• 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:
    The pyrimidylquinazolines of the formula I <IMAGE> in which R<1> and R<2> are hydrogen, alkyl with 1 to 6 C atoms, alkenyl with 2 to 6 C atoms, cycloalkyl with 5 to 7 C atoms, R<3> is hydrogen, alkyl with 1 to 6 C atoms, alkenyl with 2 to 6 C atoms, phenyl, phenylalkyl with 1 to 4 C atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonylamino with 1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl, are prepared by a) reacting a compound of the formula II <IMAGE> where X is a mercapto radical or a halogen atom, with a compound of the formula III <IMAGE> or b) reacting 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline with a compound of the formula V <IMAGE> in which Hal is a halogen atom, or c) in a compound of the formula VI.
    公开号:SU1052158A3
    申请号:SU813261941
    申请日:1981-03-25
    公开日:1983-10-30
    发明作者:Бендер Хейнц；Рабе Томас；Бон Хельмут；Марторана Пьеро
    申请人:Касселла Аг (Фирма)；
    IPC主号:
    专利说明:

    ;
    ii
    2
    have the indicated meanings
    nny intermediate product
    vSj-Bg
    v 1
    where R, R and R are specified
    meanings
    interact with the compound
    NH,
    cbijO Sr
    where X is chlorine or bromine, in the environment of a solvent or dispersant, and select PT the target product in free form or in the form of a salt.
    This invention relates to a process for the preparation of novel pyrimidylquinazoline derivatives of the formula, W. DoD Lophydoride, C — C-alkyl, and R. C — C-alkenyl, C — C cycLoalkyl, hydrogen,, -alkyl, Co-C-alkenyl, phenyl, benzyl, bromine, nitro, amino, C-C2-alkylcar -15 bonilamino in the alkyl radical or formyl, or their salts, which have pharmacological properties, and can be used in medicine. A known method for the preparation of amine derivatives by the interaction of halogen-enamel ions and amines in G13 solvent medium. The 4-amino-6, 7-dimethoxyquinazoline derivatives are known to have pharmacological properties, and they have the ability to lower blood pressure 23. The purpose of the invention is to obtain new pyrimidylquinazoline derivatives of the formula that have improved biological activity. This goal is achieved by the fact that piperazine of the general formula 35 HN NH
    subjected to interaction with the compound of the formula I g and f p not in the same
    R, and R. have indicated
    where R. is the value of LNG (1,1) iHiO-4ATsr "-x .... 1. e X - chlorine bromine obtained intermediate product rmula ZSHg (iH.o vV: H30-U .. (they interact with the compound of the formula - - O Succ-Kg, C) ± Na € - chlorine, R; ,, R 2 and RJ has the indicated values, solvent or dispersion, and isolate the desired product in free form or as a salt. This goal is achieved by having piperazine of the general formula HN NH reacting with a mixture of the formula Su-Br and the resulting intermediate of formula V4-: R2 and Rj have the indicated values of R, chen, are subjected to interaction with the compound of the formula X where is X is chlorine or bromine, in a solvent or dispersant medium, and isolate the desired product in free form or as a salt. Inorganic and organic acids, such as hydrogen chloride, hydrogen bromide, naphthalene disulfonic acid (1 , 51 phosphoric nitric, sulfuric, oxalic, dairy, wine, acetic, salicylic, benzoic, formic, propionic, trimethylacetic, diethyl acetic, low, amber, pimeline, fumaric maleic, block, sulfamine chamines. ov1po, gluconic, ascorbic new, isonicotinic, methanesulfonic-hand, "-toluolsulfonovuyu, citric or adipic acid. Preferably, pharmaceutically acceptable acid addition salts are used. Acid addition salts are prepared in the usual manner by mixing the components in a suitable diluent or dispersant. As the latter, you can use, for example, liquid, water, alcohols, hydrocarbon, etc. The compounds of formula 1 and their pharmaceutically acceptable acid addition salts have excellent headlamp macologic properties. They, in particular, have a reduction in circulatory pressure, due to which they can be used to treat hypertension. The compound of formula 1 has a great superiority over lime compounds. Example 1. To a solution of 5 g of anhydrous piperazine in 50 ml of dioxa, 2.5 g of 2-chloro-4-amino-, -6,7-dimethoxyquinazoline are added and the mixture is heated for 12 hours. Then it is concentrated, the residue is dissolved in water and the hydrochloric acid is adjusted to pH 2.5. The acidic aqueous solution is extracted with methylene chloride, then the aqueous phase is alkalinized with sodium hydroxide. The precipitate is precipitated, which is recrystallized from ethanol. 