Substituted furo[2,3-g]indazoles for the treatment of glaucoma

• US 20070135430A1
• Filed: 11/24/2004
• Published: 06/14/2007
• Est. Priority Date: 11/26/2003
• Status: Active Grant

• Current Assignee: Alcon Incorporated
• Original Assignee: Alcon Incorporated
• Inventors: Dantanarayana, Anura P., May, Jesse
• Granted Patent: US 7,476,687 B2
• Time in Patent Office: Days
• US Class Current: 514/235.200
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered

Abstract

Substituted furo[2,3-g]indazoles for lowering intraocular pressure and treating glaucoma are disclosed.

Claims

1. A method of treating glaucoma or lowering or controlling intraocular pressure in a subject comprising administering to the subject a compound represented by the following Formula A:

2. The method of claim 1, wherein for the compound of Formula A:

R, R¹ and R² are independently chosen from hydrogen, C_1-4alkyl;

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

R⁴ is hydrogen, C_1-4alkyl;

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

R⁷ is chosen from C═

OR⁹;

C_1-6alkyl substituted with hydroxyl, C_1-6alkoxy, OC(═

O)C_1-8, CO₂H, CO₂C_1-6alkyl, C(═

O)NR¹²R¹³, S(O)_mNR¹²R¹³, NR¹⁴R¹⁵, phenyl or a saturated or unsaturated 5 or 6-membered heterocyclic ring which can contain 1-4 heteroatoms selected from N, O, or S and can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, halogen, haloC_1-4alkyl, phenyl or pyridinyl;

or R⁷ can be chosen from a heterocyclic ring selected from an oxazole such as oxazol-2-yl, 4,5-dihydro-oxazol-2-yl, or benzoxazol-2-yl, an oxazine such as 5,6-dihydro-[1,3]oxazin-2-yl, a thiazole such as thiazol-2-yl, 4,5-dihydro-thiazol-2-yl, or benzothiazol-2-yl, an imidazole such as imidazol-2-yl, or imidazolidin-2-yl, [1,2,4]oxadiazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-5-yl, or [1,2,4]thiadiazol-3-yl which can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, phenyl or pyridinyl, or C_1-6alkyl substituted with phenyl or pyridinyl;

but R⁷ cannot be hydrogen, lower alkyl, hydroxyl, lower alkoxy, amino, mono- or di-loweralkyl amino, lower alkanoylamino, or halogen;

R⁸ is selected from C_1-6alkyl, phenyl which can be substituted with C_1-6alkyl, C_1-6alkoxy, NR¹(C═

O)C_1-6alkyl, or halogen;

R⁹ is chosen from hydroxyl;

C_1-6alkoxy;

C_1-6alkoxy substituted with phenyl or pyridinyl which can be substituted with C_1-4alkoxy or halogen;

NR¹⁶R¹⁷;

C_1-6alkyl;

or C_1-6alkyl substituted with hydroxyl, C_1-6alkoxy, NR¹²R^1-3, CO₂H, CO₂C_1-4alkyl, S(O)_mNR¹²R¹³, halogen, or phenyl or a heterocyclic ring selected from pyrrolidinyl, imidazoyl, morpholinyl, oxazolyl, isoxazolyl, thiazolyl, or tetrazolyl, or pyridinyl which can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, halogen, haloC_1-4alkyl;

R¹¹ is NH₂;

NR¹R²;

C_1-6alkyl substituted with hydroxyl, C_1-6alkoxy, CO₂H, CO₂C_1-6alkyl, phenyl or a saturated or unsaturated 5 or 6-membered heterocyclic ring which can contain 1-4 heteroatoms selected from N, O, or S and can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, halogen, haloC_1-4alkyl;

R¹² and R¹³ are independently selected from hydrogen;

C_1-6alkyl;

CH₂Z, where Z is selected from phenyl, pyridinyl, furanyl, thiophenyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and which can be substituted with C_1-6alkyl, C_1-6alkoxy, halogen, or haloC_1-4alkyl;

C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, CO₂H, CO₂C_1-6alkyl, NR¹COC_1-6alkyl, or halogen;

or R¹², R¹³, and the intervening nitrogen atom 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, C_1-4alkoxy or halogen;

R¹⁴ and R¹⁵ are independently selected from hydrogen, C_1-6alkyl, hydroxyl, C_1-6alkoxy, (C═

O)—

R¹¹, S(O)_mR⁸, phenyl or pyridinyl which can be substituted with C_1-6alkyl, C_1-6alkoxy, halogen, or haloC_1-4alkyl;

or R¹⁴ , R¹⁵ and the nitrogen atom to which they are attached can form a heterocyclic ring selected from pyrrolidine, piperazine, or piperidine, which can be substituted with C_1-6alkyl, phenyl, or pyridinyl;

R¹⁶ and R¹⁷ are independently selected from hydrogen;

C_1-6alkyl;

hydroxyl;

C_1-6alkoxy;

CH₂Z, where Z is selected from phenyl, pyridinyl, furanyl, thiophenyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and which can be substituted with C_1-6alkyl, C_1-6alkoxy, halogen, or haloC_1-4alkyl;

C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, halogen, NR¹(C═

O)C_1-6alkyl, or a phenyl or a heterocyclic ring selected from a pyrrole, such as pyrrolidin-2-yl, an imidazole such as imidazo-2-yl or imidazo4-yl, a morpholine such as morpholin-3-yl, a piperidine such as piperidin-4-yl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, pyridinyl, which can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, halogen, haloC_1-4alkyl, phenylC_1-4alkyl, oxo (═

O);

or R¹⁶, R¹⁷, and the intervening nitrogen atom 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, oxo (═

O), C_1-4alkoxy, or phenyl;

m is 0-2;

A is N; and

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

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

3. The method of claim 2, wherein the compound of Formula A is:

1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid amide;

1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid methyl amide fumarate;

1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid (1-hydroxy-cyclopropylmethyl)-amide;

or

1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide.

4. The method of claim 3, wherein the compound of Formula A is 1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide.

5. A compound of Formula A:

6. The compound of claim 5, wherein for Formula A:

wherein R, R¹ and R² are independently chosen from hydrogen, C_1-4alkyl;

R³ is selected from hydrogen, C_1-4alkyl, or R² and R³can complete a pyrrolidine or piperidine ring, which can be substituted with C_1-4alkyl;

R⁴ is hydrogen, C_1-4alkyl;

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

R⁷ is chosen from C═

OR⁹;

C_1-6alkyl substituted with hydroxyl, C_1-6alkoxy, OC(═

O)C_1-8, CO₂H, CO₂C_1-6alkyl, C(═

O)NR¹²R¹³, S(O)_mNR¹²R¹³, NR¹⁴R¹⁵, phenyl or a saturated or unsaturated 5 or 6-membered heterocyclic ring which can contain 1-4 heteroatoms selected from N, O, or S and can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, halogen, haloC_1-4alkyl, phenyl or pyridinyl;

or R⁷ can be chosen from a heterocyclic ring selected from an oxazole such as oxazol-2-yl, 4,5-dihydro-oxazol-2-yl, or benzoxazol-2-yl, an oxazine such as 5,6-dihydro-[1,3]oxazin-2-yl, a thiazole such as thiazol-2-yl, 4,5-dihydro-thiazol-2-yl, or benzothiazol-2-yl, an imidazole such as imidazol-2-yl, or imidazolidin-2-yl, [1,2,4]oxadiazol-5-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-5-yl, or [1,2,4]thiadiazol-3-yl which can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, phenyl or pyridinyl, or C_1-6alkyl substituted with phenyl or pyridinyl;

but R⁷ cannot be hydrogen, lower alkyl, hydroxyl, lower alkoxy, amino, mono- or di-loweralkyl amino, lower alkanoylamino, or halogen;

