COMPOSITIONS AND METHODS FOR THE TREATMENT OF SOMATOSENSORY DISORDERS

• US 20110245208A1
• Filed: 03/30/2011
• Published: 10/06/2011
• Est. Priority Date: 03/30/2010
• Status: Active Grant

• Current Assignee: Algynomics, Inc. (Proove Biosciences Inc.)
• Original Assignee: Algynomics, Inc. (Proove Biosciences Inc.)
• Inventors: Diatchenko, Luda, Maixner, William
• Granted Patent: US 8,716,349 B2
• Time in Patent Office: Days
• US Class Current: 514/158
• 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 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• 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 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 31/635 having a heterocyclic ring, e.g. sulfadiazine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12Q 1/6883 : for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 : Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism

Abstract

A method of combating a somatosensory disorder in a subject, comprising administering to the subject an effective amount of a composition comprising bupranolol and/or pharmaceutically acceptable derivative(s) thereof. Compositions useful for such administration are described, including salts, esters, solvates, etc. of tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine, in which such salt, ester, solvate, etc. compound is in enantiomeric excess or homoenantiomeric in the R isomer thereof, or is formulated with racemic mixtures of the R and S stereoisomers of the salts, esters, solvates, etc. of tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine. Combination therapy compositions of opioid receptor agonists and such compounds are also described. A method is disclosed of referential genotypic screening of candidate subjects in connection with therapeutic intervention using the compositions of the disclosure to combat the somatosensory disorder.

Claims

1. A method of combating a somatosensory disorder in a subject, comprising administering to the subject an effective amount of a composition comprising bupranolol and/or pharmaceutically acceptable derivative thereof.

2. The method of claim 1, wherein the somatosensory disorder is selected from the group consisting of chronic pain conditions, idiopathic pain conditions, fibromyalgia syndrome, myofascial pain disorders, tension headache, migraine headache, phantom limb sensations, irritable bowel syndrome, chronic lower back pain, back pain, chronic fatigue syndrome, multiple chemical sensitivities, temporomandibular joint disorder, post-traumatic stress disorder, chronic idiopathic pelvic pain, Gulf War Syndrome, vulvar vestibulitis, osteoarthritis, rheumatoid arthritis, neuropathic pain, and angina pectoris.

3. The method of claim 1, wherein the composition comprises a pharmaceutically acceptable derivative of bupranolol.

4. The method of claim 3, wherein the pharmaceutically acceptable derivative of bupranolol is selected from the group consisting of pharmaceutically acceptable bupranolol salts, bupranolol esters, bupranolol solvates, and prodrugs of bupranolol.

5. The method of claim 3, wherein the pharmaceutically acceptable derivative of bupranolol is selected from the group consisting of pharmaceutically acceptable bupranolol salts and bupranolol esters.

6. The method of claim 1, wherein said administering comprises oral administration.

7. The method of claim 1, wherein said administering comprises parenteral administration.

8. The method of claim 1, wherein said administering comprises non-parenteral administration.

9. The method of claim 1, wherein said administering comprises transdermal administration.

10. The method of claim 1, wherein said administering comprises injection administration.

11. The method of claim 1, wherein the composition comprises tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl] amine, or a salt, ester, solvate or other derivative thereof, in enantiomeric excess or homoenantiomeric in the R isomer thereof.

12. The method of claim 1, wherein the composition comprises tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl] amine, or a salt, ester, solvate or other derivative thereof, in a racemic mixture of the R and S isomers thereof.

13. The method of claim 1, wherein the composition further comprises an opioid receptor agonist.

14. The method of claim 1, wherein the composition comprises R-tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl] amine, or a salt, ester, solvate or other derivative thereof, and morphine.

15. The method of claim 1, wherein the administering further comprises contemporaneously administering an opioid receptor agonist.

16. The method of claim 1, wherein the subject is identified by a screening process comprising referential genotypic screening indicative of susceptibility to the somatosensory disorder.

17. The method of claim 16, wherein said referential genotypic screening indicative of susceptibility to a somatosensory disorder comprises:

determining a genotype of a candidate subject with respect to a gene selected from the group consisting of ADRB2, ADRB3, COMT, and combinations thereof; and

comparing the genotype of the candidate subject with at least one reference genotype associated with the susceptibility to develop the somatosensory disorder, wherein the reference genotype is selected from the corresponding group consisting of an ADRB2 genotype, an ADRB3 genotype, a COMT genotype, and combinations thereof.

18. The method of claim 17, wherein the somatosensory disorder is selected from the group consisting of chronic pain conditions, idiopathic pain conditions, fibromyalgia syndrome, myofascial pain disorders, tension headache, migraine headache, phantom limb sensations, irritable bowel syndrome, chronic lower back pain, back pain, chronic fatigue syndrome, multiple chemical sensitivities, temporomandibular joint disorder, post-traumatic stress disorder, chronic idiopathic pelvic pain, Gulf War Syndrome, vulvar vestibulitis, osteoarthritis, rheumatoid arthritis, neuropathic pain, and angina pectoris.

