Substituted 3-phenylpropylamine derivatives for the treatment of ophthalmic diseases and disorders

Patent metadata

Field	Value
Publication number	US-2016229831-A1
Application number	US-201514849859-A
Country	US
Kind code	A1
Filing date	Sep 10, 2015
Priority date	Mar 12, 2013
Publication date	Aug 11, 2016
Grant date	—

Abstract

The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are substituted 3-phenylpropylamine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compositions are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease.

First claim

We claim:

1 . A compound of Formula (C), or a pharmaceutically acceptable salt thereof:

wherein,
A is selected from —O— or —CH 2 —;
Y is

R A is OH, R B is H; or optionally, R A and R B together form an oxo;
R 1 and R 2 are each independently selected from hydrogen, C 1 -C 4 alkyl, —C(═O)R 3 ; and
R 3 is selected from alkyl, alkoxy, or —OCH 2 OC(O)R 4 , wherein R 4 is an alkyl or alkoxy.

2 . The compound of claim 1 , wherein A is —O—.

3 . The compound of claim 1 , wherein A is —CH 2 —.

4 . The compound of claim 1 , wherein R A is OH and R B is H.

5 . The compound of claim 1 , wherein R 1 and R 2 are both hydrogen.

6 . The compound of claim 1 , wherein R 1 is hydrogen and R 2 is C 1 -C 4 alkyl.

7 . The compound of claim 1 , wherein R 1 is hydrogen and R 2 is —C(═O)R 3 .

8 . The compound of claim 1 , wherein Y is

9 . The compound of claim 1 , wherein Y is

10 . A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
(R)-3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol; 3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol; (1R)-3-Amino-1-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-(pyridin-4-ylmethoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-(pyridin-3-ylmethoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol; (1R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)propan-1-ol; (R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide; 3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1,1-dioxide; (R)-1-(4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-1-yl)ethanone; (R)-3-Amino-1-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propan-1-ol; (1R)-3-Amino-1-(3-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)propan-1-ol; (1R)-3-Amino-1-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-(piperidin-4-ylmethoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)propan-1-ol; (R)-Methyl 4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate; (R)-3-Amino-1-(3-(pyrimidin-5-ylmethoxy)phenyl)propan-1-ol; (1R)-3-Amino-1-(3-(chroman-3-ylmethoxy)phenyl)propan-1-ol; (R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran 1-oxide; (R)-3-Amino-1-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-((S)-pyrrolidin-2-ylmethoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)propan-1-ol; 3-Amino-1-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)propan-1-one; 3-Amino-1-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)propan-1-one; 3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl) methyl)sulfonyl)phenyl)propan-1-one; 3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one; (R)-3-Amino-1-(3-(thiophen-2-ylmethoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-(thiophen-3-ylmethoxy)phenyl)propan-1-ol; (R)-tert-Butyl 4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate; (E)-3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-en-1-amine; 3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-amine; (R)-3-(Methylamino)-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol; 1-((S)-2-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-1-yl)ethanone; 5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one; 4-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one; 6-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpiperidin-2-one; 5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-2-one; 5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpyrrolidin-2-one; N-(3-(3-Amino-1-hydroxypropyl)phenyl)-6-oxopiperidine-3-carboxamide; 3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1,2-thiazinane 1,1-dioxide; (R)-1-(3-((1H-Pyrrol-2-yl)methoxy)phenyl)-3-aminopropan-1-ol; (R)-3-Amino-1-(3-(furan-2-ylmethoxy)phenyl)propan-1-ol; (R)-3-Amino-1-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)propan-1-ol; (R)-1-(3-(((1H-Indol-6-yl)methyl)amino)phenyl)-3-aminopropan-1-ol; (R)-1-(3-((1H-Indol-6-yl)methoxy)phenyl)-3-aminopropan-1-ol; (R)-3-Amino-1-(3-(benzofuran-2-ylmethoxy)phenyl)propan-1-ol; 3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-yn-1-amine; 3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propan-1-ol; 3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)propan-1-ol; 3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol; 3-Amino-1-(3-(2-(pyridin-3-yl)ethyl)phenyl)propan-1-ol; 3-Amino-1-(3-(2-(thiophen-3-yl)ethyl)phenyl)propan-1-ol; (E)-1-(3-(3-Amino-1-hydroxypropyl)styryl)pyrrolidin-2-one; 1-(3-(3-Amino-1-hydroxypropyl)phenethyl)pyrrolidin-2-one; 3-Amino-1-(3-(2-(pyrrolidin-1-yl)ethyl)phenyl)propan-1-ol; (E)-1-(3-(2-(1H-Imidazol-1-yl)vinyl)phenyl)-3-aminopropan-1-ol; 1-(3-(2-(1H-Imidazol-1-yl)ethyl)phenyl)-3-aminopropan-1-ol; (E)-3-Amino-1-(3-(2-(pyridin-2-yl)vinyl)phenyl)propan-1-ol; 3-Amino-1-(3-(2-(pyridin-2-yl)ethyl)phenyl)propan-1-ol; (E)-3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)propan-1-ol; and 3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol.

11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (C) as represented in claim 1 , or a pharmaceutically acceptable salt thereof.

12 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 10 , or a pharmaceutically acceptable salt thereof.

13 . A method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of Formula (C) as represented in claim 1 , or a pharmaceutically acceptable salt thereof.

14 . A method for treating an ophthalmic disease or disorder in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of claim 10 , or a pharmaceutically acceptable salt thereof.

15 . The method of claim 13 , wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy.

16 . The method of claim 14 , wherein the ophthalmic disease or disorder is age-related macular degeneration or Stargardt's macular dystrophy.

Assignees

• Acucela Inc

Inventors

• Kuksa Vladimir A
• Orme Mark W
• Hong Feng
• Kubota Ryo

Classifications

• A61P27/02

  Ophthalmic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D209/14

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title

• C07D333/20

  by nitrogen atoms (nitro, nitroso radicals C07D333/12) · CPC title