Pyrrolopyridazine compound

A technology of pyridazine derivatives and pyrrole, applied in the field of pyrrolopyridazine derivatives, can solve problems such as ulcer recurrence

Inactive Publication Date: 2003-06-04
SANKYO CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the above agents have excellent therapeutic effects on ulcerative diseases, ulcers may recur after interruption of treatment

Method used

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  • Pyrrolopyridazine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] 3-Acetoxymethyl-7-(4-fluorobenzyloxy)-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d ]Pyridazine

[0152] To 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d at room temperature ] A solution of 0.679 g (2.00 mmol) of pyridazine in acetic acid (40 ml) was added with 6.58 g (12.0 mmol) of ammonium cerium(IV) nitrate, and then stirred at 60°C for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 1 / 1). The obtained oil was crystallized from hexane to obtain 0.225 g (28%) of the title compound as light yellow crystals. .

[0153] Melting point: 122-123°C

[0154] Mass spectrum (CI, m / z): 398 (M + +1).

[0155] NMR spectroscopy (CDCl 3 , Δppm): 0.13-0.20 (m...

Embodiment 2

[0157] 7-(4-Fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d] Pyridazine

[0158] To 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d at room temperature ] A solution of 67.9 g (200 mmol) of pyridazine in acetic acid (800 ml) was added with 329 g (600 mmol) of ammonium cerium(IV) nitrate, followed by stirring at 55°C for 8 hours. Water was added to the reaction mixture, extracted with ethyl acetate, the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, methanol (500 ml) and 2N lithium hydroxide aqueous solution (160 ml) were added to the residue, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was neutralized with 1N hydrochloric acid, methanol was distilled off under reduced pressure, and extracted with chloroform. The extract was washed with saturated brine, and then dried ...

Embodiment 3

[0164] 7-(4-Fluorobenzyloxy)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridin Oxazine

[0165] To 7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2, 3-d] A solution of 64.3 g (181 mmol) of pyridazine in dichloromethane (900 ml) was added with 472 g (5.43 mol) of activated manganese dioxide, and then stirred at room temperature for 18 hours. The reaction mixture was filtered through Celite (trade name), the filtrate was concentrated under reduced pressure, and the resulting crude crystals (45.7 g) were washed with ethyl acetate and hexane to obtain 44.3 g (69%) of the title compound as pale yellow crystals.

[0166] Melting point: 138.5-139.5°C

[0167] Mass spectrum (CI, m / z): 354 (M + +1).

[0168] NMR spectroscopy (CDCl 3 , Δppm): 0.19-0.26 (m, 1H), 0.40-0.47 (m, 1H), 0.71-0.78 (m, 1H), 0.84-0.91 (m, 1H), 0.92 (d; J=5.9Hz, 3Hz ), 2.75(s, 3Hz), 4.19(dd; J=14.6Hz, 7.1Hz, 1H), 4.35(dd; J=14.6Hz, 6.6Hz, 1H), 5.6...

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Abstract

A pyrrolopyridazine compound represented by the general formula (I) or a pharmacologically acceptable salt thereof. (In the formula, R<1> is C2-6 alkenyl, C2-6 halogenoalkenyl, optionally substituted C3-7 cycloalkyl, or optionally substituted C1-6 alkyl substituted by C3-7 cycloalkyl; R<2> is C1-6 alkyl; R<3> is hydroxymethyl, C2-6 aliphatic acyloxymethyl, optionally substituted (C6-10 aryl)carbonyloxymethyl, (C1-6 alkoxy)carbonyloxymethyl, formyl, carboxy, (C1-6 alkoxy)carbonyl, or optionally substituted (C6-10 aryl)oxycarbonyl; R<4> is optionally substituted C6-10 aryl; and A is imino, oxygen, or sulfur.) The pyrrolopyridazine compound is highly effective in inhibiting the secretion of gastric hydrochloric acid, protecting the gastric mucosa, and the like. It is useful as a medicine, especially a preventive / remedy for ulcerative diseases.

Description

Technical field [0001] The present invention relates to a pyrrolopyridazine derivative or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing a pyrrolopyridazine derivative as an effective ingredient (especially a preventive or therapeutic composition for ulcer disease), a pyrrolopyridazine Use of an azine derivative or a pharmacologically acceptable salt thereof in the manufacture of a pharmaceutical composition (especially a preventive or therapeutic composition for ulcer disease), or a method for preventing or treating a disease (especially ulcer disease), so The method includes administering a pharmacologically effective amount of a pyrrolopyridazine derivative or a pharmacologically acceptable salt thereof to warm-blooded animals (especially humans). Background technique [0002] It has been thought that peptic ulcers will occur when there is an imbalance between the attack factors and the defense factors on the gastric mucosa. Suppressing th...

Claims

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Application Information

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IPC IPC(8): A61K31/5025A61P1/04C07D207/00C07D237/00C07D487/04
CPCA61K31/5025C07D487/04A61P1/04A61P31/04
Inventor 岩渕晴男萩原昌彦柴川信彦松言圭二藤原宽
Owner SANKYO CO LTD
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