IP Library › Granted Patent US 10,047,041

Granted Patent B2

US 10,047,041 · App. 15/506,211 · Granted Aug 14, 2018

Amino-phenyl-sulfonyl-acetate derivatives and use thereof

Inventors: Jae Ho Yoo (Yongin-si, KR); Seung Chan Kim (Suwon-si, KR); Soo Yeon Jung (Seoul, KR); Hyoung Rok Bak (Seoul, KR); Young Mee Chung (Yongin-si, KR); Sung Jun Kim (Yongin-si, KR); Sook Kyung Park (Seoul, KR); Seog Beom Song (Suwon-si, KR); Shin-Young Ryu (Seoul, KR); Mi Young Yoon (Cheonan-si, KR); Dong Hyun Ko (Gwacheon-si, KR); Sun Young Park (Yongin-si, KR); Chi Hye Park (Seongnam-si, KR); Nak Hyun Choi (Yongin-si, KR)

Assignee: CJ HEALTHCARE CORPORATION

C07C317/14 C07D213/36 C07D307/52 C07D307/79 C07D317/46 C07D319/16

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Quick Facts

Patent No.: US 10,047,041
App. No.: 15/506,211
Granted: Aug 14, 2018
Kind: B2

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Abstract

The present invention relates to a novel amino-phenyl-sulfonyl-acetate derivative or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition for preventing or treating diabetes comprising the same as an active ingredient.

Claims (221)

1. A compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof:

wherein

X is C or O;

Y is NH or O;

m is an integer of 1 or 2;

n is an integer of 0 or 1;

R 1 is hydrogen, C 1-4 alkyl, or C 1-4 alkoxy; or forms a C 5-10 hydrocarbon ring connected with R 2 ;

R 2 is absent or hydrogen, halogen, aryloxy, or aryl or heteroaryl selected from the group consisting of phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, and thienyl,

wherein the aryl or heteroaryl is unsubstituted, or independently substituted with at least one substituent selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, haloalkyl, C 1-4 hydroxyalkyl, hydroxy, halogen, nitro, cyano, amino, C 1-4 alkyl-amino, acetyl-amino, formyl, —(C═O)—(C 1-4 alkyl), —(C═O)-morpholino, —(C═O)—NR 6 R 7 , morpholino, piperazinyl, piperidinyl, C 1-4 alkyl-SO 2 —C 1-4 alkoxy, —SO 2 —(C 1-4 alkyl), and —SO 2 —NR 6 R 7 directly or through a straight or branched C 1-4 alkyl chain, or forms an unsubstituted or halogen substituted 5- to 7-membered ring joined through two adjacent substituent groups, said ring comprising 0 to 2 oxygen atoms;

R 3 and R 4 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro, cyano, amino, C 1-4 alkyl-amino, acetyl-amino, formyl, —(C═O)—(C 1-4 alkyl), —(C═O)-morpholino, —(C═O)—NR 6 R 7 , morpholino, piperazinyl, piperidinyl, —SO 2 —(C 1-4 alkyl), or —SO 2 —NR 6 R 7 ;

R 5 is hydroxy, C 1-4 alkoxy, or C 1-4 alkyl-aminooxy; and

R 6 and R 7 are each independently hydrogen or C 1-4 alkyl,

wherein

when X is O, then n is 0 and R 2 is absent; and

when X is C, then n is 1, and provided further that when R 2 is hydrogen, then R 1 is C 1-4 alkyl or C 1-4 alkoxy, or R 3 is halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro, cyano, amino, C 1-4 alkyl-amino, acetyl-amino, formyl, —(C═O)—(C 1-4 alkyl), —(C═O)-morpholino, —(C═O) —NR 6 R 7 , morpholino, piperazinyl, piperidinyl, —SO 2 —(C 1-4 alkyl), or —SO 2 —NR 6 R 7 .

2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is hydrogen, methyl, or ethoxy, or forms a C 5-10 hydrocarbon ring connected with R 2 .

3. The compound or pharmaceutically acceptable salt thereof of claim 1 ,

wherein R 2 is absent; R 2 is hydrogen; halogen; aryloxy; or R 2 is phenyl or pyridinyl which is unsubstituted or independently substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkyl-SO 2 —C 1-4 alkoxy, hydroxy, and halogen, or forms an unsubstituted or halogen-substituted 5- to 7-membered ring joined through two adjacent substituent groups, said ring comprising 0 to 2 oxygen atoms.

