US3391158A - 5-(3-indolyl)-2, 3-dihydro-1h-1, 4-benzodiazepine - Google Patents

Description

United States Patent 3,321,158 5-(S-INDOLYL)-2,3-DIHYDRO-lH-1,4- BENZODIAZEPHNE Rodney Ian Fryer, North Caldwell, and Leo Henrylr Stern bach, Upper Montclair, N.J., assignors to Hotfmann-La Roche Inc, Nutley, N.J., a corporation of New Jersey No Drawing. Continuation-impart of application Ser. No. 545,25tt, Apr. 26, 1966. This application Oct. 3, 1967, Ser. No. 674,6d7

3 Claims. (Ci. 260-32615) ABSTRACT OF THE DISCLOSURE 5(3-indolyl)2,3-dihydro-1H-1,4 benzodiazepine useful as an antidepressant and intermediates in the preparation thereof.

Cross reference to related applications This application is a continuation-in-part of Ser. No. 545,258, Fryer and Sternbach, filed Apr. 26, 1966.

Detailed description of invention This invention is directed to 5-(3-indolyl)-2,3-dihydrolH-l,4-benzodiazepine, which is useful as an antidepres sant. This compound, which can be administered as a base per se or in the form of an acid addition salt, has potent central nervous system antidepressant properties with minimal undesirable side effects, such as sedation, and is useful as an antidepressant. It prevents the uptake of norepinephrine by cardiac tissues and produces stimulation when given in combination with small doses of tetrabenazine, i.e., 0.2 mg./kg. s.c. tetrabenazine. It is useful in reversing both exogenous and endogenous depression, for example, it is useful in reversing depression caused by the administration of a depressant such as tetrabenazine, and is also useful in potentiating the stimulant effect of other stimulants, such as amphetamine and cocaine. S-(3-indolyl)-2,3'dihydro-lH-1,4-benzodiazcpine can be administered internally, either as the base or in the form of a pharmaceutically acceptable acid addition salt, cornpounded in conventional pharmaceutical formulations. Thus, it can be administered enterally or parenterally. Dosages can be adjusted to individual requirements such as, for example, the compound of this invention can be administered in dosages of from about 1 mg./kg. to about 50.0 rug/kg. per day. These dosages can be administered in a single daily dosage form, i.e., in a single tablet or capsule containing from 5 mg. to 25 mg. of this com pound, or in divided dosage forms. The compound of this invention can be administered in conventional solid and liquid formulations such as tablets, capsules, dragees, suppositories, suspensions, solutions, emulsions or the like, which can contain standard pharmaceutical carriers or excipients such as lactose, corn starch, talc, calcium stearate, polyalkylene glycols, ethanol, vegetable oils, cocoa butter and the like. Moreover, such formulations can be subjected to standard pharmaceutical expedients such as sterilization, and can contain standard pharmaceutical additives such as buffers for the adjustment of pH, emulsifying agents, preservative agents, agents for the adjustment of osmotic pressure and the like. Such compositions can also contain other pharmaceutically active materials.

3,3%l,l58 Patented .fuiy 2, i968 ice As indicated above, 5-(3-indolyl)-2,3-dihydro-lH-l,4- benzodiazepine can be administered in the form of pharmaceutically acceptable acid addition salts. This compound forms such salts with both organic and inorganic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, succinic acid, maleic acid, paratoluene sulfonic acid and the like. Nonpharmaceutically acceptable aid addition salts can be converted into the base per se or into pharmaceutically acceptable acid addition salts by conventional metathetic reactions or by neutralization.

The potent central nervous system antidepressant properties of the compound of this invention is seen in that it reverses both exogenous and endogenous depression caused by the administration of large doses of a depressant such as tetrabenazine, which doses are sufficient to produce 100 percent ptosis in mice. The ED for the compound of this invention which is sufficient to prevent ptosis in mice which have had rug/kg. p.o. of tetrabenazine administered thereto was 3 mg./kg. p.o., as calculated by the method disclosed in Pletscher et al. Progress Drug Research, 2: 417 (1960); Whereas imipramine, a common antidepressant, had an ED as calculated by the same method, of 2 rug/kg. p.o.

