IL24925A - 5-basic substituted 5,6-dihydro-6-oxomorphanthridines - Google Patents
5-basic substituted 5,6-dihydro-6-oxomorphanthridinesInfo
- Publication number
- IL24925A IL24925A IL2492566A IL2492566A IL24925A IL 24925 A IL24925 A IL 24925A IL 2492566 A IL2492566 A IL 2492566A IL 2492566 A IL2492566 A IL 2492566A IL 24925 A IL24925 A IL 24925A
- Authority
- IL
- Israel
- Prior art keywords
- lower alkyl
- formula
- dihydro
- denotes
- hydrogen
- Prior art date
Links
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Pyridine Compounds (AREA)
Description
-basic substituted S ie-dih dro-e-oxomorphajatb i^i es I (we) DR. A. WANDER S.A., a 3wiss company, of 3001 Berne, Monbijoustrasse 115, Switzerland do herehy declare the nature of this invention and' in what manner the same is to he performed, to- e particularly descrihed 'and ascertained in and hy the following statement': - BASIO . SUBSTITUTED 5 , 6 ΡΙΗΐΰηθ-6-OXQMOnniAimmiSIITEQ This invention is generally concerned with heterocyclic compounds, and. more specifically with 5-basic substituted 5 , 6-dihydro-6-oxomorphanthridines of the formula: and acid addition salts thereof. In formula I R denotes straight or branched alkylene with 2 to 4 carbon atoms ;..R^ and R^ are the same or different and denote hydrogen or lower alkyl; one of both R-j denotes hydrogen ,the other ^ is halogen or lower alkyl; and R^ denotes lower alkyl. "lower alkyl" is intended to indicate, throughout the specification and claims, .an alkyl residue having from 1 to 3 carbon atoms.
The said compounds (I) are obtained by reacting amines of the formula X-H, if desired after prior, or during simultaneous, action by a- condensing agent, with reactive esters of alcohols of the formula Y-R-OH. In these formulae, X and Y are mutually interchangeable .. X has the meaning of a ll-R^-5 , 6-dihydro-6-oxo-5-morphanthridinyl residue having halogen or lower alkyl as a sub-stituent in one of both benzene nuclei; .and Y has the meaning of the basic group meaning stated earlier.
As reactiye esters of alcohols of the formula Y-R-OH those of carbonic acid, hydrohalic acids, or sulphonic acids such as p-toluene sulphonic acid, are1 especially suitable. The use of a condensing agent is indicated if 5-unsubstituted lactams are re- acted wit hydrohalic or sulphonic acid esters. Suitable condensing agents are alkali metals, their hydrides and amides or other alkali metal compounds, e.g. sodium amide, sodium hydride, sodium ethylate, phenyl potassium, phenyl lithium, potassium tert. butoxide, and the like. If products of formula I are to be prepared, wherein and/or R2 denote hydrogen, the condensation may preferably be performed after previous substitution of this hydrogen by suitable protective groups, such as benzyl or allyl, which are split off subsequently by known methods, for instance, by hydrogenolysis.
The ll-alkyl-5,6-dihydro-6-oxomorphanthridines having halogen or lower alkyl as a substituent in one of both benzene nuclei, which are used in this procedure as starting materials, may be obtained with excellent yield by ring closure of the corresponding substituted o-isocyanato-l,l-diphenylalkanes, e.g. with the aid of aluminium chloride, the isocyanates being in turn obtained from the corresponding substituted o-amino-1,1-diphenyl-alkanes.
The desired compounds (I) are also obtained by cyclization of N-aminoalkylated o-amino-o '-carboxy(or alkoxycarbonyl)-l,l-diphenylalkanes of the formula: wherein R, ^, R,,, R^, and ^ have the meaning indicated above, ^ represents hydrogen or an acyl residue, especially benzoyl or acetyl, and R.- denotes hydrogen or lower alkyl, with cleavage of water, an alcohol, an acid, or an ester, respectively. Ring closure is effected, according to the nature of the substituents R-. and Rg, by moderate or strong heating of the starting compound, in the presence or absence of a suitable solvent like xylol or dioxane.
