Sparsentan, PS433540, RE-021

  

Sparsentan(PS433540,RE-021)

• C₃₂H₄₀N₄O₅S
• Average mass592.749

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

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

J. Med. Chem., 2002, 45 (18), pp 3829–3835

DOI: 10.1021/jm020138n

http://pubs.acs.org/doi/abs/10.1021/jm020138n

 BMS 248360 A DIFFERENT COMPD

The ET_A receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4‘-(2-oxazolyl)-[1,1‘-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT₁ receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT₁ antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4‘-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2‘-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1‘-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT₁ and ET_Areceptors. Compound 15 represents a new approach to treating hypertension.

Scheme 2 ^{a  DIFFERENT COMPD}

^a (a) DIBAL, toluene; (b) NaBH₄, MeOH; (c) (Ph)₃P, CBr₄, THF (51% from 9); (d) compound 7, NaH, DMF; (e) 1 N HCl; (f) compound 4, (Ph₃P)₄Pd, aqueous Na₂CO₃, EtOH/toluene; (g) 6 N aqueous HCl/EtOH (60% from 10); (h) 13, sodium triacetoxy borohydride, AcOH, (i) diisopropylcarbodiimide, CH₂Cl₂ (31% from 12).

..........
WO 2010135350
http://www.google.com/patents/WO2010135350A2?cl=en
Compound 1 :

Scheme IV

Scheme V

Formula IV 1
Scheme VII

Formula Vl

A solution of 2-(2,4-dimethylphenyl)benzenesulfonic acid (Compound 12) (0.5 g, 1.9 mmol) in 50 mL of anhydrous acetonitrile was prepared and transferred to a round-bottom flask. After flushing with nitrogen gas, N-bromosuccinimide (0.75 g, 4.2 mmol) was added followed by 50 mg (0.2 mmol) of benzoyl peroxide. The solution was heated at reflux for 3 hours. The solvent was removed in-vacuo and the resulting syrup purified by silica gel chromatography (1 :1 hexanes/EtOAc) to yield Compound 13 as a white solid. ¹H NMR (500 MHz, CD3CN) 8.12 (d, J = 7.5 Hz, IH), 7.92 (t, J = 7.5 Hz, IH), 7.78 (d, J= 7.5 Hz, IH), 7.74-7.71 (m, 2H), 7.68-7.65 (m, 2H), 5.12 (s, 2H), 4.70 (s, 2H). Example 4 2-(4-Bromomethyl-2-ethoxymethylphenyl)benzenesulfonic acid (Compound 14)

A solution of 20 mg (0.058 mmol) of (l-bromomethylbenzo[3,4- d])benzo[l,2-f]-2-oxa-l,l-dioxo-l-thiocycloheptane (Compound 13) in ethanol was stirred at elevated temperature until the starting material was consumed to give crude product (compound 14) that was used directly in the next step without isolation or purification.
Example 5
2-(4-((2-Butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl>2- ethoxymethylphenyl)benzenesulfonic acid (Compound 15)

To the above ethanol solution of crude 2-(4-bromomethyl-2- ethoxymethylphenyl)benzenesulfonic acid (Compound 14) described in Example 4 was added approximately 25 mL of anhydrous DMF. The ethanol was removed from the system under reduced pressure. Approximately 15 mg (0.065 mmol) of 2-butyl-l,3- diazaspiro[4.4]non-l-en-4-one (compound 7 in Scheme IV) was added followed by 300 μL of a IM solution of lithium bis-trimethylsilylamide in THF. The solution was allowed to stir at room temperature for 3 hours. The solvents were removed under reduced pressure and the remaining residue purified by preparative RP-HPLC employing a Cl 8 column and gradient elution (H₂O:MeCN) affording the title compound as a white solid; [M+H]+ calcd for C₂₇H₃₄N₂O₅S 499.21, found, 499.31 ; ¹H NMR (500 MHz, CD3CN) 8.04 (t, J= 5.5 Hz, IH), 7.44-7.10 (m, 2H), 7.28 (s, IH), 7.22 (d, J= 8.0 Hz, 2H), 7.08- 7.04 (m, 2H), 4.74 (br s, 2H), 4.32 (d, J= 13.0 Hz IH), 4.13 (d, J= 13.0 Hz IH), 3.40- 3.31 (m, 2H), 2.66 (t, J= 8 Hz, 2H), 2.18-2.13 (m, 5H), 1.96-1.90 (m, 2H obscured by solvent), 1.48 (m, 2H), 1.27 (s, J= 7 Hz, 2H), 1.16 (t, J= 7 Hz, 3H), 0.78 (t, J= 7.5 Hz, 3H).
Example 6
2-(4-((2-Butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl>2- ethoxymethylphenyl)benzenesulfonyl chloride (Compound 16)

To a solution of DMF (155 μL, 2 mmol, 2 equiv.) in dichloromethane (5 mL) at 0 ⁰C was added dropwise oxalyl chloride (175 μL, 2 mmol, 2 equiv.) followed by a dichloromethane (5 mL) solution of 2-(4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l- en-3-yl)methyl)-2-ethoxymethylphenyl)benzenesulfonic acid (Compound 15) (0.50 g, 1.0 mmol). The resulting mixture was stirred at 0 ⁰C for ~2 hours, diluted with additional dichloromethane (25 mL), washed with saturated sodium bicarbonate solution (10 mL), water (10 mL), and brine (10 mL), dried over sodium sulfate, and then concentrated to give crude sulfonyl chloride (compound 16) that was used without purification.
Example 7
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)

[0062] To a solution of 5-amino-3,4-dimethylisoxazole (60 mg, 0.54 mmol) in THF at -60 °C was added dropwise potassium tert-butoxide (1 mL of 1 M solution) followed by a solution of crude 2-(4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3- yl)methyl)-2-ethoxymethylphenyl)benzenesulfonyl chloride (Compound 16) (0.28 g, 0.54 mmol) in THF (4 mL). The resulting mixture was stirred at about -60 °C for 1 hour, allowed to warm to room temperature overnight, and then quenched with IN HCl solution to about pH 4. Standard workup of extraction with ethyl acetate, washing with water, drying, and concentration provided the final compounds as a white solid. ¹H NMR (400 MHz, CDCl₃) 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).

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, PS433540, RE-021, Bristol-Myers Squibb, ORPHAN DRUG, Retrophin
O=S(C1=CC=CC=C1C2=CC=C(CN3C(CCCC)=NC4(CCCC4)C3=O)C=C2COCC)(NC5=NOC(C)=C5C)=O

Etelcalcetide, AMG 416, KAI-4169, velcalcetide

H-L-Cys-OH
S— S
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂



AMG 416 IS  (Ac-D-Cys(L-Cys-OH)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂)

Etelcalcetide (AMG 416, KAI-4169, velcalcetide)

The main chain has 7 amino acids, all in the D-configuration. The side-chain cysteine residue is in the L-configuration. The molecular formula of AMG 416 (free base) is C38H73N21O10S2, and has a calculated average molecular mass of 1048.3 Da.

D-Argininamide, N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-, disulfide with L-cysteine, hydrochloride (1:?)

N-Acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide disulfide with L-cysteine hydrochloride

http://www.amgenpipeline.com/pipeline/
WO 2011/014707. , the compound may be represented as follows:
H-L-Cys-OH
S— S
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂
The main chain has 7 amino acids, all in the D-configuration and the side-chain cysteine residue is in the L-configuration. The amino terminal is acetylated and the carboxyl-terminal is amidated. This compound ("AMG-416") has utility for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients. A liquid formulation comprising AMG-416 may be administered to a subject intravenously. The hydrochloride salt of AMG-416 may be represented as follows:
H-L-Cys-OH
S— S
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ · x(HCl)
Therapeutic peptides pose a number of challenges with respect to their formulation. Peptides in general, and particularly those that contain a disulfide bond, typically have only moderate or poor stability in aqueous solution. Peptides are prone to amide bond hydrolysis at both high and low pH.
Disulfide bonds can be unstable even under quite mild conditions (close to neutral pH). In addition, disulfide containing peptides that are not cyclic are particularly prone to dimer formation. Accordingly, therapeutic peptides are often provided in lyophilized form, as a dry powder or cake, for later reconstitution.
A lyophilized formulation of a therapeutic peptide has the advantage of providing stability for long periods of time, but is less convenient to use as it requires the addition of one or more diluents and there is the potential risk for errors due to the use of an improper type or amount of diluent, as well as risk of contamination. In addition, the lyophilization process is time consuming and costly.
H-L-Cys-OH
S— S
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂
Generic Name:Etelcalcetide
Synonym:KAI-4169
CAS Number:1262780-97-1
N-acetyl-D-cysteinyl-S-(L-cysteine disulfide)-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide
Mechanism of Action:Activates calcium sensing receptor on parathyroid glands reducing PTH synthesis and secretion
Indication: secondary hyperparathyroidism associated with chronic kidney disease
Development Stage: Phase III
Developer:KAI Pharmaceuticals/Amgen Inc.
H-L-Cys-OH
S— S
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ · x(HCl)

HYDROCHLORIDE
Generic Name:Etelcalcetide Hydrochloride
AMG 416, KAI-4169, previously also known as velcalcetide hydrochloride
CAS :1334237-71-6
Chemical Name:N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide disulfide with L-cysteine hydrochloride
Mechanism of Action:Activates calcium sensing receptor on parathyroid glands reducing PTH synthesis and secretion
Indication: secondary hyperparathyroidism associated with chronic kidney disease
Development Stage: Phase III
Developer:KAI Pharmaceuticals/Amgen Inc.
Method for preparing etelcalcetide and its salts, particularly hydrochloride. See WO2014210489, for a prior filing claiming stable liquid formulation of etelcalcetide. Amgen, following its acquisition of KAI Pharmaceuticals, and Japanese licensee Ono Pharmaceuticals are developing etelcalcetide, a long-acting iv isozyme-selective peptide-based protein kinase C epsilon inhibitor and agonist of the calcium-sensing receptor, for treating secondary hyperparathyroidism (SHPT) in patients with end-stage renal disease receiving dialysis.
In August 2015, an NDA was submitted seeking approval of the drug for SHPT in patients with chronic kidney disease (CKD) on hemodialysis (HD) in the US.
In September 2015, Amgen filed an MAA under the centralized procedure in the EU for the approval of etelcalcetide for treating SHPT in patients with CKD on HD therapy.
KAI is also investigating a transdermal patch formulation of the drug for treating primary HPT.

AMG 416

Secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis

AMG 416 is a peptide agonist of the human cell surface calcium-sensing receptor (CaSR). It is being investigated as a treatment for secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis.

Etelcalcetide is a novel calcimimetic agent that suppresses the secretion of parathyroid hormone and is in clinical development for the treatment of SHPT in patients with CKD on hemodialysis. Etelcalcetide is administered intravenously three times per week at the end of each dialysis session. It acts by binding to and activating the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in parathyroid hormone (PTH). Sustained elevations in PTH are known to be associated with significant clinical consequences for patients with CKD.

The submission includes data from three Phase 3 studies, all of which met the primary endpoints, including two pooled placebo-controlled trials in more than 1,000 patients and a head-to-head study evaluating etelcalcetide compared with cinacalcet.

About Secondary HyperparathyroidismSHPT is a common and serious condition that is often progressive among patients with CKD, and it affects many of the approximately two million people throughout the world who are receiving dialysis, including 450,000 people in the U.S. The disorder develops early in the course of CKD and usually manifests as increased levels of PTH as a result of increased production from the parathyroid glands (four small glands in the neck). Patients with end stage renal disease who require maintenance dialysis often have substantial elevations of PTH that are commonly associated with abnormal calcium and phosphorus levels and an increased risk of significant clinical consequences.

About Etelcalcetide (AMG 416)Etelcalcetide is a novel calcimimetic agent in clinical development for the treatment of SHPT in CKD patients on hemodialysis that is administered intravenously at the end of the dialysis session. Etelcalcetide binds to and activates the calcium-sensing receptor on the parathyroid gland, thereby decreasing PTH levels.

About Sensipar^® (cinacalcet)Sensipar^® (cinacalcet) is the first oral calcimimetic agent approved by the FDA for the treatment of SHPT in adult patients with CKD on dialysis. Sensipar is not indicated for use in adult patients with CKD who are not on dialysis because of an increased risk of hypocalcemia. The therapy is also approved in the U.S. for treatment of hypercalcemia in adult patients with parathyroid carcinoma and hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy. Sensipar binds to the calcium-sensing receptor, resulting in a drop in PTH levels by inhibiting PTH synthesis and secretion. In addition, the reductions in PTH lower serum calcium and phosphorus levels.

