- New Acetohydrazides Incorporating 2-Oxoindoline and 4-Oxoquinazoline: Synthesis and Evaluation of Cytotoxicity and Caspase Activation Activity
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In our search for new small molecules activating procaspase-3, we have designed and synthesized a series of new acetohydrazides incorporating both 2-oxoindoline and 4-oxoquinazoline scaffolds. Biological evaluation showed that a number of these acetohydrazides were comparably or even more cytotoxic against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI?H23, lung cancer) in comparison to PAC-1, a first procaspase-3 activating compound, which was used as a positive control. One of those new compounds, 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N′-[(3Z)-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetohydrazide activated the caspase-3 activity in U937 human lymphoma cells by 5-fold higher than the untreated control. Three of the new compounds significantly induced necrosis and apoptosis in U937 cells.
- Anh, Duong Tien,Duc, Phan Huy,Duc-Anh, Lai,Hai, Pham-The,Han, Sang-Bae,Huan, Le Cong,Huong, Le-Thi-Thu,Kang, Jong Soon,Kim Oanh, Dao Thi,Lee, Hye Jin,Nam, Nguyen-Hai,Park, Eun Jae,Thanh Hai, Dinh Thi,Tran, Phuong-Thao,Truong, Bui Xuan
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Read Online
- (E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity
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In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3H)-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds. In term of caspase activation activity, several compounds were found to exhibit potent effects, (e.g. compounds 7 b, 5n, and 5l). Especially, compound 7 b activated caspases activity by almost 200% in comparison to that of PAC-1. Further docking simulation also revealed that this compound potentially is a potent allosteric inhibitor of procaspase-3.
- Huan, Le Cong,Phuong, Cao Viet,Truc, Le Cong,Thanh, Vo Nguyen,Pham-The, Hai,Huong, Le-Thi-Thu,Thuan, Nguyen Thi,Park, Eun Jae,Ji, A Young,Kang, Jong Soon,Han, Sang-Bae,Tran, Phuong-Thao,Nam, Nguyen-Hai
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Read Online
- 6-Nitro-Quinazolin?4(3H)?one Exhibits Photodynamic Effects and Photodegrades Human Melanoma Cell Lines. A Study on the Photoreactivity of Simple Quinazolin?4(3H)?ones
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Photochemo and photodynamic therapies are minimally invasive approaches for the treatment of cancers and powerful weapons for competing bacterial resistance to antibiotics. Synthetic and naturally occurring quinazolinones are considered privileged anticancer and antibacterial agents, with several of them to have emerged as commercially available drugs. In the present study, applying a single-step green microwave irradiation mediated protocol we have synthesized eleven quinazolinon?4(3H)?ones, from cheap readily available anthranilic acids, in very good yields and purity. These products were irradiated in the presence of pBR322 plasmid DNA under UVB, UVA and visible light. Four of the compounds proved to be very effective DNA photocleavers, at low concentrations, being time and concentration dependent as well as pH independent. Participation of reactive oxygen species was related to the substitution of quinazolinone derivatives. 6-Nitro-quinazolinone in combination with UVA irradiation was found to be in vitro photodestructive for three cell lines; glioblastoma (U87MG and T98G) and mainly melanoma (A?375). Thus, certain appropriately substituted quinazolinones may serve as new lead photosensitizers for the development of promising biotechnological applications and as novel photochemo and photodynamic therapeutics.
- Panagopoulos, Anastasios,Balalas, Thomas,Mitrakas, Achilleas,Vrazas, Vassilios,Katsani, Katerina R.,Koumbis, Alexandros E.,Koukourakis, Michael I.,Litinas, Konstantinos E.,Fylaktakidou, Konstantina C.
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Read Online
- Design, synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents
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In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure–activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.
