IL23869A - 1-(2-dimethylaminoethyl)-1-phenylindene and 1-(2-(methylamino)-ethyl)-1-phenylindene - Google Patents

Description

l-(2-DIMETHYLAMIN0ETHYL)-l -PHENYL INDENE AND 1- 2-( ETHYLAMINO) ESHYlJ -1-PHENYLINDENE the compounds Λ /ί.

The present Invention relates to /tfWW/ Pl 1ΦίΗΉ4$> Ι l- (2-dlmethylamlnoethyl) -l- # subject to a depressed condition.

Important advances in the treatment, of mentally disturbed patients of the excited type through the use of central nervous system depressant compounds, commonly referred to as tranquilizers, have been made. At the opposite end of the spectrum of psychotic states are the depressed or repressed subjects for whom treatment with stimulant drugs or various types of shock treatment has been used. More recently certain drugs which are known as antidepressants have come into use for treatment of the latter conditions. These drugs are char- acterized by an ability to relieve the depression of such subjects, although they exert no stimulating effect on the alertness, mood, or activity of normal subjects in contrast to the well-known psychostimulants, such as amphetamine, caffeine, or the analeptic drugs. Psychostimulants characteristically in- crease the blood pressure and reduce the appetite, while the new class of antidepressant substances frequently have just the reverse effect.

The measurement of antidepressant effects in the laboratory Is accomplished by means of a group of tests refer- red to generally as reserplne antagonism tests. One of the effects of reserpine on which its pharmacologic use is based is its ability to induce a depressed state. In the mouse, concomitant pharmacologic or physiologic effects are exerted, including hypothermia, ptosis, and miosis. Antidepressant drugs, such as imipramine and amitriptyline have the capacity of In one/ such tests, a predetermined dose of test compound is administered orally to each mouse of several groups of test mice. One hour later reserpine, 2.0 mg./kg., is injected intravenously, and one hour following the reserpine dose ptosis is measured by placing each mouse on a platform ,; away from light and estimating the extent of closure of the palpebral fissure. Ptosis is significant if the opening is not greater than 50 of normal. The reserpine effect is significantly modified if the palpebral opening is greater than 50$ of normal. In a similar test the reduction of rectal temperature following reserpine is used as a parameter. Reserpine alone produces a significant reduction of rectal temperature in mice. Antidepressant drugs will prevent this effect.

Antidepressant drugs can be distinguished from psychostimulant drugs such as amphetamine by reversing the order of administration in the above test. That is, by administering reserpine first followed by the test drug, the extent of reversal of reserpine effect can be determined. Psychostimulants characteristically have the abilit to reverse the reserpine effects, while the antidepressants do not. That is, the antidepressants will prevent but not reverse the reserpine effects in mice.

The above tests are conducted according to accepted pharmacological technique, by administering various doses of drugs to groups of test animals and then constructing a dose response curve. Prom this, the value, or dose causing the effect in 50$ of the animals, is calculated. Amitriptyline and imlpramlne exhibit values for the prevention of reserpine ptosis in mice of 12.5 mg./kg. and 6.5 mg./kg., respec-tively. 1- (2-Dimethylaminoeth l) τ-l-phenylindene hydrochloride In mice of 3.8 mg./kg. and 1 (meth lamino)ethyl^-l-phenyl- indene hydrochloride exhibits an of 3.0 mg./kg. In the prevention of reserpine hypothermia, amitriptyline exhibits an EDcjo value of 1° mg./kg., while l-(2-dimethylaminoethyl) -1- phenyllndene hydrochloride exhibits ED^0 of 7.5 mg./kg. It is evident, therefore, that the administration of l-(2-dimethyl-aminoethyl) -1-phenyllndene hydrochloride elicits a truly outstanding antireserpine effect in animals characterizing the material as an antidepressant agent.

