6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one | 228851-51-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one
• 英文别名: 6-methoxy-3,3,14-trimethyl-7,14-dihydro-3H-benzo[b]pyrano[3,2-h]acridin-7-one；3,3,14-Trimethyl-6-methoxy-3,14-dihydro-7H-4-oxa-14-azabenzo[a]naphthacene-7-one；11-methoxy-2,7,7-trimethyl-8-oxa-2-azapentacyclo[12.8.0.03,12.04,9.016,21]docosa-1(22),3,5,9,11,14,16,18,20-nonaen-13-one
• CAS: 228851-51-2
• 化学式: C₂₄H₂₁NO₃
• 分子量: 371.436
• InChiKey: UOISCARHVYSQMT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  28
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one 在 吡啶 、 potassium permanganate 作用下， 以 水 、 丙酮 为溶剂， 反应 32.0h， 生成 6-Methoxy-3,3,14-trimethyl-1,7-dioxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-2-yl Propionate
  参考文献：
  名称：

  Structure−Activity Relationships and Mechanism of Action of Antitumor Benzo[b]pyrano[3,2-h]acridin-7-one Acronycine Analogues

  摘要：

  The cytotoxic and antitumor activities of cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 3, 6-9 were strongly correlated with their ability to give covalent adducts with purified, as well as genomic, DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 in aqueous medium accounted for the intense activity of the cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 10-13. Compounds without acyloxy or hydroxy group at position 1, such as 15, 17, 18, and 22, were inert with respect to DNA and almost devoid of significant cytotoxic activity. Condensation of 5-amino-2,2-dimethyl-2H-chromene (26) with 3-bromo-2-naphthoic acid (27), followed by cyclization, gave access to 6-demethoxy analogues. Diacetate 32 and cyclic carbonate 33, both belonging to the latter series, were less reactive toward DNA and less cytotoxic than their 6-methoxy counterparts 3 and 34. DNA alkylation appears thus to play an important role in the antitumor properties of benzo[b]pyrano[3,2-h]acridin-7-one derivatives.

  DOI：

  10.1021/jm030790y
• 作为产物：
  描述：

  1,3-Dihydroxy-5,12-dihydro-benzo[b]acridin-12-one 在 sodium hydride 、 potassium carbonate 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 26.25h， 生成 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one
  参考文献：
  名称：

  Synthesis and Cytotoxic and Antitumor Activity of Benzo[b]pyrano[3,2-h]acridin-7-one Analogues of Acronycine

  摘要：

  Benzo[b]acronycine (6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one, 4), an acronycine analogue with an additional aromatic ring linearly fused on the natural alkaloid basic skeleton, was synthesized in three steps, starting from 3-amino-2-naphthalenecarboxylic acid (5). Eight 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters (17-24) were obtained by catalytic osmic oxidation, followed by acylation. All these compounds were significantly more cytotoxic than acronycine, when tested against L1210 leukemia cells in vitro. The potency of the cyclic carbonate 24 was in the range of the most active drugs currently used in cancer chemotherapy. Two selected diesters (17 and 24) were evaluated in vivo against P388 leukemia and colon 38 adenocarcinoma implanted in mice. Both compounds were markedly active at doses 16-fold lower than the dose of acronycine itself. Against colon 38 adenocarcinoma, compounds 17 and 24 were highly efficient, inhibiting tumor growth by more than 80%. Diacetate 17 was the most active, inhibiting tumor growth by 96% at 6.25 mg/kg, with two of seven mice being tumor-free on day 43.

  DOI：

  10.1021/jm990972l

文献信息

• Acronycine derivatives, preparation method and pharmaceutical compositions
  申请人：Adir et Compagnie

  公开号：US06288073B1

  公开（公告）日：2001-09-11

  A compound selected from those of formula (I): in which: X and Y represent hydrogen, halogen, hydroxy, mercapto, cyano, nitro, alkyl, alkoxy, trihaloalkyl, optionally substituted amino, methylenedioxy, or ethylenedioxy, R1 represents hydrogen, or alkyl, R2 represents hydrogen, hydroxy, alkyl, alkoxy, alkylcarbonyloxy, or optionally substituted ammo, R3 and R4 represent hydrogen, or alkyl, A represents —CH═CH—, or —CH(R5)—CH(R6)— wherein R5 and R6 are as defined in the description, their isomers, N-oxides, and pharmaceutically-acceptable acid or base addition salts thereof, and medicinal products containing the same which are useful in the treatment of cancer.

