1297537-33-7

Usage

Uses

1. Used in Pharmaceutical Industry:
5-acetyl-N-(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl-1H-pyrazole-3-carboxamide is used as a potential therapeutic agent for the treatment of various diseases, including cancer. Its unique molecular structure allows it to interact with specific biological targets, making it a promising candidate for drug development.
2. Used in Chemical Research:
5-acetyl-N-(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl-1H-pyrazole-3-carboxamide is also used in chemical research as a starting material or intermediate for the synthesis of other complex molecules with potential applications in various fields, such as materials science, pharmaceuticals, and agrochemicals.
3. Used in Prostate Cancer Treatment:
As a metabolite of Darolutamide, 5-acetyl-N-(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl-1H-pyrazole-3-carboxamide may have potential applications in the treatment of prostate cancer. Darolutamide, a potent androgen receptor antagonist, has shown strong efficacy in prostate cancer models, and the metabolite could potentially enhance or complement its therapeutic effects.

Synthetic route

3-acetyl-1H-pyrazole-5-carboxylic acid + (S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 10 - 20℃; Inert atmosphere;	87.5%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere;	79.5%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere;

(S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) + C6H5ClN2O2 → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 3h;	87.1%

2-chloro-4- (1H-pyrazol-3-yl)benzonitrile (1297537-37-1) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triphenylphosphine / ethyl acetate / 0.25 h / Inert atmosphere 1.2: 20 °C 2.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride; diisopropyl (E)-azodicarboxylate; triphenylphosphine / n-heptane; dichloromethane; water; ethyl acetate 2: water View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 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 View Scheme

3-acetyl-1H-pyrazole-5-carboxylic acid + (S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) + 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran (96042-30-7) + isopropyl alcohol (67-63-0) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
In water

2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride (1297537-39-3) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: methanol; water 2: hydrogenchloride; diisopropyl (E)-azodicarboxylate; triphenylphosphine / n-heptane; dichloromethane; water; ethyl acetate 3: water View Scheme

4-bromo-2-chlorobenzonitrile (154607-01-9) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme

2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (1297537-35-9) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme

(S)-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl-2-yl)amino tert-butyl ester → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester (37622-89-2) + (S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Stage #1: (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile With potassium tert-butylate In toluene at 0℃; for 1h; Inert atmosphere; Stage #2: 5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester In toluene at 0 - 20℃; for 2h; Inert atmosphere;	15.4 g

2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (548797-51-9) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions

Yield

Multi-step reaction with 4 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 View Scheme

C23H29ClN4O4 → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

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

Upstream product

• 1297537-39-3 2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride 
• 154607-01-9 4-bromo-2-chlorobenzonitrile 
• 1297537-35-9 2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile 
• 37622-89-2 5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester 
• 1297537-41-7 (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile 
• 1297537-37-1 2-chloro-4-(1H-pyrazol-5-yl)benzonitrile 
• 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 
• 96042-30-7 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 
• 67-63-0 isopropyl alcohol 
• 1297537-37-1 2-chloro-4- (1H-pyrazol-3-yl)benzonitrile 

Downstream Products

• 1297540-28-3 (S)-3-acetyl-N-(1-(3-(4-cyano-3-(methylthio)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide 
• 1297538-32-9 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 N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide 
• 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 

Relevant academic research and scientific papers

SUBSTITUTED PYRAZOLE COMPOUNDS, COMPOSITIONS CONTAINING SAME, AND USE THEREOF

The present invention provides substituted pyrazole compounds, compositions containing same, and use thereof. The substituted pyrazole compounds comprise a compound represented by formula (I) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof. The compound represented by formula (I) can serve as a tissue selective androgen receptor modulator (SARM), particularly serving as a drug for treating prostate cancer and other AR-dependent conditions and diseases in which AR antagonism is desired.

Metabolism and mass balance of the novel nonsteroidal androgen receptor inhibitor darolutamide in humans

The biotransformation and excretion of darolutamide were investigated in a phase I study. Six healthy male volunteers received a single dose of 300 mg 14C-darolutamide as an oral solution in the fasted state. Plasma, urine, and feces samples were analyzed for mass balance evaluation by liquid scintillation counting (LSC). Metabolite profiling and identification were determined using liquid chromatography mass-spectrometry with off-line radioactivity detection using LSC. Complete mass balance was achieved, with mean radioactivity recovery of 95.9% within 168 hours (63.4% in urine, 32.4% in feces). The administered 1:1 ratio of (S,R)- and (S,S)darolutamide changed to approximately 1:5, respectively, in plasma. Darolutamide and the oxidation product, keto-darolutamide, were the only components quantifiable by LSC in plasma, accounting for 87.4% of total radioactivity, with a 2.1-fold higher plasma exposure for keto-darolutamide. Aside from darolutamide, the most prominent metabolites in urine were O-glucoronide (M-7a/b) and N-glucuronide (M-15a/b), as well as pyrazole sulfates (M-29, M-24) and glucuronides (M-21, M-22) resulting from oxidative cleavage of the parent. The darolutamide diastereomers were mainly detected in feces. In vitro assays showed that darolutamide metabolism involves a complex interplay between oxidation and reduction, as well as glucuronidation. Interconversion of the diastereomers involves oxidation to keto-darolutamide, primarily mediated by CYP3A4, followed by reduction predominantly catalyzed by cytosolic reductase(s), with aldo-keto reductase 1C3 playing the major role. The latter reaction showed stereoselectivity with preferential formation of (S,S)-darolutamide.

Synthesis process of darolutamide

The invention relates to a synthesis process of darolutamide. Compared with an existing synthetic process route in which the reaction steps are 10 steps or more, the process of the invention has the advantages of less reaction steps in the route, high reaction yield of each step, simplicity and convenience in operation, and effective improvement of the total yield and industrial operability of thereaction.

Discovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants

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.

Preparation method of N-[(1S)-2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]-1-methylethyl]-5-(1-hydroxyethyl)-1H-pyrazol-3-carboxamide

The invention relates to a preparation method of N-[(1S)-2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]-1-methylethyl]-5-(1-hydroxyethyl)-1H-pyrazol-3-carboxamide, and in particular relates to two novel methods for preparing an intermediate (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile and a method for preparing N-[(1S)-2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]-1-methylethyl]-5-(1-hydroxyethyl)-1H-pyrazol-3-carboxamide from the intermediate.

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.

ANDROGEN RECEPTOR MODULATING CARBOXAMIDES

Compounds of formula (I) 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 particularly useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.

ANDROGEN RECEPTOR MODULATING COMPOUNDS

Compounds of formula (I) wherein R1 to R16, A. B and E are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as tissue-selective androgen receptor modulators (SARM) and are particularly useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.