meget hygroskopisk stof.
7 DK 167532 Bl 1 ® 5 HNMR (80MHz, CDClg, HMDS) 6 9,35 (d, 2H, CH=N), 8,56 0 - I 0 (t, IH, ' 8,15 (m, 2H, CH=C-N), 3,45 (m, 2H, CH-S), 2,37 (t, 2H, CH2C0), 2,22-1,4 (m, 12H, 10 © CH2-C-N + CH2-C-C0 + CH2-C-S), 1,2 (stor s, 22H, (CH2)l;L), 0,82 (t, 3H, CH3).
15 T0XIC0L0GI
Forbindelserne ifølge opfindelsen er blevet indgivet til mus til bestemmelse af værdien for akut LD^q. For samtlige forbindelser ifølge opfindelsen var LD,_q større end 20 300 mg/kg (IP eller SC) og 600 mg/kg (PO).
FARMACOLOGI
Et bevis for den farmaceutiske interesse knyttet til for-25 bindeiserne ifølge opfindelsen er blevet etableret ved de i det følgende beskrevne farmaceutiske eksperimenter.
Inhibering af blodpladeaggregering på New Zealand kaniner 30 Disse eksperimenter blev gennemført på blodplader med plasma fra New Zealand kaniner.
Blodprøver blev udtaget fra den auriculære arterie og an bragt i citratpuffer (3,8%); pH 7,4); blodet blev yder- 35 ligere centrifugeret i 15 minutter ved 1200 o/min.
δ
Prøven til afprøvning blev præpareret med DMSO og derpå hældt ud over plasma med et højt indhold af blodplader i et minut, hvorpå man tilsatte en dosis på 2,5 nM PAF.
5 Bestemmelsen foretages på et apparat af typen "Cronolog Coultronics", som bestemmer procentvis transmission svarende til den maksimale højde af toppen før desaggregeringen.
10 Den procentvise variering af inhiberingen med hensyn til den procentvise transmission beregnes (kontrollen: ren DMSO).
Den anvendte metode er beskrevet detaljeret i Laboratory 15 Investigations, bind 41, nr. 3, side 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 20 inhibited by Membrane-Active Drugs".
De opnåede resultater viser, at forbindelserne ifølge opfindelsen inhiberer aggregeringen fremkaldt med 2,5 nM PAF. Man foretog fem afprøvninger på fem forskellige ka-25 niner, hvilket gjorde det muligt at beregne værdien IC^q for de forskellige forbindelser, idet man anvendte en lineær regressionsafprøvning.
Man fandt følgende værdier for IC5Q på blodplader: 30 — fi
Forbindelsen fra eksempel 1: 3,04 x 10 M
-5
Forbindelsen fra eksempel 2: 3,7 x 10 M
Forbindelsen fra eksempel 3: 3,86 x 10~^ M
-5
Forbindelsen fra eksempel 4: 1,7 x 10 M 35
Claims (2)
- 2. Fremgangsmåde til fremstilling af 2-(1-pyridylalkano yloxymethylen) tetrahydrof uran- og -tetrahydrothiophensalte ifølge krav 1, kendetegnet ved, at man i et inert opløsningsmiddel ved stuetemperatur og i nærvær af triisopropylbenzensulfonylchlorid og pyridin omsætter 25 en forbindelse med formlen: -CX X CH20H 30 med en forbindelse med formlen: HO - C - (CH2)n-Y II 35 » 0 hvori X, n og R har den i krav 1 anførte betydning, og Y er halogen, førende til mellemproduktet med formlen: -Q. X CH.-O-C-(CH_) _Y *!* || b H o hvori X, n, R og Y har den tidligere anførte betydning, 10 hvorpå man tilsidst substituerer Y med pyridin.
