IL30966A - Phenylpropiophenones and method of using them - Google Patents

Description

PHENYLPROPIOPHENONES AND METHOD OF USB/WS Ttf£/1 30966 2 This invention relates to new pharmaceutical compositions ." More particularly, this invention relates to pharma ceutical compositions which are useful as anti-depressants.

In accordance with the present invention there in provided a pharmaceutical composition for the therapeutic treatment of depression comprising a compound of the formula: C-CH-CHjr- as oils or low melting solids, or converted into their solid non-toxic salts. The following equation illustrates the process described above. · / The active components of the present in vention are physiologically active in warm-blooded animals as antidepressants or stimulants. The dosage of the compounds of this invention will depend on the route of administration, age, weight, and condition of the warm-blooded animal. Λ total daily dose of from 1 mg. to about 200 mg. per kilogram of body weight given singly or in divided dosage several times daily embraces the effective range of treatment of most conditions for which the compounds are useful. A dosage unit of 10 mg. to 150 mg. is usually sufficient . or daily treatment . Parenteral administration generally requires smaller doses than oral administration.

One of the criteria for assessing antidepressant activity is the inhibition of depression of exploratory behavior (in mice) induced by 2-oxo-3-isobutyl-9, 10-dimethoxy-l, 2, 3, , 6, -hexahydro[ll,bH]benzo[a] - quinolizine ( tetrabenazine) . Untreated mice, when placed in the center of a horizontal disc, will walk rapidly to the edge of the disc and peer over the edge. A reference depressant agent, such as tetrabenazine, wi completely suppress this exploratory behavior. However exploratory behavior is restored to mice which have been treated with one of the active components of this invention prior to treatment with 2-oxo-3-isobutyl-9,10-dimethoxy-l,2J3, ,6,7-hexahydro[ll,bH]benzo[a]= quinolizine (tetrabenazine). A clinically used reference antidepressant agent, such as imipramine, 5-( 2-dimethylaminopropyl ) -10, ll-dihydro-5H-dibenz [b, f] -azepine hydrochloride, also restores the exploratory be havior of tetrabenazine-treated mice. Tests of this type are described in the following literature: Vernier, V. G . , Hanson, H. M. and Stone, C. A., The First Hahnemann Symposium, Ed. Nodine, J. H. and Moyer J. M., Lea and Febigli, Philadelphia, Pa., 1962, pp. 683-690. Also, Greenblatt, E. N., and Osterberg, A. C, Toxicology and Applied Pharmacology, 1, 566-578 (1965). Table I shows the lowest dose at which the active components of this invention show this antidepressant activity.

TABLE I Activity of compounds in preventing tetrabenazine-induced depression in mice ' I succinate salt Another test which has been used to demonstrate anti-depressant activity is the ability to reverse the hypothermia in mice caused by reserpine. (a) Reports by Garattinl, S., et al.: J. Pharmacol., 14, 509 (1962); (b) Jori A. and Garattini, S. ibid. 17, 480 (1965); (c) Jori A;, e ai.: ibid.., 18, 326 (1966)] discuss the observation that agents which are anti-depressant also reverse the hypothermia caused by reserplne . Two groups of 10 mice are treated with reserplne (solublized with propylene glycol and citric acid) at a dose of 5 mg./kg. intraperitoneally . Eighteen hours later, at which time the mean rectal temperature has been reduced 10 to 15 °F., one group is treated with one of the components of the present invention at a dose of 10 mg./kg. intraperitoneally and the other group is treated with starch at a dose of 0.2 ml./20 g. body weight. Rectal temperatures are recorded by the use of a Tri-R-Electro-nic Thermometer using a 16 gauge probe inserted 3 cm. into the rectum. Two hours after treatment with the active components of the present invention, the hypothermic effects are significantly reversed as shown in the following Table II .

