ZSTK 474
4-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]morpholine
ZSTK474; 475110-96-4; 4,4′-(6-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)dimorpholine; ZSTK-474; ZSTK 474; TCMDC-137004;
2-(2-Difluoromethylbenzimidazol-1-yl)-4,6-bis(morpholino)-1,3,5-triazine
2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine
Zenyaku Kogyo (Innovator)
phase2………Treatment of Solid Tumors Therapy
ZSTK474 is a cell permeable and reversible P13K inhibitor with an IC₅₀ at 6nm. It was identified as part of a screening library, selected for its ability to block tumor cell growth. ZSTK474 has shown strong antitumor activities against human cancer xenographs when administered orally to mice without a significant toxic effect.
Phosphatidylinositol 3-kinase (PI3K) has been implicated in a variety of diseases including cancer. A number of PI3K inhibitors have recently been developed for use in cancer therapy. ZSTK474 is a highly promising antitumor agent targeting PI3K. We previously reported that ZSTK474 showed potent inhibition against four class I PI3K isoforms but not against 140 protein kinases.
However, whether ZSTK474 inhibits DNA-dependent protein kinase (DNA-PK), which is structurally similar to PI3K, remains unknown. To investigate the inhibition of DNA-PK, we developed a new DNA-PK assay method using Kinase-Glo. The inhibition activity of ZSTK474 against DNA-PK was determined, and shown to be far weaker compared with that observed against PI3K. The inhibition selectivity of ZSTK474 for PI3K over DNA-PK was significantly higher than other PI3K inhibitors, namely NVP-BEZ235, PI-103 and LY294002.
Other Names: ZSTK-474
Chemical Formula: C19H21F2N7O2
CAS Number: 475110-96-4
Molecular Weight: 417.41
WO 2002088112
The condensation of 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine
with 2-(difluoromethyl)-1H-benzimidazole by means of K2CO3 in DMF gives
2-chloro-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazine ,
which is then condensed with morpholine by means of K2CO3 in DMF to afford the target trisubstituted triazine.
aReagents and conditions: (i) K2CO3, DMF, room temp; (ii) morpholine, DMF or THF, room temp; (iii) NaH or K2CO3, DMF or DMSO, 120 °C.
- 2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine(compound 19)
Melting point: 211-214°C
NMR(CDCl3) δ : 3.79(8H, t, J=4Hz), 3.88(8H, t, J=4Hz), 7.3-7.4(2H, m), 7.56(1H, t, J=53Hz), 7.88(1H, d, J=7Hz), 8.32(1H, d, J=7Hz)
MS m/z: 417(M+
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J. Med. Chem., 2011, 54 (20), pp 7105–7126
DOI: 10.1021/jm200688y
1 (0.35 g, 84% yield): mp (EtOH) 217–219 °C (lit. 211–214 °C);
1H NMR (CDCl3) δ 8.33 (dd, J = 7.3, 1.4 Hz, 1H), 7.89 (dd, J = 7.2, 1.5 Hz, 1H), 7.56 (t, JHF=53.6 Hz, 1H), 7.46–7.37 (m, 2H), 3.91–3.86 (m, 8H), 3.81–3.76 (m, 8H).
Kawashima, S.; Matsuno, T.; Yaguchi, S.; Sasahara, H.; Watanabe, T.Preparation of Heterocyclic Compounds as Antitumor Agents. PCT Int. Appl. WO 02088112, 2002;
Chem. Abstr. 2002, 137, 370113.
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2-(difluoromethyl)-1H-benzimidazole
A mixture of o-phenylenediamine (5.41 g, 50 mmol) and difluoroacetic acid (9.6 g, 100 mmol) in 4 M HCl (20 mL) was heated under reflux for 1 h and diluted with hot water (50 mL). The solution was treated with charcoal and filtered through Celite before being neutralized with aqueous NH3. The resulting white precipitate was collected, washed with water, and dried to give 2-(difluoromethyl)-1H-benzimidazole (6.07 g, 72% yield): mp 156–158 °C; 1H NMR (DMSO-d6) δ 13.28 (br, 1H), 7.76–7.68 (m, 1H), 7.61–7.54 (m, 1H), 7.36–7.26 (m, 2H), 7.26 (t,JHF= 53.3 Hz, 1H).
Ge, F.; Wang, Z.; Wan, W.; Lu, W.; Hao, J.One-pot synthesis of 2-trifluoromethyl and 2-difluoromethyl substituted benzo-1,3-diazoles Tetrahedron Lett. 2007, 48, 3251–3254
TRIAZINE, PYRIMIDINE AND PYRIDINE ANALOGS AND THEIR USE AS THERAPEUTIC AGENTS AND DIAGNOSTIC PROBES [US2011275762]2011-11-10
| PATENT | SUBMITTED | GRANTED |
|---|---|---|
| Heterocyclic compound and antitumor agent containing the same as active ingredient [US7071189] | 2004-06-17 | 2006-07-04 |
| Treatment of prostate cancer, melanoma or hepatic cancer [US2007244110] | 2007-10-18 | |
| Heterocyclic compound and antitumor agent containing the same as effective ingredient [US7307077] | 2006-11-02 | 2007-12-11 |
| IMMUNOSUPPRESSIVE AGENT AND ANTI-TUMOR AGENT COMPRISING HETEROCYCLIC COMPOUND AS ACTIVE INGREDIENT [US7750001] | 2008-05-15 | 2010-07-06 |
| PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY [US2011009405] | 2011-01-13 | |
| SUBSTITUTED PYRIMIDINES AND TRIAZINES AND THEIR USE IN CANCER THERAPY [US2011053907] | 2011-03-03 | |
| IMMUNOSUPPRESSIVE AGENT AND ANTI-TUMOR AGENT COMPRISING HETEROCYCLIC COMPOUND AS ACTIVE INGREDIENT [US2010267700] | 2010-10-21 | |
| AMORPHOUS BODY COMPOSED OF HETEROCYCLIC COMPOUND, SOLID DISPERSION AND PHARMACEUTICAL PREPARATION EACH COMPRISING THE SAME, AND PROCESS FOR PRODUCTION OF THE SAME [US8227463] | 2010-09-30 | 2012-07-24 |
| PYRAZOLO[1,5-a]PYRIDINES AND THEIR USE IN CANCER THERAPY [US2010226881] | 2010-09-09 | |
| PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLE SULFONAMIDES AND THEIR USE IN CANCER THERAPY [US2010249099] | 2010-09-30 |
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Zenyaku Kogyo
Sector: Health Care
Industry: Biotech & Pharma
Sub-Industry: Specialty Pharma
Zenyaku Kogyo Co. Ltd. produces pharmaceuticals. The Company manufactures and sells over-the-counter drugs, health foods, and prescription medicines, as well as skin care products.
Address:
5-6-15 Otsuka
Bunkyo, 112-8650
Japan
Phone: 81-3-3946-1111
Fax: 81-3-3946-1130
Web url: www.zenyaku.co.jp
Otsuka
Bunkyo
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