Furthermore, the antidepressant properties of the corn pound of this invention can be seen by the fact that it potentiates the stimulant effect caused by the administration of small doses of te'trabenazine. Tetrabenazine, a common antidepressant, has stimulant effects at very small doses. By administering a dose of tetrabenazine in a small amount, which amount is not suflicient to produce stimulation. in combination with a small dose of the compound of this invention, stimulant activity is produced. This can be seen by the fact that the minimum effective dose of the compound of this invention that produced a greater than 12% change in the avoidance rate of foot shock in rats, which had 0.2 mg/kg. s.c. of tetrabenazine administered thereto, was 1.50 mg./kg. i.p., measured by the continuous avoidance of foot shock test described in Heise et al. Psychopharmcologia 3: 264 (1964). On the other hand, imipramine had a minimum effective dose, as measured by the same test, of 1.50 mg./kg. i.p.

Furthermore, the compound of this invention potentiates the stimulant effect of conventional stimulants such as dsamphetamine and cocaine. By administering inactive dosages of d-amphetamine (0.25 mg./kg. i.p.) and cocaine (4.0 rug/kg. i.p.) in combination with the compound of this invention, stimulant activity is produced. In the case of d-amphetamine, the minimum effective dose of the compound of this invention which produced a greater than 12% change in the avoidance of foot shock in rats having administered thereto 0.25 rug/kg. i.p. of d-amphetamine was 1.00 mg./ kg. i.p. [measured by the continuous avoidance of foot shock test described in Heise et al. Psychopharmcologia 3: 264 (1964)]. In the case of cocaine, the minimum effective dose of the compound of this invention in rats having administered thereto 4.0 rug/kg. s.c. cocaine, as measured by the continuous avoidance of foot shock test described in Heise et al. Psychopharmcologia 3: 264 (1964), was 0.10 mg./kg. i.p.

Additionally, the stimulant effect of the compound of this invention is demonstrated by the fact that this compound prevents the uptake of norepinephrine by cardiac 3 4 tissues. Norepinephrine, a stimulant, is released to and wherein X is a halogen and R is hydrogen or acyl. The taken up from the blood stream by the heart, during 21 end product 5-(3-indolyl)-2,3-dihydro 1H 1,4-benzoheartbeat. By retarding the heart from taking up norepidiazepine is of the formula nephrine, there results a greater amount of the norepinephrine stimulant in the blood stream. This can be seen from 5 the results obtained in the test wherein mice which were injected with the compound of this invention at various dose levels had, 45 minutes later, 1.28 mg. of norepinephll rine injected intravenously. These mice were sacrificed by cervical dislocation, 45 minutes later, and each mouse heart was rapidly excised and frozen immediately in a Dry Ice-acetone mixture, weighed and homogenized in 5 ml. of ice-cold 5% trichloroacetic acid. The norepinephrine uptake was determined -by the method disclosed in Herttmg et Bntlsh. Journ' Pharm' chm" 18:161 The starting material indoles of Formula I can be preresults when are exprflssed as of pared by a reaction of indole with an o-halobenzoyl halide norepmephrme per gram of heart tissue are given in the in the presence of a Grignard reagent Such as phenyl followmg table nesium bromide, methyl magnesium iodide or the like. 20 The Grignard reagent has the function of forming the a. e engnard eager e a mdolrl NEPHRINE BY MOUSE HEART mide or indolyl magnesium 1od1de, wh1ch then undergoes reaction with the o-halobenzoyl halide to form the desired product of Formula I. In this reaction the 1,3-bis-(2-halobenzoy1)-indole is also formed, and this compound can [In vivo uptake of Hg-Norepinephrinc] Specific radio- Percent inactivity (m hihition of g uptake either be hydrolyzed, with or without isolation, to yield the corresponding compound of Formula I wherein R g-/ s'prsiga is hydrogen, or can itself be subjected to reaction with {20in ethylenediamine whereby there is obtained a 5-[3-(N-o- 2& O0 halobenzoyl-indolyl)] 2,3 dihydro 1H 1,4-benzo- 52 s 70 U diazepine which can then be hydrolyzed to yield the de- 5 77 sired 5-(3-indolyl)-2,3-dihydro 1H 1,4-benzodiazepine.

