DE1620282B - Process for the preparation of new substituted 10 (omega piperazinopropyl) phenothiazines and their salts - Google Patents
Process for the preparation of new substituted 10 (omega piperazinopropyl) phenothiazines and their saltsInfo
- Publication number
- DE1620282B DE1620282B DE1620282B DE 1620282 B DE1620282 B DE 1620282B DE 1620282 B DE1620282 B DE 1620282B
- Authority
- DE
- Germany
- Prior art keywords
- dioxanyl
- ethyl
- piperazine
- salts
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000003839 salts Chemical class 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 5
- -1 piperazinopropyl Chemical group 0.000 title description 13
- 150000002990 phenothiazines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 13
- 230000000701 neuroleptic effect Effects 0.000 claims description 4
- 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 claims description 3
- 230000001387 anti-histamine Effects 0.000 claims description 3
- 239000000739 antihistaminic agent Substances 0.000 claims description 3
- 239000003176 neuroleptic agent Substances 0.000 claims description 3
- 229950000688 phenothiazine Drugs 0.000 claims description 3
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 2
- 150000002736 metal compounds Chemical class 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 13
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 229960001076 chlorpromazine Drugs 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 230000002903 catalepsic effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 2
- PRMGVNCDUJBHQW-UHFFFAOYSA-N 3-(trifluoromethyl)-10h-phenothiazine Chemical compound C1=CC=C2SC3=CC(C(F)(F)F)=CC=C3NC2=C1 PRMGVNCDUJBHQW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000009132 Catalepsy Diseases 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 description 2
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229960003910 promethazine Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 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
- HRSFWIYFGGDGQO-UHFFFAOYSA-N 1-benzylpiperazine;hydrochloride Chemical compound Cl.C=1C=CC=CC=1CN1CCNCC1 HRSFWIYFGGDGQO-UHFFFAOYSA-N 0.000 description 1
- IOEDYYKJRCADRS-UHFFFAOYSA-N 2-(2-chloroethyl)-1,3-dioxane Chemical compound ClCCC1OCCCO1 IOEDYYKJRCADRS-UHFFFAOYSA-N 0.000 description 1
- 206010001022 Acute psychosis Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010012218 Delirium Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000001459 mortal effect Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UXWKNNJFYZFNDI-UHFFFAOYSA-N piperazine;dihydrobromide Chemical compound Br.Br.C1CNCCN1 UXWKNNJFYZFNDI-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940066767 systemic antihistamines phenothiazine derivative Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
N-(CH2J3-N N-(CFiJ2-R IN- (CH 2 J 3 -N N- (CFiJ 2 -RI
N-MeN-Me
in der X ein Wasserstoffatom oder den Trifluormethylrest bedeutet und R einen unsubstituierten oder durch eine oder mehrere Methylgruppenin which X denotes a hydrogen atom or the trifluoromethyl radical and R denotes an unsubstituted one or by one or more methyl groups
substituierten l,3-Dioxanyl-(2)- oder 1,3-Dioxol- 20 in der X die bereits angegebene Bedeutung hat und anyl-(2)-Rest darstellt, sowie von ihren Salzen, Me ein einwertiges Metall darstellt, mit einer Verdadurch gekennzeichnet, daß man in bindung der allgemeinen Formel IIIsubstituted 1,3-Dioxanyl- (2) - or 1,3-Dioxol- 20 in which X has the meaning already given and represents anyl (2) radical, as well as of their salts, Me represents a monovalent metal, with a Verd cause characterized in that in connection with the general formula III
an sich bekannter Weise eine Metallverbindunga metal compound in a manner known per se
eines Phenothiazins der allgemeinen Formel II / \of a phenothiazine of the general formula II / \
Hai—(CH2)3—N N—(CH2),-R IIIHai - (CH 2 ) 3 - NN - (CH 2 ), - R III
IIII
3030th
in der X die bereits angegebene Bedeutung hat und Me ein einwertiges Metall darstellt, mit einer Verbindung der allgemeinen Formel IIIin which X has the meaning already given and Me is a monovalent metal, with a Compound of the general formula III
Hal-(CH2)3-NHal- (CH 2 ) 3 -N
N-(CH2)2-RN- (CH 2 ) 2 -R
IIIIII
4040
in der Hai ein Chlor- oder Bromatom darstellt und R die oben angegebene Bedeutung hat, reagieren läßt und gewünschtenfalls die erhaltenen Basen der allgemeinen Formel I mit Säuren in die entsprechenden Salze umwandelt.in which Hai represents a chlorine or bromine atom and R has the meaning given above, react and, if desired, can convert the bases of the general formula I obtained into the corresponding ones with acids Converts salts.
