Sparsentan (PS433540,RE-021)

• C₃₂H₄₀N₄O₅S
• Average mass592.749

FDA APPROVED 2023/2/17, Filspari

4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide 

4′-[(2-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methvn-N-(3,4- dimethyl-5-isoxazolyl)-2′-ethoxymethyl [ 1 , l’-biphenyll -2-sulfonamide

Sparsentan
PS433540; RE-021, formerly known as DARA
CAS :254740-64-2
4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5- dimethylisoxazol-3-yl)-2-(ethoxymethyl)biphenyl-2-sulfonamide
Mechanism of Action:acting as both an Endothelin Receptor Antagonist (ERA) and Angiotensin Receptor Blocker (ARB).
Indication: Focal Segmental Glomerulosclerosis (FSGS).Focal Segmental Glomerulosclerosis (FSGS) is a rare and severe nephropathy which affects approximately 50,000 patients in the United States. Most cases of FSGS are pediatric.
Development Stage: Phase II
Developer:Retrophin, Inc

• OriginatorBristol-Myers Squibb
• DeveloperRetrophin
• ClassAntihypertensives; Isoxazoles; Small molecules; Spiro compounds; Sulfonamides
• Mechanism of ActionAngiotensin type 1 receptor antagonists; Endothelin A receptor antagonists
• Orphan Drug Status Yes – Focal segmental glomerulosclerosis
• • 09 Jan 2015 Sparsentan receives Orphan Drug status for Focal segmental glomerulosclerosis in USA
  • 31 Dec 2013 Phase-II/III clinical trials in Focal segmental glomerulosclerosis in USA (PO)
  • 07 May 2012I nvestigation in Focal segmental glomerulosclerosis in USA (PO)

Sparsentan is an investigational therapeutic agent which acts as both a selective endothelin receptor antagonist and an angiotensin receptor blocker. Retrophin is conducting the Phase 2 DUET trial of Sparsentan for the treatment of FSGS, a rare and severe nephropathy that is a leading cause of end-stage renal disease. There are currently no therapies approved for the treatment of FSGS in the United States. Ligand licensed worldwide rights of Sparsentan (RE-021) to Retrophin in 2012 .The Food and Drug Administration (FDA) has granted orphan drug designation for Retrophins sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS) in January 2015.

In 2006, the drug candidate was licensed to Pharmacopeia by Bristol-Myers Squibb for worldwide development and commercialization. In 2012, a license was obtained by Retrophin from Ligand. In 2015, Orphan Drug Designation was assigned by the FDA for the treatment of focal segmental glomerulosclerosis.

Sparsentan, also known as RE-021, BMS346567, PS433540 and DARA-a, is a Dual angiotensin II and endothelin A receptor antagonist. Retrophin intends to develop RE-021 for orphan indications of severe kidney diseases including Focal Segmental Glomerulosclerosis (FSGS) as well as conduct proof-of-concept studies in resistant hypertension and diabetic nephropathy. RE-021, with its unique dual blockade of angiotensin and endothelin receptors, is expected to provide meaningful clinical benefits in mitigating proteinuria in indications where there are no approved therapies

Sparsentan, sold under the brand name Filspari, is a medication used for the treatment of primary immunoglobulin A nephropathy.^[1] Sparsentan is an endothelin and angiotensin II receptor antagonist.^[1][4] It is taken by mouth.^[1]

The most common side effects include swelling of the extremities, low blood pressure, dizziness, high blood potassium, anemia, injury to the kidney, and increased liver enzymes in the blood.^[5]

It was approved for medical use in the United States in February 2023.^[5][6][7] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[8]

PATENT

WO 2000001389

https://www.google.co.in/patents/WO2000001389A1?cl=en

Example 41

4′- [(2-Butyl-4-oxo- 1.3-diazaspiro [4.4! non- l-en-3-yl)methyll -N-(3.4- dimethyl-5-isoxazolyl)-2′-hydroxymethyl[l, l’-biphenyl! -2-sulfonamide

A. 4′-[(2-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methyll-N-(3.4- dimethyl-5-isoxazolyl)-N-[(2-trimethylsilylethoxy)methyl]-2′- hydroxym ethyl [1, l’-biphenyl] -2-sulfonamide P14 (243 mg, 0.41 mmol) was used to alkylate 2-butyl-4-oxo-l,3- diazaspiro[4.4]non-l-ene hydrochloride according to General Method 4. 41A (100 mg, 35% yield) was isolated as a slightly yellow oil after silica gel chromatography using 1:1 hexanes/ethyl acetate as eluant. B. 4′- [(2-Butyl-4-oxo- 1 ,3-diazaspiro [4.41 non- l-en-3-yl)methvn -N-0.4- dimethyl-5-isoxazolyl)-2′-hydroxymethyl[l,l’-biphenyn-2- sulfonamide

