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Tianagliflozin IND filed by Tianjin Institute of Pharmaceutical research

March 30, 2016 3:20 am / Leave a comment

Tianagliflozin,

taigeliejing, 6-deoxydapagliflozin

Molecular Formula:	C₂₁H₂₅ClO₅
Molecular Weight:	392.8732 g/mol

Tianjin Institute Of Pharmaceutical Research,

(3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methyloxane-3,4,5-triol

1-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-b-D-glucopyranose

D-Glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-deoxy-, (1S)-

1–[4–Chloro–3–(4–ethoxybenzyl)phenyl]–1,6–dideoxy–β–d–glucopyranose

6-deoxydapagliflozin

https://pubchem.ncbi.nlm.nih.gov/compound/67891767#section=Top

A SGLT-2 inhibitor potentially for the treatment of type 2 diabetes.

CAS N. 1461750-27-5

The structures of dapagliflozin and 6-deoxydapagliflozin (1)

,deletion of the 6-OH in the sugar moiety of dapagliflozin led to the discovery of a more potent SGLT2 inhibitor, 6-deoxydapagliflozin (1, ). In an in vitro assay, 1 was a more active SGLT2 inhibitor, with IC ₅₀ = 0.67 nM against human SGLT2 (hSGLT2), as compared with 1.1 nM for dapagliflozin, leading to the identification of 1 as the most active SGLT2 inhibitor discovered so far in this field. Also in an in vivo assay, 1 also introduced more urinary glucose in a rat urinary glucose excretion test (UGE) and exhibited more potent blood glucose inhibitory activity in a rat oral glucose tolerance test (OGTT) than dapagliflozin.

Given the fact that 6-dexoydapagliflozin (1) is a very promising SGLT2 inhibitor that could be used to treat type 2 diabetes, led to preclinical trials

 Tianjin Institute Of Pharmaceutical Research,天津药物研究院

SPECTRAL DATA of Tianagliflozin

1 as a white solid (3.65 g, 93 %). R _f = 0.35 (EtOAc);

m.p.: 148–149 °C;

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.35 (d, 1H, J = 8.4 Hz), 7.25 (s, 1H), 7.18 (d, 1H, J = 8.0 Hz), 7.08 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J = 8.4 Hz), 4.95 (d, 1H, J = 5.2 Hz, OH), 4.90 (d, 1H, J = 4.4 Hz, OH), 4.79 (d, 1H, J = 5.6 Hz, OH), 3.92–4.01 (m, 5H), 3.24–3.29 (m, 1H), 3.18–3.22 (m, 1H), 3.09–3.15 (m, 1H), 2.89–2.95 (m, 1H), 1.29 (t, 3H, J = 7.0 Hz, CH₂ CH ₃), 1.15 (d, 3H, J = 6.0 Hz, CHCH ₃) ppm;

¹³C NMR (100 MHz, DMSO-d ₆): δ = 156.85, 139.65, 137.82, 131.83, 131.16, 130.58, 129.52, 128.65, 127.14, 114.26, 80.71, 77.98, 75.77, 75.51, 74.81, 62.84, 37.55, 18.19, 14.62 ppm;

IR (KBr): v¯¯¯ = 3,564 (w), 3,385 (s), 2,981 (s), 2,899 (s), 2,861 (s), 1,613 (m), 1,512 (s), 1,477 (m), 1,247 (s), 1,102 (s), 1,045 (s), 1,012 (s) cm⁻¹;

HR–MS: calcd for C₂₁H₂₉ClNO₅ ([M + NH₄]⁺) 410.1729, found 410.1724.

PATENT

CN 103864737

http://www.google.com/patents/CN103864737A?cl=en

PATENT

WO 2014094544

http://www.google.com/patents/WO2014094544A1?cl=en

Figure imgf000032_0001

-27-

1 D1 -6 Optionally, the step (7 ‘) is the step (7’) in place:

LS l- [4 – D (I- Dl- 6)

(DMSO-d _6, 400 MHz), δ 7.35 (d, 1H, J = 8.0 Hz), 7.28 (d, 1H, J ‘. 2.0 Hz), 7.17 (dd, IH, / = 2.0 Hz and 8.4 Hz), 7.05 (d, 2H, _J: 8.8 Hz), 6.79 (d, 2H, 8.8 Hz): 4.924,95 (m, 2H), 4,81 (d, IH, 6,0 Hz), 3.93- 3.99 (m, 5H), 3,85 (d, 1H, J = 10,4 Hz), 3,66 (dd, IH, 5,2 Hz and 11,6 Hz), 3.17-3,28 (m, 3H), 3.02-3.08 _(m: IH), 1.28 (t, 3H, J = 7,0 Hz), 0,80 (s, 9H), -0.05 (s, 3H), -0.09 (s, 3H) .

