IE44449B1 - 11-methylene-6-piperazinyl-morphanthridine derivatives - Google Patents
11-methylene-6-piperazinyl-morphanthridine derivativesInfo
- Publication number
- IE44449B1 IE44449B1 IE1723/76A IE172376A IE44449B1 IE 44449 B1 IE44449 B1 IE 44449B1 IE 1723/76 A IE1723/76 A IE 1723/76A IE 172376 A IE172376 A IE 172376A IE 44449 B1 IE44449 B1 IE 44449B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- methylene
- hydrogen
- solution
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 4
- 239000000460 chlorine Substances 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 150000003839 salts Chemical group 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- IDWNSAXOQLJYOF-UHFFFAOYSA-N 11h-benzo[c][1]benzazepine Chemical compound C1=NC2=CC=CC=C2CC2=CC=CC=C21 IDWNSAXOQLJYOF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 7
- 239000000164 antipsychotic agent Substances 0.000 abstract description 2
- 229940005529 antipsychotics Drugs 0.000 abstract description 2
- 229910052736 halogen Chemical group 0.000 abstract description 2
- 150000002367 halogens Chemical group 0.000 abstract description 2
- 230000000561 anti-psychotic effect Effects 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000001939 inductive effect Effects 0.000 abstract 1
- 150000002894 organic compounds Chemical class 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- 239000008096 xylene Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- -1 β-hydroxyethyl Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-YPZZEJLDSA-N carbon-10 atom Chemical group [10C] OKTJSMMVPCPJKN-YPZZEJLDSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000537 electroencephalography Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Case 500-5386 IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS This invention provides new compounds of formula I, I wherein R1 is hydrogen, alkyl of 1 to 4 carbon atoms, or hydroxyalkyl of 1 to 4 carbon atoms, and R2 is hydrogen or halogen, useful as anti-psychotics and sleep-inducing agents.
Description
Tiie present invention relates to morphanthridine derivatives.
The present invention provides compounds of formula I, wherein Ry is hydrogen, alkyl of 1 to 4 carbon atoms, or hydroxyalkyl of 1 to 4'carbon atoms, and Rj is hydrogen , fluorine, chlorine or bromine. When Ry is alkyl, it is preferably methyl. When Ry is hydroxyalkyl, this preferably has 2 to 4 carbon 10 atoms. The hydroxy group is preferably bound to the terminal carbon atom away from the nitrogen atom to which Ry is bound. Ry is, for example, β-hydroxyethyl. Ry is preferably hydrogen or alkyl.
When Rj is different to hydrogen, then 15 it is especially fluorine or chlorine.
The 'present invention also provides a process for the production of a compound of formula I, as defined above, which comprises reacting a compound of formula II, II wherein R^ is as defined above, and X is chlorine, with a compound of formula III, /~\ H-N, N-R, \_/ x III wherein R^ is as defined above.
The process may be effected in known manner for su'.h condensations.
The reaction may be conveniently effected in an inert organic solvent, for example, xylene or dioxane, at temperatures between 50" and 170°C, preferably between 100° and 140°C.
The resulting compounds of formula I may be isolated and purified in conventional manner. λ compound of formula II, used as starting material may be obtained by a) reacting a compound of formula IV, 444© wherein R^ is as defined above, with a compound of formula V, CH^-MgY V wherein Y is chlorine, bromine or iodine, especially bromine, under conventional conditions for a Grignard reaction, b) hydrolysing the resulting reaction complex to give a 11-methyl-ll-hydroxy reaction product, c) dehydrating the 11-methyl-ll-hydroxy reaction product in conventional manner to give a compound of formula VI, Ιθ wherein as defined above, and d) converting the compound of formula VI in conventional manner into a compound of formula II.
Insofar as the preparation of any starting material is not particularly described, this is knovm or the compound may be produced and purified in known manner or in analogous manner to methods described herein or in analogous manner to known processes.
Free base forms of compounds of formula I may be converted into acid addition salt form in conventional manner and vice versa. Suitable acids for salt formation include hydrochloric acid, methanc-sulphonic acid or maleic acid.
