Organic Compounds as Smo Inhibitors

a technology of organic compounds and smo inhibitors, applied in the field of organic compounds as smo inhibitors, can solve the problems of pathological consequences, hedgehog signaling pathway activity,

Inactive Publication Date: 2010-02-18
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]The present invention relates generally to novel compounds relating to the diagnosis and treatment of pathologies relating to the Hedgehog pathway, including but not limited to tumor formation, cancer, neoplasia, and non-malignant hyperproliferative disorders. The present invention includes novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action involve methods of inhibiting tumorigenesis, tumor growth and tumor survival using agents that inhibit the Hedgehog and Smo sign

Problems solved by technology

However, aberrant activity of the Hedgehog signaling pathway, due to mutations that c

Method used

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  • Organic Compounds as Smo Inhibitors
  • Organic Compounds as Smo Inhibitors
  • Organic Compounds as Smo Inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

(R)-4-(4,5-Dimethyl-6-phenoxy-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic methyl ester

[0216]

[0217]To a solution of (R)-4-(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (compound 54, 40 mg, 0.106 mmol) in 2 mL toluene is added phenol (45 mg, 0.48 mmol), potassium phosphate (40.6 mg, 0.19 mmol) and di-tbu X-Phos (5.3 mg, 0.014 mmol) in a 2 drum screw-top vial. The vial is evacuated and flushed with nitrogen, followed with the addition of palladium (II) acetate (2 mg, 0.01 mmol). The reaction mixture is flushed with nitrogen again and heated to 100° C. for 16 h. The mixture is filtered through Celite and the filtrate is concentrated to afford a brown oil. The crude product is purified by HPLC, eluting with 15-95% acetonitrile in water (both mobile phases modified with 3% n-PrOH) to provide the desired product as a white solid (9 mg, 22%).

[0218]1H NMR (400 MHz, DMSO-d6) δ=8.69 (s,...

example 2

2-[(R)-4-(4,5-Dimethyl-6-phenoxy-pyridazin-3-yl)-2-methyl-3,4,5,6-tetra-hydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol

[0220]

[0221]To a solution of (R)-4-(4,5-dimethyl-6-phenoxy-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic methyl ester (98 mg, 0.226 mmol) in 2 mL anhydrous THF is added 3 M methylmagensium bromide (600 μL, 1.8 mmol) in a 2 drum septum-top vial at −78° C. under nitrogen atmosphere. The reaction mixture is stirred at −78° C. for 1.5 h, before being warmed to 0° C. and stirred for additional 2 h. The reaction mixture is quenched with sat. aq. NH4Cl at −78° C. and diluted with DCM. The organic solution is washed with brine, dried over Na2SO4 and concentrated to afford the crude material. The resulting solid is purified by prep. HPLC, eluting with 10% 100% acetonitrile in water (both mobile phases modified by 3% n-PrOH). Fractions containing the desired product are combined and freeze-dried to afford a white solid (58 mg, 59%).

[0222]1H NMR ...

example 3

5%.

[0227]1H NMR (400 MHz, CDCl3) δ=8.83 (s, 1H), 8.16 (s, 1H), 7.41-7.32 (m, 4H), 7.14-7.10 (m, 1H), 4.79-4.77 (m, 1H), 4.39-4.35 (m, 1H), 3.96 (s, 3H) 3.52-3.45 (m, 2H), 3.35-3.42 (m, 1H), 3.24-3.21 (m, 1H), 3.12-3.07 (m, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 1.44 (d, J=6.7 Hz, 3H).

[0228]MS (m / z, MH+) meas. 434.4, calc. 434.2.

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Abstract

The present invention relates generally to novel compounds relating to the diagnosis and treatment of pathologies relating to the Hedgehog pathway, including but not limited to tumor formation, cancer, neoplasia, and non-malignant hyperproliferative disorders. The present invention includes novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action involve methods of inhibiting tumorigenesis, tumor growth and tumor survival using agents that inhibit the Hedgehog and Smo signaling pathway.

Description

[0001]This application claims priority to U.S. Provisional Application Ser. No. 61 / 081,900 filed 18 Jul. 2008, the contents of which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION[0002]Hedgehog (Hh) signaling was first identified in Drosophila as an important regulatory mechanism for embryonic pattern formation, or the process by which embryonic cells form ordered spatial arrangements of differentiated tissues (Nusslein-Volhard et al. (1980) Nature 287, 795-801). In mammalian cells, three Hedgehog genes, Sonic Hedgehog (Shh), Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh), have been identified. Hedgehog genes encode secreted proteins, which undergo post-translational modifications, including autocatalytic cleavage and lipid modification (palmitoylation) at the N-terminus and cholesterol modification of the C-terminus.[0003]The lipid-modified N-terminal Hedgehog protein triggers the signaling activity of the protein pathway, and cell to cell commu...

Claims

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Application Information

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IPC IPC(8): A61K31/502C07D403/14C07D237/26A61K31/501A61P35/00
CPCC07D401/12C07D401/14C07D403/12C07D403/14C07D471/04C07D237/26C07D237/20C07D413/14A61K31/4523A61K31/4427A61K31/501A61P13/08A61P17/06A61P17/14A61P19/08A61P27/02A61P35/00A61P3/10
Inventor HE, FENGPEUKERT, STEFANMILLER-MOSLIN, KARENYUSUFF, NAEEMCHEN, ZHUOLIANGLAGU, BHARAT
Owner NOVARTIS AG
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