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PDE9 inhibitors for treating sickle cell disease

A composition and drug technology, applied in the direction of extracellular fluid diseases, medical preparations containing active ingredients, blood diseases, etc.

Pending Publication Date: 2021-06-18
IMARA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, due to these challenges, many patients are given subeffective doses of HU

Method used

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  • PDE9 inhibitors for treating sickle cell disease
  • PDE9 inhibitors for treating sickle cell disease
  • PDE9 inhibitors for treating sickle cell disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0184] Embodiment 1. Synthesis and preparation of compound 1

[0185] Compound 1 is 6-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H- disclosed in WO 2013 / 053690 Enantiomers of imidazo[1,5-a]pyrazin-8-one. 6-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]- Compound 1 was prepared by chiral selective purification of 3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one. Compound 1 can also be prepared using the methods disclosed in WO 2017 / 005786 (the content of which is incorporated herein by reference in its entirety).

[0186]

[0187] The compound 1 API product used in ongoing clinical development is an immediate-release tablet. Coatings can be used to ensure consistency of appearance across tablet strengths and placebo.

[0188] Early clinical studies were performed by directly filling compound 1 drug substance into opaque white gelatin capsules (powder in capsule, PIC) without excipients or processing aids. Excipient blended tabl...

Embodiment 2

[0210] The development of embodiment 2.300mg tablet

[0211] Development activities for 300mg tablets showed that the addition of hydroxypropyl cellulose (HPC-SSL-SFP) and increasing the percentage level of microcrystalline cellulose (Avicel PH200) resulted in increased tablet hardness and reduced loss during friability testing. Accept the result. However, adding HPC has increased the average disintegration time from less than one minute to about 37 minutes. Various percentage levels of HPC-SSL-SPF were evaluated in the 300 mg tablet formulation. The formulations evaluated are shown in Table 2 below.

[0212] Table 2. Optimization of HPC-SSL-SPF percentage levels used in formulations.

[0213]

[0214]

[0215] Various formulations of hydroxypropylcellulose (HPC-SSL-SFP) at different percentage levels were evaluated to determine which formulation produced acceptable results. Table 3 below shows the formulation used to develop the 300 mg film-coated tablet.

[0216...

Embodiment 3

[0254] Example 3. Compound 1 reduces leukocyte adhesion and activation

[0255] Polymorphic monocytes (PMNs), especially neutrophils, play a key role in the pathogenesis of sickle cell disease (SCD), and activated neutrophils have been shown to adhere to each other, platelets, and vascular endothelium Attachment is stronger. Recently, various drugs targeting leukocytes bound to endothelial cells have been developed in clinical studies of patients. Compound 1 was able to increase the expression of fetal hemoglobin in patient-derived cells and a mouse model of SCD, and reduce vascular occlusion in a mouse model of SCD. In this example, the ability of Compound 1 to reduce the adhesive properties of neutrophils in SCD patients and to reduce sE-selectin (sE-Sel) and PMN activation markers in a murine SCD model was investigated.

[0256] Endothelial E-selectin (E-Sel) slows leukocyte rolling followed by immobilized adhesion and migration of activated leukocytes. Plasma levels o...

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Abstract

The present disclosure relates to PDE9 inhibitors, and pharmaceutical compositions comprising the PDE9 inhibitors. In one aspect, an oral pharmaceutical composition comprises about 100 mg to about 300 mg of 6-[(3S,4S)-4-methyl-l-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[l,5-a]pyrazin-8-one (Compound 1), or a pharmaceutically acceptable salt, solvate, or polymorph thereof; a filler selected from about 4% to about 6% by weight of pre-gelatinized starch and / or from about 15% to about 50% microcrystalline cellulose; and a processing aid selected from about 1% to about 2.5% by weight of colloidal silicon dioxide and / or from about 0.5% to about 1.5% by weight of magnesium stearate, the pharmaceutical composition is in the form of a solid tablet suitable for administration to a patient. In some embodiments, the composition has a friability of no more than about 0.3% weight loss and a has a disintegration time of less than about 15 minutes, as determined by USP friability and USP disintegration tests.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 725,725, filed August 31, 2018, the contents of which are hereby incorporated by reference in their entirety. technical field [0003] The present disclosure relates to methods of making and using pharmaceutical compositions comprising cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 9 inhibitors (hereinafter referred to as PDE9 inhibitors). Background technique [0004] Sickle cell disease (SCD, also known as sickle cell anemia (SCA)) is an inherited disorder leading to a vaso-occlusive process responsible for a majority of deaths in SCD patients. SCD disease is caused by point mutations in the hemoglobin (HBB) gene that produce abnormal sickle-shaped hemoglobin (HbS or HbSS), which polymerizes and produces hard and sticky sickle-shaped red blood cells. Sickled RBCs lead to chronic inflammation, increased cell adhesion, o...

Claims

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Application Information

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IPC IPC(8): A61K31/4985C07D487/04
CPCC07D487/04A61K31/4985A61K31/17A61K9/2054A61K9/2059A61P7/00A61K2300/00A61K9/2009A61K9/2095A61K9/2866A61K9/2013A61K31/506A61P7/06A61K9/0053A61K9/284
Inventor 爱德华·乔治·卡拉马伊黛博拉·林恩·莱特黑德·多宾斯迈克尔·保罗·德哈特詹姆斯·麦克阿瑟符施茵
Owner IMARA INC