2-piperazinyl-4-amino-6, 7-dimethoxyquinazoline is obtained. Output 85% of theoretical. The temperature of the flashes 235.S. 2.9 g of 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline in 50 ml of ethanol, 4 g of potash to 2.2 g of 1,3-dimethyl-5-nitro-6-chloropyrimidinedione-2.4 during the day stirred at room temperature. Then, the mixture is watered and the residue is dissolved in 20 ml of 0.5 N hydrochloric acid. The mixture is again filtered off with suction, the residue is suspended in aqueous soda solution, filtered off with suction and recrystallized from aqueous dimethylformamide. 4- 4-amino-6,7-dimethoxyquinazolin-2-yl -1-1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl piperazine is obtained. M.p. . Calculated,%: C 50.8; H 5.1; M 23.7, ° Found;%: C 50, 3,1N 23.5; About 20.4. Output 87% of theoretical. The 1, 3-dimethyl-5-nitro-b-chloropyrimidinedione- (2,4) used as the starting product is obtained by the following method. To 50 ml of concentrated sulfuric acid at 15 ° C, 17 g of 1,3-dimethyl-6-dimethyl-b-chloropyrimidinedione- (2,4) is added in portions. Then it is cooled down to 3-5 ° C and 17 ml of fuming nitric acid is added dropwise to the mixture slowly while stirring. Then the stirred solution is poured onto ice, while a semi-solid precipitate falls out. The mixture is extracted with methylene chloride, the organic phase is dried over magnesium sulphate and the solution is concentrated in vacuo using a water jet pump. An oil remains which hardens after a short time. The substance is recrystallized from ligroin (ethyl acetate, K). 1,3-dimethyl-5-nitro-6-chloropyrimidinedione-2.4 is obtained. The yield is 95% of theoretical. The temperature of the seeding is 92 ° C. The 2-piperazinyl as the starting material 4-amino-b, 7-dimethoxyquinazoline is obtained by the following method: Example 2. To a mixture of 30 g of piperazine and 500 NUI of toluene, 20 g of 1,3-dimethyl-b-chloropyrimidinedione-2.4 is added and the mixture is boiled over 3 h. This is then filtered with suction and then the filtrate is concentrated in vacuo using a water-jet pump. Recrystallized from ethyl acetate to give 1, 3-dimethyl-6-piperazinyl pyrimidinedione-12, 4 / Yield 75% of theoretical. The temperature of the flasher is 117 ° C.
    2.4 g of 2-chloro-4-amino-b, 7-dimethoxyquinazoline, 4.5 g of 1,3-dimethyl-6-piperazinyl pyrimidinedione-2.4 and 50 1IL of ethanol for 8 hours while heating the J autoclave. The mixture is then cooled and concentrated in vacuo using a water jet pump. The residue is dissolved in water and then recrystallized from dimethylformamide. Prouchgst 4- 4-amino-b, 7-dimethoxyquinaZOLIN-2-IL-1-1,3-dimethyl-2,4-dkoksopyrimidin-b-il-piperaein, m.p. ..
    Calculated,%: C 5b, 2; H 5.9, N 23.0; About 15.0.
    C2OH25 "704
    Found,%: C 56.0, H 6.0; N 23.0, O 14.7.
    Yield 81% of theoretical.
    Example 3 3.5.2 g. 4-4-amino-b, 7-limethoxyquinazolin-2-yl -1-1, 3-dibutyl-2,4-dioxopyrimidin-b-yl-piperazine dissolved in 20 m glacial acetic acid. Then;
    while cooling with ice, a mixture of 1.7 g of bromine and 20 m of glacial acetic acid is added in drops. The mixture is then stirred at room temperature for 2 hours. It is sucked off and recrystallized from ethanol. . Hydrobromide 1-4-amino-b, 7-dimethoxyxylamine-2-yl-1-1, 3-dibutyl-2,4-dioxo-5-bromo- is obtained. pyrimidine-b il piperazine. M.p. better decomposition.
    H 5.5; 23,
    Calculated: With 46.5; 14, b; About 9.5
    N
    S2bN5, Vg.2M, 0
    I
    Found,%: C 46.7; H 5.3; in 23.5; N 14.7; About 9.8.
    Yield 61% of theoretical.
