6,7-dimethoxy-4-methylphthalazin-1(2H)-one | 10001-36-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6,7-dimethoxy-4-methylphthalazin-1(2H)-one
• 英文别名: 4-methyl-6,7-dimethoxy-1(2H)-phthalazinone；6,7-dimethoxy-4-methyl-2H-phthalazin-1-one
• CAS: 10001-36-2
• 化学式: C₁₁H₁₂N₂O₃
• 分子量: 220.228
• InChiKey: LZSMTBAWOWDVII-UHFFFAOYSA-N

物化性质

• 熔点：
  249-254 °C
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  59.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6,7-dimethoxy-4-methylphthalazin-1(2H)-one 在 [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate 、 potassium tert-butylate 、 三氯氧磷 作用下， 以 甲苯 为溶剂， 反应 13.0h， 生成 (R)-6,7-dimethoxy-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine
  参考文献：
  名称：

  MRTX0902 的设计和发现，一种 SOS1:KRAS 蛋白质-蛋白质相互作用的强效、选择性、脑渗透性和口服生物可利用抑制剂

  摘要：

  SOS1 是主要的鸟嘌呤核苷酸交换因子之一，可调节 KRAS 循环通过其“开”和“关”状态的能力。破坏 SOS1:KRAS G12C蛋白质-蛋白质相互作用 (PPI) 可以增加负载 GDP 的 KRAS G12C 的比例，为将 SOS1:KRAS 复合物的抑制剂与靶向 GDP 负载的 KRAS G12C的抑制剂（如 MRTX849）组合提供强有力的机制原理。在本报告中，我们详细介绍了 MRTX0902 的设计和发现——一种有效、选择性、脑渗透性和口服生物可利用的 SOS1 结合剂，可破坏 SOS1:KRAS G12C生产者价格指数。MRTX0902 与 MRTX849 联合口服给药相对于任一单一药物的抗肿瘤活性显着增加，包括 MIA PaCa-2 肿瘤小鼠异种移植模型中一部分动物的肿瘤消退。

  DOI：

  10.1021/acs.jmedchem.2c00741
• 作为产物：
  描述：

  3,4-二甲氧基苯甲酸甲酯 在 盐酸 、 溴 、 palladium diacetate 、 一水合肼 、 溶剂黄146 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 、 乙腈 为溶剂， 反应 19.75h， 生成 6,7-dimethoxy-4-methylphthalazin-1(2H)-one
  参考文献：
  名称：

  [EN] SOS1 INHIBITORS
  [FR] INHIBITEURS DE SOS1

  摘要：

  本发明涉及抑制七无子同源物1（SOS1）活性的化合物。具体而言，本发明涉及化合物、药物组合物和使用方法，例如使用本发明的化合物和药物组合物治疗癌症的方法。

  公开号：

  WO2021127429A1

文献信息

• Phenylalkylamino-alkyl derivatives of quinazolinone and phthalazinone
  申请人：Boehringer Ingelheim GmbH

  公开号：US04134980A1

  公开（公告）日：1979-01-16

  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; and N 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; and N 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 where R.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; and n 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 where R.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; and n 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 A By 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, and Z 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 B By 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, and Z 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 C By 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 D By 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, and Z 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 E For 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.

