Substituted amine derivative and medicinal composition comprising same as the active ingredient

A compound and substituent technology, applied in the field of new substituted amine derivatives, can solve the problems of sufficient compound activity and insufficient physical and chemical stability

Inactive Publication Date: 2011-10-12
KOTOBUKI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] These compounds showed uric acid inhibitory activity, but it cannot be said that the activity of the compounds reported here is sufficient, and the stability and physicochemical stability in vivo are not sufficient.

Method used

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  • Substituted amine derivative and medicinal composition comprising same as the active ingredient
  • Substituted amine derivative and medicinal composition comprising same as the active ingredient
  • Substituted amine derivative and medicinal composition comprising same as the active ingredient

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0164]

[0165] 1,2,3,5-Tetra-O-benzoyl-2-C-methyl-D-ribofuranose 10.282g and 4-amino-6-bromo-7H-pyrrolo[2,3-d] A suspension of 4.215 g of pyrimidine-5-carbonitrile in 180 mL of acetonitrile was placed under ice cooling, 8.0 mL of DBU and 12.8 mL of TMSOTf were added, and stirred at 60°C for 17 hours. The reaction liquid was poured into saturated sodium bicarbonate water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / chloroform) to obtain 5.394 g of pale yellow crystals of the above-mentioned title compound.

[0166] 1 H-NMR (CDCl 3 )δ=1.68(s, 3H), 4.78-4.90(m, 3H), 5.66(br-s, 2H), 6.87(s, 1H), 7.26-7.33(m, 1H), 7.44-7.52(m, 6H), 7.59-7.64(m, 3H), 7.94-7.97(m, 2H), 8.12-8.15(m, 4H), 8.39(s, 1H).

reference example 2

[0168]

[0169] To a MeOH 130 mL solution of 4.394 g of the compound obtained in Reference Example 1 was added 171 mg of NaOMe, and stirred at room temperature for 4.5 hours. Active Dowex was added to the reaction solution to make the pH = 5, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain 1.036 g of colorless crystals of the title compound.

[0170] 1 H-NMR (DMSO-d 6)δ=0.82(s, 3H), 3.75-3.90(m, 3H), 4.40(br-s, 1H), 4.93(m, 1H), 5.17(m, 1H), 5.30-5.32(m, 1H) , 6.03(br-s, 1H), 7.04(br-s, 2H), 8.17(s, 1H).

Embodiment 1

[0172]

[0173] Compound (1) represented by the above formula is produced using the following method.

[0174] To a solution of 200 mg of the compound obtained in Reference Example 2 in 5 mL of isobutanol, 229 mg of C-biphenyl-4-yl-methylamine and 0.28 mL of diisopropylethylamine were added, and the mixture was refluxed for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain 63 mg of the title compound (1) as pale yellow crystals.

[0175] 1 H-NMR (DMSO-d 6 )δ=0.72(s, 3H), 3.71-3.74(m, 1H), 3.86-3.90(m, 2H), 4.03-4.05(m, 1H), 4.64-4.73(m, 2H), 5.07(s, 1H), 5.37(d, J=6.8Hz, 1H), 5.94(m, 1H), 6.18(br-s, 2H), 6.40(br-s, 1H), 7.33-7.37(m, 1H), 7.43 -7.47(m, 4H), 7.66(d, J=8.1Hz, 4H), 8.03(s, 1H), 8.14(m, 1H).

[0176] The following compounds (2) to (6) were synthesized by the same method.

[0177] Compound (2)

[0178]

[0179] 1 H-NMR (CD 3 OD)δ=0.8...

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Abstract

A compound represented by general formula (I) [wherein --- represents a single bond or a double bond; L represents -NH- or the like; X1 represents N or C, provided that in the case where X1 is N, X2 represents C-R and in the case where X1 is C, X2 represents N-R1 or the like; Y's may be either the same or different and represent CH2 or the like; A represents a non-natural sugar residue represented by general formula (II) [wherein m represents 0 to 1; --- represents a single bond or a double bond; X represents 0 or the like; and R3 to R9 may be either the same or different and represent a hydroxyl group or the like]; and B represents a group represented by general formula (III) [wherein n and k represent 0 to 5; --- represents a single bond or a double bond; Z1 to Z16 may be either the same or different and represent CH or the like; R10 and R11 may be either the same or different and represent a lower alkoxy group having 1 to 5 carbon atoms or the like; and R15 represents a hydrogen atom or the like]], a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. Because of having an excellent CNT2 inhibitory activity and showing a high in vivo stability and stable physicochemical properties, the aforesaid compound is useful as a remedy for hyperuricemia.

Description

technical field [0001] The present invention relates to novel substituted amine derivatives. In addition, it also relates to a pharmaceutical composition using the substituted amine derivative as an active ingredient, especially a pharmaceutical composition for preventing or treating diseases caused by abnormal plasma uric acid levels. Background technique [0002] Gout is abnormal purine metabolism accompanied by joint damage (joint damage), kidney damage (renal damage), urinary tract stones, and cardiovascular disorders (cardiovascular disorders) caused by hyperuricemia and urate precipitation. There are unexplained primary (gout in the narrow sense) and inborn metabolic abnormalities or secondary metabolic abnormalities caused by hyperuricemia during chemotherapy for malignant tumors. Uric acid is derived from purines synthesized from food and nucleic acids in living organisms, and is excreted into urine by the kidneys as a final product. Excessive intake of these purin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/14A61P43/00C07D239/70A61K31/517A61K31/519A61K31/7042A61K45/00A61K45/06A61P3/06A61P3/10A61P9/10A61P13/02A61P13/04A61P19/06
CPCA61K31/517A61K31/519A61K31/7042A61K45/06C07D239/70C07D409/04C07D487/04C07H19/14A61P11/00A61P13/00A61P13/02A61P13/04A61P13/12A61P19/06A61P29/00A61P3/00A61P3/04A61P3/06A61P37/06A61P43/00A61P7/00A61P9/10A61P9/12A61P3/10A61K2300/00
Inventor 富山泰德崎一夫岩井辰宪
Owner KOTOBUKI PHARMA CO LTD
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