DK150487B - Analogifremgangsmaade til fremstilling af triazolo-thieno-diazepin-1-oner eller alkalimetalsalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af triazolo-thieno-diazepin-1-oner eller alkalimetalsalte deraf Download PDFInfo
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- DK150487B DK150487B DK085078AA DK85078A DK150487B DK 150487 B DK150487 B DK 150487B DK 085078A A DK085078A A DK 085078AA DK 85078 A DK85078 A DK 85078A DK 150487 B DK150487 B DK 150487B
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- DK
- Denmark
- Prior art keywords
- thieno
- triazolo
- diazepin
- general formula
- preparation
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 10
- -1 ALKALIMETAL SALTS Chemical class 0.000 title claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 230000002152 alkylating effect Effects 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VJPWKZXLXLULNC-UHFFFAOYSA-N 12-bromo-9-(2-bromophenyl)-3lambda4-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,8,10-tetraene 3-oxide Chemical compound N=1N(Br)CN(C=2S(=O)C=CC=2CN=2)C=1C=2C1=CC=CC=C1Br VJPWKZXLXLULNC-UHFFFAOYSA-N 0.000 description 1
- DHRCAMFEWSTUIN-UHFFFAOYSA-N 12-chloro-9-phenyl-3lambda4-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,8,10-tetraene 3-oxide Chemical compound N=1N(Cl)CN(C=2S(=O)C=CC=2CN=2)C=1C=2C1=CC=CC=C1 DHRCAMFEWSTUIN-UHFFFAOYSA-N 0.000 description 1
- ZVZFWQPYEHJGDC-UHFFFAOYSA-N 8-bromo-6-(o-chloro-phenyl)-2-methyl-4h-s-triazolo[3,4-c]thieno[2,3-e]1,4-diazepin-1-one Chemical compound C12=NN(Br)CN2C=2S(=O)C(C)=CC=2CN=C1C1=CC=CC=C1Cl ZVZFWQPYEHJGDC-UHFFFAOYSA-N 0.000 description 1
- FNGWVUPXUNZLRG-UHFFFAOYSA-N 8-bromo-6-(o-chlorophenyl)-4h-s-triazolo(3,4-c)thieno-(2,3-e)-1,4-diazepin-1-one Chemical compound ClC1=CC=CC=C1C1=NCC2=NNC(=O)N2C2=C1C=C(Br)S2 FNGWVUPXUNZLRG-UHFFFAOYSA-N 0.000 description 1
- 241000881711 Acipenser sturio Species 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- ZMANIHNIYGCFHF-UHFFFAOYSA-N SN1N=C2C(=CC=C1)SC=C2 Chemical compound SN1N=C2C(=CC=C1)SC=C2 ZMANIHNIYGCFHF-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960005152 pentetrazol Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
150487
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte triazolo-thieno-diazepin-1-oner med den almene formel I
E3
5 I
o 1 -4^ 10 1 2 hvori R betegner et chlor-, brom- eller iodatom, R be- 3 15 tegner hydrogen eller et halogenatom, og R betegner hydrogen eller en alkylgruppe med 1-3 carbonatomer eller 3 alkalimetalsalte af de forbindelser, hvori R betegner hydrogen, hvilken analogifremgangsmåde er ejendommelig ved det i kravets kendetegnende del anførte.
20 Por fremgangsmåde (a) gælder det, at hydrolysen fortrinsvis udføres i surt medium, fortrinsvis under anvendelse af en hydrogenhalogenidsyre, ved temperaturer mellem stuetemperatur og reaktionsblandingens tilbagesvalingstemperatur, fortrinsvis ved tilbagesvalingstem- 25 peraturen. Forbindelserne med den almene formel II kan herved være opløst i opløsningsmidler, såsom lavere alkoholer eller andre organiske opløsningsmidler, der ikke indvirker på reaktionen. Hydrolysen kan dog også udføres uden tilsætning af et opløsningsmiddel.
