Tricyclic Lactams for Use in the Protection of Hematopoietic Stem and Progenitor Cells Against Ionizing Radiation

Inactive Publication Date: 2015-10-22
G1 THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0030]Methods and tricyclic lactam compounds are provided to minimize the effects of ionizing radiation (IR) on hematopoietic stem cells and/or h

Problems solved by technology

IR causes extensive DNA damage to exposed cells, including both normal cells and abnormally proliferating cells such as cancer and tumor cells.
It is difficult, however, to selectively administer therapeutic ionizing radiation to the abnormal tissue.
Thus, normal tissue proximate to the abnormal tissue is also exposed to potentially damaging doses of ionizing radiation throughout the course of treatment.
Such techniques, however, only attempt to strike a balance between the therapeutic and undesirable effects of the radiation and full efficacy has not been achieved.
In addition, exposure to IR may occur through occupational, environmental, or disaster or terroristic events.
Incidents such as the 1979 accident at Three Mile Island or 2011 accident at the Fukushima nuclear power plant, both of which released radioactive material into the reactor containment building and surrounding environment, illustrate the potential for harmful exposure.
Intentional infliction of harmful radiation can occur during war and aggression.
Hematologic toxicity (i.e., IR-induced bone marro

Method used

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  • Tricyclic Lactams for Use in the Protection of Hematopoietic Stem and Progenitor Cells Against Ionizing Radiation
  • Tricyclic Lactams for Use in the Protection of Hematopoietic Stem and Progenitor Cells Against Ionizing Radiation
  • Tricyclic Lactams for Use in the Protection of Hematopoietic Stem and Progenitor Cells Against Ionizing Radiation

Examples

Experimental program
Comparison scheme
Effect test

Example

Example 1

Synthesis of Compound 2

Scheme 1

[0359]Compound 2 is synthesized according to the method of A. Haidle et al., See, WO 2009 / 152027 entitled “5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives for MARK inhibition.”

Example

Example 2

Synthesis of Compound 3

Scheme 1

[0360]Step 1: A round-bottomed flask inerted with a nitrogen atmosphere is charged with Compound 2, ethanol, and lithium borohydride at ambient temperature. The reaction is stirred at ambient temperature and monitored by thin layer chromatography (TLC) or high-performance liquid chromatography (HPLC). Once Compound 2 can no longer be detected, the reaction is quenched with an aqueous acid such as aqueous hydrochloric acid, diluted with ethyl acetate and the layers separated. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product, a primary alcohol, is purified by silica gel column chromatography eluting with a hexane-ethyl acetate gradient and used directly in the next step.

[0361]Step 2: A round-bottomed flask inerted with a nitrogen atmosphere is charged with the primary alcohol prepared in step 1, DMF and phosphorus tribromide. The reaction is stirred at ambient temperature and monitored ...

Example

Example 3

Synthesis of Compound 5

Scheme 1

[0362]A round-bottomed flask inerted with a nitrogen atmosphere is charged with tetrahydrofuran and the lactam 4, described below. The reaction is cooled to −78° C. and lithium diisopropylamide solution (2M in THF / heptane / ethyl benzene) is added dropwise. To the resulting enolate is added Compound 3, dropwise, and the reaction is allowed to warm to room temperature overnight. The reaction is diluted with saturated brine and the layers are separated. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

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Abstract

This invention is in the area of tricyclic lactam compounds and methods for protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC), from the damage associated with ionizing radiation (IR) exposure using selective radioprotectants.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of provisional U.S. Application No. 61 / 980,883, filed Apr. 17, 2014, provisional U.S. Application No. 61 / 980,895, filed Apr. 17, 2014, provisional U.S. Application No. 61 / 980,918, filed Apr. 17, 2014, and provisional U.S. Application No. 61 / 980,939, filed Apr. 17, 2014, which are hereby incorporated by reference for all purposes.GOVERNMENT INTEREST[0002]The U.S. Government has certain rights in this invention arising from support under Grant No. 5R44AI084284 awarded by the National Institute of Allergy and Infectious Diseases.FIELD OF THE INVENTION[0003]This invention is in the area of compounds and methods for protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC), from the damage associated with ionizing radiation (IR) exposure using selective radioprotectants.BACKGROUND[0004]Ionizing radiation (IR) is an important therapeutic modality to treat a range of cancers and other proliferati...

Claims

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Application Information

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IPC IPC(8): A61K31/5377A61K31/527A61K45/06
CPCA61K31/5377A61K31/527A61K45/06A61K31/519C07D471/20C07D487/14C07D487/20
Inventor STRUM, JAY COPELANDBISI, JOHN EMERSONROBERTS, PATRICK JOSEPHGASTON, RICKY D.GADWOOD, ROBERT C.
Owner G1 THERAPEUTICS INC
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