QUINOLONE AND TETRAHYDROQUINOLONE AND RELATED COMPOUNDS HAVING NOS INHIBITORY ACTIVITY

• US 20080234237A1
• Filed: 03/24/2008
• Published: 09/25/2008
• Est. Priority Date: 03/23/2007
• Status: Active Grant

• Current Assignee: NeurAxon, Inc. (Knight Therapeutics (Barbados) Inc.)
• Original Assignee: NeurAxon, Inc. (Knight Therapeutics (Barbados) Inc.)
• Inventors: Renton, Paul, ANDREWS, John, ANNEDI, Subhash C., RAKHIT, Suman, DOVE, Peter, SILVERMAN, Sarah, RAMNAUTH, Jailall, PATMAN, Joanne, MADDAFORD, Shawn
• Granted Patent: US 8,173,813 B2
• Time in Patent Office: Days
• US Class Current: 514/165
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 Anxiolytics
• 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: A61P 25/36 Opioid-abuse
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

The present invention features quinolones, tetrahydroquinolines, and related compounds that inhibit nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing various medical conditions.

Claims

1. A compound having the formula:

2. The compound of claim 1,

wherein,

Q is (CHR⁶)_1-3;

R¹ and each R⁶ is, independently, H, optionally substituted C_1-6 alkyl, optionally substituted C_1-4 alkaryl, optionally substituted C_1-4 alkheterocyclyl, or optionally substituted C_2-9 heterocyclyl;

each of R² and R³ is, independently, H, Hal, optionally substituted C_1-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted C_1-6 alkaryl, optionally substituted C_2-9 heterocyclyl, or optionally substituted C_1-4 alkheterocyclyl;

each of R⁴ and R⁵ is, independently, H, (CH₂)_r2NHC(NH)R^2A, or (CH₂)_r2NHC(S)NHR^2A

wherein Y¹ and Y² are each H, or Y¹ and Y² together are ═

O;

wherein one, but not both, of R⁴ and R⁵ is H;

or a pharmaceutically acceptable salt or prodrug thereof.

3. The compound of claim 1, wherein Y¹ and Y² together are ═

O, and Q is (CHR⁶)₂.

4. The compound of claim 1, wherein Y¹ and Y² are each H, and Q is (CHR⁶)₂.

5. The compound of claim 1, wherein Y¹ and Y² together are ═

O, and Q is CHR⁶.

6. The compound of claim 1, wherein Y¹ and Y² are each H, and Q is CHR⁶.

7. The compound of claim 1, wherein Y¹ and Y² together are ═

O, and Q is (CHR⁶)₃.

8. The compound of claim 1, wherein Y¹ and Y² are each H, and Q is (CHR⁶)₃.

9. The compound of claims 1, wherein R⁴ or R⁵ has the formula:

10. The compound of claim 9, wherein R^2A has the formula:

11. The compound of claim 10, wherein R^2A has the formula:

12. The compound of claims 1, wherein R² or R³ has the formula:

13. The compound of claim 12, wherein R^2A has the formula:

14. The compound of claim 13, wherein R^2A has the formula:

15. The compound of claim 11, wherein X¹ is CH and X² is S.

16. The compound of claim 14, wherein X¹ is CH and X² is S.

17. The compound of claim 1, wherein said compound has the formula of:

18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.

19. A method of treating or preventing a condition in a mammal caused by the action of nitric oxide synthase (NOS), wherein said method comprises administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof to said mammal.

20. The method of claim 19, wherein said mammal is a human.

21. The method of claim 19, wherein said condition is migraine headache (with or without aura), chronic tension type headache (CTTH), migraine with allodynia, medication overuse headache, neuropathic pain, AIDS associated painful neuropathy, chronic headache, central post-stroke pain (CPSP), medication-induced hyperalgesia or allodynia, acute pain, chronic pain, diabetic neuropathy, trigeminal neuralgia, chemotherapy induced neuropathic pain, bone cancer pain, chemical dependencies or addictions, CNS disorders, neurodegenerative diseases or nerve injury, cardiovascular related conditions, diabetic nephropathy, inflammatory diseases, or gastrointestinal disorders.

22. The method of claim 21, wherein said medication-induced hyperalgesia or allodynia is opioid-induced hyperalgesia/allodynia or triptan (5-HT_1D/1B agonists)-induced hyperalgesia or allodynia.

23. The method of claim 21, wherein said chemotherapy induced neuropathic pain is induced by Paclitaxol, cis-Platin, or Doxorubicin.

24. The method of claim 21, wherein said chemical dependency or addiction is drug addiction, cocaine addiction, nicotine addiction, methamphetamine-induced neurotoxicity, ethanol tolerance, dependence, or withdrawal, or morphine/opioid induced tolerance, dependence, hyperalgesia, or withdrawal.