  该专利涉及一种新型的N-(苯基烷基氨基烷基)取代的喹唑啉酮和邻苯二氮酮及其无毒、药理学可接受的酸盐，以及制备这些化合物的各种方法。该化合物及其盐可用作降低心率和轻度降压剂。其中，化合物的通式为##STR1##其中A是##STR2##其中R.sub.1是1至3个碳原子的氢或烷基；R.sub.2是1至3个碳原子的烷氧基；R.sub.3是1至3个碳原子的烷氧基或与R.sub.2一起形成亚甲二氧基或乙二氧基；R.sub.4是氢、1至3个碳原子的烷基或苄基；R.sub.5是氢或1至3个碳原子的烷基；R.sub.6是氢或1至3个碳原子的烷氧基；R.sub.7是1至3个碳原子的烷氧基或与R.sub.6一起形成亚甲二氧基或乙二氧基；N为2或3；以及其无毒、药理学可接受的酸盐。 其中，特别优选的亚属包括通式I的化合物，其中R.sub.1和R.sub.5均为氢、甲基、乙基、正丙基或异丙基；R.sub.4是氢、甲基、乙基、正丙基、异丙基或苄基；R.sub.2、R.sub.3和R.sub.7均为甲氧基、乙氧基、正丙氧基或异丙氧基；R.sub.6是氢、甲氧基、乙氧基、正丙氧基或异丙氧基；R.sub.2和R.sub.3互相结合，形成亚甲二氧基或乙二氧基；R.sub.6和R.sub.7互相结合，形成亚甲二氧基或乙二氧基；n为2或3；以及其无毒、药理学可接受的酸盐。 其中，特别优选的亚属包括通式I的化合物，其中R.sub.2和R.sub.3分别为6-和7-位的甲氧基，或者互相结合形成亚甲二氧基或乙二氧基；R.sub.4是氢或甲基；R.sub.5是氢；R.sub.6是3-位的氢或甲氧基；R.sub.7是4-位的甲氧基或与R.sub.6一起形成亚甲二氧基或乙二氧基；n为2或3；以及其无毒、药理学可接受的酸盐。 通式I所包含的化合物可以通过以下方法制备： 方法A：通过将通式II的化合物（其中R.sub.2、R.sub.3、A和n的含义与通式I相同，Z是离去基团，例如氯、溴、碘、烷基磺酰氧或芳基磺酰氧）与通式III的苯基烷胺反应，其中R.sub.4、R.sub.5、R.sub.6和R.sub.7的含义与通式I相同。反应在惰性溶剂中进行，例如醚、四氢呋喃、甲基甲酰胺、二甲基甲酰胺、二甲基亚砜、氯苯或苯，具体温度取决于取代基Z的反应性，在-50℃至+250℃之间，但最好在所用溶剂的沸点下进行。有益的是加入酸中和剂，例如碱金属醇盐、碱金属氢氧化物、碱金属碳酸盐（尤其是碳酸钾）或三级有机碱（特别是三乙胺或吡啶），或者加入反应促进剂，例如碘化钾。 方法B：通过将通式IV的化合物（其中A、R.sub.2和R.sub.3的含义与通式I相同）与通式II的苯基烷胺反应，其中R.sub.4、R.sub.5、R.sub.6和n的含义与通式I相同，Z的含义与通式II相同。反应在惰性溶剂中进行，例如丙酮、二甲基甲酰胺、二甲基亚砜或氯苯，具体温度取决于取代基Z的反应性，在0℃至150℃之间，但最好在所用溶剂的沸点下进行。有益的是加入酸中和剂，例如碱金属醇盐、碱金属氢氧化物、碱金属碳酸盐（尤其是碳酸钾）、碱金属氨基或三级有机碱（特别是三乙胺或吡啶），或者加入反应促进剂，例如碘化钾。 方法C：通过在催化活化氢存在下，将通式V的醛（其中R.sub.2、R.sub.3、A和n的含义与通式I相同）或其缩醛与通式III的胺反应进行还原胺化反应。还原胺化反应在氢气存在下进行，使用氢化催化剂，例如钯化木炭，在5大气压下，在溶剂中进行，例如甲醇、乙醇或二噁烷，在0℃至100℃之间进行，但最好在20℃至80℃之间。 方法D：通过将通式VI的胺（其中R.sub.2、R.sub.3、R.sub.4、A和n的含义与通式I相同）与通式II的苯基化合物反应，其中R.sub.5、R.sub.6和R.sub.7的含义与通式I相同，Z的含义与通式II相同。反应在惰性溶剂中进行，例如丙酮、二氯甲烷、二甲基甲酰胺、二甲基亚砜或氯苯，具体温度取决于取代基Z的反应性，在0℃至150℃之间，但最好在所用溶剂的沸点下进行。有益的是加入酸中和剂，例如碱金属醇盐、碱金属氢氧化物、碱金属碳酸盐（尤其是碳酸钾）或三级有机碱（特别是三乙胺或吡啶），或者加入反应促进剂，例如碘化钾。 方法E：用于制备通式I的喹唑啉酮衍生物，通过将通式VII的苯并噁嗪-4-酮（其中R.sub.1、R.sub.2和R.sub.3的含义与通式I相同）与通式VIII的烷基二胺反应，其中R.sub.4、R.sub.5、R.sub.6和R.sub.7的含义与通式I相同。反应最好在溶剂中进行，例如苯、二噁烷、低级烷酸（例如冰醋酸）或二甲基甲酰胺，可选地在酸催化剂的存在下，在50℃至150℃之间进行，但最好在所用溶剂的沸点下进行。最好的溶剂是冰醋酸。但是，该反应也可以在无溶剂情况下进行。 如果方法A到E的最终产物是通式I的化合物，其中R.sub.4是苄基，则可以脱苄基以得到相应的R.sub.4为氢的化合物。最好的脱苄基方法是催化氢化，例如在乙醇或乙酸乙酯中使用氢气和钯化木炭催化剂，在25℃至75℃的温度下，在1至7大气压的氢气压力下进行。另一方面，如果方法A到E的最终产物是通式I的化合物，其中R.sub.4是氢，则可以在桥氮原子上烷基化以形成相应的R.sub.4为烷基的化合物。烷基化是使用传统的烷基化试剂进行的，例如使用烷基卤化物，例如碘化甲基、碘化乙基或溴化异丙基，或使用二烷基硫酸酯，例如二甲基硫酸酯，在丙酮、二甲基甲酰胺或二噁烷中进行，可选地在无机或三级有机碱的存在下，在0℃至50℃之间进行。也可以通过与甲醛和甲酸的混合物反应进行甲基化，最好在该混合物的沸点下进行。 通式I所包含的化合物是有机碱，因此可以与无机或有机酸形成酸加合盐。无毒、药理学可接受的酸加合盐的例子包括与盐酸、磷酸、氢溴酸、硫酸、乳酸、酒石酸、马来酸、8-氯茶碱或类似物形成的盐。通式II到X的起始化合物或已在文献中描述，或可以通过已知方法制备，具体方法如下例所示。
• [EN] BENZYLAMINO TRICYCLIC COMPOUND AND USE THEREOF<br/>[FR] COMPOSÉ BENZYLAMINO TRICYCLIQUE ET SON UTILISATION<br/>[ZH] 苄氨基三并环类化合物及其应用
  申请人：MEDSHINE DISCOVERY INC