Milestones

• 25 Aug 2015 Preregistration for Secondary hyperparathyroidism in USA (IV)
• 29 May 2015 Pooled analysis efficacy and adverse events data from two phase III trials in secondary hyperparathyroidism released by Amgen
• 21 Apr 2015 Amgen plans to submit Biological License Application to USFDA and Marketing Authorisation Application to EMA for Secondary hyperparathyroidism

PATENT

WO2011014707
http://www.google.com/patents/WO2011014707A2?cl=en

PATENT

WO 2015154031
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015154031&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription
The hydrochloride salt of AMG 416 has the chemical structure:
H-L-Cys-OH
I
s— s
I
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ · x(HCl)
(SEQ ID NO:l)
The main chain has 7 amino acids, all in the D-configuration. The side-chain cysteine residue is in the L-configuration. The molecular formula of AMG 416 (free base) is C38H73N21O10S2, and has a calculated average molecular mass of 1048.3 Da.
AMG 416 and a method for its preparation are described in International Pat. Publication No. WO 2011/014707, which is incorporated herein by reference for any purpose. As described in International Pat. Publication No. WO 2011/014707, AMG 416 may be assembled by solid-phase synthesis from the corresponding Fmoc-protected D-amino acids. After cleavage from the resin, the material may be treated with Boc-L-Cys(NPyS)-OH to form the disulfide bond. The Boc group may then be removed with trifluoroacetate (TFA) and the resulting product purified by reverse-phase high pressure liquid chromatography (HPLC) and isolated as the TFA salt form by lyophilization. The TFA salt can be converted to a pharmaceutically acceptable salt by carrying out a subsequent salt exchange procedure. Such procedures are well known in the art and include, e.g., an ion exchange technique, optionally followed by purification of the resultant product (for example by reverse phase liquid chromatography or reverse osmosis).
There is a need for an efficient method of producing AMG 416, or a pharmaceutically acceptable salt thereof (e.g., AMG 416 HC1), and particularly one appropriate for commercial scale manufacturing.
In a first aspect, provided is a method for preparing AMG 416, the method comprising: providing a resin-bound peptide having a structure selected from the group consisting of Fmoc-D-Cys(Trt)-D-Ala-D- Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:2) and Ac-D-Cys(Trt)-D-Ala-D- Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:3); cleaving the peptide from the solid support; and activating the side chain of the D-Cys residue of the cleaved peptide.
In a second aspect, provided is a method for preparing AMG 416, the method comprising: providing a peptide having a structure of Ac-D-Cys(SPy)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ (SEQ ID NO:4); and contacting the peptide with L-Cys to produce a conjugated product.
In yet a third aspect provided is a method for preparing AMG 416, the method comprising: providing a resin-bound peptide having a structure selected from the group consisting of Fmoc-D-Cys(Trt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:2) and Ac-D-Cys(Trt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:3); cleaving the peptide from the solid support, i.e., to provide an unsupported peptide, and activating the side chain of the D-Cys residue of the unsupported peptide to generate an AMG 416 SPy intermediate (where SPy is 2-pyridinesulfenyl or S-Pyr), dissolving the AMG 416 SPy intermediate in an aqueous 0.1% TFA (trifluoroacetic acid solution), and purifying the AMG 416 SPy derivative by HPLC.
The term "AMG 416", also known as etelcalcetide, formerly known as velcalcetide or KAI-4169, refers to a compound having the chemical name: N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-arginamide disulfide with L-cysteine, which has the following structural formula:
H-L-Cys-OH
I
s— s
I
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂
Reference to AMG 416, or to any compound or AMG 416 fragment, intermediate, or precursor as described herein, is intended to encompass neutral, uncharged forms thereof, as well as pharmaceutically acceptable salts, hydrates and solvates thereof.
The terms "AMG 416 hydrochloride" and "AMG 416 HC1" are interchangeable and refer to a hydrochloride salt form of AMG 416 having the following structural formula:
H-L-Cys-OH
I
s— s
I
Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ · xHCl
BRIEF DESCRIPTION OF THE DRAWINGS
 FIG. 1 shows the chemical structure of AMG 416 (Ac-D-Cys(L-Cys-OH)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂) (SEQ ID NO: l).



 FIG. 2 shows the chemical structure of Rink Amide AM resin and Ac-D-Cys(Trt)- D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-Resin (SEQ ID NO:3).

FIG. 3 shows a reaction scheme in which the SPy intermediate product (Ac-D-Cys(SPy)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂) (SEQ ID NO:4) is formed from the peptidyl-resin (Ac-D-Cys(Trt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-NH-Resin) (SEQ ID NO:3).

FIG. 4 shows a reaction scheme in which a TFA salt of AMG 416 is formed from the SPy intermediate (AA^1_7(SPy)).

FIG. 5 shows a reaction scheme in which the HC1 salt of AMG 416 is formed from the TFA salt of AMG 416.

FIG. 6 shows a reaction scheme in which Boc-D-Arg(Pbf)-OH is formed from Boc-D-Arg-OH.

FIG. 7 shows a reaction scheme in which D-Arg(Pbf)-OH is formed from Boc-D-Arg(Pbf)-OH.

EXAMPLE 5
Purification of the SPy Intermediate and Production of AMG 416 HC1
An alternative method for preparation of AMG 416 HC1 salt is described here. As described in Example 2 above, the SPy intermediate product was dried at 20°C under full vacuum after cleavage from the resin, precipitation and filtration. The precipitate was then dissolved in a 0.1% TFA aqueous solution and loaded onto a C-18 column for HPLC purification. The column was run at <60 bar and the solution temperature was 15-25 °C throughout. The eluents were 0.1% TFA in acetonitrile and 0.1% TFA in water. The fractions were stored at 5°C, they were sampled and then fractions were pooled. The combined pools from two runs were diluted and a concentration/purification run was performed using the same HPLC column to decrease the total volume and remove additional impurities. The fractions were stored at 5°C.
The fractions containing the AMG 416 SPy intermediate were subjected to azeotropic distillation to change the solvent from the 0.1% TFA to a 15% water in IPA solution, charging with IPA as needed. To the resultant AMG 416 SPy intermediate in IPA solution was then added L-Cysteine 1.15 eq and the reaction was allowed to proceed at room temperature for conjugation to occur and to form the AMG 416 TFA salt as described above in Example 4. The AMG 416 TFA solution was added to a solution of 12M aqueous HC1, 0.27 L/kg and IPA 49.4 L/kg over 3 hours via subsurface addition, resulting in direct precipitation of the AMG 416 4.5 HC1 salt. The batch was aged for 3 hours and sampled for analysis.
The material was filtered and slurry washed with 96 wt% IPA, 10 L/kg. The cake was then re-slurried for 4 hours in 10 L/kg of 96% wt% IPA. The material was filtered and further slurry washed with 96% IPA, 10 L/kg and then IPA 10 L/kg. The material was dried under full vacuum at 25°C. The dry cake was dissolved in water 8 L/kg and the batch was concentrated via distillation to remove residual IPA and achieve the desired concentration. The solution temperature was kept below 25 °C throughout the distillation.