- Dung, Do T. M.,Park, Eun J.,Anh, Duong T.,Hai, Pham-The,Huy, Le D.,Jun, Hye W.,Kwon, Joo-Hee,Young Ji,Kang, Jong S.,Tung, Truong T.,Dung, Phan T. P.,Han, Sang-Bae,Nam, Nguyen-Hai
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- Visible-Light Photosynthesis of CHF2/CClF2/CBrF2-Substituted Ring-fused Quinazolinones in Dimethyl Carbonate
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With eco-friendly and sustainable CO2-derived dimethyl carbonate as the sole solvent, the visible-light-induced cascade radical reactions have been established as a green and efficient tool for constructing various CHF2/CClF2/CBrF2-substituted ring-fused quinazolinones.
- Gui, Qing-Wen,He, Wei-Min,Huang, Wen-Jie,Lu, Zi-Qin,Ouyang, Wen-Tao,Teng, Fan,Xun, Changping,Yang, Hao,Zhu, Meng-Xue
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- Novel (Z)-N'-(2-oxoindolin-3-ylidene)-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides and an anticancer composition comprising the same as an active ingredient
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(Z)- N' - (2-oxoindolin -3 - ylidene) -2 - (4-oxoquinazolin -3 (4H) - yl) acetohydrazide and an anticancer composition containing the same as an active ingredient. , It will be described below. (Z)- N' - (2-oxoindoline -3 - ylidene) -2 - (4-oxazoline -3 (4H) - yl) acetohydrazide according to the present invention activates procacaspase -3 to promote the conversion to caspase -3, so that it can be used as a proliferation inhibitor for various cancer cells. The compound according to the present invention can be developed as an active ingredient of a potent anticancer agent.
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Paragraph 0097
(2021/05/18)
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- Preparation method of lapatinib key intermediate
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The invention belongs to the field of drug synthesis, and relates to a preparation method of a lapatinib key intermediate, in particular to a preparation method of 6-iodoquinazoline-4-ketone. The synthesis method is simple to operate and high in yield, and can meet the requirements of industrial production.
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Paragraph 0019-0022
(2020/05/09)
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- Design, synthesis, and anticancer activities of sodium quinazolin-4-diselenide compounds
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Substituted 4-chloroquinazoline reacted with sodium diselenide to give novel sodium quinazoline-4-diselenide compounds. The reaction provides an efficient and facile approach to the synthesis of sodium quinazoline-4-diselenide compounds. Structures of title compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. MTT assay was adopted to show anticancer activities of the compounds. Compounds 5a and 5h showed good activities against cancer-cell lines MDA-MB-435, MDA-MB-231, A549, SiHa, and HeLa. In addition, 5a exhibited quite good anticancer effects on relative above cell lines with 10μM concentration compared with oxaliplatin and gefitinib of the commercial anticancer drugs.
- Zhang, Yuchun,Niu, Pengpeng,Wen, Quanwu,Sun, Lin,Wang, Weili,Xu, Shengguang,Liu, Gang
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p. 497 - 502
(2019/11/03)
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- Design, Synthesis and Bioevaluation of Two Series of 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines
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Two series of 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-benzylpiperidin-4-yl)quinazolin-4-amines were designed initially as potential acetylcholine esterase inhibitors. Biological evaluation demonstrated that N-(1-benzylpiperidin-4-yl)quinazolin-4-amines significantly inhibited AChE activity. Especially, two compounds of them were found to be the most potent with relative AChE inhibition percentages of 87 percent in comparison to donepezil. The docking studies with AChE showed similar interactions between donepezil and four derivatives. N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines also exhibited significant DPPH scavenging effects. The two series of compound also exerted moderate to good cytotoxicity against three human cancer cell lines, including SW620 (human colon cancer), PC-3 (prostate cancer), and NCI?H23 (lung cancer), with 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one being the most cytotoxic agent. 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one significantly induced early apoptosis and arrested the SW620 cells at G2/M phase. From this study, two compounds of N-(1-benzylpiperidin-4-yl)quinazolin-4-amines could serve as new leads for further design and AChE inhibitors, while 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one could serve as a new lead for the design and development of more potent anticancer agents.
