• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Novel substituted 2-piperidino-4-amino-6,7-dimethoxy-quinazolines having the formula <CHEM> wherein R is an alkyl containing 1 to 5 carbons, a cycloalkyl containing 3 to 7 carbons, benzyl, an alkoxy containing 1 to 5 carbons, benzyloxy, or a group -NR<1>R<2>, wherein R min or R sec is hydrogen or a chained alkyl containing 4 to 5 carbons or wherein R<1> and R<2>, together with the nitrogen atom, form a cyclic amino group containing 3 to 7 carbons, which amino group may be substituted by one or two lower-alkyl groups, or their pharmaceutically acceptable salts.
    公开号:SU1042616A3
    申请号:SU813250801
    申请日:1981-02-18
    公开日:1983-09-15
    发明作者:Юхани Хонканен Эркки；Марьяна Хейтава Майя；Юхани Кайрисало Пекка；Тапио Норе Пентти；Олави Карппанен Хейкки；Туомо Илари Тааккари Аско
    申请人:Орион-Ихтюмя Ой (Фирма)；
    IPC主号:
    专利说明:

    dimethoxyquinazoline. M.p. 134 13bs, yield 30%.
    Example 2. 2- (4-Pyrrolidinocarbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride.
    A solution of 2.4 g (0.01 mol) of 2-chloro-4-amino-6, 7-dimethoxyquinazoline and 1.82 g (0.01 mol) of 4-pyrrolidinocarbonylpiperidine in 30 ml of isoamine alcohol is boiled under reflux in a for 18 hours. After cooling, the precipitated product is filtered off, washed with diethyl ether and dried. 1.0 g of 2- (4-pyrrolidinocarbonylpiperidino) -4-amino-6,7-dimethoxyhydroxyneane hydrochloride hydrochloride is obtained, mp. 201-203c, yield 24%.
    Example 3. 2- (4-Pyrrolidinocarbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride.
    g. Solution 1, .0 g (0.004 mol) of S-methyl-H-cyaio-I - (3,4-imethoxyphenyl.) isothiourea and 0.78 g (0.004 mol) of 4-pyrrolidinocarb6nylpiperidine in 15 ml of glycol dimethyl ether are boiled with reflux for 5 hours. After cooling, water is added and the solution is extracted with chloroform. The extract is washed with water and dried, an ethereal solution of hydrogen chloride is added to the extract, whereby the product crystallizes. After recrystallization from a water-ethanol (80:20) mixture, 0.35 g of 2- (4-pyrrolidinocarbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride is obtained. T. pl. 201-203 ° C, yield 21%.
    Example 4. 2- (4-Ethoxycarbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride.
    A mixture of 39.1 g (0.1 mol) of methyl-N- (2-cyano-4,5-dimethoxyphenyl) - (4 is sicarbonylpiperidino) thioformamidate and 160 g (3 mol) of ammonium chloride (alternatively 3 mol of urea- hydrochloride) in 400 ml of formamide is heated for 24 hours in a stream of nitrogen g with stirring and the temperature of 120 ° C is cooled and 400 ml of water is added. The precipitated product is filtered, washed with cold water and acetone, and dried. 20.0 g of 2- (4-ethoxycarbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride are obtained. M.p. 260-265s, yield 50%.
    Example 5. 2- (4-Pyrrolidinocarbonylpiperidino) -: 4-amino-6,7-dimethoxychione azoline.
