CA2209167C - Hydroxylamine derivatives useful for enhancing the molecular chaperon production and the preparation thereof - Google Patents

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

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CA2209167C
CA2209167C CA002209167A CA2209167A CA2209167C CA 2209167 C CA2209167 C CA 2209167C CA 002209167 A CA002209167 A CA 002209167A CA 2209167 A CA2209167 A CA 2209167A CA 2209167 C CA2209167 C CA 2209167C
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optionally substituted
alkyl
halo
phenyl
naphthyl
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CA2209167A1 (en
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Laszlo Vigh
Peter Literati Nagy
Jeno Szilbereky
Laszlo Urogdi
Andrea Jednakovits
Laszlo Jaszlits
Katalin Biro
Ede Marvanyos
Mihaly Barabas
Erzsebet Hegedus
Laszlo Koranyi
Maria Kurthy
Gabor Balogh
Ibolya Horvath
Zsolt Torok
Eva Udvardy
Gyorgy Dorman
Denes Medzihradszky
Bea Mezes
Eszter Kovacs
Erno Duda
Beatrix Farkas
Attila Glatz
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Abstract

A method of increasing expression of a molecular chaperon by a cell and/or enhancing the activity of a molecular chaperon in cells is provided. The method comprises treating a cell that is exposed to a physiological stress which induces expression of a molecular chaperon by the cell with an effective amount of a certain hydroxylamine derivative to increase the stress. Alternatively, a hydroxylamine derivative can be administrated to a cell before it is exposed to a physiological stress which induces expression of a molecular chaperon by the cell.
Preferably, the cell to which a hydroxylamine derivative is administered is a eukaryotic cell. The hydroxylamine derivative corresponds to the formulae (I) or (II). The invention also provides novel hydroxylamine derivatives falling within the scope of the formulae (I) and (II) as well as pharmaceutical and/or cosmetical compositions comprising the said compounds.

Description

i HYDROXYLAMINE DERIVATIVES USEFUL FOR ENHANCING THE MOLECULAR CHAPERON
PRODUCTION AND THE PREPARATION THEREOF
----1. BACKGROUND OF THE INVENTION

Molecular chaperons are proteins which mediate protein folding. They bind non-covalentlv to exposed surfaces of proteins that are newly synthesized or are denatured or misfolded, and assist theni to fold into correct conformations. Molecular chaperons are also involved in a number of cellular processes such as protein syntlzesis. protein translocation and DNA
replication.

Molecular chaperons include heat shock proteins, which are proteins whose expression increases significantly in cells followin- an exposure to unusually high temperature (heat shock) or an ex-posure to a wide variety of physiological stresses. This increase in the molecular chaperon ex-pression in turn provides cells with protection against the adverse effects of hyperthermia, as demonstrated by the thermotolerance of cells for othenvise lethal temperatures if the cells are pre-conditioned by a brief exposure to high temperature.

Physiological stresses indttcing heat shock protein expression include a wide variety of patho-logical conditions associated with many diseases. The synthesis of heat shock proteins in cells exposed to such stresses, , indicates the protection of the cell against the physiological stresses.
like also in the case of the heat shock response One such pathological condition associated with induction of molecular chaperons is ischemic injury. Ischemic injun. to tissues results from deterioration of blood supply for any possible.
For instance, prolonged coronary occlusion causes severe damage to mvocardium, leadinQ to myocardial necrosis and jeopardizing the chances for recovery even if the blood flow is restored.
In brain. to significant damages may frequently be caused by ischemia, leading to death of the brain-tissue.

It was observed that the amount of heat shock protein hsp70 increased in the myocardium during ischemia leading to necrosis even if the duration of ischemia is short. In these cases, likewise in a heat shock. the enhanced hsp70 content of the cells protects the same against the consequences of a next iscfiemia. which would otlierwise cause necrosis (DAS. D.K.. et al.
Cardiovascular Res.: 578. 1993). It lias also been observed when rat cells in culture were subjected to iscliemia.
J. Clin. Invest.. 93: 759-767 (1994)). Accordinglv. lleat shoch proteins synthesized by mvocar-~ dial cells provide protection asainst ischemic injuries.

The situation in brain-tissue is similar. wherein cerebral iscliemia results in increased expression of heat shocl: protein in the brain tissue. Experinients have also proved that pretreatment of ani-mals with sub-lethal iscliemia induces heat stress protein (hsp70) and protects the brain auainst more severe subsequent ischemic insult. (Simon, et al.. Neurosci. Lett. .
163:1 '15-137 (199 -,)).

Yet another example of physiological stress on tissues and orLans associated with molecular chaperon induction is provided by inflammatory diseases. Inflammation is a non-specific re-sponse of liost cells to entrv of foreign material, such as in case of infection bv various bacterial and viral pathogens. and involves aggregation and activation of leukocvtes to the injurv site.
which results in production and release of high levels of reactive oxygen species and evtolcines.
These cytokines and reactive oxygen radicals attack the pathogen, but also damage the host tis-sues (Jaquier.Sarlin, Experientia, 50: I031-1038 /1994/). It is believed that as a protection a~~ainst these toxic mediators of intlammation, the host tissues increase production of molecular chaperons. Molecular chaperons thus produced protect host cells from damaaes caused by reac-tive oxygen species and protect cells from cytotoxicity of TNF and other cytokines and reactive oxyuen radicals. In animal studies, it has been denlonstrated the pre-exposure of an animal to heat shock. with resulting increase of a heat shock protein (hsp70) expression. resulted in re-niarkable decrease in pulmonary inflammation. Accordingly, molecular chaperons serve anti-inflammatory function.

The above examples illustrate ability of molecular chaperons to protect cells against various physiological stresses disturbing cellular homeostatic balance and causinQ
injury to cells. Mo-lecular chaperons have also been shown to be advantageous in treating neoplasms. For examp.le, it has been reported that when tumor cells are transfixed with a gene encodina a molecular chap-eron (65 kd hsp), they lose or show decrease in their tumori2enicity (W01994/011513).
Furthermore. it has also been reported that tumor cells. in response to heat stress, express molecular chaperons in increased amount. However, they are present not in cyto-plasm, but on the surface of cell membranes. (Ferrarini.M. et al, Int.J.Cancer. 51:613-619 /1992/). Increased presence of molecular chaperons on cell surfaces correlates with increased sensitivity of Nh (naturai killer) cells toward the tumor cells. allowinQ
better taruetin_. inTiltral-ina. and I:iliinR of tht tumor cells b~ NK celis (k:urosawa.S. et al.
Eur..i.imrnunol.
23:1029/1993/).

In view of the advantaEes associated with increased molecular chaperon ex.pression in cells. a method whicli increas::d such expression or increased activity of molecular chaperons would be hiuhly desirable.

.2. SUMMARY OF THE INVENTION

The invention relates to methods for increasina expression or enhancing activity of molecular chaperons bv a cell. In particular, accordina to one non-limitina embodiment of the invention. a method is provided comprisins; trcating a cell that is exposed to a physiological stress with an effective amount of a cliemical compound during, before or after the physiological stress which increases expression of a molecular chaperon in the cell beyond the amount induced by the physiological stress, wherein the chemical compound is a hydroxylamine derivative the tautomeric forms of which are represented by formulae (I) and (11 ):
X
x ~ L/~lv/'~~R -~-__- N R
?0 oi- its salt, including the optically active stereoisomers thereof. wherein A is an alkvl. substituted alkvl, aralkyl. aralkyl substituted in the aryl and/or in the alkyl nioiety.
an-i, substituted aryl. lieteroarvl or substituted heteroaryl LIroup, Z is a covalent bond, oxygen or =NR' wherein R' is selected from the -aroup consistinc-7 of hvdro-~en, an alkyl, substituted alkyl, aryl. substituted aryl. aralkyl, or aralkvl substituted in the aryl and/or in the alkvl moietv, R is an alkvl or substituted alkyl.

X in the tautomer of formula (I) is halogen or a substituted hydroxy or amino, monosubstituted amino or disubstituted amino aroup and X in the tautomer of formula (II) is oxygen, imino or substituted imino Qroup and R' is hydrogen, an aikvl_ substituted alkyl, a:vl, substituted aryl, aralkvl, aralkvl havinz subst;-tuted aryl and/or alkvl moie-,!. acyl or substituted acyl group.

and the compounds of formula (I) optionally contain intramolecular rin~~
structures formed bv coupling X and a reactive substituent.

An other non-limitina embodiment of the invention is the method of enhancina the activity of a molecular cllaperon in a cell exposed to a physiological stress which comprises administerina, an effective amount of a hvdroxylamine derivative of structure (I) or (II). as described above. Thus.
the activity of molecular chaperon is increased beyond the anlount induced by the physiological stress alone. In either of these niethods. it is preferred that the cell to which the livdroxylanline derivative is administered to is an euharvotic cell.

Accordin!2 to the invention eucarvotic celis are treated with tile hydroxviamine derivatives as defined above.

Another aspect of the invention is the method of treatment, or possible prevention of diseases connected with functioning of the chaperon system or associated with damages of the cell- or cell-or~anellum membrane, wherein for suppressin~: the patliological condition effective amount of a hydroxylamine derivative of the formula (I) or (II) is administered to the host organism.

Still another aspect of the invention is the use of the hydroxylamine derivatives of the forniula (I) or (II) or the salts thereof in the preparation of pharmaceutical compositions which can be used in the treatment of cardiovascular, vascular, cerebral, tumorous diseases, diseases of the skin and/or mucous membrane or those of the epitllelial cells of renal tubules, as well as in the preparation of cosmetical compositions.

The invention further relates to novel llvdroxvlamine derivatives possessing a wide range of bioloEiical effect and are useful for enhancing the level of molecular chaperon in organisms or the activitv of the said molecular chaperons and for the preparation of pharmaceutical and cosmetical compositions applicable to this purpose.

A further aspect of the invention is represented by the pha:maceutical and cosmetical composi-2~ tions which comprise novel hvdroxylamine derivatives toQether with carriers and auxiliaries gen-erally acceptable in such compositions.

The present invention is based, at least in part, on an unexpected discovery that hvdroxvlamine derivatives havinc, structures as described above, when used in the treatment of cells, are capable of increasing the amount of molecular chaperons produced by that cell or enhancino the activity thereof. This effect is particularly great when the cell is under physiological stress which induces 4a molecular chaperon expression. In such cases, the chemical compound enhances expression of molecular chaperons by the cell beyond that amount induced by the physiological stress alone. This discovery is significant in view of the role molecular chaperons play in cells defending themselves against pathological effects of various diseases. Thus, if a compound is able to increase the amount or enhance the activity of molecular chaperons being expressed by cells, this allows the cells to be protected against the deleterious effects of the diseases and to repair damages caused by them.

In another non-limiting embodiment of the invention, there is provided a pharmaceutical composition for increasing expression of a molecular chaperon expressed by an eukaryotic cell that is exposed to a physiological stress to increase the expression of the molecular chaperon by the cell beyond the amount induced by the physiological stress comprising (a) a chemical compound and (b) a pharmaceutically acceptable carrier or auxiliary, wherein the chemical compound is a hydroxylamine derivative, the tautomeric forms of which are represented by formulae (I) and ( I I), x }C
A '~. Z 0 A , ~
Z ~1 R 0-11-11R
or its salt and/or any optically active stereoisomer thereof, wherein:

(a) Z is oxygen or =NR3, wherein R3 is:

4b hydrogen, a straight or branched C1_21-alkyl, optionally substituted by: cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-e alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1_$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-S alkyl;
phenyl; or naphthyl;

X in the tautomer of formula (I) is:
halogen, substituted hydroxy group -OQ, wherein Q is C1-21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl; or Q is C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy;

4c nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or NR1R2, wherein R1 and R2, independently from each other, are:

hydrogen;

straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1_B alkyl optionally substituted by one to three halo;

Cl_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4:

hydrogen, C1_21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

4d C3_8-cycloalkyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-6 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-e alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1_$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1_$ alkyl;
phenyl; or naphthyl; or 4e C1_8-alkanoyl, a C1-B-alkoxy-carbonyl, a C1_8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1_8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-$-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-Cl-$ alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1_8 alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

A is straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-6 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-g alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or 4f a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

A 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-$ alkyl;

or (b) Z is a covalent bond, 4g (bl) X in the tautomer of formula (I) is halogen, and (bl)(i) R is a group of the formula (b), --- (G H ~ )~,- CH--- ~C N , )m- N b t ~

y wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1_9 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR', wherein R' is hydrogen or C1-8-alkanoyl, a C1_$-alkoxy-carbonyl, a C1_8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-$-alkanoyl, naphthyl-C1-8-alkanoyl C3-8-cycloalkyl-C1_-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1_8-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3_$ cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; Cl_a alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3; and 4h A is group of the formula (a) (~I4n 0 (ci) wherein Y' is halo, C1-$ alkoxy, halo-C1_8 alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1-4alkyl quaternary derivative or the N-oxide thereof, with the proviso that when A is pyridyl, or a group of the formula (a) wherein Y' is halo or alkoxy, R' is other than H; or (bl)(ii) R is a group of the formula (d), (c H 2 ) k --- CH--- (C N Z) rn --- jr~ (d ~
l ' UH
y and A is a group of the formula (c), 4i y 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;

(b2) X in the tautomer of formula (I) is:
substituted hydroxy group -OQ, wherein Q is C1-21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or Q is C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1-e alkyl;
phenyl; or naphthyl; or NR1R2, wherein R' and R2, independently from each other, are:

straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

4j C3_8-cycloalkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; Cl-B alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl; or R1 and Rz, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring, or X when taken together with R optionally form a dioxazine or oxadiazine ring of formula (I') A
~

~-0 or (I"), Ft A

wherein R" is a straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated 4k hetero ring, optionally further containing one or more nitrogen, oxygen, or sulfur; phenyl; or naphthyl;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4:

C1_21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C3-$-cycloalkyl;

C1-$ alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1_$ alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1_21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-e alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1_8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1_8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or C1_8-alkanoyl, a C1-$-alkoxy-carbonyl, a C1_8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1_8-alkanoyl, naphthyl-C1-$-alkanoyl, C3_8 cycloalkyl-C1_8-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1_8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-$ cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

R is C1_21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

A is straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-e alkoxy; nitro; amino 4m optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C1_8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-$ alkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1_e alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1_8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

4n any of which group optionally substituted by cyano, hydroxyl, halo, C1_8 alkyl optionally substituted by one to three halo, C1_6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1_6-alkoxy, nitro, amino optionally substituted by one or two C1_8 alkyl;

or (b3) X in the tautomer of formula (I) is NH2;
R is a group of the formula (e) ( (c~Z)k--C--(cHz)~ ~'r I ~~6 Ys wherein RS and R6 independently from each other are hydrogen, straight or branched C1-9 alkyl, C3-B cycloalkyl, or R5 and R6when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; and optionally substituted by C1_4 alkyl, Y4 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-B alkyl optionally substituted 4o by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

Y5 is hydrogen or C1_4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl; or -OR', wherein R' is C1-$-alkanoyl, a C1_8-alkoxy-carbonyl, a C1_8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-$-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1_8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; k is 1, 2 or 3, and m is 1, 2 or 3;
and A is straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1_8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or 4p a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-$ alkyl optionally substituted by one to three halo, C1_6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl.

In another non-limiting embodiment of the invention, there is provided a pharmaceutical composition for increasing activity of a molecular chaperon in an eukaryotic cell that is exposed to a physiological stress to 4q increase the activity of the molecular chaperon in the cell beyond the amount induced by the physiological stress comprising (a) a chemical compound and (b) a pharmaceutically acceptable carrier or auxiliary, wherein the chemical compound is a hydroxylamine derivative the tautomeric forms of which are represented by formulae (I) and (II), x A yryryyy /f' ~ ~

/ ~ (1 ~~~y~~=~ ~.. 5~~~
4 n \~ / `h(R R
or its salt and/or any optically active stereoisomer thereof, wherein:

(a) Z is oxygen or =NR3, wherein R3 is:
hydrogen, a straight or branched C1_21-alkyl, optionally substituted by: cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

Cl-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or 4r phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl;

X in the tautomer of formula (I) is:
halogen, substituted hydroxy group -OQ, wherein Q is C1_21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1_$ alkyl; phenyl; or naphthyl; or Q is C1_$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or NR1R2, wherein R1 and RZ, independently from each other, are:

hydrogen;
straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C3_8-cycloalkyl 4s phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl; or R1 and RZ, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4:

hydrogen, C1_21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;
C3-$-cycloalkyl;
C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1_8 alkyl;
phenyl; or naphthyl; and R' is 4t hydrogen, a straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_$ alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or C1_8-alkanoyl, a C1-$-alkoxy-carbonyl, a C1_8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-$-alkanoyl, naphthyl-C1-a-alkanoyl, C3-8 cycloalkyl-C1-$-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1_8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1_$ alkyl optionally substituted by one to 4u three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two Cl-$ alkyl; phenyl; or naphthyl;

A is straight or branched C1-z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1_8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1_8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1-e alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

4v a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1_6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl;

or (b) Z is a covalent bond, (bl) X in the tautomer of formula (I) is halogen, and (b1)(i) R is a group of the formula (b), -T (Ct-~ ~ ),,---- C H--- ~C 3-I ~ ~M-('~ (b) wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-9 alkyl, 4w C3_8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, an N-C1_4 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR', wherein R7 is hydrogen or C1_8-alkanoyl, a C1-$-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-Cl-$-alkanoyl, C3_$-cycloalkyl-Cl_$-alkanoyl, phenyl-C1_8 alkoxyl-carbonyl, naphthyl-C1_8-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;
optionally substituted by one to three cyano; hydroxyl;
halo; C1_8 alkyl optionally substituted by one to three halo;

C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3, and A is group of the formula (a) cytn 0 (c) wherein Y' is halo, C1-$ alkoxy, halo-C1-$ alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group 4x containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1-9 alkyl quaternary derivative or the N-oxide thereof, with the proviso that when A is pyridyl, or a group of the formula (a) wherein Y' is halo or alkoxy, R7 is other than H; or (bl)(ii) R is a group of the formula (d), --(CH2 )k---CH- (CH'z )M--~1 I , y and A is a group of the formula (c), C C
tt y 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;

(b2) X in the tautomer of formula (I) is:

4y substituted hydroxy group -OQ, wherein Q is C1-z1-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl; or Q is C1_8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1_$ alkyl;
phenyl; or naphthyl; or NR1R2, wherein R1 and R2, independently from each other, are:

straight or branched C1-Z1 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C3-$-cycloalkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-$ alkyl optionally substituted by one to three halo;
C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-B alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring, or X when taken together with R optionally form a dioxazine or oxadiazine ring of formula (I') 4z 00 i or (I"), A
<\

wherein R" is a straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; phenyl; or naphthyl;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4 is :

C1_zl-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_$ alkoxy; nitro; amino optionally substituted by one or two C1_a alkyl; phenyl; or naphthyl;

C3-$-cycloalkyl;
C1-8 alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further 4aa optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_$ alkoxy;
nitro; amino optionally substituted by one or two C1-B alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-e alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1_21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1_$ alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or C1_$-alkanoyl, a C1-$-alkoxy-carbonyl, a Cl-$ alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1_8-alkanoyl, naphthyl-C1_8-4bb alkanoyl, C3_8 cycloalkyl-C1_8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-e alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3_8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

A is straight or branched C1_21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-$ alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1_8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_$ alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing 4cc one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1_8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1_6-alkoxy, nitro, amino optionally substituted by one or two C1_8 alkyl;

or (b3) X in the tautomer of formula (I) is NH2;
R is a group of the formula (e) 4dd I z -(CN Z)k---- C --- (C H Z )tr; N
Y~
wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-$ cycloalkyl, or R5 and R6when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; and optionally substituted by C1_4 alkyl, Y4 is hydrogen or C1-9 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

Y5 is hydrogen or C1_4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl; or -OR7, wherein R7 is C1_8-alkanoyl, a C1_8-alkoxy-carbonyl, a C1_8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-$-alkanoyl, naphthyl-C1_8-alkanoyl, C3_$ cycloalkyl-C1-$-alkanoyl, phenyl-C1_8 alkoxyl-carbonyl, naphthyl-C1_8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, 4ee thienyl-sulphonyl, furyl-sulphonyl;, k is 1, 2 or 3, and m is 1, 2 or 3;

and A is straight or branched Cl-z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-$ alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1_8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

4ff a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-$ alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1_$ alkyl.

In another non-limiting embodiment of the invention, there is provided a pharmaceutical composition or a cosmetical composition for the treatment of a pathological condition connected with the function of the chaperon system or associated with the injury of the membrane of a cell or cell organellum, or optionally for the prevention of such pathological condition, comprising (a) a chemical compound, and (b) a pharmaceutically or cosmetically acceptable carrier or auxiliary, wherein the chemical compound is a hydroxylamine derivative the tautomeric forms of which are represented by formulae (I) and (II), 4gg x X
z N~,.a~R A z -~~ ~ R
or its salt and/or any optically active stereoisomer thereof, wherein:

(a) Z is oxygen or =NR3, wherein R3 is:
hydrogen, a straight or branched C1-21-alkyl, optionally substituted by: cyano; hydroxyl; halo; C1-e alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

Cl-$ alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

X in the tautomer of formula (I) is:
halogen, 4hh substituted hydroxy group -OQ, wherein Q is C1_21-alkyl optionally substituted by:
cyano; hydroxyl; halo; Cl_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl; or Q is C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1_8 alkyl;
phenyl; or naphthyl; or NR1R2, wherein R' and R2, independently from each other, are:

hydrogen;
straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1_$ alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
Cl_B alkoxy; nitro; amino optionally substituted by one or two C1_e alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring;

and 4ii X in the tautomer of formula (II) is oxygen or =NR4, wherein R4 is :

hydrogen, C1-21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;
C3_$-cycloalkyl;

C1-$ alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1_21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;
C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

4jj nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1_$ alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or C1-8-alkanoyl, a C1_8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl naphthyl-C1-$-alkanoyl, C3_$ cycloalkyl-C1-8-alkanoyl, phenyl-C1_$ alkoxyl-carbonyl, naphthyl- C1-$ alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

A is straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two Cl-$ alkyl; phenyl; or naphthyl;

C1_8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further 4kk optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1_8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1_$ alkyl optionally substituted by one to three halo, C1_6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1_6-alkoxy, nitro, amino optionally substituted by one or two C1_8 alkyl;

or (b) Z is a covalent bond, (bl) X in the tautomer of formula (I) is halogen, and (bl)(i) R is a group of the formula (b), -(CH Z) , -C H-(CH~ ),,,--- N
6 b) "s, ~

wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-$ cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR7, wherein R' is hydrogen or C1-$-alkanoyl, a C1-8-alkoxy-carbonyl, a C1_8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1_8-alkanoyl, naphthyl-C1_8-alkanoyl, C3_$-cycloalkyl-C1_8-alkanoyl, phenyl-C1-g alkoxyl-carbonyl, naphthyl-C1-$-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, 4mm C3_8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;
optionally substituted by one to three cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1_8 alkoxy; nitro; amino optionally substituted by one or two Cl-$ alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3, and A is group of the formula (a) c y I HO L (ci) wherein Yl is halo, C1-$ alkoxy, halo-C1-$ alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1_4 alkyl quaternary derivative or the N-oxide thereof, with the proviso that when A is pyridyl, or a group of the formula (a) wherein Y' is halo or alkoxy, R' is other than H; or (b1)(ii) R is a group of the formula (d), 4nn - (CH 2)k-- C H -(CH )m-N
(d) (i H ~~.
Y
and A is a group of the formula (c), 0 c-N
~
~
rZ
y and the optional substituents Y 2 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;

(b2) X in the tautomer of formula (I) is:
substituted hydroxy group -OQ, wherein Q is C1-21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl; or Q is C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_$ alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or 4oo NR1R2, wherein R1 and R2, independently from each other, are:

straight or branched C1_21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

C3_8-cycloalkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1_8 alkyl optionally substituted by one to three halo;
C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring, or X when taken together with R optionally form a dioxazine or oxadiazine ring of formula (I') ~ ;
~+

or (I"), N
A- \

4pp wherein R" is a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo;
C1-8 alkyl optionally substituted by one to three halo;

C1-$ alkoxy; nitro; amino optionally substituted by one or two C1_$ alkyl; or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more nitrogen, oxygen, or sulfur; phenyl; or naphthyl;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4 is :

C1_21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl;
C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; Cl-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1_8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; and R' is hydrogen, 4qq a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-g alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1-g alkoxy;

nitro; amino optionally substituted by one or two C1_8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or C1-$-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-$ alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-$-alkanoyl, naphthyl-C1_8-alkanoyl, C3-$ cycloalkyl-C1-$-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl- C1-$ alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-$ cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally -substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-e alkyl; phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

4rr A is straight or branched C1_21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1_B alkyl optionally substituted by one to three halo; C1-6 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1_8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1_$ alkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed 4ss heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1_6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl;

or (b3) X in the tautomer of formula (I) is NH2;
R is a group of the formula (e) ---(CHZ)k--C--(C:HZ)rn; N~
!
Ys wherein R5 and R6 independently from each other are hydrogen, straight or branched C1_4 alkyl, C3_8 cycloalkyl, or R5 and R6when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; and optionally substituted by C1_9 alkyl, 4tt Y4 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-e alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

Y5 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl; or -OR', wherein R' is C1-e-alkanoyl, a C1_$-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-$-alkanoyl, naphthyl-C1-$-alkanoyl, C3-$ cycloalkyl-C1_$-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1_e alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;, k is 1, 2 or 3, and m is 1, 2 or 3;

and A is straight or branched C1_21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1_$ alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1_6-alkoxy, nitro, or amino optionally substituted by one to two C1-$ alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy;

4uu nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogenn, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1_8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl.

4vv In another non-limiting embodiment of the invention, there is provided a use of a compound of the formula (I) Y, A~''`~ ~'#=~`'d0 wherein a) Z is a covalent bond X is halo, and al) R is a group of the formula (b), (CHZ)k- c H-- ~CH z )m---- N b wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-$ cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-9 alkyl-quaternary derivative or N-oxide thereof, 4ww Y6 is -OR7, wherein R7 is hydrogen or C1_8-alkanoyl, a C1_8-alkoxy-carbonyl, a C1-$ alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-Cl_8-alkanoyl, naphthyl-C1-$-alkanoyl, C3-$ cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1_8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3, and A is a group of the formula (a) y n 0 (ci>

, wherein Yl is halo, C1-$ alkoxy, halo-C1-8 alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1_4 alkyl quaternary derivative or the N-oxide thereof, with the proviso that 4xx when A is pyridyl or naphthyl, or a group of the formula (a) wherein Y' is halo or alkoxy, R' is other than H, or a2) R is a group of the formula (d), --(cHI )k-cH- (CHN
UH
Y
A is a group of the formula (c), 0 (c) Y

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) Z is oxygen or =NR3 wherein R3 is hydrogen or C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo;
C1-$ alkyl optionally substituted by one to three halo;
C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl, X is -NR1R2, wherein R1 and R2 independently from each other are:

hydrogen;

4yy straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-B alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or R1 and RZ, when taken together with the nitrogen atom adjacent thereto, form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur, A is straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl; or C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;

4zz nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; and R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1_4-alkyl, C3-8-cycloalkyl or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, 6 is hydrogen or -OR', wherein R' y is hydrogen or C1_g-alkanoyl, a C1_8-alkoxy-carbonyl, a C1-$
alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-$-alkanoyl, naphthyl-C1-$-alkanoyl, C3-$
cycloalkyl-C1-8-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1-$ alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

k is 1, 2 or 3, and m is 1, 2 or 3, or c) Z is oxygen 4aaa X is substituted hydroxy group -OQ, wherein Q is as defined above;

R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1_4-alkyl, C3-$-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OR', wherein R' is hydrogen or C1_8-alkanoyl, a Cl_$-alkoxy-carbonyl, a C1-$ alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-$-alkanoyl, C3_$ cycloalkyl-C1-$-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1-$
alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano; hydroxyl;

halo; C1_8 alkyl optionally substituted by one to three halo;
C1_8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

k is 1, 2 or 3, and m is 1, 2 or 3, and A is straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1_$ alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two Cl-g alkyl; phenyl; or naphthyl; or 4bbb C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl; or d) Z is a covalent bond, X is OQ, wherein Q is C1-4 alkyl, and R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, y6 is hydrogen, k is 1, 2 or 3, and m is 1, 2 or 3; and A is phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing 1 to 4 nitrogen in the ring, a 3- to 8- membered unsaturated condensed heterocyclic group containing 1 to 5 nitrogen in the ring, 4ccc a 3- to 6-membered unsaturated hetero-monocyclic group cotainning one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogenn, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen;

for the treatment of a disease connected with the function of the chaperon system or associated with the injury of a cell or cell organellum or optionally preventing the same.
In another non-limiting embodiment of the invention, there is provided a use of a compound of the formula (I) X
A~~

wherein a) Z is a covalent bond X is halo, and al) R is a group of the formula (b), 4 ddd --- (CHZ)t~--- CH-- ~C H2} M_N b y wherein R5 and R6 independently from each other are hydrogen, straight or branched C1_4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-Cl-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR', wherein R' is hydrogen or C1-$-alkanoyl, a C1-$-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-Cl-$-alkanoyl, naphthyl-C1_$-alkanoyl, C3-$ cycloalkyl-Cl-8-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1-$ alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3, and A is a group of the formula (a) 4eee W 7 ct ) , wherein Y1 is halo, C1-8 alkoxy, halo-C1-$ alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1-4alkyl quaternary derivative or the N-oxide thereof, with the proviso that when A is pyridyl or naphthyl, or a group of the=formula (a) wherein Y' is halo or alkoxy, R7 is other than H, or a2) R is a group of the formula (d), - (C H,)I,---- C H --- (CH z )m--r N
(d) UH
y A is a group of the formula (c), 4fff z Y

and the optional substituents Y2 and Y3, one of which must be present in the molecule, are oxygen or C1-4alkyl, 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) Z is oxygen or =NR3 wherein R3 is hydrogen or C1_21-alkyl optionally substituted by: cyano; hydroxyl; halo;
Cl_$ alkyl optionally substituted by one to three halo;

C1-$ alkoxy; nitro; amino optionally substituted by one or two C1_$ alkyl; phenyl; or naphthyl, X is -NR'R2, wherein R1 and R2 independently from each other are:

hydrogen;
straight or branched C1_21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1_$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C1-$ alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, optionally substituted by: cyano; hydroxyl; halo; C1-e alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

4ggg phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; Cl-$ alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur, A is straight or branched C1_21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1_$ alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; and R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, 4hhh straight or branched C1-4-alkyl, C3-8-cycloalkyl or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1_4 alkyl-quaternary derivative or N-oxide thereof, Y6 is hydrogen or -OR7, wherein R7 is hydrogen or C1-$-alkanoyl, a C1_8-alkoxy-carbonyl, a C1_8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1_8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-$ alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-$ cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

k is 1, 2 or 3. and m is 1, 2 or 3, or c) Z is oxygen X is substituted hydroxy group -OQ, wherein Q is as defined above;

R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1_4-alkyl, C3-$-cycloalkyl, or 4iii R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OR', wherein R' is hydrogen or C1-8-alkanoyl, a C1_8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1_8-alkanoyl, naphthyl-C1_$-alkanoyl, C3_$ cycloalkyl-C1-$-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1-a alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-$ cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano; hydroxyl;
halo; C1_8 alkyl optionally substituted by one to three halo;
C1-$ alkoxy; nitro; amino optionally substituted by one or two C1_$ alkyl; phenyl; or naphthyl;

k is 1, 2 or 3, and m is 1, 2 or 3, and A is straight or branched C1-Z1-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1_8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1_8 alkyl; or d) Z is a covalent bond, X is OQ, wherein Q is C1_4 alkyl, and R is a group of the formula (b), wherein R5 and R6 independently from each other are 4jjj hydrogen, straight or branched C1-9-alkyl, C3_8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1_4 alkyl-quaternary derivative or N-oxide thereof, Y6 is hydrogen, k is 1, 2 or 3, and m is 1, 2 or 3; and A is phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing 1 to 4 nitrogen in the ring, a 3- to 8- membered unsaturated condensed heterocyclic group containing 1 to 5 nitrogen in the ring, a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed 4kkk heterocyclic group containing one or two sulfur and one to three nitrogen;

in the manufacture of a medicament for the treatment of a disease connected with the function of the chaperon system or associated with the injury of a cell or cell organellum or optionally preventing the same.

In another non-limiting embodiment of the invention, there is provided a hydroxylamine derivative of the formula (I) A~~

wherein Z is a covalent bond, X is -NR'R2, wherein R' and R2 independently from each other are:

hydrogen, straight or branched C1_6-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_$ alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl;

C3-$-cycloalkyl; or R1 and R2, when taken together with the nitrogen atom attached thereto, form a 3 to 7-membered saturated heterocyclic ring;

R is a group of the formula (e) -(GHZ)k--c--(C:H~; N~
I
ys wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-9 alkyl, C3-$ cycloalkyl, or R5 and R6when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; and optionally substituted by C1-4 alkyl, Y4 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

Y5 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-$ alkyl; phenyl; or naphthyl; or -OR7, wherein R' is hydrogen or C1_$-alkanoyl, a Cl-a-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, 4mmm naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1_8-alkanoyl, C3_8 cycloalkyl-C1-$-alkanoyl, phenyl-C1_8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-$ cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;

k is 1, 2 or 3, and m is 1, 2 or 3; and A is C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-$-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl optionally substituted with one or more halo, Cl-$ alkyl or halo-C1-8 alkyl, acylamino, the acyl moiety of which is C1_8-alkanoyl, a C1_8-alkoxy-carbonyl, a C1-$-alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-$-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-C1-$-alkanoyl, phenyl-C1_8 alkoxyl-carbonyl, naphthyl-C1-a-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-$-cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano;
hydroxyl; halo; C1_8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

nitro; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

4nnn a 3- to 6-membered unsaturated hetero-monocyclic group cotainning one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogenn, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen;

wherein the hetero atoms are optionally substituted by one or more C1-9-alkyl;

with the proviso, that when A is phenyl, phenyl substituted with halo or C1_8-alkoxy or phenyl C1-$-alkyl substituted with C1-$-alkoxy or a pyridyl group, then at least one of R1, R2, and R7 is other than H.

In another non-limiting embodiment of the invention, there is provided a hydroxylamine derivative of the formula (II) as defined herein, wherein a) Z is covalent bond, X is oxygen, R' is hydrogen, C1-4-alkyl or C1_6-alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, 4ooo R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-9-alkyl, C3-$-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1_4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OR7 wherein R7 is H, k is 1, 2 or 3, and m is 1, 2 or 3, and A is straight or branched C1-z1-alkyl, phenyl, naphthyl, pentalenyl, or anthracenyl optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-$ alkoxy; nitro; amino optionally substituted by one or two C1_$ alkyl; phenyl; or naphthyl;
C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-$ alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_8 alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl;

naphthyl;

4ppp a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group cotainning one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogenn, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen;

with the proviso that when A is other than C1-21 alkyl and R' is hydrogen, Y 6 is hydrogen, or b) Z is covalent bond, oxygen or =NR3 wherein R3 is hydrogen or C1-z1-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, X is =NR4, wherein R4 is hydrogen, C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1_8 alkyl optionally substituted by one to 4 qqq three halo; C1_8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1_8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1_8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

R is a group of the formula (b), D
-(CHI)~-CH-~CHz) N b y wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl C3-$-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1_4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OR7 , wherein R7 is H or C1_$-alkanoyl, a C1_$-alkoxy-carbonyl, a C1_$ alkylsulphonyl, 4rrr phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1_8-alkanoyl, naphthyl-C1_8-alkanoyl, C3-8-cycloalkyl-C1_8-alkanoyl, phenyl-C1-$ alkoxyl-carbonyl, naphthyl-C1-g alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3_8-cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano;
hydroxyl; halo; C1_$ alkyl optionally substituted by one to three halo; C1_$ alkoxy; nitro; amino optionally substituted by one or two C1-e alkyl; phenyl; or naphthyl;

k is 1, 2 or 3, and m is 1, 2 or 3, A is C3-$-cycloalkyl, Cl-$ alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-B alkyl optionally substituted by one to three halo; C1-$ alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-$ alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; and R' is straight or branched C1_21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-6 alkyl optionally substituted by one to three halo; C1-e alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

C1_8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl 4sss optionally substituted by one to three halo; C1-e alkoxy;
nitro; amino optionally substituted by one or two C1-$ alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1_8 alkyl optionally substituted by one to three halo;
C1_8 alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl; or c) Z is oxygen, X is oxygen, R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-$-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-9 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OR7 wherein R7 is H or C1_8-alkanoyl, a C1-$-alkoxy-carbonyl, a C1-$ alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1_8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-Cl-$-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1_$

alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3_e-cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;

k is 1, 2 or 3, and m is 1, 2 or 3; and 4ttt A is straight or branched C1_21- alkyl optionally substituted by: cyano; hydroxyl; halo; C1-a alkyl optionally substituted by one to three halo; C1-B alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-s alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-$ alkyl;

R' is C1-q-alkyl or C1_8-alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, or d) Z is =NH, X is oxygen, and dl) R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OH, k is 1, 2 or 3, and m is 1, 2 or 3;

4uuu A is straight or branched C1-21- alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-B alkoxy; nitro; amino optionally substituted by one or two C1_8 alkyl; phenyl; or naphthyl;

C3-$ cycloalkyl; or C1_8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl; phenyl optionally substituted with halo, C1-$-alkyl, halo C1-8-alkyl, C1-$- alkoxy or nitro, and R' is C1-Z1-alkyl or C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl.

In another non-limiting embodiment of the invention, there is provided a hydroxylamine derivative of the formula (I"), P,n A \ J
N-ti wherein A is phenyl optionally substituted with halo or nitro, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to 4vvv five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group cotainning one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogenn, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen, R' is hydrogen; and R" is w-amino-C1-5-alkyl optionally mono- or disubstituted on the amino group, wherein the amino substituents may be independently from each other one or two straight or branched C1_8_alkyl or C3-$-cycloalkyl or the two amino substituents, when taken together with the nitrogen atom attached thereto form a 3 to 7-membered, saturated heterocyclic ring, or the C1_4 alkyl-quaternary derivative or the N-oxide thereof, with the proviso, that when A is 3-pyridyl, R" is other than 1-piperidinyl-methyl.

3. BRIEF DESCRIPTION OF THE FIGURES AND CHEMICAL FORMULAE
3.1 BRIEF DESCRII'TION OF THE FIGURES

Figure I shows the cllanges in hsp level on H9c2 rat mvocardium exposed to lieat sllock by the etfect of treatment with N-[2-hvdroxy-3-(1-piperidinyl)-propoxy]-3-pyridinecarboximidovl chlo-ride maleate. This compound is labeled B on the Fi;,~ures and referred to as compound B in the followings as well.

Fi",ure 2 shows the results of the above experiment obtained by Western blot analysis based on densitometric evaluation.
Finrure 3 shows the results of hsp70 mRNA Northern blot analysis obtained during examination of the effect of compound B on cellular hsp expression at transcription level.

Figure 4 shows the results of hsp26 mRNA Northern blot analysis obtained on Saccharomyces cerevisiae cells durin- examination of the effect of compound B on hsp activation.

Figure 5 shows the effect of benzvl alcohol on the adenylate cyclate activation and the membrane state of plasma.

Fiaure 6 shows the hsp gene expression rate on HeLa cells, using luciferase reporter Qene for the test.

Figure 7 illustrates the effect of compound B on hsp72 cell surface expression in K562 cell line.
Figure 8 shows the interaction of compound B and different lipid membranes showina the in-crease of surface pressure.

Figure 9 shows the effect of compound B in the concentration of 10mM and 100 mM on the bi-laver (L,) =:>T hexaoonal (Hii) phase transfer of large unilamellar vesicules prepared from di--~,u1mit,_w1-phosphatidvl ethanolamine.

Fioure 10 is the diagram of the effect of compound B on the serum TNF level in healthy and STZ
diabetic rats.

Fi`;ure 11 shows the effect of compound B against the grow-th inhibiting effect of keratinocyte =
cyclohexylimide.

Figure 12 shows the effect of compound B a~~ainst the cell damaging effect of cycloheYimide on endothelial cells.

Fi-ure 13 shows the cytoprotective effect of compound B a-ainst the cell damaprin~~ effect of cy-cloltetimide on HeLa cell line.

Fiaure 14 shows the effect of compound B against the grow-th inhibiting effect of cyclo-hexylimide on H9c2 rat myocardium cell line.

Figure 15 shows the effect of cotnpound B on the P1 transcription factor activity in AB 1380 yeast cells.

Fi~~ure 16 shows the effect of compound B on the AP 1 transcription factor activity in JF 1 yeast cells.

Figure 17 shows the effect of compound B on the P 1 transcription factor activity in AB 1380 yeast cells.

