Methods and compounds for treating retinol-related diseases

• US 7,973,079 B2
• Filed: 09/15/2008
• Issued: 07/05/2011
• Est. Priority Date: 09/27/2007
• Status: Expired due to Fees

• Current Assignee: Acucela Inc. (Kubota Pharmaceutical Holdings Co. Ltd.)
• Original Assignee: ReVision Therapeutics, Inc.
• Inventors: Mata, Nathan L., Bui, Tam V., Phan, Kim B., Haddach, Mustapha
• Primary Examiner(s): NOLAN, JASON MICHAEL
• Application Number:
  US12/210,802
• Publication Number:
  US 20090088435A1
• Time in Patent Office: 1,023 Days
• Field of Search: 562/433, 562/507, 564/163, 514/617, 514/619, 514/622, 514/532, 514/529
• US Class Current: 514/622
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine

Abstract

Compounds that reduce serum retinol levels are used to treat ophthalmic conditions associated with the overproduction of waste products that accumulate during the course of the visual cycle. We describe methods, compounds, and compositions to treat, for example, the macular degenerations and dystrophies or to alleviate symptoms associated with such ophthalmic conditions.

Claims

1. A pharmaceutical composition comprising a compound of Formula (I):

2. The pharmaceutical composition of claim 1 having the structure of Formula (II):

3. The pharmaceutical composition of claim 2 wherein A is O.

4. The pharmaceutical composition of claim 3 wherein B is —

(CH₂)_n and n is 2-6, or B is —

(C₃-C₈)cycloalkyl.

5. The pharmaceutical composition of claim 4 wherein E is (C═

O)—

OR, a carboxylic acid bioisostere, —

(C═

O)—

NR¹R, —

(C₁-C₇)alkyl-(C═

O)—

OR, or —

(C₁-C₇)alkyl-(C═

O)—

NR¹R.

6. The pharmaceutical composition of claim 5 wherein R is

7. The pharmaceutical composition of claim 4 wherein E is (C═

O)—

OR.

8. The pharmaceutical composition of claim 7 wherein R is H.

9. The pharmaceutical composition of claim 1 selected from the group consisting of:

5-(2-tert-butyl-4-chlorophenoxy)-N-(4-hydroxyphenyl)pentanamide, 7-(2-tert-butyl-4-chlorophenoxy)-N-(4-hydroxyphenyl)heptanamide, 4-(5-(2-tert-butyl-4-chlorophenoxy)pentanamido)benzoic acid, 4-(3-((2-tert-butyl-4-chlorophenoxy)methyl)cyclopentanamido)benzoic acid, 5-(2-tert-butyl-4-chlorophenoxy)pentanoic acid, 4-(2-tert-butyl-4-chlorophenoxy)butanoic acid, 2-(3-((2-tert-butyl-4-chlorophenoxy)methyl)cyclopentyl)acetic acid, 7-(2-tert-butyl-4-chlorophenoxy)heptanoic acid, 4-(5-(2-tert-butyl-4-chlorophenoxy)pentanamido)benzamide, 3-((2-tert-butyl-4-chlorophenoxy)methyl)cyclohexanecarboxylic acid, 3-((2-tert-butyl-4-chlorophenoxy)methyl)cyclopentanecarboxylic acid, 3-((2-tert-butyl-4-chlorophenylamino)methyl)cyclopentanamide, 4-(3-((2-tert-butyl-4-chlorophenoxy)methyl)cyclopentanecarboxamido)benzoic acid, and 5-(2-tert-butyl-4-chlorophenylthio)pentanoic acid

10. The pharmaceutical composition of claim 1 wherein the pharmaceutical composition is formulated for oral administration.