DK150485B - Analogifremgangsmaade til fremstilling af 8-methylthio-10-(4-(3-hydroxypropyl)piperazino)-10,11-dihydrobenzo(b,f)thiepin - Google Patents
Analogifremgangsmaade til fremstilling af 8-methylthio-10-(4-(3-hydroxypropyl)piperazino)-10,11-dihydrobenzo(b,f)thiepin Download PDFInfo
- Publication number
- DK150485B DK150485B DK629370A DK629370A DK150485B DK 150485 B DK150485 B DK 150485B DK 629370 A DK629370 A DK 629370A DK 629370 A DK629370 A DK 629370A DK 150485 B DK150485 B DK 150485B
- Authority
- DK
- Denmark
- Prior art keywords
- piperazino
- methylthio
- hydroxypropyl
- benzene
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- -1 4- (3-HYDROXYPROPYL) PIPERAZINO Chemical class 0.000 title 1
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 title 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 239000000155 melt Substances 0.000 claims 2
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims 1
- 150000004683 dihydrates Chemical class 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000003208 petroleum Substances 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 208000009132 Catalepsy Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 206010047853 Waxy flexibility Diseases 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 230000000794 anti-serotonin Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000003420 antiserotonin agent Substances 0.000 description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
- 229960001076 chlorpromazine Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002631 hypothermal effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 229960003279 thiopental Drugs 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 1
- KMAWVRYYKYVCNR-UHFFFAOYSA-N benzo[b][1]benzothiepine Chemical compound C1=CC2=CC=CC=C2SC2=CC=CC=C21 KMAWVRYYKYVCNR-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- CKQQMPJQZXIYMJ-UHFFFAOYSA-N dihydrate;dihydrochloride Chemical compound O.O.Cl.Cl CKQQMPJQZXIYMJ-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 230000002276 neurotropic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001562 ulcerogenic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/14—[b,f]-condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
150435 - Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af forbindelsen 8-methylthio-l(M4-(3-hy= droxypropyl)piperazino]-10,11-dihydrobenzo(b,f)thiepin med formlen
SCH
v~^ N N'(CH0),OH (I) V / 2 3 eller syreadditionssalte deraf. Disse forbindelser har en udpræget farmakodynamisk virkning, hvilket betinger deres eventuelle anvendelighed som neurotrope og psykotrope lægemidler. De har især en moderat til meget kraftig 2 150485 centraldæmpende virkning, er til dels kataleptisk højvirksomme, og endvidere udviser de en høj hypotermisk virkning og potenserer hypnotikavirkningen, og de har også en antiserotonin-, antihistamin- og karudvidende virkning, 5 Den ifølge opfindelsen fremstillede forbindelse 8-methyl= thio-10-[4-(3-hydroxypropyl)piperazino]-10,ll-dihydro= dibenzo(b,f)thiepin er blevet afprøvet farmakologisk i form af dihydrochlorid-dihydratet. Den akutte toksicitet overfor mus efter intravenøs indgivelse (LD,^) andrager 10 44 mg/kg. Ved drejestangsprøven efter intravenøs indgivelse til mus fremkalder stoffet allerede i små doser forstyrrelser af bevægelsernes koordination, og den gennemsnitlige virksomme dosis ved denne prøve (ED,-g) på tidspunktet for den maksimale virkning (40 minutter efter indgivelse 15 af stoffet) er 0,11 mg/kg. Forbindelsen potenserer endvidere thiopentalnarkosen hos mus væsentligt efter intravenøs indgivelse. Tærskeldosen, som allerede statistisk signifikant forlænger thiopentalsøvnen, andrager 0,025 mg/kg. Forbindelsen er ligeledes meget virksom ved ka-20 talepsiprøven med rotter, idet den dosis, som udløser katalepsi hos 50% af dyrene efter intraperitoneal indgivelse (ED5Q), andrager 0,62 mg/kg. Allerede fra doser på 0,1 mg/kg udviser forbindelsen efter intraperitoneal indgivelse en antiserotoninvirkning hos rotter ved forsøg 25 in vivo. Ved en dosis på 10 mg/kg i.p. har forbindelsen ingen indflydelse på reserpinptosen hos mus. Efter oral indgivelse af en dosis på 50 mg/kg antagoniserer det kun på statistisk ubetydelig måde reserpinets ulcerogene virkning på rotter. Endelig blev der for forbindelsen 30 endvidere konstateret.en udpræget antihistaminvirkning på marsvin in vivo ved histamin-dotoxikationsprøven og endvidere en udpræget hypotermisk, karudvidende og betydelig betændelseshæmmende virkning.
