WO2009114993A1 - 一类哒嗪酮类化合物及其制备方法和用途 - Google Patents
一类哒嗪酮类化合物及其制备方法和用途 Download PDFInfo
- Publication number
- WO2009114993A1 WO2009114993A1 PCT/CN2009/000295 CN2009000295W WO2009114993A1 WO 2009114993 A1 WO2009114993 A1 WO 2009114993A1 CN 2009000295 W CN2009000295 W CN 2009000295W WO 2009114993 A1 WO2009114993 A1 WO 2009114993A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- group
- unsubstituted
- heterocyclic group
- pyridazinone
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Definitions
- the invention belongs to the field of pharmacy, and particularly relates to a novel class of pyridazinone compounds with 6-(3-(trifluoromethyl:)phenyl:)pyridazine-3 (2-ketone) as a mother nucleus and preparation thereof Method and use, the above compound has
- Pyridazinone compounds exhibit a wide range of biological activities, such as antidepressants, vasodilators, cardiotonics, analgesics/anti-inflammatory drugs, antihypertensives, and as acaricides, herbicides, and others in agriculture.
- inhibitors such as acetylcholinesterase, aldose reductase, monoamine oxidase, CDKs, COX-2, and P38 MAP kinase.
- pyridazinone compounds that exhibit certain antitumor activity.
- As a GSK-3 ⁇ inhibitor a class of pyridazinone compounds is reported in the patent document US 2007/0072866 A1,
- Patent document CN200380105057 defines wherein ⁇ is C(0)NHR and NHC(0)R; US2007/0072866A1 is a heterocyclic substitution.
- Azinone compound the structural formula is It can be used to treat inflammatory diseases, diabetes, Alzheimer's disease or cancer.
- the range of the pyridazinone compounds described therein covers almost all of the substituents. However, in fact, its R 4 is mainly aryl substituted, mainly halogen, and R 2 is a more type of substitution, which is only H substitution.
- a pyridazinone derivative applied by Aventis is a CDK2 inhibitor, and its patent document number is WO2004/046130.
- WO2005085231 WO2005/111019 and US2007/0173503. Its structure is Wherein X is C(0)NHR, NHC(0)R and a nitrogen-containing heterocycle, R 2 is H, and R 3 is an aromatic ring and a heterocyclic ring.
- Another object of the present invention is to disclose a process for producing the above pyridazinone compounds.
- R is -OH, -SH, a substituted or unsubstituted phenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted Crdo alkyl group, a substituted or unsubstituted 3 1 () cycloalkyl group, a substitution Or unsubstituted heterocyclic group, -OR a , -NHR a , -NR a R b or -SR a ,
- R b are each independently substituted or unsubstituted d-do alkyl, substituted or unsubstituted a C 3 -C 1Q cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted arylhetero group or a substituted or unsubstituted heterocyclic group;
- the aryl group is a 5- or 6-membered ring containing 1 to 3 N atoms
- the heterocyclic group is a 3- to 7-membered monocyclic or 8-membered bicyclic ring containing 1 to 3 N atoms, and the heterocyclic group is optionally substituted by thio or oxo.
- the above pyridazinone compounds show high anti-tumor activity, especially anti-hepatocarcinoma activity, for example, compound YHHU-646 has obvious anti-liver cancer effect in animals; and, the pyridazinone compound has obvious effect on proliferation of vascular endothelial cells.
- Inhibitory activity indicates that this kind of compound is an inhibitor of vascular endothelial cell proliferation, and it is one of its anti-tumor mechanisms by inhibiting tumor angiogenesis; this mechanism of action makes it possible for the above pyridazinone compounds to treat various types of tumors.
- the above pyridazinone compound can be obtained by a Setter reaction of different m-trifluoromethylbenzaldehyde with methyl acrylate to obtain a 1,4-dicarbonyl compound, and then directly adding a hydrazine compound to the reaction solution to form a ring. Further, a pyridazinone compound is produced by dehydrogenation of ⁇ 2 ⁇ 2 ⁇ 20 . Alternatively, a differently substituted benzene ring-modifying compound can be obtained by a coupling reaction to obtain a desired pyridazinone compound.
- R is -OH, -SH, a substituted or unsubstituted C 6 -C 12 aryl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted carbonyl group of a Crdo, a substituted or unsubstituted group.
- R b are each independently a substituted or unsubstituted d-do hydrocarbon group, a substituted or unsubstituted C 3 -C 1Q cycloalkyl group, a substituted or unsubstituted C 6 -C 12 aryl group, a substituted group Or an unsubstituted arylhetero group or a substituted or unsubstituted heterocyclic group;
- the substituent is selected from the group consisting of halogen, -OH, -N0 2 , C r C 6 hydrocarbyl, carboxyl, C r C 6 alkoxycarbonyl a C 6 -C 12 aryl group, a -NH 2 , a dC 6 hydrocarbyl-substituted amino group, a hydroxy-substituted dC 6 hydrocarbyl group, a hydroxy-substituted C r C 6 alkoxy group, an unsubstituted or dC 6 hydrocarbyl-substituted heterocyclic ring Base and -CF 3 ;
- the aryl group is a 5- or 6-membered ring containing 1 to 3 hetero atoms selected from N, 0 and S; the heterocyclic group is a 3- to 7-membered monocyclic or 8-membered bicyclic ring. There are 1 to 3 hetero atoms selected from N, 0 and S, and the heterocyclic group is optionally substituted by thio or oxo. It is still another object of the present invention to disclose a pharmaceutical composition comprising the above pyridazinone compound.
- the pharmaceutical composition comprises a therapeutically effective amount of one or more of the above pyridazinone compounds and a pharmaceutically acceptable adjuvant.
- Figure 1 shows the effects of compounds YHHU-744, YHHU-755, YHHU-756, YHHU-759, YHHU-776 and Sorafenib on human liver cancer Bel-7402 nude mice.
- Example 2 Preparation of 6-m-trifluoromethyl-p-ethylstilbene-pyridazine-3(2)-one 9a 8F (100 mg, 0.4 mmol) was weighed into a 10 ml microwave reaction tube, and 3 ml of a 70% aqueous solution of ethylamine was added thereto, and MW (80 W, 110 ° C, 20 min) was added.
- Example 8 Preparation of 6-(4-(2-dimethyl-Ethyl)ethyl-)-3-trifluoromethylphenyl)-pyridazine-3(2)-one 9e 8F (100 mg, 0.4 mmol) was weighed into a 10 ml microwave reaction tube, and 3 ml of 2-dimethylaminoethylamine was added as a solvent, MW (80 W, 110 ° C, 30 min). After the reaction, ethyl acetate was extracted. The organic layer was dried and concentrated, and then separated through a silica gel column, and the mobile phase was methanol-dichloromethane (1:20) to give the object 9e.
- Example 9 6- Preparation of (4-cyclohexylamino-3-trifluoromethylphenyl)-pyridazine-3(2)-one 9f 8F (100 mg, 0.4 mmol) was weighed into a 10 ml microwave reaction tube, and excess cyclohexylamine was added as a solvent, MW (80 W, 140 ° C, 30 min). After the reaction was completed, ethyl acetate was extracted, and the organic layer was dried and concentrated. After separation through a silica gel column, the mobile phase was ethyl acetate-dichloromethane (1:2) to give the object 9f.
- RESULTS Sulfurodamine B Sulforhodamine B
- Tumor cells were cultured in RPMI 1640 or DMEM medium (Gibco) containing 10% fetal bovine serum at 37 ° C, 5% C0 2 .
- DMEM medium Gibco
- 0.4-1.0 x 10 4 cells/well were seeded in 96-well plates, respectively.
- a 10-fold dilution of the target compound was added; the compound contained at least 5 concentrations.
- the culture solution was discarded, and the cells were fixed with 10% cold trichloroacetic acid.
- Inhibition rate (OD value is compared to well-OD value) / OD value control hole X 100% According to the concentration inhibition rate, the half-inhibitory concentration IC 5 is calculated by the Logit method. . The results are shown in Tables 1 and 2.
- YHHU-744, YHHU-755, YHHU-756, YHHU-759, YHHU-776 and positive control were all formulated to the required concentration with 0.1% Tween-80 and distilled water.
- the nude mice were subcutaneously inoculated with human hepatoma Bel-7402 cells. After the tumors were grown to 300-450 mm 3 , the animals were randomly divided into groups (dO dosage and dosing schedule are shown in Table 1. 2-3 tumor volumes per week were measured, Rat weight, record data. The tumor volume (V) is calculated as:
- V l/2xaxb 2 where a and b represent length and width, respectively.
- mice were continuously intragastrically administered with compounds YHHU-744, YHHU-755, YHHU-756, YHHU-759 and YHHU-776 once a day for 11 consecutive days and continued for 17 days. After the administration, the tumor was significantly reduced. By the 11th day, except for the compound YHHU-744 (regression 4/5), all the tumors in the other groups (5/5) completely resolved, and did not relapse at the end of the experiment (see Table 3 for the results). , figure 1). Moreover, the mice were well tolerated by the above compounds and showed no significant toxicity.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
一类哒嗪酮类化合物及其制备方法和用途
技术领域
本发明属于药物学领域, 具体涉及以 6-(3- (三氟甲基:)苯基:)哒嗪 -3(2 - 酮为母核的一类全新的哒嗪酮类化合物及其制备方法和用途, 上述化合物具
背景技术
哒嗪酮类化合物显示了广泛的生物活性, 比如作为抗抑郁药、 血管舒张 药、 强心药、 止痛 /抗炎药、 抗高血压药及在农业上作为杀螨剂、 除草剂, 其 它还有作为乙酰胆碱酯酶、醛糖还原酶、单胺氧化酶、 CDKs、 COX-2、 P38MAP 激酶的抑制剂等。 也有部分哒嗪酮类化合物显示了一定的抗肿瘤活性。 作为 GSK— 3β抑制剂, 专利文献 US2007/0072866A1报道了一类哒嗪酮化合物, 其
专利文献 WO 03/059891及 WO 2005/007632公开了用于治疗因 P38MAP 激酶活性和 /或 TNF活性失调引起或加重的疾病或病症。上述专利文献中的哒
嗪酮类化合物, 结构式为
, 可用于治疗炎性疾病、 糖尿病、 阿耳 茨海默氏病或癌症。其所述的哒嗪酮类化合物的范围几乎将所有取代基覆盖,
但实际上其 R4主要为芳基取代, 为主要为卤素, R2为各类较多类型取代, 仅为 H取代。
与本申请最为相关的文献为抗肿瘤活性专利文献, 为 Aventis 公司申请 的一种哒嗪酮衍生物为 CDK2 抑制剂, 其专利文献号为 WO2004/046130 ,
另外, 专利文献 WO2006/124874中 RAF激酶抑制剂可用于抗肿瘤及欧洲 专利文献 0655223中抗肿瘤抑制剂也提到哒嗪酮类化合物,但与本申请的所覆 盖的化合物截然不同。
此外其他文献中还描述另外很多哒嗪酮衍生物, 它们与本申请化合物的 不同之处在于取代模式、 部分和 /或 6-位芳环的选择, 或者化合物应用范围的 不同。
众所周知,肝癌是第五大常见的男性肿瘤疾病,是第八大常见的女性肿 瘤疾病。 在 2007年, 估算的新增肝癌患者将有 80%在发展中国家中产生, 仅我国就占了总数的 55%。 而在发展中国家, 59%的肝癌可归咎于 HBV, 33%的肝癌可归咎于 HCV。 尤其近年来, 由于亚太国家乙肝病毒感染肆虐, 肝癌发病率不断上升, 对治疗肝癌药物有巨大的市场需求。 发明内容
本发明的一个目的是公开下述结构通式 I所示的一类全新的哒嗪酮类化 合物。
本发明的另一个目的是公开上述的哒嗪酮类化合物的制备方法。
本发明的又一个目的是公开上述的哒嗪酮类化合物在制备抗肿瘤药物中
的用途。
本发明提供结构通式 I所示的一类哒嗪酮类化合物:
其中,
R为 -OH、 -SH、取代或未取代的 C6-C12的芳基、取代或未取代的芳杂基、 取代或未取代的 Crdo的烃基、 取代或未取代的 3 1()的环烃基、 取代或未 取代的杂环基、 -ORa、 -NHRa、 -NRaRb或 -SRa,
其中 1^和 Rb各自独立地为取代或未取代的 d-do的烃基、 取代或未取 代的 C3-C1Q的环烃基、 取代或未取代的 C6-C12的芳基、 取代或未取代的芳杂 基或者取代或未取代的杂环基;
所述取代基选自卤素、 -OH、 -N02、 CrC6烃基、 羧基、 CrC6烃氧基羰 基、 C6-C12的芳基、 -NH2、 d-C6烃基取代的氨基、 羟基取代的 d-C6烃基、 羟基取代的 CrC6烃氧基、 未取代或 d-C6烃基取代的杂环基和 -CF3 ;
所述芳杂基为 5元或 6元环, 含有 1~3个选自 N、 0和 S的杂原子; 所述杂环基为 3元〜 7元的单环或 8元的二环, 含有 1~3个选自 N、 0 和 S的杂原子, 且所述杂环基非必需地被硫代或氧代。
优选地, 上述的结构通式 I所示的哒嗪酮类化合物中:
R为 -OH、 -SH、 取代或未取代的苯基、 取代或未取代的芳杂基、 取代或 未取代的 Crdo的烷基、 取代或未取代的 3 1()的环烷基、 取代或未取代的 杂环基、 -ORa、 -NHRa、 -NRaRb或 -SRa,
其中 1^和 Rb各自独立地为取代或未取代的 d-do的烷基、 取代或未取
代的 C3-C1Q的环烷基、 取代或未取代的苯基、 取代或未取代的芳杂基或者取 代或未取代的杂环基;
所述取代基选自卤素、 -OH、 -N02、 CrC6烷基、 羧基、 CrC6烷氧基羰 基、 苯基、 -N¾、 d-C6烷基取代的氨基、 羟基取代的 d-C6烷基、 羟基取代 的 d-C6烷氧基、 未取代或 d-C4烷基取代的杂环基和 -CF3 ;
所述芳杂基为 5元或 6元环, 含有 1~3个 N原子;
所述杂环基为 3元 ~ 7元的单环或 8元的二环, 含有 1~3个 N原子, 且 所述杂环基非必需地被硫代或氧代。
进一歩优选地, 所述化合物具体为:
C66MT/600Z OAV
S6Z000/600ZM3/X3d
上述哒嗪酮类化合物显示了很高的抗肿瘤, 特别是抗肝癌活性, 如化合 物 YHHU-646有明显的动物体内抗肝癌疗效; 并且, 该哒嗪酮类化合物对血 管内皮细胞增殖有明显的抑制活性, 说明该类化合物为血管内皮细胞增殖抑 制剂, 通过抑制肿瘤血管生成是其抗肿瘤机制之一; 这一作用机制使上述哒 嗪酮类化合物有可能治疗多种类型的肿瘤。
