Combination therapy for pain in painful diabetic neuropathy

• US 20070042969A1
• Filed: 08/18/2006
• Published: 02/22/2007
• Est. Priority Date: 03/26/2004
• Status: Abandoned Application

• Current Assignee: UCB Pharma GmbH (UCB SA)
• Original Assignee: SRZ Properties Incorporated
• Inventors: Stohr, Thomas, Rauschkolb-Loffler, Christine, Koch, Brigitte
• Application Number:
  US11/506,577
• Publication Number:
  US 20070042969A1
• Time in Patent Office: Days
• US Class Current: 514/7.300
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 38/04 Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof enzyme inhibitors A61K38/005; gastrins A61K38/2207, somatostatins A61K38/31, melanotropins A61K38/34 ; protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/05 Dipeptides

Abstract

A method for treating pain in painful diabetic neuropathy comprises administering in combination a first agent that comprises a compound as defined herein, illustratively lacosamide, and a second agent effective to provide enhanced treatment of pain, by comparison with the first agent alone. The second agent illustratively comprises an analgesic, an anticonvulsant, an antidepressant or an NMDA receptor antagonist.

Claims

1. A method for treating pain in painful diabetic neuropathy in a subject comprising administering in combination to the subject a first agent that comprises a compound of Formula (I)

2. The method of claim 1, wherein, in the compound of Formula (I) present in the first agent, one or both of R₂ and R₃ are heterocycles independently selected from the group consisting of furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, and when N is present in the heterocycle, N-oxides thereof;

said heterocycles being independently unsubstituted or substituted with at least one electron-withdrawing group and/or at least one electron-donating group.

3. The method of claim 1, wherein the first agent comprises a compound of Formula (III)

4. The method of claim 3, wherein, in the compound of Formula (III),

R₄ is one or more substituents independently selected from the group consisting of hydrogen and halo;

R₃ is selected from the group consisting of lower alkoxy lower alkyl, aryl, N-lower alkoxy-N-lower alkylamino, and N-lower alkoxyamino; and

R₁ is lower alkyl.

5. The method of claim 4, wherein, in the compound of Formula (III), R₃ is lower alkoxy lower alkyl.

6. The method of claim 3, wherein, in the compound of Formula (III),

no more than one R₄ substituent is fluoro and all others are hydrogen;

R₃ is selected from the group consisting of methoxymethyl, phenyl, N-methoxy-N-methylamino, and N-methoxyamino; and

R₁ is methyl.

7. The method of claim 3, wherein, in the compound of Formula (III),

R₄ is hydrogen;

R₃ is methoxymethyl; and

R₁ is methyl.

8. The method of claim 3, wherein the compound of Formula (III) is selected from the group consisting of

(R)-2-acetamido-N-benzyl-3-methoxy-propionamide;

(R)-2-acetamido-N-benzyl-3-ethoxy-propionamide;

O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;

O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;

N-acetyl-D-phenylglycinebenzylamide;

D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; and

D-1,2-(O-methylhydroxylamino)-2-acetamide acetic acid benzylamide.

9. The method of claim 3, wherein the compound of Formula (III) is substantially enantiopure.

10. The method of claim 3, wherein the compound of Formula (III) is lacosamide.

11. The method of claim 10, wherein the lacosamide is administered at a dose of about 50 mg to about 6 g/day.

12. The method of claim 10, wherein the lacosamide is administered at a dose of about 100 to about 1000 mg/day.

13. The method of claim 10, wherein the lacosamide is administered at a dose of about 200 to about 600 mg/day.

14. The method of claim 10, wherein the lacosamide is administered in an amount providing a daily dose effective to provide a plasma concentration of lacosamide of about 0.1 to about 15 μ

g/ml (trough) and about 5 to about 18.5 μ

g/ml (peak), calculated as an average over a plurality of treated subjects.

15. The method of claim 3, wherein the compound of Formula (III) is administered according to a regimen wherein daily doses are increased until a predetermined daily dose is reached which is maintained during further treatment.

