IE43159B1 - 11-aminoalkylmorphanthridin-11-ols - Google Patents

Description

The compounds of the present invention may be represented by the following formula: R t Z=C\ X X in which Z is 7 \ or z ' and R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or halophenyl such as p-chlorophenyl, R^, Rg and R^ are the same or different and selected from hydrogen or alkyl of 1 to 4 carbon atoms, X and Y are hydrogen, hydroxy, halogen such as chloro, bromo and fluoro, alkoxy of 1 to 4 carbon atoms such as methoxy and ethoxy, alkyl of 1 to 4 carbon atoms such as methyl and ethyl, thio-alkyl of 1 to 4 carbon atoms such as thiomethyl and thioethyl, R1 -S02-N% or trifluoromethyl, and Am is in which R^ and are selected from hydrogen, alkyl of 1 to 4 carbon atoms such as methyl, ethyl or isopropyl, a phenyl-alkyl of 7 to 13 carbon atoms such as benzyl, phenethyl or phenylisopropyl, a cycloalkyl of 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl and cyclohexyl and cycloalkyl-C1_4 alkyl groups in which the cycloalkyl group contains 3 to 7 carbon atoms such as cyclopentylethyl and cyclohexyl-methyl, or (b) a heterocyclic group selected from morpholino, pyrrolidino, piperidino, alkyl piperazino such as Nmethylpiperazino, E-phenyl-Ch _, alkyl piperazino groups such as N-benzyl piperazino and N—(hydroxy-C3_^ alkyl)-piperazino groups such as 4-(β-hydroxyethyl) piperazino.

In preferred compounds of the invention either both X and Y are hydrogen or X is hydrogen and Y is 2-chloro.

The compounds of the present invention may be conveniently prepared from the corresponding 5,6-dihydromorphanthrin-llones which may be represented by the following formula: 159 ln which X and Y are as previously defined. These compounds are known compounds and may be prepared from the corresponding 6-chloromorphanthridones hy hydrogenation.

Representative of the compounds that may be employed as starting materials are: ,6-dihydromorphanthrin-ll-one, 2-ch.loro-5,6-dihydromorphanthrin-ll-one, 2-fluoro-5,6-dihydromorphanthrin-11-one, 2- ehloro-6-methy1-5,6-dihydromorphanthrinll-one, 3- chloro~5,6-dihydromorphanthrin-ll-one, 2-trifluoromethyl-5,6-dihydromorphanthrinll-one, 6-phenyl-5,6-dlhydromorphanthrln-ll-one, 2-methoxy-5,6-dihydromorphanthrln-ll-one, 2-thlomethyl-5,6-dihydromorphanthrin-ll-one, 8-chloro-5,6-dihydromorphanthrin-11-one s _and 2-chloro-8-me thy1-5,6-dihydromorphanthrinll-one.

In the preferred practice of the invention the compounds ln which Am is a tertiary amine are prepared by reacting a selected 5,6-dihydromorphanthrin-ll-one with a disubstituted aminoalkyl metal halide under conditions generally used for reacting a Grignard reagent with a - 4 43159 xetone to form a tertiary alcohol. The reactants are advisably combined in an anhydrous solvent such as etnyl ethei·, tetranydrofuran .,r ethyl ether ih combination with benzene. After tiie reactants have beer; combined, the mixture can, if desired, be heated at reflux to promote the reaction. Once the reaction is terminated, water is added to the reaction mixture to hydrolyze the Grignard adduct to the desired tertiary alcohol. The resulting product can then be isolated from tne mixture by evapcra10 tion of the solvent. The desired product can be purified by reci-ystalllnation from a suitable solvent such as benzene.

The described process may be illustrated as follows: Am-OH-CH-CH MgCl t I t 31S9 in which all symbols are as previously defined.

Representative of the aminoalkyl halides which may be employed in the process are the following: dimethylaminopropyl chloride, diethylaminopropyl chloride, ethylpropylaminopropyl chloride, NjN-dimethylainino-2-methylpropyl chloride, dibenzylaminopropyl chloride, N-methyl-N-benzylaminopropy1 chloride, di-phenethylaminopropyl chloride, piperidinopropyl chloride, and pyrrolidlnopropyl chloride.