PATENT

CN 104045614

[0066] The added 100mL dried over anhydrous methanol 0. 5g of sodium metal, nitrogen at room temperature with stirring, until the sodium metal disappeared. Followed by addition of 5. 2g (10mmol) of compound 6, stirring was continued at room temperature for 3 hours. To the reaction system was added 5g strong acid cation exchange resin, stirred at room temperature overnight, the reaction mixture until pH = 7. The resin was removed by suction, and the filtrate evaporated to dryness on a rotary evaporator, the residue was further dried on a vacuum pump to give the product I-D1-6, as a white foamy solid.

PATENT

WO 2014139447

http://link.springer.com/article/10.1007%2Fs40242-014-4043-9#/page-1

Med Chem. 2015;11(4):317-28.

Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.

Cai W, Jiang L, Xie Y, Liu Y, Liu W, Zhao G¹.

Abstract

A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed.

http://www.ncbi.nlm.nih.gov/pubmed/25557661

Paper

Discovery of 6-Deoxydapagliflozin as a Highly Potent Sodium-dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Authors: Zhang, Lingyu; Wang, Yuli; Xu, Huaqiang; Shi, Yongheng; Liu, Bingni; Wei, Qunchao; Xu, Weiren; Tang, Lida; Wang, Jianwu; Zhao, Guilong

Source: Medicinal Chemistry, Volume 10, Number 3, May 2014, pp. 304-317(14)

http://www.ingentaconnect.com/content/ben/mc/2014/00000010/00000003/art00009?crawler=true

CLIP

A facile synthesis of 6-deoxydapagliflozin

Keywords. Carbohydrates Drug research Hydrogenolysis Dapagliflozin SGLT2 inhibitor

http://link.springer.com/article/10.1007/s00706-013-1053-0/fulltext.html

The synthetic route to the target compound 1 is shown in Scheme 3. The starting material methyl 2,3,4-tri-O-benzyl-6-deoxy-6-iodo-α–d-glucopyranoside (3) was prepared from commercially available methyl α–d-glucopyranoside (2) according to a known method [5, 6].

Iodide 3 was reductively deiodinated to give 4 in 91 % yield under hydrogenolytic conditions using 10 % Pd/C as catalyst in the presence of Et₃N as base in THF/MeOH at room temperature.

when the iodide 3 was treated with Barton–McCombie reagent (n-Bu₃SnH/AIBN) [7] in toluene at room temperature no reaction occurred; however, when the reaction was carried out at elevated temperatures, such as reflux, a complex mixture formed with only a trace amount (3 %, entry 1) of the desired product 4.

When the iodide 3 was treated with LiAlH₄ in THF at 0 °C to room temperature, another complex mixture was produced with only a trace amount (2 %, entry 2) of 4.

When Pd(OH)₂ was used as the hydrogenolysis catalyst instead of 10 % Pd/C, the desired 4 was indeed formed (14 %, entry 4), but most of the starting material was converted to a few more polar byproducts, which were believed to result from the cleavage of at least one of the benzyl groups.

pdf available

Monatshefte für Chemie – Chemical Monthly

December 2013, Volume 144, Issue 12, pp 1903-1910

http://download.springer.com/static/pdf/721/art%253A10.1007%252Fs00706-013-1053-0.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs00706-013-1053-0&token2=exp=1458808857~acl=%2Fstatic%2Fpdf%2F721%2Fart%25253A10.1007%25252Fs00706-013-1053-0.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs00706-013-1053-0*~hmac=bd1c3c2bdc3712f5540267c99f732b2f7588020a868aa23021792a2a2a58d65e