    Example 4. To a mixture of 24 mp of acetic anhydride and 12 ml of formic acid was added 5.6 g of 4-4-amino-6, 7-dimethoxyquinazolin-2-yl -1-1, 3-dicyclohexyl-2,4-dioxopyrimidine b-yl-piperazine, and the mixture is stirred at C80 ° C1 for 5 h. Then concentrated in vacuo, obtained with water and a mixture of water. The residue is treated Oh 5n. natrov1lm liquor, suction and recrystallized from dimethylformamide. Ps teach 4-4-amino-6,7-dimethoxyquinazalin-2-yl -1-1, 3-dicyclohexyl-2, 4-dioxp-5-formylpyrimidine-b-yl-piperoraZIN. M.p. after decomposition.
    Calculated,%; C 62.9; H 6.9JN 16.6, O 13.5.
     . C3iH.
    Found,%: C 62.8; H 6.6 | N 16.5, O 13.2.
    Yield 81% of theoretical.
    Example 5. 4.7 g of 4- 4-amino-6, 7-dimethoxyquinazolin-2-yl -1-1, 3-dimethyl-2,4-dioxo-5-nitropyrimidin-b-yl-piperazine suspended in 300 ml ethanol, add 0.4 g of palladium carbon 110% NO | and the mixture is hydrogenated for 20 hours at room temperature and normal pressure, agitated with hydrogen 1. Then the precipitate is removed and the residue is immediately dissolved in hot dimethylformamide and the dimethylformamide solution still. the hot state is filtered off from the catalyst. Then the dimethylformamide solution is concentrated on -vacuum in a vacuum obtained with a water jet pump, and the residue is recrystallized from aqueous dimethylphosphate. A 4- (4-amino-6,7-dimethoxyquinaeolin-2-yl -1-1,3-dimetsh1-2, 4-dioxo-57 alcnopyrimidin-6-yl) pipe Razin. 1. pl. 327 S.
     Found,%; C54.0; H €, I; N 25,0;
    014.7.
    Calculated,%: C 54.3 N 6.9; N 25.3 / R 14.5.
    1 Exit 78% of theoretical.
    Analogously to examples 1 and 2 receive the following substances table. one
    2 L:. . . ..
    t a b l and IV a 1
    Ing,
    ii
    sn
    325
    n
    H
    297 314
    331
    -CH2319 322
    328
    316 324
    Continued table. one,
    That blitz
    权利要求:
    Claims (2)
    [1]
    . 1. The method of obtaining pyrimidylquinazoline General formula
    NH -R · "
    (5H 3 OFLA-J V 0 *. ·. ··. · ·: · · · · Where 1C and R- are hydrogen, C 1 * C 6 -alkyl, Cg-C is alkenyl,
    Cj-Cj-cycloalkyl,. Rj is hydrogen, CyCg alkyl. · C - C.-alkenyl, phenyl, / benzyl, bromine, nitro, amino, C ^ -C ^ -alkylcarbonylamino in the alkyl radical or · ',. ·, · Formyl, • or their salts, except it is clear that piperazine has a total I -----, 'nc neither <_ The interaction with X is chlorine or bromine, and the resulting intermediate of the formula € H 3 0 (JHjO is reacted with a compound of the formula . ΗαίΑκ ^ Ο f
    Bi where HaR is chlorine,.
    , s Rg and R 3 have the indicated meanings in a solvent or dispersant medium, and the desired product is isolated in free form or in the form of a salt.
