Taranabant ( MK-0364)
701977-09-5
N-[3-(4-Chlorophenyl)-2(S)-(3-cyanophenyl)-1(S)-methylpropyl]-2-methyl-2-[5-(trifluoromethyl)pyridin-2-yloxy]propionamide
N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)butan-2-yl]-2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]oxypropanamide
Taranabant (codenamed MK-0364) is a cannabinoid receptor type 1 inverse agonist being investigated as a potential treatment forobesity due to its anorectic effects.[1][2] It was discovered by Merck & Co.
In October 2008, Merck has stopped its phase III clinical trials with the drugs due to high level of central side effects, mainlydepression and anxiety.[3][4][5][6]
The compound had also been in clinical evaluation in chronic cigarette smokers as an aid for smoking cessation.
Paper
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http://pubs.rsc.org/en/content/articlelanding/2013/cs/c2cs35410a#!divAbstract
PATENT![Taranabant.png]()
WO 2003077847
http://www.google.co.in/patents/WO2003077847A2?cl=en
PAPERS
Convenient total synthesis of taranabant (MK-0364), a novel cannabinoid-1 receptor inverse agonist as an anti-obesity agent
Tetrahedron 2007, 63(52): 12845
Wallace, D.J.; Campos, K.R.; Shultz, S.; Klapars, A.; et al.
New efficient asymmetric synthesis of taranabant, a CB1R inverse agonist for the treatment of obesity
Org Process Res Dev 2009, 13(1): 84
Lin, L.S.; Lanza, T.J. Jr.; Jewell, J.P.; Liu, P.; Shah, S.K.; Qi, H.; Tong, X.; Wang, J.; Xu, S.S.; Fong, T.M.; Shen, C.P.; Lao, J.; Xiao, J.C.; Shearman, L.P.; Stribling, D.S.; Rosko, K.; Strack, A.; Marsh, D.J.; Feng, Y.; Kumar, S.; Samuel, K.; Yin, W.; Ploeg, L.H.; Goulet, M.T.; Hagmann, W.K.
Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- [[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity
J Med Chem 2006, 49(26): 7584
Cole, P.; Serradell, N.; Rosa, E.; Bolos, J. Taranabant Drugs Fut 2008, 33(3): 206
PAPER
Chen, C.-Y.; Frey, L.F.; Shultz, S.; et al. Catalytic, enantioselective synthesis of taranabant, a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity
Org Process Res Dev 2007, 11(3): 616
http://pubs.acs.org/doi/abs/10.1021/op700026n
Chiral amide 1 (MK-0364, taranabant) is a potent, selective, and orally bioavailable cannabinoid-1 receptor (CB-1R) inverse agonist indicated for the treatment of obesity. An asymmetric synthesis featuring a dynamic kinetic resolution via hydrogenation for the preparation of the bromo alcohol 5 is disclosed. Conversion of the alcohol intermediate to the chiral amide 1 is accomplished in good overall yield.
N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (1, MK-0364). hemisolvate (approximately 94 wt %, 94% isolated yield from amine salt).
1H NMR (CDCl3): δ 8.35 (s, 1H), 7.83 (dd, J = 2.38, 8.70 Hz, 1H), 7.45 (d, J = 7.57 Hz, 1H), 7.31 (t, J = 7.99 Hz, 1H), 7.24 (m, 2H), 7.07 (d, J = 8.34 Hz, 2H), 6.88 (d, J = 8.63 Hz, 1H), 6.72 (d, J = 8.33 Hz, 2H), 5.88 (d, J = 8.95 Hz, 1H), 4.34 (m, 1H), 3.13 (dd, J = 3.04, 12.72 Hz, 1H), 2.82 (m, 2H), 1.76 (s, 3H), 1.72 (s, 3H), 0.87 (d, J = 6.72 Hz, 3H).
13C NMR (CDCl3): δ 173.4, 163.9, 144.5 (q, J = 4.30 Hz), 142.4, 137.5, 136.3 (q, J = 3.02 Hz), 133.0, 132.2, 132.0, 130.7, 130.0, 129.3, 128.5, 123.7 (q, J = 271.45 Hz), 121.1 (q, J = 33.32 Hz), 118.6, 112.7, 112.6, 82.1, 53.6, 48.6, 38.2, 25.4, 25.1, 18.4.
Anal. Calcd for C27H25ClF3N3O2: C 62.85; H 4.88; N 8.14. Found: C 62.95; H 4.74; N 8.00.
References
- Armstrong HE, Galka A, Lin LS, Lanza TJ Jr, Jewell JP, Shah SK, et al. “Substituted acyclic sulfonamides as human cannabinoid-1 receptor inverse agonists.” Bioorganic & Medicinal Chemistry Letters. 2007 Apr 15;17(8):2184-7. PMID 17293109. doi:10.1016/j.bmcl.2007.01.087
- Fong TM, Guan XM, Marsh DJ, Shen CP, Stribling DS, Rosko KM, et al. “Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), in rodents.” Journal of Pharmacology and Experimental Therapeutics. 2007 Jun;321(3):1013-22. PMID 17327489.doi:10.1124/jpet.106.118737
- “Press release by Merck”. Retrieved October 2008.
- Aronne LJ, Tonstad S, Moreno M, Gantz I, Erondu N, Suryawanshi S, Molony C, Sieberts S, Nayee J, Meehan AG, Shapiro D, Heymsfield SB, Kaufman KD, Amatruda JM (May 2010). “A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study”. International Journal of Obesity (2005) 34 (5): 919–35. doi:10.1038/ijo.2010.21.PMID 20157323.
- Kipnes MS, Hollander P, Fujioka K, Gantz I, Seck T, Erondu N, Shentu Y, Lu K, Suryawanshi S, Chou M, Johnson-Levonas AO, Heymsfield SB, Shapiro D, Kaufman KD, Amatruda JM (June 2010). “A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes”. Diabetes, Obesity & Metabolism 12 (6): 517–31. doi:10.1111/j.1463-1326.2009.01188.x. PMID 20518807.
- Proietto J, Rissanen A, Harp JB, Erondu N, Yu Q, Suryawanshi S, Jones ME, Johnson-Levonas AO, Heymsfield SB, Kaufman KD, Amatruda JM (August 2010). “A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study”. International Journal of Obesity (2005) 34 (8): 1243–54. doi:10.1038/ijo.2010.38. PMID 20212496.
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| Systematic (IUPAC) name | |
|---|---|
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N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-butanyl]-2-methyl-2-{[5-(trifluoromethyl)-2-pyridinyl]oxy}propanamide
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| Clinical data | |
| Routes of administration |
Oral |
| Identifiers | |
| CAS Number | 701977-09-5  |
| ATC code | A08AX |
| PubChem | CID: 11226090 |
| UNII | X9U622S114 |
| Chemical data | |
| Formula | C27H25ClF3N3O2 |
| Molecular mass | 515.95 g/mol |
///////////CC(C(CC1=CC=C(C=C1)Cl)C2=CC=CC(=C2)C#N)NC(=O)C(C)(C)OC3=NC=C(C=C3)C(F)(F)F
C[C@@H]([C@@H](CC1=CC=C(C=C1)Cl)C2=CC=CC(=C2)C#N)NC(=O)C(C)(C)OC3=NC=C(C=C3)C(F)(F)F
Filed under: Uncategorized Tagged: TARANABANT