    A solution of 3.6 g (0.01 mol) of 2- (4-ethoxycarbonyl) -piperidino-4-amino-6/7-dimethoxyquinazoline in 10 ml of pyrrolidine is boiled for 42 hours under reflux. The solvent is distilled off under reduced pressure and the residue is crystallized from ethanol-water (80:20). 3.6 g of 2- 4-pyrrolidinocarbonyl .. piperidine-4-amino-6,7-dimethoxyquinazoline are obtained. M.p. 312-314 C, you; hrd 94%. Example 6. 2- (3-Pyrrolidinocarbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline. A mixture of 41.6 g (0.1 mol) methyl-N- (2-cyano-4, Zgdimethoxyphenyl) - (3-pyrrolidinocarbonylpiperidino) thioformamidate and .160 g-ammonium chloride in 400 ml of formamide is heated for 24 hours in a stream of nitrogen at 400 ml of water are added, the mixture is added. sedate with concentrated am-. Myak and extracted with chloroform. The extract is washed with water and the solvent is distilled off under reduced pressure. The residue is crystallized from a mixture of ethanol - water (80:20). 30.8 g of 2- (3-pyropolydine carboxylic acid ino) -4-amino-6,7-dimethoxy quinazoline are obtained, mp, 134-136 ° C, yield 80 %, PRI mme R 7, 2- (4-Pyrrolidinocarbonylpiperidino) -4-amino-6,7- / -dimethoxyquinazoline hydrochloride. When using 41.6 g of methyl-I- (2-cyano-4,5-dimethoxyphenyl) -4-pyrrolidinocarbonylpiperidno-thiofolamidate as the starting material according to the method of example 4, 35.8 g of 2- (4-pyrrolidinocarbonylpiperidino) -4 is obtained -amino-6,7-dimethoxy quinazoline hydrochloride, T, mp, 201–203 ° C, yield 85%; Example, 2- (4-Neopentylox Carbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride. npii using 43.3 g of methyl-Y- (2-cyano-4,5-dimethoxyphenyl) - (4-neopentnloxycarbonylpiperidino) thioformamidate as starting material according to the method of example 4, 16.0 g of 2- (4-neopentyloxycarbonylpiperidino) - 4-amino-6,7-dimethoxyquinazoline hydrochloride, T, pl. 269-272-C, 37% yield, EXAMPLE 9, 2- (4-Piperidinocarbonylpiperidino) -4-amino-6,7, -Yi and methoxy-sichinazoline, When using 43 g methyl-H- (2-cyano -4,5-dimethoxyphenyl) - (4-pi-peridinocarbonylpiperidino) thioformamidate as a starting material according to the method of example 6, 24 g of 2- (4-piperidinocarbonyl 1I perilino) -4-amino-6,7-dimethoxycholine zoline is obtained, mp. , 125-128 ° C, 61% yield, Example 10, () -2- (3-Etocium to Carbonylpiperidino) -4-amino-b, 7-dimethoxyquinazoline, When using 39.1 g of (+) - methyl-N- (2-cyano-4,5-dimethoxyphenyl) - (3-ethoxycarbonylpipercdino) THOijibp mamidate as ref a single material according to the method of example 6, 24.0 g of (+) - 2- (3-ethoxycarbonyl, piperidino) -4-amino-6,6-dimethoxyquinazoline, T, mp, 227-230c t) are obtained, 2% yield 67%, Example 11. (-J-2- 3-Ethoxycarbonylpiperidino) -4-amino-6,7-dimboxyquinaeolin. When using 39.1 g of (-) - methyl-I- (2-cyano-4,5-dimethoxyphenyl) - (2-ethoxycarbonylpipvridino) thioformamidate as the starting material according to the method of Example 6 semi-. 25.0 g of (-) - 2- (3-ethoxycaponyl. J piperilino) -4-amino-6,7-dimethoxytol quinazolane, T. mp, 227-229 C ,, 0 (0.2 n NS, ce5 g / 100 ml), EXIT 69%, Example 12. 2- (4- (1-Aetidinyl (carbonylpiperidino) -4-gshino-6, 7-dimethoxychinazoline. When using 2- (4-ethoxycarbonyl) -piperidino-4 α-amino-6,7-dimethoxyquinazoline and azetidine as a starting material according to the procedure of Example 5, (1-azetidinyl) carbonylpiperidinoT-4-amino-6, 7-dimethoxyxyquinazoline is obtained. mp. 238-244C, yield 80%. Example 13. 2- 4-Carbamoyl-piperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride. A mixture of 180 g (0.5 mol) methyl-N-. -2 (2-cyano-4 , 5-dimethoxyfvil) - (4 | -carbamoylpiperidino) thiofohlbmid and 780 g of ammonium chloride in 2600 tm of phosmide are heated under stirring for 24 hours in a stream of nitrogen at 120 ° C. After cooling, 1300 ml of water is added and the cooled product is cooled filtered, washed with water and acetone and dried. I get 130 g of 2- (4-carbonylpiperidino) -4- "-g1mino-6,7-dimethoxyquinazoline hydrochloride, So pl, 273-27bs, yield 80%, Example 14, 2- (4-tert-Bu1.ylcarbamoylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride. A mixture of 1.3 g (0.003 mol) methyl-K- (2-cyano-4,5-dimethoxyphenylJ- (4-tert-butylcarbamoylpiperidino) 1 thioformamidate and 39 g of ammonium chloride in 10 ml of formamide is heated with stirring under a stream of nitrogen for 24 After cooling, water and trisodium nitride, ammonia to pH 9.0 are added, the solution is extracted with chloroform. The extract is washed with water and stripped under reduced pressure. g 2- (4-tert-butylcarbamoyl pippvridino) -4-amino-6,7-dimeto sihinaeolin hydrochloride, mp 129-132 C, yield. EXAMPLE EXAMPLE 15. 2- 2-Methylpiperidino) karbonilpiperkdiio (-4-amino-6, 7-dimethoxyquinazoline gndrohlorid.
