Substituted 3-phenylpropylamine derivatives for the treatment of ophthalmic diseases and disorders

a technology of ophthalmic diseases and derivatives, which is applied in the field of substituting 3phenylpropylamine derivatives for the treatment of ophthalmic diseases and disorders, can solve the problems of generating photochemical damage to the retina

Inactive Publication Date: 2016-08-11
ACUACELA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0003]We have identified a need for effective therapies for treating ophthalmic diseases or disorders resulting in ophthalmic dysfunction including those described above. In particular, we have identified a pressing need for compositions and methods for treating Stargardt's disease and age-related macular de

Problems solved by technology

Light is essential for vision but can also generate pho

Method used

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  • Substituted 3-phenylpropylamine derivatives for the treatment of ophthalmic diseases and disorders
  • Substituted 3-phenylpropylamine derivatives for the treatment of ophthalmic diseases and disorders
  • Substituted 3-phenylpropylamine derivatives for the treatment of ophthalmic diseases and disorders

Examples

Experimental program
Comparison scheme
Effect test

example 6

Preparation of (R)-3-amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol

[0443]

[0444](R)-3-amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol was prepared following the method used in Example 4:

[0445]Step 1: Reaction between 2-(bromomethyl)pyridine and phenol (7, Intermediate I) following the method used in Example 4 gave after purification by flash chromatography (40% EtOAc:hexane) (R)-tert-butyl (3-hydroxy-3-(3-(pyridin-2-ylmethoxy)phenyl)propyl)carbamate as a pale yellow solid. Yield (0.26 g, 88%); 1H NMR (400 MHz, CDCl3): δ 8.59 (d, J=4.8 Hz, 1H), 7.71 (t, J=7.6, 1.6 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.27-7.20 (m, 2H), 7.03 (s, 1H), 6.96 (d, J=10.4 Hz, 1H), 6.87 (d, J=5.6 Hz, 1H), 5.21 (s, 2H), 4.87 (bs, 1H), 4.73-4.70 (m, 1H), 3.50-3.48 (m, 1H), 3.21-3.11 (m, 1H), 1.84-1.61 (m, 2H), 1.45 (s, 9H); MS: m / z 359.26 [M+H]+.

[0446]Step 2: Deprotection of (R)-tert-butyl (3-hydroxy-3-(3-(pyridin-2-ylmethoxy)phenyl)propyl)carbamate following the method used in Example 4 gave after purificat...

example 7

Preparation of (1R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propan-1-ol

[0447]

[0448](1R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propan-1-ol was prepared following the method below.

[0449]Step 1: K2CO3 (0.72 g, 5.24 mmol) and phenol (7, Intermediate I) (0.3 g, 1.05 mmol) were added to a solution of (tetrahydro-2H-thiopyran-3-yl)methyl 4-methylbenzenesulfonate (0.29 g, 1.10 mmol) in DMF (10 mL). The reaction mixture was heated at 100° C. under reflux overnight and then cooled. The reaction mixture was extracted with EtOAc, organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (EtOAc:hexane 10-40% gradient) gave tert-butyl ((3R)-3-hydroxy-3-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propyl)carbamate as a light green solid. Yield (0.21 g, 52%); 1H NMR (400 MHz, CDCl3): δ 7.24 (t, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 2H), 6.78 (d, 1H), 4.87 (bs, 1H), 4.71 (bs, 1H), 3.84-3.80 (m, ...

example 8

Preparation of (R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)propan-1-ol

[0451]

[0452](R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)propan-1-ol was prepared following the method used in Example 7:

[0453]Step 1: Pyridine (7.6 mL, 98.4 mmol) was added at 0° C. to a solution of (tetrahydro-2H-thiopyran-4-yl)methanol (1.3 g, 9.84 mmol) in CH2Cl2 (20 mL) followed by the addition of TsCl (2.0 g, 10.83 mmol). The reaction mixture was stirred at ambient temperature for 18 h, diluted with H2O (200 mL) and extracted with CH2Cl2 (200 mL). Drying over anhydrous Na2SO4 followed by concentration in vacuo gave (tetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate as an off white solid. The crude was carried forward to the next step without additional purification. Yield (0.75 g, 30%).

[0454]Step 2: Reaction between (tetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate and phenol (7, Intermediate I) following the method used in Example 7 gave after puri...

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Abstract

The present invention relates generally to compositions and methods for treating neurodegenerative diseases and disorders, particularly ophthalmic diseases and disorders. Provided herein are substituted 3-phenylpropylamine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compositions are useful for treating and preventing ophthalmic diseases and disorders, including age-related macular degeneration (AMD) and Stargardt's Disease.

Description

CROSS REFERENCE[0001]This application is a division of U.S. application Ser. No. 14 / 205,117, filed Mar. 11, 2014, which claims the benefit of U.S. Provisional Application No. 61 / 777,903, filed Mar. 12, 2013, the content of which applications are hereby incorporated by reference in their entirety.BACKGROUND[0002]Neurodegenerative diseases, such as glaucoma, macular degeneration, and Alzheimer's disease, affect millions of patients throughout the world. Because the loss of quality of life associated with these diseases is considerable, drug research and development in this area is of great importance.BRIEF SUMMARY OF THE INVENTION[0003]We have identified a need for effective therapies for treating ophthalmic diseases or disorders resulting in ophthalmic dysfunction including those described above. In particular, we have identified a pressing need for compositions and methods for treating Stargardt's disease and age-related macular degeneration (AMD) without causing further unwanted si...

Claims

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Application Information

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IPC IPC(8): C07D335/02C07D213/38C07D211/26C07D307/81C07D307/14C07D211/60C07D233/96C07D311/04C07D207/09C07D211/76C07D333/12C07D207/26C07D279/02C07D211/96C07D209/08C07D233/64C07D309/06
CPCC07D309/06A61K31/445C07D335/02C07D211/26C07D307/81C07D307/14C07D239/26C07D311/58C07D207/09C07D211/76C07D333/20C07D209/14C07D279/02C07D213/30C07D311/04C07D333/12C07D233/96C07D233/64C07D211/96C07D211/60C07D209/08C07D207/26A61K31/4409A61K31/505A61K31/44A61K31/382A61K31/351A61K31/343A61K31/4406A61K31/341A61K31/4465C07D213/38C07D207/08C07D211/22C07D307/12C07D307/80C07D309/04C07D333/16A61P25/28A61P27/02
Inventor KUKSA, VLADIMIR A.ORME, MARK W.HONG, FENGKUBOTA, RYO
Owner ACUACELA INC
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