In the following Examples all temperatures are uncorrected and are in degrees Centigrade. Ether means diethyl ether. 44446 EXAMPLE 1: raz:in-l-vl) morphai-itRridi.net a') SfSbloroxll^m.efchylerieymorchsnthridine g of 5,6-dihydro-ll-methylene-morphanthridin-6-one are boiled for. 2 hours with 3 ml-of Ν,Ν-dimethylaniline and 80 ml of phosphoryl chloride. The resulting dark solution is concentrated in a vacuum. The residue is treated with xylene and once again the mixture is evaporated in a vacuum. The residue is dissolved in 80 ml of xylene and the solution is poured onto icewater. The mixture is extracted twice with xylene. The xylene extracts are combined, washed in turn with dilute hydrochloric acid, water and a saturated sodium chloride aqueous solution, dried over sodium sulphate and treated with active 'charcoal. The xylene solution is filtered through aluminium oxide and concentrated to a volume of loo to 150 ml In a vacuum. This solution contains 6-chloro-ll-methylene-morphanthridine which is used directly in step b).-20 b) ll-MethylenepS-(4-methvlpiperazln-l-yl)-morPhanfchridine The xylene solution Of 6-ehloro-ll-methylene-morphanthridine Is treated with 8 g of N-methylpiperazine and the mixture is boiled for 4 hours. The hydrochloride salt of N-methylpiperazine precipitates out of solution. The mixture is treated with water and 25 ml of a concentrated sodium hydroxide aqueous solution. The organic phase is shaken twice with ether, washed with water and extracted with 2N hydrochloric acid.
The acid extract Is made alkaline with 2N aqueous sodium Hydroxide solution and the resulting oily phase which separates out is extracted twice with ether. The ether extracts are combined, washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulphate, treated vzith active charcoal and then filtered through aluminium oxide. Recrystallization from ether/petroleum ether yields ll-methylene-6-(4-methylpiperazin-l-yD-morphanthridine as prisms; M.Pt. 119° 120°.
In analogous manner to that described in Example I using the appropriate starting materials of formulae II and III the following compounds of formula I are obtained, wherein :- :.Ho.R1R2 M.Pt. 2 H ii jl9O-l95°C 1) 2) (_2O8-211 °C 1) 3) 3 HO-CH2-CH2- H 151-155°C 2) 4 5 BO-CH2-CH2~ H Cl Cl 147-149°C 130-138°C 2) 6 CH3 Cl 162-164 °C 7 H F 125-126°C 8 ch3 F 138-14O°C & 4 4 49 decomposition . . 2} . maleate salt form. 3) methane sulphonate salt form The production of the 5,,6-dihydro-3-halo-ll5 methylene-morphanthridin-6-enes used as starting materials of formula IV may be effected as follows r-_ a) luora-reorghanthridiri-G ,ΙΙ^ίίοηε A solution of 88 g of chromium (VI) trioxide in 60 ml of water is added dropwise Over 4 hours to a stirred solution of 5,6-dihydro~3-fluoro-mOrphanthridin-6-one in 1.5 litres of acetic acid warmed to 60°C. The mixture is then heated for 1 hour under reflux, cooled and then poured onto icewater. The crystals formed are separated Off and washed with water. After drying the heading compound M.Pt. 28215 285°C (sublimation) is obtained.
In analogous manner 3-chloro-5,6-dihydro-morphanthridin-6,Tl-dione is.obtained, melting at 293-295°C. 150 ml of absolute tetrahydrofuran is added in portions with an exothermic reaction to a Grignard solution of 5.6 g of magnesium, 30.6 g of methyl iodide and 80 ml of ether. The solution Is cooled to 10°G. In a nitrogen gas atmosphere this solution Is treated in small portions with a suspension of 19 g of. 5,6-dihydro-3-fluoro-morphanthridin-6,11-dione in .200 ml of absolute tetrahydrofuran. The mixture is stirred for 4 hours at room temperature and then poured onto an ice-cold ammonieal ammonium chloride aqueous solution. The mixture is then ' extracted with ether. The ether extracts are washed with brine and concentrated to dryness. The hard residue containing 5,6-dihydro-3-fluoro-ll-hydroxy-ll-methylmorphanthridin-6-one is dissolved in a little acetone, treated .with 18 g of pyridine hydrochloride and warmed in the presence of a stream of nitrogen. After the acetone is removed, the mixture is warmed for 90 minutes to 130" - 140vc, cooled somewhat, treated with water, separated from the water and dried. After recrystallization from acetone/petroleum ether the heading compound melting at 220" - 23O°C (crystal change from 160"C) is obtained.
In analogous manner 3-chloro-5,6-dihydro-llmethylene-morphanthridin-6-one melting at 247" - 249"C is obtained.