- 3. Lægemidler, kendetegnet ved, at de som en væsentlig bestanddel indeholder en effektiv mængde af mindst ét af saltene ifølge krav 1 i kombination med et 15 passende excipiens eller bærestof. 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8712693 | 1987-05-29 | ||
| GB878712693A GB8712693D0 (en) | 1987-05-29 | 1987-05-29 | Tetrahydrofurans etc |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK291088D0 DK291088D0 (da) | 1988-05-27 |
| DK291088A DK291088A (da) | 1988-11-30 |
| DK167532B1 true DK167532B1 (da) | 1993-11-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK291088A DK167532B1 (da) | 1987-05-29 | 1988-05-27 | 2-(1-pyridylalkanoyloxymethylen)tetrahydrofuran- og -tetrahydrothiophensalte, fremgangsmaade til fremstilling deraf og laegemidler indeholdende saadanne salte |
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| Country | Link |
|---|---|
| US (1) | US5017588A (da) |
| JP (1) | JPH0631228B2 (da) |
| KR (1) | KR960005152B1 (da) |
| AR (1) | AR243885A1 (da) |
| AT (1) | AT395715B (da) |
| AU (1) | AU610789B2 (da) |
| BE (1) | BE1002146A3 (da) |
| CA (1) | CA1317959C (da) |
| CH (1) | CH674985A5 (da) |
| DE (1) | DE3818106A1 (da) |
| DK (1) | DK167532B1 (da) |
| ES (1) | ES2009924A6 (da) |
| FI (1) | FI89353C (da) |
| FR (2) | FR2615854B1 (da) |
| GB (2) | GB8712693D0 (da) |
| GR (1) | GR1000147B (da) |
| HK (1) | HK101790A (da) |
| IE (1) | IE61341B1 (da) |
| IN (1) | IN168799B (da) |
| IT (1) | IT1219698B (da) |
| LU (1) | LU87229A1 (da) |
| MA (1) | MA21289A1 (da) |
| MY (1) | MY103289A (da) |
| NL (1) | NL192203C (da) |
| NO (1) | NO170086C (da) |
| NZ (1) | NZ224775A (da) |
| OA (1) | OA08878A (da) |
| PT (1) | PT87585B (da) |
| SE (1) | SE466449B (da) |
| SG (1) | SG93790G (da) |
| TN (1) | TNSN88049A1 (da) |
| ZA (1) | ZA883731B (da) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8701727D0 (en) * | 1987-01-27 | 1987-03-04 | Scras | Tetrahydrofuran derivatives |
| GB8712694D0 (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. |
| ES2013834A6 (es) * | 1989-01-30 | 1990-06-01 | Uriach & Cia Sa J | Procedimiento para la obtencion de derivados 4-sustituidos de 2-alcoxitetrahidrofurano. |
| US5118708A (en) * | 1989-06-23 | 1992-06-02 | Norwich Eaton Pharmaceuticals, Inc. | Use of 5-phenyl-2-furan esters, amides and ketones as neuroprotective agents |
| US20110097352A9 (en) * | 1992-01-29 | 2011-04-28 | Pharmexa Inc. | Inducing cellular immune responses to hepatitis B virus using peptide and nucleic acid compositions |
| KR100326276B1 (ko) * | 1999-12-14 | 2002-03-08 | 정명식 | 테트라하이드로푸란 유도체, 이의 제조방법 및 이를포함하는 항진균제 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1088880A (en) * | 1964-11-18 | 1967-10-25 | Vantorex Ltd | ª‡-cycloalkyleneimino-substituted esters |
| GB8701727D0 (en) * | 1987-01-27 | 1987-03-04 | Scras | Tetrahydrofuran derivatives |
| GB8712694D0 (en) * | 1987-05-29 | 1987-07-01 | Scras | Tetrahydrofurans etc |
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- 1988-05-27 DE DE3818106A patent/DE3818106A1/de active Granted
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- 1988-05-27 JP JP63128593A patent/JPH0631228B2/ja not_active Expired - Lifetime
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- 1988-05-28 KR KR1019880006343A patent/KR960005152B1/ko not_active Expired - Fee Related
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| Date | Code | Title | Description |
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| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |