SUBSTITUTED UREAS

• US 20080280886A1
• Filed: 05/08/2008
• Published: 11/13/2008
• Est. Priority Date: 05/08/2007
• 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:
  US12/117,043
• Publication Number:
  US 20080280886A1
• Time in Patent Office: Days
• US Class Current: 514/220
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 211/58 attached in position 4

Abstract

Disclosed herein are urea-based 5-HT receptor modulators, pharmaceutically acceptable salts and prodrugs thereof, the chemical synthesis thereof, and medical use of such compounds for the treatment and/or management of 5-HT receptor-mediated disorders.

Claims

1. A compound having structural Formula I:

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, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ are independently selected from the group consisting of hydrogen and deuterium; 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, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ is deuterium.

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, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ independently has deuterium enrichment of no less than about 98%.

4. 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, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ 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, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ 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, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ independently has deuterium enrichment of no less than about 10%.

7. 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, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ independently has deuterium enrichment of no less than about 1%.

8. 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.

9. 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.

10. The compound as recited in claim 9, 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.

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

12. The compound as recited in claim 9, wherein each of said positions represented as D have deuterium enrichment of at least 90%.

13. The compound as recited in claim 9, wherein each of said positions represented as D have deuterium enrichment of at least 50%.

14. The compound as recited in claim 9, wherein each of said positions represented as D have deuterium enrichment of at least 10%.

15. The compound as recited in claim 9, wherein each of said positions represented as D have deuterium enrichment of at least 1%.

16. A pharmaceutical composition comprising the compound as recited in claim 1 and one or more pharmaceutically acceptable carriers.

17. The pharmaceutical composition as recited in claim 16, further comprising another therapeutic agent.

18. The pharmaceutical composition as recited in claim 16, wherein the therapeutic agent is selected from the group consisting of antipsychotic medications, NMDA-receptor modulator, 5-HT receptor modulators, endothelin converting enzyme (ECE) inhibitors, thromboxane enzyme antagonists, potassium channel openers, thrombin inhibitors, growth factor inhibitors, platelet activating factor (PAF) antagonists, anti-platelet agents, Factor VIIa Inhibitors, Factor Xa Inhibitors, renin inhibitors, neutral endopeptidase (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-PDE5 agents, beta-PDE5 agents, antiarrhythmic agents, diuretics, anti-diabetic agents, PPAR-gamma agonists, mineralocorticoid enzyme antagonists, aP2 inhibitors, protein tyrosine kinase inhibitors, antiinflammatories, antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents, cytotoxic agents, antimetabolites, farnesyl-protein transferase inhibitors, hormonal agents, microtubule-disruptor agents, microtubule-stablizing agents, topoisomerase inhibitors, prenyl-protein transferase inhibitors, cyclosporins, TNF-alpha inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gold compounds, and platinum coordination complexes.

19. The pharmaceutical composition as recited in claim 18, wherein the therapeutic agent is an antipsychotic medication.

20. The pharmaceutical composition as recited in claim 19, wherein the antipsychotic medication is selected from the group consisting of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, haloperidol, haloperidol decanoate, droperidol, pimozide, amisulpride, aripiprazole, bifeprunox, clozapine, melperone, norclozapine, olanzapine, risperidone, paliperidone, quetapine, symbyax, tetrabenazine, and ziprazidone.

21. The pharmaceutical composition as recited in claim 18, wherein the therapeutic agent is a NMDA-receptor modulator.

22. The pharmaceutical composition as recited in claim 21, wherein the NMDA-receptor modulator is selected from the group consisting of ketamine, phencyclidine, amantadine, ibogaine, memantine, nitrous oxide, and dextromethorphan.

23. The pharmaceutical composition as recited in claim 18, wherein the therapeutic agent is a 5-HT receptor modulator.

24. The pharmaceutical composition as recited in claim 23, wherein the 5-HT receptor modulator is selected from the group consisting of agomelatine, alpha-methyl-5-HT, DOI, cyproheptadine, ketanserin, lysergic acid diethylamide, mesulergine, mirtazapine, nefazodone, pizotifen, and trazodone.

25. A method for the treatment, prevention, or amelioration of one or more symptoms of a 5-HT receptor mediated disorder, comprising administering a therapeutically effective amount of a compound as recited in claim 1.

26. The method as recited in claim 25, wherein the 5-HT receptor mediated disorder is selected from the group consisting of psychosis, schizophrenia, schizoaffective disorders, psychotic depression, affective disorders, dementia, anxiety, sleep disorders, appetite disorders, bipolar disorders, restless leg syndrome, social anxiety disorders, dysthymia, psychosis secondary to hypertension, migraine, vasospasm, ischemia, motor tics, tremor, psychomotor slowing, bradykinesia, neuropathic pain, Parkinson'"'"'s disease, Huntington'"'"'s disease, Alzheimer'"'"'s disease, spinocerebellar atrophy, Tourette'"'"'s Syndrome, Friedrich'"'"'s Ataxia, Machado-Joseph'"'"'s disease, Lewy Body dementia, dystonia, progressive supranuclear palsy, frontotemporal dementia, dyskinesia, dystonia, myoclonus, tremor associated with dopamine modulation therapy, thrombotic conditions associated with myocardial infarction, thrombotic or ischemic stroke, idiopathic and thrombotic thrombocytopenic purpura, peripheral vascular disease, and Raynaud'"'"'s disease.

27. The method as recited in claim 25, 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.

28. The method as recited in claim 25, 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.

29. The method as recited in claim 25, 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.

30. The method as recited in claim 29, wherein the cytochrome P₄₅₀ isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

31. The method as recited in claim 25, 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.

32. The method as recited in claim 31, wherein said cytochrome P₄₅₀ or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP2B1, 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.

33. The method as recited in claim 25, 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.

34. The method as recited in claim 33, 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.