R⁸ is selected from C_1-6alkyl, phenyl which can be substituted with C_1-6alkyl, C_1-6alkoxy, NR¹(C═

O)C_1-6alkyl, or halogen;

R⁹ is chosen from hydroxyl;

C_1-6alkoxy;

C_1-6alkoxy substituted with phenyl or pyridinyl which can be substituted with C_1-4alkoxy or halogen;

NR¹⁶R¹⁷;

C_1-6alkyl;

or C_1-6alkyl substituted with hydroxyl, C_1-6alkoxy, NR¹²R¹³, CO₂H, CO₂C_1-6alkyl, S(O)_mNR¹²R¹³, halogen, or phenyl or a heterocyclic ring selected from pyrrolidinyl, imidazoyl, morpholinyl, oxazolyl, isoxazolyl, thiazolyl, or tetrazolyl, or pyridinyl which can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, halogen, haloC_1-4alkyl;

R¹¹ is NH₂;

NR¹R²;

C_1-6alkyl substituted with hydroxyl, C_1-6alkoxy, CO₂H, CO₂C_1-6alkyl, phenyl or a saturated or unsaturated 5 or 6-membered heterocyclic ring which can contain 1-4 heteroatoms selected from N, O, or S and can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, halogen, haloC_1-4alkyl;

R¹² and R¹³ are independently selected from hydrogen;

C_1-6alkyl;

CH₂Z, where Z is selected from phenyl, pyridinyl, furanyl, thiophenyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and which can be substituted with C_1-6alkyl, C_1-6alkoxy, halogen, or haloC_1-4alkyl;

C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, CO₂H, CO₂C_1-6alkyl, NR¹COC_1-6alkyl, or halogen;

or R¹², R¹³, and the intervening nitrogen atom 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, C_1-4alkoxy or halogen;

R¹⁴ and R¹⁵ are independently selected from hydrogen, C_1-6alkyl, hydroxyl, C_1-6alkoxy, (C═

O)—

R¹¹, S(O)_mR⁸, phenyl or pyridinyl which can be substituted with C_1-6alkyl, C_1-6alkoxy, halogen, or haloC_1-4alkyl;

or R¹⁴ , R¹⁵ and the nitrogen atom to which they are attached can form a heterocyclic ring selected from pyrrolidine, piperazine, or piperidine, which can be substituted with C_1-6alkyl, phenyl, or pyridinyl;

R¹⁶ and R¹⁷ are independently selected from hydrogen;

C_1-6alkyl;

hydroxyl;

C_1-6alkoxy;

CH₂Z, where Z is selected from phenyl, pyridinyl, furanyl, thiophenyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and which can be substituted with C_1-6alkyl, C_1-6alkoxy, halogen, or haloC_1-4alkyl;

C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, halogen, NR¹(C═

O)C_1-6alkyl, or a phenyl or a heterocyclic ring selected from a pyrrole, such as pyrrolidin-2-yl, an imidazole such as imidazo-2-yl or imidazo-4-yl, a morpholine such as morpholin-3-yl, a piperidine such as piperidin-4-yl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, pyridinyl, which can be unsubstituted or substituted with C_1-6alkyl, C_1-6alkoxy, halogen, haloC_1-4alkyl, phenylC_1-4alkyl, oxo (═

O);

or R¹⁶, R¹⁷, and the intervening nitrogen atom 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, oxo (═

O), C_1-4alkoxy, or phenyl;

m is 0-2;

A is N; and

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

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

7. The compound of claim 6, wherein for Formula A:

R⁷ is not a substituted C_1-6alkyl.

8. The compound of claim 7, wherein the compound is:

1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid amide;

1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid methyl amide fumarate;

1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid (1-hydroxy-cyclopropylmethyl)-amide;

or

1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide.

9. The compound of claim 8, wherein the compound is 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide.