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N-substituted-N'-substituted urea derivative and use thereof as TNF-Alpha production inhibitor

A technology of urea derivatives and substituted urea, applied in the field of new N-substituted-N'-substituted urea derivatives, can solve problems such as tissue disorder and deterioration

Inactive Publication Date: 2004-05-05
SANTEN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] TNF-α (Tumor Necrosis Factor-α: Tumor Necrosis Factor-α) is currently recognized as a cytokine that is widely involved in biological defense and immune mechanisms, but continuous and excessive production of TNF-α can cause tissue disorders and become the cause of various diseases. cause or main cause of deterioration

Method used

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  • N-substituted-N'-substituted urea derivative and use thereof as TNF-Alpha production inhibitor
  • N-substituted-N'-substituted urea derivative and use thereof as TNF-Alpha production inhibitor
  • N-substituted-N'-substituted urea derivative and use thereof as TNF-Alpha production inhibitor

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0088] (1S)-1-Benzyl-2-(4-methyl-piperazin-1-yl)ethanamine (reference compound 1-1)

[0089]

[0090] Under a nitrogen atmosphere, lithium aluminum hydride (531 mg) was suspended in anhydrous ether (14 ml) while ice-cooling, and 1-[(2S)-2-amino-3-phenylpropionyl]-4-methanol was added dropwise A solution of piperazine (1.48g) in anhydrous tetrahydrofuran (7ml). Stir at room temperature for 4 hours. Under ice-cooling, ethyl acetate was slowly added dropwise to the reaction solution until no foaming occurred. Then, 2N aqueous sodium hydroxide solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (reference compound 1-1, 1.25 g).

[0091] [α] D20 +9.1° (c=1.0, chloroform)

[0092] IR (Film, cm-1) 3288, 2936, 2795, 1601, 1495, 1455, 1374, 1283, 1166, 1013

reference example 2

[0094] 3-(1-pyrrolidinyl)propylamine (reference compound 2-1)

[0095]

[0096] N-[3-(1-Pyrrolidinyl)propyl]phthalimide (729 mg) and hydrazine monohydrate (284 mg) were dissolved in methanol (9 ml), and heated under reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and 4N aqueous sodium hydroxide solution was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (reference compound 2-1, 216 mg).

[0097] IR (Film, cm-1) 3283, 2932, 2874, 2786, 1584, 1460, 1386, 1350, 1293, 1203, 1145, 877

[0098] The following compounds were obtained in the same manner as in Reference Example 2.

[0099] 3-(1-piperidinyl)propylamine (reference compound 2-2)

[0100] IR (Film, cm-1) 3286, 2933, 2853, 1592, 1469, 1442, 1124

[0101] ·[(3RS)-1-Methyl-3-piperidinyl]methylamine (reference compound 2-3)

[0102...

reference example 3

[0107] 2-(1-Homopiperidinyl)ethylamine 2 hydrochloride (reference compound 3-1)

[0108]

[0109] To a solution of N-(tert-butoxycarbonyl)-2-(1-homopiperidinyl)ethylamine (2.31 g) in diethyl ether (5 ml) was added 4N hydrogen chloride in ethyl acetate (24 ml) under a nitrogen atmosphere. After stirring at room temperature for 15 minutes, the precipitated substance was collected by filtration to obtain the title compound as crystals (reference compound 3-1, 1.59 g).

[0110] mp 162~173℃

[0111] IR (KBr, cm-1) 3510, 3384, 2938, 2624, 2045, 1604, 1572, 1463

[0112] The following compounds were obtained in the same manner as in Reference Example 3.

[0113] 2-(4-Methyl-1-piperidinyl)ethylamine 2 hydrochloride (reference compound 3-2)

[0114] mp 155~161℃

[0115] IR (KBr, cm-1) 3477, 3395, 2956, 2630, 1600, 1566, 1502, 1455, 1054, 962

[0116] 2-[4-(Dimethylamino)-1-piperidinyl]ethylamine 3 hydrochloride (reference compound 3-3)

[0117] mp 250℃ and above

[0118] IR (...

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PUM

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Abstract

N-Substituted-N'-substituted urea derivatives represented by the following formula, analogs thereof or pharmaceutically acceptable salts thereof are herein provided. These compounds show a TNF-alpha production inhibitory activity.

Description

technical field [0001] The present invention relates to novel N-substituted-N'-substituted urea derivatives, pharmaceutical compositions containing the compounds, TNF-α production inhibitors and therapeutic agents for autoimmune diseases. Background technique [0002] TNF-α (Tumor Necrosis Factor-α: Tumor Necrosis Factor-α) is currently recognized as a cytokine that is widely involved in biological defense and immune mechanisms, but continuous and excessive production of TNF-α can cause tissue disorders and become the cause of various diseases. causes or main causes of deterioration. For example, as examples of TNF-α-related diseases, joint rheumatism, systemic lupus erythematosus (SLE), dyscrasia, acute infectious disease, allergy, fever, anemia, diabetes, etc. (Yamazaki, Clinical Immunology, 27 , 1270, 1995). In addition, it has been reported that TNF-α plays an important role in the pathogenesis of chronic rheumatism and Crohn's disease, which are autoimmune diseases. ...

Claims

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Application Information

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IPC IPC(8): A61K31/4453A61P37/06A61P43/00C07D207/09C07D211/26C07D211/46C07D211/58C07D211/70C07D217/04C07D295/13
CPCC07D217/04C07D211/58C07D211/70C07D211/26C07D295/13C07D207/09A61K31/4453C07D211/46A61P37/06A61P43/00
Inventor 三田四郎堀内正人伴正和须原宽
Owner SANTEN PHARMA CO LTD
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