173937-91-2

Usage

Uses

Used in Pharmaceutical Industry:
Atrasentan is used as a palliative treatment for bone pain due to metastatic prostate cancer and disease progression. It functions as an endothelin (ETA) receptor antagonist, helping to alleviate pain and slow down the progression of the disease.
Used in Oncology:
Atrasentan is used as a selective antagonist of the endothelin-A (ETA) receptor in the treatment of metastatic prostate cancer. By binding selectively to the ETA receptor, it may inhibit endothelin-induced angiogenesis and tumor cell proliferation, providing a targeted approach to managing the disease.

InChI:InChI=1/C29H38N2O6.ClH/c1-4-6-14-30(15-7-5-2)26(32)18-31-17-23(21-10-13-24-25(16-21)37-19-36-24)27(29(33)34)28(31)20-8-11-22(35-3)12-9-20;/h8-13,16,23,27-28H,4-7,14-15,17-19H2,1-3H3,(H,33,34);1H/t23-,27-,28+;/m1./s1

Synthetic route

2-[(2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-3-((S)-4-benzyl-2-oxo-oxazolidine-3-carbonyl)-2-(4-methoxy-phenyl)-pyrrolidin-1-yl]-N,N-dibutyl-acetamide → atrasentan (173937-91-2)

Conditions	Yield
With lithium hydroxide; dihydrogen peroxide In tetrahydrofuran for 0.5h;	78%

5-((E)-2-nitroethenyl)-1,3-benzodioxole (1485-00-3, 22568-48-5) + palladium → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 10 steps 1: 78 percent / DBU / tetrahydrofuran; propan-2-ol / 4 h / Ambient temperature 2: 12.34 g / H2 / Raney nickel / ethanol / 3040 Torr 3: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 4: 2.775 g / C2H5ONa / ethanol / Heating 5: 91 percent / CH2Cl2 / 1 h / Ambient temperature 6: 95 percent / NaOH 7: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 8: 4 N aq. HCl / dioxane 9: iPr2NEt / acetonitrile 10: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme
Multi-step reaction with 9 steps 1: 78 percent / DBU / tetrahydrofuran; propan-2-ol / 4 h / Ambient temperature 2: 12.34 g / H2 / Raney nickel / ethanol / 3040 Torr 3: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 4: 91 percent / CH2Cl2 / 1 h / Ambient temperature 5: 95 percent / NaOH 6: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 7: 4 N aq. HCl / dioxane 8: iPr2NEt / acetonitrile 9: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

N,N-dibutylbromoacetamide (40124-27-4) → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: iPr2NEt / acetonitrile 2: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

dibutylamine (111-92-2) + (+-)-2-chloro-1-<6-methoxy-8-nitro-<4>quinolyl>-ethanol → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / 1,2-dichloro-ethane / 0.83 h / -20 - 20 °C 2: iPr2NEt / acetonitrile 3: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4.5-dihydro-3H-pyrrole-3-carboxylate (173864-46-5) → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 8 steps 1: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 2: 2.775 g / C2H5ONa / ethanol / Heating 3: 91 percent / CH2Cl2 / 1 h / Ambient temperature 4: 95 percent / NaOH 5: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 6: 4 N aq. HCl / dioxane 7: iPr2NEt / acetonitrile 8: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme
Multi-step reaction with 7 steps 1: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 2: 91 percent / CH2Cl2 / 1 h / Ambient temperature 3: 95 percent / NaOH 4: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 5: 4 N aq. HCl / dioxane 6: iPr2NEt / acetonitrile 7: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxy-phenyl)-4-nitro-butanoate (173864-45-4) → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 9 steps 1: 12.34 g / H2 / Raney nickel / ethanol / 3040 Torr 2: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 3: 2.775 g / C2H5ONa / ethanol / Heating 4: 91 percent / CH2Cl2 / 1 h / Ambient temperature 5: 95 percent / NaOH 6: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 7: 4 N aq. HCl / dioxane 8: iPr2NEt / acetonitrile 9: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme
Multi-step reaction with 8 steps 1: 12.34 g / H2 / Raney nickel / ethanol / 3040 Torr 2: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 3: 91 percent / CH2Cl2 / 1 h / Ambient temperature 4: 95 percent / NaOH 5: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 6: 4 N aq. HCl / dioxane 7: iPr2NEt / acetonitrile 8: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

ethyl 4-(1,3-benzodioxol-5-yl)-N-tert-butoxycarbonyl-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 95 percent / NaOH 2: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 3: 4 N aq. HCl / dioxane 4: iPr2NEt / acetonitrile 5: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

(2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-3-((S)-4-benzyl-2-oxo-oxazolidine-3-carbonyl)-2-(4-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 4 N aq. HCl / dioxane 2: iPr2NEt / acetonitrile 3: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

(2R,3S,4S)-4-Benzo[1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 7 steps 1: 2.775 g / C2H5ONa / ethanol / Heating 2: 91 percent / CH2Cl2 / 1 h / Ambient temperature 3: 95 percent / NaOH 4: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 5: 4 N aq. HCl / dioxane 6: iPr2NEt / acetonitrile 7: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

ethyl c-(1,3-benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-3-carboxylate → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: 91 percent / CH2Cl2 / 1 h / Ambient temperature 2: 95 percent / NaOH 3: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 4: 4 N aq. HCl / dioxane 5: iPr2NEt / acetonitrile 6: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

rac-(2R,3R,4S)-1-(tert-butoxycarbonyl)-4-(benzo[d][1,3]dioxol-6-yl)-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 2: 4 N aq. HCl / dioxane 3: iPr2NEt / acetonitrile 4: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

