IE46263B1 - A morphanthridine derivative - Google Patents
A morphanthridine derivativeInfo
- Publication number
- IE46263B1 IE46263B1 IE654/82A IE65482A IE46263B1 IE 46263 B1 IE46263 B1 IE 46263B1 IE 654/82 A IE654/82 A IE 654/82A IE 65482 A IE65482 A IE 65482A IE 46263 B1 IE46263 B1 IE 46263B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- formula
- morphanthridine
- addition salt
- acid addition
- Prior art date
Links
- IDWNSAXOQLJYOF-UHFFFAOYSA-N 11h-benzo[c][1]benzazepine Chemical class C1=NC2=CC=CC=C2CC2=CC=CC=C21 IDWNSAXOQLJYOF-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 8
- 150000003839 salts Chemical group 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 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 claims description 3
- -1 4-methyl-l-piperazinyl Chemical group 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000009132 Catalepsy Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010047853 Waxy flexibility Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000003176 neuroleptic agent Substances 0.000 description 2
- 230000000701 neuroleptic effect Effects 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 230000035873 hypermotility Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229960005333 tetrabenazine Drugs 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
The present invention provides a process for the production of the compound of formula I which comprises reacting a compound of formula II, wherein X is a leaving group, with a compound of formula III, /~\ HN N-CH, III \_/ 3 The reaction may be effected in conventional manner for the production of similar compounds. X is preferably chlorine.
The process may be conveniently effected at a temperature of from 50° to 170°C in an inert organic solvent such as xylene or dioxane.
A compound of formula II may be produced in known manner from 3-fluoro-5,6-dihydromorphanthridin-6-one and may be reacted further without purification.
The free base form of the compound of formula I 15 may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include hydrochloric acid or fumaric acid.
In the following Example all temperatures are in degrees Centigrade and are uncorrected.
EXAMPLE 1: -^£hx3r^-/-J4-methy l-l-£i£eraziny 1) -morghanthridine_ g 3-fluoro-5,6-dihydromorphanthridin-6-one, 80 ml phosphorus oxychloride and 2 ml Ν,Ν-dimethylaniline are boiled for 4 hours. The excess phosphorus oxychloride is distilled off in a vacuum and the residue is partitioned between ice-watqr and xylene. The xylene phase is washed with dilute hydrochloric acid and water. The xylene phase is dried over sodium sulphate. The resultant solution containing the imidochloride of the above lactam is concentrated to 50 ml and boiled with 6 ml N-methyl-piperazine for 4 hours.
The cooled reaction mixture is treated With water, made alkaline with concentrated sodium hydroxide solution and extracted with ether. The ether phase is washed with water and extracted with dilute hydrochloric-acid. The acid phase is made alkaline and shaken with ether. The ether phase is dried over sodium sulphate, and concentrated, and petroleum ether is added when only a little volume remains whereupon the title compound in free base form of M.Pt. 118° - 119° crystallizes out.
The compound of formula I exhibit; pharmacological activity. In particular the compound exhibits non-cataleptagenic activity as indicated in standard tests. Por example in one standard test an inhibition of spontaneous motility is observed in mice on p.o. administration of from about 20 to 50 mg/kg of the compound. On the other hand the compound did not significantly induce catalepsy.
Additionally the compound on administration of from 0.1 to 1 mg/kg i.p. to mice inhibits the hypermotility induced by 4,cc-dimethyl-m-tyramine. Furthermore, on administration of 2 to 20 mg/kg p.o. of the compound to rats in the sleep/wake cycle test carried out in accordance with the principle of H.Kleinlogel et al European J.Pharmacol. 33, 159-163 (1975) an increase in sleep phase II characteristic for neuroleptics is observed.
The compound is therefore indicated for use as a neuroleptic. Furthermore, the compound decreases the wake phase in the above-mentioned sleep/wake test and is therefore indicated to have sleep-promoting properties.
Additionally, the compound inhibits the catalepsy induced by tetrabenazine in rats on i.p. administration and is therefore indicated to have anti-depressant proper20 ties.
The compound also exhibits a muscle relaxing effect in rabbits on i.v. administration in the method according to Teschendorf et al., Arch.Exp.Pharmacol. 266, 467-468 (1970) and is therefore indicated to have myotonolytic pro25 perties.
An indicated daily dosage for the preferred neuroleptic use is from 25 to 400 mg, conveniently administered 46363 in divided doses 2 to 4 times a day in unit dosage form containing from about 6 to about 200mg of the compound, or in sustained release form.
I The compound 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 form 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 with a pharmaceutical carrier or diluent. Such compositions may be in the form 6f, for example, a solution or a tablet.
Claims (7)
1. A process for the production of 3-fluoro-6(4-methyl-l-piperazinyl)-morphanthridine of formula X, which comprises reacting a compound of formula II, II wherein X is a leaving group, with a compound of formula III, r~\ HN N-CH \./ 3 III
2. A process for the production of the compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to the Example.
3. A compound of formula I, whenever produced by a process according to claim 1 or 2.
4. The compound of formula I, as defined in claim 1.
5. 5. The compound of formula I in acid addition salt form.
6. A pharmaceutical composition comprising the compound of claim 3 or 4 in free base form, or in pharmaceutical acceptable acid addition salt form, in association
7. 10 with a pharmaceutical carrier or diluent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1415776A CH624682A5 (en) | 1976-11-10 | 1976-11-10 | |
| IE2279/77A IE46262B1 (en) | 1976-11-10 | 1977-11-08 | Morphanthridines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE820654L IE820654L (en) | 1978-05-10 |
| IE46263B1 true IE46263B1 (en) | 1983-04-20 |
Family
ID=25713905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE654/82A IE46263B1 (en) | 1976-11-10 | 1977-11-08 | A morphanthridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IE46263B1 (en) |
-
1977
- 1977-11-08 IE IE654/82A patent/IE46263B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE820654L (en) | 1978-05-10 |
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