The compounds of formula I exhibit pharmacological activity. In particular, the compounds of formula I (a) inhibit the locomotor activity In mice in a test carried out according to the principles of Caviezel and Baillod, Pharma Acta Helv. 33, 465-4 84 (195 8) , (b) inhibit the arousal' reaction of rabbits as determined by electroencephalography in a test carried, out according to the method of Stille et al., Int. J. Neuropharmacology A_, 375-391 (1965) and/or (c) have a significant effect on the sleep of· rats, significantly increasing the deep sleep phase, in a test carried out according to the method of Stille et al, Psychopharmacologica .28, 325337 (1973).' As a result of their activity in tests a) and b) the compounds are therefore indicated for use as antipsychotics. An indicated daily dose is from 5 to 500 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from to 250 mg or in sustained release form.
The compounds of formula I, wherein f?2 Ts halogen, especially the compound of Example 6, exhibits especially interesting activity in tests a) and b).
As result of their activity in test c) the compounds are indicated for use as hypnotics. An indicated daily dose is from 1 to 100 mg, conveniently administered iO in a single dose shortly before the time v/hen sleep is required.
The compounds of formula I, wherein R2 is hydrogen, especially the compound of Example 2, exhibit particularly interesting activity in test c).
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association v/ith a pharmaceutical carrier or diluent.
Such compositions may be in the form of, for example, a solution or a tablet.
Claims (14)
1. CLAIM!. wherein R^ *2 which comprises is hydrogen, alkyl of 1 to 4 carbon atoms, or hydroxyalkyl of 1 to 4 carbon atoms, and is hydrogen t fluorine, chlorine or bromine, reacting a compound of. formula IX, wherein R 2 is as defined above, and X is chlorine, with a compound of formula III, III wherein R^ is as defined above
2. A process for the production of a compound of 5 formula I, as stated in claim 1, substantially as hereinbefore described with reference to any one of the Examples
3. A compound of formula I, whenever produced by' a process according to claim 1 or 2.
4. A compound of formula I, as defined in'claim 1. 10
5. ll-methylene-6-(4-methylpiperasinyl-l-yl)morphanthridine.
6. A compound of claim 4, wherein R^ and R 2 are both H.
7. A compound of claim 4, wherein R^ and R^ are 15 respectively HO-CH 2 -CH 2 - and H.
8. A compound of claim 4, wherein R^ and are respectively HO-CH 2 -CH 2 - and Cl. t.
9. A compound of claim 4, wherein R^ and.R 2 are respectively H and Cl.
10. A compound of claim 4, wherein R^ and R 2 are respectively CH^ and Cl.
11. ' A compound of claim 4, wherein R^ and R 2 are respectively H and F.
12. A compound of claim 4, wherein R^ and R, are respectively CH^ and F.
13.v A compound according to any one of claims 3 to 12 in. acid addition salt form.
14. , A pharmaceutical composition comprising a compound according to any one of claims 3 to 12 in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1024775A CH601287A5 (en) | 1975-08-06 | 1975-08-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE44449L IE44449L (en) | 1977-02-06 |
| IE44449B1 true IE44449B1 (en) | 1981-12-02 |
Family
ID=4361070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1723/76A IE44449B1 (en) | 1975-08-06 | 1976-08-04 | 11-methylene-6-piperazinyl-morphanthridine derivatives |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5219690A (en) |
| AU (1) | AU1661376A (en) |
| BE (1) | BE844881A (en) |
| CA (1) | CA1070685A (en) |
| CH (1) | CH601287A5 (en) |
