Sitasentan TBC 11251

Sitasentan,TBC 11251

210421-64-0

N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-[2-(6-methyl-1,3-benzodioxol-5-yl)acetyl]thiophene-3-sulfonamide

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 (ET_A) receptor selectively (by a factor of 6000 compared to the ET_B).^[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 ET_B 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 (ClinicalTtrials.gov 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 :

• liver enzyme abnormalities (increased ALT and AST)
• headache
• edema
• constipation
• nasal congestion
• upper respiratory tract infection
• dizziness
• insomnia
• flushing

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.

http://www.google.com/patents/WO2007149568A2?cl=en

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

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.

EXAMPLE 1

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.

EXAMPLE 3

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.

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1HNMR(CDCl3):88.88(brs,1H),7.59(s,2H),6.72(s,1H),6.69(s,111),5.94(s,2H),4.22(s,2H),2.22(s,311),2.21(s,3H);

IR(KBrpellet):3455,3233,

3109,2899,1674,1632,1505,1487,1395,1373cm-1;

HRMS:[M+H]*455.0137

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see

Current Opinion in Investigational Drugs (PharmaPress Ltd.) (2001), 2(4), 531-536.

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Synthesis of Sitaxsentan sodium
Yingyong Huaxue (2007), 24, (11), 1310-1313. Publisher: (Kexue Chubanshe, ) CODEN:YIHUED ISSN:1000-0518.

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http://www.google.co.in/patents/WO2007106494A2?cl=en

Table 1: Sitaxsentan Sodium Lyophilized Formulation

References

• 2
• Citing liver damage, Pfizer withdraws Thelin, Associated Press, December 12, 2010
• 3
• Girgis, RE; Frost, AE; Hill, NS; Horn, EM; Langleben, D; McLaughlin, VV; Oudiz, RJ; Robbins, IM et al. (2007). “Selective endothelinA receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease”. Annals of the rheumatic diseases 66 (11): 1467–72. doi:10.1136/ard.2007.069609. PMC 2111639. PMID 17472992.
• 4
• “UPDATE 1-Encysive gets Canadian approval for hypertension drug”. Reuters. 30 May 2007. Retrieved 2007-07-08.
• 5

External links

• http://www.drugs.com/nda/thelin_050714.html
• Mucke HAM: Sitaxsentan for the Oral Treatment of Pulmonary Arterial Hypertension: Benefits from Endothelin Receptor Subtype Selectivity? Clinical Medicine: Therapeutics 2009:1 111–121.
• ATS 2005. The International Conference of the American Thoracic Society. 20–25 May 2005. San Diego, CA.
• Robyn J. Barst, MD; Stuart Rich, MD, FCCP; Allison Widlitz, MS, PA; Evelyn M. Horn, MD; Vallerie McLaughlin, MD and Joyce McFarlin, RN : Clinical Efficacy of Sitaxsentan, an Endothelin-A Receptor Antagonist, in Patients With Pulmonary Arterial Hypertension Chest. 2002;121:1860-1868.
• American Heart Association. Primary or Unexplained Pulmonary Hypertension

Sitaxentan

Systematic (IUPAC) name
N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-[2-(6-methyl-2H-1,3-benzodioxol-5-yl)acetyl]thiophene-3-sulfonamide
Clinical data
AHFS/Drugs.com	International Drug Names
Licence data	EMA:Link
Legal status	AU: Prescription Only (S4) UK: POM
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%)
Identifiers
CAS number	184036-34-8 210421-64-0 (sodium salt)
ATC code	C02KX03
PubChem	CID 216235
IUPHAR ligand	3950
DrugBank	DB06268
ChemSpider	21106381
UNII	J9QH779MEM
KEGG	D07171
ChEMBL	CHEMBL282724
Synonyms	Sitaxsentan; TBC-11251
Chemical data
Formula	C18H15ClN2O6S2
Molecular mass	454.906 g/mol

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