公开(公告)号：US4415578A

公开(公告)日：1983-11-15

申请号：US347086

申请日：1982-02-08

申请人： George Y. Lesher ,  Baldev Singh

发明人： George Y. Lesher ,  Baldev Singh

IPC分类号： C07D213/38 ,  A61K31/44

CPC分类号： C07D213/38

摘要： 3-Methyl-4-(4-pyridinyl)benzeneamines, useful as cardiotonic agents, are prepared by reaction of pyridine, benzoyl chloride and an appropriate 3-methyl-N,N-di-lower-alkylbenzeneamine in the presence of copper powder and decomposing the reaction mixture with alkali and, if desired, reacting a resulting 3-methyl-4-(4-pyridinyl)-N,N-di-lower-alkylbenzeneamine with hydrogen bromide and pyridine to obtain 3-methyl-4-(4-pyridinyl)benzeneamine.

摘要翻译： 可用作强心剂的3-甲基-4-（4-吡啶基）苯胺通过吡啶，苯甲酰氯和合适的3-甲基-N，N-二低级烷基苯胺在铜粉和 如果需要，将所得3-甲基-4-（4-吡啶基）-N，N-二低级烷基苯胺与溴化氢和吡啶反应，得到3-甲基-4-（4 - 吡啶基）苯胺。

公开(公告)号：US4377585A

公开(公告)日：1983-03-22

申请号：US284771

申请日：1981-07-20

申请人： George Y. Lesher ,  Donald F. Page

发明人： George Y. Lesher ,  Donald F. Page

IPC分类号： C07D213/40 ,  A61K31/44

CPC分类号： C07D213/40

摘要： Disclosed and claimed are a cardiac composition and a method for increasing cardiac contractility using an effective amount of a cardiotonic 4-[4-(or 3)-AcNH-phenyl]-2-R.sub.2 -3-R.sub.3 -5-R.sub.5 -6-R.sub.6 -pyridine (I) or pharmaceutically-acceptable salt thereof, where R.sub.2 is hydrogen, methyl, ethyl or hydroxyl, R.sub.6 is hydrogen, methyl or ethyl, R.sub.3 and R.sub.5 are each hydrogen or methyl, and Ac is hydrogen, hydroxyacetyl, acetoxyacetyl, .alpha.-hydroxypropionyl, .alpha.-acetoxypropionyl, methyoxyacetyl, 2-butenoyl or carbamyl or when NHAc is attached to the 4-position of the phenyl ring Ac also is formyl, n-propanoyl, 2,2-dimethyl-n-propanoyl or 3-carboxypropanoyl or when NHAc is attached to the 3-position of the phenyl ring Ac also is acetyl. Novel compounds shown and claimed are 4-[4-(or 3)-Ac'NH-phenyl]-2-R.sub.2 -3-R.sub.3 -5-R.sub.5 -6-R.sub.6 -pyridines (II) or pharmaceutically-acceptable acid-addition salts thereof, where R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are defined as above for I and Ac' is hydroxyacetyl, acetoxyacetyl, .alpha.-hydroxypropanoyl, .alpha.-acetoxypropionyl, methoxyacetyl, 2-butenoyl or carbamyl or where Ac'NH is attached to the 4-position of the phenyl ring Ac' is formyl, n-propanoyl, 2,2-dimethyl-n-propanoyl or 3-carboxypropanoyl. Also disclosed and claimed is the process for preparing said novel compounds (II).

摘要翻译： 公开并要求保护的是心脏组合物和使用有效量的强心剂4- [4-（或3）-AcNH-苯基] -2-R2-3-R3-5-R5-6- R6-吡啶（I）或其药学上可接受的盐，其中R 2是氢，甲基，乙基或羟基，R 6是氢，甲基或乙基，R 3和R 5各自是氢或甲基，Ac是氢，羟基乙酰基，乙酰氧基乙酰基， α-羟基丙酰基，α-乙酰氧基丙酰基，甲氧基乙酰基，2-丁烯酰基或氨基甲酰基，或当NHAc与苯环的4-位连接时，Ac也是甲酰基，正丙酰基，2,2-二甲基 - 正丙酰基或3- 羧基丙酰基或当NHAc与苯环的3-位连接时，Ac也是乙酰基。 所示和要求保护的新化合物是4- [4-（或3）-Ac'NH-苯基] -2-R2-3-R3-5-R5-6-R6-吡啶（II）或药学上可接受的酸加成 其盐，其中R2，R3，R5和R6如上对I所定义，Ac'是羟基乙酰基，乙酰氧基乙酰基，α-羟基丙酰基，α-乙酰氧基丙酰基，甲氧基乙酰基，2-丁烯酰基或氨基甲酰基，或其中Ac'NH连接到4 苯环Ac'的位置是甲酰基，正丙酰基，2,2-二甲基 - 正丙酰基或3-羧基丙酰基。 还公开并要求保护的是制备所述新化合物（II）的方法。

