69567-10-8

In recent years, the function of pharmacological chaperones as a "thermodynamic stabilizer"has been attracting attention in combination therapy. The coadministration of a pharmacological chaperone and recombinant human acid α-glucosidase (rhGAA) leads to improved stability and maturation by binding to the folded state of the rhGAA and thereby promotes enzyme delivery. This study provides the first example of a strategy to design a high-affinity ligand toward lysosomal acid α-glucosidase (GAA) focusing on alkyl branches on 1-deoxynojirimycin (DNJ); 5-C-heptyl-DNJ produced a nanomolar affinity for GAA with a Ki value of 0.0047 μM, which is 13-fold more potent than DNJ. The protein thermal shift assay revealed that 10 μM 5-C-heptyl-DNJ increased the midpoint of the protein denaturation temperature (Tm) to 73.6 °C from 58.6 °C in the absence of the ligand, significantly improving the thermal stability of rhGAA. Furthermore, 5-C-heptyl-DNJ dose dependency increased intracellular GAA activities in Pompe patient's fibroblasts with the M519V mutation. The introduction of C5 alkyl branches on DNJ provides a new molecular strategy for pharmacological chaperone therapy for Pompe disease, which may lead to the development of higher-affinity and practically useful chaperones.

A method is provided for treating a mammal infected with respiratory syncytial virus (RSV) comprising administering to the mammal an RSV inhibitory effective amount of a compound or its pharmaceutically acceptable salt of the formula STR1 wherein R1 is alkyl, aralkyl, aroyl or acyl and R2, R3, R4 and R5 are H or acyl.

The conformations of nitrogen-in-the-ring sugars and their N-alkyl derivatives were studied from 1H NMR analyses, mainly using 3J(H,H) coupling constants and quantitative NOE experiments.No significant difference was seen in the ring conformation of 1-deoxynojirimycin (1), N-methyl-1-deoxynojirimycin (2), and N-butyl-1-deoxynojirimycin (3).Hiowever, it was shown that the C6 OH group in 1 is predominantly equatorial to the piperidine ring, while that in 2 or 3 is predominantly axial, and its N-alkyl group is oriented equatorially.In the furanose analogues 1,4-dideoxy-1,4-imino-D-arabinitol (4) and its N-methyl (5) and N-butyl (6) derivatives, the five-membered ring conformation differed significvantly by the presence or absence of the N-substituted group and the length of the N-alkyl chain.Compound 3 reduced its inhibitory effect on almost all glycosidases, resulting in an extremely specific inhibitor for processing α-glucosidase I since N-alkylation of 1 is known to enhance both the potency and specificity of this enzyme in vitro and in vivo.This preferred (C6 OH axial) conformation in 2 and 3 appears to be responsible for their strong α-glucosidase I activity.Compound 4 is a good inhibitor of intestinal α-glucohydrolases, α-glucosidase II, and Golgi α-mannosidases I and II, but is N-alkyl derivatives 5 and 6 markedly decreased inhibitory potential for all enzymes tested.In the case of 2,5-dideoy-2,5-imino-D-mannitol (DMDP, 7), which is a potent toward β-galactosidase inhibitor, its N-methyl (8) and N-butyl (9) derivatives completely lost potency β-galactosidase as well.N-alkylation of compounds 4 and 7, known well as potent yeast α-glucosidase inhibitors, resulted in a serious loss of inhi bitory activity toward yeast α-glucohydrolases.Activity of these nine sugar analogues against HIV-1 replication was determined, based on the inhibition of virus-induced cytopathogenicity in MT-4 and MOLT-4 cells.Compounds 2 and 3, which are better inhibitors of α-glucosidase I than 1, proved active with EC50 values of 69 and 49 μg/mL in MT-4 cells and 100 and 37 μg/mL in MOLT-4 cells, respectively, while none of the furanose analogues exhibited any inhibitory effects on HIV-1.The change in potency and specifity of bioactivity by N-alkylation of nitrogen-in-the-ring sugars appears to be correlated with their conformational change.