The Grignard reagents may be prepared by conventional methods such as those disclosed in United States Patent No. 2,996,503 and United States Patent No. 3,381,000.

Representative of the final compounds which may he prepared are: 11-(3-dimeth.y laminopropyl)-5,6-dlhydromorphanthrldin-ll-ol, 2-chloro-ll-(3-dimethylaminopropyl)-3,6-dihydi-o morphanthrldln-ll-ol, 11-(3-N-ethy.l -N-n-propylaminopropy l) -5,6-dlhydr ni orphan thr Idin-11- »1, 2- methoxy-ll-(3-N-benzyl-N-methylaminopropyl)5.6- dihydromorphan thr id in-1l-o1, and 3- methyl-ll-(3-dimethylamino-2-methylpropyl)5.6- dihydromorphanthridin-ll-ol.

The compounds in which Am is a primary or secondary amino group may be prepared by conventional chemical procedures and techniques which may be illustrated as follow - 6 4 31 in which X and Y are as previously defined and fere with or partake in the reactions. not inter7 U59 Representative of the secondary amines which may be used in the illustrated reaction are the following: 3-methylamino-l-propyne, and 3-formamido-1-propyne.

Representative of the compounds which may be prepared by the Illustrated methods are tlie following: ll-(3-methylaminopropyl)-bjb-dlhydromorphanthridin-ll-ol, 2-chloro-ll-(3-methylaminopropyl)-5,6-dihydromorphanthridin-11-ol, 2-chloro“8-mefchyl-ll-(3-methylaminopropyl)-5,6dihydromorphanthridin-ll-ol, ll-aminopropyl-5,6-dihydromorphanthridin-11-ol, 2-cbloro-ll-aminopropyl-5j6-dihydromorphanthridinll-ol, 2-fluoro-ll-aminopropyl-5,6-dihydromorphanthi'ldinll-ol, 8-methoxy-ll-aminopropyl-5,6-dihydromorphanthridinll-o1, and 11-(3-benzylaminopropyl)-5,6-dlhydromorphanthridinll-ol.

The compounds in which Z is R may be conveniently prepared by oxidation of the corresponding saturated compounds with active manganese dioxide in benzene under reflux conditions.

The process may be illustrated as follows: In which ail symbols are as previously -twi’int·* and Ιο not interfere -..'ith ,r partake in the reaction.

\ Representative of the compoumls wh'.ch can be prepared by the described process are the I’olio-.vln'·: 11-(3-dlmeth/lamtnopropyl)-iaorphanthrldin-ll-cl, 2-ehloro-ll-(3-dimethylaminopropyl)-morphanthridin-li-ol, n-( 3-N-ethyl-N-n-propylar:iihopropyl) -morphanthridin-ll-ol, 2-me thoxy-11-(3-N-bensyl-K-metnylaminopropyl) morphanthridin-ll-oi, and. a-met ny1-11-(3-d imethylam in o-2-me t hy1propy1) 15 morphanthriflin-ll-ol. 3159 R A The compounds in which Z is / \ and R is other than hydrogen also may be prepared by treating the corresponding unsaturated compound with a Grignard reagent under normal Grignard reaction conditions.

The process may he illustrated as follows: in which all symbols are as previously defined and do not interfere with or partake in the reaction.

