Патент USA US3085942код для вставки
United States Patent 0 iC€ 3,085,932 , Patented Apr. 16, 1963 1 2 3,085,932 The compositions of this invention are prepared simply by intimately mixing the two active components. The THERAPEUTIC COMPOSITION COMPRISING 3,3 mixture is then embodied into a suitable dosage form. DIETHYL - 5 - METHYL - 2,4 - PEPERIDINEDIONE AND 1 Suitable dosage forms include capsules, pressed or coated tablets, syrups, oily suspensions, etc. The methods by 7-CHLORO-2-lviETHYLAM[N0-5-PHENYL 3H-1,4-BENZODIAZEPINE-4-OXIDE Saul Howard Rubin, Nutley, and Gerhard Zbinden, Essex which such dosage forms are obtained are well known in Foils, N.J., assignors to Hoifmann-La Roche Inc., Nut the art. ley, N.J., a corporation of New Jersey In addition to the active ingredients, the compositions No Drawing. Filed Dec. 21, 1961, Ser. No. 161,270 of this invention may contain the various adjuvants con 7 Claims. (Cl. 167—52) 10 ventionally used in the formulation of pharmaceutical preparation. Exemplary of the adjuvants'that may be em This invention relates to novel therapeutic composi ployed in producing the compositions in encapsulated or tions. More particularly, the invention relates to therapeu tablet form are ?llers, such as coprecipitated aluminum tic compositions comprising a mixture of 3,3-diethyl-5 hydroxide-calcium carbonate, dicalcium phosphate or lac methyl-2,4-piperidinedione with 7-chloro-2-methylamino 5-phenyl-3H-l,4-benzodiazepine 4-oxide or one of its 15 tose in the presence of disintegrating agents, such as maize medicinally acceptable acid addition salts. The compositions of the present invention have been starch; and lubricating agents, such as talc, calcium stear ate, etc. The compositions may, moreover, be produced in the form of suspensions in oil, for example, in a vege found to be useful in the inducement of sound sleep. They are especially well suited for use, however, in the table oil, such as arachis oil. Such suspensions may con treatment of patients with sleep problems associated with 20 tain sweetening agents and preservatives of the type nor mally employed in the art. anxiety, tension or other common emotional disturbances. The ratio of the active components comprising the These compositions, therefore, fill a long existing need products of this invention can be varied within rather in the treatment of patients with heart disease or other Wide limits. For example, the products may contain from‘ chronic ailments, in the treatment of neuropsychiatric patients and in the treatment of patients in pre- and post 25 about 4 to about 120 parts by weight of 3,3-diethyl-5 methyl-2,4-piperidinedione for each part by Weight of 7 operative states. _ chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4 3,3~diethyl-S-methyl-2,4-piperidinedione is a non-nar oxide or for each part by weight of a salt thereof. The cotic, sedative-hypnotic which possesses high therapeutic preferred products of the invention, however, contain activity and, at the same time, manifests low toxicity. It has been found that 7-chloro-2-m'ethylamino-S-phenyl 30 from about 15 parts by weight to about 25 parts by weight of 3,3-diethyl-5-methyl-2,4-piperidinedione for each part 3H-1,4-benzodiazepine 4-oxide, and medicinally accept by weight of 7-chloro-2-methylamino-5-phenyl-3H-1,4 able salts thereof, compounds ‘which, in therapeutic doses, do not have hypnotic properties, cause sleep potentiation of 3,3-diethyl-5-methyl-2,4-piperidinedione. Moreover, in some animal species, particularly in the ' 35 dog, administration of 3,3-diethyl-5-methyl-2,4-piperi benzodiazepine 4-oxide, or salt thereof. A typical adult dosage of the active ingredients com prising the present compositions may vary within the range of from about 175 mg. to 225 mg. of 3,3-diethyl-5-methyl 2,4-piperidinedione with from about 8 mg. to about 12 dinedione appears to induce an initial phase of excitation which phase is followed by a sedation phase and a hyp mg. of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzo notic phase. It has been found that 7-chloro-2-methyl— diazepine 4-oxide, or salt thereof. For example, a hard methyl-2,4-piperidinedione. On the contrary, it appears to suppress this initial excitation. Such effect, while high ly advantageous, was entirely unexpected. amino-5-phenyl~3H-1,4-benzodiazepine 4-oxide, or salt thereof, may be administered to the patient at bedtime. amino-5-phenyl-3H-1,4-benzodiazepine 4-oxide does not 40 shell capsule containing 200 mg. of 3,3-diethyl-5amethyl— 2,4-piperidinedione and 10 mg. of 7-chloro-2-methyl potentiate the excitation phase induced by 3,3-diethyl-5 Thus, the present invention comprises therapeutically In cases of severe insomnia, a second capsule may be 45 prescribed. Smaller doses may, of course, be recom active compositions comprising a mixture of 3,3-diethyl-5 mended in particular cases, for example, in the treatment methyl-2,4-piperidinedione with 7-chloro-2-methylamino of children and debilitated patients. It should 1be fully 5-phenyl-3H-1,4-benzodiazepine 4-oxide. A medicinally understood, however, that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope of this invention. For a fuller understanding of the nature and objects of this invention, reference may be had to the following examples which are given merely as illustrative of the in acceptable acid addition salt of 7-chloro-2-methylamino-5 phenyl-3H-1,4-benzodiazepine 4-oxide can be used, if de