DIHYDRONAPHTHYRIDINYL AND RELATED COMPOUNDS FOR USE IN TREATING OPHTHALMOLOGICAL DISORDERS

• US 20100286136A1
• Filed: 05/07/2010
• Published: 11/11/2010
• Est. Priority Date: 05/08/2009
• Status: Abandoned Application

• Current Assignee: Dilara Mccauley, Simon Jones
• Original Assignee: Dilara Mccauley, Simon Jones
• Inventors: Jones, Simon, McCauley, Dilara
• Application Number:
  US12/775,577
• Publication Number:
  US 20100286136A1
• Time in Patent Office: Days
• US Class Current: 514/230.5
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/10 for accommodation disorders, e.g. myopia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The invention provides methods of using dihydronaphthyridinyl and related compounds to treat opthalmological disorders, such as, wet age-related macular degeneration, diabetic retinopathy, and high myopia. Pharmaceutical compositions and methods of synthesizing the dihydronaphthyridinyl and related compounds are provided.

Claims

1. A method of treating a disorder selected from the group consisting of wet age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, intraocular neovascularization, retinal vein occlusion, retinopathy of prematurity, angioid streak, high myopia, macular edema, ocular histoplasmosis, retinal detachment, retinitis pigmentosa, ischemic retinopathy, iris neovascularization, corneal neovascularization, retinal neovascularization, diabetic retinal ischemia, proliferative vitreoretinopathy, uveitis, iritis, inflammatory eye disease, and dry age-related macular degeneration, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I-A:

2. The method of claim 1, wherein R₁ is hydrogen;

alkyl, alkoxyalkyl, alkoxy-CHF₂, alkoxy-CH₂F, alkoxy-CF₃, C_3-6 cycloalkyl, C_3-6 heterocycloalkyl, aryl, heteroaryl, or (C₁-C₆alkylene)-R_1a;

wherein R_1a is C_3-6 cycloalkyl, C_3-6 heterocycloalkyl, aryl, or heteroaryl, each of which may be independently optionally substituted with 1, 2, or 3 R₅ substituents.

3. The method of claim 1, wherein R₁ alkoxyalkyl.

4. The method of claim 1, wherein R₁ is —

CH₂—

O—

CH₃, —

CH₂—

O—

CF₃, —

CH₂—

O—

CHF₂, —

CH₂—

O—

CH₂F, —

CH₂—

O—

CH₂—

CH₃, —

CH₂—

O—

CH—

(CH₃)₂, or —

CH₂—

CN.

5. The method of claim 1, wherein Y is CH₂,

6. The method of claim 1, wherein Y is CH₂.

7. The method of claim 1, wherein R₃ is

8. The method of claim 7, wherein

9. The method of claim 7, wherein

10. The method of claim 1, wherein

11. The method of claim 1, wherein

12. The method of claim 1, wherein R₄ is hydrogen.

13. The method of claim 1, wherein n and p are 1.

14. The method of claim 1, wherein the compound is a compound of formula I-B2:

15. The method of claim 14, wherein A₁ is N or C—

R₅; and

A₂, A₃, and A₄ are C—

R₅.

16. The method of claim 1, wherein the compound is a compound of formula I-C1:

17. The method of claim 16, wherein R₁ is —

(CH₂)_x—

O—

(CH₂)_x—

H, wherein X represents independently 1, 2, or 3.

18. The method of claim 16, wherein R₂ is haloalkyl

19. The method of claim 16, wherein R₂ is —

CF₃.

20. The method of claim 16, wherein R₃ is

21. The method of claim 16, wherein R₄ represents independently methyl, ethyl, or propyl.

22. The method of claim 16, wherein n and p are 1.

23. The method of claim 1, wherein the compound is:

(1-(4-hydroxy-3-methoxybenzyl)-4-isobutylpiperidin-4-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

7-((4-isobutyl-4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)piperidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

(3-(cyclopropylmethyl)-1-(4-hydroxy-3-methoxybenzyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

7-((3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

(S)-7-((3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

(R)-7-((3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

(3-(cyclopropylmethyl)-1-(3-fluoro-4-hydroxybenzyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

(3-(cyclopropylmethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

or a pharmaceutically acceptable salt thereof.

