CH436308A - Process for the preparation of 6-basic substituted morphanthridines - Google Patents
Process for the preparation of 6-basic substituted morphanthridinesInfo
- Publication number
- CH436308A CH436308A CH1189766A CH1189766A CH436308A CH 436308 A CH436308 A CH 436308A CH 1189766 A CH1189766 A CH 1189766A CH 1189766 A CH1189766 A CH 1189766A CH 436308 A CH436308 A CH 436308A
- Authority
- CH
- Switzerland
- Prior art keywords
- base
- formula
- preparation
- morphanthridines
- addition salts
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 5
- 239000002253 acid Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- PWRPUAKXMQAFCJ-UHFFFAOYSA-N Perlapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2CC2=CC=CC=C12 PWRPUAKXMQAFCJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 230000004899 motility Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- -1 1-piperazinyl Chemical group 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000002903 catalepsic effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung 6-basisch substituierter Morphanthridine Die Erfindung betrifft ein Verfahren zur Herstellung 6-basisch substituierter Morphanthridine der Formel:
EMI1.1
sowie von Säureadditionssalzen davon. In Formel I bedeutet R1 eine Alkyl- oder Hydroxyalkylgruppe mit 1 bis 3 C-Atomen, wobei letztere acyliert sein kann, oder eine Alkoxyalkylgruppe mit höchstens 5 C-Atomen, R2 und R. sind gleich oder verschieden und bedeuten Wasserstoff oder Halogen. Allfällige Substituenten in den Benzolkernen befinden sich vorzugsweise in 3- oder 8-Stellung.
Die gewünschten Produkte (I) werden erfindungsgemäss erhalten, wenn man Verbindungen der Formel:
EMI1.2
worin R2 und R3 die genannte Bedeutung haben, mit reaktionsfähigen Estern von Alkoholen der Formel RI-OH, worin R1 die genannte Bedeutung hat, umsetzt, wobei die Reaktionsgemische in Form der freien Basen oder von Säureadditionssalzen gewonnen werden.
Als reaktionsfähige Ester von Alkoholen der Formel R1-OH kommen insbesondere Halogenwasserstoffsäureester in Betracht. Die Umsetzung erfolgt vorzugsweise in einem inerten Lösungsmittel, z. B. Benzol, durch Erwärmen auf Rückflusstemperatur.
Die in der beschriebenen Weise erhaltenen Basen sind in den meisten Fällen kristallisierbar, sonst im Hochvakuum unzersetzt destillierbar, und bilden mit anorganischen und organischen Säuren, beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Phosphorsäure, Essigsäure, Oxalsäure, Weinsäure, To luolsulfonsäure und dergleichen, in Wasser beständige Additionssalze, in welcher Form die Produkte ebenfalls verwendet werden können.
Die in der beschriebenen Weise erhaltenen Basen und ihre Säureadditionssalze sind neue Verbindungen, die als Wirkstoff in Arzneimitteln oder als Zwischenprodukte zur Herstellung von solchen Verwendung finden. Insbesondere fallen die Produkte als Neuroplegika, Neuroleptika und Analgetika in Betracht. Einzelne davon eignen sich zur Behandlung psychotischer Zustände. Diese Wirksamkeit äussert sich pharmakologisch in starker Motilitätsdämpfung bei Mäusen, die mit kataleptischer Wirkung einhergehen kann. Die Motilitätsdämpfung wird durch Messung der Laufaktivität nach der Methode von Caviezel und Baillod [Pharm. Acta Helv. 33, 469 (1958)] erfasst. Die Laufaktivitätswerte einiger erfindungsgemässer Produkte sowie deren Toxizität werden in der folgenden Tabelle I mit den entsprechenden Zahlen für Chlorpromazin verglichen.
Tabelle l Wirkstoff Toxizität Maus Laufaktivität Maus
LDso mg/kg p. o. EDso mg/kg p. o.
Chlorpromazin 135 3,5 6-(4-Methyl-1 -piperazinyl)- morphanthridin 415 1,7 3 -Chlor-6-(4-methyl- 1 piperazinyl)- morphanthridin 530 4,6 8-Chlor-6-(4-methyl-1-piperazinyl)- morphanthridin 180 0,18
Beispiel 1
Zu einer auf 600 C erwärmten Lösung von 5,54 g 6-(1-Piperazinyl)-morphanthridin in 50 ml Benzol wird eine Lösung von 1,42 g Methyliodid in 30 ml Benzol getropft. Das Gemisch wird während 30 Minuten unter Rückfluss erwärmt. Nach dem Abkühlen nutscht man das Hydroiodid des Ausgangsmaterials ab und dampft das Filtrat im Vakuum zur Trockne ein.