30 Ved fremgangsmåde (b) opløses hydrazinforbindel sen III fortrinsvis i et indifferent opløsningsmiddel, f.eks. toluen, xylen, benzen eller et chlorcarbonhydrid og omsættes med en opløsning af phosgen i det samme opløsningsmiddel eller også med gasformig phosgen ved tem- 35 peraturer mellem 0°C og reaktionsblandingens kogepunkt.
Herved tilsættes phosgenet hensigtsmæssigt ved stuetemperatur, og blandingen opvarmes derpå lidt efter lidt til kogepunktet.
2 150487
Der opnås gode udbytter ved de to fremgangsmåder.
O
Et slutprodukt med den almene formel I, hvori R betegner hydrogen, kan let overføres i det tilsvarende 5 alkalisalt ved behandling med natriumhydrid, natiiumamid eller natriumalkoholater i tetrahydrofuran, dioxan eller en lavere alkohol. Ved omsætning med et sædvanligt al-kyleringsmiddel, såsom et alkylhalogenid, et dialkylsul-fat eller -tosylat opnår man den tilsvarende N-alkylfor- 3 10 bindelse (R = alkyl med 1-3 carbonatomer).
Udgangsstofferne med den almene formel II er kendt fra litteraturen. De kan f.eks. opnås ved den i DE-offentliggørelsesskrift nr. 24 35 041 anførte metode ved haloge-nering af en i 1-stilling usubtsitueret thienotriazolobenzodiazepin 15 og erstatning af halogenatomet med en alkoxygruppe.
Forbindelser med den almene formel III er kendt fra EE-fremlæggelsesskrift nr. 24 10 030. De kan fremstilles ved omsætning af en tilsvarende 2-mercaptothienodiazepin med hydrazin.
Forbindelserne med den almene formel I har værdi-20 fulde terapeutiske egenskaber. De har ved farmakologiske prøver vist sig at have anxiolytisk, antikonvulsiv og sederende virkning ved overordentlig ringe toxicitet og at være overlegne i forhold til de nærmest beslægtede triazolothienodiazepiner, som er beskrevet i US pa-25 tentskrift nr. 3.965.111 (svarende til DE-offentliggørelsesskrift nr. 22 53 107). Forbindelserne, scsn fremstilles ved fremgangsmåden ifølge opfindelsen, afviger specielt fra nævnte kendte forbindelser ved at have et chlor-, brom- eller iodatom i 8-1 stillingen (R ). Den overlegne virkning fremgår af føl- 1 gende forsøgsresultater: 3 150487 to
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4 150487
Ved forsøgene anvendtes albinomus (NMRI) med en legemsvægt på 20 til 25 g og albinorotter (FW49) med en legemsvægt på 140 til 200 g. Prøveforbindelserne blev suspenderet i olivenolie og i alle tilfældene indført i 5 maven ved hjælp af halssonde.
1. Pentetrazolantagoisme:
Den dosis, ved hvilken den letale virkning af 125 mg/kg pentylentetrazol, der indgives intraperitone-alt 1 time efter indgiften af prøveforbindelsen, ophæves 10 for 50% af dyrenes vedkommende (M.I. Gluckman, Curr.
Ther. Res. 7, 721 [1965]). » 2. Konfliktsituation (Inhibition af Passive avoidance):
Den dosis, ved hvilken dyrene, der befinder sig i konfliktsituation, 10 gange trykker på en knap for at 15 opnå en foderpille, endskønt et samtidig indkoblet signal angiver, at der sammen med foderpillen vil ske en afstraffelse i form af et elektrisk stør (J. Geller, Arch.
Int. Pharmacodyn., 149, 243 [1964]).
LD^q, dvs. den dosis, ved hvilken 50% af dyrene 20 overlever (Litchfield og Wilcoxon, J. Pharmacol. Exptl.
Therap. 96, 99 [1949]), er for 8-brom-6-(o-chlorphenyl)-4H-s-triazolo[3,4-c]thieno[2,3-e]1,4-diazepin-1-on >2000 mg/kg hos mus.
De angivne værdier blev ved alle forsøgene tilve-25 jebragt grafisk.
