Epoxysuccinic acid derivatives

A technology of epoxy succinic acid and derivatives, which can be used in pharmaceutical combinations, organic active ingredients, medical preparations containing active ingredients, etc., can solve problems such as not yet disclosed

Inactive Publication Date: 2002-07-10
NIPPON CHEMIPHAR CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no disclosure of N-substituted carbamoyl groups attached to the oxirane ring (such as diphenylme

Method used

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  • Epoxysuccinic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1 (2S, 3S)-3-diphenylmethylcarbamoyloxirane-2-carboxylic acid ethyl ester (No. 2 compound)

[0063] To a solution of (2S, 3S)-3-ethoxyformyloxirane-2-carboxylic acid (8.01g, 50.0mmol) in ethyl acetate (120ml), N-hydroxysuccinate was added successively under ice cooling Imide (5.76 g, 50.0 mmol) and N,N'-dicyclohexylcarbodiimide (5.75 g, 50.0 mmol). The mixture was stirred at 5°C for 1 hour, and a solution of aminodiphenylmethane (9.17 g, 50.0 mmol) in ethyl acetate (30 ml) was added. The mixture was stirred at 5°C for 1 hour and at room temperature for another 1 hour. The resulting N,N'-dicyclohexylurea (DC-Urea) was filtered off, and the filtrate was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane to obtain the desired white crys...

Embodiment 2

[0067] Example 2 (2S, 3S)-3-diphenylmethylcarbamoyloxirane-2-carboxylic acid (No. 1 compound)

[0068] Ethyl (2S,3S)-3-diphenylmethylcarbamoyloxirane-2-carboxylate (5.50 g, 16.9 mmol) from Example 1 was dissolved in ethanol (300 ml). To the solution was added 0.5N sodium hydroxide ethanol solution (40.4ml, 20.2mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, water (300ml) was added and washed with two 100ml portions of ether. The pH of the aqueous phase was adjusted to 1-2 with 2N hydrochloric acid, then extracted with three 100ml portions of ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the desired white powdery crystalline product (4.76 g, yield: 95%). 1 H-NMR (400MHz, CD 3 OD) δ:

[0069] 3.57(1H,d,J=2Hz), 3.71(1H,d,J=2Hz), 6.23

[0070] (1H, s), 7.2-7.4 (10H, m...

Embodiment 3

[0071] Example 3 (2S, 3S)-3-diphenylmethylcarbamoyloxirane-2-sodium carboxylate (sodium salt of No. 1 compound)

[0072] The compound obtained in Example 2 (100 mg, 0.336 mol) was dissolved in ethyl acetate (10 ml). To the resulting solution was added a solution of sodium bicarbonate (28.2mg, 0.336mmol) in water (10ml). The mixture was shaken vigorously. The aqueous phase was separated, then concentrated to dryness under reduced pressure to obtain the desired product as a white powder (106 mg, yield: 99%). 1 H-NMR (400MHz, D 2 O) δ:

[0073] 3.47(1H,d,J=2Hz), 3.63(1H,d,J=2Hz), 6.15

[0074] (1H, s), 7.3-7.5(10H, m).IR(KBr)cm -1 :

[0075] 3412, 3219, 3064, 3030, 1670, 1632, 1552, 1495,

[0076] 1454, 1448, 1398, 1317, 1285, 1248, 1093, 1086,

[0077] 1051, 1030, 1007, 960, 899, 862, 783, 758, 742,

[0078] 698, 677, 642, 602, 571, 482.

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PUM

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Abstract

Epoxysuccinic acid derivatives having general formula (I): (wherein R<1> represents hydrogen, alkyl, aryl or aralkyl; R<2> and R<3> independently represent each aryl, aralkyl or alkyl; and X represents -O- or -NR<4>- wherein R<4> represents hydrogen, alkyl or aralkyl) is used in the prevention and treatment of bone diseases such as osteoporosis, malignant hypercalcemia, and bone Behcet's disease, in the treatment of osteoarthritis and rheumatoid arthritis in association with the abnormal hyperergasia of cathepsin L activity, and as a remedy for diseases in which cathepsins L and B participate such as muscular dystrophy and amyotrophy.

Description

field of invention [0001] The present invention relates to novel epoxysuccinic acid derivatives and pharmaceutical compositions using them for the treatment of bone diseases. Background of the invention [0002] In bone tissue, bone resorption and osteogenesis are carried out simultaneously by osteoclasts and osteoblasts, respectively. The structure and quantity of bone are maintained by its balance. However, excessive bone resorption will result in bone diseases such as osteoporosis, hypercalcemia malignant, and Paget's syndrome. [0003] The process of bone resorption (eg, decalcification) by osteoclasts can be divided into two steps, dissolution of minerals and degradation of bone matrix. The degradation of bone matrix is ​​thought to be carried out by the action of lysosomal enzymes. Among the lysosomal enzymes, cathepsin L and isozymes are cysteine ​​proteases that play key roles according to recent research [Kakegawa and Katsunuma, Molecular Medicine 30(10), 1310-1...

Claims

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Application Information

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IPC IPC(8): C07D303/48
CPCC07D303/48A61P19/00C07D303/46A61K31/335
Inventor 野村丰高桥俊弘原薰吉野康真崎光夫
Owner NIPPON CHEMIPHAR CO LTD
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