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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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Sitasentan TBC 11251

Figure US20120202744A1-20120809-C00005

Sitasentan,TBC 11251



Sitaxentan sodium (TBC-11251) is a medication for the treatment of pulmonary arterial hypertension (PAH).[1] It was marketed as Thelin by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market due to concerns about liver toxicity.[2]

Sitaxentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Sitaxentan blocks the binding of endothelin to its receptors, thereby negating endothelin’s deleterious effects.

Mechanism of action

Sitaxentan is a small molecule that blocks the action of endothelin (ET) on the endothelin-A (ETA) receptor selectively (by a factor of 6000 compared to the ETB).[3] It is a sulfonamide class endothelin receptor antagonist (ERA) and is undergoing Food and Drug Administration (FDA) review for treating pulmonary hypertension. The rationale for benefit compared to bosentan, a nonselective ET blocker, is negligible inhibition of the beneficial effects of ETB stimulation, such as nitric oxide production and clearance of ET from circulation. In clinical trials, the efficacy of sitaxentan has been much the same as bosentan, but the hepatotoxicity of sitaxentan outweighs its benefits. Dosing is once daily, as opposed to twice daily for bosentan.

Regulatory status

On December 10, 2010 Pfizer announced it would be withdrawing sitaxentan worldwide (both from marketing and from all clinical study use), citing that it is a cause of fatal liver damage.[2]

Sitaxentan was approved for marketing in the European Union in 2006, in Canada in 2006[4] and in Australia in 2007. By February 2008 it had been launched commercially in Germany, Austria, The Netherlands, the United Kingdom, Ireland, France, Spain and Italy.

In March 2006, the FDA recommended an approvable status to sitaxentan but said it would not yet approve the product. In July 2006, sitaxentan received a second approvable letter stating that efficacy outcome issues raised in the context of the STRIDE-2 study were still unresolved. In July 2007, Encysive commenced a formal dispute resolution process in a preliminary meeting with the FDA. In September 2007 the company announced that it was making preparations for another phase III clinical trial (intended to be named STRIDE-5) to overcome the FDA’s concerns.[5] The takeover by Pfizer resulted in a reconfiguration and extension of these plans, to include combination therapy with sildenafil. The Sitaxentan Efficacy and Safety Trial With a Randomized Prospective Assessment of Adding Sildenafil (SR-PAAS) was an ongoing program of three clinical trials conducted in the United States ( identifiers: NCT00795639, NCT00796666 and NCT00796510) with anticipated completion dates between June 2010 and January 2014.


N-(4-Chloro-3-methyl-5-isoxazolyl)-2-[2-(6-methyl-1,3-benzodioxol-5-yl)acetyl]-3-thiophenesulfonamide sodium salt, Sitaxsentan sodium salt, TBC-11251 sodium salt, Thelin

  • CAS Number 210421-74-2
  • Empirical Formula  C18H14ClN2NaO6S2
  • Molecular Weight 476.89

Adverse effects

Adverse effects observed with sitaxentan are class effects of endothelin receptor antagonists, and include :

Because sitaxentan inhibits metabolism of warfarin, a decreased dose of warfarin is needed when co-administered with sitaxentan. This is because warfarin acts to prevent blood from clotting, and if it remains unmetabolized, it can continue to thin the blood.

As used herein “sitaxsentan” refers to N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2- methyl-4,5-(methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide. Sitaxsentan is also known as TBCl 1251. Other chemical names for sitaxsentan include 4-chloro-3-methyl-5-(2- (2-(6-methylbenzo[d][l ,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole and N-(4- chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methylphenylacetyl]-thiophene-3- sulfonamide.

The chemical name for sitaxsentan is N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2- methyl-4,5-(methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide, and its structural formula is as follows:


Sitaxsentan is a potent endothelin receptor antagonist that has oral bioavailability in several species, a long duration of action, and high specificity for ETA receptors.


Preparation of 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d] [l,3|dioxol-5-yl)aeetyl)-3- thienylsulfonamido)isoxazole, or N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methy 1-4,5- (methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide, or N-(4-chIoro-3-methyl-5- isoxazolyl)-2-[3,4-(methylenedioxy)-6-methylphenylacetyl]-thiophene-3-sulfonamide.

