• 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:
    This invention relates to substituted 1,4-dihydropyridines showing interesting physiological activities, particularly on the cardiovascular system. 1,4-Dihydropyridines in accordance with the invention are substituted in the 4-position by a 2-chloropyrid-3-yl or a 2-methylthiopyrid-3-yl group, in the 3- and 5-positions by a methoxycarbonyl or ethoxycarbonyl group and in the 2- and 6-positions by a methyl group. Acid addition salts of these compounds are included in the present invention. The compounds can be prepared by reacting an appropriate 2-substituted nicotinaldehyde with an alkyl acetoacetate. Compounds in accordance with the invention have shown anti-hypertensive activity at very low doses.
    公开号:SU1007556A3
    申请号:SU762386167
    申请日:1976-08-12
    公开日:1983-03-23
    发明作者:Телон Жан-Мари；Швейсгют Бернар；Коньакк Жан-Клод
    申请人:Эксашими (Фирма)；
    IPC主号:
    专利说明:

    The designation refers to the obtaining of riOBbix 1 5H-dig; | Drsp; T-tones total | 1Ormul1. - -JXliT Ni O a h ,, L, .rpp-p J G M SI where R is methyl or zl; X is a chlorine atom or: L, 11, which can be used in chemical industry as a means of diminishing pressure. Known cnccoti for the preparation of substituted 1, -I dihydropyridines with the action of eromat and that with an ester of I — ketoacids and ammonia (Ganch synthesis); 1, the invention aims to develop new compounds possessing and, pharmaceutically-sesk 41 properties, Postaag e; on cent / db it is reached according to the sp - of obtaining l.ii-di-hydropyridine; of general formula 1, for the key g TQH, that aldehyde is about the general formula is SI O where X has the indicated meanings, interacts with alkylacetyl acetate in the general form where R has the indicated values, in a water-borne ammonia solution. When the reaction is carried out, E is water with an ethanol-solution Moth; -thisterection of the product is: gd: aL kilylacetylacetate: ammonia is equal; ; 2: Compounds of the general formula P may be obtained by oxidizing mi oxidants, such as manganese dioxide or Saretta reagent (complex pyridine chromium anhydride) pyridines, substituted with 2p of the general formula M f / vv f 62 where X has the indicated values, and organic A solvent such as chloroform or dichloromethane. Compounds of the general formula U can be obtained either by reducing the nicotinic acid substituted in position 2 or the methyl ester of this acid or the ethyl ester of this acid by reducing aluminum with lithium iridide and and a mixture of potassium borohydride - lithium chloride in an organic solvent such as ether or tetrahydrofuran. Example 1. 4- (2-Chop-3 pyridyl) -3; 5 dicarbethoxy-2, 6-dimethyl 1 5 h-dihydropyridine (R-ETIHL, X-chloro). A solution of 15 g of 2-chloro-nicotinaldehyde, 15 l of concentrated ammonia and 27.5 g of ethyl acetoacetate in 80 ml of ethanol is refluxed for 8 hours. The reaction mixture is then kept at ambient temperature all night. The resulting kristyzly are dried, thoroughly washed with iso-ethanol. Obtain 20 g of A- (2pyridyl) -3,5 Dicarbethoxy-i 6-dimethyl-1, 4-dihydropyridine, | -1ms ;; of course a kind of slightly yellow crystals /: ov, t, pl. 20b-208 ° C, Example 2. 4- (2-Chloro-3-pyri / -, yl) - 3, 5-Dicarbomethoxy-2, 6-dimethyl- 1, V di-hydropyridine (R- methyl, P | 1 processes are carried out analogously to example i, but using 1 g of 2-chloronicotin;} ldegid and 23.8 g of methyl acetoacetate to obtain 19.1 g (2-chloro-3-pyridyl) - 3, 5 dicarbomethoxy-2, 6-dimethyl; 4 - dihydropyridine, having the appearance of p-c-allov of light yellow color, t, 1 l 262-264 C. L e rm e p 3 3 Methanol 2-thiocetylpyridine, To a solution of 57.6 g of methyl 2-thiomethyl nicotinic acid ester and 18; 7 g of boron potassium hydride in 600 ml of hydrochloric acid fused in 1.9 g of small portions while stirring lithium chloride and ligand reaction mixture under reflux for fh After cooling, water and ice are added to the reaction mixture and the organic compounds are removed with ether. -2-thiomethylpyridine, having the form of white crystals, mp: Example, 2-Thiomethyl nicotine aldehyde. To a solution of 45.5 g of 3 methanol-2 methylpyridine in 1 l {chloroform is poured with vigorous stirring in small portions 29 g of dichloride manganese. After the addition is complete, stirring is continued for 6 hours at room temperature, and then filtered on celite. Evaporation of the filtrate makes it possible to extract tif, 9 g of 2-thiomethyl nicotinal aldehyde, having the form of white crystals, m.p. 45 ° C. EXAMPLE 5. (2-Thiomethyl-3-pyridyl) -3.5 Dicarbethoxy-2.5 dimethyl-1, 4-dihydropyridine (R - ethyl X - SCHj). A solution of 10 g of 2-thiomethyl nicotinaldehyde, 7.85 ml of concentrated ammonium hydroxide in 17 ethyl acetate / acetate in 30 ml of ethanol is refluxed for 5 hours. After cooling, it is poured into ice water, the reaction mixture is taken up in ether and dried with sodium sulfate. After evaporation of the solvent, 13.6 g of KOTopbie crystals are obtained; the crystals are recrystallized from cyclohexane-ether (9-1), and 8.6 g (2-thiomethyl-3-g 1ridyl) -3,5-dicarbethoxy-2,6- dimethyl-1, -dihydropyridine, having the form of white crystals so pl. . EXAMPLE D 6. 4- (2-Thiomethyl-3-pyridyl) -3,5-dicarbomethoxy-2,6-dimethyl-4, A-dihydropyridine (R is methyl,). The process is carried out analogously to example 5, but using 17 g of 2-thiomethyl-nicotinaldehyde and 26 g of methyl acetylacetate to obtain 15 g of - (2-thiomethyl-3-pyridyl-3.5-dicarbomethoxy-2,6-dime © tyl-1, 4-dihydropyridine having: a kind of white crystals, .121) p. 1, A-Dihydropyridines of general formula I in an experiment on dogs when administered intravenously (femoral vein shows the ability to cause a significant increase in coronary debit per unit of work when used in doses of 5-20 mcg per 1 kg of weight. When applied to rats (males) at the age of weeks with congenital hypertension when administered intraperitoneally, these compounds reduce the resistance of peripheral and coronary vessels and reduce the load on the heart.The duration of action is 2-10 minutes These compounds can be used, for example, in treating angina pectoris in daily doses of mg. The proposed method allows to obtain new compounds that have valuable chemical and pharmaceutical properties.