- Lan, Ta Thu,Anh, Duong Tien,Pham-The, Hai,Dung, Do Thi Mai,Park, Eun Jae,Jang, Sun Dong,Kwon, Joo Hee,Kang, Jong Soon,Thuan, Nguyen Thi,Han, Sang-Bae,Nam, Nguyen-Hai
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- A preparation method of the lapatinib
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The invention discloses a lapatinib preparation method. In the synthesis method, the initial raw materials of 2-amino-5-iodobenzoic acid and a cyclization reagent are used for preparing a midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III), quinazoline sulfide (V) is generated through the midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III) under the condition of sulpho-reagent and methine halide, and a target molecule is further synthesized. Due to reaction, the lapatinib yield of a final product is increased, generation of an unstable midbody of 4-chloroquinazoline product is avoided, meanwhile, use of corrosive phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride and other chlorinating agents is avoided, and the lapatinib preparation method is suitable for industrial production.
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Paragraph 0017; 0037-0045
(2018/03/24)
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- Novel compound having tumor diagnosis or tumor growth inhibitory activity on EGFR mutant and medical uses comprising the same
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The present invention relates to a novel compound having activities of diagnosing a tumor having an epidermal growth factor receptor (EGFR) mutant and inhibiting tumor growth, a salt thereof, a contrast medium comprising the same, and a pharmaceutical composition for treating or preventing EGFR-related cancer diseases comprising the same as an active ingredient. The novel compound or the salt thereof according to the present invention does not inhibit a wild type EGFR but selectively inhibits an EGFR variant, and thus can treat and prevent EGFR-related cancer diseases, including lung cancer, colon cancer or breast cancer. Particularly, the compound or the salt thereof according to the present invention can effectively treat and prevent non-small cell lung cancer upon which Iressa or Tarceva cannot have any significant effect. In addition, the compound or the salt thereof according to the present invention responses with a target of Gefitinib-sensitive cancer cells or cancer cells showing EGFR T790M mutation rather than wild type EGFR over-expressed cancer cells, and thus can be used advisably as a contrast medium capable of clearly differentiating EGFR-related cancer cells by imaging.COPYRIGHT KIPO 2017
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Paragraph 0067-0069
(2017/04/03)
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- Compounds capable of inhibiting ErbB/HDAC and preparation method thereof, and pharmaceutical composition comprising compounds and application thereof
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The invention relates to compounds capable of inhibiting ErbB/HDAC and a preparation method thereof, and a pharmaceutical composition comprising the compounds and application thereof. The compounds are disclosed as Formula 1. The compounds or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof, or the pharmaceutical composition comprising the compounds can be used for preparing ErbB kinases and HDAC activity inhibitors and also preparing ErbB-kinase/HDAC-activated mediated disease curatives.
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Paragraph 0070; 0071; 0072; 0073; 0074
(2017/07/31)
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- Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy
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By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a–l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC50values 0.12 nM, 0.72 nM and 3.2 nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC50values between 0.49 and 8.76 μM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC.
- Ding, Chao,Chen, Shaopeng,Zhang, Cunlong,Hu, Guangnan,Zhang, Wei,Li, Lulu,Chen, Yu Zong,Tan, Chunyan,Jiang, Yuyang
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- Discovery of ErbB/HDAC inhibitors by combining the core pharmacophores of HDAC inhibitor vorinostat and kinase inhibitors vandetanib, BMS-690514, neratinib, and TAK-285
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By combining the core pharmacophores of HDAC inhibitor vorinostat and kinase inhibitors vandetanib, BMS-690514, neratinib, and TAK-285 with 1,2,3-triazole as linker, eight novel 6-substituted-4-aminoquinazolin derivatives were synthesized and characterized by 1H NMR, 13C NMR, and high resolution mass spectrometry. Their inhibitory activities against five enzymes (VEGFR2, HER2, EGFR, HDAC1, and HDAC6) and five cancer cell lines (A549, BT-474, A431, SK-BR-3, and NCI-H1975) were evaluated. The bioassay results show that the introduction of triazole linked vorinostat-like segment dramatically changed the selectivity profiles of newly synthetic compounds relative to vandetanib, BMS-690514, neratinib, and TAK-285. Among them, compound 6b exerted outstanding enzymatic and cellular activities through its simultaneous and synergistic inhibitions on multiple pathways, which might have the great potential to confer the better benefits than single-targeted inhibitors in cancer therapy.
