Method for dual inhibition of SGLT1 and SGLT2 using diphenylmethane derivatives

• US 9,340,521 B2
• Filed: 03/18/2013
• Issued: 05/17/2016
• Est. Priority Date: 03/18/2013
• Status: Active Grant

• Current Assignee: Green Cross Corporation (Green Cross Holdings Corporation)
• Original Assignee: Green Cross Corporation (Green Cross Holdings Corporation)
• Inventors: Kim, Jae Eun, Park, Kisoo, Son, Ickhwan, Cha, Man-Young, Choi, Soongyu, Song, Kwang-Seop, Lee, Suk Ho, Seo, Hee Jeong, Kim, Min Ju, Park, Eun-Jung, Park, So Ok, Kong, Younggyu, Kang, Hyunku, Jung, Myung Eun, Kim, Hyun Jung, Lee, Jun Sung, Kim, Mi-Soon, Lee, Min Woo, Lee, Kinam
• Primary Examiner(s): Lau, Jonathan S
• Application Number:
  US13/845,466
• Publication Number:
  US 20140274918A1
• Time in Patent Office: 1,156 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: C07D 309/10 Oxygen atoms
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention relates to a method for dual inhibition of sodium-dependent glucose cotransporter 1 (SGLT1) and sodium-dependent glucose cotransporter 2 (SGLT2) present in the intestine and kidney by using the compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof:

wherein ring A, ring B, X and Y have the same meanings as defined in the specification.

Claims

1. A method for dual inhibition of sodium-dependent glucose cotransporter 1 and sodium-dependent glucose cotransporter 2 in a mammal, which comprises administering the compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof to the mammal:

2. The method of claim 1, wherein said ring A is selected from the group consisting of:

3. The method of claim 1, wherein said ring B is selected from the group consisting of:

4. The method of claim 1, wherein said ring A is an indane, indene, dihydrobenzofuran, dihydroisobenzofuran, benzofuran, dihydrobenzothiophene, benzothiophene, tetrahydronaphthalene, dihydronaphthalene, chroman, chromene, isochroman, isochromene, benzodioxole, benzodioxane, benzooxazine, tetrahydroquinoline, tetrahydroquinoxaline, tetrahydroisoquinoline, indazole, indole, indoline, benzoimidazole, benzooxazole, benzothiazole, benzotriazole, quinazoline, quinoxaline, cinnoline, phthalazine, or benzotriazine ring, which is optionally substituted with a substituent as defined in claim 1.

5. The method of claim 1, wherein the compound of formula I is selected from the group consisting of:

(1) (2S,3R,4R,5S,6R)-2-(7-bromo-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(2) (2S,3R,4R,5S,6R)-2-(7-bromo-6-(4-ethoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(3) (2S,3R,4R,5S,6R)-2-(7-bromo-6-(4-ethylbenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(4) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(5) (2R,3S,4R,5R,6S)-2-(hydroxymethyl) -6-(6-(4-methoxybenzyl)-7-methyl-2,3-dihydro-1H-inden-4-yl)tetrahydro-2H-pyran-3,4,5-triol;

(6) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(7) (2S,3R,4R,5S,6R)-2-(6-(4-ethoxybenzyl)-7-methyl-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(8) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethylbenzyl)-2,3-dihydrobenzofuran-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(9) (2S,3R,4R,5S,6R)-2-(5-chloro-6-(4-ethoxybenzyl)chroman-8-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(10) (2S,3R,4R,5S,6R)-2-(5-chloro-6-(4-methoxybenzyl)chroman-8-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(11) (2S,3R,4R,5S,6R)-2-(5-chloro-6-(4-ethylbenzyl)chroman-8-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(12) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-methoxybenzyl)-2,3-dihydrobenzofuran-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(13) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(14) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-ethylbenzyl)chroman-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(15) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-methoxybenzyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(16) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-ethylbenzyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(17) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(18) (2S,3R,4R,5S,6R)-2-(5-chloro-6-(4-cyclopropylbenzyl)chroman-8-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(19) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethylbenzyl)-2-methyl-2,3-dihydrobenzo[b]thiophen-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(20) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;

(21) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-ethoxybenzyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;

