1-SUBSTITUTED ALKYL-2-OXO-1,2-DIHYDROQUINOXALINE DERIVATIVES

Abstract: A compound which is a l-alkyl-2-oxo-1,2-dihydroquin­ oxaline derivative of formula [1]: wherein R₁ is hydrogen or lower alkyl, R₂ is hydrogen, lower alkoxy or halogen, and A is lower alkylene, or a pharmaco­ logically acceptable non-toxic salt thereof.

Description: This invention relates to 1-substituted alkyl-2-oxo-1,2-dihydroquinoxaline derivatives having sympatholytic α-receptor blocking activity useful for the treatment of hypertension. Known 1-substituted-2-oxo-3-substituted-1,2-dihydroquinoxaline derivatives having pharmacological activity are: 1-(amino, lower alkylamino or dilower alkylamino)-lower alkyl-2-oxo-3-lower alkyl-1,2-dihydroquinoxaline useful as a tranquilizer (Japan. Pat. Publ. No. 45-19907); 1-diethylaminoethyl-2-oxo-3-(benzyl or substituted benzyl)-1,2-dihydroxyquinoxaline having antispasmolytic or platelet aggregation activity (Japan. Pat. Publ. No. 46-11183, Japan. Pat. Unexam. Publs. No. 56-97226 and No. 56-97228); 1-alkyl-2-oxo-3-substituted carbamoyloxymethyl-1,2-dihydroquinoxaline effective against arteriosclerosis and thrombosis (Japan. Pat. Unexam. Publ. No. 49-24981); 1-alkyl-2-oxo-3-(tetrazole-5-yl carbamoyl)-1,2-dihydroquinoxaline useful for the treatment of extrinsic asthma and urticaria (Japan. Pat. Unexam. Publ. No/ 50-29583); 1-substituted phenyl-2-oxo-3-(alkyl, carboxyalkyl or dicarboxyalkyl)-1,2-dihydroquinoxaline is useful against inflammation and rheumatoid arthritis (Japan. Pat. Unexam. Publ. No. 55-115875); and 1-(phenyl or substituted phenyl)-2-oxo-3-(amino or alkaneamide)1,2-dihydroquinoxaline-4-oxide having an antispastic action, ataractic action of psycholeptic activity (Japan. Pat. Unexam. Publ. No. 56-92277). Further quinoxaline derivatives which are useful for the treatment of hypertension are known, i.e. : 1-isopropylamino-3-(2-(2-quinoxalyl)phenyl-2-propanol (Japan. Pat. Publ. No. 43-9220), 2-methyl-3-(2-(4-phenyl or tryl)-(piperazinyl)ethoxyquinoxaline (Japan. Pat. Publ. No. 48-21949), 5-halogeno-6-(2-imidazolin-2-yl-amino)-quinoxaline (Japan. Pat. Unexam. Publ. No. 48-97878), 2-methyl-3-(2-hydroxyquinoxaline-6 or 7-yl) alanine (Japan. Pat. Unexam. Publ. No. 52-97933), 5- or 8-(2-hydroxy-3-substituted amino-propoxy)-2-oxo-3-methyl quinoxaline (Japan. Pat. Unexam. Publ. No. 55-162783) and 4-fluoro-N-{2-[4-(5-quinoxalyl)-1-piperazinyl]ethyl}benzamide (Japan. Pat. Unexam. Publ. No. 60-104063). It is of great importance to find excellent pharmaceuticals having stronger inhibitory activities. EP-A-0,032,564 discloses that the following compound (caroverin) has various pharmaceutical properties: We have found certain 1-[1-(4-substituted piperazinyl)]alkyl-2-oxo-3-lower alkyl or non-substituted-1,2-dihydroquinoxalines having sympatholytic α-receptor blocking activity with pharmaceutically interesting properties. The present invention provides a compound which is a 1-alkyl-2-oxo-1,2-dihydroquinoxaline derivative of formula [1]: wherein R₁ is hydrogen or C₁₋₆ (preferably C₁₋₄) alkyl, R₂ is hydrogen, C₁₋₆ (preferably C₁₋₄) alkoxy or halogen, and A is C₁₋₆ (preferably C₁₋₄) alkylene, or a pharmacologically acceptable non-toxic salt thereof. The compound of formula [1] can be provided in the form of a pharmacologically acceptable non-toxic salt. Examples of salts are salts of inorganic acids such as hydrochloride, sulfate or phosphate salts, and salts of organic acids such as acetate, propionate, glycolate, gluconate, malate, tartrate, succinate, mandelate, glutamate, aspartate, methanesulfonate and toluenesulfonate salts. The compound of formula [1] can be produced by the following process. A 2-oxo-1,2-dihydroquinoxaline derivative of formula [2]: as defined above is reacted with a hydroxyalkyl halide of formula X₁-A-OH wherein X₁ is a halogen and A is as defined above in an organic solvent, to obtain a 1-hydroxyalkyl-2-oxo-1,2-di-hydroquinoxaline derivative of formula [3] wherein R₁ and A have the same meanings hereinabove, then halogenating the said compound [3] with halogenating agent to obtain 1-halogenoalkyl-2-oxo-1,2-dihydroquinoxaline of the formula wherein X is halogen, and R₁ and A have the same meanings hereinabove, thereafter reacting the said compound [4] with an amine of the formula wherein R₂ has the same meaning hereinabove, in the presence of a base and in an organic solvent, and if desired converting the resultant compound of formula [1] into a