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Solid forms of a selective cdk4/6 inhibitor

a selective cdk4/6, solid form technology, applied in the direction of cellulosic plastic layered products, natural mineral layered products, drug compositions, etc., can solve the problems of difficult dispersion of hard agglomerates, unsuitable for further development, and the use of free bases as a base presented challenges for pharmaceutical development, so as to improve yield

Inactive Publication Date: 2016-01-07
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes the analysis of two different forms (also known as polymorphs) of a compound using infrared spectroscopy and powder X-ray diffraction techniques. The results show that the two forms have different chemical structures and can be easily distinguished based on the peaks in the spectra. This information can be used in the development and manufacture of the compound.

Problems solved by technology

While compound 1 is a potent and selective CDK4 / CDK6 inhibitor, its use as a free base presented challenges for pharmaceutical development.
The free base provided by traditional salt break procedures, e.g., as in Example 4 of WO 2005 / 005426, was highly static prone and formed small primary particles, which agglomerated into large, hard agglomerates that were difficult to disperse by sieving and were unsuitable for further development.

Method used

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  • Solid forms of a selective cdk4/6 inhibitor
  • Solid forms of a selective cdk4/6 inhibitor
  • Solid forms of a selective cdk4/6 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 4-(6-amino-pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester

[0161]

Step A. Preparation of 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

[0162]To a vessel was added 5-bromo-2-nitropyridine (10.0 g, 1.0 equiv.) along with DMSO (25 mL, 2.5 vol). N-Boc piperazine (13.8 g, 1.5 equiv.) was added, followed by triethylamine (7.5 g, 1.5 equiv.) and LiCl (2.1 g, 1.0 equiv.). The mixture was warmed to 60-65° C. for a minimum of 12 hours.

[0163]Water (5 mL, 0.5 vol) was added slowly to the vessel at 60-65° C. The mixture was kept at 60-65° C. for one hour, then cooled to room temperature. The slurry was kept at 20-25° C. for 1 hour and then filtered onto a #2 Whatman™ paper filter. The cake was rinsed with water (50 mL, 5 vol.). The crude solids were collected and transferred back to a clean vessel.

[0164]Water (100 mL, 10 vol.) was added to the vessel containing the solids and the mixture was warmed to 35-40° C. for 2 hours, then filtered while warm...

example 2

Preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

[0167]

Step A. Preparation of 5-bromo-2-chloro-6-cyclopentylamino-pyrimidine

[0168]To a vessel was added absolute ethanol (3000 mL, 3.0 vol) followed by 5-bromo-2,4-dichloropyrimidine (mw 227.87; 1000 g, 1.0 equiv.). Triethylamine (612 mL, 1.0 equiv.) was added, and then cyclopentylamine (mw 85.15; 520 mL, 1.2 equiv.) was added slowly over 2 hours to control the mild exotherm. After completion of cyclopentylamine addition, the reaction was seeded with 5-bromo-2-chloro-6-cyclopentylamino-pyrimidine (5 g, 0.5 wt %) to induce crystallization, if needed. The reaction was stirred at 25° C. for 2 hours.

[0169]Water (2500 mL, 2.5 vol) was added to the vessel at 20-25° C. at a rate of 30 mL / min. The mixture was cooled to 8-12° C. at 2° C. / min. The slurry was kept at 8-12° C. for 1 hour and then filtered onto a #2 Whatman™ paper filter. The cake was rinsed with n-heptane (2000 mL). The cake was reslurried with...

example 3

Preparation of 4-{6-[6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester

[0176]

[0177]A dry, nitrogen purged reactor was charged with tetrahydrofuran (900 mL, 15 mL / g). The batch temperature was set at 20° C. and agitation at 250 RPM was started. The reactor was charged with 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (63.4 g, 0.2278 moles, 1.3 equiv.) and the mixture held at 20° C. for 30 min to dissolve the starting material. The reactor was charged with isopropylmagnesium chloride (93.9 g, 0.193 moles, 1st charge 1.1 eq) (2.0M in THF, 1.1 equiv.) by pump over 30 min. The batch was maintained at 20° C. for 40 min. The reactor was charged with 6-bromo-2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (60.1 g, 0.1755 moles, 1 eq.) all at once and rinsed with THF (50 mL rinse). An additional charge of isopropylmagnesium chloride (93.9 g, 0.193 moles, 1.1 eq...

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Abstract

This invention relates to the crystalline free base of acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, formula (1) having improved properties, to pharmaceutical compositions and dosage forms comprising the free base, and to methods for making and using such compounds, compositions and dosage forms in the treatment of cell proliferative diseases, such as cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of priority to U.S. Provisional Application No. 61 / 767,761, filed on Feb. 21, 2013, which is incorporated by reference herein in its entirety.FIELD OF THE INVENTION[0002]This invention relates to the free base of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one having improved physicochemical properties. The invention also relates to pharmaceutical compositions and dosage forms comprising the free base, and to methods for making and using such compounds, compositions and dosage forms in the treatment of cell proliferative diseases, such as cancer.BACKGROUND OF THE INVENTION[0003]The compound 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (also referred to herein as “compound 1”), may be represented by the structure:and is also known as palbociclib or PD-0332991. Compound 1 is a potent and select...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/04
CPCC07D471/04C07B2200/13A61P35/00A61K9/14A61K9/48A61K31/519
Inventor CHEKAL, BRIAN PATRICKIDE, NATHAN D.
Owner PFIZER INC
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