PATENT

WO2014210489
SEE
https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=2A32CFD9CE075079399E9DD298899C9D.wapp2nC?docId=WO2014210489&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription
EXAMPLE 1
Solubility of AMG 416 in Succinate Buffered Saline
In this study, the solubility of AMG 416 in succinate buffered-saline was investigated. AMG 416 HC1 (103 mg powder, 80 mg peptide) was dissolved in 200 iL of sodium succinate buffered saline (25 mM succinate, 0.9% saline, pH 4.5). After briefly vortexing, a clear solution was obtained with a nominal concentration of 400 mg/mL. Because expansion of the solution volume was not determined, the solubility of AMG 416 can be conservatively stated as at least 200 mg/mL. Although the maximal solubility was not determined in this experiment, AMG 416 is soluble in pH 4.5 succinate buffered saline to concentrations of at least 200 mg/mL.

REFERENCES

1. "Amgen Submits New Drug Application For Novel Intravenous Calcimimetic Etelcalcetide (AMG 416)”
2. "Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects
3. "Evidence for Chronic Kidney Disease-Mineral and Bone Disorder Associated With Metabolic Pathway Changes”

KAI-4169, a novel calcium sensing receptor agonist, decreases serum iPTH, FGF-23 and improves serum bone markers in a phase 2 study in hemodialysis subjects with chronic kidney disease-mineral and bone disorder
49th Congr Eur Renal Assoc - Eur Dialysis Transpl Assoc (May 24-27, Paris) 2012, Abst SAO054

KAI-4169, a novel peptide agonist of the calcium sensing receptor, attenuates PTH and soft tissue calcification and restores parathyroid gland VDR levels in uremic rats
49th Congr Eur Renal Assoc - Eur Dialysis Transpl Assoc (May 24-27, Paris) 2012, Abst SAO014

Long term safety and efficacy of velcalcetide (AMG 416), a calcium-sensing receptor (CaSR) agonist, for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients
Kidney Week (November 5-10, Atlanta, GA) 2013, Abst SA-PO575

Preclinical PK and PD relationship for KAI-4169, a novel calcimimetic
93rd Annu Meet Endo Soc (June 4-7, Boston) 2011, Abst P1-198

KAI-4169, a novel calcimimetic for the treatment of secondary hyperparathyroidism
93rd Annu Meet Endo Soc (June 4-7, Boston) 2011, Abst P2-98

Characterization of KAI-4169, a novel peptide for the treatment of chronic kidney disease - Mineral and bone disorder, in a phase I study in healthy males
44th Annu Meet Am Soc Nephrol (ASN) (November 8-13, Philadelphia) 2011, Abst FR-PO1238

WO2011014707A2

Jul 29, 2010

Feb 3, 2011

Kai Pharmaceuticals, Inc.

Therapeutic agents for reducing parathyroid hormone levels

//////////////Etelcalcetide,  AMG 416, KAI-4169, velcalcetide

BMS-248360, A NEW SARTAN ON HORIZON

2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-[(3,3-dimethyl-2-oxopyrrolidin-1-yl)methyl]phenyl]-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide

4‘-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2‘-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1‘-biphenyl]-2-sulfonamide,

4'- . (2-Butyl-4-oxo- 1 ,3-diazaspiro [4.41 non-l-en-3-yl)methyll -N-C3.4- dimethyl-5-isoxazolyl)-2^,-[(3.3-dimethyl-2-oxo-l- pyrrolidinvDmethyll [1.1 '-biphenyl] -2-sulfonamide

4‘-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2‘-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1‘-biphenyl]-2-sulfonamide

BMS-248360

PRECLINICAL .....treating hypertension

Bristol Myers Squibb Co, INNOVATOR

Hypertension remains one of the largest unmet medical needs in the 21st century, especially when one considers that hypertension is the portent of future debilitating cardiovascular disease. While many drugs are available for treating the disease, approximately one-third of the hypertensive population is still not adequately treated. Of the more recent avenues explored for treating hypertension, disruption of the effects of either angiotensin II (AII) or endothelin-1 (ET-1) has shown promise. These endogenous vasoactive peptides are among the most potent vasoconstrictors and cell proliferative factors identified to date. AII is the effector molecule of the renin−angiotensin system (RAS), and a large number of AII receptor (AT₁) antagonists, including irbesartan , have been developed for treating hypertension

SYNTHESIS

picked from.......http://www.drugfuture.com/synth/syndata.aspx?ID=324487

EP 1094816; JP 2002519380; US 2002143024; WO 0001389

The intermediate biphenyl aldehyde (XI) is prepared by two related methods. 4-Bromo-3-methylbenzonitrile (I) is oxidized to aldehyde (II) via radical bromination with N-bromosuccinimide/benzoyl peroxide, followed by treatment with trimethylamine N-oxide. Suzuki coupling of aryl bromide (II) with the pinacol boronate (III) affords biphenyl (IV). After protection of the aldehyde moiety of (IV) as the corresponding ethylene ketal (V), its cyano group is reduced to aldehyde (VI) employing DIBAL in THF. Subsequent reduction of (VI) with NaBH4 leads to alcohol (VII), which is further converted into the benzyl bromide (VIII) by means of CBr4/PPh3. Bromide (VIII) is condensed with the spiro imidazolone (IX) in the presence of NaH, to produce (X). Then acidic hydrolysis of the ethylene ketal and SEM groups of (X) gives rise to the intermediate aldehyde (XI)

NEXT

Alternatively, reduction of 4-bromo-3-formylbenzonitrile ethylene ketal (XII) by means of DIBAL leads to aldehyde (XIII), which is further reduced to alcohol (XIV) with NaBH4. After bromination of (XIV) with CBr4/PPh3, the resultant benzyl bromide (XV) is condensed with the spiro imidazolone (IX), yielding (XVI). Then, acidic ketal hydrolysis in (XVI) furnishes aldehyde (XVII). Suzuki coupling between aryl bromide (XVII) and boronic acid (XVIII) gives biphenyl (XIX). The SEM group of (XIX) is then removed under acidic conditions to provide (XI)

Reductive amination of the biphenyl aldehyde (XI) with 4-amino-2,2-dimethylbutanoic acid (XX) in the presence of NaBH(OAc)3 produces aminoacid (XXI). This is finally cyclized to the corresponding lactam by treatment with DIC

Coupling of 2-bromobenzenesulfonyl chloride (I) with 5-amino-3,4-dimethylisoxazole (II) affords sulfonamide (III), which is further protected as the N-methoxyethoxymethyl derivative (IV) employing MEM-chloride in DMF. Lithiation of bromosulfonamide (IV), followed by treatment with trimethyl borate and acidic work up leads to the boronic acid intermediate (V). This is then subjected to Suzuki coupling with 4-bromo-3-methylbenzaldehyde (VI) to yield the biphenyl adduct (VII). After reduction of aldehyde (VII) to the benzylic alcohol (VIII) with NaBH4, reaction with methanesulfonyl chloride and diisopropylethylamine gives rise to the mesylate (IX) (1-3).