pharmacologically acceptable non-toxic salt thereof. In the compound (2) R₁ is hydrogen or C₁₋₆ alkyl, preferably C₁₋₄ alkyl, which may optionally be branched. Examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl. The compounds (2) can be produced by the process disclosed in J. Am. Chem. Soc., 75: 328 (1953) and ibid. 76: 287 (1954). The group A in the above hydroxyalkyl halide is C₁₋₆ alkylene, for example methylene, ethylene, methylmethylene, propylene, 1-methylethylene, dimethylethylene or 1-ethylmethylene. Ethylene is preferred. The group X in the above hydroxyalkyl halide is a halogen such as chlorine or bromine. In general chlorine is preferred. The preferred compound is ethylene chlorohydrine. The reaction of the compound (2) with the hydroxyalkyl halide proceeds in an organic solvent such as t-butanol. The above reaction proceeds preferably in an aqueous alkali such as a hydroxy alkali, and preferably under heating. Isolation of the product (3) can be performed by adding water to the reaction mixture and extracting with a water immiscible organic solvent. The above compound (4) can be produced by halogenating the compound (3) with a halogenating agent. Examples of the halogenating agent are known halogenating agents such as SOCl₂, PCl₅ or POCl₃. The halogenation reaction can be carried out, in general, in an inert organic solvent such as chloroform. The reaction proceeds at room temperature. The product (4) can be isolated by adding a water immiscible organic solvent such as chloroform, washing with dilute aqueous alkali, dehydrating the organic layer and removing the solvent therefrom. The compound (4) can be purified, if required, for example by silica-gel column chromatography. The compound (1) can be produced by reacting the compound (4) with the amine (5). The group R₂ in the amine (5) is hydrogen, C₁₋₆ alkoxy or halogen. Examples of C₁₋₆ alkoxy are C₁₋₄ alkoxy which may optionally be branched, such as methoxy, ethoxy, propoxy, isopropoxy, 1-methylethoxy, butoxy, isobutoxy, sec-butoxy or t-butoxy. An example of the halogen is chlorine. Accordingly examples of the amine (5) are 4-phenylpiperazine, 4-(o-, m- or p-chlorophenyl)-piperazine or 4- (o-, m- or p-methoxyphenyl)-piperazine. The reaction of the compound (4) and the amine (5) conventionally proceeds in an inert organic solvent such as benzene under heating. In the reaction hydrogen halogenide is generated so that the reaction preferably is carried out in the presence of an acid binder, for example a tertiary organic amine such as triethylamine. The compound (1) can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with a water immiscible organic solvent such as benzene or chloroform. The thus obtained compound (1) is purified, if required, by column chromatography using silica-gel, activated alumina or an adsorption resin with an elution solvent such as chloroform-methanol or benzene-ethyl acetate. The compound (1) is in general produced in the form of a free base, but it can be produced in the form of a conventional salt thereof. For example, the hydrochloride can be prepared by dissolving the compound (1) in a C₁₋₆ alcohol such as methanol or ethanol, adding a calculated molar amount of hydrochloric acid, and isolating the precipitated material, or if not precipitated, by adding ether therein to precipitate. Pharmacological actions of the compound (1) are illustrated below: A test sample is prepared by dissolving a compound in the examples in a small amount of methanol, adding a two-molar amount of hydrochloric acid in methanol to precipitate the material, or if not precipitated, adding diethyl ether therein to precipitate, filtering the precipitate, and drying in vacuo to obtain the dihydrochloride. The thus obtained test sample is dissolved in distilled water or physiological saline before use. (1) α-blocking action: A rat, Wistar, male, body weight 200 g, was sacrificed by bleeding. The extirpated spermatic duct was hung in Tyrode's solution at 37°C. The specimen duct was loaded at 0.5 g tension and nutrient solution was bubbled with a mixed gas of oxygen-carbon dioxide (95:5). A constrictor, noradrenaline, 2 x 10⁻⁵M was added in a nutrient solution to constrict the spermatic duct. At the maximum constriction, the spermatic duct was washed with nutrient solution, and this operation was repeated at 20 minute intervals until a constant constriction was observed. Thereafter a test compound, used after