Functionalized N,N-dialkylamino phenyl ethers and their method of use

Patent metadata

Field	Value
Publication number	US-11325883-B2
Application number	US-201816764424-A
Country	US
Kind code	B2
Filing date	Nov 20, 2018
Priority date	Nov 22, 2017
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

Pharmaceutical compositions of the invention comprise functionalized N,N-dialkylamino phenyl ethers derivatives having a disease-modifying action in the treatment of diseases associated with lysosomal storage dysfunction that include Gaucher's disease, and any disease or condition involving lysosomal storage dysfunction.

First claim

What is claimed is:

1. A compound having formula (I):

Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, wherein:
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, C 1 -C 10 branched alkyl, alkenyl, alkynyl, C 3 -C 10 cycloalkyl, cycloalkenyl, alkyl-cycloalkyl and alkyl-cycloalkenyl optionally substituted with a C 1 -C 5 alkyl group;
R 2 is at each occurrence independently selected from the group consisting of H, OH, halogen, CN, NO 2 , C 1 -C 10 alkoxy, C 3 -C 10 branched alkoxy, C 1 -C 10 haloalkoxy, C 3 -C 10 branched haloalkoxy, NR 8 R 9 , C(O)OR 10 , C 1 -C 10 thioalkyl, C 3 -C 10 branched thioalkyl, C 1 -C 10 halothioalkyl, —S(O)C 1 -C 10 alkyl, —S(O)C 3 -C 10 branched alkyl, —S(O)C 1 -C 10 haloalkyl, —S(O)C 3 -C 10 branched haloalkyl, —SO 2 C 1 -C 10 alkyl, —SO 2 C 3 -C 10 branched alkyl, —SO 2 C 1 -C 10 haloalkyl, —SO 2 C 1 -C 10 branched haloalkyl, SO 2 NR 11 R 12 , —NR 11 SO 2 R 13 , C(O)—NR 11 R 12 ;
R 3 is a substituted or unsubstituted aryl or heteroaryl group of 1-10 carbon atoms, wherein the heteroaryl group comprises 1-4 heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, S(O), SO 2 , and wherein the aryl or heteroaryl group may be optionally substituted with a substituent selected from the group consisting of H, OH, halogen, CN, NO 2 , C 1 -C 10 alkoxy, C 3 -C 10 branched alkoxy, C 1 -C 10 haloalkoxy, C 3 -C 10 branched haloalkoxy, NR 8 R 9 , C(O)OR 10 , C 1 -C 10 thioalkyl, C 3 -C 10 branched thioalkyl, C 1 -C 10 halothioalkyl, —S(O)C 1 -C 10 alkyl, —S(O)C 3 -C 10 branched alkyl, —S(O)C 1 -C 10 haloalkyl, —S(O)C 3 -C 10 branched haloalkyl, —SO 2 C 1 -C 10 alkyl, —SO 2 C 3 -C 10 branched alkyl, —SO 2 C 1 -C 10 haloalkyl, —SO 2 C 1 -C 10 branched haloalkyl, SO 2 NR 11 R 12 , —NR 11 SO 2 R 13 , C(O)—NR 11 R 12 ;
R 4 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, and C 3 -C 7 branched alkyl;
R 5 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, and C 3 -C 7 branched alkyl;
m is 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R 6 is selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl and C 3 -C 7 branched alkyl;
R 7 is selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl and C 3 -C 7 branched alkyl; or R 6 and R 7 may optionally be taken together with the atoms to which they are bound to form a ring containing 4 to 7 members, and wherein the ring may optionally comprise a member selected from the group consisting of O, S, and NR 14 ;
R 8 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, and C 3 -C 7 branched alkyl;
R 9 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, and C 3 -C 7 branched alkyl;
R 10 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, and C 3 -C 7 branched alkyl;
R 11 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, and C 3 -C 7 branched alkyl;
R 12 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, and C 3 -C 7 branched alkyl;
R 13 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, and C 3 -C 7 branched alkyl; and
R 14 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 linear alkyl, and C 3 -C 7 branched alkyl.

2. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II)

Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

3. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III)

Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

4. The compound of claim 1 , wherein the compound of formula (I) is a compound of (IV)

Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

5. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
2-([1,1′-Biphenyl]-2-yl)-1-(4-(dimethylamino)-ethoxy)phenyl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-[1,1′-biphenyl]-2-yl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-2′-methyl-[1,1′-biphenyl]-2-yl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)ethenone,
2-(2′-Chloro-[1,1′-biphenyl]-2-yl)-1-(4-(2-(dimethylamino)ethoxy)phenyl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-2′-methoxy-[1,1′-biphenyl]-2-yl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(3′-fluoro-4′-methoxy-[1,1′-biphenyl]-2-yl)ethenone,
2-(2′,4′-Difluoro-[1,1′-biphenyl]-2-yl)-1-(4-(2-((dimethylamino)ethoxy)phenyl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(3′-cyano-[1,1′-biphenyl]-2-yl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(2′-fluoro-[1,1′-biphenyl]-2-yl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(2′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-5-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethenone,
1-(4-(2-(Dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-[1,1′-biphenyl]-2-yl)-4-methylpentan-1-one,
2-(2-cyclopropylphenyl)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-4-methylpentan-1-one,
1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-[1,1′-biphenyl]-2-yl)-4-methylpentan-1-one,
3-cyclopropyl-1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-[1,1′-biphenyl]-2-yl)propan-1-one,
1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-[1,1′-biphenyl]-2-yl)butan-1-one,
1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-(4′-fluoro-[1,1′-biphenyl]-2-yl)pentan-1-one,
2-(4′-fluoro-[1,1′-biphenyl]-2-yl)-1-(4-(2-(methylamino)ethoxy)phenyl)butan-1-one,
2-(4′-fluoro-[1,1′-biphenyl]-2-yl)-1-(4-(2-(methylamino)ethoxy)phenyl)pentan-1-one, and
2-(4′-fluoro-[1,1′-biphenyl]-2-yl)-4-methyl-1-(4-(2-(methylamino)-ethoxy)phenyl)pentan-1-one.

6. A composition comprising at least one compound according to claim 1 and at least one excipient.

7. A method for treating or preventing a disease or conditions that involve lysosomal storage dysfunction, said method comprising administering to a subject in need thereof an effective amount of at least one compound according to claim 1 .

8. The method of claim 7 , wherein the disease or conditions that involve lysosomal storage dysfunction is Gaucher's disease, Tay-Sachs disease, Sandhoffs disease, Sandhoff-Jatzkewitz disease, Fabry disease, Niemann Pick disease Type C, Pompe disease, type III A mucopolysaccharidosis, Sanfilippo syndrome, α-mannosidosis, GM1 gangliosidosis, or GM2 gangliosidosis.

9. The method of claim 7 , wherein the at least one compound is administered in a composition further comprising at least one excipient.

Assignees

• Temple University—Of the Commonwealth System of Higher Education

Inventors

• Melenski Edward G
• Childers Wayne E
• Jacobson Marlene A
• Abou-Gharbia Magid A

Classifications

• A61P31/10

  Antimycotics · CPC title

• C07C225/16 Primary

  and containing six-membered aromatic rings · CPC title

• A61K31/135 Primary

  having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)} · CPC title

• C07C217/22

  by carbon atoms having at least two bonds to oxygen atoms · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title