Mesylate (IX) is condensed with ethyl 2-propyl-4-ethylimidazole-5-carboxylate (X) yielding (XI). Simultaneous ester group hydrolysis and MEM group deprotection under acidic conditions gives rise to the imidazolecarboxylic acid (XII). This is finally coupled with methylamine via activation with CDI to produce the desired N-methyl carboxamide (1-3).

Reductive amination of the biphenyl aldehyde (XI) with 4-amino-2,2-dimethylbutanoic acid (XX) in the presence of NaBH(OAc)3 produces aminoacid (XXI). This is finally cyclized to the corresponding lactam by treatment with DIC

PAPER

J. Med. Chem., 2002, 45 (18), pp 3829–3835

DOI: 10.1021/jm020138n

http://pubs.acs.org/doi/abs/10.1021/jm020138n

 BMS 248360

The ET_A receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4‘-(2-oxazolyl)-[1,1‘-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT₁ receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT₁ antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4‘-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2‘-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1‘-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT₁ and ET_Areceptors. Compound 15 represents a new approach to treating hypertension.

Scheme 2 ^a  

^a (a) DIBAL, toluene; (b) NaBH₄, MeOH; (c) (Ph)₃P, CBr₄, THF (51% from 9); (d) compound 7, NaH, DMF; (e) 1 N HCl; (f) compound 4, (Ph₃P)₄Pd, aqueous Na₂CO₃, EtOH/toluene; (g) 6 N aqueous HCl/EtOH (60% from 10); (h) 13, sodium triacetoxy borohydride, AcOH, (i) diisopropylcarbodiimide, CH₂Cl₂ (31% from 12).

15 as a white solid (40 mg, 31%): 

mp 104−110 °C;

¹H NMR (CDCl₃) δ 0.90 (t, J = 7.0 Hz, 3H), 1.08 (s, 3H), 1.14 (s, 3H), 1.36 (m, 2H), 1.61 (m, 2H), 1.75−2.06 (m, 13H), 2.17 (s, 3H), 2.39 (m, 2H), 4.18 (m, 2H), 4.71 (m, 2H), 7.02−7.93 (m, 7H);

¹³CNMR (CDCl₃ ) δ 7.82, 11.91, 14.79, 23.36, 25.50, 25.61, 27.11, 28.81, 29.88, 35.33, 38.42, 41.48, 44.59, 46.24, 46.47, 109.29, 125.15, 125.76, 129.68, 130.58, 131.76, 133.20, 134.07, 137.15, 138.27, 139.11, 139.57, 155.81, 162.68, 162.91, 181.25, 187.83.

Anal. (C₃₆H₄₅N₅O₅S) C, H, N, S.

.................................

PATENT

US 2002143024

http://www.google.com/patents/US20020143024

Zhang, H.-Y. et al., Tetrahedron, 1994, 50, 11339-11362.

N-(3,4-Dimethyl-5-iso-xazolyl)-2′-formyl-4′-(hydroxy-methyl)-N-[[2-(tri-methylsilyl)ethoxy]- methyl][1,1′- biphenyl]-2- sulfonamide

Example 3 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-formyl-N-(3,4-dimethyl-5-isoxazolyl)-[1,1′-biphenyl]-2-sulfonamide

[0414]

 

 

Example 3 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-formyl-N-(3,4-dimethyl-5-isoxazolyl)-[1,1′-biphenyl]-2-sulfonamide

A. 4′-Cyano-2′-(1,3-dioxolan-2-yl)-N-(3,4-dimethyl-5-isoxazolyl)-N-(2-methoxyethoxymethyl)[1,1′-biphenyl]-2-sulfonamide

A mixture of 2B (1.28 g, 2.73 mmol), ethylene glycol (1.69 g, 27.3 mmol) and p-toluenesulfonic acid (38 mg) in toluene (30 mL) was heated at 130° C. for 5 h, while a Dean-Stark water separator was used. After cooling, the mixture was diluted with EtOAc. The organic liquid was separated and washed with H₂O and brine, dried and concentrated. The residue was chromatographed on silica gel using 5:4 hexane/EtOAc to afford 3A (1.1 g, 79%) as a colorless gum: R_f=0.57, silica gel, 1:2 hexane/EtOAc.

B. 2′-(1,3-Dioxolan-2-yl)-4′-formyl-N-(3,4-dimethyl-5-isoxazolyl)-N-(2-methoxyethoxymethyl)[1,1′-biphenyl]-2-sulfonamide

 To 3A (1.1 g, 2.14 mmol) in THF (21 mL) at 0° C. was added DIBAL-H (1M in CH₂Cl₂, 4.28 mL 4.28 mmol) dropwise. The reaction was stirred at RT overnight. MeOH (20 mL) was added and the reaction was stirred for 5 min. The mixture was poured into cold 0.1 N HCl solution (150 mL), shaken for 5 min, and then extracted with 3:1 EtOAc/hexane. The combined organic extracts were washed with H₂O and brine, dried and concentrated. The residue was chromatographed on silica gel using 3:4 hexane/EtOAc to afford 3B (710 mg, 64%) as a colorless gum: R_f=0.45, silica gel, 2:3 hexane/EtOAc.

 C. 2′-(1,3-Dioxolan-2-yl)-4′-hydroxymethyl-N-(3,4-dimethyl-5-isoxazolyl)-N-(2-methoxyethoxymethyl) [1,1′-biphenyl]-2-sulfonamide

 3B (710 mg, 1.4 mmol) was subjected to sodium borohydride reduction according to General Method 11 to afford 3C, which was used for the next reaction step without further purification.