Der Rückstand wird aus Äther/Petroläther zur Kristallisation gebracht und aus Aceton/Petroläther umkristallisiert, wobei man 2,4 g 6-(4-Methyl 1 -piperazinyl)-morphanthridin vom Schmelzpunkt 137,5-138,50 C erhält.
In analoger Weise wie im vorerwähnten Beispiel erhält man aus entsprechenden Ausgangsstoffen die in der nachfolgenden Tabelle II genannten Produkte. Darin haben R1, R2 und Rs die früher angegebene Bedeutung.
In der rechten Kolonne bedeutet Ac Aceton, Ä Äther, Ch Chloroform und Pe Petroläther.
Process for the preparation of 6-basic substituted morphanthridines The invention relates to a process for the preparation of 6-basic substituted morphanthridines of the formula:
EMI1.1
as well as acid addition salts thereof. In formula I, R1 denotes an alkyl or hydroxyalkyl group with 1 to 3 carbon atoms, the latter can be acylated, or an alkoxyalkyl group with at most 5 carbon atoms, R2 and R. are identical or different and denote hydrogen or halogen. Any substituents in the benzene nuclei are preferably in the 3- or 8-position.
The desired products (I) are obtained according to the invention when compounds of the formula:
EMI1.2
in which R2 and R3 have the meaning mentioned, are reacted with reactive esters of alcohols of the formula RI-OH, in which R1 has the meaning mentioned, the reaction mixtures being obtained in the form of the free bases or of acid addition salts.
Particularly suitable reactive esters of alcohols of the formula R1-OH are hydrohalic acid esters. The reaction is preferably carried out in an inert solvent, e.g. B. benzene, by heating to reflux temperature.
The bases obtained in the manner described are in most cases crystallizable, otherwise they can be distilled without decomposition in a high vacuum, and form with inorganic and organic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, toluenesulfonic acid and the like, addition salts stable in water, in which form the products can also be used.
The bases obtained in the manner described and their acid addition salts are new compounds which are used as active ingredients in medicaments or as intermediates for the preparation of such use. In particular, the products come into consideration as neuroplegics, neuroleptics and analgesics. Some of them are suitable for the treatment of psychotic states. This efficacy manifests itself pharmacologically in a strong reduction in motility in mice, which can be associated with cataleptic effects. The motility damping is determined by measuring the running activity according to the method of Caviezel and Baillod [Pharm. Acta Helv. 33, 469 (1958)]. The running activity values of some products according to the invention and their toxicity are compared in Table I below with the corresponding figures for chlorpromazine.
Table 1 active substance toxicity mouse running activity mouse
LDso mg / kg p. o. ED so mg / kg p. O.
Chlorpromazine 135 3.5 6- (4-methyl-1-piperazinyl) -morphanthridine 415 1.7 3 -chloro-6- (4-methyl-1-piperazinyl) -morphanthridine 530 4.6 8-chloro-6- (4th -methyl-1-piperazinyl) -morphanthridine 180 0.18
example 1
A solution of 1.42 g of methyl iodide in 30 ml of benzene is added dropwise to a solution, heated to 600 ° C., of 5.54 g of 6- (1-piperazinyl) -morphanthridine in 50 ml of benzene. The mixture is refluxed for 30 minutes. After cooling, the hydroiodide of the starting material is suction filtered and the filtrate is evaporated to dryness in vacuo.
The residue is crystallized from ether / petroleum ether and recrystallized from acetone / petroleum ether, 2.4 g of 6- (4-methyl 1 -piperazinyl) morphanthridine having a melting point of 137.5-138.50 ° C. being obtained.
In a manner analogous to that in the aforementioned example, the products listed in Table II below are obtained from appropriate starting materials. Here R1, R2 and Rs have the meaning given earlier.
In the right column, acetone means acetone, ether, Ch chloroform and Pe means petroleum ether.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1189764 | 1964-05-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH436308A true CH436308A (en) | 1967-05-31 |
Family
ID=4377947
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1189766A CH436308A (en) | 1964-05-27 | 1964-05-27 | Process for the preparation of 6-basic substituted morphanthridines |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH436308A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2320103A1 (en) * | 1975-08-06 | 1977-03-04 | Sandoz Sa | NEW DERIVATIVES OF MORPHANTHRIDINE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
-
1964
- 1964-05-27 CH CH1189766A patent/CH436308A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2320103A1 (en) * | 1975-08-06 | 1977-03-04 | Sandoz Sa | NEW DERIVATIVES OF MORPHANTHRIDINE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
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