Substituted alkyl diaryl derivatives, methods of preparation and uses

Patent metadata

Field	Value
Publication number	US-10207989-B2
Application number	US-201314429223-A
Country	US
Kind code	B2
Filing date	Sep 18, 2013
Priority date	Sep 20, 2012
Publication date	Feb 19, 2019
Grant date	Feb 19, 2019

Abstract

Compounds according to Formula I are provided: and salts thereof, wherein Q 1 , Q 2 , R 3 , R 4 , X, and Y are as defined herein. Methods for preparing compounds of Formula I are also provided, as well as methods of treating cellular proliferative disorders, such as cancer, using compounds of Formula (I).

Q 2 -X—Y—CHR 3 —CHR 4 -Q 1   (I)

First claim

What is claimed is:

1. A compound of Formula I or a salt thereof;
Q 2 -X-Y—CHR 3 —CHR 4 -Q 1   (I)

wherein:
Q 1 is substituted phenyl, with up to 5 substituents selected from the group consisting of:
fluoro; bromo; nitro; —NR 10 R 11 ; aroylamino; carboxy; cyano; carboxamido; trifluoromethyl; —O—R 10 ; and [—N(—R 1 )—(CH 2 ) m —C(—R 5 )(—R 6 )—(CH 2 ) n —COOR 7 ] z ;
wherein at least the 4-position of Q 1 is substituted;

Q 2 is substituted phenyl, with up to 5 substituents selected from the group consisting of:
fluoro; chloro; nitro; —NR 10 R 11 ; aroylamino; cyano; carboxy; carboxamido; trifluoromethyl; —O—SO 2 —OH; —O—P(═O)(OR 8 ) 2 ; —O—R 10 ; [—N(—R 9 )—(CH 2 ) m —C(—R 5 )(—R 6 )—(CH 2 ) n —COOR 7 ] z ; and a C 1 -C 10 saturated or unsaturated, straight or branched, cyclic or acyclic, chiral or achiral hydrocarbyl group, wherein optionally at least one carbon atom of the hydrocarbyl group is replaced by —N(—R 1 )—, —O— or —S—;

wherein at least one of Q 1 and Q 2 is substituted with a substituent other than unsubstituted phenyl;
X is —CH(R 2 )—;
Y is —S(═O) 2 —;
R 1 and R 2 are each independently selected from the group consisting of H and a C 1 -C 10 saturated or unsaturated, straight or branched, cyclic or acyclic, chiral or achiral hydrocarbyl group, wherein optionally at least one carbon atom of the hydrocarbyl group is replaced by —O— or —S—;
R 3 and R 4 are H;
R 5 and R 6 are each independently selected from the group consisting of H; halo; and C 1 -C 10 saturated or unsaturated, straight or branched, cyclic or acyclic, chiral or achiral hydrocarbyl group, optionally substituted with one or more of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, carboxy, carboxamido, amino, (C 1 -C 6 ) alkyl, (C 1 -C 10 ) dialkyl amino, or acylamino; or
R 5 and R 6 may combine to form a saturated or unsaturated carbocyclic ring with from 3 to 6 carbon atoms, wherein one or more carbon atoms is optionally replaced with —N(—R 1 )—, —O—, or —S—;
R 7 is selected from the group consisting of H; and a C 1 -C 10 saturated or unsaturated, straight or branched, cyclic or acyclic, chiral or achiral hydrocarbyl group; and an inorganic cation or an organic cation to form a salt;
R 8 is selected from the group consisting of H and (C 1 -C 7 ) hydrocarbyl;
R 9 is selected from the group consisting of H and —(CH 2 ) m —C(—R 5 )(—R 6 )—(CH 2 ) n —COOR 7 ;
R 10 is selected from the group consisting of H, branched or unbranched (C 1 -C 6 )alkyl, and (C 2 -C 8 )acyl;
R 11 is selected from the group consisting of H, branched or unbranched (C 1 -C 6 )alkyl, and (C 2 -C 5 )acyl;
m and n are each independently 0-2; and

z is 1-2.