dissolving and diluting with distilled water, was added to the nutrient solution, and after three minutes noradrenaline was added to constrict the duct specimen. The reaction was recorded at an isotonic condition. A suppressive ratio (%) was calculated as the ratio of suppression on the constriction with the test compound to the constriction with adding noradrenaline. The results are shown in Table 1. Furthermore the constrictor noradrenaline was replaced by barium chloride (2 x 10⁻³M), also shown in Table 1. As shown in the Table, since the test sample did not show the suppressive action against constriction for barium chloride at 10⁻⁶g/ml, the above constriction suppressive action by noradrenaline is not based upon non-specific smooth muscle suppression, but is an action through the α-receptor. (2) Hypotensive action: A rat, Wistar, male, body weight 320-430 g, was anaesthetized with urethane (1.0 g/kg, i.p.). The blood pressure was measured through pressure-transducer by cannulation in the femoral artery. The test compound, dissolved and diluted in physiological saline before use, was administered at 0.05 ml/100 g body weight through a cannula in the femoral artery. The test compound obtained in Example 4 showed hypotensive action of approximately 30% at 10 µg/kg administration and approximately 40% at 100 µg/kg, which continued after 60 minutes administration. The test compound obtained in Example 7 showed the same level of hypotensive activity as the compound in Example 4. The maximum hypotensive activity of the test compound in Example 7 is slightly stronger than that of Example 4. However prolongation of activity is less than that of Example 4 for the 100 µg/kg administered group. The following Examples further illustrate the present invention. Referential Example 1 1-(2-hydroxyethyl)-2-oxo-1,2-dihydroquinoxaline: 2-hydroxyquinoxaline (7.31 g, 50 mM) and 5N-NaOH (50 ml) were added to t-butanol (150 ml). Ethylene chlorohydrin (20.13 g, 0.25 M) was added therein and stirred at 60°C for 165 minutes. The organic solvent was removed in vacuo . Water was added to the residue and extracted with chloroform (once with 250 ml and twice with 50 ml). The combined chloroform layer was dried with anhydrous sodium sulfate and concentrated in vacuo . The residue was charged on a column of silica-gel (Wakogel C-200, Wako Pure Chem. Co.) and eluted with chloroformmethanol (50:1) to obtain 1-(2-hydroxyethyl)-2-oxo-1,2-dihydroquinoxaline (8.11 g, yield : 85.4%). Examples 1 - 6 1-[2-(4-substituted phenylpiperazinyl)ethyl]-2-oxo-1,2-dihydroquinoxaline: Thionylchloride (0.42 ml) was added dropwise under ice-cooling into 1-(2-hydroxyethyl)-2-oxo-1,2-dihydroquinoxaline (0.95 g, 5 mM) dissolved in chloroform (10 ml), and stirred at room temperature for chlorination. Benzene (30 ml) and triethylamine were added to the reaction mixture, amine (10 mM) was further added and the mixture was refluxed. Dilute aqueous potassium carbonate was added to the reaction mixture and extracted with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo . The residue dissolved in a small amount of chloroform was charged on a column of silica-gel (C-200, 80g) and eluted with chloroform-methanol to obtain 1-[2-(4-substituted phenylpiperazinyl)ethyl]-2-oxo-1,2-dihydroquinoxaline. Table 2 illustrates the chlorination time, type of amine, amount of amine used, amount of triethylamine used, reflux time, ratio of eluent and yields. Compound of Example 1 Compound of Example 2 Compound of Example 3 Compound of Example 4 Compound of Example 5 Compound of Example 6 Referential Example 2 1-(2-hydroxyethyl)-2-oxo-3-methyl-1,2-dihydroquinoxaline: 3-Methyl-2-hydroxyquinoxaline (4.8g, 30 mM) was added to t-butanol (90 ml). 5N NaOH (30 ml) was added therein, heated at 60°C. Ethylene chlorohydrin (10.2 ml, 150 mM) was added therein and stirred at 60°C for 3-4 hours. The Precipitated by-product was removed by filtration and the filtered solution was concentrated in vacuo . The residue was extracted with chloroform (100 ml) and water (100 ml). The aqueous layer was extracted several times with chloroform (100 ml). The combined chloroform layer was dried with anhydrous sodium sulfate and concentrated in vacuo . Acetone (150 ml) was added to the residue, heated, and cooled for recrystallization to obtain 1-(2-hydroxyethyl)-2-oxo-3-methyl-1,2-dihydroquinoxaline as needle crystals. Yield: 5.19 g (yield: 85.8%). Examples 7 - 9 