Deprotection of 41A (100 mg, 0.14 mmol) according to General Method 8 (ethanol) gave the title compound as white solid in 46% yield following silica gel chromatography (96:4 methanol/chloroform eluant):

MS m/e 565 (ESI+ mode); HPLC retention time 3.21 min (Method A);

HPLC purity >98%.

Example 42

4′-[(2-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methvn-N-(3,4- dimethyl-5-isoxazolyl)-2′-ethoxymethyl [ 1 , l’-biphenyll -2-sulfonamide

A. 4′- [(2-Butyl-4-oxo- 1 ,3-diazaspiro [4.41 non- l-en-3-yl)methyll -N-(3 ,4- dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyll-2′- hvdroxym ethyl [1 , l’-biphenyl] -2-sulfonamide

Triethylsilane (6 ml) and TFA (6 ml) were added to a solution of 5F (960 mg, 1.5 mmol) in 15 ml dichloromethane at RT. The mixture was stirred at RT for 2 h and was then concentrated. The residue was taken up in ethyl acetate and was washed successively with aqueous sodium bicarbonate, water, and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel using 100:2 dichloromethane/methanol to afford 42A (740 mg, 77%) as a colorless gum. Rf=0.13, silica gel, 100:5 dichloromethane/methanol. B. 4′- [(2-Butyl-4-oxo- 1.3-diazaspiro [4.41 non- l-en-3-yl)methyll -N-(3.4- dimethyl-5-isoxazolyl)-N-r(2-methoxyethoxy)methyll-2′- ethoxymethyl[l.l’-biphenyll-2-sulfonamide A mixture of 42A (100 mg, 0.15 mmol), iodoethane (960 mg, 6.1 mmol) and silver (I) oxide (180 mg, 0.77 mmol) in 0.7 ml DMF was heated at 40 ° C for 16 h.. Additional iodoethane (190 mg, 1.2 mmol) and silver (I) oxide (71 mg, 0.31 mmol) were added and the reaction mixture was heated at 40 ° C for an additional 4 h. The mixture was diluted with 1:4 hexanes/ethylacetate and was then washed with water and brine. The organic layer was dried over sodium sulfate and was then concentrated. The residue was chromatographed on silica gel using 200:3 dichloromethane/methanol as eluant to afford 42B (51mg, 49%) as a colorless gum. Rf=0.35, silica gel, 100:5 dichloromethane/methanol.

C. 4^,-[(2-Butyl-4-oxo-1.3-diazaspirof4.41non-l-en-3-yl)methyll-N-(3.4- dimethyl-5-isoxazolyl )-2′-ethoxym ethyl [ 1. l’-biphenyll -2-sulfonamide

42B (51 mg) was deprotected according to General Method 7 to afford the title compound in 80% yield following preparative reverse-phase HPLC purification: white solid; m.p. 74-80 ° C (amorphous); IH NMR (CDCL, )δ0.87(tr, J=7Hz, 3H), 0.99(tr, J=7Hz, 3H), 1.32(m, 2H), 1.59(m, 2H), 1.75-2.02(m, 11H), 2.16(s, 3H), 2.35(m, 2H), 3.38 (m, 2H), 4.23(m, 2H), 4.73(s, 2H), 7.11-7.85 (m, 7H); MS m/e 593 (ESI+ mode); HPLC retention time 18.22 min. (Method E); HPLC purity >97%.

PATENT

WO 2001044239

http://www.google.co.in/patents/WO2001044239A2?cl=en

……………………

Dual angiotensin II and endothelin A receptor antagonists: Synthesis of 2′-substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics
J Med Chem 2005, 48(1): 171

PATENT

WO 2010135350

http://www.google.com/patents/WO2010135350A2?cl=en

Compound 1 :

Example 8 l-Bromo-2-ethoxymethyl-4-hydroxymethylbenzene (Compound 17)

To a solution of ethyl 4-bromo-3-ethoxymethylbenzoate (9.4 g, 33 mmol) in toluene (56 mL) at about -10 ⁰C was added 51 g of a 20% diisobutylaluminum hydride solution in toluene (ca. 70 mmol). The reaction was stirred at the same temperature for about 30 minutes until the reduction was completed, and then quenched with icy 5% NaOH solution to keep the temperature below about 10 °C. Organic phase of the resulting mixture was separated and the aqueous phase was extracted with toluene. The combined organic phase was concentrated in vacuo to a final volume of ~60 mL toluene solution of l-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (Compound 17) that was used in next step without purification.