| DE (1) | DE2633782A1 (en) |
| DK (1) | DK342976A (en) |
| ES (1) | ES450498A1 (en) |
| FI (1) | FI62664C (en) |
| FR (1) | FR2320103A1 (en) |
| GB (1) | GB1551442A (en) |
| GR (1) | GR70677B (en) |
| IE (1) | IE44449B1 (en) |
| IL (1) | IL50198A0 (en) |
| NL (1) | NL7608567A (en) |
| NO (1) | NO145538C (en) |
| NZ (1) | NZ181684A (en) |
| PH (1) | PH11347A (en) |
| PT (1) | PT65435B (en) |
| SE (1) | SE7608519L (en) |
| ZA (1) | ZA764731B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH624682A5 (en) * | 1976-11-10 | 1981-08-14 | Sandoz Ag | |
| DE2918778A1 (en) * | 1979-05-10 | 1980-11-20 | Basf Ag | 6-SUBSTITUTED 11-ALKYLENE MORPHANTRIDINE |
| IT1207417B (en) * | 1982-03-15 | 1989-05-17 | Menarini Sas | AZEPINA-6-ONE WITH ACTIVITIES TRICYCLIC COMPOUNDS DERIVED FROM PHARMACOLOGICAL, AND PROCEDURES OF 5,6-DIHYDRO-11H-DIBENZO (B, E) RELATED MANUFACTURE |
| JPS6266910U (en) * | 1985-10-11 | 1987-04-25 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3389139A (en) * | 1963-06-14 | 1968-06-18 | Wander Ag Dr A | 6-homopiperazino and piperazinomorphanthridines |
| CH436308A (en) * | 1964-05-27 | 1967-05-31 | Wander Ag Dr A | Process for the preparation of 6-basic substituted morphanthridines |
| DE1670053A1 (en) * | 1966-02-18 | 1970-08-13 | Boehringer Mannheim Gmbh | Process for the preparation of new derivatives of morphanthridine |
-
1975
- 1975-08-06 CH CH1024775A patent/CH601287A5/xx not_active IP Right Cessation
-
1976
- 1976-07-28 DE DE19762633782 patent/DE2633782A1/en not_active Withdrawn
- 1976-07-28 FI FI762153A patent/FI62664C/en not_active IP Right Cessation
- 1976-07-28 SE SE7608519A patent/SE7608519L/en unknown
- 1976-07-29 DK DK342976A patent/DK342976A/en unknown
- 1976-07-29 NO NO762644A patent/NO145538C/en unknown
- 1976-08-02 NL NL7608567A patent/NL7608567A/en not_active Application Discontinuation
- 1976-08-04 IE IE1723/76A patent/IE44449B1/en unknown
- 1976-08-04 IL IL50198A patent/IL50198A0/en unknown
- 1976-08-04 PT PT65435A patent/PT65435B/en unknown
- 1976-08-04 GR GR51411A patent/GR70677B/el unknown
- 1976-08-04 PH PH18752A patent/PH11347A/en unknown
- 1976-08-04 BE BE169558A patent/BE844881A/en unknown
- 1976-08-04 NZ NZ181684A patent/NZ181684A/en unknown
- 1976-08-04 CA CA258,374A patent/CA1070685A/en not_active Expired
- 1976-08-04 JP JP51092409A patent/JPS5219690A/en active Pending
- 1976-08-04 GB GB32458/76A patent/GB1551442A/en not_active Expired
- 1976-08-05 AU AU16613/76A patent/AU1661376A/en not_active Expired
- 1976-08-05 ES ES450498A patent/ES450498A1/en not_active Expired
- 1976-08-06 FR FR7624028A patent/FR2320103A1/en active Granted
- 1976-08-06 ZA ZA00764731A patent/ZA764731B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA764731B (en) | 1978-03-29 |
| AU1661376A (en) | 1978-02-09 |
| NZ181684A (en) | 1978-04-28 |
| GB1551442A (en) | 1979-08-30 |
| CA1070685A (en) | 1980-01-29 |
| NO145538B (en) | 1982-01-04 |
| PH11347A (en) | 1977-11-02 |
| PT65435A (en) | 1976-09-01 |
| ES450498A1 (en) | 1977-12-16 |
| PT65435B (en) | 1978-05-10 |
| FI62664B (en) | 1982-10-29 |
| GR70677B (en) | 1982-12-06 |
| NO762644L (en) | 1977-02-08 |
| FR2320103B1 (en) | 1978-12-22 |
| IE44449L (en) | 1977-02-06 |
| IL50198A0 (en) | 1976-10-31 |
| DE2633782A1 (en) | 1977-02-17 |
| NL7608567A (en) | 1977-02-08 |
| FI62664C (en) | 1983-02-10 |
| DK342976A (en) | 1977-02-07 |
| CH601287A5 (en) | 1978-07-14 |
| JPS5219690A (en) | 1977-02-15 |
| BE844881A (en) | 1977-02-04 |
| NO145538C (en) | 1982-04-14 |
| FI762153A (en) | 1977-02-07 |
| FR2320103A1 (en) | 1977-03-04 |
| SE7608519L (en) | 1977-02-07 |
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