Fi-ure 18 shows the test results obtained on isolated functioning ischemic rat heart model wlzerein the model was treated with compound B, determined by Western blotting 2 hours after ischemia.

Figure 19 shows the test results obtained on isolated functioning ischemic rat heart model wherein the model was treated with compound B, determined by Western blotting 3 hours after ischemia.

Figure 20 shows the wound healing on STZ diabetic rats after heat injury by treatment of cream containing 1% compound B.

Figure 21 shows the wound healing on STZ diabetic rats after heat injury by treatment of cream containing 2% compound B.

Figure 22 shows the wound healing on STZ diabetic rats after heat injury by treatment of cream =
containing 4% compound B.

Fi2ure 23 shows the wound healing on STZ diabetic rats after heat injury by treatment of cream containing I% compound B. but evaluated visually.

FiLTure 24 sliows the wound healin, on STZ diabetic rats after heat injury by treatment of cream containing 2% compound B, but evaluated visuallv.

~ Fi,ure 25 sliows the wound healin~~ on STZ diabetic rats after heat injurv by treatment of cream containing 4% compound B. but evaluated visually.

Fiu,ure 26 shows the comparison photo~~raphs (ti-eated and control) made in the above tests by di`lital epiluminescence microscopic technique.

Fi,uure 27 shows the hsp72 level of the samples obtained in the previous tests determined bv Western blottin~ at the treatments with creams containin~~ 1. 2 and 4%
compound B.

Fi`,ure 28 sliows the hsp72 levels determined by immunohistochemical analvsis (treated and control) on SCID mice exposed to UV-B ray and treated with compound B.

Fi~~ure 29 sliows the hsp72 levels determined by Western blotting on SCID mice skin biopsv samples exposed to UV-B ray and treated with compound B.

7a 3.2 BRIEF DESCRIPTION OF THE CHEMICAL FORMULAE
x X

A 0 ~ /0\
z N R z NR R
R

A \

R { R
N
A \

Y' n O Ca~
-(CHz)k-CH-(CHZ)m-N/ (b) I 6 \R6 7b O \ C ~
C N

Y
-(CH2)k-CH-(CHZm-N C (~ ) i zR
-(CHZ)k-C-(CHz)-N ~ Q ) ~R6 Y

NR~ RZ
A (i) N-OH

R-~ ( 2 }

7c X

HNR' R6 HNR4 Rz (4) (s) HZN-O-R C(OQ)4 (6) 7) NHZ

N-OH
NR
A-o Hal 7d NR~
A-NR
C ~0 ) Hal A R'HN-O-R
Cl C~2) C~~) NR{
A ~ 13~
N- OH
~
R

A-O A-N=C=O
ct (is) A-C
~~6}
\ Hal 7e 4. DETAILED DESCRIPTION OF THE INVENTION

4.1 I-IYDROXYLAMINE DERIVATIVES OF THE INVENTION

I-Ivdroxylamine derivati~~es, the tautomeric forms of which are represented by formulae (I) and ' (II), can be used in accordance with the invention described herein. In the above formulae A is an alkyl, substituted alkyl, aralkyl, aralkyl substituted in the aryl and/or in the alkyl moiety, arvl, substituted aryl, heteroaryl or substituted heteroaryl group, Z is a covalent-bond, oxygen or =NR' wherein R' is selected from the group consistina of hydro-gen, an alkyl. substituted alkyl. aryl. substituted ary1, aralkyl and aralkyl substituted in the aryl and/or in the alkyl moiety, R is an alkyl or substituted alkyl, X in the tautomer of formula (I) is halogen or a substituted hydroxy or amino, monosubstituted amino or disubstituted amino group and X in the tautomer of formula (II) is oxygen, imino or substituted imino group and R' is hydrogen, an alkyl, substituted alkyl, aryl, substituted aryl, aralkvl, aralkyl having substi-tuted aryl or alkyl moietv, acyl or substituted acyl group, and the compounds of formula (I) optionally contain intramolecular ring structures formed by ~
coupling X and a reactive substituent.

Where õalkyl" is mentioned, it means straight or branched alkyl groups comprising short and lon,, chains as well.

The typical number of carbon atonis of a preferred short chain alkyl group ran-ges from 1 to 8 and might be methvl-, ethyl-, propyl-, isopropyl-, butvl-, isobutyl-, sec-butyl-, pentyl-, tc.~i-t-pentvl-, hexyl-, heptvi-, and octvl- groups and the like, more preferably I to 6 and might be methvl-, ethyl-. propyl-, isopropyl-, butvl-, isobutyl-, sec=-butyl-, pentyl-, tei-t-pentvl-, and 1lexyl- groups.
The typical number of carbon atoms of a preferred Iong chain alkyl group ran~~es from 9 to 21 1~ and might be nonyl-, decyl-, undecyl-, dodecyl-, tridecyl, tetradecyl-, pentadecvl-, hexadecyl-, Izeptadecyl, octadecyl-, nonadecyl-, eicosyl- and heneicosyl- groups and the like, more preferablv from 9 to 17 and might be nonyl-, decyl-, undecyl-, dodecvl-, tridecyl, tetradecyl-, pentadecyl-.
hexadecvl-, and heptadecyl- groups.

A preferred cycloalkvl group means a cycloalkyl group having a short cycloalkyl chain ranges from 3 to 8 and might be cyclopropyl-, cyclobutyl-, cvclopentvl-, cyclohexyl-.
cycloheptvl- and cyclooctyl- groups and the like, more preferably from 3 to 7 and might be cyclopropyl-, cvclobu-tyl-, cyclopentyl-, cyclohexyl- and cycloheptyl- groups.

Optionally substituted aryl or alkyl means an arvl- or alkyl group having one or more substituents such as cvano-, hydroxyl-, short chain alkyl-(e.g. methyl-, ethyl-, propyl-, isopropyl-, butvl-, 2-5 isobutyl-, sec-butvl-, pentyl-, tert-pentyl-, hexyl-, heptyl-, octyl- and the like), short chain alkoxy-(e.g. methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, pentyloxy-, tert-pentyl-oxy-, hexyloxy- and the like), aryl- (e.g. phenyl-, naphthyl-, and the like), nitro-, amino-, mono-(short chain alkyl)-substituted amino- (e.g. methyl, ethyl, propyl, isopropvl, tert-butyl)-amino and the like, di-(short chain alkyl)-substituted amino-(e.g. dimethylamino-, 30 diethylamino-, dipropylamino-, diisopropylamino-, dibutylamino-, dipentylamino-, dihexy-lamino- and the like), monohalogen-, dihalogen- or trihalogen (short chain)-alkyl- (e.g, cllloromethvl, 2,2-dichloroethvl, trifluoromethyl- and the like) group or halogen atom (e.g.
fluoro-. chloro-, bromo-. and iodine atom) and the like as well.

A preferred aralkvl group means a short chain alkyl group as written above.
substi-tuted with one or more (optionallv substituted) aryl groups and might be benzvl-, benzhydryl-, trityl-, 1-phenvl-ethvl-, 2-phenvlethyl-. 2-benzhydryl-etlivl-. 3-phenylpropvl-, I-methyl-2-phenyl-ethyl-, 1-phenylbutvl-, 4-tritylbutyl-, 1.1-dimethvl-2-phenylethyl-. 4-phenylbutvl-, 5-phenylpentvl-, 6-phenvihexyl-groups and the like, more preferablv lower alkyl group from 1 to 4 carbon atom, substituted xvith a phenN*l ~~roup and miaht be benzyl-. 1-phenylethvl-. 2-phenvlethvl-. and 1-methvl-2-phenvlethvl groups_ A pre-ferred aryl <,~roup might be phenvl-, naphthyl-, pentalenyl-, anthracenyl-groups and the like, nlore preferably plienyl- and naphthvl ~~roups.

A preferred 3-8 membered, more preferablv 5-8 menibered. N-containing saturated heterocvclic ~~roup means a saturated heterocyclic group containing 1-4 nitrogen atoms and mi~~ht be aziridi-nyl-, azetidinyl-, oxaziranyl-, pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl-, perhydro-tiazolyl-, perhydro-isoYazolyl-, piperidinyl-, piperazinyl-, perhydro-pyrimidinyl-, perhvdro-pyridazinvl-, morpholinyl-, perhidro-1 H-azepinvl- groups and the like.

A preferred heteroaryl group means an unsaturated. 3-8 membered, more preferably 5-6 mem-bered. 1-4 N-containing unsaturated hetero-monocvclic group and mi(lht be pyrrolvl-, pvrrolinyl-, imidazolyl-, pyrazolyl-. pyridyl- group and its N-oxide, pirimidinyl-, pyrazinyl-, pyridazinyl-, triazolyl-, tetrazolyl-, dilivdrotriazinvl- group and the like; or means unsaturated, 1-5 N-containin~~ condensed heterocvclic aroup and might be indolvl-, isoindolyl-, indolizinvl-. ben-ziinidazolyl-, quinolvl-. isoquinolvl-, indazolyl-, benzotriazolyl-, tetrazolopyridyl-, tetrazolopyri-dazinyl-, dihydro-triazolopyridazinyl- group and the like; or means a 3-6 membered, more pref-erably 5-6 membered, 1-2 oxygen- and 1-3 N-containing unsaturated hetero-monocyclic group and might be oxazolyl-, isoxazolvl-, oxadiazolyl- (e.g. 1,2,4-oxadiazolyl- and others) group and the like; or means unsaturated. 1-2 oxygen- and 1-3 N-containing condensed heterocyclic group and might be benzoxazolyl-, benzoxadiazolyl- group and the like; or means a 3-8 membered, more preferably 5- 6 membered, 1-2 sulftir- and 1-3 N-containing unsaturated hetero-monocyclic group and might be thiazolyl-, 1,2-thiazolyl-, thiazolinyl-, thiadiazolyl-group and the like: or means a 3-8 membered, more preferably 5-6 membered, one S-containing unsaturated hetero-monocyclic group and might be thienyl-group; or means one 0-containing unsaturated hetero-monocyclic group and might be fiiryl-group; or means unsaturated, 1-2 sulfur-and 1-3 N-containing condensed heterocyclic group and might be benzothiazolyl-, benzothiadiazolvl- group and the like.

A preferred ,.acyl" group when taken in itself or forming part of an acylated group, preferably means an acyl group which might be a short chain alkanoyl- (e.g. formyl-.
acetyl-, propionvl, 5 butyryl- and the like), a short chain alkoxy-carbonyl- (e.g. methoxy-carbonvl-, ethoxy-carbonyl-, propoxy-carbonvl-, butoxy-carbonyl-, tej-t-butoxy-carbonyl- and the like). a short chain alkyl- =
sulphonvl- (e.g. methyl-sulphonyl-, ethyl-sulphonvl- and the like), arvl-sulplionvl- (e.g. phenyl-sulplionvl- and the like), aroyl- (e.g. benzoyl, naphthovl- and the like), aryl-(short chain al-kznoyl)- (e.g. phenyl-acetyl-. phenvl-propionyl- and the like). cyclo-(short chain alkvl)-(short 10 cliain alkanoyl)- (e.g. cvclohexvl-acetyl and the like). aryl-(short chain alkoxv)-carbonyl- (e.g.
benzvloYy-carbonyl and the like), aryl-carbamoyl- (e.g. phenvl-carbamoyl-, naphtlivl carbamoyl-and the like), cycloalkyl-carbamoyl- (e.g. cyclohexyl-carbamoyl- and the like), hetero-monocvclic sulphonvl- (e.g. thienyl-sulphonyl-, tiu-yl-sulphonyl- and the like) group; and the acyl group can be optionallv substituted with 1-3 substituents as written above in the õoptionallv substituted" section.

A preferred co-amino-alkyl group means a short chain alkyl ~.;roup containin~~
substituted N-atom in the c,)-position of the alkyl chain and in which the alkyl chain is optionally substituted with one or more substituents, preferablv with one or two halogen (e.g. chloro-, bromo-, fluoro-, iodo-), hvdroxyl group or acylated hydroxyl group, where the acyl ~;roup has been defined earlier: more preferably with one or two short chain alkyl (yroups and the ..alkyl"
definition is the same as written above. The N-atom in the a) position of the alkyl chain can be substituted with one or two short chain alkyl substituents, preferably methyl-, ethyl-, tert-butyl- and the like; with cycloalkvl carbamoyl- (e.g. cyclohexyl-carbamoyl- and the like), more preferably the N-atom can be a part of a saturated heterocyclic group which contains 1-4 nitrogen atoms and might be aziridinyl-, azetidinyl-, oxaziranyl-, pyrrolidinyl-,imidazolidinyl-, pyrazolidinyl-, perhydro-tiazolyl-, perhy-dro-izoxazolyl-, piperidinyl-, piperazinyl-, perhydro-pyrimidinyl-, perhydro-pvridazinyl-, mor-pholinyl-, perhidro-lH-azepinyl- groups and the like; the N-atom in the co position can be substi-tuted with an aryl group (e.g. phenyl and the like), and can be quaternarized by a short chain alkyl substituent or oxidized as well.

If desired, the free bases of the general formulae (I) and (II) may be transformed to acid addition salts by reacting with organic acids and mav be acetate, maleate and the like;
or by reacting with inorganic acids and mav be hydrochloride. hydrobromide, hydroiodide, sulphate, pliosphate and the like; or bv reacting with amino acids and may be arginine-salt, glutamic acid salt and the like.
In a non-limiting embodiment of the hydroxylamine derivative of structure (I), Z is a covalent bond and X is a halogen, preferablv cllloro or bromo. Preferred compounds belonging to this group has as A (i) aralkyl or aralkyl having substituted arvl moiety, preferably phenvl alkyl or phenyl alkvl having one or more substituents, preferably alkoxy; (ii) aryl or substituted aryl. pref-erably phenyl or substituted phenvl, preferably substituted phenyl containing one or more of al-kyl, halooen. haloalkyl. alkoxv or nitro group; (iii) naphthyl; (iv) an N-containing heteroarvl f7roup, includino- those which may be condensed with a benzene ring, preferably piridyl; (v) an S-containin<,~ heteroarvl aroup or (vi) an O-containing heteroaryl group.
Preferred compounds be-longing to this group has as R (i) (w-amino-alkyl, (ii) c.)-amino-alkyl having mono or disubstituted amino nioiety; (iii) co-amino alkvl having substituted alkyl moiety; (iv) c,)-amino alkyl havin`, mono or disubstituted amino moiety and also substituted alkvl moiety, with a hydroxy or acyloxv group being preferred substituent group for the alkyl moiety. Of the c.o-amino-alkyl group of (i) to (iv), particularly preferred are those with 3-8 carbon atom alkyl moiety.

Certain types of the hydroxylamine derivative of structure (I) having covalent bond as Z and halogen as X are disclosed in the U.S. Patent Nos. 5,147,879, 5,328,906, and 5,296,606. These compounds can be prepared by procedures described in the cited US patents, preferably by dia-zotization of the correspondina X = NH2 derivatives in the presence of the appropriate hydrohal-ide. The starting compounds can be obtained by known procedures described e.()'. in HunQarian Patent No. 177.578 (1976), namely by coupling an amidoxime of structure 1(RI =
R` = H) with e.g. a reactive derivative of structure 2 in the presence of a base, and can be diazotized usually without isolation or purification. The terminal groups A and R of the compounds can be further amidified or derivatized, as desired.

In another non-limiting embodiment of the hydroxylamine derivative of structure (I). Z is cova-lent bond and X is a substituted hydroxy group OQ, wherein Q is an unsubstituted or substituted alkyl or aralkyl group. In a preferred embodiment, Q is a linear or branched alkyl. In these com-pounds, A is aryl or heteroaryl, preferably a N-containing heteroaromatic group; and R is pref-erably a (i) c.ramino-alkyl, (ii) (o-amino-alkyl having mono or disubstituted amino moiety; (iii) o)-amino alkyl having substituted alkyl moiety; (iv) w-amino alkyl having mono or disubstituted amino moiety and also substituted alkyl moiety, with a hydroxy or acyloxy group being preferred substituent group for the alkyl moiety. Of the c,.>-amino-alkyl group of (i) to (iv), particularlv preferred are those witli 3-8 carbon atom alkyl moiety.

A special group of the livdroxvlamine derivatives of structure (I). wherein Z
is covalent bond and X is OQ, is of structure (I'). Structure (I') contains a ring closed throu`,h the hydroxv group.
These compounds represent a cvclic form of the compounds of structure (I).
wherein R is a-CH,-CH(OH)-R". R" being a linear or branched alkyl. or a substituted linear or branched alkyl. pref-erably co-amino-alkyl which is optionally substituted on its amino ~;roup and preferably contains Ci_; straielit or branched alkyl chain. Most preferably, R" is an c,)-amino-alkvi mono- or disubsti-tuted on the a;nino group, ivhcrein the amino-substituents. indepcndently from each other rn:a~ be one or two straiaht or branched alkyl or cvcloalkyl, or the two amino-substituents, together with the adjacent N-atom form a 3 to 7, preferably 5 to 7-membered hetero ring, which optionallv contains additional lietero atom. Of these, preferred compounds have A that is a phenvi. substi-tuted phenvl. N-containing heteroarvl. substituted N-containing heteroarvl. S-containing het-eroaryl. or substituted S-containinc heteroaryl.

Hydroxylaniine derivatives of structure (I) having covalent bond as Z and OQ
as X 11ave been disclosed in the Hungarian Patent No. 216830. These compounds can be pre-pared from the corresponding halogen derivatives of the above group (hydroxylamine derivatives of structure (I). wlierein Z is covalent bond and X is halogen) bv procedures described in the Hung. Pat. No. 216830, e.g., by reaction with alkoxides, or by alkaline ring closure for the cyclic compounds of structure (I').

In a non-limiting embodiment of the hvdroxylamine derivative of structure (I), Z is covalent bond and X is NR'R-, wherein R' and R2, independently from each other, are H. a linear or branched alkyl, a substituted linear of branched alkyl, cycloalkyl, or Rl and R', together with the nitrogen atom attached thereto. form a saturated ring containing 3 to 7 members, preferably 5-7 membered 2 ~ saturated ring.

Of the compounds described in the immediately preceding paraaraph, especially preferred are those wherein R is a(i ) co-amino-alkyl, (ii) co-amino-alkyl having mono or disubstituted amino moiety; (iii) w-amino alkyl having substituted alkvl moiety; (iv) (t)-amino alkvl havina mono or disubstituted amino moiety and also substituted alkyl moiety, with a hvdroxv or acyloxy group bein, preferred substituent group for the alkyl moiety. Of the co-amino-alkyl group of (i) to (iv).
particularly preferred are those with 3-8 carbon atom alkyl moiety. Of these compounds, further preferred ones have A that is (i) aralkyl or aralkyl liaving substituted aryl moiety. preferably phenvl alkvl or phenyl alkyl having one or more substituents. preferablv alkoxv; (ii) aryl or sub-stituted arvl. preferably phenyl or substituted phenyl, preferably substituted phenvl containing one or more of alkyl, halogen, haloalkyl, alkoxy, nitro, or acylamino group;
(iii) naphthyl; (iv) an N-containing heteroaryl group, includina those which may be condensed with a benzene ring, preferablv piridvl: (v) an S-containing heteroaryl group or (vi) an 0-containing heteroaryl group.
Hydroxylamine derivatives of structure (I) having covalent bond as Z and NR'R2 as X include botli known and new derivatives. Compounds where X is NH2 are disclosed in Hungarian Patent No. 177578 (1976) and can be synthesized by alkylation of unsubstituted amidoxinze derivatives of structure 1(structure l, whereiii R1=R2 =H) witli a reactive derivative of structure 2 in pres-ence of a base.

A special group of the hydroxylamine derivatives of structure (I) , wherein Z
is covalent bond and X is NR1R', is provided by structure (I"). Structure (I") represents a cyclic form of structure (1) which contains a ring closed through NR'Rz group. These compounds can be derived from compounds of structure (I), wherein R' is H and R is CH?-CH(OH)-R", R" being a linear or branched alkyl or a substituted linear or branched alkyl.

Of the compounds of structure (I"), preferred are those wherein A is (i) aryl or substituted aryl, preferably phenyl or substituted phenyl, preferably substituted phenyl containing one or more of alkyl. halogen, haloalkyl, alkoxy. amino or nitro group; (ii) naphthyl; (iii) an N-containin~~ het-eroarvl group. including those which mav be condensed witll a benzene ring;
(iv) S-containing heteroaryl (yroup; and (v) O-containina heteroaryl group. Especially preferred of these com-pounds contain R" which is (i) co-amino-alkyl having mono or disubstituted amino moiety, or (ii) c)-amino alkyl having mono or disubstituted amino moiety and also substituted alkyl moiety.
preferably the alkyl moiety of c.o-amino-alkyl of (i) and (ii) contains 1-5 carbon atoms. Espe-cially preferred are the co-amino-alkyl group having disubstituted amino moiety, wherein the substituents, together with the nitrogen atom attached thereto, form a 3-7 member, preferablv 5-7 member, saturated heterocyclic ring. The heterocyclic ring may contain additional heteroatom(s).
In these co-amino-alkyl groups the amino-substituent is preferably a linear or branched alkvl group or cycloalkyl. In the compounds of the general formula (I") RI is hydrogen, unsubstituted or substituted straight or branched alkyl, cycloalkyl, unsubstituted aralkyl or aralkyl substituted in the aryl- and/or alkyl moiety.

The compounds of structure (I") can be prepared by the ring closure between atoms N(4)-C(5).
The required open chain derivatives are compounds of structure (I) wherein Z
is a covalent bond.
X is =NRlR2, wherein R' is as defined in connection with the compounds of the formula (I") above, R2 is H and R is a aroup of the formula -CH,-CHY'-R" wherein Y5 represents a leaving 5 group, e.g., a halogen atom. Such derivatives could be obtained from the corresponding Y'=OH

compounds with inorganic halogenating agents. e.(,,., thionyl chloride or phosphorus pentachlo-ride. The halogenation can be carried out with or without an inert solvent e.a. benzene, chloro-form, tetrahydrofurane etc., usually by boiling. After removinc, the excess of the rea~~ent, e.`~., by evaporation of the thiom-l chloride, the crude halogen derivative is cyclized -either after or with-out isolation or purification - by treatment with a strong base, e.g., potassium butoxide in t-butanol to give compound I", which is finally isolated and purified by standard procedures (extraction, recrystallization. etc).

In a non-limiting embodiment of the hydroxylamine derivative of structure (1).
Z is oxygen and X
is OQ, wllerein Q is an alkyl, substituted alkyl, aralkyl, or aralkyl having substituted aryl or sub-stituted alkyl moiety. The alkyl or substituted alkyl that is Q has preferably 1-4 carbon atoms.
Of these compounds, preferred ones have A that is an alkyl or substituted alkyl, preferably of 1-4 carbon atoms, or aralkyl or aralkyl having substituted aryl or substituted alkyl moiety. Of these compounds, preferred have R that is (i) w-amino-alkyl, (ii) (o-amino-alkyl having mono or disubstituted amino moiety; (iii) c,)-amino alkyl having substituted alkyl moiety; (iv) c.o-amino alkyl having mono or disubstituted amino moiety and also substituted alkyl moiety, with a hv-droxy or acyloxy group being preferred substituent group for the alkyl moiety.

These hydroxylamine derivatives of structure (I), wherein Z is oxygen and X is OQ, can be ob-tained in the reaction of 0-substituted hydroxylamines havin~ structure 6 (see e.g., Ger. Off.
2,651,083 (1976)) and orthoesters having structure 7. The condensation is usually carried out in the reaent itself, as a solvent, preferably by boiling. After evaporation, the product is isolated by crystallization, occasionally, (if there is an amine function in the side chain R) in the form of acid addition salt.

In a non-limiting embodiment of the hydroxylamine derivative of structure (I).
Z is oxygen and X
is NR'R`, wherein R' and R2, independently from each other, are H, a linear or branched alkyl, a substituted linear or branched alkyl, cycloalkyl, aryl, substituted aryl, or R' and R2, together with =
the nitrogen atom attached thereto, form a saturated rina containing 3 to 7 members, preferably 5-7 membered saturated ring. Of these compounds especially preferred are those wherein R is a (i) ca-amino-alkyl, (ii) ca-amino-alkyl having mono or disubstituted amino moiety: (iii) co-amino alkvl havina substituted alkyl moiety; (iv) c)-amino alkvl having mono or disubstituted amino moiety and also substituted alkyl moiety, with a hydroxy or acyloxy group being preferred sub-stituent group for the alkvl moiety. Of the c.)-amino-alkyl group of (i) to (iv), particularly pre-5 fei-red are those with 3-3 carbon atom alkyl moiety. Of these compounds. it is preferred tliat A
is (i) alkvl or substituted alkyl: (iii) aralkyl or aralkvl having substituted aryl and/or substituted alkyl moiety; or (iv) ar-, -1 or substituted aryl, preferably phenvl or substituted phenyl.

Preparation of the compounds can be prepared as described herebelow, wherein the methods de-pend on the nature of X. namely w-llether X is an unsubsituted amino (I~,TH_,) er a substituted 10 amino functionality.

(i) Preparation of the compounds where X is NH2 can be accomplished by the addition of hvdroxylamine of structure 6 to an or,anic cyanate of structure A-O-CN (see, e.(".. Chem. Ber.
98. 144 (1965)). The reaction is carried out preferably in an inert organic solvent, usuallv at room ten7perature. The isolation often requires chromatographic purification.
15 (ii) The compounds having X that is monosubstituted amino group (e.g., NHR') are prepared from known haloformimidates of structure 9 (see e.g. Houben-Weil, "Met1loden der Or-,cyanischen Chemie," Band E/4, p.544 (1983) and a compound of structure 6 . in the presence of an organic base (e.g., triethylamine) or an inorganic base. such as sodium carbonate in an inert solvent, as benzene, tetrahydrofurane, etc., followed by standard work-up and purification proce-dures.

(iii) Derivatives where X is a disubstituted amino group are prepared by the reaction of a sec-ondary amine of structure 5 with a compound of structure I, where Z is oxygen and X is OQ
(preparation of these derivatives is described above). These amination reactions are performed in polar organic solvents, e.g., ethanol, by refluxing, if necessary.
In another non-limiting embodiment of the hydroxylamine derivative of structure (I), Z is =NR', wherein R3 is hydrogen, an alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, or aralkyl having substituted aryl or substituted alkyl moiety; and X is NR'R 2, wherein R' and R'`, inde-pendently from each other, are H. a linear or branched alkyl, a substituted linear of branched al-kvl, aryl or substituted aryl, cvcloalkyl, or R' and R', together with the nitrogen atom attached thereto, form a saturated ring containing 3 to 7 members, preferably 5-7 membered saturated ring.

Of these compounds, it is further preferred that A is an alkyl. substituted alkyl, aralkyl, aralkyl havino- substituted aryl or substituted alkvl moiety. aryl, or substituted aryl group. Preferred R
for compounds belonging to this group of hvdroxylamine derivative is (i) c,)-amino-alkyl, (ii) c,)-amino-alkyl having mono or disubstituted amino moiety; (iii) cw-amino alkyl havin~~ substituted alkvl moiety; (iv) co-amino alkvl having mono or disubstituted amino moiety and also substituted alkyl moiety, witli a hvdroxy or acyloxy group being preferred substituent group for the alkyl moiety. It is preferred that the alkyl moiety of ca-amino-alkyl of (i) to (iv) contain 3-8 carbon atoms.

The ltvdroxylarnine derivatives of structure (I'), wlierein Z is NR3 and:X is NR' R`, can be pie-pared by aminolysis of the corresponding isourea derivatives belonging to a`roup of compounds described above (this group corresponds to the hydroxylamine derivatives of structure (I) having Z is oxygen and X is NR1 R'`) with ammonia or a primary or secondary amine.
The reaction is carried out preferably in a polar solvent, e.g., water or ethanol, using excess of the amine. Alter-natively, haloformamides of structure 10 (Houben-Weil "Methoden der Organischen Chemie,"
Band E/4, page >;; (1983)) can be reacted with a compound having structure 6 in the presence of an organic or inorganic base to give compounds of this group as well. The reaction carried out in inert organic solvent, usually at ambient temperature.

The compounds wherein R is a group of the formula (b) wherein R' is acyl, are prepared bv es-terifying the corresponding compounds containing hydrogen as R7 . The alkyl-or aryl esters are usually obtained by using an acid chloride or anhydride in the presence of a tertiary amine or an inorganic base, preferably in an inert solvent.

Another group of hydroxylamine derivatives useful in the present invention have structure (II), which represents the tautomeric form of the compounds of structure (I). In a non-limitina em-bodiment of the hydroxylamine derivative of structure (II), Z is covalent bond and X is oxygen.
Preferred compounds belonging to this group has A that is (i) alkyl, aralkyl or aralkyl having substituted aryl or alkyl moiety; (ii) aryl or substituted aryl, preferably phenyl or substituted phenyl having one or more substituents, preferred substituent groups including an alkyl, haloal-kyl or alkoxy group; (iii) an N-containing heteroaryl group, preferably piridyl; or (iv) S-containing heteroaryl group. For compounds belonging to this group, preferred R is (i) c)-amino-alkyl, (ii) co-amino-alkyl having mono or disubstituted amino moiety;
(iii) co-amino alkyl having substituted alkyl moiety; (iv) co-amino alkyl having mono or disubstituted amino moiety and also substituted alkyl moiety, with a hydroxy or acyloxy group being preferred substituent group for the alkyl moiety. Of the w-amino-alkyl group of (i) to (iv), particularly preferred are those witli 3-8 carbon atom alkyl moiety. Preferred compounds of this group lias R' that is liv-drogen. an alkyl. substituted alkyl. aryl, substituted aryl, aralkyl, or aralkyl having substituted aryl or alkyl nioiety.

i Compounds belonging to this group are disclosed in the Hungarian Patent No.
216830.
The routes for tlieir preparation are described therein, most preferabfv, they can be obtained by acvlation of 0-substituted hvdroxvlamine derivatives havin_ structure 6 (see also, e.u.. Ger. Off. 2.65 1.053 (1976)) with an acid'chloride having structure 11.
This route can be enlployed also for the preparation of those new derivatives, where R' is other tl]a.n bvdrogFn.
using compound of structure 12 - instead of structure 6- as starting material.

In another non-limitinz embodiment of the hydroxylamine derivative of structure (11), Z is chemical bond: X is =NR', wherein R4 is H, an alkyl. substituted alkyl, aryl.
substituted aiyl.
aralkyl, aralkyl having substituted arvl or substituted alkyl group, cycloalkyl; and R' that is an alkvl, substituted alkyl. aryl, substituted aryl, aralkyl. or aralkyl having substituted aryl or substi-tuted alkyl moiety. Among these compounds preferred are those wherein A is (i) aralkyl or aral-kyl having substituted aryl nloiety, preferably phenyl alkyl or phenyl alkyl having one or more substituents, preferably alkoxy; (ii) aryl or substituted aryl, preferably plienyl or substituted phenyl, preferably substituted phenyl containing one or'more of alkyl, haloalkyl or nitro ;roup;
(iii) naphthyl; (iv) an N-containing lieteroaryl group, preferably piridyl; or (v) S-containing het-eroaryl group. Preferred compottnds belon-ing to tliis group has as R (i) aa-amino-alkyl, (ii) w-amino-alkyl having niono or disubstituted amino moiety; (iii) w-amino alkyl having substituted alkyl moiety; (iv) co-amino alkyl having mono or disubstituted amino moiety and also substituted alkyl moiety, with a hydroxy or acyloxy group being preferred substituent group for the alkyl moiety. Of the w-amino-alkyl -roup of (i) to (iv), particularly preferred are those with 3-8 car-bon atom alkyl moietv.

These compounds can be prepared either by 0-alkylation of a N,N'-disubstituted amidoxime of structure 13 with a chemical compound having structure 2(for the reaction conditions, see preparation of compounds of structure I, wherein Z is covalent bond and X is NR'RZ), or by 0-acylating an N.0-disubstituted hydroxylamine of the formula 12 with an imidoyl halide of the formula 16, the reaction beinQ carried out in an inert solvent, preferably in the presence of an organic or inorganic acid sca,.'anger.

The compounds wherein R is a group of the formula (b) wherein R7 is acvl. are prepared bv es-terifvin; the corresponding compounds containing hvdrogeiz as R'. The alkvl-or arvl esters are usuallv obtained by usin~; an acid chloride or anhydride in the presence of a tertiary amine or an inor"=anic base, preferably in an inert solvent.

~ In another non-limiting embodiment of the hydroxylamine derivative of structure (II), Z is oxy-gen and X is oxyben. Preferred conipounds belonging to this group has A that is an alkyl. substi-tuted alkyl. aralkyl, or aralkyl 'with substituted aryl or alkyl moiety. R is preferred to be (i) w-amino-alkyl. (ii) w-amino-alkvl having mono or disubstituted amino moiety;
(iii) w-amino alkyl havin- substituted alkyl moict}=: (i.) w-amino all:yl having n~ono or d2substituted amino moiety and also substituted alkvl moietv, with a hvdroxy or acvloxv group being preferred substituent ,,roup for the alkyl moiety. Of the w-amino-alkyl croup of (i) to (iv), particularly preferred are those with 'i-8 carbon atom alkvl nioietv. Preferred compounds of this group has R' that is hy-dro`.;en. an alkyl, st-bstituted alkyl, aryl, substituted aryl. aralkyl, or aralkyl with substituted aryl or alkyl moiety.

1~ Compounds belonging to this group are disclosed in Hung. Patent No. 218480.
They are prepared by acylation of a hydroxylamine having structure 6 or struc-ture 12 with a chloroformate havin- structure 14 , in a similar manner as with the simple acid chlorides, as described for the synthesis of compounds of strttcture II
wherein Z is covalent bond and X is oxvgen. The reaction requires the presence of a base, inorganic or oraanic, and can be performed in an inert solvent, e.~~., in chloroform. The side-product salt is removed, e.g.. by ex-traction with water. and the product is isolated from the organic solution.

In yet another non-limiting embodiment of the hydroxylamine derivative of structure (II). Z is oxygen; X is =NR4. wherein R 4 is alkvl, substituted alkvl, aralkyl, aralkvl havin~, substituted aryl or substituted alkyl croup, arvl.. substituted arvl, heteroaryl or substituted heteroaryl group. In these compounds A is preferablv alkvl, substituted alkyl, aryl, substituted aryl. most preferably unsubstituted or substituted phenvl. aralkyl or aralkyl with substituted aryl or alkyl moiety. and R
is preferably w-aminoalkyl, whicli suitably contains a hydroxy or acyloxy group in the alkyl chain, and is optionally substituted on the amine nitrogen, wherein the alkyl chain of the said w-aminoalkyl group preferably contains 3 to 8 carbon atoms. In these compounds R' is preferably alkyl, arvl or aralkyl which groups may be unsubstituted or substituted.

These compounds are N-substituted analoRues of hydroxylamine derivatives of structure (1).
wlierein Z is oxygen and X is NR1R2, and can be prepared. similarly from haloformimidates having structure 9 and a chemical compound having structure 12 , in the presence of an organic base (e.g., triethvlamine) or inorvanic base, e.g. sodium carbonate in an inert solvent, as benzene, ~ tetrahvdrofurane etc., followed by standard work-up and purification procedures.

In another non-limitin<-, embodinient of the hydroxylamine derivative of structure (II). Z is =NR'.
wlierein R' is selected from the group consisting of hydrogen. an alkyl, substituted alkvl. an=l.
substituted arvl, aralkyl, and aralkvl having substituted aryl or substituted alkvl moietv: and X is o~:y~~en. P~=eferred conmpounds of this srraup have A that is (i) aralkvl or aralkvl having substi-tuted alkyl or aryl nioietv, preferably phenylalkyl or phenvlalkyl having one or more substituents:
(ii) aryl or substituted aryl. preferably phenyl or substituted plienyl, preferably substituted phenyl containina one or more of alkvl, alkoxy, halogen. haloalkyl or nitro group;
(iii) an N-containin`, heteroaryl ~~roup: or (iv) an alkvl or substituted alkyl. linear or branched, preferablv containing 4 to 12 carbon atoms. or (v) a cycloalkyl group. Preferred compounds belonging to this group has (i) u)-amino-alkyl, (ii) m-amino-alkyl having mono or disubstituted amino moietv; (iii) co-amino alkyl having substituted alkyl moiety; (iv) w-amino alkyl having mono or disubstituted aniino moietv and also substituted alkvl moiety. with a hydroxy or acyloxy ;roup being preferred sub-stituent group for the alkyl moietv. Of the c.o-amino-alkyl group of (i) to (iv), particularly pre-ferred are those with 3-8 carbon atom alkyl moiety. In these compounds R' is preferably llydro-gen, an alkyl, substituted alkyl, aralkyl or aralkyl liaving substituted aryl or alkyl moietv, ai-vl.
substituted aryl, acyl or substituted acyl group.

These compounds are disclosed in a co-pending Hungarian Patent No. 218480 and can be prepared by reaction of a hydroxvlamine compound having structure 6 or structure 12 with an isocyanate having structure 15, in an inert solvent, usually by simple stirring of the mix-ture at room temperature for 2-24 hours. Finally, the products are isolated -after evaporation of the solvent - preferably by crystallization.

In a non-limitin2 embodiment of the hydroxylamine derivatives of structure (II). Z is =NR'.
wherein R' is selected from the group consisting of hydrogen, an alkyl.
substituted alkvl, aryl.
substituted aryl. aralkyl. and aralkyl havina substituted aryl or substituted alkyl moietv; X is =NR4, wherein R4 is H. an alkyl, substituted alkvl, aryl. substituted arvl, aralkyl, aralkvl having substituted aryl or substituted alkyl eroup, cycloalkvl, ; and R' is an alkvl.
substituted alkvl. aral-kyl, or aralkyl having substituted aryl or substituted alkyl moiety, or arvl or substituted an '. Pre-ferred compounds belonging to this group have as R; hydrogen, alkyl or substituted alkvl R4 is hydrogen or an aryl group, A is alkyl, substituted alkyl, aryl or substituted aryl. or aralkyl. which may be substituted in the aryl and/or alkyl moiety. Of these compounds, preferred ones have R
that is (i) co-amino-alkyl, (ii) c.o-amino-alkyl having mono or disubstituted amino moiety; (iii) ca-5 amino alkvl having substituted alkvl moiety; (iv) co-atnino alkyl having mono or disubstituted amino moiety and also substituted alkyl moiety, with a hydroxy or acyloxy group being preferred substituent `~roup for the alkyl moiety. Of the o)-amino-alkvl group of (i) to (iv), particularly preferred are those with 3-8 carbon atom alkyl moiety.

Preparation of compounds belon~~ing to this group can be accomplist:ed by aminclysis of the of 10 the corresponding isourea derivatives (compounds having structure (II), wherein Z is oxy`en and X is NR4) with a primary or secondary amine or ammonia. The reaction is carried out preferably in a polar solvent. e.g., water or ethanol, using an excess of the amine.
Alternatively, lialofor-mamidines having structure 10 can react with a compound of structure 12 in the presence of an organic or inorganic base in inert solvents, usually at their boiling point.

15 One non-limiting embodiment of the hydroxylamine derivative of structure (I) defines a novel group of compounds, wherein X is halogen, preferably a chloro or bromo; Z is a chemical bond and A is a group of the formula (a) wherein Y' is halo, alkoxy, a nitro group or a haloalkyl group, preferably haloalkyl containing 1-4 carbon atoms; and n is 1. 2, or 3; or O-containing heteroaryl, preferably furyl. S-containing heteroaryl (preferably thienyl). or N-containing heteroarvl group 20 (preferably piridyl, quinolyl, or isoquinolyl) which may be condensed with a benzene ring and R
is a group having structure (b), wherein RS and R6, independently from each other, are H, a linear or branched alkyl, preferably a substituted linear or branched alkyl, preferably C1-4 alkyl, or cy-cloalkyl, or R5 and R6, when taken together with the nitrogen atom attached thereto, form a 3 to 7, preferably 5 to 7, membered saturated heterocyclic ring, Y6 is -OR7, wherein R7 is H or an acyl group, preferably alkyl carbonyl, substituted alkyl carbonyl, aryl carbonyl or substituted arvl car-bonyl, or aminoacyl or substituted aminoacyl; k is 1, 2 or 3; and m is 1, 2, or 3, with the proviso, that when A is piridyl or naphtyl, or a group of the formula (a) wherein YI is halo or alkoxy, then R7 is other than H. These compounds may optionally contain.as A an N-containing heteroaro-matic group with N-quaternarv C 1-4 alkyl or the oxide of the said N-containing heteroaromatic group and/or an R wherein the ring formed by the terminal groups R6 and R7 is an N-quaternary or N-oxidized saturated heterocyclic ring. Preferred are among these compounds those wherein A is a group of the formula (a) wherein Y' is trifluoromethyl. This group of the hydroxylamine derivatives of the formula (I) also includes the opticallv active stereoisomers of the compounds wherein X is halo., A is piridyl. Z is a chemical bond, and R is the group of the formula (b) wherein R' and R6 independently from eacll other are H, straight or branched alkyl, preferably C i-.~ alkyl or cycloalkyl, or R' and R~', together with the adjacent N atom form a 3 to 7-membered, preferably 5 to 7-membered heterocyclic ring. Y`' is -OR', wherein R' is aminoacyl, k is 1,2 or 3 and m is 1,2or3.