  公开号：WO2023280317A1

  公开（公告）日：2023-01-12

  提供了一种苄氨基三并环类化合物及其应用，具体涉及式(Ⅹ)所示化合物及其药学上可接受的盐。
• 苄氨基取代的杂多环化合物及其组合物、制剂和用途
  申请人：北京福元医药股份有限公司

  公开号：CN115536660A

  公开（公告）日：2022-12-30

  本发明属于药物化学技术领域，涉及苄氨基取代的杂多环化合物及其组合物、制剂和用途。具体而言，该杂多环的通式结构如式I所示。本发明的化合物针对SOS1具有优异的体外抑制活性，使其可以作为SOS1抑制剂，具有抑制细胞增殖及血管生成的作用，具有良好的抗肿瘤活性，对于治疗哺乳动物(包括人类)的肿瘤性疾病具有良好的效果。
• EBELEIN, W.;AUSTEL, V.;HEIDER, J.;DAEMMGEN, J.;KADATZ, R, LILLIE, CH.;KOB+
  作者：EBELEIN, W.、AUSTEL, V.、HEIDER, J.、DAEMMGEN, J.、KADATZ, R, LILLIE, CH.、KOB+

  DOI：——

  日期：——
• SOS1 INHIBITORS
  申请人：Mirati Therapeutics, Inc.

  公开号：EP4076418A1

  公开（公告）日：2022-10-26