SUBSTITUTED 1,5-BENZODIAZEPINE COMPOUNDS

Abstract: Compounds of the formula wherein R₁ is alkyl, alkenyl, alkynyl, cycloalkyl, or substituted alkyl, and R₄ is aryl or heterocyclo are disclosed. These compounds are useful as cardiovascular agents and especially as anti-hypertensive agents.

Description: This invention relates to substituted 1,5-benzodiazepine compounds of formula I and pharmaceutically acceptable salts thereof R₁ is straight or branched chain lower alkyl of 1 to 5 carbons; R₂ is straight or branched chain lower alkyl of 1 to 5 carbons; R₃ is straight or branched chain lower alkyl of 1 to 5 carbons; R₄ is 2-nitrophenyl, 3-nitrophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-phenyl, 2,3-dichlorophenyl, 2-chloro-3-nitrophenyl, or 4-(2,1,3-benzoxadiazol)-yl; and R₁₀ is hydrogen. This invention in its broadest aspects relates to substituted 1,5-benzodiazepine compounds of formula I above, to compositions and the method of using such compounds as cardiovascular agents. Known in the art (Chemical Abstracts, vol. 66, no. 9, page 3629, abs. no. 37969m) are 1,5-diazepine derivatives (A) useful as antispasmodics muscle relaxants, sedatives, tranquillizers and analgesics: Applicant has previously described 1,5-benzodiazepine compounds useful as antihypertensive agents due to their calcium entry blocking activity in EP-A-0 208 964. Applicant has also described calcium entry blocking 1,5-benzodiazepine compounds having an acyl or hydrogen at the 1-position in EP-A-0 211 429. The term lower alkyl used in defining various symbols refers to straight or branched chain hydrocarbon radicals having from one to five carbons. The compounds of formula I can be prepared by reacting an unsubstituted 1,5-benzodiazepine of the formula with a reagent of the formula (III) R₁-L in a suitable solvent wherein L is a leaving group such as iodo, chloro, bromo, or tolylsulfonyl. The unsubstituted 1,5-benzodiazepines of formula II can be prepared as follows. For example, by treating a 3-[(2-aminophenyl)-amino]-2-alkenoic acid ester of the formula in a suitable solvent with an aldehyde of the formula (V) R₄CHO in the presence of acetic acid. The intermediate of formula (IV) can be prepared by treating 1,2-benzenediamine of the formula with the β-keto ester of the formula in a suitable solvent in the presence of acetic acid and heat. Compounds prepared by the above-mentioned reactions are those wherein: R₁ is straight or branched chain lower alkyl of 1 to 5 carbons; R₂ is straight or branched chain lower alkyl of 1 to 5 carbons, especially methyl; R₃ is straight or branched chain lower alkyl of 1 to 5 carbons; R₄ is mono substituted phenyl wherein said substituent is selected from halo, CF₃, nitro, disubstituted phenyl wherein said substituents are selected from halo, CF₃, and nitro, or 2,1, 3-benzoxadiazolyl. R₁₀ is hydrogen. Most preferred are the above compounds wherein: R₁ is methyl. R₂ is methyl. R₃ is methyl, ethyl, or isopropyl, especially ethyl. R₄ is 2-nitrophenyl, 3-nitrophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-phenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3,-dichlorophenyl, 2-chloro-3-nitrophenyl, or 4-(2,1,3-benzoxadiazol)-yl, especially 3-nitrophenyl. The compounds of formula I which contain basic amino groups form salts with a variety of inorganic and organic acids. The non-toxic pharmaceutically acceptable salts are preferred, although other salts may also be useful in isolating or purifying the product. Such pharmaceutically acceptable salts include those formed with hydrochloric acid, methanesulfonic acid, sulfuric acid, acetic acid or maleic acid. The salts are obtained by reacting the product with an equivalent amount of the acid in a medium in which the salt precipitates. The compounds of formula I and the pharmaceutically acceptable salts thereof are useful as cardiovascular agents. These compounds act as calcium entry blocking vasodilators and are especially useful as anti-hypertensive agents. Thus, by the administration of a composition containing one (or a combination) of the compounds of this invention the blood pressure of a hypertensive mammalian (e.g., human) host is reduced. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day, preferably from about 1 to about 50 mg. per kilogram per day, is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, or intravenous routes can also be employed. As a result of the calcium entry blocking activity of the compounds of formula I, it is believed that such compounds in addition to being anti-hypertensives may also be useful as antiarrhythmic agents, as anti-anginal agents, as antifibrillatory agents, as anti-asthmatic agents, and in limiting myocardial infarction. The compounds of this invention can also be formulated in combination with a diuretic, or a beta-adrenergic agent, or angiotensin converting enzyme inhibitor. Suitable diuretics include the thiazide diuretics such as hydrochlorothiazide and bendroflumethiazide, suitable beta-adrenergic agents include nadolol, and suitable angiotensin converting enzyme inhibitors include captopril. The compounds of formula I can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg. of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer or flavor, in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained. The following examples are illustrative of the invention. Temperatures are given in degrees centigrade. Example 1 2, 5-Dihydro-1, 4-dimethyl-2-(3-nitrophenyl )-1H1,5-benzodiazepine-3-carboxylic acid, ethyl ester a) 3-[(2-Aminophenyl)amino]-2-butenoic acid, ethyl ester A solution containing 1,2-benzenediamine (16.2 g., 15.0 mmole), ethylacetoacetate (19.5 g., 15.0 mmole), and acetic acid (0.6 ml.) in benzene (125 ml.) is heated at reflux temperature for 2 hours using a water separator. The reaction is allowed to cool down to room temperature and the solvent is stripped off. The residue is crystallized from isopropyl ether-hexanes to give 19.5 g. of dull white solid 3[(2-aminophenyl)amino]-2-butenoic acid, ethyl ester; m.p. 73 - 81°. b) 2,5-Dihydro-4-methyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, ethyl ester A solution of 3-[(2-aminophenyl)amino]-2-butenoic acid, ethyl ester (5.0 g., 22.7 mmole) in absolute ethanol (30 ml.) is treated with 3-nitro-benzaldehyde (3.43 g., 22.7 mmole) and acetic acid (0.25 ml.). The reaction is allowed to stir under argon at room temperature for 24 hours. The solvent is evaporated and the residue is purified by flash chromatography (35% ethanol in hexanes). The product is crystallized from dichloromethaneisopropyl ether to give 3.51 g. of orange solid 2, 5-dihydro-4-methyl-2-(3-nitrophenyl)-1H-1, 5-benzo-diazepine-3-carboxylic acid, ethyl ester, m.p. 147.5 - 150°. TLC (silica gel; ethyl acetate: hexanes, 1:1) R f = 0.35. c) 2,5-Dihydro-1,4-dimethyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, ethyl ester A reaction mixture containing 2, 5-dihydro-4-methyl-2-(3-nitrophenyl)-1H-1, 5-benzodiazepine-3-carboxylic acid, ethyl ester (1,5 g., 4.25 mmole) in dry dimethylformamide (5 ml.) is treated with methyl iodide (581 mg., 5.5 mmole) and then allowed to stir at room temperature for 24 hours. The reaction mixture is diluted with ethyl acetate and is washed with sodium bicarbonate, water, and brine. After drying over magnesium sulfate, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (30% ethyl acetate in hexanes). The yellow foam obtained (701 mg.) is crystallized from ether-hexanes to provide yellow crystalline 2,5-dihydro-1,4-dimethyl-2-(3-nitro-phenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, ethyl ester; m.p. 113 - 115.5°. TLC (silica gel; ethyl acetate:hexanes, 1:1) R f = 0.5. Examples 2 and 3 Following the procedure of Example 1 the following compounds within the scope of this invention can be prepared: are prepared from sufficient bulk quantities by mixing the product of Example 1 and cornstarch with an aqueous solution of the gelatin. The mixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with granulation. This mixture is then compressed in a tablet press to form 1000 tablets each containing 100 mg. of active ingredient. In a similar manner, tablets containing 100 mg. of the product of Examples 2 or 3 can be prepared. A similar procedure can be employed to form tablets containing 50 mg. of active ingredient. The active substance, preservatives, and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters. The solution is filtered through a sterile filter and aseptically filled into presterilized vials which are closed with presterilized rubber closures. Each vial contains 5 ml. of solution in a concentration of 100 mg. of active ingredient per ml. of solution for injection. In a similar manner, an injectable solution containing 100 mg. of active ingredient per ml. of solution can be prepared for the product of Examples 2 or 3. are prepared from sufficient bulk quantities of the product of Example 1 Avicel , and a portion of the stearic acid. The slugs are ground and passed through a #2 screen, then mixed with the hydrochlorothiazide, lactose, cornstarch, and remainder of the stearic acid. The mixture is compressed into 350 mg. capsule shaped tablets in a tablet press. The tablets are scored for dividing in half. In a similar manner, tablets can be prepared containing 100 mg. of the product of Examples 2 4 or 3.

Claims: A compound of the formula including a pharmaceutically acceptable salt thereof wherein: R₁ is straight or branched chain lower alkyl of 1 to 5 carbons; R₂ is straight or branched chain lower alkyl of 1 to 5 carbons; R₃ is straight or branched chain lower alkyl of 1 to 5 carbons; R₄ is 2-nitrophenyl, 3-nitrophenyl, 2-chlorophenyl, 3-chlorophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-phenyl, 2,3-dichlorophenyl, 2-chloro-3-nitrophenyl, or 4-(2,1,3-benzoxadiazol)-yl; and R₁₀ is hydrogen. A compound according to claim 1 wherein: R₁ is methyl; R₂ is methyl; and R₃ is methyl, ethyl or isopropyl. A compound according to claim 2 wherein: R₃ is ethyl; and R₄ is 3-nitrophenyl. A composition useful in reducing blood pressure in a mammal comprising a pharmaceutically acceptable carrier and an anti-hypertensively effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

Inventors: ATWAL, KARNAIL SINGH
Applicants: E.R. SQUIBB & SONS, INC.
Application year: 1987
Main classification: C07D243
IPC codes: A61K31, A61P9, C07D401, C07D403, C07D417, C07D243, C07D413