4. The compound or pharmaceutically acceptable salt thereof of claim 3 , wherein R 2 is absent; R 2 is hydrogen; bromo; phenyloxy; benzofuranyl; 2,3-dihydrobenzo[b][1,4]dioxynyl; or R 2 is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxymethyl, methyl-sulfonyl-propoxy, hydroxy, fluoro, and chloro.

5. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 and R 4 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro, cyano, or amino.

6. The compound or pharmaceutically acceptable salt thereof of claim 5 , wherein R 3 and R 4 are each independently hydrogen, fluoro, methyl, or methoxy.

7. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 5 is hydroxy.

8. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein

when X is C,

Y is NH or O;

m is an integer of 1 or 2;

n is an integer of 1;

R 1 is hydrogen, methyl, or ethoxy, or forms a tetrahydro-naphthalene ring connected with R 2 ;

R 2 is hydrogen; bromo; phenyloxy; benzofuranyl; 2,3-dihydrobenzo[b][1,4]dioxynyl; or phenyl, pyridinyl, or benzo[d][1,3]dioxolyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxymethyl, methyl-sulfonyl-propoxy, hydroxy, fluoro, and chloro;

R 3 and R 4 are each independently hydrogen, fluoro, methyl, or methoxy; and

R 5 is hydroxy.

9. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein

when X is O,

Y is NH;

m is an integer of 1 or 2;

n is an integer of 0;

R 1 is hydrogen;

R 2 is absent;

R 3 and R 4 are both hydrogen; and

R 5 is hydroxy.

10. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of:

1) 2-(4-((2′-methyl-biphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

2) 2-(4-(3-(benzofuran-5-yl)benzylamino)phenylsulfonyl)acetic acid,

3) 2-(4-(3-phenoxybenzylamino)phenylsulfonyl)acetic acid,

4) 2-(4-(3-bromobenzylamino)phenylsulfonyl)acetic acid,

5) 2-(4-((2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

6) 2-(4-((2′,6′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

7) 2-(4-((4′-fluorobiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

8) 2-(4-((3′-methoxybiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

9) 2-(4-((4-fluoro-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

10) 2-(4-((2′,4-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

11) 2-(4-((4-methoxy-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

12) 2-(4-((2-fluoro-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

13) 2-(4-((2-methoxy-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

14) 2-(4-((4-fluoro-2′,3′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

15) 2-(4-((4-fluoro-2′,4′- dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

16) 2-(4-((2-fluorobiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

17) 2-(4-((2-methoxybiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

18) 2-(4-((4-methoxy-2′,3′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

19) 2-(4-(2-methoxybenzylamino)phenylsulfonyl)acetic acid,

20) 2-(4-(3-methoxybenzylamino)phenylsulfonyl)acetic acid,

21) 2-(4-(2-methylbenzylamino)phenylsulfonyl)acetic acid,

22) 2-(4-(4-ethoxybenzylamino)phenylsulfonyl)acetic acid,

23) 2-(4-(furan-3-yl-methylamino)phenylsulfonyl)acetic acid,

24) 2-(4-(3-(pyridin-3-yl)benzylamino)phenylsulfonyl)acetic acid,

25) 2-(4-(3-(pyridin-4-yl)benzylamino)phenylsulfonyl)acetic acid,

26) 2-(4-(3-(benzo[d][1,3]dioxol-5-yl)benzylamino)phenylsulfonyl)acetic acid,

27) 2-(4-(3-(2,2-difluoro-benzo[d][1,3]dioxol-5-yl)benzylamino)phenylsulfonyl)acetic acid,

28) 2-(4-(3-(4-fluoro-benzo[d][1,3]dioxol-5-yl)benzylamino)phenylsulfonyliacetic acid,

29) 2-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzylamino)phenylsulfonyl)acetic acid,

30) 2-(4-(3-(2-methylpyridin-4-yl)benzylamino)phenylsulfonyl)acetic acid,

31) 2-(4-(3 -(2-hydroxypyridin-4-yl)benzylamino)phenylsulfonyl)acetic acid,

32) 2-(4-(3 -(2-methoxypyridin-4-yl)benzylamino)phenylsulfonyl)acetic acid,

33) 2-(4-(3 -(2-ethoxypyridin-4-yl)benzylamino)phenylsulfonyl)acetic acid,

34) 2-(4-((4′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

35) 2-(4-(biphenyl-3-yl-methylamino)phenylsulfonyl)acetic acid,

36) 2-(4-((3′,4′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

37) 2-(4-((2′,4′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

38) 2-(4-((2′,3′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

39) 2-(4-((2′,5′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

40) 2-(4-((4′-ethylbiphenyl-3-yl-methylamino)phenylsulfonyl)acetic acid,

41) 2-(4-((2′-ethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

42) 2-(4-((3′,5′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

43) 2-(4-((4′-methoxy-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

44) 2-(4-((4′-methoxy-2′,6′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

45) 2-(4-((3′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

46) 2-(4-((3′,4′-dimethoxybiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

