CH535255A - Hydroxyalkyl piperazino-10,11-dihydro dibenzo - (b,f) thiepines - Google Patents
Hydroxyalkyl piperazino-10,11-dihydro dibenzo - (b,f) thiepinesInfo
- Publication number
- CH535255A CH535255A CH1554670A CH1554670A CH535255A CH 535255 A CH535255 A CH 535255A CH 1554670 A CH1554670 A CH 1554670A CH 1554670 A CH1554670 A CH 1554670A CH 535255 A CH535255 A CH 535255A
- Authority
- CH
- Switzerland
- Prior art keywords
- sep
- formula
- alkyl
- carbon atoms
- piperazino
- Prior art date
Links
- 150000003551 thiepines Chemical class 0.000 title abstract description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 title abstract 2
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 229910052987 metal hydride Inorganic materials 0.000 claims abstract description 3
- 150000004681 metal hydrides Chemical class 0.000 claims abstract description 3
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- DBQYUWWOBWTUPV-UHFFFAOYSA-N 5,6-dihydrobenzo[b][1]benzothiepine Chemical class C1CC2=CC=CC=C2SC2=CC=CC=C12 DBQYUWWOBWTUPV-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 230000000794 anti-serotonin Effects 0.000 abstract description 3
- 230000002908 adrenolytic effect Effects 0.000 abstract description 2
- 239000003874 central nervous system depressant Substances 0.000 abstract description 2
- 230000002276 neurotropic effect Effects 0.000 abstract description 2
- 230000000506 psychotropic effect Effects 0.000 abstract description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 2
- 101100295738 Gallus gallus COR3 gene Proteins 0.000 abstract 1
- 125000005055 alkyl alkoxy group Chemical group 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 229940001470 psychoactive drug Drugs 0.000 abstract 1
- 239000004089 psychotropic agent Substances 0.000 abstract 1
- 125000004001 thioalkyl group Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 230000003472 neutralizing effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 208000009132 Catalepsy Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 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
- 239000000155 melt Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229960003279 thiopental Drugs 0.000 description 3
- 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 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 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
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 2
- 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 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
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000001387 anti-histamine 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
- 238000001727 in vivo Methods 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 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 2
- 229960003147 reserpine Drugs 0.000 description 2
- 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 2
- 239000002904 solvent Substances 0.000 description 2
- HQOCWPHRUQRXEC-UHFFFAOYSA-N 3-[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)piperazin-1-yl]propan-1-ol Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2CC1N1CCN(CCCO)CC1 HQOCWPHRUQRXEC-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 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
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- CKQQMPJQZXIYMJ-UHFFFAOYSA-N dihydrate;dihydrochloride Chemical compound O.O.Cl.Cl CKQQMPJQZXIYMJ-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- 230000000304 vasodilatating effect Effects 0.000 description 1
Classifications
-
- 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
- C07D409/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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)
Abstract
Hydroxyalkyl piperazino-10,11-dihydrodibenzo b,f thiepines Dibenzothiepines of formula I, where Z=CHR2(OH) R'=H, hal, CF3, 1-4C alkyl alkoxy, or thioalkyl, R2=H or 1-4C alkyl, and n=1-4, and salts of I, are prepd by redn of the corresp carbonyl cpds (I, Z=COR3 where R3=H, 1-4C alkyl, alkoxy, or OH with a complex metal hydride appropriate to the type of carbonyl present. I are neuro and psychotropics, with strong CNS depressant and catalytic activity, as well as being anti-serotonins anti-histamins, and adrenolytics.
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von pharmakodynamisch wirksamen Hydroxyalkylpiperazinoderivaten der 10,11-Dihydrodibenzo-(b,f)-thiepinreihe der Formel
EMI1.1
worin RI ein Wasserstoff- oder Halogenatom, eine Trifluormethylgruppe, einen Alkyl-, Alkoxy- oder Alkylthiorest mit 1 bis 4 Kohlenstoffatomen, R2 ein Wasserstoffatom oder einen Alkylrest mit 1 bis 4 Kohlenstoffatomen und e eine ganze Zahl von 1 bis 4 bedeutet, und deren Salzen.
Diese Stoffe zeigen eine bedeutende pharmakodynamische Wirksamkeit und können als neuro- und psychotrope Heilmittel Anwendung finden.