公开(公告)号：US4376775A

公开(公告)日：1983-03-15

申请号：US285379

申请日：1981-07-20

申请人： George Y. Lesher ,  Donald F. Page

发明人： George Y. Lesher ,  Donald F. Page

IPC分类号： C07D213/40 ,  C07D213/54 ,  A61K31/44

CPC分类号： C07D213/40

摘要： Disclosed and claimed are N-R-N-40 [4-(4-2-R.sub.2 -3-R.sub.3 -5-R.sub.5 -6-R.sub.6 -4-pyridinyl)phenyl]ureas (I) or pharmaceutically-acceptable acid-addition salts thereof, where R is hydrogen, methyl or ethyl, R.sub.2 is hydrogen, methyl, ethyl or hydroxyl, R.sub.6 hydrogen, methyl or ethyl, and R.sub.3 and R.sub.5 are each hydrogen or methyl, their cardiotonic use and their preparation.

摘要翻译： 公开并要求保护的是NRN-40 [4-（4-2-R2-3-R3-5-R5-6-R6-4-吡啶基）苯基]脲（I）或其药学上可接受的酸加成盐，其中 R是氢，甲基或乙基，R2是氢，甲基，乙基或羟基，R6是氢，甲基或乙基，R3和R5分别是氢或甲基，它们的强心使用及其制备。

公开(公告)号：US4374141A

公开(公告)日：1983-02-15

申请号：US293248

申请日：1981-08-17

申请人： George Y. Lesher ,  Chester J. Opalka, Jr. ,  Donald F. Page

发明人： George Y. Lesher ,  Chester J. Opalka, Jr. ,  Donald F. Page

IPC分类号： C07D213/82 ,  C07D471/04 ,  C07D401/04 ,  A61K31/455

CPC分类号： C07D213/82 ,  C07D471/04

摘要： Shown is a process for preparing cardiotonically active 1,3-dihydro-3-R-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-ones, where Q is hydrogen or lower-alkyl, R is lower-alkyl, lower-hydroxyalkyl, lower-alkoxyalkyl or Y-NB where Y is lower-alkylene and NB is di-(lower-alkyl)amino or 4-morpholinyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two substituents, by reacting a 2-RNH-5-PY-6-Q-nicotinamide with an alkali metal hypohalite. Also shown are cardiotonic compositions and a method for increasing cardiac contractility using 2-RR'N-5-PY-6-Q-nicotinamides or pharmaceutically acceptable acid-addition salts thereof, where R' is hydrogen or methyl. Also shown is the process for preparing said 2-RR'N-5-PY-6-Q-nicotinamides by reacting a 2-halo-5-PY-6-Q-nicotinamide with an amine of the formula RR'NH.

摘要翻译： 示出了制备强心活性的1,3-二氢-3-R-6-PY-5-Q-2H-咪唑并[4,5-b]吡啶-2-酮的方法，其中Q是氢或低级烷基 R是低级烷基，低级羟烷基，低级烷氧基烷基或Y-NB，其中Y是低级亚烷基，NB是二 - （低级 - 烷基）氨基或4-吗啉基，PY是4-或3-吡啶基或 具有一个或两个取代基的4-或3-吡啶基，通过使2-RNH-5-PY-6-Q-烟酰胺与碱金属次卤酸盐反应。 还示出了强心剂组合物和使用2-RR'N-5-PY-6-Q-烟酰胺或其药学上可接受的酸加成盐增加心脏收缩力的方法，其中R'是氢或甲基。 还示出了通过使2-卤代-5-PY-6-C-烟酰胺与式RR'NH的胺反应来制备所述2-RR'N-5-PY-6-Q-烟酰胺的方法。

公开(公告)号：US4366319A

公开(公告)日：1982-12-28

申请号：US273480

申请日：1981-06-15

申请人： George Y. Lesher ,  Baldev Singh

发明人： George Y. Lesher ,  Baldev Singh

IPC分类号： C07D213/30 ,  C07D213/38 ,  C07D263/58

CPC分类号： C07D213/30 ,  C07D213/38

摘要： 5-PY-benzoxazol-2(3H)-ones, cardiotonic agents, are prepared by reacting 2-amino-4-PY-phenol with a carbonylating agent, e.g., carbonyldiimidazole, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. 5-PY-benzoxazol-2(3H)-ones or pharmaceutically-acceptable acid-addition or cationic salts thereof are disclosed as active components in cardiotonic compositions for increasing cardiac contractility and in the method for increasing cardiac contractility in a patient requiring such treatment.