The starting materials of Formula I wherein R is hydrogen can also be prepared by reacting indole with a tertiary The com ound of this invention, i.e., 5- 3-1ndol l 2,3- m 63 4 benzodiazepine can be p gp Se amide of ortho halobenzoic acid, e.g., N,N di-lower alkyl o-halobenzanude, 1n the presence of phosphorous oxyeral methodsone embodlment compqund 15 chloride. The starting material compound of Formula I pared by reacting 3-(2-haloben2oyl)-mdole with ethylene wherein R1 is acyl can also be formed by acylafion, diamine. The halogen in the halobenzoyl moiety of the cord to means known per Se of a compound of Formula I indole starting material can be any of the four halogens, A0 wherein R1 is hydrogen Chlorine bromine: iodine or fluorine but chlorine I The following examples are illustrative but not limitamine and fluorine are preferred and fluorine is especially tive of this invention An temperatures are Stated in preferred. The reaction is preferably effected in the degrees centigrade presence of an organic base such as pyridine, picoline,

quinoline or the like. Moreover, this reaction is suitably Example 1 effected at an elevated temperature, i.e., between about 5 25 C. and the reflux temperature of the reaction medium. In a 2 l. three-necked flask equipped with a mercury The reaction can be conducted in the presence of an inert sealed stirrer, a pressure equalizing dropping funnel and organic solvent such as a lower alkanol such as ethanol, reflux condenser fitted with a Dry Ice condenser and dry ether, aromatic hydrocarbons such as benzene, toluene, ing tube, was placed 24.3 of magnesium turnings. A Cumefle the like, and it is preferred t utilize the solution of 176 g. of bromobenzene in 300 m1. of ether organic base and/or an excess of the ethylenediamine as was placed in the separatory funnel and 70 ml. of this the reaction medium. In another embodiment,5-(3-indosolution was then added to the flask. A warm Water bath lyl)-2,3-dihydro-1H-1,4-benzodiazepine is prepared by (ca. 45) and agitation of the stirrer by hand was used hydrolysis of 5-[3-(N-acyl-indolyl)]-2,3-dihydro-lH-1,4- to help initiate the reaction. After the reaction had benzodiazepine. The acyl moiety can be any hydrolyzable started, an additional 30 ml. of bromobenzene solution acyl moiety, for example, lower alkanoyl such as acetyl, was added to the flask and stirring was begun; the Warm benzoyl, substituted benzoyl such as halobenzoyl, or the water bath was then replaced by an ice water bath. The like. The starting material 5-[3-(N-acyl-indolyl)]-2,3-diremainder of the ether solution was added during 1 hr.; hydro-1H-1,4-benzodiazepine can be prepared by reaction the cooling bath was removed after the initial vigorous of 3-(2-halobenzoyl)-l-acyl-indole with ethylenediamine 6O reaction had subsided somewhat. After completion of the according to procedures above-described for reacting addition of the ether solution, the resultant mixture was nonacylated compounds. heated with a warm water bath (45-50") for 20 minutes.