sired. Since, however, 3,3-diethyl-5-methyl-2,4-piperi dinedione is somewhat unstable in an 'acid environment, when that compound is used in admixture with an acid addition salt of 7-chloro-2-methylamino-5-phenyl-3I-I-1,4 benzodiazepine 4-oxide, there should be present also a su?icient quantity of alkali, for example, an alkaline filler, such as coprecipitated aluminum hydroxide-calcium car vention and are not to‘ be construed in a limiting sense. Example 1 The following ingredients, in the quantities indicated, were intimately mixed in a suitable container. bonate, to render the ?nished product basic, or at least neutral, in reaction. In general, any one of many medic 60 7-chloro-2-m'ethylamino-5-phenyl-3H-1,4~ Grams inally acceptable acid addition salts of 7-chloro-2-methyl amino-5-phenyl-3H-1,4-benzodiazepine 4-oxide can be used in the practice of this invention. These include salts benzodiazepine 4-oxide __________________ __ 1,020 ' 3,3-diethyl-5-methyl-2,4-piperidinedione _____ __ 20,400‘ of 7 - chloro-Z-methylamino-S-phenyl-BH-1,4-benzodiaze— Coprecipitated aluminum hydroxide-calcium pine 4-oxide with conventional mineral acids, such as 65 hydrochloric acid, hydrobromic acid, nitric acid, phos carbonate _____________________________ __ 400 Starch __________________________________ __ 5,400 T alc ___________________________________ __ 1,5 00' phoric acid; and with conventional organic acids, such as Lactose ________________________________ __ 1,280 benzoic acid, toluene sulfonic acid, acetic acid, citric acid,’ maleic acid, tartaric acid, lactic acid, etc. In producing The mixture was then passed through a Fitzpatrick com the preferred products of the invention, however, 7-chloro 70 minuting machine, following which the milled powder 2-methy1amino-S-phenyl-SH-1,4-benzodiazepine 4 - oxide, was mixed and re-blended. or the hydrochloric acid salt thereof, is used. then passed into hard-shell capsules. The powdery mixture Was 3,085,982 3 In this example, 200 parts by weight of 3,3-diethyl-5 methyl-2,4-piperidinedione and 20 parts by weight of comprising a mixture of 3,3-diethyl-5-methyl-2,4-piperi dinedione and 7~chloro-2-methy1amino-5-phenyl-3H-1,4~ 7 - chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine benzodiazepine 4-oxide with a solid pharmaceutical ad~ 4-oxide were ?rst intimately admixed. To this mixture, juvant, there being present in said composition, for each part by weight of said 1,4-benzodiazepine-4-oxide com ponent, from about 4 to about 120 parts by weight of said 2,4-piperidinedione component. 5. A therapeutic composition for internal administra tion in shaped unit dosage form for oral administration 65.0 parts by weight of coprecipitated aluminum hydrox ide-calcium carbonate were added. This mixture was granulated with a mixture of 5 parts by weight of gelatin and 5 parts by weight of cornstarch. Thereafter, the granulate, thus obtained, was mixed with 3.6 parts by weight of cornstarch, 4.0 parts by weight of talc and 0.4 parts by weight of magnesium stearate. comprising a mixture of 3,3-diethyl-5-methyl-2,4-piperi dinedione and a medicinally acceptable acid addition salt The product was then compressed into tablets by con ventional means. 4 4. A therapeutic composition for internal administra tion in shaped unit dosage form for oral administration Example 2 of 7 - chloro-2-methylamino-5-phenyl-3H-1,4-benzodiaze 15 pine 4-oxide with a solid pharmaceutical adjuvant, there We claim: being present in said composition, for each part by weight 1. A therapeutic composition comprising 3,3-diethyl-5 of said 1,4-benzodiazepine-4-oxide component, from methyl-2,4-piperidinedione and a compound selected from about 4 to about 120 parts by weight of said 2,4-piperi the group consisting of 7-chloro-Z-methylamino-S-phenyl dinedione component. 3H-1,4-benzodiazepine 4-oxide and a medicinally accept 20 6. The composition of claim 5 wherein the hydro able acid addition salt thereof, there being present in said chloride salt of 7-chloro-2-methylamino-5-phenyl-3H-1,4 composition, for each part by weight of said 1,4-benzo diazepine-4-oxide component, from about 4 to about 120 parts by weight of said 2,4-piperidinedione component. benzodiazepine 4-oxide is employed. 7. A process for treating insomnia which comprises internally administering a therapeutic composition com‘ 2. The composition of claim 1 which contains pharma 25 prising from about 175 mg. to about 225 mg. of 3,3-di— ceutical adjuvant material. ethyl-5-methyl-2,4-piperidinedi0ne and from about 8 mg. 3. A therapeutic composition for internal administra to about 12 mg. of a compound selected from the group tion in unit dosage form comprising a mixture of 3,3 consisting of 7-chloro-2-methylamino-5-phenyl-3H-1,4 diethyl-S-methyl-2,4-piperidinedione and a compound benzodiazepine 4-oxide and a medicinally acceptable acid selected from‘ the group consisting of 7-ch1oro-2-methyl 30 addition salt thereof. amino-5-phenyl-3H-1,4-benzodiazepine 4-oxide and a medicinally acceptable acid addition salt thereof with a pharmaceutical adjuvant, there being present in said com position, for each part by weight of said 1,4-benzodiaze pine-4-oxide component, from about 4 to about 120 parts 35 by weight of said 2,4-piperidinedione component. References Cited in the ?le of this patent Physicians’ Desk Reference, page 798 (Hyptran), page 710 (Noludar), January 1961. The New England J. of Med, Apr. 27, 1961, pages 870-873, vol. 264, No. 17.