1297538-32-9

Usage

Uses

Used in Prostate Cancer Treatment:
ODM-201 is used as a next-generation androgen receptor-directed therapy for prostate cancer. It is effective in inhibiting the activity of some mutant ARs emerging during antiandrogen therapies, including the F876L mutation version which is resistant to enzalutamide and ARN-509 (the second-generation antiandrogens). This makes ODM-201 a potential treatment option for patients with progressive metastatic castration-resistant prostate cancer.
Used in Anticancer Applications:
ODM-201 is used as an anticancer agent in the treatment of prostate cancer. It inhibits AR transactivation in U2OS osteosarcoma cells expressing human wild-type and mutant ARs. ODM-201 also prevents androgen-induced AR nuclear translocation in AR-overexpressing HS-HEK293 and LNCaP cells and suppresses androgen-induced proliferation of VCaP cells.
Used in Preclinical Models:
ODM-201 is used in in vivo studies to evaluate its efficacy in reducing tumor growth. In a VCaP castrated mouse xenograft model, ODM-201 (50 mg/kg per day) has been shown to reduce tumor growth. Additionally, it inhibits tumor growth without increasing serum testosterone levels in a VCaP intact mouse xenograft model, demonstrating its potential as a therapeutic agent for prostate cancer treatment.

References

Moilanen, Anu Maarit, et al. "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies." Sci Rep 5.2(2015):12007. Fizazi, Karim, et al. "ODM-201, a new generation androgen receptor inhibitor for castration-resistant prostate cancer: Preclinical and phase I data." Genitourinary Cancers Symposium of the Conquer-Cancer-Foundation of 2013. Fizazi, K, et al. "Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial." Lancet Oncology 5.9(2014):975-85.

Synthetic route

C21H21ClN6O3 → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
With sodium hydroxide In ethanol; water at 20℃;	93.3%

5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 0℃; for 6h;	92.9%

C13H13ClN4*ClH + C6H7N2O3(1-)*Na(1+) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	87.5%

5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃;	85.9%
With sodium tetrahydroborate In ethanol at 0 - 20℃; for 3.5h;	80.2%
With sodium tetrahydroborate; ethanol In ethanol	76%
With sodium tetrahydroborate; ethanol	76%

(S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) + C6H8N2O3 (1401584-94-8) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at -10℃; for 2h; Inert atmosphere;	73.2%

(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (1297537-33-7) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
With hydrogenchloride; sodium borohydrid In ethanol; water
With sodium tetrahydroborate; ethanol at 22℃; for 4h; Large scale;	214 kg

4-bromo-2-chlorobenzonitrile (154607-01-9) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetonitrile; water / 0.5 h / Inert atmosphere; Reflux 1.2: 2.5 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / water / 2 h / 10 °C 2.2: 4 h / 0 - 5 °C 3.1: triphenylphosphine; hydrogenchloride; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 10 - 20 °C / Inert atmosphere 5.1: sodium tetrahydroborate; ethanol / ethanol View Scheme
Multi-step reaction with 5 steps 1.1: trans-bis(triphenylphosphine)palladium dichloride; sodium carbonate / water; tetrahydrofuran / 40 °C 2.1: hydrogenchloride / ethanol / Reflux 3.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 3.2: 24 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere 5.1: sodium tetrahydroborate / tetrahydrofuran; methanol / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate / tetrahydrofuran; water / 3 h / 40 °C / Inert atmosphere 2.1: hydrogenchloride / ethanol / 2 h / 30 °C / Inert atmosphere 3.1: triphenylphosphine / ethyl acetate / 0.5 h / Inert atmosphere 3.2: 3 h / 20 °C / Inert atmosphere 3.3: 1 h / 20 °C / Inert atmosphere 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / -10 °C / Inert atmosphere View Scheme