A method of inhibiting lentivirus is disclosed which comprises mammalian host susceptible to said lentivirus with a virally inhibitory effective amount of an O-acylated derivative of 1,5-dideoxy-1,5-imino-D-glucitol and their N-alkyl, N-acyl and N-aroyl derivatives in which from one to four of the free hydroxyl groups are O-acylated with carboxylic alkanoyl radicals selected from the group consisting of ω,ω,ω-trifluoroalkanoyl having from three to eight carbon atoms, carboxylic cycloalkanoyl groups having from four to eight carbon atoms and carboxylic acyclic alkanoyl groups having from two to ten carbon atoms, wherein the N-aroyl groups contain from 7 to 14 carbon atoms, the N-acyl groups contain from 4 to 8 carbon atoms and the N-alkyl groups contain from 1 to 14 carbon atoms.

O-acylated derivatives of 1,5-dideoxy-1,5-imino-D-glucitol are disclosed that contain an N-alkyl or N-aroyl radical in which from one to four of the free hydroxyl groups are O-acylated with carboxylic alkanoyl radicals selected from the group consisting of ω,ω,ω-trifluoro alkanoyl having from three to eight carbon atoms, carboxylic cycloalkanoyl groups having from four to eight carbon atoms and carboxylic acyclic alkanoyl groups having from two to ten carbon atoms, wherein the N-aroyl radical is selected from the group consisting of p-decylbenzoyl, 3-(p-chlorophenoxy)propanoyl, 2-(acetyloxy)benzoyl, [1,1'-biphenyl]-4-ylcarbonyl, 2-thiopheneacetyl, trans-3-furanacryloyl 3-methoxyphenylacetyl and 3-(trifluoromethyl)benzoyl, and wherein the N-alkyl contains from one to fourteen carbon atoms, provided that when N-alkyl contains from one to five carbon atoms the O-acylated groups are ω,ω,ω-trifluoro alkanoyl or carboxylic cycloalkanoyl.

The present invention relates to stabilizing agents for enzymes which comprises an enzyme stabilizing amount of an N-substituted moranoline derivative of the formula (III): STR1 wherein R1 is phenyl lower alkynyl, phenoxy lower alkenyl or phenoxy lower alkynyl, wherein the phenyl moiety is unsubstituted, or a glucose oligomer thereof.

Antiviral O-acylated derivatives of 1,5-dideoxy-1,5-imino-D-glucitol are disclosed that contain an N-alkyl or N-aroyl radical in which from one to four of the free hydroxyl groups are O-acylated with carboxylic alkanoyl radicals selected from the group consisting of ω,ω,ω-trifluoro alkanoyl having from three to eight carbon atoms, carboxylic cycloalkanoyl groups having from four to eight carbon atoms and carboxylic acyclic alkanoyl groups having from two to ten carbon atoms, wherein the N-aroyl radical is selected from the group consisting of p-decylbenzoyl, 3-(p-chlorophenoxy)propanoyl, 2-(acetyloxy)benzoyl, [1,1'-biphenyl]-4-ylcarbonyl, 2-thiopheneacetyl, trans-3-furanacryloyl, 3-methoxyphenylacetyl and 3-(trifluoromethyl)benzoyl, and wherein the N-alkyl contains from one to fourteen carbon atoms, provided that when N-alkyl contains from one to five carbon atoms the O-acylated groups are ω,ω,ω-trifluoro alkanoyl or carboxylic cycloalkanoyl.

O-acylated derivatives of 1,5-dideoxy-1,5-imino-D-glucitol and their N-alkyl, N-acyl and N-aryl derivatives in which from one to four of the free hydroxyl groups are acylated with acyl groups having from one to eight carbon atoms and in which the N-alkyl and N-acyl substituents contain from four to fourteen carbon atoms and the N-aryl substituents contain from seven to fourteen carbon atoms are disclosed, provided that when N-aryl is benzyloxycarbonyl, the O-acyl groups contain four to eight carbon atoms.

A combined fructose 1,6-diphosphate aldolase reaction and catalytic reductive amination has been used in the asymmetric synthesis of azasugars structurally corresponding to N-acetylglucosamine, N-acetylmannosamine, and deoxyhexoses. The 6-deoxyazasugars w

A process for preparing a 1-deoxynojirimycin of the formula STR1 in which R is hydrogen, optionally substituted alkyl or aralkyl, which comprises converting D-glucose to an aminosorbitol STR2 protecting the amino group of the aminosorbitol with an alkalinically detachable group to form the protected compound of the formula STR3 in which X is an alkalinically detachable protective group, microbiologically oxidizing the protected compound to an oxidation product of the formula STR4 alkalinically splitting off the protective group X to form an aminosorbose of the formula STR5 and reducing the aminosorbose.

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