Sie besitzen insbesondere eine starke zentraldämpfende Aktivität, zum Teil sind sie auch kataleptisch hochwirksam, ferner haben sie eine Antiserotonin- und Antihistaminwirkung, sowie eine adrenolytische Wirkung.
Ein typisches Beispiel für die Verbindungen gemäss Erfindung stellt das 8-Methylthio-10-[4-(3-hydroxypropyl) piperazino]-10,11-dihydrodibenzo(b,f)thiepin dar, welches in Form seines Dihydrochlorid-dihydrats pharmakologisch geprüft wurde. Seine akute Toxicität bei Mäusen nach intravenöser Verabreichung (LD 50) beträgt 44 mg/kg. Im Drehstabtest nach intravenöser Verabreichung den Mäusen löst der Stoff bereits in sehr kleinen Gaben Störungen der Koordination der Bewegungen aus; die mittlere wirksame Gabe in diesem Test (ED 50) in dem Zeitpunkt der maximalen Wirkung (40 Minuten nach Verabreichung des Stoffes) ist 0,11 mg/kg; ferner potenziert der Stoff wesentlich die Thiopentalnarkose bei Mäusen nach intravenöser Verabreichung. Die Schwellengabe, welche den Thiopentalschlaf schon statistisch signifikant verlängert, beträgt 0,025 mg/kg.
Ebenfalls im Katalepsietest bei Ratten ist der Stoff hochwirksam; die Gabe, welche die Katalepsie bei 50 o/o der Tiere nach intraperitonealer Verabreichung auslöst (ED 50), beträgt 0,62 mg/kg. Bereits von der Gabe 0,1 mg/kg an weist der Stoff nach intraperitonealer Verabreichung eine Antiserotoninwirkung bei Ratten in Versuchen in vivo auf. In der Gabe von 10 mg/kg i.p. beeinflusst der Stoff die Reserpinptose bei Mäusen nicht; nach oraler Verabreichung der Gabe von 50 mg/kg antagonisiert er bloss in statistisch unbedeutsamer Weise die ulcerogene Wirkung des Reserpins bei Ratten. Schliesslich wurde bei diesem Stoff noch eine ausgeprägte Antihistaminwirkung bei Meerschweinchen in vivo im Histamin-Detoxikationstest, ferner eine ausgeprägte hypothermische, gefässerweiternde und bedeutsame entzündungshemmende Wirkung gefunden.
Im Vergleich mit dem bekannten neuroleptischen Präparat Chlorpromazin ist der genannte Stoff 5mal wirksamer beim Test des Drehstabes, 10mal wirksamer beim Test der Thiopentalnarkosepotenzierung, etwa 13mal wirksamer im Katalepsietest; zugleich ist er nur ein wenig giftiger, so dass sein Wirkungsindex den des Chlorpromazins mehrmals übertrifft.
Gemäss Erfindung stellt man die Verbindungen der Formel I so her, dass man Carbonylverbindungen der Formel II
EMI1.2
worin Rt und n dasselbe wie in Formel I und R3 ein Wasserstoffatom, einen Alkyl- oder Alkoxyrest mit 1 bis 4 Kohlenstoffatomen oder eine Hydroxylgruppe bedeutet, reduziert, wonach man die erhaltenen Basen gegebenenfalls durch Neutralisieren mit anorganischen oder organischen Säuren in entsprechende Salze überführt.
Die Reduktion führt man zweckmässig mit Komplexmetallhydriden durch, und zwar vorzugsweise mit Natriumborohydrid im Falle, dass die Carbonylverbindung der Formel II ein Aldehyd oder ein Keton darstellt, gegebenenfalls mit Lithiumaluminiumhydrid oder Natrium-bis (2-methoxyäthoxy)dihydroaluminat im Falle, dass die Carbonylverbindung der Formel II eine Carboxylsäure oder einen Ester darstellt.
Bei der ersten Arbeitsweise verwendet man als Reaktionsmedium bevorzugt wasserfreie oder wässrige Alkohole, bei der zweiten Arbeitsweise ist es notwendig, die Reduktion in wasserfreien Lösungsmitteln vom Äthertyp, beispielsweise in Diäthyläther, Tetrahydrofuran u. ähnl., durchzuführen.
Die erfindungsgemäss erhaltenen Verbindungen der Formel I sind starke, in der Mehrzahl kristallisierbare Basen, welche durch Neutralisieren mit anorganischen oder organischen Säuren sehr gut kristallisierte Salze liefern. Für therapeutische Anwendungszwecke sind insbesondere die Hydrochloride und Maleate gut geeignet, in erster Linie zur Zubereitung von oralen Arzneiformen, die Methansufonate eignen sich zur Zubereitung von Injektionsformen.
