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    (Aminoalkoxy-aryl)-substituted isoquinolinones and naphthydrinones and salts thereof, and hypotensive compositions and methods employing them
    1.
    发明授权
    (Aminoalkoxy-aryl)-substituted isoquinolinones and naphthydrinones and salts thereof, and hypotensive compositions and methods employing them 失效
    （氨基烷氧基 - 芳基） - 取代的异喹啉酮和萘啶酮及其盐，以及使用它们的低血压组合物和方法

    公开(公告)号：US4154837A

    公开(公告)日：1979-05-15

    申请号：US867308

    申请日：1978-01-06

    申请人： Joachim Heider ,  Volkhard Austel ,  Wolfgang Eberlein ,  Rudolf Kadatz ,  Jurgen Dammgen ,  Walter Kobinger ,  Christian Lillie

    发明人： Joachim Heider ,  Volkhard Austel ,  Wolfgang Eberlein ,  Rudolf Kadatz ,  Jurgen Dammgen ,  Walter Kobinger ,  Christian Lillie

    IPC分类号： A61K31/444 ,  A61K31/47 ,  A61K31/472 ,  A61P9/00 ,  A61P9/12 ,  C07D217/24 ,  C07D471/04

    CPC分类号： C07D471/04 ,  C07D217/24

    摘要： Compounds of the formula ##STR1## wherein A is benzo, mono-, di- or tri-substituted benzo, the substituents being selected from the group consisting of lower alkoxy, amino and nitro, or pyrido;R.sub.1 is hydrogen or lower alkyl;R.sub.2 is alkyl of 1 to 6 carbon atoms or --X--R.sub.6, where X is straight alkylene of 1 to 4 carbon atoms or hydroxy-substituted straight alkylene of 1 to 4 carbon atoms; andR.sub.6 is amino; carbalkoxy of 2 to 6 carbon atoms; phenyl; mono-, di- or tri-substituted phenyl, the substituents being selected from the group consisting of lower alkyl and lower alkoxy; phenoxy; or mono-, di- or tri-substituted phenoxy, the substituents being selected from the group consisting of lower alkyl and lower alkoxy;R.sub.3 is hydrogen or hydroxyl;R.sub.4 is hydrogen, lower alkyl or lower alkoxy;R.sub.5 is hydrogen or lower alkyl; andN is 0, 1 or 2;And non-toxic, pharmacologically acceptable acid addition salts thereof. The compounds as well as the salts are useful as antiarrhythmics, .beta.-adrenergic-receptor blockers and anti-anginous agents.

    摘要翻译： 其中A是苯并，一或二取代或三取代的苯并，其取代基选自低级烷氧基，氨基和硝基，或吡啶并。 R1是氢或低级烷基; R2是1至6个碳原子的烷基或-X-R6，其中X是1至4个碳原子的直链亚烷基或1至4个碳原子的羟基取代的直链亚烷基; R6为氨基; 2至6个碳原子的烷氧基; 苯基; 单取代，二取代或三取代的苯基，所述取代基选自低级烷基和低级烷氧基; 苯氧基 或单 - ，二 - 或三 - 取代的苯氧基，所述取代基选自低级烷基和低级烷氧基; R3是氢或羟基; R4是氢，低级烷基或低级烷氧基; R5是氢或低级烷基; 和N IS 0，1或2; 和非毒性，药理学上可接受的酸添加量。 化合物和盐可用作抗心律失常药，β-肾上腺素能受体阻断剂和抗麻痹剂。

    Phenylalkylamino-alkyl derivatives of quinazolinone and phthalazinone
    2.
    发明授权
    Phenylalkylamino-alkyl derivatives of quinazolinone and phthalazinone 失效
    喹唑啉酮和酞嗪酮的苯基烷基氨基 - 烷基衍生物

    公开(公告)号：US4134980A

    公开(公告)日：1979-01-16

    申请号：US827142

    申请日：1977-08-24

    申请人： Wolfgang Eberlein ,  Volkhard Austel ,  Joachim Heider ,  Jurgen Dammgen ,  Rudolf Kadatz ,  Christian Lillie ,  Walter Kobinger

    发明人： Wolfgang Eberlein ,  Volkhard Austel ,  Joachim Heider ,  Jurgen Dammgen ,  Rudolf Kadatz ,  Christian Lillie ,  Walter Kobinger

    IPC分类号： C07D239/91 ,  A61K31/50 ,  A61K31/502 ,  A61K31/505 ,  A61K31/517 ,  A61P9/06 ,  A61P9/12 ,  B01J23/00 ,  C07D237/00 ,  C07D237/32 ,  C07D239/88 ,  C07D239/90 ,  C07D317/00 ,  C07D319/00 ,  C07D405/12 ,  C07D491/04 ,  C07D491/056 ,  C07D239/72

