Multi-functional small molecules as anti-proliferative agents

A technology for multifunctional, small molecule compounds, applied in the field of multifunctional small molecules as anti-proliferative preparations, which can solve the problems of destruction of the efficacy of pharmaceutical compositions, high health care costs, and limited effectiveness.

Inactive Publication Date: 2010-02-03
CURIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, combined toxicity of multiple agents due to off-target side effects and drug-drug interactions often limits the effectiveness of this approach
Also, it is often difficult to combine compounds with different pharmacokinetics into a single dosage form, which entails the need for multiple drug treatments at different time intervals, creating issues with patient compliance , will destroy the efficacy of the pharma

Method used

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  • Multi-functional small molecules as anti-proliferative agents
  • Multi-functional small molecules as anti-proliferative agents
  • Multi-functional small molecules as anti-proliferative agents

Examples

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preparation example Construction

[0296] Methods of preparing pharmaceutical compositions containing active ingredients are well known in the art, for example, by mixing, granulating, or tabletting methods. The active therapeutic ingredient is usually mixed with a pharmaceutically acceptable carrier, and the pharmaceutically acceptable carrier is compatible with the active ingredient. For oral administration, the active formulation is mixed with additives customary for oral purposes, such as vehicles, stabilizers, or inert diluents, and converted by conventional methods into a suitable dosage form. Forms such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions, and the like as detailed above.

[0297] The dosage of the compounds of the invention administered to the patient is below that which would induce toxicity in the patient. In certain embodiments, the dose of the compound administered to the patient is less than the dose that results in the concentration of th...

Embodiment 1

[0432] Example 1: 2-(4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolinyl-6- Oxygen)-N-hydroxyacetamide (compound 1) preparation method

[0433] Step 1a. 6,7-Dimethoxyquinazolinyl-4(3hydro)-one (Compound 0102)

[0434] A mixture of methyl 2-amino-4,5-dimethoxybenzoate 0101 (2.1 g, 10 mmol), ammonium formate (0.63 g, 10 mmol) and formamide (7 ml) was stirred, And heated to 190-200°C for 2 hours. The mixture was then cooled to room temperature. The resulting precipitate was isolated, washed with water and dried to afford the title compound 0102 (1.8 g, 84.7%) as a brown solid: LCMS: m / z 207 [M+1] + ; 1 H NMR (dimethylsulfoxide.) δ3.87(s, 3H), 3.89(s, 3H), 7.12(s, 1H), 7.43(s, 1H), 7.97(s, 1H), 12.08(bs , 1H).

[0435] Step 1b. 6-Hydroxy-7-methoxyquinazolinyl-4(3hydro)-one (Compound 0103)

[0436] To stirred methanesulfonic acid (68 mL) was added 6,7-dimethoxyquinazolinyl-4(3hydro)-one (0102) (10.3 g, 50 mmol) in portions. Subsequently, L-methionine (8.6 g, 57.5 mmol) was ...

Embodiment 2

[0450] Example 2: 4-(4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolinyl-6- The preparation method of oxy)-N-hydroxybutyramide (compound 3)

[0451] Step 2a. Ethyl 4-(4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolinyl-6-oxy)butanoate (Compound 0110-3)

[0452] The title compound 0110-3 was prepared as a yellow solid (220 mg, 80.5%) from compound 0109 (200 mg, 0.63 mmol) obtained in step 1f and ethyl 4-bromobutyrate (135 mg, 0.69 mmol) prepared by a method similar to that described in the preparation method of compound 0110-1 (Example 1): LCMS: m / z 434 [M+1] + ; 1 H NMR (deuterated chloroform.) δ1.36(t, 3H), 2.23(m, 2H), 2.57(t, 2H), 4.03(s, 3H), 4.32(m, 4H), 7.15(t, 1H ), 7.25 (m, 1H), 7.87 (s, 1H), 8.00 (m, 2H), 8.15 (bs, 1H), 8.57 (s, 1H).

[0453] Step 2b. 4-(4-(3-Chloro-4-fluoroanilino)-7-methoxyquinazolinyl-6-oxyl)-N-hydroxybutanamide (Compound 3)

[0454] The title compound 3 was prepared as a gray solid (25 mg, 12%) from compound 0110-3 (200 mg, 0.23 mmol) as des...

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Abstract

The present invention relates to the compositions, methods, and applications of a novel approach to selective inhibition of several cellular or molecular targets with a single small molecule. More specifically, the present invention relates to multi-functional small molecules wherein one functionality is capable of inhibiting histone deacetylases (HDAC) and the other functionality is capable of inhibiting a different cellular or molecular pathway involved in aberrant cell proliferation, differentiation or survival.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application No. 60 / 843590, filed September 11, 2006, and US Provisional Application No. 60 / 895889, filed March 20, 2007. The entire content of the aforementioned application is hereby incorporated by reference. Background technique [0003] The elucidation of the complex and multifactorial nature of many diseases involving multiple pathogenic pathways and numerous molecular components suggests that multitargeted therapies may be more beneficial than single-targeted therapies. Recently, combination therapy using two or more agents for many of these diseases in the fields of oncology, infectious disease, cardiovascular disease, and other complex pathologies has demonstrated that this is more effective than the use of the individual components. This combined approach has advantages in overcoming drug resistance, reducing toxicity and, in some cases, producing synergistic therapeutic effects...

Claims

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Application Information

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IPC IPC(8): C07D239/88C07D239/93A61K31/517A61P35/04A61P25/16A61P25/28
CPCY02A50/30
Inventor 蔡雄钱长庚史蒂文·古尔德翟海啸
Owner CURIS INC
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