TABLE II Reversal of Hypothermic Effects of Reserpine in mice From the above table it is seen that the active components of the present invention are qualitatively similar to the reference compound, We have also found that one of the compounds of the present invention; namely, 3-methylamino-2- phenylpropiophenone hydrochloride, is surprisingly unique in that, in addition to the expected central nervous system stimulant and antidepressant activity, it shows depressant activity, one, by protecting animals against convulsive seizures caused by strychnine and two, by reducing their ability to traverse a horizontal rod in a normal manner. This combination of depressant . and stimulant-antidepressant activity indicates a wide range of therapeutic utility in mental disorders of various types, for example, in the management of depressive states, in the treatment of convulsive disorders such as epilepsy, and in the alleviation of anxieties. It has been reported [Gluckman, M. I., Pharmacology of oxazepan (Serax), a new antianxiety agent, Curr. Therap . Res., 1 , 721 ( 1965 ) ] that there is a high degree of correlation between anticonvulsant effects in animals and antianxiety effects in man. One measure ol* depressant activity is the ability to prevent con-vulsive seizures in warm-blooded animals, e.g, mice, caused by strychnine sulfate . Graded dose levels of the compounds are administered intraperitoneally in a 2% aqueous starch medium to groups of 10 mice at each dose. Strychnine sulfate, dissolved in aqueous saline is admin-istered subcutaneously at doses estimated to cause tonic extensor seizures in 95$ of the mice ( 0.82 milligrams per kilogram of body weight). Strychnine is administered J>0 minutes after drug treatment. The median effective dose is calculated by the method of Lltch-field, J. T. & Wilcoxon, F . , "A Simplified Method of Evaluation, Dose-Effect Experiments", Journal of Pharmacology & Experimental Therapeutics , Volume 96, page 99-113 ( 19^9) .

The dose of 3-methylamino-2-phenylpropiophenone hydrochloride which protects 50 per cent of the mice from \_ convulsive seizures caused by strychnine sulfate is 6 milligrams per kilogram intraperitoneally .

Another measure of depressant activity is the ability to protect against seizures produced by electroshock .

Compounds are administered to groups of 10 mice at a dose of 50 mg./kg. Thirty minutes later mice are subjected to maximal electroshock (60 cycle, 50 mA, 0.2 seconds) via corneal electrodes. If less than 5 mice show protection against tonic extensor seizures, the compound is considered inactive. If 5 or more mice are protected, at least 2 more graded doses are administered to groups of 10 mice each and a median effective dose estimated. The Compound ^-amino-2-phenylproplophenone hydrochloride shows a median effective dose for protection against electroshock seizures of 16.5 mg./kg. The Compound 3-ethylamino-2-phenyl-propiophenone hydrochloride shows a median effective dose for protection against electroshock seizures of 12.5 mg./kg.

A third measure of depressant activity is the loss of ability of warm-blooded animals, such as mice, to traverse a horizontal rod. Groups of 10 mice are treated at a dose of 100 mg./kg. and are tested at 15 and j50 minutes after treatment. If 5 or more mice lose the ability to traverse the rod, groups of 6 mice are- then treated with at least two more graded doses, and a median effective dose is estimated. The median effective dose for 3-methylamino-2-phenylpropiophenone hydrochloride is 25 mg./kg.

DETAILED DESCRIPTION The examples Which follow describe the preparation of the active components of the present invention and their use in formulations of representative pharmaceutical preparations .

EXAMPLE 1 Preparation of 3-Ethylamino-2-phenylpropiophenone hydro- chloride Ten grams of methylenedesoxybenzoin is added to 20 ml. of liquid ethylamine and the solution is stirred for 1 hour. Ether is added and the solution is evaporated to remove the excess ethylamine. This gives j5-ethylamino-2-phenylpropiophenone as an oil CHC13 ( 7* 5.9^ jtf) . This oil is dissolved in fresh max ether and extracted with 2 N hydrochloric acid. The aqueous acid, solution is cooled and basified with sodium hydroxide, and extracted with ether. The dried ethereal extract is treated with hydrogen chloride to give 3-ethylamino-2-phenylpropiophenone hydrochloride, as a white solid . Recrystallization from acetone-ether yields the product, melting point 116.5-119°C . , dec.

