CARIPRAZINE
CAS 839712-12-8 (free base)
CAS 1083076-69-0…HYDROCLORIDE SALT
trans-N-[4-[2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N’,N’-dimethylurea
Trans-1-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3- dimethyl-urea
trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexylamine
trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,
3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea
IN PHASE 3 FOR MAJOR DEPRESSION
see................http://newdrugapprovals.org/2015/01/07/cariprazine-for-major-depressive-disorder/
Journal of Medicinal Chemistry, 2013 , vol. 56, 22 pg. 9199 – 9221
Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist,tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate (4).
This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.
3-(trans-4-(2-(4-(2,3-Dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea (2).
(ref…………Ágai-Csongor, É.; Domány, G.; Nógrádi, K.; Galambos, J.; Vágó, I.; Keserű, G. M.; Greiner, I.; Laszlovszky, I.; Gere, A.; Schmidt, É.; Kiss, B.; Vastag, M.; Tihanyi, K.; Sághy,K.; Laszy, J.; Gyertyán, I.; Zájer-Balázs, M.; Gémesi, L.; Kapás, M.; Szombathelyi,Z.Discovery of cariprazine (RGH-188): A novel antipsychotic acting on dopamine D3/D2receptors Bioorg. Med. Chem. Lett. 2012, 22, 3437– 3440)
Using 50 (40 mg, 112 μmol) as the amine, following general procedure F the product was eluted (CHCl3/CH3OH, 20:1 to 10:1) to give the title compound as a white solid (27 mg, 56%).
mp: 208–209 °C.
1H NMR
δ 7.18–7.10 (m, 2H), 6.99–6.92 (m, 1H), 4.12 (d, J = 7.5 Hz, 1H), 3.64–3.49 (m, 1H), 3.07 (br s, 4H), 2.88 (s, 6H), 2.63 (br s, 4H), 2.50–2.39 (m, 2H), 2.07–1.94 (m, 2H), 1.82–1.72 (m, 2H), 1.52–1.37 (m, 2H), 1.31–1.18 (m, 1H), 1.18–0.99 (m, 4H).
13C NMR
δ 157.8 (C), 151.3 (C), 134.0 (C), 127.5 (C), 127.4 (CH), 124.5 (CH), 118.6 (CH), 56.7 (CH2), 53.4 (CH2), 51.3 (CH2), 49.8 (CH), 36.1 (CH3), 35.7 (CH), 34.0 (CH2), 33.9 (CH2), 32.1 (CH2).
HPLCtR = 8.60 min, >99% purity.
HRMS (m/z): [MH]+ calcd for C21H32Cl2N4O, 427.2026; found, 427.2022.
synthesis
see................http://newdrugapprovals.org/2015/01/07/cariprazine-for-major-depressive-disorder/
see................http://newdrugapprovals.org/2015/01/07/cariprazine-for-major-depressive-disorder/
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