Indolealkylamino-withasteroid conjugates and method of use

• US 9,084,800 B2
• Filed: 11/05/2012
• Issued: 07/21/2015
• Est. Priority Date: 11/07/2011
• Status: Active Grant

• Current Assignee: Natreon, Inc.
• Original Assignee: Natreon, Inc.
• Inventors: Ghosal, Shibnath, Veeraragavan, Muruganandam, Kalidindi, Sanyasi R.
• Primary Examiner(s): Tate, Chris R
• Assistant Examiner(s): Winston, Randall
• Application Number:
  US13/669,207
• Publication Number:
  US 20130115316A1
• Time in Patent Office: 988 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/585 containing lactone rings, e.g. oxandrolone, bufalin
• CPC Class Codes: A61K 36/38 Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
• CPC Class Codes: A61K 47/541 Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07J 71/001 Oxiranes

Abstract

A group of indolealkylamino-withasteroid conjugates, isolated and purified from Withania somnifera, are described. A synthetic method of making an indolealkylamino-withasteroid compound is provided. In vitro acetyl cholinesterase inhibitory activity and methods for treatment of dementia and dementia-related disorders, such as Alzheimer'"'"'s disease, and anxiety and depressive disorders in mammals are demonstrated with these novel compositions.

Claims

1. An isolated compound of Formula (I), or a salt thereof:

2. The compound of Formula (I) according to claim 1, wherein R¹ is 5-methoxy, R² is methyl, R³ is hydroxyl, and is a carbon-carbon double bond.

3. The compound of Formula (I) according to claim 1, wherein R¹ is hydroxyl, R² is methyl, R³ is hydroxyl, and is a carbon-carbon double bond.

4. A pharmaceutical or nutraceutical composition comprising the isolated compound of claim 1 and a pharmaceutically acceptable carrier.

5. The compound of Formula (I) according to claim 1, wherein R¹ is selected from 4-, 6-, or 7-methoxy, R² is hydrogen, R³ is hydroxyl, and is a carbon-carbon double bond.

6. The compound of Formula (I) according to claim 1, wherein R¹ is hydroxyl, R² is hydrogen, R³ is hydroxyl, and is a carbon-carbon double bond.

7. The compound of Formula (I) according to claim 1, wherein R¹ is 5-hydroxyl, R² is methyl, R³ is hydroxyl, and is a carbon-carbon double bond.

8. The compound of Formula (I) according to claim 1, wherein R¹ is selected from 4-, 6-, or 7-methoxy, R² is methyl, R³ is hydroxyl, and is a carbon-carbon double bond.

9. The compound of Formula (I) according to claim 1, wherein R¹ is selected from 4-, 6-, or 7-hydroxyl, R² is hydrogen, R³ is hydroxyl, and is a carbon-carbon double bond.

10. The compound of Formula (I) according to claim 1, wherein R¹ is selected from 4-, 6-, or 7-hydroxyl, R² is methyl, R³ is hydroxyl, and is a carbon-carbon double bond.

11. A method of making a compound of Formula (I), or a salt thereof:

12. The method of claim 11, further comprising after step (b):

adding neutral alumina of about pH 6.8-7.8 to the reaction mixture.

13. The method of claim 12, wherein the molar ratio of compound (2) to compound (1-a) is about 1:

2.

14. The method of claim 12, wherein the mass ratio of compound (2) and compound (1-a) to neutral alumina is about 1:

10.