19. A Composition for treatment of a somatosensory disorder, comprising:

(a) bupranolol or a pharmaceutically effective derivative thereof;

(b) a pharmaceutically acceptable carrier; and

(c) a second therapeutic agent for the somatosensory disorder.

20. The composition of claim 19, wherein the second therapeutic agent is selected from the group consisting of analgesic agents, anti-inflammatory agents, adjunctive analgesics, adrenergic receptor beta-2 (ADBR2) antagonists, adrenergic receptor beta-3 (ADBR3) antagonists, and catechol-O-methyltransferase (COMT) modulators.

21. The composition of claim 19, wherein the second therapeutic agent comprises an analgesic agent selected from the group consisting of acetaminophen, codeine, etorphine, hydromorphone, methadone, morphine, fentanyl, levorphanol, meperidine, oxycodone, propoxyphene, hydrocodone, tramadol, nalbuphine, butorphanol, pentazocine, buprenorphine, naloxone, naltrexone, and nalmefene.

22. The composition of claim 19, wherein the second therapeutic agent comprises an anti-inflammatory agent selected from the group consisting of aspirin, salicylic acid, celecoxib, diclofenac, diflunisal, ibuprofen, fenoprofen, ketoprofen, oxaprozin, indomethacin, meloxicam, piroxicam, mefenamic acid, nabumetone, naproxen, sulindac, etodolac, ketorolac, and tolmetin.

23. The composition of claim 19, wherein the second therapeutic agent comprises an adjunctive analgesic selected from the group consisting of baclofen, carbamazepine, carisoprodol, cyclobenzaprine, lamotrigine, orphenadrine, phenyloin, valproate, levetriracetam, methocarbamol, metaxalone, diazepam, clonazepam, lorazepam, alprazolam, tizanidine, gabapentin, pregabalin, topiramate, amitriptyline, desipramine, duloxetine, milnacipran, nortriptyline, paroxetine, citalpram, buproprion, venlafaxine, zonisamide, clonidine, dextromethorphan, ketamine, anantadine, memantine, dronabinol, tetrahydrocannabinol, and cannabidiol.

24. The composition of claim 19, wherein the second therapeutic agent comprises an adrenergic receptor beta-2 (ADBR2) antagonist selected from the group consisting of butoxamine [DL-erythro-α

-(2,5-dimethoxyphenyl)-β

-t-butyl aminopropanol hydrochloride], ICI 118,551 [(−

)-1-(2,3-[dihydro-7-methyl-1H-inden-4-yl]oxy)-3-([1-methylethyl]-amino)-2-butanol], H35/25 [1-(4′

-methylphenyl)-b2,2-1-isopropylaminopropanol], estrogen propranolol, sotalol, timolol, carteolol, carvedilol, nadolol, penbutolol, labetalol, and pindolol.

25. The composition of claim 19, wherein the second therapeutic agent comprises an adrenergic receptor beta-3 (ADBR3) antagonist selected from the group consisting of L 748337 [(S)-Λ

/-[4-[2-[[3-(acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]ethyl]phenyl]benzenesulfonamide], CL 316234 [disodium(R,R)-5-(2-[{2-(3-chlorophenyl)˜

2-hydroxyethyl}-amino]propyl)-1,3-benzodioxole-2,2,dicarboxylate], and SR 59230A [(1-(2-ethylphenoxy)-3-[[(1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol)].

26. The composition of claim 19, wherein the second therapeutic agent comprises a catechol-β

-methyltransferase (COMT) modulator selected from the group consisting of S-adenosylmethionine (SAMe), estrogen compounds, progesterone and clonidine.

27. A composition for contemporaneous administration to combat a somatosensory disorder, comprising R-tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine, or a derivative thereof, and an opioid receptor agonist.

28. The composition of claim 27, wherein the opioid receptor agonist comprises morphine.

29. The composition of claim 27, comprising a salt, ester or solvate of R-tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine.

30. A method of combating hyperalgesia incident to administration of an opioid receptor agonist to a subject, comprising contemporaneously administering to said subject an effective amount to combat said hyperalgesia, of R-tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine, or a derivative thereof.

31. The method of claim 30, wherein said administering comprises administration of a salt, ester or solvate of R-tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl] amine.

32. A method of suppressing opioid agonist-dependent cAMP production in a cellular assay, comprising administration to a cellular population used in said assay of an effective amount of R-tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine, or a derivative thereof.

33. The method of claim 32, wherein said administration comprises administration of a salt, ester or solvate of R-tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine.

34. A method of modulating ADRB2 and 6TM MOR interaction to mediate analgesia in a subject, comprising administering to the subject an effective amount therefor of R-tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine, or a derivative thereof.

35. The method of claim 34, wherein said administering comprises administration of a salt, ester or solvate of R-tert-butyl[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]amine.