    权利要求:
    Claims (3)
    [1]
    1. METHOD FOR PRODUCING 1,4-DYHYDROPIRZCINS of the general formula wherein R is methyl or ethyl;
    X is a chlorine atom or SCHg, characterized in that the aldehyde of the general formula where X has the indicated meanings, is reacted with an alkylacetylacetate of the general formula
    CHjCOCHgCOOR, “where R has the indicated meanings, in a water-alcohol solution of ammonia.
    [2]
    2. The method of claim 1, wherein the reaction is carried out in an aqueous ethanol solution.
    [3]
    3 · Method popp, 1 and 2, characterized in that the molar ratio of aldehyde: alkylacetylacetate: ammonia is 1: 2: 1.
    SU ,,. 1007556
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    同族专利:
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    CH612678A5|1979-08-15|
    CA1079284A|1980-06-10|
    ES450582A1|1977-11-16|
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    SE7608959L|1977-02-13|
    NO762790L|1977-02-15|
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    CS194774B2|1979-12-31|
    AU504839B2|1979-11-01|
    DK362676A|1977-02-13|
    JPS5422986B2|1979-08-10|
    PT65456A|1976-09-01|
    NO144457C|1981-09-02|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE1670824C3|1967-03-20|1978-08-03|Bayer Ag, 5090 Leverkusen|1,4-Dihydropyridine-33-dicarboxylic acid alkyl ester|
    DE1813436C3|1968-12-07|1979-01-11|Bayer Ag, 5090 Leverkusen|N-substituted 2,6-dimethyl-1,4-dihydropyridines|
    DE1923990C3|1969-05-10|1978-11-23|Bayer Ag|Process for the preparation of N-substituted M-dihydropyridine-S.S-dicarboxylic acid esters|
    ZA7152B|1970-01-24|1971-10-27|Bayer Ag|New pharmaceutically active 1,4-dihydropyridines|
    DE2005116C3|1970-02-05|1980-02-14|Bayer Ag, 5090 Leverkusen|Symmetrical 1,4-dihydropyridine-3,5-dicarboxylic acid esters|
    DE2117573C3|1971-04-10|1978-07-27|Bayer Ag, 5090 Leverkusen|Process for the preparation of asymmetrical 1,4-dihydropyridine-3,5dicarboxylic acid esters, and their use as medicaments|
    DE2117571C3|1971-04-10|1979-10-11|Bayer Ag, 5090 Leverkusen|Asymmetrical 1,4-dihydropyridine-33-dicarboxylic acid esters, process for their preparation and their use as pharmaceuticals|
    DE2210672C3|1972-03-06|1980-03-20|Bayer Ag, 5090 Leverkusen|N-substituted asymmetrical 1 ^ -dihydropyridine-S ^ -dicarboxylic acid esters, process for their preparation and their use as medicaments|
    DE2218644C3|1972-04-18|1982-08-19|Bayer Ag, 5090 Leverkusen|Basic esters of 1,4-dihydropyridines, processes for their preparation and their use as pharmaceuticals|
    DE2248150A1|1972-09-30|1974-04-04|Bayer Ag|DIHYDROPYRIDINE POLYESTER, METHOD FOR MANUFACTURING AND USING THEM AS A MEDICINAL PRODUCT|DE2738153A1|1977-08-24|1979-03-08|Bayer Ag|2-PYRIDYL-1,4-DIHYDROPYRIDINE, THE METHOD FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT|
    DE2949464A1|1978-12-18|1980-06-26|Sandoz Ag|BENZOXADIAZOLES AND BENZOTHIADIAZOLES, THEIR PRODUCTION AND USE|
    CH639659A5|1978-12-18|1983-11-30|Sandoz Ag|NEW 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND USE.|
    US4497808A|1981-12-30|1985-02-05|Ciba-Geigy Corporation|N-Oxide compounds useful in the treatment of cardiovascular ailments|
    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|
    US4414213A|1982-03-22|1983-11-08|Mead Johnson & Company|Dihydropyridyl cyclic imidate esters and their pharmaceutical use|
    US4771057A|1986-02-03|1988-09-13|University Of Alberta|Reduced pyridyl derivatives with cardiovascular regulating properties|
    US6001857A|1992-10-30|1999-12-14|Bayer Aktiengesellschaft|Heterocyclyl substituted dihydropyridines|
    DE4236707A1|1992-10-30|1994-05-05|Bayer Ag|4-heterocyclyl substituted dihydropyridines|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB33501/75A|GB1511694A|1975-08-12|1975-08-12|Pyridine derivatives|
    GB4518875|1975-10-31|
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