- Ding, Chao,Li, Dan,Wang, Yan-Wei,Han, Sai-Sai,Gao, Chun-Mei,Tan, Chun-Yan,Jiang, Yu-Yang
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p. 1220 - 1227
(2017/06/19)
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- 6-furan [...] -4-amine compound and process for preparation thereof and use
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The invention belongs to the field of drug synthesis, and relates to 6-furyl quinazoline-4-amines in the general formula I (refer to the Specification), particularly to an N-[3-chlorine-4-[(3-fluorophenyl) methoxyl] phenyl]-6-(2-furyl) quinazoline-4-amine compound with a quaternary heterocyclic ring or a spiral structure, as well as a preparation method and medical application thereof. The compound provided by the invention is subjected to the in vitro EGFR and HER-2 kinase inhibitory activity and antineoplastic activity tests, and the result shows that the compound has excellent EGFR and HER-2 kinase inhibitory activity, and can be used for further preparing a novel antitumor drug.
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Paragraph 0052; 0053
(2017/04/03)
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- Sulfur-containing 6 - furan [...] -4 - amine compound and process for preparation thereof and use
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The invention belongs to the field of medicine synthesis, relates to a chemical compound containing sulphur-6-furan group chinazoline-4-amine with a general formula (I) shown in the Specification, in particular to a N-[3-chlorine-4-[(3-fluorophenyl) methoxyl] phenyl]-6-(2-furyl) chinazoline-4-amine chemical compound with a sulpho-quaternary heterocycle or a loop-coil structure, and a preparation method and medical application thereof. An external anti-tumour activity test result shows that the chemical compound has good anti-tumour acitivity, and can be further prepared into a new anti-tumour medicine.
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Paragraph 0017; 0025; 0026
(2016/10/09)
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- Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties
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DNA-encoded chemical libraries are increasingly used to identify leads for drug discovery or chemical biology. Despite the resurging interest in covalent inhibitors, libraries are typically designed with synthon filtered out for reactive functionalities that can engage a target through covalent interactions. Herein, we report the synthesis of two libraries containing Michael acceptors to identify cysteine reactive ligands. We developed a simple procedure to discriminate between covalent and high affinity non-covalent inhibitors using DNA display of the library in a microarray format. The methodology was validated with known covalent and high affinity non-covalent kinase inhibitors. Screening of the library revealed novel covalent inhibitors for MEK2 and ERBB2.
- Zambaldo,Daguer,Saarbach,Barluenga,Winssinger
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supporting information
p. 1340 - 1351
(2016/07/21)
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- INHIBITORS OF CDK8/19 FOR USE IN TREATING ESTROGEN RECEPTOR POSITIVE BREAST CANCER
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The invention provides a selective inhibitor of CDK8/19 for use in a method of treating a patient having estrogen receptor positive (ER+) breast cancer, including breast cancer that is resistant to antiestrogen therapy. In some embodiments, the selective inhibitor of CDK8/19 is administered in combination with antiestrogen therapy. In some embodiments, the selective inhibitor of CDK8/19 is administered to ER + HER2+ breast cancer patients in combination with HER2-targeting drugs.
