Methods and compositions for the treatment and management of hemoglobinopathy and anemia

A technology for hemoglobinopathies and anemias, applied in the field of treatment, prevention and/or control of hemoglobinopathies and other anemias, which can solve problems such as unproven efficacy

Inactive Publication Date: 2007-02-14
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the efficacy of this compound has not been proven

Method used

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  • Methods and compositions for the treatment and management of hemoglobinopathy and anemia
  • Methods and compositions for the treatment and management of hemoglobinopathy and anemia
  • Methods and compositions for the treatment and management of hemoglobinopathy and anemia

Examples

Experimental program
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specific example

[0161] Specific examples of compounds have the formula:

[0162]

[0163] in:

[0164]One of X and Y is C=O, the other of X and Y is C=O or CH 2 ;

[0165] R 6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chlorine or fluorine;

[0166] R 7 is m-phenylene or p-phenylene or -(C n h 2n )-, wherein the value of n is 0-4;

[0167] R 8 and R 9 Each independently is hydrogen or an alkyl group of 1 to 8 carbon atoms, or R 8 and R 9 Linked together is tetramethylene, pentamethylene, hexamethylene, or -CH 2 CH 2 x 1 CH 2 CH 2 -, where X 1 is -O-, -S-, or -NH-; and

[0168] R 10 is hydrogen, an alkyl group of 1 to 8 carbon atoms, or a phenyl group.

[0169] Preferred immunomodulatory compounds of the invention are 4-(amino)-2-(2,6-dioxo(3-piperidinyl))-isoindoline-1,3-dione and 3-(4- Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. This compound can be obtained by standard synthetic methods (see, eg, US Patent 5,635,517, which is incorporated here...

Embodiment 1

[0309] 6.1. Example 1: Differentiation of bone marrow-derived CD34+ hematopoietic progenitor cells into dendritic cells demonstrates upregulation of erythroid-specific genes

[0310] BM-CD34 + Cells were obtained from Cambrex (East Rutherford, NJ) and cultured in BIT 95000 (StemCell Teclmologies, UK) in Iscove's MDM for 6 days. In order to study the effect of 4-(amino)-2-(2,6-dioxo(3-piperidinyl))-isoindoline-1,3-dione on dendritic cells, in the presence or CD34+ blasts were cultured for 6 days in the absence of 4-(amino)-2-(2,6-dioxo(3-piperidinyl))-isoindoline-1,3-dione. After 6 days in culture, the phenotypic characteristics of the cells for erythrocyte markers (CD36, CD71, glycophorin A and fetal hemoglobin) were determined by flow cytometry. Gene expression was monitored on days 1, 3, and 6 of CD34+ differentiation by microarray analysis ( figure 1 ).

[0311] RNA purification and microarray analysis. Using RNAeasy (Qiagen) from CD34 +Total RNA is isolated from the ...

Embodiment 2

[0316] 6.2. Example 2: CD34 + cells differentiate into red blood cells

[0317] Differentiation of bone marrow (BM) CD34+ hematopoietic progenitors: BM-CD34+ progenitors were obtained from Cambrex and cultured in Iscove's MDM containing BIT 95000 (serum replacement; StemCell Teclmologies) in the presence of growth factors. During the first 6 days, CD34 + Cells were expanded with SCF (100ng / ml), Flt3-L (100ng / ml) and IL-3 (20ng / ml) and passed through in the presence of SCF (50ng / ml) and Epo (2U or 4U / ml) Differentiate into erythrocytes by culturing for 6 days. To study IMiD TM In the presence or absence of 4-(amino)-2-(2,6-dioxo(3-piperidinyl))-isoindoline-1,3-dione or 3-(4- In the case of amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione, differentiate CD34+ progenitor cells for 6 days ( Image 6 ).

[0318] Flow cytometry: Surface antigen expression was analyzed by flow cytometry (FACScan, Coulter) after 6 days of culture. Cells were double-stained on day 6 us...

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Abstract

The present invention relates to immunomodulatory compounds, in particular a class known as IMiD TM , more specifically the compounds 4-(amino)-2-(2,6-dioxo(3-piperidinyl))-isoindoline-1,3-dione and 3-(4- Use of amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for use in CD34 + The expression of genes for fetal hemoglobin, genes essential for erythropoiesis, and genes encoding alpha hemoglobin stabilizing proteins is induced in the cell population. These compounds are useful in the treatment of hemoglobinopathy, such as sickle cell anemia or beta-thalassemia, or anemia caused by disease, surgery, accident, or the introduction or ingestion of toxins, poisons or drugs.

Description

[0001] This application claims priority to US Provisional Application 60 / 526,910, filed December 2, 2003, which is hereby incorporated by reference in its entirety. 1. Field of invention [0002] The present invention relates to a method for the treatment, prevention and / or management of hemoglobinopathies (such as sickle cell anemia) and other anemias (such as disease- or drug-induced anemia), which method comprises the administration of an IMiD TM thalidomide analog members, specifically IMiD TM 4-(amino)-2-(2,6-dioxo(3-piperidinyl))-isoindoline-1,3-dione (also known as α-(3-aminophthal Imino) glutarimide; Celgene Corporation) and 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione (also known as 3-(4'aminoisoindolin-1'-one)-1-piperidine-2,6-dione; Celgene Corporation), and pharmaceutical compositions comprising such compounds. 2. Background of the invention [0003] 2.1. Sickle cell anemia and other hemoglobinopathies [0004] Sickle cell anemia ("SCA") is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/454A61KA61K45/06C12N5/07C12N5/074C12N5/0789
CPCA61K45/06A61K38/1816A61K38/18A61K38/19A61K31/454A61P35/00A61P37/02A61P43/00A61P7/00A61P7/06A61K2300/00A61K31/4523
Inventor 劳瑞·穆塔-德帕塞维尔凯乐·W·H·陈海伦·布拉迪
Owner CELGENE CORP
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