    CPC分类号： C07D491/04 ,  C07D237/32 ,  C07D239/90

    摘要： Compounds of the formula ##STR1## wherein A is ##STR2## where R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.2 is alkoxy of 1 to 3 carbon atoms;R.sub.3 is alkoxy of 1 to 3 carbon atoms or, together with R.sub.2, methylenedioxy or ethylenedioxy;R.sub.4 is hydrogen, alkyl of 1 to 3 carbon atoms or benzyl;R.sub.5 is hydrogen or alkyl of 1 to 3 carbon atoms;R.sub.6 is hydrogen or alkoxy of 1 to 3 carbon atoms;R.sub.7 is alkoxy of 1 to 3 carbon atoms or, together with R.sub.6, methylenedioxy or ethylenedioxy; andN is 2 or 3;And non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as heart rate reducers and mild antihypertensives.This invention relates to novel N-(phenylalkylaminoalkyl)-substituted quinazolinones and phthalazinones and nontoxic acid addition salts thereof, as well as to various methods of preparing these compounds.More particularly, the present invention relates to a novel class of N-substituted quinazolinones and phthalazinones represented by the formula ##STR3## wherein A is ##STR4## where R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.2 is alkoxy of 1 to 3 carbon atoms;R.sub.3 is alkoxy of 1 to 3 carbon atoms or, together with R.sub.2, methylenedioxy or ethylenedioxy;R.sub.4 is hydrogen, alkyl of 1 to 3 carbon atoms or benzyl;R.sub.5 is hydrogen or alkyl of 1 to 3 carbon atoms;R.sub.6 is hydrogen or alkoxy of 1 to 3 carbon atoms;R.sub.7 is alkoxy of 1 to 3 carbon atoms or, together with R.sub.6, methylenedioxy or ethylenedioxy; andN is 2 or 3;Or a non-toxic, pharmacologically acceptable acid addition salt thereof.A preferred sub-genus thereunder is constituted by compounds of the formula I whereR.sub.1 and R.sub.5 are each hydrogen, methyl, ethyl, n-propyl or isopropyl;R.sub.4 is hydrogen, methyl, ethyl, n-propyl, isopropyl or benzyl;R.sub.2, r.sub.3 and R.sub.7 are each methoxy, ethoxy, n-propoxy or isopropoxy;R.sub.6 is hydrogen, methoxy, ethoxy, n-propoxy or isopropoxy;R.sub.2 and R.sub.3, together with each other, are methylenedioxy or ethylenedioxy;R.sub.6 and R.sub.7, together with each other, are methylenedioxy or ethylenedioxy; andn is 2 or 3;and non-toxic, pharmacologically acceptable acid addition salts thereof.A further, especially preferred sub-genus thereunder is constituted by compounds of the formula I whereR.sub.2 and R.sub.3 are methoxy in the 6- and 7-position, respectively, or, together with each other, methylenedioxy or ethylenedioxy;R.sub.4 is hydrogen or methyl;R.sub.5 is hydrogen;R.sub.6 is hydrogen or methoxy in the 3-position;R.sub.7 is methoxy in the 4-position or, together with R.sub.6, methylenedioxy or ethylenedioxy; andn is 2 or 3;and non-toxic, pharmacologically acceptable acid addition salts thereof.The compounds embraced by formula I may be prepared by the following methods:Method ABy reacting a compound of the formula ##STR5## wherein R.sub.2, R.sub.3, A and n have the same meanings as in formula I, andZ is a leaving-group, such as chlorine, bromine, iodine, alkylsulfonyloxy or arylsulfonyloxy,with a phenylalkylamine of the formula ##STR6## wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 have the same meanings as in formula I.The reaction is carried out in an inert solvent, such as ether, tetrahydrofuran, methylformamide, dimethylformamide, dimethylsulfoxide, chlorobenzene or benzene, and depending upon the reactivity of substituent Z, at a temperature between -50 and +250.degree. C, but preferably at the boiling point of the particular solvent which is used. The presence of an acid-binding agent, such as an alkali metal alcoholate, an alkali metal hydroxide, an alkali metal carbonate, especially potassium carbonate, or a tertiary organic base, particularly triethylamine or pyridine, or of a reaction accelerator, such as potassium iodide, is of advantage.Method BBy reacting a compound of the formula ##STR7## wherein A, R.sub.2 and R.sub.3 have the same meanings as in formula I, with a phenylalkylamine of the formula ##STR8## wherein R.sub.4, R.sub.5, R.sub.6 and n have the same meanings as in formula I, andZ has the same meanings as in formula II.The reaction is carried out in an inert solvent, such as acetone, dimethylformamide, dimethylsulfoxide or chlorobenzene, and, depending upon the