Example 9 l-Bromo-2-ethoxymethyl-4-methanesulfonyloxymethylbenzene (Compound 18)

To a solution of 1 -bromo-2-ethoxymethyl-4-hydroxymethylbenzene (Compound 17) (8.4 g, 33 mmol) in toluene (60 mL) prepared in Example 8 at about -10 °C was added methanesulfonyl chloride (7.9 g, 68 mmol). The reaction was stirred at the same temperature for about 30 minutes until the reduction was completed, and then quenched with icy water to keep the temperature at about 0 °C. The organic layer was separated and washed again with icy water to provide a crude product solution of 1 – bromo-2-ethoxymethyl-4-methanesulfonyloxymethylbenzene (Compound 18) that was used without purification.

Example 10

1 -Bromo-4-((2-butyl-4-oxo- 1 ,3 -diazaspiro [4.4]non- 1 -en-3 -yl)methy l)-2- ethoxymethylbenzene bisoxalic acid salt (Compound 19)

To the crude solution of 1 -bromo-2-ethoxymethyl-4- methanesulfonyloxymethylbenzene (Compound 18) (1 1 g, 33 mmol) in toluene (80 mL) prepared in Example 9 was added a 75% solution of methyltributylammonium chloride in water (0.47 mL). The resulting mixture was added to a solution of 2-butyl-4-oxo-l,3- diazaspiro[4.4]non-l-ene (compound 7 in Scheme VI) (7.5 g, 32 mmol) in dichloromethane (33 mL) pretreated with a 10 M NaOH solution (23 mL). The reaction mixture was stirred at room temperature for 2 hours until compound 18 was not longer detectable by HPLC analysis and then was quenched with water (40 mL). After stirring about 10 minutes, the organic layer was separated and aqueous layer was extracted with toluene. The combined organic phase was washed with water and concentrated to a small volume. Filtration through a silica gel pad using ethyl acetate as solvent followed by concentration yielded 1 -bromo-4-((2-buty 1-4-oxo- 1 ,3 -diazaspiro [4.4]non- 1 -en-3 – yl)methyl)-2-ethoxymethylbenzene as a crude oil product.

The crude oil was dissolved in ethyl acetate (22 mL) and warmed to around 50 °C. Anhydrous oxalic acid (4.6 g) was added to the warm solution at once and the resulting mixture was stirred until a solution was obtained. The mixture was cooled gradually and the bisoxalic acid salt (compound 19) was crystallized. Filtration and drying provided pure product (compound 19) in 50-60% yield from ethyl 4-bromo-3- ethoxymethylbenzoate in 3 steps. ¹H NMR (400 MHz, CDCl₃) 12.32 (bs, 4H), 7.58 (d, J = 7.8, IH), 7.36 (s, IH), 7.12 (d, J= 7.8, IH), 4.90 (s, 2H), 4.56 (s, 2H), 3.68 (q, J= 7.5, 2H), 2.87-2.77 (m, 2H), 2.40-1.95 (m, 8H), 1.62-1.53 (m, 2H), 1.38-1.28 (m, 4H), and 1.82 (t, J= 7.5, 3H).

Example 11

N-(3,4-Dimethyl-5-isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en- 3yl)methyl-2-ethoxymethylphenyl)phenylsulfonamide (Compound 1)

To a suspension of l-bromo-4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non- l-en-3-yl)methyl)-2-ethoxymethylbenzene bisoxalic acid salt (Compound 19) (5.0 g, 8.3 mmol) in toluene (20 niL) under nitrogen was added water (30 mL) and pH was adjusted to 8-9 by addition of a 2 M NaOH solution at room temperature. The organic phase was separated and mixed with 2-(N-(3,4-dimethyl-5-isoxazolyl)-N- methoxymethylamino)sulfonylphenylboronic acid pinacol ester (Scheme VII, Formula IX, where R⁸is methoxymethyl and M = boronic acid pinacol ester) (3.6 g, 8.5 mmol), bis(dibenzylideneacetone)palladium(0) (Pd(dba)₂) (0.12 g), and a standard phosphine ligand. After a 2 M sodium carbonate solution was added, the reaction mixture was warmed to 70 ⁰C and stirred until the reaction was complete by HPLC analysis. The reaction was cooled to room temperature and quenched with water, and then separated in phases. The organic phase was treated with activated carbon, filtered through a pad of silica gel, and was concentrated to afford a crude mixture.

