Epelsiban

Epelsiban

557296
GSK-557296
GSK-557296-B

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione

see..............http://newdrugapprovals.org/2015/01/04/epelsiban-being-developed-by-glaxosmithkline-for-the-treatment-of-premature-ejaculation-in-men/

see..............http://newdrugapprovals.org/2015/01/04/epelsiban-being-developed-by-glaxosmithkline-for-the-treatment-of-premature-ejaculation-in-men/

PAPER

J. Med. Chem., 2012, 55 (2), pp 783–796

DOI: 10.1021/jm201287w

http://pubs.acs.org/doi/abs/10.1021/jm201287w

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione (69 EPELSIBAN)

A ………………………. gave colorless needles (75%)

mp 140 °C.

1H NMR (CDCl3) δ 7.49 (d, J =7.8 Hz, 1H, pyridyl-4H),

7.26–7.15 (m, 4H, indanyl-arylH),

7.10 (d, J =8.1 Hz, 1H, pyridyl-5H),

6.68 (s, 1H, NCHpyridyl),

6.49 (d, J = 2.8 Hz, 1H, lactam-NH),

4.10 (dd, J = 10.1 Hz, 4.0 Hz, 1H, NCHindanyl),

4.01 (d, J = 4.5 Hz, NCHsec-butyl),

3.75–2.71 (m, 13H, 8× morpholinyl-H, indanyl-3H, -1H, -2H),

2.62 and 2.58 (2s, 6H, pyridyl-2Me,-6Me),

1.64–1.52 (m, 1H, CHHMe),

0.98–0.79 (m, 2H, CHHMe, CHMeCH2),

0.70 (t, J = 7.1 Hz, 3H, CH2Me),

0.45 (d, J = 6.8 Hz, 3H, CHMe).

LCMS m/z 519 (MH+) single component, gradient 2 (tR 2.70 min).

HRMS calcd for C30H38N4O4(MH+) 519.29658, found 519.29667.

HPLC: 100% (tR 10.388 min).

benzenesulfonic acid;(3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione,CAS 1159097-48-9

UNII-H629P9T4UN, GSK557296B, Epelsiban besylate (USAN), Epelsiban besylate [USAN], 1159097-48-9, H629P9T4UN

EPELSIBAN BESYLATE SALT

To a ……………………………….give the besylate (3.214 g, 92.6%) as white crystals of 69B

mp 179–183 °C.

1H NMR (CD3OD) δ 8.30 (d, 1H, J = 8.1 Hz, pyridyl-4H),

7.84–7.80 (m, 2H, PhSO3– 2× ortho-H),

7.78 (d, J = 8.3 Hz, 1H, pyridyl-5H),

7.45–7.38 (m, 3H, PhSO3– 2×meta-H, para-H),

7.23–7.09 (m, 4H, indanyl-arylH),

6.08 (broad s, 1H, NCHpyridyl),

4.00 (d, J =4.6 Hz, 1H, NCHsec-butyl),

3.92 (d, J = 9.9 Hz, 1H, NCHindanyl),

3.78–3.39 and 3.14–2.80 (m, 13H, 8× morpholinyl-H, indanyl-3H, -1H, -2H)),

2.79 and 2.78 (2s, 6H, pyridyl-2Me, -6Me),

1.85–1.74 (m, 1H, CHHMe),

1.59–1.48 (m, 1H, CHHMe),

1.15–1.01 (m, 1H, CHMeCH2),

0.92 (d, J =6.3 Hz, 3H, CHMe),

0.85 (t, J = 7.3 Hz, 3H, CH2Me).

LCMS m/z 519 MH+ single components, tR2.72 min;

circular dichroism (CH3CN) λmax 225.4 nm, dE −15.70, E15086; λmax 276 nm, dE 3.82, E5172.

HRMS calcd for C30H38N4O4 (MH+) 519.2971, found 519.2972.

Anal. (C30H38N4O4·C6H6O3S·3.0H2O) C, H, N, S.

see..............http://newdrugapprovals.org/2015/01/04/epelsiban-being-developed-by-glaxosmithkline-for-the-treatment-of-premature-ejaculation-in-men/

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CARIPRAZINE

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

http://pubs.acs.org/doi/abs/10.1021/jm401318w

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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ISOEUGENOL

ISOEUGENOL


(E)-2-Methoxy-4-(prop-1-enyl) phenol (isoeugenol 6): To 8.0 g of ethyleneglicol placed in a three-neck round-bottom flask of 100 mL are added 7.90 g of KOH (134 mmol), and submerged in a sand bath. To the mixture eugenol 5.0 g (30.5 mmol) is added and the system is refluxed at 160 °C for about approximately 5 hours; at this time the reaction is stopped. The excess of KOH is neutralized with 25 mL of a 6 mol L^-1 hydrochloric acid solution, the mixture is extracted with CHCl₃ (2 × 50 mL) and the organic phase is dried with anhydrous Na₂SO₄and the solvent evaporated under vacuum. After chromatographic column purification, 4.25 g of a brown oil was obtained (85%).


