Highly Active Anti-Neoplastic and Anti-Proliferative Agents

a technology of antineoplastic and anti-proliferative agents, which is applied in the field of compounded drugs, can solve problems such as non-cancerous cellular hyperproliferation, and achieve the effect of increasing the efficacy of treatmen

Inactive Publication Date: 2016-10-27
G1 THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]In one embodiment, a compound / method of the present invention is used in combination with another therapy to treat the T, B or NK abnormal cellular proliferation, cancer or disorder. The second therapy can be an immunotherapy. For example, the compound can be conjugated to an antibody, radioactive agent or other targeting agent that directs the compound to the diseased or abnormally proliferating cell. In another embodiment, the compound is used in combination with another pharmaceutical or a biologic agent (for example an antibody) to increase the efficacy of treatment with a combined or a synergistic approach. In an embodiment, the compound can be used with T-cell vaccination, which typically involves immunization with inactivated autoreactive T cells to eliminate a pathogenic autoreactive T cell population. In another embodiment, the compound is used in combination with a bispecific T-cell Engager (BiTE), which is an antibody designed to simultaneously bind to specific antigens on endogenous T cells and malignant cells, linking the two types of cells.

Problems solved by technology

Non-cancerous cellular hyperproliferation presents a similar problem.

Method used

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  • Highly Active Anti-Neoplastic and Anti-Proliferative Agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4yl)amino]ethyl]carbamate, Compound 1

[0237]

[0238]To a solution of 5-bromo-2,4-dichloropyrimidine (3.2 g, 0.0135 mol) in ethanol (80 mL) was added Hunig's base (3.0 mL) followed by the addition of a solution of N-(tert-butoxycarbonyl)-1,2-diaminoethane (2.5 g, 0.0156 mole) in ethanol (20 mL). The contents were stirred overnight for 20 hrs. The solvent was evaporated under vacuum. Ethyl acetate (200 mL) and water (100 mL) were added and the layers separated. The organic layer was dried with magnesium sulfate and then concentrated under vacuum. Column chromatography on silica gel using hexane / ethyl acetate (0-60%) afforded tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. 1HNMR (d6-DMSO) δ ppm 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351 (M+H).

example 2

Synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate, Compound 2

[0239]

[0240]To tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (1.265 g, 3.6 mmol) in THF (10 mL) was added the acetal (0.778 mL, 5.43 mmol), Pd(dppf)CH2Cl2 (148 mg), and triethylamine (0.757 mL, 5.43 mmol). The contents were degassed and then purged with nitrogen. To this was then added CuI (29 mg). The reaction mixture was heated at reflux for 48 hrs. After cooling, the contents were filtered over CELITE™ and concentrated. Column chromatography of the resulting residue using hexane / ethyl acetate (0-30%) afforded tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate. 1HNMR (d6-DMSO) δ ppm 8.18 (s, 1H), 7.63 (brs, 1H), 7.40 (brs, 1H), 5.55 (s, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 3.15 (m, 2H), 1.19-1.16 (m, 15H). LCMS (ESI) 399 (M+H).

example 3

Synthesis of tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate, Compound 3

[0241]

[0242]To a solution of the coupled product (2.1 g, 0.00526 mole) in THF (30 mL) was added TBAF solid (7.0 g). The contents were heated to and maintained at 65 degrees for 2 hrs. Concentration followed by column chromatography using ethyl acetate / hexane (0-50%) afforded tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate as a pale brown liquid (1.1 g). 1HNMR (d6-DMSO) δ ppm 8.88 (s, 1H), 6.95 (brs, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H), 3.59 (m, 4H), 3.34 (m, 1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399 (M+H).

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Abstract

This invention is in the area of improved compounds and methods for treating selected cancers and hyperproliferative disorders.

Description

RELATED APPLICATIONS[0001]This application is a divisional of U.S. application Ser. No. 14 / 213,784 which is related to and claims the benefit of provisional U.S. Application No. 61 / 798,772, filed Mar. 15, 2013, provisional U.S. Application No. 61 / 861,374, filed on Aug. 1, 2013, provisional U.S. Application 61 / 911,354, filed on Dec. 3, 2013, and provisional U.S. Application No. 61 / 949,795, filed on Mar. 7, 2014. The entirety of each of these applications is hereby incorporated by reference for all purposes.GOVERNMENT INTEREST[0002]The U.S. Government has rights in this invention by virtue of support under Grant No. 5R44AI084284 awarded by the National Institute of Allergy and Infectious Diseases.FIELD[0003]This invention is in the area of improved compounds and methods for treating selected cancers and hyperproliferative disorders.BACKGROUND[0004]Cancer is a group of diseases categorized by uncontrolled growth and spread. In the United States in 2013, approximately 1.6 million new ca...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/527A61K51/04A61K31/5377A61K47/48
CPCA61K31/527A61K47/4863A61K51/0459A61K31/5377C07D487/20A61K31/529A61K51/0468A61K47/6803A61K47/6867C07D487/14A61P1/04A61P17/02A61P17/06A61P17/10A61P19/02A61P35/00A61P35/02A61P37/02A61P37/06A61P43/00A61K47/545
Inventor STRUM, JAY COPELANDBISI, JOHN EMERSONROBERTS, PATRICK JOSEPHTAVARES, FRANCIS XAVIER
Owner G1 THERAPEUTICS INC
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