Treatment of movement disorders by administration of 5-hydroxytryptamine receptor/alpha2 adrenergic receptor antagonist compositions

• US 20020035057A1
• Filed: 08/27/2001
• Published: 03/21/2002
• Est. Priority Date: 09/15/1999
• Status: Active Grant

• Current Assignee: Thomas Giduz, Virginia Pact Richter
• Original Assignee: Thomas Giduz, Virginia Pact Richter
• Inventors: Giduz, Thomas, Richter, Virginia Pact
• Granted Patent: US 7,030,108 B2
• Time in Patent Office: Days
• US Class Current: 514/1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs

Abstract

A method of combating movement disorder in a patient experiencing or susceptible to same, by administering to the patient an effective amount of a neurotransmission modulating composition including a 5HT antagonist and/or α₂ antagonist. The antagonist may for example include a piperazinoazepine compound such as mirtazapine that is a receptor antagonist for 5HT2/3 and α₂ receptors.

Claims

1. A method of combating movement disorder in a patient experiencing or susceptible to same, by administering to the patient an effective amount of a neurotransmission modulating composition comprising a 5HT antagonist and/or α

₂ antagonist.

2. The method of claim 1, wherein the composition comprises a 5HT antagonist.

3. The method of claim 1, wherein the composition comprises a 5HT antagonist including at least one of 5HT2 antagonists and 5HT3 antagonists.

4. The method of claim 1, wherein the composition comprises an α

₂ antagonist.

5. The method of claim 1, wherein the composition comprises a compound that is both a 5HT antagonist and an α

₂ antagonist.

6. The method of claim 1, wherein said movement disorder comprises dyskinesia.

7. The method of claim 1, wherein said movement disorder comprises a condition selected from the group consisting of tremors, akathisias, asterixis, athetosis, choreaathetosis, tics, chorea/choreaform movements, dystonias, spasticity, restless legs syndrome, hyperkinetic movement disorders, hemiballismus, myoclonus, and tardive dyskinesia.

8. The method of claim 1, wherein said movement disorder comprises tremor.

9. The method of claim 1, wherein said movement disorder comprises a peripheral neuropathy-associated tremor.

10. The method of claim 1, wherein said movement disorder comprises at least one tremor condition selected from the group consisting of Parkinsonian tremors, rubral tremors, post-traumatic tremors, drug-induced tremors, cerebellar tremors, and Tourette syndromal tremors.

11. The method of claim 1, wherein said movement disorder derives from neurological impairment of the basal ganglia.

12. The method of claim 1, wherein said movement disorder comprises a disorder selected from the group consisting of Parkinsonian tremor, action tremor and levodopa-induced dyskinesias.

13. The method of claim 1, wherein said composition comprises at least one compound selected from the group consisting of:

(a) tetracyclic compounds of the formula;

 

or a salt thereof, wherein

A represents a pyridine ring or a halogen substituted pyridine ring,

R₁ represents hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, halogen, OH, SH or CF₃,

R₂ represents hydrogen or a lower alkyl or aralkyl group, and

n and m may each be 1, 2 or 3 with the proviso that the sum of m and n must be 2, 3 or 4;

(b) imidazolines;

(c) ergot alkaloids; and

(d) indolealkylamine alkaloids.

14. The method of claim 1, wherein said composition comprises at least one tetracyclic compound of the formula:

15. The method of claim 1, wherein said composition comprises an α

₂ antagonist selected from the group consisting of;

atipamezole;

idazoxan;

imiloxan;

N-(2-(N-Methanesulfonamido-2,3-dihydroindol-5-yl)ethyl)(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2,3-Dihydroindol-5-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2-(N-Methanesulfonamido-2,3-dihydroindol-6-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2-(N-Propanesulfonamido-2,3-dihydroindol-6-yl)ethyl(-N-((R)-(+)-5-methoxy-2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2-(N-Isobutanesulfonamido-2,3-dihydroindol-6-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2-(N-Methyl-2,3-dihydroindol-5-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-N-methylamine;

N-(2-(N-Methyl-2,3-dihydroindol-6-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-N-methylamine;

N-(2-(2,3-Dihydroindol-6-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2-(2,3-Dihydroindol-5-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2-(Indol-6-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2-(N-Methanesulfondamido-1,3-dihydroisoindol-5-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2-(N-Methyl-1,3-dihydroisoindol-5-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine;

N-(2-(1,3-Dihydroisoindol-5-yl)ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylanine;

N-(2-(N-Methyl-2,3-dihydro-1H-indol-5-yl)-ethyl(-N-((R)-(+)-5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-N-methylamine; and

5-{2-(((R)-(+)-5-Methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)methylamino)-ethyl}-1,3-dihydro-indol-2-one.

16. The method of claim 1, wherein said composition comprises a 5HT antagonist including a therapeutic agent selected from the group consisting of ergonovine (Ergotrate), pizotifen, mianserin, Ketanserin (Sufrexal), Ondansetron (Zofran), ritanserin, clozapine (Clozaril), risperidone (Risperdal), methysergide (Sansert), and cyproheptadine (Periactin).

17. The method of claim 1, wherein said 5HT antagonist comprises a therapeutic agent selected from the group consisting of

indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicyclo[3,2,1]-oct-3-yl-ester;

benzo[b]thiophen-3-yl-carboxylic acid-endo-9-methyl-azabicyclo-[3,3,1]non-3-yl-ester;

5-fluoro-1-methyl-indol-3-yl-carboxylic acid-endo-9-methyl-9-aza-bicyclo[3,3,1]non-3-yl-ester;

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl4H-carbaz ol-4-one;

1-methyl-indazol-3-yl-carboxylic acid-9-methyl-9-aza-bicyclo-[3,3,1]-non-3.alpha.-yl-amide;

endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3,3,1]non-4-yl)-benzamide; and

3-[5-methyl-1H-imidazol-4-yl]-1-(1-methyl-1H-indol-3-yl)-1-propanone.

18. The method of claim 1, wherein the composition comprises a presynaptic α

₂ antagonist and a postsynaptic 5HT antagonist.

19. The method of claim 1, wherein the composition comprises mirtazapine.

20. The method of claim 19, wherein mirtazapine is administered orally to the patient.

21. The method of claim 20, wherein mirtazapine is administered orally in a dose of from about 10 to about 100 milligrams per day.

22. The method of claim 20, wherein mirtazapine is administered orally in a dose of from about 15 to about 60 milligrams per day.

23. The method of claim 1, wherein the composition comprises a noradrenergic and serotonergic neurotransmission-modulating agent.

24. The method of claim 1, wherein the composition does not mediate sedation in dosages effective for combating movement disorder.

27. The method of claim 26, wherein said serotonergic antagonist is a 5HT2 and/or 5HT3 antagonist.

28. The method of claim 27, wherein said 5HT2 and/or 5HT3 antagonist is concurrently an α

₂ receptor antagonist.

29. The method of claim 26, wherein said serotonergic antagonist comprises mirtazapine.

30. The method of claim 26, wherein said movement disorder comprises Parkinsonian tremor.

25. A method of combating movement disorder in a patient experiencing or susceptible to same, comprising administering to the patient an effective amount of a piperazinoazepine compound that is a receptor antagonist for at least one receptor selected from the group consisting of 5HT and α

₂ receptors.

26. A method of combating movement disorder in a patient experiencing or susceptible to same, comprising administering to the patient an effective amount of a serotonergic antagonist for at least one receptor selected from the group consisting of 5HT and α

₂ receptors.