reactivity of substituent Z, at a temperature between 0 and 150.degree. C, but preferably at the boiling point of the particular solvent which is used. The presence of an acid-binding agent, such as an alkali metal alcoholate, an alkali metal hydroxide, an alkali metal carbonate, especially potassium carbonate, an alkali metal amide or a tertiary organic base, particularly triethylamine or pyridine, or of a reaction accelerator, such as potassium iodide, is of advantage.Method CBy reacting an aldehyde of the formula ##STR9## wherein R.sub.2, R.sub.3, A and n have the same meanings as in formula I, or an acetal thereof, with an amine of the formula III in the presence of catalytically activated hydrogen.The reductive amination is carried out with hydrogen in the presence of a hydrogenation catalyst, such as palladized charcoal, at a hydrogen pressure of 5 atmospheres, in a solvent, such as methanol, ethanol or dioxane, and at a temperature between 0 and 100.degree. C, but preferably between 20 and 80.degree. C.Method DBy reacting an amine of the formula ##STR10## wherein R.sub.2, R.sub.3, R.sub.4, A and n have the same meanings as in formula I, with a phenylalkyl compound of the formula ##STR11## wherein R.sub.5, R.sub.6 and R.sub.7 have the same meanings as in formula I, andZ has the same meanings as in formula II.The reaction is carried out in an inert solvent, such as acetone, methylene chloride, dimethylformamide, dimethylsulfoxide or chlorobenzene, and, depending upon the reactivity of substituent Z, at a temperature between 0 and 150.degree. C, but preferably at the boiling point of the particular solvent which is used. The presence of an acid-binding agent, such as an alkali metal alcoholate, an alkali metal hydroxide, an alkali metal carbonate, especially potassium carbonate, or a tertiary organic base, particularly triethylamine or pyridine, or of a reaction accelerator, such as potassium iodide, is of advantage.Method EFor the preparation of a quinazolinone derivative of the formula I, by reacting a benzoxazin-4-one of the formula ##STR12## wherein R.sub.1, R.sub.2 and R.sub.3 have the same meanings as in formula I, with an alkylenediamine of the formula wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 have the same meanings as in formula I.The reaction is advantageously carried out in a solvent, such as benzene, dioxane, a lower alkanoic acid such as glacial acetic acid, or dimethylformamide, and optionally in the presence of an acid catalyst at a temperature between 50 and 150.degree. C, but preferably at the boiling point of the particular solvent which is used. The preferred solvent is glacial acetic acid. The reaction may, however, also be performed without a solvent.If the end product of methods A through E is a compound of the formula I wherein R.sub.4 is benzyl, the same may be de-benzylated to yield the corresponding compound wherein R.sub.4 is hydrogen. The de-benzylation is preferably effected by means of catalytic hydrogenation, for example with hydrogen in the presence of a catalyst such as palladized charcoal, in a solvent such as ethanol or ethylacetate, at a temperature between 25 and 75.degree. C and at a hydrogen pressure of 1 to 7 atmospheres.On the other hand, if the end product of methods A through E is a compound of the formula I wherein R.sub.4 is hydrogen; the same may be alkylated at the bridge nitrogen atom to form the corresponding compound where R.sub.4 is alkyl. The alkylation is carried out with a conventional alkylating agent, for example with an alkyl halide such as methyl iodide, ethyl iodide or isopropyl bromide, or with a dialkylsulfate such a dimethylsulfate, in a solvent such as acetone, dimethylformamide or dioxane, optionally in the presence of an inorganic or tertiary organic base, at a temperature between 0 and 50.degree. C. A methylation may also be effected by reaction with a mixture of formaldehyde and formic acid, preferably at the boiling point of said mixture.The compounds embraced by formula I are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid, maleic acid, 8-chlorotheophylline or the like.The starting compounds of the formulas II through X are either described in the literature or may be prepared by known methods, as described in the examples below.