These novel compounds can be prepared using procedures that are analoaous to those described in U.S. Patent Nos. 5,147,879; 5,328,906; and 5,296.606. For example:

(i) Derivatives wl-iere both R' and R`' are other than hydrogen, are prepared by tl-ie diazotiza-tion of the corresponding NH2 derivatives (the hydroxylamine derivatives of structure (I).
wherein Z is covalent bond and X is NH2) in the presence of the appropriate hvdro~~en halide, similarly to the procedure described in U.S. Patent Nos. 5.147,879; 5,328,906;
and 5,296.606.
The starting compounds can be obtained also by a known procedure described, e.g., in Hungarian Patent No. 177578, namely by coupling an amidoxime havin~~ structure 1, wherein R' and R' of 1> structure I is H, with e.g. a reactive derivative having structure 2 in the presence of a base, and can be diazotized usually without isolation or purification.
(ii) If in the desired structure R7 is H and m is 1, the synthesis can be accomplished by the reaction of an oxyrane having structure 3 and amine havin~; structure 4. This procedure also can be used for the synthesis of R'=H derivatives.
(iii) Compounds where R is a group of the structure (b) . and where R7 in this group is an acyl group, are prepared by the esterification of the corresponding R'=H
derivatives. Alkyl or arvl esters are usually obtained with an acid chloride or anhydride in the presence of a tertiary amine or an inorganic base, preferably in an inert solvent, or in certain cases by the Schotten-Bauman procedure using aqueous inorganic base in a two-phase system. For the preparation of the ami-noacyl esters, carboxyl-activated N-protected amino acid derivatives (e.g., active esters) are used as reagents in procedures basically known from the peptide chemistry. This coupling also re-quires the presence of a base (e.g. triethylamine). The isolation and purification of the products are performed by using standard preparative techniques; the final preparation is often in the form of a salt with appropriate inorganic or organic acids. StartinQ from chiral amino acids, the prod-. --ucts are frequently diastereomers, possessing the second chiral center in the R group. During the isolation, these diastereomers often separate, and the product can be obtained in stereo-pure form.

Compounds having structure (1) wherein Z is chemical bond. X is halo, preferably chloro or bromo A is a~_roup of the formula (c) and R is a group of the formula (d); one or both of Y" and Y' , from which at least one must be present in the molecule, are oxygen, or an alkyl or substi-tuted alkvl having 1-4 carbon atoms; k is 1, 2, or 3; and m is 1, 2, or 3. Y' and Y3 are attached bv the dotted line, which means the optional presence of these substituents, are also novel hvdroxy-lamine derivatives. When the compound is a mono- or bivalent cation, the anion thereof is one or two halide, preferably iodide ion.

These hydroxylamine derivatives are prepared by the chemical modifications (i.e., N-oxidation or quaternerization) of the terminal pyridine and/or piperidine groups in their unsubstituted precur-sors. For the oxidation, preferably peracids, e.g. substituted perbenzoic acids are used in inert solvents cllloroform, dichloromethane). If both oxidizable groups are present in the mole-cule, mono- or dioxides may form depending on the quantitv of the reaaent used. At the end of the reaction. the excess reagent is decomposed and the product is isolated by evaporation. The quaternerization can be accomplished with alkyl halides (e.g., methyliodide), preferably bv re-fluxing the reagent in a suitable solvent, e.g., acetone. The product is often insoluble in the me-dium, and can be isolated by simple filtration.

Yet another novel group of compounds belonging to the hydroxylamine derivatives having structure (I) are those wherein Z is a chemical bond. A is aralkyl, substituted aralkyl, preferably phenylalkyl Nvhich may have one or more alkoxy, preferably alkoxy having 1 to 4 carbon atom.
phenvl, substituted phenyl having one or more substituents, preferred substituent groups includ-ing an alkyl, preferably alkyl or haloalkyl having I to 4 carbon atom, halo, acylamino or nitro group; or a N-containing heteroaryl group, which may be condensed with benzene ring, prefera-bly pyrrolyl, pyridyl, isoquinolyl or quinolyl, or a sulfur containing heteroaromatic group, pref-erably thienyl, wherein the heteroaryl groups may be substituted with one or more alkyl, pref-erably alkyl having 1 to 4 carbon atoms; X is -NR'R2, wherein R' and R2, independently from each other, are H. a linear or branched alkyl, a substituted linear or branched alkyl, preferably alkyl having 1 to 6 carbon atoms, a cycloalkyl or Rt and R'` taken together with the nitrogen atom attached thereto may form a 3 to 7, preferably 5 to 7, membered saturated hetero ring; R is a group of the formula (e), wherein R' and R6, independently from each other, are H, a linear or branched alkyl, or a substituted linear or branched alkyl, preferably alkyl having 1 to 4 carbon atoms, or cycloalkyl, or RS and R6 taken together with the nitrogen atom attached thereto form a -7, preferably 5-7 membered saturated hetero ring, which may contain additional hetero atoms and substituents, the substituents being preferably alkyl having I to 4 carbon atoms;. Y4 is H or an alkyl or substituted alkvl having 1-4 carbon atoms; Y' is H. or an alkvl or substituted alkyl hav-in~; 1-4 carbon atoms. or OR7. wherein R7 is H or an acyl; k is 1, 2, or 3;
and tn is 1, 2, or 3, with the proviso that when A is phenvl which is unsubstituted or substituted with halogen or alkoxv, or phenylalkyl substituted with alkoxy. or a pyridyl group, and R7 is H. then at least one of R' and R'` is other than H. or when A is phenyl which is unsubstituted or substituted with halogen or alkoxv;
phenylalkyl substituted wit11 alkoxy: or pyridyl, arid Rt arid R'` are c;ach H, then R7 is other than H.

The compounds wherein X is an NH-) derivative, are prepared - similarly to the above-mentioned procedure - by the reaction of the corresponding intermediates having structure 1,wherein R, and R' of structure 1 are H, with a compound having structure 2. The alkvlating agent (havin~~
structure 2) may contain hydroxyl and/or amino substituents. The reaction requires the presence of an inorganic or organic base, in a preferable manner alcoholic alcoholate solution is used as =
medium and base. The products are often isolated in the form of salt with a suitable organic or inoruanic acid.

Another (Troup of the above novel compounds is characterized by R' and R', one or both of them bein- other than H in these derivatives. Such structures can be prepared in two ways:

(i) An amidoxime having structure 1, which already contains the required substituents R1 and/or R`, can react with a reactive compound of structure 2 . similarly to the procedure de-scribed in the previous paragraph. The substituted amidoximes of structure 1, used as starting materials, are known from the literature [Chem. Rev. 62, 155-183 (1962)].
(ii) Substitution of the halogen atoms in the compounds having structure (I), wherein Z is covalent bond and X is halogen, by an amine of structure 5 can result in similar compounds as well. In the case of derivatives bearing an OH substituent in the R group (Y4=OH), this hydroxyl group has to be protected before, and deprotected after the substitution reaction, otherwise for-mation of the cyclic derivatives of structure (I') is favored. For the protection, acetyl type pro-tecting groups, e.g., tetrahydropyranyl group, have proven most satisfactory.
The protection is carried out by the reaction of the unprotected compound with dihvdropyrane, followed by the halogen/amine displacement, which usually requires refluxing in a solvent, e.g., in alcohol. The deprotection of the product, finally, can be accomplished b acidic treatment, e.g., by boiling the ethanolic solution in the presence of e.g. p-toluenesulphonic acid.

As mentioned, a group of the novel compounds also includes those wherein Y' is an acyloxy group. Thev can be prepared bv acylation of the corresponding Y'=OH
derivatives, which are either known from the literature (e.g., Hung. Patent No. 177578) or described in the present in-vention. The reactions can be accomplished identically to what is described for the analo"'ous halo derivatives, wherein R7 is an acyl group (metliod (iii)).

The novel hydroxylamine derivatives of the formula (I) also include those wherein Z is oxygen or an =NR3 group wherein R3 is an unsubstituted or substituted alkyl group, X is -NR'R`, R' and R2 independently from each other are hvdrogen, unsubstituted or substituted straight or branched alkyl. unsubstituted or substituted aryl, preferably phenyl or unsubstituted or substituted arzlkyl group or R' and R2 wllen taken to~~etlier with the nitrogen atom attached thereto, form a 3 to 7 membered, preferably 5 to 7 membered saturated heterocvclic ring which optionally contains one or more hetero atoms. In these compounds A is an unsubstituted or substituted alkyl or unsubsti-tuted or substituted an.l. preferably phenyl or substituted pllenyl group or an unsubstituted or substituted aralkyl group and R is a group of the formula (b) wherein R' and R`', independently from each other are H, straight or branched alkyl, preferably C alkyl, or cycloalkvl, or R' and R", together with the N-atom attached thereto, form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocyclic ring, Y6 is H or -OR7, wherein R7 is H or acyl, preferably un-substituted or substituted alkylcarbonyl or arylcarbonyl, k is 1, 2 or 3 and m is 1, 2 or 3.

The novel hydroxylamine derivatives, wherein Z is oxygen and X is -OR, wherein Q is an un-substituted or substituted alkyl or unsubstituted or substituted aralkyl group. A is an unsubsti-tuted or substituted alkoxy group or an unsubstituted or substituted aralkyl group and R is a group of the formula (b), wherein R' and R6, independently from each other are H, straight or branched alkyl, preferably CI-4 alkyl, or cycloalkyl, or R5 and R6, together with the N-atom at-tached thereto, form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocyclic ring, Y6 is H or -OR7, wherein R7 is H or acyl, preferably unsubstituted or substituted alkylcarbonyl or arylcarbonyl, k is 1, 2 or 3 and m is 1, 2 or 3, fall also within the scope of compounds of formula (I).

R5 and R6, independently from each other, are H, straight or branched alkyl, preferably CI-4 alkyl or cycloalkyl, or R' and R6, when taken together with the N atom attached thereto form a 3 to 7-membered, preferably 5 to 7-membered heterocyclic ring, YG is H or -OR'. R7 is H or acyl, pref-erably unsubstituted or substituted alkylcarbonyl or arylcarbonyl, k is 1, 2 or 3 and m is 1, 2 or 3.

Another group of the novel hydroxylamine derivatives of the formula (I) is represented by those wherein A is unsubstituted or substituted aryl, preferably phenyl or N-containing heteroaromatic group, preferablv piridyl or S-containing heteroaromatic group, Z is a chemical bond. X is -OQ
wherein Q is Ci-4 alkyl and R is a-roup of the formula (b). wherein R and R`', independently 5 from each other are H. straight or branched alkyl, preferably Ci-4 alkyl or cvcloalkvl, or R' and R`', when taken together with the N atom attached thereto form a 3 to 7-membered. preferably 5 to 7-membered heterocvclic ring. Y6 is H, k is 1. 2 or 3 and m is 1, 2 or 3.

These compounds are prepared by the reaction of the corresponding hydroxylamine derivatives of the formula (I) wherein X is halo and the corresponding alcoholates .
preferably in an alcohol 10 corresponding to the alcoholate, preferably by refluxing. The reaction mixture is treated with metliods known in the art and the product is isolated by chromatographv or salt-formin".

The novel hydroxylamine derivatives of the formula (11) also include the group of compounds wherein X is oxygen, A is Ci-20 strai(Tht or branched alkyl, unsubstituted or substituted aryl, pref-erably phenyl or haloplienyl, unsubstituted or substituted aralkyl, naphtyl or N-containing het-15 eroaromatic group, preferably piridyl, Z is a chemical bond. R' is H. Ci-4 alkyl or aralkyl, pre1=
erably phenvlalkyl, R is a group of the formula (b), wherein R5 and R6, independently trom each other, are H. straight or branched alkyl, preferably Ci~ alkyl or cycloalkyl, or R' and R~', when taken to(Yether with the N atom attached thereto form a 3 to 7-membered, preferably 5 to 7-membered heterocyclic ring, Y6 is H or -OR7 , R' is H, k is 1, 2 or 3 and m is 1, 2 or 3, with the 20 proviso, that when A is other than alkyl and R' is H, YG is H.

The novel compounds wherein Z is a covalent bond, oxygen or an =NR3 group wherein R'' is hydrogen or an unsubstituted or substituted alkyl group, X is =NR4, wherein R4 is hydrogen, an unsubstituted or substituted alkyl or unsubstituted or substituted aryl, preferably phenyl group, or substituted or unsubstituted aralkyl, preferably phenylalkyl, fall also within the scope of com-25 pounds or formula (II). In these compounds A is an unsubstituted or substituted alkyl or an un-substituted or substituted aryl preferably phenyl or substituted phenyl, or unsubstituted or substi-tuted aralkyl, preferably phenylalkyl, or cycloalkyl, R' is an unsubstituted or substituted alkyl or unsubstituted or substituted aryl, preferably phenyl, or unsubstituted or substituted aralkyl. pref-erably phenvlalkyl, R is a group of the formula (b), wherein R5 and R6.
independently from each other, are H. straight or branched alkyl, preferably Ci-4 alkyl or cycloalkvl, or R' and R6, when taken together with the N atom attached thereto form a 3 to 7-membered, preferablv 5 to 7-membered heterocyclic ring, V' is H or -OR7 , R' is H or acyl, preferably unsubstituted or substi-tuted alkylcarbonyl or arylcarbonyl, k is 1, 2 or 3 and m is 1, 2 or 3.

Novel hydroxylamine derivatives are also those of the formula (II) wherein X
is oxygen, A is unsubstituted or substituted alkyl. unsubstituted or substituted aralkyl, preferably phenylalkvl. Z
is oxygen, R' is alkyl or aralkyl. preferably phenylalkyl, R is a group of the formula (b), wherein R5 and R~', independently from each other, are H, straight or branched alkyl, preferablv C 1-4 alkyl or cvcloalkyl, or R5 and R~', when taken together with the N atom attached tliereto form a to 7-membered, preferably 5 to 7-membered heterocyclic ring, Y~' is H or -OR7 , R7 is H or acyl. pref-erably unsubstituted or substituted alkylcarbonyl or arylcarbonyl, k is 1, 2 or 3 and m is 1. 2 or 3.

The hydroxylamine compounds of the formula (II), wherein X is oxygen and Z is =NH. are also novel compounds.

One group of these compounds is formed by those wherein A is unsubstituted or substituted al-kyl, cycloalkyl, unsubstituted or substituted aralkyl. preferably phenylalkyl, unsubstituted phenyl or phenyl substituted with halo, alkyl. haloalkyl, alkoxy or nitro, R is a group of the formula (b), wllerein R5 and R', independently from each other. are H, straight or branched alkyl, preferably Ci-.~ alkyl or cycloalkyl. or R5 and R~', when taken together with the N atom attached thereto form a 3 to 7-membered, preferably 5 to 7-membered heterocyclic ring, Y6 is H or -OH, k is 1, 2 or 3 andinis 1,2or3.

An other group of these compounds is formed by those wherein A is a group of the formula (a), wlierein Y' is haloalkvl, preferablv trifluoromethyl and n is 1, 2 or 3, R' is H and R is a group of the formula (b), wherein RS and Rt', independently from each other, are H.
straight or branched alkyl, preferably CI-4 alkvl or cycloalkyl, or R' and R6, when taken together with the N atom at-tached thereto form a 3 to 7-membered, preferably 5 to 7-membered heterocyclic ring, Y6 is H or -OH,kis 1,2or3 andmis 1,2or3.

The novel hydroxylamine derivatives according to the invention also include the cyclic com-pounds of the formula (I"), wherein A is unsubstituted phenyl or phenyl substituted with halo or nitro, or N-containing heteroaryl, R' is H and R" is an co-amino-alkyl group mono- or disubsti-tuted on the amino group, the alkyl chain of which having 1 to 5 carbon atoms and the anzino substituents, independently from each other, may be one or two straight or branched alkyl or cy-cloalkyl, or the two amino-substituents, together with the N atom adjacent thereto, form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocyclic ring, or a Ci-4 alkyl N-quaternary derivative thereof, with the proviso, that when A is 3-piridyl. R" is different from 1-piperidinylmethyl.

4.2 METHOD OF INCREASING MOLECULAR CHAPERON EXPRESSION IN CELLS
i The present invention relates to a method of enhancing expression of a molecular chaperons in cells. by treating cells and tissues with an effective amount of a hydroxylamine derivative. Hy-droxylamine derivatives, the tautomeric forms of which are represented by formulae (I) or (II), can be used for this tnethod. Structures of the fot'rriulae (I) and (II) are discusse,u in details in Section 4.1.

In one non-limitin- embodiment of the invention. a method of increasino, molecular chaperon expression in cells exposed to stress is provided. In this method, the cells exposed to a physio-logical stress which induces expression of molecular chaperons by the cells are treated witli an effective amount of hydroxylamine derivatives, the tautomeric forms of which are represented by formulae (I) and (II), after occurrence of the stress. The hydroxylamine derivatives increase the expression of molecular chaperons in these cells bevond the amount induced by the physiological stress.

In another non-limitin-, embodiment of the invention, the cells are treated with the hydroxy-lamine derivatives before they are exposed to a physiological stress. The hydroxylamine deriva-tives increase the molecular chaperon expression beyond the amount induced by the physiologi-cal stress.

The term "molecular chaperon," as used herein, refers to protein which assists other proteins to fold into correct or active conformations, usually by non-covalently binding to the proteins.
Chaperons not only assist in the correction and restoration of proteins newly synthesized but also of those that have been denatured or misfolded. Molecular chaperons include, among others, heat shock proteins (hsp) from which hsp70 and hsp 72 are of especial importance in connection with the invention, as well as the IgG heavy chain binding protein (BiP), and glucose regulated proteins (grp). Examples of hsp and grp include, but are not limited to, those belonging to the ti following classes: hsp70, hsp60, hsp90, grp94, grp80, and hsp27.

Preferably, eukaryotic cells which are treated with the hydroxylamine derivatives are mammalian cells, more preferably human cells. The term "eukaryotic cell" refers to both eukaryotic cells that are in vitr=o (cells that are outside a living organism, e.g. in culture condition) and in 1.=irv (cells that are within a living oraanism, e.g., cells comprising tissues and organs).

From the eucaryotic cells of a living organism, neurons, muscle cells, vessel wall cells, especiallv endothelial cells. epithelial cells and cells of the immune system can preferably be treated in ac-cordance with the method of the invention. Plant cells, including cells of livin- plant oro-anisms can also preferably be treated in accordance with the method of the invention.

Under the term '`physiological stress." as used herein, conditions or factors affecting the cell which would induce the '`stress response" of the cell ,e.g., induction of chaperon protein svnthe-sis sliould be understood. . Fhysiological stresses inelude factors that cause injury to cells or those disturbing llomeostatic balance of cells. These are, for example, the metabolic, oxidative.
local meclianical stresses or stresses caused by hypoxia. ischemia, heat shock, radiation or toxic materials. An important form of metabolic stress is caused by diabetes mellitus.

Another important appearance form of physiological stresses includes those leading to the for-mation of free radicals or increase of the quantity of cytokines in the environment of cells. Inju-ries in cells that are associated with various pathological conditions provide examples of physiological stresses.

In one non-limitin, embodiment of the invention, the physiological stress that induces cells to express molecular chaperon as a response to physiological stresses leading to cardiovascular, vascular, cerebral, allergic. immune, autoimmune diseases, viral and bacterial infections, skin and mucosal diseases or diseases of renal tubuli of epithelial origin or causing conditions to be treated by cosmetical interventions.

Such cardiovascular diseases include most preferably atherosclerosis provoked by physiological stress, coronarial diseases, or cardiovascular diseases caused by hypertonia or pulmonary hyper-tonia.

Characteristic cerebral diseases are, among others, those caused by the cerebrovascular ischemia provoked by physiological stress, stroke, traumatic head injury, senile neurodegenerative dis-eases, especially senile dementia, AIDS dementia, alcohol dementia, Alzheimer's disease. Park-inson disease or epilepsy.

Characteristic diseases provoked by skin and mucosal diseases are the dermatological diseases or ulcerous diseases of the gastrointestinal system.

WO 97/16439 PCT/FdU96/00064 Durin~~ the above diseases. the phvsiological stress induces cllaperon expression in the cells.
11owever, this effect is no sufficient enough to protect against cell damages caused by the dis-eases. The treatment with the above hvdrotivlamine derivatives which is associated with en-hancement of chaperon expression or increase of cllaperon activity makes possible the eliniina-tion of structural deviations caused by the disease and thus. reryeneration of cells.

In one non-limiting example of the invention. the physiological stress is heat shock or exposure of cells to unusuallv lii`,h temperature. In another non-limitinG example of the invention, the physiological stress is cellular injurv associated with ischemia. Ishemic lesion of cells. especiall-,lleart muscle and cerebral cells is caused bv cardiovascular disorders caused by vascular occlu-sion or rapture, such as coronary or cerebral thrombosis or vascular occlusion, stroke, enibolism.
or chronic vascular spasm. Ischenlia induces "stress response" in cells.
resultin(ir in increased aniount of llsp, wllich in turn protect the cells against deleterious effects of ischemia. (Mestril, R. et al, .I. itlol. C'e11. Ccu=cliol. 27: 45 (199>).

By treating these cells with an effective amount of hydroxylarnine derivatives to those cells. mo-lecular cliaperon expression in the cells can be increased beyond the amount induced by ischemic condition as well as the activity of molecular chaperons can be enhanced.

In connection with this matter, when an oro-an is taken out of an animal for transplantation, such removal is a physiological stress causing injurv to the cells comprising that or`~an, inducing chaperon expression. In such a case, administration of the hydroxylamine derivatives before or after the oman removal could increase the amount of chaperon produced bv the cells of the organ or the activity tliereof, thus providing cytoprotective effect.

Neuronal injuries, besides ischemia, can be induced by many other stresses as well, which induce molecular chaperon production in the neuronal cells. In addition, excitotoxic neuronal injuries also induce production of molecular chaperons by neuronal cells and are included within the term "physiolo~ical stress."

In yet another example of the invention, physiological stress is provided by the toxic mediators of inflammation, such as oxidative radicals and cytokines, such as TNF, which are produced by macrophages. Cells exposed to increased amount of these toxic mediators are shown to express an increased amount of hsp, which in turn provide protection to these cells against the toxicity.
(Kantenawa, S. et al, Semin. Immun. 3: 49-56 (1991). Various inflammatory diseases including pulmonan= inflammatory conditions, such as adult distress syndrome, induce expression of hsp by the cells, which in turn exert cytoprotective effect. (Jacquier-Salin, M.R.
et al., Experientia 50: 1031-1038 (1994)). When the amount of molecular chaperons in cells is increased beyond that induced by TNF and reactive oxygen species, the cells can be better protected against these cytotoxic factors and better enable to repair the damages caused by these.

Factors affecting the physiological state of cell membranes. including cell membrane fluidity, 5 also provide examples of physiological stress. Increase of molecular chaperon expression in these cells beyond that induced by disturbance of the physiological state of cell membranes can pro-vide better protection and also allow the cells to repair the cell membranes.

The phrase " an effective amount of the hydroxylamine derivatives," as used herein in connec-tion with enhancina rnolecuiar cliaperon production iii cells tindcr physiological stress, or cells 10 wliicli will be subsequently exposed to physiological stress, refers to an amount which will in-crease the expression of molecular chaperon beyond the level induced bv the physiological stress alone. Such amount can be readilv determined by one skilled in the art.
Preferably, for cells in vitro. the effective amount is between 10'6 - 10-; M. More preferably. the effective amount is between 10-6 - 5xl0-4 M.

15 When administering to an animal, the effective amount varies depending on various factors, such as a mode of administration, but determining effective range is within the skill of one skilled in the art and will not require undue experimentation. For example, when the hydroxylamine de-rivative is administered intravenously, the effective amount is preferably between 0.1 - 10 ni`;/kgbw, more preferably 0.5 - 2.0 m~~/kgbw; and when administered oraliv, the effective 20 amount is preferably between 10-500 m-r/ko-bw, more preferably between 50 -100 m(,T/k( bw.
An increase in the molecular chaperon expression in cells can be detected using well established laboratory procedures such as Northern or Western blotting procedure.

An example of the Western blotting technique that can be used is set forth herein: Cells are cul-tured in vitro at 37 C in Dulbecco's modified Eagle's medium (DMEM) supplemented with 25 10% fetal calf serum (GIBCO) in 5% CO2. Hydroxylamine derivatives the tautomeric forms of which are represented by formulae (I) and (II) can be added to the cell culture, for example. 10' M of the compound is administered to cells 16 hours before the physiological stress, or after the time period following the physiological stress. However, the concentration of the hydroxy-lamine derivative, as well as the time of the administration of that compound, can be varied as 30 desired by the experimental design.

Six hours after the heat shock. cells are washed two times in phosphate-buffered saline solution (PBS) then scrapped from the surface of the culture dishes in PBS. Then cells are spun for 5 min.
at 1500 rpm and taken up in 100 l modified solubilizing buffer (Molecular Cloning, A Luhnru-tor)., jLtanunl. Ed. Sambrook, Fritsclle. Maniatis. Bold Spring Harbor Laboratory Press (1989)) containing 50 mM Tris-HCI, pH8.0; ~ mM EDTA: 150 mM NaCl; 15 Tritox N-100; 1 PMSF: 2 g/ml aprotinin: I g/ml chymostatin; I g/ml pepstatin: and sonicated for _3 x 2o sec (2 min.
intervals, settin~ 8).

Protein concentration is then determined from 5~il samples by the Bradford assay (M.M. Brad-ford. Anal. 13iochern., 72: 248-254 (1976)) in three parallel. Samples are adjusted to 100 21/30 ~tl protein concentration with the above buffer and the next buffer so that the final concentration of the components in the buffer in the saniple will be: 1 10 mM Tris-HCI pH 6.8.
8. i mM niercap-toethanol, 3% SDS, 3 o glycerol and some bromopheno( blue and shaken at rooni temperature for 30 min. The sample thus obtained can then be used for to run a gel-electrophoresis.

When chaperon enhancing effect of the hydroxylamine derivatives of the invention is examined for cells in vivo, a physiological stress is applied to an animal, e.g., ischemia or STZ-induced diabetes. In case of ischemia, myocardial ischemia can be induced in an animal as described in Example 8; and diabetic condition can be induced as described in Example 10. A
hydroxy-lamine derivative of the present invention can be administered to the animal before it is exposed to physiological stress. during the stress or afterwards. As stated previouslv, the timin- of the administration can be N-aried according to an experimental design.

The following steps of protein preparation from relevant tissues obtained from the animals thtts treated are carried out at 0-4 C. Tissues, such as liver tissues (about 15-20 2) are homo(zenized with a domestic mixer for 2 min. in 80 ml lysis buffer solution containing 50 mM Tris-HCI pH
8.0, 5 mM EDTA, 150 mM NaC(. 0.1 % SDS, 1Triton X-100 and 1-1 mM protease inhibitors (PMSF, benzamidine. amino-caproic-acid). The homogenate is then centrifuged at 20000xg for min. in a Sorvall*RC 28S centrifuge.

Protein concentration of the preparation is determined by the Bradford assay and adjusted to 5 mg/ml. The samples containing 1.8 mc, protein are solubilized before gel-electrophoresis with 0.6 ml buffer containinsz 110 mM Tris-HCI pH 6.8.8.3 mM mercaptoethanol. 3%
SDS. 3% Qlvc-30 erol and some bromophenol blue and shaken at room temperature for 30 min.

The protein samples obtained from cell cultures or from animal tissues. both of which are de-scribed above. are used for electrophoresis and subsequent immunoblotting (both procedures are *Trade-mark well known in the art and described in detail in Nlolectrlar Cloning, A
Laboratory iLlunzrcrl. Ed.
Sambrook. Fritsclle. Maniatis. Bold Spring Harbor Laboratorv Press (1989):
Protein Blottrn;
Protocols.for the Immobilon-P Ti=ansfer iLlembrane, 3. Laboratory Manual.
Millipore : and U.K.
Laemmli. Nature : 227: 680-685 (1970).

~ For example. electrophoresis can be carried out according to Laemmli (U.K.
Laemmli, Nature, 2217:680-685 (1970)) on 8-18 % polyacrylamide gel at constant voltage 50 V for overni-ght. Pro-teins are either stained with Coomassie Brilliant Blue R-250 or transferred to Immobilone PVDF
(Millipore) at constant current (300 mA) for 3 hours at 4 C in transfer buffer (10 mM CAPS
pI-1 11, 10 methanol) (Protein f3lottin,; Protocol.l= fcn- the Im.mobilo!a-P
Ti=crr.sfnr rVemhrancr, ~.
Laboratory Manual, Millipore). After transfer, non-specific sites of the membrane are blocked with 2 % bovine serum albumin (BSA) in TPBS (phosphate buffered saline with 0.1 % Tween 20) for overnight at 4 C. The blot can then be incubated witli an antibody directed as a moiecu-lar chaperon, e.~u. GRP94 monoclonal antibody (SPA-850, StressGen) diluted 1:3000, with HSP60 monoclonal antibody (SPA-600, StressGen) with 1:2700 dilution, with HSP72 mono-clonal antibody (C92F34-5, StressGen) diluted 1:1350 or witll HSP90 monoclonal antibody (AC88, StressGen) diluted 1:2000, for 1 hour at room temperature. Then the membrane is washed with TPBS buffer for one hour, and incubated with horseradish peroxidase conjugated anti-rat (Sigma. 1:4000 dilution. for grp-94) or anti-mouse (Sigma, adsorbed with human and rat serum proteins, I:3000 dilution, for Hsp60, HSP72 or HSP90) secondary antibody for additional 1 hour respectively. After successive washing with TPBS the membrane is developed with ECL
(enhanced chemiluminescence) system (Amersham).
~
The changes in the stress protein content can be quantified using a Bio-Rad densitometer (Model 1650) and a Hewlett-Packard Integrator (HP 3394A). Dilution series are prepared from protein solution containing known amount of chaperon, the above process is repeated with the dilutions 2.5 and the chaperon concentration of the test samples are determined from the calibration curve obtained from the dilution tests.

Northern hybridization is another experimental procedure available for determining the level of molecular chaperon enhancement (by measuring the mRNA level) by the hydroxylamine deriva-tives of the invention. The cells or tissues can be obtained as described in connection with the Western blotting procedure. Total RNA from those cells and tissues can be extracted usin, RNAgents (Promega) according to the manufacturer's instructions (Protocols and Applications Guide, 2"d edition, 1991. Promega Corporation). The frozen tissue samples (about 50 to 100 mg *Trade-mark each) are homogenized in 1,0 denaturing 4M guanidine-thiocyanate; 42 mM sodium citrate: 0,83 m 13-mercaptoethanol; 0,1%Nonidet P-40) at4"C (Brinkman-homogenization). Then 1/10 vol.
3M sodium acetate (pH 4.0) is added and the homogenate are extracted with acidic phenol (phenol:chloroform:isoamylalcohol 25:24:1) for 10 seconds by vortex. The sample is incubated on ice for 15 minutes, and then centrifuged (4 C; 20 min., 10,000 xg). The aqueous phase is then transferred to a new Eppendorf-tube the process is repeated and the aqueous phase is precipitated at -20 C overnight with equal volume of isopropanol. Following centrifu;gation (4 C; 20 min.
10,000 xg) the precipitate is washed twice with 95% ethanol and dried at room temperature. The RNA is suspended in 20 l diethyl-pyrocarbonate (DEPC)-treated water and the concentrate is measured at 260-280 nm by spectrophotometry. Eight g of total RNA is run on formaidellvde-agarose gel by capillary transfer. the RNA on the gel is blotted onto nvlon membrane according to the manufacture's instructions (Zeta-Probe GT, BioRad).

In individual samples, the molecular cllaperon mRNA content is compared with the mRNA level of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene in the samples.
cDNA probes (for example, full length human hsp70 cDNA when the mRNA probed is hsp70, and Apa-Ncol fraament of the rat GAPDH cDNA) are labeled with alpha-32P CTP using Random Prime DNA
Labelin~~ Kit (USB). Radiolabeled DNA fragments are purified on Sephadex G-50 (Pharmacia) column as described (Ausubel et al. (eds)): Current Protocols in Molecular Biolo-v: JOHN
WILEY & SONS: 1987).

Prehvbridizations are carried out at 65 C in H-buffer (0.25M Na.)HPO4, pH
7.2, 7% SDS) for 15 minutes. Hybridizations are carried out overnight (65 C; H-buffer) with isotope labeled cDNA
probe concentration of at least 106 cpm/ml. The membrane is then washed with 20 mM
Na2HPO4, pH 7.2, 5% SDS (65 C; 2x15 min.)and evaluated by autoradiography. The same membrane is used for probing the hsp70 mRNA and the GAPDH and mRNA measurement used as internal standard.

The present invention further includes a method of treating or preventing various pathological conditions, i.e. diseases associated with the functioning of chaperon system and damaaes in the membranes of cells and cell-organelli by administering an effective amount of hydroxylamine derivatives, the tautomeric forms of which are represented by structures (I) and (II) to control pathological conditions in the organism. In the pathological conditions, characteristic molecular chaperon expression is induced in the cells. Increased molecular chaperon expression in those cells can assist them in repairing the damages caused by the pathological conditions and also in restoring the cellular homeostatic balance.

Such pathological conditions include ischemia, tumorous diseases, infections caused by patho-genic microorganisms, autoimmune diseases and dermatosis.

As used herein, "treatin~;" refers to an amelioration in the clinical condition of the subject, and does not necessarily indicate that a complete cure is achieved. An amelioration refers to a de-creased duration of illness or severity of illness, or subjective improvement in the quality of life of the subject or a prolonged survival of the patient.

An effective amount of hydroYylamine of the invention for treatment refers to an amount suffi-cient to result in the amelioration of clinical condition as described above.
An effective amount depends on factors sucli as the route of administration and can easily be determined by one skilled in the art. The hvdroxylamine derivatives of the present invention can be administered parenterally or orally, preferably orally or topically, and the effective amount is 10-500 m~~/kgbw.
More preferably. the effective amount is 20-100 mg/kgbw .

By using the method of treatment according to the present invention, the myocardium, brain tissues and kidney can be protected against tissue damage or necrosis caused by ischemia, wherein the method comprises administering to a subject an effective amount of hvdroxylamine derivatives of the invention to decrease, prevent, or reverse the deleterious effect of prolonged ischemia.

The present invention includes use of a hydroxylamine derivatives, the tautomeric forms of which are represented by formulae (I) and (II) to manufacture a medicament for the treatment of pathological conditions described herein.

In a method for measurinQ the protective effect of the hydroxylamine derivatives animal test is used as set forth herein. Rats are anaesthetized with sodium-pentobarbital (Nembutal 60mg/kg body weight, i.p.) and artificially ventilated with room air (2 ml/100 g; 54 stroke/minutes) via tracheotomy. The right carotid artery is then catheterized and connected to a pressure transducer (BPR-01, Stoelting) for the measurement of systemic arterial blood pressure (BP) by means of a preamplifier (Hg-02, Experimetria). Hydroxylamine derivatives of the invention are adminis-tered via cannule to jugular vein (i.v.) or orally (p.o.). Heart rate (HR) is meastured by a cardiota-chometer (HR-01, Experimetria); and the electrocardiogram (ECG standard lead II) is recorded on a devices recorder (MR- 12, Medicor) by means of subcutaneous steel needle electrodes. The cllest is opened by a left thoracotomv and the heart is then exteriorized by a Elentle pressure on the right side of the rib caee. A compression was applied under the main left coronarv arterv as described by Selye H. et al. "Simple techniques for the surgical occlusion of coronary vessels in the rat", Angiology 1960 Oct; 11:398 - 407. The heart is carefully replaced in the chest and the animal left to 5 recover. Rectal temperature is monitored and kept constant at 37 C. The experimental protocol is initiated with a 15 nlinute stabilization period. If sustained blood pressure less than 70 nunHL, .
or arrhvthmia were observed during this period the animal was excluded from fiirther experimen-tation. Myocardial iscliemia is then induced witll coronary occlusion for 5 minutes and reperfu-sion is allowed for 10 niinutes.

10 During the entire experiment, blood pressure (BP). heart frequency (HR) and EKG are continu-ouslv registered on a multiscriptor (R61-6CH. Medicor *). Hydroxylaiiline derivatives are ad-ministered at 5 to 60 minutes before the occlusion by i.v. or p.o. treatment.
The doses of the hydroxylamine derivative can be 0.5; 0.75; 1.0 mg/kg i.v. and 100 of bodv weight p.o., while the reference substance Bepridil is given in a dose of 1.0 mg/kg i.v.
The mean duration ol' ventricular tachycardia (VT) and/or ventricular fibrillation (VF) durin~; the first 3 minutes of reperfusion is measured and analyzed.

The present invention also includes a method of maintaining a cell membrane fluidity, wheii the cell membrane fluidity is affected as a result of a physiological stress. The method comprises the treatment of a cell or cell-organellum having altered membrane fluidity with an effective amount -)0 of hydroxylamine derivatives to restore the fluidity of said membrane. The experimental proto-col set forth in connection with Example 9 (Steady State DPH fluorescence anisotropy) can be used for determining the effect of a hydroxvfamine derivative of the invention on the cell mem-brane fluidity.

As mentioned, the present invention includes a method of treating pathological conditions asso-25 ciated with cell membrane or cell-organellum membrane. One example of such pathological condition is provided by diabetes mellitus as well as the diseases associated with mitocondrium damage, such as ALS (amyotrophic lateral sclerosis), Alzheimer disease, Parkinson disease.
Huntinaton disease (HD), certain cardiomyopathies, such as those of toxic oriQin, caused bv al-cohol or heavy metals. inflammatory or viral cardiomyopathy or autoimmune cardiomyopathy.
J0 Hydroxylamine derivatives. the tautomeric forms of which are represented by structures (I) and (II), can be used in this method.

The method of the present invention can be used in the treatment of tumorous diseases. the method comprising administering an effective amount of hydroxylamine derivatives to the tu-morous organism to prevent formation or growth of tumors. HvdroYylamine derivatives, the tautomeric forms of which are represented by structures (1) and (II), can be used in this metllod.
4.3. PHARMACEUTICAL AND COSMETICAL COMPOSITIONS CONTAINING THE
HYDROXYLAMINE DERIVATIVES

As already mentioned, the invention also relates to the use of hydroxylamine derivatives of the general formulae (I) and (II), including the optically active strereoisomers thereof, in the prepara-tion of pharmaceutical compositions (and optionally cosmetical compositions) useful in the treatment of cardiovascular, vascular, allergic, immune, autoimmune diseases, diseases caused bv viral or bacterial infection, tumorous, skin and mucous diseases and renal tubule diseases pro-voked by physiological stress as well as those conditions caused also bv physiological stresses whicli can be treated by cosmetical intervention, wherein formulae (I) and (II). or its salts. itlclud-ing the opticallv active stereoisomers thereof, A is an alkyl, substituted alkyl, aralkyl, aralkyl substituted in the aryl and/or in the alkyl moiety, aryl, substituted aryl, heteroaryl or substituted heteroaryl group, Z is a covalent bond, oxygen or =NR3 wlierein R3 is selected from the group consistin" of hydro-gen, an alkyl, substituted alkyl, aryl, substituted aryl. aralkyl, or aralkyl substituted in the aryl and/or in the alkyl moiety, R is an alkyl or substituted alkyl, X in the tautomer of formula (I) is halogen or a substituted hvdroxy or amino, monosubstituted amino or disubstituted amino group and X in the tautomer of formula (II) is oxygen, imino or substituted imino group and R' is hydrogen, an alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, aralkyl having substi-tuted aryl and/or alkyl moiety, acyl or substituted acyl group, and the compounds of formula (I) optionally contain intramolecular ring structures formed by coupling X and a reactive substituent.

By using these compounds, compositions for both preventive and curative purposes can be pre-pared, which, when administering in or applying on human or animal organism can be useftil in preventing or controlliny the cell damages cause by the above diseases thus relieving or eliminat-ing the pathologic condition of the organism.

These compositions can be prepared bv methods known per se in the preparation of cosmetics and pharmaceutical compositions, by tnixing the active material and the corresponding carriers S and/or auxiliaries. The compositions generally contain 0,5 to 99,5 % by weight active com-pound. The amount of active material in the composition is determined by the nature and seri-ousness of disease, the age of patient and the mode of treatment. The hydroxylamine derivatives of the formula (I) and (11) can be formulated to compositions to be used orally and parenterally as well as topically.

The daily dosis of the active compound is about 10 to 500 m/kg, preferably 20 to 100 mg/k~~, wliich, especially in case of oral compositions, is distributed to 2-3 administration.