16. The method of claim 3, wherein the compound of Formula (III) is administered in one to three doses per day.

17. The method of claim 3, wherein the compound of Formula (III) is administered orally or intravenously.

18. The method of claim 1, wherein the second agent comprises at least one drug other than a compound of Formula (I), selected from the group consisting of analgesics, anticonvulsants, antidepressants and NMDA receptor antagonists.

19. The method of claim 1, wherein the second agent comprises at least one analgesic selected from the group consisting of acetaminophen, alfentanil, allyiprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl-morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, nalorphine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, NO-naproxen, NCX-701, ALGRX-4975, pharmaceutically acceptable salts thereof, and combinations thereof.

20. The method of claim 1, wherein the second agent comprises at least one anticonvulsant selected from the group consisting of acetylpheneturide, albutoin, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitoin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, fosphenyloin, gabapentin, ganaxolone, lamotrigine, levetiracetam, lorazepam, mephenyloin, mephobarbital, metharbital, methetoin, methsuximide, midazolam, narcobarbital, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenyloin, phenethylate, pregabalin, primidone, progabide, remacemide, rufinamide, suclofenide, sulthiame, talampanel, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, zonisamide, pharmaceutically acceptable salts thereof, and combinations thereof.

21. The method of claim 1, wherein the second agent comprises at least one antidepressant selected from the group consisting of adinazolam, adrafinil, amineptine, amitriptyline, amitriptylinoxide, amoxapine, befloxatone, bupropion, butacetin, butriptyline, caroxazone, citalopram, clomipramine, cotinine, demexiptiline, desipramine, dibenzepin, dimetacrine, dimethazan, dioxadrol, dothiepin, doxepin, duloxetine, etoperidone, femoxetine, fencamine, fenpentadiol, fluacizine, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-oxide, indalpine, indeloxazine, iprindole, iproclozide, iproniazid, isocarboxazid, levophacetoperane, lofepramine, maprotiline, medifoxamine, melitracen, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nefopam, nialamide, nomifensine, nortriptyline, noxiptilin, octamoxin, opipramol, oxaflozane, oxitriptan, oxypertine, paroxetine, phenelzine, piberaline, pizotyline, prolintane, propizepine, protriptyline, pyrisuccideanol, quinupramine, reboxetine, ritanserin, roxindole, rubidium chloride, sertraline, sulpiride, tandospirone, thiazesim, thozalinone, tianeptine, tofenacin, toloxatone, tranylcypromine, trazodone, trimipramine, tryptophan, venlafaxine, viloxazine, zimeldine, pharmaceutically acceptable salts thereof, and combinations thereof.

22. The method of claim 1, wherein the second agent comprises at least one NMDA receptor antagonist selected from the group consisting of amantadine, D-AP5, aptiganel, CPP, dexanabinol, dextromethorphan, dextropropoxyphene, 5,7-dichlorokynurenic acid, gavestinel, ifendopril, ketamine, ketobemidone, licostinel, LY-235959, memantine, methadone, MK-801, phencyclidine, remacemide, selfotel, tiletamine, pharmaceutically acceptable salts thereof, and combinations thereof.

23. The method of claim 1, wherein the painful diabetic neuropathy is diabetic distal sensory polyneuropathy.

24. The method of claim 1, wherein the first agent and second agent are, in combination, effective for treatment of an aspect of pain selected from the group consisting of average daily pain, overall pain, present pain intensity, pain interference with sleep, the subject'"'"'s perception of pain interference with general activity, the subject'"'"'s global impression of change in pain, clinical global impression of change in pain, the subject'"'"'s perception of different neuropathic pain qualities, quality of life and proportion of pain-free days.

25. The method of claim 1, wherein the painful diabetic neuropathy is associated with diabetes mellitus Type I or Type II.

26. The method of claim 1, wherein the first agent and second agent are administered in separate dosage forms by the same or different routes at the same or different times.

27. The method of claim 1, wherein the first agent and second agent are administered together in a single pharmaceutical dosage form further comprising at least one pharmaceutically acceptable excipient.

28. The method of claim 1, wherein the enhanced treatment of pain comprises greater reduction of intensity and/or duration of pain by comparison with the first agent alone.