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

Patent metadata

Field	Value
Publication number	US-12226428-B2
Application number	US-202318330293-A
Country	US
Kind code	B2
Filing date	Jun 6, 2023
Priority date	Nov 24, 2017
Publication date	Feb 18, 2025
Grant date	Feb 18, 2025

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)

wherein
R1 is H and R2 is selected from one of the substituents (i) and (ii) below; or
R1 is selected from one of the substituents (i) and (ii) below and R2 is H; or
R1 and R2 are both represented by substituent (i) below; or
R1 and R2 are both represented by substituent (ii) below; or
R1 is substituent (i) and R2 is substituent (ii); or
R1 is substituent (ii) and R2 is substituent (i);

wherein * indicates the attachment point; and
wherein 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 pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof for the treatment of Parkinson's disease, and one or more pharmaceutically acceptable excipients,
wherein the compound 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;
(Id-iia): (4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl hydrogen sulfate;
(Id-iib): (4aR,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-7-yl) hydrogen sulfate;
(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); and
(Id-iiab): (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diyl bis(hydrogen sulfate).

2. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition is an oral pharmaceutical composition.

3. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition is a solid oral dosage form.

4. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition is a tablet or a capsule.

5. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition further comprises another agent which is useful in the treatment of a neurodegenerative disease or disorder.

6. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition further comprises another agent which is useful in the treatment of Parkinson's disease.

7. The pharmaceutical composition according to claim 1 ,
wherein said compound is the compound represented by formula (Id-ia) below

8. The pharmaceutical composition according to claim 1 , wherein said compound is the compound represented by formula (Id-ib) below

9. The pharmaceutical composition according to claim 1 , wherein said compound is the compound represented by formula (Id-iab) below

10. The pharmaceutical composition according to claim 7 , wherein said pharmaceutical composition is an oral pharmaceutical composition.

11. The pharmaceutical composition according to claim 8 , wherein said pharmaceutical composition is an oral pharmaceutical composition.

12. The pharmaceutical composition according to claim 9 , wherein said pharmaceutical composition is an oral pharmaceutical composition.

13. The pharmaceutical composition according to claim 7 , wherein said pharmaceutical composition is a solid oral dosage form.

14. The pharmaceutical composition according to claim 8 , wherein said pharmaceutical composition is a solid oral dosage form.

15. The pharmaceutical composition according to claim 9 , wherein said pharmaceutical composition is a solid oral dosage form.

16. The pharmaceutical composition according to claim 7 , wherein said pharmaceutical composition is a tablet or a capsule.

17. The pharmaceutical composition according to claim 8 , wherein said pharmaceutical composition is a tablet or a capsule.

18. The pharmaceutical composition according to claim 9 , wherein said pharmaceutical composition is a tablet or a capsule.

19. The pharmaceutical composition according to claim 7 , wherein said pharmaceutical composition further comprises another agent which is useful in the treatment of Parkinson's disease.

20. The pharmaceutical composition according to claim 8 , wherein said pharmaceutical composition further comprises another agent which is useful in the treatment of Parkinson's disease.

21. The pharmaceutical composition according to claim 9 , wherein said pharmaceutical composition further comprises another agent which is useful in the treatment of Parkinson's disease.

22. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is (4aR,10aR)-1-propyl-7-((triisopropylsilyl)oxy)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-ol.

Assignees

• H Lundbeck As

Inventors

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

Classifications

• A61K31/473 Primary

  ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D405/12 Primary

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title