Pyrrolopyridazines as potassium ion channel inhibitors

A compound and enantiomer technology, applied in the field of pyrrolopyridazine compounds as potassium ion channel inhibitors, can solve the problems of neurotoxicity and gastrointestinal discomfort, and achieve the effect of reducing risks

Active Publication Date: 2015-10-28
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although these drugs are effective in combating graft rejection, cyclosporin A and FK-506 are known to cause a variety of adverse side effects, including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort

Method used

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  • Pyrrolopyridazines as potassium ion channel inhibitors
  • Pyrrolopyridazines as potassium ion channel inhibitors
  • Pyrrolopyridazines as potassium ion channel inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0393] 5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridine-3-sulfonamide

[0394]

[0395]

[0396] According to Fang et al., J. Med. Chem. , 53:7967-7978 (2010), with 2-methyl-1-pyrroline (0.831 g, 10.0 mmol, commercially available), NCS (10.7 g, 80.0 mmol) and NaOMe in MeOH (3M, 20 mL, 60.0 mmol) to synthesize commercially available methyl 3-chloro-1H-pyrrole-2-carboxylate (1.50 g, 94.0%, yellow solid). LCMS ( Condition 6 ): retention time 1.71 min, [M+1] = 160.10. 1 H NMR (400 MHz, CDCl 3 ) δ 3.90 (s, 3 H), 6.25 (t, J = 3.0 Hz, 1 H), 6.86 (t, J = 3.0 Hz, 1 H), 9.17 (br s, 1 H).

[0397] Synthesis of Monochloramine Reagent

[0398] Ammonium chloride (3.00 g, 56.1 mmol) was dissolved in diethyl ether (110 mL) and the solution was cooled to -5°C. Concentrated ammonium hydroxide (28 M, 4.70 mL, 120 mmol) was added dropwise. Commercial bleach (2 M, 72.0 mL, 0.144 mol) as sodium hypochlorite was added via the addition funnel over 15 min. The react...

Embodiment 2

[0418] N-((5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)sulfonyl)acetamide

[0419]

[0420]

[0421] CH 2 Cl 2(2 mL) to the suspension was added triethylamine (0.0140 mL, 0.0990 mmol), followed by acetyl chloride (0.00351 mL, 0.0490 mmol). The reaction mixture was stirred at ambient temperature for 12 h. The reaction mixture was quenched by adding water and washed with CH 2 Cl 2 (2 x 10 mL) extraction. The combined extracts were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue was analyzed by preparative HPLC ( Condition 10, Purification as described in General Methods) gave N-((5-(4-(benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridine-3 as a yellow solid -yl)sulfonyl)acetamide (8.00 mg, 47.9%). LCMS ( Condition 2 ): retention time 1.89 min, [M+1] = 497.6. HPLC ( Condition 15 ): retention time 20.82 min, purity 98.40%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.85 (s, 3 H), ...

Embodiment 3

[0423] N-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)acetamide

[0424]

[0425]

[0426] According to the method described in Example 1 for the preparation of 5-(4-(benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)-N-(tert-butyl)pyridine -3-sulfonamide method using N-benzyl-2,5-dichloropyrrolo[1,2-b]pyridazin-4-amine (150 mg, 0.513 mmol), 5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (226 mg, 1.03 mmol, commercially available), Pd(TPP) 4 (59.3 mg, 0.0510 mmol) and Cs 2 CO 3 (502 mg, 1.54 mmol) prepared 2-(5-aminopyridin-3-yl)-N-benzyl-5-chloropyrrolo[1,2-b]pyridazin-4-amine (100 mg, 47.3 %, off-white solid). The residue was purified by combiflash (REDISEP®, silica gel, 12 g, 2% MeOH / DCM) and the product obtained was further purified by washing with diethyl ether. LCMS ( Condition 4 ): retention time 2.00 min, [M+1] = 350.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 4.67 (d, J = 6.0 Hz, 2 H), 5.45 (br s, 2 H), 6.04 (s, 1 H),...

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Abstract

A compound of formula (I) wherein A, R1, R3, and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.

Description

[0001] 【CROSS-REFERENCE TO RELATED APPLICATIONS】 [0002] This application claims priority to US Provisional Application No. 61 / 775,742, filed March 11, 2013, the contents of which are incorporated herein by reference. 【Technical field】 [0003] The present invention provides potassium channel function inhibitors (especially voltage-gated K + Channel K v Subfamily 1 inhibitors, more especially K v 1.5 channels (which has been combined with ultra-fast activation delay rectification K + Current I Kur association) and / or K v 1.3 channels and / or K v 1.1 channel inhibitors) pyrrolopyridazine compounds and pharmaceutical compositions containing these compounds. The present invention further provides the use of these compounds for the treatment and prevention of arrhythmias, I Kur - Methods of related diseases and other diseases mediated by ion channel function. 【Background technique】 [0004] It is believed that the ultra-fast activation delayed rectification K + Current ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P9/00A61K31/5025
CPCC07D487/04A61K31/5025A61P1/00A61P11/00A61P25/06A61P25/08A61P25/28A61P29/00A61P37/00A61P9/00A61P9/06A61P9/12A61P3/10
Inventor H.芬利A.K.阿迪塞钱P.古纳加J.洛德P.斯里尼瓦素
Owner BRISTOL MYERS SQUIBB CO
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