24. The method of claim 1, wherein the compound is:

(3-(cyclopropylmethyl)-1-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

(3-(cyclopropylmethyl)-1-(5-methoxy-2-methyl-2,3-dihydrobenzofuran-6-yl)methyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

5-((3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]thiazol-2(3H)-one;

5-((3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)benzo[d]thiazol-2(3H)-one;

3-(cyclopropylmethyl)-1-(4-hydroxy-4-(6-methoxypyridin-3-yl)cyclohexyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

(3-(cyclopropylmethyl)-1-(2,2-dimethylchromoa-6-yl)methyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

7-((3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-6-carbonyl)pyrrolidin-1-yl)methyl)quinolin-2(1H)-one;

5-(1-(3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one;

(1-((1H-indazol-5-yl)methyl)-3-(cyclopropylmethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

(3-(cyclopropylmethyl)-1-(4-hydroxy-4-(6-methoxypyridin-3-yl)cyclohexyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

6-((3-(cyclobutylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

6-((3-isopentyl-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

6-((3-benzyl-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

6-((3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

5-((3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

5-((3-isobutyl-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

7-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

(S)-7-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

(R)-7-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

5-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]thiazol-2(3H)-one;

5-(1-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one;

(1-(4-hydroxy-4-(6-methoxypyridin-3-yl)cyclohexyl)-3-(methoxymethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one;

6-(1-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one;

5-(1-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-3-methylbenzo[d]oxazol-2(3H)-one;

(1-(4-cyclopropyl-4-hydroxycyclohexyl)-3-(methoxymethyl)pyrrolidin-3-yl)(3-trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

6-chloro-7-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinolin-2(1H)-one;

6-chloro-5-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

5-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one;

5-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

(R)-6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one and (S)-6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

3-ethyl-6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2(3H)-one;

5-bromo-6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3,5-dimethylbenzo[d]oxazol-2(3H)-one;

5-((3-(ethoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

5-((3-(methoxymethyl)-3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

5-((3-isopropyl-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

2-(1-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-3-yl)acetonitrile;

5-((3-(hydroxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

(3-(methoxymethyl)-1-(4-(6-methoxypyridin-3-yl)cyclohexyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

(1-(4-hydroxy-4-(pyrimidin-5-yl)cyclohexyl)-3-(methoxymethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

(3-(methoxymethyl)-1-(4-(pyrimidin-5-yl)cyclohexyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

(1-(4-(4-fluorophenyl)cyclohexyl)-3-(methoxymethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

6-((4-isobutyl-4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)piperidin-1-yl)methyl)-3-methylbenzo[d]thiazol-2(3H)-one;

6-((4-isobutyl-4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)piperidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

2-(3-(methoxymethyl)-1-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carbonyl)-7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile;

5-((3-(methoxymethyl)-3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

6-(3-(methoxymethyl)-1-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile;

5-((3-(methoxymethyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

5-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one;

5-(2-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)propan-2-yl)-3-methylbenzo[d]oxazol-2(3H)-one;

5-(1-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)cyclopropyl)-3-methylbenzo[d]oxazol-2(3H)-one;

6-(1-(3-(ethoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one;

74(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylquinoxalin-2(1H)-one;

7-(1-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-1-methylquinoxalin-2(1H)-one;

5-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)-3-methyl-3,5,6,7-tetrahydro-2H-indeno[5,6-d]oxazol-2-one;

6-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)-1-methyl-7,8-dihydro-1H-indeno[4,5-d]oxazol-2(6H)-one;

6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-1-methylindolin-2-one;

6-(1-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-1-methylindolin-2-one;

(1-(4-(5-fluoropyridin-2-yl)cyclohexyl)-3-(methoxymethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

(1-(4-fluoro-4-(6-methoxypyridin-3-yl)cyclohexyl)-3-(methoxymethyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

(3-(methoxymethyl)-1-(4-(pyrimidin-2-yl)cyclohexyl)pyrrolidin-3-yl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone;

or a pharmaceutically acceptable salt thereof.

25. The method of claim 1, wherein the compound is:

26. The method of claim 1, wherein the compound is:

27. The method of claim 1, wherein the disorder is wet age-related macular degeneration.

28. The method of claim 1, wherein the disorder is choroidal neovascularization or diabetic retinopathy.

29. The method of claim 1, wherein the patient is a human.