Representative of the compounds which may be prepared, are the following: 11-(3~am inopropyl)-6-methy1-5>6-dihydromorphanthrldin-ll-ol, 11-(3-aminopropyl)-6-phen.yl-5,6-dlhydromorphanthrldln-ll-ol, ll-(3-methylaminopropyl)-6-mechyl-5,6-dih.ydromorphanthrldln-ll-ol, 2-chloro-ll-(3-inethylamlnopropyl)-6-mech.yI-5,6dihydromorphanthridin-ll-ol, 11-( 3-dimethylaminopropyl)-6-phenyl-5,6-dlhydromorphanthridin-ll-ol, 2-chloro-ll-(3-dimechylaminopropyl)-6-phenyl5,6-dihydromorphanthridin-ll-ol, 11-(3-dlmefchylaminopropyl)-6-mefchy1-5,6-dihydromorphanthridin-ll-ol, 2-chloro-ll-(3-dlmefchylaiT!incprop.yl)-6-mefchyl5.6- dihydromorphanthridin-ll-ol, 2-methoxy-ll-(3-dimethylaminopropyl)-6-mefchyl5.6- dlhydromorphanthrldln-ll-ol, >i-chloro-11-( 3-d imethylaiiilnoprupyl) -6-methyJ5.6- dihydroniorphanchridln-ll-ol, 11-(3-plperidinopropyl)-6-mefchy1-5,6-dlhydromorphanfchridin-11- ol, 2-chloro-ll-(3-piperidinoprop.yl)-6-methyl-5,6dihydro-morphanthridin-ll-ol, 11-(3-piperidlnopropyl)-6-phenyl-5,6-dihydroraorphanfchridin-ll-ol, 8-chloro-11-(3-piperidinoprepyl)-6-phenyl-5,6d ί hy 1 r otno rpnanfchrid in-11-ο1, 11-( l-pyri'ol id lno propy 1)-t—iin.-’-tiy 1-5,6-dlhydr”nr-rphan tln-ld in-1 l-o 1, 2-chloro-ll-(3-pyrrolidinopropyl)-6-mo'.‘nyl5.6- dihydromorphanthridin-ll-ol, and 11-(3-pyrrolidinoprop.yl)-6-phenyl-5j 6-dihydro::iorphanthridin-ll-ol. 159 The compounds of the invention form pharmaceutically acceptable acid addition salts with organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, maleic acid, succinic acid and glutamic acid. The compounds also form lower alkyl quaternary ammonium salts with reagents such as methyl chloride, ethyl bromide and diethyl sulfate.

The compounds of the present invention are unique in pharmacologic activity. They are highly potent and relatively non-toxic antidepressant agents which appear to possess no undesirable side effects such as anticholinergic activity. In the standard antidepressant test, the compounds 11-(3-dimethylaminopropyl)-5,6-dihydromorphanthridinll-ol and 2-chloro-ll-(3-dimethylaminopropyl)-5,6-dihydromorphanthridin-ll-ol in intraperitoneal doses of 5 to 30 mg/kg were found to antagonize reserpine-induced depression in mice. As antidepressants the compounds appear to be at least ten times more potent than that of imipramine, a well-known antidepressant. In addition, the compounds were found in standard animal tests to have an oral LD^q of approximately 200 mg/kg, which is substantially greater than that of imipramine. Surprisingly the compounds were found to possess no significant anticholinergic activity.

When intended for use as pharmaceutical compositions, the compounds are preferably utilized in the form of acid addition salts. However, the free base form of the compound may be used. The active ingredient is usually combined with conventional pharmaceutical additives such as diluents, flavoring agents and the like. Convenient dosage forms for the compounds are tablets, capsules or liquids for oral or parenteral administration.

In clinical practice, the daily dosage of the active ingredient may range from 5 mg- t° 50 mg. or more. The exact amoun' to be administered will, of course, vary with the patient s size and the severity cf his depression.

A typical tablet can have the following composition: 11-(3-dimethylaminopropyl)-5,6-dihydromorphanthridin-ll-ol 10 mg.

Lactose U.S.P. 136-5 mg.

Corn Starch U.S.P. 20.0 mg.

Corn Starch (as 10% starch paste) 3.4 mg.

Magnesium Stearate 1.3 mg.

Suitable size tablets can be prepared using a 5/16 inch diameter standard concave punch.

Capsules may be prepared by filling No. 3 hard gelatin capsules with the following ingredients, thoroughly mixed: 2-chloro-ll-(3-dimethylaminoprop.yl)- 5,6-dihydromorphanthridln-ll-ol 10 mg. Lactose U.S.P. 155 mg. Starch U.S.P. 16 mg. Talc U.S.P. 8 mg.