The crude reaction mixture was dissolved in ethanol (40 mL) after palladium catalyst was removed and was treated with 6 M HCl solution (ca. 40 mL). The mixture was warmed to 75-80 °C and stirred for about 2 hours until the reaction was completed by HPLC analysis. After the mixture was cooled to room temperature, the pH of the mixture was adjusted to 8 by addition of 10 M NaOH solution. The mixture was stirred for 2 more hours and the pH was adjusted to 6 by adding 2 M HCl and the crystal seeds. Filtration of the crystalline solid followed by drying provided N-(3,4-dimethyl-5- isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en-3yl)methyl-2- ethoxymethylphenyl)phenylsulfonamide (Compound 1) as a white solid.¹H NMR (400 MHz, CDCIa) 8.03 (dd, J= 8.0 and 1.2, IH), 7.60 (td, J = 7.5 and 1.5, IH), 7.50 (td, J = 7.7 and 1.5, IH), 7.36 (s, IH), 7.28 (d, J= 2.1, 1 H), 7.25 (dd, J = 7.5 and 1.2, IH), 7.09 (dd, J= 7.9 and 1.6, IH), 6.61 (bs, IH), 4.77 (AB quartet, J= 15.5 and 8.1, 2H), 4.18 (AB quartet, J= 12.0 and 35, 2H), 3.45-3.32 (m, 2H), 2.39 (t, J= 7.5, 2H), 2.26 (s, 3H), 2.02- 1.84 (m, 8H), 1.82 (s, 3H), 1.63 (quint, J= 7.5, 2H), 1.37 (sextet, J= 7.3, 2H), 1.07 (t, J = 7.0, 3H), and 0.90 (t J= 7.3, 3H).

US20040002493 *	Aug 20, 2001	Jan 1, 2004	Kousuke Tani	Benzoic acid derivatives and pharmaceutical agents comprising the same as active ingredient
US20070054806 *	Sep 6, 2006	Mar 8, 2007	Bayer Cropscience Gmbh	Novel sulfonamide-comprising solid formulations
US20070054807 *	Sep 8, 2006	Mar 8, 2007	Bayer Cropscience Gmbh	Storage-stable formulations of sulfonamides

.

Sparsentan

Clinical data
Trade names	Filspari
Other names	RE-021, PS433540
AHFS/Drugs.com	Monograph
MedlinePlus	a623018
License data	US DailyMed: Sparsentan
Pregnancy category	Contraindicated
Routes of administration	By mouth
ATC code	C09XX01 (WHO)
Legal status
Legal status	US: ℞-only[1] EU: Rx-only[2][3]
Identifiers
CAS Number	254740-64-2
PubChem CID	10257882
DrugBank	DB12548
UNII	9242RO5URM
KEGG	D11776
ChEBI	CHEBI:229526
ECHA InfoCard	100.275.317
Chemical and physical data
3D model (JSmol)	Interactive image
show SMILES
show InChI

• Clinical trial number NCT03762850 for “A Study of the Effect and Safety of Sparsentan in the Treatment of Patients With IgA Nephropathy (PROTECT)” at ClinicalTrials.gov