For purposes of oral adininistration, the compositions are formulated into draoee, granulate. if desired, solution or suspension. Parenteral compositions include aqueous suspensions and sterile injectable solutions, while rectal administration forms are, among others, suppositories, and topi-cal forms include ointments, cremes, emulsions and gels.

For preparing tablets, the active ingredient is mixed with suitable carriers, such as starch ~~elatin, lactose, mao-nesium stearate, talc. gumiarabicum and silicagel, the mixture is granulated and pressed into tablets.

In the preparation of dragees, a mixture similar to the above is prepared from the active ingredi-ent and ausiliaries, the mixture is granulated, the granulate is pressed into a core, which is then coated with sugar, e.g. by using a sugar-containing aqueous polyvinylpirrolidon solution.

For preparing capsule forms, the active ingredient is mixed with auxiliaries, such as starch. talc, silica, microcrystalline cellulose, and the mixture is filled into hard or soft gelatin capsules.
These oral compositions may be completed with absorption promoting or retardinQ additives.

Syrups or elixirs or drops can be prepared by using, besides the active ingredient, sweeteners, methyl- or propyl-paraben and, if desired, tasting additives, by mixing the aqueous solution of the active ingredient therewith.

= For rectal administration, suppositories can be prepared by using the suitable auxiliaries, such as cocoa butter or polyethylene glycol.

Compositions suitable for parenteral administration can be the injections, prepared bv dissolving the active ingredient in sterile isotonic saline solution, or aqueous suspensions, which can be prepared by using suitable dispersin- and wetting agents, such as propylene glycol or butvlene glycol. 5 The cremes and ointments for topical use can be prepared by using primary or secondary alco-hols, such as cetyl alcoliol, stearvl alcohol. glycerin, natural fats and oils, such as olive oil, wheat germ oil, lanolin, longer hydrocarbons. such as vaseline as well as cellulose derivatives. These compositions may also contain preservatives, such as methyl-p-hydroxy benzoate.

The conipUslLioll fVI' use as LosYiletlCs or rI1cd1cc7l cosmetics can be prepared in a sim.ilar v:ay.
Preferably, the lipophylic components are mixed, and the water-soluble components are dis-solved in water, optionally by slight warmin~~. If desired, the pH of the latter is adjusted to the suitable value and the emulsion thus obtained is stirred until cooling. The active ingredient is added to the mixture of the mixture thus obtained in the form of aqueous solution.

The pharmaceutical and cosmetical compositions, which contain the novel 1lydroxylamine de-rivatives described in details under 4.1. in this specification can be prepared according to the above processes as well. These compositions form also an object of the invention.

One embodiment of the pharmaceutical and cosmetical compositions according to the invention contains hydroxylamine derivatives according to the formula (I) in an amount of 0,5 to 99,5 ib by wei-ht to`~ether with carriers and auxiliaries generally used in such compositions, wherein a) X is halo, preferably cllloro or bromo, Z is chemical bond, and al) A is a group of the formula (a), wherein Y' is halo, alkoxy, haloalkyl or nitro and n is 1, 2 or 3, or an 0-containing heteroaryl group, preferably furyl, S-containing heteroaryl, prefera-bly thienyl, or an N-containing heteroaromatic group optionally condensed with a benzene ring, or the N-C1-4 alkyl quaternary derivative or N-oxide thereof, preferably piridyl, quinolyl or iso-quinolyl, R is a group of the formula (b), wherein R' and R6, independently from each other are H, straight or branched alkyl, preferably CI-4 alkyl or cycloalkyl, or RS and R6 together with the N-atom adjacent thereto form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocy-clic ring, Y6 is -OR', wherein R7 is H or acyl, preferably unsubstituted or substituted alkylcar-bonyl, arylcarbonyl or aminoacyl, k is 1, 2 or 3 and m is 1, 2 or 3, or an N-Ci-4 alkyl quaternary derivative or N-oxide thereof, with the proviso, that when A is piridyl or naphtvl, or.a group of the formula (a) wherein Y' is halo or alkoxy, then R' is other than H. or a2) A is a group of the formula (c), R is a~~roup of the formula (d) and the optional substituents Y'` and Y' from which at least one must be present in the molecule, is oxygen or CI-4 alkyl, and k is 1. 2 or 3 and m is 1, 2 or 3, and when the compound is a mono- or bivalent cation, the anion is one or two halide ion, preferably iodide, or b) X is -NR'R', wherein R' and R2, independently from each other, are H.
unsubstituted or substituted straight or branched alkyl- unsubstituted or stibstituted aryl, preferably phenvl, un-substituted or substituted aralkyl, or R' and R'' together with the N-atom adjacent thereto, form a 3 to 7-membered, preferably 5 to 7-membered heterocyclic ring, which may contain one or more additional hetero atom(s), A is unsubstituted or substituted aryl, preferably phenyl, or unsubstituted or substituted aralkyl, Z is oxy~;en or =NR3, wherein R' is H or unsubstituted or substituted alkyl, and R is a group of the formula (b), wherein R' and R~', independently from each other are H.
strai(ylit or branched alkyl, preferably CI_4 alkyl or cycloalkyl. or R5 and R(' together with the N-atom adjacent thereto form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocy-clic ring, Y~' is H or -OR7, ~vherein R7 is H or acyl, preferablv unsubstituted or substituted alkyl-carbonyl or arylcarbonyl, k is 1, 2 or 3 and m is 1. 2 or 3, or c) X is -OQ, wherein Q is unsubstituted or substituted alkyl or aralkyl, Z is oxygen and R is a group of the formula (b), wherein R' and R6, independently from each other are H, straight or branched alkyl, preferably C 1-4 alkyl or cycloalkyl, or R5 and R6 together with the N-atom adjacent thereto form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocy-clic ring, Y6 is H or -OR7, wherein R' is H or acyl, preferably unsubstituted or substituted alkvl-carbonyl, arylcarbonyl or aminoacyl, k is 1, 2 or 3 and m is 1, 2 or 3, or d) A is unsubstituted or substituted aryl, preferably phenyl or an N-containing heteroaro-matic group, preferably piridyl or an S-containing heteroaromatic group, Z is a chemical bond, X is -OQ, wherein Q is Ci-4 alkyl, and R is a group of the formula (b), wherein R' and R~', independently from each other are H.
straight or branched alkyl, preferably C i-4alkyl or cvcloalkvl. or R5 and R6 together with the N-atom adjacent thereto form a 3 to 7-membered, preferablv 5 to 7-membered saturated lieterocv-5 clicring,Y6 isH,kis 1.2or3 andmis 1,2or3.

Another ~._*roup of the pharmaceutical and cosmetical compositions according to the inventioil includes those which, to-ether with pharmaceutically and cosmetically acceptable carriers and/or auxiliaries contain in an amount of about 0.5 to 99,5 % by weight a hydroxylamine derivative of the formula (I) or the saits aiid/or tlie upticaily active stereoisomers tl-iereut; wherein 10 X is -NR'R2, w-herein R' and R`, independently from each other, are H or unsubstituted or substituted straight or branched alkyl, preferably Ci_6 alkyl or cycloalkvl or, R' and R' together with the N atom adjacent thereto form a 3-7-membered, preferably 5 to 7-membered saturated lletero ring, A is unsubstituted or substituted aralkyl, preferably phenylalkyl substituted with one or 15 more alkoxy, preferablv C 1 -4alkoxy, unsubstituted phenyl or phenyl substituted with one or more halo, alkyl or haloalkvl, acylamino or nitro, or unsubstituted or substituted N-containing llet-eroaromatic group which is optionally condensed wit11 a benzene ring, preferably pirrolyl. piridyl, isoquinolvl or quinolvl, or an S-containin~~ heteroaryl group, preferably thienyl, wherein the llet-eroaryl groups niay have one or more substituents, preferably one or more alkvl, preferablv Ci-4 20 alkyl, Z is a chemical bond, and R is a group of the formula(e), wherein R' and R6. independently from each other are H, straight or branched alkyl, preferably Ci-4alkyl or cycloalkyl, or R' and R6 together with the N-atom adjacent thereto form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocy-25 clic ring which may contain additional hetero atoms and may have substituent(s), preferably C i-, alkyl, Y4 is H or unsubstituted or substituted Ci-4alkyl, Y' is H.
unsubstituted or substituted Cl-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 A is unsubstituted phenyl or phenyl substituted with halo or alkoxy or phenvlalkyl substituted with alkoxY or a piridyl group and R7 is H, at least one of R' and R'' is other than H, 30 and when A is unsubstituted phenyl or phenyl subsituted with halo or alkoxy or phenylalkyl substituted with alkoxy or a piridyl group, and R' and R'` are both H, R7 is other than H.
Anotlier aroup of the pharmaceutical and cosmetical compositions according to the invention includes those which, together with pharmaceutically and cosmetically acceptable carriers and/or auxiliaries contain in an amount of about 0,5 to 99.5 % bv weight a hydroxylamine derivative of the formula (II) or the salts and/or the optically active stereoisomers thereof, wherein a) X is o:cygen.

A is Ci-20 straight or branched alkyl, unsaturated or saturated aryl, preferably phenyl or haloalkyl-phenyl, unsubstituted or substituted aralkyl, naphtyl or an N-containin`~ heteroaromatic group, preferably piridyl, Z is a chemical bond, R' is H, Ci-4 alkyl or aralkyl, preferably phenvlalkyl, and R is a group of the formula (b). wherein R' and R6, independently from eacli other are H, straight or branched alkyl, preferably C 1-4 alkyl or cvcloalkyl, or R' and R6 together with the N-atom adjacent thereto form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocy-clic ring, y6 is H or -OR', wherein R' is H, k is l, 2 or 3 and m is 1, 2 or 3, with the proviso that when A is other than alkyl and R' is H. Y6 is H, or b) X is =NR 4, wherein R4 is H, unsubstituted or substituted alkyl or unsubstituted or substituted aryl, preferably phenyl, or unsubstituted or substituted aryl, preferably phenylalkvl, A is unsubstituted or substituted alkyl or unsubstituted or substituted aryl, preferably plienyl or substituted phenyl, or unsubstituted or substituted aralkyl, preferably phenylalkyl. or cycloalkyl, Z is a chemical bond, oxygen or =NR3, wherein R3 is H or unsubstituted or substituted alkyl, R' is unsubstituted or substituted alkyl or unsubstituted or substituted aryl, preferably phenyl, or unsubstituted or substituted aralkyl, preferably phenylalkyl, and R is a group of the formula (b), wherein R' and R6, independently from each other are H, straight or branched alkyl, preferably C1-a alkyl or cycloalkyl, or R' and R6 together with the N-atom adjacent thereto form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocy-clic ring, Y6 is H or -OR~, wherein R~ is H or acyl, preferably unsubstituted or substituted alkyl-carbonyl or arylcarbonyl, k is 1, 2 or 3 and m is 1, 2 or 3, or c) X is oYygen.

A is unsubstituted or substituted alkyl, unsubstituted or substituted aralkyl, preferably phenylalkyl, Z is oxygen, R' is alkyl or aralkyl, preferably phenylalkyl, R is a graup of tl.e formula (b), tivherei:: R' and R6, independently from cach other are H, strai~~ht or branched alkyl, preferably Ci-4 alkyl or cycloalkyl, or R' and R6 together with the N-atom adjacent thereto form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocy-clic ring, Y6is H or -OR7, wherein R7 is H or acyl, preferably unsubstituted or substituted alkyl-carbonvl or arvlcarbonyl, k is 1. 2 or 3 and m is 1, 2 or 3, or d) X is oxygen.
Z is =NH, and dl) A is unsubstituted or substituted alkyl, cycloalkyl. unsubstituted or substituted aral-kyl, preferably phenylalkyl, unsubstituted phenyl or phenyl substituted with halo, haloalkvl, alk-oxy or nitro, R' is alkyl or aralkyl, preferably phenylalkyl, and R is a group of the formula (b), wherein R5 and R6, independently from each other are H.
straight or branched alkyl, preferably CI-4 alkyl or cycloalkyl, or RS and R 6 together with the N-atom adjacent thereto form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocy-clic ring, Y6 is H or -OH, k is 1, 2 or 3 and m is 1, 2 or 3, or d2) A is a group of the formula (a) wherein Y' is haloalkyl, preferably trifluoromethyl and n is 1, 2 or 3, R'isHand R is a group of the formula (b), wherein R5 and R6, independently from each other are H, straight or branched alkyl, preferably C1-4 alkyl or cycloalkyl, or R' and R 6 together with the N-atom adjacent thereto form a 3 to 7-membered, preferably 5 to 7-membered saturated heterocy-clicring,Y6 is H or -OH, k is 1, 2 or 3 and m is 1, 2 or 3.

Another group of the pharmaceutical and cosmetical compositions according to the invention includes those which. to`ether with pharmaceutically and cosmeticallv acceptable carriers and/or auxiliaries contain in an amount of about 0,5 to 99.5 % by weight a hydrotylamine derivative of the formula (I") or the salts and/or the optically active stereoisomers thereof, wherein A is unsubstituted phenvl or phenyl substituted with halo or nitro or an N-containing het-eroaryl `roup. preferably piridvl.

R' is H and R" is an a)-aminoalkyl group which may be mono- or disubstituted. wherein the alkyl chain contains 1 to carbon atoms and the amino-substituents. independentlv from each other are one or two straight or branched alkyl or cycloalkyl, or wherein the two amino-substituent to-('Yether with the N-atom adjacent thereto form a 3 to 7-membered..preferablv 5 to 7-menlbered heterocyclic ring or the N-Ci-4 alkyl quaternary derivative thereof, with the proviso that when A is piridyl. R" is other than l-piperidinylmethyl.

The embodiments of the invention are illustrated in the following examples more in details. It sliould be understood, liowever, that the scope of protection is not limited to the specific em-bodiments set forth in the Examples.

5. CHEMICAL AND COMPOSITION EXAMPLES
Example 1:

N-[2-hvdroxv-3-(1-nineridinvl)nronosvl-2-thionhenecarboximidovl chloride monohvdrochloride 5.0 g(15.6 mmol) of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-2-thiophenecarboximidamide monohydrochloride (Example 44) was dissolved in 19 ml of water, then 6.1 ml of concentrated hydrochloric acid was added. The solution was cooled to -5 C, then a cold solution of 4.4 g = (63.8 mmol) of sodium nitrite in 2.4 ml of water was added dropwise.
Throughout the reaction the internal temperature was maintained at 0 C. When addition was completed the mixture was stirred for a further one hour. Cold benzene (60 ml) was added and the mixture was made alka-line with slow addition of a cold solution of 3.2 g (80 mmol) of sodium hydroxide in 45 ml of water. The or2anic phase was separated and washed successively with 20 ml portions of water until the pH<9 (3-5 times). The organic solution was dried over anhydrous sodium sulfate, treated with charcoal, filtered and evaporated in vacuum (t < 45 C) to give 2.6 g of oil. This resi-due was dissolved in 5 nil of isopropyl alcohol and acidified (pH 2) with isopropyl alcollol con-taining dry hydrochloric acid. The product was crystallized from n-hexane to give off-w-Ilite ma-terial.

Yield: 2.0 g ('18 %) Mp.: 115-123 C

Followin~,7 the process described in the previous example the following compoiuids were pre-pared:

Elamplc.~ 2:

N-(2-hydroxy-3-(1-nineridirn,l)nropoxyl-l-isoguinolinecarhorimidovl chloride monohvdro-chloride Starting material: Exanrple 46 Yield: 48 %
Mp.: 168-172 "C

IR (KBr): 3425, 3128, 29=17, 2866, 2650, 2540, 1622, 1597, 1556, 1452, 1385, 1-~)64, 1329, 1296, 1281, 1240, 11 17, 1092, 1024, 1015, 978, 9-~3, 903, 881. 795, 743. 718, 658, 559 cm-1 Example 3:

N-f2-hydroxv-3-(1-niperidinvl)nronoxvl-3-guinolinecarboYimidovl chloride (Z)--2-butenedioate (1:1) Starting material: Example 42 In this case the final product was isolated at the end of the work-up procedure by dissolving the crude base in acetone, and adding an equivalent amount of maleic acid.

Yield: 67 %
Mp.: 159-162 C

IR (KBr): 3427, 3019, 29-17. 2886. 2689, 1583, 1-177, 1-I50, 1352. 1293, 1221.
1194, 1132, 1072. 1045. 939. 919. 872, 833, 754, 650. 557 cni-1 Ecrntple -l:

5 N-(2-hvdroxy-3-(1-piperidinvl)propoxvl-3-nitro-benzenecarboximidovl chloride monohy-drochloride Starting material: Excrmple 40 Yield: 58 %
Mp.: 185-189 'C
Exumplc 5:

N-12-hvdroxv-3-(1-pipcridinvl)propoxvl--l-nitro-bcnzenccarboximidovl chloride monohv-drochloride Startin~~ material: Exunrplc 43 Yield: 47 %
Mp.: 180-182 "C
IR (KBr): 3331, 2953, 2853, 2735, 2654, 2577, 2548, 1605, 1568, 1516, 1456, 1348, 1261, 1165, 1 1 19, 1072, 1059. 1007, 960, 933, 862, 849. 754.
719, 690. 673, 627, 581, 550. 478 cni ' Example 6:

N-[2-hvdroxv-3-(1-niperidinvl)nropoxv] -2-nitro-benzenecarboximidovl chloride monohvdrochloride Starting material: Exanzple 45 Yield: 50 %
Mp.: 159-162 C
IR (KBr): 3298, 2983, 2932, 2746, 1593, 1574, 1535, 1445, 1391, 1354, 1317, 1288, 1242, 1198, 1117, 1092, 1069, 1020, 968, 947, 914, 852, 793, 756, 708, 577 cm-1 Example 7:

N-[2-hvdroxv-3-(1-niperidinvl)nroporvl-2-furanecarboximidovl chloride monohvdrochloride Procedure:

I-Chloro-2-hydroxy-3-(I-piperidinyl)-propane [J.Org.Chenz. 33(2) p.523-30 (1968)] (3.0 116.9 mmol) was dissolved in water (1.8 ml). Solid NaOH (1.19 g, 29.8 mmol) was added, and the riYi;cture was stirred at room tenlperature for i hour. N-I-lydroxy-2-furanecarboximidamide (1.92 g, 15.2 mmol) was added, and the mixture was kept on stirring at room temperature over-night. Concentrated HC1 (2.1 ml) was added to adjust the pH to approx. 4, and the solution was evaporated in vacuum to dryness.

The residue (5.4 g) was dissolved in cc. HCI (37 nil), cooled to 0 - 5 C, and an aqueous solution ofNaNO2 (5.6 g. 80 mmol in 23 ml water) was added dropwise in 30 min. The solution was made alkaline then by addition of 2N NaOH solution (102 ml) to pH = 10. and extractcd with ethyl acetate (2 x 130 ml). The combined organic phases were washed witll water, dried over anh. NaSO:t and evaporated. The residue (2.0 g) was redissolved in a small volume of ethyl acetate (20 ml) and the product -was precipitated by addition of isopropanolic HC1 solution (3.2 N. 3 ml). The obtained white precipitate was filtered, washed, and finally recrystallized from isopropanol.

Yield: 11 %
Mp.: 139-141 C
IR (KBr): 3427, 3267, 3094. 2955, 2922, 2964, .2745, 1637, 1584, 1479. 1452, 1391, 1319, 1281, 1259, 1157, 1117, 1074, 1024, 999, 980, 943, 887, 854, 843. 743, 710, 596 cm-1 Following the process described in the previous example the following compound was prepared:
Example 8:

N-[2-hydroxv-3-(1-pineridinvl)proposvl-4-nvridinecarboYimidovl chloride (Z)--2-butenedioate (1:1) In this case the final product was isolated at the end of the work-up procedure by dissolving the crude base in acetone, and adding an equivalent amount of maleic acid.

VVO 97116439 PCT/fiU96/00064 Yield: 25 %
Nvlp.: 165.5 - 169 C
` Example 9:
.

N-[3-((l,1-dimethvlethvl)amino1-2-hvdroxypropoxvl-3-trifluoromethvibenzene-carhoximidovl chloride monohvdrochloride Procedure:
a) 50 g(0.2=15 mol) ot zli-tritlttoromethvl-benzamidoxime and 33.7 g(0.6 mol) of potassium liv-droxide was dissolved in a milture of dimethyl sulphoxide and 170 ml of water, and the mixture was cooled to 0 C. 48 ml (0.6 mol) of epichlorohvdrine was added, and the reaction mixture was stirred at 0 C for 5 hours, then kept in a refriaerator overnight. Next day 250 ml of water was added, and the mixture was extracted with ethyl acetate (4x250 ml). The combined organic phases were waslied with water, dried, treated with charcoal and evaporated to dryness, to yield m-trifluoromethyl-N-(2.3--epoxypropoxy)-benzamidine, as a colorless oil.

Yield: 61 g (96 %) b) To the obtained oil 400 ml of 18 `% of hydrochloric acid solution and 60 tnl of ether were added, and the mixture was cooled to -5 C, while stirring. 17.4 g(0.25 mol) of sodium nitrite, dissolved in 60 ml of water was added slowly in 40 min., and the reaction mixture was stirred for another 20 minutes. The mixture was extracted then with ether (2x 160 ml), and the combined organic phases were washed with water twice. To the ethereal solution 340 ml of 20 %
of sodium hy-droxide solution was added, and the two-phase system was refluxed for 1 hour, while stirrinQ.
The phases were then separated, the organic layer was washed with brine until neutral, dried and evaporated to dryness to give m-trifluoromethyl-N-(2,3-epoxypropoxy)-benzimidovl chloride. as a colorless oil.

Yield: 30.5 g (45 %) c) A mixture of 1.19 g (4.2 mmol ) N-[(2,3-epoxy)propoxy]-3-trifluoromethyl-benzenecarboximidoyl chloride and 0.89 ml (8.5 mmol) of tert-butylamine in 12 ml of isopropyl alcohol was refluxed for 2 hours. Solvent was removed under reduced pressure.
The residue was dissolved in ethyl acetate. and 0.98 ml of methanolic hydrogen chloride solution (4.3 N) was added and the mixture was concentrated to small volume under vacuum, then diluted with etlier.
The precipitate that formed was recovered, washed with cold ether and dried.

Yield: 0.48 g (32 %) Mp.: 150-153 C
IR (KBr): 3423, 32 33, 2978, 2880, 2784, 1620, 1570, 1479, 1441, 1400, 1383, 1 340, 12 38, 1167, 1128. 1101. 1072. 1038, 982, 930, 897, 804. 787, 714, 694 cm 1 Following the process described in the previous example the following compounds were pre-pared:

Example 10:
N-(2-hvdroxv-3-((1-methvlethvl)aminolnroporvl-3-trifluoromethvl-benzene-carboYimidovl chloride monohvdrochloride Yield: 30 %
Mp.: 105-108 C
IR (KBr): 3358, 2984, 2883. 2804, 1595, 1441, 1383, 1335, 1238. 1184, 1171, 1 121, 1099, 1074, 1011. 995, 947, 906, 891, 798, 779, 696, 681, 567 crri' E_rample 11:

N-[3-(cvclohexvlamino)-2-hvdroxynropoxv] -3-trifluoromethvl-benzenecarborimidov l chloride monohvdrochloride Yield: 35 %
Mp.: 147-149.5 C
IR (KBr): 3381, 2951. 2860, 2820, 1580, 1439, 1344, 1246, 1161, 1126, 1099, 1074, 1003, 986, 932, 903, 872, 802, 787, 716, 692, 681, 648 cm-1 Example 12:

N-(3-(diethyiamino)-2-hvdroYvproposvl-3-trifluoromethvl-benzenecarboYimidovl chloride monohvdrochloride Yield: 21 %

Mp.: 121-128 C
IR (KBr): 3425, 3289, 2951, 2667. 1818, 1443. 1337, 1238, 1178. 1115, 1078.
1049, 997, 910, 804, 781. 696. 683 cni-1 Example 13:
N-12-hvdrosv-3-(1-niperidinvl)proposvl-3-tritluoromethvl-benzenecarbosimidovl chloride monohvdrochloride Yield: 13 %
Mp.: 119-123 "C
IR (KBr): 3.366, 2937, 2854. 2737, 2673, 2538, 1616, 1570, 1439, 1404, 1337, 1290, 1236, 1199, 1165, 1129, 1101, 1074, 1030, 984, 972, 93 -'), 901.
829, 804, 788, 717, 699, 685, 646 cm-Exurnple 14:

N-(2-hvdroxv-3-(1yiperidin-l-oxide-l-vl)propoYvl-N'-oYv-3-nvridinecarboximidovl chloride Procedure:

To a solution of N-[2-hydroxy- 3-(1-piperidinyl)propoYy)-3-pyridinecarboximidoyl chloride (5.0 g; 17.1 mmol) in chloroform (50 ml) m-chloroperbenzoic acid (7.0 g; 40 mmol) was added in small portions, and the mixture was stirred at room temperature for 2 hours.
The solvent was removed, the residue was dissolved in 80 ml of ethyl acetate, extracted with water, dried and evaporated. The obtained oily product was finally crystallized with acetone to give the product as an off-white solid.

Yield: 2.21 ? (6.7 mmol; 40 %) Mp.: 140-142 C

IR (KBr): 3437, 3071, 2943, 2880, 2590, 1801, 1578, 1475, 1454, 1433, 1375, 1294, 1259, 1194, 1165, 1121, 1088, 1043, 1011, 995, 924, 905, 888, 845, 808, 710, 671, 554, 513, 413 cm 1 Example 15:

N-(2-hvdroxv-3-(piperidin-l-oxide-l-vl)propoYvl-3-pvridinecarborimidovl chloride 5 Procedure:

To a solution of N-[2-hydroxy- 3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl cliloride (2.0 g: 6.8 mmol) in cliloroform (20 ml) m-chloroperbenzoic acid (1.6 g of 70 %
purity: 6.5 mmol) was added. and the mixture was stirred at room temperature for 30 minutes. The solution was made alkaline witli 10 % of sodium hydroxide solution, then separated. and the organic layer was 10 washed with brine, dried and evaporated. The solid residue was recrystallized with ethyl acetate, the precipitate was filtered off, waslled and dried, to give the product as a white solid.

Yield: 1.03 g (48 %) Mp.: 127-130 C
IR (KBr): 3454, 2988, 2945, 2880. 2585, 1585, 1512, 1=179, 1443, 1416, 1393, 15 1350, 1331, 1289, 1 18 3, 1134, 1072, 1051, 1030, 997, 953, 939, 879, 847, 808, 702, 519, 417 cm t Example 16:
N'-12-hvdroxv-3-(1-methvl-l-niperidinium-l-vl)propoYvl-N-methvl-pvridinium-3-20 carboximidovl chloride diiodide Procedure:
A mixture of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride (1.0 g;
3.4 mmol) and 1.2 ml (20 mmol) of methyl iodide was refluxed in acetone (10 ml) under nitro-gen for 2 hours. The resulting dark yellow precipitate was filtered off. and washed with acetone 25 to give the crude product (1.8 g) which was then recrystallized from 20 ml of ethanol.
Yield: 1.2 g (60 %) Mp.: 153-157 C

IR (KBr): 3462, 3406, 3317. 3040, 2941, 2878. 2831, 1729, 1636, 1589, 1504, .
1462, 1378, 1350. 1290, 1209, 1171. 1121, 1069, 1047. 1030, 1001.
941, 897. 868, 818, 706, 673, 635, 589 cm ' Example 17:

N-[2-acetoxv-3-(l-piperidinvl)propoxvl-3-nvridinecarboximidovl chloride (Z)--2-butenedioate (1:1) Procedur::
1.48 c), (5.0 mmol) of N-[2-hydroxy-3-(1-piperidinvl)propoxN,]-3-pyridine-carboYimidoyl cllloride was dissolved in _>" ml of acetic anlrydride. The temperature of the reaction was raised up to 40 "C.
After 30 minutes at room temperature the solvent was completely removed in wrcuum, the resi-due was dissolved in 30 ml of diethyl etlier, treated with charcoal, filtered and the solvent was removed under reduced pressure to give 1,74 g of orange-colored oil.

The residue was dissolved in 10 nil of acetone, and a solution of 0.6 (,-(5.17 mmol) of maleic acid in 10 ml of acetone was added. The crystalline product was removed by filtration and washed with acetone to aive 1.43) g off-white material. Recrystallization, with decolorization.
from 9 ml of isopropyl alcohol produced the title compound.

Yield: 1.22 g (54 %) Mp.: 143-144 C
Example 18:

(S)-N-f 2-[2-0-(1,1-dimethvlethvloxvcarbonvlamino)-3-phenylnropionylorvl-3-(1-piperidinyl)pronoxyl-3-nvridinecarboximidovl chloride (Z)-2-butenedioate (1:1) Procedure:
6.7 c, (25.5 mmol) of N-(tert-butoxycarbonyl)-D-phenvlalanine was dissolved in 50 ml of di-chloromethane. The solution was cooled to 0 C, and 4.0 ml of triethylamine and then 2.5 ml (26 mmol) of ethyl chloroformate was added dropwise. The mixture was stirred for 20 minutes at 0 C, then a solution of 7.5 g(26 mmol) of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-' pyridinecarboximidoyl chloride in 50 ml of dichloromethane was added in 30 minutes. The reac-tion mixture was stirred at room temperature for 1 hour. The solution was eYtracted. first ,vith 10 % acetic acid (2x100 ml), then with water, dried with anhydrous sodium sulfate. and evaporated to dryness. The residue (10.7 ;) was dissolved in 71 ml of acetone and 1.53 ~(13 mmol) of maleic acid was added. The resultina solid was filtered off and washed with acetone. `
a Yield: 4.0 g (6.0 mmol: 23 %) Mp.: 146.5-148 C

[a][) = + 21.5 (c = 1. MeOH) IR (I{Br): 3393. 2978, 1744. 1697, 1582, 1518, 1468. 1454. 1420. 1381, 1358, 13131, 1290, 1256. 1213, 1169, 1126, 1099, 1084, 1045, 1016, 930.
908, 870. 750. 690, 575 cm-1 Following the process described in the previous example the following compound was prepared:
E_rumple 19:

(R)-N-12-(2-(S)-(1,1-dimethvlethvloxvcarbonvlamino)-3-phenvlnronionvloxvl-3-(1-Diperidinvl)nropoxvl-3-pvridinecarboximidovl chloride (Z)-2-butenedioate (1:1) Yield: 25 %

This compound has the same physical data (Mp.; IR) as written in Exumple 18.
[a],) = - 23.6 (c = 1. NiIeOH) E,ecrnzple 20:

N-[2-benzovloxv-3-(1-pineridinvl)pronoxvl-3-nvridinecarbosimidamide (Z)-2-butenedioate (1:1) Procedure:
20.9 g (75.0 mmol) of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine-carboximidamide [Hung. Pat. 177.578 (1976)] was dissolved in 300 ml of benzene. To this solution 150 ml of 1 N
sodium hydroxide solution was added, followed by dropwise addition of 19.5 ml (168 mmol) of benzoyl chloride. After stirring the mixture intensively for 2 hours, 7.1 g (67 mmol) of sodium carbonate and a further portion of benzoyl chloride (9.75 ml; 84 mmol) was added, and the stir-ring was continued overnight. The phases were then separated, the organic layer was extracted with 1 N sodium hydroxide solution and water, dried and evaporated to dryness.
The residue (41 Or oil) was dissolved in 150 ml of acetone. and 8.7 g(75 mmol) maleic acid was added. The ob-tained precipitate was filtered off, washed with acetone, and dried.

Yield: 29.1 g (78 %) Mp.: 194-195 C

Following the process described in the previous example the following compound was prepared:
Ercrmple 21:

N-(2-benzovlorv-3-(1-niperidinyl)propoxvl-3-nvridinecarboximidovl chloride (Z)-2-butenedioate (1:1) Starting material : U.S. Patent 5,147.879 (1992) Yield: 64 %
Mp.: 134-136 "C
IR (KBr): 2955. 2939, 2517, 1718, 1583, 1477, 1452. 1410. 1370. 1354, 1317, 1268, 12109. 1173, 1117, 1057, 1043, 998. 968. 939, 903. 870, 748.
723, 714, 652. 582 cm-I

Example 22:
N-12-nalmitovloxv-3-(1-piperidinvl)propoxvl-3-pyridinecarboximidamide monohvdrochloride Procedure:

14.7 g (52.8 mmol) of i,T-[2-hydroxy--'I-(1-piperidinyl)propoxy]-3-pyridine-carboximidamide [Hung. Pat. 177.578 (1976)] was dissolved in 160 ml of chloroform. 7.7 ml (55 mmol) of triethy-lamine was added, followed bv dropwise addition of a solution of palmitoyl chloride (14.7 g;
56.5 mmol) in 85 ml of chloroform. The mixture was stirred overnight at room temperature. Next day further amount of 3.8 ml of triethylamine and 7.4 g of palmitovlchloride was added, and the stirring was continued for one more day. The solution was extracted then with water, 5 % acetic acid and water, successively, dried over anh. sodium sulfate, and evaporated to dryness.

The residue (28.2 g oil) was dissolved in ethyl acetate, and the product was precipitated by addi-tion of 30 ml of 1 N HC1/ethvl acetate. The thick, white precipitate was filtered off, washed with ethyl acetate and dried.

Yield: 10.9 g (37 %) Mp.: 110-113 C

Following the process described in the previous example the following compounds were pre-pared:

Ercrmpl e 23:

N-12-palmitovlorv-3-(1-piperidinvl)propoYvl-3-gyridinecarhoximidovl chloride dihvdro-chloride Startin~.: material: U.S. Patent 5.147,879 (1992) Note: the reaction was carried out by refluYing.
Yield: 72 %
Mp.: 69-73.5 C
IR (KBr): 3425, 2922, 2853. 2648, 2544, 1742, 1632. 1468, 1416. 1377, 1287.
1183, 1113, 1087. 1032, 984, 708, 675 cm 1 Exanzple 24:
N-12-(2-furovloxv)-3-(1-nineridinvl)propoxvl-3-pvridinccarboximidamide (Z)-2-butenedioate (1:1) Note: the product was isolated in the form of maleate salt.
Yield: 52 %
Mp.: 167-171.5 C
EYample 25:

N-12-(o-chlorobenzovloxv)-3-(1-nineridinvl)pronoxvl-3- pvridinecarboximidamide mono-hvdrochloride Note: the reaction was carried out by refluxing. Yield: 50 %

Mp.: 91 - 94 C

E_rannple 26.-N-(2-(p-methoYvbenzovloxy)-3-(1-pigeridinvl)nroporvl-3-pvridinec<irboYimidamide mono-hvdrochloride 5 Note: the reaction was carried out by refluxing.
Yield: 71 %
Mp.:152-155 C
E.rample ? i:

10 N-f 2-(m-trifluromethylbenzoyloxy)-3-(1-niperidinyl)nropoxyl-3-nyridinecarboYimid.imidc monohvdrochloridc Note: the reaction was carried out by retluYing.
Yield: 45 %
Mp.: 144 - 147 C
L'xample 28:

N-(2-(2-thenoyloxv)-3-(1-piperidinvl)propoxvl-3 pvridinecarboximidamide (Z)-2-butenedioate (1:1) Note: the reaction was carried out by ref]uYing. and the product was isolated in the tornl of maleate salt.

Yield: 58 %
Mp.: 168 - 176 C
Example 29:

N-(2-aceto.r=v-3-[(1-niperidinvl)nropoxvl-3-nvridinecarboximidamide monohvdrochloride Procedure:

2.5 g (9.0 mmol) of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide was dissolved in 27 ml of chloroform, 1.6 g (16 mmol) of acetic anhydride was added and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness, and dissolN-ed in isopropyl alcohol containing the equimolar quantitv (9 mmol) of dry hvdrogen chloride. The so-lution was cooled and the solid were filtered. Recrvstallization from isopropyl alcohol `~ave white crystalline compound.

Yield: 1.9 or (59 %) 1LIp.: 10 7 C:
Excrmple 30:

N-(2-(3-Pvridinecsirbonvlosv)-3-(1-taiperi(liravl)I nrapoxv-3-rry.riclinec.irlhnxiniislami(lfr-(Z)-2-butenedioate (1:1) Procedure:

To a solution of N-[2-hydroYy-3-(1-piperidinyl)propoxvJ-S-pyridinecarboxiinid-amide (1.68 6 n1mo1) in dry pyridine 1.68 a (7.4 mmol) of nicotinic anhydride was added and kept at rooni temperature overnight. The mixture was evaporated, the residue was dissolved in 30 ml of'ethvl acetate, filtered, the filtrate was extracted with 10 % NaHCO; solution. dried and evaporated.
The obtained oil was dissolved in 20 ml of acetone. and 0.53 u of maleic acid was added to result in precipitation. The product was filtered off and washed with acetone.

Yield: 1.84 a (61 %) Mp.: 157-160 C

Example 31:

N-13-(1-piperidinyl)proporyl-3-pyridinecarboximidamide dihvdrochloride Procedure:

2.86 g(51.1 mmol) of potassium hydroxide was dissolved in 20 ml of abs.
ethanol, then 6.45 g .
(47.0 mmol) N-hydroxy-3-pyridinecarboximidamide and 7.7 g(47.7 mmol) 1-chloro-3-(1-piperidinyl)-propane were added and refluxed for 9 hours. The solid was removed by filtration and the filtrate was evaporated. The crude product was dissolved in 100 ml of chloroform, washed with 1 N of sodium hydroxide solution then three times of water. The organic laver was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in a small amount of abs. ethanol and isopropyl alcohol containing dn=
hydrochloric acid was added (pH 2) to afford off-white crystals.

Yield: 4.8 ; (38 %) Mp.: 95-100 C (dec.) IR (KBr, base): 5422, 3294, 3107, 2984, 2957, 2870, 2818, 1649. 1616. 1593, 1-179, 1462, 1441, 1381, 1-~)09. 1194. 1 123, 1094. 1059, 1042, 982. 910. 858, 816. 712. 559 cnl-' Following the process described in the previous example the following compounds were pre-pared:

Eramplc.~ 32:

N-f3-(1-niperidinvl)propoxvl-3-trifluoromethvl-benzenccarbtlximidamide monohvdro-chloride Yield: 42 %
Mp.: 1 16-1 19 C

1 -5 IR (KBr. base):3412, 3082. 2949. 2874, 2827, 1655, 1485, 1447, 1383.
325,1283, 1171, 1121, 1094, 1072, 986. 920. 905, 808, 700, 677, 627 cm E:cample 33:
N-13-(1-piperidinyl)propoxv]-(3,-1-dimethoxvphenvl)methanecarboximidamide dihvdrochloride Yield: 35 %
Mp.: 207-209 C
Example 34:

N-f2,2-dimethvl-3-(1-piperidinvl)propoxvl-3-pvridinecarboximidamide Yield: 38 % (oil) IR (KBr): 3323, 2935, 2888. 2785, 1637, 1477, 1393, 1360, 1157, 1111, 1057, 995, 943, 860, 814, 789, 708, 627 cm ' Example 35:

N-13-(4-methvl-l-piperazinvl)propoYVl-3-pvridinecarbosimidamide monohvdrochloride Yield: 23 %
Mp.: 127-130 C
IR (KBr): 3387, 29-I7, 2878, 2802. 1730. 16 39, 1450. 1389, 1283. 1242. 1194, 1150. 108 3, 1015. 964, 933. 814, 710 cm-1 Example 36:

N-f 3-(1-piperidinvl)pronoxvl-3-nitro-benzenecarboximidamide monohvdrochloride Yield: 51 %
Mp.: 158-162 C
Example 3 ~ :

N-13-(1-piperidinvl)propoxyl-benzenecarboximidamide dihvdrochloride Yield: 64 %
Mp.: 207-209 C
Example 3$:

N-(2-hvdroxv-3-f (1-niperidinvl)propoxvl-2,4,6-trimethvl-benzenecarbosimidamide Yield: 44 %
Mp.: 199-201 C
IR (KBr): 3410, 3103, 2943, 2912, 2814, 2791, 1634, 1582, 1441, 1383, 1350, 1321, 1304, 1254, 1204, 1146, 1111, 1099, 1065, 993, 878, 851, 785, 754,525cm~

WO 97116439 PCT/fIU96/00064 Excrmple 39:

N-12-hvdro:ev-3--(1-oiperidinvl)propoxvl-=l-acetamino-benzenecarboximidamide monohvdrochloride Yield: 25 %
Mp.: 133-1i7 C
Excmzple 40:

N-12-hvdroev-3-f (1-nineridinvl)nropoxvl-3-nitro-benzenecarboximidamide dihvdrochlo-ride Yield: 38 %
Mp.: 190-193 C
Excrmple 41:

N-(2-hvdroxv-3-((1-niperidinvl)gropoxvl-2-(1,5-dimethvl)-nvrrolcarboximidamide mono-hvdrochioride Yield: 20 %
Mp.: 144-147 "C
IR (KBr. base): 3458, 3369, 2930, 2849, 1622. 1587, 1502, 1468, 1437, 1396, 1354.1323, 1279. 1254, 1200. 1157, 1115, 1078. 1042. 988, 962, 930. 870. 856, 758, 737, 694, 609 cm 1 E.rample 42:

N-[2-hydroxy-3-((1-nineridinyl)propoxv] -3-guinolinecarboximidamide dihvdrochloride Yield: 36 %
Mp.: 210-211 C

Example 43:

N-f2-hydroxv-3-(1-niperidinvl)pronosyl--l-nitro-benzenecarboximidamide dihvdrochloride 5 Yield: 77 %
Nlp.: 184-189 C
Erumplc,~ -l-l:
N-(2-hvdroxv-3-(1-piperidinvl)propoxvl-2-thionhenecarboximidamide dihvdro-10 chloride Yield: 73 %
Mp.: 157-170 C
IR (KBr): 3280 (b). 2940, 1655, 1420. 1120, 1018, 1002. 857, 710 cm-1 15 Example -15:

N-f2-hvdroxv-3-(1-niperidinvl)nropoxvl-2-nitro-benzenecarboximidamide dihvdrochloride Yield: 47 %
Mp.: 200-208 C
20 IR (KBr): 3300 (b). 2960. 1670, 1535, 1347, 1155, 1020, 1002. 860, 800, 753 cm 1 Example 46:

N-(2-hvdroxv-3-(1-piperidinvl)pronoxvl-l-isoguinolinecarboximidamide dihvdrochloride 25 Yield: 56 %
Mp.: 208-216 C

Example -l':

N-(3-((1,1-dimethvletllvl)aminol-2-hvdroxvnroposyl-3-trifluoromethvl-benzenecarboximidamide dihvdrochloride Procedure:

A mixture of 21.0 g (80.8 mmol) of tn-trifluoromethyl-N-(2. _' -epoxypropoxy)-benzamidine (Esamplc.~ 9,~'a). 105 ml of tert-butylamine, 210 ml of ether and 84 ml of 4 N
sodium hydroxide solution was retluYed for 5 hours. The phases were separated, the ethereal laver was washed with brine, dried and evaporated to drvness. The resulting oil (25.8 (r) was dissolved in 250 nil of acetone, treated with charcoal. then 39 ml of 4 N HCI/ethyl acetate solution was added, while stirrinc, resulting in precipitation of a white solid, which was filtered off and washed with ace-tone.

