Deuterated pyridazinone compound and application thereof

A technology of compounds and uses, which is applied in the field of preparation of drugs for the treatment of metabolic-related diseases, and can solve problems such as restrictions on the use of thyroid hormones

Pending Publication Date: 2022-02-18
HAISCO PHARMA GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To date, the therapeutic use of naturally occurring thyroid hormones has been limited by adverse side effects associated with hyperthyroidism, especially cardiovascular toxicity

Method used

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  • Deuterated pyridazinone compound and application thereof
  • Deuterated pyridazinone compound and application thereof
  • Deuterated pyridazinone compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] (R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d] Pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Compound 1)

[0065] (R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl )oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitril (compound 1)

[0066]

[0067]The first step: ethyl 1-(methyl-d3)-2-oxocyclopentane-1-carboxylate (1b)

[0068] ethyl 1-(methyl-d3)-2-oxocyclopentane-1-carboxylate(1b)

[0069] Add 1a (0.65Kg, 4.16mol) in a 10L three-necked flask, dissolve in acetone (6000mL), add potassium carbonate (2.00Kg, 3.32mol) while stirring, and add deuteroiodomethane (1.80Kg, 12.41mmol) dropwise at room temperature , stirred at room temperature for 100 h after dropping, filtered with suction, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1) to obtain the title compound 1b (580.10 g, 90%).

...

Embodiment 2

[0106] (R)-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazine-4 -yl)oxyl]phenyl-2,6-d2)-3,5-dioxa-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (compound 2 )

[0107] (R)-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl -2,6-d2)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (compound 2)

[0108]

[0109] The first step: 1-(5-methylcyclopent-1-en-1-yl)pyrrolidine (2c)

[0110] 1-(5-methylcyclopent-1-en-1-y1)pyrrolidine (2c)

[0111] 2a (6.05g, 61.22mmol) was dissolved in toluene (70mL), 2b (6.53g, 91.84mmol) and p-toluenesulfonic acid monohydrate (1.16g, 6.12mmol) were added, and the reaction was carried out under reflux at 130°C for 16h. Cool to room temperature, and distill under reduced pressure to obtain the title compound 2c (5.01 g, 65%). No purification required.

[0112] The second step: 1,4-dichloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyridazine (2e)

[0113] 1,4-dic...

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PUM

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Abstract

The invention discloses a deuterated pyridazinone compound as shown in a formula (I), a stereoisomer, a solvate, a co-crystal or pharmaceutically acceptable salt and a composition thereof, and a corresponding preparation method, and provides application of the compound in preparation of medicines for treating thyroid hormone receptor mediated diseases. In the formula (I), R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from H and D respectively and are not H at the same time.

Description

technical field [0001] The invention relates to a deuterated pyridazinone compound and its stereoisomers, solvates, co-crystals, pharmaceutically acceptable salts, and uses thereof in the preparation of medicines for treating metabolic-related diseases. Background technique [0002] Thyroid hormones are critical for normal growth and development and for maintaining metabolic balance. Thyroid hormones are produced by the thyroid gland and are secreted into the circulation in two different forms: 3,5,3',5'-tetra-iodo-L-thyronine (T4) and 3,5,3' - Tris-iodo-L-thyronine (T3). Although T4 is the predominant form secreted by the thyroid, T3 is the more physiologically active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues but mainly in the liver and kidney. The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs). TRs belong to a superfamily known as nuclear receptors. Thyroid hormone receptors are...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/53A61P3/04A61P3/10A61P3/06A61P1/16A61P9/10A61P9/00A61P35/00A61P5/14
CPCC07D403/12A61P3/04A61P3/10A61P3/06A61P1/16A61P9/10A61P9/00A61P35/00A61P5/14
Inventor 李瑶王文晶张国彪任磊赵剑飞张晨余彦倪佳严庞科
Owner HAISCO PHARMA GRP INC
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