Pharmacological treatment for sleep apnea

• US 20030130266A1
• Filed: 10/31/2002
• Published: 07/10/2003
• Est. Priority Date: 12/14/2001
• Status: Active Grant

• Current Assignee: Board of Trustees of The University of Illinois
• Original Assignee: Board of Trustees of The University of Illinois
• Inventors: Radulovacki, Miodrag, Carley, David W.
• Granted Patent: US 7,160,898 B2
• Time in Patent Office: Days
• US Class Current: 514/220
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• 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 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/48 Ergoline derivatives, e.g. lysergic acid, ergotamine
• 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 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 : Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives

Abstract

The present invention relates generally to pharmacological methods for the prevention of amelioration of sleep-related breathing disorders via administration of agents or combinations of agents that possess serotonin-related pharmacological activity.

Claims

1. A method of preventing or ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of at least one serotonin receptor antagonist, in free base or quaternized form, selected from the group consisting of zatosetron, tropisetron, dolasetron, hydrodolasetron, mescaline, oxetorone, homochlorcyclizine, perlapine, loxapine, olanzapine, chlorpromazine, haloperidol, r (+) ondansetron, cisapride, norcisapride, (+) cisapride, (−

) cisapride, (+) norcisapride, (−

) norcisapride, desmethylolanzapine, 2-hydroxymethylolanzapine, and 1-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)-oxime.

2. The method of claim 1 wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.

3. A method of preventing or ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of at least one serotonin receptor antagonist, in quaternized form, selected from the group consisting of ondansetron, ketanserin, risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide.

4. The method of claim 3 wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring.

5. A method of preventing or ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of

(a) at least one of a serotonin receptor antagonist

(i) in free base or quaternized form selected from the group consisting of zatosetron, tropisetron, dolasetron, hydrodolasetron, mescaline, oxetorone, homocblorcyclizine, perlapine, loxapine, olanzapine, chlorpromazine, haloperidol, r (+) ondansetron, cisapride, norcisapride, (+) cisapride, (−

) cisapride, (+) norcisapride, (−

) norcisapride, desmethylolanzapine, 2-hydroxymethylolanzapine, and 1-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)-oxime,;

(ii) in quaternized form selected from the group consisting of ondansetron, ketanserin, risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide; and

(iii) and mixtures thereof; and

(b) a serotonin receptor agonist.

6. The method of claim 5 wherein the serotonin receptor antagonist in the quaternized form is methylated, ethylated, or benzylated.

7. The method of claim 5 wherein the serotonin receptor agonist is selected from the group consisting of 8-OH-DPAT, sumatriptan, L694247, buspirone, alnitidan, zalospirone, ipsapirone, gepirone, zolmitriptan, risatriptan, 311C90, α

-Me-5-HT, BW723C86, and MCPP.

8. The method of claim 5 wherein the serotonin receptor agonist is a 5-hydroxytryptamine₁ receptor subtype agonist.

9. The method of claim 5 wherein the serotonin receptor agonist is a 5-hydroxytryptamine₂ receptor subtype agonist.

10. The method of claim 5 wherein the effects of the serotonin receptor agonist are exerted in the central nervous system.

11. The method of claim 5 wherein the effects of the serotonin receptor antagonist are exerted in the peripheral nervous system.

12. The method of claim 5 wherein the effects of the serotonin receptor agonist are exerted in the central nervous system and wherein the effects of the serotonin receptor antagonist are exerted in the peripheral nervous system.

13. A method of preventing or ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of

(a) at least one of a serotonin receptor antagonist

(i) in their free base or quaternized form selected from the group consisting of zatosetron, tropisetron, dolasetron, hydrodolasetron, mescaline, oxetorone, homochlorcyclizine, perlapine, loxapine, olanzapine, chlorpromazine, haloperidol, r (+) ondansetron, cisapride, norcisapride, (+) cisapride, (−

) cisapride, (+) norcisapride, (−

) norcisapride, desmethylolanzapine, 2-hydroxymethylolanzapine, 1-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)-oxime;

(ii) and in their quaternized form selected from the group consisting of ondansetron, ketanserin, risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-20 carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide; and

(iii) mixtures thereof; and

(b) an effective amount of a selective serotonin reuptake inhibitor.

14. The method of claim 13 wherein the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine and paroxetine.

15. The method of claim 13 wherein the selective serotonin reuptake inhibitor is selected from the group consisting of fluvoxamine, sertraline, citalopram, norfluoxetine, r(−

) fluoxetine, s(+) fluoxetine, demethylsertraline, demethylcitalopram, venlafaxine, milnacipran, sibutramine, nefazodone, R-hydroxynefazodone, (−

)venlafaxine, and (+) venlafaxine.

16. A method of preventing or ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof

(a) an effective amount of at least one serotonin receptor antagonist selected from the group consisting of zatosetron, tropisetron, dolasetron, hydrodolasetron, mescaline, oxetorone, homochlorcyclizine, perlapine, ondansetron (GR38032F), ketanserin, loxapine, olanzapine, chlorpromazine, haloperidol, r (+) ondansetron, cisapride, norcisapride, (+) cisapride, (−

) cisapride, (+) norcisapride, (−

) norcisapride, desmethylolanzapine, 2-hydroxymethylolanzapine, 1-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)-oxime, risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide; and

(b) at least one selective serotonin reuptake inhibitor selected from the group consisting of fluvoxamine, sertraline, fluoxetine, paroxetine, citalopram, norfluoxetine, r(−

)fluoxetine, s(+)fluoxetine, demethylsertraline, demethylcitalopram, venlafaxine, minacipran, sibutramine, nefazodone, R-hydroxynefazodone, (−

) venlafaxine, and (+)venlafaxine.