Wednesday, 9 July 2014

HSD-621 is a potent and selective 11β-HSD1 inhibitor


Figure imgf000051_0001

(R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide
2-​Thiopheneacetamide, 5-​[[(2R)​-​4-​[4-​fluoro-​2-​(trifluoromethyl)​phenyl]​-​2-​methyl-​1-​piperazinyl]​sulfonyl]​-​α-​hydroxy-​α-​(trifluoromethyl)​-​, (αR)​-
1257229-37-0
C19 H18 F7 N3 O4 S2
.....................
The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. We developed a series of potent and selective 11-HSD1 inhibitors. These compounds showed excellent potency against both human and mouse 11-HSD1 enzymes and displayed good pharmacokinetics and ex vivo inhibition of the target in mice.Compounds HSD-016 and HSD-621 were ultimately selected as clinical development candidates. Both compounds have attractive overall pharmaceutical profiles and demonstrated good oral bioavailability in mouse, rat and dog. When orally dosed in C57/BL6 diet-induced-obesity (DIO) mice, HSD-016 and HSD621 were efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, both compoundswere well tolerated in drug safety assessment studies.

Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes 
(ACS Medicinal Chemistry Letters) Wednesday November 28th 2012
Author(s): Zhao-Kui WanEva ChenailHuan-Qiu LiManus IpekJason XiangVipin SuriSeung HahmJoel BardKristine SvensonXin XuXianbin TianMengmeng WangXiangping LiChristian E. JohnsonAriful QadriDarrell PanzaMylene PerreaultTarek S. MansourJames F. TobinEddine Saiah,
DOI:10.1021/ml300352x
GO TO: [Article]http://pubs.acs.org/doi/full/10.1021/ml300352xandhttp://pubs.acs.org/doi/suppl/10.1021/ml300352x/suppl_file/ml300352x_si_001.pdf  nmr data as 18b
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure–activity relationship of a series of piperazine sulfonamide-based 11β-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11β-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.
WO 2010141550
EXAMPLES The title compounds of Examples 1.1, 1.2, and 1.3 were prepared as shown in
Scheme 1 below. Detailed synthesis procedures are provided below.
Scheme 1