EXAMPLE 2 Preparation of 3-Propylamino-2-phenylpropiophenone hydro- . . chloride Following the procedure of Example 1 and using h-propylamine in place of ethylamine, the product 3-propylamino.-2-phenylpropiophenone is obtained as a colorless oil, which is converted, as in Example 1, to a white crystalline hydrochloride, melting point 154.5-157°C, dec. using. cyclopropylamine in place of ethylamine, the product 3-cyclopropylamino-2-phenylpropiophenone is obtained. The product is converted to the hydrochloride which when recrystallized from chloroform-ethyl acetate is a white solid , melting point 1 7-150UC, dec.

EXAMPLE k Preparation of -Chloro-3-methylamino-2-phenylpropiophe- none hydrochloride This compound is ¾b¾¾j5¾¾ by adding 11.6 grams of' 2-phenyl-4 ' -chlbroacrylophenone to 15 ml. of liquid methylamine using the procedure described in Example 1. The product, k 1 -chloro-3-methylamino-2-phenylpropiophehone, is converted to the hydrochloride, a white solid, melting point 166-168°C, dec.

EXAMPLE 5 Preparation of 3-Methylamino¾- p-methoxyphenyl)propio- pnenone hydrochloride' When 17 grams of 2-(p_-methoxyphenyl)acrylo-phenone is' added to JO ml.' of liquid methylamine following the procedure described in Example 1, the product, 2-methylamino-2-(p_-methoxyphenyl)propiophenone is converted to the hydrochloride, a white solid, melting point 148-151°C, dec. (from a mixture of methanol and ether) .

EXAMPLE 6 Preparation of 2-(p-Chlorophenyl)acrylophenone A mixture of 6 grams of p_-chlorobenzyl phenyl ketone, 480 ml. of methanol, 50 ml. of >1 formaldehyde and 1 ml . of piperidine is stirred and refluxed for 18 hours . The solution is filtered and the filtrate is diluted with 200 ml. of water. The mixture is extracted with methylene chloride and the extracts are washed with dilute sulfuric acid, sodium bicarbonate and water. The methylene chloride extract is then dried and evaporated to give the product, 2-(p_-chlorophenyl)acrylophenone as a colorless oil (strong carbonyl absorption at 5.99 fi) · EXAMPLE 7 Preparation of 3- ethylamlno-2-(p-chlorophenyl)proplo- pheno e hydrochloride" When 0 grams of 2-(p-chlorophenyl)acrylo-phenone is added to 60 ml. of liquid methylamine following the procedure described in Example 1, the product 3-methylamino-2-(p_-chlorophenyl)propiophenone is converted to the hydrochloride, a white solid. After re-crystallization from a mixture of chloroform and ethyl acetate, the product melts at 153.5-158.5 °C . , dec.

EXAMPLE 8 Preparation of 3-Methylamino-2-phenylpropiophenone ' succinate A solution of 1 gram of 3-methylamino-2-phenylpropiophenone in ethyl alcohol is added, to an alcoholic solution of succinic acid. The resultant solution is allowed to stand for several hours. The 3-methylamino-2-phenylpropiophenone succinate slowly separates as a white crystalline solid.

EXAMPLE 9 Preparation of 3-Ethylamino-2"-phenylpropiophenone fumarate An alcoholic solution of 3-ethylamino-2-phenylpropiophenone is added to an alcoholic solution of fumaric acid. The resultant solution is cooled, and 3-ethylamino-2-phenylpropiophenone fumarate separates as a white crystalline solid.

EXAMPLE 10 Preparation of 3-Propylamino-2-phenylpropiophenone maleate An alcoholic solution of 3-propylamino-2-phenylpropiophenone is treated with an alcoholic solution of maleic acid. The resultant solution is cooled, and the 3-propylamino-2-phenylpropiophenone maleate separates as a white crystalline solid.

