N’-(5,6,7,8-Tetrahydroquinolin-8-ylidene)-4-(2-pyridyl)piperazine-1-carbothiohydrazide

http://criticaloutcome.com/110819_COTI-2%20Fact%20Sheet.pdf

http://www.slideshare.net/trevorheisler/about-coti2

MW 366.483, C19 H22 N6 S

Caspase 9 Activators
PKB beta/Akt2 Inhibitors

Critical Outcome Technologies,

Critical Outcome Technologies (COTI) (Originator)  preclinical for ovary cancer

http://drugdiscovery.pharmaceutical-business-review.com/news/critical-outcome-technologies-receives-orphan-drug-designation-for-coti-2-180614-4296271

Critical Outcome Technologies has announced that the US Food and Drug Administration (FDA) has granted COTI-2 an Orphan Drug Designation for the treatment of ovarian cancer.
Critical Outcome Technologies president and CEO Dr Wayne Danter said that receiving the Orphan Drug Designation for COTI-2 speaks to the need for new treatment options for patients with ovarian cancer.

http://drugdiscovery.pharmaceutical-business-review.com/news/critical-outcome-technologies-receives-orphan-drug-designation-for-coti-2-180614-4296271

• COTI-2 | A Potential Breakthrough Therapy for Many Cancers June 11, 2013
• About COTI-2 Late preclinical drug candidate discovered using CHEMSAS® – the company’s proprietary, artificial intelligence-based drug discovery technology 2
• COTI-2 highlights 1 Potential breakthrough therapy for many cancers 2 Active against many cancers with mutations of the p53 gene 3 > 50% of all human cancers have a p53 mutation 3
• Why p53 is important? p53 is a tumour suppressing gene If mutated, cancers can develop & grow without control A mutation of the p53 gene is the most common mutation found in human cancer cells 4
• The future of cancer treatments COTI-2 targets and primarily destroys tumor cells Traditional chemotherapy kills growing & dividing cells, cancer or healthy COTI-2 would treat genetic mutations common in many types of cancer Most current treatments are organ specific (i.e. treatment for lung cancer, colon cancer, etc.) 5
• COTI-2 development progress Easily synthesized oral formulation with no stability issues Effective alone or in combination with approved cancer drugs In final two-species toxicity studies prior to FDA filing enabling human trials 6

http://www.google.com/patents/WO2008083491A1?cl=en

EXAMPLES

Synthesis of COTI-2 The synthesis of COTI-2, as depicted above, was conducted according to the following synthetic methodology:

DCM R T

H₂N-NH₂

lmidazol-1 -yl-(4-pyridin-2-yl-piperazin-1 -yl)-methanethione (or intermediate 3 above) was formed as follows. Λ/-(2-pyridyl) piperazine (MW 163.22, 0.91 ml, 6.0 mmoles, 1 eq) 2 was added to a solution of 1 ,1 ‘- thiocarbonyldiimidazole (MW 178.22, 1.069 g, 6.0 mmoles, 1 eq) 1 in 50 ml of dichloromethane at room temperature. The reaction mixture was stirred overnight at room temperature. The mixture was washed with water, dried \ over sodium sulfate, filtered and concentrated to provide imidazol-1-yl-(4- pyridin-2-yl-piperazin-1-yl)-methanethione (MW 273.36, 1.354 g, 4.95 mmol, 83% yield) 3, which was used without further purification. TLC (CH₂CI₂/MeOH: 95/5): Rf = 0.60, Product UV and Ninhydrin stain active. ¹H-NMR (400 MHz, CDCI₃), δ ppm: 3.72 (s, 4H), 4.02 (s, 4H), 6.67 (d, 1 H, J = 7 Hz), 6.72 (dd, 1 H, J = 7 and 5 Hz), 7.11 (s, 1 H), 7.24 (s, 1 H), 7.54 (t, 1 H, J = 7 Hz), 7.91 (s, 1 H), 8.20 (d, 1 H, J = 5 Hz).

Hydrazine hydrate (MW 50.06, 0.26 ml, 5.44 mmoles, 1.1 eq) was added to a solution of imidazol-1-yl-(4-pyridin-2-yl-piperazin-1-yl)- methanethione 3 (MW 210.30, 1.040 g, 4.95 mmol, 1 eq) in 30 ml of ethanol at room temperature. The reaction mixture was stirred under reflux for 2 hours. A white precipitate formed. This white solid was filtered off and rinsed with diethyl ether to yield 1-[Λ/-(2-pyridyl)-piperazine)-carbothioic acid hydrazide (MW 237.33, 0.86 g, 3.62 mmol, 73% yield) 4 as a white solid, and used without further purification. TLC (CH₂CI₂/MeOH: 95/5): Rf = 0.20, Product UV and Ninhydrin stain active. ¹H-NMR (400 MHz, DMSO-d₆), δ ppm: 3.53 (s, 4H), 3.85 (s, 4H), 6.66 (dd, 1 H, J = 8 and 5 Hz), 6.82 (d, 1 H, J = 8 Hz), 7.55 (t, 1 H, J = 8 Hz), 8.12 (d, 1 H, J = 5 Hz).

COTI-2

Finally, COTI-2 was formed as follows. 1-[Λ/-(2-pyridyl)-piperazine)- carbothioic acid hydrazide (MW 237.33, 0.475 g, 2.0 mmol, 1 eq) 4 and 6,7- dihydro-5H-quinolin-8-one (MW 147.18, 0.306 g, 2.0 mmol, 1 eq) 5 was dissolved in 15 ml of ethanol at room temperature. The mixture was then stirred under reflux for 20 hours. A yellow solid precipitated out of the solution. This solid was filtered off then rinsed with methanol and diethyl ether to yield COTI-2 (MW 366.48, 0.60 g, 1.64 mmol, 82% yield) as a yellow solid. TLC (CH₂CI₂/MeOH: 95/5): Rf = 0.75, Product UV and Ninhydrine stain active. HPLC analysis showed a mixture of isomers (approximately in 80/20 ratio), and >98% purity. During the HPLC Method Development, as expected, this product tends to be hydrolyzed in presence of TFA in mobile phase solution. MS (ESI+, 0.025% TFA in 50/50 MeOH/H₂O): [M+H]⁺ = 367.1 , [M+Na]⁺ = 389.1 ; ¹H-NMR (400 MHz, CDCI₃), δ ppm (Major isomer): 2.09 (m, 2H), 2.92 (m, 4H), 3.67 (m, 4H), 4.27 (m, 4H), 6.69 (dd, 1 H, J = 8 and 5 Hz)₁ 7.25 (dd,

1 H, J = 8 and 5 Hz), 7.55 (d, 2H, J = 8 Hz), 8.23 (d, 1 H, J = 5 Hz), 8.63 (d, 1 H, \ J = 5 Hz), 14.76 (s, 1 H). δ ppm (Minor isomer): 2.09 (m, 2H), 3.14 (t, 4H, J = 6 Hz), 3.80 (m, 4H), 4.27 (m, 4H), 6.66 (m, 1 H), 7.31 (dd, 1 H, J = 8 and 5 Hz), 7.52 (m, 1 H), 7.70 (d, 1 H, J = 8 Hz), 8.23 (d, 1 H, J = 5 Hz), 8.53 (d, 1 H, J = 5 Hz), 15.65 (s, 1 H).

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