Pyrazolo[3,4-e]benzoxazoles for the treatment of glaucoma

• US 20060069096A1
• Filed: 11/15/2005
• Published: 03/30/2006
• Est. Priority Date: 12/15/2003
• Status: Abandoned Application

• Current Assignee: Anura P. Dantanarayana, Jesse A. May
• Original Assignee: Anura P. Dantanarayana, Jesse A. May
• Inventors: May, Jesse A., Dantanarayana, Anura P.
• Application Number:
  US11/274,437
• Publication Number:
  US 20060069096A1
• Time in Patent Office: Days
• US Class Current: 514/235.500
• CPC Class Codes: A61K 31/424 condensed with heterocyclic ring systems, e.g. clavulanic acid
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

Pyrazolo[3,4-e]benzoxazoles and analogues thereof for lowering intraocular pressure and treating glaucoma are disclosed.

Claims

1-9. -9. (canceled)

10. A compound of Formula I:

Wherein 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, or when Y is carbon R⁴ can also be halogen;

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

R⁷ is chosen from C═

OR⁹, S(O)_mR¹⁰, NR¹—

(C═

O)—

R¹¹,

C_1-6-alkyl substituted with;

hydroxyl, C_1-6alkoxy, NR¹²R¹³, CO₂H, CO₂C_1-6alkyl, C(═

O)NR¹²R¹³ or S(O)_mNR¹²R¹³, 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_1-4alkyl;

or R⁷ can be chosen from a heterocyclic ring selected from oxazol-2-yl, 4,5-dihydro-oxazol-2-yl, 5,6-dihydro-[1,3]oxazin-2-yl, thiazol-2-yl, 4,5-dihydro-thiazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl, imidazol-2-yl, 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_1-4alkyl;

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

R⁹ is chosen from hydroxyl, C_1-6alkoxy, NR¹⁴R¹⁵, C_1-6alkyl, or C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, NR¹²R¹³, CO₂H, CO₂C_1-6alkyl, S(O)_mNR¹²R¹³, halogen, or a heterocyclic ring selected from pyrrolidin-2-yl, imidazo-2-yl, imidazo4-yl, morpholin-3-yl, oxazolyl, isoxazolyl, thiazolyl, or tetrazolyl, which can be unsubstituted or substituted with C_1-4alkyl;

R¹⁰ is chosen from NR¹²R¹³, C_1-6alkyl, or C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, NR¹¹R¹², CO₂H, CO₂C_1-6alkyl;

R¹¹ is C_1-6alkyl substituted with hydroxyl, C_1-6alkoxy, 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_1-4alkyl;

R¹² and R³ are independently selected from hydrogen, C_1-6alkyl, C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, 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 or C_1-4alkoxy;

R¹⁴ and R¹⁵ are independently selected from hydrogen, C_1-6alkyl, hydroxyl, C_1-6alkoxy, C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, halogen or 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 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;

R¹⁶ is chosen from no atom, hydrogen, C_1-6alkyl, or C_1-6alkyl substituted with halogen, HO, or C_1-6alkoxy;

---═

double or single bond in the oxazole ring;

when R¹⁶ is no atom, --- is a double bond, and when --- is a single bond, R⁷is Q, where Q is oxygen, sulfur, or NR¹ attached to the oxazole ring by a double bond;

m is 0-2;

A is N or CH;

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

the dashed bonds in this ring denote a suitably appointed single and double bond; and

pharmaceutically acceptable salts, solvates, or prodrugs thereof.

11. The compound of claim 10, wherein for Formula l:

A═

N;

X═

N;

Y═

C; and

--- in the oxazole ring is a double bond; and

pharmaceutically acceptable salts, solvates and prodrugs thereof.

12. The compound of claim 11, wherein for Formula I:

R¹, R²═

H.

13. The compound of claim 12, wherein for Formula I:

R³=methyl.

14. A compound selected from the group consisting of:

(S)-2-[7-(Methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazol-1-yl]-1-methylethylamine;

1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole -7-carboxylic acid amide;

1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole -7-carboxylic acid methylamide; and

pharmaceutically acceptable salts, solvates and prodrugs thereof.

15. A topical ophthalmic composition comprising a pharmaceutically effective amount of a compound in an ophthalmically acceptable vehicle, wherein the compound is of Formula I:

Wherein 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, or when Y is carbon R⁴ can also be halogen;

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, S(O)_mR¹⁰, NR¹—

(C═

O)—

R¹¹,

C_1-6alkyl substituted with;

hydroxyl, C_1-6alkoxy, NR¹²R¹³, CO₂H, CO₂C_1-6alkyl, C(═

O)NR¹²R¹³ or S(O)_mNR¹²R¹³, 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_1-4alkyl;

or R⁷ can be chosen from a heterocyclic ring selected from oxazol-2-yl, 4,5-dihydro-oxazol-2-yl, 5,6-dihydro-[1,3]oxazin-2-yl, thiazol-2-yl, 4,5-dihydro-thiazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl, imidazol-2-yl, 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_1-4alkyl;

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

R⁹ is chosen from hydroxyl, C_1-6alkoxy, NR¹⁴R¹⁵, C_1-6alkyl, or C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, NR¹²R¹³, CO₂H, CO₂C_1-6alkyl, S(O)_mNR¹²R¹³, halogen, or 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;

R¹⁰ is chosen from NR¹²R¹³, C_1-6alkyl, or C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, NR¹¹R¹², CO₂H, CO₂C_1-6alkyl;

R¹¹ is C_1-6alkyl substituted with hydroxyl, C_1-6alkoxy, 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_1-4alkyl;

R¹² and R¹³ are independently selected from hydrogen, C_1-6alkyl, C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, 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 or C_1-4alkoxy;

R¹⁴ and R¹⁵ are independently selected from hydrogen, C_1-6alkyl, hydroxyl, C_1-6alkoxy, C_2-6alkyl substituted with hydroxyl, C_1-6alkoxy, halogen or a heterocyclic ring selected from pyrrolidin-2-yl, imidazo-2-yl, imidazo4-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 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;

R¹⁶ is chosen from no atom, hydrogen, C_1-6alkyl, or C_1-6alkyl substituted with halogen, HO, or C_1-6alkoxy;

---═

double or single bond in the oxazole ring;

when R¹⁶ is no atom, --- is a double bond, and when --- is a single bond, R⁷ is Q, where Q is oxygen, sulfur, or NR¹ attached to the oxazole ring by a double bond;

m is 0-2;

A is N or CH;

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

the dashed bonds in this ring denote a suitably appointed single and double bond; and

pharmaceutically acceptable salts, solvates, or prodrugs thereof.

16. The ophthalmic composition of claim 15, wherein for the compound of Formula I:

A═

N;

X═

N;

Y═

C; and

--- in the oxazole ring is a double bond; and

pharmaceutically acceptable salts, solvates and prodrugs thereof.

17. The ophthalmic composition of claim 16, wherein for the compound of Formula I:

R¹, R²═

H.

18. The ophthalmic composition of claim 17, wherein for the compound of Formula I:

R³=methyl.

19. The ophthalmic composition of claim 15, wherein the compound of Formula I is selected from the group consisting of:

(S)-2-[7-(Methoxymethyl)-1H-pyrazolo[3,4-e]benzoxazol-1-yl]-1-methylethylamine;

1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole -7-carboxylic acid amide;

1-[(S)-2-Aminopropyl]-1H-pyrazolo[3,4-e]benzoxazole -7-carboxylic acid methylamide;

and pharmaceutically acceptable salts, solvates and prodrugs thereof.