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von neuen substituierten 10-(ro-Piperazinopropyl)-phenothiazinen der allgemeinen Formel IThe invention relates to a process for the preparation of new substituted 10- (ro-piperazinopropyl) -phenothiazines of the general formula I.
6060
N—(CH2)3—N N—(CH2)2—R IN- (CH 2 ) 3 -NN- (CH 2 ) 2 -RI
in der X ein Wasserstoffalom oder den Trifluormethylrest bedeutet und R einen unsubstituierten oder durch eine oder mehrere Methylgruppen substituiertenin which X is a hydrogen atom or the trifluoromethyl radical and R denotes an unsubstituted or substituted by one or more methyl groups
65 in der Hai ein Chlor- oder Bromatom darstellt und R die oben angegebene Bedeutung hat, reagieren läßt und gewünschtenfalls die erhaltenen Basen der allgemeinen Formel I mit Säuren in die entsprechenden Salze umwandelt. 65 in which Hai represents a chlorine or bromine atom and R has the meaning given above, allows it to react and, if desired, converts the bases of the general formula I obtained with acids into the corresponding salts.
Dabei arbeitet man bevorzugt unter den folgenden Bedingungen:It is preferable to work under the following conditions:
Als Phenothiazinverbindung der allgemeinen Formel II wird die Natrium- oder Lithiumverbindung verwendet. Die Reaktion erfolgt in einem wasserfreien Lösungsmittel, das gegenüber den beiden zur Reaktion gebrachten Verbindungen inert ist, wie Diäthyläther, Tetrahydrofuran, Dioxan, Benzol, Toluol oder Xylol, und man arbeitet bei der Siedetemperatur des Reaktionsmilieus. Nach Beendigung der Reaktion trennt man das gebildete Metallhalogenid durch Filtration ab und isoliert die erhaltene Verbindung der allgemeinen Formel I aus dem Filtrat durch übliche Maßnahmen.The sodium or lithium compound is used as the phenothiazine compound of the general formula II used. The reaction takes place in an anhydrous solvent that is opposite to the two Reaction brought compounds is inert, such as diethyl ether, tetrahydrofuran, dioxane, benzene, toluene or xylene, and one works at the boiling point of the reaction medium. After the In the reaction, the metal halide formed is separated off by filtration and the compound obtained is isolated of the general formula I from the filtrate by customary measures.
Die für die Durchführung dieses Verfahrens erforderlichen Verbindungen der allgemeinen Formel III können nach an sich bekannten Methoden erhalten werden, beispielsweise durch folgende Stufen:The compounds of the general formula III required for carrying out this process can be obtained by methods known per se, for example by the following stages:
1. Man läßt 2 Mol N-Benzylpiperazin mit 1 Mol des Chlorids der allgemeinen Formel Cl—(CH2)2—R in einem Lösungsmittel (Äthyläther, Benzol oder Toluol) bei Siedetemperatur reagieren, wobei der bei der Reaktion gebildete Chlorwasserstoff gleich abgefangen wird.1. 2 moles of N-benzylpiperazine are allowed to react with 1 mole of the chloride of the general formula Cl— (CH 2 ) 2 —R in a solvent (ethyl ether, benzene or toluene) at boiling point, the hydrogen chloride formed in the reaction being captured immediately .
2. Die erhaltene Verbindung der allgemeinen Formel 2. The compound of the general formula obtained
-CH2-N N—(CH2J2-R-CH 2 -NN- (CH 2 J 2 -R
reduziert man mit Wasserstoff in Gegenwart auf Kohle abgeschiedenen Palladiums.is reduced with hydrogen in the presence of palladium deposited on carbon.
3. Die erhaltene Verbindung der allgemeinen Formel3. The compound of the general formula obtained
HNHN
N-(CH2)2-RN- (CH 2 ) 2 -R
kondensiert man mit einem Bromid der allgemeinen Formel Hai — (CH2)3 — Br (Molverhältnis 2 : 1 zwecks Bindung des frei werdenden HBr) in einem wasserfreien Lösungsmittel (Äthyläther, Benzol oder Toluol) bei Siedetemperatur.condensation is carried out with a bromide of the general formula Hai - (CH 2 ) 3 - Br (molar ratio 2: 1 for the purpose of binding the HBr released) in an anhydrous solvent (ethyl ether, benzene or toluene) at the boiling point.
Die Salze der Verbindungen der allgemeinen Formel I werden durch Umsetzung der Base mit Mineral, Säuren oder organischen Säuren in einem geeigneten Lösungsmittel, wie Acetonitril oder Aceton, erhalten.The salts of the compounds of general formula I are made by reacting the base with mineral, Acids or organic acids in a suitable solvent such as acetonitrile or acetone.
Die neuen Produkte der allgemeinen Formel I und ihre Salze sind wegen ihren pharmakologischen Eigenschaften von großen Interesse, insbesondere wegen ihrer neuroleptischen Wirkung und Antihistaminwirkungen. So haben sich beispielsweise das N-[3-(3-Trifluormethylphenothiazinyl-(10))-propyl]-N'-[2-(l,3-dioxanyl-(2))-äthyl]-piperazin und seine Salze als wirksame Depressoren für das Zentralnervensystem, insbesondere wegen ihrer neuroleptischen Wirkung erwiesen.The new products of general formula I and their salts are pharmacological because of their Properties of great interest, especially for their neuroleptic and antihistamine effects. For example, the N- [3- (3-trifluoromethylphenothiazinyl- (10)) -propyl] -N '- [2- (1,3-dioxanyl- (2)) -ethyl] -piperazine and its salts as effective central nervous system depressors, especially because of their neuroleptic properties Proven effect.
Als Beispiel wurde das N - [3 - (3 - Trifluormethylphenothiazinyl - (10)) - propyl] - N' - [2 - (1,3 - dioxanyl - (2)) - äthyl] - piperazin - disuccinat untersucht. Verglichen wurde dessen akute Toxizität mit derjenigen des Chlorpromazins bei digestiver Verabreichung bei Mäusen von 20 bis 22 g Gewicht. Dabei wurden je Dosis 10 Tiere verwendet und die Todesfälle nach 48 Stunden festgestellt. Beide Verbindungen wurden durch Magenintubation verabreicht. Es wurden folgende Ergebnisse erzielt:As an example, the N - [3 - (3 - trifluoromethylphenothiazinyl - (10)) - propyl] - N '- [2 - (1,3 - dioxanyl - (2)) - ethyl] - piperazine - disuccinate investigated. Its acute toxicity was compared with that of chlorpromazine after digestive administration in mice weighing 20 to 22 g. 10 animals and the deaths were used per dose found after 48 hours. Both compounds were administered by gastric intubation. There were achieved the following results:
phenothiazinyl-( 10))-propyl]-
N'-[2-(!,3-dioxanyI-(2))-
äthyl]-piperazin-disuccinatN- [3- (3-trifluoromethyl-
phenothiazinyl- (10)) - propyl] -
N '- [2 - (!, 3-dioxanyI- (2)) -
ethyl] piperazine disuccinate
ChlorpromazinMortality%
Chlorpromazine
Man sieht deutlich, daß das N-[3-(3-Trifluormethylphenothiazinyl - (10)) - propyl] - N' - [2 - (1,3 - dioxanyl - (2)) - äthyl] - piperazin - disuccinat sehr viel weniger toxisch ist als das Chlorpromazin.It can be clearly seen that the N- [3- (3-trifluoromethylphenothiazinyl - (10)) - propyl] - N '- [2 - (1,3 - dioxanyl - (2)) - ethyl] - piperazine - disuccinate very much is less toxic than chlorpromazine.
Weiter wurde die kataleptische Wirksamkeit von N - [3 - (- Trifluormethylphenothiazinyl -(10))- propy I]-N' - [2 - (1,3 - dioxanyl - (2)) - äthyl] - piperazin - disuccinat mit derjenigen des Chlorpromazins verglichen, und zwar wurde diese Untersuchung an Ratten nach der Technik von J. R. B ο i s s i e r und P. S i m ο η (»therapie«, 18 (1963), S. 1257) durchgeführt, die darin besteht, daß der Versuch gemacht wird, die jeweils gleichseitigen Vorder,- und Hinterpfoten der Tiere zu kreuzen; ein Tier wird danach als kataleptisch betrachtet, wenn es diese Haltung akzeptiert und beibehält. Für die Untersuchung wurden Gruppen von je fünf Ratten herangezogen. Die zu untersuchenThe cataleptic effectiveness of N - [3 - (- Trifluoromethylphenothiazinyl - (10)) - propy I] -N ' - [2 - (1,3 - dioxanyl - (2)) - ethyl] - piperazine - disuccinate compared with that of chlorpromazine, and Although this study on rats was carried out according to the technique of J. R. B ο i s s i e r and P. S i m ο η ("Therapie", 18 (1963), p. 1257) carried out, which consists in the fact that the attempt is made, each to cross equilateral front and rear paws of the animals; an animal is thereafter considered to be cataleptic considered when it accepts and maintains this attitude. Groups were used for the study used by five rats each. To investigate
den Verbindungen wurden intraperitoneal in einer Dosis von 15 mg/kg verabreicht. Das Ausmaß der Katalepsie wurde nach 1, 2, 3, 4 und 5 Stunden registriert, und zwar unter Beachtung folgender Bewertung: the compounds were administered intraperitoneally at a dose of 15 mg / kg. The extent of the Catalepsy was registered after 1, 2, 3, 4 and 5 hours, taking the following assessment into account:
»1«, wenn das Tier die Beibehaltung der aufgezwungenen Haltung akzeptiert;
»0,05«, wenn das Tier diese Haltung nur einseitig akzeptiert, und"1" if the animal accepts the forced attitude to be maintained;
"0.05" if the animal only accepts this attitude unilaterally, and
»0«, wenn das Tier die Beibehaltung der aufgezwungenen Haltung verweigert."0" if the animal refuses to maintain the forced posture.
Die in der nachfolgenden Tabelle angegebenen Werte entsprechend jeweils der Summe der Be-Wertungen bei fünf Tieren:The values given in the table below correspond in each case to the sum of the ratings with five animals:
Wie man sieht, ist die kataleptische WirksamkeitAs you can see, the effectiveness is cataleptic
des N - [3 - (3 - Trifluormethylphenothiazinyl - (10))-propyl - N' - [2 - (1,3 - dioxanyl - (2)) - äthyl] - piperazindisuccinats deutlich höher als diejenige des Chlorpromazins. Dieser ausgeprägten Eigenschaft entspricht die antipsychotische Wirksamkeit N - [3 - (3 - Trifluormethylphenothiazinyl - (10)) - propyl] - N' - [2 - (1,3 - dioxanyl - (2)) - äthyl] - piperazin - disuccinat beim Menschen. des N - [3 - (3 - trifluoromethylphenothiazinyl - (10)) - propyl - N '- [2 - (1,3 - dioxanyl - (2)) - ethyl] - piperazine disuccinate is significantly higher than that of chlorpromazine. This distinctive property corresponds to the antipsychotic efficacy of N - [3 - (3 - trifluoromethylphenothiazinyl - (10)) - propyl] - N '- [2 - (1,3 - dioxanyl - (2)) - ethyl] - piperazine - disuccinate in humans.
Das N - [3 - (3 - Trifluormethylphenothiazinyl - (10))-propyl] - N' - [2 - (1,3 - dioxanyl - (2)) - äthyl] - piperazindisuccinat wurde klinisch an mehr als 100 Kranken erprobt (50 Patienten wurden mit Tabletten mit 10 mg Wirkstoff und 63 Patienten mit Tabletten mit 100 mg Wirkstoff behandelt). Dabei wurde festgestellt, daß das N - [3 - (3 - Trifluormethylphenothiazinyl - (10))-propyl] - N' - [2 - (1,3 - dioxanyl - (2)) - äthyl] - piperazindisuccinat ein starkes Neuroleptikum ist. Es kann in Mengen bis zu 1 g verabfolgt werden. Dabei bleibt noch eine ausreichende Toleranz bis zu 1,5 g. Es kann bei Psychosen angewandt werden, und zwar gut bei akuten,manisch depressiven und chronischen Psychosen, paranoiden oder schizophrenen Delirien.The N - [3 - (3 - trifluoromethylphenothiazinyl - (10)) - propyl] - N '- [2 - (1,3 - dioxanyl - (2)) - ethyl] - piperazine disuccinate was clinically tested on more than 100 patients (50 patients were given tablets containing 10 mg Active ingredient and 63 patients treated with tablets with 100 mg active ingredient). It was found that the N - [3 - (3 - trifluoromethylphenothiazinyl - (10)) - propyl] - N '- [2 - (1,3 - dioxanyl - (2)) - ethyl] - piperazine disuccinate is a potent neuroleptic. It can be administered in amounts up to 1 g. It remains still a sufficient tolerance up to 1.5 g. It can be used in psychosis, and well in acute, manic depressive and chronic psychosis, paranoid or schizophrenic delirium.
Die nachfolgende Tabelle 3 zeigt die Antihistamwirkung verschiedener Phenothiazinderivate, und zwar
an Hand von beim Meerschweinchen durch subkutane Verabreichung von 20 mg/kg des jeweils untersuchten
Produkts antagonisierten Histamin-Einheitsletaldosen. Als Histamin-Einheitsletaldosis wurde bei der
Untersuchung eine Dosis von 0,8 mg Histamindihydrochlorid pro Kilogramm Körpergewicht angesehen.
Das Histamin wurde 30 Minuten nach der zu untersuchenden Verbindung intravenös verabreicht.
Die Tabelle enthält außerdem die bei oraler Applikation
bestimmten DL5Ü-Werte für die untersuchten
Verbindungen sowie die entsprechenden Werte für das als Vergleichssubstanz herangezogene Promethazin.
The following Table 3 shows the antihistam effect of various phenothiazine derivatives, specifically on the basis of unit mortal doses of histamine antagonized in guinea pigs by subcutaneous administration of 20 mg / kg of the product investigated in each case. During the investigation, a dose of 0.8 mg histamine dihydrochloride per kilogram of body weight was regarded as the histamine unit lethal dose. The histamine was administered intravenously 30 minutes after the compound to be tested.
The table also contains the DL 5Ü values determined on oral administration for the compounds investigated and the corresponding values for the promethazine used as comparison substance.
Tabelle 3 S N — (CH2)3 — N N-(CHj)2-RTable 3 SN - (CH 2 ) 3 - N N- (CHj) 2 -R
RInvestigated connections
R.
\-CH
\
/0 —CH
/
\0 —CH
\
Zahl der beim Meerschweinchen durch
subkutane Verabreichung der unter
suchten Verbindung in Mengen von
20 mg/kg antagonisierten Histamin-
EinheitsletaldosenAntihistamine effect in vivo
Number of guinea pigs through
subcutaneous administration of the under
sought connection in quantities of
20 mg / kg antagonized histamine
Unit doses
(mg/kg per os)DL 50
(mg / kg per os)
-CH■ /
-CH
CH3 \
CH 3
O — CH2 - CH CH 2
O - CH 2
O —CH2 \
O -CH 2
Es folgt ein Beispiel Tür die Durchführung der Erfindung.The following is an example of a door for practicing the invention.
N-[3-(3-Trifluormethylphenothiazinyl-(10))-propyl]-N'-[2-( 1,3-dioxanyl-(2))-äthyl]-piperazinN- [3- (3-Trifluoromethylphenothiazinyl- (10)) -propyl] -N '- [2- (1,3-dioxanyl- (2)) -ethyl] -piperazine
Man stellt die Natriumverbindung des 3-Trifluormethylphenothiazins, ausgehend von 26,7 g (0,1 Mol) 3-Trifluormethylphenothiazin und 2,3 g (0,1 g-At) Na-The sodium compound of 3-trifluoromethylphenothiazine is produced, starting from 26.7 g (0.1 mol) 3-trifluoromethylphenothiazine and 2.3 g (0.1 g-atom) Na-
trium, in 500 ml flüssigem Ammoniak her. Nach der Umsetzung verdampft man den Ammoniak und setzt 500 ml wasserfreies Toluol zu. Man gibt dann zu der erhaltenen Lösung tropfenweise die Lösung von 25 g (0,09 Mol) N -(3 - Chlorpropyl) - N' - [2- (1,3 - dioxanyl-(2))-äthyl]-piperazin in 200 ml Toluol und läßt 18 Stunden lang unter Rückfluß und Rühren sieden. Nach dem Abkühlen filtriert man den gebildeten Niederschlag ab, wäscht das Filtrat mit Wasser,trium, in 500 ml of liquid ammonia. After the reaction, the ammonia is evaporated and set Add 500 ml of anhydrous toluene. The solution of 25 g is then added dropwise to the resulting solution (0.09 mol) N - (3 - chloropropyl) - N '- [2- (1,3 - dioxanyl- (2)) - ethyl] piperazine in 200 ml of toluene and refluxed with stirring for 18 hours. After cooling, the formed is filtered Precipitate, wash the filtrate with water,
trocknet und engt im Vakuum ein. Man erhält 33 g N-[3-(3-Trifluormethylphenothiazinyl-(10))-propyl]-N'-[2-(l,3-dioxanyl-(2))-äthyl]-piperazin in Form eines bräunlichen Öls, aus dem das Disuccinat hergestellt wird, dessen (im Kapillarrohr bestimmter) Schmelzpunkt bei 1380C liegt.dries and concentrates in a vacuum. 33 g of N- [3- (3-trifluoromethylphenothiazinyl- (10)) propyl] -N '- [2- (1,3-dioxanyl- (2)) ethyl] piperazine are obtained in the form of a brownish oil, from which the disuccinate is produced whose located (in the capillary tube certain) melting point of 138 0 C.
Summenformel laut Analyse: C34H44F3N3O10S. Molekulargewicht: 743,8.Molecular formula according to analysis: C 34 H 44 F 3 N 3 O 10 S. Molecular weight: 743.8.
Das Produkt ist wenig löslich in Wasser, löslich in Methanol und praktisch unlöslich in Benzol.The product is sparingly soluble in water, soluble in methanol and practically insoluble in benzene.
Das als Ausgangsmaterial dienende N-(3-Chlorpropyl) - N' - [2 - (1,3 - dioxanyl - (2)) - äthyl] - piperazin wird in folgender Weise erhalten:The starting material used is N- (3-chloropropyl) - N '- [2 - (1,3 - dioxanyl - (2)) - ethyl] - piperazine is obtained in the following way:
A. Herstellung von N-Benzyl-A. Manufacture of N-Benzyl
N'-[2-(l,3-dioxanyl-(2))-äthyl]-piperazinN '- [2- (1,3-dioxanyl- (2)) ethyl] piperazine
Man behandelt die Lösung von 85,3 g (0,57 Mol) 2-(2-Chloräthyl)-1,3-dioxan und 200g (1,14MoI) N-Benzylpiperazin in 425 ml wasserfreiem Toluol 16 Stunden lang unter Rühren am Rückflußkühler. Nach dem Abkühlen filtriert man das ausgefallene N-Benzylpiperaziniumchlorid ab, engt das Filtrat unter Vakuum ein und destilliert den sich ergebenden öligen Rückstand. Man erhält 148,4 g (90%) N-Benzyl - N' - [2 - (1,3 - dioxanyl - (2)) - äthyl] - piperazin in Form eines farblosen Öls, das bei 155° bis 165° C bei 0,001 mm Hg siedet (nf = 1,5280) und das nach und nach erstarrt. Nach Umkristallisieren aus Hexan erhält man die Verbindung in Form weißer Kristalle. Schmelzpunkt: 45 bis 46°C.The solution of 85.3 g (0.57 mol) of 2- (2-chloroethyl) -1,3-dioxane and 200 g (1.14 mol) of N-benzylpiperazine in 425 ml of anhydrous toluene is treated for 16 hours with stirring on the reflux condenser . After cooling, the precipitated N-benzylpiperazinium chloride is filtered off, the filtrate is concentrated in vacuo and the resulting oily residue is distilled. 148.4 g (90%) of N-benzyl - N '- [2 - (1,3 - dioxanyl - (2)) - ethyl] - piperazine are obtained in the form of a colorless oil which is at 155 ° to 165 ° C boils at 0.001 mm Hg (nf = 1.5280) and gradually solidifies. After recrystallization from hexane, the compound is obtained in the form of white crystals. Melting point: 45 to 46 ° C.
B. Herstellung von N-[2-(l,3-Dioxanyl-(2))-äthyl]-piperazin B. Preparation of N- [2- (1,3-Dioxanyl- (2)) ethyl] piperazine
Man schüttelt eine Mischung aus 58 g (0,2 Mol) N-Benzyl-N'-[2-(l,3-dioxanyl-(2))-äthyl]-piperazin, 400 ml absolutem Äthanol und 3 g zu 5% auf Kohle abgeschiedenem Palladium bei 500C in Wasserstoffatmosphäre. Nach Absorption· von 4480 ml Wasserstoff läßt man abkühlen, filtriert den Katalysator ab, engt das Filtrat im Vakuum ein und destilliert den sich ergebenden öligen Rückstand. Man erhält 34,8 g (87%) N-[2-(1,3-Dioxanyl-(2))-äthyl]-piperazin in Form eines farblosen Öls, das bei 0,1 mm Hg bei 118 bis 12O0C siedet (n !i = 1,4920).A mixture of 58 g (0.2 mol) of N-benzyl-N '- [2- (l, 3-dioxanyl- (2)) - ethyl] piperazine, 400 ml of absolute ethanol and 3 g of 5% is shaken Palladium deposited on carbon at 50 ° C. in a hydrogen atmosphere. After 4480 ml of hydrogen have been absorbed, the mixture is allowed to cool, the catalyst is filtered off, the filtrate is concentrated in vacuo and the resulting oily residue is distilled. This gives 34.8 g (87%) of N- [2- (1,3-dioxanyl (2)) - ethyl] piperazine in the form of a colorless oil which was 0.1 mm Hg at 118 to 12O 0 C boils (n ! i = 1.4920).
C. Herstellung von N-(3-Chlorpropyl)-N'-[2-(l,3-dioxanyl-(2))-äthyI]-piperazin C. Preparation of N- (3-chloropropyl) -N '- [2- (1,3-dioxanyl- (2)) -ethyI] -piperazine
Man behandelt die Lösung von 30 g (0,15MoI) N-[2-(l,3-Dioxanyl-(2))-äthyl]-piperazin und 11,8 g (0,075 Mol) l-Brom-3-chlor-propan in 150 ml wasserfreiem Benzol 5 Stunden lang unter Rühren am Rückflußkühler. Nach dem Abkühlen filtriert man das ausgefallene N-[2-(l,3-Dioxanyl-(2))-äthyl]-piperaziniumbromid ab, engt das Filtrat im Vakuum ein und destilliert den sich ergebenden öligen Rückstand. Man erhält 14,1g (68%) N-(3-Chlorpropyl)-N'-[2-(l,3-dioxanyl-(2))-äthyl]-piperazin in Form eines klaren gelblichen Öles, das bei 0,07 mm Hg bei 152 bis 155° C siedet (n !i = 1,4940) und dessen in Aceton hergestelltes und aus Aceton umkristalüsiertes Disuccinat bei 104 bis 105° C schmilzt.The solution of 30 g (0.15 mol) of N- [2- (1,3-dioxanyl- (2)) ethyl] piperazine and 11.8 g (0.075 mol) of l-bromo-3-chloro propane in 150 ml of anhydrous benzene for 5 hours with stirring on the reflux condenser. After cooling, the precipitated N- [2- (1,3-dioxanyl- (2)) - ethyl] piperazinium bromide is filtered off, the filtrate is concentrated in vacuo and the oily residue that results is distilled. 14.1 g (68%) of N- (3-chloropropyl) -N '- [2- (1,3-dioxanyl- (2)) - ethyl] piperazine are obtained in the form of a clear yellowish oil, which at 0, 07 mm Hg boils at 152 to 155 ° C (n ! I = 1.4940) and its disuccinate, prepared in acetone and recrystallized from acetone, melts at 104 to 105 ° C.