PREPARATION. 1- (2-Dimethylaminoethyl) -l-phenyllndene is prepared from 3-phenylindene by alkylation thereof with a 2-dimethyl-aminoethyl halide such as the bromide,, chloride or iodide or other alkylating agent capable of introducing the 2-dimethyl-aminoethyl group. An example of such other alkylating agent is a reactive ester of 2-dlmethylaminoethanpl such as the ester of £-toluenesulfonic acid. The alkylation of 3-phenyl-indene with a 2-dlmethylaminoe"thyl halide or other reactive ester of 2-dimethylaminoethanol is conducted on an alkali metal salt of 3-.phenylIndene . The intermediate alkali metal salt is prepared by reaction of 3-phenylindene with a strong base such as sodium amide, sodium hydride, lithium amide, butyl lithium, sodium triphenylmethyl, or others. The alkali metal salt of 3-phenylindene is preferably prepared in situ and allowed to react with the 2-dimethylaminoethyl halide without Isolation. For this reason, the alkali metal base em ployed for salt formation may be looked upon simply as a condensing agent for the reaction between 3-phenylindene and 2-dimethylaminoethyl halide.

There results from this reaction a mixture of iso I Under some reaction conditions, the mixture may contain di-alkylated products as well. This mixture of products can be separated by conventional methods, including distillation and fractional crystallization of acid addition salts thereof from appropriate solvents and solvent mixtures. The individual pure products can then be unequivocally identified by interpretation of .their nuclear magnetic resonance spectra. It has been found that the high degree of antireserpine activity re-ferred to above is unique to both l-(2-dlmethylamlnoethyl) -IT phenylindene, 1-^2-(methylamlno)ethyl7"-l-phenylindene and their salts as distinguished from l-(2-dlmethylaminoethyl) -3-phenylindene, the latter substance having been found to be., essentially inactive in the antagonism of reserplne ptosis in the mouse.

Compound I is one of the active agents used in the antidepressant process, of the present invention. Compound II is substantially inactive. Compound II may exist as an isomer or mixture of. isomers where the double bond is in either the 1,2-position or in the 2,3-position, as is indicated by the dotted line and double headed arrow in the above formula.

PROCEDURE. - ether and treated with 0.4 mole of freshly prepared butyl lithium solution while protected from atmospheric moisture by dry nitrogen gas. A temperature of 20-30°C. is maintained during the addition' of the butyl lithium solution, after which the solution is refluxed for ½ hour. The reaction mixture is then diluted with 200 ml. of ether and added to a- solution of 0.5 mol of β-dimethylaminoethyl chloride in 100 ml. of ether. A further reflux period of 2 hours is then commenced, after which the reaction mixture is allowed to cool and then extract-ed with 200 ml, of 6N-hydrochloric acid. The aqueous layer is separated, basifled, and extracted with ether. The ether extracts are dried, the solvent removed by distillation, and the residue distilled in vacuo, b.p. 154-163/0.2 mm, nD20, 1.5906 , yield, 56.7 g. This material, 1- (2-dimethylaminoethyl) -1 -phenylindene, qontamlnated with" a minor amount of l- (2-dl-methylaminoethyl) -3-phenylindene, is then dissolved in 850 ml. of ether and treated with anhydrous hydrogen chloride to precipitate the hydrochloride salts. The precipitate is collected by filtration and pure 1 - (2-dimethylaminoethyl) -/^-phenyl-indene hydrochloride is obtained by recrystallization thereof from n-propanol (5 ml./g.), m.p. 198-199°C.

Anal.: C, 76.23; H, 7.28.

The nuclear magnetic resonance spectrum measured on a deuterium oxide solution of the pure sample of 1- (2-dimethyl-aminoethyl) -1-phenylindene hydrochloride described in the preceding paragraph with sodium 3-(trimethylsilyl) -1-propanesul-fonate as reference using a Varian A-60 MR Spectrometer op-erating at 60 mc . revealed the following: A pair of doublets at 6.87 and 6.54 ppm, J = 5.7 cps, relative area 2 corresponding to the two vinyl protons; aromatic proton proton peaks at 2.2 to 2.»9 pprn, relative area 10. The foregoing observations are consistent with the identity of the product as having the structure designated by the name l-(2-di- methylaminoethyl) ÷1-phenylindene, The pure free base 1- (2Tdimethylaminoethyl) -1- phenyllndene may be obtained by treatment of the pure hydrochloride salt having the physical constants listed above with a solution of a strong alkali such as aqueous sodium hydroxide. The pure free base obtained in this fashion has the following properties: b.p. 147-148/0.7 mm.