A. Preparation of (4-chIoro-3-methyl-5-(2-(2-(6-methylbenzo[d] [l,3]dioxol-5-yl)acetyl)- 3-thienylsuIfonamido)isoxazole 1. Preparation of 5-chloromethyI-6-methylbenzo[d][l,3]dioxole

To a mixture of methylene chloride (130 L), concentrated HCl (130 L), and tetrabuylammonium bromide (1.61 Kg) was added 5-methylbenzo[d][l,3]dioxole (10 Kg) followed by the slow addition of formaldehyde (14 L, 37 wt% in water). The mixture was stirred overnight. The organic layer was separated, dried with magnesium sulfate and concentrated to an oil. Hexane (180 L) was added and the mixture heated to boiling. The hot hexane solution was decanted from a heavy oily residue and evaporated to give almost pure 5-chloromethyl-6-methylbenzo[d][l,3]dioxole as a white solid. Recrystallization from hexane (50 L) gave 5-chloromethyl-6-methylbenzo[d][l,3]dioxole (80% recovery after recrystallization). 2. Formation of (4-chloro-3-methyl-5-(2-(2-(2-methyIbenzo[d][l,3]dioxol-5-yl) acetyl)-3-thienylsulfonamido)isoxazole

A portion of a solution of 5-chloromemyl-6-methylbenzo[d][l,3]di-oxole (16.8 g, 0.09 mol) in tetrahydrofuran (THF)(120 mL) was added to a well stirred slurry of magnesium powder, (3.3 g, 0.136 g-atom, Alfa, or Johnson-Mathey, -20 +100 mesh) in THF (120 mL) at room temperature. The resulting reaction admixture was warmed up to about 40-450C for about 2-3 min, causing the reaction to start. Once the heating activated the magnesium, and the reaction began, the mixture was cooled and maintained at a temperature below about 8 0C. The magnesium can be activated with dibromoethane in place of heat.

A flask containing the reaction mixture was cooled and the remaining solution of 5- chloromethlybenzo[d][l,3]dioxole added dropwise during 1.5 hours while maintaining an internal temperature below 8 0C. Temperature control is important: if the Grignard is generated and kept below 8 0C5 Wurtz coupling is suppressed. Longer times at higher temperatures promote the Wurtz coupling pathway. Wurtz coupling can be avoided by using high quality Mg and by keeping the temperature of the Grignard below about 8 0C and stirring vigorously. The reaction works fine at -20 0C, so any temperature below 8 0C is acceptable at which the Grignard will form. The color of the reaction mixture turns greenish.

The reaction mixture was stirred for an additional 5 min at 0 0C, while N2-methoxy- N2-methyl-3-(4-chloro-3-methyl-5-isoazolylsulfamoyl)-2-thiophenecarboxamide (6.6 g, 0.018 mol) in anhydrous THF (90 mL) was charged into the addition funnel. The reaction mixture was degassed two times then the solution of N2-methoxy-N2-methyl-3-(4-chloro-3- methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide was added at 0 0C over 5 min. TLC of the reaction mixture (Silica, 12% MeOHZCH2Cl2) taken immediately after the addition shows no N2-methoxy-N2-methyl-3-(4-chloro-3-methyl-5-isoxazolysulfamoyl)-2-thio- phenecarboxamide. The reaction mixture was transferred into a flask containing IN HCl (400 mL, 0.4 mol

HCl, ice-bath stirred), and the mixture stirred for 2 to 4 min, transferred into a separatory funnel and diluted with ethyl acetate (300 mL). The layers were separated after shaking. The water layer was extracted with additional ethyl acetate (150 mL) and the combined organics washed with half-brine. Following separation, THF was removed by drying the organic layer over sodium sulfate and concentrating under reduced pressure at about 39 0C to obtain the title compound. EXAMPLE 2

1.0 g Sitaxentan was dissolved in 10 ml ethyl acetate and 5 ml hexanes were added. The formed suspension was heated until a clear solution was obtained. Upon cooling light yellow plates were formed. After filtration and drying under vacuum 515 mg of sitaxentan polymorph A was obtained as light yellow plates in very high purity.


Preparation of 4-chloro-3-methyl-5-(2-(2-(6-methyIbenzo[dJ [l,3]dioxol-5-yl)acetyl)-3- thienylsulfonamido)isoxazole, Sodium Salt

The crystalline sitaxsentan from Example 2 is dissolved in ethyl acetate and washed with saturated NaHCO3 (5 x 10 mL). The solution is washed with brine, dried over Na2SO4 and concentrated in vacuo to obtain a solid residue. 10 mL OfCH2Cl2 is added and the mixture is stirred under nitrogen for 5 to 10 minutes. Ether (15 mL) is added and the mixture stirred for about 10 min. The product is isolated by filtration, washed with a mixture of CH2Cl2 /ether (1 :2) (10 mL) then with ether (10 mL) and dried under reduced pressure to obtain 4-Chloro-3-methyl-5-(2-(2-(6-methyIbenzo[d][l ,3]dioxol-5-yl)acetyl)-3- thienylsulfonamido)isoxazole, sodium salt.