Yield: 22.8 (T (70 %) Mp.: 186-192 C (dec.) IR (KBr): 3418, 2984, 2785, 2625, 2527, 2401, 1664, 1585, 1487, 1437. 1 381,1329, 1173).
1155, 1130, 1078. 905. 874, 820, 692. 642, 594 cm-1 Example 48:
N-12-hvdroxv-3-(1-niperidinvl)proporvl-N'-butvl-3-pvridinecarboximidamide monohvdrochloride Procedure:
a) Preparation of N-[2-[(2-tetrahydropyranyl)oxy]-3-(1-piperidinyl)propoxy]-3--pyridinecarboximidoyl chloride (21.3 g, 71.4 mmol) of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride was dissolved in 500 ml of chloroform, acidified with ethereal hydrochloric acid solution to pH=3, then 32.6 ml (0.357 mol) of 3,4-dihydro-2H-pyrane was added. The mixture was stirred at room temperature for 20 hours.
washed three times with 200 ml portions of 2 N sodium hydroxide solution and four times with the same amount of water. The organic phase was dried over sodium sulfate, filtered and evapo-rated under reduced pressure. The oily residue was dissolved in 600 ml of ethyl acetate and 'washed four times with 150 ml portions of a pH=5 buffer solution. The organic solution was dried, filtered and evaporated Yield: 24.5 - (90 %) b) A mixture of 3.7 g (9.68 mmol) ofN-[2-[(2-tetrahydropyranyl)oxy]-3-(1-piperidinyl)propoxy]- ')-pyridinecarboximidoyl chloride and 40 ml (0.41 mol) n-butylamine was refluxed for 3 hours. The excess of amine was evaporated in vacuunz affording dark-broNvn oil.
which was dissolved in 40 ml of ethanol containing 3.0 g of 4-toluenesulphonic acid and the tnixttire was heated at 60 C for one hour. The solvent was removed under reduced pressure. the residue was made alkaline (pH 10) with 2 N of sedium hydroxide solution then extracted thrc:e times with chloroform. The or~,anic solution was dried over sodium sulfate.
filtered and the sol-vent was evaporated in raczurm. The dark oily residue was purified bv chromatography to give the pure base, which was dissolved in 20 ml of ethanol and acidified with eduivalent amount of dry hydrochloric acid dissolved in isopropyl alcohol to give the title coinpound as a palc-yellow crvstalline solid.

Yield: 1.22 g( 34 %) Mp.: 120-122 C
IR (KBr, base): 3319, 3293, 3040, 2959, 2928. 2854, 2842, 2552, 1612, 1580, 1450. 1427, 1399, 1333, 1315. 1221. 1196, 1171, 1126, 1103, 1051, 1022, 964. 928, 899, 858, 829, 719, 692, 602 cn1-' Followin- the process described in the previous example the followin`~
compound was prepared:
E.tanzple -19:

N-(2-hvdroxv-3-(1-nineridinvl)propoxvl-N'-cvclohexvl-3-nvridinecarboximidamide mono-hvdrochloride Yield: 0.89 g (24 %) Mp.: 130-134 C
IR (KBr): 3280, 2935, 2853, 2640, 1720, 1619, 1551, 1514, 1452, 1404, 1313, 1236, 1194, 1155, 1124, 1111, 1090, 1040, 978, 828, 735, 627 cm WO 97/16439 PCT/fI(T96/00064 E_rcrmple 50:

N-(2-hydroxy-3-(1-piperidinvl)gropoxvl-N'-(l,l-dimethvlethvl)-benzenecarboximidamide Procedure:

Into a solution of 0.92 ~(5.2 mmol) of 1-chloro-2-hydroxy-_3-(1-piperidinyl)-propane in 2 ml of water 0.42 g(10.4 mmol) sodium hydroxide was added and stirred for one hour.
To this mixture was added 1 0 g (5.2 nin1ol) ofN-hvdroxv-N'-(1,1-dimethvlethvl)-benzeneca.rboximidami(ie dil;-solved in 20 ml of ethanol and refluxed for 4 hours. Solvent was evaporated and 50 ml of water was added and three times was extracted with 50 nil portions of chloroform.
The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated in vucuznn. The yellow oilv residue was slowly crystallized in refrigerator. The crystals were triturated with diethvl etlier and filtered off:

Yield: 0.55 g (31 %) Mp.: 134-137 C

IR (KBr): 3427, 3254, 2929, 2853, 2814, 1739, 1603, 1510, 1445. 1391, 1367, 1302, 1281, 1 190, 1 140, 1 1 17, 1094, 1067, 1036, 993, 963, 922, 841, 789, 716. 675 cm 1 Example 51:
N-(2-hvdroxv-3-(1-nineridinvl)nronoxvl-N',N'-diethvl-3-pvridinecarboximidamide mono-hvdrochloride Procedure:
0.66 g (16.6 mmol) of sodium hydroxide was dissolved in 25 ml of abs. ethanol, then 1.61 g(8.3 mmol) N-hydroxy-N',N'-diethyl-3-pvridinecarboximidamide and 1.48 g (8.3 mmol) 1-chloro-2-hydroxy-3-(1-piperidinyl)-propane were added and refluxed for 5 hours. Solvent was evaporated and 50 ml of water was added and three times was extracted with 50 ml portions of ethyl acetate.
The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated in tiac-zczrm. The yellow oily residue was purified by chromatography to give the pure base, which -vvas dissolved in 20 ml of ethyl acetate and acidified with equivalent amount of dry hvdrochloric acid dissolved in ethyl acetate to give the title compound as a white crystalline solid.

Yield: 1.3 g (42 %) Mp.: 113-117 C

i E.rcrmple 52:

N-12-hvdroxv-3-(1-niperidinvl)pronotvl-hexadecanoicamide monohvdrochloride P.ccedure:

1.74 ~.* (10 tnmol) 1-aminoo:cy-2-hvdroxy-3-(1-piperidinyl)propane was dissolved in 20 ml of chloroform and cooled to 0 . A solution of palmitoylchloride (2.85 g: 10 mmol) in 10 ml of chloroform was added dropwise in 10 min. After stirring the mixture for 15 niinutes the obtained wliite precipitate was filtered off, washed with chloroform, and dried.

Yield: 3.2 g (71 %) Mp.: 147-150 C
IR (KBr): 3242, 3090, 2951, 2916, 2849, 1730. 1653, 1520, 1472, 1439, 1371, 1300. 1229, 1169. 11 36, 1099, 1070, 1009, 993, 962, 928, 858, 760, 719, 602. 471 cm-1 Followina the process described in the previous example the following compounds were pre-pared:

Example 53:

N-f 3-(1-piperidinvl)nropoxyl-3-trifluoromethvl-benzamide Startina material: EP 365,364 (1990) Yield: 69 % (oil) IR (KBr): 3425, 2941, 2864, 2775, 1674, 1614, 1566, 1520, 1483, 1441, 1393, 1337, 1319, 1277, 1187, 1129, 1072, 922, 914, 750, 698, 650 cm' 'WO 97/16439 PCT/HU96/00064 Examplc~ 54:

N-12-hvdroxv-3-(1-niperidinvl)propoxvl naphthalene-l-carbosamide Yield: 54 %
Mp.: 104 - 107 C

IR (KBr): 3375, 2934, 1641. 1593, 1564, 1439, 1340, 1325, 1113, 1026, 941, 810, 779 cm-1 Example 55:

10 N-(2-hvdroxy-3-(1-piperidim,l)proposvl-N'-hentvl-urea Procedure:

To the solution or 1.23 a (7.1 mmol) of 1-aminooxy-2-hvdroxy-3-(1-piperidinyl)--propane dissolved in 20 ml of cllloroforni 1.0 g (7.1 mmol) of heptyl isocvanate was added and the reaction mixture was stirred for 20 hours. Solvent was evaporated in vcrcutun and the residue 15 was purified bv chromatography to give pure colorless oil. White crvstalline product was ob-tained by triturating with petroleunl etlier.

Yield: 81 %
Mp.: 49-51 C

Following the process described in the previous example the followin(i compound was prepared:
20 Example 56:

N-12-hvdroxv-3-(1-piperidinvl)propoxvl-N'-propvl-urea Yield: 50 % (oil) IR (KBr): 3319,2934,2878,2802,1666,1551,1456,1393,1308,1155 1092,1040,993,889,793 cm 1 Example > 7:

N-cvclohexvl-N'-(2-hvdroxv-3-(1-piperidinvl)propoxv)-urea Yield: 67 %
Mp.: 108-110 C
IR (KBr): 3319.3287.3188.2930,2853,2797.1637,1574.1452,1354.
13 31.1 300,1101,1098,991 cm 1 Example 58:

N-hexyl-N'-(2-hvdroxv-3-(1-piperidinvl)nronoxvl-urea Yield: 27 %
Mp.: 50-52 C
IR (KBr): 3310,29 32,2858.2804,1666.15_51.14i4,1377,1 '106, 1092,1040,995,791,725,604 crri 1 Example 59:

N-(3-chlorophenvl)-N'-f 2-hvdroxv-3-(1-piperidinvl)propoxvl-urea Yield: 34 %
Mp.: 117-118 C
IR (KBr): 3250,2939,2900,1670,1597,1551,1491,1429.1329,1252,1119, 972,775,718,700 cm 1 Example 60:

N-evclohexvl-N'-f2-hvdroxv-3-(N-cvclohexvlcarbamovl-N-(1,1-dimethvlethvl)-aminolpronoxvl-urea Yield: 44 % =
Mp.: 151-152 C

IR (KBr):
3312,2932.2854,1668,1616.1555,1450,1393,1364,1354,1252.1220.1130:941.891 cm-1 Eczmple 61:

N-hexvl-N'-13-(1-nineridinvl)r)ronoxvl-u rea Yield: 85 % (oil) IR (KBr): 3354.2932.'_'856,2810,2777,1666,1543.1486,1377,1308,115 5, 11 34,1076 cm-L.YU/11plL' 62:

N-tert-butvl-N'-1(2-hvdroxv-3-(1-12ineridinvl)nropoxv)1-urea Yield: 38 %
Mp : 71-73 C

IR (KBr): 3314.2945.2916,1651,1555,1460,1393.1384,1335.1254,111 l, 988,903,839,781 cni1 Eainple 63:

N-(3-nitro-nhenvl)-N'-((2-hvdroxv-3-(l-niperidinyl)propoxv)1-urea Yield: 54 %
Mp : 137-139 C
IR (KBr): 3281:2943.2818,1672,1607,1560,1529,1486,1437.1354, 1283,1115,802.739 cm l Example 6-1:
5,6-Dihydro-5-(1-piperidinyl)methvl-3-(3-nvridyl)-4H-1,2,4-oxadiazine Procedure:

r a) 17.5 g (0.05 mole) of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide dihvdrochloride was dissolved in 50 ml of thionyl chloride, boiled for one hour, then the mixture was evaporated to dryness. The residue was dissolved in 300 ml of methanol, treated with char-coal and after filtration the solvent was evaporated in reduced pressure. The residue was dis-solved in the minimum amount of ethanol and refrigerated to yield crystalline N-[2-chloro- -' )-(1- piperidinvl)propoxy]- 3-pvridine-carboxiinidamide dihvdrochloride as intermediate compound.

Yield: 13.2 a (71 %) =
Mp.: 127-145 C

b) 13.2 g (35.7 mmol) ofN-[2-chloro-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidamide dihydrochloride u-as added to a solution of 16.5 g (143.5 mmole) of potassiuni tert-butoYide dis-solved in 150 nil of tei-t-butanol. The mixture was boiled for 6 hours, then evaporated in vucutull.
100 ml of 5 % sodium hn=drotide solution was added and the mixture was extructed three tim::s with 300 ml portions of ethyl acetate.

The organic laver was dried over sodium sulfate, filtered and evaporated to dryness. The residuc was triturated with diethvl ether to yield the title compound as white crystals.

Yield: 3.5 - (38 %) Mp.: 157.5-158 C
l~
E_ramI.Ve 65:

N43-1(1,1-dimethvlethvl)aminol-2-hvdrotvprc-poxv 1-3-trifluoromethvl-henzamide Procedure:

1.3 ml (15.2 mmol) of epichlorohydrine was added to a solution of 1.6 ml (15.2 mmol) of tert-but-v-lamine in 8 ml of ethanol during 10 minutes with stirring, keeping the temperature below 20 C, and allow to stand for 3 days.

Separately, 0.8 g(14.3 mmol) of potassium hydroxide was dissolved in a mixture of 20 ml of ethanol and 3 ml of water and into this solution 3.42 g (15.2 mmol) of N-hydroxy-3-(trifluoromethyl)-benzamide potassium salt and the formerly prepared solution of epichlorohy-drine and tert-butylamine were added. The reaction mixture was stirred and boiled for 10 hours.
then the solvent was evaporated. The residue was triturated with 20 ml of dichloromethane and 10 ml of water, the organic phase was separated, washed with 5 ml of water and 5 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated.
The oily residue was crystallized in a mixture of acetone-hexane to yield white powder as title compound.

Yield: 0.85 g (17.3 %) WO 97/16439 PCT/1{U96/00064 Mp.: 156-158 C

IR (KBr): 2976. 2858. 1612. 1556. 1379. 1352. 1313. 1273. 1165, 1130. 1072.
694 cm"1 Example 66:

Methyl-N-[2-hvdroxv-3-(1-piperidinyl)nronoxvl-3-nvridinecarboximidate W-2-butenedioate (1:1) Procedure:
11.4 'g, (38.2 mmol) of N-[2-hydroxy- 3-(1-piperidinyl)propoYy]-3-pyridinecarbox-imidoyl chloride was dissolved in 60 nil of abs. methanol, then 25 ml (0.1 mole) of 25 ,% methanolic solution of sodium methoxide was added dropwise during 5 minutes.
The reaction mixture -,vas boiled for a half an hour and evaporated. The residue was stirred witll 210 ntl of dichloromethane for a lialf an hour, sodium chloride was filtered off and the liltrate was washed with 50 ml of water, then with 50 ml of saturated sodium chloride solution, dried over ma(,rnesium sulfate and evaporated in reduced pressure. The crude product (9.8 (y) was puri-fied by cliromatography to yield the title compound as a pale-yellow oil.
Yield: 2.9 g (29 %) Elementary analyses for C15H23N303 calcd. found C % 61.4 61.2 H % 79.0 79.1 N % 14.3 14.5 Example 67:
Diethyl-N-[2-hvdroxv-3-(1-piperidinvl)-propoxvl-iminocarbonate Procedure A mixture of 0.87 g (5 mmole) of 1-aminooxy-2-hydroxy-3-(1-piperidinyl)-propane and 1.1 g (5.5 mmole) of tetraethyl orthocarbonate was stir-red at 100 C for 3 hours in the presence of 0 catalytic amottnt of p-toluenesulfonic acid. After evaporation the residue was purified by column chromatography (Merck Kiesel;el 60; eluent: chloroform/methanol-cc. NH4OH 30-5:0.2) to give the title compound as a pale-yellow oil. Yield: 27.7 % (oil) i ''C-NMR (d, CDC13): 1-54.9 (s. C=N), 76.5 (t, N-OCH?), 66.6 (d. CHOH), 64.5 (t. CH;CH~).
64.1 (t, CH;CH, ), 61.5 (t. CHCH2N). 54.8 (t, piperidine), 26.0 (t, piperidine). 24.2 (t, piperidine), 14.9 (q, CH;), 14.1 (q. CH3) Excrrnple 68.
N-(3-((1,1-dimethvlethvl)amino]-2-hvdroxvnronoxv)-O-ethvt-N'-nhenvl-isourea Procedure:

18.4 g (0. 1 mole) of etlivl N-phenyl-chloroformimidate (F. Lengfeld and.1.
Stieglitz: Am. Chem.
J. 16, 70 (1894)) and 16.2 g(0.1 mole) of 1-aminoory-2-hydroxy-3-[(1,1--dimethyletliyl)amino]-propane [Ger.Off. 2 651 083] were dissolved in 200 ml of tetrahydrotiu-rane, 13.9 ml (0.1 mole) of triethylamine was added and the mixture was stirred at room tempera-ture for 10 hours. Triethylamine hydrochloride that formed was filtered, and the filtrate was evaporated in vaczarm, the residue was dissolved in 200 ml of chloroform and washed with 50 ml of water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude oily residue was purified by chromatography to give the title compound as a pale yellow oil.

Yield: 18.5 g (59.8 %) Elementary analysis for C16H27N303 calcd. found C % 62.1 62.3 H % 8.8 8.5 N % 13.6 13.7 Esample 69:
N-13-(1-piperidinvl)-nronoxvl-O-nhenvl isocarboxamide Procedure ~
3.16 g (20 mmole) of 1-aminooxy- 3-(1-piperidinyl)-propane were dissolved in 50 ml of benzene.
2.4 g(20 mmole) of phenyl cyanate was added and the mixttire was stirred at room temperature for 12 hours. Further 0.16 g (1.3 mmole) cyanate was added and the mixture was stirred fiu=ther 12 hours. After evaporation the residue was dissolved in methanol and the solution was clarified bv activated carbon and evaporated. The product was crystallized from ethyl acatate/ethyl alcohol to give white material.

Yield: 46.9 %

Mp.: 63-70 C (ethyl acetate) "C-NMR (d. D,O): 152,4; 129,9: 125.8; 119,9; 70.3; 57,4: 54.3: 53,2; 23.0;
22.7; 21Ø
Example 70:

N-12-Hvdroxy-3-(1-nineridinvl)pronoxyl-N'-pentamethvlene- O-ethvl-isourea Procedure:

2.7 g (0.01 mole) of diethyl-N-[2-hydroxy-3-(1-piperidinyl)propoxy]-iminocarbonate (see in Ex-ample 67) and 0.99 ml (0.01 mole) of piperidine were dissolved in 40 ml of tetrahydrofitrane and stirred at room temperature for 2 hours. then evaporated to dryness. The residue was purified by chromatography to yield the title compound as an oil.

Yield: 2.1 g (67.1 %) Elementary analysis for C16H3iN303 calcd. found C % 61.3 61.1 H % 10.0 9.8 N % 13.4 13.6 -Example 71: =
N,N-dimethvl-N'-(2-hvdroxv-3-(1-piperidinvl)-propoxyl-N"-phenvl-auanidinc hvdrochlo-ride Procedure 1150 mg (6.58 mmole) of 1-aminooxy-2-hydroxy-3-(1-piperidinvl)-propane (Ger.
Off. 2 651 083) was dissolved in chloroform and 750 mg of Na2CO3 was added., then a solution of 1206 m`~ (6.58 mmole) of N.N-dimethyl-N'-phenyl-chloroformamidine (BR 888646 /1959/, Baver.
auth.: Kuhle and Eue L.; CA 57, 136961 /1962/) in 10 ml of chloroform was added dropwise.
After 5 hours the solid state was filtered and the filtrate was evaporated.
This residue (1800 m~~
oil) was dissolved in 10 ml of ethyl acetate. and the product was precipitated by addition of 10.46 nll of 0.54 N HCI/ethvl acetate. The yellow precipitate was filtered off washed, and finally re-crystallized from acetone, after ethvl acetate.
Yield: 28 %
Mp.: 127 129 C

IR (KBr): 3220, 2093. 2840. 2690. 2620,1608, 1580, 1475, 1433, 1375, 1250.
1070, 1050. 1000.
925, 900, 760, 705 cm'1.

Example 72:

N-[3-1(1.1-dimethvlethvl)aminol-2-hvdroxvpropoxv]-N'-phenvt-auanidine Procedure:

3.1 g(0.01 mole) of N-[3-[(1,1-dimethylethyl)amino]-2-hydroYypropoxy]-O-ethyl-N'-phenvl-isourea (see in Example 68) was dissolved in 20 ml of tetrahydrofuran and 200 ml of 25.% of ammonium-hydroxide solution and 0.26 g (5 mmol) of ammonium chloride were added and the mixture was kept at room temperature for 15 hours. The mixture was evaporated to dryness and purified by chromatography to yield the title compound as an oil.
Yield: 1.7 g (60.7 %) Elementary analysis for C14H24N402 calcd. found C % 60.0 60.2 H % 8.6 8.9 N % 20.0 19.8 Example 73:
N,N'-dirihenyl-N-[2-hvdroxv-3-(1-gineridinvl)-proporvi-benzenecarboxnmidine hvdro-chloride Procedure 3.55 g (20 mmol) of 3-piperidino-2-hydroxv-l-propane was dissolved in 2.5 ml of water, 0.8 g (20 mmol) of NaOH was added, and the mixture was stirred at room temperature for 1 hour.
Then a solution of 6.49 g (20 mmol) of N,N'-diphenvl-N-hydroxy-benzenecarboxamidine hvdro-chloride in 60 ml of ethyl alcohol was added dropwise, and further 0.8 tal (20 mmole) NaOH. The obtained yellow suspension was boiled for 2 hours. Then the precipitated sodium chloride "vas filtered off,, washed witli ethyl alcohol. Solvent was evaporated and 40 ml of ethyl acetate was added and two times was extracted witli 40 ml portions of distilled water. The organic phase was dried over sodium sulfate, filtered. The product was precipitated by addition of 5.5 nil of ).67 N
HCI/ethyl acetate. The precipitate was filtered off; washed, and finally recrvstallized from methanol/ether.
Yield: 42%
Mp.:151-155 C (methanol/ether) 13C-NMR (d, CDC13): 159.6, 148.0, 140.9, 131.0, 129.7, 129.3, 128.9, 128.5.
127.9, 127.5. 64.2, 60.2, 54.5, 22.7, 21.9.
E_ticrnzple 74:
N-[3-(1-niperidinvl)-nropoxvl-N-methvl-N'-phenvl-O-ethvl-isocarboxnmide Procedure for the preparation of this compound is the same as written in the Example 68, using 1-methylaminooxy-2-hydroxy-3-(1-piperidinyl)-propane and ethyl-N-phenyl-chloroformimidate as starting materials.
Yield: 56 % (oil) Elementary analysis for C17H29N303 calcd. found C% 66,4 66,2 H% 9,5 8,9 'N% 13,7 13,9 Exaniple 75:

N-f 2-hvdrorv-3-(1-piperidinvl)proporvl-N-methvl-N'-nhenvl-auanidine Procedure for the preparation of this compound is the same as written in the Example 72, using N-[2-hydroxy-3-(1-piperidinyl)propoxy]-N-methyl-N'-phenyl-O-ethyl-isourea (see Example 74.) as startinQ materials.

Yield: 43 % (oil) Elementary analysis for C16H26N4O2 calcd. found C% 62.7 62.2 H % 8.5 8.8 N % 18. 3 18.4 E.rumple 76 N,N,N'-trimethvl-N'-(3-(1-nineridinvl)-nropoxvl N"-phenvl--auanidine Procedure 344 mg (2.0 mmole) 1-methylaminooxy-2-hydroxy- 3-(1-piperidinyl)-propane was dissolved in chloroform and 220 mg of Na.2CO3 was added., then a solution of 438 mg (2.0 mmole) of N.N-dimethyl-N'-phenyl-chloroformamidine hydrochloride in 3 ml of chloroform was added drop-wise. After 8 hours the solid state was filtered and the filtrate was evaporated. This residue was dissolved in ethyl acetate and the product was extracted by addition of HCl solution (pH=1) to water. The aqueous phase was made alkaline then by addition of 2N NaOH
solution to pH=11, and extracted with ethyl acetate. The organic phase was evaporated, and the further purification was made by column chromatography to give the title compound as a yellow oil.

Yield: 10 % (oil) "C-NMR (d, CDC13):156.6, 150.5, 128.4, 121.4, 120.5, 70.0, 55.9, 54.4, 40.6, 39.4, 25.8, 25.6, 24.3.

Exan2ple 77:

/R/(+)-N-[2-hydroxyl-3-(1-piperidinvl)pronoayl-3-nvridinecarboaimidovl chloride (Z)-2-butenedioate (1:1) Procedure:
5 2.16 g(3.26 mmole) of (S)-N-[2-[2-(R)-(1,1-dimethylethyloxycarbonylamino)-3--phenylpropionyloxy]-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride (Z)-2-butenedioate (1:1) (see Example 18) was suspended in 40 ml of methanol and boiled for 1 hour, then evaporated to dryness. The residue was triturated with 20 ml of ethyl acetate, the precipitate was filtered, washed with ethyl acetate. This crude product was recrystallized in isopropyl alco-10 hol to yield the title compound.

Yield: 1.16 g (85%) Mp.:136-13 7 C

[a]I): +5.6 (c=1, MeOH, t=27 C) 15 ESaInJ)l e 78:

N-(3-nineridino-l-nropoxy)-3-nvridinecarboximidoyl chloride dihvdrochloride After cooling to 0 C a mixture of 10 ml of distilled water and 4.36 ml of concentrated hydro-chloric acid, 2 g (7.62 mmoles) ofN-(,-piperidino-l-propoxy)-3-pyridinecarboxamidine (see Example 31) are added under stirring. To the yellow solution 2.7 g (3.81 mmoles) of sodium 20 nitrite dissolved in 10 ml of water are added dropwise at -5"C during 30 minutes. After stirring the ~~reenish soltition at -5"C for 1.5 hours, the pH of the solution is adjusted to 10 by adding I N
aclueous sodium hydroxide solution under cooling. then the solution is extracted 3 times =ith 40 ml of chloroform. The organic phase is washed with 20 ml of water, dried over sodium sulfate and evaporated. The residue is purified by column chromatography (Merck Kiesel~~el 60: eluent:
25 chloroform/niethanol 1:1) to obtain 1.7 (79.2%) of the base corresponding.;
to the title com-pound.

The title hvdrochloride is prepared from the base obtained by adding an ethanolic solution of hN=drouen chloride. rn.p.: 165-167 C.

IR (KBr): 3015, 2945, 2617, 2515, 2088, 1982, 1600, 1570, 1437, 1402, 1200, 1060, 988, 912, 808 cm-'.

The above starting material can be prepared as follows:

After dissolving 2.86 g (51.06 mmoles) of potassium hydroxide in 20 ml of abs.
ethanol, 6.45 g (47.0 mmoles) of 3-pyridinecarboxamide oxime are portionwise added while stirring. After dis-solution, 7.7 g (47.66 mmoles) of 1-(3-chloropropyl)piperidine dissolved in 5 ml of ethanol are dropwise added. After 9-hour reaction, the precipitated potassium chloride is filtered off, the ethanolic solution is clarified by activated carbon and evaporated. After taking up in 100 ml of chloroform, the evaporation residue is washed 3 times with 100 ml of I N
sodium hydroxide solution each, then with 50 ml of water. After separation, the organic phase is dried over sodium sulfate, filtered and evaporated. The oily residue becoines crystalline on cooling. The crystals are triturated with about 20 ml of ether, filtered and dried to give a beige product in a yield of 4.8 g (38.9%).

IR (KBr): 3422, 3107, 2937, 2870, 2819. 1640, 1479, 1391, 1 309, 1 194,1 123, 1059, 1042, 982. 916 cm-'.

Following the process described in the previous example the following compound was prepared:
E.ycmrple 79:

O-(3-piperidinopropvl)-3-nitro-benzhydroximovl chloride hydrochloride Yield: 50%
Mp.: 173-175 C

IR (KBr): 3420. 2926. 2953, 2649. 2546, 1514, 1591, 15331, 1452, 1354, 1259.
1251 1049. 994, 73') cm'.

5.2. FORMULATION EXAMPLES
Example 1: Tablet Tablet containin`.; 50 nlg active material is prepared from the following components: N-[2-hydroxy- ')-(1-piperidinyl)-propoxy)-2-thiophene-carboximidoyl chloride monochloride 50.0 nlg corn starch 100.0 mg lactose 95.0 mo talc 4,5 mg magnesium stearate 0,5 mg The active compound is finely ground, mixed with the additives, the mixture is homogenized and granulated. The granulates are pressed into tablets.

Example 2: Tablet Tablet containing 5 mg active material is prepared from the following components:
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-2-nitro-benzimidoyl chloride monochloride 5,0 mg corn starch 75,0 mg lactose 7,5 mg colloidal silica 7,5 mg magnesium stearate 5,0 mg The composition is prepared from the above components in accordance with example 1.
Example 3: Tablet Tablet containing 5 mg active material is prepared from the followino coniponents:
N-[2-benzyloxy- 3-( l -piperidinyl)-propoxy]-3-pyridine-carboximidamide-(Z)-2-butenedioate (1:1) 5,0 mg corn starch 75,0 mg gelatin 7,5 mg microcrystalline cellulose (Apical) 25,05 mg inagnesium stearate 2.5 mg The composition is prepared from the above components in accordance with example 1.
Example 4: Capsule Capsule containing 10 mg active material is prepared from the follo-'ving components:
N-[2-palmitoyloxy-3-(piperidinyl)-propoxy]-3-pyridine-carboximidamide monohydrochloride 10 mg lactose 80 ma-corn starch 25 mg talc ; mg colloidal silica 3 mg magnesium stearate 2 mg The active material is mixed with the additives, the mixture is homogenized and filled into gela-tine capsules.
' Example 5: Capsule Capsule containing 20 mg active material is prepared from the following components:
N-[2-hydroxy-3-(piperidinyl)-propoxy]-2-thiophene-carboxiinidoyl chloride monohydrochloride 20 mg inierocrystailine celluiose: (Apicai) 99 mg amorphous silica I mg The active material is mixed with the additives, the mixture is homogenized and filled into gela-tine capsules.

Exanlple 6: Dragee Dragee containing 25 ni(y active material is prepared from the following components:
N- -dimethyl-ethyl)-amino]-2-hydroxy-propoxy }-3-trifluoromethyl-benzamidine hydrochloride 25 mg carboxymethyl cellulose 295 mg stearic acid 20 mg cellulose acetate phtalate 40 mg The active material is mixed witli the carboxymethyl cellulose and stearic acid, and the niixture is ~~ranulated in the solution of cellulose acetate phtalate in 200 ml ethanol-ethyl acetate. A core is pressed from the granulate which is covered by aqueous polvvinylpirrolidone solution contain-? 5 ing 5% sugar.

Example 7: Injection Injection solution is prepared from the following components:
N-[?-hvdroxy- 3-piperidinyl)-propoxy]-2-nitro-i0 benzimidovl chloride 5, 0 0 stei-ile physiological saline solution 2.0 ml Example 8: Ointment Ointment is prepared from the following components:
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-2-thiophene-carboximidoyl chloride monohydrochloride 7.5 g stearic acid 18,0 g cetyl stearyl alcohol 15,0 g glycerin monostearate 4,0 g sodium lauryl sulfate 1,5 g i 0 n-ietliyl p-hydroxy benzoate 0,2 g distilled water 150 ml The stearic acid. cetyl stearyl alcohol and glycerin monostearate are melted together. The sodium laurvi sulfate and methyl-p-hydroxy benzoate are dissolved in 100 nil water under slight warming and then added to the lipophylic components while stirring until the temperature decreases to room temperature. Subsequently. the solution of active conipound in 50 water is added and thor-oughly mixed.

Example 9: Ointnient Ointment is prepared from the following components:
N-[2-hydroxy- -')-piperidinyl-propoxy]-2-nitro-benzimidoyl chloride nionohydrocllloride 7,0 g polysorbate 4.0 g liquid paraffin 4.0 g cetN=1 stearyl alcohol 12,0 ~~
white vaseline 20,0 g glycerin monostearate 4.0 or methyl p-hydroxy benzoate 0.2 a ethvl alcohol 1 .8 g distilled .vater 150 ml The composition is prepared as described in Example 8.

Example 10: Cream C ream is prepared from the folloxving components:

N-[2-hydroxy-3-piperidinyl-propoxy]-4-pyridine-carboximidoyl chloride (Z)-2-butenedioate (1:1) 10,00, white vaseline 90.0 g white wax 3,0 g 5 cetyl stearyl alcohol 3,0 g sodium tetraborate 4,0 g methyl p-hydroxy benzoate 0.2 g distilled water 90 ml The solution of the water-soluble components is added to the warm mixture of the lipophylic 10 cornponents as in Exaniple 8, and the aqueous sulution of the active coiiipourid is added to the final emulsion.

EXAMPLE 6: EFFECT OF N-[2-HYDROXY-3-(1-PIPERIDINYL)PROPOXY]-3-HSP (EXAMINED ON TRANSLATIONAL LEVEL) 6.1 Background 20 Experiments set fortll in this section were conducted to determine whether N-[2-hvdroxy-,-(1-piperidinyl)propoxy]- 3-pyridinecarboximidoyl chloride maleate acts to increase the expression of molecular chaperon by a cell. The accunzulation of different heat shock proteins subsequent to a period of exposure to heat shock alone. and to heat shock in combination with N-[2-hydroxy- 3-(1-piperidinyl)propoxy]- ')-pyridinecarboximidoyl chloride maleate administration, was examined 25 bv addin~~ 10-' M ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate before. durin~~. or immediately after hypertliermic treatment of heart myogenic cells (H9c2 cells).

6.2 Materials & Methods 6.2 (a) Cell culture conditions: 30 The embryonic rat heart-derived cell line H9c2 tvas obtained from European Col-lection of Animal cell Cultures (ECACC) (88092904). The cells were maintained at 37 C in Dulbecco's modified Eagle's medium (DMEM) supplemented Nvith 10 %
fetal calf serum (GIBCO) in JOUAN C02 thermostat (5% CO2).

6.2 (b) N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treatment and heat shock conditions:
Heat shock was performed at 43 C in CO2 themlostat for the given time intervals (20, 40, 60, 90 and 120 min.). Cells were then taken back to 37 C for 6 hours and proteins were extracted for SDS-PAGE. When N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate was added before heat shock, 10-5 M N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate was administered for 16 hours before the stress. In other set of experiments, N-[2-hydroxy-3-(1-piperidinyl)propoxyJ-3-pyridinecarboximidoyl chloride i 0 maleate was added in 1 0-5 1vT concentration right after heat stress, during the 6 hours recovery period. The experiments were repeated three times.

6.2 (c) Western Blot For SDS-PAGE, cells were grown in 6 cm Petri dishes. The amount of the cells at the start of the experiment was 8 x 105 and were still subconfluent when proteins Nvere extracted.
After the 6 hours recovery cells were washed two times in PBS then scrapped from the surface of the dishes in PBS. Then cells were spun for 5 min. at 1500 rpm and taken up in 100 l modified solubilizinl; buffer (Molecular Cloning, A Laboratory Manual, Ed. Sambrook, Fritsche, Ma-iliatis, Bold Spring Harbor Laboratory Press (1989)) containing 50 mM Tris-HC1. pH8.0; 5 mM
LDTA; 150 mM NaCI; 15 Tritox N-100; 1 PMSF: 2 g/ml aprotinin; I g/ml chymostatin; I
pp/ml pepstatin; and sonicated for 3 x 2o sec (2 min. intervals, setting 8).
Protein concentration was determined from 5 l samples by the Bradford assay (M.M. Braford. Anal. 13iochenz., 72: 248-254 (1976)) in three parallel.
Sanlples were adjusted to 100 g/30 l Nvith the above buffer and the next buffer so that the concentration of the buffer in the sample will be: 1 10 mM Tris-HCl pH 6.8, 8.3 mM mercaptoethanol, 3% SDS.
3%glycerol and some bromophenol blue and shaken at room temperature for 30 min.
Electrophoresis was carried out according to Laemmli (U.K. Laemmli, Nature.
227:680-685 (1970)) on two 8-18 % polyacrylamide gel at constant volta~~e 50 V
for overnight.
Proteins were either stained with Coomassie Brilliant Blue R-2~0 or transferred to Immobilone PVDF membrane (Millipore) at constant current (300 mA) for ; hours at 4 C in transfer buffer (10 mM CAPS , pH 11, 10 % methanol) (Protein Blotting Protocols_for the Immohilon-P
Ti=crnsfer Membrane, 3. Laboratory Manual, Millipore). After transfer. non-specific sites of the niembrane Nvere blocked with 2 % BSA in TPBS (phosphate buffered saline with 0.1 % Txveen 20) for overnight at 4 C. The blot was incubated with GRP94 monoclonal antibody (SPA-850, StressGen) diluted 1:3000, with HSP60 monoclonal antibody (SPA-600, StressGen) with 1:2700 dilution, with HSP72 monoclonal antibody (C92F34-5, StressGen) diluted 1:1250 or with HSP90 monoclonal antibody (AC88, StressGen) diluted 1:2000, for 1 hour at room temperature.
Then it was washed with TPBS buffer for one hour, and incubated with horseradish peroxidase conjugated anti-rat (Sigma, 1:4000 dilution, for GRP-94) or anti-mouse (Sigma, adsorbed with human and rat serum proteins, 1:3000 dilution, for Hsp60, HSP72 or HSP90) secondary antibody for I liour respectively. After successive washing with TPBS the membrane was developed with ECL system (Amersham).
A total-prolein dilution series was blotted and developed paraliel with the sam-ples every time, and a calibration curve was calculated The changes in the stress protein content was quantified using a Bio-Rad densitometer (Model 1650) and a He-'vlett-Packard Integrator (HP 3394A) and corrected according to the calibration curve. When making the calculations the densitometric data of the given protein band at 37 C without N-[2-hydroxy-3-( l-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treatment was considered as 100% and all the other intensities were compared to that sample.

6.2 (d) Statistical analysi Data are reported as nieans +SE. Statistical comparison and calculation -%vas per-formed by one-,.vav analysis of variance with Posthoc Newman-Keuls test (Pharniacolo(lical Ca1-culation System). Statistical significance was defined as P <0.05.

6.3 Results ?D Hsp6O : N-[2-hydroxv-'-(I-piperidinyl)propoxy]--'I-pyridinecarboximidoyl chloride maleate ti-eatment accomplished at 37 C has no measurable effect on the level of this hsp. Heat shock at 4') C alone, lasting for 20 min. can increase the amount of hsp60 almost by twofold. By extend-in- the duration of heat treatment. no fui-ther elevation could be observed in the level of this pro-tein. When N-[2-hydroxy-3-(1-piperidinyl)propoxy]--")-pyridinecarboximidoyl chloride maleate 30 was added at a concentration of 10' M 16 hours before heat stress, the amount of hsp60 in-creased by about fivefold (compared to 37 C control) even if samples exposed to 20 min. heat treatment. This effect ofN-[2-hN-droxy-:')-(1-piperidinyl)propoxN,]--')-p~'ridinecarboximido,,=1 cllloride nialeate on the level of hsp60 was evident also in samples heat treated for 40 and 60 min., respectively, however started to decline thereafter. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate added during the recovery phase was also effective though to a significantly lesser extent then observed by adding this compound before the stress.

