Deuterated benzylbenzene derivatives and methods of use

一种化合物、基团的技术，应用在治疗受SGLT抑制作用影响的疾病和病症领域，能够解决有害副作用、不能提供充分血糖控制等问题

Inactive Publication Date: 2011-08-10
THERAKOS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs are often used in combination and even sometimes may not provide adequate blood sugar control or may have harmful side effects

Method used

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  • Deuterated benzylbenzene derivatives and methods of use
  • Deuterated benzylbenzene derivatives and methods of use
  • Deuterated benzylbenzene derivatives and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0199]

[0200] where R 3 independently represents hydrogen, deuterium, halogen, or C 1-C 6 Alkyl; R 8 Independently represent hydroxyl, cyano, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkoxy, or (C 3 -C 10 Cycloalkyl) C 1 -C 3 Alkoxy, (C 3 -C 7 Cycloalkyl) C 3 -C 5 Alkenyloxy, or (C 3 -C 7 Cycloalkyl) C 3 -C 5 Alkynyloxy; and R 11 , R 12 and R 13 each independently represents hydrogen or deuterium;

[0201] where at least (i) R 11 , R 12 and R 13 one of which is deuterium, or (ii) R 8 from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkoxy, and (C 3 -C 10 Cycloalkyl) C 1 -C 3 Alkoxy, (C 3 -C 7 Cycloalkyl) C 3 -C 5 Alkenyloxy and (C 3 -C 7 Cycloalkyl) C 3 -C 5 Alkynyloxy, wherein an alkyl, alkenyl, alkynyl, or cycloalkyl, or cycloalkenyl group or moiety is partially or fully substituted with de...

Embodiment 1

[0438] This example illustrates the preparation of Compound 5 according to the method provided in Scheme 9. The general method can be applied to other compounds of the invention.

[0439] Diagram 9

[0440]

[0441] Preparation of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (2)

[0442]

[0443] To 5-bromo-2-chlorobenzoic acid (1500 g, 6.41 mol) and oxalyl chloride (975 g, 7.69 mol) in DCM (2.8 L) was added DMF (9 mL). Once the vigorous gas evolution ceased, the reaction was stirred at room temperature for 10 hours. The solution was concentrated under vacuum to obtain a yellow residue. The residue was dissolved in DCM (1.2 L), then the stirred mixture was cooled to -3 °C and phenetole (799 g, 6.54 mol) was added. After the addition was complete, aluminum(III) chloride (973 g, 6.54 mol) was added over 1 hour while keeping the reaction temperature below 4°C. The mixture was poured onto 10 kg of ice and stirred at 4°C for 1 hour. The suspension was diluted with ...

Embodiment 2

[0454] (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2- Preparation of d-3,4,5-triol (6)

[0455]

[0456] Compound 6 was prepared using a method similar to that described in Example 1 above, using ethylbenzene instead of phenetole as the starting material. 1 H-NMR (CD3 OD, 400MHz): δ736~7.25(m, 3H), 7.08(s, 4H), 4.11~3.99(dd, J=20.4 and 12Hz, 2H), 3.89~3.84(dd, J=11.7 and 1.8Hz, 1H ), 3.70~3.65(m, 1H), 3.45~3.37(m, 3H), 3.27(m, 1H), 2.65~2.55(q, J=15 and 7.5Hz, 2H), 1.21~1.16(t, J =7.5Hz, 3H); MS ESI (m / z): 394 [M+H] + , the calculated value is 393.

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PUM

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Abstract

Provided are compounds having an inhibitory effect on sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions that are affected by SGLT inhibition.

Description

[0001] References to related applications [0002] This application claims priority to US Provisional Application No. 61 / 134,968, filed July 15, 2008, which is incorporated herein by reference. technical field [0003] The present invention provides compositions comprising a compound having an inhibitory effect on the sodium-dependent glucose cotransporter SGLT. The invention also provides pharmaceutical compositions, and methods of using the compounds alone or in combination with other therapeutic agents for the treatment of diseases and conditions affected by SGLT inhibition. Background technique [0004] According to the World Health Organization, approximately 150 million people worldwide suffer from diabetes. The two main forms of diabetes are type I diabetes, in which the pancreas fails to produce insulin, and type II diabetes, in which the body does not respond properly to the insulin it produces (insulin resistance). Type II diabetes accounts for 90% of all diabete...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/04
CPCA61K45/06C07H7/04C07D309/10A61K31/35A61P19/06A61P3/00A61P3/04A61P3/06A61P43/00A61P7/10A61P9/04A61P9/10A61P9/12A61P3/10A61K2300/00
Inventor 布赖恩·西德吕彬华雅克·Y·罗贝热陈元伟彭坤董佳家许百华杜计燕张丽丽唐新星徐鸽冯焱胥敏
Owner THERAKOS INC
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