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Showing posts with label RE-021. Show all posts
Showing posts with label RE-021. Show all posts

Sunday 18 October 2015

Sparsentan, PS433540, RE-021

  Figure imgf000137_0001

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
Figure imgf000030_0001

Figure imgf000033_0001
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
Figure imgf000136_0001
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
Figure imgf000137_0001
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
Abstract Image BMS 248360 A DIFFERENT COMPD
The ETA 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 ETAreceptors. Compound 15 represents a new approach to treating hypertension.
Figure
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 :
Figure imgf000003_0001
Scheme IV
Figure imgf000013_0003
Scheme V
Figure imgf000015_0001
Formula IV 1
Scheme VII
Figure imgf000016_0001
Formula Vl
Figure imgf000016_0002
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)
Figure imgf000019_0001
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)
Figure imgf000019_0002
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)
Figure imgf000020_0001
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)
Figure imgf000021_0001
[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)
Figure imgf000021_0002
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)
Figure imgf000022_0001
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)
Figure imgf000022_0002
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)
Figure imgf000023_0001
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, 2001Jan 1, 2004Kousuke TaniBenzoic acid derivatives and pharmaceutical agents comprising the same as active ingredient
US20070054806 *Sep 6, 2006Mar 8, 2007Bayer Cropscience GmbhNovel sulfonamide-comprising solid formulations
US20070054807 *Sep 8, 2006Mar 8, 2007Bayer Cropscience GmbhStorage-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