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Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents

A compound and alkyl technology, applied in the field of 5-substituted-indeno[1, can solve problems such as unmet needs

Inactive Publication Date: 2004-12-08
BRISTOL MYERS SQUIBB PHARMA CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] There is a continuing, unmet need for cdk inhibitors for the treatment of proliferative diseases

Method used

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  • Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents
  • Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents
  • Acylsemicarbazides as cyclin dependent kinase inhibitors useful as anti-cancer and anti-proliferative agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment I

[0103] Preparation of 3-(4-methoxyphenyl)-5-(acetamido)indeno[1,2-c]pyrazol-4-one

[0104]

[0105] Step 1. Synthesis of 2 from dimethyl 3-nitrophthalic acid

[0106] A solution of dimethyl 3-nitrophthalic acid (25 g, 105 mmol) in methanol (100 mL) was treated with 5% Pd / C (2.5 g) and hydrogenated on a Parr shaker at 50 psi for 2 h . The solution was filtered (andoridite), the filtrate was collected, and the solvent was removed under reduced pressure. The residue was redissolved in acetic anhydride (20 mL) treated with pyridine (0.05 mL) and heated to 80°C for 1 min. The reaction was cooled and stirred at 25°C for 2 hours. The solvent was removed under reduced pressure and the residue was recrystallized from ethanol to give the product as a white solid (21 g, 79%). The melting point is 104-105°C. C 12 h 14 NO 5 The CIMS m / e calculated value is: 252.0872, the measured value is 252.0888; C 12 h 13 NO5 Anal. Calcd.: C, 57.37; H, 5.22; N, 5.58; Measured: C, 57.67; H, ...

Embodiment II

[0112] Preparation of 3-(4-methoxyphenyl)-5-(chloroacetamido)indeno[1,2-c]pyrazol-4-one

[0113]

[0114] Step 1. Synthesize 13 from 12

[0115] A suspension of 12 (1.0 g, 3.0 mmol) in methanol (10 mL) was treated with conc. HCl (1 mL), heated to reflux for 2 hours, and the reaction was cooled to collect the product as a green solid (0.7 g, 81%). Melting point 273°C, C 17 h 13 N 3 o 2 CIMS m / e calculated value: 292.1086, measured value: 292.1080; C 17 h 13 N 3 o 2 Anal. Calcd.: C, 69.85; H, 4.83; N, 14.37; Measured: 69.99; H, 4.59; N, 14.44.

[0116] Step 2. Synthesize 14 from 13

[0117] A suspension of 13 (20 mg, 0.07 mmol) in dioxane (2 mL) was washed with saturated NaHCO 3 (1 mL) in water was treated with chloroacetyl chloride (30 mL, 0.21 mmol). The reaction was heated to 50°C and stirred for 2 hours. The reaction was cooled, poured into water (2 mL), extracted with ethyl acetate (10 mL), the organic layer was separated and dried (MgSO 4 ), and the solvent...

Embodiment III

[0119] Preparation of 3-(4-methoxyphenyl)-5-(cyclopropylamido)indeno[1,2-c]pyrazol-4-one

[0120] Prepared in a similar manner as described in Example II, using cyclopropylacetyl chloride as starting material. Melting point 289°C; C 21 h 18 N 3 o 3 CIMS m / e Calculated: 360.1348, Measured: 360.1330.

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Abstract

The present invention relates to the synthesis of a new class of indeno[1,2-c]pyrazol-4-ones of formula (I): that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cdk1-7 and their regulatory subunits know as cyclins A-G. This invention also provides a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof. Alternatively, one can treat cancer or other proliferative diseases by administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents.

Description

[0001] Cross-references in relation to applications [0002] This application is a continuation-in-part of U.S. Application Serial No. 09 / 692,023, filed October 19, 2000, entitled "Acylsemicarbazide Compounds and Uses Thereof," which is provisional application 60 / 160,713 non-provisional applications. Provisional Application 60 / 160,713, filed October 20, 1999, is entitled "Acylsemicarbazide Compounds as Cyclin-Dependent Kinase Inhibitors as Anticancer and Antiproliferative Agents." These applications are incorporated herein in their entirety as if set forth in their entirety. technical field [0003] The present invention generally relates to novel 5-substituted-indeno[1,2-c]pyrazol-4-one compounds for use as inhibitors of cyclin-dependent kinases (cdk), medicaments comprising the compounds Compositions, methods of using them to treat proliferative diseases, and intermediates and methods of making them. Background technique [0004] Cell cycle-mediated cell division is on...

Claims

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Application Information

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IPC IPC(8): A61K31/416A61K31/4439A61K31/454A61K31/496A61K31/5377A61K31/541A61P31/04A61P35/00A61P43/00C07D231/54C07D401/04C07D401/12C07D403/04C07D405/04C07D405/12C07D409/04C07D409/12C07D409/14
CPCC07D401/12C07D409/04C07D231/54C07D403/04C07D409/12C07D405/04C07D409/14C07D401/04A61P31/04A61P35/00A61P43/00
Inventor D·纽吉埃尔D·卡里尼S·迪梅奥A·维德万斯E·尤
Owner BRISTOL MYERS SQUIBB PHARMA CO
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