ZSTK 474

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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

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WO 2002088112

http://www.google.co.in/patents/EP1389617A1?cl=en

The condensation of 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine

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with 2-(difluoromethyl)-1H-benzimidazole by means of K2CO3 in DMF gives

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2-chloro-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazine ,

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which is then condensed with morpholine by means of K2CO3 in DMF to afford the target trisubstituted triazine.

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^aReagents and conditions: (i) K₂CO₃, DMF, room temp; (ii) morpholine, DMF or THF, room temp; (iii) NaH or K₂CO₃, DMF or DMSO, 120 °C.

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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

http://pubs.acs.org/doi/abs/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, J_HF= 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

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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,J_HF= 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

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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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