NZ198986A

NZ198986A - Anti-depressant compositions containing certain 5-(3-amino-propyl)-11-phenyl-5h-dibenzo(b,e)(1,4)-diazepines

Info

Publication number: NZ198986A
Application number: NZ198986A
Authority: NZ
Inventors: C R Taylor
Original assignee: Robins Co Inc A H
Priority date: 1981-09-24
Filing date: 1981-11-17
Publication date: 1986-02-21
Also published as: ES507970A0; IL64257A0; JPH0315637B2; GB2106894B; ES8207157A1; SE8106594L; AU7851381A; LU83798A1; PH16696A; NO813838L; FR2513249B1; PL234420A1; CH657126A5; IE812770L; IL64257A; IT1146729B; JPS5865280A; GB2106894A; YU62482A; AU576010B2

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 98986 198986 Priority D&ieia'j: • /?3 Complete Specification Filed: . .RrU~;?5 Class: CP. .. ft 61 &?-.1. £§§... Publication Date: ••• • P.O. Journal, No: . .'35??. ......... Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "METHOD OF, AND COMPOSITIONS FOR, TREATING DEPRESSION WITH 5-(AMINO-ALKYL)-11-PHENYL-5H-DIBENZO[b, e][1,4] DIAZEPINES" WE, A.H. ROBINS COMPANY, INC. a corporation organised under the laws of the State of Virginia, U.S.A. of 1407 Cummings Drive, Richmond, Virginia 23220, U.S.A. hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement - 1 - (followed by _ page I A.). - 1A - f?8986 METHOD OF AND COMPOSITIONS FOR TREATING DEPRESSION WITH 5-(AMINOALKYL)-11-PHENYL-5H-DIBENZO [b,e][l,4]DIAZEPINES BACKGROUND OF THE INVENTION 1. Field of Invention. The present invention relates to a method of and compositions for treating depression with certain 5-(aminoalkyl)-ll-phenyl-5H-dibenzo[b,e][l,4]diazepines. Some of the compounds are novel. 2. Description of the Prior Art. Wander, A. in British Patent 907,646 discloses preparation of certain of the dibenzodiazepines utilized in the method of this invention; e.g., the active ingredient of the compound of example 1 below in the form of the maleate salt. Wander, A. in British Patent 959,994 discloses utility of reduced forms; e.g., 5-(aminoalkyl)-ll-phenyl-10,ll-dihydro-5H-dibenzo[b,e][1,4]diazepines as t parasympathologics, antihistamines, spasmolytics, tranquillizers and psychic energizers. Greig, M.E., et al, in J. Med. Chem. 14, No. 2 page 153 (1971) discloses anaphylaxis activity of certain dibenzodiazepine homologs in mice particularly 2-chloro-5-[2-(dimethylamino)ethyl]-ll-phenyl-5H-dibenzo[b,e][l,4]diazepine. SUMMARY OF THE INVENTION The compounds useful in the method of treating depression and in the compositions in this invention have the formula: - 2 - 198986 X Formula I (CH2)3NR1R2 independently wherein R and R are/selected from the group consisting of hydrogen or methyl, and X is selected from the group consisting of hydrogen, chlorine, bromine and fluorine, and the pharmaceutically acceptable acid addition salts thereof. 1 2 Compounds wherein R and R are both hydrogen or one is methyl and one is hydrogen are novel. Such compounds and processes for their production are described and claimed in N.Z. Patent Specification No. 206992 which has been divided from this specification. Pharmaceutically acceptable acid addition salts are those salts which are physiologically compatible, such salts being formed either by strong or weak acids. Representative of strong acids are hydrochloric, sulfuric and phosphoric acids. Representative of weak acids are fumaric, maleic, succinic, oxalic, cyclohexamic, and the like. For the purpose of demonstrating antidepressant utility for the compounds of Formula I, the procedure given by Englehardt, E.L., et al., J. Med. Chem 1_1(2): 325 (1968) which has been indicative in the past of usefulness of compounds for treating human depression was used as follows: 20 mg/kg of the compound to be tested was administered to five adult female mice (ICR-DUB strain), intraperitoneally, 30 minutes prior to the administration of a ptotic dose (32 mg/kg, I.P„) of tetrabenazine (as the methane sulfonate salt). Thirty minutes later, the presence or absence of complete eyelid closure (ptosis) was assessed in each animal. An (Median Effective Dose) may be established for each tested compound in blocking tetrabenazine induced depression in mice, following the procedure given by Litchfield et al., J. Pharmacol. Exp. Therap. 