47) 2-(4-((4′-chloro-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

48) 2-(4-((4′-chloro-2′-(trifluoromethyl)biphenyi-3-yl)methylamino)phenylsulfonyl)acetic acid,

49) 2-(4-((2′,4′,6′-trimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

50) 2-(4-((2′-methoxybiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

51) 2-(4-((4′-fluoro-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

52) 2-(4-((2′-(trifluoromethyl)biphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

53) 2-(4-((5′-chloro-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

54) 2-(4-((2′,6′-dimethoxybiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

55) 2-(4-((2′-(hydroxymethyl)biphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

56) 2-(4-((2′,6-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

57) 2-(4-((4-fluoro-2′,6-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

58) 2-(4-((2′,6-dimethylbiphenyl-3-yl)methoxy)phenylsulfonyl)acetic acid,

59) 2-(4-((2′-ethyl-6-methylbiphenyl-3-yl)methoxy)phenylsulfonyl)acetic acid,

60) 2-(4-((2′-methylbiphenyl-3-yl)methylamino)phenylsulfinyl)acetic acid,

61) 2-(4-((2′,6-dimethylbiphenyl-3-yl)methylamino)phenylsulfinyl)acetic acid,

62) 2-(4-((4-fluoro-2′,6-dimethylbiphenyl-3-yl)methylamino)phenylsulfinyl)acetic acid,

63) 2-(4-(3-phenoxybenzylamino)phenylsulfinyl)acetic acid, and

64) 2-(4-((9,10-dihydrophenanthrene-3-yl)methylamino)phenylsulfinyl)acetic acid.

11. The compound or pharmaceutically acceptable salt thereof of claim 1 ,

wherein

X is C;

Y is NH or O;

m is an integer of 1 or 2;

n is an integer of 1;

R 1 is hydrogen, C 1-4 alkyl, or C 1-4 alkoxy; or forms a C 5-10 hydrocarbon ring connected with R 2 ;

R 2 is halogen, aryloxy, or aryl or heteroaryl selected from the group consisting of phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, and thienyl,

wherein the aryl or heteroaryl is unsubstituted, or independently substituted with at least one substituent selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, hydroxy, halogen, nitro, cyano, amino, C 1-4 alkyl-amino, acetyl-amino, formyl, —(C═O)—(C 1-4 alkyl), —(C═O)-morpholino, —(C═O)—NR 6 R 7 , morpholino, piperazinyl, piperidinyl, C 1-4 alkyl-SO 2 —C 1-4 alkoxy, —SO 2 —(C 1-4 alkyl), and —SO 2 —NR 6 R 7 directly or through a straight or branched C 1-4 alkyl chain, or forms an unsubstituted or halogen substituted 5- to 7-membered ring joined through two adjacent substituent groups, said ring comprising 0 to 2 oxygen atoms;

R 3 and R 4 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro, cyano, amino, C 1-4 alkyl-amino, acetyl-amino, formyl, —(C═O)—(C 1-4 alkyl), —(C═O)-morpholino, —(C═O)-NR 6 R 7 , morpholino, piperazinyl, piperidinyl, —SO 2 —(C 1-4 alkyl), or —SO 2 —NR 6 R 7 ;

R 5 is hydroxy, C 1-4 alkoxy, or C 1-4 alkyl-aminooxy; and

R 6 and R 7 are each independently hydrogen or C 1-4 alkyl; or

X is O;

Y is NH or O;

m is an integer of 1 or 2;

n is the integer of 0;

R 1 is hydrogen, C 1-4 alkyl, or C 1-4 alkoxy; or forms a C 5-10 hydrocarbon ring connected with R 2 ;

R 2 is absent;

R 5 is hydroxy, C 1-4 alkoxy, or C 1-4 alkyl-aminooxy; and

R 6 and R 7 are each independently hydrogen or C 1-4 alkyl.

12. A pharmaceutical composition for

treating diabetes comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

13. The pharmaceutical composition of claim 12 , wherein the compound or a pharmaceutically acceptable salt thereof enhances glucose metabolism.