上述哒嗪酮类化合物可以通过不同的间三氟甲基苯甲醛与丙烯酸甲酯 的 Setter反应得到 1,4-二羰基化合物, 然后直接向反应液中加入肼类化合物 "一锅煮"反应成环, 再用 Οια2·2Η20脱氢等生成哒嗪酮类化合物。或者通过 偶联反应得到不同取代的苯环修饰化合物,进而得到所要的哒嗪酮类化合物。
上述的哒嗪酮类化合物的制备方法具体为:
方法
和,
方法 3:
β 9
上述各制备方法中, R为 -OH、 -SH、 取代或未取代的 C6-C12的芳基、 取 代或未取代的芳杂基、取代或未取代的 Crdo的烃基、取代或未取代的 C3-C1() 的环烃基、 取代或未取代的杂环基、 -ORa、 -NHRa、 -NRaRb或 -SRa,
其中 1^和 Rb各自独立地为取代或未取代的 d-do的烃基、 取代或未取 代的 C3-C1Q的环烃基、 取代或未取代的 C6-C12的芳基、 取代或未取代的芳杂 基或者取代或未取代的杂环基;
所述取代基选自卤素、 -OH、 -N02、 CrC6烃基、 羧基、 CrC6烃氧基羰
基、 C6-C12的芳基、 -NH2、 d-C6烃基取代的氨基、 羟基取代的 d-C6烃基、 羟基取代的 CrC6烃氧基、 未取代或 d-C6烃基取代的杂环基和 -CF3 ;
所述芳杂基为 5元或 6元环, 含有 1~3个选自 N、 0和 S的杂原子; 所述杂环基为 3元〜 7元的单环或 8元的二环, 含有 1~3个选自 N、 0 和 S的杂原子, 且所述杂环基非必需地被硫代或氧代。 本发明的又一目的是公开包含上述哒嗪酮类化合物的药物组合物。 该药 物组合物包含治疗有效量的一种或多种上述的哒嗪酮类化合物及药学上可接 受的辅料。 附图说明
图 1 为化合物 YHHU-744、 YHHU-755 , YHHU-756 , YHHU-759 , YHHU-776和 Sorafenib对人肝癌 Bel-7402裸小鼠移植瘤的疗效。 具体实施方式
下面用实施例进一歩说明本发明, 但不限制本发明。
实施例 1:重要中间体 6-(4-氟 -3-三氟甲基)苯基 -哒嗪 -3(2 )-酮 8F的制备
35°C下, 将 NaCN(24.5 mg, 0.5 mmol)溶于 5 ml干燥的 DMF中, N2保 护, 滴入 4-氟 -3-三氟甲基-苯甲醛 (1.03 g, 5 mmol), 滴完后继续搅拌 30分钟,
再滴入丙烯酸甲酯 (0.52 g, 6 mmol) , 反应 4小时后, 直接加入水合肼 (0.72 g, 12.5 mmol) , 升高温度至 60°C, 反应 8小时。
停止反应, 温度降至室温, 加入水 20ml, 乙酸乙酯 (20mlx3)萃取, 合并 有机层, 饱和食盐水洗涤 (10mlx3), 无水 Na2S04干燥, 过滤, 减压蒸干, 残 余物过硅胶柱分离, 乙酸乙酯-石油醚 (1 :2)做流动相,得灰白色蓬松固体 6-(4- 氟 -3-三氟甲基)苯基 -4,5-二氢 -哒嗪 -3(2? )-酮(0.73 g, 产率 56%)。将其溶于乙 腈 (10 ml)中, 加入 CuCl2 ¾0 (272 mg, 2.02 mmol) , 剧烈搅拌下回流反应 1 小时。 冷却至室温后, 过滤除去剩余的 CuCl2, 滤液减压蒸干, 残余物加乙 酸乙酯 100 ml , 饱和 NaHC03溶液 (20 ml)洗涤, 再用饱和食盐水洗涤 (20 mlx2) , 无水 Na2S04干燥, 过滤, 减压蒸干, 残余物过硅胶柱分离, 乙酸乙 酯-二氯甲烷 (1 : 3)做流动相, 得目标产物 8F (130mg, 产率 50%)。
lR NMR(DMSO-i 6, 300 MHz): δ 11.50 (IH, bs), 8.17 (3H, m), 7.63 (IH, t, J=9.8 Hz ), 7.03 (IH, dd, J=5.6, 1.1 Hz)。 实施例 2: 6-间三氟甲基 -对乙雌苯基 -哒嗪 -3(2 )-酮 9a的制备
称取 8F (lOOmg, 0.4mmol) 于 10ml微波反应管中, 加入 3ml 70%乙胺水 溶液, MW(80W, 110°C ,20min), 反应结束后, 乙酸乙酯提取, 有机层干燥浓 缩后过硅胶柱分离, 流动相为乙酸乙酯-二氯甲烷 (1 :2), 得到目标物 9a (32.9mg, 产率 30%)。
^ NMR (CDC13, 300 MHz): δ 11.88 (IH, bs), 11.42 (IH, bs), 7.89 (IH, s), 7.80 (IH, m), 7.72(1H, m), 7.05 (IH, d, J=9.6 Hz ), 6.79 (IH, d, J=9.6 Hz ), 3.28 (2H, q, J=7.2 Hz ), 1.34 (3H, t, J=7.2Hz )。
实施例 3: 6-(4-(2 基乙雌 )-3-三氟甲基苯基) -哒嗪 -3(2//)-酮 9b的制备
称取 8F (lOOmg, 0.4mmol) 于 10ml微波反应管中,加入 3ml乙胺醇作溶 剂, MW(160W, 180°C ,20min), 反应结束后, 乙酸乙酯提取, 有机层干燥浓缩 后过硅胶柱分离, 流动相为乙酸乙酯-二氯甲烷 (1 :2), 得到目标物 9b。
¾ NMR (CDC13, 300 MHz): δ 8· 14(1Η, s), 8.12(1Η, d, J=11.3 Hz), 7.63 (3H,m), 7.38 (lH,bs), 6.83(1H, d, J=9A Hz), 4.00(2H, t, J=4.0 Hz ) , 3.57 (2H,m)。 实施例 4: 6-(4-(4-甲基哌嗪基) -3-三氟甲基苯基) -哒嗪 -3(2 )-酮 9c的制备
称取 8F (lOOmg, 0.4mmol) 于 10ml微波反应管中, 加入 3ml N-甲基哌嗪 作溶剂, MW(100W, 170°C ,3 Omin) , 反应结束后, 乙酸乙酯提取, 有机层干 燥浓缩后过硅胶柱分离, 流动相为甲醇-二氯甲烷 (1 : 10), 得到目标物 9c。
!H NMR(DMSO-i 6, 300 MHz): δ 8.09 (3H,m), 7.59(1H, d, J=9.5 Hz), 6.98 (1H, d, J=9.8 Hz), 2.90(4H, t, J=4.0 Hz), 2.44(4H,m), 2.22(3H, s)。 实施例 5: 6-(4-甲氧基 -3-三氟甲基苯基) -哒嗪 -3(2 )-酮 9d的制备
称取 8F (lOOmg, 0.4mmol) 于 10ml微波反应管中, 加入过量甲醇钠甲醇 溶液, MW(80W, 130°C ,20min), 反应结束后, 乙酸乙酯提取, 有机层干燥浓 缩后过硅胶柱分离, 流动相为乙酸乙酯-二氯甲烷 (1 :2), 得到目标物 9d。
lR NMR (CDC13, 300 MHz): δ 11.43 (IH, bs), 8.01(1H, s), 7.94 (IH, dd, J=8.8, 1.2 Hz), 7.73 (IH, d, J=9.8 Hz), 7.10 (IH, d, J=8.9 Hz), 7.08 (IH, d, J=10.2 Hz ) , 3.97 (3H, s)。 实施例 6: 6-(4- (哌啶 -1-基) -3-三: 甲基苯基) -哒嗪 -3(2 )-酮 7a的制备
CH3CN/H20,回流 称取 100mg 3,6-二氯哒嗪 (0.67mmol) 及 1.2eq 5a、 1.5eq K2C03、 3mol% PdCl2(PPh3)2于 25ml两口瓶中, 加入 6ml CH3CN和 4ml H20, 抽换 N2后, 回流搅拌, 反应结束后, 乙酸乙酯提取, 有机层干燥浓缩后, 直接用冰醋酸 转出于 10ml 圆颈瓶中, 回流, 反应结束后, 碱化后, 乙酸乙酯提取, 有机 层干燥浓缩后过硅胶柱分离纯化, 流动相为乙酸乙酯-二氯甲烷 (1 :2), 得到目 标物 7a。
^ NMR (CDCI3, 300 MHz): δ 11.38 (IH, bs), 8.02 (IH, d, J=2.1 Hz), 7.90 (IH, dd, J=8.4, 2.4Hz), 7.75 (IH, d, J=9.9 Hz), 7.36 (IH, d, J=8.8 Hz), 7.08 (IH, d, J=9.9 Hz ) , 2.90 (4H, t, J=3.3 Hz), 1.72(4H,m), 1.58 (2H,m)。
CH3CN/H20,回流
称取 100mg 3,6-二氯哒嗪 (0.67mmol) 及 1.2eq 5b、 1.5eq K2C03、 3mol% PdCl2(PPh3)2于 25ml两口瓶中, 加入 6ml CH3CN和 4ml H20, 抽换 N2后, 回流搅拌, 反应结束后, 乙酸乙酯提取, 有机层干燥浓缩后, 直接用冰醋酸 转出于 10ml 圆颈瓶中, 回流, 反应结束后, 碱化后, 乙酸乙酯提取, 有机 层干燥浓缩后过硅胶柱分离纯化, 流动相为乙酸乙酯-二氯甲烷 (1 : 1), 得到目 标物 7b。
¾ NMR (CDC13, 300 MHz): δ 12.00 (IH, bs), 8.08 (IH, d, J=1.8 Hz), 7.96 (IH, dd, J=8.4, 1.8Hz), 7.76 (IH, d, J=9.9 Hz), 7.42 (IH, d, J=8.6 Hz), 7.11 (IH, d, J=9.9 Hz ), 3.86 (4H, t, J=4.4 Hz), 2.99 (4H, t, J=4.6 Hz). 实施例 8: 6-(4-(2-二甲雌)乙雌) -3-三氟甲基苯基) -哒嗪 -3(2 )-酮 9e 的制备
称取 8F (lOOmg, 0.4mmol) 于 10ml微波反应管中, 加入 3ml 2-二甲胺基 乙胺作溶剂, MW(80W, 110°C ,3 0min), 反应结束后, 乙酸乙酯提取, 有机层 干燥浓缩后过硅胶柱分离, 流动相为甲醇-二氯甲烷 (1 :20), 得到目标物 9e。
lH NMR(DMSO-i 6, 300 MHz): δ 8.03 (IH, d, J=9.8 Hz), 7.93 (2H,m), 6.94 (IH, d, J=10.0 Hz), 6.92 (IH, d, J=8.5 Hz), 5.67 (IH, d, J=4.2 Hz), 3.26 (2H, dd, J=6.3 Hz), 2.50 (2H,m), 2.19 (6H, s). 实施例 9: 6-(4-环己胺基 -3-三氟甲基苯基) -哒嗪 -3(2 )-酮 9f的制备
称取 8F (lOOmg, 0.4mmol) 于 10ml微波反应管中, 加入过量环己胺作溶 剂, MW(80W, 140°C ,3 0min), 反应结束后, 乙酸乙酯提取, 有机层干燥浓缩 后过硅胶柱分离, 流动相为乙酸乙酯-二氯甲烷 (1 :2), 得到目标物 9f。
^ NMR (CDC13, 300 MHz) : δ 11.26 (IH, bs), 7.86 (IH, d, J=2.1 Hz), 7.77 (IH, dd, J=8.6, 1.8 Hz), 7.69 (IH, d, J=9.8 Hz), 7.04 (IH, d, J=9.8 Hz), 6.81 (1H, d, J=9.0 Hz ), 4.49 (IH, d, J=6.5 Hz ), 3.43 (IH, bs), 2.05 (2H, m ), 1.77 (2H, m ): 1.35 (6H, m)。 实施例 10: 6-(4-(4 基哌啶 -1-基) -3-三氟甲基苯基) -哒嗪 -3(2 )-酮 9g的 制备
称取 8F (lOOmg, 0.4mmol) 于 10ml微波反应管中,加入过量 4-羟基哌啶 无溶剂, MW(100W, 150°C ,3 Omin) , 反应结束后, 乙酸乙酯提取, 有机层干 燥浓缩后过硅胶柱分离, 流动相为乙酸乙酯-二氯甲烷 (1 :2), 得到目标物 9g。
^ NMR (CDCI3, 300 MHz): δ 10.79 (IH, bs), 8.03 (IH, d, J=2.1 Hz), 7.90 (IH, dd, J=8.6, 1.6 Hz), 7.73 (IH, d, J=10.3 Hz), 7.39 (IH, d, J=8.7 Hz), 7.08 (IH d, J=9.9 Hz ) , 3.89 (IH, bs), 3.17 (2H, m ) ,2.84 (2H, m ) , 2.02 (2H, m ) , 1.76 (2H, m ) , 1.45 (IH, d, J=4.0 Hz ). 实施例 11:重要中间体 6-(4-甲基 -3-三氟甲基)苯基 -哒嗪 -3(2 )-酮 4a的
制备
35 °C下, 将 NaCN(24.5 mg, O. leq)溶于 5 ml干燥的 DMF中, N2保护, 滴入 4-甲基 -3-三氟甲基苯甲醛(l .Oeq ) , 滴完后继续搅拌 30分钟, 再滴入丙 烯酸甲酯 (l . leq), 反应 4小时后, 直接加入水合肼 (5.0eq), 升高温度至 60°C, 反应 8小时。
停止反应, 温度降至室温, 加入水 20ml, 乙酸乙酯 (20mlx3)萃取, 合并 有机层, 饱和食盐水洗涤 (10mlx3), 无水 Na2S04干燥, 过滤, 减压蒸干, 残 余物过硅胶柱分离, 乙酸乙酯-石油醚 (1 :2)做流动相,得灰白色蓬松固体 6-(4- 甲基 -3-三氟甲基)苯基 -4,5-二氢 -哒嗪 -3(2^)-酮, 将其溶于乙腈 (10 ml)中, 加 入 CuCl2_2H20 (1.5eq), 剧烈搅拌下回流反应 1小时。冷却至室温后, 过滤除 去剩余的 CuCl2, 滤液减压蒸干, 残余物加乙酸乙酯 100 ml, 饱和 NaHC03 溶液 (20 ml)洗涤, 再用饱和食盐水洗涤 (20 mlx2), 无水 Na2S04干燥, 过滤, 减压蒸干, 残余物过硅胶柱分离, 乙酸乙酯-二氯甲烷 (1 :2)做流动相, 得目标 产物 4a。
lR NMR (CDC13, 300 MHz): δ 11.0 3 (IH, bs), 8.01(1H, s), 7.94 (IH, dd, J=8.6, 1.2 Hz), 7.73 (IH, d, J=9.8 Hz), 7.10 (IH, d, J=8.7 Hz), 7.08 (IH, d, J=9.9 Hz ) , 1.97 (3H, s)。 实施例 12: 6-(4-( V-叔丁基氧羰基哌嗪基 )-3-三氟甲基)苯基 -哒嗪 -3(2//)-
酮 4b的制备
35 °C下, 将 NaCN(24.5 mg, O. leq)溶于 5 ml干燥的 DMF中, N2保护, 滴入 4-(N-叔丁基氧羰基哌嗪基 )-3-三氟甲基苯甲醛( l .Oeq ),滴完后继续搅拌 30分钟, 再滴入丙烯酸甲酯 (l . leq) , 反应 4小时后, 直接加入水合肼 (5.0eq), 升高温度至 60°C, 反应 8小时。
停止反应, 温度降至室温, 加入水 20ml, 乙酸乙酯 (20mlx3)萃取, 合并 有机层, 饱和食盐水洗涤 (10mlx3), 无水 Na2S04干燥, 过滤, 减压蒸干, 残 余物过硅胶柱分离, 乙酸乙酯-石油醚 (1 :2)做流动相, 得 6-(4-(N-叔丁基氧羰 基哌嗪基) -3-三氟甲基)苯基) -4,5-二氢 -哒嗪 -3(2? )-酮, 将其溶于乙腈 (10 ml) 中, 加入 CuCl2_2H20 (1.5eq), 剧烈搅拌下回流反应 1小时。 冷却至室温后, 过滤除去剩余的 CuCl2, 滤液减压蒸干, 残余物加乙酸乙酯 100 ml, 饱和 NaHC03溶液 (20 ml)洗涤,再用饱和食盐水洗涤 (20 mlx2) ,无水 Na2S04干燥, 过滤, 减压蒸干, 残余物过硅胶柱分离, 乙酸乙酯-二氯甲烷 (i : iM故流动相, 得目标产物 4b。
lH NMR(DMSO-i 6, 300 MHz): δ 13.27 (1H, bs), 8.12 (3H,m), 7.65 (1H, d, J=8.8 Hz), 7.01 (1H, dd, J=1.9, 9.9 Hz), 3.45 (4H,m), 2.87 (4H,m), 1.43 (9H,s) . 实施例 13: 6-(4-对三氟甲基苯乙炔基 -3-三氟甲基)苯基 -哒嗪 -3(2 )-酮 9h 的制备
将 8Br(50mg, 0.18mmol), 5mol% PdCl2(PPh3)2, 5mol% Cul, 置于干燥的两 口瓶中, 抽换 N2后加入 5eq EtN( -Pr)2及 1.2eq对三氟甲基苯乙炔, 加入重蒸 干燥的 DMF, 30°C反应结束后, 乙酸乙酯提取, 有机层干燥浓缩后过硅胶柱 分离, 流动相为乙酸乙酯-石油醚 (1 : 2), 得到目标物 9h。
¾ NMR(CDC13, 300 MHz): δ 12.05 (IH, bs), 8.04 (IH, s), 8.17 (2H, m), 7.58 (IH, d, J=7.6 Hz), 7.32 (2H, d, J=8.9 Hz), 7.40 (2H, d, J=8.9 Hz), 7.08 (IH, d, J=7.6 Hz
称取 8Br (50mg, 0.18mmol), 1.2eq苯硼酸, 1.5mol% Pd2(dba)3, 3.0mol% Xantphos (4,5-双二苯基膦 -9,9-二甲基氧杂蒽) , 3eq K2C03于 10ml微波反应 管中,加入 1.5ml CH3CN和 1.0mlH2O,抽换 N2后, MW( 65W, 120°C, 20min) , 反应结束后, 乙酸乙酯提取, 有机层干燥浓缩后过硅胶柱分离, 流动相为乙 酸乙酯-石油醚 (1 :2), 得到目标物 9i。
Ή NMR(CDC13, 300 MHz): δ 13.00 (1H, bs), 8.04 (1H, s), 7.90 (2H, m), 7.58 (1H, d, J=7.9 Hz), 7.35 (5H, m), 7.08 (1H, d, J=l .9 Hz)。 实施例 15: 体外抗肿瘤活性