1-[2-(4-substituted phenylpiperazinyl)ethyl]-2-oxo-3-methyl-1,2-dihydroquinoxaline: Thionylchloride (0.44 ml. 6mM) was added under ice-cooling to 1-(2-hydroxyethyl)-2-oxo-3-methyl-1,2-dihydroquinoxaline (1.02 g, 5mM) dissolved in chloroform (15 ml), and stirred at room temperature for 4-6 hours. Benzene (20 ml) and triethylamine (4.18 ml, 30 mM) were added to the reaction mixture, amine (10 mM) was further added and the mixture was refluxed for 24 hours. The reaction mixture was concentrated in vacuo and chloroform (60 ml) and water (100 ml) were added to the residue, then extracted with chloroform. The water layer was extracted 2-3 times with chloroform (60 ml). The combined extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue, dissolved in a small amount of chloroform, was charged on a column of silica-gel (C-200, 160 g) and eluted with chloroform-methanol (200:1) to obtain 1-[2-(4-substituted phenylpiperazinyl)ethyl]-2-oxo-1,2-dihydroquinoxaline. Table 3 illustrates the type of amine, the amount used and yields. Compound of Example 7 Compound of Example 8 Compound of Example 9

Claims: Claims for the following Contracting States : CH, DE, FR, GB, IT, LI A compound which is a 1-alkyl-2-oxo-1,2-dihydroquinoxaline derivative of formula [1]: wherein R₁ is hydrogen or C₁₋₆ alkyl, R₂ is hydrogen, C₁₋₆ alkoxy or halogen, and A is C₁₋₆ alkylene, or a pharmacologically acceptable non-toxic salt thereof. A compound according to Claim 1 wherein R₁ is methyl and A is ethylene. A compound according to Claim 1 or 2 wherein R₂ is hydrogen, methoxy or chlorine. A process for preparing a compound as defined in Claim 1 which comprises reacting a compound of formula [4]: wherein X is a halogen and R₁ and A are as defined in Claim 1 with an amine of formula [5]: wherein R₂ is as defined in Claim 1, in the presence of a base and in an organic solvent, and if desired converting the resultant compound of formula [1] into a pharmacologically acceptable non-toxic salt thereof. A process according to Claim 4 wherein the compound of formula [4] is prepared by halogenating a compound of formula [3]: wherein R₁ and A are as defined in Claim 4 with a halogenating agent. A process according to Claim 5 wherein the compound of formula [3] is prepared by reacting a compound of formula [2]: wherein R₁ is as defined in Claim 5 with a hydroxyalkyl halide of formula: X₁-A-OH wherein X₁ is a halogen and A is as defined above in an organic solvent. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier or diluent. A compound as defined in Claim 1 for use in a method of treatment of the human or animal body by therapy. A compound as defined in Claim 1 for use in a method of treatment of hypertension. Use of a compound as defined in Claim 1 in the manufacture of a medicament for the treatment of hypertension. Claims for the following Contracting States : ES A process for preparing a compound which is a 1-alkyl-2-oxo-1,2-dihydroquinoxaline derivative of formula [1]: wherein R₁ is hydrogen or C₁₋₆ alkyl, R₂ is hydrogen, C₁₋₆ alkoxy or halogen, and A is C₁₋₆ alkylene, or a pharmacologically acceptable non-toxic salt thereof which comprises reacting a compound of formula [4]: wherein X is a halogen and R₁ and A are as defined above with an amine of formula [5]: wherein R₂ is as defined above, in the presence of a base and in an organic solvent, and if desired converting the resultant compound of formula [1] into a pharmacologically acceptable non-toxic salt thereof. A process according to Claim 1 wherein the compound of formula [4] is prepared by halogenating a compound of formula [3]: wherein R₁ and A are as defined in Claim 1 with a halogenating agent. A process according to Claim 2 wherein the compound of formula [3] is prepared by reacting a compound of formula [2]: wherein R₁ is as defined in Claim 2 with a hydroxyalkyl halide of formula: X₁-A-OH wherein X₁ is a halogen and A is as defined above in an organic solvent. A process according to any one of Claims 1 to 3 which further comprises mixing the compound of formula [1] or a pharmacologically acceptable non-toxic salt thereof with a pharmaceutically acceptable carrier or diluent.

Inventors: HAYASHI, EIICHI, HONDA, EIICHI, KINOSHITA, HIROYUKI, SAITO, TETSU, SHIBATA, KENSUKE, SUZUKI, YUKIO, TAKAYANAGI, NORIYASU, YASO, MASAO
Applicants: ASAHI KASEI KOGYO KABUSHIKI KAISHA
Application year: 1988
Main classification: C07D241
IPC codes: A61K31, A61P9, C07D241, A61P25