Beispiele
1. Zu einer Lösung von 30,0 g 8-Chor-10[4-3-oxobutyl piperazino]-10,1 1-dihydrodibenzo(b,f)thiepin in 800 ml Methanol gibt man bei 500 C eine Lösung von 10,0 g Natriumborhydrid in 40 ml Wasser zu, welche vorher mit 1 ml einer 100/oigen Natriumhydroxidlösung versetzt wurde.
Man erwärmt das Reaktionsgemisch unter Rühren an einem Wasserbad 3 Stunden auf 700 C, danach dampft man Methanol unter vermindertem Druck ab, den Rückstand verdünnt man mit 700 ml Benzol und wäscht die Lösung mit Wasser.
Durch Abdampfen des Lösungsmittels erhält man in fast theoretischer Ausbeute ein amorphes Gemisch von stereoisomeren 8-Chlor-10-[4-(3-hydroxybutyl)piperazino]-10,11- dihydrodibenzo(b,f)thiepinen, aus dem man durch Kristallisation aus Petroläther das eine Razemat mit F. 970 C und durch Aufarbeitung der Mutterlaugen und Kristallisation aus Cyklopentan das zweite Razemat mit F. 77-780 C gewinnt.
Durch Neutralisation des amorphen Basengemisches mit Maleinsäure in Äther erhält man das kristallisierte Maleat mit F. 155-1600 C (Äthanol), welches offenbar beide Stereoisomeren enthält.
2. Zu einer Lösung von 0,92 g Lithiumaluminiumhydrid in 25 ml Äther tropft man eine Lösung von 5,0 g 8-Chlor 10-[4-(2-methoxycarbonyläthyl)piperazino]-10,11-dihydro- dibenzo(b,f)thiepin in einem Gemisch von 60 ml Äther und 5 ml Tetrahydrofuran innerhalb 20 Minuten zu. Das Reaktionsgemisch rührt man zunächst 2 Stunden bei Zimmer.
temperatur, danach kocht man es 3,5 Stunden unter Rückfluss. Nach Abkühlen tropft man 1 ml Wasser, 1 ml einer 150/obigen Natriumhydroxidlösung und 3 ml Wasser zu, rührt das Gemisch 20 Minuten, saugt den ausgeschiedenen Niederschlag ab, trocknet das Filtrat mit Magnesiumsulfat und dampft es ab. Man erhält 3,3 g (71 0/o) der kristallisierten Base des 8-Chlor-10-[4-(3-hydroxypropyDpiperazino-10,1 1- dihydrodibenzo(b,f)-thiepins, welche nach Umkristallisieren aus Äthanol bei 114-1160 C schmilzt. Durch Neutralisieren der Base mit Methansulfonsäure in Äthanol erhält man das kristalline Dimethansulfonat, welches als Monohydrat mit F. 166-1670 C vorliegt.
Durch Neutralisieren der Base mit Maleinsäure in Äthanol lässt sich das kristalline Dihydrogenmaleat mit F. 139-1400 C (Äthanol) herstellen.
3. Ähnlich wie im vorstehenden Beispiel reduziert man 52 g 8-Methylthio-10-[4-(2-methoxycarbonyläthyl) piperazinoj-10,1 1-dihydrodibenzo(b,f)thiepin mit 13,9 g Lithiumaluminiumhydrid in einem Gemisch von 200 ml Tetrahydrofuran und 150 ml Äther. Man erhält 46,5 g (96 0/o) der Base des 8-Methylthio-10-[4-(3-hydroxypropyl) piperazino]-10,11-dihydrodibenzo(b,tthiepins, welche kristallin erstarrt und nach Umkristallisieren aus einem Benzol Petroläthergemisch bei 93-950 C schmilzt. Durch Neutralisieren mit Methansulfonsäure in Äthanol erhält man das entsprechende Methansulfonat, welches bei 194-1960 C (Äthanol) schmilzt.
Durch Neutralisieren der Base mit Salzsäure in Äthanol erhält man das entsprechende Dihydrochlorid, welches in Form des Dihydrats kristallisiert.