  从式(I)中选择的化合物，其中：X和Y代表氢、卤素、羟基、巯基、氰基、硝基、烷基、烷氧基、三卤代烷基、可选取代的氨基、亚甲二氧基或乙二氧基；R1代表氢或烷基；R2代表氢、羟基、烷基、烷氧基、烷基羰氧基或可选取代的氨基；R3和R4代表氢或烷基；A代表-CH═CH-或-CH(R5)-CH(R6)-，其中R5和R6在说明中定义；它们的异构体、N-氧化物和药学上可接受的酸或碱加合物，以及含有它们的药物产品，可用于癌症治疗。
• Benzo[b]pyrano[3,2-h]acridin-7-one compounds
  申请人：LES LABORATOIRES SERVIER

  公开号：US20040063702A1

  公开（公告）日：2004-04-01

  A method for treating a living body afflicted with a cancer selected from lung and ovarian carcinoma, comprising the step of administering to the living animal body an amount of a compound selected from those of formula (I): 1 wherein: X and Y represent group selected from hydrogen, halogen, mercapto, cyano, nitro, alkyl, trihaloalkyl, trihaloalkylcarbonylamino, —ORa, —NRaRb, —NRa—C(O)-T 1 , —O—C(O)-T 1 , —O-T 2 -NRaRb, —O-T 2 -ORa, —NRa-T 2 -NRaRb, —NRa-T 2 -ORa and —NRa-T 2 -CO 2 Ra wherein Ra, Rb, T 1 , T 2 are as defined in the description, or X and Y together form a methylenedioxy or ethylenedioxy, R 1 represents hydrogen or alkyl, R 2 represents a group selected from hydrogen, —ORa, —NRaRb, —NRa—C(O)-T 1 , —O—C(O)-T 1 , —O-T 2 -NRaRb, —O-T 2 -ORa, —NRa-T 2 -NRaRb, —NRa-T 2 -ORa and —NRa-T 2 -CO 2 Ra wherein Ra, Rb, T 1 and T 2 are as defined hereinbefore, R 3 and R 4 represent hydrogen or alkyl, W represents a group of formula —CH(R 5 )—CH(R 6 )—, —CH═C(R 7 )—, —C(R 7 )═CH— or —C(O)—CH(R 8 )— wherein R 5 , R 6 , R 7 and R 8 are as defined in the description, their isomers and N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same are useful in the treatment of cancer.

  一种治疗患有肺癌和卵巢癌的生物体的方法，包括向生物体内注射一定量的化合物，所述化合物的选择公式为(I)中的一种：其中，X和Y代表从氢、卤素、巯基、氰基、硝基、烷基、三卤代烷基、三卤代烷基羰基氨基、-ORa、-NRaRb、-NRa-C(O)-T1、-O-C(O)-T1、-O-T2-NRaRb、-O-T2-ORa、-NRa-T2-NRaRb、-NRa-T2-ORa和-NRa-T2-CO2Ra中选择的基团，其中Ra、Rb、T1和T2如上所述，或X和Y共同形成亚甲二氧基或乙二氧基，R1代表氢或烷基，R2代表从氢、-ORa、-NRaRb、-NRa-C(O)-T1、-O-C(O)-T1、-O-T2-NRaRb、-O-T2-ORa、-NRa-T2-NRaRb、-NRa-T2-ORa和-NRa-T2-CO2Ra中选择的基团，其中Ra、Rb、T1和T2如上所述，R3和R4代表氢或烷基，W代表公式-CH(R5)-CH(R6)-、-CH═C(R7)-、-C(R7)═CH-或-C(O)-CH(R8)-中的一种基团，其中R5、R6、R7和R8如上所述，它们的异构体和N-氧化物，以及与药学上可接受的酸或碱形成的加合物盐，和含有它们的药物制剂在癌症治疗中有用。
• New benzo [b] pyrano [3,2-h] acridin-7-one compounds
  申请人：——

  公开号：US20030073841A1

  公开（公告）日：2003-04-17

  A compound selected from those of formula (I): 1 wherein: X and Y represent group selected from hydrogen, halogen, mercapto, cyano, nitro, alkyl, trihaloalkyl, trihaloalkylcarbonylamino, —ORa, —NRaRb, —NRa—C(O)-T 1 , —O—C(O)-T 1 , —O-T 2 -NRaRb, —O-T 2 ORa, —NRa-T 2 NRaRb, —NRa-T 2 -ORa and —NRa-T 2 -CO 2 Ra wherein Ra, Rb, T 1 , T 2 are as defined in the description, or X and Y together form a methylenedioxy or ethylenedioxy, R 1 represents hydrogen or alkyl, R 2 represents a group selected from hydrogen, —ORa, —NRaRb, —NRa—C(O)-T 1 , —O—C(O)-T 1 , —O-T 2 -NRaRb, —O-T 2 -ORa, —NRa-T 2 -NRaRb, —NRa-T 2 -ORa and —NRa-T 2 -CO 2 Ra wherein Ra, Rb, T 1 and T 2 are as defined hereinbefore, R 3 and R 4 represent hydrogen or alkyl, W represents a group of formula —CH(R 5 )—CH(R 6 )—, —CH═C(R 7 )—, —C(R 7 )═CH— or —C(O)—CH(R 8 )— wherein R 5 , R 6 , R 7 and R 8 are as defined in the description, their isomers and N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same which are useful in the treatment of cancer.

  从式(I)中选择的化合物：其中，X和Y代表氢，卤素，巯基，氰基，硝基，烷基，三卤代烷基，三卤代烷基羰基氨基，-ORa，-NRaRb，-NRa-C（O）-T1，-O-C（O）-T1，-O-T2-NRaRb，-O-T2ORa，-NRa-T2NRaRb，-NRa-T2-ORa和-NRa-T2-CO2Ra，其中Ra，Rb，T1，T2如描述中所定义，或X和Y共同形成甲基二氧或乙基二氧基，R1代表氢或烷基，R2代表从氢，-ORa，-NRaRb，-NRa-C（O）-T1，-O-C（O）-T1，-O-T2-NRaRb，-O-T2-ORa，-NRa-T2-NRaRb，-NRa-T2-ORa和-NRa-T2-CO2Ra中选择的基团，其中Ra，Rb，T1和T2如前所述定义，R3和R4代表氢或烷基，W代表式为-CH（R5）-CH（R6）-，-CH═C（R7）-，-C（R7）═CH-或-C（O）-CH（R8）的基团，其中R5，R6，R7和R8如描述中所定义，它们的异构体和N-氧化物，以及与药学上可接受的酸或碱形成的加合物盐，以及含有它们的医药产品，可用于癌症的治疗。
• [EN] NOVEL ACRONYCINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS<br/>[FR] NOUVEAUX DERIVES DE L'ACRONYCINE, LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENT
  申请人：ADIR ET COMPAGNIE

  公开号：WO1999032491A1

  公开（公告）日：1999-07-01

  (EN) The invention concerns compounds of formula (I) in which: X, Y represent a hydrogen atom, a halogen atom or a hydroxy, mercapto, cyano, nitro, alkyl, alkoxy, trihalogenoalkyl, amino group optionally substituted, methylenedioxy or ethylenedioxy; R1 represents a hydrogen atom or an alkyl group; R2 represents a hydrogen atom or a hydroxy, alkyl, alkoxy, alkylcarbonyloxy, amino group optionally substituted; R3, R4 represent a hydrogen atom or an alkyl group; A represents a -CH=CH- group or a -CH(R5)-CH(R6)- group in which R5 and R6 are as defined in the description. The novel compounds have antitumoral properties which make them particularly adapted to be used for treating cancers and in particular solid tumours.(FR) Composés de formule (I) dans laquelle X, Y représentent un atome d'hydrogène, d'halogène ou un groupement hydroxy, mercapto, cyano, nitro, alkyle, alkoxy, trihalogénoalkyle, amino éventuellement substitué, méthylènedioxy ou éthylènedioxy, R1 représente un atome d'hydrogène ou un groupement alkyle, R2 représente un atome d'hydrogène ou un groupement hydroxy, alkyle, alkoxy, alkylcarbonyloxy, amino éventuellement substitué, R3, R4 représentent un atome d'hydrogène ou un groupement alkyle, A représente un groupement -CH=CH- ou un groupement -CH(R5)-CH(R6)- dans lequel R5 et R6 sont tels que définis dans la description. Les nouveaux composés possèdent des propriétés antitumorales qui les rendent particulièrement adaptés pour une utilisation dans le traitement des cancers et notamment des tumeurs solides.

