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Substituted cyslopentane and cyclopentene compounds useful as neuraminidase inhibitors

A compound and alkyl technology, applied in the field of substituted cyclopentane and cyclopentene compounds used as neuraminidase inhibitors, can solve the problem of no disclosure of cyclopentane and cyclopentene derivatives, etc.

Inactive Publication Date: 2001-01-31
BIOCRYST PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] However, none of these documents disclose the cyclopentane and cyclopentene derivatives of the present invention

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Embodiment 1 (±) 4-azidocyclopent-2-en-1-one (2, scheme 1)

[0134] Under stirring, 4-bromocyclopent-2-en 1-one (1, 3.5 g, 21.7 mmol) was added dropwise to a solution of sodium azide (2.12 g, 32.6 mmol) in DMF (15 ml) cooled at 0 , prepared by the method of Depuy et al. J. Org. Chem. 29, 3503, 1964) in DMF (5 ml) for 5 minutes. The reaction mixture was stirred at 0°C for 30 minutes and diluted with ethyl acetate (20ml). The reaction mixture was washed with water (2×20ml) and brine (2×20ml), dried (MgSO 4 ),filter. The filtrate was concentrated in vacuo to give an oily residue. Purification by flash column chromatography (silica gel, 10-15% ethyl acetate in hexanes) afforded 1.9 g (71%) of compound 2 as an oil.

[0135] 1 H NMR (CDCl 3 ): δ2.35(dd, J=18.6 and 2.4Hz, 1H), 2.77(dd, J=18.6 and 6.6Hz, 1H), 4.67(dd, J=4.9 and 2.6Hz, 1H), 6.35(dd, J=5.6 and 1.5Hz, 1H), 7.54 (dd, J=5.5 and 2.4Hz, 1H).

Embodiment 2

[0136] Example 2 (±) 3β-[1'-acetylamino-1'-bis(ethoxycarbonyl)]methyl-4α-azidocyclopent-1-one (3, scheme 1)

[0137] To a solution of diethyl acetamidomalonate (1.25 g, 5.7 mmol) in ethanol (10 mL) was added freshly chopped sodium metal (0.03 g, 1.4 mmol) under nitrogen. The reaction solution was stirred at room temperature until all the sodium metal was dissolved. The reaction mixture was cooled to -40°C, and a solution of compound 2 (0.7 g, 5.7 mmol) in ethanol (5 ml) was added dropwise. The reaction mixture was stirred at -40°C for 30 minutes and quenched with trifluoroacetic acid (0.1 ml, 1.4 mmol). The solvent was removed in vacuo to afford crude compound 3 as a white solid. The solid was dissolved in ethyl acetate, washed with water, dried and concentrated in vacuo. The resulting solid was crystallized from ether / hexane to afford 1.29 (63%) of compound 3 as a white solid, mp 121-122°C.

[0138] 1 H NMR (CDCl 3 ): δ1.26(t, J=7.2 Hz, 3H), 1.29(t, J=7.2Hz, 3H), 2.05(...

Embodiment 3

[0139] Example 3 (±)3 β-[1'-Acetamido-1'-bis(ethoxycarbonyl)]methyl-4α-tert-butoxycarbonylaminocyclopent-1-one (4, scheme 1)

[0140] A mixture of compound 3 (0.5 g, 1.5 mmol), di-tert-butyl dicarbonate (0.39 g, 1 / 77 mmol) and 10% Pd / C (0.14 g) in ethyl acetate (25 ml) was hydrogenated at 45 psi 1 hour. The catalyst was filtered off, and the filtrate was concentrated in vacuo to afford crude compound 4. Recrystallization from ether / hexane gave 0.28 g (45%) of compound 4 as a white solid, mp 135-136°C.

[0141] 1 H NMR (CDCl 3 ): δ1.27(m, 6H), 1.45(s, 9H), 2.10(s, 3H), 2.33(m, 2H), 2.75(m, 2H), 3.25(m, 1H), 4.14(m, 1H), 4.28(m, 4H), 4.83(s, 1H), 6.98(s, 1H); IR(KBr) 3365, 2980, 1739, 1689, 1519, 1394, 1275cm -1 : mS (CI-): 413 (10%, M-1). Elemental Analysis: Calculated Values ​​(C 19 h 30 N 2 o 8 ): C, 55.06; H, 7.30; N, 6.76 Found: C, 54.63; H, 7.17; N, 6.74

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Abstract

Compounds represented by formulae (I, II or III), wherein U is CH, O, or S; Z is -C(R2)(R3), -CH-N(R2)(R3), C(R3)[(CH2)nR2], CH-C(R3)(R8)(CH2)nR2, C[(CH2)nR2]-[CH(R3)(R8)], C[(R3)][CH[(CH2)nR2](R8)]; R1 is H, (CH2)nOH, (CH2)nNH2, (CH2)nNR10R11, (CH2)nOR11, (CH2)nSR11, or (CH2)n halogen; R9 is (CH2)nCO2H, (CH2)nSO3H, (CH2)nPO3H2, (CH2)nNO2, CH(SCH3)3, esters thereof, or salts thereof.

Description

technical field [0001] The present invention relates to novel substituted cyclopentane and cyclopentene compounds and their derivatives as neuraminidase inhibitors, pharmaceutical compositions containing said compounds for preventing, treating or alleviating viral, bacterial and other infections, And methods of using said compounds. The present invention also relates to novel intermediates or precursors useful in the preparation of the novel substituted cyclopentane and cyclopentene compounds of the present invention. background of the invention [0002] Despite the wealth of information available, influenza remains a potentially intimidating disease of humans, lower mammals, and birds. Once infection occurs, there is no effective vaccine and no combination therapy. [0003] Influenza virus consists of 8 segments of single-stranded RNA, which are packaged sequentially in virus particles. Each segment encodes a major viral protein. The replication complex is enclosed in a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61KA61K31/195A61K31/196A61K31/215A61K31/385A61K31/4164A61K31/423A61P31/12A61P43/00C07CC07C229/32C07C229/48C07C233/47C07C247/14C07C271/24C07C279/16C07C279/24C07C309/66C07C323/41C07C323/43C07C323/59C07C323/60C07DC07D233/54C07D233/56C07D261/20C07D339/08C07D521/00
CPCC07D231/12C07C247/14C07D339/08C07C2101/08C07D261/20C07C233/47C07C323/60C07C271/24C07C229/48C07C279/24C07C323/59C07C309/66C07D249/08C07D233/56C07C279/16C07C2101/10C07C2601/08C07C2601/10A61P31/04A61P31/12A61P31/16A61P43/00C07C69/74
Inventor Y·S·巴比P·昌德J·A·蒙哥马利
Owner BIOCRYST PHARM INC
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