14. The pharmaceutical composition of claim 12 , wherein R 1 is hydrogen, methyl, or ethoxy, or forms a C 5-10 hydrocarbon ring connected with R 2 .

15. The pharmaceutical composition of claim 12 ,

16. The pharmaceutical composition of claim 15 ,

wherein R 2 is absent; R 2 is hydrogen; bromo; phenyloxy; benzofuranyl; 2,3-dihydrobenzo[b][1,4]dioxynyl; or R 2 is phenyl, pyridinyl, or benzo[d][1,3]dioxolyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, methoxy, ethoxy, trifluoromethyl, hydroxymethyl, methyl-sulfonyl-propoxy, hydroxy, fluoro, and chloro.

17. The pharmaceutical composition of claim 12 ,

wherein R 3 and R 4 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro, cyano, or amino.

18. The pharmaceutical composition of claim 17 , wherein R 3 and R 4 are each independently hydrogen, fluoro, methyl, or methoxy.

19. The pharmaceutical composition of claim 12 , wherein R 5 is hydroxy.

20. The pharmaceutical composition of claim 12 , wherein

when X is C,

Y is NH or O;

m is an integer of 1 or 2;

n is an integer of 1;

R 1 is hydrogen, methyl, or ethoxy, or forms a tetrahydro-naphthalene ring connected with R 2 ;

R 3 and R 4 are each independently hydrogen, fluoro, methyl, or methoxy; and

R 5 is hydroxy.

21. The pharmaceutical composition of claim 12 , wherein

when X is O,

Y is NH;

m is an integer of 1 or 2;

n is an integer of 0;

R 1 is hydrogen;

R 2 is absent;

R 3 and R 4 are both hydrogen; and

R 5 is hydroxy.

22. The pharmaceutical composition of claim 12 , wherein the compound is selected from the group consisting of:

1) 2-(4-((2′-methyl-biphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

2) 2-(4-(3-(benzofuran-5-yl)benzylamino)phenylsulfonyl)acetic acid,

3) 2-(4-(3-phenoxybenzylamino)phenylsulfonyl)acetic acid,

4) 2-(4-(3-bromobenzylamino)phenylsulfonyl)acetic acid,

5)2-(4-((2′,6′-dimethyl-4′-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

6) 2-(4-((2′,6′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

7) 2-(4-((4′-fluorobiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

8) 2-(4-((3′-methoxybiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

9) 2-(4-((4-fluoro-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

10) 2-(4-((2′,4-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

11) 2-(4-((4-methoxy-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

12) 2-(4-((2-fluoro-2′-methylbiphenyl--yl)methylamino)phenylsulfonyl)acetic acid,

13) 2-(4-((2-methoxy-2′-methylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

14) 2-(4-((4-fluoro-2′,3′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

15) 2-(4-((4-fluoro-2′,4′- dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

16) 2-(4-((2-fluorobiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

17) 2-(4-((2-methoxybiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

18) 2-(4-((4-methoxy-2′,3′-dimethylbiphenyl-3-yl)methylamino)phenylsulfonyl)acetic acid,

19) 2-(4-(2-methoxybenzylamino)phenylsulfonyl)acetic acid,

20) 2-(4-(3-methoxybenzylamino)phenylsulfonyl)acetic acid,

21) 2-(4-(2-methylbenzylamino)phenylsulfonyl)acetic acid,

22) 2-(4-(4-ethoxybenzylamino)phenylsulfonyl)acetic acid,

23) 2-(4-(furan-3-yl-methylamino)phenylsulfonyl)acetic acid,

24) 2-(4-(3-(pyridin-3-yl)benzylamino)phenylsulfonyl)acetic acid,

25) 2-(4-(3-(pyridin-4-yl)benzylamino)phenylsulfonyl)acetic acid,

26) 2-(4-(3-(benzo[d][1,3]dioxol-5-yl)benzylamino)phenylsulfonyl)acetic acid,

27) 2-(4-(3-(4-fluoro-benzo[d][1,3]dioxol-5-yl)benzylamino)phenylsulfonyl)acetic acid,

28) 2-(4-(3-(4-fluoro-benzo[d][1,3]dioxol-5-yl)benzylamino)phenylsulfonyl)acetic acid,

29) 2-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzylamino)phenylsulfonyl)acetic acid,

30) 2-(4-(3 -(2-methylpyridin-4-yl)benzylamino)phenylsulfonyl)acetic acid,