25. The method of claim 21, wherein said CNS disorder is epilepsy, anxiety, depression, attention deficit hyperactivity disorder (ADHD), psychosis, or dementia.

26. The method of claim 21, wherein said neurodegenerative disease or nerve injury is acute spinal cord injury, AIDS associated dementia, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis (ALS), Huntington'"'"'s disease, multiple sclerosis, neurotoxicity, or head trauma.

27. The method of claim 21, wherein said cardiovascular related condition is stroke, coronary artery bypass graft (CABG) associated neurological damage, hypothermic cardiac arrest (HCA), post-stroke pain, cardiogenic shock, reperfusion injury, or vascular dementia.

28. The method of claim 21, wherein said inflammatory disease is osteoarthritis or neuroinflammation.

29. The method of claim 21, wherein said gastrointestinal disorder is ileostomy-associated diarrhea, dumping syndrome, or visceral pain.

30. The method of claim 21, wherein said condition is stroke, reperfusion injury, neurodegeneration, head trauma, CABG, migraine headache with and without aura, migraine with allodynia, chronic tension type headache, neuropathic pain, central post-stroke pain (CPSP), morphine/opioid induced hyperalgesia or chronic pain.

31. The method of claim 19, wherein said condition is central post-stroke pain (CPSP).

32. The method of claim 19, wherein said method further comprises administering to said mammal an opioid.

33. The method of claim 32, wherein said opioid is alfentanil, butorphanol, buprenorphine, dextromoramide, dezocine, dextropropoxyphene, codeine, dihydrocodeine, diphenoxylate, etorphine, fentanyl, hydrocodone, hydromorphone, ketobemidone, loperamide, levorphanol, levomethadone, meperidine, meptazinol, methadone, morphine, morphine-6-glucuronide, nalbuphine, naloxone, oxycodone, oxymorphone, pentazocine, pethidine, piritramide, propoxyphene, remifentanil, sulfentanyl, tilidine, and tramadol.

34. The method of claim 19, wherein said method further comprises administering to said mammal an antidepressant.

35. The method of claim 34, wherein said antidepressant is a selective serotonin re-uptake inhibitor.

36. The method of claim 35, wherein said selective serotonin re-uptake inhibitor is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline.

37. The method of claim 34, wherein said antidepressant is a norepinephrine-reuptake inhibitor.

38. The method of claim 37, wherein said norepinephrine-reuptake inhibitor is amitriptyline, desmethylamitriptyline, clomipramine, doxepin, imipramine, imipramine oxide, trimipramine;

adinazolam, amiltriptylinoxide, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, amineptine, butriptyline, demexiptiline, dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine, melitracen, metapramine, norclolipramine, noxiptilin, opipramol, perlapine, pizotyline, propizepine, quinupramine, reboxetine, or tianeptine.

39. The method of claim 34, wherein said antidepressant is a selective noradrenaline/norepinephrine reuptake inhibitor.

40. The method of claim 39, wherein selective noradrenaline/norepinephrine reuptake inhibitor is atomoxetine, bupropion, reboxetine, or tomoxetine.

41. The method of claim 34, wherein said antidepressant is a dual serotonin/norepinephrine reuptake inhibitor.

42. The method of claim 41, wherein said dual serotonin/norepinephrine reuptake inhibitor is duloxetine, milnacipran, mirtazapine, nefazodone, or venlafaxine.

43. The method of claim 34, wherein said antidepressant is a monoamine oxidase inhibitor.

44. The method of claim 43, wherein said monoamine oxidase inhibitor is amiflamine, iproniazid, isocarboxazid, M-3-PPC (Draxis), moclobemide, pargyline, phenelzine, tranylcypromine, or vanoxerine.

45. The method of claim 34, wherein said antidepressant is a reversible monoamine oxidase type A inhibitor.

46. The method of claim 45, wherein said reversible monoamine oxidase type A inhibitor is bazinaprine, befloxatone, brofaromine, cimoxatone, or clorgyline.

47. The method of claim 34, wherein said antidepressant is a tricyclic.

48. The method of claim 47, wherein said tricyclic is amitriptyline, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, or trimipramine.

49. The method of claim 34, wherein said antidepressant is adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxi-de combination, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, lithium, litoxetine;

lofepramine, medifoxamine, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindone, pizotyline, ritanserin, rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, trazodone, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viloxazine, viqualine, zimelidine, or orzometrapine.

50. The method of claim 19, wherein said method further comprises administering to said mammal an antiepileptic.

51. The method of claim 50, wherein said antiepileptic is carbamazepine, flupirtine, gabapentin, lamotrigine, oxcarbazepine, phenyloin, retigabine, topiramate, or valproate.