96: - 3 - \99966 99-113 (1949). The preferred dibenzodiazepine useful in the method and compositions of this invention is the active agent of Example 1; namely, 5-(3-dimethylaminopropyl)-ll-phenyl-5H-dibenzo[b,e][l,4]diazepine. It is therefore an object to provide a method of treating depression in non-human animals. It is a furthur object to provide pharmaceutical compositions for use in treating depression in human and other animals. Additional objections and advantages of the present invention will be apparent to one skilled in the art and others will become apparent from the following description of the best mode of carrying out the present invention and from the appended claims. DETAILED DESCRIPTION OF THE INVENTION In the method of this invention the usual dosage forms of active substances comprised of the active ingredient of Formula I with a suitable pharmaceutical carrier to provide solutions, syrups, elixirs, tablets, capsules, suppositories, powders, and the like are employed. The compounds of Formula I wherein the 5-position is substituted by the 3-dimethylaminopropyl radical are prepared by cyclodehydration of the N-(3-dimethylamino-propyl)-o-benzamido-diphenylamines as in British Patent 907,646 using a dehydrating-condensation catalyst; for example, phosphorus pentoxide or oxyhalogenides of phosphorus, preferably the latter, in a suitable solvent; e.g., 1,1,2,2-tetrachloro ethane. The equation is: - 4 - I98984 The novel compounds of Formula I wherein the 5-position is substituted by the 3-aminopropyl radical are prepared by cyclodehydration of novel N-[3-(l-phthalimido)propyl3-o-benzamido-diphenylamines (lib) and thereafter converting the phthalimido moiety to amino (NI^) with hydrazine and acid. The equation is: wherein X has the values assigned under Formula I. Compounds of Formula III are also novel. Compounds of formula lib and processes for their production are described and claimed in N.Z. Patent Specification No. 206991 which has been divided from the current specification. The novel compounds of Formula I wherein the 5-position is substituted by 3-monomethylpropyl amine are prepared by further reaction of the 3-aminopropyl compound with triethylorthoformate followed by reaction with sodium borohydride (procedure of Crocket & Blanton, 1974(1): 55-6 Synthesis). The equation is as follows: 410 I 98986 5 The starting benzamido compounds II (ila and lib) are prepared by a modification of the procedure of British Patent 907,646. Ortho-nitro-diphenylamine is first reductively alkylated with a solution of p-chloropropyl 5 dimethylamine or J>-( 1-phthalimido)-1-chloropropane and following this the nitro moiety is reduced with hydrogen over.palladium on carbon to give the corresponding ortho amino compound. The amino radical in the ortho position is then reacted with a benzoyl halide or a substituted 10 benzoyl halide. The equation is as follows: 15 o2n vi I 1) NaH J, 2) Cl-(CH2)3Q 20 25 50 V IV Pyridine CI X NH sn (CH2)3 Q 35 Q = -n(ch3)2 or 1-phthalimido. II ,r; \-u. 15 IfaAtiiu-- ^ \/? 