Substituted 5-chroman-5-YL-ethylamine compounds and their use for the treatment of glaucoma

• US 20050171190A1
• Filed: 02/23/2005
• Published: 08/04/2005
• Est. Priority Date: 08/30/2002
• Status: Abandoned Application

• Current Assignee: Alcon Incorporated
• Original Assignee: Alcon Incorporated
• Inventors: Dantanarayana, Anura P., May, Jesse A.
• Application Number:
  US11/063,286
• Publication Number:
  US 20050171190A1
• Time in Patent Office: Days
• US Class Current: 514/450
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 307/80 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 311/58 other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 311/74 Benzo[b]pyrans, hydrogenated in the carbocyclic ring
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Substituted 5-chroman-5-yl-ethylamine compounds are disclosed. Also disclosed are methods for the lowering and controlling of normal or elevated intraocular pressure as well as a method for the treatment of glaucoma using compositions containing one or more of the compounds of the present invention.

Claims

1. A compound represented by Formula I.

2. The compound of claim 1, wherein R¹ is hydrogen or C_1-4alkyl;

R² is hydrogen, C_1-4alkyl, or R¹ and R² represent (CH₂)_2-4 to complete a heterocyclic ring;

R³ is hydrogen, hydroxyl, C_1-4alkoxy, or halogen;

R⁴ and R⁵ are, independently selected from hydrogen, halogen, nitrile, C_1-4alkoxy, C_1-6alkylthiol, C_1-4alkyl, C_1-4alkyl substituted with halogen or C_1-6alkoxy, or R⁴ and R⁵ represent (CH₂)_m to complete a cycloalkyl ring, or R⁴ and R⁵ together complete a phenyl or thiophene ring which is unsubstituted or substituted with halogen, C_1-4alkyl, or C_1-4alkoxy;

m=3-4;

n=0-2;

R⁶ is hydrogen, hydroxyl, C_1-4alkoxy, C_1-4alkoxy substituted with hydroxyl, halogen, or NR⁷R⁸, OC(═

O)C_1-6alkyl, ═

O, NR⁷R⁸, C_1-4alkyl, or C_1-4alkyl substituted with hydroxyl, halogen, or NR⁷R⁸, wherein when n=0, R⁶ is not hydrogen;

X is C_1-4alkoxy or hydroxyl;

R⁷ and R⁸ are independently selected from hydrogen, C_1-4alkyl, or C(═

O)C_1-6alkyl;

or pharmaceutically acceptable salts or solvates thereof.

3. The compound of claim 1, wherein said R² is hydrogen or C_1-4alkyl.

4. The compound of claim 1, wherein R¹ and R³ are hydrogen;

R² is C_1-4alkyl;

R⁴ and R⁵ are independently selected from halogen, nitrile, C_1-4alkoxy, C_1-6alkylthiol, C_1-4alkyl, C_1-4alkyl substituted with halogen, or R⁴ and R⁵ together represent (CH₂)_m to complete a cycloalkyl ring, or R⁴ and R⁵ together complete a phenyl or thiophene ring which is unsubstituted or substituted with halogen, C_1-4alkyl;

m=3-4;

n=1;

R⁶ is hydroxyl, C_1-4alkoxy, C_1-4alkoxy substituted with hydroxyl, halogen, or NR⁷R⁸, OC(═

O)C_1-6alkyl, NR⁷R⁸, or C_1-4alkyl substituted with hydroxyl, halogen, or NR⁷R⁸, wherein when n=0, R⁶ is not hydrogen;

X is C_1-4alkoxy or hydroxyl;

R⁷ and R⁸ are independently selected from hydrogen, C_1-4alkyl, or C(═

O)C_1-6alkyl.