Enkeltdoserne af de her omhandlede forbindelser ligger ved 0,1 til 50, fortrinsvis 0,5 til 25 mg (oralt) og 5 til 150 mg som dagsdosis.
De omhandlede forbindelser kan anvendes alene el-30 ler i kombination med andre virksomme stoffer fremstillet ifølge opfindelsen. Egnede anvendelsesformer er f.eks. som tabletter, kapsler, stikpiller, opløsninger, saft, emulsioner eller dispergerbare pulvere.
35 5 150487
Eksempel 1 8-Brom-6-(o-chlorphenyl)-4H-s-triazolo[3,4-c]thieno[2,3- e]1/4-diazepin-1-on.
12,3 g (0,03 mol) 8-brom-6-(o-chlorphenyl)-1-5 methoxy-4H-s-triazolo[3,4-c]thieno[2,3-e]1,4-diazepin koges i 2 timer under tilbagesvaling i 300 ml 48%'s brombrintesyre, fortyndes derpå med 500 ml vand og efter afkøling frasuges krystallerne. De optages i methylen-chlorid. Opløsningen vaskes med mættet natriumbicarbo-10 natopløsning, tørres og inddampes. Remanensen omkrystalliseres af methanol. Man opnår den ovenfor angivne forbindelse i et udbytte på 10 g = 85% af det teoretiske udbytte. Smp. 235-238°C.
15 Eksempel 2 8-Brom-6-(o-chlorphenyl)-4H-s-triazolo[3,4-c]thieno[2,3- e]-1,4-diazepin-1-on.
11 g (0,03 mol) 7-brom-5-(o-chlorphenyl)-2-hy-drazino-3H[2,3-e]-thieno-1,4-diazepin suspenderes i 250 20 ml toluen, hvorefter der tilsættes 100 ml af en 15%'s opløsning af phosgen i toluen. Efter omrøring i 1 time ved stuetemperatur og omrøring i 2 timer ved kogetemperatur udrystes reaktionsblandingen efter afkøling med mættet natriumbicarbonatopløsning. Den organiske fase 25 inddampes efter tørringen, og efter omkrystallisation af methanol får man 9,1 g = 77% af det teoretiske udbytte af ovenstående forbindelse med smp. 233-235°C.
Analogt med de eksemplerne 1 og 2 beskrevne fremgangsmåder opnår man følgende forbindelser: 30
Eksempel · Forbindelse_Smp. °C
3 8-Chlor-6-(o-chlorphenyl)-4H-s-tri- azolo-[3,4-c]thieno[2,3-e]1,4-dia-zepin-1-on 219-222 4 8-Brom-6-(o-bromphenyl)-4H-s-tria-zolo-[3,4-c]thieno[2,3-e]1,4-dia- 35 zepin-1-on 212-214 5 8-Iod-6-(o-chlorphenyl)-4H-s-tirazo- lo- [ 3,4-c ] thieno [ 2,3-e]1,4-diazepin-1-on 215-217 6 8-Chlor-6-phenyl-4H-s-triazolo[3,4- c]-thieno[2,3-e]1,4-diazepin-1-on 170-172 6 150487
Eksempel 7 8-Brom-6-(o-chlorphenyl)-2-methyl-4H-s—triazolo[3,4-c] -thieno-[2,3-e]1,4-diazepin-1-on.
2 g (0,005 mol) 8-brom-6-(o-chlorphenyl)-4H-s-5 triazolo-[3,4-c]thieno[2,3-e]1,4-diazepin-1-on (jfr.
eksempel 1) opløses i 50 ml tetrahydrofuran, og der tilsættes lidt efter lidt 250 mg af en 50%’s natriumhydrid-dispersion. Efter ca. 1 times omrøring udfældes natriumsaltet. Man tilsætter 3 ml methyliodid og omrører i 2 10 timer ved 60°C. Reaktionsblandingen inddampes i vakuum, remanensen fortyndes med vand og ovennævnte forbindelse udrystes med methylenchlorid. Efter tørring kromatogra-ferer man over SiO^ og opnår til slut 1,2 g = 60% af det teoretiske udbytte af titelforbindelsen. Smp. 136-137°C.