Hsp72 : The amount of resting hsp72 was rather low in H9c2 cells, the effect of different treat-ments on hsp70 level, however, was dramatic. There was already a significant increase at 20 min.
heat shock, and at 40 min. heat treatment the amount was almost 10 times higher than that of detected in control cells. Heat treatment at longer duration resulted in no significant change com-pared to 40 inin. samples. Administration of N-[2-hydroxy-;-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate before heat stress had a very profound effect. At 60 min.
heat stress the hsp72 level increased by about 50 times when comparing to 37 C samples, but a si(ynificant increase could be detected already at heat stress lasting for 40 inin. These highly in-duced amounts of hsp72 were stable in cells heat shocked for 120 min. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-;-pyridinecarboximidoyl chloride maleate added during the recovery phase Nvas also effective though to a lesser degree.

I-Isp9O : At 20 min. heat treatment, high temperature shock alone was unable to induce elevated level of HSP90, however, if N-[2-hydroxy-3-(l -piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate added before the heat stress, the level of Hsp90 increased by about fivefold. The hiohest effect of the drug preincubation could be observed iollowing its conibination with 60 min. heat treatment. It was interesting to note, that in the case of HSP90 N-[2-hydroxy- 3-( I-piperidinyl)propoxy)- 'i-pvridinecarboximidoyl chloride maleate added followin~~ 43 C 60 min.
treatnient was as effective (if not more) as if added before high temperature stress. Obviously.
incubation at high temperature Ion(ler than 90 min. the effect of N-[2-hydroxy-3-(1-piperidin), l)propoxy]-3-pyridinecarboximidoyl chloride maleate is fading.

Grp94: The formation of the stress protein Grp94 was induced followinc, a 20 min. heat shock.
This effect peaked at thermal treatment for 60 min. whereas a sharp decline has already been detected in case of 90 min. samples. The capability of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate to induce the level of Grp94 NN-as the most pronounced in case if the compound was added before the stress but significant raise could be seen if the - 30 preaddition of the drug was combined with a 20 min. long heat shock (~N-here there was a 4 times increase compared to 43 C treatment). On the other hand, addition of the compound during recovery from heat stress lasting for 40 or 60 min. ,vas almost as effective as the administration of N-[2-hydroxy-3-(I-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate for 16 hours long before the stress.

Figure 2 shows the Western blot analysis of proteins from H9c2 cells. Probes used are: hsp60 antibody, shown in (1); hsp72 antibody, shown in (2); hsp90 antibody, shown in (3) and grp94 antibody, shown in (4). Lane (-) represents cells kept in the absence of N-[2-hydroxy-3-( I-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate at 37 C; and lane (+) represents cells kept in its presence (concentration of 10' M for 16 hours). Heat shock at 43 C was per-formed for the times indicated on the figure. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate at 10'5 M was added 16 hours before the heat treatment (lane (B)) or during the recovery period (lane(A)).

An overview of the effect of the various treatments on the amount of different hsp in H9c2 heart cells is provided in Fig. 1. The amount of stress proteins in cells exposed to heat stress (43 C) alone is represented by (A); the amount of stress proteins in cells treated with 10" M N-[2-]iydroxy-3-(1-piperidinyl)propoxy]- ')-pyridinecarboximidoyl chloride maleate before the heat treatment is represented by (B); and the amount of stress proteins in cells treated with 10'' M N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl cllloride maleate during the six hour recovery period is represented by . The horizontal axis represents the time duration of the heat treatment and the vertical axis represents the relative amount of stress proteins.

1-leat treatnient alone induced all kinds of HSPs investigated in this study.
The increase was the less pronounced in the case of hsp60. The level of hsp60 elevated up to about twofold after expo-stu=e of cells to 20 min. heat, wliereas no further increase could be detected at longer heat treat-mrnts. The largest effect of heat stress could be seen for hsp72. as its amount increased to about 12 times. When N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate was added 16 hours before the heat treatment the level of all HSPs increased further up to at least twofold as compared to that observed upon heat stress. It ,A,as also clear that the level of hsp72 increased in a much higher extent amongst HSPs by combining heat stress and N-[2-]iN-droxy- 'i-(1-piperidinyl)propoxy]- 3-pyridinecarboximidoyl chloride maleate if compared again to the induction detected for heat stress alone. When N-[2-hydroxy-i-(1-piperidinyl)propoxy]- 'I -pyridinecarboximidoyl chloride maleate was administered durin`~ the recovery phase almost in all cases examined. content of hsp(s) increased, but a,ain elevation of hsp72 was the most pro-nounced.

6.4 Discussion Western blot analysis revealed a remarkable accumulation of different classes of HSPs examined after the exposure of heart cells to heat shock. Addition of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate either before or after high tem-` > perature stress multiplied the effect of heat treatment upon the production of HSPs. Accordingly, N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate acts in syn-ergy with temperature stress by inducing the formation of all classes of molecular chaperones.
EXAMPLE 7: EFFECT OF N-[2-HYDROXY-3-(1-PIPERIDINYL)-PROPOXY]-3-SION OF HSP (EXAMINED ON TRANSCRIPTIONAL LEVEL) 7.1 Background Brief exposure to iscliemia (e.g., by repeated stunning) can precondition the heart and protect it fi=om subsequent lethal ischemia. as evidenced by decreased incidence of ventricular fibrillation, 15 reduced infarct size and better recoverv of regional mvocardial function during the reperfusion of ischemic heart. Such precondition has been demonstrated to induce the expression of HSPs, es-pecially hsp72. In this section, the effect of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate on the expression of hsp72 is investigated by examining the mRNA accumulation in a cell following ischemia and comparing it to the situation where 20 ischenlia is combined =ith administration of N-[2-hydroxy-3-( I-piperidinyl)propoxy]- 3-pyridinecarboximidoyl chloride maleate.

7.2 Materials & Methods 7.2 (a). Induction of Heat Stress Experiments were carried out in SPRD male rats. Animals were anaesthetized with Nembutal in 25 a dose of 60 mc/kg/i.p. Body temperature of the rats were maintained with an infra lamp placed over the abdomen and the rectal temperature was measured. After a 25-40 minute period the temperature of the rats increased to 42.0-42.2 C and this temperature was maintained for 15 minutes. After a recovery period (2 hrs). tissue samples were collected from the left and riaht ventricles.

30 7.2 (b) Induction of Cardiac Ischemia Experiments were carried out in SPRD male rats. The animals were anaesthetized with Nembu-tal in a dose of 60 mg/kg/i.p. After opening the chest and pericardium, the LAD coronary artery was occluded for 5 minutes and then the incidence and duration of ventricular tachycardia and fibrillation in the reperfusion period (10 minutes) were investigated. Tissue samples were col-lected from the left and right ventricles.

7.3 Northern Blot Method Total RNA was extracted using RNAgents kit (Promega) according to the manu-facturer's instructions (Protocols and Applications Guide, 2"d edition, 1991, Promega Corpora-tion). Briefly, the frozen tissue samples (the tissue samples from the left and right ventricles of rats subjected to heat stress or cardiac ischemia).The tissue samples weighing 50 to 100 mg were homogenized in 1,0 ml denaturizing solution at +4 C by Brinkrnan homogenization. Then 1/10 vol. 3M sodium acetate (pH 4.0) was added and the homogenate were extracted with acidic phe-nol (phenol:chloroform:isoamylalcohol 25:24:1) for 10 seconds by vortex. The sample was in-cubated on ice for 15 minutes, and then centrifuged (4 C; 20 min, 10,000 xg).
The aqueous 1> phase was transferred to a new Eppendorf-tube, the process was repeated and the aqueous was precipitated at -20 C overnight. Following centrifugation (4 C; 20 min.
10,000 x(l) the precipi-tate was washed twice with 95% ethanol and dried at room temperature. The RNA
was sus-pended in 20 1 DEPC-treated water. Eight g of total RNA was run on formaldehyde-agarose gel by capillar), transfer, the RNA on the gel was blotted onto nylon membrane according to the manufacture's instructions (Zeta-Probe GT, BioRad).
The hsp72 mRNA content of individual samples was compared with the mRNA level of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene level of the corresponding probes.
DNA probes (full length human hsp70 cDNA and Apa-Ncol fragment of the rat GAPDH cDNA) was labeled with alpha-3zP CTP using Random Primed DNA Labelin(i Kit (USB).
Radiolabeled DNA fragments were purified on Sephadex G-50 (Pharniacia) column as described (Ausubel et al. (eds)): Current Protocols in Molecular Biology: JOHN WILEY & SONS: 1987).
Prehybridizations were carried out at 65 C in H-buffer (0.25M Na2HPO4, pH
7.2.

7% SDS) for 15 minutes. Hybridizations were carried out overnight (65 C; H-buffer) with iso-tope labeled probe concentration of at least 106 cpm/nil. The membrane was washed with 20 mM Na-)HPO4. pH 7.2. 5% SDS (65 C; 2x15 min.) and evaluated by autoradiography. The =
same membrane was used for the hsp70 probe as well as for the measurement of GAPDH and mRNA used as internal standard.

7.4 Results Coronary occlusion for 5 minutes was followed by reperfusion which provoked ventricular tachycardia and fibrillation in the rats. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate pretreatment (0.5-, 0.75-, 1.0 mg/kg of body weight i.v.
5 min. before the occlusion) reduced significantly the mean duration of ventricular tachycardia and improved the survival rate by preventing ventricular fibrillation.

Whereas all animals (n=6) from the control group died during the phase of reperfusion, the N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treated (100 mg/kg p.o.) ones not only survived the reperfusion after the 5 min. occlusion, but a highly increased expression of hsp72 gene was detected in their heart muscle preparations.

Figure 3 is the Northern blot analysis of total RNA isolated from left ventricles of rat heart, illus-trating the results obtained from the experiment. Control (lane 1); heat treated (lane 2); sham operated (lane 3); iscl7eniia (lane 4); N-[2-hydroxy-3-( I-piperidinyl)propoxy]- 3-pyridinecarboximidoyl chloride maleate plus ischemia (lane 5); and N-[2-hydroxy-3-(1-piperidin),l)propoxy]-3-pyridinecarboximidoyl chloride maleate (lane 6). GADPH
,vas measured as an internal probe. For heat shock, the rectal temperature was maintained at 42 C for 15 min-utes.

It is noted that in the absence of stress, administration of N-[2-hvdroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate alone was unable to activate the hsp72 gene.

EXAMPLE 8: PROTECTIVE EFFECT OF HYDROXYLAMINE DERIVATIVES OF
THE INVENTION AGAINST CARDIAC ISCHAEMIA

Male Sprague-Dawley rats (380-450a b.w.) were anaesthetized witll sodium-pentobarbital (Nembutal 60mg/k- body weight, i.p.) and artificially ventilated with room air (2 ml/100 (y; 54 stroke/minutes) via tracheotomv. The riglit carotid artery was catheterized and connected to a pressure transducer (BPR-01, Stoelting) for the measurement of systemic arterial blood pressure (BP) by means of a preamplifier (Ho-02. Experimetria).
Hydroxylamine deriva-tives disclosed in Example 5 were administered via the venous camiule to _jugular vein (i.v.) and - 30 orally (p.o.). Heart rate (HR) was measured by a cardiotachometer (HR-0I.
Experimetria). The electrocardiogram (ECG standard lead 11) was recorded on a devices recorder (MR-12, Medicor) bv nieans of subcutaneous steel needle electrodes. The chest was opened by a left thoracotomv and the heart was exteriorized by a gentle pressure on the right side of the rib cage. A 4-0 silk suture was quickly placed under the main left coronary artery as described by Selve et al. (1960).
The heart was carefully replaced in the chest and the animal left to recover.
Rectal temperature was monitored and kept constant at 37 C. The experimental protocol was initiated with a 15 mi-nute stabilization period during which the observation of a sustained blood pressure less than 70 mmHg and or the occurrence of arrhytlunia led to exclusion. Myocardial ischemia was induced with coronary occlusion for 5 minutes and reperfusion allowed for 10 minutes.
During the entire experiment, BP, HR and ECG were continuously registered on a multiscriptor (R61-6CH, Medicor). Hydroxylamine derivatives, the tautomeric forms of which are represented by structures (1) and (II), were administered 5 to 60 minutes before the occlusion after i.v. and p.o. treatment, respectively. The doses of the hydroxylaniine derivatives of Ex-ample 5 were 0.5, 0.75; 1.0 mg/kg i.v. and 100 mg/kb of body weight p.o., while the reference substance Bepridil was given in a dose of 1.0 mg/kg i.v.

The mean duration of ventricular tachycardia (VT) and/or ventricular fibrillation (VF) during the first ") minutes of reperfusion was analyzed by one-way analysis of variance.
The incidence of VF was analyzed using a chi-square test. The haemodynamic variables were analyzed using a chi-square test. The liaemodynamic variables were analyzed using Student's "i"-test. The critical level of significance was set at p<0.05. All results were expressed as a mcans +S.E.M. Drugs were administered i.v. in a dose of I my~/kgbw 5 min.
before the occlu-slon.
The liydroxylamine derivatives that are found to be particularly advantageous for protectino an animal a~,ainst ischemic/reperfusion injury are listed below.
Survival (%) indicates the percent of animals survived the effects of 5 minutes coronary occlusion.
Code Survival (%) Example 77 i.v. I lng/kgbNN, 67 Example 78 ., 100 Example 8 100 Example 13 õ 60 Example 9 ., 100 Example 10 67 Example 5 õ 80 Example 6 100 Example 79 100 Example 1 õ 100 Example 16 67 Example 65 õ 78 Example 54 80 Example 20 100 Example 22 100 Example 47 õ 100 Example 39 60 Example 51 õ 75 Example 64 100 Example 56 ., 67 Example 57 67 Example 58 ., 100 Example 59 õ 86 Example 60 60 Example 61 83 Example 55 .. 80 Example 66 ,. 57 Example 62 57 Example 63 .. 50 Exainple 4 .. 50 Control (non-treated) n=24 10 In addition to the above compounds. the following compounds have also been found to provide advantageous results:

N-[2-hydroxy-3-(pyrrolidin-l-yl)-propoxy]-3-pyridincarboximidoyl chloride (Z)-2-butendioate ~ (1:1) (U.S. 5,328.906. Example 12. l mg/kgbw i.~., survival %: 67);
N-[2-hydroxy-3-(diethyl-amino)-propoxy]-3-pyridincarboximidoyl chloride hydrochloride (1:1) (U.S. 5.328.906. Example 11, 1m`~/k(,bw i.v., survival %: 62):

N-[2-hydroxy-3-prop-2-yl-amino)-propoxy]-3-pyridincarboxiinidoyl chloride (Z)-butendioate (1:1) (U.S. 5,328,906, Example 13/4, lmg/kgbw i.v., survival %: 60);
N-[2-hydroxy-3-(morpholin-1-yl)-propoxy]-3-pyridincarboxamidoyl chloride (Z)-2-butendioate (1:1) (U.S. 5,328,906, Example 12, lmg/kgbw i.v., survival %: 71);

5 N-[2-hydroxy-3-(1-piperidyl)-propoxy]-a-(3,4-dimethoxy-phenyl)-acetimidoyl chloride (U.S. 5,328,906, Example 14, lmg/kgbw i.v., survival %: 67);
N-[2-hydroxy-3-(tert-butyl-amino)-propoxy]-3-pyridincarboxamidoyl chloride (Z)-2-butendioate ( i:1) (U.S. 5,328,906, Example 13i5, lmg/kgbw i.v., survival %: 57);
O-(3-piperidino-2-hydroxy-l-propyl)-benzhydroximic acid 10 chloride hydrochloride (U.S. 5,147,879, Example 1, lmg/kgbw i.v., survival %: 100);
N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride (Z)-2-butendioate (1:1) (U.S. 5,147.879, Example 2, 1 mg/kgbw i.v., survival %: 100, 20 mg/kgbw p.o. survival %:
100);

15 EXAMPLE 9: EFFECT OF N-[2-HYDROXY-3-(1-PIPERIDINYL)PROPOXY]-3-PYRIDINECARBOXIMIDOYL CHLORIDE MALEATE IN CELL MEMBRANE REPAIR
AND PRESERVATION OF MEMBRANE FLUIDITY

9.1 ALTERATION IN CELL MEMBRANE FLUIDITY ASSOCIATED WITH CELLULAR
20 INJURY INDUCED BY SERUM DEPRIVATION STRESS AND EFFECT OF N-[2-HYDROXY-3-(1-PIPERIDINYL)PROPOXY]-3-PYRIDINECARBOXIMIDOYL CHLORIDE
MALEATE IN REVERTING THE ALTERNATION IN FLUIDITY

9.1 (a) Background One approach to modeling pathophysiological events caused by the stress of 25 metabolic impairment accompanying diabetes is to decrease the level of insulin in the culturing medium. Since insulin is provided by the supplemented serum. partial or total deprivation seemed to be an optimal tool to detect changes in different regulatory levels of the cell.

Serum deprivation is widely used method for cell arrest in G 1/S phase, i.e., cell cycle syncl-u-onization (Ashihara, T. Methods ofEnzymology, 58:248-249 (1979)). It has been observed that cultured cells are undergoing apoptotic processes in the lack of serum supplemen-tation (Cohen, et al., Adv. In Immunology 50: 50-85 (1991)) and it has been studied as an alter-native shock of staurosporin or toposiomerase inhibitors in Balb/3T3 cells (Kulkarni, G.V. et al., J. Cell. Sci. 107: 1169-1179 (1994)), or heat shock and glutamine deprivation in Ehrlich cells (Rowlands, A.G. et al., Eur. J. Biochenz. 175 : 93-99 (1988)) to investigate the inhibited protein synthesis by the phosphorylation of the eukaryotic initiation factor (eIF2 alpha). Moreover, there are evidences on the induction of cytoprotection in serum deprived cells by administering exter-nal HSP72 (Johi-ison, A.D. et al., Lz Vitro Celi I3ev. Biol. Atrisll. 29A:807-812 (1993)). Increases in the relative synthesis of HSP82 and HSP72 by serum deprivation (Toye, P. et al., Mol. Bio-chenz. Parasitvl. 3 5, 11-10 (1989)) was also shown.
Ischemic and hypoxic injury of the myocardiuni and other organs is mediated by progressive membrane dysfunction and damage. lt was also demonstrated that alteration in membrane fluidity occurs during metabolic impairment of cardiac cells (Buja L.M. et al., ln vivo 5: 2 3 3-238 (1991)). Membrane fluidity primarily reflects the orientation and rate of the move-nient of membrane constituent lipids and any alteration of its level greatly influences the funda-mental membrane function (Quinn. P.J. et al. Prog. Biophys. Molec. Biol. 53:
71-103 (1989);
Schlanie, M. et al. , Biochinz. Biophys. Acta, 1045: 1-8 (1990)).
ln this experiment, investigation was conducted to determine whetller changes in plasma membrane fluidity participate in the development in the cellular injury induced by serum deprivation and whether the serum deprivation induced fluidity alteration can be reverted by the administration of N-[2-hydroay- ')-(1-piperidinyl)propoxy]- 3-pyridinecarboximidoyl chloride maleate.
9.1 (b) Materials and Methods Experiments were carried out using WEH 1 mouse fibrosarcoma and H9c2 rat heat-t muscle cell lines divided into three groups:
= control (10% FCS fetal calf serum) = serum deprived = N-[2-hydroxy-3-(1-piperidinyl)propoay]-3-pyridinecarboximidoyl chloride maleate (10-' M) treated and serum deprived 9.1 (b) (1) Serum deprivation and MTT test We have screened various cell lines, drug concentrations, pretreatment and depri-vation times and we have found the most appropriate conditions as follows:
5x10-4 /ml H9c2 rat heart muscle cell (n=6) and WEHI mouse fibrosarcoma cell (n=7) have been plated on 24 well plates in 10% FCS DMEM (Dulbecco modified Eagle's medium) and incubated for 2 hours at 3 7 C, 5% CO2. Medium has been discarded and replaced by 10% FCS DMEM containing 10"5 M
N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate. After further incubation on the above circumstances for 6 hours, plates have been washed intensively by PBS
and serum deprived. Pretreated cells were administered with N-[2-hydroxy-3-(I-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate until the end of the experiment.
Foliowing 18 hours starvation, most of the ceils were detached, i.e., died, observed microscopi-cally, in serum deprived culture, while N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridinecarboximidoyl chloride maleate pretreated cultures have shown similar picture to the control cells. Cell viability was measured by MTT test based on the method of Plumb et al.
(C'anc'('r Res. 49: 4435-4444 (1989)) The tetrazolium salt method involving conversion of MTT
(')-(4>-dimethylthiazol-2y1)-2,5-diphenyltetrazolium bromide) to colored formazan by alive cells, served as an indirect measurement of cell viability. MTT has been added directly to the nZedium at a concentration of 1 mg/nil. After 2 hr incubation at 37 C in dark, the supernatant was removed and 200 l of 0.05 M HC1 in isopropanol was added immediately to the cells.
O.D. of the plates was read at 570nm on an ELISA plate reader (Labsystems Multiskan Bio-2() chromatic type:348). Experiments have been carried out in each case at least in triplicates. Rela-tive cell viability was calculated defining control group as 100%.

9.1 (b) (2) Determination Of Steady-State Fluorescence Anisotropv Cell suspensions of Ix 10' cells/ml in PBS were labeled by the addition of DPH-PA (3-[p- (6-Phenyl)-1,3,5-hexatrienyl] phenylpropionic acid) dissolved in tetrahydrofuran at a final concentration of 0.1 M and incubated for 10 min. at 3 7 C. The amount of organic sol-vent added was 0.05% to avoid its effect on cell membranes. The membrane probe DPH-PA -Nvas selected due to charge properties of the probe that enable DPH-PA to localize predominantly within the outer leaflet of the plasma membrane, with the diphenyl-hexatriene moiety intercalat-ing between upper portions of fatty acyl chains (Kitagawa, S., et al. J.
Alentbrune Biol. 1 19:221-227 (1991)). DPH-PA exhibits strong fluorescence enhancement upon binding to lipids, provid-in<~ a means of evaluating fluorescence anisotropy as a function of lipid ordering. Fluorescence measurements were carried out at 37 C using a Quanta Master QM- I T-fortilat luminescence spectrometer (Photon Technology Int. Inc., NJ, USA) equipped with polarizers in the excitation and in the two emission light path. Excitation and emission wavelengths were 360 nm (5 mn slit width) and 430 nm (5 nm slit width), respectively. The measured fluorescence intensities were corrected for background fluorescence and light scattering from the unlabeled sample. The fluo-rescence anisotropy was calculated as rs= (IVV - G.IVH) / (IVV +(2 x Gx IVH)) where IVV and IVH are observed intensities measured with polarizers parallel and perpendicular to the vertically polarized exciting beam, respectively. The factor G equals IVH/IHH and corrects for the inability of the instrument to transmit differently polarized liglit equally and for the differ-ence in sensitivity of the two emission channel (Kitagawa, S., et al. J.
Membrane Biol. 119:221 -227 (1991)). IHV and IHH are the fluorescence intensities determined at vertical and horizontal positions of the emission polarizer when the excitation polarizer is set horizontally.

9.1 (b) (3) Statistical analvsis Data are reported as means +SEM. Statistical comparison and calculation was performed by one way analysis of variance with Postlioc NeNvman-Keuls test (Pharinacological Calculation System). Statistical significance was defined as 11<0.05.
9.1 (c) Results 9.1 (c) (1) Seruni deprivation as a model to test cytoprotective effect of N-[2-hvdroxv-3-(1-L)iUeridinvl)propoxv]- 3-pvridinecarboximidoyl chloride maleate Sei-um depi-ived WEHI and H9c2 cells showed 74.8% and 50.5% relative cell viability, respec-tively. In case if 10-' M N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-p)=ridinecarboximidoyl chlo-ride maleate was present in the culture medium the administration resulted in an almost total survival of WEHI (93%) and a high protection in H9c2 heart muscle cells (82.75%). Decrease of i-elative cell viability by serum deprivation and its protection by N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate in both cell lines Nvere sianifi-cant.

9.1 (c) (2) Effect ofN-[2-hydroxv-,-(1-piperidinvl)propox-,=1-3-pvridinecarboximido~,l chlo-ride maleate on the fluidity of serum deprived mammalian cells To exaniine the effect of serum deprivation on the plasma membrane fluidity of cultured mam-malian cells fluorescence anisotropy measurements have been accomplished by using the plasma membrane probe DPH-PA. The physical properties of the cell plasma membranes Nvere significantly altered by serum deprivation. Serum deprivation caused a pronounced decrease in fluorescence anisotropy of DPH-PA that is an abnormal increase in plasma membrane fluidity in both cell models investigated. Upon the addition of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate we observed an almost complete preservation of the membrane physical state. These changes were obviously consistent with the tendencies described on cell viability.

9.1 (d) DISCUSSION

By resulting in metabolic impairnients, deprivation of normal culture medium in both type of cells studied reduced their viability as tested with the MTT
method. This effect was alnlost fully reverted upon the addition of N-[2-hydroxy-3-(1-pip.eridinyl)propoxy]-3-pyridinecarboxiinidoyl chloride nialeate. Deprivation of serum induced also prominent altera-tions in the fluidity of plasma membranes which is known to contribute to the membrane dis-1 5 function accompanyin~~ myocardial injury. In contrarv, serum deprived cells, grown in the pres-ence of N-[2-hydroxy-3-(1-piperidinyl)propoxy]- ')-pyridinecarboximidoyl chloride maleate, were able to preserve (or retain) partially their normal plasma membrane phvsical state.

EXAMPLE 10: EFFECT OF INSULIN AND N-[2-HYDROXY-3-( I-PIPERIDINYL)-PROPOXY]- ~)-PYRIDINECARBOXIMIDOYL CHLORIDE MALEATE ON THE LEVEL OF

10.1 Background Anoxia, glucose starvation and several other conditions that adversely affect the function of en-doplasmic reticulum (ER) induce the synthesis of the glucose regulated class of stress proteins (GRPs) (Lin. H.Y., et al. Mol. Biol. Cell. 4: 1 109-1 119 (1993)). The 94 kDa member of GRPs.
GRP-94, i0% homologous to 90 kDa stress protein. is a lumenal calcium-binding protein of ER.
ToLether v.,ith other proteins of ER, GRP-94 appears to function as a molecular chaperon (Nigem, S.K., et al. J. Biol. Chem.263:1744-1749 (1994)). It is assumed that the accumulation of =
inolecular chaperone GRP-94 should have a beneficial effect on the repairing of cellular dama`e induced by STZ diabetes in rats. Accordingly, in the experiments set forth herein we compared the various levels of GRP-94 in livers derived from healthy, diabetic, N-[2-hvdroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treated and insulin plus N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treated rats.
10.2 Materials & Methods 10.2 (a) Test substances : N-[2-hydroxy-3-(l-piperidinyl)propoxy]-3-5 pyridinecarboximidoyl chloride maleate(BIOREX Ltd.) insulin (Protophane HM inj.) 10.2 (b) Animals: Cr1 (VAF plus) Wistar male rats (250-300 g) Animals were housed 7 per cage at 23-25 C at 50-60% relative.

humidity with 12/12 hours light-dark cycle. Free access was given to chow and tap water 10 10.2 (c) Induction of diabetes: A single dose of STZ (45 mg/kg i.v.) was given in fasting state.
10.2 (d) Animals were divided into the following groups:

a. Healthy animals 1. Saline treated healthy for I weeks (n=5) 15 2. Saline treated llealthy for 2 weeks (n=5) 3. Saline treated healthy for 4 weeks (n=5) 4. N-[2-hydroxy-3-(1-piperidinyl)propoxy]- 'I-pyridinecarboximidoyl chloride maleate treated for I weeks (n=7) 5. N-[2-hydroxy-3-( )-(I -piperidinyl)propox3-pyridinecarboximidoyl chloride maleate 20 treated for 2 weeks (n=7) 6. N-[2-hydroxy-3-(I-piperidinyl)propoxy]-3-pyridinecarboximidoyl cllloride nialeate treated for 4 weeks (n=7) b. STZ-diabetic animals 25 7. Saline treated diabetic for 1 weeks (n=5) 8. Saline treated diabetic for 2 weeks (n=5) 9. Saline treated diabetic for 4 weeks (n=5) 10. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-:')-pyridinecarboximidoyl chloride maleate ti-eated diabetic for 1 weeks (n=7) 11. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treated diabetic for 2 weeks (n=7) 12. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treated diabetic for 4 weeks (n=7) c. Insulinized STZ-diabetic animals 13. 1-week insulin treated diabetic (n=7) 14. 2-week insulin treated diabetic (n=7) 15. 4-week insulin treated diabetic (n=7) d. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treated and insulinized diabetic animals 16. l-week insulin and N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride nzaleate treated diabetic (n=7) 17. 2-week insulin and N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treated diabetic (n=7) 18. 4-week insulin and N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treated diabetic (n=7) After the treatnients liver was removed, and was immediately frozen at -70 C
in liquid nitrogen.
N-[2-hydroxy- 3-( I-piperidinyl)propoxy]- 3-pyridinecarboximidoyl chloride maleate treatment (wherever applicable): 20 mg/kg/day, p.o. Insulin treatment: twice daily in a dose required to niaintain normal ~,lucose level.

10.2 (e) Determination the level of GRP-94.

Extraction of total soluble protein from rat liver.

All steps -%vere carried out at 0-4 C. Rat livers (about 15-20 g) ,,vere homogenized with a domestic mixer foi- 2 niin. in 80 ml of a modified single detergent lysis buffer solution containin( ' ~, 50 n1M
Tris-HCl pH 8Ø 5 mM EDTA, 150 mM NaCl, 0.1 % SDS, I io Triton X-100 and 1 -1 m1\4 pro-tease inhibitors (PMSF, benzamidine, amino-caproic-acid). The homogenate was centrifu~~ed at =
20000x~~ for 30 min. in a Servile RC 28S centrifuoe. The majority of the supernatant was frozen to -20 C as a stock sample), I ml was used for the analysis.

Protein concentration was determined by the Bradford assay (Guide to Protein Purification, Methods in Enzimology, vol. 182, M.P. Deutscher (Ed.), Academic Press (1990)) in three parallel and was adjusted to 5 mg/ml.

= Electrophoresis and immunoblotting Laboratory tecluiiques for electrophoresis and immunoblotting are described in detail in Molecu-lar Cloning, A Laboratory Manual, Ed. Sambrook, Fritsche, Maniatis, Bold Spring Harbor Labo-ratory Press (1989); Protein Blotting Protocols foi- the Inzmobilon-P Transfer Membrane, 3.
Laboratory Manual, Millipore ; and U.K. Laemmli, Nature : 227: 680-685 (1970).
Each sample consisted of 1.8 Y-iig protein was solubilized for gel-eiectrophoresis with 0.6 ml buffer containing 110 mM Tris-HCl pH 6.8,8.3 mM mercaptoethanol, 3% SDS, 3% glycerol and some bromophe-nol blue and shaken at room temperature for 30 min. Electrophoresis was carried out on 8 %
polyacrylamide gel with 30 pg protein per lane at constant voltage 50 V for overnight. Proteins were either stained with Coomassie Brilliant Blue R-250 or transferred to Immobilone PVDF
membrane (Millipore) at constant current (300 mA) for i hours at 4 C in traiisfer buffer (10 mM

CAPS pH 11,10 % methanol). Non-specific sites of the membrane were blocked with 2 % BSA
in TPBS (phosphate buffered saline with 0.1 % Tween 20) for overnight at 4 C.
The blot was incubated witli GRP-94 monoclonal antibody (SPA-850, StressGen) diluted 1:3000 for 1 hour at room temperature. Then it was washed witli TPBS buffer for another one hour, and incubated xvith horseradish peroxidase conjugated anti-rat secondary antibody (Sigma, 1:4000 dilution) for 1 hour. Aiter successive washin~~ with TPBS the membrane was developed witli ECL system (Anlersham).

A total-protein (9/1 sample) dilution series was blotted and developed parallel with the samples every time. and a calibration curve was calculated. The changes in the stress protein content was quantified using a Bio-Rad densitoineter model 1650) and a He-%vlett-Packard Integrator (I 1P
255 33194A) and corrected according to the calibration curve.
Statistical analysis Data are reported as nleans +SEM. Statistical comparison and calculation was performed by one-way analysis of variance witli Posthoc Newman-Keuls test (Pharmacological Calculation = System). Statistical si~~nificance ,vas defined as P<0.05.

10.3 Results Significant decrease of relative GRP-94 content is observed in I week, 2-weeks and 4-weeks diabetic rats. This effect in I week and 2-weeks diabetic animals could completely be reverted upon N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate treat-ment. Administration of insulin alone or in combination with N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate in 1 week and 2-weeks samples almost doubled the levels of this protein compared to the control state.

In contrast to the previous findings, treatment of rats diabetic for 4 weeks by N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate alone, resulted in no significant alteration in the relative amount of GRP-94. Moreover, both in the insulinized groups, irrespec-tive eitller treated or not by N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate, we observed a recovery of GRP-94 to the control level.

EXAMPLE 11: EFFECT OF N-[2-HYDROXY-3-( I-PIPERIDINYL)-PROPOXY]-3-P1'RIDINECARBOXIMIDOYL CHLORIDE MALEATE IN PROTECTING EPIDERMAL
CELLS AGAINST DAMAGES CAUSED BY EXPOSURE TO HEAT AND UV LIGHT
11.1 Materials & Methods 1-laCaT cell line is a spontaneously immortalized, ancuploid human keratinocyte cell line derived fi=om nornial human adult skin (Boukamp et al., J. Cell Biol. 106:761-771 (1988)), HaCaT is a cell line with full epidermal differentiation capacity. with normal keratinization and with nontu-moro-enic character. This rapidly niultiplying keratinocyte line with hinh ditharnol sensitivity is also characterized by the presence of steroid receptors. HaCaT cells (4 x 105 cells per Petri-dish with a diameter of 35 mm) were seeded and grown in DMEM supplemented with 5%
fetal calf serum (Gibco, Cat. No. 01 1-6290H) under a humidified atmosphere of 5% CO-) at 37 C. 24 hours after platinn, the cultures were rinsed with PBS and treated by heat or liaht.

The confluent cultures of the cells ,vere exposed to heat (42. 44. 46, 47. 48 C) or UV light (C'VA 1. 2. 4, 6 J/cm2 ). Heat exposure was provided in circulating water baths. As a UV li9ht source, 'Waldmann PUVA 4000 .vas used with an energy spectrum of the final output bet"veen 320 an 390 nm. peaking at 365 nm. The energy output was monitored bv an IL-1700 radiometer eduipped ~vith tJVA and UVB sensor.

The morphology of the cells was monitored using phase contrast microscopy (Opton Axioplan Microscope, with Plan-Apochromat Ph phase contrast objectives). The following factors were considered as indicators of cytotoxicity: (a) reduced density of adherent cells; (b) loss of regular ..cobble-stone" pattern with enlargement of intercellular spaces; alteration of cell shape, e.g., impeded cell spreading, swelling, pycnotic shrinking, fragmentation; and (d) cytoplasmic changes, e.g., condensation or vacuolization. Cell viability was also examined, using Trypan-blue exclusion test.

11.2 Results Sensitivity of HaCaT keranitocytes to heat-stress was determined by examining their viability.
The results indicated that 24 hours after being exposed to heat at a temperature of 48 C, there wet-e practically no living cells (2.7%). compared to the control (100%) at 37 C. Viability of HaCaT keratinocytes 24 hrs after a 45 "C heat exposure proved to be 59%. There were no mor-phological chanoes in HaCaT cultures I hr after the heat exposure. 24 I1rs after the heat treat-ment at 46 C or higher temperature significant (p<0.01) cell detachment and morphological changes occurred, such as the loss of regular õcobble-stone" pattern with the enlargement of in-tercellular spaces, swelling, pycnotic shrinking, and vacuolization of HaCaT
keranitocytes. Fol-lowing UV exposure, it was found that reduction of viable cells were directly correlated -vvith the dose of UVA.

Preconditioning the cells witli heat (42 "C for I hour) or N-[2-hydroxy-3-( I-piperidin),l)propoxy]-'I-pyridinecarboximidoyl chloride maleate (at a concentration of 5 x 10-' M
for one hour) provided the cells with protection against a 48 "C lieat exposure. When cells were examined 24 hours after the 48 "C treatment, it was found that compared to cells that were not treated, the cell viability increased to 48% (when preconditioned with 42 "C) and 84 %(,.vith N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl cliloride maleate pre-treatment).
The most pronounced protection (increase of 140 % in viability) could be observed in case of a combined treatment (with 42 C and N-[2-hydroxy- 3 )-(1-piperidinyl)propoxy]-pyridinecarbosimidoyl chloride nlaleate).
v - 30 Heat preconditioning v,=ith 42 C, but not with 44 "C and 45 C. induced a prominent reduction of cytotoxicity due to UV-light. A treatment with 42 "C provided protection both at exposure of 2 and 4,1/cm2. Viability of pretreated HaCaT kerationocytes increased to 132%
(at 2 J/cm2 ) and to 218% (at 4 J/cm') compared to UV -exposed cells without pretreatment (100%).

12. EXAMPLE: EFFECT OF N-[2-HYDROXY-3-(1-PIPERIDINYL)-PROPOXY]-3-PYRIDINECARBOXIMIDOYL CHLORIDE MALEATE IN INDUCING MOLECULAR
CHAPERON EXPRESSION IN HUMAN SKIN TISSUES

Ultraviolet UVB light (290-320 nm) is one of the components of sunlight and is known to cause dainage to the skin. The role of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate in reducing damages caused to the skin tissues by the UVB exposure was investigated, as well as the effect of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate in increasing the expression of molecular chaperon in the skin tissues.

12.1 Materials & Methods I-luman skin tissues were grafted onto immunodeficiency (SCID) mice. The experimental proto-col involved a treatment of one group of the mice with N-[2-hvdroxy- 3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate (5.0 mg/kg i.p.) and the other with the solvent NaCI
solution (300 l) for 7 days. On day 8, both groups of mice were exposed to UVB light (100 m,l/cm') 24 hours subsequent to the exposure, skin biopsies were taken for histological (sections stained with heniatoxylin and eosin), and immunohistological examinations (indirect immuno-i7ourescence technique with monoclonal antibody. mAB).

12.2 Results In UV-irradiated mice that was pretreated with N-[2-hydroxy-')-(1-piperidinyl)propoxy]--')-pyridinecarboximidoyl chloride maleate. clinical sians of injuries due to UV
exposure could not he observed. In contrast, in one of the untreated animals a pustulous reaction of the transplanted area was found. Furthermore, indirect immunofluorescence studies using mAB
hsp72 showed an intense, linear stainin`~ along the basement membrane zone of human and mouse skin of the N-[2-hydroxv- 3-(1-piperidinyl)propoxy]- 3-pyridinecarboximidoyl chloride maleate treated animals.
_30 The same reaction could not be observed in the skin of the untreated animals. In addition. a nu-WO 97/16439 PCT/Hi196100064 clear type of staining of granulocytes was present in the pustule (inflammatory skin reaction) of the untreated animal.

Accordingly, adniinistration of N-[2-hydroxy-3-(l-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride maleate to skin tissues resulted in increased formation of hsp72 in skin tissues and provided protection against injuries from UV exposure.

12.3 Deterniination of the level of HSP-70 from skin: Western blot analysis of proteins derived from UVB and UVB+N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride nlaleate treated human skin grafted in SCID-mouse.

Methods:
a. Extraction of total soluble protein from skin.

1_5 All steps were carried out at rooni temperature. Skin (about 9-35 mb) was cut into tiny pieces and homogenized with frosted-glass pestle in Eppendorf tubes for 2 min. in (2 l/ g skin) of 2 tinies concentrated Laemmli buffer (65mM Tris-HCI, pH 6.8; 5% [3-mercaptoethanol; 2% SDS;
10% glycerol; 0,1 % bromophenolblue; all of these materials were Sigma products). Then sam-ples were solubilized for another 60 min. with continuos shakin(l. The homogenates were centri-iu~.;ed at 10.000 rpm i'or 10 min. prior loading to the gel.

b. Electrophoresis and immunoblotting [5, 7, 8]

Electrophoresis were carried out on 8 % polyacrylamide gel -vvith 10 i of sample per lane at constant voltage (50 V) for overnight.
Proteins were either stained with Coomassie Brilliant Blue R-250 or transferred to Immobilone I'VDF membrane (Millipore) at constant current (300 mA) for 3 llours at 4"C in transfer buffer ( l OmM CAPS pH 11.10 % methanol).
Non-specific sites of the membrane were blocked xvith 2 % BSA in TPBS
(phospliate buffered saline witli 0,1 % Tween 20) for overnight at 4 C. The blot were incubated with HSP-70 monoclonal antibody (SPA-8dc... StressGen) diluted 1:1500 for 1 hour at room temperature.
Then it was washed three times =ith TPBS buffer for another one hour. and incubated with horseradish peroxidase conjugated anti-nlouse secondarv antibody (Sigma.
1:1500 dilution) for I

hour.
After successive washing (three times) with TPBS, the membrane was developed with ECL
System (Amersham).