EXAMPLE 11 Preparation o 2-(p-Tolyl)-acrylophenone 2-(p_-Tolyl )-acetophenone (20.Y g.) is dis--solved in methanol (80 ml.). After addition of formaldehyde ( >7fo , 24 ml.), piperidine, (1 ml.), and acetic acid (1 ml.), the solution is rel'luxed for 4 hours. The cooled solution is diluted with water (100 cc) and extracted with methylene chloride. The organic layer is rinsed with sulphuric acid (2 N, "50 cc) and water (100 ml.), dried (magnesium sulfate) and . concentrated under reduced pressure to give 2-(p_-tolyl)-acrylophenone as a tan oil ( ^ C=0 6.05 ) .

EXAMPLE 12 Preparation of 3-Methylamino-2-(p-tolyl)-propiophenone' succinate 2-(p_-Tolyl)-acrylophenone (19 g.) is added to methylamine (50 ml.). After stirring for 1 hour, the excess amine is evaporated under reduced pressure at room temperature. The residual oil is dissolved in ether and the basic portion precipitated with hydrogen chloride gas. After decanting the ether, the hydrochloride is dissolved in water, layered with ether, and converted to the free base by addition of dilute aqueous sodium hydroxide . The aqueous layer is extracted once more with ether, and the combined dried (magnesium sulfate) ethereal solutions evaporated under reduced pressure at room temperature. The residual 3-methylamino-2-(p_-tolyl)propiophenone is con-verted to the succinate and the latter crystallized from methanol (melting point 136-137UC).

EXAMPLE 13 Preparation of 2- (p-Tolyl J - ' -methylacrylophenone £-Methylbenzyl-£-tolylketone (44.8 g.) is dissolved in methanol (160 cc). . Formaldehyde ( 7 , 50 ml.), acetic acid (1 ml.), and piperidine (1 ml.) are added and the solution refluxed for 4 1/2 hours .

After cooling, water (200 ml.) is added and the solution is extracted with methylene chloride (150 ml.) three times. The organic layer is rinsed with sulphuric acid (2 N, 50 ml.), dilute sodium bicarbonate (50 ml.), and water. The dried (magnesium sulfate) solution is evaporated to give 2-(p_-tolyl) -41 -methylacrylophenone as an oil which solidifies upon standing ( }s.C=0 = 6.05. melting point 46-49.5uC).

EXAMPLE 14 Preparation of 3-Methylamino-2-(p-tolyl)-4 ' -methylpropio- phenone succinate 2-(p_-Tolyl)-4 ' -methylacrylophenone (20 g.) is added to liquid methylamine (60 ml.). The solution is stirred for 2 hours, and the excess amine is then evap-orated at room temperature . The residual material is dissolved in ether and the basic portion precipitated with hydrogen chloride gas. After decanting the ether, the hydrochloride is dissolved in water, layered with ether and converted to the free base by addition of dilute aqueous sodium hydroxide. The aqueous layer is extracted once more with ether, and the combined dried (magnesium sulfate) ethereal solutions evaporated under reduced pressure at room temperature. The residual 3-methylamino-2-(p_-tolyl)-4 ' -methylpropiophenone is dissolved in ethanol and converted to the succinate salt by addition of an ethanolic solution of succinic acid. Crystallization from ethanol gives 3-raethylamino- 2-(p_-tolyl)- '-methylpropiophenone succinate as a white crystalline solid, melting point 130-132°C.

EXAMPLE 15 The present compounds can be dispensed in dosage unit forms such as hard shell capsules or soft shell capsules. A formulation found useful in the preparation of such capsules is as follows: 3-Methylamino-2-phenylpropiophenone hydrochloride 2.0 grams Lactose, U.S. P. 300 grams Magnesium stearate (0.5 ) 3 «125 grams .125 grams The formulation is thoroughly mixed and placed as equal quantities in 100 capsules.