(22) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-cyclopropylbenzyl)chroman-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(23) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-methoxybenzyl)chroman-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(24) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl) benzo[d][1,3]dioxol-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(25) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-methoxybenzyl)benzo[d][1,3]dioxol-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(26) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethylbenzyl)benzo[d][1,3]dioxol-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(27) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-cyclopropylbenzyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(28) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-vinylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(29) (2S,3R,4R,5S,6R)-2-(5-chloro-6-(4-methoxybenzyl)chroman-8-yl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;

(30) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-methoxybenzyl)-2,3-dihydrobenzo[b]thiophen-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(31) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-3-methyl-2,3-dihydrobenzofuran-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(32) (2S,3R,4R,5S,6R)-2-(7-(difluoromethyl)-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(33) (2S,3R,4R,5S,6R)-2-(7-bromo-6-(4-ethylbenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(34) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-methoxybenzyl)-2,3-dihydrobenzo[b]thiophen-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(35) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethylbenzyl)-2,3-dihydrobenzo[b]thiophen-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(36) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-methoxybenzyl)thiochroman-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(37) (2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(3-(4-methoxybenzyl)-4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)tetrahydro-2H-pyran-3,4,5-triol;

(38) (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydronaphthalen-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(39) (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)-5,6,7,8-tetrahydronaphthalen-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(40) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-methylbenzyl)benzo[d][1,3]dioxol-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(41) (2R,3S,4R,5R,6S)-2-(hydroxymethyl)6-(6-(4-methylbenzyl)-2,3-dihydro-1H-inden-4-yl)tetrahydro-2H-pyran-3,4,5-triol;

(42) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-methylbenzyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(43) (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethylbenzyl)-5,6,7,8-tetrahydronaphthalen-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(44) (2S,3R,4R,5S,6R)-2-(3-(4-ethylbenzyl)-4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(45) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-methylbenzyl)chroman-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(46) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-methylbenzyl)-2,3-dihydrobenzofuran-7-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(47) (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(48) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;

(49) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-(methylthio)benzyl)benzo[d][1,3]dioxol-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(50) (2S,3R,4R,5S,6R)-2-(8-chloro-7-(4-(methylthio)benzyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(51) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethoxybenzyl)benzo[d][1,3]dioxol-4-yl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;

(52) (2S,3R,4R,5S,6R)-2-(5-chloro-6-(4-methylbenzyl)chroman-8-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(53) (2S,3R,4R,5S,6R)-2-(6-(benzo[b]thiophen-2-ylmethyl)-7-chlorobenzo[d][1,3]dioxol-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(54) (2S,3R,4R,5S,6R)-2-(8-chloro-7-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(55) (2S,3R,4R,5S,6R)-2-(6-(benzo[b]thiophen-2-ylmethyl)-7-chloro-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(56) (2S,3R,4R,5S,6R)-2-(7-(benzo[b]thiophen-2-ylmethyl)-8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(57) (2S,3R,4R,5S,6R)-2-(4-bromo-3-(4-ethylbenzyl)-5,6,7,8-tetrahydronaphthalen-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(58) (2S,3R,4R,5S,6R)-2-(4-bromo-3-(4-ethoxybenzyl)-5,6,7,8-tetrahydronaphthalen-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(59) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydrobenzo[b]thiophen-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(60) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydrobenzo[b]thiophen-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(61) (2R,3S,4R,5R,6S)-2-((hydroxymethyl)-6-(7-methyl-6-(4-methylbenzyl)benzo[d][1,3]dioxol-4-yl)tetrahydro-2H-pyran-3,4,5-triol;

(62) (2S,3R,4R,5S,6R)-2-(5-chloro-6-(4-cyclobutylbenzyl)chroman-8-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(63) (2R,3S,4R,5R,6S)-2-((hydroxymethyl)-6-(6-(4-methoxybenzyl)-7-methylbenzo[d][1,3]dioxol-4-yl)tetrahydro-2H-pyran-3,4,5-triol;

(64) (2S,3R,4R,5S,6R)-2-(6-(4-ethylbenzyl)-7-methylbenzo[d][1,3]dioxol-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; and

(65) (2S,3R,4R,5S,6R)-2-(6-(4-ethoxybenzyl)-7-methylbenzo[d][1,3]dioxol-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.