The 5-[3-(N-acyl-indolyl)]-2,3-dihydro-lH-l,4-benzo- A solution of 130 g. of indole in 300 ml. of dry benzene diazepine intermediates are novel componds within the (prepared by distilling benzene and discarding the first scope of this invention, as are the starting material 3-(2- fraction) was added dropwise with stirring at room temhalobenzoyl)-indoles of the formula perature in the course of 1l.5 hrs. The resultant greenish solution was heated under gentle reflux for 1 hr. and then cooled in an ice bath. A solution of 179 g. of o-fluorobenzoyl chloride in 200 ml. of benzene was added H with vigorous stirring in the course of 2 hrs. The ice bath was then removed and the resultant mixture heated J T under gentle reflux for 45 minutes. During this heating \N/ period there was a rapid color change from brown to a deep red (the mixture became very viscous and was somewhat diflicult to stir).

The flask was then cooled in ice and the complex hydrolyzed by the dropwise addition of 400 ml. of ammonium chloride in water (stirring was difiicult during the initial stages of the hydrolysis). Stirring was continued at room temperature for 45 minutes after all of the ammonium chloride solution was added. The red solid (any particles of the red, viscous product adhering to the walls of the flask were scraped ofl using a spatula) was collected on a filter, washed with 400 ml. of water and 400-600 ml. of ether. Thin layer chromatography (fluorescent silica gel plate, ethyl acetate-hexane, l/ 1) showed this solid to be a mixture of 3-(2-fluorobenzoyl)- indole and 1,3-bis(2-fluorobenzoyl)-indole. The solid was then covered with 600 ml. of acetone, the mixture heated on a steam bath until boiling and then 200 ml. of aque bus 5% sodium hydroxide was added thereto along with 100 ml. of methanol. The alkali-containing mixture was then heated for minutes with acetone being added as needed to maintain the original volume. Also, as the 1,3-bis(2-fluorobenzoyl)-indole was hydrolyzed during the heating, a small amount of the less soluble 3-(2-fluorobenzoyl) occasionally separated as a pale-orange solid. The mixture was then poured into 1800 ml. of water and the resultant suspension cooled in ice for 2 hrs. The resultant yellow-orange solid was collected and washed with 2 l. of water. The product was recrystallized by dissolving in a mixture of 600 ml. of acetone and 500 ml. of methanol and filtering while hot through a steamjacket funnel. The filtrate was concentrated on the steam bath until crystals started to separate and then the mixture was refrigerated (0-5") overnight. The resultant solid was filtered and washed with ether yielding 3-(2- fiuorobenzoyl)-indole as off-white colored crystals, M.P. 195197. Concentration of the filtrate yielded additional product.

The filtrate obtained after hydrolyzing the reaction mixture with ammonium chloride and collecting the red solid, was combined with the water and ether washings. The organic layer was separated, Washed three times with 250 ml. portions of water, dried over sodium sulfate and concentrated to dryness at reduced pressure. The resultant red, viscous, semi-solid mixture was covered with 150 ml. of ethanol and heated on the steam bath for 10 minutes, making certain that all of the red, oily material came in contact with the solvent. After refrigeration for 2-3 hrs. the solid was collected and washed free of the red color with ethanol. The white 1,3-bis(2-fluorobenzoyl)-indole thus obtained as a white solid was hydrolyzed in a mixture of 300 ml. of hot acetone and 150 ml. of 10% aqueous sodium hydroxide by heating on the steam bath for 20 minutes. The hydrolysis mixture was then poured into 1600 ml. of water and cooled in ice for 23 hrs. The product was obtained by filtration and was washed with approximately 2 l. of water and then dried at 70 in a vacuum oven overnight yielding 3-(2-fiuorobenzoyl)-indole as white prisms, M.P. 195- 198. An examination of the combined product on thin layer chromatography showed only one spot at Rf 0.17 using a fluorescent silica gel plate and an ethyl acetatehexane (1/ 1) solvent system.