方法:化合物体外抗肿瘤活性采用磺酰罗丹明 B Sulforhodamine B, SRB) 方法。 肿瘤细胞用 RPMI 1640或 DMEM培养基 (Gibco)培养, 内含 10%胎牛 血清, 培养条件为 37°C, 5% C02。 根据肿瘤细胞类型, 分别接种 0.4-1.0 xlO4 细胞 /孔于 96孔板, 24小时后, 加入 10倍稀释的目标化合物; 化合物至少 含 5个浓度。 化合物处理 72小时后, 弃去培养液, 用 10%冷三氯醋酸固定 细胞。然后用磺酰罗丹明 B(Sulforhodamine B,SRB)溶液染色。洗去未结合 SRB 后,用 Tris溶解与蛋白结合的 SRB, 用酶标仪在 515nm波长下测定 OD值, 以下列公式计算细胞生长抑制率:
抑制率 =(OD值对照孔一 OD值给難 )/ OD值对照孔 X 100% 根据各浓度抑制率, 采用 Logit法计算半数抑制浓度 IC5。。 结果见表 1 和表 2。
表 1 YHU-646对多种体外培养的肿瘤细胞增殖的影响
IC50( M)
细胞株 肿瘤类型
YHHU-646
SK-OV-3 卵巢癌 0.003
MDA-MB-231 乳腺癌 >20
A498 1 N病 755 4.12
HT-29 结肠癌 6.3
NCI-H460 肺癌 24.1
A549 肺癌 -
SIMM-7721 肝癌 <0.1
SW-620 结肠癌 5.8
Bel-7402 肝癌 0.0007
SK-BR-3 乳腺癌 7.5
HUVEC 人脐静脉内皮细胞 (正常细胞) 0,03 表 2 部分化合物的合成方法及对体外培养的人肝癌细胞 BEL-7402增殖的
S6ZOOO/600ZN3/X3d £66 I/600Z OAV
zz
S6ZOOO/600ZN3/X3d £66 I/600Z OAV
9Z
S6Z000/600ZN3/X3d £66 I/600Z OAV
LZ
上述实验结果证明: 以 6-(3- (三氟甲基:)苯基:)哒嗪 -3(2 -酮为母核的在芳 基 4位含 N、 0、 S或 C给电取代的一类全新的哒嗪酮类化合物均有很显著的 抗肿瘤活性。 实施例 16: 化合物 YHHU-744、 YHHU-755、 YHHU-756、 YHHU-759 和 YHHU-776对人肝癌 Bel-7402裸小鼠移植瘤的疗效
1、 受试化合物
化合物名称和批号: YHHU-744, 白色粉末, 批号: No.c001471-106 ;
YHHU-755, 白色粉末, 批号: No.c001471-102; YHHU-756, 白色粉末, 批 号: No.c00147-106; YHHU-759, 白色粉末, 批号: No.c001471-102; YHHU-776, 白色粉末, 批号: No.c001471-107 o 阳性对照药为 Sorafenib (索 拉非尼)。
配制方法: YHHU-744, YHHU-755、 YHHU-756、 YHHU-759、 YHHU-776 和阳性对照药均用 0.1% Tween-80和蒸馏水配成所需浓度。
2、 实验动物:
BALB/cA-nude裸小鼠, 6-7周, $, 购自上海斯莱克实验动物有限责任 公司。 合格证号: SCXK(^)2007_0005。 饲养环境: SPF级。
3、 实验歩骤
裸小鼠皮下接种人肝癌 Bel-7402细胞, 待肿瘤生长至 300-450mm3后, 将动物随机分组 (dO 给药剂量和给药方案见表 1。 每周测 2-3次瘤体积, 称 鼠重, 记录数据。 肿瘤体积 (V)计算公式为:
V= l/2xaxb2 其中 a、 b分别表示长、 宽。
4、 结果
荷瘤小鼠连续灌胃化合物 YHHU-744、 YHHU-755、 YHHU-756、 YHHU-759和 YHHU-776, 每天 1次, 连续 11天, 持续观察至 17天。 给药 后肿瘤明显缩小, 至第 11天时, 除化合物 YHHU-744外 (消退 4/5), 其它组 所有肿瘤 (5/5)均完全消退, 至实验结束时未再复发 (结果见表 3, 图 1)。 而且 小鼠对以上化合物的耐受性均很好, 没有明显毒性。
表 3 化合物 YHHU-744、 YHHU-755、 YHHU-756、 YHHU-759、 YHHU-776和 Sorafenib对人肝癌 Bel-7402裸小鼠移植瘤的疗效
肿瘤体积 抑瘤率 动物数 肿瘤消退
(mm3) (%)
溶剂 PO, QD>11 395.7 10 0
Yhhu-744 100 PO, QD>11 343.7 98 5 4
Yhhu-755 100 PO, QD>11 350.4 100 5 5
Yhhu-756 100 PO, QD>11 294.6 100 5 5
Yhhu-759 100 PO, QD>11 367.9 100 5 5
Yhhu-776 100 PO, QD>11 338.2 100 5 5
Sorafenib 60 PO,QDX16 279.8 50 5 0
Claims
1、 结构通式 I所示的一类哒嗪酮类化合物:
其中,
R为 -OH、 -SH、取代或未取代的 C6-C12的芳基、取代或未取代的芳杂基、 取代或未取代的 Crdo的烃基、 取代或未取代的 3 1()的环烃基、 取代或未 取代的杂环基、 -ORa、 -NHRa、 -NRaRb或 -SRa,
其中 1^和 Rb各自独立地为取代或未取代的 d-do的烃基、 取代或未取 代的 C3-C1Q的环烃基、 取代或未取代的 C6-C12的芳基、 取代或未取代的芳杂 基或者取代或未取代的杂环基;
所述取代基选自卤素、 -OH、 -N02、 CrC6烃基、 羧基、 CrC6烃氧基羰 基、 C6-C12的芳基、 -NH2、 d-C6烃基取代的氨基、 羟基取代的 d-C6烃基、 羟基取代的 CrC6烃氧基、 未取代或 d-C6烃基取代的杂环基和 -CF3 ;
所述芳杂基为 5元或 6元环, 含有 1~3个选自 N、 0和 S的杂原子; 所述杂环基为 3元〜 7元的单环或 8元的二环, 含有 1~3个选自 N、 0 和 S的杂原子, 且所述杂环基非必需地被硫代或氧代。
2、 根据权利要求 1所述的哒嗪酮类化合物, 其特征在于, 其中,
R为 -OH、 -SH、 取代或未取代的苯基、 取代或未取代的芳杂基、 取代或 未取代的 Crdo的烷基、 取代或未取代的 3 1()的环烷基、 取代或未取代的 杂环基、 -ORa、 -NHRa、 -NRaRb或 -SRa,
其中 1^和 Rb各自独立地为取代或未取代的 d-do的烷基、 取代或未取 代的 C3-C1Q的环烷基、 取代或未取代的苯基、 取代或未取代的芳杂基或者取 代或未取代的杂环基;
所述取代基选自卤素、 -OH、 -N02、 CrC6烷基、 羧基、 CrC6烷氧基羰 基、 苯基、 -N¾、 d-C6烷基取代的氨基、 羟基取代的 d-C6烷基、 羟基取代 的 d-C6烷氧基、 未取代或 d-C4烷基取代的杂环基和 -CF3 ;
所述芳杂基为 5元或 6元环, 含有 1~3个 N原子;
所述杂环基为 3元 ~ 7元的单环或 8元的二环, 含有 1~3个 N原子, 且 所述杂环基非必需地被硫代或氧代。
3、根据权利要求 2所述的哒嗪酮类化合物, 其特征在于, 所述化合物具 体为:
S6lOOO/600iM3/X3d f66Ml/600Z OAV
S6Z000/600ZM3/X3d
≤6iOOO/600ZN3/X3d
4、权利要求 1所述的结构通式 I所示的哒嗪酮类化合物的制备方法,其 特征是, 该制备方法选自下述方法中的任意一种:
β 9
其中, R的定义与权利要求 1相同。
5、 权利要求 1 ~ 4中任意一项所述的结构通式 I所示的哒嗪酮类化合物 在制备血管内皮细胞增殖抑制剂的药物中的用途。
6、 权利要求 1 ~ 4中任意一项所述的结构通式 I所示的哒嗪酮类化合物 在制备抑制肿瘤血管生成, 即抗肿瘤的药物中的用途。
7、 根据权利要求 6所述的用途, 其特征在于, 所述肿瘤包括肝癌。
8、一种具有抗肿瘤活性的药物组合物, 其特征在于, 包含治疗有效量的 一种或多种权利要求 1 ~ 4中任意一项所述的哒嗪酮类化合物及药学上可接 受的辅料。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09721727A EP2253625B1 (en) | 2008-03-18 | 2009-03-18 | Pyridazinones, the preparation and the use thereof |
US12/933,104 US8501731B2 (en) | 2008-03-18 | 2009-03-18 | Derivatives of 6[3-(trifluoromethyl)phenyl]pyridazin-3(2H)-one having antitumor activity |
JP2011500030A JP5255691B2 (ja) | 2008-03-18 | 2009-03-18 | ピリダジノン類化合物及びその調製方法と使用 |
US13/921,009 US9212146B2 (en) | 2008-03-18 | 2013-06-18 | Substituted pyridazinones for the treatment of tumors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200810034796.7 | 2008-03-18 | ||