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- CDK8/CDK19 SELECTIVE INHIBITORS AND THEIR USE IN ANTI-METASTATIC AND CHEMOPREVENTATIVE METHODS FOR CANCER
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The invention relates to the compounds and methods for inhibiting the Cyclin-Dependent Kinase Inhibitor (CDKI) pathway. More particularly, the invention relates to compounds and methods for inhibiting the CDKI pathway for studies of and intervention in senescence-related and other CDKI -related diseases. The invention provides new compounds having improved solubility and/or potency, and methods for their use. In various aspects, the invention relates to the treatment of cancer. The invention provides methods for chemoprevention and prevention of tumor recurrence or metastasis. The invention further provides diagnostic techniques for treatment for certain cancer types. The invention utilizes specific inhibitors of CDK8/19 and/or measurement of CDK8 levels in a patient.
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- Kinase scaffold repurposing for neglected disease drug discovery: Discovery of an efficacious, lapatanib-derived lead compound for trypanosomiasis
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Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns b
- Patel, Gautam,Karver, Caitlin E.,Behera, Ranjan,Guyett, Paul J.,Sullenberger, Catherine,Edwards, Peter,Roncal, Norma E.,Mensa-Wilmot, Kojo,Pollastri, Michael P.
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p. 3820 - 3832
(2013/06/27)
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- Synthesis and SAR optimization of quinazolin-4(3H)-ones as poly(ADP-ribose)polymerase-1 inhibitors
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We have demonstrated that quinazolin-4(3H)-one, a nicotinamide (NI) mimic with PARP-1 inhibitory activity in the high micromolar range (IC50 = 5.75 μM) could be transformed into highly active derivatives with only marginal increase in molecular weight. Convenient one to two synthetic steps allowed us to explore extensive SAR at the 2-, and 5- through 8-positions of the quinazolin-4(3H)-one scaffold. Substitutions at the 2- and 8-positions were found to be most favorable for improved PARP-1 inhibition. The amino group at 8-position resulted in compound 22 with an IC50 value of 0.76 μM. Combination of the 8-amino substituent with an additional methyl substituent at the 2-position provided the most potent compound 31 [8-amino-2-methylquinazolin- 4(3H)-one, IC50 = 0.4 μM] in the present study. Compound 31 inhibited the proliferation of Brca1-deficient cells with an IC50 value of 49.0 μM and displayed >10-fold selectivity over wild type counterparts. Binding models of these derivatives within the active site of PARP-1 have further supported the SAR data and will be useful for future lead optimization efforts.
- Kulkarni, Shridhar S.,Singh, Satyakam,Shah, Janki R.,Low, Woon-Kai,Talele, Tanaji T.
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experimental part
p. 264 - 273
(2012/07/14)
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- PHOSPHORUS CONTAINING QUINAZOLINE COMPOUNDS AND METHODS OF USE
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Disclosed are novel quinazoline derivatives containing phosphorus substitutions and methods for the treatment of hyperproliferative diseases (e.g. cancer) using the compounds. These compounds are type I receptor protein kinase inhibitors useful in treating disorders related to abnormal protein kinase activities such as cancer and inflammation in mammals. Also disclosed are pharmaceutical compositions containing the compounds, methods for the preparation of the compounds and their pharmaceutically acceptable salts.
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Page/Page column 42-43
(2011/02/24)
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- Novel chimeric histone deacetylase inhibitors: A series of lapatinib hybrides as potent inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and histone deacetylase activity
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Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.
- Mahboobi, Siavosh,Sellmer, Andreas,Winkler, Matthias,Eichhorn, Emerich,Pongratz, Herwig,Ciossek, Thomas,Baer, Thomas,Maier, Thomas,Beckers, Thomas
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supporting information; scheme or table
p. 8546 - 8555
(2011/02/28)
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- NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES
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The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth
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Page/Page column 37; 68
(2009/06/27)
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- Discovery and structure-activity relationships of a novel class of quinazoline glucokinase activators
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We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).
