Catecholamine prodrugs for use in the treatment of Parkinson's disease

Patent metadata

Field	Value
Publication number	US-11110110-B2
Application number	US-202016872802-A
Country	US
Kind code	B2
Filing date	May 12, 2020
Priority date	Nov 24, 2017
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

Abstract

The present invention provides compounds of formula (I) that are prodrugs of catecholamine for use in treatment of neurodegenerative diseases and disorders. The present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating neurodegenerative or neuropsychiatric diseases and disorders using the compounds of the invention, in particular Parkinson's disease.Accordingly, the present invention relates to compounds of formula (Id)whereinR1 is H and R2 is selected from one of the substituents (i) and (ii) below; orR1 is selected from one of the substituents (i) and (ii) below and R2 is H; orR1 and R2 are both represented by substituent (i) below; orR1 and R2 are both represented by substituent (ii) below; orR1 is substituent (i) and R2 is substituent (ii); orR1 is substituent (ii) and R2 is substituent (i);wherein * indicates the attachment point; andwherein the carbon atom at the attachment point on substituent (i) is in the S-configuration; or a pharmaceutically acceptable salt thereof.

First claim

The invention claimed is:

1. A method for the treatment of a neurodegenerative disease selected from Parkinson's Disease, Huntington's disease, Restless leg syndrome and Alzheimer's disease; or a neuropsychiatric disease or disorder selected from schizophrenia, attention deficit hyperactivity disorder and drug addiction; wherein said method comprises administering to a patient in need thereof a pharmaceutical composition comprising a compound according to formula (Id):

or a pharmaceutically acceptable salt thereof, wherein:
R1 is H and R2 is substituent (i) below; or
R1 is substituent (i) below and R2 is H; or
R1 and R2 are both represented by substituent (i) below;

wherein * indicates the attachment point; and
wherein the carbon atom at the attachment point on substituent (i) is in the S-configuration;
and one or more pharmaceutically acceptable excipients.

2. The method according to claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is selected from the group consisting of:
(Id-ia): (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid;
(Id-ib): (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid; and
(Id-iab): (2S,2′S,3S,3′S,4S,4′S,5R,5′R,6S,6′S)-6,6′-(((4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl)bis(oxy))bis(3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid);
or a pharmaceutically acceptable salt of any of these compounds.

3. The method according to claim 1 , wherein said compound or pharmaceutically acceptable salt thereof is the compound represented by formula (Id-ia) below:

or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 , wherein said compound or pharmaceutically acceptable salt thereof is the compound represented by formula (Id-ib) below:

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 , wherein said compound or pharmaceutically acceptable salt thereof is the compound represented by formula (Id-iab) below:

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 , wherein said pharmaceutical composition is free of the compound of formula (I):

7. The method according to claim 1 , wherein said compound or pharmaceutically acceptable salt thereof is in a solid form.

8. The method according to claim 1 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound according to formula (Id).

9. The method according to claim 1 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of:

(Id-ia) ((2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid);

(Id-ib) ((2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid); or

(Id-iab) ((2S,2′S,3S,3′S,4S,4′S,5R,5′R,6S,6′S)-6,6′-(((4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl)bis(oxy))bis(3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid)).

10. The method according to claim 1 , wherein said pharmaceutical composition is for oral administration.

11. The method according to claim 10 , wherein said pharmaceutical composition for oral administration is a tablet or a capsule.

12. The method according to claim 1 , wherein the method is for treatment of Parkinson's Disease.

13. The method according to claim 1 , wherein the patient is a human being.

14. The method according to claim 3 , wherein said pharmaceutical composition is free of the compound of formula (I):

15. The method according to claim 4 , wherein said pharmaceutical composition is free of the compound of formula (I):

16. The method according to claim 5 , wherein said pharmaceutical composition is free of the compound of formula (I):

17. The method according to claim 3 , wherein the method is for treatment of Parkinson's Disease.

18. The method according to claim 4 wherein the method is for treatment of Parkinson's Disease.

19. The method according to claim 5 , wherein the method is for treatment of Parkinson's Disease.

20. The method according to claim 1 , wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound according to formula (Id) or a pharmaceutically acceptable salt thereof.

Assignees

• H Lundbeck As

Inventors

• Jensen Klaus Gjervig
• Kværnø Lisbet
• Jørgensen Morten
• Juhl Martin

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07H15/02

  Acyclic radicals, not substituted by cyclic structures · CPC title

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title