SUBSTITUTED PIPERIDINYL QUINAZOLINES

Abstract: 2-(4-(1-hydroxy-1-substitutedmethyl)piperidino)-4-amino-6,7-dimethoxyq uinazolines with the formula <IMAGE> in which R is a cycloalkyl containing 3 to 7 carbon atoms, an alkenyl containing 2 to 6 carbon atoms, or a benzyl group. The compounds are prepared e.g. by reacting methyl N-(2-cyano-4,5-dimethoxyphenyl)(4-(1-hydroxy-1-substitutedmethyl)piper idino)thioformamidate with ammonium chloride in formamide at about 120<o>C. The compounds lower the blood pressure.

Description: SUBSTITUTED PIPERIDINY QUINAZOLINES _ *\ The invention concerns .2-(4-substitutedpiperidino)- 4*~amino-6,7-dimethoxyquinazolines. These new compounds have valuable pharmacological properties. Patents FR 2 350 101 and PR 2 389621 refer to 2-(4-phenylpiperidino)-4-amino-6,7-dimethoxyq * uinazoline and corresponding compounds, in which the phenyl group is subs- tituted with a fluoro or methoxy group. Published patent application PI 80 0481 refers to 2-(4-alkylcarbonylpiperidino)- and 2-(4-cycloalkylcarbonyl~ piperidino)-4-amino-6,7-dimethoxyquinazoline. These compounds lower the blood pressure. This invention deals with compounds of the formula in which R is a cycloalkyl containing 3 to 7 ' carbon atoms, an alkenyl containing 2 to 6 carbon atoms, or a benzyl group. This invention also deals with the methods or the preparation of the compounds with formula I, in which a) a compound with the formula is reacted with ammonia, ammonium halide, .urea, or urea hydrohalide, or b) ac * CDmpouh.d:with the formula in which Z is a cyano or amidino group, is reacted with a compound with the ormula in which Z' is a cyano or amidino group, or c) a compound with the formula in which X is a halogen such as chlorine, is reacted with a -compound with the formula or, d) a compound with the formula is reacted with a compound with formula VI, or e) a carbonyl compound with the formula i3 reduced to the corresponding alcohol. The invention also deals with the compounds of for¬ mula II, which are valuable intermediates for the prepara- tion of the 'formula I compounds * . The formula I compounds: can be used as pharmaceuti¬ cal agents for the treatment of hypertension. The methods a, b, c and d are carried out as de¬ scribed in PI 80 0481. Pormula VI compounds can be pre- pared from the corresponding ketones by reduction. ' - . 4-(1- ydroxyethyl.)piperidiήe is lάfow from J. " Org. " Chem. « 31 (1976.) 1732. The method;e-reduction is carried out with hydrogen under about 1 to 7 atm pressure and at ab'out 20 to 100 C using common hydrogenation catalysts such as palladium, platinum or nickel. Other reducing agents can also be used, e.g. sodium borohydride or aluminium isopropoxide. The effect of the compounds, administered perorally, on spontaneus hypertension v/as studied in rats and compared with that of the compounds described in PI 800481. A dose of 0.5 umol/rat- of the compound of example 3 produced a 30 mmHg decrease in blood pressure within 3 hours of the administration. This was more than with the compounds- * in PI 800481. ' The toxicity of the new compounds? is also somewhat less than that of the known compounds^ The following examples illustrate the invention. Example 1 1.3 g of NaBH 4 in 15 ml of water is added at 0 °G toa-solution of 4.7 g (0.026 mol) of 4-cyclopentylcarbonyl- piperidine in 5 " 0 ml of methanol. This is stirred for 1 h at 0 °C and for 2 h at 20 °C. The methanol is evaOorated OMP off, water is added and the solution is extracted with chloroform and the ' extract evaporated to dryness. 3.4 g of 4-(1-hydroxy-1-cyclopentylmethyl)piperidine (VI) is ob¬ tained; p. 123 - 5 °C, yield 72 %. 2.9 g (0.016 mol) of 4-(1-Hydroxy-1-cyclopentyl- methyl)piperidine in 25 ml of ethyl acetate is added in small portions at 0 - 5 °C to a solution of 3.5 g (0.016 mol) of 3,4-dimethoxy-6-isothiocyanatobenzonitrile in 25 ml of ethyl acetate. The solution is stirred at 0 °C for 18 h. The precipitate obtained is filtered, washed with cold .. ' ethyl acetate and dried. 4.1 g of 2-(4-(1-hydroxy-1-cyclo- pentyl ethyl)piperidino)thioformamido-4,5-dimethoxyben z o- nitrile is obtained; mp. 196 - 200 °C, yield 64 . A solution of 4.04 g (0.01 mol) of 2-( -(1-hydroxy- 1-cyclopentyl ethyl)piperidino)thioformamido-4,5-dimethoxy- benzonitrile, 4.0 g of methyl iodide and 0.6 g of calcium oxide in 3.0 ml of ethyl acetate is slowly warmed to 60 C and kept at that temperature for 18 h. The cooled mixture is filtered, the filtrate washed with dilute ITaOH solution a-tt water and evaporated to dryness. 3.6 g of methyl "" -- ' U-(2-cyano-4,5-dimethoxyphenyl)-(4-(1-hydroxy-1-cyclo- pentyl ethyl)piperidino)thio ormamidate (II) is obtained; mp. 41 - 4 °C, yield 86 %. A solution of 4.17 g (0.01 mol) of methyl N-(2-cyano- , -dimethoxyphenyl)-(4-( -hydroxy-1-cyclopentylmethyl)- piperidinothioformamidate and 15 g of ammonium chloride in 45 ml of formamide is heated and stirred under nitrogen . flow for 24 h at 120 °C. The mixture is cooled -and water is added, followed by extraction with chloroform. The extract is washed several times with water and the sol¬ vent Is removed under reduced pressure. The residue is dissolved in acetone and dry HC1 gas Is led Into the so¬ lution. 2.8 g of 2-(4--(1-hydroxy-1-cyclopentylmethyl)- piperidino)-4-amino-6,7-dimethoxyquinazoline hydrochloride is obtained; mp. 269 - 73 °C, yield 66 %. Example 2 Method e: 1.2 g of NaBH.in 10 ml of water is added in an ice bath to a solution of 4.35 g (0.01 mol) of 2-(4-cyclohexylcarbonylpiperidino)-4-amino-6,7-dimethoxy- quinazoline hydrochloride and 20 ml of 0.5 N NaOH solution in 80 ml of methanol. -The solution is stirred for 1 h at 0 °C and for 18 h at 20 °C. Some of the methanol is removed under reduced pressure, the precipitate formed is filtered off, washed with water and dried. The product is dissolved • in acetone and precipitated with gaseous HC1. 2-(4-hydroxy- 1-cyclohexylmethyl)piperidino)-4-amino-6,7-dimehoxyquinazo- line hydrochloride is obtained; mp. 196 - 200 C. Method b: 0.75 g (0.03 mol) of sodium hydride is . added to a solution of 1.78 g (0.01 mol) of 2--amino-4,5-di- methoxybenzonitrile and 2.38 g g (0.01 mol) of 1-cyano- 4-.(: -hydroxy-1-cyclohexylmethyl)piperidine in 25 ml of dry dimethylformamide. The .solution is heated under a nitrogen atmosphere for 5 h at 80 °G, cooled, and water is added and extracted with chloroform. The solvent is removed un¬ der reduced pressure. The residue is dissolved in acetone into which dry HC1 gas is led. Desired product is ob¬ tained. Method c: A solution of 2.4 g (0.01 mol) of 2-chloro- 4-amlno-6,7-dimethoxyquinazoline and 2.0 g (0.01 mol) of 4-(l-hydroxy-1-cyclohexylmethyl)piperidine in 30 ml of iso- a yl alcohol is refluxed for 18 h and cooled. The precipi¬ tated product is filtered, washed with ether and dried. De- sired product is obtained. Method d: A solution of 2.5 g (0.01 mol) of S-methyl- N-cyano-N'-(3-,4 r dimethόxyphenyl)isothiou ea * and -3.0 g (0.01 mol) " o 4-(1-hydroxy-1-cyclohexylmethyl)piperidine in 35 ml of diglycoldimethylether Is refluxed for 5 h and cooled. 7ater is added to the mixture, followed by extraction with chloroform. The solvent is evaporated off from the extract, and the residue is dissolved in acetone, into which HC1 gas is led. Desired product is obtained. - UR£ OMPI