 IR (film) n_max/cm^-1: 3503 (O-H), 3057 (C=CH-Ar), 3014 (CH=CH), 2936, 2930, 2843, 1603, 1506, 1367, 1030, 963. 

¹H NMR (400.1 MHz, CDCl₃): d 1.86 (3H, dd, J 1.5 and 6.6 Hz, CH₃); 3.90 (3H, s, OCH₃); 5.55 (1H, s, OH); 6.08 (1H, dq, J 6.6 and 15.7 Hz, H2'); 6.32 (1H, dd, J 1.5 and 15.7 Hz, H1'); 6.85 (3H, m, H3, H5 and H6). 


¹³C NMR (100.6 MHz, CDCl₃): d 18.3 (CH₃); 55.8 (OCH₃); 107.8 (C5); 114.3 (C6); 119.3 (C3); 123.4 (C4); 130.6 (C2); 130.7 (C1); 144.7 (C2'); 146.5 (C1').

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532008000300024

Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053

J. Braz. Chem. Soc. vol.19 no.3 São Paulo  2008

http://dx.doi.org/10.1590/S0103-50532008000300024 

CHILE

















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Production of 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid ethylester

EXAMPLE 7
Production of 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid ethylester

Preparation:
4.98 g (30 mmole) p-hydroxybenzoic acid ethylester
3.06 g (30 mmole) phenylacetylene
31.26 g (120 mmole) tin tetrachloride
22.24 g (120 mmole) tributylamine
150 ml 1,2-dichlorethane
Method:
Under an argon atmosphere, a solution of 4.98 g (30 mmole) phydroxy-benzoic acid ethylester, 3.06 g (30 mmole) phenylacetylene, 31.26 g (120 mmole) tin tetrachloride and 22.24 (120 mmole) tributylamine in 150 ml 1,2-dichlorethane are heated for 1 h with recycling. Then 60 ml 4 M KOH and 30 ml ethanol are added to the reaction mixture and heated for 1 h with recycling. Following cooling, the solution is acidified with 4 M HCl and extracted twice with 150 ml diethylether each time. The purified organic phases are dried through MgSO₄ and the solvent is removed on the rotary evaporator. The remaining residue undergoes absorptive filtering (silica gel, MTBE) and the raw product obtained in this way is cleaned by column chromatography (silica gel, toluene/MTBE=8/1 (v/v)). 2.63 g (9.8 mmole, 33%) 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid-ethylester are obtained.
Yield: 2.63 g (9.8 mmole, 33%) 4-hydroxy-3-(1-phenyl-vinyl)-benzoic acid-ethylester.  

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.36 (t, ³J=7.1 Hz, 3H, CH₃), 4.33 (q, ³J=7.1 Hz, 2H, OCH₂), 5.44 (d, ²J=0.9 Hz, 1H, ═CH₂), 5.91 (d, ²J=0.9 Hz, 1H, ═CH₂), 6.97 (d, ³J=8.5 Hz, 1H, PhH), 7.34 (m, 5H, PhH), 7.89 (d, ⁴J=2.1 Hz, 1H, PhH), 7.96 (dd, ³J=8.5 Hz, ⁴J=2.1 Hz, 1H, PhH).  

¹³C-NMR (100 MHz, CDCl₃): δ [ppm]=14.3 (CH₃), 60.8 (OCH₂), 115.8 (CH_arom), 117.5 (═CH₂), 122.9 (Cq_arom), 126.9 (2×CH_arom) 127.5 (Cq_arom), 128.8 (3×CH_arom), 131.3 (CH_arom), 132.3 (CH_arom), 138.7 (Cq_arom), 144.3 (Cq_olefin), 157.1 (Cq_arom), 166.3 (COOEt).

MS (EI, 70EV): m/z [%]=268 (M⁺, 98), 267 (100), 253 (35) 239 (32), 225 (13), 223 (24), 194 (6), 165 (20), 152 (12), 115 (5), 111 (6), 104 (7).


 http://www.google.com/patents/US6809225


 




 






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