GSK 923295, a CENP-E Inhibitor

GSK-923295A

1088965-37-0

Synonym: GSK-923295; GSK 923295; GSK923295.

CENP-E Inhibitor

IUPAC/Chemical name: 

3-Chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide

3-​chloro-​N-​[(1S)​-​2-​[[2-​(dimethylamino)​acetyl]​amino]​-​1-​[[4-​[8-​[(1S)​-​1-​hydroxyethyl]​imidazo[1,​2-​a]​pyridin-​2-​yl]​phenyl]​methyl]​ethyl]​-​4-​(1-​methylethoxy)​- Benzamide,

3-Chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

3-Chloro-N-[1-(N,N-dimethylglycinamido)-3-[4-[8-[1(S)-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl]phenyl]propan-2(S)-yl]-4-isopropoxybenzamide

C32H38ClN5O4
Exact Mass: 591.26123
Molecular Weight: 592.12822
Elemental Analysis: C, 64.91; H, 6.47; Cl, 5.99; N, 11.83; O, 10.81

Kinesin-like protein KIF11 inhibitor; Centromere protein E inhibitor
GSK-923295 is a novel antimitotic inhibitor of centromere-associated protein E (CENP-E) with potential anticancer activity. GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts.
GSK-923295, a small-molecule inhibitor of centromere associated protein (CENP), is in early clinical development at Cytokinetics for the treatment of refractory cancer. No recent development has been reported for early clinical research which had been ongoing at GlaxoSmithKline.
Clinical study showed that GSK923295  had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.
GSK923295 is a first-in-class, specific allosteric inhibitor of CENP-E kinesin motor ATPase with K_i of 3.2 nM, and less potent to mutant I182 and T183. Phase 1.
The compound potently inhibits CENP-E ATPase activity and exerts broad-spectrum antiproliferative activity against cancer cells and xenografts. GSK-923295 has demonstrated a broad spectrum of activity against a range of human tumor xenografts grown in nude mice, including models of colon, breast, ovarian, lung and other tumors.
Cytokinetics was developing GSK-923295, the lead from a series of small-molecule mitotic kinesin spindle protein inhibitors, for treating cancer including advanced solid tumors. However, since October 2014, the program was no longer listed on the Cytokinetics' website
In 2001, a strategic alliance was established between Cytokinetics and GlaxoSmithKline to discover, develop and commercialize novel small-molecule therapeutics targeting mitotic kinesins for applications in the treatment of cancer and other diseases.
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PATENT
US8772507
http://www.google.com/patents/US8772507

1,1-Dimethylethyl [(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate

To a solution of 4-bromo-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0° C. was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stirred for an additional 2 h at 0° C. The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stirred at RT for half an hour. Lithium aluminium salts crashed out of solution and were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%). ESMS [M+H]⁺: 331.2.
1,1-Dimethylethyl {(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate

To a solution of 1,1-dimethylethyl [(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0° C. was added dropwise diisopropyl azodicarboxylate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to warm to RT over 5 h. The reaction was then concentrated in vacuo and product was triturated out of solution using ethyl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3×100 mL), and dried to afford the title product as a white solid (57%). ESMS [M+H]⁺: 460.4.
1,1-Dimethylethyl {(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-d oxo-1,3-dihydro-21′-isoindol-2-yl)methyl]ethyl}carbamate

A solution of 1,1-dimethylethyl {(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (21.7 mmol), 1-ethoxyvinyltri-n-butylin (43.5 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (5 mol %) were stirred in anhydrous dioxane (300 mL) at 100° C. for 3 h. The reaction was then concentrated in vacuo and redissolved in a solution of tetrahydrofuran and water (3:1, 400 mL). The mixture was treated with N-bromosuccinimide (108.8 mmol) and stirred at RT for half an hour. The reaction solution was then concentrated to dryness and redissolved in ethyl acetate (150 mL). Precipate formed upon addition of hexanes (350 mL) and was filtered and dried to afford the title product as yellow solid (71%). ESMS [M+H]⁺: 502.4.
1,1-Dimethylethyl [(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate

A mixture of 1,1-dimethylethyl{(1S)-2-{4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na₂SO₄), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid. MS (ES+) m/e 541 [M+H]⁺.
3-Chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

A mixture of 1,1-dimethylethyl [(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4 M HCl in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness and redissolved in DMF (30 mL). To this solution was added N,N-diisopropylethylamine (2.14 g, 16.55 mmol) and pentafluorophenyl 3-chloro-4 [(1-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na₂SO₄), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS (ES+) m/e 637 [M+H]⁺.
N-[(1S)-2-Amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide

A mixture of 3-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57° C. overnight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound (1.67 g, 100%) as a pale yellow powder. MS (ES+) m/e 507 [M+H]⁺.
3-Chloro-N-[(1S)-2-[(N,N-dimethylglycyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide

A mixture of N-[(1S)-2-amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.912 g, 1.80 mmol), EDCI (0.69 g, 3.6 mmol), N,N-diisopropylethylamine (0.466 g, 3.6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Na₂SO₄), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH₂Cl₂) to give the title compound (0.515 g, 48%) as a pale yellow solid. MS (ES+) ink 592 [M+H]⁺.
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WO2005107762
https://www.google.im/patents/WO2005107762A2
Example 1

cheme E:
ide

NaHCO_j, IPA 100 'C

1 , 1 -Dimethylethyl [( 1 S)-2-(4-bromophenyl)- 1 -(hydroxymethyl)ethyl]carbamate:

To a solution of 4-bromo-N-{[(l ,1 -dimethylethyl)oxy] carbonyl }-L- phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0 °C was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stiπed for an additional 2 h at 0 °C, The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stiπed at RT for half an hour. Lithium aluminium salts crashed out of solution which were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%).
ESMS [M+H]⁺: 331.2.
1,1 -Dimethylethyl {(lS)-2-(4-bromophenyl)-l-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]ethyl}carbamate:

To a solution of 1 ,1 -dimethylethyl [(lS)-2-(4-bromophenyl)-l -
(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0 °C was added dropwise diisopropyl azodi carboxyl ate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to wai to RT over 5h, The reaction was then concentrated in vacuo and product was tritarated out of solution usingl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3 x 100 mL), and dried to afford the title product as a white solid (57%).
ESMS [M+H]⁺: 460.4.
1 ,1 -Dimethylethyl {(15)-2-[4-(bromoacetyl)phenyl]-l -[(l,3-dioxo-l ,3-dihydro-2H-isoindol- 2-yl)methyl]ethyl}carbamate:

A solution of 1,1 -dimethyl ethyl {(lS)-2-(4-bromophenyl)-l-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (21.7 mmol), 1-ethoxyvinyltri-n-butylin (43.5 mmol), and /ra/?s--dichlorobis(triphenylphospine)palladιum(II) (5 mol%) were stiπed in anhydrous dioxane (300 mL) at 100 °C for 3h. The reaction was then concentrated in vacuo and redissolved in a solution of tetrahydrofuran and water (3:1, 400mL) and treated with N- bromosuccinimide (108.8 mmol) and stined at RT for half an hour. The reaction solution was then concentrated to dryness and redissolved in ethyl acetate (150 mL) and precipate formed upon addition of hexanes (350 mL). The precipitate was filtered and dried to afford the title product as yellow solid (71%). ESMS [M+Η]+: 502.4. l,l-Dimethylethyl [(lS)-2-(l ,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-l-({4-[8-(l- hydroxyethyl)imidazo[l,2-β]pyridin-2-yl]phenyl}methyl)ethyl]carbamate:

A mixture of l_!l-dimethylethyl{(lS)-2-{4-(biOinoacetyl)phenyl]-l-[(l,3- dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), l-(2- amino-3-pyτidinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4,72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na₂S0₄), and concentrated to give the title compound (1.79 g, S7%) as a light pink solid. MS(ES+) m/e 541 [M+Η]⁺.
3-Chloro-N-[(lS)-2-(l,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)-l-({4-[8-(l- hydroxyethyl)imidazo[l,2-Λ]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l - methylethyl)oxy]benzamide:

A mixture of 1,1 -dimethylethyl [(15)-2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-fl]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4M ΗC1 in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness ,redissolved in DMF (30 mL), and to this solution was added N,N-diisopropylethylamine (2.14 g, 16,55 mmol) and pentafluorophenyl 3-chloro-4 [(l-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na SO ), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS(ES+) m/e 637 [M+H]⁺.
N-[(lS)-2-Amino-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-α]p>tidin-2- yl]phenyl}methyl)eth)'l]-3-chloro-4-[(l-methylethyl)oxy]benzamide:

A mixture of 3-chloro-N-[(lS)-2-(l,3-dioxo-l ,3-dihydro-2N-isoindol-2-yl)-l-
({4-[8-(l -hydiOxyethyl)imidazo[l,2-β]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l- methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57°C ovemight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound(1.67 g, 100%) as a pale yellow powder. MS(ES+) m/e 507 [M+H]⁺.
3-Chloro-N-[(15)-2-[(7VN-dimethylglycyl)amino]-l-({4-[8-(l-hydroxyethyl)imidazo[l ,2- «]pyitdin-2-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide:

A mixture ofN-[(lS)-2-amino-l-({4-[S-(l-hydroxyethyl)imidazo[l,2- α]pyridin-2-yl]phenyl)methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide (0.912 g, 1 ,80 mmol), EDCI (0.69 g, 3,6 mmol), NN-diisopropylethylamine (0.466 g, 3,6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Νa₂S0 ), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH₂Cl₂) to give the title compound ( 0.515 g, 48%) as a pale yellow solid. MS(ES+) m/e 592 [M+H]⁺.