摘要翻译： 5-氨基-4-PY-苯酚与羰基化试剂例如羰基二咪唑反应制备5-苯基恶唑-2（3H） - 酮，强心剂，其中PY是4-或3-吡啶基或4- 或具有一个或两个低级烷基取代基的3-吡啶基。 公开了5-PY-苯并恶唑-2（3H）酮或其药学上可接受的酸加成盐或阳离子盐作为用于增加心脏收缩力的强心剂组合物中的活性成分，以及在需要这种治疗的患者中提高心肌收缩力的方法。

公开(公告)号：US4365065A

公开(公告)日：1982-12-21

申请号：US299292

申请日：1981-09-03

申请人： George Y. Lesher ,  Richard E. Philion

发明人： George Y. Lesher ,  Richard E. Philion

IPC分类号： C07D213/50 ,  C07D213/64 ,  C07D213/73 ,  C07D213/74 ,  C07D213/75 ,  C07D213/80 ,  C07D213/82 ,  C07D213/85 ,  C07D213/38

CPC分类号： C07D213/64 ,  C07D213/50 ,  C07D213/73 ,  C07D213/74 ,  C07D213/75 ,  C07D213/80 ,  C07D213/82 ,  C07D213/85

摘要： 1-R.sub.1 -3-[amino, cyano, carbamyl, halo, lower-alkylamino, di-(lower-alkyl)amino or lower-acylamino]-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones or pharmaceutically-acceptable acid-addition or cationic salts thereof are useful as cardiotonic agents, where R.sub.1 is hydrogen, lower-alkyl or lower-hydroxyalkyl. 1-R.sub.1 -3-amino-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by hydrolyzing the corresponding 3-cyano compounds to produce the corresponding 3-carbamyl compounds and reacting the latter with a reagent capable of converting carbamyl to amino. The 1-R.sub.1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by reacting (pyridinylmethyl) lower-alkyl ketones with dimethylformamide di-(lower-alkyl) acetal to produce 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone and reacting said ketones with N-R.sub.1 -o-cyanoacetamide to produce the 1-R.sub.1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones. Also shown are the conversions: of the 3-cyano compounds to the 3-H compounds; of the 3-H compounds to the 3-halo compounds; of the 3-halo compounds to the 3-[mono-(lower-alkyl)- or di-(lower-alkyl)amino] compounds; and, of the 3-amino compounds to the 3-lower-acylamino or 3-[mono-(lower-alkyl)- or di-(lower-alkyl)amino] compounds.

摘要翻译： 1-R1-3- [氨基，氰基，氨基甲酰基，卤素，低级烷基氨基，二 - （低级烷基）氨基或低级酰基氨基] -6-（低级烷基）-5-（吡啶基） ） - 吡啶酮或其药学上可接受的酸加成盐或阳离子盐可用作强心剂，其中R 1是氢，低级烷基或低级 - 羟基烷基。 通过水解相应的3-氰基化合物制备相应的3-氨基甲酰基化合物并使后者反应，制备1-R1-3-氨基-6-（低级烷基）-5-（吡啶基）-2（1H） - 吡啶酮 使用能够将氨基甲酰转化为氨基的试剂。 通过使（吡啶基甲基）低级烷基酮与二甲基甲酰胺二（低级烷基）缩醛反应制备1-R1-3氰基-6-（低级烷基）-5-（吡啶基）-2（1H） - 吡啶酮 制备1-（吡啶基）-2-（二甲基氨基）乙烯基低级烷基酮，并使所述酮与N-R 1 - 邻 - 氰基乙酰胺反应，得到1-R1-3-氰基-6-（低级烷基）-5 - （吡啶基）-2（1H） - 吡啶酮。 还显示了3-氰基化合物与3-H化合物的转化率： 的3-H化合物与3-卤素化合物的反应; 的3-卤代化合物与3- [单（低级 - 低级 - 烷基） - 或二 - （低级 - 烷基）氨基]化合物反应; 和3-氨基化合物的3-低级酰基氨基或3- [单（低级 - 低级烷基） - 或二 - （低级 - 烷基）氨基]化合物。