Example 2 In a 1 l. round-bottomed flask, equipped with a reflux condenser protected by a drying tube was placed 100 g. of 3-(2-fiu0r0benzoyl)-indole, 500 ml. of pyridine and 234 ml. of ethylenediamine. The mixture was heated under relux for 20 hrs., cooled to room temperature and the supernatant liquid was then decanted from the white, oily mass at the bottom of the flask. The supernate was concentrated at reduced pressure to remove all of the pyridine and excess ethylenediamine. The resultant oily residue was dissolved immediately, while hot in 1 l. of dichloromethane (agitation while heating on the steam bath assisted in solubilizing the oil). The dichloromethane solution was cooled in the refrigerator overnight and the solid was collected, washed with two ml. portions of dichloromethane and dried in a vacuum oven at 70 for 3 hrs. yielding 5-(3-indolyl)-2,3-dihydro-1H- 1,4-benzodiazepine as pale-yellow needles, MP. 212- 216 (thin layer chromatography on fluorescent silica gel plates showed one spot using a solvent system of 4 parts of 96% ethanol to 1 part of ammonium hydroxide).

The filtrate and the dichloromethane Wash were combined, washed with water (3X 350 ml.) and then extracted with 2 N sulfuric acid (3X 300 ml.). The sulfuric acid extract was made basic (pH 10-11) at 0-10 With ca. 900 ml. of 10% sodium hydroxide, and the resulting solution was then extracted with dichloromethane (3X 500 ml.). The organic layers were combined, washed with saturated brine (3X 250 ml.), dried over sodium sulfate and concentrated to ca. 250 ml. and kept in the refrigerator overnight. The product was obtained by filtration and was washed with dichloromethane (2x 25 ml.) and dried yielding additional 5-(3-indolyl)-2,3-dihydro-lH-l,4-benzodiazepine, M.P. 2l2-21 6.

The recrystallization of the product was effected as follows: 52 g. of 5-(3-indolyl)2,3-dihydro-1H-1,4-benzodiazepine was dissolved in 900 ml. of hot ethanol and while boiling, water was added slowly until crystals began to separate (ca. 350 ml. of water used). After refrigeration (0 5) overnight, the resultant yellow solid was collected and washed with water (2x 100 ml.), The produce was dried at 80 in a vacuum oven giving purified product, M.P. 223225.

Example 3 A solution of indole (15.9 g), 2-fluoro-N,N-dimethylbenzarnide (44.8 g.) and phosphorus oxychloride (15 ml.) was heated with vigorous stirring. After reaching 88 a vigorously exothermic reaction occurred and icebath cooling was applied. The temperature rose to and then gradually fell to below 60. The mixture was heated for 3 hrs. at 80. The resultant brown solution was cooled in ice, basified carefully with 3 N sodium hydroxide (pH 9), (the temperature was moderated during basification by the addition of chopped ice), and extracted with dichloromethane. The dichloromethane was washed with 0.1 N hydrochloric acid, water, dried over sodium sulfate and filtered over 100 g. of synthetic magnesia silica gel (Florisil 30-60 mesh). Evaporation of the solvent gave an amber oil which was treated with ether and refrigerated yielding pale-yellow prisms of 3-(2-fluorobenzoyl) -indole which upon recrystallization from ethanol gave white prisms, M.P. -198".

Example 4 A solution of 19 g. of 1-acetyl-3-(2-fluorobenzoyl)- indole in a mixture of 85 ml. of pyridine and 65 ml. of ethylenediamine was heated under reflux for 21 hrs. The mixture was concentrated at reduced pressure and the residue partitioned between dichloromethane and 2 N hydrochloric acid. The acid layer was separated, cooled in ice and basified (pH 910) with 5% sodium hydroxide to hydrolyze any 5-[3-(N-acetyl-indolyl)]-2,3-dihydrolH-l,4-benzodiazepine remaining in the reaction mixture. The resultant yellow, oily suspension was stirred at room temperature for 1.25 hrs. and extracted with dichloromethane. The organic layer was separated, washed with water, dried and concentrated to small volume. Refrigeraation and filtration yielded 5-(3-indolyl)2,3-dihydro-1H- 1,4-benzodiazepine as yellow crystals, M.P. 210 214".