5. The compound of claim 1, wherein said compound is:

5-(2-Aminopropyl)-8-bromo-6-methoxy-chroman-3-ol;

5-((R)-2-Aminopropyl)-8-bromo-6-methoxy-chroman-3-ol;

5-(2-Aminopropyl)-6-methoxy-8-methyl-chroman-3-ol;

5-((R)-2-Amino-1-hydroxy-propyl)-8-bromo-6-methoxy-chroman-3-ol;

Cyclopropanecarboxylic acid 5-((R)-2-aminopropyl)-8-bromo-6-methoxy-chroman-3-yl ester;

[5-(2-Aminopropyl)-6-methoxy-8-methyl-chroman-3-yl]-methanol;

5-(2-Aminopropyl)-8-iodo-chroman-3,6-diol;

or

[4-(2-Aminopropyl)-5-methoxy-7-methyl-2,3-dihydro-benzofuran-2-yl]-methanol;

or combinations thereof.

6. The compound of claim 1, wherein said X is hydroxyl.

7. The compound of claim 1, wherein said X is an alkoxy group.

8. A method of controlling normal or elevated intraocular pressure comprising administering a pharmaceutically effective amount of a composition comprising at least one compound of claim 1.

9. The method of claim 8, wherein R¹ is hydrogen or C_1-4alkyl;

R² is hydrogen, C_1-4alkyl, or R¹ and R² represent (CH₂)_2-4 to complete a heterocyclic ring;

R³ is hydrogen, hydroxyl, C_1-4alkoxy, or halogen;

R⁴ and R⁵ are independently selected from hydrogen, halogen, nitrile, C_1-4alkoxy, C_1-6alkylthiol, C_1-4alkyl, C_1-4alkyl substituted with halogen or C_1-6alkoxy, or R⁴ and R⁵ represent (CH₂)_m to complete a cycloalkyl ring, or R⁴ and R⁵ together complete a phenyl or thiophene ring which is unsubstituted or substituted with halogen, C_1-4alkyl, or C_1-4alkoxy;

m=3-4;

n=0-2;

R⁶ is hydrogen, hydroxyl, C_1-4alkoxy, C_1-4alkoxy substituted with hydroxyl, halogen, or NR⁷R⁸, OC(═

O)C_1-6alkyl, ═

O, NR⁷R⁸, C_1-4alkyl, or C_1-4alkyl substituted with hydroxyl, halogen, or NR⁷R⁸, wherein when n=0, R⁶ is not hydrogen;

X is C_1-4alkoxy, hydroxyl or halogen;

R⁷ and R⁸ are independently selected from hydrogen, C_1-4alkyl, or C(═

O)C_1-6alkyl;

or pharmaceutically acceptable salts or solvates thereof.

10. The method of claim 8, wherein R¹ and R³ are hydrogen;

R² is C_1-4alkyl;

R⁴ and R⁵ are independently selected from halogen, nitrile, C_1-4alkoxy, C_1-6alkylthiol, C_1-4alkyl, C_1-4alkyl substituted with halogen, or R⁴ and R⁵ together represent (CH₂)_m to complete a cycloalkyl ring, or R⁴ and R⁵ together complete a phenyl or thiophene ring which is unsubstituted or substituted with halogen, C_1-4alkyl;

m=3-4;

n=1;

R⁶ is hydroxyl, C_1-4alkoxy, C_1-4alkoxy substituted with hydroxyl, halogen, or NR⁷R⁸, OC(═

O)C_1-6alkyl, NR⁷R⁸, or C_1-4alkyl substituted with hydroxyl, halogen, or NR⁷R⁸, wherein when n=0, R⁶ is not hydrogen;

X is C_1-4alkoxy or hydroxyl;

R⁷ and R⁸ are independently selected from hydrogen, C_1-4alkyl, or C(═

O)C_1-6alkyl.

11. The method of claim 8, wherein said compound is:

5-(2-Aminopropyl)-8-bromo-6-methoxy-chroman-3-ol;

5-((R)-2-Aminopropyl)-8-bromo-6-methoxy-chroman-3-ol;

5-(2-Aminopropyl)-6-methoxy-8-methyl-chroman-3-ol;

5-((R)-2-Amino-1-hydroxy-propyl)-8-bromo-6-methoxy-chroman-3-ol;

Cyclopropanecarboxylic acid 5-((R)-2-aminopropyl)-8-bromo-6-methoxy-chroman-3-yl ester;

[5-(2-Aminopropyl)-6-methoxy-8-methyl-chroman-3-yl]-methanol;

5-(2-Aminopropyl)-8-iodo-chroman-3,6-diol;

or

[4-(2-Aminopropyl)-5-methoxy-7-methyl-2,3-dihydro-benzofuran-2-yl]-methanol;

or combinations thereof.

