Picture credit....Bethany Halford
Originator Bristol-Myers Squibb
Bristol-Myers Squibb Company, Université de Montréal
|Molecular Weight:||513.58922 g/mol|
Imidazo[2,1-b] -1,3,4-thiadiazole, 2-methoxy-6-[6-methoxy-4-[[5-methyl-2-(4-morpholinyl)-4- thiazolyl]methoxy]-2-benzofuranyl]-
Phase I Thrombosis
- 02 Apr 2015 Bristol-Myers Squibb plans a phase I trial in Thrombosis (In volunteers) in United Kingdom (NCT02439190)
- 01 Aug 2014 Preclinical trials in Thrombosis in USA (PO)
Class Imidazoles; Small molecules; Thiadiazoles
Thromboembolic diseases remain the leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), synthetic pentasaccharides, and antiplatelet agents such as aspirin and clopidogrel (PLAVIX®).
Current anti-platelet therapies have limitations including increased risk of bleeding as well as partial efficacy (relative cardiovascular risk reduction in the 20 to
30% range). Thus, discovering and developing safe and efficacious oral or parenteral antithrombotics for the prevention and treatment of a wide range of thromboembolic disorders remains an important goal.
Alpha-thrombin is the most potent known activator of platelet aggregation and degranulation. Activation of platelets is causally involved in atherothrombotic vascular occlusions. Thrombin activates platelets by cleaving G-protein coupled receptors termed protease activated receptors (PARs). PARs provide their own cryptic ligand present in the N-terminal extracellular domain that is unmasked by proteolytic cleavage, with subsequent intramolecular binding to the receptor to induce signaling (tethered ligand mechanism; Coughlin, S.R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic the sequence of the newly formed N-terminus upon proteolytic activation can induce signaling independent of receptor cleavage. Platelets are a key player in atherothrombotic events. Human platelets express at least two thrombin receptors, commonly referred to as PARI and PAR4. Inhibitors of PARI have been investigated extensively, and several compounds, including vorapaxar and atopaxar have advanced into late stage clinical trials. Recently, in the TRACER phase III trial in ACS patients, vorapaxar did not significantly reduce cardiovascular events, but significantly increased the risk of major bleeding (Tricoci, P. et al, N. Eng. J. Med., 366(l):20-33 (2012). Thus, there remains a need to discover new antiplatelet agents with increased efficacy and reduced bleeding side effects.
There are several early reports of preclinical studies of PAR4 inhibitors. Lee, F-Y. et al., "Synthesis of l-Benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole Analogues as Novel Antiplatelet Agents", J. Med. Chem., 44(22):3746-3749 (2001) discloses in the abstract that the compound
"was found to be a selective and potent inhibitor or protease-activated receptor type 4 (PAR4)-dependent platelet activation. "
Compound 58 is also referred to as YD-3 in Wu, C-C. et al, "Selective Inhibition of Protease-activated Receptor 4-dependent Platelet Activation by YD-3", Thromb. Haemost., 87: 1026-1033 (2002). Also, see Chen, H.S. et al, "Synthesis and platelet activity", J. Bioorg. Med. Chem., 16: 1262-1278 (2008).
EP1166785 Al and EP0667345 disclose various pyrazole derivatives which are useful as inhibitors of platelet aggregation.\
Ci8Hi905 [M+H]+ m/z 315.1227, found 315.1386. 1H NMR (CDC13, 600 MHz) δ 1.68 (s, 6H), 3.77 (s, 3H), 5.19 (s, 2H), 5.19 (s, 2H), 6.04 (d, J = 2.03 Hz, 1H), 6.15 (d, J = 2.03 Hz, 1H), 7.27 (broad t, 1H), 7.36 (broad t, 2H), 7.52 (broad d, 2H).
1 C. 2-(Benzyloxy)-6-hydroxy-4-methoxybenzaldehyde
ID. 1 -(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)ethanone
Alternatively, Example IF, 6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2- bromoimidazo[2,l-b][l,3,4]thiadiazole, was prepared as follows:
A 1000-mL, three-necked flask equipped with a magnetic stirring bar and purged with a nitrogen atmosphere was charged with dry NMP (200 mL) followed by 1- (4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-chloroethanone (Example 1EE, 50 g, 150 mmol) and 5-bromo-l,3,4-thiadiazol-2-amine (27.2 g, 151 mmol). The resulting mixture was stirred at 80 °C for 8h. TLC (8:2 dichloromethane/pet. ether) and LC/MS showed intermediate uncyclized material (m/z 476) and the reaction mixture was stirred at 120 °C for 3h. The reaction mixture was cooled to RT, quenched with water and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. The thick brown residue was purified by silica gel chromatography (0 to 100% dichloromethane in pet. ether) to give a brown solid. This material was triturated with EtOAc and dried to obtain the title imidazothiadiazole (24 g, 50 mmol, 33%>) as a light brown solid. (See the procedure set forth above for analytical data).
1 G. 6-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2, 1 - b][l,3,4]thiadiazole
D): 2.293 min. HRMS(ESI) calcd for C21H18N3O4S [M+H]+ m/z 408.1013, found 408.1024. 1H NMR (CDC13, 600 MHz) δ 3.81 (s, 3H), 4.18 (s, 3H), 5.16 (s, 2H), 6.37 (d, J = 1.75 Hz, 1H), 6.67 (broad s, 1H), 7.07 (s, 1H), 7.31 (broad t, 1H), 7.37 (broad t, 2H), 7.45 (broad d, 2H), 7.81 (s, 1H).
94AA. Methyl 3-bromo-2-oxobutanoate
94 A. Methyl 5-methyl-2-morpholinothiazole-4-carboxylate
Example 94. 4-(4-(((6-Methoxy-2-(2-methoxyimidazo[2, 1 -b] [ 1 ,3,4]thiadiazol-6-yl) benzofuran-4-yl)oxy)methyl)-5 -methylthiazol-2-yl)morpholine
251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 263
|Patent ID||Date||Patent Title|
|US2015094297||2015-04-02||IMIDAZOTHIADIAZOLE AND IMIDAZOPYRAZINE DERIVATIVES AS PROTEASE ACTIVATED RECEPTOR 4 (PAR4) INHIBITORS FOR TREATING PLATELET AGGREGATION|
////////BMS 986120, phase 1, Bristol-Myers Squibb , Imidazoles, Small molecules, Thiadiazoles, 1478712-37-6