15
Claims (4)
150487 Analogifremgangsmåde til fremstilling af triazolo-thieno-diazepin-1-oner med den almene formel I R3 5
0 N
1 I 10 <C~0_r2 1. hvori R betegner et chlor-, brom- eller iodatom, R be- 3 tegner hydrogen eller et halogenatom, og R betegner hy-15 drogen eller en alkylgruppe med 1-3 carbonatomer, eller 3 alkalimetalsalte af de forbindelser, hvori R betegner hydrogen, kendetegnet ved, at man a) underkaster en forbindelse med den almene formel II Alk-0—ST' 20 i /»O'—< "vO \=— N II 1 2 25 hvori R og R har den ovenfor angivne betydning, og Alk betegner en lavere alkylgruppe, skånsom hydrolyse eller at man b) omsætter en forbindelse med den almene formel III
30. KH-KH, 111 1 2 35 hvori R og R har den ovenfor angivne betydning, med phosgen, og at man om ønsket på sædvanlig måde alkylerer
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2708121 | 1977-02-25 | ||
| DE19772708121 DE2708121A1 (de) | 1977-02-25 | 1977-02-25 | Triazolo-thieno-diazepin-l-one, verfahren zu ihrer herstellung und arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK85078A DK85078A (da) | 1978-08-26 |
| DK150487B true DK150487B (da) | 1987-03-09 |
| DK150487C DK150487C (da) | 1987-10-19 |
Family
ID=6002117
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK085078A DK150487C (da) | 1977-02-25 | 1978-02-24 | Analogifremgangsmaade til fremstilling af triazolo-thieno-diazepin-1-oner eller alkalimetalsalte deraf |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US4333944A (da) |
| JP (1) | JPS53105497A (da) |
| AT (1) | AT358050B (da) |
| AU (1) | AU518863B2 (da) |
| BE (1) | BE864318A (da) |
| BG (1) | BG28577A3 (da) |
| CA (1) | CA1070301A (da) |
| CH (2) | CH641462A5 (da) |
| CS (1) | CS203183B2 (da) |
| DD (1) | DD135382A5 (da) |
| DE (1) | DE2708121A1 (da) |
| DK (1) | DK150487C (da) |
| ES (2) | ES467292A1 (da) |
| FI (1) | FI62839C (da) |
| FR (1) | FR2381775A1 (da) |
| GB (1) | GB1584906A (da) |
| GR (1) | GR64419B (da) |
| HU (1) | HU176483B (da) |
| IE (1) | IE46425B1 (da) |
| IL (1) | IL54120A (da) |
| IT (1) | IT1102280B (da) |
| LU (1) | LU79115A1 (da) |
| NL (1) | NL7802084A (da) |
| NO (1) | NO142839C (da) |
| NZ (1) | NZ186559A (da) |
| PH (1) | PH15987A (da) |
| PL (1) | PL115163B1 (da) |
| PT (1) | PT67707B (da) |
| RO (1) | RO74147A (da) |
| SE (1) | SE436205B (da) |
| SU (3) | SU882411A3 (da) |
| YU (1) | YU43978A (da) |
| ZA (1) | ZA781085B (da) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2708121A1 (de) * | 1977-02-25 | 1978-09-07 | Boehringer Sohn Ingelheim | Triazolo-thieno-diazepin-l-one, verfahren zu ihrer herstellung und arzneimittel |
| DE3829419C1 (da) * | 1988-08-31 | 1989-12-28 | Accumulatorenwerke Hoppecke Carl Zoellner & Sohn Gmbh & Co Kg, 5790 Brilon, De | |
| CA2120939A1 (en) * | 1991-10-11 | 1993-04-15 | Tetsuya Tahara | Therapeutic agent for osteoporosis and diazepine compound |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE755139A (fr) * | 1969-08-21 | 1971-02-22 | Upjohn Co | Derives de benzodiazepinones, leurs intermediaires, et leur preparatio |