52. The method of claim 19, wherein said method further comprises administering to said mammal a non-steroidal anti-inflammatory drug (NSAID) or acetaminophen.

53. The method of claim 52, wherein said NSAID is acemetacin, aspirin, celecoxib, deracoxib, diclofenac, diflunisal, ethenzamide, etofenamate, etoricoxib, fenoprofen, flufenamic acid, flurbiprofen, lonazolac, lornoxicam, ibuprofen, indomethacin, isoxicam, kebuzone, ketoprofen, ketorolac, naproxen, nabumetone, niflumic acid, sulindac, tolmetin, piroxicam, meclofenamic acid, mefenamic acid, meloxicam, metamizol, mofebutazone, oxyphenbutazone, parecoxib, phenidine, phenylbutazone, piroxicam, propacetamol, propyphenazone, rofecoxib, salicylamide, suprofen, tiaprofenic acid, tenoxicam, valdecoxib, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide, N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide, 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, and 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one).

54. The method of claim 19, wherein said method further comprises administering to said mammal an antiarrhythmic.

55. The method of claim 19, wherein said method further comprises administering to said mammal a GABA-B antagonist.

56. The method of claim 19, wherein said method further comprises administering to said mammal an alpha-2-adrenergic receptor agonist.

57. The method of claim 19, wherein said method further comprises administering to said mammal a serotonin 5HT_1B/1D agonist.

58. The method of claim 57, wherein said serotonin 5HT_1B/1D agonist is eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, donitriptan, or zolmitriptan.

59. The method of claim 19, wherein said method further comprises administering to said mammal an N-methyl-D-aspartate antagonist or glutamate receptor antagonist.

60. The method of claim 59, wherein said N-methyl-D-aspartate antagonist or glutamate receptor antagonist is amantadine;

aptiganel;

besonprodil;

budipine;

conantokin G;

delucemine;

dexanabinol;

dextromethorphan;

dextropropoxyphen;

felbamate;

fluorofelbamate;

gacyclidine;

glycine;

ipenoxazone;

kaitocephalin;

ketamine;

ketobemidone;

lanicemine;

licostinel;

midafotel;

memantine;

D-methadone;

D-morphine;

milnacipran;

neramexane;

orphenadrine;

remacemide;

sulfazocine;

FPL-12,495 (racemide metabolite);

topiramate;

(α

R)-α

-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid;

1-aminocyclopentane-carboxylic acid;

[5-(aminomethyl)-2-[[[(5S)-9-chloro-2,3,6,7-tetrahydro-2,3-dioxo-1H,5H-pyrido[1,2,3-de]quinoxalin-5-yl]acetyl]amino]phenoxy]-acetic acid;

α

-amino-2-(2-phosphonoethyl)-cyclohexanepropanoic acid;

α

-amino-4-(phosphonomethyl)-benzeneacetic acid;

(3E)-2-amino-4-(phosphonomethyl)-3-heptenoic acid;

3-[(1E)-2-carboxy-2-phenylethenyl]-4,6-dichloro-1H-indole-2-carboxylic acid;

8-chloro-2,3-dihydropyridazino[4,5-b]quinoline-1,4-dione 5-oxide salt with 2-hydroxy-N,N,N-trimethyl-ethanaminium;

N′

-[2-chloro-5-(methylthio)phenyl]-N-methyl-N-[3-(methylthio)phenyl]-guanidine;

N′

-[2-chloro-5-(methylthio)phenyl]-N-methyl-N-[3-[(R)-methylsulfinyl]phenyl]-guanidine;

6-chloro-2,3,4,9-tetrahydro-9-methyl-2,3-dioxo-1H-indeno[1,2-b]pyrazine-9-acetic acid;

7-chlorothiokynurenic acid;

(3S,4aR,6S,8aR)-decahydro-6-(phosphonomethyl)-3-isoquinolinecarboxylic acid;

(−

)-6,7-dichloro-1,4-dihydro-5-[3-(methoxymethyl)-5-(3-pyridinyl)-4-H-1,2,4-triazol-4-yl]-2,3-quinoxalinedione;

4,6-dichloro-3-[(E)-(2-oxo-1-phenyl-3-pyrrolidinylidene)methyl]-1H-indole-2-carboxylic acid;

(2R,4S)-rel-5,7-dichloro-1,2,3,4-tetrahydro-4-[[(phenylamino)carbonyl]amino]-2-quinolinecarboxylic acid;

(3R,4S)-rel-3,4-dihydro-3-[4-hydroxy-4-(phenylmethyl)-1-piperidinyl]-2H-1-benzopyran-4,7-diol;