- Iino, Tomoharu,Sasaki, Yasuhiro,Bamba, Makoto,Mitsuya, Morihiro,Ohno, Akio,Kamata, Kenji,Hosaka, Hideka,Maruki, Hiroko,Futamura, Mayumi,Yoshimoto, Riki,Ohyama, Sumika,Sasaki, Kaori,Chiba, Masato,Ohtake, Norikazu,Nagata, Yasufumi,Eiki, Jun-ichi,Nishimura, Teruyuki
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scheme or table
p. 5531 - 5538
(2010/04/05)
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- Processes and intermediates for the preparation of N4-phenyl-quinazoline-4-amine derivatives
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This invention provides compounds of Formula (I), wherein B, G, A, E, R1, R2, R3, m and n are as defined herein, which are useful as type I receptor tyrosine kinase inhibitors, and methods of use thereof in the treatment of hyperproliferative disorders in mammals.
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Page/Page column 61
(2009/09/05)
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- METHOD FOR PRODUCTION OF QUINAZOLIN-4-ON DERIVATIVE
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In reacting an anthranilic acid derivative represented by the general formula (1), especially the anthranilic acid derivative selected from anthranilic acid, anthranilamide and anthranilate, with formamide, the reaction is attained under the condition of coexistence of acetic acid and a base as a catalyst in the reaction liquid, and it has made it possible to produce a quinazolin-4-one derivative represented by the general formula (2) and useful as a material for medicine intermediates, at high yield with no side production.
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Page/Page column 7
(2009/01/23)
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- 4-Aminoquinazoline derivatives and methods of use thereof
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This invention relates to novel 4-aminoquinazolines, their derivatives, pharmaceutically acceptable salts, solvates, and hydrates thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering inhibitors of the EGFR and HER-2.
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Page/Page column 13-14
(2008/06/13)
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- MULTI-FUNCTIONAL SMALL MOLECULES AS ANTI-PROLIFERATIVE AGENTS
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The present invention relates to the compositions, methods, and applications of a novel approach to selective inhibition of several cellular or molecular targets with a single small molecule. More specifically, the present invention relates to multi-functional small molecules wherein one functionality is capable of inhibiting histone deacetylases (HDAC) and the other functionality is capable of inhibiting a different cellular or molecular pathway involved in aberrant cell proliferation, differentiation or survival.
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Page/Page column 169
(2008/06/13)
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- Highly functionalised sulfur-based silica scavengers for the efficient removal of palladium species from active pharmaceutical ingredients
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The use of multidentate sulfur-based silica scavengers 1,2, and 3 as highly effective adsorbents for the removal of precious metals, specifically palladium residues in this paper, from highly functionalised synthetic intermediates and APIs is described. The synthesis and purification of the polar and electron-rich reaction products, containing multiple functional groups, from palladium-catalysed removals of commonly used protecting groups such as benzyl, benzyloxycarbonyl, and allyloxycarbonyl and Sonogashira, Suzuki, Heck, and Buchwald-Hartwig coupling reactions is reported. The significant levels of residual palladium species, typically associated with these reaction products, are successfully and rapidly removed to below acceptable regulatory levels, of less than 5 ppm, by simple, unoptimised treatment with the designed silica scavengers at room temperature. Performance aspects, including broad solvent compatibility, excellent stability, and high metal affinity, combined with large-scale availability, ease of handling, and minimal loss of API make these silica scavengers particularly useful to process development groups.
- Galaffu, Nicola,Man, Siud Pui,Wilkes, Robin D.,Wilson, John R. H.
