HEDGEHOG PATHWAY ANTAGONISTS AND THERAPEUTIC APPLICATIONS THEREOF

• US 20100286114A1
• Filed: 12/10/2008
• Published: 11/11/2010
• Est. Priority Date: 12/13/2007
• Status: Active Grant

• Current Assignee: Siena Biotech S.p.A.
• Original Assignee: Siena Biotech S.p.A.
• Inventors: Pericot Mohr, Gal.la, Minetto, Giacomo, Bakker, Annette Cornelia, Thomas, Russell John, Ferruzzi, Pietro
• Granted Patent: US 8,592,463 B2
• Time in Patent Office: Days
• US Class Current: 514/210.18
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

Heterocyclic compounds that modulate the hedgehog signaling pathway, pharmaceutical composition thereof and their therapeutic applications.

Claims

1. Compounds of formula I

2. The compounds of claim 1, of formula Ia

3. The compounds of claim 2, wherein

X is N;

R₃ is H;

linear, branched or cyclic (C₁-C₆)alkyl, oxaalkyl, alkylcarbonyl, alkylsulphonyl, oxaalkylarbonyl, alkoxycarbonyl, alkylamino carbonyl, oxaalkenyl, alkenylcarbonyl, oxaalkenylcarbonyl, alkenyloxycarbonyl or alkenylaminocarbonyl group optionally substituted with carbamoyl or one or more fluorine atoms;

Ar;

Ar-aminocarbonyl;

a linear or branched (C₁-C₄)alkyl, alkylamino, azaalkyl, oxaalkyl, alkylcarbonyl, alkoxycarbonyl or alkylaminocarbonyl group substituted with one or two Ar and optionally substituted with one or more fluorine atoms;

4. The compounds of claim 2, wherein X is CH.

5. The compounds of claim 3 wherein

R₃ is

6. The compounds of claim 5 wherein q is 1 and Q is carbonyl;

linear, branched or cyclic (C₁-C₆)alkyl, (C₁-C₅)alkylcarbonyl or carbonyl(C₁-C₅)alkyl optionally substituted with one or more fluorine atoms.

7. The compounds of claim 4, wherein q is zero and R₃ is is selected from

8. A pharmaceutical composition containing a compound according to claim 1 with a pharmaceutically acceptable carrier or excipient.

9. A method of treatment or prevention of osteoporosis or cancer comprising administering to a subject in need thereof an effective amount of the compound according to claim 1.

10. The method of claim 9 wherein the cancer is selected from non-small cell lung carcinoma;

small-cell lung cancer;

breast cancer;

ovarian tumours;

digestive tract tumours;

brain cancer;

prostate cancer;

pancreatic cancer;

basal cell carcinoma;

malignant melanoma;

squamous cell carcinomas;

multiple myeloma;

lymphoma;

mesenchymal cancers;

chronic myeloid leukaemia;

endometrial carcinoma;

hepatocellular carcinoma.

11. A method for the treatment of diseases, conditions, or dysfunctions that benefit from the inhibition of the hedgehog pathway, which comprises administering to a subject in need thereof an effective amount of a compound according to claim 1.

12. A method according to claim 11 for the treatment of osteoporosis or cancer, particularly non-small cell lung carcinoma;

small-cell lung cancer;

breast cancer;

ovarian tumours;

digestive tract tumours;

brain cancer;

prostate cancer;

pancreatic cancer;

basal cell carcinoma;

malignant melanoma;

squamous cell carcinomas;

multiple myeloma;

lymphoma;

mesenchymal cancers;

chronic myeloid leukaemia;

endometrial carcinoma;

hepatocellular carcinoma.

13. A method according to claim 9, wherein said effective amount ranges from about 0.01 to about 200 mg/kg daily.

14. A method according to claim 11, wherein said effective amount ranges from about 0.01 to about 200 mg/kg daily.