EXAMPLE 13: EFFECT OF N-[2-HYDROXY-3-(1-PIPERIDINYL)PROPOXY]-3-(PYRIDINECARBOXIMIDOYL CHLORIDE MALEATE IN ACTIVATION OF HSP FOR-MATION AND PROTECTION OF OXIDATIVE PHOSPHORYLATION

131.1 Bacl.ground It has been shown that exposing Saccharomyces cerevisiae cells to heat shock (5 min. at 42-44"C) resulted in an impairment of coupling of oxidative phosphorylation and mitochondrial electron transport system, affecting the ability of he cells to synthesize ATP
(Patriarca et al., Bio-cliemistry and Cell Biology, 70:207-214, 1992). However, when the cells were pre-treated with N-[2-hydroxy- 3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate for a short period of time at 37 C prior to heat shock, it lessened the impairment of the coupling and pro-tected mitocllondrial ATP synthesis. Inhibition of cytoplasmic RNA or protein synthesis during heat shock appears to prevent this protection of mitochondrial activity.
Accordingly, one of the roles of hsp seems to be that of protecting the coupling of oxidative phosphorylation and mito-chondrial electron transport systeni which is disturbed when cells are exposed to physiological sti-ess, e.o., heat shock.

ln this section, N-[2-hvdroxy-3-( I-piperidinyl)propoxy]- 3-piridinecarboximidoyl chloride nialeate is administered to cells prior to being exposed to heat shock, and its effect on protecting couplinf, of oxidative phosphorylation with mitochondrial transport system against the heat stress is examined.

It ,vas also investigated if the activity of AP-1 and P 1 transcription factors can be modulated by N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate in yeast cells exposed to various stress conditions.

1 3.2 Materials & Methods 30 The experiniental protocol for determining the impairment of oxidative phosphon,lation and niitocliondrial ATP synthesis in Saccharomyces cerevisiae is provided in Patriarca et al.. Bio-cheMislly and Cell Biology, 70:207-214, 1992.

To S. cerevisiae cells that were maintained at 25 0 C, varying concentration of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate was introduced (concentrations between 10 to 100 M), cells were then incubated for one hour at 25 C in the presence ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate.
The temperature was then increased to 42 C, and the oxygraph measurements were taken as described in the Patriarca reference.

Tiie cells treated with N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboximidoyl chlo-ride maleate were tested for concomitant induction of hsp genes, using Northern Blotting proce-dure. The method of extracting. purifyinb mRNAs from eukaryotic cells, and analyzing the RNA
thus obtained usinu Northern blotting procedure is well known in the art and described in Ma-niatis, and Maresca, el al. Archi>>es Aledical Research 24: 247-249 (1993), both of the references beino fully incorporated herein. The Northern blotting protocol is also described in Exanlple 7, set fortli above. Hsp 26 and hsp70 DNA sequences were used as probes.
1 3. ~ Results 13.3.1 hi~~ure 4 is the Northern blot analysis of hsp26 niRNA induced in S.cerevisiae, illustrating the results obtained from the experiment. The concentration of the chemical compound administered to the cells and the duration of incubation in the compouiid are indicated.

In the cells that were incubated in the presence of N-[2-hydroxv-3-(1-piperidin),l)propoxy]- 3-piridinecarboximidovl cliloride maleate (10-100 M) for 5 min. to 1 liour at 25 C, the induction of IZsp 26 was observed. The results also seem to indicate that the induction occurs even after 5 minute incubation.

2~ ]t was also found that concentrations bevveen 10 and 100 M of test compound was effective in lessenina the impairment of the couplin<, between oxidative phosphorylation and mitochondrial electron transport system that results from heat shock. The pT-otection from the impairment of mitochondrial ATP svnthesis was in the ranue obtained when tltermotolerance was induced by pre-conditioninu, the cells by exposing them to the intermediate temperature of 37 C (40-60%
protection).

13.3.2 The effect of benzyl alcohol on (a) adenylate cyclase activity and (b) the physical state of bovine thyroid plasma membranes are shown on Fig. 5. Effect of benzyl alcohol on (a) the adenylate cyclase activity and (b) the physical state of bovine thyroid plasma membranes. The change in adenylate cyclase activity (a) is shown for basal (o-o), TSH-stimulated (-), forskolin-stimulated (0-0), choleratoxin-stimulated (V-V), and fluoride-stimulated (0-0) enzyme activity. The mem-branes were incubated with the drugs prior to the addition of coupling factors. The physical state =
of the membrane was evaluated by following the steady-state fluorescence anisotropy (b) of sev-eral fluorophores embedded in the membranes: DPH (o-o), 12-AS ( - ) and TMA-DPH (0-A).
Measurements were performed at 37 C. The fYourophore/lipid molar ratio was always 1:500.
13.3.3 Our experiments proved that N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboxiinidoyl chloride maleate exerts a significant influence on the activity of AP-I and its effect is determined hy the actual metabolic conditions of the cells. While N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pii-idinecarboxiinidoyl chloride nzaleate increases the activity of AP-1 if the supply of nutrients is inadequate, in rich niedium it does decrease the activity of the factor.
The effect of the drug is most pronounced in dense, late log cultures. The opposite tendency could be seen for P 1. Its activity decreased if N-[2-hydroxy-3-( I-piperidin),l)propoxy]- ' )-pyridine carboximidoyl chloride maleate was adniinistered to cells in a minimal niedium. It is conceivable, that the downregula-tion of P-1 was elicited by the very clianges in the cells anti-stress machinery caused by the N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate induced AP-1 ac-tivation. It is noted, that P-1 responded to all types of stresses but its activity was not influenced by the test nZaterial. Our important findings, especially with AP-1 could explain many facets of the in vivo activity of the drug and will be discussed in details.

The effect of N-[2-hydroxy-3-( I-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate (B) on hsp gene expression in tissue culture is shown in Fig. 6. HeLa cells were transfected with a reporter plasniid construct in which the promoter of liuman hsp70 gene was fused to the lu-ciferase reporter gene. The effect of heat shock and/or N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate on the hsp promoter was determined by measuring the activitv of luciferase in luminometer and by determining the hsp protein level (expressed from tlic chromosomal gene) on Western blot.

Samples are:

1: no DNA control; 2: l0 g transfected DNA at to , no heat shock; 3: 10 g transfected DNA at to 60 min. heat shock 24 h later; 4: as earlier+N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboximidoyl chloride maleate (B) at to; 5: 10 g transfected DNA at to + N-[hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate (B) at to;
6: 10 g trans-fected DNA at to 60 min. heat shock 24 h later N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboximidoyl chloride maleate (B) added at the time of heat shock;
7: 10 g transfected DNA at to 60 min. heat shock 24 h later N-[2-hydroxy-3-(1-piperidinyl)propoxy]-piridinecarboximidoyl chloride maleate (B) added at 0 time and at the time of heat shock; 8:
l0 g transfected DNA at to with no heat shock, N-[2-hydroxy-3-(l-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride inaleate (B) added at 0 time and 24 h later.
EXAMPLE 14: EFFECT OF N-[2-HYDROXY-3-(1-PIPERIDINYL)PROPOXY]-3-PIRIDINECARBOXIMIDOYL CHLORIDE MALEATE IN INDUCING MOLECULAR
CHAPERON IN TUMOR CELLS

Nonlethal lieat shock increases the sensitivitv to lysis mediated by NK cells by 1.5-fold and that lieat shock plus treatment with N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine car-boximidoyl chloride maleate has a synergistic effect on the lisability of K562 cells. This addi-tional effect accounted for N-[2-hvdroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl cliloride maleate clearly resulted from the elevated plasma membrane expression of lisp72, since i17 i=i>>o antibody blocking studies (using hsp72 specific monoclonal Ab) revealed a stron~~ inhibi-tion of NK-lysis.

On Fig. 7. the effect ofN-[2-hvdroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride nialeate (B) on heat shock induced hsp72 levels is shown. N-[2-hydroxy-3-(1-piperidin),l)propoxy]-3-piridinecarboximidoyl chloride maleate alone did not increase hsp72 levels wliile the combination of heat shock and N-[2-hvdroxy-3-(1-piperidinyl)propoxy]-3-piridiilecarboximidoyl chloride maleate treatment resulted in a significant increase of hsp72 ex-pression compared to heat shock alone.
14.1 Background Heat shock proteins are known to be located in the cytoplasm, where they perform a variety of 5 chaperoning functions. In tumor cells, however, hsp is reported to be expressed also on the sur-face of cell membrane (Ferrarini.M. et al. Int.J. Cancer, 51,613 619, (1992)).
Experiments seem to indicate that increased hsp (e.g., hsp70) on cell surface is induced by exposure of tumor cells to nonlethal heat shock, and this increase correlates with an increased sensitivity of IL-2 specific, CD-3 natural killer cells (NK) toward tumor cells. Since NK cells are reported to participate in iililtrating and killing tumor cells in vivo (Kurosawa,S. et al. Eur. J.
Imrnunol. 23:1029, (1993)), this increased sensitivity of NK cells towards tumor cells allows better targeting of the tumor cells by NK cells. Thus, if the expression of hsp can be induced in tumor cells, 'A'ith increased hsp on the cell surface, it can allow better targeting and killing of these cells by the NK cells. In this section, the effect of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chlo-ride nialeate in inducing expression of hsp72 in tumor cells is examined.
14.2 Materials & Methods I-Iuman K562 cells, a mycloid tumor cell line derived from a patient with chronic myelogenous leukemia in blast phase (ATCC. CCL243) was used (Lozzio.BC an Lozzio, BB Blood 45:321, 1975). Exponentially growing cells were treated with 5x 1 0-5 M N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate during the nonlethal temperature (42 C) for 2 hours. Following a recovery period of 16 hrs at 37 C, cells were tested for the level of hsp72 content by flow-cytometry (Multhoff et al., Int. J. Cancer: 61. 272-279, (1995)). Treat-ment with N-[2-hydroxy-3-(I-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate resulted in an enhanced level of hsp72 in the tumor cells.

EXAMPLE 15: INTERACTION OF N-[2-HYDROXY- 3-( I-PIPERIDINYL) PROPOXY]- 3-PIRIDINECARBOXIMIDOYL CHLORIDE MALEATE WITH LIPID MEMBRANES. A
1\4ONOLAYER STUDY.
15.1 Backaround The mechanism(s) by which stress (physical, pathophysiological, etc.) is detected as a signal and transduced to the transcriptional apparatus is hitherto unknown. It was assumed that the physical state of the membrane lipid matrix, which determines the structure and function of the membrane-bound proteins, is directly involved in the perception of temperature changes and that under heat shock (HS) conditions perturbance of membrane structure causes transduction of a signal that induces transcription of HS genes. Parallelly with the induction of stress tolerance, N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboxiinidoyl chloride maleate was shown to enhance the efficacy of cells to detect and signal various stress conditions by upregulating the expression of some chaperone genes.
It is known that monolayer technique using monomolecular lipid layers spread at the air-water interface is an effective tool for the verification of the presence of interactions between membranes and mzmbra::e active agents. The behavior of the bilayer system is very si-nilar to that of the respective monolayer system in many aspects (molecular area of membrane constitu-ents, phospholipase action, orientation of inserted proteins, etc.) . By measuring the surface pres-sure changes caused by molecules inserted into monolayers it becomes possible to get insight into the molecular diniension of the interaction.
The crucial prerequisite of the assumption that some N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate mediated early triggering events in stress responses may occur in the cell membrane is to serve evidences on the direct physical interaction of N-[2-hydroxy-3-( I-piperidinyl)propoxy]- 3-piridinecarboximidoyl chloride maleate with membrane constituents. The aim of the present study was to investigate the interaction of N-[2-hydroxy-3-( ] -piperidinyl)propoxy]-3-piridinecarboximidovl chloride maleate with membranes by using different lipid monolayers as model system for biological niembranes.

15.2 Materials and Methods Monolayer experiments were carried out in a Teflon dish, with a volume of 6.5 ml. and a surface area of 8.8 cm2 at 25 C in a KSV3000 Langmuir-Blodgett instrument (KSV
Instruments Ltd.. Helsinki. Finland) essentially as described. Monomolecular lipid layers consisting of 1?-dipalmitovl-sn-glvicero-3-phosphocholine (DPPC). e-g yolk phosphatidylglvicerol (EggpG) or bovine heart cardiolipin (BHCL) NN-ere spread from chloroform lipid solutions to give the desired initial surface pressure on a subphase of 10 mM Na-phosphate (pH 7.0). The subphase was con-tinuouslv stirred with a magnetic bar. N-[2-hydroxy-3-(1-piperidinyl)propoxv]-3-pvridine car-boximidovl chloride nialeate, dissolved in H20, was added underneath the monolaver through a = hole in the Teflon chamber connected to the subphase. The injected volumes were always <1 %

of the total subphase volume. The surface pressure was measured by the Wilhelmy method using a platinum plate. The surface pressure increase data were extracted from the raw data files by using the LB5000 software of the Langmuir-Blodget measuring system.

15.3 Results The interaction of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride nlaleate with different phospholipids was tested by measuring the drug-induced surface pressure increase of lipid monolayers spread at the air-water interface (Figure 8.). Monolayers in the present study have been formed from DPPC, EggPG and BHCL and increasing anlount of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate was added in two concentrations (10"~' M, 10-' M) to the subphase. The addition of the drug underneath a lipid monolayer resulted in a surface pressure increase which was dependent on the concentration of N-[2-hydroxy- 3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate in the sub-phase in all cases. There was, however, a prominent difference in the surface pressure profile of the different lipid nlonolayers, In case of zwitterionic DPPC, the pressure changed quickly after the iiljection ofN-[2-liydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate, then it stayed at a constant level. By using monolayers containing the negatively charged BHCL the surface pressure profile showed a typical insertion kinetics, that is the pressure in-creased for about two minutes after which it reached an equilibrium level. In the presence of PG, the insertion kinetics of the drug was similar to that observed with BHCL, however, after reach-inu a certain value, the pressure started to decrease. The rate of pressure decrease was dependent on the concenlration of the dru~~ in the subphase. One possible explanation for this phenomena is the removal of N-[2-hvdroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride nialeate - Ea;PG complexes from the interface since the decrease of pressure continued, even after reachin, the initial pressure of the pure lipid monolayer.
To get fiirther insight into the specific interaction of N-[2-hydroxy-3-(1-piperidim=I)propoxy]- 3-piridinecarboximidoyl chloride maleate with lipid monolayers the drug induced surface pressure increase was measured at different initial surface pressure (Figure 8.) The method of extrapolation to high initial surface pressure allows the estimation of limitino insertion pressures for the molecule, at ,N?hich it is no longer able to insert into the monolayer.
The extrapolated limiting initial surface pressures were 89 mN/m and '19 mN/m for BHCL and for DPPC. respectively. In case of monolayers containing the negatively charged BHCL. the WO 97116439 PCT/fIU96/00064 pressure increases were always higher than those found for the zwitterionic DPPC by suggesting the importance of electrostatic interactions.
Our investigations serves with the first evidence, that upon the administration of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate in a physiologically > relevant concentrations, it is able to interact with lipid membranes, in a head-group specific man-ner.
In Fig. 8. the interaction of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboxi-midoyl chloride maleate (B) and the monomolecular lipid layers is shown. At the arrows N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate was added to the subphase at the indicated concentrations. In ria. 9. the surface pressure inerease is presented after the injection of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboxiinidoyl chloride maleate (B) underneath monolayers of BHCL or DPPC at different initial pressures. The N-[2-hydroxy- 3)-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate concentration in the subphase was 10 mol. The linear re-ression analysis of the experimental data resulted in 1 -5 correlation coefficients of 0.844 and 0.995 for BHCL and DPPC monolayers respectively.
EXAMPLE 16: THE PROTECTIVE EFFECT OF N-[2-HYDROXY-3-(1-PIPERIDINYL) PRO-POXY]- -)-PIRIDINECARBOXIMIDOYL CHLORIDE MALEATE AGAINST CYTOTOXIC
CYTOKINES AND CYCLOHEXIMIDE
16.1 Background The purpose of these studies was to investigate a possible connection between the pro-duction of cytokines and the pathophysiol.ogical changes N-[2-hydroxy- 3-(1-2> piperidinyl)propoxy]- 3-piridinecarboximidoyl chloride maleate seenls to be protective against.
Our data suggest that N-[2-hvdroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidovl chloride nialeate is a cvtoprotective agent for tissue cultured cells treated xvith cytotoxic cytoki-nes. N-[2-hydroxv-3-(1-piperidim,l)propoxy]-3-piridinecarboximidoN-l chloride nialeate treatment increased the survival rate of TNF treated WEHI 164 (and other mammalian) cells. This effect was c-o17ce771r=alion dependel7t, but was not directhyproportional to the drug concentration. The extent of protection provided by the N-[2-hydroxy- ~-(1-piperidinyl)propoxv]-3-pvridine carbox-imidoyl chloride maleate treatment was variable froni experiment to experiment. though the in-creased resistance of the treated cells to cvtotoxic cytokines was clearly a tendencl, in all experi-inents. The protection provided by N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboxi-midoyl chloride maleate treatment was not veiy high, however, in a living animal even this de-gree of protection could have been sufficient to moderate or prevent pathophysiological proc-esses.
16.2 Aim of study Serum TNF levels and inducibility of macrophages from STZ diabetic and control ani-mals were measured. LPS-induced serum TNF activities were significantly enhanced in STZ-iiiduced diabetic rats (6-18 weeks of age) colnpared with those of non-diabetic rats, during the first month of diabetes.

163 ) Results The mean serum TNF concentration (measured by radioimmunoassay) of the diabetic group was significantly higher (480 96 U/ml) than in healthy controls (345 t 48 U/ml). (Foss et al. 1992 Braz. J. Med. Biol. Res. 25,239 reported similar results in human patients). Within the diabetic gt-oup. there was no correlation between serum TNF levels and duration of diabetes. We have not found hinlogicallv active TNF in the sera of diabetic animals by the cytotoxicity assay on L929 cells. The difference between the RIA and cytotoxicity measurements indicate the pres-ence of liigli levels of soluble TNF receptor antagonists (a protective, anti-inflammatory mole-cule), sugoesting the involvement of TNF in diabetic complications.
N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate had an unc;xpected proliferative effect on yeast cells (and on different, cultured, normal_ diploid animal 2 ~ or human cells). The influence of N-[2-hydroxy-3-( I-piperidinyl)propoxv]-3-pyridine carboximi-doN,l chloride maleate was especially impressive in the presence of low concentrations of the ~.~rowth inhibitory antibiotic, cycloheximide. Yeast cell colonies grown in the presence of N-[2-hvdroxv-1-(I-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate and cycloheximide did not sllow an increased incidence of genetic changes (antibiotic resistant mutations), only hi-her metabolic resistance against the inhibitory effect of cycloheximide on protein synthesis.
Accordin- to our measurements the effects of N-[2-hvdroxy-3-(1-piperidinvl)propoxy]- ')-piridinecarboximidovl chloride maleate can be traced down to the increased activity of the AP-1 transcription factor. which mediates the effects of both mito"enic factors and different types of stress. The results also indicate that the above test compound and similar compounds influence the detixity of AP-1 and possibly other transcription factors, by maintaining the effects of growth factors and metabolic stress conditions.
In Fig. 10. LPS induced TNF production in vitro of macrophages isolated from STZ diabetic (1) and normal (2) animals, in Fig. 11. the N-[2-hydroxy-3-(l-piperidinyl)propoxy]-piridinecarboximidoyl chloride maleate induced protection of keratinocytes against the growth inhibitory effect of cycloheximide, in Fig. 12. the N-[2-hydroxy-3-(1-piperidinyl)propoxy] -' )-piridinecarboximidoyl chloride maleate (B) induced protection of cells (endothelial cells) against toxic effects of cycloheximide, in Fig. 13. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboximidoyl chloride n.aleate (B) prote,ction of human cervical I IeLa cells against the growth inhibitory effect of the antibiotic cycloheximide, in Fig. 14. the N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate (B) induced protection of heart muscle cells against the growth inhibitory effect of the antibiotic cycloheximide, and in Fig. 15.
the effect ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate (B) on P 1 transcription factor activity in AB 1380 veast cells are demonstrated. Row 6. represents the mean values. Row 5. is empty. In Fig. 16. the effect of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate on API
transcription factor ac-tivity in .TF 1 yeast cells are demonstrated. Row 11. represents the mean values. In Fig. 17. the effect of N-[2-hvdroxy- 3-(1-piperidinyl)propoxy]- ')-piridinecarboximidoyl chloride maleate (B) on 131 transcription factor activity in AB 1380 yeast cells are demonstrated.
Row 6. represents the mean values. Row 5. is empty.

EXAMPLE: CARDIOPROTECTIVE EFFECTS OF N-[HYDROXY-3-(1-PIPERIDINYL)PROPOXY]-3-PIRIDINECARBOXIMIDOYL CHLORIDE
MALEATE IN ISOLATED RAT HEARTS
17.1 The objective of the study was to investigate the cardioprotective and antiarrhythmic effect of N-[2-hydroxv-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate in isolated ?0 workin`~ rat hearts.

WO 97/16439 PCTlHU96/00064 17.2 Methods After a 10-min. aerobic working perfusion, hearts (n=10 in each group) were subjected to a 10-min. coronary occlusion followed by a 3-min. reperfusion in the presence of 0.05, 0.5, 5Ø 20.0, and 50 mg/L N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboximidoyl chloride maleate, respectively.

In the further studies rats were pretreated with the most effective (20 mg/kg) dose of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate, one and five hours before isolation of the hearts, respectively. After excision of the hearts, they were subjected to the coronary occlusion prorocol detailed above while perfused in presence/absence of 20 mg/i N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate.
In separate experiments the effects of heat stress, iscllemia, N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate and their combination were studied on myocai-dial HSP-70 protein content. Isolated hearts were subjected to 15 min. heat-stress (42 "C), g,lobal normothennic ischemia, and N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboximidoyl chloride maleate perfusion followed by 120 and 180 min.
reperfusion, respectively.
17. 3 Results Before ischemia, N-[2-hydroxy-3-(1-piperidin),l)propoxy]-,-piridinecarboximidoyl chloride maleate increased coronary flow (CF) with a bell-shaped concentration-response relationship. Other cardiac functional paranieters were not cllanged by lower concentrations of the dru~~. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate at 50 m~~/L
caused si`~nificant bradvcardia, a reduction in aortic flow (AF) and +dP/dt,,,, and an increase in left ventricular end-diastolic pressure (LVEDP) before ischemia. In the control group, coronary occlusion markedly decreased CF. AF, +/-dP/dt,,,,,, and increased LVEDP. N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl cllloride maleate alleviated ischemia-induced deterioration of cardiac funetion Nvith a bell-sliaped concentration-response relationship. The concentration of 20 mg/L N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate showed the most pronounced anti-ischemic effect. Reperfusion after 10 min. coronary occlusion triggered ventricular fibrillation (VF) in all hearts of the control group. Higher concentrations of N-[2-hydroxy-3-(1-piperidinN=1)propoxy]- 3-piridinecarboximidoyl chloride maleate resulted in a dose-dependent antiarrhytlunic eff'ect.

After one hour pretreatment N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carboximidoyl chloride maleate still afforded cardioprotection, and potentiated the acute effects of the compound. Five hours after pretreatment, the cardioprotective effect was not observable, however, some of the acute effects of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine ' 5 carboximidoyl chloride maleate perfusion were increased.
The compound alone did not increase myocardial HSP-70 content. Stetyocardial content was markedly elevated due to heat stress, however, ischemia resulted in a mild HSP-70 elevation. Nevertheless, when ischemia was induced in the presence of 20 mg/l N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate, HSP-70 content was increased to approriiiziately the same levcl as found after heat stress.
We conclude that N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate exerts an anti-ischemic, and an antiarrhythmic effect. The concentration of 20 m` /L was found to produce both marked anti-ischemic and antiarrhythnlic effect in the isolated rat heart. When the direct anti-ischemic effect of the drug disappears after one hour, it still increases the degree of protection afforded by acute N-[2-hydroxy- 3-( I-piperidinyl)propoxy]-3-pyridine carboxiniidoyl chloride maleate treatnient. N-[2-hydroxy-3-(1-piperidinvl)propoxy]-3-pyridine carboximidoyl cliloride maleate and ischemic stress together induces a rapid de novo synthesis of HSP-70 in the rat heart. N-[2-hydroxy-3-(1-piperidin),l)propoxy]-3-piridinecarboximidoyl chloride maleate alone does not affect HSP-70 synthesis.
In Figs. l 8-19. the hsp protein levels, determined by Western blotting are demonstrated from control, heat shocked, ishemia treated, the N-[2-hydroxy- 3-( I-piperidinyl)propoxv]- 3-piridinecarboximidoyl chloride maleate treated (B) and iscliemia + hydroxy- 3-( I-piperidinyl)propoxy]- ')-pyridine carboximidoyl cllloride maleate treated (Ischemia+B) rats fol-loNN~ed by 2(Fi~,. 18.) or 3 hours (Fig. 19) recovery.

EXAMPLE 18: CHAPERON-BOOSTER N-[2-HYDROXY- 3-(1-PIPERIDINYL) PROPOXY]-O1= SKIN DAMAGES: ULTRAVIOLET LIGHT B PROTECTION IN HUMAN SKIN
GRAFTED SEVERE COMBINED IMMUNODEFICIENCY DISEASE MICE AND ACCEL-ER.-%TED WOUNTD HEALING IN DIABETIC RAT.
18.1 Background Hsps appear to play a general role in the physiological protection of the skin from envi-ronmental stress. As molecular chaperones they participate in prevention and repair of damages caused by various exposures, such as mechanical trauma, light, heat and chemical injuries, in-fections, etc. (E.V.Maytin, JID 104:448, 1995.) In pathological conditions, such as diabetes mellitus attenuated function of certain hsps has been reported (M.Cherian and E.C. Abraham, Biochem. Biophys. Res. Com. 212:184, 1995). Since N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate was shown to act as a chaperon booster (Vigh et al., in preparation) we would expect iliat the drug is able to enhance most various protection and repair mechanisms.
The purpose of this study was to test the effect of systemic (i) and topical (ii) administra-tion ofN-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate:
(i) in protection against UVB light induced skin injury in human skin grafted on severe com-bined immunodeficiency disease (SCID) tnice, (ii) in repair of destroyed wound healing process in STZ-diabetic rats.

(i) Human skin transplanted SCID mice treated by N-[2-hydroxy-3-(]-piperidinyl)propoxy]-3-piridinecarhoximidoyl chloride maleate (5.0 mg/k(, i.p.) or vehicle were exposed to UVB light (100 m.i/cnr'). After 24 h skin biopsies were taken for histological examination and for hsp72 determination using inimunohistological and Western blotting techniques.
Pretreatment with N-[2-h%droxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate prevented UVB
light induced skin injury deterniined clinically and histologically. Intensive hsp72 staining of linear basement membrane could be observed by immunofluorescence technique and increased amount of hsp72 was measured by Western blotting of N-[2-hydroxy- 31-( ]-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate treated skin samples.
18.2 Methods (ii) Streptozotocin-induced diabetic (STZ) rats with partial - to full thickness thermal 30 wounds created on bilateral thoracic depilated skin hy electroheating probe (3 mm of diameter;

60 C; for 30, 60 and 90 sec.), treated by topical application of 1%, 2% or 4%
N-[2-hydroxy- 3-(1-piperidiny l)propoxy]- 3-piridinecarboximidoyl chloride maleate containing creani or vehicle were used to determine the wound healing in form of self-control, side to side comparison.
Wound closure was recorded photographically and using the digital epiluminescence micro-scopic technique. Wound areas were measured by planimetry 48 h and 21 days after heat injury.
Level of hsp72 of skin biopsy sanlples was determined using Western blot analysis.
18.3 Results Treatment with 4% N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate containing cream significantly (p< 0.01) accelerated wound closure and ele-vated the hsp72 level in skin biopsy samples compared to vehicle control.
Our results lead to the conclusion that the administration of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate provides protection against inju-ries from UV exposure and has potential therapeutic applications for the clinical treatment of conditions with defect in wound repair or after surgical intervention.
On Fig. 20., 21. 22 the effect of 1%, 2%, 4% N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine carbolimidoyl cllloride maleate (B) containing cream are demonstrated on wound healing. On Fio. 23, 24, 25 the results are shown according to the grade of wounds.

On Fig. 26. the pliotographic pictures of untreated and N-[2-hydroxy-3-(1-piperidinyI)propoxy]-3-pit=idinecarboximidoyl chloride nialeate (B) treated wounds are shown.

Fio. 27. sllows the hsp72 protein levels of bioxy specimens irom control N-[2-hydroxy-3-( I-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate (B) (1 %, 2% and 4%) treated Nvounds.

On Fig. 28 the irnmunhistochemical evaluation of hsp72 protein after N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-piridinecarboximidoyl chloride maleate (B) treatment is sllown.

? 5 On Fig. 29. the hsp72 levels from N-[2-hvdroxy- 3-( I-piperidinyl)propoxy]-3-pyridine carboxi-midoyl chloride maleate (B) treated and untreated (Control) skin samples of SCID mice are dem-onstrated.
19. EVALUATION OF STIMULATORY EFFECT OF HYDROXYLAMINE DERIVATIVES, STRESSES

a.) Cell culture conditions From the applied cells the 3T3 and L-929 mouse fibroblasts were cultured in MEM medium and grew in monolayer, the U-937 human leukemia cells were maintained in RPMI-1640 me-dium, in suspension culture, while the HeLa human epithelial cells were cultured in DMEM
medium and in monolaver form. Cell cultures were maintained as described in example 6.2 (a) with the difference that cells were cultured in the above mentioned culture mediums.
b.) Conditions of the experiments Experiments were carried out applying stress before and after the drucy treatment. Stress was provoked by heat, by chemical agent, HgCI?treatment. The test compounds were applied in the treatments at the 10-5 M concentration.
Cytotoxicity studies, whicli were performed by a 3 days assay, and were evaluated by MTT
(Cytotechnology 11:49-58) indicated that all of the test compounds had a 50%
crowth inhibitory effect at a concentration larber than 10-4 M. Consequently, the concentration used in HSP72 studies has no significant cytotoxic effect.
19.1. Experiments with heat stress These experiment were performed on 3T3 and L-929 mouse fibroblast cells furthermore on U-937 human leukemia cells.
The experiments on 3T3 cell app)ying lieat stress were performed as described in the 6.2. (c ) point of example 6. -with the difference that stress was induced by a 30 min. exposure at 4 3 C
temperature and treatment witli the test compounds was performed 15 min.
before or 100 miil.
aiier the heat stress.
]minunodeteetion was carried out using t17e HSP72 specific SPA 810 (StressGene) primary and the horse-radish peroxidase conju~~ated A9044 (Sigma) secondary ?~ antibodies. Densitometric evaluation was performed by a LKB Ultrascan*XL
densitometer.
Results are sununarized in Table 2 and Table 3.

*Trade-mark Table 2 Stimulatory effect of hydroxylamine-derivatives by the invention on the heat stress induced HSP72 production in 3T3 cells if treatment precedes stress exposure.

Compounds HSP72 level relative to the stress exposed control N-[2-hydroxy-3-( I -piperidinyl)-propoxy]-3-pyridine-carboximidoyl-chloride-maleate +++
5.6-dihydro-5-(I -piperidinyl)-methyl-(3-piridyl)-4H-1,2,4-oxadiazine +++
3-( ~-piridyl)-5-[(1-piperidinyl)-methyl]-5,6-dihydro-I 5 6H-1,4.2-dioxazine-(Z)-2-butenedioate (1:1) ++
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-benz-iinidoyl-chloride monohydrochloride +
N-[2-hydroxy- 3-(1-piperidinyl)-propoxy]-N',N'-diethyl-3-pyridine-carboximidamide monohydrochloride +++
3 )-(3-piridyl)-.5-diethylaminomethyl-5,6-dihydro-6H-1,4?-dioxazine hydrochloride +
3-phenyl-5-[(1-piperidinyl)-methyl]-5,6-dihydro-61-I-1,4.2-dioxazine hydrochloride ++
/R/ (+)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-p~,ridine-carboximidoyl-chloride-(Z)-2-butenedioate (1:1) +++
(-) N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-~-pyridine-carboximidoyl-chloride-(Z)-2-butenedioate (1:1) +++
N-[2-hydroxy- 'i-(piperidinyl)-propoxy]-naphtalene-l-carboxamide +++
'-('-piridyl)-5-t-butylamino-5,6-dihydro-6H-1,4?-dioxazine +
N-(2-hydroxy-3-piperidino-propoxy)-eth_ylurethane +
N-['_'-palmito~=loxy- 3-(1-piperidinyl)-propoxy]-3-pyridine-carboximidamide monohydrochloride +++

N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-N'-propyl-urea +++
N-(3-cl-Aoro-phenyl)-N'-[2-hydroxy-3-(1-piperidinyl)-propoxy]-urea +++ 5 N-(3-piperidino-l-propoxy)-3-pyridine-carboximidoyl-chloride dihydrochloride +++
O-(3-diethylamino-propoxy)-3-pyridine- carboximidoyl-chloride hydrochloride +++

O-(3-piperidino-propyl)-3-nitro-L= enzhydroximoyl-chloride hydrocliloride ~++
1- ( [3-(t-butylamino)-2-hydroxy-propoxy]-imino } -I -(m-trifluoromethyl-phenyl)-ethane acetate +++
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-benzylurethane 0 N'-[2-hydroxy-3-(1-methyl-l-piperidinium-1 -yl)-propoxy]-1 5 N-methyl-piridinium-3-carboximidoyl-chloride diiodide +++
N-hexyl-N'-[ 3-(1-piperidinyl)-propoxy]-urea ++
N-cyclohexyl-N'-[2-acetoxy-3-(1-piperidinyl)-propoxy]-urea hvdrochloride 0 N-[2-liydroxy-3-( l -piperidinyl)-propoay]-2-nitro-benzimidoyl-chloride monohydrochloride +++
N-[2-hydroxy- 31-( l -piperidinyl)-propoxy]- 3-quinoline-carboximidarnide dihvdrochloride +++
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-NN'-diphenyl-benzamidine 0 N.N-dimethyl-N'-[2-hvdroxy-3-(1-piperidinyl)-propoxy]-N"-phenyl-~._*uanidine 0 N.N-dimethyl-N'-phenN=1-N"-[ 3-( I -piperidinyl)-propoxy]-~.;uanidine hydrochloride ++
N-methyl-N-[ 31-(1-piperidinyl)-propoxy]-benzamide hvdrochloride +
~.G-dihydro-3-(-1-chloro-phenyl)-~-[N-methyl-piperidinium-1-E1]-methyl-4H-1,2.4-oxadiazine iodide ++
Methyl-; N-[3-(1-piperidinyl)-propoxy] }-3-pyridine-carboximidate maleate 0 N-methyl-N-[3-(1-piperidinyl)-propoxy]-m-trifluoromethyl-benzamide hydrochloride +++
N-[3-(1-piperidinyl)-propoxy]-N'-tetramethylene-3-pyridine-carboxamidine hydrochloride +++
N-[3-(1-piperidinyl)-propoxy]-N-methyl-N'-(n-hexyl)-urea 0 Table 3.
Stimulatory effect of hydroxylamine-derivatives by the invention on the heat stress induced HSP72 production in 3T3 cells if treatment followed stress exposure.

Conipounds HSP72 level relative to the stress exposed control N-[2-hydroxy-3-(1-piperidinyl)-propoxy]- 3-pyridine-carboxiniidoyl-cllloride maleate 0 N-[2-hydroxy- 3-(1-piperidinyl)-propoxy]-2-nitro-henzimidoyl-chloride monohydrochloride 0 5,6-dihydro-5--(1-piperidinyl)-methyl- 3-( 'f-piridyl)-4H-1.2,4-oxadiazine 0 O-( 3-piperidino-propyl)-3-nitro-benzhydroximoyl-chloride hydrochloride +
N-[2-palmitoyloxy-3-(1-piperidinyI)-propoxy]-3-pyridine-carboximidamide monohydrochloride +
N-hexyl-N'-[2-hydrox},- 3-(1-piperidinyl)-propoxy]-ul ea +++
N-[2-hydroxy- '-(1-piperidinyl)-propoxy]-naphtalene-l-carboxamide ++
N-[2-hydroxy- ')-(1-piperidinyl)-propoxy]-4-pyridine-carboximidoN,l-chloride-(Z)-butenedioate (1:1) ++

N'-[2-hydroxy-3-(1-methyl-l-piperidinium-1-yl)-propoxy]-N-methyl-piridinium-3-carboximidoyl-chloride diiodide +++
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-quinoline-carboximidamide dihydrochloride +++ .
In the Table 0 indicates that the treatment altered by 20 % the stress induced hsp721evel in the cells, while +, ++, +++ indicate 21-50 %, 51-100 % and >100 % increase in the hsp72 lev-els. respectively, relative to the level of the stress exposed control.
Experiments using heat shock on U-937 leukemia and L-929 mouse fibroblast cells were cun=ied out similarly as described above, but drug treatments in these tests always preceded the IZeat stress. The compound N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridine-carboximidoyl-chloride maleate was tested at the 10-5 M concentration under these experimental conditions.
The treatment resulted in a more than 50 % increase in the heat stress induced hsp72 level.
19.2. Experiments witl1 stress induced by chemical aaent These experinients were performed on HeLa, human epitlielial and U-937, human leukemia cells usin- HgC12 to induce stress response. Drug treatment was carried out before cells were exposed to the stress. Test cultures were prepared and treatments were performed as in the ex-periments with the 3MI cells. After the drug treatment cells were incubated at 37 C for 15 min.

than all the cultui-es except two (non stressed control) were exposed to 0.5 ghnl concentration of HoCH and the incubation was followed. The induced amount of hsp72 was measured 6 hours aftei- the exposure to stress. The applied concentration of H~~C12 ) resulted in 15-30% of maximal hsp72 level.
On HeLa cells N-[2-hydroxy- 3-( l-piperidinyl)-propoxy-benziinidoyl-chloride inonohydro-chloride and N-[3-(1-piperidinyl)-propoxy]- 3-nitro-benzimidoyl-chloride monolrydrochloride increased by more than 20% and b_y more than 50%, respectively the stress induced hsp72 level.
On U-9 3 7 cells N-[2-hydroxy- 3-(1-piperidinyl)-propoxy- 3-pyridine-carboximidoyl-chloride maleate treatment enhanced by more than 20% the stress induced hsp72 level relative to the stress exposed control.

19.3. Experiments on primary tissue explants These experiments were performed on rat spleen and testicular tissue explants applying heat stress after treatment with the experimental compounds. Experiments on spleen suspension were carried out as follows.
Spleens of CFY rats weighing 200 g were removed aseptically, and were homogenized in 10% fetal bovine serum containing MEM culture medium. The concentration of the cell suspen-sion was adjusted to 50-100 mg/5 ml.
Five ml cell suspension was given into each of the culture dishes of 6 cm of diameter and ti-ie explants were incubated for one hour in a 5% CO7 containing hurriidifyed air at 37 C then cultures were treated with the 10-5 M concentration of the test compounds.
After further 15 min.
incubation at 37 C the cultures were exposed to heat shock at 43 C for 30 min. in an incubator.
The an-iount of the induced hsp72 was measured after a further 6 hours incubation at 37 C.

Results are presented in Table 4. and enhanced levels of hsp72 are scored by the same scale as in Table 2. and 3.

Table 4.

Stimulatory effect of hydroxylamine-derivatives by the invention on heat stress induced hsp72 expression in rat spleen explant Compounds Level of hsp72 relative to the stress exposed control 2 ~ N- i 3-[(1.1-dimethyl-ethyl)-amino]-2-hydroxy-propoxy }- 3-trifluoro-niethyl-benzamide +
N-[2-hydroxy- 3-(1-piperidinyl)-propoxy]-N'-hept\,l-urea +++
N-( -',-chloro-pllenyl)-N'-[2-hydroxy-3-( I -piperidirrvl)-propoxy]-urea +++
' 30 5.6-dihydro-5-(.1-piperidinyl)-methyl--')-(3-piridyl)-4H-, 1.2.4-oxadiazine 0 Experiments on rat testicular explant were performed as follows.
Testis of CFY rats weighing of 200 g were removed in sterile conditions and the released testicular tubuli were suspended in 10% fetal bovine serum containing MEM
culture medium in that way that five ml suspension contained 50-100 mg tissue. The explants were incubated in 5%

C02 containing humidified air at 37 C for one hour, then the cultures were treated with 10-5 M
concentration of the tested compounds. After a further incubation for 15 min.
at 37 C , explants were exposed to heat shock at 43 C for 30 min. The amount of the induced hsp72 was measured after a further 6 hours incubation at 37 C .