The compounds may also be employed to prepare the corresponding 11-aminoalkylidenemorphanthridines, which are useful as anti-Parkinson agents and for the treatment of hypertension.

The following examples illustrate the practice of the invention: 3159 Example 1 11-(3-Dlmethylaminopropyl)-5,6d ihydromor phan thrid in-13 -ο1 A solution of 5,6-dihydromorphanthridin-ll-one (20.9 g., 0.1 M) In 200 ml. of tetrahydrofuran is added dropwise to the Grignard reagent prepared from 48.6 g. (0.4 M) of dimethylaminopropyl chloride, 9.73 g. (0.4 M) of magnesium shavings, and 150 ml. of tetrahydrofuran. The mixture is refluxed for two hours, cooled in ice, and 75 ml. of saturated ammonium chloride solution is added dropwise. The solids are filtered and the solvent removed from the filtrate at reduced pressure. The solid residue is dissolved in 400 ml. of hot acetonitrile and cooled to give 11-(3-dimethylaminopropy1)5,6-dihydrom<>rphanthrldln-ll-olj m.p. 179-182°.

Anal. Calcd. for C.^H^NgO: C, 76.99; H, 8.16; N, 9.45.

Pound: C, 76.82; H, 8.17; N, 9-50.

Example 2 2-Chloro-ll-(3-dimethylaminopropyl)5,6-dihydromorphanthridin-ll-ol A solution of 97.5 g. (0.4 M) of 2-chloro-5,6-dihydromorphanthrld.in-11-one in 800 ml. of tetrahydrofuran is aided to the Grignard reagent prepared from 194 g. (1.6 M) cdimethylaminopropyl chloride, 38.9 g. (l.6 M) of magnesium shavings, and 400 ml. of tetrahydrofuran. After refluxing two hours, the mixture is cooled in ice and decomposed with 230 ml. or saturated ammonium chloride solution. The solids are filtered and the solvent removed from the filtrate. The residue is dissolved in 800 ml. of 431S9 boiling ethanol and 400 ml, of water and 2U g. of charconJ are added. Filtration and cooling give 2-chloro-ll-(3dimethylaminopropyl)-5,6-dihydromorphanthrldin-ll-ol, m.p. 135-137°. In analytical sample recrystallised from 9 volumes of 2:1 ethanol-water has a melting point of 137-138°.

Anal. Calcd. for Ch gfig^ClNgO: C, 00.97; H, 7.01: Cl, 10.72; N, 3.47.

Found: C, 68.92; H, 7.06; Cl, 10.fl; K, 8.41.

Kx.'ifnpii-· j ,C-ijlfi.ydro-J 1-( 3-μίpo-rl! iuopropyl)morphanthrldln-I1 -q 1 A solution of 62.7 g. (θ·3 M) of 5,6-dlhydroinorphanfchridin-ll-one in 400 ml. of tefcrahydrofuran is added dropwise to the Grignard reagent from 140 g. (0.1 M) of 1-(3chloropropyl)piperidine, 21.9 g. (O.o M) of magnesium shavings, and 400 ml. ot’ tetrahydrofuran. The mixture is refluxed for 18 hours, cooled in ice and decomposed with l80 ml. of saturated ammonium chloride solution. The solids are filtered and extracted with hot fetrahydi'ofuran. The combined organic solutions are concentrated to give tine product, m.p. 185-190°. Reerystallisation from p00 ml. of dioxane gives 5,6-dihydro-ll-(3-piperidinopiOpyl)morphanthridln-ll-ol, m.p. 196-200°.

Anal Calcd. for cp, .JL-,βΝρΟ: C, 70.53.: Η, :'.39; N, 8.33.