2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (1297537-35-9) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / 2 h / 10 °C 1.2: 4 h / 0 - 5 °C 2.1: triphenylphosphine; hydrogenchloride; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 10 - 20 °C / Inert atmosphere 4.1: sodium tetrahydroborate; ethanol / ethanol View Scheme
Multi-step reaction with 4 steps 1.1: hydrogenchloride / ethanol / Reflux 2.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 2.2: 24 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere 4.1: sodium tetrahydroborate / tetrahydrofuran; methanol / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water; methanol / 2 h / 10 °C 2.1: triphenylphosphine / ethyl acetate / Inert atmosphere 2.2: 10 - 20 °C / Inert atmosphere 2.3: 30 - 45 °C / Inert atmosphere 3.1: potassium tert-butylate / toluene / 1 h / 0 °C / Inert atmosphere 3.2: 2 h / 0 - 20 °C / Inert atmosphere 4.1: sodium tetrahydroborate; ethanol View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethanol / 2 h / 30 °C / Inert atmosphere 2.1: triphenylphosphine / ethyl acetate / 0.5 h / Inert atmosphere 2.2: 3 h / 20 °C / Inert atmosphere 2.3: 1 h / 20 °C / Inert atmosphere 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / -10 °C / Inert atmosphere View Scheme

2-chloro-4- (1H-pyrazol-3-yl)benzonitrile (1297537-37-1) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: triphenylphosphine; hydrogenchloride; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 10 - 20 °C / Inert atmosphere 3: sodium tetrahydroborate; ethanol / ethanol View Scheme
Multi-step reaction with 3 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 1.2: 24 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere 3.1: sodium tetrahydroborate / tetrahydrofuran; methanol / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triphenylphosphine / ethyl acetate / Inert atmosphere 1.2: 10 - 20 °C / Inert atmosphere 1.3: 30 - 45 °C / Inert atmosphere 2.1: potassium tert-butylate / toluene / 1 h / 0 °C / Inert atmosphere 2.2: 2 h / 0 - 20 °C / Inert atmosphere 3.1: sodium tetrahydroborate; ethanol View Scheme

ethyl 5-((tert-butyldimethylsilyl)oxy)-2-diazo-3-hydroxyhexanoate → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine; trifluoroacetic anhydride / dichloromethane / 5 h / -10 - 30 °C 2.1: octane / 1 h / Reflux 2.2: 4 h / Reflux 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 h / 25 - 30 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 0 °C View Scheme

ethyl-5-((tert-butyldimethylsilyl)oxy)-2-diazohex-3-enoate → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: octane / 1 h / Reflux 1.2: 4 h / Reflux 2.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 h / 25 - 30 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 0 °C View Scheme

5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 h / 25 - 30 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 0 °C View Scheme

(S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere 2: sodium tetrahydroborate / tetrahydrofuran; methanol / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / toluene / 1 h / 0 °C / Inert atmosphere 1.2: 2 h / 0 - 20 °C / Inert atmosphere 2.1: sodium tetrahydroborate; ethanol View Scheme

(S)-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl-2-yl)amino tert-butyl ester → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / water; 1,4-dioxane / 3 h / 10 °C 2.1: potassium tert-butylate / toluene / 1 h / 0 °C / Inert atmosphere 2.2: 2 h / 0 - 20 °C / Inert atmosphere 3.1: sodium tetrahydroborate; ethanol View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / ethanol / 65 - 70 °C 2: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / ethanol / 65 - 70 °C 2: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / dichloromethane / 20 °C 3: sodium hydroxide / ethanol; water / 20 °C View Scheme

2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (548797-51-9) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: potassium carbonate / acetonitrile; water / 0.5 h / Inert atmosphere; Reflux 1.2: palladium catalyst / 2 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / water; methanol / 2 h / 10 °C 3.1: triphenylphosphine / ethyl acetate / Inert atmosphere 3.2: 10 - 20 °C / Inert atmosphere 3.3: 30 - 45 °C / Inert atmosphere 4.1: potassium tert-butylate / toluene / 1 h / 0 °C / Inert atmosphere 4.2: 2 h / 0 - 20 °C / Inert atmosphere 5.1: sodium tetrahydroborate; ethanol View Scheme

