• 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:
    Compounds of the formula: where R is an optionally substituted aryl or heteroaryl group; R1 and R are each independently C1-C4 alkyl or 2-methoxyethyl; and Y is -(CH2)n- where n is 2, 3 or 4, -CH2CH(CH3)-or -CH2C(CH3)2-; and their pharmaceutically acceptable salts. The compounds have utility as anti-ischaemic and antihypertensive agents and as synthetic intermediates to other dihydropyridine calcium antagonists.
    公开号:SU1417795A3
    申请号:SU853901005
    申请日:1985-05-11
    公开日:1988-08-15
    发明作者:Алкер Давид；Фрейзер Кэмпбелл Симон；Эдвард Кросс Петер
    申请人:Пфайзер Корпорейшн (Фирма)；
    IPC主号:
    专利说明:


    with
    SP
     CH
    The invention relates to the field of chemistry of heterocyclic compounds, in particular, to a new method for the preparation of 1,4-dihydropyridine derivatives of the general formula
    H R CHjOOCxXxCOOC H.
    tt
    CH3Y CH2-0- {CH2J2 OH Н
    where R is 2,3-dichlorophenyl, 2-chloro 3 trifluoromethylphenylLe or. 15
    2-chloropyrido-3-yl with Ca-antagonistic activity.
    The aim of the invention is to develop
    A 10% aqueous solution of sodium carbonate and water, dried over sodium sulfate and evaporated. Recrystallization of the residue from ethyl acetate gives 7- (2, 3-dichlorophenyl) -8 ethoxycarbonyl-6 me totoxycarbonylmethyl-3-oxo-2,3, tetrahydropyrido (1,2-c) -1,4-oxazine (4, 70 g), mp. 172-173 S.
    Found,%: C 53.27; H 4.27; N 3.15.
    .
    Calculated ,,%: C 53.27; H 4.44; N 3.27. .
    B. A mixture of sodium bordehydride (1.52 g and 7- (2, 3-dichlorophenyl) -8-ethoxycarbonyl-6-methoxycarboxy-1-5-methyl-3-oxr 2,3,7,9-tetrahydropyrido (1,2 -c) - 1,4-oxazine (9.00 g) in ethanol
    a new method of obtaining new 20 (SO ml) is stirred at room temperature.
    compounds that can be used as antihypertensive drugs, as well as semi-products for the synthesis of antihypertensive drugs.
    Example 1gA. A solution of 2-4- (2, 3-dichlorophenyl) -3-ethoxycarbonyl-5 temperature for 16 h and then evaporated. The residue is taken up in dichloromethane and the solution is washed with water, 2 M hydrochloric acid and water, dried 25 over sodium sulfate and evaporated.
    The residue is recrystallized from ether to give 4- (253-dichlorophenyl) -3 methoxyncarbonyl-6-methyl-1, 4-dihydro-ethoxycarbonyl-2- (2-hydroxyethoxy-pyrid-2-yl-methoxy} acetic acid methyl-5-methoxycarbonyl- 6-methyl-1,4- (9.16 g), 3j60 g of carbonyldiimidazole 30 dihydropyridine (6.00 g), mp, 120- and N-methylmorpholine (3.5 ml) in tetra- 121 C, hydrofuran (30 ml) was stirred at room temperature for 16 hours, and then evaporated. The residue was taken up in dichloromethane and the resulting solution was washed with 2 M hydrochloric acid.
    35
    Examples 2 and 3. The following compounds are prepared analogously to the procedure of Example -1, part (A) and (B) from the corresponding starting materials. The results are shown in the table.
    2-Chloro-3-trifluoro-methylphenyl 123-4
    2-Chlorpyrid 3-yl 76-8
    The study of the pharmacological properties of the compounds indicated
    formulas
    I
    The ability of compounds to inhibit the movement of calcium into the cell is demonstrated by their effectiveness in reducing the reduction of vascular tissue in vitro, which is
    0
    A 10% aqueous solution of sodium carbonate and water, dried over sodium sulfate and evaporated. Recrystallization of the residue from ethyl acetate gives 7- (2, 3-dichlorophenyl) -8 ethoxycarbonyl-6-me totoxycarbonylmethyl-3-oxo-2,3, tetrahydropyrido (1,2-c) -1,4-oxazine (4 , 70 g), mp. 172-173 S.
    Found,%: C 53.27; H 4.27; N 3.15.
    .
    Calculated ,,%: C 53.27; H 4.44; N 3.27. .
    B. A mixture of sodium bordehydride (1.52 g) and 7- (2, 3-dichlorophenyl) -8-ethoxycarbo, nyl-6-methoxycarbon-1-5-methyl-3-oxr-2,3,7,9-tetrahydropyrido (1,2-с) - 1,4-oxazine (9.00 g) in ethanol
    temperature for 16 hours and then evaporated. The residue is taken up in dichloromethane and the solution is washed with water, 2 M hydrochloric acid and water, dried over sodium sulfate and evaporated.