    A mixture of 44.5 g (0.1 mol) of methyl-N- (2-cyano-4,5-dimethoxyphenyl) - {4- {2-methylpiperidino) carbonylpiperidino / thioforma resin and 160 g of ammonium chloride in 500 ml of formamide is heated for 24 hours at 120 ° C. The product is obtained according to the procedure of Example 6. 29.4 g of (2-methylpiperidino) carbonylpiperidino3-4-amino-b, 7-dimethoxyquinazoline hydrochloride are obtained. T, Sq. 140-143 C, yield 71%, V
    Example 16, (Azacyclohept-1-yl-carbonyl piperidino-4-amino-6, 7-dimethoxyquinazoline hydrochloride.
    A mixture of 89 g (0.2 mol) methyl-N- (2-cyano-4,5-dimethoxyphenyl) (azadiclohept-1-yl-carbonyl) piperidino} thioformamidate and 300 g of ammonium chloride in 1000 ml of formamide is heated for 24 hours at 120 ° C, the Product is isolated according to the method of Example 6. 45.5 g of (azacyclohept-1-yl-carbonyl) piperidino-4-amino-6, 7-dimethoxy-hydroxychloride hydrochloride are obtained. 234-235 yield 55%,
    Example 17, (Azacyclorkt-1-yl-carboni / Opiperidino-3-amino-6, 7-dimethoxyquinazoline hydrochloride,
    When used, 22.95 g (0.05 mol) of methyl-N- (2-cyano-4,5-dimethoxyphenyl) - (4- (azacyclot-1-yl-carbonyl) piperidino-4-amino-b, 7 dimethoxyquinazoline hydro-. chloride, T, mp, 237-239C, yield 60%,
    Example 18, (n -) - 2- (3-Pyrrolidinocarbonylpiperidino) -4-amino-C, 7-dimethoxyquinazoline hydrochloride,
    When using 2.2 g (0.0053 mol) (+) - methyl-L- (2-cyano-4, 5-dimethoxyphenyl) - (3-pyrrolidinocarbonylpiperidino) thioformamidate by the method of example 6, I get 1.8 g
    + -2- (3-pyrrolidinocarbonylpipe-j Ridino) -4-amino-6,7-dimethoxyquinazoline hydrochloride, T, mp, 184,188 ° C, / o (/ 4-31 0.5 ° yield 81%,
    Example 19, (-) - 2- (3-Pyrrolidinocarbonylpiperidino) -4-amino-6, 7-dimethoxyquinaeoline hydrochloride.
    When using 2.5 g (0.006 mol) of (-) - methyl-N- (2-cyanot -4,5-dimethoxyphenyl) - (3-pyrrolidinocarbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride, T, mp , 182-l88c. ± 0.5, yield 83%,
    Example 20, (2,5-Dime. Ylpyrrolidinocarbonyl) piperidine-4-umino-b, 7-dimethoxyquinaeol-. on hydrochloride.
    Using 3.8 g of 0.006 mol of methyl-Nr-cyano- (4,5-dimethylpyrrolidinocarbonyl) piperidino3 thioforms, the date as starting material according to the method of example 6 is obtained 0.50 g of 2-4- (2,5-dimethylpyrrolidinocarboNS1) piperidine} -4-amino-6,7-dimethoxyquinazoline hydrochloride. Mp. 248, yield 19%.
    Example 21 (2,6-Dimethylpiperidinocarbonyl) piperidino-4-amino-b, 7-dimethoxyquinazoline hydrochloride.
    Using 3.7 g (0.008 mol of methyl-K- (2-yano-4,5-dimethoxyfvnil) -4- (2,6-dimethylpiperidinocarbonyl) piperidino thioformamidate by the method of Example 6, 0.6 g (2.6- dimethylpiperidinocarbonyl) piperidiOHOJ-4-amino-6,7-dimethoxyquinazoline hydrochloride, mp 270-274 ° C, yield 16%.
    Example 22. 2- (4-AdetilpipeReidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride ,.
    When using 10.0 g (0.028 mol of methyl-N- (2-cyano-4,5-dimethoxyphenyl) - (4-acetylpiperidino) thioformamidate as the starting material according to the method of example 6, 2.3 g of 2- (4-acetylpiperidino) are obtained. -4-amino-6,7-dimethoxyquinazoline hydrochloride, mp. 140-142 ° C, yield 22%.
    Example 23, 2- (4-Propionylpiperino) -4-amino-6,7-dimethoxyquinazoline hydrochloride.
    When using 5.6 g (0.015 mol) of methyl-K- (2-diano-4,5-dimethoxyphenyl) - {4-propionylpiperidino) thioformamidate as starting material according to the method of example 6, 9 g of 2- (4-propionylpiperidino) is obtained -4-amino-6, 7-dimethoxyquinazoline hydrochloride, T, pl. 167-170 ° C, yield 32%.
