Neuraminic acid derivatives, their preparation and their medical use

a technology of neuronal acid and derivatives, applied in the field of neuronal acid, can solve the problem of second-infection of surrounding cells

Inactive Publication Date: 2002-09-26
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0419] 4-(N,N-Dimethylamino)pyridine and 4-pyrrolidinopyridine can be used in a catalytic amount in combination with one or more other bases. In addition, it may facilitate the reaction to carry it out in the presence of one or more of: quaternary ammonium salts, such as benzyltriethylammonium chloride and tetrabutylammonium chloride; and crown ethers, such as dibenzo-18-crown-6.
[0652] In some cases, the compounds of the present invention can be prepared efficiently by carrying out the above steps in a different order, as will be appreciated by the skilled reader.

Problems solved by technology

Subviruses dissociate from the cell as a result of sialidase on the subvirus surface breaking down the sialic acid, thereby resulting in secondary infection of surrounding cells.

Method used

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  • Neuraminic acid derivatives, their preparation and their medical use
  • Neuraminic acid derivatives, their preparation and their medical use
  • Neuraminic acid derivatives, their preparation and their medical use

Examples

Experimental program
Comparison scheme
Effect test

example 12

4-Guanidino-9-O-tetradecanoyl-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero--D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (Compound No. 31-41)

[1400] 29

[1401] 12(i) Methyl 4-(N,N'-bis-t-butoxycarbonylguanidino)-7-tetradecanoyl--8,9-O-isopropylidene-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero-D)-gala-cto-non-2-enopyranosoate

[1402] 440 mg (0.73 mmol) of methyl 5-thioacetamido-4-(N,N'-bis-t-butoxyca-rbonylguanidino)-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galac-to-non-2-enopyranosoate [prepared as described in Example 9(i)] were dissolved in 15 ml of methylene chloride, and 132 mg (1.08 mmol) of dimethylaminopyridine and 247 mg (1.0 mmol) of tetradecanoyl chloride were added to the resulting solution. The mixture was then stirred at room temperature for 30 minutes, after which 109 mg (1.08 mmol) of triethylamine were added, and the mixture was stirred for 15 hours. The reaction mixture was then poured into a 2-layer solution of 30 ml of ethyl acetate and 15 m...

example 13

5-Acetamido-4-guanidino-9-O-hexanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glyce-ro-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (Compound No. 1-36)

[1462] 30

[1463] 13(i) Diphenylmethyl 5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-ino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoat-e

[1464] 100 mg (0.24 mmol) of methyl 5-acetamido-4-(N,N'-bis-t-butoxycarbon-ylguanidino)-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-gal-acto-non-2-enopyranosoate [prepared as described in Example 6(ii)] were dissolved in 3 ml of methanol, and 0.5 ml of a 0.1 N methanolic solution of sodium methoxide was added to the resulting solution. The mixture was then stirred at room temperature for 1 hour, after which the reaction mixture was neutralized with a 4 M solution of hydrogen chloride in dioxane, and the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in 1 ml of distilled water and 280 ml of a 1 N aqueous solut...

example 14

5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glyce-ro-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (Compound No. 1-38)

[1515] 31

[1516] 14(i) Diphenylmethyl 5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-ino)-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2--enopyranosoate

[1517] 50 mg (0.072 mmol) of diphenylmethyl 5-acetamido-4-(N,N'-bis-t-buto-xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non--2-enopyranosoate [prepared as described in Example 13(i)] were dissolved in 2 ml methylene chloride, and 11 mg (0.11 mmol) of triethylamine and 16 mg (0.086 mmol) of octanoyl chloride were added to the resulting solution, whilst ice-cooling. The mixture was then stirred at 0.degree. C. for 1 hour. At the end of this time, the reaction mixture was poured into a 2-layer solution of 5 ml of ethyl acetate and 3 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was separated and ...

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Abstract

Compounds of formula (I) or their salts or esters: [wherein R1 is alkyl or haloalkyl; R2 and R3 each represents hydrogen or aliphatic acyl; X is hydroxy, halogen, alkoxy, or a group of formula RaO-, where Ra is aliphatic acyl; Y is a group of formula RbRcN- or RbRcN-O-, where Rb and Rc each is hydrogen or alkyl; and Z is oxygen or sulfur] have excellent sialidase inhibitory activity and are therefore useful for the treatment and prevention of influenza and other viral diseases where the replication of the virus is susceptible to sialidase inhibitors.

Description

[0001] This application is:[0002] (1) a C-I-P of Ser. No. 09 / 232,539 filed Jan. 18, 1999, which is a continuation of Ser. No. 08 / 895,952 filed Jul. 17, 1997; and[0003] (2) a C-I-P of Ser. No. 09 / 249,420 filed Feb. 12, 1999, which is a continuation of International Application No. PCT / JP97 / 02810 filed Aug. 12, 1997.[0004] The present invention relates to a series of new neuraminic acid derivatives which have excellent sialidase inhibitory activity and which are therefore useful for the treatment and prevention of influenza and other viral diseases where the replication of the virus is susceptible to sialidase inhibitors. The invention also provides methods and compositions using these compounds for the treatment or prevention of influenza and similar viral infections, as well as processes for the preparation of these compounds.[0005] The compounds of the present invention have a 2-deoxy-2,3-didehydro-N-acylneuraminic acid structure. Sialic acid is N-acetylneuraminic acid.[0006] The i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D309/28
CPCC07D309/28Y10S530/807
Inventor HONDA, TAKESHIKOBAYASHI, YOSHIYUKIYAMASHITA, MAKOTO
Owner DAIICHI SANKYO CO LTD
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