F. 223-2260 C (wäss. Äthanol).
In oben angeführter Weise wurden ferner folgende Verbindungen der Formel I hergestellt: Beispiel
Nr. Rl R2 n Form F. o
4 H H 1 Base 108-110
Maleat 129-130
5 H H 2 Base 138
Maleat 156
6 Cl H 1 Maleat 165-166
7 Cl H 3 Base 116-117
Dihydrogenmaleat 136-138
8 OCH H 2 Dihydrogenmaleat 113-114
The invention relates to a process for the preparation of pharmacodynamically active hydroxyalkylpiperazino derivatives of the 10,11-dihydrodibenzo- (b, f) -thiepin series of the formula
EMI1.1
wherein RI is a hydrogen or halogen atom, a trifluoromethyl group, an alkyl, alkoxy or alkylthio radical having 1 to 4 carbon atoms, R2 is a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms and e is an integer from 1 to 4, and salts thereof .
These substances show significant pharmacodynamic effectiveness and can be used as neuro- and psychotropic remedies.
In particular, they have a strong central depressant activity, in some cases they are also highly cataleptically effective, and they also have an antiserotonin and antihistamine effect and an adrenolytic effect.
A typical example of the compounds according to the invention is 8-methylthio-10- [4- (3-hydroxypropyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepin, which has been pharmacologically tested in the form of its dihydrochloride dihydrate . Its acute toxicity in mice after intravenous administration (LD 50) is 44 mg / kg. In the torsion bar test after intravenous administration to the mice, the substance causes disturbances in the coordination of movements even in very small doses; the mean effective dose in this test (ED 50) at the time of maximum effect (40 minutes after administration of the substance) is 0.11 mg / kg; furthermore, the substance considerably potentiates thiopental anesthesia in mice after intravenous administration. The threshold dose that statistically significantly increases thiopental sleep is 0.025 mg / kg.
The substance is also highly effective in the catalepsy test in rats; the dose which triggers catalepsy in 50% of the animals after intraperitoneal administration (ED 50) is 0.62 mg / kg. Already from the administration of 0.1 mg / kg on, after intraperitoneal administration, the substance has an antiserotonin effect in rats in experiments in vivo. In the administration of 10 mg / kg i.p. the substance does not affect reserpine ptosis in mice; after oral administration of 50 mg / kg it antagonizes the ulcerogenic effect of reserpine in rats in a statistically insignificant manner. Finally, a marked antihistamine effect in guinea pigs in vivo in the histamine detoxication test, as well as a marked hypothermic, vasodilating and significant anti-inflammatory effect were found with this substance.
Compared with the well-known neuroleptic preparation chlorpromazine, the substance mentioned is 5 times more effective in the test of the torsion bar, 10 times more effective in the test of thiopental anesthesia potentiation, about 13 times more effective in the catalepsy test; at the same time it is only a little more toxic, so that its index of action exceeds that of chlorpromazine several times.
According to the invention, the compounds of the formula I are prepared in such a way that carbonyl compounds of the formula II
EMI1.2
where Rt and n are the same as in formula I and R3 are a hydrogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms or a hydroxyl group, after which the bases obtained are optionally converted into corresponding salts by neutralization with inorganic or organic acids.
The reduction is conveniently carried out with complex metal hydrides, preferably with sodium borohydride in the case that the carbonyl compound of the formula II is an aldehyde or a ketone, optionally with lithium aluminum hydride or sodium bis (2-methoxyethoxy) dihydroaluminate in the case that the carbonyl compound of the Formula II represents a carboxylic acid or an ester.
In the first procedure, the reaction medium used is preferably anhydrous or aqueous alcohols, in the second procedure it is necessary to carry out the reduction in anhydrous solvents of the ether type, for example in diethyl ether, tetrahydrofuran and the like. similar. to perform.
The compounds of the formula I obtained according to the invention are strong, mostly crystallizable bases which, when neutralized with inorganic or organic acids, give very well crystallized salts. The hydrochlorides and maleates are particularly well suited for therapeutic purposes, primarily for the preparation of oral dosage forms, the methanesulfonates are suitable for the preparation of injection forms.
Examples
1. To a solution of 30.0 g of 8-chloro-10 [4-3-oxobutyl piperazino] -10.1 1-dihydrodibenzo (b, f) thiepin in 800 ml of methanol, a solution of 10, 0 g of sodium borohydride in 40 ml of water to which 1 ml of a 100% sodium hydroxide solution has been added beforehand.