公开(公告)号：US4354026A

公开(公告)日：1982-10-12

申请号：US238229

申请日：1981-02-26

申请人： George Y. Lesher ,  William B. Dickinson

发明人： George Y. Lesher ,  William B. Dickinson

IPC分类号： C07D213/50 ,  C07D401/04

CPC分类号： C07D213/50

摘要： 3-Hydrazino-6-PY-pyridazine or pharmaceutically-acceptable acid-addition salt thereof is useful as a cardiotonic agent, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. 6-PY-3-pyridazinol is prepared by reacting 6-PY-3-pyridazinol with a chlorinating agent to produce 3-chloro-6-PY-pyridazine and reacting said 3-chloro compound with hydrazine to produce said 3-hydrazino compound. 3-Hydrazino-6-PY-pyridazine or pharmaceutically-acceptable acid-addition salt thereof is disclosed as the active component in cardiotonic compositions for increasing cardiac contractility and in the method for increasing cardiac contractility in a patient requiring such treatment. The novel intermediate 3-chloro-6-PY-pyridazine is prepared as noted above.

摘要翻译： 3-肼基-6-PY-哒嗪或其药学上可接受的酸加成盐可用作强心剂，其中PY是4-或3-吡啶基或具有一个或两个低级烷基取代基的4-或3-吡啶基。 6-PY-3-哒嗪醇是通过使6-PY-3-哒嗪醇与氯化剂反应制得3-氯-6-PY-哒嗪并使所述3-氯化合物与肼反应生成所述3-肼基化合物。 公开了3-肼基-6-PY-哒嗪或其药学上可接受的酸加成盐作为用于增加心肌收缩力的强心剂组合物中的活性成分，以及在需要这种治疗的患者中提高心肌收缩力的方法。 如上所述制备新型中间体3-氯-6-PY-哒嗪。

公开(公告)号：US4351941A

公开(公告)日：1982-09-28

申请号：US317548

申请日：1981-11-02

申请人： George Y. Lesher ,  Chester J. Opalka, Jr. ,  Donald F. Page

发明人： George Y. Lesher ,  Chester J. Opalka, Jr. ,  Donald F. Page

IPC分类号： C07D213/50 ,  C07D213/64 ,  C07D213/73 ,  C07D213/74 ,  C07D213/75 ,  C07D213/80 ,  C07D213/82 ,  C07D213/85 ,  C07D401/04

CPC分类号： C07D213/64 ,  C07D213/50 ,  C07D213/73 ,  C07D213/74 ,  C07D213/75 ,  C07D213/80 ,  C07D213/82 ,  C07D213/85

摘要： 2-[R.sub.1 NHN(R)]-3-Q'-5-PY-6-Q-pyridines or pharmaceutically-acceptable acid-addition salts thereof are useful as cardiotonic agents, where Q is hydrogen or lower-alkyl, PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, Q' is hydrogen or halo, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and R.sub.1 is hydrogen or when R is other than hydrogen R.sub.1 is the same as R. These compounds are prepared by reacting a 2-halo-3-Q'-5-PY-6-Q-pyridine with R.sub.1 NHNHR where 2-halo is bromo or chloro. Also shown are: the use of said 2-[R.sub.1 NN(R)]-3-Q'-5-PY-6-Q-pyridines as cardiotonic agents; and, the intermediates, 2,3-dihalo-5-PY-6-Q-pyridines, and their preparation from 3-nitro-5-PY-6-Q-2(1H)-pyridinones.