J. Med. Chem., 1997, 40 (11), pp 1690–1697
DOI: 10.1021/jm9700068
Current Opinion in Investigational Drugs (PharmaPress Ltd.) (2001), 2(4), 531-536.
Synthesis of Sitaxsentan sodium
Yingyong Huaxue (2007), 24, (11), 1310-1313. Publisher: (Kexue Chubanshe, ) CODEN:YIHUED ISSN:1000-0518.

Table 1: Sitaxsentan Sodium Lyophilized Formulation


 1Barst RJ, Langleben D, Frost A et al. (2004). “Sitaxsentan therapy for pulmonary arterial hypertension”. American Journal of Respiratory Critical Care Medicine 169 (4): 441–447. doi:10.1164/rccm.200307-957OC. PMID 14630619.


External links


US20010021714 * Apr 4, 1996 Sep 13, 2001 Ming Fai Chan Compounds such as n-(4-bromo-3-methyl-5-isoxazolyl)-2-n-benzylbenzo(b)thiophene-3-sufonamide administered as endothelin peptide receptor antagonists
1 * WU C ET AL: “Discovery of TBC11251, a Potent, Long Acting, Orally Active Endothelin Receptor-A Selective Antagonist” JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 40, no. 11, 23 May 1997 (1997-05-23), pages 1690-1697, XP002164198 ISSN: 0022-2623
Patent Submitted Granted
Crystalline N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4.5-(methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide [US2008026061] 2008-01-31
Gnrh agonist combination drugs [US2005215528] 2005-09-29
Patent Submitted Granted
Respiratory Drug Condensation Aerosols and Methods of Making and Using Them [US2009258075] 2009-10-15
Method and Composition for Treating Alzheimer’s Disease and Dementias of Vascular Origin [US2010173872] 2010-07-08
Method and Composition for Treating Alzheimer’s Disease and Dementias of Vascular Origin [US2010184725] 2010-07-22
Formulations of sitaxsentan sodium [US2008076812] 2008-03-27
Methods and compositions for treatment of sleep apnea [US2008085313] 2008-04-10
Processes for the preparation of 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole [US2008086010] 2008-04-10
Method and composition for treating alzheimer’s disease and dementias of vascular origin [US2004092427] 2004-05-13
Method for preventing or treating pulmonary inflammation by administering an endothelin antagonist [US2003004199] 2003-01-02
Methods and Compositions for Treatment of an Interstitial Lung Disease [US2009004268] 2009-01-01
Methods and compositions for treatment of diastolic heart failure [US2007232671] 2007-10-04
Patent Submitted Granted
Isoxazolyl endothelin antagonists [US6043265] 2000-03-28
Aminoguanidine hydrazone derivatives, process for producing the same and drugs thereof [US6350749] 2002-02-26
Method for preventing or treating pain by administering an endothelin antagonist [US6573285] 2002-06-27 2003-06-03
Method for preventing or treating erectile dysfunction by administering an endothelin antagonist [US6268388] 2001-07-31
Method and composition for potentiating the antipyretic action of a nonopioid analgesic [US7351692] 2003-12-25 2008-04-01
Method and Composition for Potentiating an Opiate Analgesic [US8114896] 2010-05-06 2012-02-14
SUBSTITUTED THIOPHENES [US7863308] 2008-10-16 2011-01-04
Respiratory drug condensation aerosols and methods of making and using them [US7550133] 2004-06-03 2009-06-23
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Method and Composition for Potentiating an Opiate Analgesic [US2010311665] 2010-12-09




Systematic (IUPAC) name
Clinical data
AHFS/ International Drug Names
Licence data EMA:Link
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 70 to 100%
Protein binding >99%
Metabolism Hepatic (CYP2C9– and CYP3A4-mediated)
Half-life 10 hours
Excretion Renal (50 to 60%)
Fecal (40 to 50%)
CAS number 184036-34-8
210421-64-0 (sodium salt)
ATC code C02KX03
PubChem CID 216235
IUPHAR ligand 3950
DrugBank DB06268
ChemSpider 21106381
KEGG D07171
Synonyms Sitaxsentan; TBC-11251
Chemical data
Formula C18H15ClN2O6S2 
Molecular mass 454.906 g/mol

  Structures and observed activities of the ETA receptor antagonists for the HipHop training set



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