    [2]
    2. The method of obtaining pyrimidylquinazolines
    SIDO YNZ general formula about
    * -Vg
    Oh <
    Moreover, the formulas j are subject to the formula. where (Qi R 2 is hydrogen, C ^ -C ^ -alkyl, C 7 -Cd-alkenyl 'Cy-C 7 cycloalkyl, yc is hydrogen, C, -C ^ -alkyl , Cj-Cg-alkenyl, phenyl, benzyl, bromo, nitro, amino, C ^ -C ^ -alkylcarbonylamino in the alkyl radical or formyl, or their salts, with the exception that piperazine general formula
    „..SU ..., 1052158 g ~
    NK NH V— / are reacted with a compound of the formula>
    ΗαΙ ^ Ν ^ Ο
    Bi where R ^ and Rj have the indicated meanings>
    where R, R i have the indicated meanings, are reacted with a compound of the formula
    NH f and the resulting intermediate product of the formula
    I
    I l
    V-7 where X is chlorine or bromine, in a solvent or dispersant medium, and the desired product is isolated in free form or in the form of a salt.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1277890A3|1986-12-15|Method of producing beta-| or beta-|-carboxylic acids
    SU522800A3|1976-07-25|The method of producing pyrazolo derivatives | pyrimidine
    US2567651A|1951-09-11|J-dialkyl-g-amino-l
    SU439983A1|1974-08-15|Method for preparing ethylenebenzoyl derivatives
    SU1052158A3|1983-10-30|Process for preparing derivatives of pyrimidylquinazolines or their salts |
    EP2266966A1|2010-12-29|A process for the preparation of febuxostat
    US4716243A|1987-12-29|α-|-aminomethylene-β-formylaminopropionitrile
    SU466658A3|1975-04-05|Production method - | -morphinans
    EP2118058B9|2012-03-28|Method for the preparation of 5-benzyloxy-2-|-3-methyl-1h-indole
    RU2042678C1|1995-08-27|Method of synthesis of 6,7-dichloro-1,5-dihydroimidazo-[2,1-b]-quinazoline-2-|-one, intermediates for their synthesis and a method of their synthesis
    JPH0730046B2|1995-04-05|Quinazoline acetic acid derivative
    SU498908A3|1976-01-05|The method of producing pyrimidinone derivatives
    SU584782A3|1977-12-15|Method of preparing aminoimidazoisoquinoline derivatives or salts thereof
    US4151210A|1979-04-24|Process for the production of phenylalkyl sulphones
    JPH06100540A|1994-04-12|5-isoquinolinesulfonic acid amide derivative
    SU718010A3|1980-02-25|Method of producing 3-/4-|-piperazine-1-yl/-1-|-propane or salts thereof
    SU505358A3|1976-02-28|The method of producing piperazine derivatives
    CH681300A5|1993-02-26|
    SU555854A3|1977-04-25|Method for preparing 1,3,4-thiadiazole derivatives or their salts
    SU535806A1|1984-06-23|Process for preparing pyrido | indoles or their salts
    SU439981A1|1974-08-15|The method of obtaining derivatives of 8-azapurinone-6
    SU507235A3|1976-03-15|The method of obtaining 2n-3-isoquinolones
    US2740785A|1956-04-03|4-hydroxy-5-alkyl-6-arylpyrimidine derivatives
    DE1213841B|1966-04-07|Process for the preparation of 3-aryl-4-halogen-pyridazonen- |
    SU501668A3|1976-01-30|The method of obtaining derivatives of 2-aminobenzylamine
    同族专利:
    公开号 | 公开日
    JPS56150088A|1981-11-20|
    ES500738A0|1982-01-16|
    EP0037495A1|1981-10-14|
    NO810870L|1981-09-28|
    IL62495D0|1981-05-20|
    CS219898B2|1983-03-25|
    GR71870B|1983-07-08|
    DD157614A5|1982-11-24|
    ES8202000A1|1982-01-16|
    PT72724A|1981-04-01|
    FI810778L|1981-09-28|
    CA1156656A|1983-11-08|
    ZA812034B|1982-05-26|
    AR227542A1|1982-11-15|
    AU6877481A|1981-10-01|
    DK115581A|1981-09-28|
    PT72724B|1982-03-24|
    DE3011809A1|1981-10-01|
    PL233882A1|1982-05-10|
    PL230320A1|1982-03-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB2007656B|1977-11-05|1982-05-19|Pfizer Ltd|Therapeutic agents|JPH0528709B2|1984-12-14|1993-04-27|Mitsui Sekyu Kagaku Kogyo Kk|
    JPH0529223B2|1985-09-18|1993-04-28|Mitsui Sekyu Kagaku Kogyo Kk|
    CA2559302C|2004-03-15|2012-06-19|Takeda Pharmaceutical Company Limited|6-amino-1h-pyrimidine-2,4-dione derivatives as dipeptidyl peptidase inhibitors|
    CA2572544C|2004-07-02|2013-02-26|Corcept Therapeutics, Inc.|Modified pyrimidine glucocorticoid receptor modulators|
    WO2012129074A1|2011-03-18|2012-09-27|Corcept Therapeutics, Inc.|Pyrimidine cyclohexyl glucocorticoid receptor modulators|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19803011809|DE3011809A1|1980-03-27|1980-03-27|PYRIMIDYL-CHINAZOLINE, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING IT AND THEIR USE|
    [返回顶部]