Deuterated 1-piperazino-3-phenyl-indanes for treatment of schizophrenia

• US 8,575,174 B2
• Filed: 06/19/2012
• Issued: 11/05/2013
• Est. Priority Date: 06/20/2011
• Status: Active Grant

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Inventors: Jorgensen, Morten, Andersen, Peter Hongaard, Jensen, Klaus Gjervig, Hvenegaard, Mette Graulund, Badolo, Lassina, Jacobsen, Mikkel Fog
• Primary Examiner(s): Jarrell, Noble
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US13/527,364
• Publication Number:
  US 20120322811A1
• Time in Patent Office: 504 Days
• Field of Search: 514/255.03, 544/403
• US Class Current: 514/255.03
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 59/002 Heterocyclic compounds
• CPC Class Codes: C07C 45/61 by reactions not involving the formation of >C = O groups
• CPC Class Codes: C07C 45/67 by isomerisation; by change of size of the carbon skeleton
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/073 with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Abstract

The present invention relates to deuterated 1-piperazino-3-phenyl-indanes and salts thereof with activity at dopamine receptors D₁ and D₂ as well as the 5HT₂ receptors in the central nervous system, to medicaments comprising such compounds as active ingredients, to the use of such compounds in the treatment of diseases in the central nervous system, and to methods of treatment comprising administration of such compounds.

Claims

1. A deuterium enriched compound of formula Y:

2. The compound of claim 1, wherein R⁶-R¹⁰ are each deuterium.

3. The compound of claim 2, wherein R³-R⁵ are each hydrogen.

4. The compound of claim 2, wherein R³-R⁵ are each deuterium.

5. The compound of claim 3, wherein the compound is

6. The compound of claim 3, wherein the compound is

7. The compound of claim 4, wherein the compound is

8. The compound of claim 4, wherein the compound is

9. The compound of claim 1, wherein R¹ and R² are each deuterium.

10. The compound of claim 9, wherein R³-R⁵ are each deuterium.

11. The compound of claim 9, wherein R³-R⁵ are each hydrogen.

12. The compound of claim 10, wherein the compound is

13. The compound of claim 11, wherein the compound is

14. The compound of claim 1, wherein the compound is the hydrogen tartrate salt of

17. The compound of claim 1, wherein the compound is isolated.

18. The compound of claim 17, wherein R⁶-R¹⁰ are each deuterium.

19. The compound of claim 18, wherein the compound is

20. The compound of claim 18, wherein the compound is

21. The compound of claim 18, wherein the compound is

22. The compound of claim 19, wherein the compound is

23. The compound of claim 21, wherein the compound is the hydrogen tartrate salt.

24. The compound of claim 21, wherein the compound is the hydrogen fumarate salt.

28. The compound of claim 1, wherein the compound is the hydrogen fumarate salt of

15. A pharmaceutical composition comprising deuterium enriched compounds of formula Y, wherein each compound of formula Y independently has the following structure:

16. The pharmaceutical composition of claim 15, wherein the compound is the hydrogen tartrate salt of

26. The pharmaceutical composition of claim 15, wherein at least 91% of the compounds of formula Y in the composition have deuterium at at least two of R¹-R¹⁰, and any atom not designated as deuterium is present at its natural isotopic abundance.

27. The pharmaceutical composition of claim 15, wherein the compound is the hydrogen fumarate salt of

25. A composition comprising deuterium enriched compounds of formula Y, wherein each compound of formula Y independently has the following structure:

29. The composition of claim 25, wherein at least 91% of the compounds of formula Y in the composition have deuterium at at least two of R¹-R¹⁰, and any atom not designated as deuterium is present at about its natural isotopic abundance.

30. The composition of claim 25, wherein at least 94% of the compounds of formula Y in the composition have deuterium at at least two of R¹-R¹⁰, and any atom not designated as deuterium is present at its natural isotopic abundance.