Alkoxy compounds for disease treatment

Patent metadata

Field	Value
Publication number	US-11446261-B2
Application number	US-202016865195-A
Country	US
Kind code	B2
Filing date	May 1, 2020
Priority date	Oct 5, 2007
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are alkoxyl derivative compounds and pharmaceutical compositions comprising these 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

What is claimed is:

1. A method of inhibiting regeneration of rhodopsin in a rod photoreceptor cell of a retina comprising contacting the retina with a compound of Formula (F) or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable salt or N-oxide thereof:

wherein,
Z is a bond, —C(R 1 )(R 2 )—, —C(R 9 )(R 10 )—C(R 1 )(R 2 )—, —X—C(R 31 )(R 32 )—, —C(R 9 )(R 10 )—C(R 1 )(R 2 )—C(R 36 )(R 37 )— or —X—C(R 31 )(R 32 )—C(R 1 )(R 2 )—;
R 1 and R 2 are each independently selected from hydrogen, halogen, C 1 -C 5 alkyl, fluoroalkyl, —OR 6 or —NR 7 R 8 ; or R 1 and R 2 together form an oxo;
R 31 and R 32 are each independently selected from hydrogen, C 1 -C 5 alkyl, or fluoroalkyl;
R 36 and R 37 are each independently selected from hydrogen, halogen, C 1 -C 5 alkyl, fluoroalkyl, —OR 6 or —NR 7 R 8 ; or R 36 and R 37 together form an oxo; or optionally, R 36 and R 1 together form a direct bond to provide a double bond; or optionally, R 36 and R 1 together form a direct bond, and R 37 and R 2 together form a direct bond to provide a triple bond;
R 3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino;
R 5 is C 5 -C 15 alkyl, carbocyclyalkyl, arylalkyl, heteroaryl alkyl or heterocyclylalkyl;
R 7 and R 8 are each independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 13 , SO 2 R 13 , CO 2 R 13 or SO 2 NR 24 R 25 ; or R 7 and R 8 together with the nitrogen atom to which they are attached, form an N-heterocyclyl;
X is —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 30 )—, —C(═O)—, —C(═CH 2 )—, —C(═N—NR 35 )—, or —C(═N—OR 35 )—;
R 9 and R 10 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, —OR 19 , —NR 20 R 21 or carbocyclyl; or R 9 and R 10 form an oxo; or optionally, R 9 and R 1 together form a direct bond to provide a double bond; or optionally, R 9 and R 1 together form a direct bond, and R 10 and R 2 together form a direct bond to provide a triple bond;
R 11 and R 12 are hydrogen;
each R 13 , R 22 and R 23 is independently selected from alkyl, heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;
R 6 , R 19 , R 30 , R 34 and R 35 are each independently hydrogen or alkyl;
R 20 and R 21 are each independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 22 , SO 2 R 22 , CO 2 R 22 or SO 2 NR 26 R 27 ; or R 20 and R 21 together with the nitrogen atom to which they are attached, form an N-heterocyclyl; and
each R 24 , R 25 , R 26 , R 27 , R 28 and R 29 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl;
each R 33 is independently selected from halogen, OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4.

2. A method of inhibiting degeneration of a retinal cell in a retina comprising contacting the retina with a compound of Formula (F) or tautomer, A stereoisomer, geometric isomer or a pharmaceutically acceptable salt, salt or N-oxide thereof:

wherein,
Z is a bond, —C(R 1 )(R 2 )—, —C(R 9 )(R 10 )—C(R 1 )(R 2 )—, —X—C(R 31 )(R 32 )—, —C(R 9 )(R 10 )—C(R 1 )(R 2 )—C(R 36 )(R 37 )— or —X—C(R 31 )(R 32 )—C(R 1 )(R 2 )—;
R 1 and R 2 are each independently selected from hydrogen, halogen, C 1 -C 5 alkyl, fluoroalkyl, —OR 6 or —NR 7 R 8 ; or R 1 and R 2 together form an oxo;
R 31 and R 32 are each independently selected from hydrogen, C 1 -C 5 alkyl, or fluoroalkyl;
R 36 and R 37 are each independently selected from hydrogen, halogen, C 1 -C 5 alkyl, fluoroalkyl, —OR 6 or —NR 7 R 8 ; or R 36 and R 37 together form an oxo; or optionally, R 36 and R 1 together form a direct bond to provide a double bond; or optionally, R 36 and R 1 together form a direct bond, and R 37 and R 2 together form a direct bond to provide a triple bond;
R 3 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl; or R 3 and R 4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl; or R 3 and R 4 together form an imino;
R 5 is C 5 -C 15 alkyl, carbocyclyalkyl, arylalkyl, heteroaryl alkyl or heterocyclylalkyl;
R 7 and R 8 are each independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 13 , SO 2 R 13 , CO 2 R 13 or SO 2 NR 24 R 25 ; or R 7 and R 8 together with the nitrogen atom to which they are attached, form an N-heterocyclyl;
X is —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 30 )—, —C(═O)—, —C(═CH 2 )—, —C(═N—NR 35 )—, or —C(═N—OR 35 )—;
R 9 and R 10 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, —OR 19 , —NR 20 R 21 or carbocyclyl; or R 9 and R 10 form an oxo; or optionally, R 9 and R 1 together form a direct bond to provide a double bond; or optionally, R 9 and R 1 together form a direct bond, and R 10 and R 2 together form a direct bond to provide a triple bond;
R 11 and R 12 are hydrogen;
each R 13 , R 22 and R 23 is independently selected from alkyl, heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;
R 6 , R 19 , R 30 , R 34 and R 35 are each independently hydrogen or alkyl;
R 20 and R 21 are each independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R 22 , SO 2 R 22 , CO 2 R 22 or SO 2 NR 26 R 27 ; or R 20 and R 21 together with the nitrogen atom to which they are attached, form an N-heterocyclyl; and
each R 24 , R 25 , R 26 , R 27 , R 28 and R 29 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl;
each R 33 is independently selected from halogen, OR 34 , alkyl, or fluoroalkyl; and n is 0, 1, 2, 3, or 4; and wherein the degeneration results from lipofuscin accumulation.

3. The method of claim 2 , wherein the retinal cell is a retinal neuronal cell.

4. The method of claim 3 , wherein the retinal neuronal cell is a photoreceptor cell.

5. A method of reducing lipofuscin pigment accumulation in a retina of a subject in need thereof comprising administering to the subject a compound of Formula (F), or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable salt or N-oxide thereof:

wherein,
Z is a bond, —C(R 1 )(R 2 )—, —C(R 9 )(R 10 )—C(R 1 )(R 2 )—, —X—C(R 31 )(R 32 )—, —C(R 9 )(R 10 )—C(R 1 )(R 2 )—C(R 36 )(R 37 )— or —X—C(R 31 )(R 32 )—C(R 1 )(R 2 )—;
R 1 and R 2 are each independently selected from hydrogen, halogen, C 1 -C 5 alkyl, fluoroalkyl, —OR 6 or —NR 7 R 8 ; or R 1 and R 2 together form an oxo;
R 31 and R 32 are each independently selected from hydrogen, C 1 -C 5 alkyl, or fluoroalkyl;
R 36 and R 37 are each independently selected from hydrogen, halogen, C 1 -C 5 alkyl, fluoroalkyl, —OR 6 or —NR 7 R 8 ; or R 36 and R 37 together form an oxo; or optionally, R 36 and R 1 together form a direct bond to provide a double bond; or optionally, R 36 and R 1 together form a direct bond, and R 37 an

Assignees

• Acucela Inc

Inventors

• Scott Ian L
• Kuksa Vladimir A
• Orme Mark W
• Little Jr Thomas L
• Gall Anna
• Hong Feng

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K31/222

  with compounds having aromatic groups, e.g. dipivefrine, ibopamine · CPC title

• C07C235/08

  having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms · CPC title

• C07C217/72

  linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring · CPC title

• C07C2601/02

  with a three-membered ring · CPC title