2. A compound according to claim 1 , or a salt thereof, wherein Q 1 has at least one substituent that is carboxy, —O—R 10 or fluoro.

3. A compound according to claim 1 , or a salt thereof, wherein Q 2 has at least one substituent selected from the group consisting of chloro; —O—R 10 ; —NR 10 R 11 ; and
[—N(—R 9 )—(CH 2 ) m —C(—R 5 )(—R 6 )—(CH 2 ) n —COOR 7 ] z .

4. A compound according to claim 2 , or a salt thereof, wherein Q 2 has at least one substituent selected from the group consisting of chloro; —O—R 10 ; —NR 10 R 11 ; and [—N(—R 9 )—(CH 2 ) m —C(—R 5 )(—R 6 )—(CH 2 ) n —COOR 7 ] z .

5. A compound according to claim 4 , or a salt thereof, wherein Q 2 has a substituent at the 4-position thereof.

6. A compound according to claim 5 , or a salt thereof, wherein Q 1 is substituted at the 2-, 4- and 6-positions with (C 1 -C 3 )alkoxy, and Q 2 is substituted in at least the 4-position with —O—R 10 or —NR 10 R 11 .

7. A compound according to claim 6 , or a salt thereof, wherein Q 2 is substituted at the 4-position with —O—R 10 or —NR 10 R 11 and substituted at the 3-position with —NR 10 R 11 , —O—R 10 or —N(—R 9 )—(CH 2 ) m —C(—R 5 )(—R 6 )—(CH 2 ) n —COOR 7 ] z .

8. A compound according to claim 1 selected from the group consisting of:
1-chloro-4-(((4-fluorophenethyl)sulfonyl)methyl)benzene;
2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)aniline;
2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenol;
4-(2-((4-chlorobenzyl)sulfonyl)ethyl)benzoic acid;
methyl 2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)acetate;
dimethyl 2,2′-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)azanediyl)diacetate;
2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)acetic acid;
2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)propanoic acid;
2-((2-methoxy-5-((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)-2-methylpropanoic acid;
2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)-2-phenylacetic acid;
2-(4-fluorophenyl)-2-((2-methoxy-5-((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)acetic acid;
2-(4-chlorophenyl)-2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)acetic acid;
2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)-3-phenylpropanoic acid;
2-cyclopropyl-2-(((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)acetic acid;
2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)-2-(1H-pyrrol-3-yl)acetic acid;
1,3,5-trimethoxy-2-(2-((4-methoxybenzyl)sulfonyl)ethyl)benzene;
and salts thereof.

9. A compound according to claim 8 , wherein the compound is selected from the group consisting of:
2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)acetic acid;
2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)aniline;
2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenol;
methyl 2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)acetate;
1,3,5-trimethoxy-2-(2-((4-methoxybenzyl)sulfonyl)ethyl)benzene;
and salts thereof.

10. The compound according to claim 9 which is sodium 2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)acetate.

11. A compound according to claim 9 which is 2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino) acetic acid, or pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 .

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt thereof, according to claim 8 .

14. The pharmaceutical composition according to claim 12 , wherein the compound is 2-((2-methoxy-5-(((2,4,6-trimethoxyphenethyl)sulfonyl)methyl)phenyl)amino)acetic acid, or pharmaceutically acceptable salt thereof.

15. A process of making a compound of Formula I or a salt thereof according to claim 1 , having a Formula Ib:

said process comprising:
oxidizing a compound of Formula Ia:

to produce a compound of Formula Ib or a salt thereof in a reaction mixture, and optionally isolating compound Formula Ib or a salt thereof from the reaction mixture, wherein Q 1 , Q 2 , R 3 , and R 4 are as defined in claim 1 .

16. The process of claim 15 , wherein the reaction takes place in the presence of an acid and a peroxide.

17. A process of making a compound of Formula I or a salt thereof according to claim 1 , having a Fo

Assignees

• Temple University—Of the Commonwealth System of Higher Education

Inventors

• Reddy M V Ramana
• Reddy E Premkumar

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C235/38

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C317/18

  with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton · CPC title