CN200810034796 | 2008-03-18 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/933,104 A-371-Of-International US8501731B2 (en) | 2008-03-18 | 2009-03-18 | Derivatives of 6[3-(trifluoromethyl)phenyl]pyridazin-3(2H)-one having antitumor activity |
US13/921,009 Continuation-In-Part US9212146B2 (en) | 2008-03-18 | 2013-06-18 | Substituted pyridazinones for the treatment of tumors |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009114993A1 true WO2009114993A1 (zh) | 2009-09-24 |
Family
ID=41090485
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2009/000295 WO2009114993A1 (zh) | 2008-03-18 | 2009-03-18 | 一类哒嗪酮类化合物及其制备方法和用途 |
PCT/CN2009/000296 WO2009114994A1 (zh) | 2008-03-18 | 2009-03-18 | 哒嗪酮类化合物在制备抗肿瘤药物中的用途 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2009/000296 WO2009114994A1 (zh) | 2008-03-18 | 2009-03-18 | 哒嗪酮类化合物在制备抗肿瘤药物中的用途 |
Country Status (5)
Country | Link |
---|---|
US (1) | US8501731B2 (zh) |
EP (1) | EP2253625B1 (zh) |
JP (1) | JP5255691B2 (zh) |
CN (2) | CN101537006B (zh) |
WO (2) | WO2009114993A1 (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015106717A1 (zh) * | 2014-01-16 | 2015-07-23 | 四川百利药业有限责任公司 | 哒嗪酮类衍生物及其制备方法和用途 |
WO2017150654A1 (en) | 2016-03-04 | 2017-09-08 | Otsuka Pharmaceutical Co., Ltd. | 5-methyl-6-phenyl-4,5-dihydro-2h-pyridazin-3-one derivative |
US11427553B2 (en) | 2017-08-04 | 2022-08-30 | Bayer Aktiengesellschaft | Dihydrooxadiazinones |
US11897867B2 (en) | 2017-08-04 | 2024-02-13 | Bayer Aktiengesellschaft | 6-phenyl-4,5-dihydropyridazin-3(2H)-one derivatives as PDE3A and PDE3B inhibitors for treating cancer |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102007026341A1 (de) | 2007-06-06 | 2008-12-11 | Merck Patent Gmbh | Benzoxazolonderivate |
DE102007032507A1 (de) | 2007-07-12 | 2009-04-02 | Merck Patent Gmbh | Pyridazinonderivate |
DE102007038957A1 (de) * | 2007-08-17 | 2009-02-19 | Merck Patent Gmbh | 6-Thioxo-pyridazinderivate |
DE102007061963A1 (de) * | 2007-12-21 | 2009-06-25 | Merck Patent Gmbh | Pyridazinonderivate |
US9212146B2 (en) * | 2008-03-18 | 2015-12-15 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Substituted pyridazinones for the treatment of tumors |
DE102008019907A1 (de) * | 2008-04-21 | 2009-10-22 | Merck Patent Gmbh | Pyridazinonderivate |
DE102008028905A1 (de) * | 2008-06-18 | 2009-12-24 | Merck Patent Gmbh | 3-(3-Pyrimidin-2-yl-benzyl)-[1,2,4]triazolo[4,3-b]pyridazinderivate |
DE102008037790A1 (de) * | 2008-08-14 | 2010-02-18 | Merck Patent Gmbh | Bicyclische Triazolderivate |
DK2361250T3 (da) | 2008-12-22 | 2013-11-04 | Merck Patent Gmbh | Nye polymorfe former af 6-(1-methyl-1h-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-benzyl}-2h-pyridazin-3-on-dihydrogenphosphat og fremgangsmåder til fremstilling deraf |
NL1037569C2 (en) * | 2009-12-18 | 2011-06-21 | Eurovet Animal Health B V | Crystalline pimobendan, process for the preparation thereof, pharmaceutical composition and use. |
CN102133217B (zh) * | 2010-01-27 | 2013-07-24 | 中国科学院上海药物研究所 | 一类以n为桥键的哒嗪酮类化合物在制备抗肿瘤的药物中的用途 |
CN105102448B (zh) | 2013-02-28 | 2018-03-06 | 百时美施贵宝公司 | 作为rock1和rock2抑制剂的苯基吡唑衍生物 |
AR094929A1 (es) | 2013-02-28 | 2015-09-09 | Bristol Myers Squibb Co | Derivados de fenilpirazol como inhibidores potentes de rock1 y rock2 |
WO2014164704A2 (en) * | 2013-03-11 | 2014-10-09 | The Broad Institute, Inc. | Compounds and compositions for the treatment of cancer |
CN103288745A (zh) * | 2013-06-25 | 2013-09-11 | 南方医科大学 | 一种2,6-二取代哒嗪酮类化合物及其应用 |
CN103804312B (zh) * | 2014-02-17 | 2016-04-20 | 四川百利药业有限责任公司 | 一类氮杂环化合物及其制备方法和用途 |
US11207320B2 (en) | 2015-08-13 | 2021-12-28 | The Broad Institute, Inc. | Compositions and methods for cancer expressing PDE3A or SLFN12 |
CN107334767B (zh) * | 2017-06-08 | 2019-03-05 | 中国医学科学院医药生物技术研究所 | 一种哒嗪酮类化合物在肿瘤治疗中的应用 |