Infrared absorption maxima (film of pure substance) : 698, 732 , 755, 775, 790, 1040, 1470, 1β15, 2550, and 2590 cm- .

The free base is soluble in the common organic solvents such as ethanol, ether,, and benzene.

Any desired pharmaceutically acceptable acid addition salt may be obtained by direct neutralization of the free base with the appropriate acid. Purification of the free base to the extent referred to above is not necessary for this purpose. If a crude form of the base is employed, care should be taken to characterize the salt formed therefrom, for instance, by nuclear magnetic resonance studies, as having the structure of Compound I.

Pharmaceutically acceptable acid addition salts are those in which the anion does not contribute significant toxicity to the salt in the dosages thereof employed in accordance with the present inventiqn. Examples of suitable salts are the acetate, propionate,1 butyrate, pamoate, tannate, mucate, citrate, malate, tosylate, mesylate, phosphate, nitrate, sul The hydrochloride salt described above is soluble in water at room temperature to the extent of 10$ by weight. It is also soluble in ethanol and in warm isopropanol from which it crystallizes on cooling. It is stable in aqueous solution.

The l-^2-(methylamino)ethyl7'-l-phenylindene may be prepared from compound I by demethylation with alkyl halofor-^ mate followed by hydrolysis and decarboxylation as shown in the following equation: C IV where X is chloro, bromo or iodo and is lower alkyl containing up to 6 carbon atoms. The demethylation step proceeds best at temperatures of from 80 to 150 C. Alternatively the l-^2,-(methylamino)ethylr-l-phenyl indene may be prepared by reacting the 1-phenyl indene salt with a N- (2-haloethyl) -N-methyl carbamic acid ester of the formula where X and are as above defined to produce Compound III directly as above shown. . The further steps of hydrolysis and decarboxylatio are as in the above equation and in the procedure following.

Compound IV: , EXAMPLE Ϊ- 2- (Methylamino) ethyl^-l-phenyljndene Hydrochloride . - l-(2-Dimethylaminoethyl) -1-phenylindene, 8.8 g. (0.033 mole) is dissolved in 15 ml. of anhydrous benzene and treated cautiously with a solution of 10.9 g. (P.l mole) of ethyl chloro-formate dissolved in 9 ml. of benzene. A vigorous reaction ensues. After the reaction subsides the mixture is heated at reflux for 6 hours, diluted with an approximately equal volume of benzene, and washed with two 15 ml. portions of dilute hydrochloric acid. The benzene layer is then dried over potassium carbonate, the drying agent removed, and the solvent evaporated in vacuo. The residual 1-^2*- (N-rcarbethoxy-N-methyl)aminoethyl7-l-phenylindene is then refluxed for 10 hours with a solution of 6 g. of potassium hydroxide in 25 ml. of 5$ aqueous ethanol. The reaction mixture is .cooled, diluted with benzene, and extracted with three 5 ml. portions of water. The mixture is dried over potassium carbonate, and the product recovered from the extract by evaporation as before. The residue is dissolved in ether and treated with hydrogen chloride, resulting in, precipitation of the desired product. This material is recrystallized first from an ethylacetate-acetonltrile mixture, and then from acetone, m.p. 176-178°C.

. Ana}. Calcd. for Cl8H19N'HCl : C, 7£.64; H, 7.05; CI, 12.41. Found: C, 75.87; H, 7.14; CI, 12.27.

Infrared absorption maxima are observed at the following wave lengths: 303O 2930; 276Ο; 2428; 1588; 1458; 790, 769, 754, 732 and 699 cm"1.

DOSAGE.

Toxicity studies were conducted in mice of the Swiss - ml./kg. of body weight of an aqueous solution containing varying doses of 1 - (2-dimethylaminoethyl) 1-phenyl -1-indene hydrochloride at a pH of 4.0-5.5 by intubation. The animals were observed for signs of side effects and the number of deaths oc-curring within 24 hours was recorded. Dose response curves were prepared. The dose eliciting detectable side effect in 50 of the animals (TD^Q) was found to be 14 mg./kg. and the dose resulting in death of 50$ of the animals (LD^0) was found to be 84 mg./kg. Side effects observed included hypoactivity, increased respiratory depth, and ataxia, The fact that the effective antidepressant dose (anti-reserpine) is 3.8 mg./kg. with signs of side effects occurring at only substantially higher doses, but yet at. a dose substantially below the lethal level, indicates a wide margin of safety.

