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Macrolide derivatives

A compound and ring structure technology, applied in the field of salt and hydrate, can solve problems such as separation without inhibition

Inactive Publication Date: 2009-06-10
TAISHO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Further, for the treatment of neutrophil-dominant non-infectious inflammatory diseases including COPD, a technique using azithromycin is disclosed (see Patent Document 1), but it is not separated from the antibacterial activity
[0013] In addition, there are reports of compounds obtained by derivatizing the 2′-hydroxyl of desosamine bonded to the 5-position of erythromycin antibiotics (see Patent Document 2, Non-Patent Document 6), but no antibacterial activity has been reported. Record of isolation from MMP-9 production inhibition

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0561] 2’-O-(3-oxobut-1-enyl)-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (Homoerisromyishin A)

[0562] Dissolve 1.0 g of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in 4 ml of chloroform, add 136 μl of 3-butyn-2-one, and stir at room temperature for 15 hours. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform:methanol:ammonia water=49:1:0.1 to 24:1:0.1) to obtain 717 mg of the title compound.

[0563] MS(ESI)m / z=817.7[M+H] +

[0564] 13C NMR (126MHz, CHLOROFORM-d) δ ppm 8.72, 11.33, 14.75, 16.22, 18.38, 21.26, 21.72, 22.19, 26.75, 27.65, 32.08, 34.80, 36.41, 40.93, 42.01, 45.44, 45.372, 69 , 68.35, 70.05, 73.17, 74.35, 77.30, 77.51, 78.21, 83.22, 83.92, 94.52, 100.69, 108.54, 164.85, 197.54

Embodiment 2

[0566] 11-Amino-11-deoxy-2’-O-(3-oxobut-1-enyl)-6-O-methylerythromycin A 11,12-cyclocarbamate

[0567] 11-amino-11-deoxy-6-O-methylerythromycin A11,12-cyclocarbamate described in literature (Journal of Organic Chemistry, 1988, volume 53, number 10, pages 2340-2345) 500 mg was reacted in the same manner as in Example 1 to obtain 330 mg of the title compound.

[0568] MS(ESI)m / z=839.5[M+H] +

[0569] 13C NMR (126MHz, CHLOROFORM-d) δ ppm 8.76, 10.55, 13.51, 13.77, 15.74, 18.14, 18.75, 19.94, 21.3, 21.60, 22.08, 28.09, 34.81, 37.61, 39.43, 45.14, 40.8, 34, 45. , 50.12, 57.86, 63.33, 65.96, 68.45, 72.91, 75.89, 77.52, 77.84, 78.48, 80.40, 84.0, 95.68, 100.68, 158.44, 176.83, 197.60, 218.06

Embodiment 3

[0571] 11-Amino-11-deoxy-2’-O-(2-methoxycarbonylvinyl)-6-O-methylerythromycin A 11,12-cyclocarbamate

[0572]Use 500 mg of 11-amino-11-deoxy-6-O-methylerythromycin A11,12-cyclocarbamate, and use 70 μl of methyl propiolate (Mechel propiolet) instead of 3-butyne -2-Kone was reacted in the same manner as in Example 1 to obtain 452 mg of the title compound.

[0573] MS(ESI)m / z=857.6[M+H] +

[0574] 1H NMR (600MHz, CHLOROFORM-d) δ ppm 0.85 (t, J = 7.57Hz, 3H) 0.89 (d, J = 7.79Hz, 3H) 1.10-1.15 (m, 6H) 1.19 (d, J = 7.34Hz, - 1.79 (m, 6H) 1.84-1.92 (m, 1H) 2.13-2.17 (m, 1H) 2.24-2.36 (m, 1H) 2.30 (s, 6H) 2.49-2.58 (m, 1H) 2.65-2.78 (m, 2H)2.81-2.87(m,1H)2.91(s,3H)2.99-3.05(m,1H)3.32(s,3H)3.45-3.51(m,1H)3.52-3.57(m,1H)3.57-3.61( m, 1H) 3.64-3.67 (m, 1H) 3.69 (s, 3H) 3.73-3.81 (m, 1H) 3.88-3.95 (m, 1H) 4.49-4.53 (m, 1H) 4.86-4.90 (m, 1H) 5.04-5.08 (m, 1H) 5.27 (d, J = 11.92Hz, 1H) 5.77 (s, 1H) 7.47 (d, J = 12.38Hz, 1H)

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Abstract

Compounds represented by formula (I) and the formula (IV) have an inhibitory activity of MMP-9 production, therefore, are useful as a medicine agent with fewer side effects than conventional MMP enzyme activity inhibitors, as a prophylactic and therapeutic drug for oncogenic angiogenesis, chronic rheumatoid arthritis, vascular intimal thickening after a percutaneous coronary transluminal angioplasty, vascular atherosclerosis, hemorrhagic apoplexy, acute myocardial infarction, chronic heart failure, aneurysm, lung cancer metastasis, adult respiratory distress syndrome, asthma, interstitial pulmonary fibrosis, chronic rhinosinusitis, bronchitis or chronic obstructive pulmonary disease (COPD).

Description

technical field [0001] The present invention relates to novel macrolide derivatives, their pharmaceutically acceptable salts and hydrates. Background technique [0002] Matrix metalloproteinases (hereinafter referred to as MMPs) are zinc-dependent endopeptidases that function extracellularly (see Non-Patent Document 1). MMP mainly decomposes and maintains the extracellular matrix (EMC) necessary for the structure of elastic fibers or tissues in vivo (such as elastin, collagen, gelatin, laminin, fibronectin), and makes the normal tissue reorganize under physiological conditions. The role of smooth repair of structural or tissue damage. Furthermore, under physiological conditions, the mRNA amount, protein amount, or enzyme activity of MMPs are controlled by various mechanisms, and excessive breakdown of the extracellular matrix will not occur. Tissue inhibitor of metalloproteinase (TIMP) is known as an in vivo enzyme inhibitor substance of MMP. [0003] On the other hand, i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08A61K31/7048A61P9/00A61P9/04A61P9/10A61P11/00A61P11/06A61P29/00A61P35/00A61P43/00
CPCC07H17/00A61K31/7052C07H17/08A61K31/7048A61P11/00A61P11/06A61P29/00A61P31/04A61P35/00A61P43/00A61P9/00A61P9/04A61P9/10
Inventor 樫村政人川村円朝贺俊文高山喜好荻田晴久
Owner TAISHO PHARMACEUTICAL CO LTD
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