Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma

• US 6,989,445 B2
• Filed: 12/14/2004
• Issued: 01/24/2006
• Est. Priority Date: 12/15/2003
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Alcon Incorporated
• Inventors: May, Jesse Albert, Dantanarayana, Anura P.
• Primary Examiner(s): Berch, Mark L.
• Assistant Examiner(s): Habte, Kahsay
• Application Number:
  US11/011,804
• Publication Number:
  US 20050130960A1
• Time in Patent Office: 406 Days
• Field of Search: 544/101, 544/60
• US Class Current: 544/101
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: C07D 498/04 Ortho-condensed systems

Abstract

Substituted [1,4]oxazino[2,3-g]indazols for lowering intraocular pressure and treating glaucoma are disclosed.

Claims

1. A compound of the formula

wherein

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

R³ is hydrogen or C_1-4alkyl, or R² and R³ together can complete a pyrrolidine or piperidine ring, which can be substituted with C_1-4alkyl;

R⁴ is hydrogen, halogen, or C_1-4alkyl;

R⁵ and R⁶ are independently hydrogen, halogen, C_1-6alkyl, C_1-6alkylthio, C_1-6alkylsulfonyl, C_1-6alkylsulfoxide, nitrile, or C_1-6alkyl substituted with halogen;

R⁷ is hydrogen, C═

OR⁹, ═

O, C_1-6alkyl, or substituted C_1-6alkyl wherein the substituent is at least one of hydroxyl, C_1-6alkoxy, NR¹²R¹³, CO₂H, CO₂C_1-6alkyl, C(═

O)NR¹²R¹³, S(O)_mNR¹²R^13, and a saturated or unsaturated 5 or 6-membered heteroaryl ring which can contain 1–

4 heteroatoms selected from N, O, or S and can be unsubstituted or substituted with C_1-4alkyl or phenyl;

R⁸ is hydrogen, C_1-6alkyl, or substituted C_1-6alkyl wherein the substituent is at least one of hydroxyl, C_1-6alkoxy, NR¹²R¹³, CO₂H, CO₂C_1-6alkyl and C(═

O)NR¹²R¹³;

R⁹ is hydroxyl, C_1-6alkoxy, NR¹⁴R¹⁵, C_1-6alkyl, or substituted C_2-6 alkyl wherein the substituent is at least one of hydroxyl, C_1-6alkoxy, NR¹²R¹³, CO₂H, CO₂C_1-6alkyl, S(O)_mNR¹²R¹³, halogen, and a heterocyclic ring selected from pyrrolidin-2-yl, imidazo-2-yl, imidazo-4-yl, morpholin-3-yl, oxazolyl, isoxazolyl, thiazolyl, or tetrazolyl, which can be unsubstituted or substituted with C_1-4alkyl;

R₁₂ and R₁₃ are independently hydrogen, C_1-6alkyl, or substituted C_2-6alkyl wherein the substituent is at least one of hydroxyl, C_1-6alkoxy, and halogen, or R¹², R¹³, and the intervening nitrogen atom together can form a heterocyclic ring selected from morpholine, thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, azetidine, pyrrolidine, piperidine, piperazine, unsubstituted or substituted with C_1-4alkyl, or C_1-4alkyl substituted with hydroxy or C_1-4alkoxy;

R¹⁴ and R¹⁵ are independently hydrogen, C_1-6alkyl, hydroxyl, C_1-6alkoxy, or substituted C_2-6alkyl wherein the substituent is at least one of hydroxyl, C_1-6alkoxy, halogen and a heterocyclic ring selected from pyrrolidin-2-yl, imidazo-2-yl, imidazo-4-yl, morpholin-3-yl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, which can be unsubstituted or substituted with C_1-4alkyl, or R¹⁴, R¹⁵, and the intervening nitrogen atom together can form a heterocyclic ring selected from morpholine, thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, azetidine, pyrrolidine, piperidine, piperazine, unsubstituted or substituted with C_1-4alkyl or C_1-4alkyl substituted with hydroxy or C_1-4alkoxy;

A is N or CH;

X and Y are either N or C, provided that X and Y cannot be the same;

and the dashed bonds denote a single or double bond.

2. The compound of claim 1 wherein the compound is selected from the group consisting of:

(S)-2-(8,9-dihydro-9-methyl-7H-[1,4]oxazino[2,3-g]indazol-1-yl)-1-methylethylamine fumarate;

1-((S)-2-Aminopropyl)-1,9-dihydro-7H-[1,4]oxazino[2,3-g]indazol-8-one hydrochloride;

1-((S)-2-Aminopropyl)-1,9-dihydro-9-methyl-7H-[1,4]oxazino[2,3-g]indazol-8-one hydrochloride; and

[1-[(2S)-2-aminopropyl]-9-methyl-1,7,8,9-tetrahydro[1,4]oxazino[2,3-g]indazol-8-yl]methanol.