 D. 4′-Bromomethyl-2′-(1,3-dioxolan-2-yl)-N-(3,4′-dimethyl-5-isoxazolyl)-N-(2-methoxyethoxymethyl) [1,1′-biphenyl]-2-sulfonamide

3C was treated with carbon tetrabromide and triphenylphosphine according to General Method 2. The crude residue was chromatographed on silica gel using 3:2 hexane/EtOAc to afford 3D (750 mg, 94%) as a colorless gum: R_f=0.74, silica gel, 1:2 hexane/EtOAc.

 E. 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-(1,3-dioxolan-2-yl)-N-(3,4-dimethyl-5-isoxazolyl)-N-(2-methoxyethoxymethyl)[1,1′-biphenyl]-2-sulfonamide

 3D (750 mg, 1.3 mmol) was treated with 2-n-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride (387 mg, 1.68 mmol) according to General Method 4. The crude residue was chromatographed on silica gel using 100:1.7 CH₂Cl₂/MeOH to afford 3E as a gum (830 mg, 93%): R_f=0.40, silica gel, 100:5 CH₂Cl₂/MeOH.

F. 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-formyl-N-(3,4-dimethyl-5-isoxazolyl)-[1,1′-biphenyl]-2-sulfonamide

3E (830 mg, 1.20 mmol) was subjected to deprotection according to General Method 7. The crude residue was chromatographed on silica gel using 100:1.5 and then 100:4 CH₂Cl₂ /MeOH to afford the title compound as a gum (480 mg, 72%): R_f=0.16, silica gel, 100:5 CH₂Cl₂/MeOH.

Example 4 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2′-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl][1,1′-biphenyl]-2-sulfonamide

 To 3F (110 mg, 0.20 mmol) in CH₂Cl₂ (4 mL) was added 4-amino-2,2-dimethylbutanoic acid hydrochloride (98 mg, 0.59 mmol) [Scheinmann, et al., J. Chem. Research (S), 414-415 (1993)] and 3 Å molecular sieves, followed by glacial acetic acid (35 mg, 0.59 mmol) and then sodium acetate (48 mg, 0.59 mmol). The mixture was stirred for 8 minutes, and NaB(AcO)₃H (124 mg, 0.59 mmol) was then added. The reaction mixture was stirred at RT for 2 h, diluted with EtOAc and filtered through celite. The filtrate was washed with H₂O and brine, dried and concentrated. This material was dissolved in CH₂Cl₂ (6 mL) and 1,3-diisopropylcarbodiimide (32 mg, 0.25 mmol) was added. The reaction mixture was stirred at RT for 2 h and diluted with CH₂Cl₂, washed with H₂O and brine, dried and concentrated. The residue was purified by preparative HPLC to provide the title compound as a white solid (40 mg, 31%, for two steps): mp 104-110° C. Analysis calculated for C₃₆H₄₅N₅O₅S.0.8 H₂O: Calc'd: C, 64.13; H, 6.97; N, 10.39; S, 4,75. Found: C, 64.18; H, 6.60; N, 10.23; S, 4.50.

Example 5 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-formyl-N-(3,4-dimethyl-5-isoxazolyl)-[1,1′-biphenyl]-2-sulfonamide (Alternative Preparation for 3F)

 A. 2-[(2′-Bromo-5′-formyl)phenyl)]-1,3-dioxolane

DIBAL-H (1.0 M solution in toluene, 445 mL, 445 mmol, 1.1 eq) was added over 30 minutes to a solution of 2-[(2′-bromo-5′-cyano)phenyl)]-1,3-dioxolane (103 g, 404 mmol, 1.0 eq) [Zhang, H.-Y. et al., Tetrahedron, 50, 11339-11362 (1994)] in toluene (2.0 L) at −78° C. The solution was allowed to warm to 0° C. After 1 hour, a solution of Rochelle's salt (125 g) in water (200 mL) was added, and the mixture was allowed to warm to room temperature and was stirred vigorously for 16 h. The organic layer was concentrated and the residue partitioned between ethyl acetate (1 L) and 1 N hydrochloric acid (800 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (800 mL), dried over sodium sulfate, and then concentrated to give 70.5 g of crude 5A as a yellow solid, which was used without further purification.

 B. 2-[(2′-Bromo-5′-hydroxymethyl)phenyl)]-1,3-dioxolane

Sodium borohydride (3.66 g, 96.7 mmol, 0.5 eq) was added to a solution of crude 5A (49.7 g, approximately 193 mmol, 1.0 eq) in absolute ethanol (1300 mL) at 0° C. After 2 hours, a solution of 10% aqueous sodium dihydrogen phosphate (50 mL) was added and the mixture was stirred and allowed to warm to room temperature. The mixture was concentrated, then partitioned between ethyl acetate (800 mL) and saturated aqueous sodium bicarbonate (500 mL). The organic layer was dried over sodium sulfate and concentrated to give 49.0 g of crude 5B as a yellow oil, which was used without further purification.

 C. 2-[(2′-Bromo-5′-bromomethyl)phenyl)]-1,3-dioxolane

Triphenylphosphine (52.7 g, 199 mmol, 1.05 eq) was added in portions over 15 minutes to a solution of crude 5B (49.0 g, approximately 189 mmol, 1.0 eq) and carbon tetrabromide (69.0 g, 208 mmol, 1.1 eq) in THF at 0° C. After 2 hours, saturated aqueous sodium bicarbonate solution (20 mL) was added, and the mixture was allowed to warm to room temperature and was then concentrated. Ether (500 mL) was added, and the resulting mixture was filtered. The filtrate was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (8:1 hexanes/ethyl acetate as eluant) to give 5C as a white solid (31.1 g, 51% yield from 2-[(2′-bromo-5′-cyano)phenyl)]-1,3-dioxolane).

 D. 2-(1,3-Dioxolan-2-yl)-4-[(2-n-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]bromobenzene

[0436] Sodium hydride (60% dispersion in mineral oil, 9.65 g, 241 mmol, 2.5 eq) was added in portions over 15 minutes to a mixture of 2-n-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride (18.7 g, 96.5 mmol, 1.0 eq) in DMF (400 mL) at 0° C. The mixture was stirred and allowed to warm to room temperature over 15 minutes. To this mixture was added via canula a solution of 5C (31.1 g, 96.5 mmol, 1.0 eq) in DMF (100 mL). After 14 hours, the mixture was concentrated in vacuo and partitioned between ethyl acetate (500 mL) and 10% aqueous sodium dihydrogen phosphate (300 mL). The organic layer was dried over sodium sulfate and concentrated to give crude 5D as an orange oil (42.7 g), which was used without further purification.