In the process mentioned above, it is not necessary to use the starting material in the form of an isolated substance. If desired, it is quite possible to combine the process with the preceding step of introducing the basic group without isolation of compound II. In this case, an o-acylamino-o '-carboxy- (or alkoxycarbonyl)-l,l-diphenylalkane having halogen or lower alkyl as a substituent in one of the phenyl residues is heated in the presence of a reactive ester of a basic alkanol of the formula have the meaning stated above, for instance, with a hydrohalic acid, sulphonic acid, or carbonic acid ester, until ring closure occurs, if desired after prior or with simultaneous treatment with a condensing agent.
Suitable condensing agents are alkali metals, their hydrides and amides or other alkali metal compounds, e.g. sodium amide, sodium hydride, sodium ethylate, phenyl potassium, phenyl lithium, potassium tert. butoxlde, and the like. In this way the desired compound of formula I is directly obtained as the reaction product.
Compounds of formula I, wherein ^ and /or Rg denote lower alkyl, can also be obtained by lower alkylatlon of corresponding primary or secondary amines of the formula: exit) t wherein R, R^, and R^ have the meaning stated above. The alkylation is performed in accordance with the usual methods,, for instance, by reaction of the amine (III) with an ester, preferably a hydrohalic acid ester, of a lower alkanol, or by reaction of the amine (III) with a lower aldehyde in the presence of a reducing agent, such as formic acid or hydrogen with a catalyst, in accordance with the known methods of reductive alkylation.
The starting compounds of formula III are in turn obtained, for instance, in accordance with one of the methods mentioned above or by reduction of corresponding nitriles.
The compounds (I) produced by one of these processes can be obtained either as free bases or in the form of their addition salts with suitable acids, e.g. hydrohalic acids, sulphuric, nitric, phosphoric, acetic, oxalic, malonic, succinic, maleic, tartaric, or toluene sulphonic acid.
The compounds of formula Γ and their acid addition salts ' are used as active substances in medicines or as intermediates for the manufacture of such substances. They are above all of interest as psychopharmacological agents, and particularly as antidepressants, and also as antihistaminic agents. For instance, the compound 2-chloro-5-(-dlmethylaminoethyl)-ll-methyl-5»6-di-hydro-6-oxomorphanthridine hydrochloride obtained according to Example 1 shows the pharmacological actions characteristic concurrently of the antidepressants and the antihistamines, and in respect of the toxicity-therapeutic effect ratio either equals or surpasses typical antidepressants on the one hand and typical antihistamines on the other.
The following Table shows a corresponding comparison of activity, using imipramine and dibenzepin hydrochloride as reference substances having a typical antidepressant action, and mepyramine maleate as a reference substance having a mainly anti-histaminic action. The antidepressant action is stated in terms of the amount of active substance (in mg/kg i.p. ) which reduces the duration of the catalepsy produced in rats by tetrabenazine (10 mg/kg i.p.), administered 60 minutee later, to less than seconds in 0 of the test animals (ED--Q). Histamine antagonism is expressed, on the one hand, by the concentration of active substance in g/ml which produces a 100 suppression of spasm, in the histamine-treated, isolated guinea-pig ileum and on the other hand, by the amount of active substance y ich, following oral administration, affords guinea-pigs a 5 $ protection against the asphyctic cramps induced by histamine aerosol (50$ protective dose, or Η0ρ.η) ..
T ab l e Toxicity Anti-tetrabenazine (mice) action (rats) Active substance LD50 ^50 (mg/kg orally) (mg/kg i.p.) 2-Chloro-5-( β-dimethylaminoethyl)-11-fliethyl-5»6-dihydro-6-oxo-morphanthridine hydrochloride 420 22 Imipramine 385 12.5 Dibenzepin hydrochloride 225 Mepyramine maleate 338 about 50 The new compounds of this invention can be administered in dosage unit form to patients suffering from states of mental depression, these pharmaceutical preparations containing, besides the active substance, organic or inorganic solid or liquid carriers suitable for enteral or parenteral administration. The pharmaceutical preparations may be, for instance, in the form of tablets, dragees, or solutions for injection, one dosage unit containing from 40 to 120 mg of active substance, depending on its nature, on the route of administration and on the physician's prescription, the effective daily dose amounting from 150 to 750 mg of active substance.