12. A method for the treatment of glaucoma comprising administering a pharmaceutically effective amount of a composition comprising at least one compound of claim 1.

13. The method of claim 12, wherein R¹ is hydrogen or C_1-4alkyl;

R² is hydrogen, C_1-4alkyl, or R¹ and R² represent (CH₂)_2-4 to complete a heterocyclic ring;

R³ is hydrogen, hydroxyl, C_1-4alkoxy, or halogen;

R⁴ and R⁵ are independently selected from hydrogen, halogen, nitrile, C_1-4alkoxy, C_1-6alkylthiol, C_1-4alkyl, C_1-4alkyl substituted with halogen or C_1-6alkoxy, or R⁴ and R⁵ represent (CH₂)_m to complete a cycloalkyl ring, or R⁴ and R⁵ together complete a phenyl or thiophene ring which is unsubstituted or substituted with halogen, C_1-4alkyl, or C_1-4alkoxy;

m=3-4;

n=0-2;

R⁶ is hydrogen, hydroxyl, C_1-4alkoxy, C_1-4alkoxy substituted with hydroxyl, halogen, or NR⁷R⁸, OC(═

O)C_1-6alkyl, ═

O, NR⁷R⁸, C_1-4alkyl, or C_1-4alkyl substituted with hydroxyl, halogen, or NR⁷R⁸, wherein when n=0, R⁶ is not hydrogen;

X is C_1-4alkoxy, hydroxyl or halogen;

R⁷ and R⁸ are independently selected from hydrogen, C_1-4alkyl, or C(═

O)C_1-6alkyl;

or pharmaceutically acceptable salts or solvates thereof.

14. The method of claim 12, wherein R¹ and R³ are hydrogen;

R² is C_1-4alkyl;

R⁴ and R⁵ are independently selected from halogen, nitrile, C_1-4alkoxy, C_1-6alkylthiol, C_1-4alkyl, C_1-4alkyl substituted with halogen, or R⁴ and R⁵ together represent (CH₂)_m to complete a cycloalkyl ring, or R⁴ and R⁵ together complete a phenyl or thiophene ring which is unsubstituted or substituted with halogen, C_1-4alkyl;

m=3-4;

n=1;

R⁶ is hydroxyl, C_1-4alkoxy, C_1-4alkoxy substituted with hydroxyl, halogen, or NR⁷R⁸, OC(═

O)C_1-6alkyl, NR⁷R⁸, or C_1-4alkyl substituted with hydroxyl, halogen, or NR⁷R⁸, wherein when n=0, R⁶ is not hydrogen;

X is C_1-4alkoxy or hydroxyl;

R⁷ and R⁸ are independently selected from hydrogen, C_1-4alkyl, or C(═

O)C_1-6alkyl.

15. The method of claim 12, wherein said compound is:

5-(2-Aminopropyl)-8-bromo-6-methoxy-chroman-3-ol;

5-((R)-2-Aminopropyl)-8-bromo-6-methoxy-chroman-3-ol;

5-(2-Aminopropyl)-6-methoxy-8-methyl-chroman-3-ol;

5-((R)-2-Amino-1-hydroxy-propyl)-8-bromo-6-methoxy-chroman-3-ol;

Cyclopropanecarboxylic acid 5-((R)-2-aminopropyl)-8-bromo-6-methoxy-chroman-3-yl ester;

[5-(2-Aminopropyl)-6-methoxy-8-methyl-chroman-3-yl]-methanol;

5-(2-Aminopropyl)-8-iodo-chroman-3,6-diol;

or

[4-(2-Aminopropyl)-5-methoxy-7-methyl-2,3-dihydro-benzofuran-2-yl]-methanol;

or combinations thereof.

16. A pharmaceutical composition comprising the compound of claim 1 and at least one carrier.

17. A method to block or bind to serotonin receptors comprising administering an effective amount of at least one compound of claim 1 to a patient.