JP7104588B2 (ja) * | 2017-09-01 | 2022-07-21 | 大塚製薬株式会社 | 5-メチル-6-フェニル-4,5-ジヒドロ-2h-ピリダジン-3-オン誘導体を含有する悪性腫瘍治療剤 |
WO2019051469A1 (en) * | 2017-09-11 | 2019-03-14 | Krouzon Pharmaceuticals, Inc. | SHP2 OCTAHYDROCYCLOPENTA [C] PYRROLE ALLOSTERIC INHIBITORS |
WO2020157236A1 (en) * | 2019-02-01 | 2020-08-06 | Bayer Aktiengesellschaft | Pyridyl substituted dihydrooxadiazinones |
CN111393374A (zh) * | 2020-05-08 | 2020-07-10 | 张建蒙 | 氧代二氢哒嗪类衍生物及其在抗肿瘤药物中的应用 |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4112095A (en) * | 1976-10-07 | 1978-09-05 | American Cyanamid Company | 6-Phenyl-1,2,4-triazolo[4,3-b]pyridazine hypotensive agents |
EP0665223A1 (en) | 1994-01-28 | 1995-08-02 | Takeda Chemical Industries, Ltd. | Antitumor agent, novel 3(2H)-pyridazinone derivatives and their preparation |
WO2003059891A1 (en) | 2002-01-18 | 2003-07-24 | Pharmacia Corporation | Substituted pyridazinones as inhibitors of p38 |
WO2004046130A1 (en) | 2002-11-19 | 2004-06-03 | Aventis Pharma S.A. | Pyridazinone derivatives as cdk2-inhibitors |
WO2005007632A1 (en) | 2003-07-18 | 2005-01-27 | Pharmacia Corporation | Substituted pyridazinones as inhibitors of p38 |
WO2005085231A1 (en) | 2004-03-02 | 2005-09-15 | Aventis Pharma S.A. | Novel 4-benzimidazol-2-ylpyridazin-3-one derivatives |
WO2005111019A1 (en) | 2004-05-18 | 2005-11-24 | Aventis Pharma S.A. | Novel pyridazinone derivatives as inhibitors of cdk2 |
WO2006124874A2 (en) | 2005-05-12 | 2006-11-23 | Kalypsys, Inc. | Inhibitors of b-raf kinase |
US20070072866A1 (en) | 2004-03-02 | 2007-03-29 | Sanofi-Aventis Deutschland Gmbh | 4-benzimidazol-2-yl-pyridazine-3-one-derivatives, production and use thereof in medicaments |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4117030A (en) * | 1977-07-11 | 1978-09-26 | The Dow Chemical Company | Vinyl ester resin compositions containing dicyclopentadiene alkenoate |
AT397085B (de) * | 1992-02-17 | 1994-01-25 | Agrolinz Agrarchemikalien | Herbizide n-cyanopyridazinone |
JP2000290261A (ja) * | 1999-04-01 | 2000-10-17 | Mitsui Chemicals Inc | ジヒドロピリダジノン誘導体およびそれを有効成分として含有する腫瘍壊死因子産生抑制剤 |
FR2850377B1 (fr) * | 2003-01-23 | 2009-02-20 | Sanofi Synthelabo | Derives d'arylalkylcarbamates, leur preparation et leur application en therapeutique |
CN1897952B (zh) * | 2003-12-26 | 2010-12-08 | 日产化学工业株式会社 | 中性白细胞增多抑制剂 |
DE102005057924A1 (de) * | 2005-12-05 | 2007-06-06 | Merck Patent Gmbh | Pyridazinonderivate |
-
2009
- 2009-03-17 CN CN200910127196XA patent/CN101537006B/zh not_active Expired - Fee Related
- 2009-03-17 CN CN2009101271955A patent/CN101538245B/zh not_active Expired - Fee Related
- 2009-03-18 JP JP2011500030A patent/JP5255691B2/ja not_active Expired - Fee Related
- 2009-03-18 EP EP09721727A patent/EP2253625B1/en not_active Not-in-force
- 2009-03-18 US US12/933,104 patent/US8501731B2/en not_active Expired - Fee Related
- 2009-03-18 WO PCT/CN2009/000295 patent/WO2009114993A1/zh active Application Filing
- 2009-03-18 WO PCT/CN2009/000296 patent/WO2009114994A1/zh active Application Filing
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4112095A (en) * | 1976-10-07 | 1978-09-05 | American Cyanamid Company | 6-Phenyl-1,2,4-triazolo[4,3-b]pyridazine hypotensive agents |
EP0665223A1 (en) | 1994-01-28 | 1995-08-02 | Takeda Chemical Industries, Ltd. | Antitumor agent, novel 3(2H)-pyridazinone derivatives and their preparation |
WO2003059891A1 (en) | 2002-01-18 | 2003-07-24 | Pharmacia Corporation | Substituted pyridazinones as inhibitors of p38 |
WO2004046130A1 (en) | 2002-11-19 | 2004-06-03 | Aventis Pharma S.A. | Pyridazinone derivatives as cdk2-inhibitors |
WO2005007632A1 (en) | 2003-07-18 | 2005-01-27 | Pharmacia Corporation | Substituted pyridazinones as inhibitors of p38 |
WO2005085231A1 (en) | 2004-03-02 | 2005-09-15 | Aventis Pharma S.A. | Novel 4-benzimidazol-2-ylpyridazin-3-one derivatives |