| JPS5418280B2 (da) * | 1971-10-30 | 1979-07-06 | ||
| US4155913A (en) * | 1973-02-08 | 1979-05-22 | Hoffmann-La Roche Inc. | Thienotriazolodiazepine derivatives |
| PH12303A (en) * | 1973-02-08 | 1979-01-16 | Hoffmann La Roche | Thienotriazolodiazepine derivatives |
| AT338799B (de) * | 1974-03-02 | 1977-09-12 | Boehringer Sohn Ingelheim | Verfahren zur herstellung neuer substituierter 6-aryl-4h-s-triazolo-(3,4c)-thieno-(2,3e)-1,4-diazepine und ihrer salze |
| DE2708121A1 (de) * | 1977-02-25 | 1978-09-07 | Boehringer Sohn Ingelheim | Triazolo-thieno-diazepin-l-one, verfahren zu ihrer herstellung und arzneimittel |
-
1977
- 1977-02-25 DE DE19772708121 patent/DE2708121A1/de active Granted
-
1978
- 1978-02-02 FI FI780336A patent/FI62839C/fi not_active IP Right Cessation
- 1978-02-20 AT AT119478A patent/AT358050B/de not_active IP Right Cessation
- 1978-02-21 GR GR55505A patent/GR64419B/el unknown
- 1978-02-21 CS CS781092A patent/CS203183B2/cs unknown
- 1978-02-22 CH CH194978A patent/CH641462A5/de not_active IP Right Cessation
- 1978-02-22 SU SU782582299A patent/SU882411A3/ru active
- 1978-02-23 IT IT48164/78A patent/IT1102280B/it active
- 1978-02-23 LU LU79115A patent/LU79115A1/de unknown
- 1978-02-23 IL IL54120A patent/IL54120A/xx unknown
- 1978-02-23 BG BG038796A patent/BG28577A3/xx unknown
- 1978-02-23 DD DD78203822A patent/DD135382A5/xx unknown
- 1978-02-24 YU YU00439/78A patent/YU43978A/xx unknown
- 1978-02-24 BE BE185480A patent/BE864318A/xx not_active IP Right Cessation
- 1978-02-24 PL PL1978204882A patent/PL115163B1/pl unknown
- 1978-02-24 SE SE7802154A patent/SE436205B/sv not_active IP Right Cessation
- 1978-02-24 JP JP2082178A patent/JPS53105497A/ja active Granted
- 1978-02-24 CA CA297,678A patent/CA1070301A/en not_active Expired
- 1978-02-24 AU AU33602/78A patent/AU518863B2/en not_active Expired
- 1978-02-24 NO NO780636A patent/NO142839C/no unknown
- 1978-02-24 HU HU78BO1701A patent/HU176483B/hu unknown
- 1978-02-24 PH PH20819A patent/PH15987A/en unknown
- 1978-02-24 DK DK085078A patent/DK150487C/da active
- 1978-02-24 ZA ZA00781085A patent/ZA781085B/xx unknown
- 1978-02-24 GB GB7524/78A patent/GB1584906A/en not_active Expired
- 1978-02-24 ES ES467292A patent/ES467292A1/es not_active Expired
- 1978-02-24 PT PT67707A patent/PT67707B/pt unknown
- 1978-02-24 NZ NZ186559A patent/NZ186559A/xx unknown
- 1978-02-24 NL NL7802084A patent/NL7802084A/xx not_active Application Discontinuation
- 1978-02-24 FR FR7805383A patent/FR2381775A1/fr active Granted
- 1978-02-24 IE IE405/78A patent/IE46425B1/en unknown
- 1978-02-25 RO RO7893321A patent/RO74147A/ro unknown
- 1978-09-19 ES ES473465A patent/ES473465A1/es not_active Expired
- 1978-11-10 SU SU782683104A patent/SU728718A3/ru active
- 1978-11-10 SU SU782683755A patent/SU793401A3/ru active
-
1981
- 1981-02-10 US US06/233,294 patent/US4333944A/en not_active Expired - Fee Related
-
1982
- 1982-07-02 CH CH406582A patent/CH641182A5/de not_active IP Right Cessation
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