3 1504-85 I sammenligning med det kendte neuroleptiske præparat "chlorpromazin" er nævnte forbindelse 5 gange mere virksom ved drej estangsprøven, 10 gange mere virksom ved thio= pentalnarkosepotenseringsprøven og ca._ 13 gange mere virk-5 som ved katalepsiprøven, og endvidere er den kun en smule giftigere, så at dens virkningsindeks overgår virkningsindekset for "chlorpromazin" mange gange.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at en sekundær amin med formlen ooa — ^SCH, (XI) 1° ΓΛ
N NH
omsættes med trimethylenoxid med formlen (CH0)0 - CH0 l^ z.
N0 (III) hvorefter det opnåede basiske produkt om ønsket overføres i et tilsvarende syreadditionssalt efter neutralisation 15 med en uorganisk eller organisk syre.
Omsætningen med trimethylenoxid forløber allerede ved stuetemperatur i egnede indifferente opløsningsmidler, f.eks. ethere og aromatiske hydrocarboner, og fører til de isolerede baser i højt udbytte. 1
Fremgangsmåden ifølge opfindelsen illustreres nærmere ved hjælp af det efterfølgende eksempel.
Claims (3)
150485 Eksempel. Til en opløsning af 10,2 g 8-methylthio-10-piperazino-10,11-dihydrodibenzo(b,f)thiepin i 80 ml absolut benzen til-dryppes under omrøring en opløsning af 2,5 g trimethylen= 5 oxid i 10 ml absolut benzen. Reaktionsblandingen opvarmes i 3 timer til kogning under tilbagesvaling, og benzenet dampes derefter af under formindsket tryk. Resten udgør den rå base af 8-methylthio-10-[4-(3-hydroxypropyl)pipera= zino]-10,ll-dihydrodibenzo(b,f)thiepin (udbytte 12,0 g).
10 Efter omkrystallisation fra en benzen-petroleumsether- blanding opnås basen fuldkommen ren og smelter ved 93-95°C. Efter neutralisation med hydrogenchlorid opnås det tilsvarende hydrochlorid, som fra vandig ethanol krystalliserer i form af dihydratet og smelter ved 223-226°C.
15 Patentkrav. Analogifremgangsmåde til fremstilling af 8-methylthio- 10-[4-( 3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo(b, f)thiepin med formlen: (I) /“”\ N N(CH,)-0H \_/ 20 eller syreadditionssalte deraf, kendetegnet ved, at en sekundær amin med formlen IL JL_Ji Jv SCH3 (ii) N NH w
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS8115A CS148854B1 (da) | 1969-12-10 | 1969-12-10 | |
| CS811569 | 1969-12-10 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK629370D0 DK629370D0 (da) | 1987-03-09 |
| DK150485B true DK150485B (da) | 1987-03-09 |
| DK150485C DK150485C (da) | 1987-10-26 |
Family
ID=5431303
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK629370A DK150485C (da) | 1969-12-10 | 1970-12-10 | Analogifremgangsmaade til fremstilling af 8-methylthio-10-(4-(3-hydroxypropyl)piperazino)-10,11-dihydrobenzo(b,f)thiepin |
Country Status (6)
| Country | Link |
|---|---|
| AT (1) | AT304558B (da) |
| CH (1) | CH542875A (da) |
| CS (1) | CS148854B1 (da) |
| DK (1) | DK150485C (da) |
| ES (1) | ES386311A1 (da) |
| NL (1) | NL7018026A (da) |
-
1969
- 1969-12-10 CS CS8115A patent/CS148854B1/cs unknown
-
1970
- 1970-12-09 CH CH1818770A patent/CH542875A/de not_active IP Right Cessation
- 1970-12-09 AT AT1107070A patent/AT304558B/de not_active IP Right Cessation
- 1970-12-10 ES ES386311A patent/ES386311A1/es not_active Expired
- 1970-12-10 NL NL7018026A patent/NL7018026A/xx unknown
- 1970-12-10 DK DK629370A patent/DK150485C/da active
Also Published As
| Publication number | Publication date |
|---|---|
| ES386311A1 (es) | 1973-03-16 |
| AT304558B (de) | 1972-12-15 |
| CH542875A (de) | 1973-10-15 |
| NL7018026A (da) | 1971-06-14 |
| DK629370D0 (da) | 1987-03-09 |
| DK150485C (da) | 1987-10-26 |
| CS148854B1 (da) | 1973-05-24 |
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