Example 5 A solution of 18 g. of 1,3-bis-(2-fluorobenzoyl)-indole in 25 ml. of ethylenediamine and 50 ml. of pyridine was heated under reflux for 21 hrs. and concentrated. The residue was partitioned between dichloromethane and 3 N hydrochloric acid and the acid layer separated and basified (in ice) with 10% sodium hydroxide to hydrolyze 4 any 5-[3-(N-fluorobenzoyl-indolyl)]2,3-dihydro-1H-1,4- benzodiazepine remaining in the reaction mixture. The viscous, yellow oil which precipitated was stirred in the alkaline solution for 1.5 hrs., and then extracted with dichloromethane. The organic layer was washed with water, dried and concentrated to approximately 80 ml. Scratching helped to initiate the crystallization of the product. After refrigeration, filtration gave 5-(3-indolyl)-2,3-dihydro-1I-I-1,4-benzodiazepine as yellow crystals, M.P. 21l 214.

Example 6 To a stirred solution of phenylmagnesium bromide (prepared from 24.3 g. of magnesium turnings, 176 g. of bromobenzene and 300 ml. of tetrahydrofuran) was added 130 g. of indole in 300 ml. of dry benzene over 1 hr. The solution was heated under gentle reflux for 1 hr., cooled in ice and 159 g. of o-fiuorobenzoyl chloride in 200 ml. of benzene added dropwise over 2 hrs. The resultant mixture was heated under reflux for 45 min., and after stirring overnight at room temperature, the mixture was immersed in ice and hydrolyzed by the dropwise addition of 250 ml. of ammonium chloride in water. The mix ture was stirred for min., filtered from a small amount of solid and the organic layer separated, washed with water, dried over sodium sulfate and concentrated to small volume. After refrigeration, the product was filtered and washed with cold ethanol yielding 1,3-bis-(2-fiuorobenzoyl)-indole as a pale pink-tinged solid which upon recrystallization from ethanol gave white needles, M.P. 132134.

Example 7 A mixture of 25 g. of 3-(2-fluorobenzoyl)-indole, 200 ml. of acetic anhydride and g. of anhydrous sodium acetate was heated under reflux for 3 hrs. After being poured into 750 ml. of water, the precipitated solid was extracted with ca. 800 ml. of ether and the organic layer washed, dried and concentrated. The residue was recrystallized from ca. 300 ml. of methanol yielding 1-acetyl-3-(2- fluorobenzoyl)-indole as white, feathery needles, MP. 117-119".

Example 8 A solution of 2 g. of 5-(3-indolyl)-2,3-dihydro-1H-1,4- benzodiazepine in methanol was treated with an equivalent of inethanolic hydrogen chloride and then a small amount of ethyl ether. After refrigeration, filtration yielded 5-(3- indolyl) -2,3-dihydro-1H-l,4-benzodiazepine hydrochloride as bright, yellow needles, M.P. (turns orange at approximately 170), 180l85 (dec.).

Example 9 A solution of 4 g. of 3-(2-fiuorobenzoyl)-indole in 50 ml. of ethylenediamine was refluxed overnight and then poured into 1 liter of water. The resultant mixture was extracted with dichloromethane and the organic layer separated, washed with Water and extracted four times, each time with 100 ml. of 1 N hydrochloric acid. The combined acid extract was basified with sodium hydroxide and extracted with dichloromethane. The organic extracts were washed, dried and evaporated. The yellow oil thus obtained was refluxed for 2 hrs. with 100 ml. of 6 N hydrochloric acid, cooled and extracted with dichloromethane. The acid layer was basified, extracted with dichloromethane, washed, dried and evaporated. The residue was dissolved in 50 ml. of pyridine and refluxed for 5 hrs. Evaporation yielded an oil which was partitioned between dichloromethane and water. The dichloromethane layer was washed, dried and evaporated. The residual oil was dissolved in ethyl acetate, filtered over synthetic magnesia silica gel (Florisil) and concentrated. The residue was crystallized from dichloromethane-petroleum ether yielding 5-(3-indolyl)-2,3-dihydro-1l-l-1,4-benzodiazepine as yellow rods, MJP, 215-223.