EXAMPLE 16 The following example represents a formulation useful in preparing tablets. These tablets can be prepared with sufficient active ingredients for a one third day's use of about 50 mg. Larger tablets can be scored and divided into halves or quantities to be given one to four times a day. Obviously also smaller tablets can be used in multiple doses to obtain the daily amount of active material . The following formulation has been useful . 3-Dimethylamino-2.-phenylpropiophenone hydrochloride 50. mg.

Corn Starch 210 mg.

Methyl cellulose 400 350 mg.

Magnesium stearate 1% 182 mg.

Total 792 mg.

The above tablet contains 50 mg. of drug which is usually given three to six times a day to obtain about the minimum amount of drug per day for a warm-blooded animal of 60 kg.

EXAMPLE 17 The compounds of the present invention can also be given in the form of tablets containing other formulations as follows: per tablet 3-Amino-2-phenylpropiophenone hydrochloride 0.05 grams Corn Starch 0. grams Ethyl Cellulose N 10 0.005 grams Magnesium stearate 1% 0.0016grams Total . .3566 The above formulation can be varied by increasing or decreasing the corn starch and by the addition of other ingredients. Also, other disintegrating agents, such as potato starch, may be used in place of corn starch. Other lubricants such as stearic acid, talc and the like can be used. Sweetening agents such as saccharin or sodium cyclohexyl sulfamate and flavoring such as peppermint oil, oil of wintergreen, orange or cherry can be used.

EXAMPLE 18 The compounds of the present invention can be given intramuscularly or subcutaneously in the following formulation: 3-Ethylamino-2-phenylpropiophenone hydrochloride 2,500 mg.

Sodium carboxymethylcellulose 10 mg.

Sodium chloride 9 mg- Tween 80 1 mg.

Benzyl alcohol 9 mg.

Sterile Water to make 50 ml.

This preparation will contain 50 mg./ml. of the active compound .

EXAMPLE 19 The compounds of the present invention can be given parenterally in the form of parenteral suspensions such as the following: 3-lsopropylamlno-2-phenylpropiophenone hydrochloride 2 .0-5 - 0 gms .

Polysorbitan 80 0 .1-0 .2 gms.

Polyethylene glycol 4000 2 .0-5 .0 gms.

Sodium chloride USP 0.5 -0.8 gms.

Benzyl alcohol 0.9 gms.

Pyrogen-free distilled water to make 100.0 ml.

Each milliliter would contain from 20 mg. to 50 mg. of drug. Obviously, other ingredients can be used in place of the above to prepare desired suspensions.

For example, as surfactants in place of polysorbitan 8θ ethylene oxide or polyoxypropylene base can be used, and other suspending agents such as carboxymethylcellulose, methylcellulose and gelatin can be used.

Other salts than sodium chloride can be used such as sodium phosphates. While benzyl alcohol is a desirable preservative, others can be used such as parabens, chlorobutanol, etc. Also, in place of polyethyl glycol 4000, other vehicles can be used such as polyethylene glycol 400.

Claims (4)

1. WHAT WE CLAIM IS: 301)00/2 s- i 1. A pharmaceutical composition for the therapeutic treatment of depression-comprising a compound, of the formula: wherein R and Ri are each selected from hydrogen (C^-Cg) alkyl and cyclo (C3-C6) alkyl, and X, and Y are each selected from hydrogen, (C1-C6) alkyl, (Ci-C6) alkoxy or halo, or a non-toxic salt thereof and a pharmaceutically acceptable non-toxic carrier or diluent therefor.

2. A composition according to Claim 1, comprising 5-¾¾^¾¾^i -2-phenylpropiophenone , or a non-toxic salt thereof.

3. · A composition according to Claim 2, comprising 3-methylamino.-2-phenylpropiophenone hydrochloride.

4. A pharmaceutical composition, substantially as hereinbefore described in any one of Examples 15 to 19· AGENTS FOR APPLICANTS