410 198986 Preparation 1 N-( 3-Diraethylaminopropyl) -o-aminodiphenylamine. A mixture of J2.0 g (0.107 mole) of N-(3-dimethylaminopropyl) -o-nitrodiphenylamine (b.p. 155°/0.4 to 174°C./ 0-35 mm), 100 ml of 200 proof ethyl alcohol and 1.5 g of 5 10% palladium-on-carbon catalyst was shaken under hydrogen atmosphere at room temperature for 1 hr. After approximately the theoretical amount of hydrogen was absorbed the catalyst was filtered off through a celite filter cake and solvent removed under reduced pressure. The residue was 10 distilled under high vacuum as follows: b-P-»°C- Amt■, g Fraction 1 80-130°/0.2 mm 4.0 2 130-137°/0.2 mm 7-0 3 137-142/0.2 mm 15.5 15 Thin layer chromatography using 20$ methyl alcohol - Q0% benzene on silica gel, showed Fraction 3 to be quite pure. Preparation 2 N-(3-Dimethylaminopropyl)-o-benzamidodiphenylamine. 20 To a solution of 15-5 9 (0.0575 mole) of N-(3-dimethyl aminopropyl) -o-aminodiphenylamine in 100 ml of pyridine cooled to about 5°C. under nitrogen atmosphere was added 17-8 g (0.063 mole) of benzoyl chloride. A small amount of benzene was used to wash the remaining benzoyl chloride into 25 the reaction vessel. The mixture was stirred for 1 hr and the vessel stoppered and placed in the refrigerator over the weekend. The solvent was then evaporated under reduced pressure. The residual oil was dissolved in 100 ml of methylene chloride and the solution washed once with 150 ml 30 of 3 N sodium hydroxide and three times with 250 ml of water. The methylene chloride layer was dried over magnesium sulfate and evaporated under reduced pressure. Residual pyridine was then removed under high vacuum (0.2 mm Hg) over night. Weight of the residual oil, the free base, was 35 24.9 g- 410 198986 Oxalate Salt - To a hot solution of 4.0 g of the free base in isopropyl alcohol was added 1.35 9 (0.0107 mole) of oxalic acid dihydrate. The precipitated oxalate salt of the title compound weighed 3-5 9 and melted at l62~5°c. The 5 salt after drying 1 hr at 97-98°C. (refluxing propyl alcohol) and overnight at room temperature all at 0.1 mm Hg., analyzed as follows: Analysis: Calculated for C2aH29N305: C,67.37r H,6.31; N,9-06 Found : 0,67-42; H,6.35; N,9-01 10 Preparation 3 Following the procedure of Preparation 2 and substituting the following for benzoyl chloride: 2-chloro-benzoyl chloride, 3-chloro-benzoyl chloride, 15 2-fluoro-benzoyl chloride, 3-fluoro-benzoyl chloride, 2-bromo-benzoyl chloride, 3-bromo-benzoyl chloride, and 4-chloro-benzoyl chloride, 20 there are obtained: N-(3-dimethylaminopropyl)-o-(2-chlorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(3-chlorobenzamido) diphenylamine, 25 N-(3-dimethylaminopropyl)-o-(2-fluorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(3-fluorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(2-bromobenzamido) 30 diphenylamine, N-(3-dimethylaminopropyl)-o-(3-bromobenzamido) diphenylamine, and N-(3-dimethylaminopropyl)-o-(4-chlorobenzamido) diphenylamine. - 8 - 198986 Preparation 4 N-[3-(l-Phthalimido)propyl]-o-aminodiphenylamine. o-Nitrodiphenylamine is reacted with sodium hydride and 3-(l-phthalimido)-l-chloropropane to give N-3-(l-phthalimido)-propyl-o-nitrodiphenylamine which is then reduced with hydrogen over palladium-on-carbon in ethanol to give the title compound. Preparation 5 When in the procedure of Preparation 2, N-3-(1-phthalimido)-propyl-o-aminodiphenylamine is reacted with each of the following acyl chlorides in excess in the manner of Preparation 2: 2-chloro-benzoyl chloride, 3-chloro-benzoyl chloride, 2-fluoro-benzoyl chloride, 3-fluoro-benzoyl chloride, 2-bromo-benzoyl chloride, 3-bromo-benzoyl chloride, and 4-chloro-benzoyl chloride, there are obtained: N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine, N-3-(l-phthalimido)propyl-o-(2-fluorobenzamido) diphenylamine, N-3-(l-phthalimido)propyl-o-(3-fluorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-bromobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-bromobenzamido) diphenylamine, and N-3-(1-phthaiimido)propyl-o-(4-chlorobenzamido) diphenylamine. The following non-limiting examples will further illustrate the compounds which are useful in the practice of the method and compositions of this invention. Those compounds comprehended by formula I above, specifically referred to herein are novel and are described and claimed in N.Z. Patent Specification No.206992, and No. 206990 which has also been divided from the current specification. 410 198986 Example 1 5-(3-Dimethylaminopropyi)-ll-phenyl-5H-dibenzo fb, e~|[ 1, 4 ]diazepine, fumarate [1:1]. A stirred mixture of 18.9 g (0.05 mole) of N-(3-dimethylaminopropyl)-o-benzamidodiphenylamine and 32.19 g 5 (0.2 mole) of phosphorus oxychloride in 50 ml of 1,1,2,2-tetrachloroethane was heated at 150°C. under nitrogen atmosphere for 1.5 hr. The mixture was cooled somewhat and poured over approximately 1000 ml of crushed ice and then diluted with enough water for a final volume of 1000 10 ml. The aqueous suspension was extracted twice with methylene chloride and the methylene chloride layer discarded. The aqueous layer was basified with 3 N sodium hydroxide and extracted with three - 250 ml portions of methylene chloride. These three methylene chloride washes 15 were combined, dried over magnesium sulfate and evaporated under reduced pressure to give a residual oil weighing 13-8 g, the free base of the title compound. The oil was dissolved in hot isopropyl alcohol and reacted with 4.5 9 (0.039 mole) of fumaric acid. The fumarate salt was 20 collected by filtration, yielding 13 g when dried, m.p. 168-I70°c. Analysis: Calculated for C28H29N3O4: C,71-32; H,6.20; N,8.91 Found : c,7l-19; H 6.19; N,8.89 Example 2 25 Following the procedure of Example 1 and substituting equal molar amounts of the following for N-(3-dimethylaminopropyl )-o-benzamidodiphenylamine: N-(3-dimethylaminopropyl)-o-(2-chlorobenzamido) diphenylamine, 30 N-(3-dimethylaminopropyl)-o-(3-chlorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(2-fluorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(3-fluorobenzamido) 35 diphenylamine, 410 10 t 98986 N-(3-dimethylaminopropyl)-o-(2-bromobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(3-bromobenzamido) diphenylamine, and N-(3-dimethylaminopropyl)-o-(4-chlorobenzamido) diphenylamine, there are obtained: ll-(2-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e][1,4]diazepine, fumarate, 3-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-e][1,4]diazepine, fumarate, 2-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-e][l,4]diazepine, fumarate, 3-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-e][1,4]diazepine, fumarate, 2-bromophenyl)-5~(3-dimethylaminopropyl)-5H-e][l,4]diazepine, fumarate, 3-bromophenyl)~5~(3-dimethylaminopropyl)-5H-e][1,4]diazepine, fumarate, and 4-chlorophenyl)-5-(3-dimethylaminopropyl)-5H- 10 11- dibenzo[b 11- dibenzo[b 11- 15 dibenzo[b 11- dibenzo[b 11- dibenzo[b 20 11- dibenzo[b,e][1,4]diazepine, fumarate. Example 3 When in the procedure of Example 1 prior to addition of fumaric acid, the following are substituted for N-(3-25 dimethylaminopropyl)-o-benzamidodiphenylamine: N-3-(1-phthalimido)propyl-o-benzamidodiphenylamine, N-3-(1-phtha1imido)propyl-o-(2-chlorobenzamido) diphenylamine, N-3-(1-phthaiimido)propyl-o-(3-chlorobenzamido) 30 diphenylamine, N-3-(1-phthalimido)propyl-o-(2-fluorobenzamido) diphenylamine, N-3-(1-phthaiimido)propyl-o-(3-fluorobenzamido) diphenylamine, 35 N-3-(l-phthalimido)propyl-o-(2-bromobenzamido) diphenylam ine, 410 t 98986 