SYN

https://doi.org/10.1021/acs.jmedchem.4c02079
J. Med. Chem. 2025, 68, 2147−2182

Sparsentan (Filspari). Sparsentan (27), marketed by Travere Therapeutics, is an oral, dual endothelin angiotensin receptor antagonist that received accelerated USFDA approval in February 2023 for reducing proteinuria in adults with primary immunoglobulin A (IgA) nephropathy who are at risk of rapid
disease progression.205206,207 Also known as Berger’s disease, IgAnephropathy is an immune-complex mediated disease characterized by deposits of IgA in the kidneys, resulting in inflammation and damage which can eventually lead to kidney failure. Typical treatment of IgA nephropathy has focused
on supportive care to slow kidney decline, for example, lowering blood pressure, reducing proteinuria, and minimizing lifestyle risk factors; immunosuppressive therapy has also been utilized, though it is controversial and carries risks.208 Sparsentan is the first nonimmunosuppressive treatment for IgA nephropathy and has received first-in-class and orphan drug designations. Accelerated approval was based on reduction of proteinuria (which is a risk factor for disease progression) during interim
analysis in phase III clinical trials. 209 endothelin type A (ETASparsentan blocks ) and angiotensin II type 1 receptors(AT1), interrupting the signaling pathway that contributes to disease progression. 210
The structure of the drug combines 211,212 elements that target both of these receptor types.
213 Thesynthesis of sparsentan (27), as shown in Scheme 50 and Scheme 51, was disclosed by Retrophin Pharmaceuticals (now Travere Therapeutics). Its telescoped sequences and isolation of intermediates as salts suggest that this route may be suitable for large-scale manufacturing.
The synthesis of the spirocyclic imidazolinone intermediate 27.7 is shown in Scheme 50.
Displacement of the benzylic bromide in 27.1 with sodium ethoxide produced ether 27.2. Reduction of the ester with sodium borohydride and zinc chloride yielded alcohol 27.3 which was then converted to mesylate 27.4. Reaction with spirocyclic imidazolinone 27.5 under phase transfer conditions
yielded 27.6 whichwasisolatedasthebisoxalatesalt (27.7).The sequence from 27.1 to 27.7 is telescoped, and no yields were given in the patent.
The construction of the biphenyl framework is shown in Scheme 51. Treatment of aryl bromide 27.8 with n-BuLi and triisopropyl borate followed by reaction with pinacol yielded boronic ester 27.9. Intermediates 27.7 and 27.9 were coupled via a Suzuki reaction to form the biphenyl which was isolated as
the camphorsulfonate salt (27.10). The synthesis was finished with deprotection of the methoxymethyl group under acidic conditions followed by recrystallization from isopropanol and heptane to yield sparsentan (27).

(206) Donadio, J. V.; Grande, J. P. IgA nephropathy. N. Engl. J. Med.2002, 347, 738−748.
(207) Fabiano, R. C. G.; Pinheiro, S. V. B.; Simões e Silva, A. C.Immunoglobulin A nephropathy: a pathophysiology view. Inflammation Res. 2016, 65, 757−770.
(208) Floege, J.; Rauen, T.; Tang, S. C. W. Current treatment of IgAnephropathy. Springer Semin. Immunopathol. 2021, 43, 717−728.
(209) Rovin, B.H.; Barratt, J.; Heerspink, H. J. L.; Alpers, C. E.; Bieler,S.; Chae, D.-W.; Diva, U. A.; Floege, J.; Gesualdo, L.; Inrig, J. K.; et al.Efficacy and safety of sparsentan versus irbesartan in patients with IgA
nephropathy (PROTECT): 2-year results from a randomised, active controlled, phase 3 trial. Lancet 2023, 402, 2077−2090.
(210) Komers, R.; Plotkin, H. Dual inhibition of renin-angiotensin aldosterone system and endothelin-1 in treatment of chronic kidney disease. Am. J. Physiol.: Regul., Integr. Comp. Physiol. 2016, 310, R877−
R884.
(211) Murugesan, N.; Tellew, J. E.; Gu, Z.; Kunst, B. L.; Fadnis, L.;Cornelius, L. A.; Baska, R. A. F.; Yang, Y.; Beyer, S. M.; Monshizadegan, H.; et al. Discovery of N-isoxazolyl biphenylsulfonamides as potent dual
angiotensin II and endothelin A receptor antagonists. J. Med. Chem.2002, 45, 3829−3835.
(212) Murugesan, N.; Gu, Z.; Fadnis, L.; Tellew, J. E.; Baska, R. A. F.; Yang, Y.; Beyer, S. M.; Monshizadegan, H.; Dickinson, K. E.; Valentine,M.T.; et al. Dual angiotensin II and endothelin A receptor antagonists:
synthesis of 2′-substituted N-3-isoxazolyl biphenylsulfonamides withimproved potencyandpharmacokinetics. J. Med. Chem. 2005, 48, 171−179.
(213) Komers, R.; Shih, A. Biphenyl sulfonamide compounds for the treatment of kidney diseases or disorders. WO 2018071784, 2018.

//////////////Sparsentan, PS433540, RE-021, Bristol-Myers Squibb, ORPHAN DRUG, Retrophin, fda 2023, approvals 2023

O=S(C1=CC=CC=C1C2=CC=C(CN3C(CCCC)=NC4(CCCC4)C3=O)C=C2COCC)(NC5=NOC(C)=C5C)=O,