Fauna: C, Π,(Α; H, 8.10; ii, d. 16. )159 Example 4 ,6-Dihydro-ll-(3-pyrrolidinopropyl)morphanthridin-11-ol A solution of 20.9 g. (0.1 M) of 5,6-dihydromorphanbhridin-ll-one in 150 ml. of tetrahydrofuran is added to the Grignard reagent prepared from 44.3 g. (0,3«) of 1(3-chloropropyl)-pyrrolidine, 7.3 g. (0.3 M) of magnesium shavings, and 150 ml. of tetrahydrofuran. The mixture is refluxed 18 hours, cooled in ice and decomposed with 60 ml. of saturated ammonium chloride solution. The solvent is removed from the filtrate and the residue taken up in 550 ml. of hot acetonitrile. Cooling gives 5,6-dihydro-ll(3-p.yrrolidinopropyl)morphanthrldln-ll-ol, m.p, 176-17'/.

An analytical sample obtained by recrystalllzatlon from 50 volumes of methanol has a melting point of 177-179°.

Anal. Calcd. for c21H2gN20: c, 78.22; H, 8.13; N, 8.69.

Pound: C, 78.20; H, 8.17; N, 8.6l.

Example 5 ll-(3~Dimethylaminopropyl) morphanthridin-ll-ol A mixture of 9.0 g. (0.03 M) of ll-(3-dimethylaminopropyl)-5,6-dihydromOrphanthridin-ll-ol and 45 g. of active Mn02 is refluxed in benzene for 5 hours. The solids are filtered and rinsed well with benzene. The filtrates a 'e concentrated and the residue is chromatographed on s:iica. Elution with toluene-methanol (4:1) gives 11-(3-dimethylaminopropyl)morphanthrldin-ll-ol which, on two recrystallizations from hexane, has a melting point of 95-102°.

Anal. Calcd. for c> /·/', H, 7.53; N, 9.52.

Pound: C, 77.37; H, 7.59; N, 9.51. ύ’3158

Claims (10)

1. CLAIMS: A compound selected from compounds of the formula Am and pharmaceutically acceptable salts thereof in which Z is R H ,N/N=C\ or /h and R is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or halophenyl, R^, R 2 , and R 3 are hydrogen or alkyl of 1 to 4 carbon atoms, X and X are hydrogen, hydroxy, chloro, bromo, fluoro, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, thio-alkyl of 1 to 4 carbon atoms, - S0 2or trifluoromethyl, and Am is (a) -Ν· in which R^ and R^ are selected from hydrogen, alkyl of 1 to 4 carbon atoms, a phenyl-alkyl of 7 to 13 carbon atoms, a cycloaikyl of 3 to 7 carbon atoms and cycloalkylC^_ 4 alkyl groups in which the cycloaikyl group contains 3 to 7 carbon atoms, or (b) a heterocyclic group selected from morpholino, pyrrolidino, piperidino, Ν— alkyl piperazino, N-phenyl-C 3 _ 4 alkyl piperazino groups and N-(hydroxy-C 3 _ 4 alkyl)-piperazino groups. A compound of claim 1 in which Am is A compound of claim 1 in which Am is a heterocyclic group. 18 10
2. 2. 4. A compound of claim 1 in which X and Y are hydrogen.
3. 3. 5. A compound of claim 1 in which X is hydrogen and Y is 2-chloro.
4. 4. 6. 11-(3-Dimethylaminopropyl)-5,6-dihydromorphanthridin-ll-ol.
5. 5. 7. 2-Chloro-11-(3-dimethylaminopropyl)-5,6-dihydromorphanthridin 11-ol.
6. 6. 8. A pharmaceutical composition which is intended for use as an antidepressant which comprises a compound of claim 1 in combination with a pharmaceutical diluent.
7. 7. 9. A pharmaceutical composition possessing a selective antidepressant activity which is devoid of anticholinergic activity which comprises 2-chloro-ll-(3-dimethylaminopropyl)-5,6dihydromorphanthridin-ll-ol in combination with a pharmaceutical diluent.
8. 8. 10. A process substantially as hereinbefore described for making a compound according to claim 1.
9. 9. 11. A compound according to claim 1 made by a process according to claim 10.
10. 10. 12. A pharmaceutical composition comprising a compound according to any of claims 1 to 7 and 11 together with a pharmaceutical diluent.