The reaction mixture is heated to 700 ° C. for 3 hours on a water bath while stirring, then methanol is evaporated off under reduced pressure, the residue is diluted with 700 ml of benzene and the solution is washed with water.
Evaporation of the solvent gives an amorphous mixture of stereoisomeric 8-chloro-10- [4- (3-hydroxybutyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepines in almost theoretical yield, from which one can crystallize Petroleum ether wins one racemate with a temperature of 970 C and the second racemate with a temperature of 77-780 C by working up the mother liquors and crystallizing from cyclopentane.
By neutralizing the amorphous base mixture with maleic acid in ether, the crystallized maleate with a temperature of 155-1600 C (ethanol) is obtained, which apparently contains both stereoisomers.
2. A solution of 5.0 g of 8-chloro 10- [4- (2-methoxycarbonylethyl) piperazino] -10,11-dihydrodibenzo (b) is added dropwise to a solution of 0.92 g of lithium aluminum hydride in 25 ml of ether f) thiepin in a mixture of 60 ml of ether and 5 ml of tetrahydrofuran within 20 minutes. The reaction mixture is initially stirred for 2 hours in the room.
temperature, then reflux for 3.5 hours. After cooling, 1 ml of water, 1 ml of a 150% sodium hydroxide solution and 3 ml of water are added dropwise, the mixture is stirred for 20 minutes, the precipitate which has separated out is filtered off with suction, the filtrate is dried with magnesium sulfate and evaporated. 3.3 g (710 / o) of the crystallized base of 8-chloro-10- [4- (3-hydroxypropydpiperazino-10,1 1- dihydrodibenzo (b, f) -thiepine, which after recrystallization from ethanol are obtained Melts 114-1160 C. By neutralizing the base with methanesulphonic acid in ethanol, the crystalline dimethanesulphonate is obtained, which is present as a monohydrate with a melting point of 166-1670 C.
By neutralizing the base with maleic acid in ethanol, the crystalline dihydrogen maleate can be produced with a temperature of 139-1400 ° C. (ethanol).
3. Similar to the previous example, 52 g of 8-methylthio-10- [4- (2-methoxycarbonylethyl) piperazinoj-10,1 1-dihydrodibenzo (b, f) thiepin are reduced with 13.9 g of lithium aluminum hydride in a mixture of 200 ml of tetrahydrofuran and 150 ml of ether. 46.5 g (96 0 / o) of the base of 8-methylthio-10- [4- (3-hydroxypropyl) piperazino] -10,11-dihydrodibenzo (b, tthiepins, which solidifies in crystalline form and, after recrystallization from a Benzene petroleum ether mixture melts at 93-950 ° C. Neutralizing with methanesulfonic acid in ethanol gives the corresponding methanesulfonate, which melts at 194-1960 ° C. (ethanol).
By neutralizing the base with hydrochloric acid in ethanol, the corresponding dihydrochloride is obtained, which crystallizes in the form of the dihydrate.
M.p. 223-2260 C (aq. Ethanol).
The following compounds of the formula I were also prepared in the manner indicated above: Example
No. Rl R2 n Form F. o
4 H H 1 base 108-110
Maleate 129-130
5 H H 2 base 138
Maleate 156
6 Cl H 1 maleate 165-166
7 Cl H 3 base 116-117
Dihydrogen maleate 136-138
8 OCH H 2 dihydrogen maleate 113-114
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS711269 | 1969-10-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH535255A true CH535255A (en) | 1973-03-31 |
Family
ID=5419644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1554670A CH535255A (en) | 1969-10-25 | 1970-10-21 | Hydroxyalkyl piperazino-10,11-dihydro dibenzo - (b,f) thiepines |
Country Status (4)
| Country | Link |
|---|---|
| AT (1) | AT304557B (en) |
| CH (1) | CH535255A (en) |
| ES (1) | ES384868A1 (en) |
| NL (1) | NL7015530A (en) |
-
1970
- 1970-10-21 CH CH1554670A patent/CH535255A/en not_active IP Right Cessation
- 1970-10-23 AT AT959370A patent/AT304557B/en not_active IP Right Cessation
- 1970-10-23 NL NL7015530A patent/NL7015530A/xx unknown
- 1970-10-24 ES ES384868A patent/ES384868A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES384868A1 (en) | 1973-07-16 |
| NL7015530A (en) | 1971-04-27 |
| AT304557B (en) | 1973-01-10 |
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| PL | Patent ceased |