    摘要翻译： 其中A是其中R 1是氢或1至3个碳原子的烷基的式“IMAGE”的化合物; R 2是1至3个碳原子的烷氧基; R3为1〜3个碳原子的烷氧基，或与R2一起亚甲二氧基或亚乙二氧基; R4是氢，1至3个碳原子的烷基或苄基; R5是氢或1〜3个碳原子的烷基; R6是氢或1〜3个碳原子的烷氧基; R 7为1〜3个碳原子的烷氧基，或与R6一起亚甲二氧基或亚乙二氧基; 和N IS 2 OR 3; 和非毒性，药理学上可接受的酸添加量; 化合物作为其有效的有效的H

    Bis-homophthalimides and salts thereof
    7.
    发明授权
    Bis-homophthalimides and salts thereof 失效
    双 - 高邻苯二甲酰亚胺及其盐

    公开(公告)号：US4031219A

    公开(公告)日：1977-06-21

    申请号：US704844

    申请日：1976-07-13

    申请人： Eberhard Kutter ,  Volkhard Austel ,  Wolfgang Eberlein ,  Joachim Heider ,  Walter Kobinger ,  Christian Lillie ,  Rudolf Kadatz

    发明人： Eberhard Kutter ,  Volkhard Austel ,  Wolfgang Eberlein ,  Joachim Heider ,  Walter Kobinger ,  Christian Lillie ,  Rudolf Kadatz

    IPC分类号： A61K31/47 ,  A61K31/472 ,  A61P9/06 ,  C07D217/24 ,  C07D221/22

    CPC分类号： C07D217/24 ,  Y10S514/821

    摘要： Compounds of the formula ##STR1## wherein A and B, which may be identical to or different from each other, are each straight alkylene of 2 to 4 carbon atoms which may have a methyl or phenyl substituent attached thereto,R.sub.1, r.sub.2, r.sub.3 and R.sub.4, which may be identical to or different from each other, are each hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, nitro, acetylamino, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or (alkyl of 1 to 3 carbon atoms)thio,R.sub.5, r.sub.6, r.sub.7 and R.sub.8, which may be identical to or different from each other, are each hydrogen, alkyl of 1 to 4 carbon atoms, phenyl-(alkyl of 1 to 4 carbon atoms) or methoxyphenyl-(alkyl of 1 to 4 carbon atoms), orR.sub.5 and R.sub.6, together with each other, are straight alkylene of 2 to 5 carbon atoms, orR.sub.7 and R.sub.8, together with each other, are straight alkylene of 2 to 5 carbon atoms, andR.sub.9 is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl-(alkyl of 1 to 6 carbon atoms),And non-toxic, pharmaceutically acceptable acid addition salts thereof; the compounds as well as the salts are useful as antiarrhythmics.

    摘要翻译： 其中A和B可以彼此相同或不同的化合物是可以具有连接到其上的甲基或苯基取代基的2至4个碳原子的直链亚烷基，R 1，R 2，R 3和 R 4可以相同或不同，分别为氢，氟，氯，溴，羟基，氨基，硝基，乙酰氨基，1〜3个碳原子的烷基，1〜3个碳原子的烷氧基或（ 1至3个碳原子）硫代，R 5，R 6，R 7和R 8可彼此相同或不同，分别为氢，1至4个碳原子的烷基，苯基 - （1至4个碳原子的烷基） 或甲氧基苯基 - （1至4个碳原子的烷基）或R 5和R 6彼此一起是2至5个碳原子的直链亚烷基，或者R 7和R 8彼此一起是2至5个直链亚烷基 碳原子，并且R 9为氢，1至6个碳原子的烷基或苯基 - （1至6个碳原子的烷基），和非毒性，药学上可接受的酸 附加费用 化合物作为反应物可用作生物反应器。

    2-Phenyl-pyrimidones
    8.
    发明授权
    2-Phenyl-pyrimidones 失效
    2-苯基 - 嘧啶酮

    公开(公告)号：US4379788A

    公开(公告)日：1983-04-12

    申请号：US327348

    申请日：1981-12-04

    申请人： Joachim Heider ,  Volkhard Austel ,  Wolfgang Eberlein ,  Rudolf Kadatz ,  Christian Lillie

    发明人： Joachim Heider ,  Volkhard Austel ,  Wolfgang Eberlein ,  Rudolf Kadatz ,  Christian Lillie

    IPC分类号： C07D239/88 ,  A61K31/513 ,  A61P9/00 ,  C07D213/82 ,  C07D239/91 ,  C07D265/22 ,  C07D471/04 ,  C07D498/04 ,  A61K31/505