Results are summarized in Table 5. and the increase in hsp72 level is scored by the same scale as in Table 4.

Table 5.

Stimulatory effect of hydroxylamine-derivatives by the invention on heat stress induced hsp72 expression in rat testicular explant Compounds Level of hsp72 relative to the stress exposed control N-[2-hydroxy- 3-(1-piperidinyl)-propoxy]-3-pyridine-carboximidoyl-chloride maleate +++
5,6-dihydro-5-( ] -piperidinyl)-methyl-3-( 3-piridyl)-4H-1.2.4-oxadiazine ++
N-[2-hydroxy- 3-(1-piperidinyl)-propoxy]-benz-imidoyl-chloride monohydrochloride +++
N- (')-[(1.1-dimethyl-ethyl)-amino]-2-hydroxy-propoxy f-3-trifluoromethvl-benzamide 0 N-[2-benzyloxy- '-(1-piperidinyl)-propoxy]- 3-pyridine-carboximidoyl-cliloride-(Z)-2-butenedioate (1:1) ++
1-( .1-piridN,l)-5-diethylaminomethN-l-5,6-dihydro-6H-1,4,2-dioxazine hvdrochloride ++
N-[2-hydroxy- ':)-( I -piperidinyl)-propoxy]-4-acetamido-benzamidine monohvdrochloride 0 3-(3-piridyl)-5-t-butylamino-5,6-dihydro-6H-1,4,2-dioxazine 0 N-[2-palmitoyloxy-3-(1-piperidinyl)-propoxy]-3-pyridine-carboxiinidamide monohydrochloride 0 N-hexyl-N'-[2-hydroxy-3-(1-piperidinyl)-propoxy]-' 5 urea ++
N-(3-piperidino-l-propoxy)-3-pyridine-carboximidoyl--propoxy)-3-pyridine-carboximidoyl-chloride dihydrochloride ++
O-(3-di ethylamino-propoxy)-3-pyridine-carboximidoyl-chloride hydrochloride 0 O-(3-piperidino-prop}'1)--')-nitro-bcnzhydroximoyl-chloride hydrochloride ++
1- ( [3-(t-butylamino)-2-hydroxy-propoxy]-imino}-1-(m-trifluoromethyl-phenyl)-ethane acetate +
N-; 3-[ 1,1-dimethyl-ethyl)-amino]-2-hydroxy-propoxy l- 3-tri-fluoromethyl-benzimidoyl-chloride monohydrochloride +
N-[' )-(dieth)llamino)-2-hydroxy-propoxy]- 3-trifluoromethyl-benzimidoyl-chloride monohydrochloride +
N-[2-palmitoyloxy-3-(1-piperidinyl)-propoxy]-3-pyridine-carboximidoyl-chloride dihydrochloride +++
N-hexyl-N'-[3-(1-piperidinyl)-propoxy]-urea 0 N-[2-hvdroxy- 3-( I -piperidinyl)-propoxv]- 3-nitro-benzimidoyl-chloride monohydrochloride +
N-[2-hydroxy-3-(1-piperidinyl)-propoxv]-2-nitro-benzlnlldoyl-chloride monohydrochloride ++
N-[2-liydroxy-~-(1-piperidinyl)-propoxy]-N'-heptyl-urea ++
N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-1-isoquinoline-carboximidamide dihvdrochloride +++
N-methvl-N-[ 3)-(1-piperidinyl)-propoxy]-benzamide hydrochloride +
5.G-dihvdro- ',-(4-chloro-phenyl)-i-[N-methvl-piperidinium-l-N=I]-methyl-4H-1?.4-osadiazine iodide +
N-[ ')-(1-piperidin),l)-propoxy]-tiophene-2-carboximidoyl--chloride-hvdrochloride ++

EXAMPLE 20: MEASUREMENT OF THE LEVEL of HSP mRNA IN THE THORACIC
AORTA OF RATS WITH GENETIC HYPERTENSION

Rats with genetic hypertension were divided into four groups of four. The groups were treated daily, orally, the first group with physiological saline, the second group with N-[2-hydroxy-3-(1-piperidinyl)]-propoxy-3-pyridine-carboximidoyl-chloride maleate (20 mg/kg) for 8 days, the third group with N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-benzimidoyl-chloride mono-Ilydrochloride (5 mg/kg) for 20 days and the fourth group with N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-2-tiophene-carboximidoyl-chloride monohydrochloride (5 mg/kg) for 20 days. Animals were sacrificed, aortas were isolated, snap frozen in liquid nitrogen and were stored at -70 C till they were used.

b) Moipllological examination of the thoracic aorta The examination was performed according to published methods (Br. J. of Pharmacol., ] 995; 115, 515-420). A 1 mm2 area of the thoracic aorta was excised and fixed in 2,5% glutaral-deliyde at rooni temperature. Post fixation was perfornied in I% osinium-tetroxide for one hour.
The tissue was dehydrated in ethanol and was embedded in Durcupan ACM.
Pictures were taken by a Hitaclli 7100 electronmicroscope and were evaluated qualitatively.
It was observed that the N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridine-cai-boximidoyl-chloride maleate and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-benzimidoyl-chloride monohydrochloride and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-2-tiophenecarboximidoyl-chloride nionohydrochloride treatment facilitated the regeneration of the cells of aorta on an average and strong fashion, respectively.
c~Quantitative measurement of hsp70 Experiments were carried out by the quantitative reverse transcription polymerase chain reaction. The principle of the metliod is that if two very siniilar, but distin-uishable templates are amplified in the same PCR reaction then the ratio of the their products is not changed durin~.; the process. When the initial amount of one of the templates is knovm and the relative amount of the products is measurable then the amount of the unknown initial template can be calculated. In the most frequently used method the known template (competitor) and the unknown template (target) differ only in the length, the competitor is shorter, consequently the PCR products are separable based on their size.
RNA was isolated from the tissues by a guanidinium-isocyanate method (Chomczynski P.
and Sacci N.: Anal. Biochem. 162: 156, 1987). The concentration and the quality of the nucleic r acid were evaluated by spectrophotometer and by agarose gel electrophoresis in denaturing con-dition (Shambrook J. et al.: Molecular Cloning. A Laboratory Manual. Cold Spring Harbour Laboratory Press, 1989). The isolated RNA was stored at -70 C.

A fragment was constructed from a hsp-70 gene coding cDNA by splicing out an internal sequence ( PCR-splicing, Riedy MC et al.: Biotechniques 18: 70, 1995). The fragment was am-plitied by primers specifically bind to the external part of the construct (Erlich A.: PC'R 'I'echnol-ogy. Principles and Applications for DNA Amplification. Stockton Press, 1989) and after measur-ing the concentration of the product it was stored at -70 C.

The reverse transcription was performed by standard conditions using 1 g isolated RNA/sample with the help oligo dT (dT16) primer. (Shambrook J. et al., the same as above) Equal amount of cDNAs. prepared from RNA samples were mixed with various amounts of synthetic competitor (derived from 3, 10 times serial dilutions) and the templates were ampli-fied by polymerase chain reaction. The temperatures applied during the cycles were the follow-in(is: denaturation (95 C, I min.). annealing (58 C I min.), synthesis (72 C, 0,5 min.).

After PCR amplification the products were separated on agarose gel (1 %) and were stained by ethidium-bromide under standard conditions. (Sambrook et al., the same as above).
The stained DNA fragments were visualized by UV-translumiator for photography.
The amount of the PCR products was measured by densitometry from the neaatives of the photos.
It was observed that the hsp-70 level in the thoracic aorta of the N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-carboximidoyl-chloride maleate. N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-benzimidoyI-chloride monohydrochloride and N-[2-lrydroxN-3-(1-piperidinyl)-propoxy]-2-tiophene-carboximidovl-chloride-monohydrochloride treated rats was more than 50%
higher than the llsp-70 in the control animals.

EXAMPLE 21: EXAMINATION OF THE INHIBITORY EFFECT ON THE AGING OF
GUINEA PIG SKIN

The inhibitory effect of the compounds, according to the invention, on the aging of the skin was examined in guinea pig. The skin of five animals per group was depilated and an 1 cm2 area was irradiated from a UV-B source of 100 mJ/cm2 of intensity on both sides.
After the irradiation one side of the skin was treated with a cream composed according to the example 10 and contain-ing 5 % (w/w) of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-3-pyridine-carboximidoyl-chloride maleate or N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-benzimidoyl-chloride monohydrochloride or N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-2-nitro-benzimidoyl-chloride-monohydrochloride while the otlzer side of the animals was treated with the same cream without the active ingredient. This was a self-controlled experiment.
The treatment started immediately after the irradiation and was performed twice daily for two weeks.
The UV-B irradiation resulted in a severe skin injury (vesicle, bull, injury of the epithelium, and wound formation) which healed 4 days earlier and the size of the wound was significantly snialler if the animals were treated with compounds according to the invention. The compounds facilitated the formation of the epithelium.
The experiment shows that the treatment increased the resistance of the skin against the LJV-B irradiation and improved the regeneration of the skin.

?~

Claims (73)

CLAIMS:
1. A pharmaceutical composition for increasing expression of a molecular chaperon expressed by an eukaryotic cell that is exposed to a physiological stress to increase the expression of the molecular chaperon by the cell beyond the amount induced by the physiological stress comprising (a) a chemical compound and (b) a pharmaceutically acceptable carrier or auxiliary, wherein the chemical compound is a hydroxylamine derivative, the tautomeric forms of which are represented by formulae (I) and (II), or its salt and/or any optically active stereoisomer thereof, wherein:

(a) Z is oxygen or =NR3, wherein R3 is:
hydrogen, a straight or branched C1-21-alkyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

X in the tautomer of formula (I) is:
halogen, substituted hydroxy group -OQ, wherein Q is C1-21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or Q is C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or NR1R2, wherein R1 and R2, independently from each other, are:

hydrogen;
straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4:

hydrogen, C1-21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;
C3-8-cycloalkyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;

hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl;

or (b) Z is a covalent bond, (b1) X in the tautomer of formula (I) is halogen, and (b1)(i) R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl C3-8-cycloalkyl-C1- -alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3; and A is group of the formula (a) wherein Y1 is halo, C1-8 alkoxy, halo-C1-8 alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1-4 alkyl quaternary derivative or the 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 (b1)(ii) R is a group of the formula (d), and A is a group of the formula (c), 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;

(b2) X in the tautomer of formula (I) is:
substituted hydroxy group -OQ, wherein Q is C1-21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or Q is C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or NR1R2, wherein R1 and R2, independently from each other, are:

straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring, or X when taken together with R optionally form a dioxazine or oxadiazine ring of formula (I') or (I"), wherein R" is a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more nitrogen, oxygen, or sulfur; phenyl; or naphthyl;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4:

C1-21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;
C3-8-cycloalkyl;

C1-8 alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl;

or (b3) X in the tautomer of formula (I) is NH2;

R is a group of the formula (e) wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; and optionally substituted by C1-4 alkyl, Y4 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

Y5 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or -OR7, wherein R7 is C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; k is 1, 2 or 3, and m is 1, 2 or 3;
and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl.
2. The composition according to claim 1 wherein the cell is treated before the physiological stress.
3. The composition according to claim 1 wherein the cell is treated after the physiological stress.
4. A pharmaceutical composition for increasing activity of a molecular chaperon in an eukaryotic cell that is exposed to a physiological stress to increase the activity of the molecular chaperon in the cell beyond the amount induced by the physiological stress comprising (a) a chemical compound and (b) a pharmaceutically acceptable carrier or auxiliary, wherein the chemical compound is a hydroxylamine derivative the tautomeric forms of which are represented by formulae (I) and (II), or its salt and/or any optically active stereoisomer thereof, wherein:

(a) Z is oxygen or =NR3, wherein R3 is:
hydrogen, a straight or branched C1-21-alkyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

X in the tautomer of formula (I) is:
halogen, substituted hydroxy group -OQ, wherein Q is C1-21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or Q is C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or NR1R2, wherein R1 and R2, independently from each other, are:

hydrogen;
straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4:

hydrogen, C1-21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;
C3-8-cycloalkyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two Cl-8 alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl;

or (b) Z is a covalent bond, (b1) X in the tautomer of formula (I) is halogen, and (b1)(i) R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;
optionally substituted by one to three cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3, and A is group of the formula (a) wherein Y1 is halo, C1-8 alkoxy, halo-C1-8 alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1-4 alkyl quaternary derivative or the 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 (b1)(ii) R is a group of the formula (d), and A is a group of the formula (c), 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;

(b2) X in the tautomer of formula (I) is:
substituted hydroxy group -OQ, wherein Q is C1-21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or Q is C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or NR1R2, wherein R1 and R2, independently from each other, are:

straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring, or X when taken together with R optionally form a dioxazine or oxadiazine ring of formula (I') or (I"), wherein R" is a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; phenyl; or naphthyl;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4 is :

C1-21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl ;

C1-8 alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl;

or (b3) X in the tautomer of formula (I) is NH2;
R is a group of the formula (e) wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; and optionally substituted by C1-4 alkyl, Y4 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

Y5 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or -OR7, wherein R7 is C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;, k is 1, 2 or 3, and m is 1, 2 or 3;
and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl.
5. The composition according to any one of claims 1 to 4, wherein the eukaryotic cell under the physiological stress is a mammalian cell.
6. The composition according to claim 5, wherein the mammalian cell is a human cell.
7. The composition according to claim 5 or 6, wherein the cell is one of a living organism.
8. The composition according to any one of claims 1 to 7 wherein the cell is a neuronal cell, muscle cell, vessel wall cell, or a cell of the immune system.
9. The composition according to claim 8, wherein the vessel wall cell is an endothelial or epithelial cell.
10. The composition according to any of claims 1 to 4 wherein the eukaryotic cell exposed to stress is a plant cell.
11. The composition according to according to claim 10 wherein the plant cell is one of a living plant organism.
12. The composition according to any one of claims 1 to 9 wherein the physiological stress is metabolic, oxidative or local mechanical stress or a stress caused by hypoxia, ischemia, heat shock, radiation or toxic materials.
13. The composition according to claim 12 wherein the stress is caused by diabetes mellitus.
14. The composition according to any one of claims 1 to 9 wherein the physiological stress causes an increase of reactive free radicals or a cytokine present in the area surrounding the cell.
15. The composition according to any one of claims 1 to 9 wherein the physiological stress leads to the occurrence of cardiovascular, vascular, cerebral, allergic, immune, autoimmune diseases, diseases of viral or bacterial origin, tumorous, skin and/or mucous diseases or the epithelial disease of renal tubulus or to a condition which can be treated by cosmetical intervention.
16. The composition according to claim 15 wherein the cardiovascular disease is caused by atherosclerosis, coronarial disease, hypertonia or pulmonary hypertonia provoked by physiological stress.
17. The composition according to claim 15 wherein the cerebral disease is caused by cerebrovascular ischemia, stroke, traumatic head injury, senile neurodegenerative disease.
18. The composition according to claim 17, wherein the cerebral disease is senile dementia, AIDS dementia, alcohol dementia, Alzheimer disease, Parkinson disease or epilepsy provoked by physiological stress.
19. The composition according to claim 15 wherein the skin and/or mucosal disease is caused by dermatosis or ulcerous disease of the gastrointestinal system provoked by physiological stress.
20. The composition according to any one claims 1 to 19 wherein the molecular chaperon is a heat shock protein (hsp).
21. The composition according to claim 20 wherein the hsp is hsp70 or hsp72.
22. A pharmaceutical composition or a cosmetical composition for the treatment of a pathological condition connected with the function of the chaperon system or associated with the injury of the membrane of a cell or cell organellum, or optionally for the prevention of such pathological condition, comprising (a) a chemical compound, and (b) a pharmaceutically or cosmetically acceptable carrier or auxiliary, wherein the chemical compound is a hydroxylamine derivative the tautomeric forms of which are represented by formulae (I) and (II), or its salt and/or any optically active stereoisomer thereof, wherein:

(a) Z is oxygen or =NR3, wherein R3 is:
hydrogen, a straight or branched C1-21-alkyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-6 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

X in the tautomer of formula (I) is:
halogen, substituted hydroxy group -OQ, wherein Q is C1-21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or Q is C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or NR1R2, wherein R1 and R2, independently from each other, are:

hydrogen;

straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4 is:

hydrogen, C1-21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;
C3-8-cycloalkyl;

C1-8 alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl- C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl;

or (b) Z is a covalent bond, (b1) X in the tautomer of formula (I) is halogen, and (b1)(i) R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;
optionally substituted by one to three cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3, and A is group of the formula (a) wherein Y1 is halo, C1-8 alkoxy, halo-C1-8 alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1-4 alkyl quaternary derivative or the 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 (b1)(ii) R is a group of the formula (d), and A is a group of the formula (c), 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;

(b2) X in the tautomer of formula (I) is:
substituted hydroxy group -OQ, wherein Q is C1-21-alkyl optionally substituted by:
cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or Q is C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or NR1R2, wherein R1 and R2, independently from each other, are:

straight or branched C1-21 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl;
phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring, or X when taken together with R optionally form a dioxazine or oxadiazine ring of formula (I') or (I"), wherein R" is a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo;
C1-8 alkyl optionally substituted by one to three halo;

C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more nitrogen, oxygen, or sulfur; phenyl; or naphthyl;

and X in the tautomer of formula (II) is oxygen or =NR4, wherein R4 is:

C1-21-alkyl, optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl;
C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R' is hydrogen, a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl- C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally -substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

R is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl;

or (b3) X in the tautomer of formula (I) is NH2;
R is a group of the formula (e) wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; and optionally substituted by C1-4 alkyl, Y4 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

Y5 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or -OR7, wherein R7 is C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;, k is 1, 2 or 3, and m is 1, 2 or 3;
and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally substituted by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl.
23. The composition according to claim 22, wherein the pathological condition is selected from the group consisting of ischemia, a neoplastic disease, an infection caused by a pathogenic microorganism, an autoimmune disease and dermatosis.
24. The composition according to claim 22, for protecting myocardium, brain tissues and kidney from tissue damage and/or necrosis caused by ischemia to ameliorate, prevent or reverse the deleterious effect of prolonged ischemia.
25. The composition according to any of claims 22 to 24 for human application.
26. The composition according to claim 22 wherein the pathological condition is selected from the group consisting of a cerebral, allergic, immune, and/or autoimmune disease, a disease, caused by viral or bacterial infections, skin and/or mucosal diseases, and an epithelial disease of renal tubuli.
27. The composition according to any one of claims 22 to 26, which is a pharmaceutical composition.
28. The composition according to any of claims 1 to 27, wherein the hydroxylamine derivative is in the tautomeric form of formula (I), wherein (a) Z is covalent bond and X is halogen;

(b) Z is covalent bond and X is a substituted hydroxy group -OQ, wherein Q is as defined in claim 1, X when taken together with R optionally form a dioxazine or oxadiazine ring of formula (I') or (I"), wherein R" is a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

(c) Z is covalent bond and X is NR1R2, wherein R1 and R2, independently of each other, are:
hydrogen;
straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl, or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7-membered saturated ring, and optionally, X when taken together with R optionally form a dioxazine or oxadiazine ring of formula (I') or (I"), wherein R" is a straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; phenyl; or naphthyl;

(d) Z is oxygen and X is a substituted hydroxy group -OQ, wherein Q is as defined in claim 1;

(e) Z is oxygen and X is NR1R2, wherein R1 and R2, independently of each other, are:

hydrogen;
straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl, or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7- membered saturated ring; or (f) Z is =NR3 wherein R3 is as defined in claim 1, and X is NR1R2, wherein R1 and R2, independently of each other, are:

hydrogen;
straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3- to 7- membered saturated ring.
29. The composition according to claim 28 wherein R"
is a straight or branched .omega.-amino-C3-8-alkyl optionally substituted on the amino by one or two C1-8 alkyl.
30. The composition according to claim 28 or 29, wherein Z is a covalent bond and X is chloro or bromo, and (a) R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 5- to 7-membered saturated heterocyclic ring, or an N-1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;
optionally substituted by one to three cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3, and A is a group of formula (a) wherein Y1 is trifluoromethyl; or pyridyl, quinolyl, isoquinolyl, furyl, or thienyl, or the N-C1-4 alkyl quaternary derivative or the N-oxide thereof, with the proviso that when A is pyridyl, or a group of the formula (a) wherein Y' is halo or alkoxy, R7 is other than H; or (b) R is a group of the formula (d), and A is a group of the formula (c), 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.
31. The composition according to claim 30 wherein:
R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 5- to 7-membered saturated heterocyclic ring, or an N-1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;
optionally substituted by one to three cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3, and A is wherein Y1 is C1-8 alkoxy and n is 1, 2 or 3; or pyridyl, quinolyl, isoquinolyl, furyl, or thienyl;
or the N-C1-4 alkyl quaternary derivative or the N-oxide thereof, with the proviso that when A is pyridyl, or a group of the formula (a) wherein Y1 is C1-8 alkoxy, R7 is other than H.
32. The composition according to claim 31, wherein A is pyridyl, R7 is C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, or furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl.
33. The composition according to claim 28 or 29 wherein Z is a covalent bond and X is a substituted hydroxy group -OQ, wherein Q is as defined in claim 1; and A is a 3- to 8-membered unsaturated hetero-monocyclic group containing 1 to 4 nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring;

a 3- to 6- membered unsaturated hetero-monocyclic group containing one or two oxygen and 1 to 3 nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8- membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8- membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen.
34. The composition according to claim 33 wherein A is a 3- to 8-membered unsaturated hetero-monocyclic group containing 1 to 4 nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring.
35. The composition according to any one of claims 1 to 26 wherein the hydroxylamine derivative has the formula (I'), wherein R" is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; phenyl; or naphthyl; and A is phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of which group optionally by cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-6 alkoxy, phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl.
36. The composition according to claim 35, wherein R" is .omega.-amino-C1-5 alkyl optionally substituted on the amino and/or alkyl chain by one or two C1-8 alkyl; and optionally substituted on the C1-C5 alkyl chain by phenyl or naphthyl.
37. The composition according to claim 35 or 36, wherein R" is an .omega.-amino- C1-5 alkyl mono- or di-substituted on the amino wherein the amino substituent, independently from each other are one or two straight or branched C1-5 alkyl or C3-8-cycloalkyl, or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more of nitrogen, oxygen, or sulfur.
38. The composition according to claim 28 or 29, wherein Z is a covalent bond, X is -NR1R2, wherein R1 and R2, independently from each other are:

hydrogen;
straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl, or R1 and R2, when taken together with the N-atom adjacent thereto, form a 3- to 7- membered saturated ring, and A is C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen.
39. The composition according to claim 38, wherein A is phenyl-C1-8-alkyl optionally substituted on the phenyl by: one to three C1-6 alkoxy, nitro or amino optionally substituted by one or two C1-8 alkyl;

phenyl optionally substituted with one or more cyano, hydroxyl, halo, C1-8 alkyl optionally substituted by one to three halo, C1-8 alkoxy, nitro, amino optionally substituted by one or two C1-8 alkyl, phenyl, or naphthyl;
naphthyl;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen.
40. The composition according to claim 39, wherein A is pyridyl, quinolyl, isoquinolyl, furyl, thienyl, or phenyl-C1-8-alkyl substituted on the phenyl by C1-6-alkoxy.
41. The composition according to any one of claims 1 to 26 wherein the hydroxylamine derivative has the formula (I"), wherein R" is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more of nitrogen, oxygen, or sulfur;
phenyl; or naphthyl;

A is phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen;

any of the group optionally substituted by:
cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;
further optionally substituted on the phenyl naphthyl, pentalenyl, or anthracenyl by one to three C1-6-alkoxy, nitro, amino optionally substituted by 1-2 C1-8 alkyl; and R1 is hydrogen, straight or branched C1-21-alkyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl, or C1-8 alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl.
42. The composition according to claim 41, wherein R" is .omega.-amino-C1-5-alkyl optionally substituted on the amino and/or alkyl chain by one or two C1-8 alkyl; and optionally substituted on the C1-C5 alkyl chain by phenyl or naphthyl.
43. The composition according to claim 41, wherein R" is an .omega.-amino-C1-8 alkyl mono- or di-substituted on the amino wherein the amino substituent, independently from each other are one or two straight or branched C1-8 alkyl or C3-8 cycloalkyl, or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring, optionally further containing one or more of nitrogen, oxygen, or sulfur.
44. The composition according to claim 38, wherein A is phenyl optionally substituted with one or more C1-8-alkyl, halo, C1-8-alkoxy, halo-C1-8-alkyl or nitro;
naphthyl;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen.
45. The composition according to claim 44, wherein A is pyridyl, quinolyl, isoquinolyl, furyl, thienyl or phenyl-C1-8-alkyl substituted on the phenyl by C1-8-alkoxy.
46. The composition according to claim 28 wherein Z is oxygen, X is a substituted hydroxy group -OQ, wherein Q is as defined in claim 1; and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl.
47. The composition according to claim 28 wherein Z is oxygen, X is -NR1R2, wherein R1 and R2, independently from each other are:

hydrogen;
straight or branched C1-21-alkyl, optionally substituted by cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or R1 and R2, together with the nitrogen atom adjacent thereto, forms a 3- to 7-membered saturated ring, and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl.
48. The composition according to claim wherein Z is =NR3 wherein R3 is as defined in claim 1, X is NR1R2, wherein R1 and R2, independently from each other are:

hydrogen;
straight or branched C1-8-alkyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C3-8-cycloalkyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

R1 and R2, when taken together with the nitrogen atom adjacent thereto, forms a 5- to 7-membered saturated ring, and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by: cyano; hydroxyl; halo;
C1-8 alkyl optionally substituted by one to three halo;

C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl.
49. The composition according to any one of claims 1 to 26 wherein the hydroxylamine derivative has the formula (II) wherein a) Z is covalent bond and X is oxygen, b) Z is covalent bond and X is =NR4 wherein R4 is:
straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C3-8-cycloalkyl, c) Z is oxygen and X is oxygen, d) Z is oxygen and X is =NR4 wherein R4 is C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl, e) Z is =NR3 wherein R3 is as defined in claim 1, and X is oxygen, or f) Z is =NR3, wherein R3 is as defined in claim 1, and X is =NR4, wherein R4 is as defined in claim 1.
50. The composition according to claim 49, wherein Z is a covalent bond; and R is an .omega.-amino-C1-8-alkyl optionally substituted on the amino and/or alkyl group and the alkyl chain with hydroxy or acyloxy, wherein the acyl moiety of the acyloxy group is selected from C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl.
51. The composition according to claim 49, wherein Z is a covalent bond; and R is an .omega.-amino-C1-8-alkyl mono- or disubstituted on the amino wherein the amino substituents, independently from each other are one or two straight or branched C1-8-alkyl or C3-8-cycloalkyl, or the two amino substituents, together with the nitrogen atom attached thereto form a 5- to 7-membered saturated hetero ring,-optionally further containing one or more of nitrogen, oxygen, or sulfur.
52. The composition according to any one of claims 49 to 51 wherein Z is a covalent bond, X is oxygen and R' is hydrogen, straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and A is phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen.
53. The composition according to claim 52, wherein A is phenyl optionally substituted with one or more C1-8-alkyl, halo-C1-8-alkyl or C1-8-alkoxy;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen.
54. The composition according to any one of claims 49 to 51, wherein Z is a covalent bond, X is =NR4, wherein R4 is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C3-8-cycloalkyl; or C3-8-cycloalkyl; and A is C1-8-alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen.
55. The composition according to claim 54 wherein A is phenyl-C1-8-alkyl optionally substituted with one or more C1-8-alkoxy in the phenyl moiety;

phenyl optionally substituted with one or more alkyl, haloalkyl or nitro;

naphthyl;
a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen.
56. The composition according to claim 55, wherein A is pyridyl,naphthyl, or thienyl.
57. The composition according to claim 49 wherein Z is oxygen, X is oxygen, R' is hydrogen, straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; Cl-B alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl.
58. The composition according to claim 49 wherein Z is oxygen, X is =NR4 wherein R4 is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R' is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl.
59. The composition according to claim 49 wherein Z is =NR3 and R3 is as defined in claim 1, X is oxygen and R' is hydrogen, straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one oxygen.
60. The composition according to claim 59 wherein A is straight or branched C4-12-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl;
phenyl-C1-8-alkyl;
phenyl optionally substituted with one or more halo, C1-8-alkyl, halo-C1-8-alkyl, C1-8-alkoxy or nitro;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen.
61. The composition according to claim 49 wherein Z is =NR3, wherein R3 is as defined in claim 1, X is =NR4, wherein R4 is as defined in claim 1, and R' is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; naphthyl; and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl.
62. Use of a compound of the formula (I) wherein a) Z is a covalent bond X is halo, and al) R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, y6 is -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is 1, 2 or 3, and m is 1, 2 or 3, and A is a group of the formula (a) wherein Y1 is halo, C1-8 alkoxy, halo-C1-8 alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1-4 alkyl quaternary derivative or the N-oxide thereof, with the proviso that when A is pyridyl or naphthyl, or a group of the formula (a) wherein Y1 is halo or alkoxy, R7 is other than H, or a2) R is a group of the formula (d), A is a group of the formula (c), 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) Z is oxygen or =NR3 wherein R3 is hydrogen or C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo;
C1-8 alkyl optionally substituted by one to three halo;

C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, X is -NR1R2, wherein R1 and R2 independently from each other are:

hydrogen;
straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur, A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is hydrogen or -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

k is 1, 2 or 3, and m is 1, 2 or 3, or c) Z is oxygen X is substituted hydroxy group -OQ, wherein Q is as defined in claim 1;

R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

k is 1, 2 or 3, and m is 1, 2 or 3, and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-6 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl; or d) Z is a covalent bond, X is OQ, wherein Q is C1-4 alkyl, and R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is hydrogen, k is 1, 2 or 3, and m is 1, 2 or 3; and A is phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing 1 to 4 nitrogen in the ring, a 3- to 8- membered unsaturated condensed heterocyclic group containing 1 to 5 nitrogen in the ring, a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen;

for the treatment of a disease connected with the function of the chaperon system or associated with the injury of a cell or cell organellum or optionally preventing the same.
63. Use of a compound of the formula (I) wherein a) Z is a covalent bond X is halo, and a1) R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, k is l, 2 or 3, and m is 1, 2 or 3, and A is a group of the formula (a) , wherein Y1 is halo, C1-8 alkoxy, halo-C1-8 alkyl or nitro and n is 1, 2 or 3, or a 3- to 8- membered unsaturated hetero-monocyclic group containing one oxygen, a 3- to 8- membered unsaturated hetero-monocyclic group containing one sulfur, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, or an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or the N-C1-4 alkyl quaternary derivative or the N-oxide thereof, with the proviso that when A is pyridyl or naphthyl, or a group of the formula (a) wherein Y1 is halo or alkoxy, R7 is other than H, or a2) R is a group of the formula (d), A is a group of the formula (c), 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) Z is oxygen or =NR3 wherein R3 is hydrogen or C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo;
C1-8 alkyl optionally substituted by one to three halo;

C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, X is -NR1R2, wherein R1 and R2 independently from each other are:

hydrogen;
straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or R1 and R2, when taken together with the nitrogen atom adjacent thereto, form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur, A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-6 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is hydrogen or -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

k is 1, 2 or 3, and m is 1, 2 or 3, or c) Z is oxygen X is substituted hydroxy group -OQ, wherein Q is as defined in claim 1;

R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, 6 is H or -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

k is 1, 2 or 3, and m is 1, 2 or 3, and A is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl; or d) Z is a covalent bond, X is OQ, wherein Q is C1-4 alkyl, and R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is hydrogen, k is 1, 2 or 3, and m is 1, 2 or 3; and A is phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;

nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or a 3- to 8-membered unsaturated hetero-monocyclic group containing 1 to 4 nitrogen in the ring, a 3- to 8- membered unsaturated condensed heterocyclic group containing 1 to 5 nitrogen in the ring, a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen;

in the manufacture of a medicament for the treatment of a disease connected with the function of the chaperon system or associated with the injury of a cell or cell organellum or optionally preventing the same.
64. The use of claim 62 or 63 wherein A is a group of the formula (a) and Y1 is halo-C1-4 alkyl.
65. The use of claim 62 or 63 wherein (a) Z is a covalent bond, X is chloro or bromo, (a1) A is a group of formula (a) wherein Y1 is halo-C1-4 alkyl;

(a2) A is a group of formula (c), wherein when the compound is a cation, the anion is an iodide; or (b) X is -NR1R2, wherein R1 and R2 independently from each other are phenyl.
66. The use of claim 62 or 63 wherein the compound is an optically active stereoisomer, and Z is covalent bond, X is halo, and R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 5- to 7-membered saturated heterocyclic ring, an N-C1-4 alkyl-quaternary derivative or N-oxide thereof;

Y6 is -OR7 wherein R7 is aminoacyl, the acyl moiety of which is C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8-alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-6-alkanoyl, C3-8-cycloalkyl-C1-8-alkanoyl, phenyl-C1-8-alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

k is 1, 2 or 3 and m is 1, 2 or 3.
67. A hydroxylamine derivative of the formula (I) wherein Z is a covalent bond, X is -NR1R2, wherein R1 and R2 independently from each other are:

hydrogen, straight or branched C1-6-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8-cycloalkyl; or R1 and R2, when taken together with the nitrogen atom attached thereto, form a 3 to 7-membered saturated heterocyclic ring;

R is a group of the formula (e) wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4 alkyl, C3-8 cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, optionally further containing one or more of nitrogen, oxygen, or sulfur; and optionally substituted by C1-4 alkyl, Y4 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

Y5 is hydrogen or C1-4 alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or -OR7, wherein R7 is hydrogen or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8 cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8 cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;

k is 1, 2 or 3, and m is 1, 2 or 3; and A is C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-8-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl optionally substituted with one or more halo, C1-8 alkyl or halo-C1-8 alkyl, acylamino, the acyl moiety of which is C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8-alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8-alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8-cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl; optionally substituted by one to three cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

nitro; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings;

a 3- to 8-membered unsaturated hetero-monocyclic group containing one sulfur; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen;

wherein the hetero atoms are optionally substituted by one or more C1-4-alkyl;

with the proviso, that when A is phenyl, phenyl substituted with halo or C1-8-alkoxy or phenyl C1-8-alkyl substituted with C1-8-alkoxy or a pyridyl group, then at least one of R1, R2, and R7 is other than H.
68. A hydroxylamine derivative of the formula (II) as defined in claim 1, wherein a) Z is covalent bond, X is oxygen, R' is hydrogen, C1-4-alkyl or C1-8-alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OR7 wherein R7 is H, k is 1, 2 or 3, and m is 1, 2 or 3, and A is straight or branched C1-21-alkyl, phenyl, naphthyl, pentalenyl, or anthracenyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

naphthyl;
a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen;

with the proviso that when A is other than C1-21 alkyl and R' is hydrogen, Y 6 is hydrogen, or b) Z is covalent bond, oxygen or =NR3 wherein R3 is hydrogen or C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl, X is =NR4, wherein R4 is hydrogen, C1-21-alkyl optionally substituted by: cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl;

R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OR7, wherein R7 is H or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8-cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl, optionally substituted by one to three cyano;
hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

k is 1, 2 or 3, and m is 1, 2 or 3, A is C3-8-cycloalkyl, C1-8 alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; and R' is straight or branched C1-21-alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C1-8 alkyl substituted with one or more phenyl, naphthyl, pentalenyl, or anthracenyl groups, further optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy;
nitro; amino optionally substituted by one or two C1-8 alkyl;
phenyl; or naphthyl; or phenyl, naphthyl, pentalenyl, or anthracenyl, optionally substituted by: cyano; hydroxyl;
halo; C1-8 alkyl optionally substituted by one to three halo;
C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or c) Z is oxygen, X is oxygen, R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl, C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3 to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OR7 wherein R7 is H or C1-8-alkanoyl, a C1-8-alkoxy-carbonyl, a C1-8 alkylsulphonyl, phenylsulphonyl, naphthylsulphonyl, benzoyl, naphthoyl, phenyl-C1-8-alkanoyl, naphthyl-C1-8-alkanoyl, C3-8-cycloalkyl-C1-8-alkanoyl, phenyl-C1-8 alkoxyl-carbonyl, naphthyl-C1-8 alkoxyl-carbonyl, phenyl-carbamoyl, naphthyl-carbamoyl, C3-8-cycloalkyl-carbamoyl, thienyl-sulphonyl, furyl-sulphonyl;

k is 1, 2 or 3, and m is 1, 2 or 3; and A is straight or branched C1-21- alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl; or C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl;

R' is C1-4-alkyl or C1-8-alkyl substituted with one or more phenyl naphthyl, pentalenyl, or anthracenyl groups, or d) Z is =NH, X is oxygen, and d1) R is a group of the formula (b), wherein R5 and R6 independently from each other are hydrogen, straight or branched C1-4-alkyl C3-8-cycloalkyl, or R5 and R6 when taken together with the nitrogen atom adjacent thereto form a 3- to 7-membered saturated heterocyclic ring, or an N-C1-4 alkyl-quaternary derivative or N-oxide thereof, Y6 is H or -OH, k is 1, 2 or 3, and m is 1, 2 or 3;

A is straight or branched C1-21- alkyl optionally substituted by: cyano; hydroxyl; halo; C1-8 alkyl optionally substituted by one to three halo; C1-8 alkoxy; nitro; amino optionally substituted by one or two C1-8 alkyl; phenyl; or naphthyl;

C3-8 cycloalkyl; or C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl, further optionally substituted by one to three C1-6-alkoxy, nitro, or amino optionally substituted by one to two C1-8 alkyl; phenyl optionally substituted with halo, C1-8-alkyl, halo C1-8-alkyl, C1-8- alkoxy or nitro, and R' is C1-21-alkyl or C1-8 alkyl substituted with one or more of phenyl, naphthyl, pentalenyl, or anthracenyl.
69. A hydroxylamine derivative of the formula (I"), wherein A is phenyl optionally substituted with halo or nitro, or a 3- to 8-membered unsaturated hetero-monocyclic group containing one to four nitrogen in the ring, an unsaturated condensed heterocyclic group containing one to five nitrogen in the ring, or an N-oxide of any of such group;

a 3- to 6-membered unsaturated hetero-monocyclic group containing one or two oxygen and one to three nitrogen, an unsaturated condensed heterocyclic group containing one or two oxygen and one to three nitrogen in the rings; or a 3- to 8-membered unsaturated hetero-monocyclic group containing one or two sulfur and one to three nitrogen, a 3- to 8-membered unsaturated condensed heterocyclic group containing one or two sulfur and one to three nitrogen, R' is hydrogen; and R" is .omega.-amino-C1-5-alkyl optionally mono- or disubstituted on the amino group, wherein the amino substituents may be independently from each other one or two straight or branched C1-8-alkyl or C3-8-cycloalkyl or the two amino substituents, when taken together with the nitrogen atom attached thereto form a 3 to 7-membered, saturated heterocyclic ring, or the C1-4 alkyl-quaternary derivative or the N-oxide thereof, with the proviso, that when A is 3-pyridyl, R" is other than 1-piperidinyl-methyl.
70. Pharmaceutical and optionally cosmetical composition for the treatment of a disease connected with the function of the chaperon system or associated with the injury of a cell or cell organellum or optionally preventing the same, wherein the composition contains 0.5 to 99.5 % by weight of a compound of the formula (I) as defined in claim 62, wherein A, Z, X and R are as defined in claim 62, together with pharmaceutically and/or cosmetically acceptable carriers and auxiliaries.
71. Pharmaceutical and optionally cosmetical composition for the treatment of cardiovascular, vascular, cerebral, allergic, immune, autoimmune diseases, diseases caused by viral or bacterial infections, tumorous, skin or mucosal diseases, wherein the composition contains 0.5 to 99.5 % by weight of a compound of the formula (II) as defined in claim 1, wherein A, Z, X and R are as defined in claim 59, together with pharmaceutically and/or cosmetically acceptable carriers and auxiliaries.
72. Pharmaceutical and optionally cosmetical composition for the treatment of cardiovascular, vascular, cerebral, allergic, immune, autoimmune diseases, diseases caused by viral or bacterial infections, tumorous, skin or mucosal diseases, wherein the composition contains 0.5 to 99.5 % by weight of a compound of the formula (II) as defined in claim 1, wherein A, Z, X and R are as defined in claim 68, together with pharmaceutically and/or cosmetically acceptable carriers and auxiliaries.
73. Pharmaceutical and optionally cosmetical composition for the treatment of cardiovascular, vascular, cerebral, allergic, immune, autoimmune diseases, diseases caused by viral or bacterial infections, tumorous skin or mucosal diseases, wherein the said composition contains 0.5 to 99.5 % by weight of a hydroxylamine compound of the formula (I") as defined in claim 69, wherein A, Z, X, R' and R" are as defined in claim 69, together with pharmaceutically and/or cosmetically acceptable carriers and auxiliaries.
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