US20070072866A1 (en) | 2004-03-02 | 2007-03-29 | Sanofi-Aventis Deutschland Gmbh | 4-benzimidazol-2-yl-pyridazine-3-one-derivatives, production and use thereof in medicaments |
US20070173503A1 (en) | 2004-03-02 | 2007-07-26 | Aventis Pharma S.A. | Novel 4-benzimidazol-2-ylpyridazin-3-one derivatives |
WO2005111019A1 (en) | 2004-05-18 | 2005-11-24 | Aventis Pharma S.A. | Novel pyridazinone derivatives as inhibitors of cdk2 |
WO2006124874A2 (en) | 2005-05-12 | 2006-11-23 | Kalypsys, Inc. | Inhibitors of b-raf kinase |
Non-Patent Citations (3)
Title |
---|
DATABASE CA accession no. STN Database accession no. 1986:564757 * |
KILIAN, U. ET AL.: "Bronchospasmolytic effects of substituted 6-phenyl-3 [2H] -pyridazinones in comparison to theophylline and enprofylline", CURRENT CLINICAL PRACTICE SERIES (1985), 19(ANTI-ASTHMA XANTHINES ADENOSINE), CODEN: CCPSEZ, 1985 * |
See also references of EP2253625A4 |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015106717A1 (zh) * | 2014-01-16 | 2015-07-23 | 四川百利药业有限责任公司 | 哒嗪酮类衍生物及其制备方法和用途 |
WO2017150654A1 (en) | 2016-03-04 | 2017-09-08 | Otsuka Pharmaceutical Co., Ltd. | 5-methyl-6-phenyl-4,5-dihydro-2h-pyridazin-3-one derivative |
KR20180118717A (ko) | 2016-03-04 | 2018-10-31 | 오츠카 세이야쿠 가부시키가이샤 | 5-메틸-6-페닐-4,5-디하이드로-2h-피리다진-3-온 유도체 |
US10611731B2 (en) | 2016-03-04 | 2020-04-07 | Otsuka Pharmaceutical Co., Ltd. | 5-methyl-6-phenyl-4,5-dihydro-2H-pyridazin-3-one derivative |
US11427553B2 (en) | 2017-08-04 | 2022-08-30 | Bayer Aktiengesellschaft | Dihydrooxadiazinones |
US11773070B2 (en) | 2017-08-04 | 2023-10-03 | Bayer Aktiengesellschaft | Dihydrooxadiazinones |
US11897867B2 (en) | 2017-08-04 | 2024-02-13 | Bayer Aktiengesellschaft | 6-phenyl-4,5-dihydropyridazin-3(2H)-one derivatives as PDE3A and PDE3B inhibitors for treating cancer |
Also Published As
Publication number | Publication date |
---|---|
US8501731B2 (en) | 2013-08-06 |
CN101538245A (zh) | 2009-09-23 |
CN101537006A (zh) | 2009-09-23 |
EP2253625A4 (en) | 2011-03-23 |
JP2011514365A (ja) | 2011-05-06 |
WO2009114994A1 (zh) | 2009-09-24 |
JP5255691B2 (ja) | 2013-08-07 |
US20110112061A1 (en) | 2011-05-12 |
EP2253625B1 (en) | 2013-03-13 |
CN101538245B (zh) | 2011-02-16 |
CN101537006B (zh) | 2012-06-06 |
EP2253625A1 (en) | 2010-11-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2009114993A1 (zh) | 一类哒嗪酮类化合物及其制备方法和用途 | |
JP2019163290A (ja) | 新規グルタミナーゼ阻害剤 | |
JP6813665B2 (ja) | 4−ピリドン化合物またはその塩、それを含む医薬組成物および剤 | |
JP5670266B2 (ja) | フラザノベンゾイミダゾール | |
TWI527800B (zh) | 作為聚(二磷酸腺苷酸-核醣)聚合酶(parp)之抑制劑之1-(芳基甲基)喹唑啉-2,4(1h,3h)-二酮及其應用 | |
TW200808771A (en) | Novel compounds II | |
JP2010514689A (ja) | 癌、炎症およびウイルス感染症の処置のためのcdk阻害剤としてのヘテロアリール−ヘテロアリール化合物 | |
JP2010514688A (ja) | インドール−4−イルピリミジニル−2−イル−アミン誘導体およびサイクリン依存性キナーゼ阻害剤としてのその使用 | |
JP2016517412A (ja) | Fasnを阻害するための新規化合物および組成物 | |
JPWO2005087749A1 (ja) | 2−アミノキナゾリン誘導体 | |
JP4716996B2 (ja) | スルホピロール | |
JP6719451B2 (ja) | キナゾリン誘導体 | |
CN115215847A (zh) | 一类kras-sos1抑制剂、其制备方法及其应用 | |
JP2023524212A (ja) | ポリ(adp-リボース)ポリメラーゼ(parp)阻害剤として有用な新規化合物 | |
JP2010111702A (ja) | 複素環化合物、その製造法および用途 | |
WO2022184119A1 (zh) | 酪氨酸激酶抑制剂及其药物应用 | |
US9212146B2 (en) | Substituted pyridazinones for the treatment of tumors | |
WO2008050808A1 (fr) | Dérivé de 2-aminoquinazoline | |
WO2022002100A1 (zh) | 新型苯并咪唑化合物 | |
CN115073468B (zh) | 咪唑并吡嗪类btk抑制剂的制备及用途 | |
JP2006505577A (ja) | 3位が複素環式基によって置換されたピリドインドロン誘導体、それらの製造法およびそれらの治療用途 | |
CN114957241B (zh) | 杂环类化合物作为激酶抑制剂的制备及其应用 | |
WO2006081741A1 (fr) | Dérivés de quinazoline ou leurs sels de qualité pharmaceutique, synthèse et applications médicales desdites substances | |
CN116514790A (zh) | 一类靶向于stat3的三联芳香杂环哌嗪类小分子有机化合物及其应用 | |
JPH04235983A (ja) | 新規キノリン誘導体およびそれを有効成分として含有する制癌剤効果増強剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09721727 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009721727 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011500030 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12933104 Country of ref document: US |