    CPC分类号： C07D213/82 ,  C07D239/91 ,  C07D265/22 ,  C07D471/04

    摘要： Compounds of the formula ##STR1## wherein A and B, together with each other and the respective carbon atoms to which they are attached, form a phenyl or pyridine ring;R.sub.1 is hydrogen, halogen, amino, nitro, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms;R.sub.2 is hydrogen or alkoxy of 1 to 3 carbon atoms;D is alkylene of 3 to 4 carbon atoms or hydroxy(alkylene of 3 to 4 carbon atoms);R.sub.3 and R.sub.5, which may be identical to or different from each other, are each hydrogen or alkyl of 1 to 3 carbon atoms;R.sub.4 is hydrogen or alkoxy of 1 to 3 carbon atoms; andR.sub.6 is straight or branched alkyl of 1 to 6 carbon atoms or --E--R.sub.7 ;where E is straight alkylene of 2 to 4 carbon atoms or hydroxy-substituted straight alkylene of 2 to 4 carbon atoms, andR.sub.7 is ##STR2## where R.sub.8 and R.sub.9 are each hydrogen, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms;and non-toxic, pharmacologically acceptable acid addition salts thereof formed with inorganic or organic acids; the compounds as well as their salts are useful as hypotensives, antiarrhythmics and .beta.-receptor-blockers.

    摘要翻译： 其中A和B与它们相连的相互连接的碳原子一起形成苯基或吡啶环; R 1是氢，卤素，氨基，硝基，1至3个碳原子的烷基或1至3个碳原子的烷氧基; R2是氢或1〜3个碳原子的烷氧基; D是3至4个碳原子的亚烷基或羟基（3至4个碳原子的亚烷基）; R 3和R 5可以相同或不同，分别为氢或1-3个碳原子的烷基; R4是氢或1〜3个碳原子的烷氧基; R6是1-6个碳原子的直链或支链烷基或-E-R7; 其中E是2至4个碳原子的直链亚烷基或2至4个碳原子的羟基取代的直链亚烷基，并且R 7是R 8和R 9各自为氢，1至3个碳原子的烷基或1至 3个碳原子; 和与无机或有机酸形成的无毒的，药学上可接受的酸加成盐; 化合物及其盐可用作低血糖，抗心律失常药和β-受体阻滞剂。

    Pyridazinone-substituted benzimidazoles and salts
    9.
    发明授权
    Pyridazinone-substituted benzimidazoles and salts 失效
    哒嗪酮取代的苯并咪唑和盐

    公开(公告)号：US4361563A

    公开(公告)日：1982-11-30

    申请号：US259537

    申请日：1981-05-01

    申请人： Volkhard Austel ,  Joachim Heider ,  Wolfgang Eberlein ,  Willi Diederen ,  Walter Haarmann

    发明人： Volkhard Austel ,  Joachim Heider ,  Wolfgang Eberlein ,  Willi Diederen ,  Walter Haarmann

    IPC分类号： A61K31/50 ,  C07D235/18 ,  C07D237/04 ,  C07D403/04

    CPC分类号： C07D237/04 ,  A61K31/50 ,  C07D235/18 ,  Y10S514/822

    摘要： Compounds of the formula ##STR1## wherein R.sub.1 is hydrogen; trifluoromethyl; alkyl of 1 to 11 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; hydroxyl; alkoxy of 1 to 6 carbon atoms; mercapto; (alkyl of 1 to 6 carbon atoms)-mercapto; phenyl-(alkyl of 1 to 3 carbon atoms); phenyl; or mono-, di- or tri-substituted phenyl, where the substituents, which may be identical to or different from each other, are each halogen, alkyl of 1 to 4 carbon atoms, (alkyl of 1 to 6 carbon atoms)-sulfinyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, mercapto or (alkyl of 1 to 6 carbon atoms)-mercapto;R.sub.2 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl-(alkyl of 1 to 3 carbon atoms); andR.sub.3 is alkyl of 1 to 6 carbon atoms; optically active antipodes thereof; and non-toxic, pharmaceutically acceptable acid addition salts of said compounds or of said optically active antiposed. The compounds are useful as cardiotonics and antithrombotics.

    摘要翻译： 其中R 1是氢的式IMAMA的化合物; 三氟甲基 1至11个碳原子的烷基; 3至7个碳原子的环烷基; 羟; 1至6个碳原子的烷氧基; 巯基 （1-6个碳原子的烷基） - 巯基; 苯基 - （1至3个碳原子的烷基）; 苯基; 或单取代，二取代或三取代的苯基，其中可以相同或不同的取代基各自为卤素，具有1至4个碳原子的烷基，（1至6个碳原子的烷基） - 亚磺酰基 ，羟基，1至6个碳原子的烷氧基，巯基或（1至6个碳原子的烷基） - 巯基; R2是氢，1至6个碳原子的烷基，3至6个碳原子的环烷基或苯基 - （1至3个碳原子的烷基）; 且R 3为1至6个碳原子的烷基; 光学活性对映体; 和所述化合物或所述光学活性药物的无毒的药学上可接受的酸加成盐。 这些化合物可用作强心剂和抗血栓药物。