Chiglitazar

Chiglitazar

CAS 743438-45-1

Ingredient	UNII	CAS	InChI Key
Chiglitazar sodium, (S)-	YN12H6OCV6	2390374-10-2	RMVIEXHXRDCWBT-UCRKPPETSA-M

• CS 038
• Carfloglitazar, (s)-
• E6EJV1J6Y0
• (2S)-3-[4-(2-carbazol-9-ylethoxy)phenyl]-2-[2-(4-fluorobenzoyl)anilino]propanoic acid
• C₃₆H₂₉FN₂O₄
• 572.6 g/mol

• (2S)-3-[4-(2-carbazol-9-ylethoxy)phenyl]-2-[2-(4-fluorobenzoyl)anilino]propanoic acid
• (2S)-3-(4-(2-CARBAZOL-9-YLETHOXY)PHENYL)-2-(2-(4-FLUOROBENZOYL)ANILINO)PROPANOIC ACID
• (2s)-3-(4-(2-carbazol-9-ylethoxy)phenyl)-2-(2-(4-fluorobenzoyl)anilino)propanoic acid
• Carfloglitazar, (s)-
• L-tyrosine, o-(2-(9h-carbazol-9-yl)ethyl)-n-(2-(4-fluorobenzoyl)phenyl)-
• O-(2-(9h-carbazol-9-yl)ethyl)-n-(2-(4-fluorobenzoyl)phenyl)-l-tyrosine

Chiglitazar was developed by Chipscreen Biosciences and was approved in China for improving glycemic control in adult
patients with type2 diabetes in October2021.

Chiglitazar (trade name Bilessglu) is a drug for the treatment of type 2 diabetes.^[1] It is a peroxisome proliferator-activated receptor (PPAR) agonist.

In China, chiglitazar is approved for glycemic control in adult patients with type 2 diabetes when used in combination with diet and exercise.^[2]

Chiglitazar is under investigation in clinical trial NCT06125587 (Chiglitazar/metformin in Non-obese Women With PCOS).

SYN

WO 2004048333

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004048333&_cid=P12-MDMUOB-48741-1

Example 15
Preparation of 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-[4-(2-carbazolylethoxy)-phenyl]
-propionic acid (compound CS038)

To a solution of 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl] -propionic acid methyl ester (0.25 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30ml) is added, and the mixture is washed with water (3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl₃/MeOH (4:1) as eluent to give the title compound (0.10 g, 36%). HRMS calcd for C36H₂₉FN₂0₄: 572.6357. Found: 572.6354. MA calcd for C₃₆H₂₉FN₂0₄: C, 75.51%; H, 5.11%; N, 4.89%. Found: C, 75.83%; H, 5.10%; N, 4.90%.

PATENT

US 10640465

https://patentscope.wipo.int/search/en/detail.jsf?docId=US249083802&_cid=P12-MDMUQY-52500-1

 The pharmacological activity of the compound is described in Chinese patent application No. CN03126974.5 and U.S. Pat. No. 7,268,157. 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propanoic acid is able to selectively activate PPAR-α, PPAR-γ and PPAR-6, and can be used to treat the diseases associated with metabolic syndrome such as diabetes, hypertension, obesity, insulin resistance, hypertriglyceridemia, hyperglycemia, high cholesterol, arteries atherosclerosis, coronary heart disease, etc. A preparation method of 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propanoic acid is disclosed in Chinese patent application No. CN03126974.5 and U.S. Pat. No. 7,268,157, and the synthetic route thereof is as follows:

EXAMPLES

Example 1: Preparation of 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propanoic Acid

(MOL) (CDX)

400 mL of toluene, 39.34 g (100 mmol) of methyl 2-[2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)propionate, 43.40 g (150 mmol) of 9-carbazole ethanol mesylate and 39.40 g (120 mmol) of cesium carbonate were sequentially added to a reaction flask, then the mixture was reacted at 90° C. for 3 hours before filtered, and the filtrate was concentrated in vacuo to remove the solvent toluene to give crude methyl 2-[2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)propionate. The purity (HPLC) was 69.8% and LC-MS (m/z) was 587 (M+1). The crude product obtained was used in the next step without further purification.

The above crude methyl 2-[2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl) propionate and 400 mL of tetrahydrofuran were added to the reaction flask and dissolved with stirring at room temperature. 16.78 g (400 mmol) of LiOH.H 2O, which had been dissolved in 200 mL of water, was added to the above solution, stirred at room temperature for 8 hours and allowed to stand to separate into layers. The upper organic phase was concentrated in vacuo. The concentrate was slurried with 800 mL of ethyl acetate and filtered, repeated for 4 times. The filter cake was added to a reaction flask, into which 550 mL of ethyl acetate and 306 mL of water were added and 210 mL of 4 mmol/L hydrochloric acid was added dropwise, then the mixture was stirred at room temperature for about 4 hours and allowed to stand to separate into layers. The upper organic phase was concentrated in vacuo to give crude 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propanoic acid (41.46 g). The crude product was recrystallized with about 373 mL of acetonitrile for 3 times to give pure 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl) propanoic acid. The weight was 23.88 g, the yield was 41.7%, the purity (HPLC) was 99.4%, and the LC-MS (m/z) was 573 (M+1). 1H NMR (DMSO-d 6) δ 2.98 (dd, 1H, CH2), 3.11 (dd, 1H, CH2), 4.28 (t, 1H, CH), 4.48 (m, 2H, CH2), 4.73 (t, 2H, CH2), 6.59 (d, 1H, Ar—H), 6.68 (d, 2H, Ar—H), 6.60 (d, 1H, Ar—H), 7.05 (d, 2H, Ar—H), 7.18 (d, 2H, Ar—H), 7.31 (m, 3H, Ar—H), 7.42 (m, 3H, Ar—H), 7.61 (m, 4H, Ar—H), 8.13 (d, 2H, Ar—H), 8.50 (d, 1H, NH).