The intraperitoneal L ^Q in the mouse is 52 , 5 mg./kg.

The oral LD^0 in the rat is 385 mg./kg. The intravenous LD^0 in the dog is estimated to be about 30 mg./kg.

The effective antidepressant dosage range for l- (2-dimethylaminoethyl) -1-phenylindene hydrochloride and 1 - 2-methylamino)ethyl7"-l-phenyllndene hydrochloride in the process of the present invention is from about 0.1 mg. to about 5 mg./kg. of body weight of the animal being treated. In this dosage range no side effects such as mydriasis, lack of salivation, or other side effects which are frequently manifested by the secondary pharmacologic properties of prior antidepressant drugs are observed. Dosage according to the present invention may be by either the oral or parenteral routes. In the ordinary case, the oral route is preferred as a matter of convenience, but occasionally when this method of dosage can-not be accomplished due to Idiosyncrasy, parenteral administra For human use, .a daily dose in the range of 10 to 300 mg. is recommended. Formulations of the following type are satisfactory for this purpose: Solution, for Injection. - A sterile aqueous sblu-tion having a concentration of 25 mg./ml. of 1- (2-dimethyl-aminoethyl) -1-phenylindene hydrochloride is prepared by dissolving 25 ,g. of the substance in 9 1. of water for injection, U.S. P., adjusting the pH 5.5 with dilute aqueous sodium hydroxide, and dilution to 10 1. This solution is then filtered sparkling clear and filled into 2 ml. glass ampoules and sealed. ' The ampoules are then sterilized by heating.

Capsules. - A dry blend of 5.0 g. of 1- (2-dimethyl-aminoethyl) -1-phenylindene hydrochloride, 19.8 g. of lactose, and 0.2 g. of magnesium stearate is prepared. This mixture is then employed to fill No.. 2 hard gelatin capsules, each with 250 mg. of the blend..

Claims (5)

23869/3

1. The compounds l-r(2-dlmethylaminoethyl)-l -phenylindeneJ arid l-r/2-(methylamino)-ethy -1-phenylindene of Formula I FORMULA I wherein R is methyl or hydrogen.

2. A process for the manufacture Of the compounds of claim 1; which comprises forming an alkali metal salt of a 3-phenylindene by reaction of 3-phenylindene with a strongly alkaline material such as sodium amide* sodium hydride, lithium amide, b yl lithium, sodium triphenylmethyl, and reacting therewith a compound of the group 2-dimethylaminoethyl lialide to obtain a compound of . !] ¾_*. or Formula I in which R is methyl 9 *^ B. N-(2-haldethyl) -N-methyl carbamic acid ester, said halogens being selected from the group of chloro, bromo andAodo , wherein an intermediate of Formula II in which R1 is a lower alkyl group of up to 6 carbon atoms is produced when using compound B as a reactant. C02R FORMULA II or alternatively forming said intermediate of Formula Π by reaction of said compound of Formula I wherein R is CHg with an alkyl haloformate of the formula XCO2R1 wherein X is selected from the group consisting of chloro, bromo and iodo at a temperature of 80-150°C. in the presence d f r dr l n d d rbox l- 23869/2

3. A purified form of the compound according to claim 1 which is produced by distillation or fractional crystallization.

4. A pharmaceutically acceptable acid salt of the compound according to claim 1.

5. The process of eliciting an antidepressant effect in an animal subject to a depressed condition which comprises administering to said animal a dose of from 0. 1 to 5 mg. /kg. of body weight of said animal of a compound selected from the group consisting of l-(2-dimethylaminoethyl)-l-phenylindene, l-j[5 -(methyl -amino)ethyf^l-phenylindene and the pharmaceutically acceptable acid addition salts thereof. DATED the 30th day of June, 1965 S. Horowitz & Co. Agents for Applicants