Hydroxylamine derivatives useful for enhancing the molecular chaperon production and the preparation thereof

A method of increasing activity of a molecular chaperon in an eukaryotic cell of a living mammalian organism that is exposed to a physiological stress comprising:

• treating the cell that is exposed to a physiological stress accompanying allergic diseases, immune diseases, autoimmune diseases, diseases of viral or bacterial origin, tumorous, skin and/or mucous diseases, epithelial disease of renal tubulus, atherosclerosis, coronarial disease, pulmonary hypertonia, cerebrovascular ischemia, stroke, or traumatic head injury with an effective amount of a chemical compound to increase the activity of the molecular chaperon in the cell beyond the amount induced by the physiological stress, wherein the chemical compound is one or more of a hydroxylamine derivative represented by formula (I),
• or a salt thereof or an optically active stereoisomer thereof,
• wherein A is an alkyl, substituted alkyl, aralkyl, aralkyl substituted in one or both of the aryl or alkyl moiety, aryl, substituted aryl, heteroaryl or substituted heteroaryl group,
• Z is a covalent bond,
• R is an alkyl or substituted alkyl,
• X is halo or substituted hydroxy or amino, monosubstituted amino or disubstituted amino group.

A method of treating a disease connected with the function of the chaperon system or associated with the injury of the membrane of a cell o cell organellum or preventing the same which comprises:

• administering to a host that has been exposed to a physiological stress accompanying allergic diseases, immune diseases, autoimmune diseases, diseases of viral or bacterial origin, tumorous, skin and/or mucous diseases, epithelial disease of renal tubulus, atherosclerosis, coronarial disease, pulmonary hypertonia, cerebrovascular ischemia, stroke, or traumatic head injury an effective amount of a chemical compound to increase the expression of a molecular chaperon by cells of the host beyond an amount induced by the physiological stress to ameliorate the effect caused by the pathological condition in the organism, wherein the chemical compound is one or more of a hydroxylamine derivative represented by formula (I),
• or a salt thereof or an optically active stereoisomer thereof, wherein
• A is alkyl, substituted alkyl, aralkyl, aralkyl substituted in one or both of the aryl or alkyl moiety, aryl, substituted aryl, heteroaryl or substituted heteroaryl group,
• Z is a covalent bond,
• R is an alkyl or substituted alkyl, and
• X is halo or a substituted hydroxy or amino, monosubstituted amino or disubstituted amino group.

Compounds of the formula (I)

• wherein
• a) X is halo,
• Z is chemical bond and
• a1) A is a group of the formula (a),
• wherein Y1 is halo, alkoxy, haloalkyl or nitro and n is 1, 2 or 3, or
• an O-containing heteroaryl, an S-containing heteroaryl, or an N-containing heteroaromatic group which may be condensed with a benzene ring, or the N—C1-4 alkyl quaternary derivative or the N-oxide thereof,
• R is a group of the formula (b),
• wherein R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6 when taken together with the N-atom adjacent thereto form a 3 to 7-membered, saturated heterocyclic ring, Y6 is —OR7, wherein R7 is H or unsubstituted or substituted alkylcarbonyl, arylcarbonyl or aminoacyl, k is 1, 2 or 3, and m is 1, 2 or 3, or an N—C1-4 alkyl-quaternary derivative or N-oxide thereof, with the proviso that
• when A is pyridyl, or a group of the formula (a), wherein Y1 is halo or alkoxy, R7 is other than H, or
• a2) A is a group of the formula (c),
• R is a group of the formula (d),
• and the optional substituents Y2 and Y3, one of which must be present in the molecule, are oxygen or C1-4 alkyl, k is 1, 2 or 3 and m is 1, 2 or 3 and, when the compound is a mono- or divalent cation, the anion is one or two halide ion, or
• b) A is unsubstituted or substituted aryl or an N-containing heteroaromatic group or an S-containing heteroaromatic group,
• Z is chemical bond,
• X is OQ, wherein Q is C1-4 alkyl, and
• R is a group of the formula (b), wherein R5 and R6 are independently H, straight or branched alkyl or cycloalkyl, or R5 and R6 when taken together with the N-atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, Y6 is H, k is 1, 2 or 3, and m is 1, 2 or 3.

Hydroxylamine derivatives of the formula (I)

• wherein
• X is NR1R2, wherein R1 and R2 are independently H or unsubstituted or substituted straight or branched alkyl, or cycloalkyl, or R1 and R2, when taken together with the N-atom attached thereto, form a 3 to 7-membered hetero ring,
• A is unsubstituted or substituted phenylalkyl substituted with one or more alkoxy, phenyl, phenyl substituted with one or more halo, alkyl or haloalkyl or acylamino or nitro, or an unsubstituted or substituted N-containing heteroaromatic group which may be condensed with a benzene ring, or an S-containing heteroaryl, wherein the hetero atoms may have one or more alkyl substituent(s), Z is a chemical bond, and
• R is a group of the formula (e),
• wherein R5 and R6 are independently H, straight or branched alkyl, or cycloalkyl, or R5 and R6 when taken together with the N-atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, which may have additional hetero atom(s) and optionally C1-4 alkyl substituent(s), Y4 is H or unsubstituted or substituted C1-4 alkyl, Y5 is H or unsubstituted or substituted C1-4 alkyl or —OR7, wherein R7 is H or acyl, k is 1, 2 or 3, and m is 1, 2 or 3, with the proviso, that
• when R7 is H, at least one of R1 or R2 is other than H, and
• when R1 and R2 are each H, R7 is other than H.