11 N~3~(1-phthalimido)propyl-o-(3-bromobenzamido) diphenylamine, and N-3-(l-phthalimido)propyl-o-( 4-chlorobenzamido) diphenylamine, there are obtained: 5-[3-(1-phthalimido)propyl]-ll-phenyl-5H-dibenzo [b)e][l,41 diazepine, 5-[ 3-(l-phthalimido)propyl]-ll-(2-chlorophenyl)-5H-dibenzo[b,e][1,4]diazepine, 5-[3-(1-phthalimido)propyl]-ll-(3-chlorophenyl)-5H-dibenzo[b,e][l,4]diazepine, 5-[3-(1-phthalimido)propyl]-ll-(2-fluorophenyl)-5H-dibenzo[b,e][l,4]diazepine, 5-[3~(1-phthalimido)propyl]-ll-(3-fluorophenyl)-5H-dibenzo[b,e][1,4]diazepine, 5-[3-(1-phthaiimido)propyl]-ll-(2-bromophenyl)~5H-dibenzo[b,e][1,4]diazepine, 5~[ 3_l( 1-phthal imido) propyl]-ll-( 3-bromo phenyl) -5H-dibenzo[b,e][l,4]diazepine, 5-[3-(1-phthalimido)propyl]-ll-(4-chlorophenyl)-5H-dibenzo[b,e] [1,4]diazepine. Example 4 5-(3-Aminopropyl)-ll-phenyl-5H-dibenzorb,e1r1.4l diazepine hydrochloride. A mixture of 0.035 mole of 5-[3-(l-phthalimido)propyl-ll-phenyl-5H-dibenzo[b,e][1,4]diazepine, 0-039 mole of hydrazine hydrate and 175 ml of 190 proof ethyl alcohol is refluxed for 2.5 hr and allowed to stand for several hours. A solution of 10 ml concentrated hydrochloric acid in 50 ml water is added to the mixture and the mixture is stirred for several hours. The mixture is filtered and the filtrate evaporated under reduced pressure. The hydrochloride salt is isolated by recrystallization from a suitable solvent and dried under reduced pressure. 410 t 98986 12 Example 5 Following the procedure of Example 4 and substituting equal molar amounts of the following for 5-[3-(1-phthalimido) propyl]-ll-phenyl-5H-dibenzo[b,elf 1,4]diazepine: ll-(2-chlorophenyl)-5~[3~(1-phthaiimido)propyl]-5H-dibenzo[b,e][ 1,4"] diazepine, ll-(3-chlorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo[b,e][1,4]diazepine, 11-(2-fluorophenyl)-5-[3-(1-phthaiimido)propyl]-5H-dibenzo[b,e][1,4]diazepine, 11-(5-f luorophenyl) -5-[ 3-( 1-ph thai imido) propyl ]-5H-dibenzo[b,e][1,4]diazepine, ll-(2-bromophenyl)-5~[3-(1-phthalimido)propyl]-5H-dibenzo[b,elf 1,4]diazepine, ll-(J-bromophenyl)~5~[?-(1-phthalimido)propyl1-5H-dibenzo[b,e][l,4]diazepine, and 11-(4-chlorophenyl)-5-[3-(1-phtha1imido)propyl]-5H-dibenzo[b,e][1,4]diazepine, there are obtained: 5-(3-aminopropyl)-ll-(2-chlorophenyl)-5H-dibenzo [b,el[1,4]diazepine hydrochloride, 5-(3-aminopropyl)-ll-(3-chlorophenyl)-5H-dibenzo [b,e][1,4]diazepine hydrochloride, 5-(3-aminopropyl)-ll-(2-fluorophenyl)~5H-dibenzo [b,el[1,4]diazepine hydrochloride, 5-(3-aminopropyl)-ll-(3-fluorophenyl)-5H-dibenzo [b,el[1,4]diazepine hydrochloride, 5-(3-aminopropyl)-ll-(2-bromophenyl)-5H-dibenzo [b,e][l,4]diazepine hydrochloride, 5-(3-aminopropyl)-ll-(3-bromophenyl)-5H-dibenzo [b,e][1,4]diazepine hydrochloride, 5-(3-sminopropyl)-ll-(4-chlorophenyl)-5H-dibenzo [b,e][l,4]diazepine hydrochloride. 410 19 8986 Example 6 N--Me thyl-11-phenyl-5H-dibenzof b, e 1 f 1,4 ] diazepin-5-propanamine, hydrochloride. The hydrochloride salt of 5~(3-aminopropyl)-11-phenyl-5H-dibenzo[b,e][l,4]diazepine is converted to the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentrating the methylene chloride layer to dryness, adding dry benzene and again concentrating to drive off the benzene. The resulting free base is dissolved in a large excess of freshly distilled triethyl-orthoformate with refluxing for several hours. The mixture is concentrated in vacuo, ethanol is added and the mixture concentrated again. The resulting imidate is dissolved in ethanol and sodium borohydride is added with stirring at 15-20°C. until thin-layer chromatography indicates the absence of substantial amount of starting material. The mixture is cooled and gradually flooded with water followed by extraction with ethylacetate. The