Claims: CLAIMS 1. Compounds with the formula in which R is a cycloalkyl containing 3 to 7 carbon atoms, an alkenyl containing 2 to 6 carbon atoms, or benzyl. '2. " Compounds according to claim 1 in which R is a- cycloalkyl containing 3 to 7 carbons. 3. Compounds according to claim 2 in which R is a cycloalkyl containing 5 or 6 carbons. 4. Compounds according to claim 3 in which R is a cyclohexyl. 5. A method for the preparation of the compounds with ormula I, in which a) a compound, with the for uia is reacted with ammonia, ammonium halide , urea, or urea hydrohalide , or b) a compound with the formula In which Z is " a cyano or amidino group, is reacted with a compound with the formula in which Z' is a cyano or amidino group, or c) a compound with the formula 10 in which X is a halogen such as chlorine, is reacted with a compound with the formula or, d) a compound with the formula is reacted with a compound with formula VI, or ^5 e) a carbonyl compound with the formula Is reduced to the corresponding alcohol. 6) Compounds with formula II. ^URE

Inventors: HONKANEN ERKKI JUHANI, KARPPANEN HEIKKI OLAVI, NORE PENTTI TAPIO, PAAKKARI ASKO TUOMO ILARI, HONKANEN, ERKKI, JUHANI, KARPPANEN, HEIKKI, OLAVI, NORE, PENTTI, TAPIO, PAAKKARI, ASKO, TUOMO, ILARI
Applicants: ORION YHTYMAE OY, ORION-YHTYMAE OY
Application year: 1982
Main classification: C07D401
IPC codes: C07D211, C07D239, C07D401