E. 4-[(2-n-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-formyl-bromobenzene

 A solution of crude 5D (6.0 g, approximately 13.6 mmol, 1.0 eq) in THF (180 mL) and 1N hydrochloric acid (30 mL) was heated at 65° C. for 1.5 hours. The mixture was cooled and then treated with saturated aqueous sodium carbonate solution (75 mL) and ethyl acetate (200 mL). The organic layer was removed and dried over sodium sulfate, concentrated, and then further dried azeotropically with toluene to give 5E as a crude yellow oil (8.2 g) which contained a small amount of toluene. This material was used without further purification.

F. 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-formyl-N-(3,4-dimethyl-5-isoxazolyl)-N-(2-methoxyethoxymethyl)[1,1′-biphenyl]-2-sulfonamide

Palladium catalyzed Suzuki coupling of 5E and [2-[[(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino]sulfonyl]phenyl]boronic acid was performed according to General Method 1 to yield 5F in 60% yield.

 G. 4′-[(2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2′-formyl-N-(3,4-dimethyl-5-isoxazolyl)-[1,1′-biphenyl]-2-sulfonamide

 Deprotection of 5F according to General Method 7 provided the title compound (5G=3F) in 73% yield: R_f=0.2 (silica gel using CH₂Cl₂/MeOH [100:5]).

PATENT

EP 1237888; WO 0144239

Example 3 4'-r(2-Butyl-4-oxo-1.3-diazaspiror4.41non-l-en-3-yl)methvn-2'-formyl-N-

(3, 4-dimethyl-5-isoxazolyl)-[ 1,1 '-biphenyl] -2-sulfonamide

A. 4'-Cvano-2^>-(1.3-dioxolan-2-yl)-N-(3.4-dimethyl-5-isoxazolyl)-N-(2- methoxyethoxymethyl) [1.1 '-biphenyl] -2-sulfonamide

A mixture of 2B (1.28 g, 2.73 mmol), ethylene glycol (1.69 g, 27.3 mmol) and p-toluenesulfonic acid (38 mg) in toluene (30 mL) was heated at 130°C for 5 h, while a Dean-Stark water separator was used. After cooling, the mixture was diluted with EtOAc. The organic liquid was separated and washed with H₂O and brine, dried and concentrated. The residue was chromatographed on silica gel using 5:4 hexane/EtOAc to afford 3A (1.1 g, 79%) as a colorless gum: R^0.57, silica gel, 1:2 hexane EtOAc.

B. 2^,-(1.3-Dioxolan-2-yl)-4'-formyl-N-(3.4-dimethyl-5-isoxazolyl)-N-(2- methoxyethoxymethyl) [1 , l'-biphenyl] -2-sulfonamide To 3A (1.1 g, 2.14 mmol) in THF (21 mL) at 0°C was added DIBAL- H (IM in CH₂C1₂, 4.28 mL 4.28 mmol) dropwise. The reaction was stirred at RT overnight. MeOH (20 mL) was added and the reaction was stirred for 5 min. The mixture was poured into cold 0.1 N HCI solution (150 mL), shaken for 5 min, and then extracted with 3:1 EtOAc/hexane. The combined organic extracts were washed with H₂O and brine, dried and concentrated. The residue was chromatographed on silica gel using 3:4 hexane/EtOAc to afford 3B (710 mg, 64%) as a colorless gum: R^O.45, silica gel, 2:3 hexane/EtOAc. C. 2'-(1.3-Dioxolan-2-yl)-4'-hvdroxymethyl-N-(3.4-dimethyl-5- isoxazolyl)-N-(2-methoxyethoxymethyl) [1.1 '-biphenyl] -2- sulfonamide

3B (710 mg, 1.4 mmol) was subjected to sodium borohydride reduction according to General Method 11 to afford 3C, which was used for the next reaction step without further purification.

D. 4^l-Bromomethyl-2^,-(1.3-dioxolan-2-yl)-N-(3.4-dimethyl-5-isoxazolyl)- N-(2-methoxyethoxymethyl) [1 , l'-biphenyl] -2-sulfonamide 3C was treated with carbon tetrabromide and triphenylphosphine according to General Method 2. The crude residue was chromatographed on silica gel using 3:2 hexane/EtOAc to afford 3D (750 mg, 94%) as a colorless gum: R^0.74, silica gel, 1:2 hexane/EtOAc.

E. 4'-[(2-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methvn- 2^,-(1.3- dioxolan-2-yl)-N-(3.4-dimethyl-5-isoxazolyl)-N-(2- methoxyethoxymethyl) [ 1. l'-biphenyll -2-sulfonamide 3D (750 mg, 1.3 mmol) was treated with 2-re-butyl-l,3- diazaspiro[4.4]non-l-en-4-one hydrochloride (387 mg, 1.68 mmol) according to General Method 4. The crude residue was chromatographed on silica gel using 100:1.7 CH₂CL/MeOH to afford 3E as a gum (830 mg, 93%): R^O.40, silica gel, 100:5 CH₂Cl₂/MeOH.

F. 4'-r(2-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methyl1-2^,- formyl-N-(3.4-dimethyl-5-isoxazolyl)-[l.l'-biphenyl1-2-sulfonamide

3E (830 mg, 1.20 mmol) was subjected to deprotection according to General Method 7. The crude residue was chromatographed on silica gel using 100:1.5 and then 100:4 CH₂C1₂ /MeOH to afford the title compound as a gum (480 mg, 72%): R^O.16, silica gel, 100:5 CH.Cl MeOH.

Example 4

4'- . (2-Butyl-4-oxo- 1 ,3-diazaspiro [4.41 non-l-en-3-yl)methyll -N-C3.4- dimethyl-5-isoxazolyl)-2^,-[(3.3-dimethyl-2-oxo-l- pyrrolidinvDmethyll [1.1 '-biphenyl] -2-sulfonamide

To 3F (110 mg, 0.20 mmol) in CH₂C1₂ (4 mL) was added 4-amino- 2,2-dimethylbutanoic acid hydrochloride (98 mg, 0.59 mmol) [Scheinmann, et al., J. Chem. Research (S), 414-415 (1993)] and 3A molecular sieves, followed by glacial acetic acid (35 mg, 0.59 mmol) and then sodium acetate (48 mg, 0.59 mmol). The mixture was stirred for 8 minutes, and NaB(AcO)₃H (124 mg, 0.59 mmol) was then added. The reaction mixture was stirred at RT for 2 h, diluted with EtOAc and filtered through celite. The filtrate was washed with H₂O and brine, dried and concentrated. This material was dissolved in CH₂C1₂ (6 mL) and 1,3-diisopropylcarbodiimide (32 mg, 0.25 mmol) was added. The reaction mixture was stirred at RT for 2 h and diluted with CH₂C1₂, washed with H₂O and brine, dried and concentrated. The residue was purified by preparative HPLC to provide the title compound as a white solid (40 mg, 31%, for two steps): mp 104- 110°C. Analysis calculated for C₃₆H₄₅N₅O₅S • 0.8 H₂O: Calc'd: C, 64.13; H, 6.97; N, 10.39; S, 4,75. Found: C, 64.18; H, 6.60; N, 10.23; S, 4.50.