摘要翻译： 2- [R1NHN（R）] - 3-Q'-5-PY-6-Q-吡啶或其药学上可接受的酸加成盐可用作强心剂，其中Q为氢或低级烷基，PY为4 - 或3-吡啶基或具有一个或两个低级烷基取代基的4-或3-吡啶基，Q'是氢或卤素，R是氢，低级烷基或低级 - 羟基烷基，并且R 1是氢或当R不是 氢R1与R相同。这些化合物通过2-卤代-3-Q'-5-PY-6-Q-吡啶与R1NHNHR反应来制备，其中2-卤代是溴或氯。 还显示：使用所述2- [R1NN（R）] - 3-Q'-5-PY-6-Q-吡啶作为强心剂; 和中间体2,3-二卤代-5-PY-6-Q-吡啶，以及它们由3-硝基-5-PY-6-Q-2（1H） - 吡啶酮的制备。

公开(公告)号：US4339584A

公开(公告)日：1982-07-13

申请号：US262187

申请日：1981-05-11

申请人： Monte D. Gruett ,  George Y. Lesher

发明人： Monte D. Gruett ,  George Y. Lesher

IPC分类号： C07D213/78 ,  C07D401/04

CPC分类号： C07D213/78

摘要： N-Hydroxy-1-R.sub.1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamides or pharmaceutically-acceptable acid-addition salts thereof, useful as cardiotonic agents, are prepared by reacting 1-R.sub.1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles with hydroxylamine and are converted by reaction with polyphosphoric acid to the corresponding cardiotonically useful 1-R.sub.1 -3-amino-5-PY-6-R-2(1H)-pyridinones, where R.sub.1 is hydrogen, lower-alkyl and lower-hydroxyalkyl, R is hydrogen or lower-alkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.

摘要翻译： 可用作强心剂的N-羟基-1-R1-1,2-二氢-2-氧代-5-PY-6-R-烟酰亚胺酰胺或其药学上可接受的酸加成盐通过使1-R1- 具有羟胺的1,2-二氢-2-氧代-5-PY-6-R-烟酰胺与通过与多磷酸的反应转化成相应的强力有效的1-R1-3-氨基-5-PY-6-R- 2（1H） - 吡啶酮，其中R 1是氢，低级烷基和低级羟基烷基，R是氢或低级烷基，PY是4-或3-吡啶基或具有一个或两个低级烷基的4-或3-吡啶基， 烷基取代基。

公开(公告)号：US4338446A

公开(公告)日：1982-07-06

申请号：US238483

申请日：1981-02-26

申请人： George Y. Lesher ,  William B. Dickinson

发明人： George Y. Lesher ,  William B. Dickinson

IPC分类号： C07D213/55

CPC分类号： C07D213/55

摘要： 2-R-4-R'-6-PY-3(2H)-pyridazinones (I) or salts thereof, which are useful as intermediates and some as cardiotonics, are prepared by reacting di-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH.sub.2.nH.sub.x An (III) to produce lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (Ia where R' is lower-carbalkoxy) and reacting Ia with hydrazine hydrate or anhydrous hydrazine to produce 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib where R' is aminocarbamyl), where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, R' is carbamyl, carboxy, aminocarbamyl or lower-carbalkoxy, n is 1 or 2, x is 1, 2 or 3, and An is an anion of a strong inorganic acid or an organic sulfonic acid. Also shown are: the preparation of II from PY-COCH.sub.3 (IV), the conversion of Ia to Ib (Id where R' is carboxy), and the use of 2-R-4-R"-6-PY-3(2H)-pyridazinones (I where R is lower-alkyl or lower-hydroxyalkyl and R" is carbamyl, aminocarbamyl or lower-carbalkoxy) as cardiotonic agents. Other intermediates are shown.

摘要翻译： 通过使二（低级 - 烷基）羟基[2（R 2）2 - [（R 1）] - 哒嗪酮（I）或其盐作为中间体，有些作为强心剂， - 氧代-2-PY-乙基]丙二酸盐（II）与式RNHNH 2·nH x A n（III）的肼盐反应，生成低级烷基2,3-二氢-2-R-3-氧代-6-PY-4 （Ia，其中R'是低级 - 烷氧基），并且使Ia与水合肼或无水肼反应，得到2,3-二氢-2-R-3-氧代-6-PY-4-哒嗪甲酰肼（Ib，其中R 其中PY为4-或3-吡啶基或具有一个或两个低级烷基取代基的4-或3-吡啶基，R为氢，低级烷基或低级羟烷基，R'为氨甲酰基，羧基，氨基甲酰基 或低碳烷氧基，n为1或2，x为1,2或3，An为强无机酸或有机磺酸的阴离子。 还显示：从PY-COCH3（IV）制备II，将Ia转化为Ib（Id，其中R'为羧基），以及使用2-R-4-R“-6-PY-3 （2H） - 哒嗪酮（I，其中R是低级烷基或低级羟基烷基，R“是氨甲酰基，氨基氨基甲酰基或低级烷酰氧基）作为强心剂。 显示其他中间体。