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Pyridin-sulfonamide compounds for treatment of conditions related to interleukin 1 beta

A compound, halogen technology, applied in the field of new pyridine-sulfonamide compounds, which can solve the problem of poor properties of disease modifiers

Pending Publication Date: 2021-08-27
ALLINKY BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, they are poorly characterized as disease modifiers and new therapeutic approaches are needed

Method used

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  • Pyridin-sulfonamide compounds for treatment of conditions related to interleukin 1 beta
  • Pyridin-sulfonamide compounds for treatment of conditions related to interleukin 1 beta
  • Pyridin-sulfonamide compounds for treatment of conditions related to interleukin 1 beta

Examples

Experimental program
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Effect test

preparation example Construction

[0109] Compound Preparation – X 1 for NR y

[0110] The substituted pyridine-sulfonamides of formula II and IIa of the invention are generally prepared via intermediate C, which is prepared as described in Scheme 1:

[0111]

[0112] plan 1

[0113] In the first step, 5,6-dichloropyridine-3-sulfonamide A was alkylated to give intermediate compound B, which was then converted to compound C by Buchwald reaction under microwave irradiation.

[0114] According to R x , R y and R 3 properties, the preparation of intermediate C may require additional synthetic transformations, such as the protection / deprotection reactions described in Scheme 1.

[0115] depends on x 1 Compounds of the invention can be prepared according to Scheme 2b, 2c or 2d.

[0116]

[0117] Scheme 2b - Synthesis of type IIb compounds

[0118] Under microwave irradiation, the Pd-catalyzed Suzuki reaction of the intermediate compound C with the corresponding boronic acid at 150°C yields type IIb ...

Embodiment 1

[0131] Example 1 - Synthesis of Intermediate B, where R x and R y For methyl: N,N-dimethyl-5,6-dichloropyridine-3-sulfonamide

[0132] To commercially available 5,6-dichloropyridine-3-sulfonamide A (1eq) and K 2 CO 3 (2eq) To a suspension in anhydrous DMF (1ml / eq) was added a solution of iodomethane (2eq) in DMF (5ml / mmol), and the resulting mixture was stirred at room temperature until the reaction was complete (overnight, TLC controlled ). Then the solvent was evaporated and ethyl acetate was added. The organic mixture was washed twice with water, and the organic layer was dried over magnesium sulfate. After evaporation of the solvent, the resulting crude product was pure enough to be used in Example 2 without purification (yellow solid, 95% yield).

Embodiment 2

[0133] Example 2 - Synthesis of Intermediate C, where R x and R y is methyl, Z 1 ,Z 2 ,Z 3 is CH, L is O, and R 3 for the opposite Cl: N,N-dimethyl-5-chloro-6-(4-(4-chlorophenoxy)-N-piperidinyl)-pyridine-3-sulfonamide

[0134] A mixture of the compound (1eq) obtained in Example 1, commercially available 4-(4-chlorophenoxy)piperidine hydrochloride (1.2eq) and TEA (2.2eq) in EtOH (4.8ml / mmol) First heated at 80°C for 5 minutes, then held at 120°C for 30 minutes under microwave irradiation (200W) (HPLC control). The solvent was then evaporated and ethyl acetate was added; the organic mixture was washed twice with water and the combined organic layers were dried over magnesium sulfate. After evaporation of the solvent, the obtained crude product was pure enough to be used in subsequent examples without purification (clear brown solid, yield 91%).

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Abstract

The present invention relates to a novel class of pyridine-sulfonamide compounds and to compositions comprising the same. The compounds and compositions are useful as medicaments in the treatment of diseases responsive to inhibition of IL-1beta, such as non-alcoholic steatohepatitis (NASH) and idiopathic pulmonary fibrosis (IPF).

Description

technical field [0001] The present invention relates to a new class of pyridine-sulfonamide compounds and compositions comprising them. The compounds and compositions (eg, pharmaceutical compositions) of the present invention are useful as medicaments for the treatment of interleukin 1β (IL-1β)-related diseases such as inflammatory and fibrotic diseases. Background technique [0002] IL-1 has been shown to be involved in a wide range of human pathologies ranging from autoinflammatory diseases to rheumatoid arthritis, and IL-1 blockers (IL-1Ra, Anakinra; anti-IL-1b monoclonal Clonal antibodies [mAb], canakinumab; and anti-IL-1a, MABp1) have been approved for clinical use, or are being evaluated in some of these diseases (Dinarello, 2009; Gabay et al., 2010; Garlanda et al., 2013; Udalova et al., 2016). [0003] IL-1 has long been associated with inflammation and innate immunity. It is now evident that this cytokine plays diverse roles in shaping and directing innate immuni...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14C07D405/04C07D405/14A61K31/497A61K31/4545A61P1/16
CPCC07D401/04C07D401/14C07D405/04C07D405/14A61K31/4545A61P1/16A61P11/00A61P29/00A61P9/00C07D213/70
Inventor 米格尔·维嘉埃斯特·卡拉斯科帕特里夏·戈麦兹佩德罗·坎普斯胡安·戈麦兹-雷诺胡安·耶苏斯·佩雷斯安吉尔·梅塞格
Owner ALLINKY BIOPHARMA
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