    Example 24, 2- (4-Valeuoylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride.
    When using 9.2 g (o, 023 mol) of methyl-N- (2-cyano-4,5-a1Imethoxyphenyl) - (5-n-valeroylpiperidino) thioformamidate. As the starting material for the method of example 6, 4.7 g of 2 - (4-n-valeropylpiperidino) -4 amino-6, 7-dimethoxyquinazoline hydrochloride, T, pl. 196-199c, yield 50%.
    Example 25, 2- (4-cyclohexylcarbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride.
    When using 9.50 g (o, 022 mol) of methyl-N- (2-cyano-4,5-dimethoxyphenyl) - (4-cyclohexylcarbonylpiperidino) -thioformate as the starting material according to the method of example 6, 3.7 g of 2- ( 4-cyclohexylcarbonylpiperidino) -4-amino-6,7-dimethoxyquinazoline hydrochloride. M.p. 290-293 ° C, yield 38%. The effect of the compounds when administered intravenously was studied in Wistar rats, weighing 240-290, and anesthesia was performed with urethane (1.5 g / kg intraperitoneally). A heating pad was placed under the animal, the heating degree of which was regulated using a thermostat connected with a mystory sensor located in the large intestine to maintain the body temperature at 38 C. A polyethylene tube cannula was inserted into the trachea and the rats were allowed to blow. , CC1 spontaneously. For: intravenous injections of a drug. A cannula was inserted into the femoral vein. Blood pressure was measured on the femoral artery to which the pressure transducer was connected (model MP-15, Micron instrument) Average arterial pressure was recorded on paper using a chart recorder. In the consciousness of the animals, we studied using a blood pressure recorder (model W -8002e, W-fW electronics, Basel). Spontaneously hypertensive animals from rats of the Okamoto-Aoki race were used. by air, using
    The effect of lowering blood pressure in rats, resulting from compounds. Formulas

    Neopyontyloxy
    : @ 5gONNg
    Decrease in blood pressure, mm Hg. Art., caused by a dose of 0.5 µmol / animal (P.O.), through
    1 h I 2 h G 5 h - 22 2G2G method of the cuff on the tail. After keeping the rats for 30 minutes at 36 ° C in the heating chamber, the animal was placed in the chamber to allow for the recording of pulsed waves. from Plexiglas and for each rat, a sixth consecutive systolic blood pressure measurement was performed. As a systolic {equal pressure, an arithmetic average value was taken for these indications. The effect of the compounds according to the invention was compared with the effect of prazosin and two other compounds, namely 2- (4-diethylaminocarbonylpiperidino) -4-amino-6,7-dimethoxyxyquinazoline (compound A for comparison) and 2- (4-morpholinocarbonylpiperidino) -4- C1MINO-6,7-dimethoxy-1% quinazoline (Compound B for comparison). The table presents data demonstrating the effect of lowering blood pressure, provided by the compounds according to the invention, both in intravenous (i.v.) and oral oral) administration. A dose of 0.1 µmol / kg was administered intravenously and the maximum decrease in blood pressure was measured. A dose of 0.5 µmol / animal was orally administered and the decrease in blood pressure was measured 1, 2 and 5 hours after administration.
    权利要求:
    Claims (1)
    [1]
    . METHOD FOR PRODUCING SUBSTITUTED 2-PIPERIDINO-4-AMINO-6,7-DIMETHOXYCHINAZOLINE of the general formula where R is lower C <-Cy-alkyl, Su-Sucycloalkyl, C t -Cy-alkoxy or RR * R 2 group,. wherein R <YT- and Sd hydrogen or C 5 alkyl with branched chain or hydrochloric 2 where R 1 and <together with the nitrogen atom to form a cyclic C ^ -C 7 · amino group which may be substituted with one or two groups nizshealkilnshi characterized in that the alkyl-I- (2-cyano-4,5-dimethoxyphenyl) acylpiperidinothioformamidate derivative of the formula wherein R 1 is lower alkyl is reacted with ammonia, ammonium halide, urea or urea hydrohalide in an organic solvent.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR2321890B1|1975-08-26|1979-09-14|Synthelabo|ES8405389A1|1981-09-09|1983-11-01|Orion Yhtymae Oy|Substituted piperidinyl quinazolines.|
    CA2077252C|1992-08-31|2001-04-10|Khashayar Karimian|Methods of making ureas and guanidines, and intermediates therefor|
    BRPI0922010A2|2008-11-14|2015-12-15|Hoffmann La Roche|quinazoline derivatives as nk3 receptor antagonists|
    TW201825475A|2016-10-05|2018-07-16|英商使命醫療公司|Novel compounds|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FI800481A|FI800481A|1980-02-19|1980-02-19|FRAMEWORK FOR THE SUBSTANCES OF ACYLPIPERIDINER|
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