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Novel sixteen-membered ring triamine lactone derivative and application thereof

A technology of sixteen rings, compounds, applied in the field of new antibiotics

Active Publication Date: 2015-07-22
镇江威特药业有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although the bispiperidine structure is helpful in improving the synthesis efficiency and reducing the cost of the drug, it is not necessarily the best pharmacophore

Method used

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  • Novel sixteen-membered ring triamine lactone derivative and application thereof
  • Novel sixteen-membered ring triamine lactone derivative and application thereof
  • Novel sixteen-membered ring triamine lactone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1. (4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3 ,5-Dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxyl-15-((((2R,3R,4R,5R,6R) -5-Hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)methyl)-5,9,13-trimethyl-7-(2 -(piperidin-1-yl)ethyl)oxahexadecano-11,13-diene-2,10-dione (compound 1)

[0077] Tylosin (9.2 g, 0.01 mol), hexahydropyridine (2.55 g, 0.03 mol), and toluene (30 ml) were added together into a three-neck flask, stirred and heated to 75°C, and formic acid (2.5 g, 0.05 mol) was slowly added dropwise ), the temperature is controlled at about 75°C, the formic acid is dropped, and the reaction is carried out at 75-80°C for 2 hours. After the reaction is over, add 15% dilute hydrochloric acid to dissolve the viscous substance in the lower layer, and separate the water layer. The benzene layer was washed twice with 90 ml of dilute hydrochloric acid, and the aqueous layers were combined. Neutralize with 30%...

Embodiment 2

[0078] Example 2. (4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3 ,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxy-15-(hydroxymethyl)-5,9,13-trimethyl yl-7-(2-(piperidin-1-yl)ethyl)oxahexadecano-11,13-diene-2,10-dione (compound 2)

[0079] Compound 1 (9.0 g, 0.01 mol) was added into a three-necked flask, and then 30 ml of hydrobromic acid and 30 ml of water were added, and reacted at 57°C for 5 hours. Cool and filter, and the filtrate is neutralized with 30%-40% sodium hydroxide solution to a pH of about 10, and the precipitated product is solid and can be filtered. If the precipitated product is viscous, dehydration is required, and 4.7 grams of crude product is obtained by drying, and the productive rate is 70%. Theoretical value of mass spectrum: 666.45, measured value: 667.40 (M+H + ).

Embodiment 3

[0080] Example 3. (4R,5S,6S,7R,9R,11E,13E,15S,16R)-6-(((2R,3R,4S,5S,6R)-4-(dimethylamino)-3 ,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxy-15-(iodomethyl)-5,9,13-trimethyl yl-7-(2-(piperidin-1-yl)ethyl)oxahexadecano-11,13-diene-2,10-dione (compound 3)

[0081] Add compound 2 (12.4 grams, 0.02 moles) dichloromethane (40 milliliters), triphenylphosphine (8 grams, 0.03 moles), pyridine (2 grams, 0.022 moles) in the there-necked flask, ice bath, make the temperature below 13°C. Iodine (8 g, 0.03 mol) was added in portions, and the temperature was controlled at 15±3°C after the addition of iodine, and stirred for 3 hours. Cool and filter, extract the filtrate twice with 30 ml of 15% dilute hydrochloric acid, combine the extracts, neutralize with 30% sodium hydroxide solution until the pH is 9-10, precipitate off-white solid product, and filter out the product. The product is dissolved in a small amount of dichloromethane, dried and concentrated, and petrol...

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Abstract

The invention discloses a novel sixteen-membered ring triamine lactone derivative and application thereof. The novel sixteen-membered ring triamine lactone derivative is a compound as shown in a general formula (I) or (II) which is described in the specification or a pharmaceutically acceptable salt thereof. In the formula, R1 is arbitrarily substituted C1-6 alkyl group or C3-8 cycloalkyl group and R2 is hydrogen or arbitrarily substituted C1-6 alkyl group or C3-8 cycloalkyl group, or R1 and R2 is connected through a chemical bond so as to allow R1-N-R2 group to compose arbitrarily substituted 3-to-5-membered or 7-to-9-membered heterocyclic group; and R3 and R4 are independently selected from the group consisting of hydrogen or C1-3 alkyl group. The compound or the pharmaceutically acceptable salt thereof has excellent antibacterial activity, is applied to treatment and prevention of animal bacterial infection and mycoplasma infection and provides a novel approach for treatment or prevention of animal bacterial infection and mycoplasma infection.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to a new antibiotic. Specifically, the present invention relates to a class of novel derivatives modified at positions 20 and 23 of 16-membered ring decarburose tylonolide, pharmaceutically acceptable salts of such derivatives, and methods for preparing such derivatives and applications of such derivatives. Background technique [0002] Since humans discovered penicillin in the 1920s and streptomycin in the 1940s, many new compounds with antibacterial activity have been continuously discovered and used as antibiotics, thus saving thousands of lives and greatly promoting modern animal husbandry. industry development. But over time, bacteria can develop resistance to existing drugs, making infections difficult to treat or even uncontrollable. At present, bacteria resistant to antibiotics has become an increasingly serious threat to public health. The long-standing drug-resistant bacteria MRSA ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08C07H1/00A61K31/706A61P31/04
CPCC07H1/00C07H17/08
Inventor 黄文江袁海卿
Owner 镇江威特药业有限责任公司
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