Example 1 A mixture of 6.44 gm of 2-chloro-ll-methyl-5, 6-dihydro-6-oxomorphanthridine, 1.07 gm of pulverized sodium amide and 50 ml of absolute dioxane is heated for 1 hour at reflux. Then a solution of 2.6 gm of β-dimethylaminoethylchloride in 10 ml of absolute dioxane is added, and the whole is heated for another 4 hour3 under reflux. The solvent is removed from the reaction mixture by evaporation in vacuo and the residue, is distributed between water and ether. The ethereal phase is extracted with dilute aqueous sulphuric acid. The acid extract is made alkaline by addition of diluted soda lye. A basic substance separates out, which is extracted. with ether. By evaporating the ethereal solution in vacuo. 8.1 gm of 2-chloro-5-( -dimethylaminoethyl)-ll-methyl-5»6-dihydro-6-oxomorphanthridine are obtained as an oil of boiling point 175-178°C/0.05 mm Hg. By treatment with alcoholic hydrochloric acid, 2-chloro-5-(-dimethylaminoethyl)-ll-methyl~5»6-dihydro-6-oxomorphanthridine hydrochloride is formed, which is obtained from me hanol/ether in the form of colorless crystals of melting point 246-252°C.
. Example 2 . 6.5 gm of 2-chloro-ll-methyl-5»6-dihydro-6-oxomorphan-thridine iri 60 ml of absolute dioxane are heated at reflux for 1 hour* with pulverized sodium amide, the latter being used in an excess of 7 over the theoretical amount, calculated on metallization. In order to expel as far as possible ammonia which has been formed during the reaction, about 10 ml of dioxane are distilled off, and the still hot reaction mixture is poured into a small shaking autoclave by rinsing with a small amount of dioxane. Upon cooling , o room temperature, 1.5 molar equivalents of ethylene . oxide are added, and the mixture is shaken at 80°C during 5 hours.
After cooling, the reaction mixture is concentrated to dryness in vacuo. The residue is boiled with 35 ml of chloroform and 20 ml of thionyl chloride during 15 hours. After evaporation to dryness in vacuo, the residue is treated with ice-water, and the resinous substance which separates out is extracted with chloroform. The combined chloroform extracts are twice washed with water, dried with sodium sulphate, and evaporated to dryness.
The resinous residue consisting of 2-chloro-5-( β-chloro-ethyl)-ll-methyl-5»6-dihydro-6-oxomorphanthridine is poured into a sealed tube by means of a small amount of dioxane. 16 gm of dimethylamine (in the form of a 33 alcoholic solution) are added, and the mixture is heated at 80°C for 4 hours. The reaction mixture is evaporated to dryness in vacuo,. The residue dissolves almost completely in warm diluted acetic acid. The solution is filtered and cleared by means of charcoal, and then the base is precipitated by addition of ammonia and extracted with ether. The combined ethereal extracts are -washed with three portions of water, dried with sodium sulphate, concentrated to a smaller volume, filtered through alumina, and evaporated to dryness. The residue is dissolved in a mixture of ethyl acetate and ethanol. The solution is slightly acidified with ethanolic hydrochloric acid and then concentrated. Upon addition of ether, 2-chloro-5-( β-dimethylaminoethyl)-ll-methyl-5 , 6-dihydro-6-oxo-morphanthridine hydrochloride is obtained in a yield of 63 of the theory. After, recrystallization from methanol/ether the product shows a melting point of 246-252°C. It is identical to the compound obtained in accordance with Example.1..