3-chloro-4-cyanoacetophenone (101667-74-7) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 16 h / 100 - 110 °C 2: acetic acid / ethanol / Reflux 3: hydrogenchloride / ethanol / 65 - 70 °C 4: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: 16 h / 100 - 110 °C 2.1: hydrazine hydrate; acetic acid / ethanol / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.2: 1 h 4.1: hydrogenchloride / ethanol / 65 - 70 °C 5.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: 16 h / 100 - 110 °C 2.1: hydrazine hydrate; acetic acid / ethanol / Reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl acetamide / 50 - 55 °C 3.2: 1 h / 20 °C 4.1: hydrogenchloride / ethanol / 65 - 70 °C 5.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C View Scheme

C12H11ClN2O → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic acid / ethanol / Reflux 2: hydrogenchloride / ethanol / 65 - 70 °C 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrazine hydrate; acetic acid / ethanol / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.2: 1 h 3.1: hydrogenchloride / ethanol / 65 - 70 °C 4.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrazine hydrate; acetic acid / ethanol / Reflux 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl acetamide / 50 - 55 °C 2.2: 1 h / 20 °C 3.1: hydrogenchloride / ethanol / 65 - 70 °C 4.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C View Scheme

C23H29ClN4O4 → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 °C 3: sodium tetrahydroborate / ethanol / 3.5 h / 0 - 20 °C View Scheme

5-acetyl-1H-pyrazole-3-carboxylic acid (949034-45-1) → N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 °C 3: sodium tetrahydroborate / ethanol / 3.5 h / 0 - 20 °C View Scheme

succinic acid anhydride (108-30-5) + N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide (1297538-32-9) → 4-(1-(3-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid (1403334-18-8)

Conditions	Yield
With dmap In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide

Upstream product

• 1297537-33-7 (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide 
• 101667-74-7 3-chloro-4-cyanoacetophenone 
• 1297537-41-7 (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile 
• 1401584-94-8 C₆H₈N₂O₃ 
• 1297537-33-7 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide 
• 1297537-37-1 2-chloro-4- (1H-pyrazol-3-yl)benzonitrile 
• 1297537-35-9 2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile 
• 154607-01-9 4-bromo-2-chlorobenzonitrile 
• 1297537-37-1 2-chloro-4-(1H-pyrazol-5-yl)benzonitrile 
• 1297537-39-3 2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride 
• 949034-45-1 5-acetyl-1H-pyrazole-3-carboxylic acid 
• 548797-51-9 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 

Downstream Products

• 1297540-05-6 1-(5-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazol-3-yl)ethyl 2-(dimethylamino)acetate 
• 1403334-18-8 4-(1-(3-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid 

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Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, downregulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also downregulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-positive 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clinically used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and downregulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.

MANUFACTURE OF A CRYSTALLINE PHARMACEUTICAL PRODUCT

The present invention relates to crystalline particles of N-((S)-l-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1 H-pyrazole-3-carboxamide (I) having specific surface area (SSA) in the range from about 8 to about 16 m2/g, preferably from about to about 15 m2/g, and to the method for the preparation of such particles. Compound (I) is a potent androgen receptor (AR) modulator which is useful as a medicament for example in the treatment of prostate cancer.

PROCESS FOR PREPARATION OF NOVEL ANDROGEN RECEPTOR ANTAGONIST

A process for the preparation of a novel androgen receptor antagonist is provided, comprising essentially conducting cyclization reaction of a compound of formula V to obtain a compound of formula VI. This method has the advantages of easily obtainable starting material, high atomic utilization rate, mild reaction conditions, and simply post-treatment. In addition, ODM-201 and its single isomers can be synthesized directionally by controlling the stereochemistry of starting material, with the advantages of simple and controllable process and suitability for industrial production.

PROCESS FOR THE PREPARATION OF ANDROGEN RECEPTOR ANTAGONISTS AND INTERMEDIATES THEREOF

The present invention relates to an improved process for the preparation of carboxamide structured androgen receptor (AR) antagonists such as N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H- pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3- carboxamide (1A) and key intermediates thereof such as 2-chloro-4- (IH-pyrazol-3-yl)benzonitrile (V). AR antagonists are useful in the treatment of cancer, particularly prostate cancer and other diseases where AR antagonism is desired.

ANDROGEN RECEPTOR MODULATING CARBOXAMIDES

Compounds of formula (I) or (II) wherein Rx, Rz, R9, R10, R14, R14′, R15, R15′, A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.