References

1.Washburn WN (2009) J Med Chem 52:1785
2.Hardman TC, Dubrey SW (2011) Diabetes Ther 2:133
3.Meng M, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JM, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN (2008) J Med Chem 51:1145
4.Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, Yamamoto Y, Ueta K, Kimata H, Nakayama K, Tsuda-Tsukimoto M (2010) J Med Chem 53:6355
5.Lee JC, Francis S, Georg GI, Dutta D, Gupta V, Tash JS, Yang Y, Zhu J-Y, Schoenbrunn E (2012) J Org Chem 77:3082
6.Bartoszewicz A, Kalek M, Stawinski J (2008) Tetrahedron 64:8843
7.Zhao GL, Lou YY, Zhang LS, Shao H, Xu WR, Tang LD, Zou MX (2012) Synth Commun 42:2885
8.Koto S, Morishima N, Miyata Y, Zen S (1976) Bull Chem Soc Jpn 49:2639
9.Kakinuma H, Oi T, Hashimoto-Tsuchiya Y, Arai M, Kawakita Y, Fukasawa Y, Iida I, Hagima N, Takeuchi H, Chino Y, Asami J, Okumura-Kitajima L, Io F, Yamamoto D, Miyata N, Takahashi T, Uchida S, Yamamoto K (2010) J Med Chem 53:3247
10.Xu J, Egger A, Bernet B, Vasella A (1996) Helv Chim Acta 79:2004
11.Lee SH, Song K-S, Kim JY, Kang M, Lee JS, Cho S-H, Park H-J, Kim J, Lee J (2011) Bioorg Med Chem 19:5813
12.Song K-S, Lee SH, Kim MJ, Seo HJ, Lee J, Lee S-H, Jung ME, Son E-J, Lee MW, Kim J, Lee J (2011) ACS Med Chem Lett 2:182
13.Lee J, Lee S-H, Seo HJ, Son E-J, Lee SH, Jung ME, Lee MW, Han HK, Kim J, Kang J, Lee J (2010) Bioorg Med Chem 18:2178
14.Kim MJ, Lee SH, Park SO, Kang H, Lee JS, Lee KN, Jung ME, Kim J, Lee J (2011) Bioorg Med Chem 19:5468
15.Skaanderup PR, Poulsen CS, Hyldtoft L, Jørgensen MR, Madsen R (2002) Synthesis 1721
Monatshefte fuer Chemie (2013), 144(12), 1903-1910
Medicinal Chemistry (Sharjah, United Arab Emirates) (2014), 10(3), 304-317
Chinese Journal of Structural Chemistry (2014), 33(1), 85-89
Xiandai Yaowu Yu Linchuang (2013), 28(6), 838-841
Chemical Research in Chinese Universities (2014), 30(5), 785-793

////////, SGLT-2 inhibitor, type 2 diabetes, Tianagliflozin, taigeliejing, 6-deoxydapagliflozin, 1461750-27-5

Clc1c(cc(cc1)C2[C@@H]([C@H]([C@@H]([C@H](O2)C)O)O)O)Cc3ccc(cc3)OCC

CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)C3C(C(C(C(O3)C)O)O)O)Cl

c1(c(cc(cc1)C2OC(C(C(C2O)O)O)C)Cc3ccc(cc3)OCC)Cl

Fluorofenidone

January 4, 2016 4:03 am / Leave a comment

2(1H)-Pyridinone, 1-(3-fluorophenyl)-5-methyl-.png

Fluorofenidone

1- (3-fluorophenyl) -5-methyl – 2 (1H) pyridone

2(1H)-Pyridinone, 1-(3-fluorophenyl)-5-methyl-

1- (3_ fluorophenyl) -5_ methylpyridine _2 (IH) – one

C₁₂ H₁₀ F N O, 203.2123

An anti-inflammatory agent potentially for the treatment of organ fibrosis.

CAS No. 848353-85-5

Synthesis

PATENT

WO 2006108354

http://www.google.co.in/patents/WO2006108354A1?cl=en

PATENT

http://www.google.com/patents/CN102241625A?cl=zh

(Compound 1)

