MAMMALIAN HEDGEHOG SIGNALING MODULATORS

• US 20090156611A1
• Filed: 11/10/2006
• Published: 06/18/2009
• Est. Priority Date: 11/11/2005
• Status: Abandoned Application

• Current Assignee: Licentia Limited
• Original Assignee: Licentia Limited
• Inventors: Oinas, Antti, Taipale, Jussi, Lahdenperä, Juhani
• Application Number:
  US12/093,182
• Publication Number:
  US 20090156611A1
• Time in Patent Office: Days
• US Class Current: 514/254.100
• CPC Class Codes: A61K 31/33 Heterocyclic compounds
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The disclosure relates to compositions for and methods of inhibiting the mammalian Hedgehog signaling pathway.

Claims

1. A composition comprising (1) a mammalian Hedgehog signaling inhibitor or pharmaceutically acceptable salt, solvate, ester, or prodrug thereof and (2) a pharmaceutically acceptable carrier, diluent, or adjuvant,

wherein the mammalian Hedgehog signaling inhibitor comprises a compound selected from the group consisting of:

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

wherein R¹ is hydrogen or unsubstituted or substituted, linear or branched C_1-10 alkyl;

R² is selected from the group consisting of hydrogen, halogen, unsubstituted or substituted, linear or branched C_1-10 alkyl, and C_1-10 alkoxy;

R³ is selected from the group consisting of hydrogen, halogen, and unsubstituted or substituted, linear or branched C_1-10 alkyl groups;

R⁴ is selected from the group consisting of hydrogen, halogen, unsubstituted or substituted, linear or branched C_1-10 alkyl, and C_1-10 alkoxy groups;

R⁵ is selected from the group consisting of hydrogen, halogen, unsubstituted or substituted, linear or branched C_1-10 alkyl groups, and N(R¹)₂;

R⁶ is selected from the group consisting of hydrogen, halogen, unsubstituted or substituted, linear or branched C_1-10 alkyl groups, N(R¹⁾₂, and C(O)R¹;

R′

is selected from the group consisting of hydrogen, halogen, unsubstituted or substituted, linear or branched C_1-10 alkyl, C_1-10 alkoxy, and SO₂R¹;

R″

is hydrogen, halogen, unsubstituted or substituted linear or branched C_1-10 alkyl, or unsubstituted or substituted aryl or heteroaryl, and

Ar is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl.

2. The composition of claim 1, wherein the mammalian Hedgehog signaling inhibitor is selected from the group consisting of:

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

3. The composition of claim 1, wherein R¹ is selected from the group consisting of hydrogen, ethyl, n-propyl, and n-amyl;

and R² is selected from the group consisting of hydrogen, chlorine, methyl, and methoxy.

4. The composition of claim 1, wherein R² is selected from the group consisting of hydrogen, ethyl, n-propyl, and n-amyl;

and R⁴ is selected from the group consisting of hydrogen, chlorine, methyl, and methoxy.

5. The composition of claim 1, wherein Ar is selected from the group consisting of phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone, pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, furyl, thiophenyl, oxazolyl, azolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, 2,2′

-bipyridinyl, pyridine[3,2,h]quinolinyl, and substituted variants thereof.

6. The composition of claim 1, wherein the mammalian Hedgehog signaling inhibitor comprises formula (XI′

) or (XI″

).

7. The composition of claim 6, wherein Ar is a phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, C_1-4 alkyl, and C_1-4 alkoxy.

19. A method of inhibiting a Hedgehog signaling pathway comprising administering to a subject in need thereof a composition according to claim 1 in an amount effective to inhibit the Hedgehog signaling pathway.

20. The method of claim 19 wherein the subject is a mammal.

21. The method of claim 20 wherein the mammal is human.

22. The method of claim 19, wherein the composition comprises about 0.1 to about 20 mg/kg of the mammalian Hedgehog signaling inhibitor.

27. The method of claim 19, wherein the subject suffers from a proliferative disorder.

29. The method of claim 27, wherein the proliferative disorder is selected from the group consisting of malignant glioma, breast cancer, basal cell carcinoma, medulloblastoma, neuroectodermal tumor, gastrointestinal cancer, ovarian fibroma, ovarian dermoids, oral squamous cell carcinoma (OSCC), small-cell lung cancer (SCLC), prostate cancer, rhabdomyosarcomas, and ependymoma.

30. A method of treating a patient suffering from a cell proliferative disorder comprising selecting the patient in need of treatment for a proliferative disorder and administering to said patient a composition according to claim 1.

31. The method of claim 30, wherein the selecting comprises identifying the proliferative disease by reviewing the patient'"'"'s medical records, physically examining the patient, performing a diagnostic test, or mixtures thereof.

32. The method of claim 31, wherein the selecting further comprises screening the patient or a biological sample from the patient for aberrant Shh pathway activity, where the selecting comprises choosing the patient with the proliferative disorder and the aberrant Shh pathway activity.

33. The method of claim 31, wherein the biological sample is a biopsy.

8-18. -18. (canceled)

23-26. -26. (canceled)

28. (canceled)