Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma

• US 20060122251A1
• Filed: 12/02/2005
• Published: 06/08/2006
• Est. Priority Date: 12/08/2004
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Alcon Incorporated
• Inventors: Chen, Hwang-Hsing, May, Jesse A.
• Granted Patent: US 7,425,572 B2
• Time in Patent Office: Days
• US Class Current: 514/406
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

Novel dioxinoindazole compounds and dioxoloindazole compounds are disclosed. Also disclosed are methods for the lowering and controlling of normal or elevated intraocular pressure as well as a method for the treatment of glaucoma using compositions of one or more of the compounds of the present invention.

Claims

1. A compound represented by Formula 1:

2. The compound of claim 1, wherein said R² and R³ form a saturated (CH₂)_m heterocycle.

3. The compound of claim 1, wherein said R³ and R⁴ form a cyclopropyl ring.

4. The compound of claim 1, wherein R¹ and R² are independently chosen from hydrogen or C_1-4 alkyl;

R³ and R⁴ are independently chosen from hydrogen or C_1-4 alkyl or R² and R³ together can be (CH₂)_m to form a saturated heterocycle;

R⁵ is chosen from hydrogen, halogen, or C_1-6 alkyl;

R⁶ and R⁷ are independently chosen from hydrogen, halogen, cyano, C_1-4 alkylthio, C_1-4 alkyl, or C_1-4 alkyl substituted by halogen;

R⁸ and R⁹ are independently chosen from hydrogen, C_1-6 alkyl, C_1-6alkoxy, ═

O, NR¹⁰R¹¹, OC(═

O)NR¹R², OC(═

O)C_1-4alkyl, a C_1-6 alkyl substituted with halogen, or NR¹⁰R¹¹, OR¹¹, CO₂R¹¹, CON R¹⁰R¹¹, SO₂R¹¹, NSO₂R¹¹, SO₂NR¹⁰R¹¹;

R¹⁰ and R¹¹ are independently chosen from hydrogen, C_1-4 alkyl, C(═

O)C_1-4 alkyl, C(═

O)OC_1-4 alkyl, C(═

O)NR¹R², or C_1-4 alkyl substituted with halogen, hydroxyl, NR¹R² or R¹⁰ and R¹¹ together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S;

m=2-4;

A=CHR⁹ or no atom;

X and Y are either N or C, wherein X and Y are different from each other; and

the dashed bonds denotes a suitably appointed single and double bond.

5. The compound of claim 1, wherein R¹ and R² are independently chosen from hydrogen or C_1-4 alkyl;

R³ is C_1-2 alkyl or R² and R³ together can be (CH₂)₃ to form a pyrrolidine;

R⁴ is hydrogen;

R⁵ is chosen from hydrogen, halogen, or C_1-4 alkyl;

R⁶ and R⁷ are independently chosen from hydrogen, halogen, C_1-4 alkyl;

R⁸ and R⁹ are independently chosen from hydrogen, C_1-4 alkyl, a C_1-4 alkyl substituted with halogen, or NR¹⁰R¹¹, OR¹¹, CO₂R¹¹, CONR¹⁰R¹¹, SO₂R¹¹, NSO₂R¹¹;

R¹⁰ and R¹¹ are independently chosen from hydrogen, C_1-4 alkyl, C(═

O)C_1-4 alkyl, C(═

O)OC_1-4 alkyl, C(═

O)NR¹R², or C_1-4 alkyl substituted with halogen, hydroxyl, NR¹R² or R¹⁰ and R¹¹ together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S;

X and Y are either N or C, wherein X and Y are different from each other; and

the dashed bonds denotes a suitably appointed single and double bond.

6. The compound of claim 1, wherein said compound is selected from the group consisting of:

2-(7,8-Dihydro-[1,4]dioxino[2,3-g]indazol-1-yl)-1-methyl-ethylamine;

(S)-2-(7,8-Dihydro-[1,4]dioxino[2,3-g]indazol-1-yl)-1-methyl-ethylamine;

(R)-2-(7,8-Dihydro-[1,4]dioxino[2,3-g]indazol-1-yl)-1-methyl-ethylamine;

[1-(2-Amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-yl]-methanol;

[1-((S)-2-Amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-yl]-methanol;

[(R)-1-((S)-2-Amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-yl]-methanol;

[(S)-1-((S)-2-Amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-yl]-methanol;

N-[1-((S)-2-Amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-ylmethyl]-methanesulfonamide;

N-[(S)-1-((S)-2-Amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-ylmethyl]-methanesulfonamide;

Ethanesulfonic acid [1-((S)-2-amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-ylmethyl]-amide;

Ethanesulfonic acid [(S)-1-((S)-2-amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-ylmethyl]-amide;

[1-((S)-2-Amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-ylmethyl]-carbamic acid methyl ester;

[(S)-1-((S)-2-Amino-propyl)-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-ylmethyl]carbamic acid methyl ester;

2-((S)-8-Aminomethyl-7,8-dihydro-[1,4]dioxino[2,3-g]indazol-1-yl)-11-methyl-ethyl amine;

(S)-2-((S)-8-Aminomethyl-7,8-dihydro-[1,4]dioxino[2,3-g]indazol-1-yl)-1-methyl-ethylamine;

N-({1-[(S)-2-aminopropyl]-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-yl}methyl)acetamide;

N-({(S)-1-[(S)-2-aminopropyl]-7,8-dihydro-1H-[1,4]dioxino[2,3-g]indazol-8-yl}methyl)acetamide;

1-(1H-[1,3]dioxolo[4,5-g]indazol-1-yl))-1-methyl-ethylamine; and

(S)-1-(1H-[1,3]dioxolo[4,5-g]indazol-1-yl))-1-methyl-ethyl amine.

7. The compound of claim 1, wherein said X is N.

8. The compound of claim 2, wherein said X is C.

9. A method of controlling of normal or elevated intraocular pressure in an eye of a patient comprising administering to the patient a composition comprising a pharmaceutically effective amount of a compound represented by Formula 1:

10. The method of claim 9 wherein the composition is topically administered to the eye.