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C-phenyl glycitol compound for the treatment of diabetes

A kind of technology of phenyl polyhydric alcohol and compound, applied in the field of C-phenyl polyhydric alcohol compound

Inactive Publication Date: 2009-07-22
TAISHO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] So far, C-phenyl glucoside derivatives with selective inhibitory activity against SGLT2 have been reported (see International Publication WO2001 / 027128); however, C-phenyl glucoside derivatives with strong inhibitory effects on both SGLT1 and SGLT2 Glucoside derivatives have not been reported

Method used

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  • C-phenyl glycitol compound for the treatment of diabetes
  • C-phenyl glycitol compound for the treatment of diabetes
  • C-phenyl glycitol compound for the treatment of diabetes

Examples

Experimental program
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Effect test

Embodiment approach 2-19

[0045] 2. The C-phenylpolyhydroxylitol compound, which is a C-phenylglucitol compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof, or a hydrate thereof,

[0046]

[0047] where R 1 ,R 2 ,R 3 , Y and Z are the same as those defined in formula (I).

[0048] 3. The C-phenylpolyhydroxylitol compound of formula (II) or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1 is a hydrogen atom, hydroxyl, C 1-4 Alkyl or C 1-4 Alkoxy, R 2 is C 1-4 alkyl or halogen atom.

[0049] 4. The C-phenyl polyhydroxylitol compound or its pharmaceutically acceptable salt or its hydrate according to embodiment 2 or 3, wherein R 3 is a hydrogen atom.

[0050] 5. The C-phenyl polyhydroxylitol compound or its pharmaceutically acceptable salt or its hydrate according to embodiment 3 or 4, wherein Y is C 1-6 Alkylene or -O-(CH 2 )n-(n is an integer of 2-4), Z is -NHCON(R B )R C , where R B and R C as defined in formula (I).

[00...

Embodiment 1

[0512] (1S)-1,5-anhydro-1-[2-hydroxy-5-[4-[4-[(2-hydroxy-1,1-dimethylethyl)amino]-4-oxobutyl Preparation of ]benzyl]-4-methylphenyl]-D-sorbitol

[0513]

[0514] (1) (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4 -[(2-Hydroxy-1,1-dimethylethyl)amino]-4-oxobut-1-en-1-yl]benzyl]-4-methylphenyl]-D-sorbose Preparation of Alcohol

[0515] To (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-3-carboxy Prop-1-en-1-yl]benzyl]-4-methylphenyl]-D-sorbitol (200 mg, 0.223 mmol) in chloroform (2.2 mL) was added to 2-amino-2-methyl- 1-propanol (40 mg, 0.446 mmol), 1-hydroxybenzotriazole (33 mg, 0.245 mmol) and WSC (60 mg, 0.312 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the solvent was evaporated und...

Embodiment 2

[0521] (1S)-1,5-anhydro-1-[2-hydroxy-5-[4-[4-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-4 Preparation of -oxobutyl]benzyl]-4-methylphenyl]-D-sorbitol

[0522]

[0523] (1) (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4 -[[2-Hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-4-oxobut-1-en-1-yl]benzyl]-4-methylphenyl] -Preparation of D-sorbitol-

[0524] According to the method described in Example 1 (1), but wherein 2-amino-2-methyl-1,3-propanediol is used instead of 2-amino-2-methyl-1-propanol, the title compound (91 mg, 44%), which is a colorless oily compound.

[0525] 1H NMR (300MHz, chloroform-D) δ ppm 1.19(s, 3H) 2.20(s, 3H) 3.15(d, J=6.06Hz, 2H) 3.49-3.83(m, 10H) 3.87-4.04(m, 3H) 4.37-4.67 (m, 4H) 4.80-4.94 (m, 3H) 5.00 (s, 2H) 6.00-6.23 (m, 2H) 6.40-6.52 (m, 1H) 6.75 (s, 1H) 6.93 (dd, J = 7.38, 1.94Hz, 2H) 7.03 (d, J = 8.24Hz, 2H) 7.11-7.35 (m, 24H) 7.35-7.46 (m, 2H).

[0526] ESI m / z=1004.5(M+Na).

[0527] (2) (1S)-1,5-anhydro-1-[2-...

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Abstract

Provided is a novel C-phenyl glycitol compound that may serve as a prophylactic or therapeutic agent for diabetes by inhibiting both SGLT1 activity and SGLT2 activity, thereby exhibiting a glucose absorption suppression action and a urine glucose excretion action. A C-phenyl glycitol compound represented by a formula (I) below (as figure 1) or a pharmaceutically acceptable salt thereof or a hydrate thereof wherein R1 and R2 are the same or different and represent a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, Y is a C1-6 alkylene group, -O-(CH2)n- (n is an integer of 1 to 4) or a C2-6 alkenylene group, provided that when Z is NHC(= NH)NH2 or -NHCON(R)RC, n is not 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(R)RC, (as figure 2).

Description

technical field [0001] The present invention relates to C-phenylglycitol compounds having inhibitory activity on sodium-dependent glucose cotransporter 1 (SGLT1) and sodium-dependent glucose cotransporter 2 (SGLT2). Background technique [0002] When people develop diabetes, fasting blood glucose levels show up as 126 mg / dL or higher. Some people have shown postprandial blood glucose levels as high as 140-200 mg / dL even though fasting blood glucose levels have dropped to within the normal range. Such a population is diagnosed with impaired glucose tolerance (hereinafter referred to as "IGT"). It has been recognized that the risk of cardiovascular disease can be reduced by delaying the onset of diabetes caused by IGT, and some supporting findings have been obtained. For example, the Da Qing IGT and diabetes study conducted in China in 1997 reported that the development of IGT into type II diabetes can be significantly inhibited by diet and exercise (see Pan XR, et al., Diab...

Claims

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Application Information

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IPC IPC(8): C07D309/12A61K31/351C07D405/10A61P3/10
CPCC07D405/10C07D309/12A61P3/10A61K31/351
Inventor 柿沼浩行小桥阳平桥本优子大井隆宏高桥仁美天田英明岩田由纪
Owner TAISHO PHARMACEUTICAL CO LTD
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