SYN

J. Med. Chem. 2024, 67, 4376−4418

Chiglitazar (Bilessglu). Chiglitazar (17), a novel nonthiazolidinedione pan-agonist of α, δ, and γ peroxisome proliferator-activated receptors (PPARs), has shown promise for the treatment of type 2 diabetes. 126 Type 2 diabetes impacts over 374 million patients worldwide and continues to
rise in incidence and prevalence globally. 127 Chiglitazar preferentially regulates expression of ANGPTL4 and PDK4 genes, which are involved in glucose and lipid metabolism. 128 Chiglitazar was developed by Chipscreen Biosciences and was approved in China for improving glycemic control in adult
patients with type2 diabetes in October2021.129 Thesynthesisof17beganwithimineformationbetweenL
tyrosine methyl ester (17.1) and 2-(4-fluorobenzoyl) cyclohexanone(17.2)with tandemaromatizationunderPd/C catalysis to generate aniline derivative 17.3 (Scheme31).130,131 Alkylation of the phenol moiety of 17.3 with mesylate17.4furnishedphenyl alkyl etherderivative17.5.132
Hydrolysisof themethylester in17.5withlithiumhydroxide followedbyacidificationwithhydrochloricacidandrecrystal lization fromacetonitrile afforded chiglitazar (17) in 42% overall yield from17.3.Thisprocessdeliveredchiglitazar in 99.4%purityat24gscale.

(126) Ji, L.; Song, W.; Fang, H.; Li, W.; Geng, J.; Wang, Y.; Guo, L.;
Cai, H.; Yang, T.; Li, H.; et al. Efficacy and safety of chiglitazar, a
novel peroxisome proliferator-activated receptor pan-agonist, in
patients with type 2 diabetes: a randomized, double-blind, placebo
controlled, phase 3 trial (CMAP). Sci. Bull. 2021, 66, 1571−1580.
(127) Chatterjee, S.; Khunti, K.; Davies, M. J. Type 2 diabetes.
Lancet 2017, 389, 2239−2251.
(128) Pan, D.-S.; Wang, W.; Liu, N.-S.; Yang, Q.-J.; Zhang, K.; Zhu,
J.-Z.; Shan, S.; Li, Z.-B.; Ning, Z.-Q.; Huang, L.; Lu, X.-P. Chiglitazar
preferentially regulates gene expression via configuration-restricted
binding and phosphorylation inhibition of PPARγ. PPAR Research
2017 2017, 2017, 1−16.
(129) Deeks, E. D. Chiglitazar: First approval. Drugs 2022, 82, 87−
92.
(130) Li, Z.; Lu, X.-P.; Liao, C.; Shi, L.; Liu, Z.; Ma, B. Substituted
arylalcanoic acid derivatives as PPAR pan agonists with potent
antihyperglycemic and antihyperlipidemic activity. WO 2004048333
A1, 2004.
(131) Sutter, M.; Sotto, N.; Raoul, Y.; Métay, E.; Lemaire, M.
Straightforward heterogeneous palladium catalyzed synthesis of aryl
ethers and aryl amines via a solvent free aerobic and non-aerobic
dehydrogenative arylation. Green Chem. 2013, 15, 347−352.
(132) Lu, X.; Li, Z.; Wang, X. Method for preparing phenylalanine
compound. U.S. Patent US 10640465 B2, 2020.

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References

1.  Ji L, Song W, Fang H, Li W, Geng J, Wang Y, et al. (August 2021). “Efficacy and safety of chiglitazar, a novel peroxisome proliferator-activated receptor pan-agonist, in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, phase 3 trial (CMAP)”. Science Bulletin. 66 (15): 1571–1580. Bibcode:2021SciBu..66.1571J. doi:10.1016/j.scib.2021.03.019. PMID 36654286. S2CID 233650336.
2.  Deeks ED (January 2022). “Chiglitazar: First Approval”. Drugs. 82 (1): 87–92. doi:10.1007/s40265-021-01648-1. PMID 34846697. S2CID 244716275.

Clinical data
Trade names	Bilessglu
Other names	Carfloglitazar
Legal status
Legal status	Rx in China
Identifiers
IUPAC name
CAS Number	743438-45-1
PubChem CID	71402018
ChemSpider	57523239
UNII	E6EJV1J6Y0
ChEMBL	ChEMBL4650349
CompTox Dashboard (EPA)	DTXSID00225352
Chemical and physical data
Formula	C36H29FN2O4
Molar mass	572.636 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

///////////Chiglitazar, Chipscreen Biosciences, CHINA 2021, DIABETES, CS 038, Carfloglitazar, (s)-, E6EJV1J6Y0,