Phenylethylamine analogs and their use for treating glaucoma

• US 20070072920A1
• Filed: 09/22/2006
• Published: 03/29/2007
• Est. Priority Date: 09/23/2005
• Status: Abandoned Application

• Current Assignee: Alcon Incorporated
• Original Assignee: Alcon Incorporated
• Inventors: Hellberg, Mark, Namil, Abdelmoula, Ward, Jennifer, Feng, Zixia
• Application Number:
  US11/525,975
• Publication Number:
  US 20070072920A1
• Time in Patent Office: Days
• US Class Current: 514/365
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics

Abstract

Phenylethylamine analogs useful for treating glaucoma are disclosed.

Claims

1. A method for lowering and controlling normal or elevated IOP, which comprises administering a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the formula:

wherein

R¹ and R² independently are H or C_1-4alkyl;

R³ and R⁴ independently are H, C_1-4 alkyl, or R³, R⁴ and the carbon atom to which they are attached can form a cyclopropyl ring;

Y is H, C_1-4alkyl, or OR⁵;

R⁵ is H or C_1-4 alkyl;

A and B independently are OH, C_1-3alkoxy, OS(O)₂W, OC(═

O)W, or OC(═

O)NW²W³;

W is C_1-4alkyl;

W² and W³ independently are H or C_1-4alkyl;

X is CH(OH)R⁶, C(═

O)R⁶, (CH₂)_nZ, or (CH₂)_mZ′

;

R⁶ is C_1-4 alkyl, (CH₂)_m2SR⁸, or (CH₂)_m2OR⁸;

n is 1-4;

m is 2-4;

m² is 1-4;

Z is OCF₃, CN, S(O)_n2R⁶, C(O)NR⁷R⁶, C(C═

O)R⁶, CH(OH)R⁶, SO₂NR⁷R⁸, NR⁶R⁹, CO2R⁶, S(O)_n2CH₂CH(OH)R⁶, S(O)_n2CH₂C(═

)O)R⁶, S(O)_n2CH₂CO2R⁶, S(O)_n2CH₂C(═

O)NR⁷R⁸, aryl, heterocyclyl, or heteroaryl;

Z′

is OH or OR⁶;

n is 0 or 1;

R⁷ is H, C_1-4alkyl, OH, or OCH₃; and

R⁸ and R⁹ independently are H or C_1-4alkyl.

2. The method of claim 1 wherein

R¹, R² are H;

R³ and R⁴ are independently H or C₁alkyl;

Y is H or OR⁵;

R⁵ is H or C₁alkyl;

A and B are independently OH, C₁alkoxy, or OC(═

O)W;

W is C_1-4alkyl;

X is (CH₂)_nZ or (CH₂)_mZ′

;

n is 1-4;

m is 2-4;

Z is OR⁶, OCF₃, S(O)_n2R⁶, aryl, heterocyclyl or heteroaryl;

Z′

is OR⁶;

R⁶ is C_1-4 alkyl, (CH₂)_mSR, or (CH₂)_mOR;

heterocyclyl or heteroaryl is;

n² is 0.

3. The method of claim 2 wherein the compound is selected from the group consisting of:

4. The method of claim 1 wherein the composition is a topically administered ophthalmic composition and the pharmaceutically effective amount of the compound is 0.1-2% (w/v).

5. A method for treating glaucoma, which comprises administering a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the formula:

wherein

R¹ and R² independently are H or C_1-4alkyl;

R³ and R⁴ independently are H, C_1-4 alkyl, or R³, R⁴ and the carbon atom to which they are attached can form a cyclopropyl ring;

Y is H, C_1-4alkyl, or OR⁵;

R⁵ is H or C_1-4 alkyl;

A and B independently are OH, C_1-3alkoxy, OS(O)₂W, OC(═

O)W, or OC(═

O)NW²W³;

W is C_1-4alkyl;

W² and W³ independently are H or C_1-4alkyl;

X is CH(OH)R⁶, C(═

O)R⁶, (CH₂)_nZ, or (CH₂)_mZ′

;

R⁶ is C_1-4 alkyl, (CH₂)_m2SR⁸, or (CH₂)_m2OR⁸;

n is 1-4;

m is 2-4;

m² is 1-4;

Z is OCF₃, CN, S(O)_n2R⁶, C(O)NR⁷R⁸, C(C═

O)R⁶, CH(OH)R⁶, SO₂NR⁷R⁸, NR⁶R⁹, CO2R⁶, S(O)_n2CH₂CH(OH)R⁶, S(O)_n2CH₂C(═

)O)R⁶, S(O)_n2CH₂CO2R⁶, S(O)_n2CH₂C(═

O)NR⁷R⁸, aryl, heterocyclyl, or heteroaryl;

Z′

is OH or OR⁶;

n² is 0 or 1;

R⁷ is H, C_1-4alkyl, OH, or OCH₃; and

R⁸ and R⁹ independently are H or C_1-4alkyl.

6. The method of claim 5 wherein

R¹, R² are H;

R³ and R⁴ are independently H or C₁alkyl;

Y is H or OR⁵;

R⁵ is H or C₁alkyl;

A and B are independently OH, C₁alkoxy, or OC(═

O)W;

W is C_1-4alkyl;

X is (CH₂)_nZ or (CH₂)_mZ′

;

n is 1-4;

m is 2-4;

Z is OR⁶, OCF₃, S(O)_n2R⁶, aryl, heterocyclyl or heteroaryl;

Z′

is OR⁶;

R⁶ is C_1-4 alkyl, (CH₂)_mSR, or (CH₂)_mOR;

heterocyclyl or heteroaryl is;

n² is 0.

7. The method of claim 6 wherein the compound is selected from the group consisting of:

8. The method of claim 5 wherein the composition is a topically administered ophthalmic composition and the pharmaceutically effective amount of the compound is 0.1-2% (w/v).