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Compositions comprising DHODH inhibitors for treatment of acute myelogenous leukemia

A technology of DHODH and acute myeloid system, applied in the direction of drug combination, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problems of unmet medical needs of acute myeloid leukemia

Pending Publication Date: 2022-07-29
RHIZEN PHARM SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] Despite current availability of interventional therapies, acute myeloid leukemia (AML) remains a significant unmet medical need

Method used

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  • Compositions comprising DHODH inhibitors for treatment of acute myelogenous leukemia
  • Compositions comprising DHODH inhibitors for treatment of acute myelogenous leukemia
  • Compositions comprising DHODH inhibitors for treatment of acute myelogenous leukemia

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0146] Preparation of Compound A .

[0147] Intermediate 1: 3'-Butoxy-3-chloro-5-fluorobiphenyl-4-amine :

[0148] 4-Bromo-2-chloro-6-fluoroaniline (0.2 g, 0.89 mmol) and 3-butoxyphenylboronic acid (0.224 g, 1.16 mmol) to prepare the title compound (3'-butoxy-3-chloro-5-fluorobiphenyl-4-amine) (0.190 g). with N 2 The mixture was degassed for 30 minutes, and the mixture was refluxed until both starting materials disappeared, as monitored by TLC. post-processing (H 2 O / AcOEt) and purification gave the desired product (0.19 g) as a yellow solid. 1 H-NMR (δppm, DMSO-d 6 ,400MHz):7.44-7.41(m,2H),7.27(t,J 7.9,1H),7.17-7.10(m,2H),6.81-6.84(m,1H),5.50(s,2H),4.01( t, J 5.3, 2H), 1.72-1.65 (m, 2H), 1.50-1.41 (m, 2H), 0.93 (t, J 7.4, 3H).

[0149] Compound A: 2-(3'-butoxy-3-chloro-5-fluorobiphenyl-4-ylcarbamoyl)benzoic acid

[0150] Intermediate 1 (90 mg, 0.31 mmol) was dissolved in about 2 ml of acetic acid. Phthalic anhydride (90 mg, 0.6 mmol) was added to the mixture an...

Embodiment 1

[0155] Antiproliferative effect of compound A in AML cell lines (MTT assay)

[0156] Compound A was tested in a panel of AML cell lines (U937, HL-60, THP-1, KG-1 and MV411). Cells were plated in 96-well plates and incubated with the desired concentration of Compound A for 72 hours (h). At the end of the incubation period, MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)) was added. The plates were placed on a shaker for 5 minutes to mix the formazan and measure the optical density at 560 nM on a spectrophotometer. Plot data using Graphpad prism for calculating GI 50 concentration.

[0157] Results: All AML cell lines tested were sensitive to Compound A with GI 50 in the range between 2.4 μM and 7.6 μM. (see Table 1).

[0158] Table 1

[0159]

Embodiment 1A

[0161] Antiproliferative effect of Compound A in AML cell lines in the presence of uridine rescue (MTT assay)

[0162] In the absence of uridine (U937, HL-60, THP-1 and MV411 cell lines) or in the presence of uridine (100 μM for U937, HL-60 and MV411 and 100 μM for THP-1 Compound A was tested at 300 μM). Cells were plated in 96-well plates and incubated with the desired concentration of Compound A for 72h. At the end of the incubation period, MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)) was added. The plates were placed on a shaker for 5 minutes to mix the formazan and measure the optical density at 560 nM on a spectrophotometer. Plot data using Graphpad prism for calculating GI 50 concentration.

[0163] Results: Addition of 100 μM or 300 μM uridine caused the activity of Compound A to shift to the right, where GI 50 >10 μM. (See Table 1A).

[0164] Table 1A

[0165]

[0166] in conclusion. Compound A inhibited the growth of AML cell li...

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Abstract

The present invention relates to a method of treating acute myelogenous leukemia (AML). In one embodiment, the present invention relates to a method of treating acute myelogenous leukemia (AML), the method comprising administering a dihydroorotate dehydrogenase (DHODH) inhibitor, alone or in combination with at least one fms-like tyrosine kinase 3 (FLT-3) inhibitor and / or a DNA polymerase inhibitor, to a subject in need thereof.

Description

[0001] Priority Details [0002] The present application claims the benefit of Indian Provisional Application No. 201941042600, filed on October 21, 2019, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to a method of treating acute myeloid leukemia (AML). In one embodiment, the present invention relates to a method of treating acute myeloid leukemia (AML) comprising administering a dihydroorotate dehydrogenase (DHODH) inhibitor alone or in combination with at least one fms-like tyrosine Acid kinase 3 (FLT-3) inhibitors and / or DNA polymerase inhibitors are administered to a subject in need thereof in combination. Background technique [0004] Leukemia is a cancerous disease of the bone marrow and blood. Four types of leukemia can be distinguished: chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia. [0005] The rapidly progressive acute myeloid l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/196A61K31/5377A61K31/7068A61P35/02
CPCA61K31/196A61K31/5377A61K31/7068A61P35/02A61K2300/00A61K31/192A61K31/497A61K45/06
Inventor S·维斯瓦纳达S·K·V·S·瓦卡兰卡
Owner RHIZEN PHARM SA
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