N,N-dibutylbromoacetamide (40124-27-4) + ethyl (2R,3R,4S)-5-(4-methoxyphenyl)-3-(3,4-(methylenedioxy)phenyl)pyrrolidine-3-carboxylate (178739-03-2) → atrasentan (173937-91-2)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile

ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+)-mandelate (195708-14-6) + N,N-dibutylbromoacetamide (40124-27-4) → atrasentan (173937-91-2)

Conditions	Yield
Stage #1: ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+)-mandelate With sodium hydrogencarbonate In water; ethyl acetate at 25℃; Stage #2: N,N-dibutylbromoacetamide With N-ethyl-N,N-diisopropylamine In acetonitrile at 10℃; for 12h; Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages;

ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+) mandelate (403614-49-3) + N,N-dibutylbromoacetamide (40124-27-4) + N-ethyl-N,N-diisopropylamine (7087-68-5) → atrasentan (173937-91-2)

Conditions	Yield
Stage #1: ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+) mandelate With sodium hydrogencarbonate In water; ethyl acetate at 25℃; Stage #2: N,N-dibutylbromoacetamide; N-ethyl-N,N-diisopropylamine In ethyl acetate; acetonitrile at 110℃; for 16h;

atrasentan (173937-91-2) → Atrasentan hydrochloride

Conditions	Yield
With hydrogenchloride In ethanol; water; ethyl acetate for 0.25h;
With hydrogenchloride In water; ethyl acetate at 0℃; for 2 - 3h; Product distribution / selectivity;
With hydrogenchloride In ethanol; water; ethyl acetate for 0.25h; Product distribution / selectivity;
With hydrogenchloride In ethyl acetate at 0 - 45℃; for 26.5 - 39.5h;

(S)-Mandelic acid (17199-29-0) + atrasentan (173937-91-2) → atrasentan (S)-mandelate salt

Conditions	Yield
In methanol; water at 50℃;

(S)-Mandelic acid (17199-29-0) + atrasentan (173937-91-2) → atrasentan (S)-mandelate salt

Conditions	Yield
In methanol; water at 40℃; Temperature;

(R)-Mandelic Acid (611-71-2) + atrasentan (173937-91-2) → atrasentan R-mandelate salt

Conditions	Yield
In water at 50℃; for 0.25h; Sonication;

Upstream product

• 1485-00-3 5-((E)-2-nitroethenyl)-1,3-benzodioxole 
• 40124-27-4 N,N-dibutylbromoacetamide 
• 178739-03-2 ethyl (2R,3R,4S)-5-(4-methoxyphenyl)-3-(3,4-(methylenedioxy)phenyl)pyrrolidine-3-carboxylate 
• 195708-14-6 ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+)-mandelate 
• 403614-49-3 ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+) mandelate 
• 7087-68-5 N-ethyl-N,N-diisopropylamine 
• 195708-08-8 (2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid ethyl ester 
• 173864-46-5 ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H-pyrrole-3-carboxylate 
• 111-92-2 dibutylamine 
• 173864-45-4 Ethyl 2-(4-methoxybenzoyl)-3-(3.4-methylenedioxy-phenyl)-4-nitro-butanoate 
• 2881-83-6 ethyl 4-methoxybenzoylacetate 
• 173864-47-6 ethyl c-(1,3-benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-3-carboxylate 
• 173864-47-6 (2R,3S,4S)-4-Benzo[1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester 

Downstream Products

• 195733-43-8 Atrasentan hydrochloride 

Relevant academic research and scientific papers

ATRASENTAN HYDROCHLORIDE CRYSTALLINE FORM 2

Atrasentan Hydrochloride Crystalline Form 2, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.

CRYSTALLINE FORM 1 OF ATRASENTAN HXDROCHLORIDE

Atrasentan Hydrochloride Crystalline Form 1, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.

CRYSTALLINE FORM 3 OF ATRASENTAN HYDROCHLORIDE

Atrasentan Hydrochloride Crystalline Form 3, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed

Crystalline form of a drug

Atrasentan Hydrochloride Crystalline Form 2, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.

Favorable modulation of health-related quality of life and health-related quality-adjusted time-to-progression of disease in patients with prostate cancer

Disclosed herein is a method for favorably modulating the health-related quality of life and the health-related quality-adjusted time-to-disease progression in a patient having prostate cancer and a method for measuring of the health-related quality-adjusted time-to-disease progression.

Endothelin antagonists

A compound of the formula (I): or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

ENDOTHELIN ANTAGONISTS

A compound of the formula (I): STR1 or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.

2,4-diarylpyrrolidine-3-carboxylic acids - Potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722

We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indan ring in SB 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylic acids (8) have been synthesized and evaluated for binding at ETA and ETB receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC50 = 0.36 nM for inhibition of ET-1 radioligand binding at the ETA receptor, with a 1000-fold selectivity for the ETA vs the ETB receptor. It is also a potent inhibitor (IC50 = 0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-1-induced contraction of the rabbit aorta with a pA2 = 9.20. The compound has 70% oral bioavailability in rats.