2-[(2,3-dihydro-1H-inden-2-yl)amino]-acetamide;

1,4-dihydro-6-methyl-5-[(methylamino)methyl]-7-nitro-2,3-quinoxalinedione;

[2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]-phosphonic acid;

(2R,6S)-1,2,3,4,5,6-hexahydro-3-[(2S)-2-methoxypropyl]-6,11,11-trimethyl-2,6-methano-3-benzazocin-9-ol;

2-hydroxy-5-[[(pentafluorophenyl)methyl]amino]-benzoic acid;

1-[2-(4-hydroxyphenoxy)ethyl]-4-[(4-methylphenyl)methyl]-4-piperidinol;

1-[4-(1H-imidazol-4-yl)-3-butynyl]-4-(phenylmethyl)-piperidine;

2-methyl-6-(phenylethynyl)-pyridine;

3-(phosphonomethyl)-L-phenylalanine;

or 3,6,7-tetrahydro-2,3-dioxo-N-phenyl-1H,5H-pyrido[1,2,3-de]quinoxaline-5-acetamide.

61. The method of claim 19, wherein said method further comprises administering to said mammal a cholecystokinin B antagonist.

62. The method of claim 19, wherein said method further comprises administering to said mammal a substance P antagonist.

63. The method of claim 19, wherein said method further comprises administering to said mammal an anti-inflammatory compound.

64. The method of claim 63, wherein said anti-inflammatory compound is aspirin, celecoxib, cortisone, deracoxib, diflunisal, etoricoxib, fenoprofen, ibuprofen, ketoprofen, naproxen, prednisolone, sulindac, tolmetin, piroxicam, mefenamic acid, meloxicam, phenylbutazone, rofecoxib, suprofen, valdecoxib, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide, N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide, 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, or 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one.

65. The method of claim 19, wherein said method further comprises administering to said mammal a DHP-sensitive L-type calcium channel antagonist, omega-conotoxin-sensitive N-type calcium channel antagonist, or a P/Q-type calcium channel antagonist.

66. The method of claim 19, wherein said method further comprises administering to said mammal an adenosine kinase antagonist.

67. The method of claim 19, wherein said method further comprises administering to said mammal an adenosine receptor A₁ agonist, an adenosine receptor A_2a antagonist or an adenosine receptor A₃ agonist.

68. The method of claim 19, wherein said method further comprises administering to said mammal an adenosine deaminase inhibitor.

69. The method of claim 19, wherein said method further comprises administering to said mammal an adenosine nucleoside transport inhibitor.

70. The method of claim 19, wherein said method further comprises administering to said mammal a vanilloid VR1 receptor agonist.

71. The method of claim 19, wherein said method further comprises administering to said mammal a cannabinoid CB1/CB2 agonist.

72. The method of claim 19, wherein said method further comprises administering to said mammal an AMPA receptor antagonist.

73. The method of claim 19, wherein said method further comprises administering to said mammal a kainate receptor antagonist.

74. The method of claim 19, wherein said method further comprises administering to said mammal a sodium channel blocker.

75. The method of claim 19, wherein said method further comprises administering to said mammal a nicotinic acetylcholine receptor agonist.

76. The method of claim 19, wherein said method further comprises administering to said mammal a K_ATP potassium channel, K_v1.4 potassium channel, Ca²⁺-activated potassium channel, SK potassium channel, BK potassium channel, IK potassium channel, or KCNQ2/3 potassium channel opening agent.

77. The method of claim 19, wherein said method further comprises administering to said mammal a muscarinic M3 antagonist, a muscarinic M1 agonist, or a muscarinic M2/M3 partial agonist/antagonist.

78. The method of claim 19, wherein said method further comprises administering to said mammal an antioxidant.

79. The method of claim 19, wherein said method further comprises administering to said mammal an antipsychotic agent.

80. The method of claim 79, wherein said antipsychotic agent is promazine, chlorpromazine, chlorprothixene, thioridazine, acetophenazine, mesoridazine, droperidol, loxapine, molindone, perphenazine, prochlorphenazine, thiothixene, trifluoperazine, fluphenazine, pimozide, flupenthixol, methotrimeprazine, pipotiazine, sertindole, clozapine, olanzapine, risperidone, aripiprazole, quetiapine, haloperidol, ziprasidone, or iloperidone.

81. The method of claim 19, wherein said method further comprises administering to said mammal a dopamine receptor antiparkinson'"'"'s agent

82. The method of claim 81, wherein said antiparkinson'"'"'s agent is levodopa, or pramipexole.

83. The method of claim 19, wherein said method further comprises administering to said mammal Fatty Acid Amide Hydrolase (FAAH) Inhibitor.