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p. 406 - 413
(2012/12/31)
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- A concise synthesis of quinazolinone TGF-β RI inhibitor through one-pot three-component Suzuki-Miyaura/etherification and imidate-amide rearrangement reactions
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A simple and efficient synthesis of dihydropyrrolopyrazole boronic acid intermediate (5) has been developed. Utilization of a three-component Suzuki-Miyaura/etherification with microwave heating led to advanced compound 11 in high yield and with easy purification. Reaction of compound 11 with methanesulfonyl chloride at room temperature furnished the 1,3 O-N rearranged product (12), which is postulated to proceed via an intramolecular mechanism. The outlined synthesis provides a highly efficient and high-yielding route that is amenable to rapid analog synthesis.
- Li, Hong-yu,Wang, Yan,McMillen, William T.,Chatterjee, Arindam,Toth, John E.,Mundla, Sreenivasa R.,Voss, Matthew,Boyer, Robert D.,Sawyer, J. Scott
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p. 11763 - 11770
(2008/03/13)
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- ALKYLQUINOLINE AND ALKYLQUINAZOLINE KINASE MODULATORS
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The invention is directed to alkylquinoline and alkylquinazoline compounds of Formula I: wherein R1, R2, R3, B, Z, G, Q and X are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of FLT3 and/or c-kit and/or TrkB, the use of such compounds to reduce or inhibit kinase activity of FLT3 and/or c-kit and/or TrkB in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to FLT3 and/or c-kit and/or TrkB. The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as cancers and other cell proliferative disorders.
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Page/Page column 58-59
(2010/11/25)
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- Cyanoguanidines and cyanoamidines as ErbB2 and EGFR inhibitors
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Cyanoguanidine quinazoline and cyanoamidine quinazolamine derivatives that are useful in the treatment of hyperproliferative diseases are disclosed. Methods of treating hyperproliferative diseases in mammals are also disclosed.
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Page/Page column 6
(2008/06/13)
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- Evaluation of kilogram-scale Sonagashira, Suzuki, and Heck coupling routes to oncology candidate CP-724,714
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The synthesis of the anti-cancer compound 2-methoxy-N-(3-{4-[3-methyl-4-(6- methyl-pyridin-3-yloxy)phenylamino]quinazolin-6-yl}-E-allyl)acetainide (CP-724,714) (1) on multikilogram scale using several different synthetic routes is described. Application of the Sonogashira, Suzuki, and Heck couplings to this synthesis was investigated to identify a safe, environmentally friendly, and robust process for the production of this drug candidate. A convergent and selective synthesis of the candidate was identified which utilizes a Heck coupling of a protected allylamine to install the critical olefin.
- Ripin, David H. Brown,Bourassa, Dennis E.,Brandt, Thomas,Castaldi, Michael J.,Frost, Heather N.,Hawkins, Joel,Johnson, Phillip J.,Massett, Stephen S.,Neumann, Karin,Phillips, James,Raggon, Jeffery W.,Rose, Peter R.,Rutherford, Jennifer L.,Sitter, Barbara,Stewart III, A. Morgan,Vetelino, Michael G.,Wei, Lulin
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p. 440 - 450
(2012/12/25)
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- FUSED PYRAZOLE DERIVATIVES AS TGF-BETA SIGNAL TRANSDUCTION INHIBITORS FOR THE TREATMENT OF FIBROSIS AND NEOPLASMS
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The disclosed invention is directed to compounds of the formula: Formula (I) and methods of using these compounds.
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Page/Page column 18
(2010/02/14)
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- PROCESS FOR PRODUCING QUINAZOLIN-4-ONE AND DERIVATIVE THEREOF
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A process for preparing quinazolin-4-one or its derivative by reacting anthranilic acid or its derivative with formic acid or its derivative in the presence of ammonia, or by reacting ammonium anthranilate or its derivative with formic acid or its derivative.
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- PROCESS FOR PRODUCING QUINAZOLIN-4-ONE DERIVATIVE
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A process for producing a quinazolin-4-one compound having the formula: [wherein R1, R2, R3 and R4 each represents a group not participating in the below-mentioned reaction, and R1, R2, R3 and R4 can be combined together to form a ring] which comprises reacting an anthranilic acid derivative having the formula: [wherein R5 is a hydrogen atom or a hydrocarbyl group] with a formic acid derivative in the presence of an ammonium carboxylate.