ethylacetate layer is washed to neutrality and salted, filtered and evaporated. Crude free base is isolated by column chromatography and reacted with ethereal hydrogen chloride and recrystsllized to give the title compound. Example 7 Following the procedure of Example 6 and substituting equal molar amounts of the following for 5-(3-aminopropyl)-ll-phenyl-5H-dibenzo[b,e][1,4]diazepine: 5-(3-aminopropyl-ll-(2-chlorophenyl)-5H-dibenzo [b,e][l,4]diazepine hydrochloride, 5-(3-aminopropyl)-ll-(3-chlorophenyl)-5H-dibenzo [b,e][1,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-fluorophenyl)-5H-dibenzo [b,e][1,4]diazepine hydrochloride, 5-(3-aminopropyl)-ll-(3-fluorophenyl)-5H-dibenzo [b,e][l,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-bromophenyl)-5H-d ibenzo [b,e][1,4ldiazepine hydrochloride, 198986 5-(3-aminopropyl)-ll-(3-bromophenyl)-5H-dibenzo [b,e][l,4]diazepine hydrochloride, and 5~(3-aminopropyl)-ll-(4-chlorophenyl)-5H-dibenzo [b,e][l,4]diazepine hydrochloride , there are obtained: ll-(2-chlorophenyl)-N-methyl~5H-dibenzo[b,e][1,4] diazepin-5-propanamine hydrochloride, 11-(3-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1,4] diazepin-5-propanamine hydrochloride, 11-(2-f luorophenyl) -N-methyl-5H-dibenzo[b, e"| [ 1,4 ] diazepin-5-propanamine hydrochloride, ll-(3-fluorophenyl)-N-methyl-5H-dibenzo[b,e][1,4] diazepin-5-propanamine hydrochloride, 11-(2-bromophenyl)-N-methyl-5H-dibenzo[ b,e][1,4] diazepin-5-propanamine hydrochloride, 11-(3-t>romo phenyl) -N-methyl-5H-dibenzo[ b, e] [ 1,4] diazepin-5-propanamine hydrochloride, and 11-(4-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1,4] diazepin-5-propanamine hydrochloride . - 15 - 198996 Formulation and Administration Effective quantities of the foregoing pharmacologically active compounds of Formula I may be administered to humans for therapeutic purposes according to usual modes of administration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutically acceptable carriers and parenterally in the form of sterile solut ions. Exemplary of solid carriers for oral administration are such as lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Exemplary of liquid carriers for oral administration are vegetable oils and water. For intramuscular administration the carrier or excipient may be a sterile, parenterally acceptable liquid; e.g. water or a parenterally acceptable oil; e.g. arachis oil contained in ampules. Although very small quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually from five milligrams or above and preferably 10, 25, 50, or 100 milligrams or even higher, preferably administered three or four times per day, depending, of course, upon the emergency of the situation, the compound used, and the particular result desired. Twenty-five to 200 milligrams appears optimum per unit dose or usual broader ranges appear to be about 10 to 500 milligrams per unit dose. Daily dosages usually required should range from about 0.5 to about 20 mg/kg/day, preferably about 0.5 to 10 mg/kg. The active ingredients of the invention may be combined with other pharmacologically active agents as stated above. It is only necessary that the active ingredient constitute an effective amount; i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages will, of course, be demonstrated according to 410 20 198986 16 standard medical principles under the direction of a physician or veterinarian. " The following formulations are representative for the pharmacologically active compounds of this invention. 