NOVEL DIPHENYLMETHANE DERIVATIVES AS SGLT2 INHIBITORS

• US 20150152075A1
• Filed: 01/09/2015
• Published: 06/04/2015
• Est. Priority Date: 06/01/2011
• Status: Active Grant

• Current Assignee: Green Cross Corporation (Green Cross Holdings Corporation)
• Original Assignee: Green Cross Corporation (Green Cross Holdings Corporation)
• Inventors: CHOI, Soongyu, SONG, Kwang-Seop, LEE, Suk Ho, KIM, Min Ju, SEO, Hee Jeong, PARK, Eun-Jung, KONG, Younggyu, PARK, So Ok, KANG, Hyunku, JUNG, Myung Eun, LEE, Kinam, KIM, Hyun Jung, LEE, Jun Sung, LEE, Min Woo, KIM, Mi-Soon, HONG, Dong Ho, KANG, Misuk
• Granted Patent: US 9,371,303 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 309/10 Oxygen atoms
• CPC Class Codes: C07D 405/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 407/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 411/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

A compound with a diphenylmethane moiety having an inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) being present in the intestine and kidney is disclosed. A pharmaceutical composition including the compound as an active ingredient, which is useful for preventing or treating metabolic disorders, particularly diabetes is disclosed. A method for preparing the compound, and a method for preventing or treating metabolic disorders, particularly diabetes, by using the compound is provided.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt or a prodrug thereof:

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

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

4. The compound of claim 1, wherein said ring B-2 is selected from the group consisting of:

5. The compound of claim 1, wherein said ring A is a benzene, indane, indene, tetrahydronaphthalene, dihydronaphthalene ring, which is optionally substituted with a substituent as defined in claim 1.

6. The compound of claim 1, wherein said ring B is a quinoline, quinoxaline, 3,4-dihydro-2H-benzo[b][1,4]dioxepine, 2,3-dihydrobenzo[b]thiophene, indazole, indole, 2,3-dihydrobenzo[b][1,4]dioxine, benzodioxole, indane, tetrahydronaphthalene, 3,4-dihydro-2H-thiochromene, dihydrobenzofuran, benzo[d][1,3]oxathiole, tetrahydroquinoline, or 3,4-dihydro-2H-benzo[b][1,4]oxazine ring, which is optionally substituted with a substituent as defined in claim 1.

7. The compound of claim 1, which 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) (2S,3R,4R,5S,6R)-2-(7-fluoro-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(6) (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;

(7) (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

(8) (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;

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

(10) (2S,3R,4R,5S,6R)-2-(5-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-methylbiphenyl-3-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;

(11) (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-methyl-5-(thiophen-3-yl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;

(12) (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-methyl-5-(thiophen-2-yl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;

(13) (2S,3R,4R,5S,6S)-2-(7-bromo-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-methoxy-tetrahydro-2H-pyran-3,4,5-triol;

(14) (2S,3R,4R,5S,6R)-2-(7-chloro-6-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

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

(16) (2S,3R,4R,5S,6R)-2-(7-(difluoromethyl)-6-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(17) (2S,3R,4R,5S,6R)-2-(2-(allyloxy)-4-chloro-5-(4-methoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;

(18) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;

(19) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl)-6-(methylsulfonyl)tetrahydro-2H-pyran-3,4,5-triol;

(20) (2S,3R,4R,5S,6R)-2-(4-chloro-3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-5-methoxyphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;

(21) (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)-5-methoxyphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;

(22) (2S,3R,4R,5S,6S)-2-(2-(allyloxy)-4-chloro-5-(4-methoxybenzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triol;

(23) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-(dimethylamino)benzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(24) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-vinylbenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(25) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(26) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-methylbenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(27) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-(methylamino)benzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol 2,2,2-trifluoroacetate;

(28) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-2,3-dimethoxyphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(29) (2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-3-hydroxy-2-methoxyphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(30) (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethylbenzyl)-3-methyl-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;

(31) (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(pyrrolidin-1-yl)benzyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;

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

(33) (2S,3R,4R,5S,6R)-2-(7-(difluoromethyl)-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-(6-(4-(azetidin-1-yl)benzyl)-7-chloro-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; and

(35) (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.

8. A method for preparing a compound of formula I-a, comprising:

a) reacting a compound of formula II with a compound of formula III to obtain a compound of formula IV; and

(b) deprotecting and reducing the compound of formula IV to obtain a compound of formula I-a,

9. The method of claim 8, wherein step (b) is carried out by deprotecting the compound of formula IV to obtain a compound of formula V, and reducing the compound of formula V to obtain the compound of formula I-a, when PG is trimethylsilyl:

10. The method of claim 8, wherein step (b) is carried out by reducing the compound of formula IV to obtain a compound of formula VI, and deprotecting the compound of formula VI to obtain the compound of formula I-a, when PG is benzyl:

11. A pharmaceutical composition, comprising as an active ingredient the compound of formula I of claim 1 or a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier.

12. A method for preventing or treating a metabolic disorder in a mammal, which comprises administering the compound of formula I of claim 1 or a pharmaceutically acceptable salt or a prodrug thereof to the mammal.

13. A method for inhibiting sodium-dependent glucose cotransporter 2 (SGLT2) in a mammal, which comprises administering the compound of formula I of claim 1 or a pharmaceutically acceptable salt or a prodrug thereof to the mammal.

14. A use of the compound of formula I of claim 1 or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for preventing or treating a metabolic disorder.