SEE
WO2008 / 138561
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Organic Process Research & Development (2010), 14(5), 1254-1263

Org. Process Res. Dev., 2010, 14 (5), pp 1254–1263

DOI: 10.1021/op100186c

http://pubs.acs.org/doi/abs/10.1021/op100186c

The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}−4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The new synthesis commences from the readily available l-phenylalaninol, which is smoothly converted through to GSK923295A using key Friedel−Crafts acylation as well as selective acylation chemistries. Downstream chemistry to GSK923295A is both high yielding and robust, and the resulting process has been demonstrated first on the kilo scale and subsequently in the pilot plant where 55 kg was successfully prepared. The resulting process is simple, uses cheaper raw materials, is greener in that it avoids using aluminum, tin, and bromination chemistries, and obviates the need for chromatographic purification. Also discussed are the route derived impurities, how they were unambiguously prepared to confirm structure and processing amendments to control their formation, and enhancements to the new process to facilitate future processing.

¹H NMR (400 MHz, CD₃OD) δ_H 1.34 (6H, d, J = 6.0, (CH₃)₂), 1.59 (3H, d, J = 7.0, CH₃CH), 2.21 (6H, s, N(CH₃)₂), 2.87−3.01 (4H, m, CH₂Ph and CH₂N(CH₃)₂), 3.49 (2H, m, CH₂NPhthal), 4.50 (1H, m, CHNH), 4.70 (1H, m, (CH₃)₂CHO)), 5.49 (1H, q, J = 7.0, CHOH), 6.88 (1H, t, J = 7.0, H-j), 7.08 (1H, d, J = 7.5, H-b), 7.33−7.37 (3H, m, H-k and H-d), 7.63 (1H, dd, J = 7.5 and 2.0, H-c), 7.78 (1H, s, H-a), 7.83 (2H, d, J = 7.0, H-e), 8.09 (1H, m, H-h), 8.27 (1H, d, J = 8.0, H-i);

¹³C NMR (100 MHz, CD₃OD) δ_C 22.2, 24.1, 39.3, 43.8, 46.1, 53.0, 63.7, 66.2, 73.0, 110.4, 113.8, 115.3, 121.2, 124.5, 126.1, 127.5, 128.4, 128.5, 130.6, 130.7, 133.3, 136.0, 139.4, 145.1, 146.1, 157.6, 168.5 and 173.6;

HRMS (ESI⁺) m/z calculated for [M+H]⁺ C₃₂H₃₉N₅O₄Cl 592.2691, found 592.2684.

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ACS Medicinal Chemistry Letters (2010), 1(1), 30-34
http://pubs.acs.org/doi/abs/10.1021/ml900018m

Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.

SEE
WO-2015037460
https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=F8D2DAAA427F9EBAB6B7CE67A7EE0772.wapp1nC?docId=WO2015037460&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText
Method for producing optically active 3-(biphenyl-4-yl)-2-[(t-butoxycarbonyl)amino]propan-1-ol
Process for preparing optically active 3-(biphenyl-4-yl)-2-[(t-butoxycarbonyl)amino]propan-1-ol, useful as an intermediate in the synthesis of pharmaceuticals described in WO2005107762 and WO2008138561 (such as GSK-923295 and tubulysin derivatives respectively). Appears to be a new area of interest to the assignee.
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WO2010118207
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010118207&recNum=278&docAn=US2010030350&queryString=%28SYK%29%2520&maxRec=1655

References

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2: Chung V, Heath EI, Schelman WR, Johnson BM, Kirby LC, Lynch KM, Botbyl JD, Lampkin TA, Holen KD. First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer. Cancer Chemother Pharmacol. 2012 Mar;69(3):733-41. doi: 10.1007/s00280-011-1756-z. Epub 2011 Oct 22. PubMed PMID: 22020315.
3: Lock RB, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, Maris JM, Wozniak AW, Gorlick R, Kolb EA, Houghton PJ, Smith MA. Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Jun;58(6):916-23. doi: 10.1002/pbc.23176. Epub 2011 May 16. PubMed PMID: 21584937; PubMed Central PMCID: PMC3163687.
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5: Wood KW, Lad L, Luo L, Qian X, Knight SD, Nevins N, Brejc K, Sutton D, Gilmartin AG, Chua PR, Desai R, Schauer SP, McNulty DE, Annan RS, Belmont LD, Garcia C, Lee Y, Diamond MA, Faucette LF, Giardiniere M, Zhang S, Sun CM, Vidal JD, Lichtsteiner S, Cornwell WD, Greshock JD, Wooster RF, Finer JT, Copeland RA, Huang PS, Morgans DJ Jr, Dhanak D, Bergnes G, Sakowicz R, Jackson JR. Antitumor activity of an allosteric inhibitor of centromere-associated protein-E. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5839-44. doi: 10.1073/pnas.0915068107. Epub 2010 Feb 18. PubMed PMID: 20167803; PubMed Central PMCID: PMC2851928.