• .E mple 3 9,96 gm (0,03. mol) of 2-acetylamino-5-chloro-2 methoxycarbonyl-l,l-diphenylethane in 50 ml of absolute dioxane are mixed with 1.29 gm (0.033 mol) of pulverized sodium amide, and the mixture is heated under reflux for 1 hour. After addition of 3.S8 gm (0.036 mol) of β-dimethylaminoethylchloride, boiling is. continued for further 16 hours. The reaction mixture is evaporated to dryness in vacuoB and. the residue is distributed, between ether and water. A strongly basic product is isolated in the usual manner by extraction with diluted acetic acid. After distillation and crystallization from acetone/petroleum ether, 6.67 gm of 2-chloro-5-( -dimethylaminoethyl)-ll-methyl-5, -dihydro-6-oxomorphanthridine are obtained, corresponding to a yield of 67.7$ of the theory. The hydrochloride obtained in the usual manner shows a melting point of 246-252°C (from methanol/ ether) and is identical to the product obtained in accordance with ' Example 1.' · Example 4 A mixture of 6.7 gm of 2-chloro-5-(P-aminoethyl)-ll-methyl-5,6-dihydro-6-oxomorphanthridine, 10 ml of 90?o formic acid and 8 ml of 38?° formaldehyde is boiled with gentle reflux during 15 hours. After addition of 15 ml of 2n-hydrochloric acid, the reaction mixture is . concentrated to dryness in vacuo. The residue is recrystallized from methanol/ether, the solution being cleared with charcoal. 6.4 gm (87.5^ of the theoretical . yield) of 2-chloro-5-( β-dimethylaminoethyl)-ll-methyl- , 6-dihydro-6-oxomorphanthridine hydrochloride of melting point 246-252°C are obtained, the substance being identical to the product obtained in accordance with Example 1.
By the same processes as described in the above Examples, but using different starting materials, in accordance with the product intended to be obtained, the following further substances in accordance with formula I can, for instance, be prepared: 2-chloro-5-(γ-dimethylaminopropyl)-ll-methy1-5» 6-dihydro-6-oxomorphanthridine hydrochloride of melting point 206-209°C ( from methanol/ether) ; 3-chloro-5~( β-dime hylaminoethyl)-ll-methyl- , 6-dihydro-6-oxomorphanthridine of melting point 75-79°C (from petroleum ether); and 3-chloro-5~(β-dimethylaminoethyl)-ll-m thyl-5, 6-dihydro-6-oxo orphanthridine hydrochloride of melting point 260-264°C Production of tablets For the manufacture of tablets, the products of this invention can for instance be mixed with lactose and granulated with water, paraffin oil, 0.5 sodium alginate or 10 gelatine solution. The dried granulate is compressed into tablets in the presence of the usual auxiliarjr agents for tabletting, such as talcum, corn starch, or magnesium stearate. In this way, there are obtained, e.g. tablets of the following composition: 2-Chloro-5-( p-dimethylaminoethyl)-ll-methyl- , 6-dihydro-6-oxomorphanthridine hydrochloride 50 mg Lactose 180 mg Paraffin oil 5 mg Gelatine 2.5 mg .. Corn starch 8 mg Talcum 4.5 mg These 250 mg tablets can be administered orally in a dosage of 3 to 15 tablets per day in the treatment of patients suffering from states of mental depression.
Production of solutions for injection For the preparation of solutions for parenteral application by injection, the products of this invention can be dissolved in appropriate solvents, for instance in an isotonic aqueous solution of glucose. The solution containing the active ingredient is filtered, drawn into ampoules, and the ampoules are sealed and subjected to sterilization. In this v/ay, there are obtained, e.g., ampoules containing: 2-Chloro-5-( β-dimethylaminoethylV-ll-methyl- - - - The solution contained in these ampoules can fo instance be administered intravenously to patients suffering from states of mental depression, and the injections can be repeated once or tvrice per day, if necessary.
Claims (2)
1. A compound selected from the class consisting of (A): 5-basic substituted 5 » 6-dihydro-6-oxomorphanthridines of the formula: ··■ ■ · .· ■ wherein R denotes straight or branched alkylene having from 2 to 4 carbon atoms, ^ and R£ are the same or different members of the class consisting of hydrogen and lower alkyl, one of both -j denotes hydrogen, the other ^ denoting a member of the group consisting of halogen and lower alkyl, and ^ denotes lower alkyl; and (B): acid-addition salts of (A).
