SUBSTITUTED CYCLOHEXANOLS

• US 20090028873A1
• Filed: 07/25/2008
• Published: 01/29/2009
• Est. Priority Date: 07/27/2007
• Status: Abandoned Application

• Current Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Sarshar, Sepehr, Gant, Thomas G.
• Application Number:
  US12/180,421
• Publication Number:
  US 20090028873A1
• Time in Patent Office: Days
• US Class Current: 424/158.100
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 215/64 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 217/74 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 2601/14 The ring being saturated

Abstract

Disclosed herein are substituted cyclohexanol opioid receptor modulators and/or neurotransmitter reuptake modulators of Formula I or Formula II, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

Claims

1. A compound having a structural formula selected from the group consisting of Formula I and Formula II:

a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently selected from the group consisting of hydrogen and deuterium;

R₂₃ is selected from the group consisting of hydrogen, —

CH₃, deuterium, —

CDH₂, —

CD₂H, and —

CD₃;

at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is deuterium, or R₂₃ is deuterium, —

CDH₂, —

CD₂H, or —

CD₃;

if a compound has structural Formula I and R₇ and R₈ are deuterium, then at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is deuterium, or R₂₃ is hydrogen, deuterium, —

CDH₂, —

CD₂H, or —

CD₃;

if R₂₃ is —

CD₃, then at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is deuterium, or the compound substantially has structural Formula I, substantially has structural Formula II, is a mixture of about 90% or more by weight of the the compound having structural Formula I and about 10% or less by weight of the compound having structural Formula II, or is a mixture of about 90% or more by weight of the compound having structural Formula II and about 10% or less by weight of the compound having structural Formula I; and

if R₁, R₂, R₃, R₄, R₅, and R₆ are deuterium, then at least one of R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is deuterium, or R₂₃ is hydrogen, deuterium, —

CDH₂, or —

CD₂H;

or the compound substantially has structural Formula I, substantially has structural Formula II, is a mixture of about 90% or more by weight of the the compound having structural Formula I and about 10% or less by weight of the compound having structural Formula II, or is a mixture of about 90% or more by weight of the compound having structural Formula II and about 10% or less by weight of the compound having structural Formula I.

2. The compound as recited in claim 1, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

3. The compound as recited in claim 1, wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ independently has deuterium enrichment of no less than about 98%.

4. The compound as recited in claim 1, wherein at least one R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ independently has deuterium enrichment of no less than about 90%.

5. The compound as recited in claim 1, wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ independently has deuterium enrichment of no less than about 50%.

6. The compound as recited in claim 1, wherein at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ independently has deuterium enrichment of no less than about 10%.

7. The compound as recited in claim 1, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

8. The compound as recited in claim 7, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

9. The compound as recited in claim 7, wherein each of said positions represented as D have deuterium enrichment of at least 98%.

10. The compound as recited in claim 7, wherein each of said positions represented as D have deuterium enrichment of at least 90%.

11. The compound as recited in claim 7, wherein each of said positions represented as D have deuterium enrichment of at least 50%.

12. The compound as recited in claim 7, wherein each of said positions represented as D have deuterium enrichment of at least 10%.

13. The compound as recited in claim 1, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

14. The compound as recited in claim 13, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

15. The compound as recited in claim 13, wherein each of said positions represented as D have deuterium enrichment of at least 98%.

16. The compound as recited in claim 13, wherein each of said positions represented as D have deuterium enrichment of at least 90%.

17. The compound as recited in claim 13, wherein each of said positions represented as D have deuterium enrichment of at least 50%.

18. The compound as recited in claim 13, wherein each of said positions represented as D have deuterium enrichment of at least 10%.

19. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a compound having a structural formula selected from the group consisting of Formula I and Formula II:

a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are independently selected from the group consisting of hydrogen and deuterium;

R₂₃ is selected from the group consisting of hydrogen, —

CH₃, deuterium, —

CDH₂, —

CD₂H, or —

CD₃; and

at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is deuterium, or R₂₃ is deuterium, —

CDH₂, —

CD₂H, or —

CD₃.

20. A pharmaceutical composition as recited in claim 19, further comprising one or more release-controlling excipients.

21. The pharmaceutical composition as recited in claim 19, further comprising one or more non-release controlling excipients.

22. The pharmaceutical composition as recited in claim 19, wherein the composition is suitable for oral, parenteral, or intravenous infusion administration.

23. The pharmaceutical composition as recited in claim 22, wherein the oral dosage form is a tablet or capsule.

24. The pharmaceutical composition as recited in claim 22, wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram.

25. The pharmaceutical composition as recited in claim 19, further comprising another therapeutic agent.

26. The pharmaceutical composition as recited in claim 25, wherein the therapeutic agent is selected from the group consisting of prokinetics, tachykinins, anticholinergics, opioids, 5-HT₃ antagonists, alpha adrenergic agents, CCK_A antagonists, NMDA receptor antagonists, serotoninergic agents, sepsis treatments, antibacterial agents, antifungal agents, anticoagulants, thrombolytics, non-steroidal anti-inflammatory agents, antiplatelet agents, NRIs, DARIs, SNRIs, sedatives, NDRIs, SNDRIs, monoamine oxidase inhibitors, hypothalamic phospholipids, ECE inhibitors, opioids, thromboxane receptor antagonists, potassium channel openers, thrombin inhibitors, hypothalamic phospholipids, growth factor inhibitors, anti-platelet agents, P2Y(AC) antagonists, anticoagulants, low molecular weight heparins, Factor VIIa Inhibitors and Factor Xa Inhibitors, renin inhibitors, NEP inhibitors, vasopepsidase inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, anti-atherosclerotic agents, MTP Inhibitors, calcium channel blockers, potassium channel activators, alpha-muscarinic agents, beta-muscarinic agents, antiarrhythmic agents, diuretics, thrombolytic agents, anti-diabetic agents, mineralocorticoid receptor antagonists, growth hormone secretagogues, aP2 inhibitors, phosphodiesterase inhibitors, protein tyrosine kinase inhibitors, antiinflammatories, antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents and cytotoxic agents, antimetabolites, antibiotics, farnesyl-protein transferase inhibitors, hormonal agents, microtubule-disruptor agents, microtubule-stablizing agents, plant-derived products, epipodophyllotoxins, taxanes, topoisomerase inhibitors, prenyl-protein transferase inhibitors, cyclosporins, cytotoxic drugs, TNF-alpha inhibitors, anti-TNF antibodies and soluble TNF receptors, cyclooxygenase-2 (COX-2) inhibitors, and miscellaneous agents.

27. The pharmaceutical composition as recited in claim 26, wherein the therapeutic agent is a prokinetic.

28. The pharmaceutical composition as recited in claim 27, wherein the prokinetic is selected from the group consisting of cisapride, domperidone, lirexapride, metoclopramide, mosapride, neurotrophin-3, norcisapride, prucalipride, renzapride, tegaserod, TS-951, and YM-53389.

29. The pharmaceutical composition as recited in claim 26, wherein the therapeutic agent is a tachykinin.

30. The pharmaceutical composition as recited in claim 29, wherein the tachykinin is selected from the group consisting of exlopitant, nepadudant, and SR-140333.

31. The pharmaceutical composition as recited in claim 26, wherein the therapeutic agent is an anti-cholinergic.

32. The pharmaceutical composition as recited in claim 31, wherein the anti-cholinergicis selected from the group consisting of oxyphencyclimine, camylofin, mebeverine, trimebutine, rociverine, dicycloverine, dihexyverine, difemerine, piperidolate, benzilone, glycopyrronium, oxyphenonium, penthienate, propantheline, otilonium bromide, methantheline, tridihexethyl, isopropamide, hexocyclium, poldine, mepenzolate, bevonium, pipenzolate, biphemanil, (2-benzhydryloxyethyl)diethyl-methylammonium iodide, tiemonium iodide, prifinium bromide, timepidium bromide, fenpiverinium, darifenacin, dicyclomine, hyoscyamine, and YM-905.

33. The pharmaceutical composition as recited in claim 26, wherein the therapeutic agent is an opioid.

34. The pharmaceutical composition as recited in claim 33, wherein the opioid is selected from the group consisting of morphine, codeine, thebain, diacetylmorphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, nicomorphine, fentanyl, α

-methylfentanyl, alfentanil, sufentanil, remifentanyl, carfentanyl, ohmefentanyl, pethidine, ketobemidone, propoxyphene, dextropropoxyphene, methadone, loperamide, pentazocine, buprenorphine, etorphine, butorphanol, nalbufine, levorphanol, naloxone, naltrexone, and tramadol.

35. The pharmaceutical composition as recited in claim 26, wherein the therapeutic agent is a 5-HT₃ antagonist.

36. The pharmaceutical composition as recited in claim 35, wherein the 5-HT₃ antagonist is selected from the group consisting of alosetron, cilansetron, granisectron, and ondansetron.

37. The pharmaceutical composition as recited in claim 26, wherein the therapeutic agent is an alpha adrenergic agent.

38. The pharmaceutical composition as recited in claim 37, wherein the alpha adrenergic agent is selected from the group consisting of lidamidine, and clonidine.

39. The pharmaceutical composition as recited in claim 26, wherein the therapeutic agent is a CCK_A antagonist.

40. The pharmaceutical composition as recited in claim 39, wherein the CCK_A antagonist is selected from the group consisting of dexloxigumide, loxiglumide, proglumide, and proxiglumide.

41. The pharmaceutical composition as recited in claim 26, wherein the therapeutic agent is a NMDA receptor antagonist.

42. The pharmaceutical composition as recited in claim 41, wherein the NMDA receptor antagonist is selected from the group consisting of dizocilpine and memantine.

43. The pharmaceutical composition as recited in claim 26, wherein the therapeutic agent is a serotoninergic agent.

44. The pharmaceutical composition as recited in claim 43, wherein the therapeutic agent is selected from the group consisting of antalarmin and Z-338.

45. The pharmaceutical composition as recited in claim 25, wherein the therapeutic agent is acetaminophen.

46. A method for the treatment, prevention, or amelioration of one or more symptoms of an opioid receptor-mediated disorder, a neurotransmitter reuptake-mediated disorder, or an opioid receptor-mediated disorder and a neurotransmitter reuptake-mediated disorder, in a subject, comprising administering a therapeutically effective amount of a compound having a structural formula selected from the group consisting of Formula I and Formula II:

a mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂, are independently selected from the group consisting of hydrogen and deuterium;

R₂₃ is selected from the group consisting of hydrogen, —

CH₃, deuterium, —

CDH₂, —

CD₂H, or —

CD₃; and

at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ is deuterium, or R₂₃ is deuterium, —

CDH₂, —

CD₂H, or —

CD₃.

47. The method as recited in claim 46, wherein the opioid receptor-mediated disorder, the neurotransmitter reuptake-mediated disorder, or the opioid receptor-mediated disorder and the neurotransmitter reuptake-mediated disorder is selected from the group consisting of fibromyalgia, RA, osteoarthritis, prostatitis, pancreatitis, herniated discs, interstitial cystitis, dysmenorrhea, parturition, premature ejaculation, spinal stenosis, degenerative disk and joint disease, migraines, endometriosis, ovarian cysts, renal calculi, drug detoxification, trigeminal neuralgia, postherpetic neuralgia, endometriosis, sciatica, odontalgia, myocardial infarctions, sports injuries, postoperative pain, oncological pain, neuropathy, restless leg syndrome, disorders associated with moderate to severe acute and/or chronic pain, disorders characterized by pain which can not be treated or is not recommended to be treated by other analgesics, anxiety disorders, and major depressive disorders.

48. The method as recited in claim 46, wherein the opioid receptor-mediated disorder, the neurotransmitter reuptake-mediated disorder, or the opioid receptor-mediated disorder and the neurotransmitter reuptake-mediated disorder can be lessened, ameliorated, or prevented by administering an opioid receptor modulator.

49. The method as recited in claim 46, wherein said compound has at least one of the following properties:

a) decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;

b) increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c) decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d) increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e) an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

50. The method as recited in claim 46, wherein said compound has at least two of the following properties:

a) decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;

b) increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c) decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d) increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e) an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

51. The method as recited in claim 46, wherein the method affects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound.

52. The method as recited in claim 51, wherein the cytochrome P₄₅₀ isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

53. The method as recited in claim 46, wherein said compound is characterized by decreased inhibition of at least one cytochrome P₄₅₀ or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

54. The method as recited in claim 53, wherein said cytochrome P₄₅₀ or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO_A, and MAO_B.

55. The method as recited in claim 46, wherein the method affects the treatment of the disease while reducing or eliminating a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.

56. The method as recited in claim 55, wherein the diagnostic hepatobiliary function endpoint is selected from the group consisting of alanine aminotransferase (“

ALT”

), serum glutamic-pyruvic transaminase (“

SGPT”

), aspartate aminotransferase (“

AST,”

“

SGOT”

), ALT/AST ratios, serum aldolase, alkaline phosphatase (“

ALP”

), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“

GGTP,”

“

γ

-GTP,”

“

GGT”

), leucine aminopeptidase (“

LAP”

), liver biopsy, liver ultrasonography, liver nuclear scan, 5′

-nucleotidase, and blood protein.