    The residue is recrystallized from ether to give 4- (253-dichlorophenyl) -3ethoxycarbonyl-2- (2-hydroxyethoxymethyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (6.00 g), mp, 120 - 121 C,
    Examples 2 and 3. The following compounds are prepared analogously to the procedure of Example -1, part (A) and (B) from the corresponding starting materials. The results are shown in the table.
    52.05
    4.80
    2.96 (52.77) (4.82) (2.93)
    55.07 5.77 6.52 (55.54) (5.60) (6.80)
    a consequence of the influx of calcium, caused by a high intercellular concentration of potassium ions. Such a test is carried out by fastening one end of the spiral-cut strips of rat aorta, the other end is connected to a force sensor. The tissue is immersed in a bath with a saline solution containing 2.5 mmol Ca and
    5.9 mmol K. Potassium chloride is added to the baiya with a pipette until a final concentration of 45 mmol is reached. The change in tension resulting from the contraction of the tissue is observed. The contents of the bath are drained and replaced with fresh brine, and after 45 minutes the test is repeated in the presence of the particular compound under the conditions of the test in saline. The concentration of compound required to reduce the 50% reduction (iCjo) ICjo values (mg / ml) is recorded to combine this general formula below:
    2, 3-Dichlorophenyl
    2-Chloro-3-trifluoromethylphenyl I, DO-IU-
    2-Chloro-pyrid3-yl
    权利要求:
    Claims (1)
    [1]
    Formula isob
    The method of obtaining 1,4-dihydropyridine derivatives of the general formula
    N B СНзООСХХг / гНб
    sn
    V n
    CH2-0- (CH2) 2-OH
    where R is 2,3-dichlorophenyl, 2-chloro-trifluoromethylphenip or 2-chloropyrid-3-yl;
    characterized in that
    oxazine derivative of general formudta
    SNPS
    SOOSgNz
    where R has the indicated meanings; subjected to reduction with sodium borohydride, in an organic solvent.
    类似技术:
    公开号 | 公开日 | 专利标题
    US4661607A|1987-04-28|Furoxanthone derivatives useful as diuretics
    SU1428199A3|1988-09-30|Versions of method of producing derivatives of 2,2,3-iminobisethanol or acid-additive salts thereof,or stereochemical isomeric forms thereof
    EP0185429A1|1986-06-25|New bicyclic heteroaryl piperazines
    DK170069B1|1995-05-15|1,4-Dihydropyridine compounds and pharmaceutical compositions containing these compounds as well as the compounds for use in the treatment of cardiovascular disease states
    EP0308897A1|1989-03-29|Quinoline derivatives
    PL185099B1|2003-02-28|Shortly acting dihydropyridines
    SU1417795A3|1988-08-15|Method of producing derivatives of 1,4-dihydropyridine
    US4683234A|1987-07-28|2,6-Dimethyl-3N,5-disubstituted-4-|3,4-dihydropyrimidine compounds and a method for treating disorders of cardiocircular system
    FI62820B|1982-11-30|OVEROKARBOXYL SYROR FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA SUSTITUERADE
    PT97252B|1998-07-31|METHOD FOR THE PREPARATION OF NEW 4-QUINOLYL-OR 4-ISOKINOLYL-DIHYDROPYRIDINES
    US4618609A|1986-10-21|Anti-ischaemic and antihypertensive 2-[pyrimidyloxy alhoxymethyl]-1,4-dihydropyridines
    SU1395143A3|1988-05-07|Method of producing derivatives of 1,6-naphthyredene in the form of racemates or enantiomers or acid-additive salts thereof
    EP0126654B1|1988-05-04|Tetrahydroisoxazolo|pyridine derivatives and preparation thereof
    US4604393A|1986-08-05|Phenyloxoalkyl piperidines and the pharmaceutical compositions containing them
    US4500527A|1985-02-19|Antihypertensive 4[|-oxyiminomethyl phenyl]-1,4-dihydropyridines
    US4735943A|1988-04-05|Eburnamonine oxime derivatives, salts thereof, and pharmaceutical agents containing the same
    EP0366548B1|1993-06-02|Dihydropyridine derivatives
    EP0197533B1|1991-08-14|Dioxolobenzisoxazole derivatives and process for preparing the same
    Valenti et al.1998|Coumarin 1, 4-dihydropyridine derivatives