A. (3_ fluorophenyl) methyl pyridine _2 (IH) 1- -5_ – -one

9. 6gDMF, 45 0g (0 2mol.) Inter-fluoro-iodobenzene, 21 8g (0. 2mol) 5_ methylpyridine _2_ (IH) -.. -one, 28g of anhydrous potassium carbonate and 1. Og copper powder, 160 ° -170 °, the reaction was stirred at reflux for 20 hours, the natural cooling to 110~120 ° C, was slowly added to about 330ml 80~90 ° C hot water, cooled to 20 ° C. Suction filtered, the filter cake was washed with about 20ml of water, remove the cake, with about 300ml of ethyl acetate ultrasound 30min, suction filtered, the filter residue was washed with 20ml of ethyl acetate. The combined ethyl acetate, washed with water three times (50ml * 3), and the filtrate layers were separated and allowed to stand for 15min, ethyl acetate fraction was concentrated to a non-steamed, hot added under stirring for about 85ml of petroleum ether, cooling to 15~20 ° C insulation ~ 1.5 hours. Filtration, the filter cake was washed twice with petroleum ether (about 20ml * 2) used to give 34. 9g crude. Recrystallized from 20% ethanol to give the product 1- (3_ fluorophenyl) -5_ methylpyridine _2 (IH) – one as a white solid # 30. Ig0 Μ P.: 132 · 1 ~133 7 °.. C.

PATENT

http://www.google.co.in/patents/WO2009149188A1?cl=zh-CN

PATENT

CN 102241625

http://www.google.com/patents/CN102241625A?cl=zh

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009111947

PAPER

http://www.mdpi.com/1420-3049/17/1/884

CN1386737A *	Jun 11, 2002	Dec 25, 2002	中南大学湘雅医学院	Antifibrosis pyridinone medicine and its prepaing process
CN1846699A	Apr 13, 2005	Oct 18, 2006	中南大学湘雅医院	Application of 1-(substituted phenyl)-5-methyl-2-(1H)-pyridone compound in preparing medicine for anti-other organifibrosis and tissue fibrosis except renal interstitial fibrosis
CN101235013A*	Mar 10, 2008	Aug 6, 2008	广东东阳光药业有限公司;张中能	Crystallized 1-(3-fluorophenyl)-5-methyl-2-(1H)pyridine and its preparation method composition and application
US20070203203	May 1, 2007	Aug 30, 2007	Tao Li J	Composition and Method for Treating Fibrotic Diseases


Patent	Submitted	Granted
COMPOUNDS AND METHODS FOR TREATING INFLAMMATORY AND FIBROTIC DISORDERS [US2009318455]	2009-12-24
COMPOSITION AND METHOD FOR TREATING PROTEINURIA [US2010099719]	2010-04-22
COMPOSITION AND METHOD FOR TREATING FIBROTIC DISEASES [US2009258911]	2009-10-15
Composition and Method for Treating Fibrotic Diseases [US2008319027]	2008-12-25
METHODS FOR TREATING ACUTE MYOCARDIAL INFARCTIONS AND ASSOCIATED DISORDERS [US2010190731]	2010-07-29
Methods for Treating Acute Myocardial Infarctions and Associated Disorders [US2011218515]	2011-09-08
METHODS OF TREATING HIV PATIENTS WITH ANTI-FIBROTICS [US2012014917]	2012-01-19
Composition and Method for Treating Fibrotic Diseases Composition and Method for Treating Fibrotic Diseases [US2009005424]	2007-08-30
Crystalline 1-(3-fluorophenyl)-5-methyl-2-(1H)pyridone, the preparation methods, compositions and applications thereof [US8232408]	2009-03-10	2012-07-31

/////////

CC1=CN(C(=O)C=C1)C2=CC(=CC=C2)F

	DR ANTHONY MELVIN CR… on ADAFOSBUVIR, адафосбувир , أدا…
	DR ANTHONY MELVIN CR… on AK 3280
	DR ANTHONY MELVIN CR… on Novobiocin, ノボビオシン;
	DR ANTHONY MELVIN CR… on CT 1812
	DR ANTHONY MELVIN CR… on ACLIMOSTAT

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Tianagliflozin IND filed by Tianjin Institute of Pharmaceutical research

1–[4–Chloro–3–(4–ethoxybenzyl)phenyl]–1,6–dideoxy–β–d–glucopyranose

Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.

Abstract

Discovery of 6-Deoxydapagliflozin as a Highly Potent Sodium-dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Fluorofenidone

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Tianagliflozin IND filed by Tianjin Institute of Pharmaceutical research

1–[4–Chloro–3–(4–ethoxybenzyl)phenyl]–1,6–dideoxy–β–d–glucopyranose

Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.

Abstract

Discovery of 6-Deoxydapagliflozin as a Highly Potent Sodium-dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

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