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- Oxo-azabicyclic compounds
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A compound selected from those of formula (I): wherein: X1, X2, and X3, represent N or —CR3in which R3is as described in the description, G1represents a group selected from those of formula
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Page column 32
(2010/02/07)
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- PHENYLALANINE DERIVATIVES AS DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
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The present invention is directed to phenylalanine derivatives which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
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- Oxo-azabicyclic compounds
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A compound selected from those of formula (I): 1wherein: X1, X2, and X3, represent N or —CR3 in which R3 is as described in the description, G1 represents a group selected from those of formulae (i/a) and (i/b): 2?in which R4, R5, and R6 are as defined in the description, G2 represents a group selected from carbon-carbon triple bond, —CH=C=CH—, C=O, C=S, S(O)n1 in which n1 represents an integer from 0 to 2 inclusive, or a group of formula (i/c): 3?in which Y1 represents O, S, —NH or —Nalkyl, and Y2 represents O, S, —NH or —Nalkyl, n is an integer from 0 to 6 inclusive, and m is an integer from 0 to 7 inclusive, Z1 represents —CR9R10, wherein R9 and R10 are as defined in the description, A represents a ring system, R1 represents a group selected from H, alkyl, alkenyl, alkynyl, optionally substituted and the group of formula (i/d): 4?in which p, Z2, B, q and G3 are as defined in the description and optionally, its optical isomers, N-oxide, and addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix mettaloprotease.
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- Oxo-azabicyclic compounds
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A compound selected from those of formula (I): wherein: X1, X2, and X3, represent N or —CR3 in which R3 is as described in the description, G1 represents a group selected from those of formulae (i/a) and (i/b): in which R4, R5, and R6 are as defined in the description, G2 represents a group selected from carbon-carbon triple bond, —CH═C═CH—, C═O, C═S, S(O)n1 in which n1 represents an integer from 0 to 2 inclusive, or a group of formula (i/c): in which Y1 represents O, S, —NH or —Nalkyl, and Y2 represents O, S, —NH or —Nalkyl, n is an integer from 0 to 6 inclusive, and m is an integer from 0 to 7 inclusive, Z1 represents —CR9R10 wherein R9 and R10 are as defined in the description, A represents a ring system, R1 represents a group selected from H, alkyl, alkenyl, alkynyl, optionally substituted and the group of formula (i/d): in which p, Z2, B, q and G3 are as defined in the description and optionally, its optical isomers, N-oxide, and addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix mettaloprotease.
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- Heteroaromatic bicyclic derivatives useful as anticancer agents
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The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts and solvates thereof, wherein A, X, R1, R3and R4are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals by administering the compounds of formula 1 and to pharmaceutical compositions for treating such disorders which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.
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- Substituted bicyclic derivatives useful as anticancer agents
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The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts and solvates thereof, wherein A, X, R1, R3and R4are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals with administering the compounds of formula 1 and to pharmaceutical compositions for treating such disorders which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.
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- Defined Dimensional Alterations in Enzyme Substrates. General Synthetic Methodology for the Bent Dihydro-lin-benzopurines
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The use of cycloaddition reactions for the synthesis of partially reduced heterocyclic systems has been shown to be an attractive approach to dihydrobenzimidazoles, dihydroquinazolines, and dihydro-lin-benzopurines.The first representatives of the bent dihydro-lin-benzopurines to be synthesized were 4,9-dihydroimidazo-quinazoline-2,8-(1H,7H)-dione (20) and 4,9-dihydro-lin-benzouric acid (21).
- Stevenson, Thomas M.,Kazmierczak, Franciszek,Leonard, Nelson J.
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p. 616 - 620
(2007/10/02)
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