    US4824855A|1989-04-25|1,4-dihydropyridine derivatives
    US5137908A|1992-08-11|4-azahexacyclododecane compounds
    US4912223A|1990-03-27|1,4-Dihydropyridines
    US4833162A|1989-05-23|Substituted benzeneacetonitriles and their use as calcium channel blockers
    GB2050375A|1981-01-07|4-Cyanophenyl-1,4- dihydropyridine compound, processes for preparation thereof and pharmaceutical composition comprising the same
    US4500708A|1985-02-19|Benzothiazine derivatives
    同族专利:
    公开号 | 公开日
    HU194172B|1988-01-28|
    CA1278573C|1991-01-02|
    FI851857L|1985-11-13|
    AT50988T|1990-03-15|
    AU4226985A|1985-11-14|
    JPH0529029B2|1993-04-28|
    EP0161917A3|1987-12-02|
    PH20931A|1987-06-05|
    FI83308B|1991-03-15|
    DE3576499D1|1990-04-19|
    IE57751B1|1993-03-24|
    EP0161917B1|1990-03-14|
    ZA853543B|1986-12-30|
    ES8609252A1|1986-09-01|
    NZ212033A|1988-02-12|
    IL75165A|1988-09-30|
    FI83308C|1991-06-25|
    DK162982C|1992-06-01|
    HUT37756A|1986-02-28|
    FI851857A0|1985-05-10|
    DK162982B|1992-01-06|
    ES8703429A1|1987-02-16|
    EP0161917A2|1985-11-21|
    AU554257B2|1986-08-14|
    YU78085A|1988-02-29|
    PL253328A1|1986-06-03|
    GR851130B|1985-11-25|
    PT80427B|1987-04-16|
    GB8412208D0|1984-06-20|
    DK207885A|1985-11-13|
    ES543033A0|1986-09-01|
    JPS60246368A|1985-12-06|
    PT80427A|1985-06-01|
    KR880000131B1|1988-03-12|
    IE851168L|1985-11-12|
    ES550965A0|1987-02-16|
    DD235867A5|1986-05-21|
    IL75165D0|1985-09-29|
    US4654353A|1987-03-31|
    KR850008156A|1985-12-13|
    NO851886L|1985-11-13|
    DK207885D0|1985-05-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1591089A|1976-12-17|1981-06-10|Fujisawa Pharmaceutical Co|1,4-dihydropyridine derivatives and process for preparation thereof|
    CA1117117A|1978-10-10|1982-01-26|Fujisawa Pharmaceutical Co., Ltd.|2-methyl-dihydropyridine compound, processesfor preparation thereof and pharmaceuticalcomposition comprising the same|
    SE7910521L|1979-12-20|1981-06-21|Haessle Ab|NEW 2-METHYL-6-SUBSTITUTED-4- -1,4-DIHYDROPYRIDINE-3,5-DIESTERS WITH HYPOTHESIVE PROPERTIES, AND PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATION|
    CS228917B2|1981-03-14|1984-05-14|Pfizer|Method of preparing substituted derivatives of 1,4-dihydropyridine|
    NZ201395A|1981-07-30|1987-02-20|Bayer Ag|Pharmaceutical compositions containing 1,4-dihydropyridines and certain of these dihydropyridines|
    DE3207982A1|1982-03-05|1983-09-08|Bayer Ag, 5090 Leverkusen|NEW 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION AND USE THEREOF IN MEDICINAL PRODUCTS|
    EP0100189B1|1982-07-22|1986-05-28|Pfizer Limited|Dihydropyridine anti-ischaemic and antihypertensive agents|
    DE3311005A1|1983-03-25|1984-09-27|Bayer Ag, 5090 Leverkusen|CHROMON- AND THIOCHROMONE-SUBSTITUTED 1,4-DIHYDROPYRIDINE DERIVATIVES, SEVERAL PROCESSES FOR THEIR PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS|
    EP0164247B1|1984-06-07|1989-01-11|Pfizer Limited|Dihydropyridines|AU593278B2|1985-08-06|1990-02-08|Boehringer Mannheim Italia S.P.A.|Pharmaceutically active 2-thiomethyl-substituted-1,4- dihydropyridines|
    GB8526411D0|1985-10-25|1985-11-27|Pfizer Ltd|Dihydropyridines|
    GB8527698D0|1985-11-09|1985-12-11|Pfizer Ltd|Dihydropyridine antiischaemic & antihypertensive agents|
    IT1213555B|1986-12-11|1989-12-20|Boehringer Biochemia Srl|2 METHYLOMETHYL HYDROPYRIDINE, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.|
    US4920225A|1986-12-22|1990-04-24|Laboratoires Syntex S.A.|Resolution of 1,4-dihydropyridine derivatives|
    GB8709447D0|1987-04-21|1987-05-28|Pfizer Ltd|Dihydropyridines|
    US6541479B1|1997-12-02|2003-04-01|Massachusetts College Of Pharmacy|Calcium channel blockers|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB848412208A|GB8412208D0|1984-05-12|1984-05-12|Quinolone inotropic agents|
    [返回顶部]