2.. 2-Chloro-5-(p-dimethylaminoethyl)-ll-methy1-5,6- dihydro-6-oxomorphanthridine and its pharmaceutically acceptable acid-addition salts. A. process for the preparation of 5-basic sub stituted 5»6-dihydro-6-oxomorphanthridines of the formula: wherein R denotes straight or branched, alkylene having from 2 to 4 carbon atoms,' R^ and R2 are the same or different and denote hydrogen or lower alkyl, one of both R^ denotes hydrogen, the other R^ denoting halogen or lower alkyl, and R^ denotes lower alkyl; as well as acid-addition salts thereof, comprising either reacting amines of the formula X-H, if desired after prior, or during simultaneous, action by a condensing agent, with reactive esters of alcohols of the formula Y-R-OH, wherein X and Y are mutually interchangeable,. X meaning a 11-R -5»6 dihydro-6-oxo-5-morphanthridinyl residue having halogen or lower alkyl as a substituent in one of both benzene nuclei, Y denoting the basic group of the formula -N<^R1, and R, R1 2 R2 and R^ having the meaning stated above; or b) Inducing cyolization of N-aminoalkylated o-amino-o'-carboxy- (or alkoxycarbonyl)-l,l-diphenylalkanes of the formula: wherein R, R^, R^, and R^ have the meaning mentioned above R^. denotes hydrogen or acyl, and Rg means hydrogen or lower alkyl; or in the case of products wherein R^ and/or R2 denote lower alkyl, lower alkylating primary or secondary amines of the formula: wherein R, R^, R^, and R^ have the meaning mentioned above; the reaction product being isolated in the form of the free base or in the form of an acid-addition salt.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH32765A CH464930A (en) | 1965-01-11 | 1965-01-11 | Process for the preparation of 5-basic substituted 5,6-dihydro-6-oxomorphanthridines |
Publications (1)
Publication Number | Publication Date |
---|---|
IL24925A true IL24925A (en) | 1969-04-30 |
Family
ID=4184485
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL2492566A IL24925A (en) | 1965-01-11 | 1966-01-05 | 5-basic substituted 5,6-dihydro-6-oxomorphanthridines |
Country Status (9)
Country | Link |
---|---|
AT (3) | AT260259B (en) |
BE (1) | BE674950A (en) |
BR (1) | BR6676352D0 (en) |
CH (1) | CH464930A (en) |
DE (1) | DE1620722A1 (en) |
ES (1) | ES321631A1 (en) |
FR (1) | FR5915M (en) |
GB (1) | GB1078266A (en) |
IL (1) | IL24925A (en) |
-
1965
- 1965-01-11 CH CH32765A patent/CH464930A/en unknown
-
1966
- 1966-01-03 AT AT2466A patent/AT260259B/en active
- 1966-01-03 AT AT221667A patent/AT260270B/en active
- 1966-01-03 AT AT221567A patent/AT260269B/en active
- 1966-01-05 GB GB5226466A patent/GB1078266A/en not_active Expired
- 1966-01-05 DE DE19661620722 patent/DE1620722A1/en active Pending
- 1966-01-05 IL IL2492566A patent/IL24925A/en unknown
- 1966-01-11 ES ES0321631A patent/ES321631A1/en not_active Expired
- 1966-01-11 FR FR45424A patent/FR5915M/fr not_active Expired
- 1966-01-11 BR BR17635266A patent/BR6676352D0/en unknown
- 1966-01-11 BE BE674950D patent/BE674950A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
AT260269B (en) | 1968-02-26 |
AT260259B (en) | 1968-02-26 |
GB1078266A (en) | 1967-08-09 |
ES321631A1 (en) | 1966-09-01 |
AT260270B (en) | 1968-02-26 |
BE674950A (en) | 1966-07-11 |
CH464930A (en) | 1968-11-15 |
DE1620722A1 (en) | 1970-08-27 |
FR5915M (en) | 1968-04-01 |
BR6676352D0 (en) | 1973-09-06 |
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