Figure imgf000049_0001
Example 1.1

Figure imgf000049_0002
3,3,3-trifluoro-2-r5-({(2R)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2-methylpiperazin- l-yl}sulfonyl)-2-thienyll-2-hvdroxypropanamide Step IA: A mixture of (R)-2-methyl-piperazine (25.0 g, 250 mmol), 2-bromo 5- fluoro benzotrifluoride (55.1 g, 227 mmol), tris(dibenzylidineacetone)dipalldium (0) (2.08g, 2.27 mmol), rac-2,2'-bis(diphenylphosphino)-l,r-binaphthyl (4.24 g, 6.81 mmol) and sodium tert-butoxide (27.3 g, 280 mmol) was mixed and purged with N2. Anhydrous toluene (500 mL) was added and purged with N2 again. The resulting mixture was heated in an oil bath at 105 0C under N2 for 3.5 hours. After cooling, the reaction mixture was concentrated and then filtered through a pad of Celite, washed with Et2O. The organic layer was concentrated, diluted with Et2O (500 mL), filtered through a pad of Celite again, and washed with IN aq. HCl (2 x 150 mL). The aqueous layer was basified with NaOH at 0 0C (pH = -10) and then was extracted with Et2O (3 x 200 mL). The combined organic layer was dried over MgSO4 and concentrated under vacuum to give (3i?)-l-[4- fluoro-2-(trifluoromethyl)phenyl]-3-methylpiperazine as a brown oil (58.5 g, 98%), which was used without further purification.
Step IB: To a solution of 5-bromothiophene-2-sulfonyl chloride (26.2 g, 100 mmol) and (3R)-l-(4-fluoro-2-(trifluoromethyl)phenyl)-3-methylpiperazine (27.6 g, lOOmmol) in DCM (200 ml) was added Et3N (41.8 ml, 300 mmol) at room temp. The reaction mixture was stirred at room temperature until completion of the reaction (about 6 hours) and then washed with aq. NaHCO3. The basic washes were back extracted with dichloromethane (DCM). The combined organic layers were washed with brine and dried over Na2SO4. The crude product was purified on a SiO2 column using hexanes/DCM as the eluent to give (R)-l-(5-bromothiophen-2-ylsulfonyl)-4-(4-fluoro-2- (trifluoromethyl)phenyl)-2-methylpiperazine as a white solid (38 g, 78 mmol, 78 % yield).
Step 1C: To a solution of (R)-l-(5-bromothiophen-2-ylsulfonyl)-4-(4-fluoro-2- (trifluoromethyl)phenyl)-2-methylpiperazine (28.1 g, 57.7 mmol) in anhydrous THF (200 ml) was added Butyllithium (28.8 ml, 57.7 mmol) at -780C. The reaction mixture was Stirred under N2 for 15 min. and then a solution of methyl 3,3,3-trifluoropyruvate (6.07 ml, 57.7 mmol) in THF (20 mL) was added via a cannula. The reaction mixture was stirred at -780C for 2 h. and then quenched with a 10 mL of 10% aq. HCl. The reaction mixture was dried over MgSO4 and CombiFlashed with DCM/hexane (15 - 100%) to provide methyl 3,3,3-trifluoro-2-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2- methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2-hydroxypropanoate as a sticky, light yellow solid (22 g, 39.0 mmol, 67.6 % yield).
Step ID, Method 1: To a solution of methyl 3,3,3-trifluoro-2-(5-((R)-4-(4-fiuoro- 2-(trifluoromethyl)phenyl)-2-methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2- hydroxypropanoate (21.5 g, 38.1 mmol) in MeOH (200 ml) was added aq. NH3 (-28-
30%, 50 mL). The reaction mixture was stirred at room temperature o/n and then diluted with ice water (700 mL). The resultant white ppt was collected by filtration, washed with water, and dried in an oven at 60 0C to give the desired product 3,3,3-trifluoro-2-(5-((R)- 4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2- hydroxypropanamide (15 g, 27.3 mmol, 71.7 % yield). The aqueous layer was extracted with DCM (4 x 100 mL), and the combined organic layers were concentrated. Purification of the concentrate by column chromatography with EA/DCM (0-40%) gave an additional 1.5 g of product.
Method 2: To a solution of methyl 3,3,3-trifluoro-2-(5-((R)-4-(4-fluoro-2-
(trifluoromethyl)phenyl)-2-methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2- hydroxypropanoate (200 mg) in MeOH (20 ml) at -780C was bubbled NH3 gas. The resultant mixture was stirred at room temperature overnight, concentrated, and dissolved in fresh DCM. The organic layer was washed with aq. NaHCO3 and dried to give 3,3,3- trifluoro-2-(5 -((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin- 1 - ylsulfonyl)thiophen-2-yl)-2-hydroxypropanamide as a white solid (150 mg). It was found that competing hydrolysis of the ester group to the corresponding acid occurred to a greater extent when using Method 1. Thus, in some instances, it may be preferable to use Method 2 when performing step D.
HRMS: calcd for Ci9Hi8F7N3O4S2 + H+, 550.06997; found (ESI-FTMS,
[M+H]1+), 550.07165. Example 1.2

Figure imgf000051_0001 desired
αR)-3,3,3-trifluoro-2-r5-ααR)-4-r4-fluoro-2-(trifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)thiophen-2-yll-2-hvdroxypropanamide
13.5 grams of 3,3,3-trifluoro-2-(5-((R)-4-(4-fiuoro-2-(trifluoromethyl)phenyl)-2- methylpiperazin-l-ylsulfonyl)thiophen-2-yl)-2-hydroxypropanamide (prepared according to a procedure similar to that described in Example 1.1) was separated was separated with a chiral column (Chiralpak ADH) in SFC Analytical Instrument; Mobile Phase was 90% CO2 /10%Methanol at flow rate 5mL/min. Early fraction (Retention 4.4min) was collected to give the title compound (5.7g); late fraction was collected to give the diastereomer described in Example 1.3 (6g, retention time 6. lmin).
HRMS: calcd for Ci9Hi8F7N3O4S2 + H+, 550.06997; found (ESI, [M+H]+), 550.0697. Example 1.3

Figure imgf000052_0001 undesired
αS)-3,3,3-trifluoro-2-r5-ααR)-4-r4-fluoro-2-qrifluoromethyl)phenyll-2- methylpiperazin-l-yl}sulfonyl)thiophen-2-yll-2-hvdroxypropanamide The title compound was obtained as the late fraction using the separation method described in Example 1.2.
HRMS: calcd for Ci9Hi8F7N3O4S2 + H+, 550.06997; found (ESI, [M+H]+), 550.0701.
US8524894Jun 4, 2010Sep 3, 2013Laboratorios Salvat, S.A.Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1
WO2005063247A1 *Dec 20, 2004Jul 14, 2005Amgen Sf LlcAryl sulfonamide compounds and uses related thereto
WO2007092435A2 *Feb 7, 2007Aug 16, 2007Wyeth Corp11-beta hsd1 inhibitors

1 comment:

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