Example 5

4'-[(2-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methyl1-2^,-formyl-N-

(3,4-dimethyl-5-isoxazolyl)-[l,l'-biphenyl]-2-sulfonamide (Alternative

Preparation for 3F)

A. 2-[(2'-Bromo-5'-formyl)phenyl)1-1.3-dioxolane

DIBAL-H (1.0 M solution in toluene, 445 mL, 445 mmol, 1.1 eq) was added over 30 minutes to a solution of 2-[(2'-bromo-5'-cyano)phenyl)]-l,3- dioxolane (103 g, 404 mmol, 1.0 eq) [Zhang, H.-Y. et al., Tetrahedron, 50, 11339-11362 (1994)] in toluene (2.0 L) at -78 °C. The solution was allowed to warm to 0 °C. After 1 hour, a solution of Rochelle's salt (125 g) in water (200 mL) was added, and the mixture was allowed to warm to room temperature and was stirred vigorously for 16 h. The organic layer was concentrated and the residue partitioned between ethyl acetate (1 L) and 1 N hydrochloric acid (800 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (800 mL), dried over sodium sulfate, and then concentrated to give 70.5 g of crude 5A as a yellow solid, which was used without further purification.

B. 2-[(2'-Bromo-5'-hvdroxymethyl)phenyl)l-1.3-dioxolane

Sodium borohydride (3.66 g, 96.7 mmol, 0.5 eq) was added to a solution of crude 5A (49.7 g, approximately 193 mmol, 1.0 eq) in absolute ethanol (1300 mL) at 0 °C. After 2 hours, a solution of 10% aqueous sodium dihydrogen phosphate (50 mL) was added and the mixture was stirred and allowed to warm to room temperature. The mixture was concentrated, then partitioned between ethyl acetate (800 mL) and saturated aqueous sodium bicarbonate (500 mL). The organic layer was dried over sodium sulfate and concentrated to give 49.0 g of crude 5B as a yellow oil, which was used without further purification. C. 2-[(2'-Bromo-5'-bromomethyl)phenyl)]-l,3-dioxolane Triphenylphosphine (52.7 g, 199 mmol, 1.05 eq) was added in portions over 15 minutes to a solution of crude 5B (49.0 g, approximately 189 mmol, 1.0 eq) and carbon tetrabromide (69.0 g, 208 mmol, 1.1 eq) in THF at 0 °C. After 2 hours, saturated aqueous sodium bicarbonate solution (20 mL) was added, and the mixture was allowed to warm to room temperature and was then concentrated. Ether (500 mL) was added, and the resulting mixture was filtered. The filtrate was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (8:1 hexanes/ethyl acetate as eluant) to give 5C as a white solid (31.1 g, 51% yield from 2-[(2'-bromo-5'-cyano)phenyl)]-l,3-dioxolane).

D. 2-( 1 ,3-Dioxolan-2-yl)-4- [ (2-re-butyl-4-oxo- 1 ,3-diazaspiro [4.4] non- 1- en-3-yl)methyl] bromobenzene Sodium hydride (60% dispersion in mineral oil, 9.65 g, 241 mmol,

2.5 eq) was added in portions over 15 minutes to a mixture of 2-rc-butyl- l,3-diazaspiro[4.4]non-l-en-4-one hydrochloride (18.7 g, 96.5 mmol, 1.0 eq) in DMF (400 mL) at 0°C. The mixture was stirred and allowed to warm to room temperature over 15 minutes. To this mixture was added via canula a solution of 5C (31.1 g, 96.5 mmol, 1.0 eq) in DMF (100 mL). After 14 hours, the mixture was concentrated in vacuo and partitioned between ethyl acetate (500 mL) and 10% aqueous sodium dihydrogen phosphate (300 mL). The organic layer was dried over sodium sulfate and concentrated to give crude 5D as an orange oil (42.7 g), which was used without further purification.

E. 4-[(2-n-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methyl1-2- formyl-bromobenzene

A solution of crude 5D (6.0 g, approximately 13.6 mmol, 1.0 eq) in THF (180 mL) and IN hydrochloric acid (30 mL) was heated at 65°C for 1.5 hours. The mixture was cooled and then treated with saturated aqueous sodium carbonate solution (75 mL) and ethyl acetate (200 mL). The organic layer was removed and dried over sodium sulfate, concentrated, and then further dried azeotropically with toluene to give 5E as a crude yellow oil (8.2 g) which contained a small amount of toluene. This material was used without further purification.

F. 4'-.(2-Butyl-4-oxo-1.3-diazaspiro■4.41non-l-en-3-yl)methyl1-2^,- formyl-N-(3,4-dimethyl-5-isoxazolyl)-N-(2-methoxyethoxymethyl) f 1.1 '-biphenyl] -2-sulfonamide Palladium catalyzed Suzuki coupling of 5E and [2-[[(3,4-dimethyl-5- isoxazolyl) [(2-methoxyethoxy)methyl] amino] sulfonyl] phenyl]boronic acid was performed according to General Method 1 to yield 5F in 60% yield.

G. 4'-[ 2-Butyl-4-oxo-1.3-diazaspiro[4■41non-l-en-3-yl)methvn-2^,- formyl-N-(3 ,4-dimethyl-5-isoxazolyl)- fi .1 '-biphenyl] -2-sulfonamide

Deprotection of 5F according to General Method 7 provided the title compound (5G = 3F) in 73% yield: R^0.2 (silica gel using CH₂ClJ eOH [100:5]).

Patent	Submitted	Granted
Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists [US6638937]	2002-10-03	2003-10-28
Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists [US6835741]	2004-06-03	2004-12-28
Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists [US6852745]	2004-07-01	2005-02-08

///////////BMS-248360, Preclinical, SARTAN, BMS, HYPERTENTION

CCCCC1=NC2(CCCC2)C(=O)N1CC3=CC(=C(C=C3)C4=CC=CC=C4S(=O)(=O)NC5=C(C(=NO5)C)C)CN6CCC(C6=O)(C)C