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

• US 9,216,961 B2
• Filed: 03/13/2015
• Issued: 12/22/2015
• 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
• Primary Examiner(s): Kosar, Andrew D
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US14/656,925
• Publication Number:
  US 20150307458A1
• Time in Patent Office: 284 Days
• US Class Current: 1/1
• 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 process for the preparation of a compound of formula (S)-(XV):

2. The process of claim 1, wherein the compound of formula (XIV) is obtained by a process

comprising treating a compound of formula (XII)

3. The process of claim 1, wherein the compound of formula (XV) is obtained in 96% enantomeric excess.

8. A product prepared by the process of claim 1.

4. A process for the preparation of a compound of formula (1R,3S)-(IV)-tartrate,

5. The process of claim 4, wherein (1R,3S)-(IV)-tartrate is crystallized from ethanol.

6. The process of claim 5, wherein racemic trans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃), 2,2-trimethyl piperazine is generated from the corresponding succinate salt thereof.

7. The process of claim 6, wherein racemic trans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-1(d₃), 2,2-trimethyl piperazine succinate is generated from the maleate salt of trans-1-(6-chloro-3-phenyl(d₅)-indan-1-yl)-3,3-dimethyl piperazine.

9. A product prepared by the process of claim 4.

10. A polymorph of the hydrogen tartrate salt of compound (IV) having the XRPD pattern as shown in FIG. 18.

11. The polymorph of claim 10, wherein the polymorph is a solvent free crystal form.