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Dihydroorotate dehydrogenase inhibitors

A solvate, alkyl technology, applied in the field of new compounds, can solve problems such as limited effectiveness

Pending Publication Date: 2021-09-28
JANSSEN BIOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Research efforts aimed at identifying additional inducers of differentiation have had limited success

Method used

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  • Dihydroorotate dehydrogenase inhibitors
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Examples

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preparation example

[0291] Exemplary compounds useful in the methods of the present invention will now be described with reference to exemplary synthetic schemes for their general preparations below and specific examples that follow.

[0292] plan 1

[0293]

[0294] According to Scheme 1, the 1,2,4-triazol-5(4H)-one compound of formula (V) (wherein PG is Bn) was prepared from ethyl 2-(benzyloxy)acetate in three steps. In the first step, 2-(benzyloxy)acetate is prepared by reacting ethyl 2-(benzyloxy)acetate with hydrazine hydrate in a suitable solvent such as EtOH, etc.; at a temperature ranging from 70°C to 85°C base) acetyl hydrazide. Make hydrazide with formula R c -Isocyanates of NCO (where R c for C 1-6 alkyl) in a suitable solvent (eg, water, etc.) to give the corresponding semicarbazides. Subsequent cyclization of semicarbazide with a suitable base such as NaOH in a suitable solvent such as water provides compounds of formula (V) (wherein PG is Bn).

[0295] Compounds of formul...

Embodiment 1

[0359] Example 1: 3-(2-Chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1, 2,4-Triazol-1-yl)-6-fluoro-1-isopropyl-2,3-dihydroquinazolin-4(1H)-one.

[0360]

[0361] Step A: 2-(Benzyloxy)acetohydrazide . To a solution of ethyl 2-(benzyloxy)acetate (55 g, 283.17 mmol) in EtOH (500 mL) was added NH 2 NH 2 ·H 2 O (28.3 g, 566 mmol, 27.5 mL). The mixture was heated to reflux at 78°C and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure to give the title product as a colorless oil (52 g, crude), which was used in the next step without further purification.

[0362] Step B: 3-((benzyloxy)methyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one . To 2-(benzyloxy)acetohydrazide (52 g, 288 mmol) in H at 0 °C 2 Ethyl isocyanate (25.1 g, 346 mmol, 27.9 mL) was added dropwise to the O (500 mL) solution. After the addition, the reaction mixture was stirred at 25°C for 12 hours. Add H to the mixture 2 O (20 mL) and NaOH (57.7 g, 1.4...

Embodiment 2

[0372] Example 2: 3-(2-Chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1, 2,4-Triazol-1-yl)-6-fluoro-1-isopropyl-2-methyl-2,3-dihydroquinazolin-4(1H)-one .

[0373]

[0374] Step A: 7-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) - 3-(2-Chloro-6-fluorophenyl)-6-fluoro-1-isopropyl-2-methyl-2,3-dihydroquinazolin-4(1H)-one . To 4-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N To a mixture of -(2-chloro-6-fluorophenyl)-5-fluoro-2-(isopropylamino)benzamide (100 mg, 179.86 μmol) in EtOH (10 mL) was added acetaldehyde (158 mg, 3.60 mmol, 202 μL), then in N 2 Under the atmosphere, the mixture was stirred at 80°C for 24 hours. Acetaldehyde (79 mg, 1.80 mmol, 101 μL) was added to the mixture, and the mixture was stirred at 80° C. for 12 hours. Acetaldehyde (79 mg, 1.80 mmol, 101 μL) was added to the mixture, and the mixture was stirred at 80° C. for 48 hours. The mixture was poured into water (...

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Abstract

Disclosed are compounds, compositions and methods for treating diseases, disorders, or medical conditions that are affected by the modulation of DHODH. Embodiments of such compounds are represented by Formula (I) as follows: 5 wherein R1, R2, R3, R4, R5a, R5b, X and Y, are defined herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of priority to US Provisional Patent Application 62 / 802,319, filed February 7, 2019, which is incorporated herein by reference in its entirety and for all purposes. technical field [0003] The present invention relates to novel compounds that are inhibitors of dihydroorotate dehydrogenase (DHODH). These compounds are useful in the treatment of diseases, disorders or medical conditions for which there is an advantage in inhibiting DHODH. The present invention also relates to pharmaceutical compositions comprising one or more of such compounds, methods of making such compounds and compositions, and the use of such compounds or pharmaceutical compositions for the treatment of cancer and autoimmunity and inflammation Use of the method for diseases, syndromes and disorders. Background technique [0004] Acute myeloid leukemia (AML) is a clonal disease of the blood and bone marrow cause...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4427A61K31/519A61K31/517C07D401/14C07D403/04C07D471/04A61P35/00A61P29/00A61K31/4353A61K31/4725
CPCC07D403/04C07D471/04C07D401/14A61K31/4725A61K31/517A61K31/519A61K31/4353A61K31/4427A61P35/00A61P29/00A61P37/06C07D401/04C07D401/10C07D403/10
Inventor J·西萨尔S·库杜克张筑明王爱华Y·西莫內
Owner JANSSEN BIOTECH INC
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