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Substituted quinazolines

A technology of metabolic reactions, compounds, applied in extracellular fluid diseases, drug combinations, organic chemistry, etc., can solve the problem of unawareness of anti-megakaryocyte potential and other issues

Inactive Publication Date: 2009-10-14
SHIRE PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this disclosure fails to recognize a completely independent anti-megakaryocyte potential (decrease in platelet count) that may be associated with certain analogs

Method used

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  • Substituted quinazolines
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] IC of anagrelide and certain 3-alkyl substituted analogues as PDE III inhibitors and antimegakaryocyte agents 50 Comparative data.

[0154] The table below shows the comparative activity of anagrelide and its analogs with respect to their effects on megakaryopoiesis (the process of producing platelets) and PDE III (the inhibition of which leads to adverse cardiovascular reactions).

[0155] Comparison of In Vitro Evaluation of Potential Therapeutic Effects and Adverse Effects of Anagrelide and Its Analogues

[0156] compound

IC against megakaryocytes 50

(thrombocytopenia activity)

IC for PDE III inhibition 50

(cardiovascular effects)

Benefit rate (therapeutic effect

compared with adverse effects)

Anagra

3-Hydroxyanagrelide

27nM

44nM

32nM

0.7nM

*0.024∶1

0.016∶1

3,3-Dimethyl anagrelide

164nM

166nM

1∶1

3-Spirocyclopropyl anagrelide

547nM

797nM

1.45∶1...

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Abstract

This invention relates to the discovery of 3-and 5-substituted analogues of the selective platelet lowering agent anagrelide with reduced potential for cardiovascular side-effects which should lead toimproved patient compliance and safety in the treatment of myeloproliferative diseases. More specifically, the present invention relates to certain imidazoquinazoline derivatives which have utility as platelet lowering agents in humans. The compounds of the present invention function by inhibiting megakaryocytopoeisis and hence the formation of blood platelets.

Description

technical field [0001] The present invention relates to 3- and 5-substituted analogs of the selective platelet lowering agent anagrelide, which have the potential to reduce cardiovascular side effects and lead to improved patient compliance and safety in the treatment of myeloproliferative diseases. More particularly, the present invention relates to certain imidazoquinazoline derivatives that have utility as platelet lowering agents in humans. The compounds of the present invention act by inhibiting megakaryocytopoiesis and thereby inhibiting platelet formation. Background technique [0002] Anagrelide hydrochloride ( ) are novel orally administered imidazoquinazolines that selectively reduce platelet counts in humans and are used in the treatment of myeloproliferative disorders (MPD) such as essential thrombocythemia (ET) For this purpose, elevated platelet counts in such diseases may place the patient at increased risk of thrombosis. The chemical structure of anagreli...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/505A61P43/00
CPCC07D487/04A61P43/00A61P7/02A61K31/505
Inventor 理查德·富兰克林伯纳德·戈尔丁
Owner SHIRE PLC
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