8 Example 10 A suppository formulation containing the following ingredients was prepared as indicated:

Per 13 gms.

suppository, gm. 5-(3-indolyl)-2,3-dihydro-1I-'-1,4-benzodiazepine 0.025 Wecobee M 1 1.230 Carnauba wax 0.045

A synthetic cocoa butter base available from E. F. Drew Company, 522 5th Ave., New York, N.Y.

The Wecobee M and carnauba Wax were melted in a suitable size glass lined container (stainless steel can also be used), mixed well and cooled to 45. The 5-(3-indolyl) 2,3 dihydro-1H-1,4-benzodiazepine, which had been reduced to a fine powder with no lumps, was added and stirred until completely and uniformly dispersed. The mixture was then poured into suppository molds to yield suppositories having an individual weight of 1.3 gms. They were cooled and removed from molds. The suppositories were then individually wrapped in wax paper for packaging (foil can also be used).

Example 11 A capsule formulation containing the following ingredients was prepared as indicated:

Per capsule, mg.

5-(3-indolyl)-2,3-dihyd-ro-1H-1,4-benzodiazepine 10 Lactose 173 Corn starch 37 Talc 5 Total weight 225 The 5-(3-indolyl)-2,3-dihydro-1H-l,4 benzodiazepine was mixed with the lactose and corn starch in a suitable mixer. The mixture was further blended by passing through a suitable comrninuting machine, e.g., a Fitzpatrick Comminuting Machine with a No. 1A screen with knives forward. The blended powder was then returned to the mixer, the tale added and blended thoroughly. The so-formed mixture was then filled into No. 4 hard shell gelatin capsules on a capsulating machine (the Parke-Davis capsulating machine or any similar type machine is suitable).

Example 12 A tablet formulation containing the following ingredients was prepared as indicated:

Per tablet, mg. 5 (3 indolyl) 2,3-dihydro-1H-1,4benzodiazepine 25.0 Lactose, spray dried 72.0 Corn starch, U.S.P. 2.0 Calcium stearate 1.0

Total weight 100.0

A parenteral formulation containing the following in gredients was prepared as indicated:

Per 1111., mg. 5 (3 indolyl) 2,3 dihydro-lH-1,4-benzodiaze pine Benzyl alcohol 20:0 Ethanol anhydrous 100.0 Dirnethylacetamide 100.0 Drew Oil 1400 q.s. 1 ml.

This is a modified coconut oil, mostly triglycerides with average chain of C1o-C12 available from E. F. Drew Company, 522 5th Ave, New York, N.Y.

The 5-(3-indolyl)-2,3-dihydro-1I-I-1,4 benzodiazepine was dissolved in the dirnethylacetamide and henzyl a1- cohol. The ethanol was then added to the so-formed solution, and the solution was brought up to final volume by adding the Drew Oil 1400. The solution was then filtered by pressure through an 0.5 micropore size filter. After this, the solution was filtered aseptically into sterile ampuls, gassed with nitrogen and sealed.

Example 14 A tablet formulation containing the following ingredients was prepared as in Example 12:

Per tablet, mg. 5 (3 indolyl) 2,3-dihydro-1H-1,4-benzodiazepine 5.1 Lactose 154.5 Corn starch 38.9 Magnesium stearate 1.5

Total weight 200.0

10 Example 15 A tablet formulation containing the following ingredients was prepared in the manner of Example 12:

Per tablet, mg. 5 (3 indolyl) 2,3-dihydro-1H-1,4-benzodiazepine 25.5 Lactose 374.5 Corn starch 96.0 Magnesium stearate 4.0

Total weight 500.0

References Cited UNITED STATES PATENTS 3,361,759 1/1968 Anthony et a1. 260326.14

NICHOLAS S. RIZZO, Primary Examiner.

I. NARCAVAGE, Assistant Examiner.