109587/428109587/428
Claims (1)
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE1695556C3 (en) | 3-alkyl-1,2,3,4,4a, 9-hexahydropyrazino [1,2-f] morphanthridine derivatives | |
| DE69219221T2 (en) | Vanadium complexes, their preparation and pharmaceutical compositions containing them | |
| DE2434911C2 (en) | Phenylethylamine derivatives and pharmaceutical compositions | |
| DE2426149B2 (en) | 7-Fluoro-substituted phenothiazines, processes for their preparation and pharmaceutical compositions containing them | |
| DE2523103B2 (en) | Substituted 2- £ N-Progargyl-N- (2-chlorophenyl) amino] -imidazolines ^), their acid addition salts, process for their preparation and their use | |
| DE69525644T2 (en) | FURANDERIVATIVES FOR INHIBITING PNEUMoCYSTIS CARINII PNEUMONIA, GIARDIA LAMBLIA AND CRYPTOSPORIDIUM PARVUM | |
| DE1620282C (en) | Process for the preparation of new substituted 10 (omega piperazmopropyl) phenothiazines and their salts | |
| DE2412520C2 (en) | Tricyclic compounds, processes for their preparation and preparations containing them | |
| DE1620282B (en) | Process for the preparation of new substituted 10 (omega piperazinopropyl) phenothiazines and their salts | |
| DE2456098C3 (en) | Xanthene and thioxanthene derivatives, processes for their preparation and pharmaceuticals containing these compounds | |
| CH615412A5 (en) | ||
| DE2359359C3 (en) | Fluorine-substituted thioxanthenes, processes for their preparation and neuroleptic agents containing them | |
| DE2730593A1 (en) | NEW AMINO-ALCOXYBENZOFURANS, METHOD FOR MANUFACTURING THE SAME PHARMACEUTICAL PRODUCTS THEREOF | |
| EP0391850B1 (en) | Unsaturated amino-dicarboxylic acid derivatives | |
| DE2560602C2 (en) | Oxygenated diarylamidines | |
| DE2029510B2 (en) | Dibenzofuran derivatives and their pharmaceutically acceptable acid addition salts, as well as processes for their preparation and pharmaceuticals containing these compounds | |
| DE3129719C2 (en) | Pharmaceutical agent | |
| DE2609574B2 (en) | 1- (4-FLUORO-3-TRIFLUOROMETHYLTHIO-PHENYL) -PIPERAZINE, ITS SALT, PROCESS FOR THE PREPARATION THEREOF AND MEDICINAL PRODUCTS | |
| DE2251872A1 (en) | COMPOUNDS DERIVED FROM 1- (3,4-DIMETHOXY-BENZYL) -6,7DIMETHOXY-1,2,3,4-TETRAHYDROISOCHINOLINE AND 2-PHENYL-GAMMA-BENZOPYRONE | |
| DE2458374A1 (en) | NOVEL 1,3-BENZODIOXOL COMPLETE | |
| DE1620281C (en) | Substituted 10 (omega piperazinopropyl) phenothiazines and their salts and a process for the preparation thereof | |
| DE1950972C3 (en) | 2,7-Dicarboxamide compounds of fluorenes and 9-fluorenone and process for their preparation | |
| DE1493928C (en) | Basically substituted ß Tetrahydro furyl propionitnle and their pharmaceutically non-toxic salts and processes for their production | |
| AT247353B (en) | Process for the preparation of new 2-chloro-4-azaphenthiazine derivatives | |
| DE1545815C (en) | Piperazindenvates and process for their preparation |