5 FORMULATIONS 1. capsules Capsules of 1Q mg and 50 mg of active ingredient per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in the amount of 10 lactose. __ 10 mg. 50 rag. Typical blend for encapsulation Per Capsule Per Capsule Active ingredient, as salt 10 50 Lactose 259 219 Starch 126 126 Magnesium stearate 4 4 15 Total 399 399 Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows: 100 250 500 mg. per mg. per mg. per Ingredients Capsule Capsule Capsule Active ingredient, 100 250 500 as salt Lactose 214 163 95 Starch 87 81 47 Magnesium stearate 4 6 8 Total 399 500 650 ?5 In each case, uniformly blend the selected active ingredient with lactose, starch, and magnesium stearate and encapsulate the blend. 2. Tablets A typical formulation for a tablet containing 5-0 mg of active ingredient per tablet follows. The formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium phosphate. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 17 - J 98986 Per Tablet, mg

1. Active ingredient 10.0

2. Corn starch 15.0

3. Corn starch (paste) 12.0

4. Lactose 35.0 5. Dicalcium phosphate 132.0 6. Calcium stearate 2.0 Total 202.0 Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 per cent paste in water. Granulate the blend with starch paste and pass the wet mass through an 8 mesh screen having a 2.4 mm sieve opening size. The wet granulation is dried and sized through a 12 mesh screen having a 1.7 mm sieve opening size. The dried granules are blended with the calcium stearate and compressed. 3. Injectable - 2% sterile solution Per cc Active ingredient mg. 20 Preservative, e.g., chlorobutanol, w/vol. percent 0.5 Water for injection q.s. Prepare solution, clarify by filtration, fill into vials, seal and autoclave. Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, compositions and methods of the present invention without departing from the spirit and scope thereof, and it is therefore understood that the invention is to be limited only by the scope of the appended claims. - 18 - 198986 WHAT WE CLAIM IS: 1. A method of treating depression in non-human animals which comprises administering an effective amount of a compound having the formula: 1 2 wherein R and R are independently selected from the group consisting of hydrogen and methyl, and X is selected from the group consisting of hydrogen, chlorine, bromine and fluorine, or a pharmaceutically acceptable acid addition salts thereof. 2. The method of claim 1 wherein the compound is 5-(3-dimethylaminopropyl)-11-phenyl-5H-dibenzo[b,e][l, 4]~ diazepine. 3. The method of claim 1 wherein the compound is

5-(3-dimethylaminopropyl)-ll-phenyl-5H-dibenzo[b,e] [1,4 ]-diazepine, fumarate [1:1]. 4. A pharmaceutical composition for treating depression in unit dosage form comprising (a) an effective amount of a compound having the formula: 198986 1 1 wherein R and R are independently selected from the group consisting of hydrogen and methyl, and X is selected from the group consisting of hydrogen, chlorine, bromine and fluorine, or a pharmaceutically acceptable acid addition salt thereof, and (b) a pharmaceutical carrier therefor. 5. A pharmaceutical composition of claim 4 wherein the compound is 5-(3-dimethylaminopropyl)-11-phenyl-5H-dibenzo[b,e][l,4jdiazepine.

6. A pharmaceutical composition of claim 4 wherein the compound is 5-(3-dimethylaminopropyl)-ll-phenyl-5H-dibenzo[b,e][1,4]diazepine fumarate.

7. A method of treating depression in an aminal, excluding a human being; which ccmprises administering an effective amount of a compound of Formula I as specifically described herein in any one of the Examples 1 to 7.

8. A pharmaceutical composition for treating depression in unit dosage form comprising (a} an effective amount of a compound of Formula I as specifically described herein in any one of the Examples 1 to 7 and (b) a pharmaceutical carrier therefor. B. </div>