  该发明涉及式(I)的化合物，其中：X、Y代表氢原子、卤素原子或羟基、硫醇基、氰基、硝基、烷基、烷氧基、三卤代烷基、氨基（可选地取代）、亚甲二氧基或乙二氧基；R1代表氢原子或烷基；R2代表氢原子或羟基、烷基、烷氧基、烷基羧酸酯氧基、氨基（可选地取代）；R3、R4代表氢原子或烷基；A代表-CH=CH-基团或-CH(R5)-CH(R6)-基团，其中R5和R6如描述中所定义。这些新化合物具有抗肿瘤性质，使它们特别适用于治疗癌症，特别是实体肿瘤。
• Benzo&lsqb;b&rsqb;pyrano&lsqb;3,2-h&rsqb;acridin-7-one compounds
  申请人：Les Laboratories Servier

  公开号：US06642248B2

  公开（公告）日：2003-11-04

  A compound selected from those of formula (I): wherein: X and Y represent group selected from hydrogen, halogen, mercapto, cyano, nitro, alkyl, trihaloalkyl, trihaloalkylcarbonylamino, —ORa, —NRaRb, —NRa—C(O)—T1, —O—C(O)—T1, —O—T2-NRaRb, —O—T2-ORa, —NRa—T2-NRaRb, —NRa—T2-ORa and —NRa—T2-CO2Ra wherein Ra, Rb, T1, T2 are as defined in the description, R1 represents hydrogen or alkyl, R2 represents a group selected from hydrogen, —ORa, —NRaRb, —NRa—C(O)—T1, —O—C(O)—T1, —O—T2-NRaRb, —O—T2-ORa, —NRa—T2-NRaRb, —NRa—T2-ORa and —NRa—T2-CO2Ra wherein Ra, Rb, T1 and T2 are as defined hereinbefore, R3 and R4 represent hydrogen or alkyl, W represents a group of formula —CH(R5)—CH(R6)—, —CH═C(R7)—, —C(R7)═CH— or —C(O)—CH(R8)— wherein R5, R6, R7 and R8 are as defined in the description, their isomers and N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base, and medicinal products containing the same which are useful in the treatment of cancer.

  从式（I）所选的化合物：其中：X和Y代表从氢，卤素，巯基，氰基，硝基，烷基，三卤代烷基，三卤代烷基羰基氨基，—ORa，—NRaRb，—NRa—C（O）—T1，—O—C（O）—T1，—O—T2-NRaRb，—O—T2-ORa，—NRa—T2-NRaRb，—NRa—T2-ORa和—NRa—T2-CO2Ra中选择的基团，其中Ra，Rb，T1，T2如描述中所定义，R1代表氢或烷基，R2代表从氢，—ORa，—NRaRb，—NRa—C（O）—T1，—O—C（O）—T1，—O—T2-NRaRb，—O—T2-ORa，—NRa—T2-NRaRb，—NRa—T2-ORa和—NRa—T2-CO2Ra中选择的基团，其中Ra，Rb，T1和T2如前述所定义，R3和R4代表氢或烷基，W代表式—CH（R5）—CH（R6）—，—CH═C（R7）—，—C（R7）═CH—或—C（O）—CH（R8）—中的基团，其中R5，R6，R7和R8如描述中所定义，其异构体和N-氧化物，以及与药学上可接受的酸或碱形成的加成盐，以及含有它们的药物制剂，用于治疗癌症。